My Medicine Notes

Table of Contents

1 Aesthetics

1.1 Botox/Xeomin Injections (botulinum toxin type A)

Good article: Botulinum toxin in facial plastic surgery

General Techniques:

  • Inject while retracting
  • Patient in a 60 degree recline
  • Touch up 2 weeks later if needed
  • Use white eyeliner to mark safety zones
  • Compress injection sites firmly away into safety zone
  • Wipe area with EtOH swab
  • Inject with muscles contracted (Frown and Forehead)

1.1.1 Reconstitution

Table 1: Dilution for 2 units per 0.1 mL
  50 unit vial 100 unit vial 200 unit vial
0.9% NaCl* 2.5 mL 5 mL 10 mL

*Preservative Free

Reconstitution and Dilution - Flip It. Don't Shake It.

  • Prior to injection, reconstitute each vial of XEOMIN with sterile, preservative-free 0.9% Sodium Chloride Injection
  • A 20 to 27-gauge short-bevel needle is recommended for reconstitution
  • Draw up an appropriate amount of preservative-free 0.9% Sodium Chloride Injection, USP into a syringe


  1. Step 1: Vial preparation
    • Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle.1
  2. Step 2: Saline injection
    • After vertical insertion of the needle through the rubber stopper, the vacuum will draw the saline into the vial. Gently inject any remaining saline into the vial to avoid foam formation. If the vacuum does not pull the saline into the vial, then XEOMIN must be discarded.1
  3. Step 3: Mixing
    • Remove the syringe from the vial and mix XEOMIN with the saline by carefully swirling and inverting/flipping the vial—do not shake vigorously.1

1.1.2 Frown Lines

Injection sites:

  1. 1 cm above eyebrow (orbital rim) at the medial edge of eye line (medial Canthus) (Corrugator muscle)
    • 2 - 4 u each side
  2. 1 cm above eyebrow (orbital rim) on the medial edge of the iris line (Limbus) (Corrugator muscle)
    • 2 u each side
  3. Standing in front of patient, inject into Procerus muscle
    • Imagine an X from medial canthus to Corrugator injection (#1)
    • 4 u (2.5 - 5 u)

Total dose:

  • Women: 20 units
  • Men: 25 units


1.1.3 Forehead Lines

General Injection Strategy:

  1. Superior half to third of forehead inject 2 units symmetrically in ridges (not valleys) (Frontalis muscle)
  2. Consider 4 sites in horizontal line
    • 2 units each (8 total)
  3. If needed add another line in a ridge consisting of 2- 3 sites in spaces between previous injections
    • Might look best if in a V shape
    • 2 units each (4 to 6 units)
  4. Approach with 30 degree angle

Total dose:

  • Women: 15 - 20 units
  • Men: 20 - 25 units

1.1.4 Injection Plan:

  • Use 8 units Glabellar
    • 4 u Precerus
    • 2 u Bilat Corrugator
  • Use 12 units Forehead
    • 1 line of 4 sites
    • 1 line of 2 sites (if needed) . . . . . .

2 Allergy/Immunology

2.1 Anaphylaxis

USE epinephrine!

  • Corticosteroids and diphenhydramine help stave off rebound anaphylaxis

2.2 Eosinophilic Esophagitis

  • Empiric 6 food elimination diet (SFED) resolves inflammation in 66% of patients
    • Milk, Wheat, Soy, Eggs, Treenuts/peanuts, and fish/shellfish
  • Food elimination based on allergy testing resolves esophageal inflammatiton in 50% of patients
    • Often (69%), patients are able to identify a single food trigger
  • Medication options for eosinophilic esophagitis include
    • Topical steroids delivered via an asthma inhaler and then swallowed
    • PPI
  • Dysphagia with eosinophilic esophagitis is often secondary to esophageal strictures, which can be treated with endoscopic dilation


  • Dairy: 50%
  • Wheat: 31%
  • Soy
  • Egg: 36%
  • Nuts
  • Fish/Shellfish


  • AFP Vol 103 No 9 May 2021
  • Zalewski A, Doerfler B, Krause A, Hirano I, Gonsalves N. Long Term Outcomes of the Six Food Elimination Diet and Food Reintroduction in a Large Cohort of Adults with Eosinophilic Esophagitis. Am J Gastroenterol. 2022 Aug 12. doi: 10.14309/ajg.0000000000001949. Epub ahead of print. PMID: 35971213.

2.3 IgG vs IgM   edit


  • IgM antibodies are produced by the body immediately after the exposure to a specific antigen
  • Mainly found in blood and lymph fluid
  • Quantity produced upon exposure to the antigen is nearly 6 times as much of IgG
  • IgM antibodies usually also have 10 binding sites (compared to only 2 in IgG)
    • Only about half of the binding sites can actually be used to bind IgM to an antigen
  • IgM is multivalent: Multiple monomers are bonded together
  • Temporary - disappear within 2 to 3 weeks following infection


  • IgG refers to an immunity for a particular disease
  • A late stage response as compared to IgM
  • Abundant in the body
  • Protects against various disease causing foreign agents
  • IgM antibodies are replaced by IgG antibodies that last for life time

3 Behavioral Medicine

3.1 5A's

5As for Adults

The 5A's provide health practitioners with five steps to better manage their patients' health issues (such as smoking cessation or weight loss):

  • ASK for permission to discuss weight and explore readiness
  • ASSESS obesity related risks and 'root causes' of obesity
  • ADVISE on health risks and treatment options
  • AGREE on health outcomes and behavioral goals and followup
  • ASSIST in accessing appropriate resources and providers


3.2 Anxiety Traps

  1. Catastrophizing: Imagining the worst possible outcome. “I will get fired if the presentation has any glitches.”
  2. Mind reading: Imagining what others are thinking. “I know he doesn’t like working with me because he thinks I’m dumb.”
  3. Fortune telling: Imagining what the future holds, but without data. “They will all hate me in the new group because I’m the only one who isn’t a physicist.”
  4. Black-and-white thinking: Considering only two possible outcomes. “I’ll either hit a home run or get fired.”
  5. Overgeneralizing: Painting all situations with a generalized outcome. “I presented to the CEO last year, and it didn’t go well. I never get things right or always fail when it comes to executive audiences.”

How to get out of the traps:

  • Pause the pattern.
  • Name the trap.
  • Separate FUD from fact. Create a two-column list. On one side list all your fears, uncertainties, and doubts, or FUD. The second column is for verified facts.
  • Tell more stories. When we’re anxious, we tend not only to believe our own stories, we believe the most extreme and negative forms of them. Instead of curbing this reflexive habit, indulge it. Compose three separate stories and ensure they’re very different from each other.
  • Walk your talk. Ask yourself what you’d advise others to do.

3.3 BATHE Technique

BATHE for Primary Care Counselling

  • Background
  • Affect
  • Trouble
  • Handling
  • Empathy

3.4 (Stop) Catastrophizing


  • On hearing uncertain news, you imagine the worst possible outcome

Catastophizers learn to choose the worst possible outcome because it allows for the greatest sense of relief when they are reassured.

Catastrophizers rush to external sources to calm themselves down:

  • checking whether anyone else has “come through” the same problem;
  • matching symptoms online to obtain a diagnosis and treatment options;
  • asking a professional to tell them that they will survive.

Once they are reassured, they feel better, they have “rewarded” this seeking behavior. The next time they feel uncertain or threatened, they will ratchet up their anxiety with a catastrophic thought, then look outwards for reassurance even faster than before.

In this way, catastrophizing soon becomes a well-entrenched habit. The greatest problem with seeking others to alleviate anxiety is that it offers only temporary relief.

Plan for tackling anxiety:

  1. Accept yourself.
    • Anxiety is energy. Look for enjoyable ways to challenge yourself and use your energy more positively:
      • Taking regular aerobic exercise.
      • Learning something new.
      • Taking up a creative passion.
  2. Take control.
    • Establish a regular "worry time".
      • Start by setting aside half an hour every day. Write down all your concerns in specific terms
      • Assign a score on a scale of 0 to 100% to estimate how distressed this possibility makes you feel
      • List all the possible explanations for your concern, then rank each one according to how likely it is to be correct
      • Score your worry for the level of distress it is causing you now. Gradually, you will be able to reduce the amount and frequency of worry time.
  3. Use the "best friend test".
    • Ask yourself what you would advise your best friend to do about each concern, and take that action
  4. Learn to self-soothe.
    • Whenever you are overwhelmed by anxiety and feel you must seek reassurance, give yourself permission to do so – but not straight away.
      • Start with 2 min.
        • Breathing slowly in through your nose and out through your mouth, or taking some gentle exercise, will help.
        • Gradually, you will find you can wait longer.
        • When you get to the point where you can wait more than 20 minutes, most people find they no longer need to be reassured by others.

3.5 Child psych

Children's Medication Clinic - serious behavioral and emotional problems not requiring inpatient

  • Up to 17yo
  • Princeton Plaze
  • 1800 Mercy dr
  • Orlando, FL 32808
  • 507-875-3700

3.6 Cognitive Behavioral Technique

  • Focuses on the identification and modification of dysfunctional thoughts to improve affect
  • Cognitive restructuring
    • Help patients change the way they think about themselves
    • Address catostrophic thinking
    • Treach patients to view a setback as a temporary lapse
    • Teach positive thinking (like replace thoughts that undermine weight management efforts)

Behavior Therapy:

  • Change behavior and the feelings will follow
  • Reinforce or extinguish a behavior (rewards, aversive stimuli, restructured environment)
  • Relaxation training (music, progressive body relaxation, yoga, deep breathing, walks, etc)

Components of Behavioral Therapy:

  1. Self-monitoring
    • Daily records of food intake, physical activity, weight
  2. Stimulus control
    • Avoidance, narrowing, use of inhibitory stimuli to reduce triggers
  3. Problem solving
    • Define the problem; brainstorm solutions; implement strategy
  4. Goal setting
    • Establish dietary and weight goals
  5. Contingency management
    • Develop recovery methods from overeating or weight gain
  6. Enlist social support
    • Recruit family/friends to help modify lifestyle behaviors
  7. Relapse prevention training
    • Expect setbacks; be prepared; view as temporary
  8. Stress management
    • Decrease negative impact of stress on positive behavior patterns
  9. Rewards
    • Congratulate self on successes, not mistakes; plan rewards for achieving goals
  10. Ongoing contact
    • To maintain progress, most programs require short interval appointments


  • OMA Review Course 2016

3.7 Coping strategies to teach patients

  • Regularly practice relaxation techniques
    • Deep breathing
    • Muscle relaxation
  • Make a list of worries in the evening before bedtime and give yourself permission to address them tomorrow
  • Enlist or accept emotional support from others
  • Reduce caffeine consumption gradually (FDA recommends <400 mg for adults)
  • Adopt effective sleep hygiene practices
  • Use a digital application to promote self-help
    • Search in app store for: wellness, sleep, stress, etc


  • JFP Vol 69, No 7 Sep 2020


STOPP is CBT in a nutshell.

  • Learn this ONE KEY SKILL and you can start to take control of your emotions and your life.
  • "Between stimulus and response there is a space. In that space lies our freedom to choose our response. In our response lies our growth and our freedom". Viktor Frankl.


  1. STOP !
    • Just pause for a moment
    • Notice your breathing as you breathe in and out. In through the nose, out through the mouth.
    • What thoughts are going through your mind right now?
    • Where is your focus of attention?
    • What are you reacting to?
    • What sensations do you notice in your body?
    • What's the bigger picture?
    • Take the helicopter view.
    • What is another way of looking at this situation?
    • What advice would I give a friend?
    • What would a trusted friend say to me right now?
    • Is this thought a fact or opinion?
    • What is a more reasonable explanation?
    • How important is this? How important will it be in 6 months time?
    • It will pass.
    • What is the best thing to do right now?
    • What is the most helpful thing for me, for others, for the situation?
    • What can I do that fits with my values?
    • Where can I focus my attention right now?
    • Do what will be effective and appropriate.


  • Practise the first two steps often for a few days - many times every day at any time.
  • Read through the steps often.
  • Carry written reminders with you (use the printable resources below).
  • Practise STOPP by running through all the steps several times a day, every day…when you don't need it.
  • Start to use it for little upsets.
  • Gradually, you will find that you can use it for more distressing situations. Like any new habit or skill, it will become automatic over time.



3.9 Empathy

How to have EMPATHY

  • Eye contact - establish
  • Muscles of facial expression
  • Posture (open/closed)
  • Affect - recognize
  • Tone of voice - recognize
  • Hear the whole person (understand the context)
  • Your response


3.10 Exposure Therapy for OCD: Exposure and Response Prevention (ERP)

Learning to gradually face your fears is one of the most effective ways to break the OCD cycle. For OCD, the technique for facing fears is called exposure and response prevention (ERP).

ERP is done by:

  • Exposing (E) yourself to situations that bring on obsessions (triggers)
  • Not engaging in the unhelpful coping strategies that include compulsions or rituals, and avoidance (Ritual Prevention- RP)


  1. Step 1: Get to know your OCD better
    • To face your fears, it is helpful to know what you are thinking (your obsessions) and identify the triggers that bring on your obsessions and compulsions.
    • You can do this by keeping track of the triggers on a daily basis for 1 week by using the Obsessive Fear Monitoring Form. (see end)
    • Because obsessions can happen frequently, writing down 3 triggers per day (e.g. 1 in the morning, 1 in the afternoon, and 1 in the evening) will be enough to give you a good overview of your obsessions and compulsions.
    • In the column labeled ¡§Fear¡¨, rate how intense the fear was in the specific situation. Use a 0-10 rating scale, where 0 = no fear and 10 = extreme fear.
    • Finally, record all the compulsions/coping strategies you used in response to the obsession. Be sure to include both behavioural and/or mental strategies you used to manage the obsession and fear.
  2. Step 2: Build a fear ladder
    • After about 1 week of tracking your obsessions and compulsions, you will be ready to make a list of all the different situations that you fear.
    • Build a fear ladder by rank, ordering your triggers from least scary to most scary. For example, if you have contamination fears, being at a friend¡¦s apartment may be a situation that is low on the fear ladder because it only evokes a fear of 1/10. But using the bathroom in a shopping mall may be a situation that is very high on the ladder because it evokes a 9/10 fear. See Examples of Fear Ladders for some ideas about building your fear ladder.
      • TIP: Build a separate ladder for each of your obsessive fears. For example, you may need a separate hierarchy for all situations related to your fear of contamination. You may also need a separate ladder for all situations related to your fear of causing something terrible to happen.
  3. Step 3: Climb the fear ladder ¡V ERP
    • Once you have built a fear ladder, you are ready to face your fears by putting yourself in situations that bring on your obsessions (exposure), while resisting doing anything to control the obsessions and the anxiety associated with them (response prevention).

KEY POINTS TO MANAGING YOUR OCD (see Facing your Fears: Exposure for more tips):

  • Bottom up. Start with the easiest item on the fear ladder first (i.e. fear=2/10) and work your way up.
  • Track progress. Track your anxiety level throughout the exposure exercise in order to see the gradual decline in your fear of a particular situation. Use the Facing Fears Form to help you do this.
  • Feeling anxious when you try these exercises is a sign that you are on the right track. If you¡¦re not anxious you might be too low on your ladder, and if you are feeling flooded with excessive anxiety, chances are you started too high up on the ladder. Remember that regardless of how intense your fear is, it will peak and then level off. What goes up must come down! Even if you do nothing about it the fear will eventually go away on its own.
  • Don¡¦t avoid. During exposure, try not to engage in subtle avoidance (e.g. thinking about other things, talking to someone, touching the doorknob only with one finger instead of the whole hand, making mental promises to de-contaminate later on, etc.). Avoidance actually makes it harder to get over your fears in the long term.
  • Don¡¦t rush. It is important to try to stay in the situation until your fear drops by at least half (e.g. from 6/10 to 3/10), or until you notice a significant reduction from your fear at the start (e.g. from 7/10 to 4/10). Also, focus on overcoming 1 fear at a time. It is a good idea to do the exposure repeatedly until the first item on the hierarchy no longer causes much of a problem for you.

Engaging in Response Prevention

  • Resist the urge. In order for exposure to work, it is important that you try to resist, as much as possible, carrying out your compulsions during or after the exposure. The whole point of ERP is to learn to face your fear without having compulsions.
  • Modeling. If you have been performing compulsions for some time, it may be difficult to know how to face a feared situation without doing them. In this case, it can be helpful to ask a family member or a close friend who does not have OCD to show you how to, for example, wash hands quickly or leave home without rechecking appliances, and then model, or copy, their behaviour.
  • Delaying and reducing ritualizing as an alternative. You might find it very difficult to completely resist a compulsion, especially the first time you are facing your fears. In that case, you can try to delay acting on the compulsion rather than not doing it at all. For example, after touching the floor (exposure), wait for 5 minutes before washing your hands, and wash for 1 minute instead of 3 minutes. Try to gradually prolong the delay, so that you can eventually resist the compulsion altogether.
  • Re-exposure. If you do end up performing a compulsion, try to re-expose yourself to the same feared situation immediately, and repeat the practice until your fear drops by half. For example, Practice 1: touch the floor and wait for 5 minutes before washing hands for 1 minute. Practice 2: touch the floor again immediately after washing, and wait for another 5 minutes before washing for 1 minute. Repeat this process until your anxiety drops from, say, 6/10 to 3/10.

How to move on.

  • Once you experience only a little anxiety when completing an exercise, you can move on to the next one.
    • For example, after several practices, you might feel very little anxiety when you wait 5 minutes to wash your hands after touching the floor. You can then challenge yourself to wait for 8 minutes before washing your hands after touching the floor. Again, repeat this practice until your anxiety drops by half or is significantly reduced from where it was at the start.


#+Obsessive Fear Monitoring Form

Date Triggers for Obsessions (specific situations, objects, people, or thoughts that provoke obsessive fears) Obsession Fear (0-10) Compulsions/Coping Strategies

#+Example Fear Ladder

Step Situation Fear Rating
3. Ask a coworker what they did on the weekend 4
2. Ask coworkers questions about how to complete tasks at work 3
1. Say ¡§hi¡¨ to coworkers 2

#+Daily Exposure Practice Form Task:_________________________ Ritual prevention (or delay)_____________________________ Expected Initial Distress rating % (before starting Exposure)________________________ Goal: Distress level % (after Exposure) _ Frequency of Exposures _ times per __ (day/week)

Day/Date Start time Stop time Distress% start Distress % end Comments

Distress Rating 0-100 (No or minimal/Moderate/Severe/Worst ever distress) Use this form when undertaking Exposure & Response Prevention (ERP), when NOT responding to the urge to perform a ritual or compulsion. It is normal to feel very anxious and distressed at the thought of either delaying or not doing the ritual

3.11 Military Psychiatry

Extreme in theater:

  • Separate / Hold / Monitor until able to address
  • Judiciously restrain
  • Neurolepticize if needed with caution

Not as extreme in theater: (PIE)

  • P - Proximity - Start treatment as far forward as possible
  • I - Immediacy - Treatment begins ASAP
  • E - Expectancy - Instill expectancy in SM that they will return to duty

4 Steps:

  1. H&P
  2. BATHE
    • Background: What happened?
    • Affect: How does it make you feel?
    • Troubles: What troubles you about _ ?
    • Handle: How are you handling _ ?
    • Empathy: Demonstrate empathy
  3. Mental Status Exam / SIG E CAPS
  4. Eval though content/process, ego mechanisms (impulses, coping skills, etc)
  5. Disposition

3.12 Mindfulness

  • Acknowldege
  • Notice triggers
  • Remember why


  • Acknoledge pain when it occurs
  • Notice whether something is making it worse in the moment
  • Remember the top 3 reasons that you want to stay off opioids
    • My kids
    • I do not want to be dependent on something
    • My health

3.13 Motivational Interviewing (MI)

  • Spirit of MI: Emphasizes personal choice and control
    • Collaborative: Partnership between patient and clinician
    • Evocative: Reasons to change come from the patient rather than the doctor
    • Autonomy supporting: Ultimately the patient decides what to do
  • Four Guiding Principles: (RULE)
    1. R - Resist the righting reflex
    2. U - Understand your patient's motivation
    3. L - Listen (actively) to your patient
    4. E - Empower your patient
  • Guiding Principles: (GRACE)
    1. G - Generate a gap (develop discrepancy)
    2. R - Roll with resistance
    3. A - Avoid arguments
    4. C - Can do (support self efficacy)
    5. E - Express empathy
  • Key Processes:
    • Engagement
      • Set the agenda collaboratively
      • Non-judgemental
      • Patient-centered
    • Focusing
      • Develop the conversation around a single issue
    • Evoking (DARN)
      • Move the conversation toward a prepatory change talk
      • D - Desire to change (want, like, wish..)
      • A - Ability to change (can, could..)
      • R - Reasons to change (if..then)
      • N - Need to change (need, have to, got to..)
      • Importance ruler (scale 1-10)
    • Planning
      • Explore barriers to change
      • Fascilitate change
      • Explore commitment
  • Practitioner Approach: (OARS)
    • O - Open questions
    • A - Affirmations
    • R - Reflections
    • S - Summaries
  • Motivational Interviewing:
    1. Agenda setting - Would you mind if I talked with you about your weight?
    2. Exploration
      • Patient's desire - Are you interested in being more active?
      • Patient's ability - Would you be able to walk for 30min each day?
      • Patient's reasons - You mentioned you are now more open to exercising. What makes you open to it now?
      • Patient's need - How important is it that you get more fit?
    3. Providing information - Obesity has been linked to a greater risk of DM. Losing even a modest amount of weight can lower your risk. There are several options available to help you.
    4. Listening and summarizing - It sounds like you are interested in seeing a dietition for nutrition advice but are worried about finding the right one.
    5. Generating options and contracting - It sounds like you have several good ideas about how to reduce your calorie intake. Which one do you think would work best? I look forward to hearing about it at our next appointment.


  • CME Bulletin - Diagnosis and Management of Obesity
  • FPM Sep/Oct 2016
  • OMA Review Course 2016

3.14 Opposite Action

Act opposite to the emotional urge in the service of pursuing values or goals.

  • Many often become obsessively focused on pain or anxiety that they allow it to limit their participation in activities
  • They can instead engage in counteractivities, within reason, despite pain or anxiety being present.
  • They can engage in activities (physical and mental) as tolerated despite feeling pain or anxiety

3.15 PLISSIT Technique


  • Permission
  • Limited Information
  • Specific Suggestions
  • Intensive Therapy

3.16 Shared decision making

  1. Identify percieved risks and benefits
  2. Address percieved risks and benefits
  3. Establish ease of use
  4. Make a plan


  • JFP 2013;62(12 suppl CME):S20-S26

3.17 Stages of Change

  1. Pre-contemplation (Start MI here)
  2. Contemplation (MI)
  3. Preparation (use CBT here)
  4. Action (CBT)
  5. Maintenance (CBT)


  • OMA Review Course 2016

3.18 Stop Catastrophizing

Catastrophize: – On hearing uncertain news, you imagine the worst possible outcome

Catastophizers learn to choose the worst possible outcome because it allows for the greatest sense of relief when they are reassured.

Catastrophizers rush to external sources to calm themselves down:

  • checking whether anyone else has “come through” the same problem;
  • matching symptoms online to obtain a diagnosis and treatment options;
  • asking a professional to tell them that they will survive.

Once they are reassured, they feel better, they have “rewarded” this seeking behavior. The next time they feel uncertain or threatened, they will ratchet up their anxiety with a catastrophic thought, then look outwards for reassurance even faster than before.

In this way, catastrophizing soon becomes a well-entrenched habit. The greatest problem with seeking others to alleviate anxiety is that it offers only temporary relief.

Plan for tackling anxiety:

  1. Accept yourself.
    • Anxiety is energy. Look for enjoyable ways to challenge yourself and use your energy more positively:
      • Taking regular aerobic exercise.
      • Learning something new.
      • Taking up a creative passion.
  2. Take control.
    • Establish a regular "worry time".
      • Start by setting aside half an hour every day. Write down all your concerns in specific terms
      • Assign a score on a scale of 0 to 100% to estimate how distressed this possibility makes you feel
      • List all the possible explanations for your concern, then rank each one according to how likely it is to be correct
      • Score your worry for the level of distress it is causing you now. Gradually, you will be able to reduce the amount and frequency of worry time.
  3. Use the "best friend test".
    • Ask yourself what you would advise your best friend to do about each concern, and take that action
  4. Learn to self-soothe.
    • Whenever you are overwhelmed by anxiety and feel you must seek reassurance, give yourself permission to do so – but not straight away.
      • Start with 2 min.
        • Breathing slowly in through your nose and out through your mouth, or taking some gentle exercise, will help.
        • Gradually, you will find you can wait longer.
        • When you get to the point where you can wait more than 20 minutes, most people find they no longer need to be reassured by others.

4 Cardiology

4.1 4 Factors of O2 consuption for heart work

  1. Rate
  2. Blood Pressure
  3. Preload
  4. Contractility

4.2 5 Most common causes of sudden card death in young athletes

  1. Herpertrophic Cardiomyopathy
  2. WPW
  3. Long QT
  4. Congenital Aortic Stenosis
  5. Anomalous coronary

4.3 Abdominal Aortic Aneurysm

Table 2: Rupture risk
Sice in cm Risk of rupture in 1 yr (%)
< 4 0
4 - 5 0.5-5
5 - 6 3 - 15
6 - 7 10 - 20
7 - 8 20 - 40
> 8 30 - 50
Table 3: Surveillance recommendations
Aneurysm diameter ACC/AHA Recommendation
> 2.5 cm but <3.0 cm No surveillance
3.0 - 3.9 cm Every 2-3 years
4.0 - 5.4 cm US or CT every 6-12 mo; Consider vascular surgery referral if > 5.0; Elective repair is recommended for appropriace candidates > 5.0cm
> 5.4 cm Surgical Repair


  • AFP Aug 2022 Vol 106 No 2

4.4 Coronary Artery Calcium Score   edit

The following definitions are used to relate the CAC score to the extent of underlying coronary artery disease (3):

  • Coronary calcium score 0: No identifiable coronary artery disease.
  • Coronary calcium score 1-99: Mild coronary artery disease.
  • Coronary calcium score 101-400: Moderate coronary artery disease.
  • Coronary calcium score > 400: Extensive coronary artery disease.

When interpreting the CAC score, it is essential to consider age and gender. Women, in general, have lower calcium scores than men.

A calcium score calculator is available here that provides CAC score distribution based on age, gender, and ethnicity.

CAC score increases with age. Hence, at a certain age, we will be expected to have a specific CAC score that would be considered normal for that age. This score would then reflect the age of our arteries or the arterial age.

If everything is normal, we would expect our arterial age to be the same as our observed age.

However, if the CAC score is high, our arterial age may be higher than our observed age. Conversely, if our CAC score is low, the arterial age may be lower than our observed age.

The table below shows how arterial age can be predicted from the CAC score

Estimated Arterial Age and 95% Confidence Intervals by Coronary Artery Calcium Score

CAC Arterial Age in Years (95% CI) CAC Arterial Age in Years (95% CI)
0 39 (32–46) 100 73 (71–74)
10 56 (53–60) 200 78 (75–80)
20 61 (59–63) 300 80 (78–83)
30 64 (62–66) 400 83 (79–86)
40 66 (65–67) 500 84 (80–88)
50 68 (67–69) 750 87 (83–92)
60 69 (68–70) 1000 89 (84–94)
70 70 (69–71) 1500 92 (87–98)
80 71 (70–72) 2000 94 (88–100)
90 72 (71–73) 2500 96 (89–102)

Guidelines for coronary calcium scoring by 2010 ACCF task force

These guidelines are latest at time of writing (July 2016):

  • intermediate cardiovascular risk and asymptomatic adults (class IIa)
  • low-to-intermediate risk and asymptomatic adults (class IIb)
  • low risk and asymptomatic (class III)
  • asymptomatic adults with diabetes mellitus, 40 years of age and older (class IIa)
CAC Comment
0 May defer statins up to 10 years; Exceptions: severe family history of premature, ASCVD, DM, severe hypercholeserolemia, active tobacco use
1-99 Risk discussion to review options for patient: Risk enhancing factors favor moderate-intensity statin therapy
100-299 Confirms intermediate risk: moderate-intensity statin therapy indicated
300+ Confirms higher risk: high-intensity statin therapy indicated


4.5 Differential Diagnosis and Treatment of Chest Wall Conditions

Condition Diagnostic considerations Treatment principles
Costochondritis Tenderness to palpation of costochondral junctions; reproduces patient's pain; usually multiple sites on same side of chest Simple analgesics; heat or ice; rarely, local anesthetic injections or corticosteroid injections
Destruction of costal cartilage by infections or neoplasm Bacterial or fungal infections or metastatic neoplasms to costal cartilages; infections occur postsurgery or in intravenous drug users; chest computed tomography imaging useful to show alteration or destruction of cartilage and extension of masses to chest wall Antibiotics or antifungal drugs; surgical resection of affected costal cartilage; treatment of neoplasm based on tissue type
Fibromyalgia Symmetric tender points at second costochondral junctions, with characteristic tender points in the neck, back, hip, and extremities and widespread pain Graded exercise is beneficial; cyclobenzaprine (Flexeril), antidepressants, and pregabalin (Lyrica) may be beneficial
Herpes zoster of thorax Clusters of vesicles on red bases that follow one or two dermatomes and do not cross the midline; usually preceded by a prodrome of pain; postherpetic neuralgia is potential complication that is more common in older patients Oral antiviral agents (e.g., acyclovir, famciclovir [Famvir], valacyclovir [Valtrex]); analgesics as needed for pain; may require narcotics or topical lidocaine patches to control pain
Painful xiphoid syndrome Tenderness at sternoxiphoid joint or over xiphoid process with palpation Usually self-limited unless associated with congenital deformity of xiphoid; analgesics; rarely, corticosteroid injections
Slipping rib syndrome Tenderness and hypermobility of anterior ends of lower costal cartilages causing pain at lower anterior chest wall or upper abdomen; diagnosis by “hooking maneuver”: curving fingers under costal margin and gently pulling anteriorly—a “click” and movement is felt that reproduces patient's pain Rest, physiotherapy, intercostal nerve blocks; if chronic and severe, surgical removal of hypermobile cartilage segment
Tietze syndrome Single tender and swollen, but nonsuppurative, costochondral junction, usually in costochondral junction of ribs two and three Simple analgesics; usually self-limiting; rarely, corticosteroid injections
Traumatic muscle pain and overuse myalgia History of trauma to chest or recent new onset of strenuous exercise to upper body (e.g., rowing); may be bilateral and affecting multiple costochondral areas; muscle groups may also be tender to palpation Simple analgesics; refrain from doing or reduce intensity of strenuous activities that provoke pain


  • Am Fam Physician. 2021 Jul ;104(1):73-78.

4.6 Eating Eggs Is Not Associated with Cardiovascular Disease

Egg consumption is not associated with the occurrence of cardiovascular events over an average of 12 years.

A meta-analysis found that eating more than one egg per day, on average, was associated with a decreased likelihood of coronary artery disease (approximately 11%). This decrease may be due to a healthy user bias; that is, eating eggs may be associated with healthy habits. (Level of Evidence = 2b)


  • Am Fam Physician. 2021 Jun 1;103(11):695.

4.7 AHA's Simple Seven

This simple, seven step list has been developed to deliver on the hope we all have–to live a long, productive healthy life.

  1. High blood pressure
  2. Cholesterol
  3. Blood Sugar
  4. Diet
  5. Physical Activity
  6. Weight
  7. Smoking


4.8 Atrial Fibrillation


  • Anticoagulation is recommended for AF at a CHA2DS2-VASc score of 2 for men and 3 for women without moderate or severe mitral stenosis or a mechanical valve.
    • The score has not been validated for mitral stenosis or mechanical valves.
  • Direct oral anticoagulants are recommended over warfarin for AF without moderate or severe mitral stenosis or a mechanical valve.
    • Warfarin is still recommended for mitral stenosis and mechanical valves.
  • Although CHA2DS2-VASc scores of 0 for men and 1 for women do not require treatment, scores of 1 for men and 2 for women are indeterminate and anticoagulation may be considered by shared decision-making.

Rate Control

  • Ventricular rate control is accepted as alternative to rhythm control for first-line management of chronic AF
  • Lenient rate control (<110bpm) is as effective as strict (<80bpm)
  • A beta-blocker is preferred for rate control in those with CAD or systolic dysfunction
  • Verapamil or diltiazem may be preferred in those with asthma
  • Amiodarone may be effective if other drugs have failed

Rhythm Control

  • Treatment of choice for urgent conversion is DC cardioversion


  • AFP Vol 101 No 2 Jan 2020
  • JAMA Vol 322 No 18 Nov 2019

4.9 Cardiac Clearance for Surgery

Risk for Major Cardiac Complications following surgery

Assign a point for each:

  1. High-risk surgery (intraperitoneal, intrathoracic, suprainguinal vascular)
  2. H/o MI or pos GXT, or current chest pain secondary to myocardial ischemia, current nitrate therapy, or EKG with pathologic Q wave
  3. H/o CHF, pulmonary edema, r paroxysmal nocturnal dyspnea; or current bilateral rales, S3, or CXR with pulmonary vascular redistribution
  4. H/o cerebrovascular disease
  5. Preoperative treatment with insulin
  6. Preoperative serum creatinine >2.0mg/dL
Score Risk class % Risk for complication
0 I 0.4
1 II 0.9
2 III 6.6
3 IV 11.0

Surgical risk category

  • High (Cardiac risk >5%)
    • Aortic or other major vascular surgery
    • Peripheral vascular surgery
  • Intermediate (Cardiac risk 1-5%)
    • Carotid endarterectomy
    • Head and neck surgery
    • Intraperitoneal or intrathoracic surgery
    • Orthopedic surgery
    • Prostate surgery
  • Low (Cardiac risk <1%)
    • Superficial procedures
    • Breast surgery
    • Cataract surgery
    • Endoscopic procedures
    • Most ambulatory surgeries


  • AFP Vol 85 No 3 Feb 2012

4.9.1 Pre-op Clearance

Cardiac Risk Index (Assign 1 point for each risk factor):

  • High risk surgery (intraperitoneal, intrathoracic, or suprainguinal vascular surgery)
  • History of ischemic heart disease
    • Current chest pain from suspected MI
    • Current or past use of nitrate therapy
    • EKG with pathologic Q waves
    • History of MI or positive exercise stress test
  • History of heart failure
    • CXR with pulmonary vascular redistribution
    • Paroxysmal nocturnal dyspnea
    • Pulmonary edema, bilateral rales, or S3 gallup
  • History of cerebrovascular disease
    • History of TIA or stroke
  • Preoperative treatment with insulin
  • Preoperative creatinin level >2 mg/dL


Points Risk of major cardiac event
0 0.4%
1 0.9%
2 6.6%
3 11%

Surgical procedures risk stratified:

Low risk (<1% risk of major adverse cardiac event)

  • Ambulatory surgery
  • Breast surgery
  • Cataract surgery
  • Endoscopic procedures
  • Superficial procedures

Higher risk (>1% risk of major adverse cardiac event)

  • Aortic and other major vascular surgery
  • Emergent procedures
  • Head and neck surgery
  • Intraperitoneal and intrathoracic surgery
  • Open urologic surgery
  • Orthopedic surgery
  • Prolonged procedures with large fluid shifts and/or blood loss

Antiplatelet management:

  • Primary prevention
    • Hold before surgery (7-10d if possible) unless risk of major adverse cardiac event is greater than risk of bleeding
  • Secondary prevention
    • Intracranial, major spinal, or other high risk bleeding surgery:
      • Hold before surgery (7-10d if possible) unless risk of major adverse cardiac event is greater than risk of bleeding
    • Most other sureries
      • Continue perioperatively, unless risk of major adverse cardiac event is greater than risk of bleeding


  • AFP Vol 95 No 10 May 2017

4.10 Cardiology Differential

  1. Coronary circulation
  2. Arrhythmia
  3. Valves
  4. Myocardium
  5. Pericardium

4.11 Cardiac Medications

  • ACE Inhibitors
    • Indications
      • Patients with hypertension, diabetes mellitus, chronic kidney disease, abnormal left ventricular function, systolic heart failure, or recent MI
    • Comments
      • Decrease mortality rates Use caution in pregnant women and in patients with angioedema, renovascular disease, or hyperkalemia
  • Angiotensin receptor blockers
    • Indications
      • Patients in whom ACE inhibitors are not tolerated
    • Comments
      • No additional benefit vs. ACE inhibitors Use caution in pregnant women and in patients with angioedema, renovascular disease, or hyperkalemia
  • Beta blockers
    • Indications
      • First-line therapy in patients with history of MI, acute coronary syndrome, systolic heart failure, angina pectoris, atrial fibrillation, or atrial flutter Consider for patients with essential tremor, hyperthyroidism, or migraine
    • Comments
      • Decrease mortality rates Use caution in older patients (may increase stroke risk) and in those with bronchospastic disease, second- or third-degree heart block, symptomatic bradycardia, or depression
  • Calcium channel blockers
    • Indications
      • Consider for patients whose symptoms are not controlled with or who cannot tolerate beta blockers, and for patients with Raynaud disease Can be used in patients with angina pectoris, atrial fibrillation, or atrial flutter
    • Comments
      • Use long-acting nondihydropyridines; avoid short-acting nifedipine Use caution in patients with second- or third-degree heart block
  • Nitrates
    • Indications
      • Patients with angina whose symptoms are not controlled with beta blockers or calcium channel blockers can use long-acting nitrates; short-acting nitrates can be used for quick relief of symptoms
    • Comments
      • Evidence lacking on mortality benefit Use caution in patients with hypotension
  • Ranolazine (Ranexa)
    • Indications
      • Patients with recent MI or stable coronary artery disease Adjunctive therapy in patients whose symptoms are not controlled with beta blockers or calcium channel blockers, or in whom beta blockers are not tolerated
    • Comments
      • Does not lower blood pressure Use caution in patients with impaired liver function and in those taking QT-prolonging medications


  • AFP Vol 97 No 6 Mar 2018

4.12 Carotid Artery Stenosis

Risk Factors:

  • Age
  • Smoking
  • Diabetes
  • HLD
  • HTN

Surgical candidates:

  • Patients with 50% stenosis of the artery and symptoms
  • Patients with 70% or more stenosis

Risk of stroke during procedure:

  • Open surgery: 2%
  • Trans-Carotid Artery Revascularization (TCAR): between 2-4%
  • Carotid Artery Stenting: 4%

After procedure: ASA or clopidogrel

4.13 Chest pain

Decision rule for likelihood of CAD as cause of Chest Pain

Component Points
Age and sex (M > 55yo; F > 65yo) 1
Known vascular disesae (CAD, Occlusive vascular disease, cardiovascular disease) 1
Pain is not elicited with palpation 1
Pain is worse with exercise 1
Patient assumes pain is of cardiac origin 1

Likelihood of CAD as cause of Chest Pain

Score Positive Likelihood Negative Likelihood
0 or 1 1.09 0.00
2 or 3 1.83 0.03
4 or 5 4.52 0.15


  • AFP Vol 96 No 5 Sep 2017

4.13.1 Chest pain causes

Other diagnoses chest pain

  • Non-ischemic cardiovascular
    • Aortic dissection*
    • Myocarditis
    • Pericarditis
  • Chest wall
  • Cervical disc disease
  • Costochondritis
  • Fibrositis
  • Herpes zoster (before the rash)
  • Neuropathic pain
  • Rib fracture
  • Sternoclavicular arthritis
  • Pulmonary
    • Pleuritis
    • Pneumonia
    • Pulmonary embolus*
    • Tension pneumothorax*
  • Psychiatric
    • Affective disorders (eg, depression)
    • Anxiety disorders
    • Hyperventilation
    • Panic disorder
    • Primary anxiety
    • Somatiform disorders
    • Thought disorders (eg, fixed delusions)
  • Gastrointestinal
    • Biliary
    • Cholangitis
    • Cholecystitis
    • Choledocholithiasis
    • Colic
  • Esophageal
    • Esophagitis
    • Spasm
    • Reflux
    • Rupture*
  • Pancreatitis
  • Peptic ulcer disease

    • Nonperforating
    • Perforating*

    *Potentially life-threatening conditions.

  • ACC/AHA/ACP Guidelines for the Management of Patients with Chronic Stable Angina. J Am Coll Cardiol 1999; 33:2092.

4.13.2 Acute Chest Pain: Outpatient Evaluation   edit


  • Typical chest pain or angina is:
    • a deep, poorly localized chest or arm discomfort (pain or pressure) associated with physical exertion or emotional stress and relieved with rest or sublingual nitroglycerin within five minutes.
  • Unstable angina is:
    • new-onset angina, angina at rest, or angina that becomes more frequent, severe, or prolonged.
  • Acute myocardial infarction is:
    • myocardial injury resulting in elevated cardiac biomarkers in the setting of acute ischemia caused by ST segment elevation myocardial infarction or non–ST segment elevation myocardial infarction.

The most common causes of chest pain in the primary care population are:

  • chest wall pain (20% to 50%)
  • reflux esophagitis (10% to 20%)
  • and costochondritis (13%)

Other potential factors include:

  • pulmonary etiologies (pneumonia, pulmonary embolism [PE])
  • psychological etiologies (panic disorder)
  • and nonischemic cardiovascular disorders (congestive heart failure, thoracic aortic dissection)
  • No definitive diagnosis may be found in as many as 15% of patients
Table 4: Predicted Pretest Probabilities of Coronary Artery Disease in Patients with Chest Pain Based on Age, Sex, and Type of Chest Pain
Age range (years) Men     Women    
  Typical Atypical Nonanginal Typical Atypical Nonanginal
40 to 49 69% 38% 25% 37% 14% 8%
50 to 59 77% 49% 34% 47% 20% 12%
60 to 69 84% 59% 44% 58% 28% 17%
70 to 79 89% 69% 54% 68% 37% 24%
> 80 93% 77% 65% 76% 47% 32%

Marburg Heart Score

Table 5: Marburg Heart Score to Predict CAD as a Cause of Chest Pain
Component Points
Sex/age (women > 65 years; men > 55 years) 1
Known clinical vascular disease (CAD, occlusive vascular disease, cerebrovascular disease) 1
Increased pain with exercise 1
Pain not elicited with palpation of chest wall 1
Patient assumes pain is of cardiac origin 1
Table 6: Prevalence of CAD as cause of chest pain given overall population risk of:
Score Likelihood ratio 2.00% 10.00% 20.00%
0 to 1 point 0.04 0.1 0.4 0.9
2 to 3 points 0.92 1.8 9.3 18.8
4 to 5 points 11.2 18.6 55.5 73.7

Nonischemic Causes of Chest Pain

  • Cardiac
    • Acute aortic dissection
    • Heart failure
      • MICE criteria (Male sex, history of myocardial Infarction, basal lung Crepitations, and ankle Edema) likely have heart failure -> Echo
    • Pericarditis
  • Gastrointestinal
    • Gastroesophageal reflux disease
      • A one-week trial of a high-dose proton pump inhibitor is modestly sensitive and specific for GERD, with a 50% reduction in reflux symptoms being moderately accurate for a final diagnosis of GERD (LR+ = 5.5; LR− = 0.24)
  • Musculoskeletal
    • Chest wall pain (33% to 50% of chest pain)
    • Costochondritis
  • Psychological
    • Panic attack
      • In the past four weeks, have you had an anxiety attack (suddenly feeling fear or panic)?
      • This question is good at supporting a diagnosis of panic disorder when patients answer yes (LR+ = 4.2) and is good at ruling it out when the answer is no (LR− = 0.09)
  • Pulmonary
    • Pneumonia
      • Egophony (LR+ = 8.6), dullness to percussion of the posterior thorax (LR+ = 4.3), and respiratory rate greater than 20 breaths per minute (LR+ = 3.5) are suggestive of pneumonia.
      • Normal temperature, heart rate, and respiratory rate with a normal pulmonary examination rules out pneumonia (LR− = 0.10)
    • Pulmonary embolism
      • Wells criteria
      • The Pulmonary Embolism Rule-out Criteria were developed to specifically rule out PE in the primary care setting.46 Patients meeting all eight criteria (50 years or younger, heart rate less than 100 beats per minute, oxygen saturation greater than 94%, no unilateral leg swelling, no hemoptysis, no surgery or trauma within four weeks, no previous deep venous thrombosis or PE, no oral hormone use) have a less than 1% likelihood of PE and thus do not need d-dimer testing or imaging.
Table 7: Wells criteria
Criteria Points
Signs or symptoms of DVT (leg swelling or pain with palpation of deep vein) 3
Diagnosis of PE is more likely than an alternative diagnosis 3
Heart rate > 100 beats per minute 1.5
Immobilization (bed rest > 3 days) or surgery in past 4 weeks 1.5
History of PE or DVT 1.5
Hemoptysis 1
Active malignancy (or cancer treatment stopped in past 6 months) 1
Table 8: Scoring
Total points Risk of PE Probability of PE(overall probability = 9.2%)
0 to 1 point Low 1.3
2 to 6 points Moderate 16.2
More than 6 points High 37.5

Those at low or intermediate risk of ACS can undergo exercise stress testing, coronary computed tomography angiography, or cardiac magnetic resonance imaging

In those with low suspicion for ACS, consider other diagnoses such as chest wall pain or costochondritis, gastroesophageal reflux disease, and panic disorder or anxiety states. Other less common, but important, diagnostic considerations include acute pericarditis, pneumonia, heart failure, pulmonary embolism, and acute thoracic aortic dissection.

The Marburg Heart Score and the INTERCHEST clinical decision rule can also help estimate ACS risk. Twelve-lead electrocardiography is recommended to look for ST segment changes, new-onset left bundle branch block, presence of Q waves, and new T-wave inversions. Patients with suspicion of ACS or changes on electrocardiography should be transported immediately to the emergency department.


  • AFP Vol 102 No 12 Dec 2020

4.13.3 Acute MI

Most useful rule to rule in MI is:

  • Chest pain with radiation to both arms, followed by radiation to the right arm

Most useful elements to rule out MI are:

  • Pleuritic chest pain
  • Sharp pain
  • Pain reproduced with palpation



  • AFP Vol 96 No 5 Sep 2017

4.13.4 2hr MI rule out

  • Rule out MI if the max trop evel is <0.014 mcg/L and absolute change over 2hrs is < 0.0004 mcg/L
  • Rule in MI if max trop level is >0.052 mcg/L or the absolute change over 2hrs is >0.009 mcg/L
  • Further observe those not in either category


  • Am J Med 2015;128(4):369-379

4.14 Coronary Artery Disease

Stable coronary artery disease:

  • Reversible supply/demand mismatch related to ischemia, a history of MI, or the presence of plaque documented on catheterization or CTA
  • Stable if asymptomatic or controlled by medications or revascularization
  • No evidence PCPI provides better outcomes than medical therapy for stable mod-severe CAD
    • ISCHEMIA Trial NEJM 4/2020


  • Lifestyle changes
    • 30-60 min of mod-intensity aerobic activity (Reduces cardiovascular mortality - RR=0.74; 95% CI 0.64-0.86)
  • Risk factor modification
  • Antiplatelet and antianginal therapy
    • If NO recent stent placement
      • If no contraindication to ASA -> ASA 75-162mg daily
      • If contraindication to ASA -> Clopidogrel 75mg daily
    • If recent stent placement
      • Dual antiplateley therapy: ASA + P2Y12 (clopidogrel, ticagrelor, or prasugrel)
        • Drug eluting stent -> Continue for 6-12 mo
        • Bare-metal stent -> Continue for 1-12 mo
  • Angina
    • Sublingual NG
    • B-blockers
    • If symptoms not controlled:
      • CCB
      • Long acting nitrate
      • Ranolazine
    • If persistent angina -> Consider CABG or PCI
  • Heart Failure
    • Preserved EF -> Lifestyle modifications
    • Reduced EF:
      • Diuretics
      • B-Blockers
      • ACE inhibitors
      • Angiotensin receptor blockers
      • Lifestyle modifications


  • AFP Vol 97 No 6 Mar 2018

4.14.1 Acute Coronary Syndrome

High likelihood of ACS:

  • Chest pain radiating to one or both arms
  • Chest pain associated with exertion, nausea, vomiting, or diaphoresis
  • Chest pain described as pressure or as "worse than previous angina or similar to a previous MI"

Low likelihood of ACS:

  • Stabbing, pleuritic, or positional chest pain
  • Pain in an inframammary location
  • Pain not associated with exertion
  • Pain is reproducible with palpation

Rule OUT CAD with Marburg Heart Score:

Factor Score
F >64y, M >54y 1 pt
Known CAD, cerebrovascular, or peripheral vascular Dz 1 pt
Pain worse with Ex 1 pt
Pain not reproducible with palpation 1 pt
Patient assumes pain is cardiac 1 pt
  • Score of 2 or less = 98% of pts with no CAD
  • Score >2 -> 23% with CAD


  • JFP Vol 63, No 5 May 2014

4.14.2 Rule to Predict CAD as cause of Chest Pain (Validated)

Give 1 point for each of these:

  • Men >55 or Women >65
  • Known vascular disease (CAD, occlusive vascular, cerebrovascular, etc)
  • Pain worse with exercise
  • Pain not elicited with palpation
  • Patient assumes pain is cardiac origin
Score Pos likelihood Neg likelihood
0 - 1 1.09 0.00
2 - 3 1.83 0.03
4 - 5 4.52 0.16


  • AFP Vol 87 No 3 Feb 2013

4.14.3 Cardiac CT (CCTA)


  1. Detection of CAD in symptomatic patients without known heart disease, either nonacute or acute presentations
  2. Detection of CAD in patients with new-onset or newly diagnosed clinical heart failure and no prior CAD
  3. Preoperative coronary assessment prior to noncoronary cardiac surgery
  4. Patients with prior electrocardiographic exercise testing - Normal test with continued symptoms or intermediate risk Duke treadmill score
  5. Patients with prior stress imaging procedures - Discordant electrocardiographic exercise and imaging results or equivocal stress imaging results
  6. Evaluation of new or worsening symptoms in the setting of a past normal stress imaging study
  7. Risk assessment post-revascularization - Symptomatic if post-coronary artery bypass grafting or asymptomatic with prior left main coronary stent of 3 mm or greater
  8. Evaluation of cardiac structure and function in adult congenital heart disease
  9. Evaluation of cardiac structure and function - Ventricular morphology and systolic function
  10. Evaluation of cardiac structure and function - Intracardiac and extracardiac structures

AHA Guidelines:

  • Asymptomatic patients should be assessed for cardiovascular risk using tools such as the Framingham Risk Score; those found to be at low risk (10-year risk of less than 10 percent) or high risk (10-year risk of more than 20 percent) do not benefit from coronary calcium assessment
    • LOE B
  • In clinically selected, intermediate-risk patients (10-year risk of 10 to 20 percent), it may be reasonable to measure the atherosclerosis burden using electron beam CT or multidetector CT to refine clinical risk prediction and to select patients for more aggressive target values for lipid-lowering therapies
    • LOE B
  • Coronary calcium assessment may be reasonable in symptomatic patients, especially in the setting of equivocal treadmill or functional testing
    • LOE B
  • Coronary calcium assessment may be considered in symptomatic patients to determine the cause of cardiomyopathy
    • LOE B
  • Coronary calcium assessment may be considered in patients with chest pain who have equivocal or normal ECG findings and negative cardiac enzyme test results
    • LOE B
  • CT coronary angiography is reasonable for the assessment of obstructive disease in symptomatic patients
    • LOE B
  • Electron beam CT and multidetector CT for detecting restenosis after stent placement cannot be recommended
    • LOE C
  • CT coronary angiography for the assessment of noncalcified plaque or to track atherosclerosis or stenosis over time is not recommended
    • LOE C
  • CT coronary angiography is not recommended in asymptomatic persons for the assessment of occult CAD
    • LOE C
  • Serial imaging for the assessment of coronary calcification progression is not indicated
    • LOE C
  • The use of hybrid scanning to assess cardiovascular risk or the presence of obstructive disease is not recommended
    • LOE C

Calcium Score:

Calcium Score Presence of CAD
0 No evidence of CAD
1-10 Min evidence of CAD
11-100 Mild evidence of CAD
101-400 Mod evidence of CAD
401+ Extensive evidence of CAD


4.15 CVA


  • BP Goal: <130/80
  • High dose statin (secondary prevention)

4.15.1 Dual Anti-Platelet Treatment

  • Initiate combined clopidogrel plus aspirin within 24 hours of a minor stroke or TIA and continue for no longer than 1 month; then switch patients to aspirin or clopidogrel monotherapy. LOE A
  • Do not use combined clopidogrel plus aspirin for long-term secondary stroke prevention. LOE A
  • Limit use of aspirin plus extended-release dipyridamole as a first choice for secondary stroke prevention because of limitations in efficacy and poor tolerability. LOE B


  • JFP Jul 2020 Vol 69, No 6

4.15.2 CVA Related Calculators

  • Dual Anti-platelet: DART app
  • ABCD2
  • SPARC Tool (Stroke/embolism risk)

4.16 D-Dimer increased plasma values

  • Plasma acts on Fibrin breaking it into Fibrin Degradation Products (FDPs).
  • One FDP is D-Dimer, which is 2 D domains of fibrin monomeres crosslinked by activated factor XIII.
  • D-dimer is generated from fibrin (NOT fibrinogen) and thus its increase indicates recent or ongoing intravascular coagulation

Associated Disorders:

  1. Arterial thromboembolic disease:
    • Myocardial infarction
    • Stroke
    • Acute limb ischemia
    • Atrial fibrilation
    • Intracardiac thrombus
  2. Venous thromboembolic disease:
    • Deep vein thrombosis
    • Pulmonary embolism
  3. Disseminated intravascular coagulation
  4. Preeclampsia and eclampsia
  5. Abnormal fibrinolysis; use of thrombolytic agents
  6. Cardiovascular disease; congestive failure
  7. Severe infection/sepsis/inflammation
  8. Surgery/Trauma (eg: tissue eschemia, necrosis
  9. Systemic inflammatory response syndrome
  10. Vasoocclussive episode of sickle cell disease
  11. Severe Liver disease (decreased clearance)
  12. Malignancy
  13. Renal disease
  14. Normal pregnancy
  15. Venous malformations


  • Graphic 60881

4.17 EKG

All EKG interpretations should address:

  • Rate
  • Rhythm
  • Intervals (PR, QRS, ST, QT)
  • Axis
  • P waves
  • Q waves
  • R wave progression
  • T waves
  • Any pathological findings

How I read:

  1. Look at rhythm strip at bottom and count across
    • Gives me: rate, regular vs not, clue into interval abnormalities
  2. Look at I and aVF
    • Gives me: axis deviation
  3. Look at V1 and II
    • gives me atrial pathology - RAE/LAE

3b) If regular rate, look at aVR

  • Gives me sinus vs ectopic focus (with caveats)
  1. Scan for Q waves (not abnormal if only in III)
  2. Look at R wave progression in V1-V6
    • Gives me: clues to LVH/RVH, BBB's, ideas extent of injury if actual MI
  3. Scan for T wave abnormalities (not unusual to find odd T's in III)

Other thoughts:

  • Sinus vs not sinus: sinus rhythm implies from sinus node - should be negative in aVR, positive everywhere else, not changing in morphology
  • Regular vs sinus arrhythmia: While no widely accepted standard values exist, I was taught there should be less than 0.04 beat-to-beat variability and that is what I use to determine regular or not regarding heart rate variability

Favorite learning resources:

4.18 Frequent symptomatic PVCs

  1. Step 1: Rule out hypothyroidism
  2. Step 2: Management
    • First line:
      • Metoprolol succinate (longer acting than tartrate)

4.19 Heart Failure

Framingham Diagnostic Criteria (Need 2 Major or 1 Major and 2 Minor):

  • Major
    • Acute pulmonary edema
    • Cardiomegaly
    • Hepatojugular reflex
    • Neck vein distension
    • Paroxysmal nocturnal dyspnea or orthopnea
    • Rales
    • Third heart sound gallop
  • Minor
    • Ankle edema
    • Dyspnea on exertion
    • Hepatomegaly
    • Nocturnal cough
    • Pleural effusion
    • Tachycardia >120bpm

Stages of Heart Failure

Stage A - (At risk of HF)

  • At high risk of heart failure, but without structural heart disease or symptoms of HF
  • Therapy Goals:
    • Treat HTN / Lipids
    • Smoking cessation
    • Regular Excercise
    • Discourage EtOH intake and illicits
    • Control metabolic syndrome
  • Therapy Management:
    • ACE I or ARB in appropriate patients for vascular disease or diabetes
    • Statins when indicated

Stage B (At risk of HF)

  • Sturctural heart disease, but without signs or symptoms of HF
  • Therapy Goals:
    • Prevent HF symptoms and worsening of cardiac remodeling
  • Therapy Management:
    • ACE I or ARB in appropriate patients
    • B-Blocker in appropriate patients
    • Select patients:
      • ICD
      • Revascularization or valvular surgery

Stage C (HF)

  • Structural heart disease with prior or current symptoms of HF
  • Therapy Goals:
    • Control symptoms
    • Patient education
    • Prevent hospitalization
    • Prevent mortality
  • Therapy Management:
    • Diuretics for fluid retention
    • ACE I or ARB
    • B-Blocker
    • Aldosterone antagonists
    • In selected patients:
      • Angiotensin receptor-neprilysin inhibitor
      • Digitalis
      • Isosorbide dinitrate/hydralazine
      • Cardiac resynchronization therapy
      • ICD
      • Revascularization or valvular surgery

Stage D (HF)

  • Refractory HF requireing specialized intervention
  • Therapy Goals:
    • Control symptoms
    • Improve quality of life
    • Reduce hospital admissions
    • Establish end-of-life goals
  • Therapy options:
    • Compassionate end-of-life care/hospice
    • Deactivate ICD
    • Extraordinary measures:
      • Heart transplantation
      • Chronic inotropes
      • Temporary or permanent mechanical support
      • Experimental surgery or drugs


  • AFP Vol 96 No 10 Nov 2017
  • AFP Vol 96 No 9 Nov 2017

4.19.1 HFrER

(EF <40)

  • NonInvasive Disease Modifying Rx:
    • ACE/ARB
    • Beta-blocker
    • Aldosterone antagonist
    • Hydralazine/ISDN
    • Ivabradine
    • Valsartan/Sacubitril
  • Sx modifying Rx
    • Diuretics
    • Digoxin
  • Common Modifiable Comorbidities
    • Anemia
    • HTN
    • T-4
    • Thiamine
    • Alcohol
    • COPD
    • CAD
  • Lifestyle and Immunizations
    • Na+/H2O
    • Weight
    • Exercise
    • Flu vaccine
    • PneumoVax


  • 2019 Spring FAFP

4.19.2 Medications

Best Beta blockers for heart failure

  • Three beta-blockers reduce mortality equally (by about 30% over one year) in patients with Class III or IV systolic heart failure.
    • carvedilol
    • metoprolol succinate
    • bisoprolol
  • Insufficient evidence exists comparing equipotent doses of these medications head-to-head to recommend any one over the others (strength of recommendation [SOR]: A, systematic review/meta-analysis).


  • J Fam Pract. 2015 February;64(2):122-123.

4.20 Henoch-Schonlein Purpura - HSP

Diagnostic Criteria

  • At least 2 of the following:
    • Palpable purpura (mandatory)
    • Age =< 20y at disease onset
    • Abdominal pain or GI bleeding
    • Vessel wall granulocytes on biopsy
  • Plus 1 of the following
    • Abdominal pain
      • Diffuse and colicky
    • Histopathology
      • Leukocytoclastic vasculitis or proliferative glomerulonephritis with predominant IgA deposition
    • Arthritis or arthralgia
      • Acute-onset joint pain or swelling
    • Kidney involvement
      • Proteinuria or hematuria


  • Consultant Oct 2016

4.21 Hyperlipidemia

Statin intensity:

High intensity Moderate intensity
Atorvastatin 40-80mg Atorvastatin 10-20mg
Rosuvastatin 20-40mg Fluvastatin XL 80mg
  Lovastatin 40mg
  Pitavastatin 40-80mg
  Pravastatin 40-80mg
  Rosuvastatin 5-10mg
  Simvastatin 20-40mg

4 Reasons for statin initiation:

  1. Secondary prevention (MI)
  2. DM - 40-75yo and LDL - 70-189
  3. LDL > 190
  4. ASCVD >7.5%

In adults without history of CVD:

  • Use a low to moderate statin for primary prevention of CVD events if the have all 3:
    1. Age 40-75yo
    2. At least 1 CVD risk factor (dyslipidemia, diabetes, hypertension, or smoking)
    3. A calculated 10-yr ASCVD score >10%
  • Adults 40-75yo with ASCVD 7.5%-10% and 1 CVD risk factor could benefit but it is much lower


  • JFP Vol 66 No 5 May 2017
  • AFP Vol 97 No 9 May 2018

4.21.1 Lipid Lowering Is Beneficial for Secondary Prevention but Not Primary Prevention in Patients 75 Years and Older

This meta-analysis inappropriately conflates studies of primary and secondary prevention, and the authors argue that their data support the use of lipid-lowering drugs in older adults. That may be true for secondary prevention, but it is clearly not proven for primary prevention. The STAREE trial is currently recruiting 18,000 older adults and randomizing them to receive atorvastatin (Lipitor), 40 mg, or placebo, and it will hopefully provide greater clarity about the use of lipids for primary prevention (results expected in 2023). (Level of Evidence = 1a−)


  • Am Fam Physician. 2021 Jun 1;103(11):695-696.

4.21.2 Hypertriglyceridemia

Prescribe fibrates and omega-3 fatty acids for patients with triglyceride levels of 500 mg per dL (5.65 mmol per L) or higher to reduce the risk of pancreatitis.

Fasting serum triglyceride levels of 150 mg per dL or higher

Risk factors

  • Obesity
  • Metabolic syndrome
  • Type 2 diabetes mellitus
  • Excessive alcohol use
  • Physical inactivity
  • Excess weight
  • Use of certain medications
  • Genetics

Management of high triglyceride levels (150 to 499 mg per dL)

  • Dietary changes
    • Lower carbohydrate intake (especially refined carbohydrates)
    • Increase fat (especially omega-3 fatty acids) and protein intake
  • Physical activity
    • Moderate- to high-intensity physical activity (>6 METS)


  • Severely elevated triglyceride levels (500 mg per dL or higher) increase the risk of pancreatitis
  • For patients with acute pancreatitis associated with hypertriglyceridemia:
    • Insulin infusion and plasmapheresis should be considered if triglyceride levels remain at 1,000 mg per dL or higher


4.21.3 Repatha

ACC/AHA guideline defines very high risk (VHR) as multiple major ASCVD events OR one major ASCVD event and multiple high-risk conditions.1

According to a recent study of 27,775 patients with a history of ASCVD in the Journal of the American College of Cardiology, more than half of ASCVD patients met VHR criteria.2

Of those:

26% of very high-risk patients had multiple major ASCVD events2

  • Recent ACS (within 12 months)
  • History of:
    • Ml (other than recent ACS above)
    • Ischemic stroke
    • Symptomatic PAD

74% of very high-risk patients had a major ASCVD event AND multiple high-risk conditions2

  • Age ≥65 years
  • Hypertension
  • Diabetes mellitus
  • Persistent LDL-C ≥100 mg/dL despite max-tolerated statin and ezetimibe
  • HeFH
  • CKD
  • Smoking
  • Prior CABG or prior PCI
  • Congestive heart failure

4.22 Hypertension

See: JNC 8

BP Goal:

    • Treatment recommended for Adults 60+ with SBP >150 mmHg with target <150 mmHg to reduce risk of stroke, cardiac events, and possibly mortality (strong evidence)
    • Remember: 60-150-140
      • Patients >60yo, consider treatment is SBP is >150mmHg or >140mmHg if they have a history of stroke or in a high cardiovascular risk
  • ACC/AHA:
    • Treatment recommended for noninstitutionalized, ambulatory, community-dwelling adults 65+ with avg SBP of 130+ mmHg with target < 130
    • No statistically significant benefit to all-cause mortality, CVD mortality, heart failure, or renal events when the lower BP cutoff was used (130/80) and the difference for fatal or nonfatal myocardial infarction was borderline nonsignificant.

Timing of anti-hypertensives:

  • Take a bedtime as significant reduction in mortality and morbidity for once-daily anti-hypertensives (LOE = 1b-)
    • NNT 20.3


  • Acute intrecerebral hemorrhage
    • If SBP >220 within 6 hrs of event - continuous drug infusion and close BP monitoring
    • If SBP 150-220 within 6 hrs of event - immediate lowering below 140 mmHg is potentially harmful
  • Acute ischemic stroke
    • <185/110 before administration of IV tPA
    • <185/105 for at least 24 hrs after initiating drug therapy
  • Post CVA
    • <130/80
  • Chronic kidney disease
    • <130/80
  • Diabetes mellitus
    • <130/80
    • ACE-I or ARB
  • Heart failure
    • With preserved EF: <130 systolic
    • With reduced EF: <130/80
  • Kidney transplant
    • <130/80
  • Stable ischemic heart disease
    • <130/80

Key Elements of Office BP Assessment:

  • Patient should avoid caffeine, exercise, and smoking for at least 30min before the visit
  • Patient should relax, sitting in a chari, with feet on floor and back supported for at least 5 min
  • Patient should have empty bladder
  • There should be no talking during the rest period and measurement
  • No clothing covering the area where the cuff is placed
  • Correct cuff size
  • Patient arm should be supported
  • Middle of the cuff should be on the patient upper arm at the level of the right atrium
  • Seperate repeaated meaurements by 1 to 2 min
  • Take the average of at least 2 measurements



  • AFP Vol 97 No 6 Mar 2018
  • AFP Vol 97 No 9 May 2018

4.22.1 Ambulatory Blood Pressure

From USPSTF Recommendations:

  • The USPSTF found convincing evidence that ABPM is the best method for diagnosing hypertension. Although the criteria for establishing hypertension varied across studies, there was significant discordance between the office diagnosis of hypertension and 12- and 24-hour average blood pressures using ABPM, with significantly fewer patients requiring treatment based on ABPM. Elevated ambulatory systolic blood pressure was consistently and significantly associated with increased risk for fatal and nonfatal stroke and cardiovascular events, independent of office blood pressure. For these reasons, the USPSTF recommends ABPM as the reference standard for confirming the diagnosis of hypertension.


  • 93784 - Ambulatory blood pressure monitoring, utilizing a system such as magnetic tape and/or computer disk, for 24 hours or longer; including recording,

scanning analysis, interpretation and report - $54.62

Other notes:

  • Only 68% of Medicare claims for ambulatory blood pressure are reimbursed.
  • Claims are likely to be reimbursed if the ICD-9 diagnosis code 796.2 is included.
  • Less than 30% of claims without a 796.2 diagnosis code were reimbursed.
  • The median reimbursement amount for an ABPM procedure was $52.01

4.22.2 Guidelines for taking home blood pressure

These are the guidelines for taking blood pressure:

  • Avoid caffeinated or alcoholic beverages 30 minutes beforehand.
  • Sit quietly for five minutes with your back supported and your legs uncrossed.
  • Support your arm, so your elbow is at or near heart level.
  • Wrap the cuff over bare skin.
  • Don't talk during the measurement.
  • Leave the deflated cuff in place, wait a minute, then take a second reading. If the readings are close, average them. If not, repeat and average the three readings.

4.22.3 JNC 8

Start all new diagnosed HTN with:

  1. valsartan/hctz (Walmart cheap combo)
    • QUARTET Study from Lancet 2021 Sep 18; 398:1043

Choice Priority of initial agent:

  • Black:
    1. Thiazide
    2. CCB
    3. ACE or ARB
  • Nonblack:
    1. Thiazide
    2. CCB
    3. ACE or ARB
  • CKD:
    1. ACE or ARB
    2. Thiazide
    3. CCB
Indication Treatment Choice
Heart Failure ACEI/ARB+BB + diuretic +spironolactone
CAD ACEI, BB, diuretic, CCB
Diabetes ACEI/ARB,CCB, diuretic
Recurrent stroke prevention ACEI,diuretic
Pregnancy labetolol (first line),nifedipine, methyldopa

Beta-1 Selective Beta-blockers –possibly safer in patients with COPD, asthma, diabetes, and peripheral vascular disease:

  • metoprolol
  • bisoprolol
  • betaxolol
  • acebutolol
Drug Class Agents ofChoice Comments
Diuretics HCTZ 12.5-50mg,chlorthalidone 12.5-25mg, indapamide 1.25-2.5mg, triamterene 100mg; K+ sparing –spironolactone 25-50mg, amiloride5-10mg, triamterene 100mg; furosemide 20-80mg twice daily, torsemide10-40mg Monitor for hypokalemia; Most SE are metabolic in nature; Most effective when combined w/ ACEI; Stronger clinical evidence w/chlorthalidone; Spironolactone -gynecomastia and hyperkalemia; Loop diuretics may be needed when GFR <40mL/min
ACEI/ARB ACEI: lisinopril,benazapril, fosinopril and quinapril 10-40mg, ramipril 5-10mg, trandolapril 2-8mg; ARB: candesartan 8-32mg, valsartan 80-320mg, losartan 50-100mg, olmesartan 20-40mg, telmisartan 20-80mg SE:Cough (ACEI only), angioedema (more with ACEI), hyperkalemia; Losartan lowers uric acid levels; candesartan may prevent migraine headaches
Beta-Blockers metoprolol succinate 50-100mg and tartrate 50-100mg twice daily, nebivolol 5-10mg, propranolol 40-120mg twice daily, carvedilol 6.25-25mg twice daily, bisoprolol 5-10mg, labetalol 100-300mg twice daily Not firstline agents –reserve for post-MI/CHF; Cause fatigue and decreased heart rate; Adversely affect glucose; mask hypoglycemic awareness
Calcium channel blockers Dihydropyridines: amlodipine 5-10mg, nifedipine ER 30-90mg; Non-dihydropyridines: diltiazem ER 180-360 mg,verapamil 80-120mg 3 times daily or ER 240-480mg Cause edema; dihydropyridines may be safely combined w/ B-blocker; Non-dihydropyridines reduce heart rate and proteinuria
Vasodilators hydralazine 25-100mg twice daily, minoxidil 5-10mg terazosin 1-5mg, doxazosin 1-4mg given at bedtime Hydralazine and minoxidil may cause reflex tachycardia and fluid retention –usually require diuretic + B-blocker; Alpha-blockers may cause orthostatic hypotension
Centrally-acting Agents clonidine 0.1-0.2mg twice daily, methyldopa 250-500mg twice daily guanfacine 1-3mg Clonidine available in weekly patch formulation for resistant hypertension

Key Points:

  • In the general population, pharmacologic treatment should be initiated when blood pressure is 150/90 mm Hg or higher in adults 60 years and older, or 140/90 mm Hg or higher in adults younger than 60 years.
  • In patients with hypertension and diabetes, pharmacologic treatment should be initiated when blood pressure is 140/90 mm Hg or higher, regardless of age.
  • Initial antihypertensive treatment should include a thiazide diuretic, calcium channel blocker, ACE inhibitor, or ARB in the general nonblack population or a thiazide diuretic or calcium channel blockerin the general black population.
  • If the target blood pressure is not reached within one month after initiating therapy, the dosage of the initial medication should be increased, or a second medication should be added.


4.22.4 Pediatric Hypertension


Blood Pressure Diagnosis
SBP and DBP <90th% Normal
SBP or DBP 90-95% or >120/80 Pre-HTN
SBP or DBP >99% Stage 1 HTN
SBP or DBP >99% +5mmHg Stage 2 HTN
  • Reassess BP every 6mo for Pre-HTN
  • Reassess BP every 2 wks for stage 1 HTN
  • When BP remains <90th%, routine surveillance every 3-6mo
  • Pediatric patients with Stage 2 HTN should not participate in high-static sports until BP is well controlled.

Possible causes of secondary pediatric HTN:

  • Chronic kidney disease
  • Renovascular hypertension
  • Pheochromocytoma
  • Primary aldosteronism
  • Cushing's syndrome
  • Aortic coarctation
  • Genetics
  • Drug-induced
  • Hyperthyroidism
  • Congenital adrenal hyperplasia
  • Obstructive sleep apnea


  • JFP Vol 63 No 3 Mar 2014

4.22.5 Primary Hypertension

  1. HTN Classification Scale
    Class SBP DBP
    Normal <120 <80
    Pre-HTN 120-139 80-90
    Stage 1 HTN 140-159 90-99
    Stage 2 HTN >160 >100


    • JFP Vol 65 No 1 Jan 2016
  2. HTN - Work up for secondary causes

    It is recommended that all children and adolescents with a new diagnosis of hypertension undergo renal ultrasound and laboratory evaluation for renal pathology (strength of recommendation [SOR]: C, consensus-based guidelines). 

    Specific diagnostic tests are recommended for newly diagnosed patients who have suspicious clinical findings suggestive of a secondary cause of hypertension based on the initial history (excess daytime sleepiness, palpitations, tremor, sweating); physical examination (abdominal bruit, thyromegaly, malar rash); or laboratory analysis (elevated serum creatinine, low thyroid-stimulating hormone) (SOR: C, consensus-based guidelines). 

    Patients with undifferentiated resistant hypertension should receive further directed evaluation for secondary causes (SOR: C, consensus-based guidelines).


    Secondary hypertension is more prevalent in younger children and in children and adolescents with stage 2 hypertension (blood pressure [BP] >99th percentile for age and height plus 5 mm Hg).1 Renoparenchymal and renovascular disease account for most cases of secondary hypertension in these children.

    70% to 85% of children <12 years and 10% to 15% of adolescents 12 to 18 years with hypertension have an underlying cause, most commonly renoparenchymal and renovascular disease.

    Such evaluation should include a renal ultrasound and laboratory testing (creatinine, urinalysis, and urine culture) to look for structural or functional anomalies.


    Secondary hypertension reportedly occurs in 5% to 10% of hypertensive patients.

    Patients at highest risk for secondary hypertension have no family history of hypertension; abrupt onset, symptomatic, or crisis hypertension; stage 2 hypertension; sudden loss of hypertensive control; and drug-resistant hypertension.

    The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that patients with the following characteristics undergo further directed evaluation for a secondary cause:8

    • younger than 30 years with no family history of hypertension
    • older than 55 years with new hypertension
    • abdominal bruit with diastolic component
    • sudden worsening of BP control
    • recurrent flash pulmonary edema
    • renal failure with abnormal urinary sediment or proteinuria
    • acute renal failure after administration of an ACE inhibitor or ARB.

    Patients with resistant hypertension (BP>140/90 mm Hg despite taking optimal doses of 3 antihypertensive medications, one of which is a diuretic) should receive particular scrutiny for an identifiable secondary cause.


    • J Fam Pract. 2014 January;63(1):41-42,54.
  3. Hypertensive Emergency Medications per Target Organs
    • Neurologic (do not increase IOP)
      • Nicardipine or clevidipine
      • Labetalol
    • Aortic (reduce dP/dtmax without reflex tachycardia and inotropy)
      • Esmolol
      • Nitroprusside (only as add-on after effective B-blockade)
      • Nicardipine or clevidipine (only as add-on after effective B-blockade)
    • Cardiac (do not potentiate ischemia or heart failure)
      • Acute MI
        • Nitroglycerin
        • Esmolol
        • Metoprolol
      • HF
        • Nitroglycerin
        • Furosemide
        • Nitroprusside
    • Renal (not renally cleared or nephrotoxic)
      • Acute Kidey Injury
        • Nicardipine or clevidipine
        • Labetalol
      • Scleroderma renal crisis
        • Oral captopril
    • Pregnancy (not toxic to fetus)
      • Hydralazine
      • Labetalol
      • Oral Nifedipine


    • Consultant Mar 2016
  4. Lab workup
    1. EKG
    2. Glu
    3. Lipids
    4. GFR
    5. H/H
    6. Calcium
    7. K
    8. UA
  5. Lifestyle effects on BP:
    Lifestyle SBP DBP
    DASH with Na rest 11.5 5.7
    Na rest (<1500mg/day) 7 3
    DASH 5-6 3
    Wt loss (9lbs/4kg) 4.5 3.2
    Exercise 4 3
    Restriction of EtOH 3 2


    • AFP Vol 91 No 3 Feb 2015
  6. Lifestyle modifications

    From ACC/AHA 2013 Lifestyle Work Group

    • Diet: Rich in vegetables, fruits, and whole grains, including low-fat dairy, poultry, fish, legumes, nuts, and nontropical vegetable oils - such as DASH or AHA diets
    • Salt consumption: <2400mg/d … Ideal is <1500mg/d
    • Regular exercise: Moderate to vigorous aerobic activity 3-4 times a week averaging 40min/session


    • >4.5 cups of fruit and vegetables daily
    • >2 3.5oz servings of fish per week (prefer oily fish)
    • >3 1oz eq servings of fiber rich whole grains daily (1.1g of fiber per 10g carb)
    • <1500mg Na daily
    • <450 calories of sugar sweetened beverages per week (do not drink these!)

    Components of DASH:

    • Total fat: 27% of calories
      • Saturated fat: 6% of calories
    • Protein: 18% of calories
    • Carbohydrates: 55% of calories
    • Cholesterol: 150 mg
    • Fiber: 30 g
    • Sodium: 1,500 mg
    • Potassium: 4,700 mg
    • Calcium: 1,250 mg
    • Magnesium: 500 mg


    • JFP Vol 63, No 10 Oct 2014
    • AFP Vol 91 No 3 Feb 2015
    • AFP Vol 93 No 11 Jun 2016
  7. Medications
    • Use ARBs over ACEs
      • There is no difference in efficacy between ARBs and ACE inhibitors with regard to the surrogate endpoint of blood pressure and outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease.
      • However, ACE inhibitors remain associated with cough and a very low risk of angioedema and fatalities.
      • Overall withdrawal rates because of adverse events are lower with ARBs than with ACE inhibitors.
      • Given the equal outcome efficacy but fewer adverse events with ARBs, risk-to-benefit analysis in aggregate indicates that at present there is little, if any, reason to use ACE inhibitors for the treatment of hypertension or its compelling indications.


    Table 9: Thiazides
    Medication T1/2 Equiv Dose
    Hydrochlorothiazide 8-15h 25mg
    Chlorthalidone 45-60h 12.5mg
    Indapamide 14-25h 2.5mg
    • Thiazide Notes:
      • CTD and indapamide have outcome data with clear benefit in reducing cardiovascular events compared to HCTZ (which has a lack of outcome data)
      • CTD and indapamide both better meet 24hr BP control given their pharmacokinetic profiles
      • Cost is comparable among all 3 - Do not use HCTZ as monotherapy for HTN
    • Spironolactone
      • Consider use when thiazide, ACE I or ARB, and CCB fails to achieve target blood pressure (SOR C)
      • For most adults with resistant HTN, spironolactone is superior to doxazosin and bisoprolol as an adjunct to triple therapy


  8. Orthostatic Blood Pressure

    Diagnostic if:

    • Systolic is <90mm Hg or decrease by 20mm Hg or more (10mm Hg in symptomatic patients)
    • Increase of 30bpm suggests postural tachycardia syndrome


    • 1 min after changing positions from supine to standing drop in systolic BP of 20 mm hg
    • 3 min after changing position drop in systolic BP of 20mm hg or drop in diastolic BP of 10mm hg
    • Pulse will often rise, but not diagnostic in and of itself.


    • Physical maneuvers:
      • Getting up slowly
      • Leg cfrossing
      • Muscle clenching
    • Increased salt and water intake
    • Compression stockings
    • Medications:
      • fludrocortisone
      • midodrine
    • Avoidance of medications:
      • Benzodiazepines
      • diuretics


    • 6% of General population
    • Up to 40% of asymptomatic older adults (70+yo) and 23% younger than 60yo will have positive orthostatic BP measurements
    • Associated with:
      • Risk of falls (HR = 1.5)
      • Coronary heart disease (HR = 1.3)
      • Stroke (HR = 1.2)
      • All cause mortality (HR = 1.4)


    • AFP Vol 95 No 5 Mar 2017
    • JFP Vol 68 No 9 Nov 2019
  9. Protocol for home BP
    • Avoid exercise, caffeine, and other stimulants 30min before measurement
    • Avoid restrictive clothing
    • Use appropriately sized cuff
    • Rest quietly before and during BP measurement
    • Position arm at heart level
    • Do not talk while the machine is measuring


    • AFP Vol 76 No 2 Jul 2007

4.22.6 Screening indications

  • Age >40
  • For those 18-39:
    • Obesity/Overweight
    • African American ethnicity
    • High-normal BP (130-139/85-89mmHg)


  • JFP Vol 65, No 1 Jan 2016

4.22.7 Secondary Hypertention

Indications to evaluate for secondary HTN:

  • Acute rise in BP in pt with previous stable BP
  • Age of onset before puberty
  • Age younger than 30yo in nonobese, nonblack with no FH of HTN
  • Malignant or accelerated HTN
  • Severe or resistant HTN

Causes of Secondary HTN

Age % with 2ry HTN Most Common Etiologies
Birth-11yo 70-85% Renal parencchymal disease
    Coarctation of the aorta
12-18yo 10-15% Renal parencchymal disease
    Coarctation of the aorta
19-39yo 5% Thyroid dysfunction
    Fibromuscular dysplasia
    Renal parencchymal disease
40-64yo 8-12% Hyperaldosteronism
    Thyroid dysfunction
    Obstructive Sleep Apnea
    Cushing syndrome
65yo+ 17% Atherosclerotic renal artery stenosis
    Renal failure

Secondary forms of HTN associated with resistant HTN

Condition Prevalence in Resistant HTN
Obstructive sleep apnea 60-70%
Primary aldosteronism 7-20%
Renal artery stenosis 2-24%
Renal parenchymal disease 1-2%
Drug induced or heavy EtOH 2-4%
Thyroid disorders <1%


Birth-18yo 19-39yo 40-64yo 65yo+
Urinalysis MRA with contrast Renin Renal Art Dopple
Urine culture CT Angio if no MRI Aldosterone MRA with contrast
Renal Ultrasonography TSH Polysomnography CT angio if no MRI
+/- Echo +/- Echo +/- 24-hr urinary free cortisol TSH
    +/- 24-hr urinary fract metanephrines Urinalysis
      +/- 24-hr urinary free cortisol
      +/- 24-hr urinary fract metanephrines

Drugs that can elevate BP

Class Examples
Anti-infective Ketoconazole
Anti-inflammatory COX-2 inhib, NSAIDs
Chemotherapeutic Vascular endothelial growth factor inhib
Herbal Ephedra, ginseng, ma huang
Illicits Amphetamines, cocaine
Immunosuppressive Cyclosporine, sirolimus, tacrolimus
Psychiatric Buspirone, carbamazepine, MAOI, SSRI, SNRIs, TCAs
Sex hormones Estroge and progesterone in OCPs, androgens
Steroid Methylprednisolone, prednisone
Sympathomimetic Decongestants, diet pills


  • AFP Vol 96 No 7 Oct 2017
  • JAMA Vol 311 No 21 Jun 2014

4.23 Max/Target heart rate


  • Max heart rate = 220 - age
  • Target heart rate = 50-85%

4.24 Metabolic Equivalents (METS)

MET Example
1 Watching TV
  Eating,dressing, cooking, toilet
2 Walking 1-2 blocks on level ground 1-2mph
3.5 Walking at slow pace (1mi/20min)
4 Climbing a flight of stairs
  Walking on level ground 4mph
  Running a short distance
8 Jogging (1mi/12min)
10 Playing strenuous sports (tennis, soccer, basketball)

See also: 14.29.2 References:

  • AFP Vol 85 No 3 Feb 2012
  • J Musc Med Mar 2012

4.25 Peripheral Arterial Disease

  • Use the ankle-brachial index for diagnosis in patients with history/physical exam findings suggestive of peripheral arterial disease (PAD). A
  • Strongly encourage smoking cessation in patients with PAD as doing so reduces 5-year mortality and amputation rates. B
  • Use structured exercise programs for patients with intermittent claudication prior to consideration of revascularization; doing so offers similar benefit and lower risks. A
  • Recommend revascularization for patients who have limb ischemia or lifestyle-limiting claudication despite medical and exercise therapy. B


  • A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device


  • Smoking cessation
  • Exercise
  • Diet
  • Medication
    • HTN Management
    • High-dose statin
    • Antiplatelet agent - preferably cloidogrel


  • JFP Dec 2020 Vol 69 No 10

4.26 Post MI Medications

  • Antiplatelet agent (like ASA 81mg/d or clopidogrel 75mg/d)
  • RAAS blockers (like lisinopril 20mg/d or losartan50mg/d)
  • B-blockers (like motoprolol 100mg bid)
  • Statins (like atorvastatin 80mg/d)


  • JFP Vol 59 No 9 Sep 2010

4.27 Troponin increased plasma values

  • Patients with elevated troponin levels and chronic renal disease, pulmonary hypertension, pulmonary embolism, chronic obstructive pulmonary disease, sepsis, or acute ischemic stroke have a 2- to 5-fold increased risk of death, even in the absence of known cardiovascular disease (strength of recommendation: B, meta-analysis, multiple prospective and retrospective observational studies.)
  • Elevated troponin raises risk of death 5-fold in pulmonary embolism patients.
  • Elevated troponin I is an independent predictor of mortality in severe sepsis.
  • Elevated troponin predicts increased death risk in up to 20% of stroke patients.


  • J Fam Pract. 2013 October;62(10):585-586, 598.

Myocardial ischemia

  1. Acute coronary syndrome
    • STEMI
    • NSTEMI
  2. Other coronary ischemia
    • Arrhythmia: tachy- or brady-
    • Cocaine/methamphetamine use
    • Coronary intervention (PCI or cardiothoracic surgery)
    • Stable coronary atherosclerotic disease in setting of increased O2 demand (eg tachycardia)
    • Severe hypertension
    • Coronary embolus
    • Aortic dissection
    • Coronary artery vasculitis (SLE, Kawasaki's)
  3. Non-coronary ischemia
    • Shock (hypotension)
    • Hypoxia
    • Hypoperfusion
    • Pulmonary embolism
    • Global ischemia
    • CT Surgery

Myocardial injury with no ischemia

  1. Comorbidities
    • Renal failure
    • Sepsis
    • Infiltrative diseases
    • Acute respiratory failure
    • Stroke
    • Subarachnoid hemorrhage
  2. Specific identifiable precipitants
    • Extreme exertion
    • Cardiac contusion
    • Burns >30% BSA
    • Cardiotoxic meds: anthracyclines, herceptin
    • Electrical shock
    • Carbon monoxide exposure
  3. Other
    • Apical ballooning (Takotsubo)
    • Myocarditis
    • Myopericarditis
    • Rhabdomyolysis involving cardiac muscle
    • Hypertrophic cardiomyopathy
    • Peripartum cardiomyopathy
    • Heart failure, malignancy, stress cardiomyopathy


  • UptoDate Graphic 54910

4.28 ASCVD Calculation Formula   edit

4.29 Recommended Lifestyle Modifications in Hypertension

  • Alcohol moderation
    • Abstain from binge drinking
    • Limit to moderate daily consumption (i.e., 1.5 standard drinks per day for women and 2 for men)
  • Diet
    • Increase consumption of dairy, fruits, polyunsaturated fats, vegetables, and whole grains
    • Increase consumption of foods high in calcium, magnesium, and potassium (e.g., avocados, legumes, nuts, seeds, tofu)
    • Increase consumption of vegetables high in nitrites (e.g., leafy vegetables, beetroot)
    • Reduce consumption of foods high in sugar, and saturated or trans fats
  • Healthy drinks
    • Consider hibiscus tea, pomegranate juice, beetroot juice, and cocoa
    • Moderate consumption of coffee, and green and black tea
  • Physical activity
    • Add strength or resistance training 2 to 3 days per week
    • Moderate intensity aerobic activity (e.g., walking, jogging, cycling, yoga, swimming) at least 5 days per week
  • Salt reduction
    • Avoid adding salt when cooking or dining
    • Limit consumption of high salt foods, including fast foods, processed foods, and soy sauce
    • Many breads and cereals are high in salt
  • Smoking cessation
    • Smoking cessation programs and adjuncts are recommended
  • Stress reduction
    • Daily mindfulness or meditation appears to improve blood pressure measurements
  • Weight loss
    • Evaluate obesity by waist-to-height ratio less than 0.5, or by ethnic-specific body mass index targets
    • Limit obesity, particularly truncal obesity


  • AFP Jun 2021 Vol 103 No 12

5 Dermatology

5.1 9 tips to help prevent derm biopsy mistakes


  • Use an excisional biopsy for a melanocytic neoplasm. (SOR C)
  • Choose a punch biopsy over a shave biopsy for rashes. (SOR B)
  • Properly photograph and document the location of all lesions before biopsy. (SOR A)
  • Provide the pathologist with a sufficient history, including the distribution and appearance of the lesion, and how long the patient has had it. (SOR A)

The 9 tips:

  1. Choose your biopsy type wisely.
    • The most common biopsy types are shave, punch, and excisional
    • Shave biopsy: lesions that are solitary, elevated, and give the impression that a sufficient amount of tissue can be sampled using this technique
    • Punch biopsy: most “rashes” (inflammatory skin disorders)
    • Excisional biopsy: melanocytic neoplasms or larger lesions.
    • Videos of biopsies:
  2. When performing a shave biopsy, avoid obtaining a sample that's too superficial.
    • The advantage of the shave biopsy is that it is minimally invasive and quick to perform
  3. Choose punch over shave biopsy for rashes.
    • Punch biopsy is the preferred technique for almost all inflammatory skin conditions (rashes)
    • A punch biopsy size of 4 mm is commonly used for rashes
  4. Choose an excisional biopsy for a melanocytic neoplasm, when possible.
    • The purpose of an excisional biopsy (which typically includes a 1 to 3 mm rim of normal skin around the lesion) is to completely remove a lesion.
    • The excisional biopsy generally is the preferred technique for clinically atypical melanocytic neoplasms (lesions that are not definitively benign)
  5. Be careful with curettage.
    • Curettage is a biopsy technique in which a curette—a surgical tool with a scoop, ring, or loop at the tip—is used in a scraping motion to retrieve tissue from the patient.
  6. Remember the importance of proper fixation and processing.
    • Promptly place sampled tissue in an adequate amount of formalin so that the tissue is submersed in it in the container
    • Failure to do so can result in improper fixation and will make it difficult to render an appropriate diagnosis.
  7. Properly photograph and document the biopsy location.
    • To properly record the site of a biopsy for future dermatologic exams, take pictures of the lesion at the time of biopsy. The photographs should clearly document the lesion in question, and should be taken far enough from the site that surrounding lesions and/ or other anatomic landmarks are also visible.
  8. Give the pathologist a pertinent history.
    • Providing the pathologist with a sufficient history, including the distribution and appearance of the lesion, and how long the patient has had it
  9. Know when to refer.


  • J Fam Pract. 2014 October;63(10):559-564.

5.2 Acne

Disease of sebaceous follicles - multifactorial (abn keratonization, excessive sebum, Propionibacterium acnes, and hormones)

  • Open Comedones: flat or slightly raised with dark substance in cental orifice
  • Closed Comedones: pale white papules with no visible orifice

Therapy is based on lesion type and severity (mild, mod, severe):

  • Noninflammatory
    • First line: topical tretinoin (predominance of comedones) if not effective -> topical antimicroials like benzoyl peroxide (preferred with inflammation) (Level 1 evidence).
    • Second line - adapalene (I)
  • Papular or pustular (Topical retinoid + benzoyl peroxide + topical antibiotic) (Oral Abx if severe)
    • First line: topical erythromycin (I), clindamycin (I), clindoxyl (I), or benzamycin (I)
    • Second line: Oral tetracycline (I), minocycline (I), or doxycycline 100mg/d(I), also erythromycin, clindamycin, ampicillin, amoxicillin (all Level 1)
    • Third line: Oral antibiotics plus topical retinoids (I)
    • Fourth line Trimethoprim-sulfamethoxazole (III)
  • Nodulocystic or treatment resistant acne or scarring (Topical retinoid + benzoyl peroxide + oral antibiotic)
    • First line: steroid injection if sparse (I), isotretinoin if severe (I)
    • Second line: antiandrogens (OCP or spironolactone)

Major recommendations from guidelines:

  • Topical retinoids are recommended as monotherapy for comedonal acne or in combination with topical or oral antimicrobials in patients with mixed or primarily inflammatory acne (LOE 1)
  • Benzoyl peroxide is an effective topical agent (LOE 1)
  • Topical antibiotic therapy is recommended only in combination with benzoyl peroxide (LOE 1)
  • Systemic antibiotic therapy is recommneded for management of moderate and severe inflammatory acne and acne resistant to topical treatments (LOE 1)
    • Preferred oral antibiotic are tetracyclines with doxycycline and minocycline more effective than tetracycline
  • Systemic antibiotic use should be limited to the shortest possible duration, typically 3 months. Concomitant and ongoing topical therapy with benzoyl peroxide or topical retinoid is recommended for maintenance. (LOE 1)
  • Combined oral contraceptives are effective in treating inflammatory acne in girls and women (LOE 1)
  • Oral isotretinoin is recommended for treatment of severe nodular acne, moderate recalcitrant acne, or acne that produces scarring or psychosocial distress (LOE 1)

First line treatment options:

Mild Benzoyl peroxide (BP) Topical retinoid Topical combination therapy*:BP + antibiotic; or Retinoid + BP; or Retinoid + BP + antibiotic
Moderate Topical combination therapy*: BP + antibiotic; or Retinoid + BP; or Retinoid + BP + antibiotic Oral antibiotic + topical retinoid + BP Oral antibiotic + topical retinoid + BP + topical antibiotic  
Severe Oral Antibiotic + topical combination therapy: BP + antibiotic; or Retinoid + BP; or Retinoid + BP + antibiotic Oral isotretinoin  
  • May be prescribed as a fixed combination product or as separate component.

Alternative options:

Mild Add topical retinoid or BP (if not on already) Consider alternate retinoid Consider topical dapsone  
Moderate Consider alternate combination therapy Consider change in oral antibiotic Add combined oral contraceptive or oral spironolactone (females) Consider oral isotretinoin
Severe Consider change in oral antibiotic Add combined oral contraceptive or oral spironolactone (females) Consider oral isotretinoin  


5.2.1 Additional Notes

Topical retinoids:

  • Prefer adapalene (photostable and can mix with BP)
  • Not spot treatment
  • Use sparingly
  • Moisturize under retinoid
  • Use pea size on each index finger tip - place on forehead, cheeks, chin and rub in thinly
  • Takes 12 weeks for full effect
  • Comedonalitic

Benzoyl Peroxide

  • Leave on > Washes
  • Concentration dependent irritant
  • Topically kills C acnes and improves acne

Topical Antibiotics

  • Topical clindamycin - only use if in same tube as BP d/t pt not adhering
  • C acnes Resistant to erythromycin

Sebum inhibitor

  • Clascoterone 1% topical - bid - 12+ yo
  • Not monotherapy


  • Dapsone
  • Azelaic acid
    • Not great clinically



  • Epiduo -
  • BP/clinda
  • Twyneo

Oral antibiotics:

  • Anti-inflammatory
  • NOT monotherapy
    • Always topical BP
  • Use for shortest possible duration
  • Tetracyclines
    • doxycycline
      • qd o bid
      • interacts with dairy
      • photosensitivity
      • intracranial htn (rare)
    • minocycline 1 mg/kg
      • ER - qd with or without food
      • IR - qd or bid
      • photosensitivity
      • intracranial htn (rare)
      • 11% vestibular symptoms with IR
    • sarcycline
    • If needed: trimethoprim 300 mg tid


  • spironolactone 50-100 mg/d with food in women only
    • cheaper
    • easier to get
    • fewer AE
  • OCPs
    • Yaz
    • Beyaz

Systemic retinoid

  • Isotretinoin

5.3 Atopic Dermatitis (New Guidelines)

Non-pharmacologic treatment options:

  • Moisturizers:
    • Use liberally, combine with bathing, patient preferences on type
  • Bathing practices:
    • Minimum perform daily
    • Soak in warm water 10-15 minutes
    • Followed by quick pat drying and immediate application (2-3 minutes) of topical moisturizer/medications.
  • Bleach baths:
    • Once or twice weekly bleach (sodium hypochlorite) is effective in clinically improving moderate-to-severe AD in children.
    • May also help adults
    • Thought to reduce skin inflammation and decrease S. Aureus colonization.
  • Wet wrap therapy (wwt):
    • Using layers of bandage, guaze, clothing, etc with topical medications. Evidence supports improvement of symptoms in children.

Pharmacologic treatment options:

  • Topical corticosteroids
  • Topical calcineurin inhibitors
  • Dupilumab
  • Phototherapy
  • Systemic immunosuppresents: cyclosporine, azathioprine, mycophenolate, methotrexate

5.4 Atypical Nevus Management

General information:

  • Sun avoidance and protection
  • Regular physician followup at least every 12 mo
  • Screen family members
  • Use diagnostic aids such as total body photography and dermoscopy
  • Biopsy of suspicious lesions
  • Instruct patients in self-examinations


  • 2mm margins to avoid reexcision
  • Re-excise with 2-5mm margins if there is involvement of margins
  • If severe cytologic atypia, do a 5mm margin


  • AFP vol 78 No 6 Sep 2008

5.5 Acne Rosacea

Chronic vascular facial disorder of 20-60yo northern/eastern european descent

  • Pathogenesis: unknown but implicated factors include bacteria, Demodex mites, vasomotor and connective tissue dysfunction, and topical steroids
  • Triad:
    1. Symmetrical erythema,
    2. papules and pustules, and
    3. telangiectasia on cheeks, forehead, and nose (absence of comedones)

Often exacerbated by sun, wind, hot drinks


  • Avoid triggers
  • First line: topical metronidazole (Daily 1% or bid 0.75%) (I) plus oral tetracycline (tapered from starting dose of 1000mg/d) (I) or minocycline (100-200mg/d) (I)
  • Second line: Sulfacetamide (III) plus oral Abx as above
  • Third line: Isotretinoin (II)


  • Cheung M, Taher M, Lauzon G., Acneiform facial eruptions, Canadian Fam Phys, Vol 51; April 2005; 527-533

5.6 Bed Bugs

Pregression of bites:

  1. Initial reaction
    1. Erythematous, pruritis macules with central hemorrhagic puncta in linear or grouped distribution
  2. Subsequent reactions
    1. Wheals, papules, vesicles

Differential Diagnosis:

  • Bedbugs
  • Fleas
  • Lice
  • Mosquitoes
  • Scabies
  • Spiders
  • Ticks


  • Vacuuming
  • Heat or cold treatment
  • Trapping - use plastic encasements to trap bedbugs and prevent migration to and from hiding spots
  • Pesticides
  • Can use petroleum jelly on legs of furnature to prevent ascending


  • AFP Vol 86 No 7 Oct 2012

5.7 Biopsy techniques

Sterile gloves offer no benefit for minor outpatient skin procedures

  • No difference in risk of infection for common outpatient skin procedures such as laceration repair or lesion excision.
  • Relative risk of infection: Non-significant 0.95 (95% CI 0.65 to 1.40)


  • AFP Vol 97 No 9 May 2018

5.8 Burns

Refer to a Burn Center:

  • Burns to the face, hands, feet, major joints, genitalia, or perineum
  • Children in health care facilities without staff trained to treat children or appropriate equipment for children
  • Concurrent trauma
  • Electrical or chemical burns
  • Full-thickness (third-degree) burns at any age
  • Greater than 10% total body surface area involved
  • Inhalation injuries
  • Need for special support (social, emotional, rehabilitative)
  • Preexisting medical issues that may complicate treatment or recovery or increase mortality risk

Topical Agents:

  • Bacitracin
  • Impregnated nonadherent gauze (Xeroform, Vaseline gauze)
  • Mafenide acetate (Sulfamylon)
  • Medical grade honey
  • Mupirocin
  • Silver sulfadiazine (Silvadene)


  • AFP Vol 101 No 8 Apr 2020

5.9 Carcinomas (Basal Cell and Cutaneous Squamous Cell)

Comparison of Basal Cell and Cutaneous Squamous Cell Carcinoma

Characteristics Basal cell carcinoma Cutaneous squamous cell carcinoma
Patient age Uncommon in adults younger than 40; up to 20% of tumors occur in adults younger than 50 Uncommon in adults younger than 50
Patient characteristics Fair skin, blue eyes, red or light-colored hair, inability to tan Few, if any, identifiable phenotypic markers associated with high risk
Tumor location Most tumors (85%) occur on the head and neck region, with 25% to 30% occurring on the nose; does not correlate well with areas of maximal sun exposure; approximately one-third occur on areas that receive little or no ultraviolet exposure More common on the back of the hands and forearms; tumors on the head and neck are most common on areas that receive maximal sun exposure
Ultraviolet light exposure Weaker association; exposure in childhood and adolescence more important Stronger association; cumulative exposure more important


  • Initial tissue sampling is typically performed using a shave technique if the lesion is raised
  • Can alternatively use a punch biopsy of the most abnormal-appearing skin
  • Pigmented lesions and those with any features concerning for melanoma risk should always be evaluated using a full-thickness technique

Risk Stratification of Low- vs. High-Risk Basal Cell Carcinoma

Basal cell and squamous cell carcinoma (clinical)        
Parameters Low risk High risk    
Location* and size† Low-risk location and < 20 mm Moderate-risk location‡ and < 10 mm — Low-risk location and ? 20 mm Moderate-risk location and ? 10 mm High-risk location§    
Borders Well defined Poorly defined    
Primary vs. recurrent Primary Recurrent    
Immunosuppression No Yes    
Site of prior radiation therapy No Yes    
Basal cell carcinoma (pathologic)        
Parameters Low risk High risk    
Growth pattern Superficial, nodular     Aggressive¶
Perineural involvement No Yes    
Squamous cell carcinoma (pathologic)        
Parameters Low risk High risk    
Degree of differentiation Well or moderately differentiated Poorly differentiated    
High-risk histologic subtype** No Yes    
Depth (thickness or Clark level)†† < 2 mm or I, II, III ? 2 mm or IV, V    
Perineural, lymphatic, or vascular involvement No Yes    

Low-risk location = trunk and extremities excluding hands, feet, nail units, pretibia, and ankles; Moderate-risk location = cheeks, forehead, scalp, neck, and pretibia; High-risk location = central face, eyelids, eyebrows, periorbital skin, nose, lips, chin, mandible, preauricular and postauricular skin/sulci, temple, ear, genitalia, hands, and feet.

Management (National Cancer Care Network guidelines)

  • BCC:
    • Excision of low-risk primary BCC with a 4-mm margin of uninvolved skin around the tumor
    • Incomplete excision of the primary tumor (i.e., pathology demonstrating tumor at the surgical margin) should be followed by immediate re-excision or Mohs micrographic surgery
  • CSCC:
    • Excision of low-risk primary CSCC with a 4-mm to 6-mm margin of uninvolved skin around the tumor
    • Mohs micrographic surgery is an appropriate option for high-risk tumors or tumors in sensitive anatomic locations

Post Diagnosis Management:

  • Annual screening of the patient for new primary skin cancers, including BCC, CSCC, and melanoma


  • AFP Sep 2020 Vol 102, No 6

5.10 Chronic Urticaria


  • Start second generation H1 antihistamine
  • If insufficient do one of the following:
    • Titrate second generation H1 antihistamine to 2 to 4 times normal dose
    • Add a different second generation H1 antihistamine
    • Add H2 antihistamine
    • Add first-generation H1 antihistamine at night
    • Add leukotriene receptor antagonist
  • If insufficient
    • Add high-potency antihistamine hydroxyzine or doxepin and titrate as tolerated
  • If insufficient
    • Consider referral for immunomodulatory therapy such as omalizumab or cyclosporine

Urticaria Causes:

  • Immunoglobulin E mediated (IgE)
    • Aeroallergens
    • Contact allergen
    • Food allergen
    • Insect venom
    • Medications
    • Parasitic infections
  • Non-IgE immunologically mediated
    • Aeroallergens (proteases)
    • Autoimmune disease
    • Bacterial infections
    • Cryoglobulinemia
    • Fungal infections
    • Lymphoma
    • Vasculitis
    • Virla infections
  • Nonimmunologically mediated
    • Contact allergen
    • Elevation of core body temperature
    • Food pseudoallergens
    • Light
    • Mastocystosis
    • Medications (direct mast cell degranulation)
    • Physicla stimuli (cold, heat, pressure, vibration)
    • Water

Conditions confused with urticaria

  • Arthropod bites
    • Lesions lasting several days, insect exposure history
  • Atopic dermatitis
    • Maculopapular, scaling, characteristic distribution
  • Bullous pemphigoid
    • Lesions lasting >24hrs, blistering, Nikolsky sign (light friction causes erosion or vesicle)
  • Contact dermatitis
    • Indistinct margins, papular, persistent lesions, epidermal component present
  • Erythema multiforme
    • Lesions lasting several days, iris-shaped papules, target appearance, may have fever
  • Fixed-drug reactions
    • Offending drig exposure, not pruritic, often bullous, hyperpigmentation
  • Henoch-Schonlein purpura
    • Lower extremity, purpuric lesions, systemic symptoms
  • Mastocytoma
    • Yellow to orange pigmentation, Darier sign (a wheal and flare up reaction with stroking the lesion), flushing, bullae, most common in children
  • Mastocytosis, diffuse cutaneous
    • Normal to yellow-brown skin color, diffuse thickening, bullae
  • Morbilliform drug reactions
    • Maculopapular, associated with medication use
  • Pityriasis rosea
    • Lesion lasting weeks, herald patch, Christmas tree pattern, often not pruritic
  • Urticaria pigmentosa
    • Smaller lesions (1-3 mm), orange to brown pigmentation, Darier sign
  • Viral exanthem
    • Not pruritic, prodrome, fever, maculopapular, individual lesions lasting days


  • AFP Vol 95 No 11 Jun 2017

5.11 Terminology

There are no universally agreed upon definitions of terms or, in particular, dimensions of primary lesions. The following was offered by Watt and Jillson as an "easy-to-remember" formula.

Primary Lesions

  • Macule
    • Circumscribed area of skin, up to 1.0 cm, with a change from normal skin color, which is neither raised above nor depressed below the surrounding skin. Many use the term for lesions much greater than 1.0 cm. Term does not include purpura
  • Patch
    • A flat, circumscribed, discoloration of skin or mucous membrane greater than 1.0 cm in diameter.
  • Papule
    • Discrete solid area of skin that is elevated by palpation above the surrounding skin and less than 1 cm in diameter. Variations include accuminate, keratotic, flat-topped, follicular, umbilicated, pedunculated, necrotitic and others
  • Plaque
    • Similar to a papule but greater that 1.0 cm in diameter. Often formed by the confluence or coalescence of papules. Secondary features may include, among others, atrophy, lichenification or hyperkeratosis.
  • Nodule
    • Discrete, solid, palpable, round or oval (elipsoidal) lesion of the skin measuring up to 1.0 cm in diameter (or long axis). Applies to processes involving any or all levels of the skin, and is a general term for any mass, benign or malignant.
  • Tumor
    • A term used by some for a "nodule" greater than 1.0 cm in diameter. Applies to processes involving any or all levels of the skin, and is a general term for any mass, benign or malignant.
  • Vesicle
    • A circumscribed fluid-filled lesion less than 1.0 cm in diameter that is usually elevated above the surrounding skin. May be described as solitary, grouped, umbilicated, dyshidrotic, spongiotic, multi-locular or uni-locular. 
  • Bulla
    • A circumscribed fluid-filled lesion greater than 1.0 cm in diameter that is usually elevated above the surrounding skin. May attain diameters of several cms and are described as tense, or flacid.
  • Pustule
    • Discrete elevated vesicle or bulla of skin, usually small, containing purulent exudate composed of inflammatory leukocytes (pus), with or without cellular debris. May be superficial, deep-seated, follicular, grouped, etc. and may arise secondarily from a vesicle. 
  • Wheal
    • An evanescent, round or irregular, often flat-topped elevation of skin with a pale red color, arising from edema in the superficial dermis. May vary from 2-3 mm to 10 or more cm in diameter, with round or arcuate configurations. Should be distinguished from angioedema, a massive edema involving the entire dermis and subcutaneous tissues.

Secondary Lesions

  • Scar
    • A hard plaque of dense fibrotic tissue covered by a thin epidermis. A mark of injury from any sort of process (physical or pathologic).
  • Atrophy
    • Atrophy usually refers to thinning of the epidermis leaving an easily wrinkled and/or shiny surface. Atrophy may also apply to dermal and/or subcutaneous tissue, with or without changes in the epidermis.
  • Ulcer
    • Loss of skin tissue or substance from the surface downward, leaving an uncovered or denuded wound that is slow to heal.
  • Erosion
    • A superficial denudation of the skin, usually implying the loss of the epidermis.
  • Fissure
    • A vertical splitting or separation of the skin.
  • Crust
    • Dried surface fluid, often serous (inspissated serum) in nature, with or without tissue debris. For purposes of this document this includes the term "scab".
  • Excoriation
    • A scratch mark, often with denudation of the skin to form a small ulcer. Exposure of the corium by mechanical removal of the epidermis.
  • Scale
    • A thin flake of epithelium (mostly composed of corneoctyes) which is separated from the underlying intact skin proper.
  • Lichenification - a thickening of the skin surface and an increase of skin markings, usually seen with chronic coalescence of papular lesions, especially atopic eczema.
  • Vegetating
    • A lushly growing, proliferating, process, usually with elevated or exophytic features.
  • Linear / Figurate
    • Technically not secondary features, but included here solely out of convenience. These are configurations that skin lesions may assume, which aid in their diagnostic identification. Figurate includes geometrical shapes (e.g. annular, arciform, cyclic, etc.).


  • Watt, T.L. and Jillson, O.F.: Archives of Dermatology 90:454, 1964.

5.12 Dermoscopy

The Two-Step Algorithm

  1. Step 1 - Determine if lesion is melanocytic or not
    1. Determine if lesion is benign or malignant
  2. Step 2 - Determine if lesion is a Nevus, Suspicious, or Melanoma
    1. Determine if need to biopsy or not
    2. Determine if digital monitoring (never for raised lesions)

A lesion is Melanocytic if it:

  1. Has a network (Except in the following:)
    • Dermatofibroma (fine network surrounding central scar)
    • Solar lentigo (fine interrupted lines and moth eaten border)
    • Ink blot lentigo
  2. Aggregated or peripheral rim of globules
    • Usually in growing nevi
  3. Streaks
    • Usually = bad
    • Think biopsy
    • Spitz nevus - juvenile melanoma
  4. Homogenous blue pigment
    • Blue nevus

Example images:


5.12.1 Non-Melanocytic Lesions


  1. Dermatofibroma
    1. Delicate network
    2. Central scar-like/crystalline
    3. Ring like globules
    4. Vessels/blush in center
  2. Seborrheic keratoses
    1. Milia-like cysts
    2. Comedo like openings
    3. Fissures and ridges (gyri and sulci)
    4. Fingerprint like
    5. Hairpin vessels
    6. Moth-eaten borders
  3. Hemangioma (vascular lesions)
    1. red
    2. maroon
    3. blue
    4. black
    5. clear
  4. Clear Cell Acanthoma
    1. Dotted or glomerular vessels distributed in a serpiginous pattern (string of pearls)


  1. Basal Cell Carcinoma (at least 1 of the following)
    1. Large grey-blue ovoid nests
    2. Multiple grey-blue globules
    3. Leaflike areas
    4. Spoke wheel areas
    5. Arborizine "tree like" telangiectasia
    6. Ulceration
  2. Squamous Cell Carcinoma - Focally scaly/keratotic and rough
    1. Glomerular vessels
    2. Hairpin vessels
    3. Keratin pearls and white circles
    4. Rosettes (strawberry pattern)
    5. Brown dots/globules aligned in a linear fashion at the periphery

5.12.2 Melanocytic Lesions

Benign Patterns:

  1. Diffuse Reticular
  2. Patchy Reticular
  3. Peripheral reticular with central hypopigmentation
  4. Peripheral reticular with central hyperpigmentation
  5. Homogenous
  6. Peripheral globules/starburst
  7. Peripheral reticular with central globules
  8. Globular
  9. Two components
  10. Symmetric multi-component (controversial)


  • Melanomas deviate from benign patterns.
  • Have one of the specific features:
    1. Atypical network
    2. Negative pigment network
    3. Streaks
    4. Off-centered blotch
    5. Atypical dots and/or globules
    6. Regression structures
      1. Scar-like depigmentation and peppering - can have appearance of blue-white veil
    7. Blue-white veil overlying raised areas
    8. Atypical vascular structures
      1. Dotted vessels over milky red backgrounds
      2. Serpentine vessels
      3. Polymorphous vessels
    9. Shiny white lines (Crystalline structures)
    10. Peripheral tan structureless areas

5.12.3 Vasculature

Non-melanocytic lesions:

  1. Hairpin - keratinizing tumors
  2. Glomerular - SCC
  3. Arborizing - BCC
  4. Crown - Seborrheic hyperplasia
  5. Dotted in serpiginous distribution - CCA

Melanocytic lesions:

  1. Comma - IDN
  2. Dotted - MM & Spitz & DN
  3. Linear and polymorphous - MM
  4. Corkscrew - MM (Mets)
  5. Irregular hairpin (serpentine) - MM & CMN
  6. Milky red area

5.12.4 Management

  1. Benign pattern -> Reassure
  2. Deviates from benign -> Biopsy
  3. For flat only slightly suspicious lesions that patients want to wait:
    • Photograph
    • Re-evaluate and rephotograph in 3mo
    • If changing -> biopsy

Palms/Soles - parallel pattern is expected:

  • If run in furrows -> benign
  • If parallel pattern runs on peaks -> melanoma

Face - pseudo-network pattern due to gland openings

5.12.5 Other


  • Photograph all lesions biopsied
    • Clinical
    • Dermatoscope

Other Resources:

5.13 Folliculitis


  • Inflammation of the hair follicle 2/2 mechanical trauma, irritation, or infection
  • Usual infectious organism is S aureus, also gram neg (after prolonged topical Ax) and pitysporum (saprophytic yeast) as well
  • Pustules in clusters on hair-bearing areas of body.


  • Pityrosporum:
    • First Line: Topical econazole (III), selenium sulfide shampoo (III), or 50% propylene glycolor etoconazole  (III) - 3 weeks treatment
    • Second line: Oral fluconazole (II), itraconazole (I), or ketoconazole (II) - 10-14 days
    • Third line: Oral antifungal plus topical agents (II)
  • Bacterial:
    • First line: Topical mupirocin (I), erythromycin (III), clindamycin (III), or benzoyl peroxide (III) - treat until lesions resolvedd
    • Second line: Oral antistaphylococcal antibiotics (flouroquinolones(I), first gen cephalosporins (III), or macrolides (III))
  • Gram negatives:
    • First line: Isotretinoin (II)
    • Second line: Ampicillin (III) or trimethoprim-sulfamethoxazole (III)


  • Cheung M, Taher M, Lauzon G., Acneiform facial eruptions, Canadian Fam Phys, Vol 51; April 2005; 527-533

5.14 Hidradenitis suppurativa

Hair removal from shaving or using depilatories, deodorants, and irritation from anything rubbing against the affected area can worsen the condition.

The Hurley classification system is used to define severity and guide treatment.

  • Stage I: single or multiple abscesses without sinus tracts or scarring
    • Medical
      • First line: Topical clindamycin
      • Second line: Topical resorcinol
    • Surgical
      • Punch debridement
      • Drain painful abscess
      • Intralesional triamcinolone
  • Stage II: abscess recurrence with sinus tracts and scarring; widely separated lesions
    • Medical (Topical Clindamycine AND)
      • First line: Tetracycline Abx
      • Second line: Adalimumab (Humira)
      • Third line: Acitretin, oral clindamycin plus rifampin
    • Surgical
      • Local excision for larger, chronic lesions or sinus tracts
  • Stage III: diffuse skin involvement with multiple sinus tracts and widespread abscess formation
    • Medical (Topical Clindamycine AND)
      • First line: Adalimumab
      • Second line: Infliximab (Remicade), anakinra (Kineret), oral clindamycin plus rifampin


  • Am Fam Physician. 2019;100(9):562-569

5.14.1 Self-Care Guidelines (for patients)

It may also help if you can avoid things that can irritate your skin, by:

  • Wearing loose-fitting clothing
  • Avoiding heat and humidity
  • Being careful not to injure your skin
  • Staying at a healthy weight
  • Don't smoke

For draining lesions:

  • Make sure to wash any red, draining area(s) of hidradenitis suppurativa with an antibacterial soap, and then apply antibiotic ointment and clean bandages.
  • If there is a large amount of drainage, change the gauze pads and dressings often.
  • Warm compresses and ibuprofen can help reduce the swelling.

More information:

5.15 Infections, Insect bites, and Stings

See also: 12.6

There are also risk factors for a systemic sting reaction:

  • A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.
    • Pucci S, Antonicelli L, Bilò MB, et al. Shortness of interval between two stings as risk factor for developing Hymenoptera venom allergy. Allergy.1994;49:894-896.
  • Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.
    • Müller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol. 2005;5:343-347.
  • Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.

Bee stings:

  • Among beekeepers, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.
  • Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result


  • The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans


  • brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.28,29 The bite takes approximately 7 days to resolve.
  • black widow spider is black; females exhibit a distinctive red or yellow hourglass marking on their ventral aspect.28,31 The pinprick sensation of a bite leads to symptoms that can include erythema, swelling, pain, stiffness, chills, fever, nausea, and stomach pain.


  • Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.
  • Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector

Flies and biting midges

  • include black flies, deer flies, horse flies, and sand flies
  • Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.43
  • Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”44 are tiny (1-3 mm long) blood-sucking flies


  • Advise patients to reduce their risk by using insect repellent, sleeping under mosquito netting, and wearing a long-sleeve shirt and long pants when traveling to endemic areas or when a local outbreak occurs


  • Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container

Symptom control

  • Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.54 For painful lesions, an oral analgesic can be prescribed.
  • For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H1- and H2-receptor antagonists can be used concomitantly.
  • Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days
  • Managing anaphylaxis
    • First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes
    • Administration of O2 and intravenous fluids is recommended for hemodynamically unstable patients.
    • Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine


  • JFP Dec 2020 Vol 69 No 10

5.16 Medications

  • Topical Antibiotics
    • Clindamycin, Erythromycin, Metronidazole
    • Uses: Mild/Mod acne/rosacea
  • Topical Keratolytics
    • Retinoids, Benzoyl peroxide, Salicylic acid, Azelaic acid
    • Uses: Acne, rosacea
  • Topical Anti-inflammatory agents
    • Azelaic acid, Topical corticosteroids, Tars
  • Topical Anti-fungals
    • Azoles, Allylamines, Benzoyl peroxide, Selenium sulfide, Pyrithione zinc
    • Uses: Seborrheic dermatitis, Malassezia folliculitis
  • Topical Miscellaneous
    • Sodium sulfacetamide, sulfer, tar, Ivermectin, Brimonidine
  • Systemic Antibiotics
    • Tetracyclines, Erythromycin, Sulfas
    • Uses: Mod/Severe acne/rosacea
  • Systemic Retinoids
    • Isotretinoin
    • Uses: Nodulocystic, severe acne; select severe rosacea
  • Oral contraceptives


  • Consultant Oct 2015

5.17 Onychomycosis

Confirmatory testing is generally unnecessary for clinically suspected onychomycosis.

  • The most cost-effective approach to a patient with clinically suspected onychomycosis is empiric therapy with oral terbinafine.
    • Chance of liver injury is 1:50,000 to 1:120,000
    • If using a more expensive alternative medicine, than confirmatory testing with periodic acid-Schiff stain reduces cost


  • AFP Vol 97 No 9 May 2018

5.18 Paronychia


  1. Drainage
    • Do not inject pulp and finger pad if using anesthesia
  2. Antibiotics (typically not needed after drainage)

Risk factors:

  • Accidental trauma
  • Artificial nails
  • Manicures
  • Manipulating hangnails
  • Occupational trauma
  • Onychocryptosis (ingrown nails)
  • Onychophagia (nail biting)


  • Apply moisturizing lotion after washing
  • Avoid chronic prolonged exposure to contact irritants and moisture
  • Avoid nail trauma, biting, picking, manipulation, and sucking
  • Avoid trimming cuticles or using cuticle removers
  • Improve glycemic control in those with DM
  • Keep affected areas clean and dry
  • Keep nails short
  • Use rubber gloves, preferably with inner cotton glove or liner, when exposed to moisture and/or irritants

Differential Diagnosis:

  • Eczema
  • Herpetic whitlow
  • Psoriasis
  • Dermatomyositis
  • Granuloma annulare
  • Hematomas from pulse oximetry
  • Pyogenic granuloma
  • Reiter syndrome
  • Food hypersensitivity
  • Melanoma
  • Pemphigus vulgaris
  • Squamous cell carcinoma


  • AFP Vol 96 No 1 Jul 2017

5.19 Pigmentation Disorders

Hyperpigmentation Disorders Description Location Etiology Treatment
Postinflammatory hyperpigmentation Irregular, darkly pigmented macules/patches Previous sites of injury or inflammation Trauma, inflammation Triple combination therapy,† hydroquinone, retinoids, azelaic acid (Finacea), chemical peels, laser therapy
Melasma Pigmented, well-defined macules; light brown, brown, or gray Face (centrofacial 63%, malar 21%, mandibular 16%) or forearms Pregnancy, oral contraceptives, phenytoin (Dilantin), idiopathic Triple combination therapy,† chemical peels, light or laser therapy, sunscreen
Solar lentigines 1- to 3-cm well-circumscribed macules; light yellow to dark brown, variegated Face, hands, forearms, chest, back, shins Acute or chronic ultraviolet exposure Triple combination therapy† with or without cryotherapy, hydroquinone, retinoids, chemical peels, cryotherapy, intense pulsed light, laser therapy
Ephelides 1- to 2-mm sharply defined macules, red or tan to light brown Face, neck, chest, arms, legs Childhood onset after sun exposure in susceptible individuals (skin types I or II) Fades in winter months so treatment may be unnecessary; cryotherapy, hydroquinone, azelaic acid, chemical peels, laser therapy
Café au lait macules 1- to 20-cm tan to brown macules, epidermal, present at birth or early childhood Most commonly trunk but may appear anywhere Increased melanin in melanocytes/basal keratinocytes Laser therapy, surgical excision
Hypopigmentation disorders Description Location Etiology Treatment
Vitiligo Hypopigmented macules and patches; sharply defined; 5 to 50 mm; coalescent Face, hands, forearms, neck, genitalia, body folds, periorificial; lip-tip pattern Unknown, possibly immune-mediated High-potency topical corticosteroids (class II and III), topical calcineurin inhibitors, narrowband ultraviolet B, psoralen and ultraviolet A, systemic corticosteroids
Pityriasis alba Hypopigmented, irregular patches; fine scale; itchy Face, head, neck, forearms Possible association with atopic dermatitis aggravated by sunlight exposure Sunscreen, topical corticosteroids, tacrolimus (Protopic) ointment
Tinea versicolor Hypopigmented or pink plaques; may be hyperpigmented; fine scale Neck, chest, back, abdomen, proximal extremities Malassezia spp. infection Topical antifungals, topical adapalene (Differin) gel
Postinflammatory hypopigmentation Loss of pigment (variable), macules, patches Varies Tinea versicolor, atopic dermatitis, pityriasis alba, psoriasis, guttate parapsoriasis, dermabrasion, chemical peels, intralesional corticosteroid use Treatment of underlying condition when applicable


  • AFP Vol 96 No 12 Dec 2017

5.20 Perioral dermatitis

  • Unknown etiology but flouronated topical corticosteroids, subclinical irritant contact dermatitis, and overmoisturization  of skin implicated.
  • F > M
  • Discrete, symmetric pinpoint papules and pustules but not on vermillion border - might have erythematous base.
  • Treatment
    • Wean any topical steroids
    • First line: Oral tetracycline (II) (250mg bid-tid for several weeks)
    • Second line: Oral erythromycin (III) 
    • Third line: Topical metronidazole (I) with or without above Abx


  • Cheung M, Taher M, Lauzon G., Acneiform facial eruptions, Canadian Fam Phys, Vol 51; April 2005; 527-533

5.21 Pruritis   edit


  1. Dermatologic
    • Atopic dermatitis
    • Contact dermatitis
    • Lichen simplex chronicus
    • Psoriasis
    • Urticaria
    • Xerosis
  2. Systemic
    • Autoimmune disorders
    • Chronic renal failure
    • Drug induced
    • Endocrine disorders
    • Hematologic (polycythemia vera) and HIV infection
    • Liver disease
    • Lymphoproliferative disorders
    • Malignancy
  3. Neurologic
    • Brachioradial pruritis
    • Multiple sclerosis
    • Notalgia paresthetica
    • Postherpetic neuralgia
    • Poststroke
    • Small-fiber polyneuropathy (DM one of most common causes)
  4. Psychogenic
    • Anxiety
    • Bipolar disorder
    • Delusional infestation
    • Depression
    • Obsessive-compulsive disorders
  5. Mixed
    • More than 1 cause found
  6. Other


  • Labs
    • CBC - hematologic or malignancy suspected
    • CMP - DM, liver, or renal disease suspected
    • ESR - autoimmune disease suspected
    • TSH - hyperthyroidism suspected
    • Hepatitis panel
    • HIV
  • Imaging
    • CXR - lymphoma suspected
    • Spinal imaging (MRI) - secondary workup for brachioradial pruritis or notalgia paresthetica


  • Non-Drug
    • Warm (not hot) water for bathing
    • Apply emollient to skin immediately after bathing
    • Use hypoallergenic body products
    • Humidify indoor spaces during winter
    • Avoid fabrics and other clothing materials that irritate the skin (like wool - use cotton)
    • Wear loose fitting clothes
    • Avoid vasodilators (caffeine, alcohol, spices, and activities that promote excessive sweating like strenuous exercise)
  • Drugs
    • Antihistamines
      • Nocturnal itch, paraneoplastic itch, systemic mastocytosis
      • diphenhydramine 25-50 mg q4-6 prn
      • hydroxyzine 25 mg tid or qid
      • loratadine 10mg qd
    • Anticonvulsants
      • neuropathic itch, uremic itch
      • gabapentin 100-300mg /d
      • pregabalin 50-300 mg/d
    • Antidepressants
      • Cholestatic itch, nocturnal itch, paraneoplastic itch, pyschogenic itch, uremic itch
      • sertraline 75-100mg qd
      • paroxetine 20-40 mg qd
      • amitriptyline 10-25 mg qd to tid
      • doxepin 10mg qd or bid
      • mirtazapine 15 mg qd
    • Antipsychotics
      • Delusion of infestation
      • olanzapine 2.5-10 mg qd
      • risperidone 1-8 mg qd
    • Opioid-receptor agents
      • Cholestatic itch, uremic itch
      • naltrexone 50 mg qd
    • Bile-acid sequestrants
      • Cholestatic itch
      • cholestyramine 4-6 mg tid - 30 min before meals
      • ursodiol 13-15 mg/kg/d


  • JFP Nov 2020 Vol 69, No 9

5.22 Psoriasis

Medications that trigger:

  • Lithium
  • B-blockers
  • Antimalarials
  • Angiotensin-converting enzyme inhibitors
  • NSAIDs


  • Localized disease
    • Topical corticosteroids
    • Coal tar
    • Vit D analogues
    • Tazarotene
    • Anthralin
    • Localized UV light/laser
    • Calcineurin inhibitors
  • Extensive disease (Mod-Severe)
    • Otezla
    • UV light
    • Methotrexate
    • Retinoids
    • Cyclosporine
    • Apremilast
    • Biologicals
    • Tumore necrosis factor inhibitors


  • Consultant Feb 2016

5.23 Rosacea

Metronidazole 0.75% 45g AAA bid ($30-40) (See My Formulary Drugs)


  • Clindamycin 1% gel worked well for 1 patient

Rosacea Triggers:

  • Extremes of temperature
  • Sunlight
  • Spicy foods
  • Alcohol
  • Exercise
  • Acute psychological stressors
  • Medications
  • Menopausal hot flashes

5.24 Sebacceous Cysts

  • Traditional wide excision
    • Dissection and removal of the cyst completely from the surrounding tissue through an elliptical incision
    • Gold standard of treatment
    • More likely leads to significant scarring in comparison with minimal excision or punch biopsy
    • Has almost no recurrence when the cyst wall is entirely removed
  • Minimal excision and punch biopsy techniques produce minimal bleeding, have faster healing times, and produce less scarring.
    • Shorter procedural time
    • Slightly higher rates of recurrence
    • The minimal incision technique:
      • Involves kneading the lesion following injection of anesthetic and expressing the cyst contents through a 2- to 3-mm incision
      • Following expulsion of the cyst contents, the loosened capsule is delivered through the small opening
      • Closure with suture is optional
    • Punch biopsy excision:
      • Similar to the minimal excision technique except that the incision is made using a single-use disposable dermal punch following injection of lidocaine
      • Expulsion of the cyst contents, with cyst wall, via lateral pressure is performed and occasionally followed by closure with one suture


  • Inflamed cysts should be allowed to convalesce prior to attempted removal
  • Rarely are these cysts truly infected
  • Inflammation is secondary to sebaceous cyst wall rupture with leakage of cyst contents


  • J Fam Pract. 2007 April;56(4):315-316

5.25 Skin Closure

Suture Materials:


Material Needle type Tie to lose 50% strength Configuration Typical use
Chromic Reverse cutting 10-14 days Monofilament Mucosa, eye wounds
Glycolide/lactide polymer Conventional or 2-3 weeks Braided Deep dermal, muscle, fascia,
(Vicryl) reverse cutting     oral mucosa, genitalia wounds
Polioglecaprone Conventional or 7-10 days Monofilament Dermal, subcuticular wounds
(Monocryl) reverse cutting      
Polydioxanone Reverse cutting 4 weeks Monofilament Muscle, fascia, dermal wounds


Material Needle Type Time to lose 50% strength Configuration Typical use
Nylon (Ethilon) Cutting edge >10 years Monofilament Skin
Polypropylene Tapered point, Indefinite Monofilament Vascular surgery, skin, tendon,
(Prolene) blunt tip     and ligaments
Silk No needle 1 year Braided Hemostasis in ligation of vessels
        or for tying over bolsters

Suture removal timing:

Location Removal Timing
Face 3-5d
Scalp 7-10d
Arms 7-10d
Trunk 10-14d
Legs 10-14d
Hands or feet 10-14d
Palms or soles 14-21d

Criteria for Tissue Adhesives:

  • Wound less than 12 hours old
  • Linear
  • Hemostatic
  • Not crossing a joint
  • Not crossing a mucocutaneous junction
  • Not in a hair-bearing area
  • Not under significant tension
  • Not grossly contaminated
  • Not infected
  • Not devitalized
  • Not a result of a mammalian bite
  • No chronic condition that might impair wound healing


  • AFP Vol 78 No 8 Oct 2008
  • AFP Vol 95 No 10 May 2017

5.26 Skin Protection

Sunburn protection:

  • Avoid outdoor activities during peak sun intensity (10 a.m. to 4 p.m.), even on cloudy days
  • Wear protective clothing (e.g., long sleeves, long pants, wide-brim hats) during the day
  • For patients at increased risk, consider clothing with a high UV protection factor (> 30)
  • Use sunglasses that provide 100% UVA and UVB protection
  • Use a broad-spectrum sunscreen with an SPF of at least 15
  • Use a sunscreen that is water-resistant (40 to 80 minutes of protection in the water)
  • Apply sunscreen to dry skin 15 to 30 minutes before exposure to the sun
  • Reapply sunscreen every two hours or earlier when sweating, swimming, or towel-drying
  • Discard any sunscreen older than three years

Insect repellent:

  • Repellents with 20-50% DEET protect up to several hours
    • DEET safe in 2nd and 3rd trimesters and children >2mo
  • Citronella acceptable for brief exposure to nuisance mosquitoes but not recommended for disease carrying mosquitoes
  • No evidence supports: electronic repellents, garlic, or B vit
  • Permethrin highly effective against ticks, mosquitoes
  • Best protection: combining permethrin clothing with DEET repellent

See also: 12.11


  • AFP Vol 91 No 11 Jun 2015
  • AFP Vol 101 No 8 Apr 2020

5.27 Tinea Management Pitfalls

  • Do not use nystatin to treat any tinea infection because dermatophytes are resistant to nystatin. (However, nystatin is often effective for cutaneous Candida infections.)
  • Do not use oral ketoconazole to treat any tinea infection because of the U.S. Food and Drug Administration boxed warnings about hepatic toxicity and the availability of safer agents.
  • Do not use griseofulvin to treat onychomycosis because terbinafine (Lamisil) is usually a better option based on its tolerability, high cure rate, and low cost.
  • Do not use combination products such as betamethasone/clotrimazole because they can aggravate fungal infections.
  • Do not use topical clotrimazole or miconazole to treat tinea because topical butenafine (Lotrimin Ultra) and topical terbinafine (OTC 1% cream) have better effectiveness and similar cost.
  • Do not, in general, treat tinea capitis or onychomycosis without first confirming the diagnosis with a potassium hydroxide preparation, culture, or, for onychomycosis, a periodic acid–Schiff stain. However, kerion should be treated aggressively while awaiting test results, and it may be reasonable to treat a child with typical lesions of tinea capitis involving pruritus, scale, alopecia, and posterior auricular lymphadenopathy without confirmatory testing. If there is no lymphadenopathy, a confirmatory test is recommended.
  • Do not treat tinea capitis solely with topical agents, but do combine oral therapy with sporicidal shampoos, such as selenium sulfide (Selsun) or ketoconazole.
  • Do not perform potassium hydroxide preparations or cultures on asymptomatic household members of children with tinea capitis, but do consider empiric treatment with a sporicidal shampoo.


  • AFP Nov 2014 Vol 90, No 10

5.28 Topical Corticosteroids


  • Ultra-high potency - use only <3wks
  • Low-to-high potency - use <3mo
  • Avoid combination steroids/antifungals (avoid adverse effects and tinea infections)
Vehicle Effect Possible uses
Ointment Emollient, higher potency Lichen
Cream Emollient Moist and weeping areas
Lotion Drying agent, spreads easily Larger areas
Gels Drying, nongreasy, nonstaining Hairy areas or face
Solution Drying agent, lower potency Hairy or intertriginous areas
Table 10: Quantity of Ointment Based on Fingertip Units
Body area Fingertip units required for one application Weight required for twice per day dosing for 30 days
Face and neck 2.5 75 g
Front of trunk 7 210 g
Back of trunk 7 210 g
One arm 3 90 g
One hand (front and back) 1 30 g
One leg 6 180 g
One foot 2 60 g


  • AFP Mar 2021 Vol 103 No 6
  • Consultant Nov 2015

5.28.1 My Favorite topical steroids

Potency Medication Price at Target for 30g
High Triamcinolone acetonide 0.5% cream $8
Intermediate Triamcinolone acetonide 0.1% cream $4
  Triamcinolone acetonide 0.1% ointment $4
Low Hydrocortisone 0.5% cream $2
  Hydrocortisone 0.5% ointment $2
  • Class 1: Clobetasol proprionate
  • Class 2: Fluicinonide/desoximetasone
  • Class 3: Betamethasone valerate/fluocinolone acetonide
  • Class 4: Trimacinolone acetonide/mometasone furoate
  • Class 5: Hydrocortisone valerate
  • Class 6: Desonide
  • Class 7: OTC hydrocortisone

5.28.2 Skin Conditions Responsive to Topical Corticosteroid Treatment

High-potency steroids (groups I and II)

  • Alopecia areata
  • Atopic dermatitis (resistant)
  • Bullous pemphigoid
  • Discoid lupus
  • Dyshidrotic eczema
  • Hyperkeratotic eczema
  • Labial adhesion
  • Lichen planus
  • Lichen sclerosus (skin)
  • Lichen simplex chronicus
  • Melasma
  • Nummular eczema
  • Poison ivy (severe)
  • Psoriasis Vitiligo

Medium-potency steroids (groups III, IV, and V)

  • Anal inflammation (severe)
  • Asteatotic eczema
  • Atopic dermatitis
  • Dermatitis (severe)
  • Infantile acropustulosis
  • Intertrigo (severe, short term)
  • Lichen sclerosus (vulva)
  • Nummular eczema
  • Scabies (after scabicide)
  • Seborrheic dermatitis
  • Stasis dermatitis

Low-potency steroids (groups VI and VII)

  • Dermatitis (diaper)
  • Dermatitis (eyelids)
  • Dermatitis (face)
  • Intertrigo
  • Perianal inflammation
  • Phimosis

Strength in vehicle ranked strongest to weakest:

  1. Ointment
  2. Cream
  3. Lotion
  4. Solution

Avoid face/genitalia with higher potency steroids


  • AFP Mar 2021 Vol 103 No 6
  • Consultant Nov 2015

5.28.3 Adverse Effects of Topical Corticosteroids

  • Cutaneous effects
    • Atrophic changes
      • Easy bruising
      • Increased fragility
      • Purpura   
      • Stellate pseudoscars   
      • Steroid atrophy   
      • Striae   
      • Telangiectasias   
      • Ulceration
    • Infections   
      • Aggravation of cutaneous infection   
      • Granuloma gluteale infantum   
      • Masked infection (tinea incognito)   
      • Secondary infections
    • Miscellaneous   
      • Contact dermatitis
      • Delayed wound healing   
      • Hyperpigmentation   
      • Hypertrichosis (hirsutism)   
      • Hypopigmentation   
      • Perioral dermatitis   
      • Photosensitization   
      • Reactivation of Kaposi sarcoma   
      • Rebound flare-up   
      • Steroid-induced acne   
      • Steroid-induced rosacea
    • Ocular changes   
      • Cataracts   
      • Glaucoma   
      • Ocular hypertension
  • Systemic effects
    • Endocrine   
      • Cushing syndrome   
      • Hypothalamic-pituitary-adrenal suppression
    • Metabolic   
      • Aseptic necrosis of the femoral head   
      • Decreased growth rate   
      • Hyperglycemia
    • Renal/electrolyte   
      • Hypertension   
      • Hypocalcemia   
      • Peripheral edema


  • AFP Mar 2021 Vol 103 No 6

5.29 Hair Loss   edit

Hair loss is a common problem that may be improved with vitamin and mineral supplementation. Vitamins and minerals are important for normal cell growth and function and may contribute to hair loss when they are deficient. While supplementation is relatively affordable and easily accessible, it is important to know which vitamins and minerals are helpful in treating hair loss.

Androgenetic alopecia (AGA), telogen effluvium (TE) are two common types of hair loss. Studies show that supplementing the diet with low levels of vitamin D can improve symptoms of these diseases. If a patient with AGA or TE has low iron levels (more commonly seen in females), supplementation is also recommended. These iron-deficient patients should also ensure their vitamin C intake is appropriate. At the present time there is insufficient data to recommend zinc, riboflavin, folic acid, or vitamin B12 supplementation in cases of deficiency. Neither vitamin E or biotin supplementation are supported by the literature for treating AGA or TE; in addition, biotin supplementation can also lead to dangerous false laboratory results. Studies show that too much vitamin A can contribute to hair loss, as can too much selenium, although more studies are needed to establish the latter relationship.

Alopecia areata (AA) occurs when the immune system attacks the hair follicle. Studies have shown a relationship between AA and low vitamin D levels. Vitamin D should be supplemented if levels are low. However, more studies are needed to determine the effect of iron and zinc supplementation on AA patients. There is currently not enough data to recommend supplementation of folate or B12. Biotin supplementation is not supported by available data for the treatment of AA. It is unclear if selenium plays a role in this disease; therefore, supplementation with this mineral is not recommended.

Iron, vitamin D, folate, vitamin B12, and selenium are vitamins and minerals that may be involved in hair graying/whitening during childhood or early adulthood. Supplementing these deficient micronutrients can improve premature graying.


  • Almohanna, Hind M et al. "The Role of Vitamins and Minerals in Hair Loss: A Review." Dermatology and therapy vol. 9,1 (2019): 51-70. 10.1007/s13555-018-0278-6

5.30 nonscarring hair and scalp disorders

Labs: Obtain the following tests:

  • Complete blood count with red blood cell indices (to assess for anemia)
  • Complete metabolic panel (to assess for signs of underlying disease)
  • Thyroid-stimulating hormone (to assess for a thyroid disorder) (see "Laboratory assessment of thyroid function", section on 'Evaluating for thyroid dysfunction')
  • Ferritin (to assess iron storage) (see "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)')
  • 25-hydroxyvitamin D levels (to assess for vitamin D deficiency) [17]

The selection of additional laboratory studies is guided by the need to rule out disorders in the differential diagnosis or to further investigate patients with signs or symptoms suggestive of a particular underlying disease, nutritional deficiency, heavy metal or other toxin exposure, or other causes of hair loss. As examples, a hormonal work-up to rule out hair loss related to hyperandrogenemia would be appropriate in women with signs of virilization, acne, and obesity, and further evaluation with antinuclear antibodies (ANAs) or other studies would be appropriate for a patient with signs or symptoms of an underlying autoimmune disease. In addition, dietary history may reveal nutritional deficiencies that should be evaluated.

  • Telogen effluvium is a form of diffuse, nonscarring hair loss that presents as a transient or chronic loss of hair (picture 1A-C). Hair loss in telogen effluvium occurs as a result of an abnormal shift in follicular cycling that leads to the premature shedding of hair. A wide variety of endogenous and exogenous factors have been linked to the induction of telogen effluvium. Examples include major surgery, serious illness, childbirth, protein or caloric malnutrition, drugs, and severe emotional distress. In some cases, the inciting cause is unclear or multiple inciting triggers are identified.
  • Anagen effluvium – Anagen effluvium is an acute loss of anagen hair fibers secondary to chemotherapy or toxin exposure and represents acute loss of greater than 80 percent of the scalp hair. Exclamation point hairs (short, 1 to 3 mm hairs with a tapered base) that result from dystrophic hair growth are a common finding. Microscopic evaluation of the proximal ends of hairs dislodged during a hair pull test demonstrates normal or dystrophic anagen hairs rather than telogen hairs. (See "Alopecia related to systemic cancer therapy".)
  • Androgenetic alopecia (male or female pattern hair loss) – Features of androgenetic alopecia that are useful for distinguishing this condition from telogen effluvium include a clinical examination that demonstrates a characteristic pattern of hair loss and miniaturized hairs (picture 7A-C). A biopsy can be useful for differentiating between these diagnoses in difficult cases. Of note, the two conditions may coexist, and telogen hair shedding can occur early in the course of androgenetic alopecia. (See "Androgenetic alopecia in males: Pathogenesis, clinical features, and diagnosis" and "Female pattern hair loss (androgenetic alopecia in females): Pathogenesis, clinical features, and diagnosis".)
  • Diffuse alopecia areata – Diffuse alopecia areata is an uncommon form of alopecia areata that is characterized by the diffuse loss of scalp hair, resulting in the appearance of generalized hair thinning (picture 8). Similar to anagen effluvium, exclamation point hairs may be present, and performance of the hair pull test may reveal dystrophic anagen hairs. A biopsy revealing an inflammatory infiltrate consistent with alopecia areata differentiates this condition from telogen effluvium. (See "Alopecia areata: Clinical manifestations and diagnosis".)
  • Loose anagen syndrome – Loose anagen syndrome is a rare, nonscarring hair loss disorder that manifests with easily extracted anagen hairs from the scalp (picture 9). Young children are typically affected, particularly females with blond hair. Characteristically, examination of shed hairs reveals anagen hairs with ruffled cuticles (picture 10).
  • Structural hair disorders – A variety of structural hair disorders causes weakening of the hair shaft that results in easily fractured hair. Unlike telogen effluvium, in which hair is shed from the follicle, these conditions result in increased breakage of hair. Close examination and 2x magnification of the loose hair will reveal broken hairs and may also reveal characteristic findings of a particular structural hair disorder.

5.31 Nonscarring Hair Loss

Hair Cycle:

  • 90% scalp hairs in anagen (growth) phase at any given time
  • 10% scalp hairs in telogen (resting) or catagen (involution) phases

Evaluation Steps

  • Is it scarring hair loss?
    • Scarring presents with:
      • pruritis
      • pain
      • erythema
      • scale
      • crust
      • obliteration of follicular pore markings leading to an abnormally smooth appearance of the skin
  • If nonscarring, what is the Distribution of loss?
    • Patterned
      • Ex: Androgenic alopecia
        • Hairline recession, increased spacing between follicles, increased visibility of scalp, and miniturized follicles
        • Most common patterned hair loss
        • Minoxidil and finasteride
    • Diffuse
      • Ex: Telogen Effluvium
        • Most common diffuse hair loss
        • An inciting event disrupts hair cycle leading to loss > 200 scalp hairs a day (Decrease hair volume >10% but <50%)
      • severe illness
      • Major surgery
      • thyroid idsease
      • pregnancy
      • Fe def anemia
      • malnutrition
      • rpid weight loss
      • Vit D def
      • Medications:
        • Using: lithium, sodium valproate, fluoxetine, warfarin, metoprolol, propranolol, retinoids, isoniaxid
        • Discontinuing: estrogen containing OCPs
        • Occurs 2-4 months after inciting event
        • Labs:
      • TSH
      • ferritin
      • 25-OH Vit D2 and D3
        • Self-limited
        • Takes 6-9 months to normalize
    • Focal
      • Ex: Alopecia Areata
        • Hair loss patches with smooth borders
        • Autoimmune often in those with atopy
        • Spontaneous regrowth in 30% patients
        • Exclamation point hairs in active areas
        • Pigmented hairs preferentially lost with regrowth initially nonpigmented or white


  • JAMA Mar 2021 Vol 325 No 9

5.32 OCP and Acne

Location of hormonal acne:

  • While typical teenage acne appears most of the forehead and cheeks, the most common areas for hormonal acne to pop up are on the lower sections of the face, including around the mouth, jawline, and neck.

Hormone levels:

  • As a rule of thumb, birth control that contains a higher level of progesterone will have a stronger androgenic effect and have a higher risk of promoting acne breakouts.
  • The reduction of androgen production will reduce the blackheads, whiteheads, and inflamed red pimples typical to acne.
  • The estrogen that is used in birth control pills is almost always Ethinyl estradiol and rarely mestranol. The usual amount is 20–50 µg.

Estrogen effect provides some anti-androgenic effect through 3 mechanisms:

  • Suppress secretion of pituitary gonadotropins, inhibit ovulation, and thus inhibit androgen production by the ovaries.
  • Block the Androgen receptors
  • Increase the liver production of SHBG and reducing circulating testosterone.

Women with acne need to avoid taking progestins with potent androgenic (acne-causing) effects, i.e., levonorgestrel and norgestrel. A better choice of progestins for women with acne would be drospirenone, norgestimate, gestodene, and desogestrel with a weaker androgenic effect.

The best birth control pills for women with Acne are pills that contain drospirenone and Ethinylestradiol. Examples of these pills are

  • Yasmin,
  • Yaz,
  • Beyaz,
  • Ocella,
  • Safyral,
  • Syeda,
  • Gianvi,
  • Loryna,
  • Nikki,
  • Vestura, and
  • Zarah.

Lo Loestrin was found to cause more acne breakouts. Several other contraceptive options exacerbate or trigger acne in some women as they are higher in progestin (i.e., they increase testosterone-like activity) and low in estrogen. These include Depo-Provera (a shot), Skyla, Lylema, Implanon, and Nexplanon (a subdermal implant).

Indications of hormonal treatment in acne

  • Severe flare-ups before menstruation
  • When oral contraception is desirable
  • Acne not responding to conventional treatment
  • Polycystic ovary syndrome
  • Late onset acne (acne tarda)
  • Ovarian or adrenal hyperandrogenism

Summary of treatment recommendations from the European acne guidelines

Type of acne First-line treatment Second-line treatment Third-line treatment Hormonal alternatives for women
Comedonal acne Topical retinoids, adapalene is preferred to tretinoin Benzoyl peroxide (BPO) or azelaic acid Not recommended
Mild to moderate papulopustular acne BPO + adapalene (f.c.) or BPO + clindamycin (f.c.) BPO or azelaic acid or systemic antibiotic + adapalene Isotretinoin or tretinoin + topical erythromycin (f.c.); or systemic antibiotics + BPO; or systemic antibiotics + azelaic acid; systemic antibiotics + adapalene + BPO (f.c.) Not recommended
Severe papulopustular acne and mild nodular acne Systemic isotretinoin Systemic antibiotics + adapalene; systemic antibiotics + azelaic acid; or systemic antibiotics + BPO + adapalene (f.c.) Systemic antibiotics + BPO Hormonal antiandrogens + topical treatment or systemic antibiotics (topical treatment is preferred)
Severe nodular acne and conglobate acne Systemic isotretinoin Systemic antibiotics + azelaic acid Systemic antibiotics + BPO; or systemic antibiotics + adapalene; or systemic antibiotics + BPO + adapalene (f.c.) Hormonal antiandrogens + systemic antibiotics (consider as third line treatment)


5.33 Rosacea   edit

[2022-04-21 Thu 08:29]

Sulfacetamide / Sulfur Typical dosing for Avar (sulfacetamide / sulfur)

  • Cream, gel, lotion, suspension: Apply a thin film to the affected area 1 to 2 times a day.
  • Cleanser, cleansing cloth/pads: Wash affected area 1 to 2 times a day.
  • Emollient foam: Apply to affected area 1 to 2 times a day. The foam may remain on the skin or may be rinsed off after 1 to 2 minutes.

5.35 Common Benign Skin Tumors   edit

Table 11: Common Benign Skin Tumors
Condition Characteristics Differential diagnosis Treatment Comments Precautions and referral criteria
Acrochordon Skin-colored to brown papules on narrow stalk Senescent intradermal nevus Cryosurgery, electrodesiccation, scissor or shave excision Do not send multiple specimens in same jar Cryosurgery should be performed with caution in persons with darker skin; refer patients with eyelid involvement
Cherry angioma Dome-shaped, small, bright red to violaceous, soft, compressible papules Pyogenic granuloma Electrodesiccation, laser ablation Numerous lesions (hundreds) and early onset can occur in Fabry disease Genetic evaluation for Fabry disease in patients with multiple lesions
Dermatofibroma Firm, raised, tan to reddish-brown papules or nodules; dimpling with lateral compression Cellular dermatofibroma, dermatofibrosarcoma protuberans Cryosurgery, intralesional steroid injection, laser ablation, punch excision Abrupt appearance of multiple lesions may occur in persons with human immunodeficiency virus infection or systemic lupus erythematosus Refer patients with cellular variant and dermatofibrosarcoma protuberans (deep invasion and metastases)
Epidermal inclusion cyst Firm, mobile, subcutaneous nodule with central punctum; painless (unless inflamed) Lipoma, abscess (vs. inflamed cyst) Excision, intralesional steroid injection with interval excision for inflamed cysts Presence of punctum helps differentiate cysts from lipomas; history helps differentiate between inflamed cyst and abscess (acute) Inflamed cysts and those that have undergone previous incision and drainage can be more difficult to excise; refer patients with facial cysts
Keratoacanthoma Rapidly growing, dome-shaped hyperkeratotic papule on sun-damaged skin Squamous cell carcinoma, verruca, hypertrophic actinic keratosis Excision, intralesional injection (methotrexate, fluorouracil, bleomycin), Mohs micrographic surgery Cannot be histologically differentiated from squamous cell carcinoma Refer patients with recurrence after complete excision
Lipoma Soft, mobile subcutaneous nodules Epidermal inclusion cyst, liposarcoma, deep hemangioma Incision or punch excision and manual expression Ultrasonography can help differentiate lipomas from other deep neoplasms Use caution with facial lipomas and recurrent lesions after excision
Pyogenic granuloma Rapidly growing, yellow to violaceous, friable nodule, often surrounded by scaly collarette Amelanotic melanoma, Spitz nevus, basal cell carcinoma, squamous cell carcinoma Laser ablation, shave excision with electrodesiccation of base Send for histologic evaluation to rule out melanoma Refer patients with recurrent lesions or facial lesions
Sebaceous hyperplasia Dome-shaped papule with central umbilication and uniform yellow lobules on magnification Basal cell carcinoma Chemical cautery, cryosurgery, electrodesiccation, laser ablation, oral isotretinoin, phototherapy, shave excision Thin shave biopsy can rule out basal cell carcinoma Basal cell carcinoma is generally red or pink and increases in size
Seborrheic keratosis Well-circumscribed, yellow to brown, “stuck-on” papules and plaques Atypical nevus, melanoma Cryosurgery, curettage, electrodesiccation, laser ablation, shave excision Consider malignancy workup for abrupt appearance of multiple lesions  

5.36 Lice Treatment

A few notes on lice treatment:

  • Do not use a combination shampoo/conditioner, or conditioner before using lice medicine.
  • Do not re–wash the hair for 1–2 days after the lice medicine is removed.
  • After each treatment, checking the hair and combing with a nit comb to remove nits and lice every 2–3 days may decrease the chance of self–reinfestation. Continue to check for 2–3 weeks to be sure all lice and nits are gone.
  • Machine wash and dry clothing, bed linens, and other items that the infested person wore or used during the 2 days before treatment using the hot water (130°F) laundry cycle and the high heat drying cycle. Clothing and items that are not washable can be dry–cleanedORsealed in a plastic bag and stored for 2 weeks.
  • Soak combs and brushes in hot water (at least 130°F) for 5–10 minutes.
  • Vacuum the floor and furniture, particularly where the infested person sat or lay. However, the risk of getting infested by a louse that has fallen onto a rug or carpet or furniture is very small. Head lice survive less than 1–2 days if they fall off a person and cannot feed; nits cannot hatch and usually die within a week if they are not kept at the same temperature as that found close to the human scalp. Spending much time and money on housecleaning activities is not necessary to avoid reinfestation by lice or nits that may have fallen off the head or crawled onto furniture or clothing.
  • Do not use fumigant sprays; they can be toxic if inhaled or absorbed through the skin


6 Drugs

6.1 Adult Immunizations

  • Pneumococcal
    • PCV 20 x1

6.2 Antidepressants and sexual function

  • Patients treated with selective serotonin reuptake inhibitors (SSRIs) and the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine have significantly higher rates of overall sexual dysfunction—includingdesire, arousal, and orgasm—than patients treated with placebo (strength of recommendation [SOR]: B, randomized controlled trials [RCTs] with heterogeneous results).
  • Patients treated with bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), have rates of overall sexual dysfunction comparable to placebo (SOR: B, RCTs with heterogeneous results).
  • Total rate of sexual dysfunction (SD) associated with selective serotonin reuptake inhibitors (SSRIs) was significantly higher than the placebo rate of 14.2%.
  • The SSRIs citalopram, fluoxetine, paroxetine, and sertraline as well as the SNRI venlafaxine, had significantly greater rates (70%-80%) of reported total sexual dysfunction, including desire, arousal, and orgasm, than placebo.
  • Paroxetine, citalopram, and venlafaxine, when compared with other antidepressants (fluoxetine, fluvoxamine, nefazodone, sertraline), generally were associated with more reports of SD, specifically complaints of erectile dysfunction in men and decreased vaginal lubrication in women.
  • The number needed to treat one additional person with general sexual functioning satisfaction was 6 (95% CI, 4-9) with bupropion.


  • J Fam Pract. 2013 November;62(11):660-661.

6.3 Bupropion

  • The medication is FDA-approved for adult depression, seasonal affective disorder, and smoking cessation.
  • Off-label, non-FDA-approved uses include anti-depressant-induced sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), depression associated with bipolar disorder, and obesity.
  • In the pediatric population, bupropion is used off-label for ADHD


6.4 Caffeine

Beverage Serving Size (oz) Caffeine (mg)
Decaffeinated coffee 8 2
Starbucks Grande Coffee 16 330
Starbucks Caffee Latte 16 150
Plain, brewed coffee 8 95
Espresso 1 64
Decaffeinated tea 8 2
Black tea, brewed 8 47
Snapple iced tea 16 18
Diet Mountain Dew 12 55
Diet Coke 12 46
Diet Pepsi 12 37
Sam's Diet Cola 12 13
SoBe Adrenaline Rush 16 152
Red Bull 8.3 76


  • JFP Vol 58 No 6 Jun 2009

6.5 CAM with evidence

  • Fish oil - hypertriglyceridemia - SOR B
    • GI complaints; may interact with anticoagulant meds; may increase risk of prostate ca
  • Glucosamine - osteoarthritis - SOR B
    • Mild GI effects, drowsiness, skin reactions, HA; use with caution in shellfish allergy; may increase warfarin effects
  • Probiotics - Preventing antibiotic associated diarrhea - SOR B
    • Flatulence, vomiting, rash, CP, increased phlegm; contraindicated in immunosuppressed or indwelling medical device
  • Soy - Hyperlipidemia - SOR C
    • GI effects; may increase risk of endometrial hyperplasia; use with caution in pts with thyroid dysfunction or hormone sensitive ca
  • St John's Wort - Depression - SOR B
    • Photosensitivity, GI effects, fatigue, increased risk cataracts. Not preg/lact; may interact with antidepressants, OCPs, cyclosporine, digoxin, indinavir, phenytoin, phenobarbital, warfarin, and more
  • Guided imagery - mood, pain, anxiety - SOR A
    • AE: None
  • Acupuncture - back, neck, shoulder pain; Osteoarthritis, HA - SOR B
    • Infection, skin irritation, hematoma, pneumothorax
  • Yoga - low back pain - SOR C
    • AE: None


  • JFP Vol 63, No 10 Oct 2014

6.6 Cannabis

6.6.1 Cannabis and Male fertility   edit

Current research suggests that cannabis may negatively impact male fertility. Further studies are needed to validate that robust findings in animal models will carry over into human experience. Clinicians should be aware of these potential effects when prescribing medical marijuana therapies to men of reproductive age, and they should consider the degree of cannabis use as a possible component of a complete male infertility workup.


  • Payne KS, Mazur DJ, Hotaling JM, Pastuszak AW. Cannabis and Male Fertility: A Systematic Review. J Urol. 2019 Oct;202(4):674-681. doi: 10.1097/JU.0000000000000248. Epub 2019 Sep 6. PMID: 30916627; PMCID: PMC7385722.

6.6.2 Prenatal cannabis exposure associated with mental disorders in children that persist into early adolescence

Prenatal cannabis exposure following the middle of the first trimester—generally after five to six weeks of fetal development—is associated with attention, social, and behavioral problems that persist as the affected children progress into early adolescence (11 and 12 years of age)


6.7 Contraception

Use the Quick Start method:

  • Start same day as prescription regardless of menstrual cycle
  • Use back-up protection for the first 7 days
  • Prescribe a year at a time

Patient Resources:


Antiepileptic drugs to avoid with OCPs:

  • Carbamazepine
  • Lamotrigine
  • Oxcarbazepine
  • Phenobarbital
  • Phenytoin
  • Primodone
  • Topiramate

Antiepileptic drugs to consider instead with OCPs:

  • Ethosuximide
  • Gabapentin
  • Levetiracetam
  • Pregabalin
  • Tiagabine
  • Valproate
  • Vigabatrin
  • Zonisamide


  • JFP Vol 66 No 11 Nov 2017

6.7.1 OCP Adverse Effect Management

  • Nausea
    • Take pill at bedtime, or at a meal
    • Use Low Estrogen pill (e.g. Loestrin 1/20)
  • Fluid Retention
    • Change to OCP with the following characteristics
      • Low Estrogenic Activity (or low Estrogen dose)
    • Examples
      • Loestrin 1/20
      • Loestrin 1.5/30
  • Appetite too active or weight gain
    • Change to OCP with the following characteristics
      • Low Estrogenic Activity (or low Estrogen dose)
      • Low Androgenic Activity
    • Examples
      • Ovcon 35
      • Ortho Novum 1/35
  • Hypertension
    • Discontinue Oral Contraceptive
    • Consider Mini-Pill (Progestin only)
  • Major Depression
    • See Major Depression Management
    • Change to OCP with the following characteristics
      • Low Progestin Activity
    • Adjunctive Measures
      • Pyridoxine 20 mg bid
  • Migraine Headache
    • Do not use Oral Contraceptives in women who have Migraine with Aura (risk of stroke)
      • Consider Progestin-Only Pill (Mini-Pill) or Intrauterine Device as alternative
    • Characteristics
      • More common during the first cycle of Oral Contraceptives
      • More common in women over age 35 years
    • General
      • Change to OCP with low Estrogenic Activity (or low Estrogen dose)
      • Examples
        • Loestrin 1/20
        • Progesterone Only OCP
        • Avoid triphasic Oral Contraceptives
        • Continuous Cycle or Seasonal Contraception (84 days OCP with 5 days withdraw)
      • Indicated for Menstrual Migraine
    • Headache during the Placebo week
      • Take estradiol 10 mcg orally for 5 of the 7 Placebo days
      • Benefit in age over 40 years (unclear if benefit extends to younger women)
  • Miscellaneous adverse effects
    • Decreased Libido
      • Increase Androgenic Activity
    • Moodiness
      • Lower Estrogenic Activity
    • Dry Eyes
      • Increase Progestin Activity (Progestin dominant pill)


6.8 Controlled medications


  • A prescription must be written in ink or indelible pencil or typewritten and must be manually signed by the practitioner. An individual may be designated by the practitioner to prepare the prescriptions for his/her signature. The practitioner is responsible for making sure that the prescription conforms in all essential respects to the law and regulation.
  • Prescriptions for schedule II controlled substances must be written and be signed by the practitioner. In emergency situations, a prescription for a schedule II controlled substance may be telephoned to the pharmacy and the prescriber must follow up with a written prescription being sent to the pharmacy within seven days. Prescriptions for schedules III through V controlled substances may by written, oral or transmitted by fax.


  • Prescriptions for schedule II controlled substances cannot be refilled. A new prescription must be issued. Prescriptions for schedules III and IV controlled substances may be refilled up to five times in six months. Prescriptions for schedule V controlled substances may be refilled as authorized by the practitioner.

6.8.1 Opioid: CDC Recommendations

Maximize use of non opioid therapy

  • Treat any mood disorder
  • PT, exercise, water aerobics
  • CBT
  • Intraarticular glucocorticoid or trigger point injections
  • Epidural steroid injections for chronic radicular low back pain
  • TENS units with poor data
  • Acetaminophen vs NSAIDS
    • For chronic LBP - both are equally effective
    • For non-LBP, NSAIDS are slightly more effective for OA
    • NSAIDs have significantly more side effects
    • COX2 have less side effects but still CV risk like NSAIDS
  • Neuropathic pain
    • Gabapentin, pregabalin, TCAs
    • Duloxetine and venlafaxine
    • Nortiptyline at low doses (10mg/d)
  • Other
    • Topical 5% lidocaine patch or gel
    • Capsaicin cream

6.8.2 Opioid: FL HB21

Main points:

  1. 3 Day limit on schedule II opioids for "acute pain" with a 7 day exemption)
    • For 7 days:
      1. have to believe it is medically necessary to treat the pain
      2. Indicate "Acute Pain Exemption" on the prescription
      3. Adequately document in the records the acute medical condition and lack of alternative treatment options that justify the deviation from 3 day supply limit
    • Acute Pain Exemption Template
      • "Patient is having significant pain caused by _ which will last more thatn three days. Trial of _ has not helped. I believe that it is medically necessary to treat this patient's pain because it is affecting their ability to _."
  2. Includes hydrocodone and codeine
  3. Opioid antagonist requirements
  4. Consult PDMP before prescribing MOST controlled substances every time


6.9 Corticosteroids

  • Systemic corticosteroids are recommended for patients within three days of the onset of symptoms of Bell palsy.
    • LOE: A
  • Systemic corticosteroids appear to be a safe and effective alternative to nonsteroidal anti-inflammatory drugs in patients with acute gout.
    • LOE: B
  • Do not prescribe systemic corticosteroids for patients with acute bronchitisor acute sinusitis.
    • LOE: B
  • Do not prescribe systemic corticosteroids for patients with allergic rhinitis.
    • LOE: C
  • There is insufficient evidence to support routine use of systemic corticosteroids for patients with lumbar radiculopathy.
    • LOE: B
  • Do not prescribe systemic corticosteroids for patients with carpal tunnel syndrome.
    • LOE: B
  • There is insufficient evidence to support routine use of systemic corticosteroids for patients with acute pharyngitis.
    • LOE: B
  • There is insufficient evidence to support routine adjunct use of systemic corticosteroids for patients with herpes zoster.
    • LOE: B


  • AFP Vol 101 No 2 Jan 2020

6.10 Coumadin (Warfarin) Dosing

Warfarin Maintenance Dosing Protocol with INR Goal 2-3 (Class IIb, Level C)

INR < 1.5 INR 1.5 - 1.9 INR 2.0 - 3.0 INR 3.1- 4.0* INR 4.1-5.0* INR 5.1- 9.0* INR > 9.0
Extra Dose; Increase weekly dose 10-20% Increase weekly dose 5-10% No change Decrease weekly dose 5-10% Hold 1 dose; Decrease weekly dose 10% Consider: Hold 2 doses; Decrease weekly dose 10-20%; Check Hct Urgent patient evaluation

Warfarin Maintenance Dosing Adjustment Nomogram for INR Goal of 2-3

Adjustment Guidelines

  • A: Baseline CBC, PT/INR required prior to continuation of warfarin therapy.
  • B: Assess patient compliance and determine if any changes have been made that may impact therapy: 1) addition of interacting drugs or herbal products; 2) changes in diet (eating/not eating) 3) changes in health status.
  • C: Based on the INR results make adjustments to the current therapy based on the ranges below:

INR < 1.5

  1. Verify compliance (if non-compliant: resume therapy at previous dose).
  2. If dosage adjustment needed: increase maintenance dose by 5%- 20%*.
    • Some clinicians recommend a 'booster dose' 1.5 to 2x the daily maintenance dose x 1
  3. Return: 3 - 7 days

INR 1.5 - 1.9

  • Verify compliance (if non-compliant: resume therapy at previous dose).
  • [* Some clinicians recommend a 'booster dose' 1.5 to 2x the daily maintenance dose x 1 ]
  • If dosage adjustment needed: increase maintenance dose by 5 - 15% (use lower end of this range for INR values close to the therapeutic range).
  • Return: 3 - 7 days

INR 2.0 - 3.0

  • No Changes Needed
  • Return: 4 weeks

INR 3.1 - 3.4

  • Dose adjustment usually not necessary if level is at the low end of this range ( 3.1 - 3.2) and at least two previous levels were therapeutic. Recheck in 3 to 7 days.
  • Consider decreasing dose by 5 - 10% and/or holding one dose.
  • Recheck in 3- 7 days.

INR 3.5 - 3.9

  • consider holding one dose.
  • evaluate any clinical changes that may have occurred with the patient (eating regularly, no new medications, etc.)
  • consider decreasing the maintenance dose by 5 -15% depending on magnitude of the INR elevation.
  • Return: 1- 3 days.

INR 4.0 - 4.9 with no significant bleeding

  • Hold warfarin until INR is within the therapeutic range.
  • Recommend lowering maintenance dose by 5%- 20%
  • Increase frequency of monitoring until problem resolved (daily initially).
  • (8th ACCP): If only minimally above therapeutic range or associated with a transient causative factor, no dose reduction may be required.

INR > 5.0

  • Review latest ACCP guidelines - ELEVATED INRs.
  • Return daily until therapeutic.


  • Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH; American College of Chest Physicians. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e152S-84S. doi: 10.1378/chest.11-2295.

6.12 Insulin Prescribing

Needle/Syringe Options:

  • 30u insulin syringes/31 ga needles
  • 50u insulin syringes/31 ga needles
  • 100u insulin syringes/31 ga needles

ReliOn NPH or Regular insulin:

  • 3 ml or 10 ml vials of 100 uits/ml

6.13 Marijuana

6.13.1 Chest CT Findings in Marijuana Smokers

Retrospective case-control study

  • evaluated results of chest CT examinations (from October 2005 to July 2020) in:
    • marijuana smokers
    • nonsmoker control patients
    • tobacco-only smokers
  • compared rates of:
    • emphysema
    • airway changes
    • gynecomastia
    • coronary artery calcification


  • Population:
    • A total of 56 marijuana smokers (34 male; mean age, 49 years ± 14 [SD])
    • 57 nonsmoker control patients (32 male; mean age, 49 years ± 14)
    • 33 tobacco-only smokers (18 male; mean age, 60 years ± 6) were evaluated
  • Higher rates of emphysema were seen among marijuana smokers (42 of 56 [0%]) than nonsmokers (three of 57 [0%]) (P < .001) but not tobacco-only smokers (22 of 33 [0%]) (P = .40).
  • Rates of bronchial thickening, bronchiectasis, and mucoid impaction were higher among marijuana smokers compared with the other groups (P < .001 to P = .04).
  • Gynecomastia was more common in marijuana smokers (13 of 34 [0%]) than in control patients (five of 32 [0%]) (P = .039) and tobacco-only smokers (two of 18 [0%]) (P = .040).
  • There was no difference in rate of coronary artery calcification between age-matched marijuana smokers (21 of 30 [0%]) and tobacco-only smokers (28 of 33 [0%]) (P = .16).


  • Airway inflammation and emphysema were more common in marijuana smokers than in nonsmokers and tobacco-only smokers, although variable interobserver agreement and concomitant cigarette smoking among the marijuana-smoking cohort limits our ability to draw strong conclusions.


6.13.2 Marijuana and Cardiovascular Disease

  • Compared with non-users, MJ use associated with
    • 88% higher odds of myocardial infarction or CAD in adults 18-74
    • 81% higher odds of stroke
  • Even higher odds in males <55 yo and females <65 yo
  • Frequent MJ smoking had
    • 2.1 times higher odds of MI or CAD
    • 1.8 times highter odds of stroke
  • No association was observed between MJ use in any form other than smoking and cardiovascular disease


  • S Shah. Association of Marijuana Use and Cardiovascular Disease: A Behavioral Risk Factor Surveillance System Data Analysis of 133,706 US Adults. AJM Vol 134 No 5 May 2021

6.14 Medication Helps

  • Ozempic 0.25 or 0.5 mg/dose comes in packs of one 1.5 mL pens (total of 1.5 mL). Quantity is typically:
    • 1.5 mL per 28 days (Note initiation is technically 42 days but most plans pay for only 34 or less day supplies)
    • 4.5 mL per 90 days
  • Ozempic 1 mg/dose comes in packs of two 1.5 mL pens (total of 3 mL). Quantity is typically:
    • 3 mL per 28 days
    • 9 mL per 84 days
  • Qsymia - 30 day for $98
    • New Patient Pack
      • Qsymia 3.75 mg/23 mg - 14-day
      • Qsymia 7.5 mg/46 mg 14 + 30 - 30-day $98
    • Titration Pack $98
      • Qsymia 11.25 mg/69 mg - 14-day
      • Qsymia 15 mg/92 mg 14 + 30 - 30-day
  • Xifaxin

6.15 Medication Resources

6.16 Medication thoughts relating to homeless persons/street

  • Albuterol
    • Enhances effects of crack cocaine
  • Benzodiazepines
    • Sought for calming and sedation effects
  • B-blockers and clonidine
    • Discontinuation can result in rebound HTN
    • B-blockers can exacerbate depression at initiation
    • Clonidine can prolong effects of heroin and other opioids
  • Buproprion
    • Can be pulverized and snorted to get high
  • Cough syrup
    • Promethazine and codeine - called lean used with marijuana
  • Calcium channel blockers, COX-2 inhibitors, NSAIDs, and DM meds
    • May exacerbate heart failure
  • Diuretics
    • Can exacerbate dehydration
  • Anticholinergic meds with diuretics
    • Can cause hyperpyrexia
  • Drugs metabolized in liver
    • Caution in those with hepatitis and alcohol use
  • Psuedoephedrine
    • Can be used for methamphetamine
  • Quetiapine
    • Enhances the effect of heroin
  • Statins
    • Can worsen outcomes in those with elevated liver tranaminases, or hepatitis


  • AFP Vol 89 No 8 Apr 2014

6.17 Medicine Reconciliation

Medication errors represent the most common patient safety error.

  • (Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients.JAMA.1997;277:307–11.)

More than 40 percent of medication errors are believed to result from inadequate reconciliation in handoffs during admission, transfer, and discharge of patients. Of these errors, about 20 percent are believed to result in harm.

  • (Rozich JD, Howard RJ, Justeson JM, et al. Patient safety standardization as a mechanism to improve safety in health care.Jt Comm J Qual Saf.2004;30(1):5–14.)

6.18 Metformin Tips   edit

  • Take with a meal to reduce the risk of stomach upset. Once-daily dosages should be taken with the evening meal.
  • Metformin is usually started at a low dosage before being titrated up. Dosages may vary between individuals.
  • Splitting dosages throughout the day (rather than taking a single dose) may improve gastric side effects such as nausea, diarrhea, and indigestion.
  • Swallow slow-release tablets whole; do not crush, break, or chew.
  • Do not drink large amounts of alcohol or drink it daily while taking metformin because this may increase your risk of lactic acidosis.
  • Monitoring of blood sugars and other regular laboratory tests including kidney function are needed.
  • May need to be temporarily discontinued before undergoing investigations requiring contrast media, or if you become dehydrated.
  • The outer case of some slow-release metformin tablets may be visible in the stools; this does not mean the drug has not been absorbed.
  • Ensure you are educated about the importance of diet and exercise in the management of type 2 diabetes because it is important to use lifestyle measures to improve your condition in addition to medications.
  • Tell your doctor if you become unwell with severe vomiting, diarrhea, or a fever because these types of illnesses may lead to severe dehydration and you may need to temporarily stop metformin. Also, talk to your doctor if you develop cold hands or feet, muscle pain, dizziness, a slow heartbeat, have trouble breathing, stomach pains, or severe nausea or vomiting.
  • Talk to your doctor or pharmacist before taking any other medications, including those bought over-the-counter, to check that they will be compatible with metformin.
  • Tell your doctor if you are pregnant or intend to become pregnant while taking metformin. It is not known how metformin affects the fetus or a breastfed infant.

6.19 Methotrexate

See also:

Major toxic effects:

  • hepatic
  • pulmonary
  • renal
  • bone marrow abnormalities

Minor toxic effects:

  • stomatitis
  • malaise
  • nausea
  • diarrhea
  • headaches
  • mild alopecia

Toxic effects are common but respond to folate supplementation:

  • Folate supplementation with 1 mg daily or 7 mg once weekly should be considered for all patients
  • Avoid taking the folate dose on the same day as the methotrexate dose.

Methotrexate administration:

  • once weekly as a single dose or in divided doses given over a 24-hour period.

To reduce the incidence of major toxic effects, methotrexate should never be given in daily doses.

Relative contraindications:

  • renal dysfunction
    • contraindicated in any patient with a creatinine clearance of less than 50 mL per minute
  • liver disease
  • active infectious disease
  • excessive alcohol consumption

Both women and men of reproductive age should use birth control during methotrexate therapy.

Potential drug interactions:

  • salicylates
  • nonsteroidal anti-inflammatory drugs
  • Trimethoprim/sulfamethoxazole (Bactrim, Septra) can enhance the cytotoxic effects of methotrexate because trimethoprim is an antifolate reductase inhibitor.
  • Other drugs that may displace methotrexate from protein binding sites include barbiturates, phenytoin, retinoids, oral sulfonylureas and tetracycline.

A premethotrexate evaluation is important to ensure proper patient selection for this effective but potentially toxic drug.

  • A baseline chest radiograph is recommended to screen for pre-existing lung disease
  • Complete blood count with differential
  • Platelet count
  • Serum creatinine
  • Blood urea nitrogen
  • Urinalysis
  • Liver function tests
  • Serum bilirubin
  • Serum albumin
  • Hepatitis A, B, and C serologies
  • HIV risk assessment/testing, if appropriate Chest radiograph

Risk Factors for Potential Hepatotoxicity

  • Excessive alcohol intake
  • Elevated serum aspartate aminotransferase levels
  • Chronic hepatitis B or C
  • Increased age
  • History of liver disease
  • History of intravenous drug abuse
  • History of inheritable liver disease
  • Diabetes (insulin enhances cytotoxicity of methotrexate)
  • Obesity (third spacing of methotrexate)
  • History of significant exposure to known hepatotoxic drugs

Patient Education Guide for the Physician

  • Tell patients to avoid alcohol including beer, wine and hard liquor because of the increased risk of liver disease.
  • Inform male and female patients of reproductive age that they should practice appropriate birth control (abstinence, oral contraceptives or condom plus foam, etc.).
  • Discuss potential drug interactions, especially salicylates and over-the-counter NSAIDs.
  • Tell patients not to start or stop an NSAID without first checking with you.
  • Tell patients to call immediately if they develop signs of infection (immunosuppression), coughing or shortness of breath (pulmonary toxicity) or unusual bleeding (liver or bone marrow suppression).
  • Emphasize the weekly dose and warn patients that daily dosing of this drug is fatal. If an accidental overdose occurs, an antidote can be used (leucovorin rescue).
  • Be sure that patients fully understand the need for close follow-up and monitoring for toxicity.
  • The most important side effects to mention are loss of appetite, nausea (rarely vomiting), diarrhea and stomatitis. There is also the potential for serious side effects; hepatotoxicity, pulmonary toxicity, myelosuppression and nephrotoxicity.
  • Warn patients about the potential development of malignancy, specifically lymphoma.

Monitor for:

  • Hepatotoxicity
    • Monitoring of serum aspartate aminotransferase (AST) and serum albumin levels is recommended for all patients receiving methotrexate.8 These laboratory assessments were correlated with serious liver disorders in a mail survey of rheumatologists.
    • Approximately 30 percent of all patients on long-term therapy have AST elevation.
    • Values exceeding two times the normal level for a period of one month warrant discontinuation of therapy
  • Nephrotoxicity
  • Pulminary toxicity
    • Symptoms include persistent dry, nonproductive cough, dyspnea or both
    • Radiograph abnormalities occurring with methotrexate therapy include interstitial and alveolar infiltrates, hilar adenopathy and pleural effusion, occasionally progressing to fibrosis, scarring and honeycomb changes
  • Bone marrow toxicity
    • Monitoring signs of myelosuppression can reduce complications such as severe anemia, potential bleeding and sepsis.8 Patients with aplastic anemia need to be treated with leucovorin rescue.
  • Labs:
    • LFTs
    • CBC
    • CMP


  • Am Fam Physician. 2000 Oct 1;62(7):1607-1612.

6.20 Metoprolol

Immediate release (metoprolol tartrate):

  • Oral: 25 to 100 mg twice daily (AHA/ACC/HRS [January 2014])
  • More frequent dosing is appropriate in the acute setting while titrating to a maintenance dose.
  • Migraine prophylaxis (50-100mg bid)
  • HTN

Extended release (metoprolol succinate):

  • Oral: 50 to 400 mg once daily (AHA/ACC/HRS [January 2014]).
    • PVCs
    • Hyperthyroidism
    • HTN
    • CHF

6.21 My (Formulary) Goto/Easy medication choices

  • Emergency Headache Abortive
    • Phenergan / Compazine
  • Monophasic ocp
    • Sprintec-28
  • Otitis Externa
    • Neomycin - polymyxin B - hydrocortisone otic
    • 10 ml
    • 5 gtts in affected ear every 6-8 hours for 10 days
  • Severe Contact Dermatitis
    • 2 shot solution:
      • Decadron + DepoMedrol
  • Rosacea
    • Metronidazole topical gel 0.75% 45 g AAA bid ($30-40)

6.22 My Medication Rules

Overall medication thoughts:

  1. Less is More
  2. Start low, go slow

No go's:

  • Do not use Niacin
    • Does not significantly reduce the risk of major vascular events but does increase the risk of serious adverse events. (…there were significant and excess adverse events related to gastrointestinal, musculoskeletal, infectious, and bleeding complications, as well as substantial excess adverse events related to loss of glycemic control among persons with diabetes and new-onset diabetes among persons without diabetes at baseline. Of great concern was a 9% increase in the risk of death (number needed to harm, 200) associated with niacin–laropiprant that was of borderline statistical significance (P=0.08).)
    • "On the basis of the weight of available evidence showing net clinical harm, niacin must be considered to have an unacceptable toxicity profile for the majority of patients, and it should not be used routinely"
    • (Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients; The HPS2-THRIVE Collaborative Group; N Engl J Med 2014; 371:203-212)
    • (Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients; The Niacin and HDL Cholesterol — Time to Face Facts; Donald M. Lloyd-Jones, M.D.; N Engl J Med 2014; 371:271-273)
  • Do not use Xanax
  • Do not prescribe Tessalon Perles - there is evidence they do not work
  • Do not use TZDs
    • Associated with weight gain, heart failure, and edema
  • Avoid Fioricet
  • Do not recommend Fish Oil for Dyslipidemia
  • Do not suggest or recommend phenylephrine - It just doesn't work


  • The best SSRI's are Lexapro (escitalopram) and Zoloft (sertraline)
  • Women with depression and anxiety get Effexor (venlafaxine) or Wellbutrin (bupropion)
  • Add Wellbutrin before maxing SSRI
  • Consider propranolol of hydroxyzine instead of benzos for an executive sedative maintaining cognitive function

Specific Meds:

  • HCTZ - only use the 25mg dose (12.5 doesn't do anything and 50mg just adds side effects)
  • Melatonin - Use 3-4 hrs before bedtime in conjunction with sleep hygeine
  • Statins - Stop at age 90 or if life expectancy is <10 years
  • PPIs - Use short term (4-8 wks) only
    • PPIs Associated with Increased Risk for Chronic Kidney Disease (20-50% increased risk)
    • (JAMA Intern Med. Published online January 11, 2016. 10.1001/jamainternmed.2015.7193)

Therapies I like:

  • Physical Therapy (SOR A)
  • Flonase (SOR A)
  • Hydroxyzine
  • ASA for migraine abortive (SOR A)
  • Pseudoephedrine for congestion (LOE A)
  • Every elderly patient should have a dog


  • If you use Abx for acute bacterial sinusitis, use right drug and dose (Augmentin 875mg bid and for >65yo, hospitalized, recent Abx use: use 2g bid)
  • Allergic rhinitis - use flonase (or similar) using 2 sprays with opposite hand into nare once daily while looking down for proper placement

6.23 On Supplements

Instead of unnecessarily taking vitamins, increase the proportion of plant foods in your diet, where required vitamins and minerals are found.

Vitamin supplements are not entirely benign!

People with vitamin deficiencies do need to supplement, but do not take vitamins to prevent chronic disease.

Here is a short summary of what the current medical scientific evidence demonstrates:

Beneficial effects: - Folic acid positively affects total cardiovascular disease - Folic acid and B-vitamins positively affect stroke

Harmful effects: - Vitamin B3 (or niacin) might increase all-cause mortality - Antioxidant mixtures did not appear to benefit cardiovascular disease but might increase all-cause mortality. - Beta-carotene (vitamin A) has been linked to cancer in smokers - Vitamin E has been linked to prostate cancer

Mixed effects: - Vitamin D: uncertain if there is an all-cause mortality effect - Further studies on multivitamins (most commonly used supplement) are needed because of the marginal benefit seen in this study

6.24 Oral Adverse Reactions of the 10 Most Commonly Filled Prescription Medications in 2019

Drug name

  1. Levothyroxine
    • Vomiting, dysgeusia (< 1%)
  2. Lisinopril
    • Dysgeusia (≥ 1%), Stevens-Johnson syndrome (≥ 1%), toxic epidermal necrolysis (≥ 1%), xerostomia (≥ 1%), angioedema (< 1%)
  3. Atorvastatin (Lipitor)
    • Anaphylaxis (< 1%), angioedema (< 1%), dysgeusia (< 1%), erythema multiforme (< 1%), hypoesthesia/paresthesia (< 1%), Stevens-Johnson syndrome (< 1%), toxic epidermal necrolysis (< 1%), vomiting (< 1%)
  4. Metformin
    • Infection (21%), nausea and vomiting (7% to 26%), taste disorder (1% to 10%)
  5. Amlodipine (Norvasc)
    • Angioedema (< 1%), dysphagia (< 1%), erythema multiforme (< 1%), gingival enlargement (< 1%), hypersensitivity reaction (< 1%), hypoesthesia/paresthesia (< 1%), increased thirst (< 1%), vomiting (< 1%), xerostomia (< 1%)
  6. Metoprolol
    • Xerostomia (1%), vomiting (frequency undefined), paresthesia (< 1%), taste disorder (< 1%)
  7. Omeprazole (Prilosec)
    • Vomiting (3%), acid regurgitation (2%), allergic reactions/anaphylaxis/hypersensitivity reaction (< 1%), angioedema (< 1%), dysgeusia (< 1%), erythema multiforme (< 1%), Stevens-Johnson syndrome (< 1%), tongue mucosal atrophy (< 1%), toxic epidermal necrolysis (< 1%), xerostomia (< 1%)
  8. Simvastatin (Zocor)
    • Anaphylaxis (< 1%), angioedema (< 1%), dry mucous membranes (< 1%), dysgeusia (< 1%), erythema multiforme (< 1%), hypersensitivity reaction (< 1%), paresthesia (< 1%), Stevens-Johnson syndrome (< 1%), toxic epidermal necrolysis (< 1%), vomiting (< 1%)
  9. Losartan (Cozaar)
    • Paresthesia (< 2%), vomiting (< 2%), anaphylaxis (< 1%), angioedema (< 1%), dysgeusia (< 1%), lip edema (< 1%), tongue edema (< 1%)
  10. Albuterol
    • Application site reaction (6%), oropharyngeal pain (≤ 5%), unpleasant taste at inhalation site (4%), vomiting (3% to 7%), hypersensitivity reaction (3% to 6%), glossitis (< 3%), infection (< 3%), oropharyngeal edema (< 3%), xerostomia (< 3%), anaphylaxis (< 1%), angioedema (< 1%), dysgeusia (< 1%), oropharyngeal irritation (< 1%), tongue ulcer (< 1%)


  • AFP Nov 2020 Vol 102 No 10

6.25 OTC Symptom Management   edit

6.25.1 Allergies

  • Flonase 2 sprays per nostril daily

6.25.2 Congestion

  • Sudafed 30-60 mg every 4 hours

6.25.3 Cough

  • Dextromethorphan 15-30 mg every 6 hours (can be a pill or cough syrup)

6.25.4 Mucous (thick) and/or Post-Nasal Drip

  • Guaifenessin 100-400 mg every 4 hours

6.25.5 Sore throats

  • Ibuprofen 400 mg every 6 hours
  • Lozenges with benzocaine in them

6.26 Placebo Effects

  • Patients with knee arthritis receiving either established orthopedic surgeries or a placebo "sham" surgery showed the same level of improvements in pain and function over 24 months in a clinical trial published in the New England Journal of Medicine.
    • Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, Hollingsworth JC, Ashton CM, Wray NP. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002 Jul 11;347(2):81-8. doi: 10.1056
  • In a massive review of treatment outcome data reported in the British Medical Journal —including data from 232 clinical trials and over 73,000 participants — antidepressants were no more effective than placebo treatments for 85% of participants.
    • Stone, M. B., Yaseen, Z. S., Miller, B. J., Richardville, K., Kalaria, S. N., & Kirsch, I. (2022). Response to acute monotherapy for major depressive disorder in randomized, placebo-controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ, 378(e067606). bmj-2021-067606
  • In an October 2022 paper published in JAMA, participants with chronic low back pain receiving a form of placebo spinal column stimulation showed the same level of improvement in pain disability as participants receiving cutting edge high frequency spinal column stimulation.
    • Hara S, Andresen H, Solheim O, et al. Effect of Spinal Cord Burst Stimulation vs Placebo Stimulation on Disability in Patients With Chronic Radicular Pain After Lumbar Spine Surgery: A Randomized Clinical Trial. JAMA. 2022;328(15):1506–1514. 10.1001/jama.2022.18231
  • A 2018 review of 17 studies examining placebo effects related to caffeine found that 13 out of the 17 studies demonstrated positive caffeine expectation effects — across outcomes ranging from physical endurance, strength performance, and cognitive function — with the size of these placebo/expectation effects often approaching the effects of direct caffeine consumption.
    • Shabir A, Hooton A, Tallis J, F Higgins M. The Influence of Caffeine Expectancies on Sport, Exercise, and Cognitive Performance. Nutrients. 2018 Oct 17;10(10):1528. doi: 10.3390/nu10101528.
  • Participants consuming a milkshake labelled as "indulgent" showed a significantly larger change in the level of their appetite hormone, ghrelin, than participants consuming a milkshake labelled "sensible", despite the two shakes containing identical calories and ingredients.
    • Crum AJ, Corbin WR, Brownell KD, Salovey P. Mind over milkshakes: mindsets, not just nutrients, determine ghrelin response. Health Psychol. 2011 Jul;30(4):424-9; discussion 430-1. doi: 10.1037/a0023467.
  • researchers have administered naloxone — a drug that blocks the effects of opioids — to participants, showing that the naloxone blocks both the effects of opioid medicine and the effects of opioid placebos. This means that expectations about the effects of the opioid medicine alone — absent any active opioid medicine — can directly trigger internal analgesic biological activity.
    • Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci. 1999 Jan 1;19(1):484-94. doi: 10.1523/JNEUROSCI.19-01-00484.1999.

6.27 Pregnancy

  • Nausea/Vomiting:
    • Likely beneficial:
      • Acupressure
      • Ginger
      • Pyridoxine
    • Unknown effectiveness:
      • Acupressure
      • Acupuncture
      • Corticosteroids
      • Prochlorperazine
      • Promethazine


  • AFP Vol 92, No6 Sep 2015

6.28 Probiotics

Conditions and evidence:

  • Irritable bowel syndrome
    • Significantly decrease IBS symptoms, abdominal pain, bloating, flatulence
    • Use Lactobacillus and Bifidobacterium species for 4-6 weeks
    • LOE A
  • Inflammatory bowel disease
    • Induce and maintain remission in ulcerative colitis - NO benefit for Crohn's disease
    • Use Lactobacillus and Bifidobacterium species for 8-12 weeks or longer
    • LOE A
  • Antibiotic associated diarrhea
    • Reduce risk of AAD
    • Use Lactobacillus alone or with Bifidobacterium species for 7 days or
    • Use Saccharomyces boulardii for 5-7 days
    • LOE A
  • Acute infectious diarrhea
    • Shorten duration and reduce severity
    • Use L casei rhamnosus for 5-7 days or
    • Use Saccharomyces boulardii for 5-7 days
    • LOE A
  • Travelor's diarrhea
    • Prevent up to 85% of cases
    • Use Saccharomyces boulardii for 3 weeks or
    • Use Lactobacillus alone or with Bifidobacterium species for 3 weeks
    • LOE B
  • Eczema
    • May prevent in first 2 years of life
    • Galacto- and fructo-oligosaccharide (9:1 ratio) and acidic oligosaccharide in infants
    • Falacto- and fructo-oligosaccharide (9:1 ratio) in infants
    • LOE B
  • Diabetes
    • Significant reduction in at least 1 of 6 parameters of glycemic control
    • Lactobacillus alone or with Bifidobacterium species for 6-8 weeks
    • LOE C

JFP Vol 65 No 1 Jan 2016

Conditions with Strength of Recommendation (SOR) A:

  • Acute Infectious Diarrhea
    • Shortened duration by approx 24hrs
    • Reduced risk of diarrhea lasting longer than 4 days
  • Travelers Diarrhea
    • Effectively prevented traveler's diarrhea in US and European travelers who visited a variety of vacation spots
  • Antibiotic-associated diarrhea
    • Effective for treating and preventing antibiotic-associated diarrhea - NNT=13
    • No significant decrease in AAD rates in hospitalized patients over age 65 
  • Clostridium difficile-associated diarrhea

Conditions with Strength of Recommendation (SOR) B:

  • DO NOT use for preventing or treating Crohn's disease or Ulcerative Colitis
    • Multiple meta-analyses with no benefit
  • Consider the probiotic Bifidobacterium bifidum MIMBb75 for patients with irritable bowel disease
    • NNT=4
    • In RCTs, probiotic supplements - but not yogurt containing probiotics - reduced IBS symptoms

Ref: J Fam Pract. 2015 Mar;64(3):151-155.

6.29 Procedural sedation and analgesia

Procedural sedation and analgesia (PSA) involves the use of short-acting analgesic and sedative medications to enable clinicians to perform procedures, while monitoring the patient closely for potential adverse effects. This process was previously (and inappropriately) termed "conscious sedation." (see 'Definitions' above.PSA may be used for any procedure in which a patient's pain or anxiety may be excessive and may impede performance. There are no absolute contraindications to PSA. Relative contraindications include: older age, significant medical comorbidities, and signs of a difficult airway. Whether the patient recently ate should be considered before performing PSA, although this may not increase aspiration risk. (See 'Indications' above and 'Contraindications and precautions' above.)The number of clinicians needed to perform PSA and the procedure safely may vary according to the patient and the procedure. In most cases, one clinician performs the procedure while another (usually a nurse) administers the sedative agents and monitors and records the patient's vital signs and clinical status. Whenever possible, we suggest that this minimum standard be met. (See 'Prerequisites and personnel' above.)Proper monitoring during PSA is crucial. The patient's blood pressure, heart rate, and respiratory rate should be measured at frequent, regular intervals; oxygen saturation (SaO2), end-tidal carbon dioxide level (EtCO2), and cardiac rhythm should be monitored continuously. (See 'Monitoring' above.)Serious complications attributable to PSA rarely occur. Significant respiratory compromise develops in less than one percent of cases. Adverse outcomes may include respiratory depression with hypoxia or hypercarbia, cardiovascular instability, vomiting and aspiration, and inadequate sedation preventing completion of the procedure. All equipment and medications necessary for airway management should be at the bedside during PSA. (See 'Complications' above and 'Equipment' above.)Ideal drugs for PSA have a rapid onset and short duration of action, maintain hemodynamic stability, and do not cause major side effects. Several medications are commonly used and no single drug is ideal for all situations (table 2). Medications used for PSA are discussed in the text. (See 'Medications' above.)PSA is most often performed in patients without major comorbidities or hemodynamic instability. In such patients, we suggest that PSA be performed using propofol (Grade 2B). Etomidate may also be used. The relative advantages and disadvantages of each drug are discussed in the text. (See 'Patients without increased risk' above.)Older patients are at increased risk of complications during PSA. Therefore, sedatives administered to older patients for PSA, regardless of the agent, should be given using a lower starting dose, slower rates of administration, and less frequent dosing intervals. (See 'Elderly patients' above.)In some circumstances, clinicians, after carefully considering the relative risks and benefits, may elect to perform PSA in patients at some increased risk of complications. In patients at risk of hypotension, we suggest that either etomidate or ketamine be used for PSA (Grade 2C). In patients who may have a potentially difficult airway or have compromised respiratory function, we suggest that ketamine be used for PSA (Grade 2C). (See 'Patients at increased risk' above.)Criteria for safe discharge following PSA are described in the text. (See 'Discharge criteria' above.)

  • Fentanyl and Midazolam:
    • One reasonable approach to dosing these medications when they are used together is as follows:Give midazolam first: 0.02 mg/kg (maximum 2 mg)Wait two minutes and observe patient response; give second dose of midazolam if necessaryGive fentanyl: 0.5 mcg/kgObserve patient; may repeat fentanyl dose every two minutes as necessary; titrate to effectUse smaller doses and longer intervals between doses in the elderly and patients with compromised hepatic or renal function


  • Propofol is given by slow injection in an initial loading dose of 0.5 to 1 mg/kg IV, followed by doses of 0.5 mg/kg IV every three to five minutes as necessary until the appropriate level of sedation is achieved.  It takes effect within approximately 40 seconds and its duration of action is approximately six minutes.  Propofol > Etomidate as no myoclonus so likely more successful procedures.
    • A sedative and amnestic but No analgesia
    • Contains egg and soy - watch with allergies
  • Etomidate is given IV over 30 to 60 seconds in doses of 0.1 to 0.15 mg/kg, less than the dose used for rapid sequence intubation. It can be redosed approximately every three to five minutes as needed. Etomidate's onset of action is almost immediate and its duration of effect is 5 to 15 minutes
    • Myoclonus
    • No analgesia
  • Midazolam is usually given IV over one to two minutes in doses of 0.02 to 0.03 mg/kg. Often in adults, midazolam is given 0.5 or 1 mg at a time and titrated to effect. No single dose should exceed 2.5 mg. Repeat doses may be given every two to five minutes as necessary.  Its time of onset is two to five minutes and its duration of action is 30 to 60 minutes
    • Anxiolysis and amnesia but No analgesia
  • Fentanyl is usually given by slow IV push in doses of 0.5 to 1 mcg/kg every two minutes until an appropriate level of sedation and analgesia is achieved. The maximum total dose is generally 5 mcg/kg or approximately 250 mcg, but higher doses may be needed in some instances.  It has 75 to 125 times the potency of morphine, a rapid onset of action (two to three minutes), and a short duration of effect (30 to 60 minutes), but has no amnestic properties.
  • Ketamine is generally given IV to adults, which enables immediate onset, but can be given intramuscularly. The duration of effect is 10 to 20 minutes. For PSA in adults, a dose of 1 to 2 mg/kg is given IV over one to two minutes. Doses of 0.25 to 0.5 mg/kg may be repeated every five to ten minutes thereafter.
    • Because of its rapid onset, relatively short duration of action, and excellent sedative and analgesic properties, it is often used for brief, painful procedures such as fracture reduction or laceration repair.
    • It produces a trance-like state and provides sedation, analgesia, and amnesia, while preserving upper airway muscle tone, airway protective reflexes, and spontaneous breathing
    • Emergence reactions


  • Sedatives administered to older patients for PSA, regardless of the agent, should be given at a lower starting dose with slower rates of administration and less frequent dosing intervals. In elderly patients without major comorbidities or hemodynamic instability, it may be best to perform PSA using an ultrashort-acting sedative such as propofol. Procedures in elderly patients with major comorbidities are probably best performed in the operating room.

6.30 Protocol for radiocontrast in high-risk patients

Pretreatment (optional):

  • Prednisone 50mg po at 13hrs, 7hrs, and 1hr before medium injection
  • Diphenhydramine 50mg IV, IM, or PO 1 hr before medium injection


  • Methylprednisolone 40mg IV or hydrocortisone 200mg IV immediately and then every 4 hours until contrast medium injetion
  • PLUS diphenhydramine 50mg IV 1 hr before contrast injection
  • NOTE: For IV steoids to be effective, administer less than 4-6hrs before medium injection


  • Consultant Oct 2017

6.31 Publix Save on Medications

$7.50/3 mo

Table 12: Heart Health/Cardiovascular
Medication Strength Quantity
clonidine 0.1 mg, 0.2 mg, or 0.3 mg tablet 90
clopidogrel 75 mg tablet 90
furosemide 20 mg, 40 mg, or 80 mg tablet 90
hydralazine 10 mg, 25 mg, 50 mg, or 100 mg tablet 90
hydrochlorothiazide 12.5 mg capsule; 25 mg or 50 mg tablet 90
jantoven (warfarin) 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg; 7.5 mg, or 10 mg tablet 90
metoprolol tartrate 25 mg, 50 mg, or 100 mg tablet 180
triamterene-HCTZ 37.5–25 mg tablets or capsules; or 75–50 mg tablets 90
Table 13: Diabetes
Medication Strength Quantity
glimepiride 1 mg, 2 mg, or 4 mg tablet 90
Table 14: Cholesterol
Medication Strength Quantity
simvastatin 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg tablet 90
Table 15: Mental Health
Medication Strength Quantity
amitriptyline HCl 10 mg or 25 mg tablet 90
buspirone 5 mg, 10 mg, or 15 mg tablet 180
sertraline 25 mg, 50 mg, or 100 mg tablet 90
Table 16: Seizure Disorders
Medication Strength Quantity
topiramate 25 mg, 50 mg, 100 mg, or 200 mg tablet 180
Table 17: Parkinson's Disease
Medication Strength Quantity
ropinirole 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg tablet 180
Table 18: Alzheimer's Disease
Medication Strength Quantity
donepezil 5 mg or 10 mg tablet 90
Table 19: Osteoporosis
Medication Strength Quantity
alendronate 35 mg or 70 mg tablet 12
Table 20: Gout
Medication Strength Quantity
allopurinol 100 mg or 300 mg tablet 90
Table 21: Arthritis/Pain
Medication Strength Quantity
meloxicam 7.5 mg or 15 mg tablet 90
Table 22: Gastrointestinal
Medication Strength Quantity
omeprazole 20 mg capsule 90
Table 23: Asthma & Allergies
Medication Strength Quantity
cetirizine HCl 5 mg or 10 mg tablet 90
Table 24: Men's Health
Medication Strength Quantity
tamsulosin 0.4 mg capsule 90
Table 25: Women's Health
Medication Strength Quantity
estradiol 0.5 mg, 1 mg, or 2 mg tablet 90

6.31.1 Publix Free Medications


Table 26: Heart Health/Cardiovascular
Medication Strength Quantity
amlodipine 2.5 mg, 5 mg, 10 mg 90
lisinopril all 180
Table 27: Diabetes
Medication Strength Quantity
metformin 850 mg 270
metformin 1000 mg 225
Table 28: Antibiotics
SMZ-TMP (tablets)
Penicilliin VK

6.32 Sick call med list

  • 1-2-3 mouthwash
  • Acetaminophen
  • Albuterol inhaler
  • Amoxicillin 500mg
  • Augmentin 1%
  • Azithromycin 250mg
  • Bacitracin Oint
  • Bacitracin Opth Oint 3.5gm
  • Benzoyl peroxide gel 5%
  • Biaxin XL 500mg
  • Bismuth subslicylate
  • Calamine lotion
  • Calcium 600mg
  • Cepacol lozenge
  • Ciprofloxacin opth oint 3%
  • Clindamycin 150mg
  • Clotrimazole fungal cream 1%
  • Dibucain oint 1oz
  • Diphenhydramine 25mg
  • Docusate 100mg
  • Doxycycline 100mg
  • Esomeprazole 20mg
  • Fiber-lax 500mg
  • Fluticasone 50mcg
  • Guaifenesine DM 10mg/5ml
  • Hydrocortisone cream 1%
  • Hydrocortisone lotion 1%
  • Hydrocortisone suppository 25mg
  • Hydroxyzine 25mg
  • Ibuprofen 800mg
  • Indomethacin 25mg
  • Loperamide 2mg
  • Loratadine 10mg
  • Lubricant eye drops 1%
  • Mucinex D 600mg
  • Mupirocin oint 2%
  • Muscle rub
  • Naphcon A Ophth Sol
  • Methocarbamol 500mg
  • Naproxen 500mg
  • Nergesic forte
  • Ondansetron-ODT 4mg
  • Oxymetazoline nasal spray 0.05%
  • Prednisone 20mg
  • Proctofoam HC 10gm
  • Promethazine 25mg
  • Psuedoephedrine 30mg
  • Saline nasal spray
  • SMZ-TMP DS 800/160mg
  • Tolnaftate antifungal powder 1%
  • Triamcinolone cream 1.10%
  • Zinc oxide

6.33 Special references

Chronic use of NSAIDs and COX-2 inhibitors:

  • Safe to use in older adults with arthritis and no history of cardiovascular disease.
  • NSAIDs are just as safe as COX-2 inhibitors.

(European Society of Cardiology. SCOT study quells concerns about NSAID safety [press release]. Aug 31, 2015)

Fish Oil:

  • Does not decrease total mortality, cardiovascular events, or cancer incidence
  • Should not be recommended to decrease dyslipidemia
  • SOR A

(Clinical Inquiry; AFP Vol 89 No 4 Feb 2014)

6.34 Topical Medications

6.35 Vitamin D

Effects of Vitamin D Supplementation on Medical Conditions Conditions Patient-oriented effects

Adverse pregnancy outcomes28–30

Possible increase in birth weight, no other definitive maternal or neonatal benefits; prenatal vitamins include recommended amounts of vitamin D


Does not improve control of asthma or enhancement of corticosteroid responsiveness

Chronic obstructive pulmonary disease exacerbation34–36

No therapeutic effect overall; two trials showed benefit in a subgroup of patients deficient in vitamin D


No therapeutic effect

Diabetes mellitus42–45

Does not prevent or help treat glucose intolerance


Does not increase energy in postmenopausal women or patients with chronic fatigue syndrome

Heart failure49,50

Small increase in ejection fraction, no increase in walking distance


Does not lower blood pressure or prevent hypertension

Menopausal symptoms27,46,47

No therapeutic effect in Women's Health Initiative study

Nonspecific musculoskeletal pain53–55

Does not decrease symptoms


No improvement in pain or cartilage loss

Upper respiratory tract infection58–60

No effect on incidence of infection

6.36 Vitamins and Supplements


  • 23,000 ED visits/yr are result of adverse events related to dietary supplements

Guideline based recommendations:

Who Population Supplement
Am Thyroid Assoc Preg women, planning to be, breastfeeding Iodine 150ug/d
Am Acad Ped Breastfeeding women Iodine 150ug/d
  Breastfed and part breastfed infants Vit D 400IU/d
  Children <1yo and adolescents Vit D 600IU/d
Am Geri Soc Community dwelling adults >65yo Vit D 1000IU/d and Ca++
Endo Soc Adults 50-70yo with 25-OH Vit D <30 Vit D 1500-2000IU/d
Nat Osteopor Found Adults <50yo Vit D 400-800IU/d
  Adults >50yo Vit D 800-1000IU/d
  Women <50yo Ca++ 1000mg/d
  Women >50yo Ca++ 1200mg/d
  Men <70yo Ca++ 1000mg/d
  Men >70yo Ca++ 1200mg/d
WHO Pregnant women Iron 30-60mg/d; folic acid 400ug/d
Am Acad of Fam Phys Adults >50yo and strict vegetarians Vit B12 1mg/d

Other effects:

  • Omega-3 fatty acid supplementation
    • No effect on major adverse cardiac events, all-cause mortality, sudden cardiac death, coronary artery revascularization, or hypertension (SOR: A)


  • AFP Vol 97 No 9 May 2018
  • Consultant Apr 2016

6.36.1 Vitamin B12 deficiency

Causes of B12 deficiency:

  • Dietary Deficiency
    • strict vegan diet, malnutrition, reduced intake of animal products
  • Decreased Intrinsic Factor Production
    • pernicious anemia, gastrectomy, atrophic gastritis, H. pylori
  • Decreased ileal B12 absorption
    • crohn's disease, celiac disease, tuberculosis of intestine, ileal resection
  • Competition for B12 in gut
    • alcoholism, bacterial overgrowth, parasites – giardiasis/fish tapeworm
  • Increased B12 requirements
    • hemolysis, HIV infection
  • Medications
    • metformin, colchicine, cholestyramine, slow-release KCL
  • Inherited/Autoimmune diseases
    • Imerslund-Grasbeck syndrome (intrinsic factor receptor defect), pernicious anemia, transcobalamin deficiency, cobalamin mutation (C-G-1 gene), cbID inborn error of cobalamin metabolism
  • Other
    • pancreatic insufficiency, Zollinger-Ellison syndrome, Nitrous Oxide abuse


6.36.2 Vitamin D

Conditions and Patient Oriented Effects of Vitamin D Supplementation

  • Adverse pregnancy outcomes:
    • Possible increase in birth weight, no other definitive maternal or neonatal benefits; prenatal vitamins include recommended amounts of vitamin D
  • Asthma:
    • Does not improve control of asthma or enhancement of corticosteroid responsiveness
  • COPD Exacerbation:
    • No therapeutic effect overall; Possible benefit from small trials in those deficient in Vit D
  • Depression:
    • No therapeutic effect
  • Diabetes mellitus:
    • Does not prevent or help treat glucose intolerance
  • Fatigue:
    • Does not increase energy in postmenopausal women or in patients with chronic fatigue syndrome
  • Heart failure:
    • Small increase in ejection fraction, no increase in walking distance
  • Hypertension:
    • Does not lower blood pressure or prevent hypertension
  • Menopausal symptoms:
    • No therapeutic effect in Women's Health Initiative study
  • Nonspecific musculoskeletal pain:
    • Does not decrease symptoms
  • Osteoarthritis:
    • No improvement in pain or cartilage loss
  • Upper respiratory infection:
    • No effect on incidence of infection


  • AFP Vol 97 No 4 Feb 2018

6.36.3 Vitamin D dosing & Falls in elderly

What is known:

  • Vitamin D deficiency linked to decrease muscle mass and increased falls/fractures.
  • Vitamin D synthesis in skin decreases with age.
  • Vitamin D with calcium widely acknowledged to reduce risk of falls in elderly

Daily dosing guidelines

  • American Geriatric Society and Institute of Medicine Guidelines recommend supplement (1000IU or higher) to achieve daily total of 4000 IU daily of Vitamin D in elderly patients with recent fall history.
  • Some critics argue the 4000IU dose may be too high and recommend 800-2000 IU/day.


7 Endocrine

7.1 Diabetes

7.1.1 DKA ad HHS Management


  • Blood glucose >250 mg/dL
  • Arterial pH <7.3
  • Bicarbonate level 15 mEq/L
  • Moderate ketonuria or ketonemia

IV Fluids:

  • Determine hydration status
    • Severe: NS at 1L/hr
    • Cardiogenic shock: Hemodynamic monitoring/pressors
    • Mild: Evaluate corrected sodium level
      • Normal/High
        • 0.45% saline - 250 to 500 mL/hr depending on hydration status
      • Low
        • NS - 250 to 500 mL/hr depending on hydration status
      • When serum glucose reaches 200 mg/dL (DKA) or 300 mg/dL (HHS), switch to 5% dextrose with 0.45% saline at 150 to 250 mL/hr


  • Establish adequate renal function (50mL/h Urinary Output)
  • Potassium level:
    • <3.3 mEq/L
      • Hold insulin and give 20-30 mEq potassium per hour until level >3.3 mEq/L
    • 3.3-5.2 mEq/L
      • Give 20-30 mEq potassium/L of IVF to keep serum potassium between 4 and 5 mEq/L
    • >5.2 mEq/L
      • Do not give potassium
      • Check every 2 hours

Regular insulin:

  • Give IV
    • 0.1u regular insulin/Kg as IV bolus
    • 0.1u regular insulin/Kg/Hr as continuous IV infusion
    • If serum glucose level does not decrease by 10% in first hour, give 0.14u regular insulin/Kg as IV bolus then continue previous
    • HHS:
      • When serum glucose reaches 300 mg/dL
        • Reduce IV regular insulin to 0.02-0.05u/Kg/hr
        • Keep serum glucose level at 200-300 mg/dL until patient is alert
    • DKA:
      • When serum glucose reaches 200 mg/dL
        • Reduce IV regular insulin to 0.02-0.05u/Kg/hr OR give rapid-acting insulin at 0.1u/Kg every 2 hours
        • Keep serum glucose at 150-200 mg/dL until DKA resolves


  • pH > 6.9
    • No bicarbonate
  • pH < 6.9
    • 100 mmol bicarbonate in 400 mL water + 20 mWq potassium chloride
      • Infuse over 2 hours
    • Repeat every 2 hours until pH > 7
    • Monitor potassium every 2 hours


  • Check venous pH and electrolyte, BUN, creatinine, and glucose every 2-4 hours until stable
  • When DKA or HHS resolves and patient is able to eat - initiate subcutaneous insulin
  • Continue IV infusion 1-2 hours after beginning subcutaneous insulin
  • In insulin naive patients - start 0.5-0.8u/Kg/day then adjust as needed


  • Corrected serum sodium
    • sodium + (1.65*glucose-100)/100
  • Effective serum osmolarity (HHS > 320)
    • (2*corrected sodium)+(Glucose/18)


  • AFP Vol 96 No 11 Dec 2017

7.1.2 DM visit EBM

  • A: A1c - q3 - 6 mo
  • B: BP - <130/80
  • C: Chol - LDL <100 annual
  • D: MDRD: GFR q6 mo
  • E: Eye exam - on Dx and annual
  • F: Foot - visual - annual


  • Kopes-Kerr C. Type 2 Diabetes: Separating Proven from Unproven Interventions. Am Fam Phys. Vol 80, No 5. 1 Sep 2009. pp450-452

7.1.3 General Notes

  • DM is 7th leading cause of death in US.
  • 1 in 4 persons with DM are unaware they have the disease.
  • If a cohort of obese persons have prediabetes and reduce their weight by 5% - the incidence of newly diagnosed diabetes in 3 years decreases from 23% to 11%.
  • Metformin, acarbose, and a combination ramiril/rosglitazone can be effective in preventing progression from prediabetes to DM.

From: Shaughnessy AF1, Erlich DR1, Slawson DC2. Type 2 Diabetes: Updated Evidence Requires Updated Decision Making. Am Fam Physician. 2015 Jul 1;92(1):22.

  • A1C levels should be low enough to decrease symptoms but not low enough to risk hypoglycemia. For many patients, this range is 8% to 9% with a fasting blood glucose level less than 200 mg per dL (11.1 mmol per L).
  • The goal of treating type 2 diabetes is to help patients live longer, healthier, productive lives. …Other than metformin, which has been shown to decrease mortality independent of its effect on glucose levels, all other available diabetes medications treat numbers, not patients.
  • For type 2 diabetes, this means abandoning tight control of blood glucose for most patients, and instead addressing risks such as smoking, hypertension, and hyperlipidemia that will actually make a difference.

(Erlich DR, et al. “Lending a hand” to patients with type 2 diabetes: a simple way to communicate treatment goals. Am Fam Physician. 2014;89(4):256,258.)

  • Normalizing blood glucose levels benefits only a small subset of patients.

(George CM, et al. Management of blood glucose with noninsulin therapies in type 2 diabetes. Am Fam Physician. 2015;92(1):27–34.)

  • …weekly self-weighing, regular consumption of breakfast, and reduced intake of fast food were associated with a lower body mass index in overweight patients.

(Raynor HA, Jeffery RW, Ruggiero AM, Clark JM, Delahanty LM; Look AHEAD Research Group. Weight loss strategies associated with BMI in overweight adults with type 2 diabetes at entry into the Look AHEAD (Action for Health in Diabetes) trial. Diabetes Care. 2008;31(7):1299–1304.)

  • …medical nutrition therapy decreases A1C level, weight, waist circumference, and triglyceride level, and increases health-related quality of life.

(Evert AB, Boucher JL, Cypress M, et al.; American Diabetes Association. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2013;36(11):3821–3842.)

  • The ADA recommends starting therapy with metformin, because it is the only medication shown to reduce mortality and complications in randomized controlled trials (RCTs).

(Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group [published correction appears in Lancet. 1998;352(9139):1558]. Lancet. 1998;352(9131):854–865.)

  • No evidence from RCTs that any of the other DM medications reduce the risk of diabetes-related complications, cardiovascular mortality, or all-cause mortality.

(American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14–S80.)


  • Vijan S. In the clinic. Type 2 diabetes. Ann Intern Med. 2015; 162(5):ITC1-16.
  • Consultant. 2015;55(7):565
  • George CM, Brujin LL, Will K, Howard-Thompson A. Management of Blood Glucose with Noninsulin Therapies in Type 2 Diabetes. Am Fam Physician. 2015 Jul 1;92(1):27-34.

7.1.4 Special tests to classify DM

Test Desc Utility
C peptide Reflects endogenous insulin production Consider in pts with possible LADA or Type 1 but neg antibodies
Zinc transporter 8 Ab Correlates with utoimmune mediated DM Consider in pts with possible LADA or Type 1 but neg antibodies
Insulinoma-associated Ag-2 Autoimmune Ab associated with DM I Distinguish DM 1 or LADA from DM 2
Insulin Ab   May be more common in LADA
Islet cell Ab   May be more common in LADA
Glutamic acid decarboxylase 65   May be more common in LADA


  • AFP Vol 93 No 2 Jan 2016

7.1.5 Management Plan for Type 2

  1. Healthy eating, weight control, increased physical activity
  2. Metformin
  3. (2 Drug) Metformin + one of the following:
    • GLP-1 Receptor Agonist
    • DPP4 Inhibitor
    • SU
    • Basal Insulin
  4. (3 Drug) Metformin + two of the previous
    • Do not mix DPP-4-I and GLP-1-RA (both work similarly)
    • Do not mix SU and insulin (increased risk of hypoglycemia)
  5. More complex insulin regimens

NOTE - guidelines do include TZDs but I do not use them d/t my concern with weight gain, cancer, edema, and HF.

Other Therapy Aspects:

  • Exercise (even if it is a little)
    • A growing body of evidence suggests that interrupting prolonged sitting with intermittent brief periods of standing or light exercise can improve glucose metabolism
  • Metformin should be used as first-line therapy to reduce microvascular complications, assist in weight management, reduce the risk of cardiovascular events, and reduce the risk of mortality in patients with type 2 diabetes mellitus. (LOE A)
  • Patients with prediabetes or new-onset diabetes should undertake extensive lifestyle changes to slow the progression of type 2 diabetes. (LOE A)
  • Patients with existing cardiovascular disease, two or more cardiovascular disease risk factors, or duration of diabetes of 10 years or more should have higher A1C goals because of a lack of benefit and the potential for increased risk of mortality compared with lower A1C goals. (LOE A)
  • Self-monitoring of blood glucose levels for patients taking noninsulin therapies does not significantly affect glycemic control. (LOE B)
  • Painful Diabetic Neuropathy - See under Neurology section


  • NEJM JW Gen Med Jul 1 2012
  • Diabetes Care 2012; 35:976

7.1.6 Diabetes self-management and support (DSME/S)

DSME/S improves diabetes outcomes, including:

  • lowering hemoglobin A1c levels;
  • reducing onset and/or advancement of diabetes complications;
  • helping people improve their lifestyle behaviors;
  • decreasing diabetes distress and depression; 
  • improving quality of life.

4 critical times for assessing the need for DSME/S referral:

  1. with a new diagnosis of type 2 diabetes;
  2. annually for health maintenance and prevention of complications;
  3. when new complicating factors influence self-management;
  4. when transitions in care occur.
  5. Diabetes Care,The Diabetes Educator, and the Journal of the Academy of Nutrition and Dietetics.

7.1.7 HbA1C and Estimated Average Glucose Level

HbA1c (%) eAG (mg/dL)
5 97
6 126
7 154
8 183
9 212
10 240
11 269
12 298

7.1.8 Self-monitoring

  • For patients who have had diabetes longer than one year and are not using insulin, evidence suggests that the benefit of self-monitoring of blood glucose in lowering A1C levels is small at six months and disappears by 12 months. Self-monitoring of blood glucose does not improve health-related quality of life, general well-being, or patient satisfaction. (SOR: B)
  • For those who have been diagnosed with diabetes for more than one year, especially those whose blood glucose levels are well controlled without insulin, the evidence supports discontinuing (or not initiating) selfmonitoring of blood glucose because of the added cost and inconvenience of testing and lack of improvement in patient-oriented outcomes.


  • (Malanda UL, Welschen LM, Riphagen II, Dekker JM, Nijpels G, Bot SD. Self-monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. Cochrane Database Syst Rev. 2012 Jan 18;1:CD005060. doi: 10.1002/14651858.CD005060.pub3.)

7.1.9 Oral medications

  1. Metformin

    See also:

    You can use metformin in anyone whose estimated glomerular filtration rate (eGFR) is > 30 mL/minute/1.73 m2 and you do not have to stop metformin in someone undergoing a dye study unless their EGFR is < 60 mL/minute/1.73 m2.

    Let me explain. We used to use serum creatinine cut-points to determine when we should prescribe metformin in patients with any degree of renal insufficiency. Now the FDA has done away with that guideline and really expanded the number of patients that we can safely keep on metformin. These are the rules:

    Test the eGFR in any patient before you start metformin. If it's > 45 mL/minute/1.73 m2, you are fine. That patient is fully eligible to be on metformin.

    For the most part, the FDA does not recommend starting metformin in patients with an eGFR between 30 and 45 mL/minute/1.73 m2. But they still consider metformin safe if your patient is on metformin already and seems to be deriving some benefit. So, patients down to an eGFR of 30 mL/minute/1.73 m2 can remain on their metformin.

    Patients with an eGFR < 30 mL/minute/1.73 m2 should not be on metformin.

    The notion that we don't have to stop metformin in every patient undergoing a radiographic dye study makes me incredibly happy. I've spent countless hours dealing with this in my patients. The specific guidelines are as follows:

    If the eGFR is > 60 mL/minute/1.73 m2, don't worry about it. They can continue taking their metformin throughout, unless it's an intra-arterial dye study. In that case, you are going to need to hold the metformin and make sure that the renal function stays stable.

    If the eGFR is < 60 mL/minute/1.73 m2—meaning between 30 and 60—then, as we did before, you stop the metformin before the patient undergoes the dye study and recheck in 48 hours to make sure that the eGFR is still in a safe range.

    For many of our patients undergoing radiographic dye studies who have an eGFR of > 60 mL/minute/1.73 m2, we are not going to need to hold the metformin. I think that will make our lives much easier and, frankly, will be better for our patients.

    These guidelines are consistent with recommendations that have been used throughout the world for many years. I really believe that they are safe and likely to help us use metformin in more of our patients who will benefit from the drug. Thank you.

  2. Metformin may work by changing gut bacteria makeup

    Randomized, placebo-controlled, double-blind study published in Nature, April 2017:

    • Population:
      • 40 Individuals with newly diagnosed Type 2 Diabetes Mellitus
    • Intervention:
      • calorie restricted diet vs metformin for 4 months.
    • Outcomes:
      • gut microbiota changes and A1c.
    • Results:
      • metformin, but not calorie restriction, had rapid effects on the composition and function of the gut microbiota in parallel with the reduction of %HbA1c and fasting blood glucose concentrations.
      • Transfer of the microbiota to germ-free mice showed that the metformin-altered microbiota could improve glucose metabolism.
      • Furthermore, transcriptome analyses of feces showed that metformin had direct effects on the gut microbiota, specifically expression of bacteria genes that regulate metal transporters.
    • Conclusion:
      • Some of metformin’s antidiabetic effects are from altered gut microbiota.
      • Additional studies are essential to further identify microbial proteins and to determine how they interact with the host targets in improving host metabolism.


  3. SUs/TZDs
    • Later generation are recommended to reduce hypoglycemia
      • Glimepiride
      • Glipizide
    • Thiazolidinediones
      • Pioglitazone

    In general:

    • Use Glipizide or Glimiperide; DO NO NOT USE Glyburide
    • NO Glyburide in elderly d/t longer half-life than glimiperide and glipizide (more likely to cause hypoglycemia

7.1.10 Insulin


AACE/ACE Approach to Starting Insulin

  • Augmentation therapy with long-acting (basal) insulin
    • A1C < 8%: total daily dosage 0.1 to 0.2 units per kg
    • A1C > 8%: total daily dosage 0.2 to 0.3 units per kg
  • Replacement therapy with basal and rapid-acting prandial (basal-bolus) insulin
    • Add prandial insulin 1 meal at a time*: start at 10% of long-acting dose or 5 units
    • Add prandial insulin before each meal: total daily dosage 0.3 to 0.5 units per kg and divide 50% basal and 50% prandial†

Insulin Approach

  1. Start with Basal Insulin
  2. Can add 1 rapid acting insulin before largest meal OR Change to premixed insulin twice daily
    • Rapid acting insulin
      • Start: 4u or 10% basal dose
      • Adjust by 1-2u weekly until target reached
    • Premixed twice daily
      • Start: divide current basal dose into 2/3 AM and 1/3PM OR into 1/2 AM and 1/2 PM
      • Adjust: Increase by 1-2u weekly until target reached
  3. If not controlled - consider basal with bolus before meals


  • Start at 0.1-0.2 unit/Kg
  • Titrate after assesssing mean 3-day FPG (3-0-3 Regimen)
    • If FG is >130 increase 3 units
    • If FG is 80-130 maintain dose
    • If FG is <80 decrease 3 units


  • Start 0.2units/kg; 1:1 basal; 80% Total NPH dose; 1/3 to 1/2 total daily insulin dose

NovoLog (insulin aspart)

  • Step 1: Inject 4units before percieved largest meal
  • Step 2: Patients measure BS before next meal or bedtime and use this reading to plan next day dose
  • Step 3: Self titrate based on Step 2
    • If less than or equal to 70 -> -1
    • If 71-130 then no change
    • If over 130 -> +1

NovoLog 70/30 (use NPH instead of 70/30)

  • Starting dose:
    • If FG <180 mg/dL -> 5units before breakfast and 5u before dinner
    • If FG is >180 -> 6u before breakfast and 6u before dinner
  • Titration:

    Premeal glu Unit adjust
    <80 -2
    80-110 0
    111-140 +2
    141-180 +4
    >180 +6

Regular insulin:

  • Estimate sensitivity using "rule of 1800"
    • BG change per unit Insulin = 1800/total Insulin daily
    • Example of 60 units/day: 1 unit drops BG 30 mg/dl
  • Protocol (uses rapid acting Insulin, e.g. Lispro)
    • Goal Blood Glucose is <150
    • Using sensitivity, how many units to drop 50 mg/dl
      • For example above, ~1 unit to drop BG 50 mg/dl
        • BG 150-199: 1 unit Bolus Insulin (regular or RA)
        • BG 200-249: 2 units Bolus Insulin
        • BG 250-299: 3 units Bolus Insulin
        • BG 300-349: 4 units Bolus Insulin
        • BG Over 350: 5 units Bolus Insulin
    • Add in coverage for meal intake
      • Based on per carbohydrate when Glucose >60 mg/dl
      • Use for Type I Diabetes, consider for Type II
      • Add to sliding scale coverage above
      • Add 1 unit Insulin per carbohydrate
      • Example: For 3 carbohydrate meal, add 3 units

A Good Resource:

2 Types of Insulin Categories:

Basal insulins:

  • Intermediate-acting insulins
    • Humulin N (NPH)
    • Novolin N (NPH)
  • Long-acting insulins
    • Basaglar (insulin glargine)
    • Lantus (insulin glargine)
    • Levemir (insulin detemir)
    • Semglee (insulin glargine)
    • Toujeo (insulin glargine)
    • Tresiba (insulin degludec)

Premeal insulins:

  • Rapid-acting insulins
    • Admelog® (insulin lispro)
    • Afrezza® (inhaled insulin)
    • Apidra® (insulin glulisine)
    • Fiasp® (insulin aspart)
    • Humalog® (insulin lispro)
    • Lyumjev® (insulin lispro-aabc)
    • Novolog® (insulin aspart)
  • Short-acting insulins
    • Humulin® R (regular)
    • Novolin® R (regular)

Basal Insulin Sliding Scale

Glucose Lev Increase by
<60 -4 units
60-79 -2 units
80-99 Maintain dose
100-119 1 units
120-140 mg/dL 2 units
141-160 mg/dL 4 units
161-180 mg/dL 6 units
>180 mg/dL 8 units

Titration for rapid-acting insulin

Premeal Glucose Adjust
level for 3 days  
<60 mg/dL -4
60-79 mg/dL -2
80-99 mg/dL -1
100-119 mg/dL Maintain dose
120-139 mg/dL 1
140-180 mg/dL 2
>180 mg/dL 3

Titration for premixed insulins

Fasting BG for 3d Adjustment of Pre-dinner BG for 3d Adjustment of
  Pre-Dinner dose   Pre-Breakfast dose
<60 mg/dL -4 <60 mg/dL -4
60-79 mg/dL -2 60-79 mg/dL -2
80-110 mg/dL Maintain Dose 80-110 mg/dL Maintain Dose
111-140 mg/dL 2 111-140 mg/dL 2
141-180 mg/dL 4 141-180 mg/dL 4
>180 mg/dL 6 >180 mg/dL 6


  • AFP Vol 84 No 2 Jul 2011
  • AFP Vol 97 No 1 Jan 2018

Physiologic Insulin Guidelines

  1. Step 1: Measure BG before meals and at bedtime, or q6 if nothing by mouth
  2. Step 2: Calculate initial total daily dose (TDD) of insulin
    • 0.3units/kg if underweight, elderly, or dialysis
    • 0.4units/kg if normal weight
    • 0.5units/kg if overweight
    • 0.6units/kg if obese, glucocorticoids, insulin resistance
  3. Step 3: 50% of TDD as long acting basal insulin
  4. Step 4: 50% of TDD as short acting nutritional insulin given in 3 divided doses 0-15min before meals
  5. Step 5: Select a scale of short-acting correctional insulin given 0-15min before meals
  6. Step 6: Subsequent daily adjustment of TDD base on previous days total units given

Correctional insulin dosing

Blood Glucose Standard Dosing
150-199mg/dL 1
200-249mg/dL 3
250-299mg/dL 5
300-349mg/dL 7
>349mg/dL 8 + call

Types of Insulin

Insulin Onset (h) Duration (h)
Glargine (Lantus) 1-2 24
Detemir (Levemir) 1-2 18-24
Isophane (NPH) 1-2 10-20
Lispro, aspart, glulisine 5-15min 3-6
Regular 1-2 6-10min


  • AFP Vol 81 No 9 May 2010
  1. Strategies for low income


    Low cost DM insulin

    • Novolin at Walmart
    • Relyon at Walmart
    • Start NPH as daily long acting

    Wal-mart Insulin

    • Reli-on brand of Novolin N (NPH) in 10 mL bottles insulin ($24.88)
      • Use NPH nightly similar to lantus or levemir
      • Start with 10u nightly and warn of hypoglycemia symptoms (at 8-10h mark)
      • When NPH is greater than 0.25 units per kg and the post meal blood sugars are above target, consider adding morning NPH and/or premeal regular insulin.
    • Reli-on brand of Novolin R (regular) in 10 mL bottles insulin ($24.88)
      • Use for additional carbs as needed
      • When NPH is greater than 0.25 units per kg and the post meal blood sugars are above target, consider adding morning NPH and/or premeal regular insulin.
      • Can try the 50/50 Rule:
        • Take the patients weight in kgs x 0.5 to calculate total daily insulin needs.
          • 50% is from basal NPH (0.25 units per kg)
          • The other 50% from bolus regular (0.25 units per kg divided into 2 to 3 meals).
    • Reli-on brand of Novolin 70/30 in 10 mL bottles insulin ($24.88)
      • 70/30 twice a day
    • Also:
      • ReliOn insulin syringes ($12.99)
      • Glucose tablets
      • Lancets ($6.24)
  2. Type 1 DM Insulin

    ADA general treatment recommendations for T1DM

    • T1DM patients should receive multidose injections (3 - 4 a day) of basal and premeal insulin or insulin pump therapy
    • Most individuals with T1DM should use rapid-acting insulin analogs to reduce hypoglycemia risk
    • Patients should match premeal insulin to carbohydrate intake, premeal blood glucose levels, and anticipated activity

    Starting therapy

    • Insulin dosing in T1DM will vary based on patient's age, weight, and residual pancreatic insulin activity
    • T1DM patients will typically require a total daily insulin dose of 0.4 - 1.0 units/kg/day
    • A typical starting dose in metabolically-stable patients is 0.5 units/kg/day
    • After calculating the total daily dose, it should be given as follows:
      • Basal insulin - given as half of the total daily dose ✝
      • Premeal insulin - half of the total daily dose divided into thirds and given before each meal
      • When first starting therapy, it is recommended that the initial basal dose be reduced by 20 - 30% to prevent hypoglycemia [11,19]
    • T1DM patients may experience a "honeymoon phase" after starting insulin therapy where the initial effects of insulin are greater than what is seen later in the disease


    • Patient weighs 80 kg
    • Total daily dose = 80 kg X (0.5 units/kg/d) = 40 units per day
    • Basal insulin = 1/2 X 40 units = 20 units of basal per day✝
    • Premeal Insulin = 1/2 X 40 units = 20 units / 3 = approximately 7 units before each meal
    • If patient is just starting therapy, the initial basal dose should be reduced by 20 - 30%. In our example: 20 units X 0.20 = 4 units, so initial basal dose would be 20 - 4 = 16 units
  3. Type 2 DM Insulin
    1. Step 1 - start with long-acting insulin or bedtime NPH
      • Initial dose: 10 units/day or 0.1 - 0.2 units/kg/day
      • Adjust dose: increase dose by 10 - 15% or 2 - 4 units once or twice weekly to achieve fasting blood sugar goal (see adjusting basal insulin and NPH dosing for other recommendations)
      • If hypoglycemia occurs: decrease dose by 10 - 20% or 4 units
      • If A1C is still above target despite achieving fasting blood sugar goal, or if A1C is not at target and insulin dose is > 0.7 - 1.0 units/kg, proceed to Step 2
    2. Step 2 - add premeal insulin before largest meal
      • Initial dose: 4 units or 10% of basal dose
      • If A1C < 8%, consider decreasing basal insulin dose by same amount
      • Adjust dose: increase dose by 1 - 2 units or 10 - 15% twice weekly to achieve pre- and postprandial goals (see adjusting premeal insulin for other recommendations)
      • If hypoglycemia occurs: decrease dose 2 - 4 units or 10 - 20%
      • For patients using bedtime NPH:
        • Consider switching to twice daily NPH by taking 80% of current bedtime NPH dose and giving 2/3 in the morning and 1/3 at bedtime.
          • Example:
          • Current bedtime NPH dose is 30 units
          • 0.80 X 30 = 24 units
          • 2/3 of 24 = 16 units in the morning
          • 1/3 of 24 = 8 units in the evening
      • If A1C still not at target, proceed to Step 3
    3. Step 3 - add premeal insulin before other meals in stepwise fashion
      • Add prandial insulin to an additional meal and use the guidelines in Step 2 to adjust
      • If not controlled with 2 preprandial doses, add to a third meal
      • Stepwise addition of prandial insulin every 3 months is associated with a lower risk of hypoglycemia and greater patient satisfaction
  4. Pre-meal Insulin

    Carbohydrate counting

    • In carbohydrate counting, premeal insulin is adjusted based on the amount of carbohydrates to be consumed in each meal
    • The carbohydrate counting method is used to determine the amount of carbohydrates in a meal
    • An insulin to carbohydrate ratio (ex. 1 unit/10g of carb) is used to calculate the premeal insulin dose
    • A typical starting ratio is 1 unit of premeal insulin for every 10 grams of carbs to be consumed
    • An individual may have different carbohydrate ratios for breakfast, lunch, and dinner because a person's response to insulin may vary throughout the day
    • Example:
      • 60 grams of carbs to be consumed for lunch
      • Patient's ratio is 1 unit of insulin for every 10 grams of carbs
      • Patient injects 6 units of premeal insulin before eating meal

    Calculate a correction factor

    • Step 1 - calculate the correction factor
      • For Regular insulin (Humulin R, Novolin R)
        • Divide 1500 by the patient's total daily dose of insulin
        • The result will equal the estimated drop in blood sugar (in mg/dl) from 1 unit of regular insulin
      • For Rapid insulin (Novolog, Humalog, Apidra, Fiasp, Admelog)>
        • Divide 1800 by the patient's total daily dose of insulin
        • The result will equal the estimated drop in blood sugar (in mg/dl) from 1 unit of rapid insulin [4,12]
      • Example:
        • Patient's total daily dose of insulin (premeal + basal) is 60 units
        • Patient uses regular insulin as premeal insulin
        • 1500/60 = 25
        • Patient can expect that for every 1 unit of regular insulin they inject, their blood sugar will come down 25 mg/dl
    • Step 2 - Once the correction factor is calculated, the patient can then figure out how much insulin to supplement
      • Example:
        • Patient from above: correction factor is 25 mg/dl
        • Patient checks pre-lunch blood sugar and it is 175 mg/dl (desired range 80 - 120 mg/dl)
        • 175 - 120 = 55 mg/dl
        • 55/25 = approximately 2
        • Patient would add 2 extra units of regular insulin to premeal dose

    Adjustments to Correction Factor

    • If pre-lunch average is not in desired range (80 - 120 mg/dl), adjust breakfast ratio
    • If pre-dinner average is not in desired range (80 - 120 mg/dl), adjust lunch ratio
    • If pre-bedtime snack average is not in desired range (80 - 120 mg/dl), adjust dinner ratio
    • If average blood sugar is > 120 mg/dl, adjust ratio by subtracting 2 - 3g of carbohydrate
      • Example:
        • Current ratio 1 unit / 10g of carb
        • Pre-lunch average > 120 mg/dl
        • Change breakfast ratio to 1 unit / 7g of carb
    • If average blood sugar is < 80 mg/dl, adjust ratio by adding 2 - 3g of carbohydrate
      • Example:
        • Current ratio 1 unit / 10g of carb
        • Pre-bedtime snack average < 80 mg/dl
        • Change dinner ratio to 1 unit / 13g of carb
        • If average blood sugar is 80 - 120 mg/dl, do not adjust ratio
  5. Insulin NPH Dosing Adjustments


    • 0.1 to 0.2 units/kg/day or 10 units/day administered as a single dose (usually at bedtime) or in 2 divided doses (ADA 2020; Lipska 2017).
    • If HbA1c >8% prior to initiation of basal insulin, 0.2 to 0.3 units/kg/day is recommended (AACE/ACE [Garber 2020]).

    For elevated fasting plasma glucose:

    • Adjust dose using evidence-based titration algorithm (eg, by 2 units every 3 days) while avoiding hypoglycemia (AACE/ACE [Garber 2020]; ADA 2020).

    For elevated HbA1c despite achieving fasting plasma glucose target:

    • Patients using once daily insulin NPH (eg, at bedtime):
      • Consider switching to a twice daily regimen by administering ~80% of the current bedtime dose in 2 divided doses (one example division would be 2/3 of the dose in the morning and 1/3 of the dose at bedtime) (ADA 2020).
    • Patients using twice daily insulin NPH:
      • Consider intensification of therapy with additional agents that target postprandial glucose rather than continuing to increase the insulin NPH dose (AACE/ACE [Garber 2020]; ADA 2020).

    For hypoglycemia:

    • If no clear reason for hypoglycemia, decrease dose by 10% to 20% (ADA 2020);
    • For severe hypoglycemia (ie, requiring assistance from another person or blood glucose <40 mg/dL) reduce dose by 20% to 40% (AACE/ACE [Garber 2020]).

    Dosage adjustment when adding prandial insulin:

    • Consider reducing the basal insulin dose by 4 units (or ~10%) if HbA1c is <8% when initiating prandial insulin (ADA 2020).

    Patients with diabetes receiving enteral feedings (ADA 2020):

    • Note: TDD of insulin is divided into a basal component (intermediate- or long-acting insulin) and nutritional and correctional components (regular insulin or rapid-acting insulins).
    • Basal component:
      • SubQ: Continue previous basal insulin dose or administer 30% to 50% of TDD as insulin NPH; if basal insulin naive, administer insulin NPH 5 units every 12 hours.

    Patients with diabetes undergoing surgery:

    • SubQ: On the evening before surgery or procedure, reduce the usual dose by 25%; on the morning of surgery or procedure, reduce the usual dose by 25% to 50% (ADA 2020; Pichardo-Lowden 2012).

    Conversion from long-acting insulin analogs to insulin NPH:

    • Consider initiating insulin NPH at 80% (eg, 20% reduction) of previous basal insulin total daily dose; administer as a single dose (usually at bedtime) or in 2 divided doses (ADA 2020; Lipska 2017).

    Dosage adjustment for concomitant therapy:

    • Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
  6. Dosing NPH Insulin in T2DM

    Twice-daily NPH regimens divide the daily dose between a morning and evening dose. In studies, dose distribution has varied widely, with some splitting the dose 50-50, some giving 2/3 in the morning and 1/3 in the evening, and others giving 1/3 in the morning and 2/3 in the evening.

    • Step 1 - Initial dose
      • If A1C > 10% and no blood sugars < 126 mg/dl in last 2 weeks ✝
        • Start with NPH 10 units twice daily
      • If A1C < 10% or any blood sugars < 126 mg/dl in last 2 weeks ✝
        • Start with NPH 6 units twice daily
      • Morning dose should be given at approximately the same time each day upon awakening
      • Evening dose should be given at bedtime
      • If patient has not been checking blood sugars, have them check and report a fasting blood sugar once they obtain a monitor
    • Step 2 - Monitor blood sugars
      • Check fasting blood sugar in the morning and predinner blood sugar in the evening on a daily basis
    • Step 3 - Determine insulin adjustment
      • After 3 consecutive days of readings, average all the blood sugars (fasting and predinner) together
      • Use this average and the table below to determine how much insulin will be added (or subtracted) to the total daily dose
    Blood sugar average (fasting and predinner) over 3 days Adjustment to total daily NPH dose
    ≥ 180 add 8 units
    160 - 179 add 6 units
    140 - 159 add 4 units
    120 - 139 add 2 units
    100 - 119 add 1 unit
    80 - 99 no change
    60 - 79 subtract 2 units
    < 60 subtract 4 or more units
    • Step 4 - Distributing the insulin adjustment
      • Average the fasting and predinner blood sugars over the last 3 days separately
      • Determine a range for each average (fasting and predinner) from the two tables below
    Table 29: Fasting blood sugar ranges
    Average blood sugar (mg/dl) Range
    > 160 3
    101 - 160 2
    ≤ 100 1
    Table 30: Predinner blood sugar ranges
    Average blood sugar (mg/dl) Range
    > 160 3
    131 - 160 2
    ≤ 130 1
  7. Converting from long-acting insulins to NPH
    • Total daily basal insulin dose: reduced by 25 - 30% upon initiation.
      • This approach helps prevent hypoglycemia but may require significant up-titration after switching.
    • Patients who are also receiving premeal insulin should be particularly cautious because NPH may potentiate the peak effect of short-acting insulins
    Blood sugar (mg/dl) Insulin dose in units of rapid or short-acting
    60-110 0
    111 - 150 2
    151 - 200 4
    201 - 250 6
    251 - 300 8
    301 - 350 10
    351 - 400 12
    > 400 14
  9. Syringes

    Syringes come in:

    • 30 unit syringe
    • 50 unit syringe
    • 100 unit syringe

7.1.11 Weight loss in pts with DM 2

  • Modest weight loss reduces insulin resistance

(American Diabetes Association. Standards of medical care in diabetes—2010 [published correction appears in Diabetes Care. 2010;33(3):692]. Diabetes Care. 2010;33(suppl 1):S11-S61)

  • Low-carbohydrate or low-fat calorie-restricted diets may produce weight loss for up to one year, after which behavior modification and physical activity are most helpful.

-Fluoxetine (Prozac) and orlistat (Xenical) produce modest short-term weight loss, but their long-term benefits are unclear and their safety is uncertain. (SOR: B)

  • Patients with diabetes can safely achieve modest short-term weight loss using fluoxetine or orlistat.
  • A greater proportion of patients with diabetes achieved a 5 or 10 percent loss from their initial body weight with orlistat compared with placebo (relative risk = 2.50 for 5 or 10 percent loss; 95% CI, 2.02 to 2.97).

(Hutton B, Fergusson D. Changes in body weight and serum lipid profile in obese patients treated with orlistat in addition to a hypocaloric diet: a systematic review of randomized clinical trials. Am J Clin Nutr. 2004;80(6):1461-1468.)

(Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Lau J. Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD004096.)

7.1.12 Iatrogenic Hypoglycemia

  • Mortality rate associated with hypoglycemia has been estimated as high as 10%.

(Skrivarhuag T, Bangstad HJ, Stene LC, et al. Long-term mortality in a  nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologica. 2006; 49(2):298-305)

  • After warfarin, insulin was the second most frequent cause of emergency hospitalizations due to adverse drug events in adults over 65.

(Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Medd. 2011;365(21):2002-2012)

  • Insulin is the most common cause of iatrogenic hypoglycemia. Patients on more complicated regimens have higher rates of hypoglycemia.

(Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361(18):1736-1747)

  • Sulfonylureas also cause hypoglycemia as they act directly on ATP-sensitive potassium channels on the beta cell membrane -> induces depolarization and insulin release independently of stimulation of physiologic insulin from glucose.

Other noninsulin medications less likely as they:

  • increase peripheral sensitivity to insulin (metformin and thiazolidinediones)
  • enhance pancreatic insulin secretion in response to oral glucose through the incretin pathway (GLP-1 agonists and DPP-4 inhibitors)
  • increasing renal loss of glucose (SGLT2 inhibitors)
  • Renal failure increases risk (both acute and chronic). Kidneys metabolize most sulfonylureas.
    • Glyburide is NOT recommended in renal insufficiency with GFR <50-60ml/min/1.73m2
    • Glipizide tends to be safer in renal insufficiency but also needs dose reductions.


  • Consultant. 2015;55(7):541-542

7.2 Hyperthyroidism

Recommendations to treat hyperthyroidism:

  TSH < 0.1 mIU/L TSH 0.1-0.4 mIU/L
>65yo Treat Consider Treat
<65yo and asymptomatic Consider Treat Observe
<65yo and:    
- Heart disease Treat Consider Treat
- Hyperthyroid symptoms Treat Consider Treat
- Osteoporosis Treat Consider Treat
- Postmenopausal Treat Consider Treat


  • AFP Vol 95 No 11 Jun 2017

7.2.1 Graves Disease

Graves disease requires one of the three treatment options:

  • an antithyroid medication (methimazole [Tapazole] or propylthiouracil)
  • radioactive iodine (I-131) ablation of the thyroid gland
  • surgical thyroidectomy

The choice of treatment depends on the benefits vs. risks in a specific clinical situation and on the patient's preference.

Antithyroid Medications.

  • Antithyroid medications are thionamides; they inhibit thyroid peroxidase, blocking the synthesis of T3 and T4
  • Graves disease remits in up to 30% of patients treated with thionamides, these medications can be used as the initial treatment, with ablation or thyroidectomy performed if remission does not occur.25,26 Once medical therapy is discontinued, relapse occurs in 30% to 70% of patients, mostly within the first year.27 After discontinuation, thyroid function should be monitored every one to three months for six to 12 months, and the patient should be instructed to contact the physician if symptoms recur.

For patients using methimazole, the prevalence of agranulocytosis is 0.17%, the incidence of hepatitis is 3.17 per 1,000 person-years, and the incidence of acute hepatic failure is 0.32 per 1,000 person-years

Patients should be instructed to discontinue medication use and contact their physician if they develop jaundice, acholic stools, dark urine, arthralgias, abdominal pain, nausea, vomiting, fever, or sore throat. A baseline complete blood count (CBC) with differential and a hepatic panel should be obtained before initiating an antithyroid medication. Subsequent routine monitoring of CBC is unnecessary, but CBC with differential should be obtained if fever and/or pharyngitis develop.

Free T4 and total T3 should be obtained four weeks after starting a thionamide and every four to eight weeks thereafter with the dosage adjusted based on results. Once free T4 and total T3 levels normalize, they should be monitored every three months. Serum TSH is of limited value early in the treatment course because levels may remain suppressed for several months after treatment is started. An antithyroid medication should be continued for 12 to 18 months, then tapered or discontinued if the TSH level is normal at the time. Elevated or above-normal TSH levels (greater than 4.0 mIU per mL) at antithyroid drug discontinuation is associated with an increased likelihood of permanent remission

Radioactive Iodine Ablation. Radioactive iodine ablation of the thyroid gland is the most common treatment of Graves disease in the United States. It is contraindicated in pregnancy. Moderate to severe Graves orbitopathy is a relative contraindication, especially in patients who smoke, because radioactive iodine may exacerbate the eye disease.32,33 In mild cases of Graves orbitopathy, radioactive iodine ablation can be performed with concomitant glucocorticoid therapy. Nonradioactive iodine impedes radioactive iodine uptake by iodide transporter; therefore, exposure to large amounts of nonradioactive iodine (e.g., iodinated contrast, amiodarone) should be avoided within three months before radioactive iodine ablation. Pregnancy should be ruled out within 48 hours before radioactive iodine ablation and avoided for six months thereafter.1 A thionamide should be discontinued at least five days before the treatment but can be restarted three to five days after to maintain control of thyroid function, because it may take up to 12 weeks to achieve the full effect of radioactive iodine.

Most patients develop permanent hypothyroidism between two and six months after radioactive iodine ablation and require thyroid hormone supplementation.1,33 Free T4 and total T3 should be measured four to eight weeks after ablation; if hyperthyroidism persists, these indices should be monitored every four to six weeks and thyroid hormone replacement started in the early stages of hypothyroidism.1

Thyroidectomy. This treatment option is preferred in patients with goiter-induced compressive symptoms and in patients with contraindications to radioactive iodine ablation or thionamides. Besides general anesthesia risk, thyroidectomy carries a risk of inadvertently injuring parathyroid glands and recurrent laryngeal nerves.


7.3 Hypothyroidism

A Total T4 measures the bound and free hormone and can change when binding proteins differ (see above). A Free T4 measures what is not bound and able to enter and affect the body tissues.

An elevated TSH and low FT4 or FTI indicates primary hypothyroidism due to disease in the thyroid gland. A low TSH and low FT4 or FTI indicates hypothyroidism due to a problem involving the pituitary gland. A low TSH with an elevated FT4 or FTI is found in individuals who have hyperthyroidism.

Two common antibodies are thyroid peroxidase antibody and thyroglobulin antibody. Measuring levels of thyroid antibodies may help diagnose the cause of the thyroid problem.

For example, positive anti-thyroid peroxidase and/or anti-thyroglobulin antibodies in a patient with hypothyroidism result in a diagnosis of Hashimoto’s thyroiditis.

While detecting antibodies is helpful in the initial diagnosis of hypothyroidism due to autoimmune thyroiditis, following their levels over time is not helpful in detecting the development of hypothyroidism or response to therapy.

TSH and FT4 are what tell us about the actual thyroid function or levels.

A stimulatory TSH receptor antibody (TSI) antibody causes the thyroid to be overactive in Graves’ Disease.

If you have Graves’ disease, your doctor might also order a thyrotropin receptor antibody test (TSHR or TRAb), which detects both stimulating and blocking antibodies.


There are many medications that can affect thyroid function testing. Some common examples include:

  • Estrogens, such as in birth control pills, or in pregnancy, cause high levels of total T4 and T3. This is because estrogens increase the level of the binding proteins. In these situations, it is better to ask both for TSH and free T4 for thyroid evaluation, which will typically be in the normal range.
  • Biotin, a commonly taken over-the-counter supplement, can cause the measurement of several thyroid function tests to appear abnormal, when they are in fact normal in the blood. Biotin should not be taken for 2 days before blood is drawn for thyroid function testing to avoid this effect.

7.3.1 Levothyroxine dosing adjustments

TSH Amt to increase
5 to <10 25-50 mcg/d
10-20 50-75 mcg/d
>20 75-100 mcg/d


  • AFP Vol 89, No 4 Feb 2014

7.3.2 When to Refer for hypothyroidism

  • Age <18yo
  • Cardiac disease
  • Coexisting endocrine diseases
  • Myxedema coma suspected
  • Pregnancy
  • Presence of goiter, nodule, or other structural thyroid gland abnormality
  • Unresponsive to therapy


  • Endocr Pract. 2008;14(6):802-803

7.4 Thyroid nodules

Associated findings with malignant nodules:

  • H/o differentiated thyroid cancer in a 1st degree relative
  • H/o radiation exposure as a child or adolescent
  • Prior diagnosis of thyroid carcinoma
  • Male sex
  • Focal uptake of 18F-flourodeoxyglucose by the thyroid
  • Personal of FH of MEN type 2 or familial medullary thyroid cancer
  • Serum calcitonin level >50-100pg/ml
  • Residence near a nuclear reactor accident


  • NEJM 373;24 Dec 2015

7.5 Testosterone

See also: Drugs

General thoughts:

  • Visceral adiposity affects leptin/inflammatory cytokines which affects testosterone (lowers) and hypothalamic dysfunction.
  • Alcohol, opioids blunt testosterone production

Signs and Symptoms hypogonadism:

  • Anemia
  • Decline in cognitive function
  • Decreased sexual function
  • Decreased or absent morning erections
  • Depressed mood
  • Incomplete sexual development
  • Increased fatigue
  • Loss of axillary and pubic hair
  • Loss of body hair
  • Loss of muscle strength and work capacity
  • Male factor infertility
  • Reduced lean body mass
  • Small testes

Causes of Hypogonadism in Men

Type Lab Origin Possible causes
Primary Decreased total Test Congenital Chrom abnormalities, cryptorchidism, FSH/LH receptor gene
  Increased LH/FSH   mutations, Klinefelter syndrome, myotonic dystrophy
    Acquired Chemotherapy, hypothyroidism, orchitis/epididymo-orchitis,
      radiation/trauma to testes, testicular torsion
Secondary Decreased total Test Congenital Kallmann syndrome, Prader-Willi syndrome, other genetic
  Decreased LH/FSH Acquired Chronic opioid use, hyperprolactinemia, pituitary tumors,
      sellar radiation, sleep deprivation, surgery, trauma
Mixed primary Decreased total Test Acquired Aging, cancer, chronic glucocorticoid use, chronic kidney disease,
and secondary Variable LH/FSH   chronic obstructive pulmonary disease, cirrhosis, diabetes mellitus,
      hemochromatosis, HIV, obesity


  • AFP Vol 96 No 7 Oct 2017
  • FMX 2016
  • JFP Vol 65, No 12 Dec 2016

7.5.1 Endocrine Guidelines:

  1. H&P - If symptoms -> test
  2. Morning Total Testosterone
  3. If low (<300ng/dL):
    1. Exclude reversible illness, drugs, nutritional deficiencies
    2. Repeat TT and also obtain LH+FSH
  4. If confirmed low TT and low or normal LH/FSH:
    1. Secondary
    2. Consider workup for pituitary disorders (prolactin, MRI)
    3. Rule out medication use, systemic illness, or chronic conditions as cause
  5. If confirmed low TT and high LH/FSH:
    1. Primary
    2. Consider chromosomal (Karyotye) testing


  • AFP Vol 96 No 7 Oct 2017
  • FMX 2016

7.5.2 Who to treat

Low T Diagnosis = low testosterone with symptoms

  • Consider testosterone replacement in those with both laboratory and clinical evidence of hypogonadism (SOR B)
  • Consider in symptomatic men with clinical symptoms to improve sexual function, well-being, lean muscle mass and bone density (++)
  • Offer to men with low T and low libido/ED in addition to pursuing additional workup and therapies (++)
  • Consider offering short term replacement to men on chronic glucocorticoids with low T levels (+)
  • Recommend AGAINST in men with breast or prostate cancer or with a PSA >4ng/ml (+)

Postmenopausal women for hypoactive sexual desire disorder

  • Recommended dosage is 300mcg/day (need compound pharmacy)
  • Begin with 6mo trial period, continue only if patient responds favorable
  • No effectiveness data after 24mo

Contraindications to starting testosterone therapy

Absolute Relative
Breast Ca Baseline Hct >50%
Polycythemia (Hct >54%) Desire for fertility
Prostate Ca Severe lower urinary tract symtoms
PSA >4mcg/L or nodule on DRE Uncontrolled HF
  Untreated OSA


  • AFP Vol 96 No 7 Oct 2017
  • FMX 2016
  • JFP Vol 65, No 12 Dec 2016

7.5.3 Tests to perform

  • Best Lab test is morning Total Testosterone (+/- fasting)
  • If abnormal, repeat at least 1 month apart (Normal ~300 to ~1000ng/dL) (SOR B)
  • If gynecomastia and morbid obesity, check:
    • estradiol
    • SHBG
  • Check LH to exclude primary vs secondary causes
    • If low - evaluate pituitary axis function
  • If need to rule out infertility:
    • Semen analysis
    • FSH
  • Chronic hypogonadism: DEXA
  • If TT < 150ng/dL
    • LH
    • FSH
    • prolactin
    • pituitary MRI
  • If Low TT, elevated FSH/LH (suggesting primary etiology)
    • Chromosomal studies to rule out Klinefelters


  • FMX 2016
  • JFP Vol 65, No 12 Dec 2016

7.5.4 Monitoring

  • Check CBC at baseline and q3 months (annual if stable)
    • If Hct >54% consider stopping therapy or periodi phlebotomy (monthly)
  • Check PSA and Perform DRE at baseline and 3 and 6 months
    • Follow screening guidelines of q6mo PSA
    • Refer to urologist if PSA increases by >1.4mcg/L over 12mo
  • Measure BMD at baseline and every 2 years if history of osteopenia or osteoporosis
  • Evaluate formulation specific adverse events episodically and yearly
  • Lipid panel and LFTs anually

For injection supplementation:

  • Check midway between injections with goal 500-600


  • AFP Vol 96 No 7 Oct 2017
  • FMX 2016
  • JFP Vol 65, No 12 Dec 2016
  • UpToDate

7.6 Add to Endo/DM

Glimepiride, glipizide, and glyburide all reduce in HbA1c about 1% to 2%.

Glimepiride is purported to have the highest incidence of hypoglycemia of the 3 agents

  • Might be due to having the longest half-life of the 3 sulfonylureas
  • Once-daily dosing at all doses

Glyburide and glipizide require twice-daily administration as their doses are increased.

All 3 agents undergo hepatic metabolism, with only glyburide having active metabolites.

  • These metabolites are cleared renally
  • Patients with reduced kidney function will experience accumulation, which can lead to increased therapeutic effects and increase the risk of hypoglycemia.

"The relative lack of advantages of glyburide compared with the other agents, combined with its increased risk of adverse effects, creates a risk-to-benefit ratio that does not favor its use. Given that the risks are increased only in patients with poor kidney function, one could simply adjust the choice of agents to select from, but owing to the lack of advantages of glyburide, it makes more sense to remove it as a choice. There is not a scenario in which glyburide is the preferred agent, but there are certain scenarios in which it is clearly the least-preferred agent."


  • Consultant360 Volume 57 - Issue 4 - April 2017

7.7 Testosterone Order   edit

Initiation (after labs)

  • ICD10: E29.1
  • Testosterone cypionate 100mg/ml 1ml (100 mg) q2 wks
  • B-D #9571 SYR/NDL 3ML 23GX1 LL, 30 syringes for 90 days / Use to inject medication
  • B-D #5195 Needles 18Gx1, 30 units for 90 days / Use to draw up medication as directed

7.8 Thyroid Nodule Testing

Thyroid ultrasonography with a survey of the cervical lymph nodes should be performed in all patients with thyroid nodules.

The serum thyroid-stimulating hormone level should be measured during the initial evaluation of a thyroid nodule.

If it is low, a radionuclide thyroid uptake scan should be performed.



8.1 Allergic rhinitis

  • Flonase/nasonex
    • Treat all symptoms also w/ nonallergic
    • Check compliance
  • 2nd gen oral antihistamines
    • Tx pruritis and rhinorrhea not well for congestion

  • Pseudoephedrine increases SBP 1 mmHg no change DBP increase pulse 3 bpm
    • Salerno SM, Jackson JL, Berbano EP. Effect of oral pseudoephedrine on blood pressure and heart rate: a meta-analysis. Arch Intern Med. 2005;165:1686-1694)


  • Consultant Apr 2010 vol 50 no 4

8.2 Allergy tips

General Allergy Tips

  • If you exercise outdoors, wait until evening to do your routine; pollen counts are lower towards night!
  • If you need to mow the lawn or do outdoor yard work, consider wearing a dust mask.
  • If you have ragweed allergies, remove the plants in your yard before they bloom to help cut down on the pollen in your area!
  • Clean your HVAC system regularly, as dust can build up over time and create irritants.
  • Purchase a HEPA filter or air filtration unit; these can really reduce the amount of allergens in your home!
  • Mold-Specific Tips
  • Don’t hang your wet clothing indoors to dry; this can make mold allergies worse.
  • Reduce the amount of mold in your home! Keep basements, bathrooms, and any other room which retains humidity well-ventilated by opening windows frequently, or purchasing a dehumidifier.
  • Heat helps mold grow, so setting up a heater alone can make the problem worse!
  • If you have a carpeted room which is prone to mildew or mold, replacing the flooring with wood or tile may be a good idea!
  • Regularly clean garbage cans, sinks, and water-based appliances with a bleach solution to keep mold from building up and spreading.

8.3 Cerumen

Cerumen is a Hydrophobic protective covering which protects ear canal from:

  • Water damage
  • Trauma
  • Foreign Bodies
  • Infection (intrinsic bactericidal activity)

Cerumen accumulation is usually asymptomatic, but can cause the following symptoms:

  • Hearing loss, Tinnitus
  • Earache, Ear fullness, Itchiness
  • Reflex cough
  • Dizziness


8.4 Chronic Rhinosinusitis

Diagnostic Criteria:

  • The presence of at least 2 of the following for 12 consecutive weeks (in order of frequency)
    • Nasal obstruction
    • Nasal drainage
    • Facial pain/pressure
    • Hyposmia/anosmia
  • Objective evidence on physical examination or radiology (Sinus CT) such as
    • Mucopurulent drainage
    • Edema
    • Polyps in middle meatus


  • AFP Vol 96 No 8 Oct 2017

8.5 Hoarseness

Vocal quality vs diagnosis:

  • Breathy
    • Inflammatory arthritis
    • Spasmodic or functinoal dysphonia
    • Vocal fold mass
    • Vocal fold paralysis
  • Halting, stangled
    • Spasmodic dysphonia
  • Hoarse, husky, muffled, or nasal sounding
    • Parkinson disease
  • Hoarseness worse early in day
    • GERD
    • Laryngopharyngeal reflux (LPR)
  • Hoarseness worse later in day
    • Myasthenia gravis
    • Vocal abuse
  • Low pitched
    • GERD
    • Hypothyroidism
    • LPR
    • Leukoplakia
    • Muscle tension dysphonia
    • Reinke edema
    • Vocal fold edema
    • Age-related vocal atrophy in women
  • Raspy or harsh
    • GERD
    • LPR
    • Muscle tension dysphonia
    • Vocal fold lesion
  • Scanning speech and dysarthria
    • Multiple sclerosis
  • Soft (loss of volume)
    • Vocal fold paralysis
    • Parkinson disease
    • Age-related vocal atrophy
  • Spoken voice lost, but whispered maintained
    • Conversion aphonia
  • Strained
    • GERD
    • LPR
    • Muscle tension dysphonia
    • Spasmodic dysphonia
  • Strained, effortful phonation
    • Muscle tension dysphonia
  • Thick, deep voice and slowed speech
    • Acromegaly
  • Vocal fatigue
    • Muscle tension dysphonia
    • Myasthenia gravis
    • Parkinson disease
    • Vocal abuse
    • Age-related vocal atrophy


  • AFP Vol 96 No 11 Dec 2017

8.6 Rhinitis


  • 15-30% of people in US
  • Coexists with asthma atopic dermatitis
  • Intranasal glucocorticoids are most effective; Alternatives include oral and nasal antihistamines and leukotriene-receptor antagonists
  • Those with refractory symptoms can consider allegen immunotherapy


  • Episodic symptoms:
    • Oral or nasal H1-antihistamine
    • +/- decongestant
  • Mild symptoms (seasonal):
    • Intranasal glucocorticoid
    • Oral or nasal H1-antihistamine
    • Leukotriene-receptor antagonist
  • Moderate-severe symptoms:
    • Intranasal glucocorticoid
    • Intranasal glucocorticoid and Oral or nasal H1-antihistamine
    • Allergen immunotherapy


  • NEJM 372;5 Jan 2015

8.7 Otitis Externa

(See My Formulary: Neomycin - polymyxin B - hydrocortisone otic 4 gtts tid)

  • Cortisporin otic 10 ml 4 drops in affected ear q6-8 hrs for 10 days


  • 2% acetic acid solution - VoSol
    • With hydrocortisone (VoSoL HC Otic)
    • With aluminum acetate (Otic Domeboro)
    • Advantages
      • Generic product is inexpensive and effective against most infections without causing sensitization
    • Disadvantages
      • Can be irritating to inflamed external auditory canal; possibly ototoxic
  • Neomycin otic preparations
    • With polymyxin B–hydrocortisone (Cortisporin)
    • With hydrocortisone-thonzonium (Coly-Mycin S)
    • Advantages
      • Effective, and generic product is inexpensive
    • Disadvantages
      • Can be a potent sensitizer, causing contact dermatitis in 15% of patients; ototoxic
  • Polymyxin B - hydrocortisone (otobiotic)
    • Advantages
      • Avoids potential neomycin sensitization
    • Disadvantages
      • No activity against Staphylococcus and other gram-positive microorganisms
  • Aminoglycoside ophthalmic solutions
    • Gentamicin sulfate 0.3% (Garamycin)
    • Tobramycin sulfate 0.3% (Tobrex)
    • Advantages
      • Less locally irritating than 2% acetic acid solution, neomycin otic preparations or polymyxin B alone
    • Disadvantages
      • Potential ototoxicity; moderately expensive
  • Quinolone otic and ophthalmic solutions
    • Ofloxacin 0.3% solution (Floxin Otic)
    • Ciprofloxacin 0.3% and hydrocortisone suspension (Cipro HC Otic)
    • Ofloxacin 0.3% (Ocuflox)
    • Ciprofloxacin 0.3% (Ciloxan)
    • Advantages
      • Highly effective without causing local irritation or sensitization; no risk of ototoxicity; twice-daily dosing
    • Disadvantages
      • Expensive; increased community exposure of an important class of antibiotics, with potential for causing resistance

8.8 Pulsatile Tinnitus

A steady rhythmic thumping, throbbing, creaking or whooshing sound in one or both ears.

Venous sinus stenosis/IIH is the most common cause of pulsatile tinnitus

Causes of pulsatile tinnitus include:

  • Atherosclerosis, which refers to hardening of the arteries. When plaque builds up and hardens, it reduces the blood flow through the body, including the ears, neck and head. This may cause the rhythmic whooshing or thumping sound in one or both ears
  • Blood vessel and artery disorders or malformations, especially near the ear. These include aneurysms and arteriovenous malformations
  • Ear abnormalities
  • Sinus wall abnormalities
  • Head and neck tumors
  • High blood pressure
  • Idiopathic intracranial hypertension, which can cause headaches, blurred vision, and pulsatile tinnitus
  • Anemia
  • Head trauma
  • Conductive hearing loss
  • Hyperthyroidism
  • Paget’s Disease

Imaging may include

  • temporal bone computerized tomography (CT) scan without contrast
  • CT angiography of head and neck
  • magnetic resonance angiography (MRA)
  • magnetic resonance imaging (MRI)
  • ultrasound


  • Rule out anemia and hyperthyroidism

If no underlying cause is found -> coping tools used for tinnitus self-management are recommended:

  • sound therapy
  • lifestyle adjustments to reduce stress
  • cognitive behavioral therapy


  • Am Fam Physician. 2021;103(11):663-671

8.9 Sinusitis

Acute Bacterial Sinusitis (see also in infectious diseases): Diagnosis:

  • Persistent symptoms
    • Nasal congestion, rhinorrhea, or cough for 10d or more without improvement
  • Severe symptoms
    • Temp over 38.5 for 3-4d
    • Purulent rhinorrhea for 3-4d
  • Worsening symptoms
    • Return of symptoms after initial resolution
    • New or recurrent fever, increase in rhinorrhea or cough


  • Amoxicillin-clavulanate is first line in children


  • NEJM 367;12 Sep 2012

Chronic Sinusitis: Diagnosis:

  • 2 of the following for over 3mo: *must have one of these 2
    • *Nasal obstruction
    • *Nasal discharge (ant/post)
    • Facial pressure/pain
    • Smell reduced

Symptom criteria supported with one of the following:

  • Nasal polyps on ant rhinoscopy or nasal endoscopy
  • Edema or purulence
  • CT scan demonstrating paranasal sinus inflammation


  • 1st line: High-volume saline irrigation with topical corticosteroids
  • If nasal polyps: Can consider short course of systemic corticosteroids (1-3wks), doxycycline (3 wks), or a leukotriene antagonist
  • If no nasal polyps: Can consider prolonged course of a macrolide (3 mon)


  • JAMA Sep 2015, Vol 314, No 9

8.10 Sore throat

Likely beneficial:

  • Corticosteroids (in those receiving antibiotics)
  • Acetaminophen - reduces pain at regular doses over 2 days

Trade-off between benefits/harm:

  • Antibiotics
  • NSAIDs - reduces pain at 2-5 days


  • Untreated symptoms of sore throat disappear by 3 days in 40% and untreated fevers in about 85%
  • 85% of persons are symptom free at 1 week


  • AFP Vol 91 No 10 May 2015

8.10.1 Over the counter patient instructions:

  • Acetaminophen will help the most but takes 24hrs to notice. You could use 2 tabs every 6 hours safely.
  • Throat lozenges with "benzocaine" in them will help numb the area
  • Honey has evidence to work with sore throats - there are lozenges with honey in them as a different option
  • Cepacol spray (has benzocaine and glycerol) numbs the throat and can be used to help with sore throat.

8.11 Tinnitis

Causes of Secondary Tinnitus

  • Infectious
    • Bacterial (Lyme disease, syphilis), fungal, viral
  • Metabolic
    • Diabetes mellitus, hyperlipidemia, vitamin B12 deficiency
  • Neurologic
    • Idiopathic intracranial hypertension, idiopathic stapedial or tensor tympani muscle spasm, multiple sclerosis, palatal myoclonus, spontaneous intracranial hypotension, type I Chiari malformation, vestibular migraine
  • Otologic
    • Cerumen impaction, cholesteatoma, foreign body, Meniere disease, middle ear effusion, otitis, otosclerosis, patulous eustachian tube, tympanic membrane perforation, vestibular schwannoma
  • Somatic
    • Head or neck injury, temporomandibular joint dysfunction
  • Toxicologic
    • Medication or substance use
  • Traumatic
    • Cerumen removal
  • Vascular
    • Arterial bruit; arteriovenous malformation; carotid atherosclerosis, dissection, or tortuosity; Paget disease; vascular tumors; venous hum

Medications Associated with Tinnitus

  • Anesthetics
    • Bupivacaine (Marcaine), lidocaine
  • Antiepileptics
    • Carbamazepine (Tegretol), pregabalin (Lyrica)
  • Anti-inflammatory agents
    • Aspirin,* nonsteroidal anti-inflammatory drugs, sulfasalazine (Azulfidine)
  • Antimalarial agents
    • Chloroquine (Aralen), quinine
  • Antimicrobial agents
    • Aminoglycosides
      • Amikacin, gentamicin, kanamycin, neomycin, tobramycin (Tobrex)
    • Macrolides
      • Azithromycin (Zithromax), erythromycin
    • Tetracyclines
      • Doxycycline, minocycline (Minocin)
    • Vancomycin
  • Antineoplastic agents
    • Platinum compounds
      • Carboplatin (Paraplatin), cisplatin
    • Protein kinase inhibitors
      • Axitinib (Inlyta), dasatinib (Sprycel), imatinib (Gleevec), lapatinib (Tykerb), osimertinib (Tagrisso), ruxolitinib (Jakafi)
    • Pyrimidine analogues
      • Capecitabine (Xeloda)
    • Taxanes
      • Paclitaxel (Taxol)
  • Antivirals for treatment of hepatitis C virus infections
    • Ribavirin (Rebetol), sofosbuvir (Sovaldi), telaprevir (Incivek)
  • Immunosuppressants
    • Calcineurin inhibitors
      • Cyclosporine (Sandimmune)
    • Interferons
    • Monoclonal antibodies
      • Ipilimumab (Yervoy), nivolumab (Opdivo), trastuzumab (Herceptin)
  • Loop diuretics
    • Furosemide (Lasix), torsemide (Demadex)
  • Paralytics (for anesthesia)
    • Quaternary ammonium compounds
      • Vecuronium
  • Phosphodiesterase type 5 inhibitors
    • Sildenafil (Viagra), tadalafil (Cialis)
  • Vaccinations
    • HPV
      • Bivalent (HPV-16, HPV-18); quadrivalent (HPV-6, HPV-11, HPV-16, HPV-18)
      • Pneumococcal polysaccharide (Pneumovax)
  • Miscellaneous
    • Atorvastatin (Lipitor), bupropion (Wellbutrin), risedronate (Actonel), varenicline (Chantix)
    • Antiarrhythmics, dopamine agonists, hormone agents, proton pump inhibitors

Tinnitus Presentation:

  • Pulsitile tinnitus:
    • Temporal bone CT without contrast or CT Angio of head and neck
  • Focal neurologic abnormaliteis
    • Refer to ER
  • Asymmetric or unilateral tinnitus
    • MRI of head and auditory canal with and without contrast
  • Asymmetric hearing loss
    • MRI of head and auditory canal with and without contrast
  • Associated with hearing changes
    • Prmpt audologic evaluation (within 4 weeks)
  • Not Bothersome tinnitus
    • History: focus on noise exposure, ototoxic meds, and medical conditions
    • Anticipatory guidance and prevention
    • Consider audiologic evaluation
  • Acute Bothersome tinnitus
    • History: Focus on recent exposure to loud noise, trauma, ototoxic meds, and infectious symptoms
    • PE: Signs of trauma, canal blockage, cranial nerve abnormalities
    • Consider audiologic evaluation
    • If signs of trauma - Perform imaging
    • If CN abnormalities - refer to ER for urgent imaging and neurological care
  • Chronic Bothersome tinnitus (>6mo)
    • Perform H&P
    • Prompt audiologic evaluation (within 4 wks)

Treatments to consider for tinnitus

  • Cognitive behavior therapy (moderate- to high-quality evidence)
  • Sound therapy (low-quality evidence)
    • Acoustic stimulation
    • Hearing aids
    • Sound/noise generation
  • Tinnitus retraining therapy (very low-quality evidence)

Treatments to consider for tinnitus-associated conditions:

  • Antidepressants
    • Nortriptyline (Pamelor; depression)
    • Sertraline (Zoloft; anxiety)
    • Trazodone (sleep disturbance)
    • Tricyclic antidepressants (disability)
  • Cognitive training (attention, concentration, memory)
  • Melatonin (sleep disturbance)

Treatments to avoid

  • Benzodiazepines
    • Clonazepam (Klonopin)
  • Anticonvulsants  
    • Acamprosate (Campral)
    • Carbamazepine (Tegretol)
    • Gabapentin (Neurontin)
    • Lamotrigine (Lamictal)
  • Repetitive transcranial magnetic stimulation
  • Electrical stimulation
    • Transcranial direct current stimulation
    • Transcutaneous electrical nerve stimulation
  • Bimodal stimulation
  • Microvascular decompression (surgical procedure)
  • Ginkgo biloba
  • Nitrous oxide
  • Hyperbaric oxygen
  • Acupuncture


  • AFP Jun 2021 Vol 103 No 11

9 Gastroenterology

9.1 Antiemetics Selection

Clinical Situation Associated Neurotransmitters Recommended Antiemetic
Vestibular nausea/Motion Sickness Histamine, acetylcholine Meclizine, scopolamine
Migraine-associated Dopamine Metoclopramide, prochlorperazine, promethazine
Gastroenteritis Dopamine, serotonin Promethazine, Serotonin antagonists
Pregnancy-induced Unknown Mild: Ginger 250mg ac/qhs; Pyridoxine
    More Severe: Ondansetron


  • AFP Vol 91, No 5 Mar 2015
  • AFP Vol 76 No 1 Jul 2007

9.2 Barrett Esophagus

Risk factors (If chronic GERD 5+ yrs and 1+ risk factor -> Endoscopy):

  • Male
  • Age >50
  • Smoking
  • Obesity
  • Diet high in fast food and meat

Nondysplastic Barrett Esophagus

  • Risk of progression to adenocarcinoma: 0.2-0.5% annually
  • Surveillance
    • If BE length 3+ cm: Every 3 years
    • If BE length 1-3 cm: Every 5 years

Low Grade Dysplasia (LGD)

  • Risk of progression to adenocarcinoma: 0.5-0.7% annually
  • Surveillance if no risk factors:
    • Every 1 year
  • If 1+ risk factors
    • RF including:
      • Multifocal LGD
      • LGD confirmed on subsequent EGD
      • BE length 3+ cm
      • Family history of esophageal adenocarcinoma
    • Endoscopic therapy:
      • Endoscopic mucosal resection or submucosal dissection followed by endoscopic ablative therapy OR
      • Endoscopic ablative therapy alone for patients without any lesions

High Grade Dysplasia/Early Esophageal Adenocarcinoma

  • Risk of progression to adenocarcinoma (HGD): 5-7% annually
  • Endoscopic therapy:
    • Endoscopic mucosal resection or submucosal dissection followed by endoscopic ablative therapy OR
    • Endoscopic ablative therapy alone for patients without any lesions


  • JAMA Aug 2022 Vol 328 No 7

9.3 Bowel Medicines

However, before turning to laxatives, try these lifestyle changes to help with constipation:

  • Eat fiber-rich foods: wheat bran, fresh fruits and vegetables, and oats
  • Drink plenty of fluids daily
  • Exercise regularly


Type of laxative (brand examples) How they work Side effects
Oral osmotics (Phillips' Milk of Magnesia, Miralax) Draw water into the colon to allow easier passage of stool Bloating, cramping, diarrhea, nausea, gas, increased thirst
Oral bulk formers (Benefiber, Citrucel, FiberCon, Metamucil) Absorb water to form soft, bulky stool, prompting normal contraction of intestinal muscles Bloating, gas, cramping or increased constipation if not taken with enough water
Oral stool softeners (Colace, Surfak) Add moisture to stool to allow strain-free bowel movements Electrolyte imbalance with prolonged use
Oral stimulants (Dulcolax, Senokot) Trigger rhythmic contractions of intestinal muscles to eliminate stool Belching, cramping, diarrhea, nausea, urine discoloration with senna and cascara derivatives
Rectal suppositories (Dulcolax, Pedia-Lax) Trigger rhythmic contractions of intestinal muscles and soften stool Rectal irritation, diarrhea, cramping

9.4 Constipation

Also see: Constipation in Elderly

Treatment for chronic idiopathic constipation:

  1. Increase dietary fiber and/or bulking agent
  2. PEG 3350 (osmotic laxative) or stimulant (bisacodyl or senna)
  3. Secretory agent (linaclotide or lubiprostone)
  4. Refer


  • Bulk Agents
    • Psyllium (10g daily), methylcelluose, calcium polycarbophil, wheat dextrin
      • Recommendation: Strong
      • Quality of evidence: Low
    • Polycarbophil
      • 1.25g 1-4x/d max 5g/d
      • Soluble fiber
    • Methylcellulose powder
      • 2g/d
      • Insoluble fiber
  • Nonabsorbed substances
    • PEG 3350 (17 g daily) (osmotic)
      • Recommendation: Strong
      • Quality of evidence: High
    • Lactulose (20 g daily) (osmotic)
      • 15 - 30 ml/d
      • Recommendation: Strong
      • Quality of evidence: Low
  • Stimulants
    • Senna (17 mg daily)
    • Bisacodyl (10mg daily)
      • Recommendation: Strong
      • Quality of evidence: Moderate
  • Secretory
    • Lubiprostone, Linaclotide
    • Recommendation: Strong
    • Quality of evidence: High
  • PAMORAs (Peripheral mu-opioid antagonists)
    • Naldemedine
    • Naloxegol
    • Methylnaltrexone

Other notes:

  • PEG 3350 (17 g daily) (Miralax) is preferred over lactulose as more effective and fewer adverse effects (LOE A)
  • Pelvic florr therapy with biofeedback is superior to laxatives, sham, and placebo in RCTS for defecatory dysfunction (LOE B)


  • JAMA Vol 315 No 2 Jan 2016
  • JAMA Vol 322 No 22 Dec 2019

9.4.1 Secondary Causes


  • Colorectal cancer
  • Colon, rectal, or anal stricture
  • Rectocele
  • Intestinal pseudo-obstrution
  • Megacolon

Neurologic Disease:

  • Spinal cord lesion
  • Stroke
  • Parkinson disease
  • Multiple sclerosis

Metabolic Disturbances:

  • Hypercalcemia
  • Hypokalemia
  • Hypomagnesemia
  • Hypothyroidism (severe)
  • Uremia


  • Opiates
  • Anticholinergics
  • CCBs
  • Anticonvulsants
  • Antispasmodics
  • Antihistamines
  • Antiemetics


  • Amyloidosis
  • Scleroderma
  • Heavy metal poisoning


  • JAMA Vol 315 No 2 Jan 2016

9.5 Cirrhosis

  • Modality of choice = US
  • Endoscopy all patients with cirrhosis to check for varices (LOE C)


  • FMX 2016

9.5.1 Ascites treatment

  • Dietary Na restriction (<2g/d)
  • Avoid NSAIDs
  • Goal is weight loss of 0.5Kg/d
  • Diuretics:
    • Spironolactone
      • Start at 100mg/d
      • Increase to 200mg
      • Takes 3-7 days to full effect
      • Watch for hyponatremia, hypokalemia, alkalosis, and gynecomastia
    • Loop

Ref: FMX 2016

9.5.2 Acute variceal hemorrhage

  • Each episode has 30% mortality rate
  • Survivors have 50-70% recurrence rate in 1yr

Ref: FMX 2016

9.6 Colorectal Cancer Screening

The U.S. Preventive Services Task Force recommends that adults at average risk (those who do not have a personal or family history of CRC or polyps, do not have inflammatory bowel disease, or a history of genetic syndromes associated with CRC) aged 50–75 years be screened for CRC by any of six available tests:

  1. Fecal occult blood test (FOBT)
  2. Fecal immunochemical test (FIT)
  3. Multitarget stool DNA (FIT-DNA)
  4. Computed tomographic colonography (CTC)
  5. Sigmoidoscopy
  6. Colonoscopy

Screen all adults ages 45-75yo

Screening strategies:

Test Interval Example
High-sensitivity guaiac fecal occult blood test (HSgFOBT) Annually  
Fecal immunochemical test (FIT) Annually  
Stool DNA-FIT 1-3 yrs Cologuard
Computer tomography colonography 5 yrs  
Flexible sigmoidoscopy 5 yrs  
Flexible sigmoidoscopy + Annual FIT 10 yrs  
Colonoscopy 10 yrs  

Strong evidence exists that screening for CRC reduces incidence and mortality.

The best test is the one that a person is willing to get. CRCCP grantees use only screening tests recommended by the United States Preventive Services Task Force (USPSTF). Those options include:

  • At-home stool tests
    • High-sensitivity guaiac fecal occult blood test (FOBT) every year.
    • High-sensitivity fecal immunochemical test (FIT) every year.
  • Tests performed in clinics
    • Colonoscopy every 10 years.
    • Sigmoidoscopy every 5 years, with FOBT or FIT every 3 years.


9.6.1 USPSTF Colon Cancer Screening

Recommendation Summary

Population Recommendation Grade
Adults ages 50 to 75 years The USPSTF recommends screening for colorectal cancer in all adults ages 50 to 75 years. A
Adults ages 45 to 49 years The USPSTF recommends screening for colorectal cancer in adults ages 45 to 49 years. B
Adults ages 76 to 85 years The USPSTF recommends that clinicians selectively offer screening for colorectal cancer in adults ages 76 to 85 years. Evidence indicates that the net benefit of screening all persons in this age group is small. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the patient's overall health and prior screening history. C
Table 31: Stool-Based Tests
Screening Method Frequency Evidence of Efficacy Other Considerations
gFOBT Every year RCTs with mortality end points: High-sensitivity versions (eg, Hemoccult SENSA) have superior test performance characteristics than older tests (eg, Hemoccult II) Does not require bowel preparation, anesthesia, or transportation to and from the screening examination (test is performed at home)
FIT Every year Test characteristic studies: Improved accuracy compared with gFOBT; Can be done with a single specimen Does not require bowel preparation, anesthesia, or transportation to and from the screening examination (test is performed at home)
FIT-DNA Every 1 or 3 y Test characteristic studies: Specificity is lower than for FIT, resulting in more false-positive results, more diagnostic colonoscopies, and more associated adverse events per screening test; Improved sensitivity compared with FIT per single screening test There is insufficient evidence about appropriate longitudinal follow-up of abnormal findings after a negative diagnostic colonoscopy; may potentially lead to overly intensive surveillance due to provider and patient concerns over the genetic component of the test
Table 32: Direct Visualization Tests
Screening Method Frequency Evidence of Efficacy Other Considerations
Colonoscopy Every 10 y Prospective cohort study with mortality end point Requires less frequent screening. Screening and diagnostic followup of positive results can be performed during the same examination.
CT colonography Every 5 y Test characteristic studies There is insufficient evidence about the potential harms of associated extracolonic findings, which are common
Flexible sigmoidoscopy Every 5 y RCTs with mortality end points: Modeling suggests it provides less benefit than when combined with FIT or compared with other strategies Test availability has declined in the United States
Flexible sigmoidoscopy with FIT Flexible sigmoidoscopy every 10 y plus FIT every year RCT with mortality end point (subgroup analysis) Test availability has declined in the United States; Potentially attractive option for patients who want endoscopic screening but want to limit exposure to colonoscopy


9.6.2 Followup colonoscopy recommendations

  • Repeat colonoscopcy is recommended 7-10 yrs after complete removal of 1 to 2 tubular adenomas smaller than 10 mm (Strong rec; Mod QOE)
  • Repeat colonoscopcy is recommended 3-5 yrs after complete removal of 3 to 4 tubular adenomas smaller than 10 mm (Weak rec; Very low QOE)
  • Repeat colonoscopcy is recommended 3 yrs after complete removal of 5 to 10 adenomas smaller than 10 mm (Strong rec; Mod QOE)
  • Repeat colonoscopcy is recommended 3 yrs after complete removal of 1 or more adenomas 10 mm or larger (Stron rec; High QOE)
  • Repeat colonoscopcy is recommended 6 months after piecemeal resection of an adenoma or sessile serrated polyp 20 mm or larger (Strong rec; Mod QOE)


  • JAMA Dec 2020 Vol 324, No 21

9.7 Colonoscopy

Key Points

  • Adenomas on initial colonoscopy affect ongoing follow-up screening recommendations.
  • A single normal colonoscopy demonstrates a lifetime CRC mortality risk 68% lower than in the general population.
  • Finding more than 10 adenomas confers the highest risk, and repeat colonoscopy is recommended in one year.
  • Finding polyps larger than 10 mm, between five and 10 sessile serrated polyps or adenomas, polyps with dysplasia, or traditional serrated adenomas confers high risk, and repeat colonoscopy is recommended in three years.

Common findings on colonoscopy reports include adenomas and polyps. Instead of defining high- and low-risk findings, task force recommendations depend on the number and size of findings.

Initial colonoscopy finding Follow-up interval, years Follow-up colonoscopy finding Follow-up interval, years
Normal (no polyps) 10
Traditional adenomas      
Tubular adenomas < 10 mm      
1 to 2 7 to 10 Normal 10
    Tubular adenomas < 10 mm  
    1 to 2 7 to 10
    3 to 4 3 to 5
    5 to 10 3
    High-risk adenoma 3
3 to 4 3 to 5 Normal 10
    Tubular adenomas < 10 mm  
    1 to 2 7 to 10
    3 to 4 3 to 5
    5 to 10 3
    High-risk adenoma 3
5 to 10 3 No evidence available
High-risk adenoma ? 10 mm or villous or tubulovillous histology, or high-grade dysplasia 3 Normal 5
    Tubular adenomas < 10 mm  
    1 to 2 5
    3 to 4 3 to 5
    5 to 10 3
    High-risk adenoma 3
> 10 1 No evidence available
Serrated polyps      
Sessile serrated polyps < 10 mm      
1 to 2 5 to 10 No evidence available
3 to 4 3 to 5 No evidence available
5 to 10 3 No evidence available
High-risk sessile serrated polyp ? 10 mm or dysplasia 3 No evidence available
Hyperplastic polyps      
Up to 20 polyps < 10 mm 10 No evidence available
Any polyps ? 10 mm 3 to 5 No evidence available
Traditional serrated adenoma 3 No evidence available


  • AFP Col 103 No 5 Mar 2021

9.8 Diarrhea

Definition: passage of 3+ unformed stools/day or passage of 250g of unformed stool/day

  • Acute: (<14d)
  • Persistent (14-29d)
  • Chronic (>30d)


  • Electrolytes and Serum creatinine - in pts with systemic toxicity or dehydration (especially elderly or infirm patients)
  • CBC - in pts with severe diarrhea and fever or toxicity (looking for left shift of neutrophils for C difficile or eosinophilia in parasitic infections)
  • Stool samples - in pts where acute diarrhea is severe, associated with fever or severe coexisting condition in a hospitalized pt, persistent diarrhea, profuse cholera-like watery diarrhea, dehydration, and dysentery)


  • Shigellosis
    • Dx with stool culture
    • Treat with Cipro 750mg daily for 3d or azithro 500mg for 3d
  • Salmonellosis
    • Dx with stool culture
  • Intestinal campylobacteriosis
    • Dx with stool culture
    • Treat with azithro 500mg for 3d
  • Infection with Shiga toxin producing E coli
    • Dx with stool culture on Sorbitol-MacConkey agar
    • Treat with supportive care
  • Noncholeraic vibrio diarrhea
    • Dx with stool culture with TCBS medium
    • Treat with Cipro 750mg daily for 3d or azithro 500mg for 3d
  • Vibrio cholerae
    • Dx with stool culture with TCBS medium
    • Treat with doxycycline 300mg single dose
  • Clostridium difficile
  • Travelors diarrhea and enterotoxigenic E coli
    • For pts with fever or dysentery: Treat with azithro 1000mg single dose
    • For pts without fever or dysentery: Treat with rifaximin 200mg 3/d for 3d; or cipro 500mg bid or 750mg daily for 1-3d
  • Norovirus
    • Treat with fluid and electrolyte therapy
  • Rotavirus
    • Treat with fluid and electrolyte therapy
  • Enteric adenoviruses
    • Treat with fluid and electrolyte therapy
  • Giardiasis
    • Dx with enzyme immunoassay or light microscopic exam of stool
    • Treat with tinidazole 2g single dose, metronidazole 250mg 3/d for 5-7d
  • Celiac disease
    • Dx: Immunoglobulin A antiendomysium and antitissue transglutaminase antibodies
  • Drug-induced diarrhea
  • Endocrine diarrhea
    • Dx: TSH, serum peptide concentrations, urinary histamine level
  • Inflammatory bowel disease
    • Dx: CBC, fecal leukocytes, ESR, fecal calprotectin
  • 9.21
  • Ischemic colitis
  • Microscopic colitis


  • NEJM 370;16 Apr 2014
  • AFP Vol 84 No 10 Nov 2011

9.8.1 Chronic Diarrhea

Defined as: A decrease in stool consistency for more than 4 weeks.

Consider 3 basic categories:

  1. Watery
    1. Secretory type - often nocturnal; unrelated to food intake; fecal osmotic gap < 50 mOsm per kg
      1. Alcoholism
      2. Bacterial enterotoxins (like cholera)
      3. Bile acid malabsorption
      4. Brainerd diarrhea (epidemic secretory diarrhea)
      5. Congenital syndromes
      6. Crohn disease (early ileocolitis)
      7. Endocrine disorders (like hyperthyroidism [increases motility])
      8. Medications
      9. Microscopic colitis (lymphocytic and collagenous subtypes) - often affects older persons
      10. Neuroendocrine tumors (like gastrinoma, vipoma, carcinoid tumors, mastocytosis)
      11. Nonosmotic laxatives (like senna, docusate sodium [Colace])
      12. Postsurgical (like cholecystectomy, gastrectomy, vagotomy, intestinal resection)
      13. Vasculitis
    2. Osmotic type - fecal osmotic gap > 125 mOsm per kg
      1. Carbohydrate malabsorption syndromes (like lactose, fructose)
      2. Celiac disease
      3. Osmotic laxatives and antacids (like magnesium, phosphate, sulfate)
      4. Sugar alcohols (like mannitol, sorbitol, xylitol)
    3. Functional type - distinguished from secretory types by hypermotility, smaller volumes, and improvement at night and with fasting
      1. Irritable bowel syndrome = most common cause of functional diarrhea.
  2. Fatty (malabsorption) - bloating and steatorrhea most of the time
    1. Characterized by:
      1. Excess gas
      2. Steatorrhea
      3. Weight loss
    2. Malabsorption syndrome - damage to or loss of absorptive ability
      1. Amyloidosis
      2. Carbohydrate malabsorption (like lactose intolerance)
      3. Celiac sprue (gluten enteropathy) - Can result in weight loss and iron deficiency anemia
      4. Gastric bypass
      5. Lymphatic damage (like congestive heart failure, some lymphomas)
      6. Medications (like orlistat [Xenical; inhibits fat absorption], acarbose [Precose; inhibits carbohydrate absorption])
      7. Mesenteric ischemia
      8. Noninvasive small bowel parasite (like Giardiasis)
      9. Postresection diarrhea
      10. Short bowel syndrome
      11. Small bowel bacterial overgrowth (> 105 bacteria per mL)
      12. Tropical sprue
      13. Whipple disease (Tropheryma whippelii infection)
    3. Maldigestion - loss of digestive function
      1. Hepatobiliary disorders
      2. Inadequate luminal bile acid
      3. Loss of regulated gastric emptying
      4. Pancreatic exocrine insufficiency
  3. Inflammatory - Inflammatory or exudative (elevated white blood cell count, occult or frank blood or pus)
    1. Inflammatory bowel disease Crohn disease (ileal or early Crohn disease may be secretory)
    2. Ulcerative colitis

      1. Ulcerative colitis or Crohn disease can be characterized by:
      1. Blood and pus in the stool
      2. Elevated fecal calprotectin level
    3. Diverticulitis
    4. Ulcerative jejunoileitis
    5. Invasive infectious diseases
      1. Clostridium difficile (pseudomembranous) colitis–antibiotic history
      2. Invasive bacterial infections (like tuberculosis, yersiniosis)
      3. Invasive parasitic infections (like Entamoeba)–travel history
      4. Ulcerating viral infections (like cytomegalovirus, herpes simplex virus)
    6. Neoplasia
      1. Colon carcinoma
      2. Lymphoma
      3. Villous adenocarcinoma
    7. Radiation colitis

Fecal osmotic gap

  • Fecal osmotic gap = 290 – 2 × (stool sodium + stool potassium)
  • Differentiates secretory from osmotic diarrhea
  • Normal fecal osmolality = 290 mOsm per kg (290 mmol per kg)

Laboratory Workup:

  • Complete blood count
  • Albumin level
  • Erythrocyte sedimentation rate
  • Liver function testing
  • Thyroid-stimulating hormone level
  • Electrolyte levels
  • A minimal stool assessment should include:
    • Fecal leukocyte level
    • Fecal occult blood test
    • If indicated:
      • Fecal calprotectin for IBD
      • Stool laxative screen
      • Fecal pH test (if <5.5, could be lactose intolerance)
      • Stool ova and parasite


  • Am Fam Physician. 2011 Nov 15;84(10):1119-1126.
  • AFP Vol 101 No 8 Apr 2020
  1. Common Causes of Chronic Diarrhea
    • Celiac disease
      • Clinical findings
        • Chronic malabsorptive diarrhea, fatigue, iron deficiency anemia, weight loss, dermatitis herpetiformis, family history
      • Tests
        • Immunoglobulin A antiendomysium and antitissue transglutaminase antibodies most accurate; duodenal biopsy is definitive
    • Clostridium difficile infection
      • Clinical findings
        • Often florid inflammatory diarrhea with weight loss
        • Recent history of antibiotic use, evidence of colitis, fever
        • May not resolve with discontinuation of antibiotics
      • Tests
        • Fecal leukocyte level; enzyme immunoassay that detects toxins A and B; positive fecal toxin assay; sigmoidoscopy demonstrating pseudomembranes
    • Drug-induced diarrhea
      • Clinical findings
        • Osmotic (e.g., magnesium, phosphates, sulfates, sorbitol)
        • Hypermotility (stimulant laxatives)
        • Malabsorption (e.g., acarbose [Precose], orlistat [Xenical])
      • Tests
        • Elimination of offending agent; always consider laxative abuse
    • Endocrine diarrhea
      • Clinical findings
        • Secretory diarrhea or increased motility (hyperthyroidism)
      • Tests
        • Thyroid-stimulating hormone level, serum peptide concentrations, urinary histamine level
    • Giardiasis
      • Clinical findings
        • Excess gas, steatorrhea (malabsorption)
      • Tests
        • Giardia fecal antigen test
    • Infectious enteritis or colitis (diarrhea not associated with C. difficile): bacterial gastroenteritis, viral gastroenteritis, amebic dysentery
      • Clinical findings
        • Inflammatory diarrhea, nausea, vomiting, fever, abdominal pain
        • History of travel, camping, infectious contacts, or day care attendance
      • Tests
        • Fecal leukocyte level, elevated erythrocyte sedimentation rate
        • Cultures or stained fecal smears for specific organisms are more definitive
    • Inflammatory bowel disease: Crohn disease, ulcerative colitis
      • Clinical findings
        • Bloody inflammatory diarrhea, abdominal pain, nausea, vomiting, loss of appetite, family history, eye findings (e.g., episcleritis), perianal fistulae, fever, tenesmus, rectal bleeding, weight loss
      • Tests
        • Complete blood count, fecal leukocyte level, erythrocyte sedimentation rate, fecal calprotectin level
        • Characteristic intestinal ulcerations on colonoscopy
    • 9.21
      • Clinical findings
        • Stool mucus, crampy abdominal pain, altered bowel habits, watery functional diarrhea after meals, exacerbated by emotional stress or eating
        • More common in women
      • Tests
        • All laboratory test results are normal
        • Increased fiber intake, exercise, dietary modification should be recommended
    • Ischemic colitis
      • Clinical findings
        • History of vascular disease; pain associated with eating
      • Tests
        • Colonoscopy, abdominal arteriography
    • Microscopic colitis
      • Clinical findings
        • Watery, secretory diarrhea affecting older persons
        • Nonsteroidal anti-inflammatory drug association possible
        • No response to fasting; nocturnal symptoms
      • Tests
        • Colon biopsy

9.8.2 Diarrhea without Fever Algorythm

  1. Diarrhea without fever
    1. Consider empiric metronidazole
  2. Giardia antigen test
    1. If positive -> treat
  3. Stool for cryptosporidium, cyclospora: acid fast stain or antigen test
    1. If positive -> treat
  4. Stool culture and Clostridium difficile antigen
    1. If positive -> treat
    2. Often enterotoxigenic Escherichia coli
    3. Treat per sensitivities or rifaximin for E. coli only
  5. Stool for ova and parasites x3
    1. Ignore nonpathogenic organisms
    2. If positive -> treat
  6. Selective serology: Stongyloides, Schistosoma
    1. If positive -> treat
  7. Evaluate for underlying pathology: post-infectious irritable bowel disease, celiac sprue, idiopathic inflammatory colitis, HIV test, treat for bacterial overgrowth


  • FP Essentials 370

9.9 Diverticulitis

Clinical Recommendations

  • Avoiding popcorn, nuts, or seeds does not decrease the risk of diverticulitis or diverticular complications.SORT: B
  • Tobacco cessation, reduced meat intake, physical activity, and weight loss are recommended interventions to decrease the risks of diverticulitis recurrence. SORT C
  • Computed tomography of the abdomen and pelvis is the most appropriate initial imaging modality in the assessment of suspected complicated diverticulitis. SORT C
  • Selected patients with uncomplicated diverticulitis can be treated without antibiotics. SORT A
  • Imaging-guided percutaneous drainage is recommended for stable patients with abscesses ≥ 3 cm in size. SORT B
  • Prophylactic partial colectomy should be considered in patients who had an abscess requiring drainage. SORT B
  • Colonoscopy should be considered six to eight weeks after resolution of a complicated case of diverticulitis unless the patient has had a high-quality colonoscopy in the past year. SORT C

Outpatient Antibiotics:

  • Oral antibiotics should be considered for uncomplicated diverticuliis only if symptoms persist or worsen after 48 to 72 hours
  • Trimethoprim/sulfamethoxazole 160/800 mg bid + metronidazole 500 mg tid
  • Amox/clavulanate 875/125 mg XR bid
  • Ciprofloxacin 500 mg bid + metronidazole 500 mg tid
  • Moxifloxacin 400 mg qd
  • Levofloxacin 750 mg qd + metronidazole 500 mg 3-4/d


  • AFP Aug 2022 Vol 106 No 2

9.9.1 Clinical Prediction Rule for Acute Diverticulitis

The presence of all three of the following indicators is considered a positive result: - Absence of vomiting - C-reactive protein level > 5 mg per dL (50 mg per L) - Tenderness limited to the left lower quadrant


  • AFP Sep 2020 Vol 102 No 6

9.10 Dyspepsia

  • Patients <60yo with dyspepsia should be tested for H. pylori infection and treated if positive (LOE: A)
  • Patients <60yo with dyspepsia should be treated with PPI if H. pylori negative (LOE: A)

EGD Indications

  • >60yo
  • Bleeding, anemia, >10% weight loss, progressive dysphagia
  • History of cancer
  • History of PUD
  • Abdominal mass on exam


  • FMX 2016
  • JAMA Vol 319 No 17 May 2018

9.10.1 Rome IV Diagnostic Criteria for Functional Dyspepsia

  • Presence of at least one of the following:
    • Postprandial fullness (3 days per week)
    • Early satiety (3 days per week)
    • Epigastric pain (1 day per week)
    • Epigastric burning (1 day per week)
  • and
    • No evidence of structural disease
  • Note: Criteria must be present for at least the past 3 months, with symptoms starting at least six months before diagnosis.


  • AFP Vol 101 No 2 Jan 2020

9.10.2 Medications Associated with Dyspepsia

  • Acarbose (Precose)
  • Antibiotics
  • Bisphosphonates
  • Corticosteroids
  • Herbs (e.g., chaste tree berry, feverfew, garlic, ginkgo, saw palmetto, white willow bark)
  • Iron
  • Metformin
  • Miglitol (Glyset)
  • Nonsteroidal anti-inflammatory drugs, including cyclooxygenase-2 inhibitors
  • Opiates
  • Orlistat (Xenical)
  • Potassium chloride
  • Theophylline


  • AFP Vol 101 No 2 Jan 2020

9.11 Flatus control

See also: Avoid Gas producing foods

Treatment Symptom addressed Effectiveness
Rifaximin Volume 3+
Probiotcs - Prescript-Assist Volume 3+
Probiotics - Bifidobacterium Volume 3+
Probiotics - Lactobacillus Volume 3+
Activated Charcoal Oral Odor 0+
Activated Charcoal Briefs Odor 3+
Activated Charcoal Pads Odor 2+
Activated Charcoal Seat cushions Odor 1+
Bismuth subsalicylate Odor 3+
Alpha-galactosidase (Beano) Volume 1+ (300 GalU).
Alpha-galactosidase (Beano) Volume 2+ (1,200 GalU).
Simethicone/loperamide Volume associated with diarrhea 0+

Food Causes of flatus:

  • Grains, including:
    • Bagels, barley, breakfast cereals, granola, oat bran, pasta, rice bran, rye, sorghum grain, wheat bran, whole wheat flour, and whole grain breads
  • Vegetables, including:
    • Beets, broccoli, brussel sprouts, cabbage, cauliflower, corn, cucumbers, leeks, lettuce, onions, parsley, and sweet peppers
  • Beans, including:
    • Black-eyed peas, bog beans, broad beans, chickpeas, lentils, lima beans, mung beans, peanuts and peanut butter, pinto beans, red kidney beans, seed flour (sesame, sunflower), soybeans and soy milk.


  • AFP Vol 79 No 12 Jun 2009

9.12 Food-Borne Illnesses   edit

Gastroenteritis (vomiting as primary symptom; fever and/or diarrhea also may be present)

  • Viral gastroenteritis
    • Most commonly rotavirus in infant or norovirus and other caliciviruses in older child or adult
    • Food poisoning due to preformed toxins
      • Vomitoxin
      • Staphylococcus aureus toxin
      • Bacillus cereus toxin
    • Heavy metals

Noninflammatory diarrhea (acute watery diarrhea without fever/dysentery; some may have fever)

  • Can be from all enteric pathogens (bacterial, viral, parasitic) - classically:
    • Enterotoxigenic Escherichia coli
    • Giardia
    • Vibrio cholerae
    • Enteric viruses
      • astroviruses
      • noroviruses and other caliciviruses
      • enteric adenovirus
      • rotavirus
    • Cryptosporidium
    • Cyclospora cayetanensis

Inflammatory diarrhea (invasive gastroenteritis; grossly bloody stool and fever may be present)

  • Shigella species
  • Campylobacter species
  • Salmonella species
  • Enteroinvasive E coli
  • E coli O157:H7
  • Vibrio parahaemolyticus
  • Yersinia enterocolitica
  • Entamoeba histolytica

Persistent diarrhea (lasting >14 days)

  • Parasites - particularly in travelors to mountainous or other areas where untreated water is consumed)
  • C cayetanensis
  • Cryptosporidium
  • E histolytica
  • Giardia lamblia

Neurologic manifestations (paresthesias, respiratory depression, bronchospasm, cranial nerve palsies)

  • Botulism (Clostridium botulinum toxin)
  • Organophosphate pesticides
  • Thallium poisoning
  • Scrombroid fish poisoning (histamine, saurine)
  • Ciguatera fish poisoning (ciguatoxin)
  • Tetradon fish poisoning (tetradotoxin)
  • Neurotoxic shellfish poisoning (brevitoxin)
  • Paralytic shellfish poisoning (saxitoxin)
  • Amnesic shellfish poisoning (domoic acid)
  • Mushroom poisoning
  • Guillain-Barre syndrome (associated with infectious diarrhea due to Campylobacter jejuni)

Systemic illness (fever, weakness, arthritis, jaundice)

  • Listeria monocytogenes
  • Brucella species
  • Trichinella spiralis
  • Toxoplasma gondii
  • Vibrio vulnificus
  • Hepatitis A and E viruses
  • Salmonella typhi and Salmonella paratyphi
  • Amebic liver abscess


9.13 Food Allergies

Most Prevalent Food Allergens

  1. Cow's milk
  2. Peanuts
  3. Eggs
  4. Shellfish
  5. Tree nuts
  6. Fish
  7. Wheat
  8. Soy


  • JFP Vol 69 No 7 Sep 2020

9.14 Gall bladder diet   edit

In general, avoid foods high in fat and increase plant based foods. Here are some safe options for low-fat proteins, fiber, and unsaturated (healthy) fats.

Low-fat protein foods include:

  • poultry
  • fish
  • zero fat dairy products
  • nuts and seeds
  • soy and soy products
  • legumes, such as beans and lentils
  • dairy alternatives, such as soy milk

Sources of fiber include:

  • fruits
  • vegetables
  • legumes
  • nuts and seeds
  • whole grains

Unsaturated fat sources include:

  • cold-water fish
  • nuts, such as walnuts
  • seeds, such as flaxseed
  • oils from fish or flaxseed

9.15 Gastrointestinal Bleeding

9.15.1 Upper GI Bleeding   edit

    • NSAID use and H. pylori infection account for approximately 80% of peptic ulcer disease and peptic ulcer bleeding
    • Erosive disorders include esophagitis, gastritis, and duodenitis; they generally have a benign course and excellent prognosis
    • Mallory-Weiss syndrome, a mucosal tear at the distal esophagus, frequently heals spontaneously, but significant bleeding may occur.
  • Antiplatelet Therapy.
    • Aspirin carries a 37% increased risk of GI bleeding and is often prescribed as part of dual antiplatelet therapy for secondary prevention
    • Anticoagulants. GI bleeding with warfarin (Coumadin) therapy has an incidence of 1% to 4% per year
    • NSAIDs. NSAIDs are associated with peptic ulcer disease and peptic ulcer bleeding.
    • Selective Serotonin Reuptake Inhibitors (SSRIs). A meta-analysis of 22 studies that included more than 1 million participants found that SSRI use increased the risk of upper GI bleeding by 55%


  • Determine the severity of the bleeding, to identify the possible source of bleeding, and to guide management decisions, such as hospitalization, transfusion, and diagnostic testing
  • NPO
  • Regular monitoring of heart rate, blood pressure, and pulse oximetry is necessary during resuscitation and stabilization

Laboratory Tests:

  • complete blood count, basic metabolic panel, coagulation panel, liver tests, and type and crossmatch
  • blood urea nitrogen/creatinine ratio greater than 36 is suggestive of upper GI bleeding when distinguishing it from lower GI bleeding (sensitivity 90%)


  • Current guidelines recommend blood transfusion for patients with upper GI bleeding when hemoglobin is less than 8 g per dL (80 g per L), including patients with coronary artery disease, recent cardiac surgery, or hematologic malignancies
  • Endoscopy: Patients with hemodynamic instability and signs of upper GI bleeding should be offered urgent endoscopy (within 24 hours of presentation or onset of bleeding) after fluid resuscitation and stabilization.
  • Proton pump inhibitors should be started upon presentation with upper GI bleeding
  • Repeat endoscopy is recommended in persons with rebleeding because hemostasis is achieved in 73% of these patients
  • Guidelines recommend resumption of aspirin for secondary prevention of cardiovascular disease immediately following endoscopy if the rebleeding risk is low or within three days if the rebleeding risk is moderate or high
    • A test of cure is recommended at least four weeks after the completion of antibiotics and one to two weeks after completion of proton pump inhibitor therapy


  • AFP Mar 2020 Vol 101 No 5

9.15.2 Lower GI Bleeding

Differential Diagnosis:

Diagnosis Distinguishing features Evaluation and treatment      
Angiodysplasia, angioectasias, or arteriovenous malformation Recurrent painless bleeding episodes; patient > 60 years Colonoscopy with endoscopic argon plasma coagulation7 Consider long-term treatment with lanreotide (Somatuline), 120 mg subcutaneously every 4 weeks (adjust dosing for patients with renal or hepatic impairment)      
Colon cancer Slow, chronic blood loss with occasional changes in bowel habit Colonoscopy with endoscopic therapy (e.g., cautery, banding, clipping, epinephrine injection) to control bleeding2 Referral to surgical and oncologic specialists      
Diverticular bleeding Acute, severe, painless bleeding; history of or suspected diverticular disease Colonoscopy with endoscopic therapy to control bleeding Consider abdominal CTA to localize the bleeding site Hemorrhoids Bleeding associated with bowel movements External: painful and itchy Internal: painless, may be itchy Fiber supplementation (decreases bleeding by 50%); banding or infrared photocoagulation for grades I to III; surgery likely required for symptomatic grade III and grade IV
Infectious colitis Bloody diarrhea with fever; new or concerning food exposures Antibiotics based on identified pathogen, except for Shiga toxin–producing Escherichia coli and Salmonella, which are treated with supportive care alone      
Inflammatory bowel disease Bloody diarrhea associated with recurrent abdominal pain and weight loss Colonoscopy with biopsies to confirm diagnosis Fecal calprotectin ≥ 250 mcg per g Rectal 5-aminosalicylic acid derivatives (e.g., mesalamine)      
Ischemic colitis Bloody diarrhea followed by acute lower abdominal pain, especially in patients with cardiac risk factors Colonoscopy or CTA to confirm diagnosis Medical management of underlying vascular disease; may require surgery      
Postpolypectomy bleeding Bleeding within 30 days of polypectomy or biopsy Colonoscopy with endoscopic therapy to control bleeding      

Common Infectious Colitis Pathogens Associated with Lower Gastrointestinal Bleeding

Organism History Treatment
Campylobacter Ingestion of undercooked poultry Azithromycin (Zithromax), 500 mg per day for 3 to 5 days
Entamoeba histolytica Travel to endemic areas (e.g., tropical Africa, Asia, Latin America) Metronidazole (Flagyl), 750 mg 3 times per day for 5 to 10 days plus Paromomycin, 25 to 35 mg per kg per day in 3 divided doses for 5 to 10 days
Salmonella Ingestion of contaminated foods (e.g., eggs, poultry); can be spread by pets (e.g., turtles, snakes) Supportive care
Shiga toxin–producing Escherichia coli Ingestion of undercooked ground beef Supportive care
Shigella Exposure to surfaces or ingestion of food or water contaminated with infected fecal matter Ciprofloxacin, 500 mg 2 times per day for 3 days

Outpatient Management for hemodynamically stable patients (HR<100bpm, SBP > 115, cap refil <3s):

  • Painful bleeding:
    • Recent travel or food exposure
      • Stool cultures and consider antibiotics
    • Intermittent with abd pain and weight loss
      • Fecal calprotectin and refer for diagnostic colonoscopy
    • Acute onset with apd pain and h/o cardiovascular disease
      • Urgent colonoscopy
    • After bowel movements and pruritic
      • Anoscopy with valsalva
      • Increase fiber in diet
      • Consider surgical referral
  • Painless bleesing
    • Intermittent bleeding, bowel habit changes, and weight loss
      • Diagnostic colonoscopy
    • Acute onset with h/o diverticular disease
      • Urgent colonoscopy
    • Painless bleeding within 30 days of polypectomy or biopsy
      • Urgent diagnostic colonoscopy
    • Recurrent bleeding with no other symptoms
      • Diagnostic colonoscopy


  • AFP Feb 2020 Vol 101, No 4

9.16 Gastroparesis


  • First line:
    • metocloprmide
  • Second line:
    • domperidone
    • erythromycin
  • Also consider:
    • antiemetic agents


  • JFP Vol 67 No 11 Nov 2018

9.17 GERD

See also:

PPI Equivalence

Drug Omeprazole equivalent
Pantoprazole 20 mg 4.5 mg
Lansoprazole 15 mg 13.5 mg
Omeprazole 20 mg 20 mg
Esomeprazole 20 mg 32 mg
Rabeprazole 20 mg 36 mg

Typical GERD

  • Clinical Presentation
    • Recurrent heartburn and acid regurgitation
    • Chest pain
    • Esophagitis
    • Peptic strictures
    • Barrett esophagus
  • Treatment
    • Lifestyle modification
      • Weight loss, smoking cessation, and elevation of head of bed
    • PPI treatment daily for 4-8 wks
      • If poor response, consider altering dosage, timing, or initiating twice a day
      • If adequate response, change to PPI as needed
    • Antireflux surgery can be considered
  • Followup
    • If good PPI response - lower or stop dose
    • If esophagitis or Barretts, continue PPI at lowest dose tolerated
    • If treatment failure or alarm symptoms, urgent endoscopy
    • If no response to PPI, esophageal manometry and endoscopy to assess esophageal motor disorders and lower esophageal sphincter function
    • If no response to PPI, continue pH monitoring and perform endoscopy to confirm pathologic pH exposure

Extraesophageal GERD

  • Clinical Presentation
    • Hoarseness
    • Wheezing
    • Chronic cough
    • Asthma
    • Chronic laryngitis
    • Teeth erosions
    • Dyspepsia
    • Belching
    • Bloating
  • Treatment
    • PPI treatment daily for 8 wks for patients with concomitant typical GERD
      • If adequate response, change to PPI as needed
    • Antireflux surgery should not be considered for patients who do not respond to PPI treatment
    • Antireflux surgery can be considered for patients who cannot tolerate PPI treatment
  • Followup
    • If good PPI response - lower or stop dose
    • If suspected extraesophageal symptoms persist with no typical GERD symptoms, pH monitoring should be considered
    • If no response to PPI, consider further diagnostics
    • If treatment failure or alarm symptoms, urgent endoscopy


  • JAMA Dec 2020 Vol 324 No 24

9.17.1 PPI's and Depression

Study examined the association between use of PPIs and depressive symptoms in an elderly population.

  • 344 inhabitants of Tuscania (Italy) aged 75 years and over
  • Use of PPIs was associated with a higher Geriatric Depression Scale (GDS) score in linear regression analysis (B = 2.43; 95% CI = 0.49-4.38; p = 0.014)
  • Use of PPIs was associated with increased adjusted probability of depression in logistic regression (OR = 2.38; 95% CI = 1.02-5.58; p = 0.045).
  • Higher PPIs dosages were associated with increased probability of depression (p for trend = 0.014).
  • This association was independent of the diagnosis of peptic disease, as well as the use of antidepressant medications.
  • No association was found between use of H2-blockers or antacids and the GDS score.

Calculation of the population attributable risk indicated that 14% of depression cases could be avoided by withdrawal of PPIs.

Mood should be routinely assessed in elderly patients on PPIs.


  • Laudisio A, Antonelli Incalzi R, Gemma A, Giovannini S, Lo Monaco MR, Vetrano DL, Padua L, Bernabei R, Zuccalà G. Use of proton-pump inhibitors is associated with depression: a population-based study. Int Psychogeriatr. 2018 Jan;30(1):153-159. doi: 10.1017/S1041610217001715. Epub 2017 Sep 13. PMID: 28899441.

9.18 Gluten Free Diet Fundamentals

  • Grains that should be avoided
    • Barley (includes malt)
    • Rye
    • Wheat
  • Safe grains
    • Amaranth
    • Buckwheat
    • Corn
    • Millet
    • Oats
    • Quinoa
    • Rice
    • Sorghum
    • Teff
  • Sources of gluten-free starches to be used as flour alternatives
    • Cereal grains (amaranth, buckwheat, corn, millet, quinoa, sorghum, teff, rice, montina)
    • Legumes (chickpeas, kidney beans, lentils, navy beans, pea beans, peanuts, soybeans)
    • Nuts (almonds, cashews, chestnuts, hazelnuts, walnuts)
    • Seeds (flax, pumpkin, sunflower)
    • Tubers (arrowroot, jicama, potato, tapioca, taro)


  • AFP Vol 89 No 2 Jan 2014

9.19 Hemorrhoids

Common Nonsurgical Measures to Treat Hemorrhoids

  • Adequate insoluble fiber (25 to 35 g per day) and water intake (1.5 to 2 L per day)
  • Behavior modification: avoid straining and prolonged periods on toilet, limit fatty foods and alcohol, perineal hygiene, weight loss
  • Calcium dobesilate (not available in the United States)
  • Flavonoids (not approved by the U.S. Food and Drug Administration; examples include diosmin, micronized purified flavonoid fraction, and rutosides)
  • Sitz baths or warm water sprays
  • Stool softeners
  • Topical analgesics, antiseptics, steroids, or vasoactive agents


  • AFP Vol 101 No 1 Jan 2020

9.20 Elevated Liver Transaminase Levels   edit

Causes of Elevated Liver Transaminase Levels

Hepatocellular damage releases ALT and AST. Elevations in ALT generally are more specific for liver injury, whereas elevations in AST can also be caused by extrahepatic disorders, such as thyroid disorders, celiac sprue, hemolysis, and muscle disorders.7 Normal ALT levels are defined as 29 to 33 IU per L (0.48 to 0.55 μkat per L) for males and 19 to 25 IU per L (0.32 to 0.42 μkat per L) for females.6 The AST:ALT ratio can suggest a specific disease or give insight into liver disease severity. In a study differentiating alcoholic liver disease from nonalcoholic liver disease, alcoholic liver disease was suggested with an AST:ALT ratio greater than 2 (mean AST:ALT values were 152:70; positive likelihood ratio [LR+] = 17, negative likelihood ratio [LR–] = 0.49). On the other hand, nonalcoholic fatty liver disease (NAFLD) was associated with a ratio of less than 1 (mean AST:ALT values were 66:91; LR+ = 80, LR– = 0.2).8 However, causes of mild, asymptomatic elevation of transaminase levels can generally be categorized as common, uncommon, and rare (Table 1).9

Situation Comments
Mildly elevated ALT level (less than 1.5 times normal) ALT value could be normal for gender, ethnicity or body mass index.
  Consider muscle injury or myopathy.
Alcoholic hepatitis Laboratory values can appear cholestatic, and symptoms can mimic cholecystitis.
  Minimal elevations of AST and ALT often occur.
AST level greater than 500 U per L The AST elevation is unlikely to result from alcohol intake alone.
  In a heavy drinker, consider acetaminophen toxicity.
Common bile duct stone Condition can simulate acute hepatitis
  AST and ALT become elevated immediately, but elevation of AP and GGT is delayed.
Isolated elevation of GGT level This situation may be induced by alcohol and aromatic medications, usually with no actual liver disease.
Isolated elevation of AP level (asymptomatic patient with normal GGT level) Consider bone growth or injury, or primary biliary cirrhosis.
  AP level rises in late pregnancy.
Isolated elevation of unconjugated bilirubin level Consider Gilbert syndrome or hemolysis.
Low albumin level Low albumin is most often caused by acute or chronic inflammation, urinary loss, severe malnutrition or liver disease; it is sometimes caused by gastrointestinal loss (e.g., colitis or some uncommon small bowel disease).
  Normal values are lower in pregnancy.
Blood ammonia level Blood ammonia values are not necessarily elevated in patients with hepatic encephalopathy.
  Determination of blood ammonia levels is most useful in patients with altered mental status of new onset or unknown origin.


9.21 Irritable Bowel Syndrome



  • Loose/frequent stools
  • Constipation
  • Bloating
  • Abdominal cramping, discomfort, pain
  • Symptom brought on by food intake/specific food sensitivities
  • Symptoms dynamic over time

Concerning for organic disease:

  • Symptom onset >50yo
  • Severe or progressive symptoms
  • Unexplained weight loss
  • Nocturnal diarrhea
  • FH of organic GI diseases (colon ca, celiac, inflammatory bowel disease)
  • Rectal bleeding or melena
  • Unexplained Fe def anemia

Diagnosis (Rome IV)

  • Recurrent abdominal pain, with onset more than 6 mo ago, occurring on average 1 day per week in past 3 months associated with 2 or more of the following:
    1. Onset related to defecation
    2. Onset associated with a change in frequency of stool
    3. Onset associated with a change in form of stool


  1. IBS with constipation - hard or lumpy stools over 25% and loose or watery stools <25%
  2. IBS wiht diarrhea - loose or watery stools over 25% and hard or lumpy <25%
  3. Mixed IBS - hard or lumpy and loose and watery each over 25% of time


  • All IBS:
    • CBC
    • Colon ca screening

IBS with constipation:

  • If severe or medically refractory - refer to GI for physiologic testing
  • Treatment:
    • Antibiotics - Neomycin
    • Antidepressants
    • Antispasmodics
    • 5-HT4 agonists - Tegaserod - NNT=17
    • OTC Laxatives
    • Probiotics
    • Selective C-2 chloride channel activator - Lubiprostone

IBS with diarrhea:

  • CRP or fecal calprotectin
  • IgA tissue transutaminase +/- quantitative IgA
  • Random biopsies if colonoscopy performed
  • tauroselcholic acid (selenium 75)
  • fecal bile acids, or serum C4 if available
  • Treatment:
    • Antibiotics - Rifaximin - NNT=11
    • Antidepressants
    • Antispasmodics
    • 5-HT3 agonists - Alosetron - NNT=7
    • Probiotics

Mixed IBS:

  • CRP or fecal calprotectin
  • IgA tissue transutaminase +/- quantitative IgA
  • Stool diary
  • Consider radiography to eval stool accumulation
  • Treatment:
    • Antibiotics
    • Antidepressants
    • Antispasmodics
    • Probiotics

Treatment: (Exercise, probiotics, antibiotics, antispasmodics, antidepressants, psychological treatments, and peppermint oil may improve IBS symptoms (SOR B))

  • FODMAP diet
  • Exercise - NNT=7.4
  • For Abdominal pain/discomfort
    • Antidepressants - NNT=4
      • SSRIs for IBS-C and TCAs for IBS-D (A)
    • Alostetron (5-HT3 antagonist)
    • Antispasmodics - peppermint oil (B); dicyclomine; NNT=5 for global assessment
  • For Constipation
    • Fiber - psyllium (B)
    • Laxatives - polyethylene glycol (C); Milk of Magnesia
    • Prosecretory agents - Linaclotide - IBS-C and Mixed
    • Lubiprostone (chloride channel activator)
  • For Bloating
    • Probiotics - NNT=4 to prevent worsening
    • Rifaximin
  • For Diarrhea
    • Antidiarrheals - loperamide (C)
    • Alosetron
    • Rifaximin
    • Eluxadoline


  • AFP Vol 86 No 5 Sep 2012
  • JFP Vol 66 No 6 Jun 2017

9.21.1 IBS Dietary Ideas

General Strategies:

  • Regular meal pattern
  • Avoidance of large meals
  • Reduced intake of fat
  • Reduce intake of insoluble fibers
  • Supplement with psyllium/ispaghula
  1. Avoid Gas producing foods

    See also: Flatus control

    Here are high gas producing foods to AVOID:

    • beans
    • onions
    • celery
    • carrots
    • raisins
    • bananas
    • apricots
    • prunes
    • Brussels sprouts
    • wheat germ
    • pretzels
    • bagels
    • alcohol
    • caffeine
  2. Low FODMAP Diet

    How to use Low FODMAP diet:

    1. Eliminating FODMAPs from the diet for six to eight weeks
    2. After symptom resolution, gradually reintroduce of foods high in fermentable carbohydrates to determine tolerance to specific fermentable carbohydrates

    Eat a diet of low fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs): (Avoid these)

    • Avoid:
      • wheat
      • barley
      • rye
      • onion
      • leek
      • white part of spring onion
      • garlic
      • shallots
      • artichokes
      • beetroot
      • fennel
      • peas
      • chicory
      • pistachio
      • cashews
      • legumes
      • lentils
      • chickpeas
      • Milk, custard, ice cream and yogurt
      • apples
      • pears
      • mangoes
      • cherries
      • watermelon
      • asparagus
      • sugar snap peas
      • honey
      • apricots
      • nectarines
      • peaches
      • plums
      • mushrooms
      • cauliflower
      • high-fructose corn syrup
      • artificially sweetened chewing gum
  3. FODMAP Food Reference

    Low FODMAPs:

    • Vegetables and Legumes
      • Bamboo shoots
      • Bean sprouts
      • Broccoli
      • Cabbage, common and red
      • Carrots
      • Celery (less than 5cm stalk)
      • Chick peas (1/4 cup max)
      • Corn (1/2 cob max)
      • Courgete
      • Cucumber
      • Eggplant
      • Green beans
      • Green pepper
      • Kale
      • Letuce e.g. Buter, iceberg, rocket
      • Parsnip
      • Potato
      • Pumpkin
      • Red peppers
      • Scallions / spring onions (green part)
      • Squash
      • Sweet potato
      • Tomatoes
      • Turnip
    • Fruit
      • Bananas, unripe
      • Blueberries
      • Cantaloupe
      • Cranberry
      • Clementne
      • Grapes
      • Melons e.g. Honeydew, Galia
      • Kiwifruit
      • Lemon
      • Orange
      • Pineapple
      • Raspberry
      • Rhubarb
      • Strawberry
    • Meats
      • Beef
      • Chicken
      • Cold cuts e.g. Ham and turkey breast
      • Fresh Fish
      • Lamb
      • Pork
      • Quorn mince
      • Tuna
    • Breads, Cereals, Grains and Pasta
      • Oats
      • Quinoa
      • Gluten free foods e.g. breads, pastaSavory biscuits
      • Buckwheat
      • Chips / crisps (plain)
      • Cornflour
      • Oatmeal (1/2 cup max)
      • Popcorn
      • Pretzels
      • Rice e.g. Basmata, brown, white
      • Tortlla chips
    • Nuts and Seeds
      • Almonds (max of 15)
      • Chestnuts
      • Hazelnuts
      • Macademia nuts
      • Peanuts
      • Pecans (max of 15)
      • Poppy seeds
      • Pumpkin seeds
      • Sesame seeds
      • Sunfower seeds
      • Walnuts
    • Dairy, Eggs, Cheese
      • Almond milk
      • Coconut milk
      • Hemp milk
      • Lactose free milk
      • Oat milk (30ml max)
      • Rice milk (200ml max)
      • Soy milk made with soy protein
      • Butter
      • Dark chocolate
      • Eggs
      • Milk chocolate (3 squares max)
      • White chocolate (3 squares max)
      • Brie
      • Camembert
      • Cheddar
      • Cottage cheese
      • Feta
      • Mozzarella
      • Parmesan
      • Swiss
    • Condiments
      • Barbeque sauce
      • Chutney (1 tbsp max)
      • Garlic infused oil
      • Golden syrup
      • Strawberry jam / jelly
      • Mayonnaise
      • Mustard
      • Soy sauce
      • Tomato sauce
    • Sweeteners
      • Aspartame
      • Acesulfame K
      • Glucose
      • Saccharine
      • Stevia
      • Sucralose
      • Sugar / sucrose
    • Drinks
      • Beer (one max)
      • Black coffee
      • Herbal tea (weak)
      • Orange juice (125ml max)
      • Peppermint tea
      • Water
      • Wine (one max)

    High FODMAPs:

    • Vegetables and Legumes
      • Garlic
      • Onions
      • Aparagus
      • Beans e.g. black, broad, kidney, lima, soy
      • Caulifower
      • Cabbage, savoy
      • Mange tout
      • Mushrooms
      • Peas
      • Scallions / spring onions (white part)
    • Fruit
      • Apples
      • Apricot
      • Avocado
      • Bananas, ripe
      • Blackberries
      • Grapefruit
      • Mango
      • Peaches
      • Pears
      • Plums
      • Raisins
      • Sultanas
      • Watermelon
    • Meats
      • Chorizo
      • Sausages
      • Processed meat
    • Breads, Cereals, Grains and Pasta
      • Barley
      • Bran
      • Cous cous
      • Gnocchi
      • Granola
      • Muesli
      • Muffins
      • Rye
      • Semolina
      • Spelt
      • Wheat foods e.g. Bread, cereal, pasta
    • Nuts and Seeds
      • Cashews
      • Pistachio
    • Dairy, Eggs, Cheese
      • Cow milk
      • Goat milk
      • Sheep's milk
      • Soy milk made with soy beans
      • Butermilk
      • Cream
      • Custard
      • Greek yoghurt
      • Ice cream
      • Sour cream
      • Yoghurt
      • Cream cheese
      • Ricota cheese
    • Condiments
      • Hommus dip
      • Jam (mixed berries)
      • Pasta sauce (cream based)
      • Relish
      • Tzatziki dip
    • Sweeteners
      • Agave
      • High Frucose Corn Syrup (HFCS)
      • Honey
      • Inulin
      • Isomalt
      • Malttol
      • Mannitol
      • Sorbitol
      • Xylito
    • Drinks
      • Apple juice
      • Coconut water
      • Fennel tea
      • Herbal tea (strong)
      • Kombucha
      • Mango juice
      • Pear juice
      • Rum
      • Sodas with HFCS


9.22 Jaundice   edit

Initial laboratory tests include (CMP, Indirect Bili, PT/INR, Hepatitis panel):

  • measurements of serum total and unconjugated bilirubin (CMP)
  • alkaline phosphatase (CMP)
  • aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) (CMP)
  • prothrombin time/international normalized ratio (PT/INR)
  • albumin (CMP) tests&search=jaundice adult&topicRef=3620&anchor=H19408002&source=see_link#H19408002

Patterns of liver test abnormalities — Liver test abnormalities can often be grouped into one of several patterns: the abnormalities may be acute, subacute, or chronic based on whether they have been present for less than six weeks (acute), six weeks to six months (subacute), or more than six months (chronic). Based on the pattern of elevation, liver test abnormalities may be grouped as hepatocellular, cholestatic, or isolated hyperbilirubinemia. Hepatocellular pattern: Disproportionate elevation in the serum aminotransferases compared with the alkaline phosphatase Serum bilirubin may be elevated Tests of synthetic function may be abnormal

Cholestatic pattern: Disproportionate elevation in the alkaline phosphatase compared with the serum aminotransferases Serum bilirubin may be elevated Tests of synthetic function may be abnormal

Isolated hyperbilirubinemia: As the term implies, patients with isolated hyperbilirubinemia have an elevated bilirubin level with normal serum aminotransferases and alkaline phosphatase

The R value (also known as the R factor) can be used to help determine the likely type of liver injury (hepatocellular versus cholestatic) in patients with elevated aminotransferases and alkaline phosphatase.

  • R value = (ALT ÷ ULN ALT) / (alkaline phosphatase ÷ ULN alkaline phosphatase)
    • (ULN = upper Limit of Normal)
    • The R value is interpreted as follows:
      • ≥5: Hepatocellular injury
      • >2 to <5: Mixed pattern
      • ≤2: Cholestatic injury

Because the serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions, it is not helpful in differentiating between the two. Common hepatocellular diseases associated with an elevated bilirubin and jaundice include viral and toxic hepatitis (including drugs, herbal therapies, and alcohol) and end-stage cirrhosis from any cause (table 2).

If both the serum aminotransferases and alkaline phosphatase are elevated, the liver test abnormalities are characterized by the predominant abnormality (eg, if the serum aminotransferases are 10 times the upper limit of normal and the alkaline phosphatase is twice the upper limit of normal, the liver test abnormalities would be characterized as primarily hepatocellular). However, making this distinction is not always possible. The degree of aminotransferase elevation can occasionally help in differentiating between hepatocellular and cholestatic processes. While ALT and AST values less than eight times the upper limit of normal may be seen in either hepatocellular or cholestatic liver disease, values 25 times the upper limit of normal or higher are seen primarily in hepatocellular diseases.

Abnormal tests of synthetic function may be seen with both hepatocellular injury and cholestasis. A low albumin suggests a chronic process, such as cirrhosis or cancer, while a normal albumin suggests a more acute process, such as viral hepatitis or choledocholithiasis. A prolonged prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and intestinal malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K suggests severe hepatocellular injury. (See "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)".)

AST to ALT ratio — Most causes of hepatocellular injury are associated with a serum AST level that is lower than the ALT. An AST to ALT ratio of 2:1 or greater is suggestive of alcoholic liver disease, particularly in the setting of an elevated gamma-glutamyl transpeptidase [19]. In a study of 271 patients with biopsy-confirmed liver disease, more than 90 percent of the patients in whom the AST to ALT ratio was two or greater had alcoholic liver disease [20]. The percentage increased to greater than 96 percent when the ratio was greater than three. In addition, 70 percent of the patients with known alcoholic liver disease had an AST to ALT ratio greater than two. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis", section on 'Liver test abnormalities'.)

However, the AST to ALT ratio is occasionally elevated in an alcoholic liver disease pattern in patients with nonalcoholic steatohepatitis, and it is frequently elevated (although not greater than two) in patients with hepatitis C who have developed cirrhosis. In addition, patients with Wilson disease or cirrhosis due to viral hepatitis may have an AST that is greater than the ALT, although in patients with cirrhosis the ratio typically is not greater than two. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Hepatic disease'.)

Magnitude of AST and ALT elevations — The magnitude of AST and ALT elevations varies depending on the cause of the hepatocellular injury [21-24]. While values may vary in individual patients, the following are typical AST and ALT patterns: Alcoholic fatty liver disease: AST <8 times the upper limit of normal; ALT <5 times the upper limit of normal. Nonalcoholic fatty liver disease: AST and ALT <4 times the upper limit of normal. Acute viral hepatitis or toxin-related hepatitis with jaundice: AST and ALT >25 times the upper limit of normal. Ischemic hepatitis (ischemic hepatopathy, shock liver, hypoxic hepatitis): AST and ALT >50 times the upper limit of normal (in addition the lactate dehydrogenase is often markedly elevated). Chronic hepatitis C virus infection: Wide variability, typically normal to less than twice the upper limit of normal, rarely more than 10 times the upper limit of normal. Chronic hepatitis B virus infection: Levels vary; the AST and ALT may be normal in inactive carriers, whereas most patients with chronic hepatitis B have mild to moderate elevations (approximately twice the upper limit of normal); with exacerbations, levels are more than 10 times the upper limit of normal.

Marked elevations in serum aminotransferase levels may be seen with: Acetaminophen (paracetamol) toxicity Idiosyncratic drug reactions Acute viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus; Epstein-Barr virus; cytomegalovirus [CMV]); other viral infections; or n acute exacerbation of chronic viral hepatitis (hepatitis B) Alcoholic hepatitis Autoimmune hepatitis Wilson disease Ischemic hepatitis Budd-Chiari syndrome Sinusoidal obstruction syndrome (veno-occlusive disease) HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and occasionally acute fatty liver of pregnancy Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma, melanoma, or myeloma) Partial hepatectomy Toxin exposure, including mushroom poisoning Sepsis Heat stroke Muscle disorders (acquired muscle disorders [eg, polymyositis], seizures, and heavy exercise [eg, long distance running])

Conditions associated with mild to moderate serum aminotransferase elevations include (table 3): Medication use Chronic viral hepatitis (hepatitis B, C, D) Alcoholic liver disease Hemochromatosis Nonalcoholic fatty liver disease Autoimmune hepatitis Wilson disease Alpha-1 antitrypsin deficiency Congestive hepatopathy Adult bile ductopenia Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma, melanoma, or myeloma) Muscle disorders (eg, subclinical inborn errors of muscle metabolism) Thyroid disorders Celiac disease Adrenal insufficiency Anorexia nervosa Macro-AST (moderate elevations in plasma AST levels due to the presence AST-immunoglobulin complexes, usually IgG) [28]

If the initial evaluation fails to identify a likely source of the aminotransferase elevation, we test for the following: Autoimmune hepatitis: Antinuclear antibodies, anti-smooth muscle antibodies, and anti-liver/kidney microsomal antibodies, IgG (see "Overview of autoimmune hepatitis", section on 'Diagnostic evaluation'). Wilson disease: Serum ceruloplasmin, evaluation for Kaiser-Fleisher rings, (see "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Initial evaluation'). Alpha-1 antitrypsin deficiency: Serum alpha-1 antitrypsin level; if indicated, alpha-1 antitrypsin phenotyping (see "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis'). Thyroid disorders: Thyroid-stimulating hormone, free T4 concentration, free T3 concentration (see "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Diagnosis of hyperthyroidism"). Celiac disease: Antibody screening with serum tissue transglutaminase antibodies [33] (see "Diagnosis of celiac disease in adults").

If the source of the liver test abnormalities is still unclear, we test for the following: Adrenal insufficiency (in patients with symptoms associated with adrenal insufficiency, such as chronic malaise, anorexia, or weight loss): 8 AM serum cortisol and plasma corticotropin (ACTH), and a high-dose ACTH stimulation test (see "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults"). Muscle disorders (in patients with symptoms such exercise intolerance, muscle pain, or muscle weakness): Creatinine kinase or aldolase (see "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations').

To confirm that an isolated elevation in the alkaline phosphatase is coming from the liver, a GGT level or serum 5'-nucleotidase level should be obtained. These tests are usually elevated in parallel with the alkaline phosphatase in liver disorders but are not increased in bone disorders. An elevated serum alkaline phosphatase with a normal GGT or 5'-nucleotidase should prompt an evaluation for bone diseases.

If the alkaline phosphatase elevation is isolated (ie, the other routine liver biochemical test levels are normal), is confirmed to be of hepatic origin, and persists over time, chronic cholestatic or infiltrative liver diseases should be considered (table 5). The most common causes include partial bile duct obstruction, primary biliary cholangitis (PBC), primary sclerosing cholangitis, and certain drugs, such as androgenic steroids and phenytoin. Infiltrative diseases include sarcoidosis, other granulomatous diseases, amyloidosis, and, less often, unsuspected cancer that is metastatic to the liver.

Acute or chronic elevation of the alkaline phosphatase in conjunction with other liver biochemical abnormalities may be due to extrahepatic causes (eg, bile duct stones, primary sclerosing cholangitis, malignant biliary obstruction) or intrahepatic causes (eg, PBC, primary sclerosing cholangitis, infiltrative disease). (See 'Extrahepatic cholestasis' below and 'Intrahepatic cholestasis' below.)

Rarely, an elevated alkaline phosphatase level is seen because of the presence of macro-alkaline phosphatase. Macro-alkaline phosphatase is due to the formation of complexes of alkaline phosphatase with immunoglobulins, which have reduced renal clearance compared with unbound alkaline phosphatase [37]. The clinical significance of these complexes is uncertain.

Conjugated (direct) hyperbilirubinemia — An isolated elevation in conjugated bilirubin is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. Dubin-Johnson syndrome and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia (with a direct-reacting fraction of approximately 50 percent) in the absence of other abnormalities of standard liver biochemical tests. Normal levels of serum alkaline phosphatase and GGT help to distinguish these conditions from disorders associated with biliary obstruction. Differentiating between these syndromes is possible but clinically unnecessary due to their benign nature. In children, other inherited disorders caused by mutations in one of a variety of bile salt transporters may need to be considered [39]. (See "Inherited disorders associated with conjugated hyperbilirubinemia".)

Patients with both conditions present with asymptomatic jaundice, typically in the second decade of life. The defect in Dubin-Johnson syndrome is altered hepatocyte excretion of bilirubin into the bile ducts, while Rotor syndrome is due to defective hepatic reuptake of bilirubin by hepatocytes [40].

Unconjugated (indirect) hyperbilirubinemia — Unconjugated hyperbilirubinemia may be observed in a number of disorders (table 6). These can be divided into disorders associated with bilirubin overproduction (such as hemolysis and ineffective erythropoiesis) and disorders related to impaired hepatic uptake or conjugation of bilirubin (such as Gilbert disease, Crigler-Najjar syndrome, and the effects of certain drugs). The evaluation typically involves evaluation for hemolytic anemia as well as obtaining a history to determine if the patient has Gilbert syndrome. In a patient with a history consistent with Gilbert syndrome (eg, the development of jaundice during times of stress or fasting), normal serum aminotransferase and alkaline phosphatase levels and mild unconjugated hyperbilirubinemia (<4 mg/dL), additional testing is not required [2]. Genetic testing can confirm the diagnosis in settings where there is diagnostic confusion. In patients with persistent or worsening unexplained unconjugated hyperbilirubinemia, symptomatic hyperbilirubinemia, or abnormal aminotransferases, a liver biopsy should be performed. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction", section on 'Diagnosis'.)

9.23 NAFLD

Evaluation of NAFLD in Primary Care

  • Calculate Fibrosis Score
    • < -1.455: Low likelihood of nonalcoholic steatohepatitis
      • Continue serial monitoring
      • Reduce cardiometabolic risk
    • -1.455 to 0.676: Intermediate
      • Consider transient elastography (Fibroscan) and fibrosis biomarker measurements
      • Low likelihood of nonalcoholic steatohepatitis
        • Continue serial monitoring
        • Reduce cardiometabolic risk
      • High likelihood of nonalcoholic steatohepatitis
        • Referral for liver biopsy
        • Evaluation for sequelae of cirrhosis
    • > 0.676: High likelihood of nonalcoholic steatohepatitis
      • Referral for liver biopsy
      • Evaluation for sequelae of cirrhosis

NAFLD Index:

NAFLD fibrosis score:

    • Assess risk of hepatic fibrosis
      • Age
      • ALT/AST
      • BMI
      • DM or glucose intolerance
      • Platelet count
      • Serum Albumin


  • AFP Vol 95 No 12 Jun 2017
  • AFP Vol 96 No 11 Dec 2017

9.23.1 Diagnosis:

  1. Exclude alcohol as etiology
    1. EtOH history
    2. GGT - usually take 80g/d
    3. Carbohydrate-deficient transferrin
      1. Can exclude "excessive" EtOH
    4. AST/ALT ratio
      1. <1 for no EtOH
  2. Exclude other hepatiglides
    1. Viral A, B, C
    2. Autoimmune
    3. Hemochromatosis
    4. Wilson's
    5. Alpha 1-antitrypsin deficiency
  3. Image
    1. Test of choice = MRI
    2. If not available, then US or CT
  4. Consider liver biopsy
    1. Definitive diagnosis
    2. Refer if persistently elevated transaminases without identified etiology


  • FMX 2016

9.23.2 Hystological Types

Type Description Significance
1 Simple steatosis Early
2 With Inflammation Early
3 With fibrosis Risk of cirrhosis
4 Balloon cells and hyaline Highest risk of cirrhosis


  • FMX 2016

9.23.3 Treatment

  1. Weight Loss
    1. Exercise (LOE A)
    2. Diet
      1. Best diet is low carbohydrate diet (LOE B)
      2. Second best is Mediterranean diet (LOE B)
  2. Pharmacotherapt
  3. Must target Obesity and Insulin resistance

Lifestyle Management for NAFLD:

  • Weight loss:
    • Aim for 7%-10% body weight
    • For those overweight or with obesity
  • General nutrition:
    • Low-fat to Mod-fat, Low-carb, or Mediterranean diet
  • Fructose intake:
    • Avoid fructose-containing beverages and foods
    • High fructose intake is associated with NAFLD
  • Physical activity:
    • 150-200min/wk of moderate to vigorous exercise
    • Vigorous activity may improve NAFLD over moderate activity
  • Alcohol intake:
    • Daily intake less than 30g for men and <20g for women
    • Limiting EtOH intake may lower risk of NAFLD
  • Coffee drinking:
    • No liver-related limitations
    • Coffee drinking may lower risk of NAFLD


  • FMX 2016
  • JFP Vol 96 No 11 Dec 2017

9.24 Pancreatitis - Chronic

Chronic Pancreatitis Treatment Options:

  • Medical
    • Analgesics (stepwise approach)
    • Antidepressants (treatment of concurrent depression)
    • Cessation of alcohol and tobacco use
    • Denervation (celiac nerve blocks, transthoracic splanchnicectomy)
    • Insulin (for pancreatic diabetes)
    • Low-fat diet and small meals
    • Pancreatic enzymes with proton pump inhibitors or histamine H2 blockers
    • Steroid therapy (in autoimmune pancreatitis)
    • Vitamin supplementation (A, D, E, K, and B12)
  • Endoscopic
    • Extracorporeal shock wave lithotripsy with or without endoscopy
    • Pancreatic sphincterotomy and stent placement for pain relief
    • Transampullary or transgastric drainage of pseudocyst
  • Surgical
    • Decompression
    • Cystenterostomy
    • Lateral pancreaticojejunostomy (most common)
    • Sphincterotomy or sphincteroplasty
    • Resection
    • Distal or total pancreatectomy
    • Pancreatoduodenectomy (Whipple procedure, pylorus-preserving, duodenum-preserving)
  • Not recommended
    • Allopurinol
    • Antioxidant therapy (vitamin C, vitamin E, selenium, methionine [no longer available in the United States])
    • Octreotide (Sandostatin)
    • Prokinetic agents (erythromycin)


  • AFP Vol 97 No 6 Mar 2018

9.24.1 Indications for surgery

  • Biliary or pancreatic stricture
  • Duodenal stenosis
  • Fistulas (peritoneal or pleural effusion)
  • Hemorrhage
  • Intractable chronic abdominal pain
  • Pseudocysts
  • Suspected pancreatic neoplasm
  • Vascular complications


  • AFP Vol 97 No 6 Mar 2018

9.25 Reflux Conservative Management

Ways to stop your reflux:

  1. Stop all caffeine, chocolate, alcohol, nicotine
  2. Elevate the head of the bed (do not use multiple pillows)
  3. Eat smaller meals more frequently
  4. Do not eat within 3 hours of going to bed
  5. Avoid wearing tight garments
  6. Follow these food rules:
Avoid Enjoy
Alcohol Fresh vegetables
Barbecue sauces Meat
Caffeine Milk
Carbonated beverages Poultry
Chocolate Seafood
Citrus fruits  
Excessive salt  
Fatty or Fried Foods  
Hot mustard  
Hot peppers  
Salad dressings  
Spicy foods  


  • JFP Vol 59 No 2 Feb 2010
  • NEJM 359;16 Oct 2008

9.26 Transaminases

9.26.1 ALT and AST

  • ALT most specific for hepatocyte injury
  • AST:ALT >2 suggests Alcohol Liver disease
  • AST:ALT >4 suggests possible Wilson's disease
  • Step 1:
    • History/Physical, Stop alcohol, eval medications, repeat labs in 2-4 wks
  • Step 2:
    • LFTs, Coags, CBC , albumin, viral serology, Ferritin, Fe, TIBC, fasting glucose, lipids
  • Step 3:
    • Avoid Hepatotoxins, Withdraw suspected medications
    • Reduce hepatic Steatosis risks: Weight loss if Overweight, Improve glucose control, Treat Hyperlipidemia, Repeat LFTs in 2-6 months
    • Obtain imaging as above if elevations persist
  • Step 4:
    • Obtain Ultrasound of right upper quadrant
    • Obtain disease specific markers
    • Complete initial labs from step 1
    • Ceruloplasmin (Wilson's Disease)
    • Antinuclear Antibody
    • Anti-Smooth Muscle Antibody
    • Alpha-1-antitrypsin
    • Anti-tissue transglutaminase Antibody: Celiac Sprue
  • Step 5:
    • If testing as above is negative for specific cause:
      • Aminotransferases exceed twice normal -> Refer to Gastroenterology for biopsy
      • Aminotransferases mildly elevated -> Follow serial Aminotransferases (AST, ALT)


  • JAMA Vol 313, No 5 Feb 2015

9.26.2 Alkaline Phosphatase (marked) with normal transaminases:

  • Confirm increase is due to gastrointestinal cause (e.g. as opposed to bone) with GGT (elevated if from liver) or fractionated Alkaline Phosphatase
  • Cholestatic Liver Disease:
    • Primary Sclerosing Cholangitis
    • Primary Biliary Cirrhosis
  • Infiltrative Conditions:
    • Malignancy
    • Amyloidosis
    • Sarcoidosis
    • Infectious disease


  • JAMA Vol 313, No 5 Feb 2015

9.26.3 Bilirubin elevation with normal transaminases:

  • Predom conjugated (direct) hyperbilirubinemia:
    • biliary obstruction
    • Intrahepatic cholestasis
    • Hepatocellular injury
    • Dubin-Johnson syndrome
    • Rotor syndrome
  • Predom unconjugated (indirect) hyperbilirubinemia:
    • Obtain:
      • haptoglobin
      • LDH
    • If abnormal -> increased bilirubin production
      • hemolysis
      • dyserythropoiesis
    • If normal and other medical problems
      • Medications
      • Portosystemic shunts
    • If normal and no other medical problems
      • Bilirubin <5mg/dL -> Gilbert syndrome
      • Bilirubin >5mg/dL -> Other etiologies like Crigler-Najar syndrome

Gilbert syndrome is in 5-10% of Western European population


  • JAMA Vol 313, No 5 Feb 2015

9.27 Ulcers

H pylori associated peptic ulcers

  • 7d treatment with PPI+2 Abx heals >90%
  • Clarithromycin + metronidazole, amoxicillin, or tinidazole
  • SOR A

NSAID associated peptic ulcers

  • 8wks of PPI > 4wks of PPI
  • SOR A

NSAID associated duadenal ulcers

  • 4wks PPI
  • SOR A

Endoscopic submucosal dissection related gastric ulcers

  • 4wks of PPI is as effective as 8wks
  • 1/3 ulcers remain unhealed
  • SOR B


  • JFP Vol 64 No 12 2015

9.27.1 Helicobacter pylori

Sequential therapy with amoxicillin plus a proton pump inhibitor (PPI) for 5 days, followed by clarithromycin and metronidazole or tinidazole for 5 days, had a better eradication rate than standard triple therapy in randomized controlled trials performed to date. It is a good alternative for the eradication of Helicobacter pylori (HP) infection in symptomatic patients. (LOE = 1b)


  • Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol


9.29 IBS

Diagnostic Criteria

  • Recurrent abdominal pain, with onset more than 6 months earlier, occurring on average at least 1 day per week in the past 3 months, and associated with 2 or more of the following features
    • Related to defecation (may be improved or worsened)
    • Associated with a change in the frequency of stool
    • Associated with a change in the form or appearance of stool
  • Additional symptoms support the diagnosis of IBS
    • Abnormal stool frequency (more than 3 times per day or less than 3 times per week)
    • Abnormal stool form (loose and watery or lumpy and hard)
    • Abnormal stool passage (urgency, straining, feeling of incomplete evacuation)
    • Passage of mucus (white material)
    • Abdominal bloating
    • Abdominal distention
    • Absence of nocturnal stools
  • Subtypes of IBS*
    • IBS with predominant diarrhea: > 25% of bowel movements are Bristol Stool Scale type 6 or 7, and < 25% are type 1 or 2
    • IBS with predominant constipation: > 25% of bowel movements are Bristol Stool Scale type 1 or 2, and < 25% are type 6 or 7
    • IBS with mixed symptoms of constipation and diarrhea: > 25% of bowel movements are Bristol Stool Scale type 1 or 2, and > 25% are type 6 or 7
    • Unclassified IBS: bowel movements cannot be accurately categorized as one of the three subtypes

Alarm Features Suggesting the Possible Need for Further Testing

  • Abdominal mass
  • Extreme diarrhea symptoms (large volume, bloody, nocturnal, progressive pain, does not improve with fasting)
  • Fever
  • Gastrointestinal bleeding (overt: melena or hematochezia; occult: anemia or fecal occult blood on testing)
  • Jaundice
  • Lymphadenopathy
  • New-onset symptoms in patients 55 years and older
  • Symptoms of chronic pancreatitis
  • Symptoms of gastrointestinal cancer or a family history of the disease
  • Symptoms of ovarian cancer or a family history of the disease
  • Tenesmus (rectal pain or feeling of incomplete evacuation)
  • Unintentional weight loss

First-Line Management of IBS and Other Functional Gastrointestinal Disorders

  • Diet
    • General
      • Patients should focus on eating in moderation, getting adequate but not excessive fiber, decreasing fatty and spicy foods, and avoiding caffeine, soft drinks, carbonated drinks, and artificial sweeteners before considering more restrictive elimination diets
    • FODMAP-restricted diet
      • Shows promise for IBS management, but questions remain regarding long-term safety, effectiveness, and practicality; if this diet is initiated, patients should be supervised by an experienced dietitian7,28,47,48
    • Gluten-free diet
      • Patients with celiac disease derive clear benefit; some patients without celiac disease markers seem to benefit (wheat contains gluten and high levels of fructans; reduction of fructans may partly explain the benefit in patients with IBS)
      • Long-term effects of a gluten-free diet on microbiome and general nutrition are uncertain; strictly adhering to this diet is difficult and expensive
      •  Recommended only for patients with proven celiac disease
  • Exercise
    • Regular daily exercise decreases symptoms of IBS and chronic constipation47
  • Fiber
    • Soluble fiber (psyllium [Metamucil]): 25 to 30 g daily has a small benefit for some patients with IBS but can worsen bloating in others
    • Insoluble fiber (bran, methylcellulose, polycarbophil [Fibercon]): 2 heaping teaspoons daily was of no benefit to patients with IBS; some benefit for chronic constipation
    • All fiber should be increased gradually to minimize bloating, distention, flatulence, and cramping
    • Worsening of gas and bloating with fiber supplementation may also suggest underlying dyssynergic defecation (pelvic floor dysfunction)
  • Osmotic laxatives
    • Polyethylene glycol (Miralax): 17 g once daily; this is the best studied osmotic laxative and is most effective for chronic constipation, with slight improvement in stool frequency in IBS-C
    • Other osmotic laxatives include lactulose, sorbitol, and mannitol
  • Probiotics
    • Probiotics, especially Bifidobacterium infantis, improve bloating, flatulence, and pain in IBS and may also help chronic constipation
  • Antispasmodics
    • Dicyclomine: 20 mg 4 times daily (maximum 40 mg four times daily) 30 minutes before meals; moderately effective for IBS7,8,42,47
    • Hyoscyamine extended release (Levbid), 0.375 to 0.75 mg 2 times daily (maximum 1.5 g per day); moderately effective for IBS42,47
    • Hyoscyamine (Levsin), 0.125 to 0.25 mg every 4 hours as needed (maximum 1.5 mg per day; 30 minutes before meals); moderately effective for IBS
    • Peppermint oil: 200 to 750 mg 2 or 3 times daily; moderately effective for IBS7,8,42,47
    • STW 5 herbal preparation (proprietary blend of 9 herbs, available over the counter): 20 drops (30 minutes before meals); antispasmodic and prokinetic actions
  • Opioid agonists
    • Diphenoxylate/atropine (Lomotil) has not been studied in IBS
    • Loperamide (Imodium): 2 to 4 mg up to 4 times daily; decreases colonic transit and increases water absorption, improves many IBS-D symptoms, including urgency and stool frequency47
    • Older clinical trials were small but demonstrated improved overall response52,53
  • Serotonin (5-HT3) receptor antagonist
    • Ondansetron (Zofran): 4 mg up to 3 times daily (many patients need to use only once daily or less); improves urgency and frequency of loose stools in IBS-D and postinfectious IBS
    • Less improvement of pain but two-thirds of patients report adequate relief; some of the benefit may be related to relief of coexisting heartburn and postprandial pain/dyspepsia54
    • Widely available, inexpensive, excellent safety profile over many decades (alosetron [Lotronex], a more potent serotonin (5-HT3) receptor antagonist approved only for more severe IBS-D in women, has significant safety concerns)
  • Antidepressants (gut-brain modulators)
    • Amitriptyline: 10 to 50 mg at bedtime (increase by 10 mg every 1 to 2 weeks) and other tricyclic antidepressants; effective for overall symptom relief in IBS-D and other functional gastrointestinal disorders7,8,47
    • Histaminergic properties are moderately sedating, and anticholinergic properties are moderately constipating55
    • Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine [Cymbalta]): strong evidence for benefit in several chronic pain disorders but not currently studied in IBS7,8
    • Selective serotonin reuptake inhibitors: slight overall improvement, probably related to relief of central and visceral hypersensitivity and psychological distress; may help constipation7,8


  • AFP Jun 2021 Vol 103 No 12

10 Geriatrics

10.1 Constipation in Elderly

Also See: Constipation in Gastroenterology


  • Lifestyle modifications:
    • Scheduled toileting after meals
    • Increased fluid intake
    • Increased dietary fiber intake
  • Additional fiber intake:
    • Forms of polycarbophil, methylcellulose, or psyllium may improve symptoms.
    • Fiber intake should be slowly increased over several weeks to decrease adverse effects.
  • The next step: an osmotic laxative:
    • Such as polyethylene glycol
  • Then a stool softener:
    • Such as docusate sodium
  • Then stimulant laxatives
  • Long-term use of magnesium-based laxatives should be avoided because of potential toxicity.


10.2 Dementia

Diagnostic Criteria for Neurocognitive Disorders:

Major neurocognitive disorder Minor neurocognitive disorder
Significant cognitive decline in at least one cognitive domain as seen in both of the following: Modest cognitive decline in at least one cognitive domain as seen in both of the following:
- Concerns expressed by the patient or reliable informant or as seen by the clinician - Concerns expressed by the patient or reliable informant or as seen by the clinician
- Objective neurocognitive testing/assessments - Objective neurocognitive testing/assessments
Interference with instrumental activities of daily living Does not interfere with instrumental activities of daily living, but they require additional time and effort
  • Cannot occur exclusively during bouts of delirium
  • Cannot be explained by another mental disorder
  • Specify one or more causal subtypes
    • Alzheimer disease
    • Lewy body dementia
    • Traumatic brain injury
    • Frontotemporal lobar
    • Parkinson disease
    • Vascular disease
    • Human immunodeficiency virus infection
    • Prion disease
    • Other medical condition
    • Huntington disease
    • Substance/medication use
    • Multiple etiologies


Cognitive domain Symptoms and observations
Executive function Difficulty in completing previously familiar multistep tasks, such as preparing a meal; no longer wanting to participate in activities of the home; difficulty in completing activities or tasks because of easy distractibility; social outings become more taxing and less enjoyable
Language Difficulty finding the correct words; using general pronouns regularly instead of names; mispronunciation of words; problems with understanding verbal and written communication
Learning and memory Forgetting to buy items or buying the same items multiple times at the store; repetition in conversations; difficulty in recalling recent events; relying on lists of tasks to complete; forgetting to pay bills
Perceptual-motor Difficulty in using familiar technology, tools, or kitchen appliances; getting lost in familiar environments
Social cognition Apathy, increase in inappropriate behaviors, loss of empathy, impaired judgment

Possible Etiologies of Dementia:

Suggested etiology Key findings on history and examination
Delirium Recent hospitalization or acute illness, inattention, fluctuating behavior changes, altered level of consciousness
Frontotemporal dementia Socially inappropriate behaviors; loss of empathy; changes in dress, eating habits, religious/political beliefs; development of compulsive behaviors; progressive aphasia
Human immunodeficiency virus infection History of high-risk sexual behavior or drug use, apathy, poor attention and concentration, hyperreflexia, slow limb movements
Hypoperfusion from heart failure Syncope, history of heart failure
Intracranial tumor Seizures, neurologic deficits
Medication adverse effects Use of anticholinergic drugs, benzodiazepines, opioids, or muscle relaxants
Neurocognitive disorder with Lewy body dementia Daytime drowsiness, daytime naps lasting more than two hours, prolonged staring spells, disorganized speech, visual hallucinations, parkinsonian symptoms
Vascular dementia History of symptoms beginning after cerebrovascular events
Other medical conditions  
- Depression Anhedonia, feelings of worthlessness, slowed speech, flat affect, sleep disturbance
- Hypothyroidism Fatigue, cold intolerance, constipation, weight gain, dry skin, prolonged deep tendon reflexes, myalgias
- Neurosyphilis History of high-risk sexual behavior or injection drug use, vision and hearing loss, decreased proprioception, stabbing extremity pains
- Niacin/vitamin B3 deficiency History of bariatric surgery or malabsorption disorders, photosensitive rash, anxiety, insomnia, diarrhea, vomiting
- Normal-pressure hydrocephalus Urinary incontinence and broad-based, shuffling gait
- Vitamin B12 deficiency Ascending paresthesias, tongue soreness, limb weakness, weight loss
- Wernicke-Korsakoff syndrome History of alcoholism, nystagmus or extraocular muscle weakness, broad-based gait and stance

10.2.1 Dementia Work Up   edit

The most common neurodegenerative conditions causing dementia are:

  • Alzheimer disease (AD)
  • Dementia with Lewy bodies
  • Frontotemporal dementia
  • Parkinson disease dementia

Less common neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multisystem atrophy, and Huntington disease can also be associated with dementia.

Non-neurodegenerative dementias may be reversible, or progression slowed or halted, if the underlying cause can be identified and adequately treated [7]. The most common of these is: Vascular dementia

Forgetfulness is the most common chief complaint; in addition, patients with dementia also have difficulty with one or more of the following [11]:

  • Retaining new information (eg, trouble remembering events)
  • Handling complex tasks (eg, balancing a checkbook)
  • Reasoning (eg, unable to cope with unexpected events)
  • Spatial ability and orientation (eg, getting lost in familiar places)
  • Language (eg, word finding)
  • Behavior


  • Patients with cognitive complaints should undergo a careful mental status examination.
  • All patients being evaluated for cognitive impairment or dementia should be screened for depression


Check these labs:

  • Complete blood cell count (CBC)
  • Serum chemistry panel and Serum electrolyte levels, including liver function tests (CMP)
  • Magnesium (Mg)
  • Thyroid function tests (TSH)
  • Hemoglobin A1c
  • Serum vitamin B12
  • Urinalysis and microscopy

Consider these:

  • Erythrocyte sedimentation rate*
  • Serologic tests for syphilis (or similar)*
  • Chest radiography*
  • Electrocardiography*
  • Toxicology screening*
  • Urine toxicology

*—To be considered, not universally needed.


Neuroimaging with a head computed tomography (CT) or magnetic resonance imaging (MRI) scan is unequivocally indicated in patients with acute onset of cognitive impairment and/or rapid neurologic deterioration.

AAN recommends structural neuroimaging with either a noncontrast head CT or MRI in the routine initial evaluation of all patients with dementia order imaging when patients present with unusual or atypical findings or when imaging findings may be reassuring for patients and families. Such differences in practice may be attributable to the context in which the patient is seen

MRI is preferred over CT because it is more sensitive for a broad range of potential pathologies while avoiding exposure to potentially harmful ionizing radiation

Magnetic resonance imaging without contrast media is the preferred imaging test to exclude other intracranial abnormalities, such as stroke, subdural hematoma, normal-pressure hydrocephalus, or a treatable mass. LOE C


  • Evidence from the history and clinical assessment that indicates significant cognitive impairment in at least one of the following cognitive domains:
    • Learning and memory
    • Language
    • Executive function
    • Complex attention
    • Perceptual-motor function
    • Social cognition
  • The impairment must be acquired and represent a significant decline from a previous level of functioning
  • The cognitive deficits must interfere with independence in everyday activities
  • The disturbances are not occurring exclusively during the course of delirium
  • The disturbances are not better accounted for by another mental disorder (eg, major depressive disorder, schizophrenia)


  • AFP Vol 97 No 6 Mar 2018

10.2.2 As fitness improves, Alzheimer's risk decreases


  • 649605 Veterans
  • Mean age: 61yo
  • Fit determined with GXT and peak METS achieved
    • Lowest: 3.8 METS - Developed ADRD at rate of 9.5/1000 person years
    • Low: 5.8 METS
    • Mod: 7.5 METS
    • Fit: 9.2 METS
    • Highest: 11.7 METS - Developed ADRD at rate of 6.4/1000 person year
Table 33: Likelihood of developing ADRD
Fitness group Adjusted hazard ratio (95% confidence interval)
Low fit 0.87 (0.85-0.90)
Mod fit 0.80 (0.78-0.83)
Fit 0.74 (0.72-0.76)
Highest Fit 0.67 (0.65-0.70)


10.2.3 Alzheimer's

10 Warning Signs:

  1. Memory loss that disrupts daily life
  2. Challenges in planning or solving problems
  3. Difficulty completing familiar tasks
  4. Confusion with time or place
  5. Trouble understanding visual images or spacial relationships
  6. New problems with words in speaking or writing
  7. Misplacing things and losing the ability to retrace steps
  8. Decreased or poor judgement
  9. Withdrawal from work or social activities
  10. Changes in mood and personality

Diagnostic criteria:

  1. Cognitive or behavioral symptoms that
    • interfere with ability to funciton
    • represent a decline from previous levels of functioning and
    • are not explained by delerium or major psychiatric disorder
  2. Cognitive impairment diagnoses through
    • history by patient/informant and
    • bedside mental status exam or neuropsychological testing
  3. Cognitive or behavioral impairment involving 2 or more of the following:
    • ability to acquire and remember new information
    • reasoning, judgement, and handling of complex tasks
    • visuospatial abilities
    • language function
    • personality or behavior

Patients must also meet:

  1. Dementia must have insidious onset and
  2. have worsening course

Nonpharmacologic Therapies for Management

  • Enjoyable leisure activities
  • Mental stimulation programs (puzzles, word games, past/reminiscence therapy, indoor gardening, baking)
  • Occupational therapy training in coping strategies and cognitice aids
  • Structured physical exercise programs


  • JFP Vol 64 No 1 Jan 2015
  • AFP Vol 95 No 12 Jun 2017

  1. Differentiate Alzeheimer Disease from Depression
      Alzeheimer Dementia Depression
    Behavior congruent with deficits Usual Unusual
    Delusions Mood independent Mood congruent
    Emotional reaction Variable Marked distress
    Mood disorder Environmentally responsive Persistent
    Pt report of deficits Variable Abundant
    Psychiatric history Unusual Usual
    Symptom duration Long Short
    Symptom progression Slow Rapid
    Valuation of accomplishments Variable Minimized


    • AFP Vol 82 No 5 Sep 2010
  2. Treatment


    • Physical exercise - 30-45min of cardio, 4-5d/wk
    • Cogniticve exercises - reading, puzzles, social games, learning
    • Social stimulation - weekly social activities
    • Diet - Mediterranean diet, nuts


    • Acetylcholinesterase Inhibitors:
      • Donepezil
      • Rivastigmine
      • Galantamine
    • NMDA Receptor Antagonist:
      • Memantine


    • Consultant Dec 2016

10.2.4 Cognition Assessment Tools

Assess Cognition:

  1. Language functions
    • Naming, reading, writing
  2. Visuospatial ability
    • Copying a figure; drawing the face of a clock
  3. Abstract reasoning
    • Explainig proverbs; describing similarities (like an apple with a pear)
  4. Executive functions
    • List making (name as many animals in 1min); drawing the face of a clock
  5. General intellectual level/fund of knowledge
    • Identify the previous 5 presidents
  6. Attention to concentration
    • Spell "world" forward and backward; subtract serial 7's from 100
  7. Memory (screening tools)
    • Mini-cog
    • MMSE
      • 81% Sensitivity; 89% Specificity
      • Assesses attention, language, memory, orientation, and visuospatial proficiency
    • Addenbrooke's Cognitive Examination
    • Montreal Cognitive Assessment
      • (free registration required)
      • 91% Sensitivity; 81% Specificity
      • Assesses attention, executive functioning, language, memory, and orientation
    • Saint Louis University Mental Status (SLUMS) Exam
      • Tests:
        • Q1-Q3: Attention, immediate recall, and orientation
        • Q4 and Q7: Delayed recall with interference
        • Q5: Numeric calculation and registration
        • Q6: Memory: immediate recall with interference (time constraint)
        • Q8: Registration and digit span
        • Q9: Visual spatial
        • Q10: Visual spatial and executive function
        • Q11: Executive function plus extrapolation


  1. SLU Mental Status
    Poss pts Question Score
    1 What day of the week is it? 1
    1 What is the year? 1
    1 What state are we in? 1
      Please remember these five objects. I will ask you what they are later. -
      - Apple, Pen, Tie, House, Car -
    3 You have $100 and you go to the store and buy a dozen apples for $3 and a tricycle for $20.  
      - How much did you spend? 1
      - How much do you have left? 2
    3 Please name as many animals as you can in one minute. 0 - 0-4
        1 - 5-9
        2 - 10-14
        3 - 15+
    5 What were the five objects I asked you to remember? 1 point for each one correct.  
    2 I am going to give you a series of numbers and I would like you to give them to me backwards. For example, if I say 42, you would say 24. 0 - 87
        1 - 648
        1 - 8537
    4 This is a clock face. Please put in the hour markers and the time at ten minutes to eleven o’clock. 2 - Hour markers okay
        2 - Time correct
    1 Please place an X in the triangle. 1
    1 Which of the above figures is largest? 1
    8 I am going to tell you a story. Please listen carefully because afterwards, I’m going to ask you some questions about it.  
      Jill was a very successful stockbroker. She made a lot of money on the stock market. She then met Jack, a devastatingly handsome man. She married him and had three children. They lived in Chicago. She then stopped work and stayed at home to bring up her children. When they were teenagers, she went back to work. She and Jack lived happily ever after.  
      - What was the female’s name? 2
      - What work did she do? 2
      - When did she go back to work? 2
      - What state did she live in? 2


    High school education   Less than High School Education
    27-30 Normal 25-30
    21-26 Mild Neurocognitive Disorder 20-24
    1-20 Dementia 1-19


  2. Mini-Cognitive Assessment Instrument (Mini-Cog)
    1. Step 1 - Ask the patient to repeat 3 unrelated words (such as "ball," "dog," and "television")
    2. Step 2 - Ask the patient to draw a simple clock set to 10 min after 11 o'clock (11:10). A correct response is a drawing of a circle with all of the numbers placed in approximately the correct positions, with the hands pointing to the 11 and 2.
    3. Step 3 - Ask the patient to recall the 3 words from step 1. One point is given for each item recalled correctly.


    Number recalled Clock test Interpretation of
        screen for dementia
    0 Normal Positive
    0 Abnormal Positive
    1 Normal Negative
    1 Abnormal Positive
    2 Normal Negative
    2 Abnormal Positive
    3 Normal Negative
    3 Abnormal Negative


    • Int J Geriatr Psychiatry. 2000;15(11):1021-1027


  3. Mini-Cog

    The Mini-Cog combines free recall of three unrelated words (presented verbally) and a version of the CDT, which is dichotomously scored as normal (all numbers present in correct sequence with the hands correctly displaying the specified time) or abnormal [20]. Mini-Cog performance is judged to be impaired if patients are unable to recall any of the three words or if they recall only one or two words and have an abnormal clock drawing.

    In primary care settings, the Mini-Cog has demonstrated reasonable sensitivity (76 to 100 percent) but relatively poorer specificity (54 to 85 percent) for identifying patients with dementia

  4. The General Practitioner Assessment of Cognition

    The General Practitioner Assessment of Cognition (available for free at comprises a patient screen and, if necessary, an informant component. Advantages of this test include validation in the primary care setting, little to no education bias, and availability in multiple languages.34 It has been studied only in Australian populations, however. The patient screen consists of recall, time orientation, clock drawing, and information components. The patient screen takes less than four minutes to complete, and the informant portion takes less than two minutes. The General Practitioner Assessment of Cognition has a sensitivity of 85% and specificity of 86%.34

  5. Saint Louis University Mental Status Examination (SLUMS)

    Like the MMSE and MoCA, the SLUMS is scored on a 30-point scale, with questions that assess orientation, calculation, semantic verbal fluency, word and story recall, reverse digit span, clock-drawing, and visuospatial function. Because this instrument includes items that more directly measure executive function, it has demonstrated better discriminability than the MMSE for MCI [68-70].

    The SLUMS form specifies different thresholds for identifying MCI (<25 points if <12 years of education, <27 points if ≥12 years of education) and dementia (<20 points if <12 years of education, <21 points if ≥12 years of education) [68]. However, across patient cohorts, a range of optimized cutoffs has emerged, yielding sensitivities of 67 to 98 percent and specificities of 61 to 87 percent for MCI and sensitivities of 84 to 100 percent and specificities of 87 to 100 percent for dementia [68-72]. Relative to the MMSE and MoCA, the SLUMS has far fewer published studies that examine its utility. More research may be required to further validate consensus cutoff points for normal cognition, MCI, and dementia.

    What does the SLU Mental Status Exam Test Do?

    • Q1-Q3: Attention, immediate recall, and orientation
    • Q4 and Q7: Delayed recall with interference
    • Q5: Numeric calculation and registration
    • Q6: Memory: immediate recall with interference (time constraint)
    • Q8: Registration and digit span
    • Q9: Visual spatial
    • Q10: Visual spatial and executive function
    • Q11: Executive function plus extrapolation


    • Read the questions aloud clearly and slowly to the examinee. It is not usually necessary to speak loudly but it is necessary to speak slowly.
    • On question No. 4, read the statement as listed on the exam. Ask the patient to repeat each of the five objects (apple, pen, tie, house, car) that you recite to make sure that the patient heard and understood what you said. Repeat them as many times as it takes for the patient to repeat them back to you correctly.
    • On question No. 5, make sure the patient is focused on you prior to reciting the information. Obtain an answer for the first part of the question (“How much did you spend”) before moving on to part two (“How much do you have left?”). Do not prompt or give hints, but do give ample time to the patient to answer the questions. If the patient asks you to repeat the question you may do so once.
    • Redirect the patient’s attention if necessary back to you to answer question No. 6. Give them one minute to complete the question. Be sure to time them.
    • On question No. 8, state each number by its individual name. 87 is pronounced eight, seven; 649 is pronounced six, four, nine; 8537 is pronounced eight, five, three, seven.
    • On question No. 9, either draw a large circle on the back of the examination form or provide the patient with a separate piece of paper with a larger circle printed on it and attach it to the original examination form. When scoring, give full credit for either all 12 numbers or all 12 ticks. If the patient puts only four ticks on the circle, prompt them once to put numbers next to those ticks (12, 3, 6 and 9) for full credit. When scoring the correct time, make sure the hour hand is shorter than the minute hand and that the minute hand points at the 10 and the hour hand points at the 11.
    • You may also provide a separate sheet with larger examples of the forms listed on question No. 10 for those with vision impairment. This sheet should be created by enlarging the figures on the examination form and can also be attached to the original form.
    • Read question No. 11 as written, and provide ample time to answer each question. Do not repeat the story but do make sure they are paying attention the first time you read it to them. Do not prompt or give hints. The answer of Chicago as the state she lives in gets no credit but you may prompt them once by repeating the question.

  6. Memory Impairment Screen (MIS)

    The MIS focuses on memory, both recall and recognition [19]. Patients are presented four written words (all nouns), which belong to different semantic categories (eg, "checkers" is a game, a "saucer" is a dish). They read the words aloud and, when given a category cue, identify the word that belongs in that category. After three minutes of distraction, patients are asked to recall the items; category cues are used for items not freely recalled. The total score is calculated as 2 x (number of items freely recalled) + (number of items recalled with cue) [20].

    Across studies, a score of ≤4 identifies individuals with dementia with variable sensitivity (43 to 86 percent) but better specificity (93 to 97 percent) [21]. Given its specific emphasis on memory, the MIS is best suited for screening for Alzheimer disease (AD) and less sensitive for other forms of dementia, especially at their early stages [22]. Age, gender, and educational level do not impact test performance

  7. Six-Item Screener (SIS)

    The SIS incorporates three memory questions and three orientation questions [24]. Patients are read three words and asked to repeat them; repetition of these items is not scored. They are then asked three temporal orientation questions (year, month, day of the week), which are scored. As with the MIS, three minutes of distraction then intervene before the patient is asked to recall the three words; recall of these items is scored.

    Further diagnostic workup for possible cognitive impairment is indicated if the patient incorrectly answers ≥2 of the 6 combined orientation and memory questions. Six-Item Screener_1.pdf

  8. Clock-Drawing Test (CDT)

    The CDT, which does not explicitly draw upon memory function, fulfills many of the requirements for an effective screening tool: convenient administration and scoring; applicability to a wide range of patients, irrespective of language, education, or cultural background; and high inter-rater reliability, test-test reliability, sensitivity, and specificity [27]. Patients are verbally asked to draw an analog clock, including all of the numbers, and set the hands to a specified time (eg, 10 minutes past 11:00). Performance on the CDT is supported by a combination of visuospatial abilities, executive function, motor execution, attention, language comprehension, and numerical knowledge.

    However, no single scoring system is clearly superior for dementia screening, and a simple subjective qualitative interpretation of the clock drawing as "normal" or "abnormal" may suffice (See Mini-Cog)

10.2.5 Mild Cognitive Impairment / Dementia

These impairments suggest cognitive decline:

  • Activities of daily living
    • Bathing
    • Dressing
    • Toileting/continence
    • Transferring/ambulation
    • Eating
  • Instrumental activities of daily living
    • Ability to use the telephone
    • Shopping
    • Food preparation
    • Housekeeping
    • Laundry
    • Mode of transportation
    • Responsibility for own medication
    • Ability to handle finances

The difference between MCI and dementia is a patient's functional status.

  • Dementia core criteria are cognitive or neurobehavioral symptoms that:
    • Interfere with work or usual daily function
    • Represent a change from the prior baseline function
    • Are not explained by delirium or a psychiatric illness
    • Include detectable impairment in 2 cognitive domains

Cognitive domains:

  • Complex attention
  • Executive function
  • Learning and momory
  • Language
  • Visuospacial
  • Social cognition

MCI Subtypes:

  1. Amnestic MCI single domain if only memory is affected
  2. Amnestic MCI multiple domain, if memory and any other cognitive domains are affected
  3. Non-amnestic MCI single domain, if any other cognitive domain is the only one affected
  4. Non-amnestic MCI multiple domain, if multiple domains other than memory are affected

Medications associated with cognitive impairment

  • Anticholinergics (diphenhydramine, hydroxyzine, meclizine, promethazine)
  • Antidepressants (TCAs, particularly those with anticholinergic effects such as amitriptyline; paroxetine)
  • Benzodiazepines (class effect, worse with long acting agents)
  • Digoxin
  • H2-receptor antagonists
  • Nonbenzodiazepine, benzodiazepine receptor agonist hypnotics (zolpidem)

Elderly patients with depression commonly complain of memory impairment.


  • JFP Vol 66 No 11 Nov 2017
  1. Modifiable risk factors for dementia

    12 Modifiable Risk Factors

    1. Diabetes
    2. Hypertension
    3. High cholesterol
    4. Smoking
    5. Obesity
    6. Physical inactivity
    7. Depression
    8. Coronary heart disease
    9. Kidney disease
    10. Diet
    11. Alcohol
    12. Mental activity

    Factors that reduce dementia risk:

    • High cognitive activity
    • Healthy diet or Mediterranean diet
    • Low-moderate alcohol intake


    • Family Practice News Sep 2017

10.3 Delirium


  • Avoid sensory deprivation (provide eyeglasses, hearing aids..)
  • Restore normal sleep/wake cycle
  • Encourage patient to resume wlaking as soon as possible
  • Prevent/treat dehydration
  • Provide nonthreatening cognitive stimulation
  • Prevent/treat constipation
  • Involve family in patient care
  • Provide adequate nutrition
  • Reorient patient to place and time (provide clocks/calendars)

Strategies for preventing delirium near the end of life

  • Correct nonmedication cause
    • Give supplemental oxygen as needed
    • Treat severe pain
    • Prevent bladder retention, but minimize catheterization
    • Ensure bowel function
    • Encourage mobilization
  • Correct medication cause
    • Minimize benzodiazepines, anticholinergics, antihistamines
    • Eliminate drug interactions; dose for renal/hepatic limits
  • Normalize sleep-wake cycle
    • Have interior lighting follow time of day
    • Reduce stimulation at night
  • Reorientation
    • Encourage appropriate use of glasses/hearing aids
    • Display a clock and other cues of date
    • Keep communication clear and consistent
    • Identify staff contacts for continuity/familiarity
    • Encourage calm reassurance from family members


  • JFP Vol 64, No 6 Jun 2015
  • JFP Vol 68 No 8 Oct 2019

10.3.1 Common Causes

  • Metabolic derangements (hypoglycemia, etc)
  • Infection
  • Toxic effects of drugs/EtOH
  • Withdrawal states
  • Fluid and electrolyte disorders
  • Primary brain disorders
  • Low perfusion states
  • Physical disorders
  • Postoperative states
  • Reactions to medicines


  • NEJM 367;25 Dec 2012

10.3.2 Pharmacology

  • Haloperidol 0.5-1mg
    • First line - Agent of choice
    • Avoid IV use due to short duration of action
    • Associated with increased mortality in older patients with dementia related psychosis
  • Olanzapine (Zyprexa) 2.5mg
    • Associated with increased mortality in older patients with dementia related psychosis
  • Quetiapine (Seroquel) 25mg
    • Associated with increased mortality in older patients with dementia related psychosis
  • Risperidone 0.5mg
    • Associated with increased mortality in older patients with dementia related psychosis
  • Lorazepam 0.5-1mg
    • May worsen delerium
  • Trazodone 25-150mg
    • Second line agent
    • Associated with increased mortality in older patients with dementia related psychosis


  • AFP Vol 90 No 3 Aug 2014

10.3.3 Clinical Featurs of Diseases that Mimic Delerium

Feature Delirium Dementia Depression Psychosis
Acute change in mental status + - - +/-
Inattention + +/- +/- +/-
Altered consciousness + - - -
Disorganized thinking + +/- + +
Altered psychomotor activity + +/- + +
Chronic duration +/- + + +/-


  • JAMA Vol 318 No 12 Sep 2017

10.4 End of Life Care

General recommendations:

  • Opiates should be used to treat dyspnea (LOE B)
  • Haloperidol and risperidone are effective in treating delerium (LOE C)
  • Corticosteroids should be used in management of bowel obstruction caused by malignancy (LOE B)
    • Octreotide has limited benefit
  • Hyoscyamine or atropine ophthalmic drops can be used to treat excessive oropharyngeal secretions (LOE C)

Common medications (Hospice Comfort Kit)

Class Medication Initial dose
Antipsychotics Haloperidol or risperidone 0.5-1mg sublingually or rectally every 4h as needed for agitation or nausea
  Each 2mg/mL  
Antipyretics Acetaminophen suppository (650mg) 650mg orally or rectally every 4h as needed for fever
Benzodiazepines Lorazepam (2mg/mL) 0.5-1mg subliingually or rectally every 4h as needed for anxiety
Opiates Morphine or oxycodone (20mg/mL) 5-10mg sublingually every 3h as needed for pain or shortness of breath
Secretion meds Hyoscyamin (0.125mg/sublingual or liq) 0.125mg of hyoscyamine or 2-3 drops of atroping sublingually every 6h
  Atropine ophthalmic 1% drops as needed for oropharyngeal secretions

Constipation in End-of-life:

  • Docusate
    • 1-2 tab 2x a day
  • Lactulose
    • 15-30 mL orally 2-3x a day
  • Magnesium hydroxide
    • 30-60 mL orally at bedtime
  • Polythylene glycol (Miralax)
    • 1 tablespoon (17g) dissolved in 4-8oz of fluid orally per day
  • Senna with docusate
    • 1-2 taba orally 2-4x a day


  • AFP Vol 95 No 6 Mar 2017

10.5 Falls

Medications associated with falls:

  • Anticonvulsants
  • Antidepressants
  • Antihypertensives
  • Antiparkinsonian drugs
  • Antipsychotics
  • Benzodiazepines
  • Digoxin
  • Diuretics
  • Laxatives
  • Opioids
  • Nonbenzodiazepine, benzodiazepine receptor agonist hypnotics
  • NSAIDs
  • Sedatives and hypnotics


  • AFP Vol 96 No 4 Aug 2017

10.5.1 Get up and Go Test


  1. Rise from sitting position
  2. Walk 10 feet
  3. Turn around
  4. Return to chair and sit down


  • >12 seconds is high risk of falling
  • Patient takes <20 seconds to complete test
    • Adequate for independent transfers and mobility
  • Patient requires >30 seconds to complete test
    • Suggests higher dependence and risk of of falls


  • Posiadlo (1991) J Am Geriatr Soc 39:142-8 [PubMed]
  • Am Fam Physician. 2018;97(12):776-784

10.5.2 Gait Evaluations

  1. Timed Up and Go Test
    • Stand up, walk 10 feet, turn, walk back and sit down
    • 12 seconds or longer = increased fall risk
  2. 4 Stage Balance Test
    • Assess ability to stand in 4 positions for 10 seconds
      1. Feet side by side
      2. Instep of 1 foot touching big toe of other foot
      3. 1 foot in front of the other
      4. On 1 foot
  3. 30 Second Cair Stand Test
    • Sit in middle of chair, hands on opposite shoulders, feet flat on floor and back straight, rise to full standing and sit back down, repeat for 30 seconds

30 Second Chair Stand Below Average Scores

60-64 <14 <12
65-69 <12 <11
70-74 <12 <10
75-79 <11 <10
80-84 <10 <9
85-89 <8 <8
90-94 <7 <4

10.5.3 Geriatric Assistive Devices

For patients who need one upper extremities for weight bearing or balance:

  • Minimal need:
    • Standard cane
  • Intermittent need:
    • Offset cane
  • Need Often:
    • Quadripod cane

For patients who need both upper extremities for weight bearing or balance:

  • Minimal need:
    • Four-wheeled walker (rollator)
  • Intermittent need:
    • Front-wheeled walker or
    • Forearm crutches
  • Need Often:
    • Front-wheeled walker or
    • Standard walker
  • Constant need:
    • Standard or front-wheeled walker

10.6 Frailty

Frailty Strength Training Prescription

  • Two to three nonconsecutive days per week
  • Moderate intensity (5 to 6 on a 10-point scale)
  • Target the major muscle groups with eight to 10 exercises per session
  • 8 to 15 repetitions per exercise; at least one set of repetitions per exercise
  • Gradually increase weight and repetitions based on tolerability
  • Strength training exercises:
    • Sit to stand
    • Heel lifts
    • Toe lifts
    • Lunges
    • Front arm raises
    • Side arm raises
    • Wall push-ups

Frailty Balance Training Prescription

  • Two or more hours per week, initially under close supervision to reduce fall risk
  • Begin with less challenging positions
  • Maintain each exercise for a minimum of five to 10 seconds, with at least one repetition per exercise
  • Start on flat surfaces and gradually advance the level of difficulty*
  • Flat surface exercises:
    • Side-by-side stance
    • Semi-tandem stance
    • Tandem stance
    • Single limb stance
    • Heel stance
    • Toe stance
  • Uneven surface exercises:
    • Step up, step down without hand support
    • Forward and backward walking
    • Sideways walking
    • Change directions while walking
  • Complex task exercises:
    • Navigate obstacles while walking
    • Pick up objects from the floor while walking
    • Carry objects of variable weight and size while walking
    • Incorporate head turns while reaching in different directions
    • Carry on conversation while walking
    • Conduct simple mathematical calculations while walking


  • AFP Feb 2021 Vol 103 No 4

10.7 Indications for Mental Health Referral

Indications for Mental Health Referral for terminal illness:

  • Diagnostic uncertainty
  • Other significant psychiatric comorbidities
  • Psychosis
  • Psychotherapy referral
  • SI or request for physician assisted dying
  • Unresponsive or intolerant to initial treatment trials


  • AFP Vol 86 No 3 2012

10.8 Medications in Geriatrics

10.9 Osteoporosis

Bone Mineral Density:

  • Normal: T-score > -1.0
  • Osteopenia: BMD between -1.0 and -2.5
  • Osteoporosis: BMD at or below -2.5
  • Severe or established osteoporosis: -25 or lower + fragility fracture

Consider Pharmacologic Therapy:

  • Postmenopausal women and men >50 with a Hip or Vertebral fragility fracture
  • T-score < -2.5 Femoral neck, total hip, or spine
  • T-score between -1.0 and -2.5 and FRAX scores:
    • Major > 20% or Hip 3% 10-yr fracture risk


  • Offer to women with osteoporosis (strong rec; high-quality evidence):
    • alendronate
    • risedronate
    • zoledronic acid
    • denosumab
  • Once initiated, pharmacologic treatment should be continued for 5 years (weak rec; low-quality evidence)
  • Bisphosphonates should be offered to men with osteoporosis (weak rec; low-quality evidence)
  • Bone density should not be monitored during the 5 year treatment period for women with osteoporosis (weak rec; low-quality evidence)



  • FMX 2016
  • JFP Vol 67 No 2 Feb 2018
  • JAMA Vol 310 No 10 Mar 2018

10.9.1 Screen males:

Screen men with scores >6:

Risk Factor Points
<55 yo 0
56-74yo 3
>75 4
<154 lbs 6
155-176 4
>176lbs 0


  • AFP Vol 82 No 5 Sep 2010

10.9.2 Recommendations

To prevent bone loss and falls:

  • Strength training for major muscle goups >2/wk
  • Balance challenges daily
  • Mod-Vigorous aerobic physical activity >150min/wk or 20-30min/d

To reduce spine loads:

  • Exercises for back extensor muscles daily
  • Spine sparing strategies
    • Hip hinge for bending
    • Step to turn instead of twisting
    • Holding loads close to body


  • FMX 2016
  • Fit to Fracture

10.9.3 Vertebral compression fractures


Medication Dosage Cost
Acetaminophen 500-1000mg q4-q8 (max 3g/d) $15
Calcitonin 200 IU/d intranasally $45
Lidocaine 5% patch Apply to affected areas q12 $220
Muscle relaxants 10mg q8 Varies
Narcotics Varies Varies
Ibuprofen 200-800mg q8 $11
Naproxen 500mg q12 $4


  • AFP Vol 94 No 1 2016

10.10 Preoperative Evaluation and Frailty Assessment in Older Patients   edit

Key Components of the Preoperative Evaluation in Older Patients

  1. Cognitive status
  2. Patient's life goals
  3. PHQ-2 and PHQ-9, if indicated
  4. Risk Analysis Index
  5. Social and living situation

Questions to Ask Older Patients Considering Surgery: Quality-of-life assessment

  • How might my life be different right after surgery or three to six months later?
  • How might surgery affect my independence?
  • What serious complications could arise?
  • Will surgery affect my life expectancy?
  • Will surgery make me feel better?


  • AFP Vol 102 No 12 Dec 2020

10.11 Mobility Assist Devices

When mobility deficit impairs ADLs at home and patient can operate assistive device safely:

  • If mobility deficit can be resolved with a cane or walker
    • One UE needed for weight bearing or balance:
      • Minimal frequency of weight bearing:
        • Standard cane
      • Intermittent frequency of weight bearing:
        • Offset cane
      • Often frequency of weight bearing:
        • Quadripod cane
    • Both UE needed for weight bearing or balance:
      • No frequency of weight bearing:
        • Four-wheel walker (rollator)
      • Intermittent frequency of weight bearing:
        • 2-wheel or standard walker
      • Often frequency of weight bearing:
        • 2-wheel walker or fore-arm crutches
      • Constant frequency of weight bearing:
        • Standard or 2-wheel walker
  • If mobility deficit cannot be resolved with a cane or walker
    • If patient has sufficient upper body strength for a manual wheelchair
      • Manual wheelchair
    • If patient has sufficient strength and postural stability to operate a scooter
      • Scooter
    • If patient is unable to operate a manual wheelchair or needs feaures provided with a power wheelchair
      • Power wheelchair


  • AFP Jun 2021 Vol 103 No 12

10.12 Osteoporosis

Risk factors for osteoporosis

  • Age ≥ 65 y
  • Early menopause
  • Excessive alcohol use
  • Family history of osteoporosis
  • Female sex
  • Low body weight (< 127 lb)
  • Physical inactivity
  • Smoking

Fracture risk can be assessed with any of a number of tools, including: • Simplified Calculated Osteoporosis Risk Estimation (SCORE): • Osteoporosis Risk Assessment Instrument (ORAI): • Osteoporosis Index of Risk (OSIRIS): https ://

  • Osteoporosis Self-Assessment Tool (OST):
  • FRAX tool5:


The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture

Diagnosis of osteoporosis is based on any 1 or more of the following criteria:

  • a history of fragility fracture not explained by metabolic bone disease
  • T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
  • a nation-specific FRAX score (in the absence of access to DXA).

Measures to prevent osteoporosis

  • Avoid smoking
  • Reduce alcohol intake
  • Increase physical activity, including a regular regimen of weight-bearing
  • exercises
  • Maintain a blood level of 25‐hydroxyvitamin D of ≥ 30 ng/mL (75 nmoL/L)
  • Ensure adequate intake of calcium (1000-1200 mg/d)

Indications for pharmacotherapy for osteoporosis in older adults

  • Osteopenia or low bone mass and a history of fragility fracture of the hip or spine
  • T-score of –2.5 or lower in the spine, femoral neck, total hip, or 33% radius
  • T-score between –1.0 and –2.5 in the spine, femoral neck, total hip, or 33% radius, if the FRAX 10-year probability for major osteoporotic fracture is ≥ 20% or the 10-year probability of hip fracture is ≥ 3% (in the United States) or above the country-specific threshold in other countries or regions
  • The country-specific FRAX score indicates treatment for osteoporosis where bone mineral density assessment by dual-energy X-ray absorptiometry is unavailable


  • J Fam Pract. 2021 June;70(5):220-228 | 10.12788/jfp.0201

10.13 One-legged Stand   edit

Successful 10-second one-legged stance performance predicts survival in middle-aged and older individuals

  • During a median follow-up of 7 years:
    • 7.2% died, with 4.6% (YES) and 17.5% (NO) on the 10-s OLS
  • HR of all-cause mortality was higher for NO individuals
    • HR 1.84 (95% CI: 1.23 to 2.78) (p<0.001)
  • Within the limitations of uncontrolled variables such as recent history of falls and physical activity, the ability to successfully complete the 10-s OLS is independently associated with all-cause mortality and adds relevant prognostic information beyond age, sex and several other anthropometric and clinical variables
  • Reference:
    • Araujo CG, de Souza e Silva CG, Laukkanen JA, et al. Successful 10-second one-legged stance performance predicts survival in middle-aged and older individuals British Journal of Sports Medicine. Published Online First: 21 June 2022. doi: 10.1136/bjsports-2021-105360

11 Hematology/Oncology

11.1 Abnormal bleeding or bruising


  • Rule out trauma or medications
  • Labs: CBC, peripheral blood smear, PT, PTT, renal and liver function tests
    • If abnormal platelet shape/size and no specific disorder evident -> Heme referral for light transmission aggregometry
    • If abnoramlly low platelet count -> Thrombocytopenia
    • If normal PT and normal PTT ->
      • Order Factor VIII, von Willebrand factor Ag, von Willenbrand factor activity
      • If all normal -> Heme referral for light transmission aggregometry
      • If abnormal -> von Willebrand disease
    • If normal PT and abnormal PTT ->
      • Order PTT mixing study
      • If it corrects ->
        • Order Factor VIII, IX, XI assays - If VIII is low check von Willebrand labs
      • If it does not correct ->
        • Lupus anticoagulant and Factor VIII inhibitor
    • If abnormal PT and normal PTT ->
      • Give vit K ->
        • If corrects - Malnutrition
        • If it does not correct - Factor VII assay
    • If normal PT and abnormal PTT ->
      • Order LFTs, Fibrinoge, Consider factor assays
        • Liver disease, Disseminated intravascular coagulation, Factor deficiency


  • AFP Vol 93 No 4 Feb 2016

11.2 Anemia


  • Ferritin <30ng/mL
    • Fe Def likely -> treat and recheck -> If no improvement check for other causes, ongoing loss, or compliance
  • Ferritin >30ng/mL
    • If suspect anemia of chronic disease and Ferritin >70ng/mL -> treat underlying cause
    • If suspect anemia of chronic disease and Ferritin <70ng/mL -> consider concominant Fe def
      • CRP high -> treat for Fe def anemia
      • CRP low -> unlikely Fe def - treat as ACD
    • If suspect thalassemia -> electropheresis


  • Consultant p838 Nov 2014

11.3 Eosinophilia

Drugs commonly associated with eosinophilia:

Class Examples
Antibiotics PCN, cephalosporins, tetracycline
NSAIDs ASA, ibuprofen
Antiepileptic agents Phenytoin, carbamazepine
Antihypertensive HCTZ
Other Ranitidine, allopurinol, sulfasalazine, cyclosporine, nevirapine


  • JFP Vol 65 No 10 Oct 2016

11.4 False A1c Readings

Falsely lower A1c:

  • Acute blood loss
  • Chronic liver disease
  • Hemodialysis
  • Antiretroviral therapy
  • Pregnancy
  • Vitamins E and C

Lower or Elevate A1c:

  • Hemoglobinopathies or hemoglobin variants
  • Malnutrition

Falsely elevate A1c:

  • Aplastic anemias
  • Hyperbilirubinemia
  • Hypertrglyceridemia
  • Fe Deficiency anemias
  • Renal failure
  • Splenectomy


  • AFP Vol 93 No 2 Jan 2016

A different view:

Factor False lower False Elevated
Erythrocyte life span Hemolytic anemia Splenectomy
  Recent blood transfusion  
Erythropoiesis Reticulocytosis Fe/B12 deficiency
Assay interference Severe hypertriglyceridemia Chronic alcoholism
Glycation High dose Vit C or E Chronic Kidney Disease


  • JAMA Vol 315, No 6 Feb 2016

11.5 Leukocytosis

If elevated:

  • Basophils
    • Allergic conditions
    • Leukemias
  • Eosinophils
    • Allergic conditions
    • Dermatologic conditions
    • Eosinophilic esophagitis
    • Idiopathic hypereosinophilic syndrome
    • Malignancies
    • Medication reactions
    • Parasitic infections
  • Lymphocytes
    • Acute/chronic leukemia
    • Hypersensitivity reaction
    • Infections (viral, pertussis)
  • Monocytes
    • Autoimmune disease
    • Infections (EBV, fungal, protozoan, rickettsial, tuberculosis)
    • Splenectomy
  • Neutrophils
    • Bone marrow stimulation
    • Chronic inflammation
    • Congenital infection
    • Medication induced
    • Reactive
    • Splenectomy


  • AFP Vol 92 No 11 Dec 2015

11.6 Lymphadenopathy Causes

MAGIC Causes

  • M - Malignancy (lymphoma [Hodkin vs non-Hodkin], solid organ cancers, acute and chronic leukemia, Waldenstrom macroglobulinemia, metastatic spread), systemic mastocytosis
  • A - Allergic alveiolitis (hypersensitivity pneumonitis), autoimmune diseases
  • G - Granulomatous diseases (sarcoidosis, Wegner granulomatosis, berylliosis)
  • I - Infection (bacterial [tuberculosis, melioidosis, cat-scratch disease], viral [HIV, Epstein-Barr virus], fungal [coccidioidomycosis, histoplasmosis], parasitic, mycobacterial, atypical bacterial), Iatrogenic (drug-induced lymphadenopathy)
  • C - COPD including bronchiectasis; Congestive heart failure, other chronic diseases leading to reactive lymphadenopathy


  • Consultant Nov 2016

11.7 Multiple Myeloma

Diagnostic Tests:

  • Initial tests
    • CBC
    • Serum albumin, calcium, creatinine, BUN, electrolytes
  • Confirmatory tests
    • 24-hr urine protein
    • Beta2-microglobulin
    • Lactate dehydrogenase
    • Serum free light chain assay
    • Serum immunofixation electrophoresis
    • Serum protein electrophoresis (
    • Serum quantitative immunoglobulins
    • Skeletal survey
    • Urine immunofixation electrophoresis
    • Urine protein electrophoresis
  • Test by oncology consultants
    • Bone marrow aspirate and biopsy with cytogenetics, flow cytometry, fluorescence in situ hybridization, and/or immunohistochemistry
  • Tests for special circumstances
    • Bone densitometry
    • PET/CT or whole-body MRI
    • Serum viscosity
    • Tissue biopsy of bony or other lesion

Findings on presentation:

  • Anemia (Hg<12g/dl) (73% of patients)
  • Bone pain (58% of patients)
  • Elevated creatinine (>1.3mg/dL) (48% of patients)
  • Fatigue or generalized weakness (32% of patients)
  • Hypercalcemia (Ca >10.1 mg/dL) (28% of patients)
  • Weight loss (24% of patients)


  • AFP Vol 95, No 6 Mar 2017

11.8 Lung Cancer Screening

Screen those over age 50 with 20-pack-year history of smoking, using low-dose CT scannign

  • Expected to reduce annual mortality from lung cancer by additional 3% or more (from 9.8% to 13%)


  • JFP Vol 70 No 7 Sep 2021

11.9 Peripheral Lymphadenopathy (LAP)   edit

Use acronym "CHICAGO" to consider all causes

  • C - Cancers:
    • Hematologic malignancies: Hodgkin's disease, Non-Hodgkin's lymphoma, Leukemia
    • Metastatic: Breast tumor, Lung, Kidney, others
  • H - Hypersensitivity syndromes: Serum sickness, Drugs
  • I - Infections: Viral (Epstein-Barr virus, cytomegalovirus, HIV), Bacterial (TB,) Fungal, Protozoan, Rickettsial (Typhus), Helminthes
  • C - Connective Tissue disorders: Systemic lupus erythematosus, Rheumatoid arthritis, Dermatomyositis
  • A - Atypical lymphoproliferative disorders: Castleman’s Disease, Wegener
  • G - Granulomatous: Histoplasmosis, Mycobacterial infections, Cryptococcus, Berylliosis, Cat scratch disease, Silicosis
  • O - Others


  • If more work-up is needed, the first step is to obtain complete blood count (CBC).
  • If autoimmune diseases are suspected, CBC, antinuclear antibody, dsDNA antibody, ESR, and rheumatoid factor and complement level should be checked


  • Ultrasonography is a useful imaging tool in the assessment of the number, size, site, shape, margins, and internal structure in patients with peripheral LAP
    • A normal or reactive node is usually oval with a hilum, whereas metastatic and lymphomatous lymph nodes generally emerge as round lesions.
      • A low long axis to short axis of lymph nodes (L/S ratio) is a significant sign of lymphoma and metastatic cancer
      • L/S ratio less than 2 was indicative of metastatic lymph nodes with 95% accuracy
  • CT scan and magnetic resonance imaging (MRI) are more useful in the evaluation of the thoracic and abdominopelvic cavity and their accuracy mainly depends on the size of the lymph nodes
Table 34: Ultrasonographic Criteria of Benign and Neoplastic Lymphadenopathy
  Shape Border L/s Ratio* Internal Echogenicity Hilum RI** PI*** Blood Flow Distribution
Benign Disorders ovoid various High>2 Isoechoic Present-Normal Low<0.8 <1.5 Hilar
Neoplastic Disorders Round sharp† Low<2 Hypoechoic Absent High> 0.8 >1.5 Peripheral or miscellaneous

*Long axis to short axis (L/S); **Resistive index (RI); ***Pulsatility index (PI); †In matted lymph nodes, the border is not sharp. The data of the table are derived from references cited in the text.


  • Lymph nodes are generally considered abnormal if their diameter exceeds 1 cm.
  • The cervical region is the most frequent site involved in peripheral LAP at any age.
  • Generalized LAP usually is indicative of an underlying disease. Some important causes include the Epstein-Barr virus, HIV, lymphoma, and autoimmune disorders.
  • Ultrasound can assess the number, size, site, shape, margins, and pattern of vascularity and the internal structure of a lymph node.
  • FNAC is more powerful in diagnosing metastatic cancers than lymphomas. Ultrasonography-guided FNAC offers more accurate information than does blinded FNAC.
  • Needle biopsy can be used as the first step in the diagnostic approach to lymphomas, but excisional biopsy of enlarged lymph nodes is still the gold standard procedure.
  • Age more than 40 years, multiple sites of LAP, supraclavicular lymph nodes, nodal diameter greater than 2 cm, firm or hard texture, fixed nodes, lack of tenderness, and abnormal chest X-ray are factors that propel the physician into tissue sampling.
  • If none of the predictive risks for malignancy is present, patients with peripheral LAP can be observed for 3 to 4 weeks before lymph node biopsy.
Table 35: Clues and Initial Testing to Determine the Cause of Lymphadenopathy
Historical clues Suggested diagnoses Initial testing
Fever, night sweats, weight loss, or node located in supraclavicular, popliteal, or iliac region, bruising, splenomegaly Leukemia, lymphoma, solid tumor metastasis CBC, nodal biopsy or bone marrow biopsy; imaging with ultrasonography or computed tomography may be considered but should not delay referral for biopsy
Fever, chills, malaise, sore throat, nausea, vomiting, diarrhea; no other red flag symptoms Bacterial or viral pharyngitis, hepatitis, influenza, mononucleosis, tuberculosis (if exposed), rubella Limited illnesses may not require any additional testing; depending on clinical assessment, consider CBC, monospot test, liver function tests, cultures, and disease-specific serologies as needed
High-risk sexual behavior Chancroid, HIV infection, lymphogranuloma venereum, syphilis HIV-1/HIV-2 immunoassay, rapid plasma reagin, culture of lesions, nucleic acid amplification for chlamydia, migration inhibitory factor test
Animal or food contact    
- Cats Cat-scratch disease (Bartonella) Serology and polymerase chain reaction
  Toxoplasmosis Serology
- Rabbits, or sheep or cattle wool, hair, or hides Anthrax Per CDC guidelines
  Brucellosis Serology and polymerase chain reaction
  Tularemia Blood culture and serology
- Undercooked meat Anthrax Per CDC guidelines
  Brucellosis Serology and polymerase chain reaction
  Toxoplasmosis Serology
Recent travel, insect bites Diagnoses based on endemic region Serology and testing as indicated by suspected exposure
Arthralgias, rash, joint stiffness, fever, chills, muscle weakness Rheumatoid arthritis, Sjögren syndrome, dermatomyositis, systemic lupus erythematosus Antinuclear antibody, anti-doubled-stranded DNA, erythrocyte sedimentation rate, CBC, rheumatoid factor, creatine kinase, electromyography, or muscle biopsy as indicated

Risk Factors for Malignancy

  • Age older than 40 years
  • Duration of lymphadenopathy greater than four to six weeks
  • Generalized lymphadenopathy (two or more regions involved)
  • Male sex
  • Node not returned to baseline after eight to 12 weeks
  • Supraclavicular location
  • Systemic signs: fever, night sweats, weight loss, hepatosplenomegaly
  • White race
Table 36: Lymph Node Groups: Location, Lymphatic Drainage and Selected Differential Diagnosis
Location Lymphatic drainage Causes
Submandibular Tongue, submaxillary gland, lips and mouth, conjunctivae Infections of head, neck, sinuses, ears, eyes, scalp, pharynx
Submental Lower lip, floor of mouth, tip of tongue, skin of cheek Mononucleosis syndromes, Epstein-Barr virus, cytomegalovirus, toxoplasmosiss
Jugular Tongue, tonsil, pinna, parotid Pharyngitis organisms, rubella
Posterior cervical Scalp and neck, skin of arms and pectorals, thorax, cervical and axillary nodes Tuberculosis, lymphoma, head and neck malignancy
Suboccipital Scalp and head Local infection
Postauricular External auditory meatus, pinna, scalp Local infection
Preauricular Eyelids and conjunctivae, temporal region, pinna External auditory canal
Right supraclavicular node Mediastinum, lungs, esophagus Lung, retroperitoneal or gastrointestinal cancer
Left supraclavicular node Thorax, abdomen via thoracic duct Lymphoma, thoracic or retroperitoneal cancer, bacterial or fungal infection
Axillary Arm, thoracic wall, breast Infections, cat-scratch disease, lymphoma, breast cancer, silicone implants, brucellosis, melanoma
Epitrochlear Ulnar aspect of forearm and hand Infections, lymphoma, sarcoidosis, tularemia, secondary syphilis
Inguinal Penis, scrotum, vulva, vagina, perineum, gluteal region, lower abdominal wall, lower anal canal Infections of the leg or foot, STDs (e.g., herpes simplex virus, gonococcal infection, syphilis, chancroid, granuloma inguinale, lymphogranuloma venereum), lymphoma, pelvic malignancy, bubonic plague

If lymph nodes are detected, note and describe:

  1. Size.
    • Nodes are generally considered to be normal if they are up to 1 cm in diameter; however, some authors suggest that epitrochlear nodes larger than 0.5 cm or inguinal nodes larger than 1.5 cm should be considered abnormal.7,8 Little information exists to suggest that a specific diagnosis can be based on node size. However, in one series10 of 213 adults with unexplained lymphadenopathy, no patient with a lymph node smaller than 1 cm2 (1 cm × 1 cm) had cancer, while cancer was present in 8 percent of those with nodes from 1 cm2 to 2.25 cm2 (1 cm × 1 cm to 1.5 cm × 1.5 cm) in size, and in 38 percent of those with nodes larger than 2.25 cm2 (1.5 cm × 1.5 cm). In children, lymph nodes larger than 2 cm in diameter (along with an abnormal chest radiograph and the absence of ear, nose and throat symptoms) were predictive of granulomatous diseases (i.e., tuberculosis, cat-scratch disease or sarcoidosis) or cancer (predominantly lymphomas).
  2. Pain/Tenderness.
    • When a lymph node rapidly increases in size, its capsule stretches and causes pain. Pain is usually the result of an inflammatory process or suppuration, but pain may also result from hemorrhage into the necrotic center of a malignant node. The presence or absence of tenderness does not reliably differentiate benign from malignant nodes.
  3. Consistency.
    • Stony-hard nodes are typically a sign of cancer, usually metastatic. Very firm, rubbery nodes suggest lymphoma. Softer nodes are the result of infections or inflammatory conditions. Suppurant nodes may be fluctuant. The term “shotty” refers to small nodes that feel like buckshot under the skin, as found in the cervical nodes of children with viral illnesses.
  4. Matting.
    • A group of nodes that feels connected and seems to move as a unit is said to be “matted.” Nodes that are matted can be either benign (e.g., tuberculosis, sarcoidosis or lymphogranuloma venereum) or malignant (e.g., metastatic carcinoma or lymphomas).
  5. Location.
    • The anatomic location of localized adenopathy will sometimes be helpful in narrowing the differential diagnosis. For example, cat-scratch disease typically causes cervical or axillary adenopathy, infectious mononucleosis causes cervical adenopathy and a number of sexually transmitted diseases are associated with inguinal adenopathy.


  • Habermann TM, Steensma DP. Lymphadenopathy. Mayo Clin Proc. 2000;75:723–32. doi: 10.1016/S0025-6196(11)64620-X. PubMed PMID: 10907389.
  • Mohseni S, Shojaiefard A, Khorgami Z, Alinejad S, Ghorbani A, Ghafouri A. Peripheral lymphadenopathy: approach and diagnostic tools. Iran J Med Sci. 2014;39(2 Suppl):158-170.
  • Am Fam Physician. 2016 Dec 1;94(11):896-903.
  • Am Fam Physician. 1998 Oct 15;58(6):1313-1320.

12 Infectious Disease

12.1 Acute Bacterial Rhinosinusitis (ABRS)

Defined as any of the following 3 presentations:

  1. Symptoms lasting for 10d and not improving
  2. Symptoms that are severe with fever over 39C, nasal discharge, and facial pain lasting 3-4d
  3. Worsening symptoms with new fever, headache, or increased nasal discharge, typically after viral URI lasting 5-6d after initially seeming to improve

Most common organisms:

  • Streptococcus pneumoniae (38%)
  • Haemophilus influenzae (35%)
  • Moraxella catarrhalis (16%)


  • Amoxacillin-clavulanate (500mg/125mg tid or 850mg/125mg bid)
  • Doxycycline (100mg bid for 5-7d)
  • If resistance -> Levofloxacin (500mg qd) or amoxicillin-clavulanate (2000mg/125mg bid) for 10d
  • Antibiotics can shorten the time to cure. 5 more people per 100 will improve more quickly at any point between 7 and 14 days if they recieve antibiotics vs placebo. Given the potential harms of antibiotics, it is NOT recommended to use antibiotics for uncomplicated acute rhinosinusitis.


  • Consultant Feb 2016

12.2 Acute Gastroenteritis in Children

  • Noninflammatory agents
    • Viruses
      • Rotavirus
      • Enteric adenovirus
      • Calicivirus
      • Astrovirus
  • Inflammatory agents
    • Bacteria
      • Salmonella
      • Shigella
      • Campylobacter jejuni
      • Yersinia enterocolitica
      • Enterohemorrhagic Escherichia coli (including O157:H7)
      • Other E. coli
      • Clostridium difficile
    • Parasites
      • Giardia intestinalis
      • Cryptosporidium


  • AFP Vol 85 No 11 Jun 2012

12.3 Acute Respiratory Tract Infections

See also:


  • For adults,
    • Regular exercise may reduce the overall severity of acute respiratory tract infections and the number of days with symptoms
    • But there is no evidence that exercise reduces the overall occurrence or duration of these infections. SOR B


  • AFP Feb 2021 Vol 103 No 3

12.4 Common Cold EBM

  • ipratropium
  • OTC analgesics
  • docongestants
  • zinc (75 mg zinc acetate or gluconate lozenges daily) - resolves cough and nasal discharge
    • Start within 24 hours of symptom onset

12.5 Coronavirus Disease 2019 (COVID-19)

Clinical Recommendation LOE
Close contacts of patients with COVID-19 should quarantine for 14 days with daily monitoring for fever and other symptoms.8 C
Telehealth can be used for initial triage of patients with respiratory symptoms of COVID-19; further care should be based on vital signs, physical examination findings, social considerations, and risk factors.11,17 C
Infection with severe acute respiratory syndrome coronavirus 2 should be confirmed by polymerase chain reaction testing using a nasopharyngeal swab.38 C
Management of COVID-19 in the outpatient setting is focused on supportive care and reducing the risk of transmission via isolating at home.41 C
Dexamethasone, 6 mg per day for 10 days, reduces mortality in hospitalized patients with COVID-19 who require supplemental oxygen (NNT = 29) and mechanical ventilation (NNT = 9), but not in hospitalized patients or outpatients who do not require supplemental oxygen.46 B
Remdesivir (Veklury) shortens time to recovery in hospitalized patients with COVID-19 but has not been proven to reduce mortality.48,49 B

Signs and Symptoms of Coronavirus Disease 2019

  • Adults
    • Anosmia or altered taste (64%)
    • Fever (56% to 99%)
    • Cough (55% to 82%)
    • Anorexia (40%)
    • Fatigue (38% to 70%)
    • Sputum production (27% to 34%)
    • Shortness of breath (19% to 57%)
    • Chills (12% to 15%)
    • Myalgias (11% to 45%)
    • Dizziness (8% to 9%)
    • Sore throat (5% to 14%)
    • Headache (3% to 14%)
    • Diarrhea (2% to 24%)
    • Chest pain (2% to 15%)
    • Nasal congestion or rhinorrhea (2% to 5%)
    • Rash or skin discoloration (1% to 20%)
    • Nausea and vomiting (1% to 19%)
    • Hemoptysis (1% to 2%)
    • Conjunctivitis (1%)
  • Children
    • Pharyngeal erythema (46%)
    • Cough (44% to 54%)
    • Fever (41% to 56%)
    • Diarrhea (8%)
    • Fatigue (8%)
    • Rhinorrhea (8%)
    • Vomiting

Remote patient monitoring via telehealth can be used to detect red flag symptoms that warrant urgent assessment, such as:

  • Fever above 100.4°F (38°C)
  • Heart rate greater than 100 beats per minute with new confusion
  • Oxygen saturation less than 95%
  • Respiratory rate greater than 20 breaths per minute

COVID-19 Resources


  • AFP Oct 2020 Vol 102 No 8

12.5.1 FLCCC - Prevention Protocol (COVID-19)

Prevention Protocol:

  • Ivermectin
    • Chronic Prevention
      • 0.2 mg/kg per dose (take with or after a meal) — twice a week for as long as disease risk is elevated in your community. Alternative: Hydroxychloroquine – 200 mg tablet daily.
    • Post COVID-19 Exposure Prevention
      • 0.4 mg/kg per dose (take with or after a meal) — one dose today, repeat after 48 hours.
      • Alternative: Hydroxychloroquine – 400 mg twice day on day 1, then 200 mg twice a day on Days 2 and 3.
  • Gargle mouthwash
    • 2 x daily – gargle (do not swallow) antiseptic mouthwash with cetylpyridinium chloride (e.g. ScopeTM, ActTM, CrestTM), 1% povidone/iodine solution or ListerineTM with essential oils.

Immune Fortifying / Supportive Therapy

  • Vitamin D3 Optimal approach to dosing requires testing of 25(OH)D level. For dosing guidance, see Table 1 if level is known and Table 2 if level is unknown.
  • Vitamin C 500–1,000 mg 2 x daily
  • Quercetin 250 mg/day
  • Zinc 30–40 mg/day (elemental zinc)
  • Melatonin 6 mg before bedtime (causes drowsiness)

12.5.2 FLCCC - Early Outpatient Treatment Protocol (COVID-19)

First line agents

  • Antiviral:
    • Ivermectin: 0.4–0.6 mg/kg per dose (take with or after a meal) — one dose daily, take for 5 days or until recovered. Use upper dose if: 1) in regions with aggressive variants (e.g. Delta); 2) treatment started on or after day 5 of symptoms or in pulmonary phase; or 3) multiple comorbidities/risk factors.
      • and/or Hydroxychloroquine (preferred for Omicron): 200 mg PO twice daily; take for 5 days or until recovered.
  • Antiseptic
    • Antiviral mouthwash: Gargle 3 x daily (do not swallow; must contain chlorhexidine, povidone-iodine, or cetylpyridinium chloride).
    • Iodine nasal spray/drops: Use 1 % povidone-iodine commercial product as per instructions 2–3 x daily. If 1 %-product not available, must first dilute the more widely available 10 %-solution and apply 4–5 drops to each nostril every 4 hours. (No more than 5 days in pregnancy.)
  • Anticoagulation/Immune fortifying
    • Aspirin 325 mg daily (unless contraindicated)
    • Vitamin D3 Optimal approach to dosing requires testing of 25(OH)D level. For dosing guidance, see Table 1 if level is known and Table 2 if level is unknown.
    • Melatonin 10 mg before bedtime (causes drowsiness)
  • Synergistic Therapies
    • Quercetin 250 mg 2 x daily
    • Zinc 100 mg/day (elemental zinc)
    • Vitamin C 500–1,000 mg 2 x daily
  • Nutritional (for 14 days)
    • Curcumin (turmeric) 500 mg 2 x daily
    • Nigella Sativa (black cumin seed) 80 mg/kg daily
    • Honey 1 gram/kg daily
  • Pulse Ox

Second line (if 1) ≥ 5 days of symptoms; 2) Poor response to therapies above; 3) Significant comorbidities):

  • Dual anti-androgen therapies
    1. Spironolactone 100 mg 2 x daily for ten days.
    2. Dutasteride 2 mg on day 1, followed by 1 mg daily for 10 days.
      • If Dutasteride not available, use Finasteride 10 mg daily for 10 days
  • Fluvoxamine
    • 50 mg 2 x daily for 10 days 7
    • Consider Fluoxetine 30 mg daily for 10 days as an alternative (it is often better tolerated). Avoid if patient is already on an SSRI.
  • Monoclonal Antibodies
    • Sotrovimab 500 mg each in a single intravenous infusion.
      • Antibody therapy is for patients within 5 days of first symptoms, non-severe symptoms, and one or more risk factors as: Age>55y; BMI>25; pregnancy; chronic lung, heart, or kidney disease; diabetes.

Third Line:

  • Corticosteroids
    • Prednisone or Methylprednisolone 1 mg/kg daily for 5 days followed by slow taper or escalation according to patient response.
    • Criteria: After day 7–10 from first symptoms and patient has either:
      • abnormal chest x-ray
      • shortness of breath
      • or oxygen saturations of 88–94 %.
        • If oxygen saturation is lower than 88 %, emergency room evaluation should be sought


  1. Vitamin D Dosing for COVID-19
    Table 37: Longer-term maintenance of serum 25(OH)D concentrations above 50 ng/mL based on body weight
    Body-weight category Dose (IU) kg/day Daily dose (IU) Once a week (IU)
    BMI ≤ 19 (under-weight) 40 – 70 2,000 – 4,000 25,000
    BMI 20–29 (non-obese person) 70 – 100 5,000 – 7,000 50,000
    BMI 30–39 (obese persons) 100 – 150 9,000 – 15,000 75,000
    BMI ≥ 40 (morbidly obese persons) 150 – 200 16,000 – 30,000 100,000
  2. Pulse Ox for COVID-19

    In symptomatic patients, monitoring with home pulse oximetry is recommended (due to asymptomatic hypoxia). The limitations of home pulse oximeters should be recognized, and validated devices are preferred. Multiple readings should be taken over the course of the day, and a downward trend should be regarded as ominous.

    Baseline or ambulatory desaturation < 94% should prompt hospital admission.

    The following guidance is suggested:

    • Use the index or middle finger; avoid the toes or ear lobe.
    • Only accept values associated with a strong pulse signal.
    • Observe readings for 30–60 seconds to identify the most common value.
    • Remove nail polish from the finger on which measurements are made.
    • Warm cold extremities prior to measurement.
  3. Calculation for ivermectin dose (0.2 mg per kg) for COVID-19
    Body weight lbs Body weight Kg Dose 0.2 mg/kg ≈ 0.09 mg/lb (Each tablet = 3 mg; doses rounded to nearest half tablet above)
    70–90 lb 32–40 kg 8 mg (3 tablets = 9 mg)
    91–110 lb 41–50 kg 10 mg (3.5 tablets)
    111–130 lb 51–59 kg 12 mg (4 tablets)
    131–150 lb 60–68 kg 13.5 mg (4.5 tablets)
    151–170 lb 69–77 kg 15 mg (5 tablets)
    171–190 lb 78–86 kg 16 mg (5.5 tablets)
    191–210 lb 87–95 kg 18 mg (6 tablets)
    211–230 lb 96–104 kg 20 mg (7 tablets = 21 mg)
    231–250 lb 105–113 kg 22 mg (7.5 tablets=22.5 mg)
    251–270 lb 114–122 kg 24 mg (8 tablets)
    271–290 lb 123–131 kg 26 mg (9 tablets = 27 mg)
    291–310 lb 132–140 kg 28 mg (9.5 tablets=28.5 mg)

    For higher doses used in our I-MASK+ Protocol please multiply the value found in the table for 0.2 mg/kg, e.g.:

    • 0.4 mg/kg: double the 0.2 mg/kg dose
    • 0.6 mg/kg: triple the 0.2 mg/kg dose

12.5.3 COVID Risk factors for Death and Hospitalization (Medicare Population)

Table 38: Table 3. Logistic Regression Model Results Assessing Potential Risk Factors for Coronavirus Disease 2019–Related Hospitalization and Death in the Primary Study Population
Covariates COVID-19–Related Death – OR (CI) COVID-19 Hospitalization - OR (CI)
Male sex (reference: female) 1.77 (1.71–1.84) 1.48 (1.45–1.52)
Aged into Medicare (reference: not aged into Medicare) 0.72 (.68–.76) 0.74 (.72–.77)
ADI national rank (reference: ADI of 1)    
 50 0.97 (.91–1.03) 1.08 (1.04–1.12)
 100 1.09 (1.00–1.18) 1.23 (1.16–1.29)
Logged COVID-19 circulation rate per 100,000(a) (change by 2×) 1.98 (1.94–2.01) 1.94 (1.92–1.96)
Logged population density by county(b) (change by 2×) 1.00 (.99–1.01) 1.02(1.01–1.03)
Influenza vaccination status (reference: nonvaccinated)    
 Standard-dose inactivated vaccine (FLUAD) 1.04 (.96–1.11) 1.01 (.96–1.06)
 High-dose inactivated vaccine (Fluzone High-Dose) 0.91 (.87–.95) 0.95 (.92–.98)
 Other influenza vaccine or administration code 1.05 (1.00–1.10) 1.05 (1.01–1.09)
Presence of medical conditions(c)    
Hypertension 1.02 (.97–1.07) 1.13 (1.09–1.16)
Obesity 1.10 (1.05–1.16) 1.16 (1.13–1.20)
Diabetes 1.23 (1.18–1.29) 1.28 (1.24–1.32)
Hospitalized for stroke or TIA 1.07 (.91–1.25) 0.94 (.84–1.06)
Coronary revascularization 1.03 (.85–1.26) 0.86 (.74–1.00)
Atrial fibrillation 0.97 (.92–1.01) 0.98 (.95–1.01)
Congestive heart failure 1.30 (1.23–1.36) 1.15 (1.11–1.19)
Hospitalized for AMI 0.99 (.85–1.16) 0.89 (.79–1.00)
Other cerebrovascular disease 0.90 (.85–.95) 0.91 (.87–.94)
COPD 1.14 (1.08–1.20) 1.10 (1.06–1.14)
Asthma without COPD 0.93 (.85–1.03) 1.06 (1.00–1.13)
Interstitial lung disease 1.08 (.97–1.20) 0.95 (.88–1.03)
Hypersensitivity pneumonitis 1.11 (.83–1.48) 1.00 (.81–1.25)
Bronchiectasis 0.85 (.73–1.00) 0.89 (.80–.99)
Chronic liver disease 1.07 (.97–1.19) 1.07 (1.00–1.14)
Neurological or neurodevelopmental conditions 1.08 (1.02–1.14) 1.14 (1.10–1.19)
Frailty conditions    
Impaired mobility 1.45 (1.29–1.65) 1.40 (1.27–1.54)
Depression 1.32 (1.26–1.38) 1.26 (1.22–1.30)
Parkinson disease 1.27 (1.17–1.39) 1.23 (1.15–1.32)
Arthritis 0.97 (.93–1.01) 0.99 (.97–1.02)
Cognitive impairment 3.16 (3.02–3.31) 2.24 (2.16–2.32)
Paranoia 1.66 (1.54–1.80) 1.63 (1.54–1.73)
Chronic skin ulcer 1.12 (1.05–1.20) 1.06 (1.01–1.11)
Skin and soft-tissue infection 1.13 (1.06–1.20) 1.12 (1.07–1.17)
Mycoses 1.57 (1.51–1.64) 1.47 (1.43–1.51)
Gout 1.06 (.99–1.14) 1.02 (.97–1.07)
Falls 1.37 (1.30–1.46) 1.36 (1.31–1.42)
Musculoskeletal problems 0.96 (.92–1.00) 1.01 (.98–1.03)
Urinary tract infection 1.22 (1.17–1.28) 1.19 (1.15–1.23)
Pneumonia 1.89 (1.79–2.00) 1.94 (1.86–2.02)
Charlson Comorbidity Index >0 1.08 (1.03–1.14) 1.09 (1.06–1.13)
Hospital admission in past 6 mo 1.43 (1.35–1.51) 1.55 (1.49–1.61)
Immunocompromised status (reference: nonimmunocompromised) 1.43 (1.34–1.53) 1.24 (1.18–1.30)
Estimated overall interaction effects of age, dual eligibility, and race(d)    
Age 80 vs 65 y 3.09 (2.94–3.25) 1.74 (1.68–1.80)
Dual eligible vs non–dual eligible 2.17 (1.92–2.44) 2.23 (2.08–2.39)
Nonwhites vs whites    
Black 2.47 (2.17–2.81) 2.81 (2.62–3.02)
Hispanic 3.11 (2.37–4.08) 3.31 (2.83–3.87)
North American Native 5.82 (3.25–10.43) 4.22 (2.90–6.16)
Asian 1.32 (.93–1.87) 1.50 (1.23–1.82)
Other/unknown 1.19 (.95–1.50) 1.16 (1.01–1.32)
Effects of dual eligibility, by race    
White (dual vs non-dual eligible) 2.25 (1.97–2.55) 2.35 (2.18–2.54)
Black 1.79 (1.54–2.09) 1.60 (1.46–1.74)
Hispanic 1.46 (1.14–1.87) 1.34 (1.16–1.54)
North American Native 3.09 (1.75–5.46) 2.44 (1.66–3.59)
Asian 1.28 (.90–1.82) 1.12 (.91–1.37)
Other/unknown 2.00 (1.52–2.63) 2.15 (1.83–2.53)
Nonwhites vs whites, non–dual eligible    
Black 2.53 (2.21–2.89) 2.92 (2.71–3.14)
Hispanic 3.23 (2.44–4.29) 3.49 (2.96–4.10)
North American Native 5.65 (3.09–10.32) 4.21 (2.85–6.21)
Asian 1.39 (.98–1.99) 1.60 (1.31–1.97)
Other/unknown 1.21 (.95–1.53) 1.17 (1.01–1.34)
Nonwhites vs whites, dual eligible    
Black 2.02 (1.74–2.35) 1.98 (1.81–2.16)
Hispanic 2.10 (1.64–2.69) 1.99 (1.72–2.29)
North American Native 7.77 (4.39–13.75) 4.37 (2.97–6.43)
Asian 0.80 (.56–1.13) 0.76 (.62–.94)
Other/unknown 1.08 (.82–1.41) 1.07 (.91–1.25)
  • (a) - County-level circulation rate log-transformed using a base of 2, where the OR is interpreted as the estimated OR of doubling the circulation rate.
  • (b) - County-level population density log-transformed using a base of 2, where the OR is interpreted as the estimated OR of doubling the circulation rate.
  • (c) - ORs obtained from logistic regression models. For the OR for the COPD and asthma without COPD groups, the reference group is people with no COPD or asthma.
  • (d) - Interaction effects estimated at median age of the cohort (73 years old), except for the effects of age.


  • ADI, area deprivation index;
  • AMI, acute myocardial infarction;
  • CI, confidence interval;
  • COPD, chronic obstructive pulmonary disease;
  • COVID-19, coronavirus disease 2019;
  • OR, odds ratio;
  • TIA, transient ischemic attack.
  • Dual-eligible: Persons who are eligible for both Medicare and Medicaid are called “dual eligibles”, or sometimes, Medicare-Medicaid enrollees.


  • Hector S Izurieta, David J Graham, Yixin Jiao, Mao Hu, Yun Lu, Yue Wu, Yoganand Chillarige, Michael Wernecke, Mikhail Menis, Douglas Pratt, Jeffrey Kelman, Richard Forshee, Natural History of Coronavirus Disease 2019: Risk Factors for Hospitalizations and Deaths Among >26 Million US Medicare Beneficiaries, The Journal of Infectious Diseases, 2020;, jiaa767,

12.5.4 COVID Ideas/Opinions

  • When Vanden Bossche initially reviewed the high vaccination rates in Israel, Vanden Bossche warned the absence of a natural immunity population to fight the virus would lead to an uncontrollable spread of the virus in the vaccinated community. The higher the vaccination rates, the more serious the spread of the virus amid the population that only carries the immune system protection provided by the vaccine.
  • "The widespread vaccination rate is creating pressure on the virus to mutate into variants with higher levels of contagion. The unvaccinated group has been keeping the pressure down by defeating the virus and carrying natural immunity. However, as the unvaccinated population is increasingly made smaller, the pressure on the virus to mutate increases. Subsequently, these mutations stay at higher or more effective levels of infection."
    • Geert Vanden Bossche

12.5.5 COVID Treatments

  1. OTC COVID Precautions

    For: Prevention, Post-exposure, and Symptomatic

    • Use a Mouthwash 2x per day
    • Gargle, do not swallow
      • Choose any mouthwash with Cetylpyridinium Chloride(CPC):
        • ACT
        • Scope
        • Crest
      • Or choose an essential oil based mouthwash like Listerine made from:
        • Thymol (thyme)
        • Menthol
        • Eucalyptus
  2. Monoclonal Antibodies:

    The new analyses show REGEN-COV reduced the risk of contracting COVID-19 (i.e., laboratory-confirmed symptomatic SARS-CoV-2 infections) by 81.6% during the pre-specified follow-up period (months 2 - 8 ), maintaining the 81.4% risk reduction during the first month after administration, which was previously reported in The New England Journal of Medicine (

    But in this trial of prophylactic use, the antibodies were delivered by subcutaneous injections, not infusions

    And eight months was the end of the study. Not necessarily the end of protection by the antibodies.

    1. Press Release

      Single dose of REGEN-COV (1,200 mg subcutaneous) reduced the risk of COVID-19 by 81.6% during the pre-specified follow-up period (months 2-8), maintaining the 81.4% risk reduction previously reported during month 1

      During the 8-month assessment period there were 0 hospitalizations for COVID-19 in the REGEN-COV group and 6 in the placebo group

      The fully human antibodies in REGEN-COV were developed to provide long-lasting protective effects without any artificial mutations or sequences

  3. COVID Pills
    1. Merck and Ridgeback Biotherapeutics
      • Drug Name: molnupiravir
      • MOA: Inhibits the replication of the coronavirus inside the body
      • Study Population: Every participant was unvaccinated and had at least one underlying factor that put them at greater risk of developing a more severe case of the virus
      • Adverse events:
        • Comparable in the molnupiravir and placebo groups, with around 10% reporting adverse events.
        • Just 1.3% of the molnupiravir group discontinued therapy due to an adverse event - less than the 3.4% of the placebo group who did so
      • Results:
        • 7.3% of patients treated with molnupiravir were hospitalized within 29 days. Of the patients who received a placebo, 14.1% were hospitalized or died by day 29.
        • No deaths were reported in patients who were given molnupiravir within the 29-day period, while eight deaths were reported in placebo-treated patients
        • Reduces the risk of hospitalization or death by around 50% for patients with mild or moderate cases of Covid
        • Molnupiravir reduced the risk of hospitalization and/or death across all key subgroups; efficacy was not affected by timing of symptom onset or underlying risk factor. Additionally, based on the participants with available viral sequencing data (approximately 40% of participants), molnupiravir demonstrated consistent efficacy across viral variants Gamma, Delta, and Mu.

          Table 39: Original data
          Group Hospitalization Death Total
          Treatment 28 0 385
          Control 53 8 377
          NNT 14.7 47.6  
          PEEV 14.06% 2.12%  
          ARR 6.8% 2.1%  
          RRR 48.3%    
          Table 40: Updated Nov 2021
          Group Hospitalization Death Total
          Treatment 48 1 709
          Control 68 9 699
          NNT 33.3 90.9  
          PEEV 9.73% 1.29%  
          ARR 3% 1.1%  
          RRR 30.4% 89%  


    2. Pfizer
      • Drug Name: PF-07321332 (Paxlovid)
      • MOA: Protease inhibitor - works by inhibiting an enzyme the virus needs to replicate in human cells
        • Used along with an HIV drug, which helps slow the metabolism of Pfizer’s pill in order for it to remain active in the body for longer periods of time at higher concentrations
      • Results:
        • Used with an HIV drug, cut the risk of hospitalization or death by 89% in high-risk adults who’ve been exposed to the virus
        • Study of 1,219 adults
        • 6 hospitalizations and 0 deaths out of the 607 trial participants who received the pill in combination with the HIV drug within five days of symptom onset. That compares with 41 hospitalizations and 10 deaths out of the 612 people who received a placebo.

          Group Hospitalizations Deaths Total
          Treatment 6 0 607
          Control 41 10 612
          NNT 17.5 62.5  
          PEEV 6.7% 1.63%  
          ARR 5.7% 1.6%  
          RRR 85.2% 100%  


  4. Current Authorized COVID-19 Outpatient Therapeutics

    Treatment Guidelines:


    • Florida Department of Health Dec 16, 2021
  5. COVID-19 Treatments Pending FDA Approval


    • Florida Department of Health Dec 16, 2021
  6. Emerging Treatment Options for COVID-19


    • Florida Department of Health Dec 16, 2021
  7. HCQ and COVID 19

    No evidence of benefit in COVID-19:

    1. Prophylaxis
      • Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers Randomized Clinical Trial
      • Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Intern Med. Published online September 30, 2020. 10.1001/jamainternmed.2020.6319
    2. Treatment
      • Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19A Randomized Clinical Trial
      • Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237).
      • In this randomized clinical trial that included 479 hospitalized adults with respiratory symptoms from COVID-19, the distribution of the day 14 clinical status score (measured using a 7-category ordinal scale) was not significantly different for patients randomized to receive hydroxychloroquine compared with placebo (adjusted odds ratio, 1.02).
      • Meaning: These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.
      • Self WH, Semler MW, Leither LM, et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(21):2165–2176. 10.1001/jama.2020.22240


    • Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Intern Med. Published online September 30, 2020. 10.1001/jamainternmed.2020.6319
    • Self WH, Semler MW, Leither LM, et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(21):2165–2176. 10.1001/jama.2020.22240
  8. COVID Ivermectin
    • Total with COVID-19: 41608
    • Ivermectin: 1072
    • Remdesivir: 40536

    Ivermectin reduced mortality vs remdesivir: OR = 0.308 p = <0.0001

    • 70% less likely to die if treated with ivermectin than remdesivir

    Total: 159561

      COVID 19   RR Died   RR Hops
    Ivermectin 4311 3.7% 0.56 25 0.8% 0.32 44
    No ivermectin 3034 6.6%   79 2.6%   99

    Small dose (0.2mg/kg/d x2d/2wk)

    • 44% reduction in infection rate RR 0.56
    • 68% reduction in mortality rate p = <0.0001
    • 56% reduction in hospitalization rate p = <0.0001


12.5.6 COVID Vaccines

  1. COVID-19 Vaccines
    Vaccine developer: Pfizer Moderna AstraZeneca Johnson & Johnson
    When approved/expected approval Dec. 11 Dec. 18 Could submit application for emergency use authorization in late March. Submitted application for emergency use authorization on Feb. 5.
    What percentage of people did it protect from getting infected in clinical studies? 95% 94.1% 70% 66%
    How many shots do you need? Two doses, 3 weeks apart Two doses, 4 weeks apart Two doses, a month apart One dose
    What are the side effects? Fatigue, headache, chills, muscle pain, especially after the second dose. Fever, muscle aches, headaches lasting a few days. Effects worse after second dose. Injection site pain, fever, muscle aches, headache. Not yet available.
    How many doses will be available, and when? 50 million, starting Dec. 18; 1.3 billion in 2021. 20 million, starting Dec. 21; 80 million for U.S. in 2021. 3 billion planned for 2021. Not yet available.
    Who is it recommended for? People 16 years and older. People 18 years and older. Not yet available. Not yet available.
    What about pregnant women and nursing moms? Pregnant women or nursing moms who want the COVID-19 vaccine should get one, experts say. The vaccine has not yet been studied in pregnant women. Read guidelines here. There's limited data. Studies in rats who were immunized before and during pregnancy found no safety concerns. The CDC says pregnant women may choose to receive the vaccine. Not yet available. Not yet available.
    Is there anyone who shouldn’t get the vaccine? People with a history of serious allergic reactions, anyone with a history of allergic reactions to vaccine ingredients including polyethylene glycol, and anyone with a history of allergic reactions to polysorbate. People with a history of serious allergic reactions, anyone with a history of allergic reactions to vaccine ingredients including polyethylene glycol, and anyone with a history of allergic reactions to polysorbate. Not yet available. Not yet available.
    Any significant side effects? 50 cases of anaphylaxis in people who received the vaccine, mostly women. Four cases of Bell's palsy, a type of temporary facial paralysis, reported in people who received the vaccine. This is not more than would be expected in the general population. 21 cases of anaphylaxis in people who received the vaccine, all in women. Four cases of Bell's palsy reported in the clinical trials including 3 in the vaccine group, and 1 in the placebo group. This is not more than would be expected in the general population. Four total serious side effects, including two cases of transverse myelitis. One person went to the hospital for fever associated with the vaccine. Four other serious cases were not related to the vaccine.
    What about people with lowered immune function? Ok for people whose immune function is lowered by HIV or immunosuppressing drugs if they have no other reasons to avoid it. There is limited safety data in this group. Ok for people whose immune function is lowered by HIV or immunosuppressing drugs if they have no other reasons to avoid it. There is limited safety data in this group. Not yet available. Not yet available.
    What about people with autoimmune diseases? No data are available on the safety or effectiveness of mRNA vaccines in people with autoimmune disease. People with autoimmune conditions may still get the shots if they have no other reasons to avoid vaccination. No data are available on the safety or effectiveness of mRNA vaccines in people with autoimmune disease. People with autoimmune conditions may still get the shots if they have no other reasons to avoid vaccination. Not yet available. Not yet available.
    Is the vaccine safe for people with a history of Guillain-Barre Syndrome (GBS)? To date, no cases of GBS have been seen in people vaccinated for COVID-19. The CDC says a history of GBS is not a reason to avoid vaccination. To date, no cases of GBS have been seen in people vaccinated for COVID-19. The CDC says a history of GBS is not a reason to avoid vaccination. Not yet available. Not yet available.


    1. Moderna

      The Moderna COVID-19 Vaccine, mRNA-1273 (100μg) is administered intramuscularly as a series of two doses (0.5 mL each), given 28 days apart.

      Study mRNA-1273-P301 is an ongoing randomized, stratified, observer-blind, placebo-controlled study to evaluate the efficacy, safety and immunogenicity of mRNA-1273 administered in 2 doses 28 days apart in adults 18 years of age and older. The study took place in 99 sites in the United States. Participants (N=30,351) were randomized 1:1 to receive intramuscular injections of either 100 μg of mRNA-1273 vaccine (n=15,181) or placebo (n=15,170) on Day 1 and Day 29. Participants were stratified by age and health risk into one of three groups: 18 to <65 years of age and not at risk for progression to severe COVID-19, 18 to <65 years of age and at risk for progression to severe COVID-19, and ≥65 years of age, with the latter two groups consisting of 41.4% of the study population. Participants were considered at risk for progression to severe COVID-19 if they had underlying comorbidities including diabetes, chronic lung disease, severe obesity, significant cardiovascular disease, liver disease, or infection with HIV. The study included 24,907 (82.1%) participants considered at occupational risk for acquiring SARS-CoV-2 infection, of whom 7,613 (25.1%) were healthcare workers. Other essential workers were also represented. The primary efficacy endpoint was efficacy of the vaccine to prevent protocol-defined COVID-19 occurring at least 14 days after the second dose in participants with negative SARS-CoV-2 status at baseline (i.e., negative RT-PCR and negative serology against SARS-CoV-2 nucleocapsid on Day 1).

      Primary Efficacy Endpoint

      The primary efficacy endpoint was efficacy of the vaccine to prevent protocol-defined COVID-19 occurring at least 14 days after the second dose in participants with negative SARS-CoV-2 status at baseline (i.e., negative RT-PCR and negative serology against SARS-CoV-2 nucleocapsid on Day 1). The primary analysis was based on the Per-Protocol Set, defined as all randomized, baseline SARS-CoV-2 negative participants who received planned doses per schedule and have no major protocol deviations. For the primary efficacy endpoint, the case definition for a confirmed COVID-19 case was defined as:•At least TWO of the following systemic symptoms: Fever (≥38ºC), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s), or •At least ONE of the following respiratory signs/ symptoms: cough, shortness of breath or difficulty breathing, OR clinical or radiographical evidence of pneumonia; and •NP swab, nasal swab, or saliva sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR

      Table 41: Table 9. Interim Analysisa for Primary Efficacy Endpoint, COVID-19 Starting 14 Days After the 2nd Dose, Per-Protocol Set
      Primary Endpoint: COVID-19 (per adjudication committee assessment) Vaccine Group N=13934 Cases n (%)(Incidence rate per 1,000 person-years) Placebo Group N=13883 Cases n (%)(Incidence rate per 1,000 person-years) Vaccine Efficacy (VE)% (95%CI)* Met Predefined Success Criterion**
      All participants 5 (<0.1)1.840 90 (0.6)33.365 94.5% (86.5%, 97.8%) Yes
      18 to <65 5 / 10407 (<0.1)2.504 75 / 10384 (0.7)37.788 93.4% (83.7%, 97.3%) NA
      65 and older 0 / 3527 15/3499(0.4)21.046 100% NA

      COVID-19: symptomatic COVID-19 requiring positive RT-PCR result and at least 2 systemic symptoms or 1 respiratory symptom. Cases starting 14 days after the 2nd dose. All potential COVID-19 cases starting 14 days after the 2nd dose in the clinical database as of 07-Nov-2020 have been sent to adjudication committee, and have been adjudicated for this analysis (07-Nov-2020 is the datacutoff date for efficacy). One case (in the placebo group) was assessed as a case by the adjudication committee but did not meet case definition based on statistical analysis plan (participant had body aches, nasal congestion, rhinorrhea, which were not protocol defined symptoms).

      *VE is calculated as 1-ratio of incidence rates (mRNA-1273/placebo) and 95% CI from the stratified Cox proportional hazard model.

      **The one-sided p-value is <0.0001 from the stratified Cox proportional hazard model to test the null hypothesis of VE≤3 0%, achieving the pre-specified efficacy boundary: the one-sided nominal alpha of 0.0049 based on 95 cases using the Lan-DeMets O'Brien-Fleming spending function

      (My Calculations)

      Absolute Risk Reduction (95% CI) -0.006 (-0.007 to -0.005)
      Relative Risk Reduction (95% CI) -0.945 (0.022 to 0.135)
      Number Needed to Treat -166.7
      Odds Ratio 0.055
      Relative Risk 0.055

      Patient Expected Event Rate: 0.65%

    2. Pfizer

      Phase 3 trials of the Pfizer-BioNTech vaccine, eight of the 17,411 people who were given the vaccine wound up becoming sick with COVID-19, compared with 162 of the 17,511 who got the placebo. Using that and other data, researchers determined that the vaccine was 95% effective at preventing COVID-19.

      Table 6. Final Analysis of Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days AfterDose 2 in Participants Without Evidence of Prior SARS-CoV-2 Infection - Evaluable Efficacy Population

      Pre-specified Age Group BNT162b2 N(a) = 18198 Cases n1(b) Surveillance Time(c)(n2(d)) Placebo N(a) =18325 Cases n1(b) Surveillance Time(c)(n2(d)) Vaccine Efficacy %(95% CI) Met Predefined Success Criterion(*)
      All participants 8 2.214 (17411) 162 2.222 (17511) 95.0(90.3, 97.6)(e) Yes
      16 to 55 years 5 1.234 (9897) 114 1.239 (9955) 95.6(89.4, 98.6)(f) NA
      > 55 years and older 3 0.980 (7500) 48 0.983 (7543) 93.7(80.6, 98.8)(f) NA
      • (*) Success criterion: the posterior probability that true vaccine efficacy > 30% conditioning on the available data is >99.5% at the final analysis
      • (a) N = number of participants in the specified group.
      • (b) n1 = Number of participants meeting the endpoint definition.
      • (c) Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
      • (d) n2 = Number of participants at risk for the endpoint.
      • (e) Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for surveillance time.
      • (f) Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time

      (My Calculations)

      Absolute Risk Reduction (95% CI) -0.008 (-0.009 to -0.007)
      Relative Risk Reduction (95% CI) -0.951 (0.024 to 0.100)
      Number Needed to Treat -125
      Odds Ratio 0.049
      Relative Risk 0.049

      Patient Expected Event Rate: 0.89%

      1. Adverse Events

        Cumulatively, through 28 February 2021 (3 months of use)

        Table 42: Table 1: General Overview: Selected Characteristics of All Cases Received During the Reporting Interval
        Characteristics Relevant cases (N=42086)
        Gender: Female 29914
          Male 9182
          No Data 2990
        Age range (years): 0.01 -107 years Mean = 50.9 years n = 34952 ≤ 17 175
          18-30 4953
          31-50 13886
          51-64 7884
          65-74 3098
          ≥ 75 5214
          Unknown 6876
        Case outcome: Recovered/Recovering 19582
          Recovered with sequelae 520
          Not recovered at the time of report 11361
          Fatal 1223
          Unknown 9400


    3. Johnson & Johnson

      Released Stats:

      • Vaccine Candidate 72% Effective in the US and 66% Effective Overall at Preventing Moderate to Severe COVID-19, 28 Days after Vaccination
      • 85% Effective Overall in Preventing Severe Disease and Demonstrated Complete Protection Against COVID-19 related Hospitalization and Death as of Day 28
      • Protection Against Severe Disease Across Geographies, Ages, and Multiple Virus Variants, including the SARS-CoV-2 Variant from the B.1.351 Lineage[1] Observed in South Africa
      • Single-shot compatible with standard vaccine distribution channels provides important tool in pandemic setting

      The Janssen vaccine is a recombinant vector vaccine that uses a human adenovirus to express the SARS-CoV-2 spike protein. SARS-CoV-2 is the virus that causes COVID-19. Adenoviruses are a group of viruses that cause infections in the respiratory and gastrointestinal tracts; the adenovirus vector used in the experimental vaccine has been modified, so that it can no longer replicate in humans and cause illness. In developing the vaccine, Janssen employed the same vector used in the first dose of its prime-boost vaccine regimen against Ebola virus disease (Ad26 ZEBOV and MVN-BN-Filo), developed under a long-standing partnership with BARDA and granted marketing authorization by the European Commission in July 2020. Unlike the two COVID-19 vaccines currently authorized by the U.S. Food and Drug Administration for emergency use (Pfizer and Moderna vaccines), the Janssen investigational vaccine requires only a single vaccination.

      The Phase 3 ENSEMBLE study is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of a single vaccine dose versus placebo in up to 60,000 adults 18 years old and older, including significant representation from those that are over age 60. The study was designed to evaluate the safety and efficacy of the Janssen investigational vaccine in protecting against both moderate and severe COVID-19 disease, with assessment of efficacy as of day 14 and as of day 28 as co-primary endpoints.

      Overall, the results indicate that the J&J vaccine is 66% effective for the prevention of moderate and severe illness, and was shown to be effective against emerging viral variants at day 28. Level of protection varied based on geographical location:

      • United States: 72%
      • Latin American countries: 66%
      • South Africa: 57%

      The primary efficacy analysis was based on the per-protocol set, which consisted of all vaccinated participants who were SARS-CoV-2 seronegative at time of vaccination and who had no major protocol deviations.

      Table 43: Table 10. Vaccine Efficacy Against Centrally Confirmed Moderate to Severe/Critical COVID-19 With Onset at Least 14 and at Least 28 Days After Vaccination, Per-Protocol Set, Study 3001
      Onset at Least: 14 Days 14 Days 14 Days 28 Days 28 Days 28 Days
      Co-primary Endpoint Subgroup Ad26.COV2.S Cases (N)aPerson-yrsb Placebo Cases (N)Person-yrs VE% (95% CI) Ad26.COV2.S Cases (N)Person-yrs Placebo Cases (N)Person-yrs VE%(95% CI)
      All participants 116(19514) 3116.6 348(19544) 3096.1 66.9%(59.0, 73.4) 66 (19306) 3102.0 193(19178) 3070.7 66.1%(55.0,74.8)
      Age 18-59 years 95(12750) 2106.8 260(12782) 2095.0 63.7%(53.9, 71.6) 52(12617) 2097.6 152(12527) 2077.0 66.1%(53.3,75.8)
      Age ≥60 years 21(6764) 1009.8 88(6762) 1001.2 76.3%(61.6, 86.0) 14(6689)1004.4 41(6651)993.6 66.2%(36.7,83.0)

      (My Calculations)

      Table 44: At 14 Days
      Absolute Risk Reduction (95% CI) -0.012 (-0.014 to -0.010)
      Relative Risk Reduction (95% CI) -0.666 (0.271 to 0.412)
      Number Needed to Treat -83.3
      Odds Ratio 0.330
      Relative Risk 0.334

      Patient Expected Event Rate (PEER): 1.78% (COVID Prevalence during study)

      Secondary Efficacy Analyses

      Efficacy Against Any Symptomatic COVID-19 Efficacy against any symptomatic COVID-19 (including mild disease) and efficacy based on a less restrictive case definition (FDA harmonized case definition), with onset at least 14 days or 28 days after vaccination, were overall similar to results obtained for the primary efficacy endpoint of efficacy against moderate to severe/critical COVID-19.

      Table 45: Table 15. Vaccine Efficacy Against Centrally Confirmed COVID-19a With Onset at Least 14 or at Least 28 Days After Vaccination, Per-Protocol Set, Study 3001
      Onset at Least: 14 Days 14 Days 14 Days 28 Days 28 Days 28 Days
        Ad26.COV2.S Cases (N)Person-yrs Placebo Cases (N)Person-yrs VE% (95% CI) Ad26.COV2.S Cases (N)Person-yrs Placebo Cases (N)Person-yrs VE%(95% CI)
      Symptomatic COVID-19, any severity(a) 117 (19514) 3116.5 351 (19544) 3095.9 66.9% (59.1, 73.4) 66 (19306) 3102.0 195 (19178) 3070.5 66.5% (55.5,75.1)
      FDA harmonized COVID-19 cases 114 (19514) 3116.6 345 (19544) 3096.3 67.2% (59.3,73.7) 65 (19306) 3102.0 193 (19178) 3070.6 66.7% (55.6, 75.2)

      a Includes mild, moderate, and severe/critical cases

      COVID-19 Requiring Medical Intervention

      The endpoint of COVID-19 requiring medical intervention is defined as participant requiring hospitalization, ICU admission, mechanical ventilation, and/or ECMO, linked to objective measures such as decreased oxygenation, X-ray or computed tomography (CT) findings, andlinked to any molecularly confirmed, COVID-19 with onset at least 14 days and at least 28 days post-vaccination.

      Table 46: Table 17. Vaccine Efficacy of First Occurrence COVID-19 Requiring Medical Intervention Based on MRU, With Onset at Least 14 or at Least 28 Days After Vaccination, Per-Protocol Set, Study 3001
      Onset at Least: 14 Days 14 Days 14 Days 28 Days 28 Days 28 Days
        Ad26.COV2.S Cases (N)Person-yrs Placebo Cases (N)Person-yrs VE% (95% CI) Ad26.COV2.S Cases (N)Person-yrs Placebo Cases (N)Person-yrs VE%(95% CI)
      Centrally Confirmed 2 (19514)3126.9 8 (19544) 3126.1 75.0%(-25.3, 97.4) 0 (19306)3106.4 5(19178) 3084.4  
      Any positive PCR 2 (19514)3125.9 14 (19544)3125.8 85.7% (37.8,98.4) 0 (19306)3106.4 7 (19178)3084.4 100%(31.1, 100.0)

      (My Calculations)

      Table 47: Of COVID Positive people, number to vaccinate for medical intervention
      Absolute Risk Reduction (95% CI) -0.023 (-0.054 to 0.008)
      Relative Risk Reduction (95% CI) -0.571 (0.099 to 1.860)
      Number Needed to Treat -43.5
      Odds Ratio 0.419
      Relative Risk 0.429

      (Vaccinated: 2 of 116; and Control: 14 of 348)


    4. NovaVax

      Primary End Point

      • The aim of the trial was to estimate, as the primary end point, the efficacy of NVX-CoV2373 for the prevention of a first occurrence of reverse-transcriptase–polymerase-chain-reaction (RT-PCR)–confirmed symptomatic mild, moderate, or severe Covid-19


      • Among the 25,452 participants in the per-protocol efficacy analysis population who were followed through April 19, 2021 (median follow-up for efficacy, approximately 3 months), 77 central laboratory–confirmed Covid-19 cases occurred: 14 cases in NVX-CoV2373 recipients and 63 in placebo recipients (incidence, 3.3 cases per 1000 person-years [95% CI, 1.6 to 6.9] and 34.0 cases per 1000 person-years [95% CI, 20.7 to 55.9], respectively). These results yielded a vaccine efficacy of 90.4% (95% CI, 82.9 to 94.6; P<0.001)
      • All the cases reported in NVX-CoV2373 recipients were mild in severity, whereas 14 moderate-to-severe cases (10 moderate and 4 severe) occurred in the placebo group, yielding a vaccine efficacy against moderate-to-severe Covid-19 of 100% (95% CI, 87.0 to 100)
      • Vaccine efficacy against confirmed Covid-19 meeting the definition of the primary end point among participants who were at high risk for acquisition or complications of Covid-19 was 91.0% (95% CI, 83.6 to 95.0)

      Side Effects:

      • After each dose, the most frequently reported solicited local adverse events were tenderness and injection-site pain.
      • The median duration of these events was 2 days or less
      • Severe (grade ≥3) local reactions were infrequent overall but were more common among NVX-CoV2373 recipients than among placebo recipients, particularly after dose 2 (1.1% of NVX-CoV2373 recipients and <1% of placebo recipients after dose 1 and 6.7% and <1%, respectively, after dose 2)
      • The most common solicited systemic adverse events were headache, myalgia, fatigue, and malaise, which were detected more frequently among NVX-CoV2373 recipients and after the second injection and lasted for a median duration of 1 day or less.


      • NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains.

      (My Calculations)

      Table 48: After 3 Months
      Absolute Risk Reduction (95% CI) -0.007 (-0.009 to -0.005)
      Relative Risk Reduction (95% CI) -0.896 (0.058 to 0.185)
      Number Needed to Treat -142.9
      Odds Ratio 0.104
      Relative Risk 0.104

      Patient Expected Event Rate: 0.77 % PEER (COVID Prevalence during study)


  2. COVID Vaccine Comparison   edit
      Pfizer Moderna J&J Novavax
    RRR 95.1 % 94.5 % 66.7 % 91 %
    NNT 125 167 83 143
    ARR 0.8 % 0.6 % 1.2 % 0.7 %
    PEER 0.89 % 0.65 % 1.78 % 0.77 %
    1. COVID Vaccine Adverse Effects

      Pfizer vaccine (after 2nd dose):

      • 66% reported pain
      • 60% fatigue
      • 52% headache
      • 38% muscle pain
      • 22% joint pain
      • 16% fever
      • 2% vomiting.

      Moderna vaccine (after 2nd dose):

      • 88% experienced pain
      • 16% fever, including 1.4% severe cases
      • 59% headache
      • 66% fatigue
      • 43% joint pain
      • 19% vomiting.


      • tenderness at the injection site for 73% of participants
      • pain upon and after vaccination for 60% of participants
      • fatigue for 50% of the participants
      • muscle pain for 48% of participants
      • headache for 44% of participants
      • malaise for 39% of participants
      • fever for 6% of participants, including severe cases for 0.37%
      • nausea and vomiting for 11% of participants, including severe cases for 0.23%
      • joint pain for 22% of participants, including severe cases for 2.44%
  3. COVID Vaccine Efficacy Calculations
    Table 49: Risk for COVID-19 Infection, Hospitalization, and Death By Age Group
    Rate compared to 18-29 years old 0-4 years old 5-17 years old 18-29 years old 30-39 years old 40-49 years old 50-64 years old 65-74 years old 75-84 years old 85+ years old
    Cases <1x 1x Reference group 1x 1x 1x 1x 1x 1x
    Hospitalization <1x <1x Reference group 2x 2x 4x 5x 8x 10x
    Death <1x <1x Reference group 4x 10x 25x 65x 150x 370x
    • All rates are relative to the 18- to 29-year-old age category. This group was selected as the reference group because it has accounted for the largest cumulative number of COVID-19 cases compared to other age groups. Sample interpretation: Compared with 18- to 29-year-olds, the rate of death is four times higher in 30- to 39-year-olds, and 370 times higher in those who are 85 years and older. (In the table, a rate of 1x indicates no difference compared to the 18- to 29-year-old age category.)
    • Updated Nov. 22, 2021
    Table 50: Risk for COVID-19 Infection, Hospitalization, and Death By Race/Ethnicity
    Rate ratios compared to White, Non-Hispanic persons American Indian or Alaska Native, Non-Hispanic persons Asian, Non-Hispanic persons Black or African American, Non-Hispanic persons Hispanic or Latino persons
    Cases 1.6x 0.6x 1.0x 1.6x
    Hospitalization 3.3x 0.8x 2.6x 2.5x
    Death 2.2x 0.9x 1.9x 2.1x
    Table 51: Estimated rates of COVID-19 disease outcomes per 100,000, by age group — United States, February 2020-September 2021
      Infection rate per 100,000     Symptomatic Illness rate per 100,000     Hospitalization rate per 100,000     Death rate per 100,000    
    Age group Estimate Rate % 95% UI Estimate Rate % 95% UI Estimate Rate % 95% UI Estimate Rate % 95% UI
    0-17 years 35490 0.3549 29,335 – 43,414 30253 0.3025 26,240 – 35,295 366 0.00366 309 – 434 0.9 0.000009 0.7-1.6
    18-49 years 54860 0.5486 45,740 – 66,055 46724 0.4672 41,213 – 53,525 1457 0.01457 1,255 – 1,704 43.7 0.000437 41.0 – 46.6
    50-64 years 43656 0.4366 36,428 – 52,439 37239 0.3724 32,859 – 42,526 3200 0.03200 2,822 – 3,671 253.5 0.002535 246.2 – 261.3
    65+ years 32363 0.3236 26,101 – 40,895 26278 0.2628 23,200 – 30,085 5807 0.05807 5,146 – 6,617 1296.5 0.012965 1274.5 – 1319.1
    All ages 44650 0.4465 38,374 – 52,262 37764 0.3776 33,821 – 42,630 2286 0.02286 2,046 – 2,579 280.7 0.002807 275.0 – 286.7
    • Adjusted rates are presented in two parts: an uncertainty interval [UI] and a point estimate. The uncertainty interval provides a range in which the true number or rate of COVID-19 infections, symptomatic illnesses, hospitalizations, or deaths would be expected to fall if the same study was repeated many times, and it gives an idea of the precision of the point estimate. A 95% uncertainty interval means that if the study were repeated 100 times, then 95 out of 100 times the uncertainty interval would contain the true point estimate. Conversely, in only 5 times out of a 100 would the uncertainty interval not contain the true point estimate.
    Table 52: Baseline COVID Rates
      Infection Symptomatic Illness Hospitalization Death
    Age group Rate % Rate % Rate % Rate %
    0-17 years 0.3549 0.3025 0.00366 0.000009
    18-49 years 0.5486 0.4672 0.01457 0.000437
    50-64 years 0.4366 0.3724 0.03200 0.002535
    65+ years 0.3236 0.2628 0.05807 0.012965
    All ages 0.4465 0.3776 0.02286 0.002807


    • Patients aged > 75 years (OR 3.25 [95% CI 1.91, 5.52])
    • Male patients (OR 1.81 [95% CI 1.02, 3.19])
    • Those with concomitant neurological disorders (OR 2.07 [95% CI 1.15, 3.74])
    • Renal disease (OR 1.91 [95% CI 0.82, 4.45])
    • Pulmonary disease (OR 1.83 [95% CI 1.05, 3.20])
    • Diabetes (OR 1.62 [95% CI 0.95, 2.76])
    • Cancer (OR 1.52 [95% CI 0.85, 2.70])
    • Those who required oxygen by face mask (OR 2.05 [95% CI 1.25, 3.38]) had a higher risk of death in our cohort
      • The risk of death was also high in those with higher CRP (OR 1.25 [95% CI 1.08, 1.45], 50 mg/L increase)
      • Serum creatinine (OR 1.09 [95% CI 0.98, 1.21], 50 μmol/L increase) levels
      • Those with low hemoglobin (OR 1.14 [95% CI 0.99, 1.32], 1 g/L decrease)
      • Platelet (OR 1.46 [95% CI 1.04, 2.04], 100 G/L decrease) count

    ICU hospitalization.

    • Patients aged ≤ 75 years (OR 2.79 [95% CI 1.67, 4.66])
    • those with concomitant pulmonary disease (OR 1.64 [95% CI 0.96, 2.78])
    • those without dementia (OR 3.57 [95% CI 0.8, 15.9])
    • those requiring oxygen by face mask (OR 1.53 [95% CI 0.97, 2.42]) were at higher risk of being hospitalized in the ICU.
    • Higher CRP (OR 1.47 [95% CI 1.28, 1.68], 50 mg/L increase)
    • hemoglobin (OR 1.31 [95% CI 1.14, 1.52], 1 g/L increase)
    • serum creatinine (OR 1.20 [95% CI 1.10, 1.32], 50 μmol/L increase) levels also increased the risk of ICU hospitalization.



    Absolute Risk Reduction (95% CI) -0.006 (-0.007 to -0.005)
    Relative Risk Reduction (95% CI) -0.945 (0.022 to 0.135)
    Number Needed to Treat -166.7
    Odds Ratio 0.055
    Relative Risk 0.055

    Patient Expected Event Rate: 0.65%


    Absolute Risk Reduction (95% CI) -0.008 (-0.009 to -0.007)
    Relative Risk Reduction (95% CI) -0.950 (0.025 to 0.102)
    Number Needed to Treat -125
    Odds Ratio 0.049
    Relative Risk 0.050

    Patient Expected Event Rate: 0.88%


    Absolute Risk Reduction (95% CI) -0.012 (-0.014 to -0.010)
    Relative Risk Reduction (95% CI) -0.666 (0.271 to 0.412)
    Number Needed to Treat -83.3
    Odds Ratio 0.330
    Relative Risk 0.334

    Patient Expected Event Rate (PEER): 1.78% (COVID Prevalence during study)

      Moderna Pfizer J&J
    PEEV 0.65% 0.88% 1.78%
    ARR -0.6% -0.8% -1.2%
    NNV 167 125 83
    Baseline(/10k) 65 88 178
    With Vaccine 3 4.4 59.5

    From Pfizer:

    Absolute Risk Reduction (95% CI) -0.008 (-0.009 to -0.007)
    Relative Risk Reduction (95% CI) -0.951 (0.024 to 0.100)
    Number Needed to Treat -125.0
    Odds Ratio 0.049
    Relative Risk 0.049

    Patient Expected Event Rate: 0.89%

      COVID -COVID  
    Vaccine 8 18190 18198
    Placebo 162 18163 18325
    Vaccine + Placebo 170 36353 36523

    For Pfizer:

    • Baseline Risk of Infection during study: 0.89%
    • Baseline risk of severe disease during study: 0.016%
    • Risk of infection with vaccine: 0.04%
    • Risk of severe disease with vaccine: 0.005%
  4. COVID Vaccines do not prevent disease


    Open up the spreadsheet and click on sheet 1b

    You will see that vaccination increases risk for omnicron variant of COVID:

    • Not vaccinated: 1 (reference)
    • 1 dose 14+ days ago: 1.57x
    • 2 doses 14+ days ago: 2.26x
    • 3 doses 14+ days ago: 4.45x

    Vaccinations do not prevent disease:

    1. Nearly 50 Passengers Aboard Royal Caribbean Cruise Ship Test Positive for COVID-19 in Miami
    2. 55 People Aboard Second Royal Caribbean Cruise Ship Test Positive for COVID-19
  5. J&J

    Cases of TTS following administration of the Janssen COVID-19 Vaccine have been reported in males and females, in a wide age range of individuals 18 years and older, with the highest reporting rate (approximately 8 cases per 1,000,000 doses administered) in females ages 30-49 years; overall, approximately 15% of TTS cases have been fatal. Currently available evidence supports a causal relationship between TTS and the Janssen COVID-19 Vaccine. The clinical course of these events shares features with autoimmune heparin-induced thrombocytopenia. In individuals with suspected TTS following administration of the Janssen COVID-19 Vaccine, the use of heparin may be harmful and alternative treatments may be needed. Consultation with hematology specialists is strongly recommended. The American Society of Hematology has published considerations relevant to the diagnosis and treatment of TTS following administration of the Janssen COVID-19 Vaccine (

    1. Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT)

      Definitive Diagnosis (must meet all five criteria):

      • COVID vaccine 4 to 42 days prior to symptom onset#
      • Any venous or arterial thrombosis (often cerebral or abdominal)
      • Thrombocytopenia (platelet count < 150 x 109/L)*
      • Positive PF4 “HIT” (heparin-induced thrombocytopenia) ELISA
      • Markedly elevated D-dimer (> 4 times upper limit of normal)

      Urgent medical evaluation for VITT is indicated if any of the following develop 4 to 42 days after vaccination:

      • Severe headache
      • Visual changes
      • Abdominal pain
      • Nausea and vomiting
      • Back pain
      • Shortness of breath
      • Leg pain or swelling
      • Petechiae, easy bruising, or bleeding

      Initial work-up (a normal platelet count is less concerning for VITT*):

      • CBC with platelet count and peripheral smear
      • Imaging for thrombosis based on signs/symptoms
      • PF4-ELISA (HIT assay); draw blood prior to any therapies
      • Fibrinogen and D-dimer

      Initiate therapy with intravenous immunoglobin and nonheparin anticoagulation pending PF4 ELISA results if: Confirmed thrombosis AND at least one of the following

      • Low platelets* OR
      • Markedly elevated D-dimer OR
      • Both


      • If thrombocytopenia and very high D-Dimer in absence of known thrombosis, particularly in the presence of severe headache, check PF4 ELISA, and consider treatment (see Q2)
      • If thrombocytopenia but no thrombosis and negative PF4 ELISA: likely ITP
      • Avoid platelet transfusions unless other treatments have been initiated AND life-threatening bleeding or imminent surgery
      • Consider referral to tertiary care center if VITT is confirmed.


12.5.7 EUA

To be considered for an EAU, a Phase 3 vaccine trial should include “well over 3,000” participants, and at least half of them should be tracked for at least two months after receiving their final dose

An EUA can last only as long as a public health emergency is in effect. But scientists anticipate that the coronavirus will continue to circulate in humans even after the COVID-19 pandemic ends. In that case, vaccine makers that want to keep their products on the market will need to have regular FDA approval — and to get it, they’ll need to keep their Phase 3 clinical trials going.

12.5.8 Masks

Definition of a significant exposure to Covid-19 as face-to-face contact within 6 feet with a patient with symptomatic Covid-19 that is sustained for at least a few minutes (and some say more than 10 minutes or even 30 minutes)

Covid-19 virus is 120 nanometers in size while the filtration potential of a N95 mask is 150-300 nanometers.

Penetration of cloth masks by particles was almost 97% and medical masks 44%.

  • MacIntyre CR, Seale H, Dung TC, et al A cluster randomised trial of cloth masks compared with medical masks in healthcare workers BMJ Open 2015;5:e006577. doi: 10.1136/bmjopen-2014-006577

Face mask use in health care workers has not been demonstrated to provide benefit in terms of cold symptoms or getting colds

  • Jacobs JL, Ohde S, Takahashi O, Tokuda Y, Omata F, Fukui T. Use of surgical face masks to reduce the incidence of the common cold among health care workers in Japan: a randomized controlled trial. Am J Infect Control. 2009 Jun;37(5):417-419. doi: 10.1016/j.ajic.2008.11.002. Epub 2009 Feb 12. PMID: 19216002.

Our analysis confirms the effectiveness of medical masks and respirators against SARS. Disposable, cotton, or paper masks are not recommended. We found no clear benefit of either medical masks or N95 respirators against pH1N1.

  • Vittoria Offeddu, Chee Fu Yung, Mabel Sheau Fong Low, Clarence C Tam, Effectiveness of Masks and Respirators Against Respiratory Infections in Healthcare Workers: A Systematic Review and Meta-Analysis, Clinical Infectious Diseases, Volume 65, Issue 11, 1 December 2017, Pages 1934–1942,

Norway’s Institute for Public Health reported that if masks did work then any difference in infection rates would be small when infection rates are low: assuming 20% asymptomatics and a risk reduction of 40% for wearing masks, 200 000 people would need to wear one to prevent one new infection per week

  • Iversen BG, Vestrheim DF, Flottorp S, Denison E, Oxman AD. COVID-19:

Should individuals in the community without respiratory symptoms wear facemasks to reduce the spread of COVID-19? [Covid-19: Bør personer i samfunnet bruke ansiktsmasker for å redusere spredningen av covid-19? Hurtigoversikt 2020] Oslo: Norwegian Institute of Public Health, 2020

Median (range) aerosol particle number emission rates were (Figure 2): 135 (85-691) particles/s for breathing, 270 (120–1380) particles/s for normal talking, 570 (180–1760) particles/s for loud talking, 690 (320–2870) particles/s for normal singing, 980 (390–2870) particles/s for loud singing, and 1480 (500-2820) particles/s for loud singing with exaggerated diction. For loud singing with a face mask, the emission rate was 410 (200–1150) particles/s. Median number of emitted particles in the size range 0.54–10 µm per second for the 12 singers. Nevertheless, many of the largest droplets travel a limited distance (<0.5 m) before their movement become vertical due to sedimentation.

  • M. Alsved, A. Matamis, R. Bohlin, M. Richter, P.-E. Bengtsson, C.-J. Fraenkel, P. Medstrand & J. Löndahl (2020) Exhaled respiratory particles during singing and talking, Aerosol Science and Technology, 54:11, 1245-1248, DOI: 10.1080/02786826.2020.1812502

In this community-based, randomized controlled trial conducted in a setting where mask wearing was uncommon and was not among other recommended public health measures related to COVID-19, a recommendation to wear a surgical mask when outside the home among others did not reduce, at conventional levels of statistical significance, incident SARS-CoV-2 infection compared with no mask recommendation.

  • Henning Bundgaard, Johan Skov Bundgaard, Daniel Emil Tadeusz Raaschou-Pedersen, et al. Effectiveness of Adding a Mask Recommendation to Other Public Health Measures to Prevent SARS-CoV-2 Infection in Danish Mask Wearers: A Randomized Controlled Trial. Ann Intern Med.2021;174:335-343. [Epub ahead of print 18 November 2020]. 10.7326/M20-6817

12.5.9 Random Stats Stuff

  1. COVID Shorten life - 5 days not 1 year

    Analysts estimate that, on average, a death from Covid-19 robs its victim of around 12 years of life. Approximately 400,000 Americans died Covid-19 in 2020, meaning about 4.8 million years of life collectively vanished. Spread that ghastly number across the U.S. population of 330 million and it comes out to 0.014 years of life lost per person. That’s 5.3 days. There were other excess deaths in 2020, so maybe the answer is seven days lost per person.

12.5.10 Outpatient COVID-19 Management


  • Inhaled budesonide 800 mg bid significantly reduces the likelihood that patients with early COVID-19 will require emergency department evaluation or hospitalization (NNT = 7-8) (LOB 1b-)
    • budesonide 400 mcg actuations - 2 actuations twice daily


  • Observational cohort study of 412 adult patients with COVID-19, aspirin use was associated with a significantly lower rate of
    • Reaching mechanical ventilation by 44%
    • ICU admissions by 43%
    • Overall in-hospital mortality by 47%

Fluvoxamine ($10):

  • Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital.
    • This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo.


  • $700
  • At the Interim Analysis, 7.3 Percent of Patients Who Received Molnupiravir Were Hospitalized Through Day 29, Compared With 14.1 Percent of Placebo-Treated Patients Who were Hospitalized or Died
  • The MOVe-OUT trial (MK-4482-002) (NCT04575597) was a global Phase 3, randomized, placebo-controlled, double-blind, multi-site study of non-hospitalized adult patients with laboratory-confirmed mild to moderate COVID-19, at least one risk factor associated with poor disease outcomes, and symptom onset within five days prior to randomization.
  • Orally administered form of a potent ribonucleoside analog that inhibits the replication of SARS-CoV-2


12.5.11 Testing Guidance for COVID-19 - Jan 2022   edit

If you get symptoms, you should avoid contact with others. A positive COVID-19 test result will not change this recommendation.

There are certain groups who are at an increased risk for severe illness from COVID-19. Severe illness means that an individual diagnosed with COVID-19 may need hospitalization, intensive care, or that they may even die.

Groups at increased risk for severe illness from COVID-19 include:

  • Older adults, especially those age 65 and older.
  • Individuals with certain medical conditions, including cancer, diabetes, chronic lung diseases, heart conditions, and a weakened immune system (immunocompromised).
  • Pregnant or recently pregnant individuals.
  1. Individuals with Symptoms and Risk Factors

    Individuals with symptoms of COVID-19 and who are at an increased risk for severe illness from COVID-19:

    • Should get tested for COVID-19 soon after symptom onset.
    • Should seek early monoclonal antibody or antiviral drug treatment and seek other medical treatment as necessary.
  2. Individuals with Symptoms and No Risk Factors

    Individuals with symptoms and who are not at an increased risk for severe illness from COVID- 19:

    • Consider getting tested for COVID-19 soon after symptom onset.
    • Seek medical treatment only as necessary.
  3. Individuals with No Symptoms

    Individuals who may have been exposed to COVID-19, but have no symptoms:

    • COVID-19 testing is unlikely to have any clinical benefits.

12.5.12 COVID Stats'n'Stuff

  1. Infectiousness
    1. Inanimate Surfaces
      1. Ct values and infectivity of SARS-CoV-2 on surfaces
        • Laboratory data showing for SARS-CoV-2 that Ct values of 29·3 (steel surface) or 29·5 (plastic surface) correlate with the detection of culturable virus, whereas Ct values of 32·5 (steel surface) or 32·7 (plastic surface) correlate with the detection of non-culturable virus.
        • SARS-CoV-2 RNA can be found on inanimate surfaces up to 28 days after discharge of patients with COVID-19, which further limits the relevance of RNA detection on surfaces.
        • A Ct (PCR cycle time) value higher than 33 obtained from a surface sample probably has no epidemiological relevance.
        • In public settings, contamination with infectious virus is even less likely than in hospitals.
          • Viral contamination can occur only in the unlikely event a SARS-CoV-2 carrier comes near to a surface.
            • The potential viral source is not permanently present next to the surface, probably has no symptoms, and may wear a face mask, resulting in a low probability of viral spread. In workplaces it was found that only five (0·6%) of 841 tests among employees were positive for SARS-CoV-2 RNA over a period of 2 weeks, with Ct values between 33 and 36.
        • Among 5500 surface samples, only 44 (0.8%) were positive, with Ct values between 34 and 38, indicating that viral loads were indeed very low on surfaces in close and permanent proximity to viral shedders.

        We propose to routinely clean public surfaces, and to consider surface disinfection only when there is evidence that a surface is contaminated with a sufficient amount of infectious virus and is likely to contribute to viral transmission that cannot be controlled by other measures, such as surface cleaning or handwashing.


    2. Community transmission (Vaccinated vs Unvaccinated)

      Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants infected with pre-alpha versus alpha versus delta variants and between unvaccinated delta-infected participants and vaccinated delta-infected participants.

      We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections.

      The SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals.

      NOTE: The Confidence intervals overlap

      The SAR in household contacts exposed to fully vaccinated index cases was 25% (95% CI 15–35; 17 of 69), which is similar to the SAR in household contacts exposed to unvaccinated index cases (23% [15–31]; 23 of 100; table 2). The 53 PCR-positive contacts arose from household exposure to 39 PCR-positive index cases. Of these index cases who gave rise to secondary transmission, the proportion who were fully vaccinated (15 [38%] of 39) was similar to the proportion who were unvaccinated (16 [41%] of 39).

      12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked index cases, further confirmed by genomic and virological analysis in three index case–contact pairs.

      Fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts.

      Real World Evidence: No difference in Secondary Attack Rate


      • Singanayagam A, Hakki S, Dunning J, Madon KJ, Crone MA, Koycheva A, Derqui-Fernandez N, Barnett JL, Whitfield MG, Varro R, Charlett A, Kundu R, Fenn J, Cutajar J, Quinn V, Conibear E, Barclay W, Freemont PS, Taylor GP, Ahmad S, Zambon M, Ferguson NM, Lalvani A; ATACCC Study Investigators. Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. Lancet Infect Dis. 2021 Oct 29:S1473-3099(21)00648-4. doi: 10.1016/S1473-3099(21)00648-4. Epub ahead of print. Erratum in: Lancet Infect Dis. 2021 Dec;21(12):e363. PMID: 34756186; PMCID: PMC8554486.
    3. Masks
  2. Mortality
    1. 2020 Excess Mortality
      Table 53: Excess Mortality across Countries in 2020
      Country Expected Age-standardised Mortality 2020 (per 100,000) Age-standardised total mortality per 100,000 Absolute excess age-standardised mortality per 100,000 Percentage increase in Mortality per Age-Adjusted 100,000
      Austria 938 1009 71 7.60%
      Belgium 956 1072 116 12.20%
      Bulgaria 1597 1788 191 12.00%
      Canada 709 751 42 6.00%
      Chile* 1041 1184 143 13.80%
      Czechia 1147 1258 111 9.70%
      Denmark 1016 972 -44 -4.30%
      England & Wales 960 1060 100 10.50%
      Estonia 1178 1178 0 0.00%
      Finland 948 919 -29 -3.10%
      France 839 895 56 6.70%
      Germany* 1016 1049 33 3.30%
      Greece* 912 957 45 4.90%
      Hungary 1420 1473 53 3.70%
      Iceland 755 724 -31 -4.10%
      Israel 864 920 56 6.50%
      Italy 728 792 63 8.7
      Latvia 1446 1414 -32 -2.20%
      Lithuania 1393 1468 75 5.40%
      Luxembourg 842 852 9.5 1.10%
      Netherlands 971 1040 70 7.20%
      Norway 893 861 -32 -3.60%
      Poland 1216 1391 175 14.40%
      Portugal 977 1043 66 6.80%
      Scotland 1134 1219 85 7.50%
      Slovakia 1219 1236 17 1.40%
      Slovenia 996 1116 120 12.00%
      South Korea 779 757 -22 -2.90%
      Spain 838 946 108 12.90%
      Sweden 883 896 13 1.50%
      Switzerland 783 817 34 4.30%
      USA 1020 1152 132 12.90%

      The USA which has often been cited as the worse affected country (often using the total number of COVID-19 deaths) has relative excess of 12.9% which although one of the highest, is below some with even higher relative excess mortality such as Poland and Chile.

      Relative standardised excess mortality is one method of measuring the impact of the SARS-nCOV2 pandemic. It is superior to comparing the total numbers of COVID-19 deaths and arguably more useful than comparing the COVID-19 death rate per 100k as it overcomes the recording bias and measures both direct and indirect consequences of the pandemic. But it has limitations. We have noted that defining the expected number of deaths and thus the excess can vary according to whether a four or five year average is used. In addition, using simple averages of historical mortality data could underestimate if there is a significant downward trend in mortality or overestimated if there are upward trends.


  3. Risk Factors
    1. Obesity
  4. Vaccines
    1. Sensible Public Health Vaccine Policy
      1. There is just no question that vaccinating low-risk cohorts (including the recovered) is not only pointless, but also dangerous. These aren’t the people who end up in the hospital dying of Corona anyway. And because the vaccinated sooner or later end up driving transmission, there is only downside and no upside here.
      2. All the vaccines are good for, is reducing the likelihood of severe disease among the old and the vulnerable. It follows that only the old and the vulnerable should be vaccinated.
      3. In these groups, carefully timed annual vaccinations, like flu shots, might well provide good protection at the height of the winter coronavirus season and limit mortality. Even here, though, you’d have to proceed carefully, to avoid causing case spikes in the newly vaccinated during that brief period where their vulnerability to infection is heightened.


    2. Adverse Effects
      1. Compared with other vaccines
        Table 54: VAERS Summary for COVID-19 Vaccines through 10/1/2021
        High-Level Summary COVID19 vaccines (Dec’2020 – present) All other vaccines 1990-present US Data Only COVID19 vaccines (Dec’2020 – present) US Data Only All other vaccines 1990-present
        Number of Adverse Reactions 778685 824864 593728 723780
        Number of Life-Threatening Events 17618 13634 9011 9725
        Number of Hospitalizations 75605 78604 34880 38211
        Number of Deaths 16,310* 9155 7437 5129
        # of Permanent Disabilities after vaccination 23712 19638 8628 12467
        Number of Office Visits 121304 43674 111693 42348
        # of Emergency Room/Department Visits 87758 209950 74464 200967
        # of Birth Defects after vaccination 528 141 330 90


      2. Myocarditis risk in Young Males (Japan)
        • As of November 14, out of every one million males who had the Moderna vaccine, such side effects were reported in 81.79 males aged 10 to 19 and 48.76 males in their 20s.
        • The figures were 15.66 and 13.32 respectively for those who had the Pfizer vaccine.


      3. Vaccine Negatives?

        The vaccines appear to induce negative efficacy against infection.

        This probably arises from a combination of

        • minimally symptomatic super-spreading among the vaccinated
        • the selective pressure that vaccine-elicited antibodies place upon the virus
        • the narrow immunity against an obsolete arrangement of the spike protein that the vaccines confer.
        • For a period of several weeks after dose 1 (and likely dose 3)
          • They also make the vaccinated more susceptible to infection
          • and mass vaccination campaigns have induced case spikes across many countries


    3. Natural Immunity vs Vaccine
      1. 138 Research Studies Affirm Naturally Acquired Immunity to Covid-19: Documented, Linked, and Quoted
        Study/report title, author, and year published and interactive url link Predominant finding on natural immunity
        1) Necessity of COVID-19 vaccination in previously infected individuals, Shrestha, 2021 “Cumulative incidence of COVID-19 was examined among 52,238 employees in an American healthcare system. The cumulative incidence of SARS-CoV-2 infection remained almost zero among previously infected unvaccinated subjects, previously infected subjects who were vaccinated, and previously uninfected subjects who were vaccinated, compared with a steady increase in cumulative incidence among previously uninfected subjects who remained unvaccinated. Not one of the 1359 previously infected subjects who remained unvaccinated had a SARS-CoV-2 infection over the duration of the study. Individuals who have had SARS-CoV-2 infection are unlikely to benefit from COVID-19 vaccination…”
        2) SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls, Le Bert, 2020 “Studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein…showed that patients (n = 23) who recovered from SARS possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2.”
        3) Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections,Gazit, 2021 “A retrospective observational study comparing three groups: (1) SARS-CoV-2-naïve individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, (2) previously infected individuals who have not been vaccinated, and (3) previously infected and single dose vaccinated individuals found para a 13 fold increased risk of breakthrough Delta infections in double vaccinated persons, and a 27 fold increased risk for symptomatic breakthrough infection in the double vaccinated relative to the natural immunity recovered persons…the risk of hospitalization was 8 times higher in the double vaccinated (para)…this analysis demonstrated that natural immunity affords longer lasting and stronger protection against infection, symptomatic disease and hospitalization due to the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity.”
        4) Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection, Le Bert, 2021 “Studied SARS-CoV-2–specific T cells in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion…thus, asymptomatic SARS-CoV-2–infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.”
        5) Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection, Israel, 2021 “A total of 2,653 individuals fully vaccinated by two doses of vaccine during the study period and 4,361 convalescent patients were included. Higher SARS-CoV-2 IgG antibody titers were observed in vaccinated individuals (median 1581 AU/mL IQR [533.8-5644.6]) after the second vaccination, than in convalescent individuals (median 355.3 AU/mL IQR [141.2-998.7]; p<0.001). In vaccinated subjects, antibody titers decreased by up to 40% each subsequent month while in convalescents they decreased by less than 5% per month…this study demonstrates individuals who received the Pfizer-BioNTech mRNA vaccine have different kinetics of antibody levels compared to patients who had been infected with the SARS-CoV-2 virus, with higher initial levels but a much faster exponential decrease in the first group”.
        6) SARS-CoV-2 re-infection risk in Austria, Pilz, 2021 Researchers recorded “40 tentative re-infections in 14, 840 COVID-19 survivors of the first wave (0.27%) and 253 581 infections in 8, 885, 640 individuals of the remaining general population (2.85%) translating into an odds ratio (95% confidence interval) of 0.09 (0.07 to 0.13)…relatively low re-infection rate of SARS-CoV-2 in Austria. Protection against SARS-CoV-2 after natural infection is comparable with the highest available estimates on vaccine efficacies.” Additionally, hospitalization in only five out of 14,840 (0.03%) people and death in one out of 14,840 (0.01%) (tentative re-infection).
        7) mRNA vaccine-induced SARS-CoV-2-specific T cells recognize B.1.1.7 and B.1.351 variants but differ in longevity and homing properties depending on prior infection status, Neidleman, 2021 “Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to the B.1.1.7 and B.1.351 variants, confirm that convalescents may not need a second vaccine dose.”
        8) Good news: Mild COVID-19 induces lasting antibody protection, Bhandari, 2021 “Months after recovering from mild cases of COVID-19, people still have immune cells in their body pumping out antibodies against the virus that causes COVID-19, according to a study from researchers at Washington University School of Medicine in St. Louis. Such cells could persist for a lifetime, churning out antibodies all the while. The findings, published May 24 in the journal Nature, suggest that mild cases of COVID-19 leave those infected with lasting antibody protection and that repeated bouts of illness are likely to be uncommon.”
        9) Robust neutralizing antibodies to SARS-CoV-2 infection persist for months, Wajnberg, 2021 “Neutralizing antibody titers against the SARS-CoV-2 spike protein persisted for at least 5 months after infection. Although continued monitoring of this cohort will be needed to confirm the longevity and potency of this response, these preliminary results suggest that the chance of reinfection may be lower than is currently feared.”
        10) Evolution of Antibody Immunity to SARS-CoV-2, Gaebler, 2020 “Concurrently, neutralizing activity in plasma decreases by five-fold in pseudo-type virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response…we conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.”
        11) Persistence of neutralizing antibodies a year after SARS-CoV-2 infection in humans, Haveri, 2021 “Assessed the persistence of serum antibodies following WT SARS-CoV-2 infection at 8 and 13 months after diagnosis in 367 individuals…found that NAb against the WT virus persisted in 89% and S-IgG in 97% of subjects for at least 13 months after infection.”
        12) Quantifying the risk of SARS‐CoV‐2 reinfection over time, Murchu, 2021 “Eleven large cohort studies were identified that estimated the risk of SARS‐CoV‐2 reinfection over time, including three that enrolled healthcare workers and two that enrolled residents and staff of elderly care homes. Across studies, the total number of PCR‐positive or antibody‐positive participants at baseline was 615,777, and the maximum duration of follow‐up was more than 10 months in three studies. Reinfection was an uncommon event (absolute rate 0%–1.1%), with no study reporting an increase in the risk of reinfection over time.”
        13) Natural immunity to covid is powerful. Policymakers seem afraid to say so, Makary, 2021 Makary writes “it’s okay to have an incorrect scientific hypothesis. But when new data proves it wrong, you have to adapt. Unfortunately, many elected leaders and public health officials have held on far too long to the hypothesis that natural immunity offers unreliable protection against covid-19 — a contention that is being rapidly debunked by science. More than 15 studies have demonstrated the power of immunity acquired by previously having the virus. A 700,000-person study from Israel two weeks ago found that those who had experienced prior infections were 27 times less likely to get a second symptomatic covid infection than those who were vaccinated. This affirmed a June Cleveland Clinic study of health-care workers (who are often exposed to the virus), in which none who had previously tested positive for the coronavirus got reinfected. The study authors concluded that “individuals who have had SARS-CoV-2 infection are unlikely to benefit from covid-19 vaccination.” And in May, a Washington University study found that even a mild covid infection resulted in long-lasting immunity.”
        The Western Journal-Makary “The data on natural immunity are now overwhelming,” Makary told the Morning Wire. “It turns out the hypothesis that our public health leaders had that vaccinated immunity is better and stronger than natural immunity was wrong. They got it backwards. And now we’ve got data from Israel showing that natural immunity is 27 times more effective than vaccinated immunity.”
        14) SARS-CoV-2 elicits robust adaptive immune responses regardless of disease severity, Nielsen, 2021 “203 recovered SARS-CoV-2 infected patients in Denmark between April 3rd and July 9th 2020, at least 14 days after COVID-19 symptom recovery… report broad serological profiles within the cohort, detecting antibody binding to other human coronaviruses… the viral surface spike protein was identified as the dominant target for both neutralizing antibodies and CD8+ T-cell responses. Overall, the majority of patients had robust adaptive immune responses, regardless of their disease severity.”
        15) Protection of previous SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: A three-month nationwide experience from Israel, Goldberg, 2021 “Analyze an updated individual-level database of the entire population of Israel to assess the protection efficacy of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19… vaccination was highly effective with overall estimated efficacy for documented infection of 92·8% (CI:[92·6, 93·0]); hospitalization 94·2% (CI:[93·6, 94·7]); severe illness 94·4% (CI:[93·6, 95·0]); and death 93·7% (CI:[92·5, 94·7]). Similarly, the overall estimated level of protection from prior SARS-CoV-2 infection for documented infection is 94·8% (CI: [94·4, 95·1]); hospitalization 94·1% (CI: [91·9, 95·7]); and severe illness 96·4% (CI: [92·5, 98·3])…results question the need to vaccinate previously-infected individuals.”
        16) Incidence of Severe Acute Respiratory Syndrome Coronavirus-2 infection among previously infected or vaccinated employees, Kojima, 2021 “Employees were divided into three groups: (1) SARS-CoV-2 naïve and unvaccinated, (2) previous SARS-CoV-2 infection, and (3) vaccinated. Person-days were measured from the date of the employee first test and truncated at the end of the observation period. SARS-CoV-2 infection was defined as two positive SARS-CoV-2 PCR tests in a 30-day period… 4313, 254 and 739 employee records for groups 1, 2, and 3…previous SARS-CoV-2 infection and vaccination for SARS-CoV-2 were associated with decreased risk for infection or re-infection with SARS-CoV-2 in a routinely screened workforce. The was no difference in the infection incidence between vaccinated individuals and individuals with previous infection.”
        17) Having SARS-CoV-2 once confers much greater immunity than a vaccine—but vaccination remains vital, Wadman, 2021 “Israelis who had an infection were more protected against the Delta coronavirus variant than those who had an already highly effective COVID-19 vaccine…the newly released data show people who once had a SARS-CoV-2 infection were much less likely than never-infected, vaccinated people to get Delta, develop symptoms from it, or become hospitalized with serious COVID-19.”
        18) One-year sustained cellular and humoral immunities of COVID-19 convalescents, Zhang, 2021 “A systematic antigen-specific immune evaluation in 101 COVID-19 convalescents; SARS-CoV-2-specific IgG antibodies, and also NAb can persist among over 95% COVID-19 convalescents from 6 months to 12 months after disease onset. At least 19/71 (26%) of COVID-19 convalescents (double positive in ELISA and MCLIA) had detectable circulating IgM antibody against SARS-CoV-2 at 12m post-disease onset. Notably, the percentages of convalescents with positive SARS-CoV-2-specific T-cell responses (at least one of the SARS-CoV-2 antigen S1, S2, M and N protein) were 71/76 (93%) and 67/73 (92%) at 6m and 12m, respectively.”
        19) Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19, Rodda, 2021 “Recovered individuals developed SARS-CoV-2-specific immunoglobulin (IgG) antibodies, neutralizing plasma, and memory B and memory T cells that persisted for at least 3 months. Our data further reveal that SARS-CoV-2-specific IgG memory B cells increased over time. Additionally, SARS-CoV-2-specific memory lymphocytes exhibited characteristics associated with potent antiviral function: memory T cells secreted cytokines and expanded upon antigen re-encounter, whereas memory B cells expressed receptors capable of neutralizing virus when expressed as monoclonal antibodies. Therefore, mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity.”
        20) Discrete Immune Response Signature to SARS-CoV-2 mRNA Vaccination Versus Infection, Ivanova, 2021 “Performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine…both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells…we observed the presence of cytotoxic CD4 T cells in COVID-19 patients that were largely absent in healthy volunteers following immunization. While hyper-activation of inflammatory responses and cytotoxic cells may contribute to immunopathology in severe illness, in mild and moderate disease, these features are indicative of protective immune responses and resolution of infection.”
        21) SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans, Turner, 2021 “Bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies… durable serum antibody titres are maintained by long-lived plasma cells—non-replicating, antigen-specific plasma cells that are detected in the bone marrow long after the clearance of the antigen … S-binding BMPCs are quiescent, which suggests that they are part of a stable compartment. Consistently, circulating resting memory B cells directed against SARS-CoV-2 S were detected in the convalescent individuals. Overall, our results indicate that mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans…overall, our data provide strong evidence that SARS-CoV-2 infection in humans robustly establishes the two arms of humoral immune memory: long-lived bone marrow plasma cells (BMPCs) and memory B-cells.”
        22) SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN), Jane Hall, 2021 “The SARS-CoV-2 Immunity and Reinfection Evaluation study… 30 625 participants were enrolled into the study… a previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals.”
        23) Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers, Houlihan, 2020 “Enrolled 200 patient-facing HCWs between March 26 and April 8, 2020…represents a 13% infection rate (i.e. 14 of 112 HCWs) within the 1 month of follow-up in those with no evidence of antibodies or viral shedding at enrolment. By contrast, of 33 HCWs who tested positive by serology but tested negative by RT-PCR at enrolment, 32 remained negative by RT-PCR through follow-up, and one tested positive by RT-PCR on days 8 and 13 after enrolment.”
        24) Antibodies to SARS-CoV-2 are associated with protection against reinfection, Lumley, 2021 “Critical to understand whether infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) protects from subsequent reinfection… 12219 HCWs participated…prior SARS-CoV-2 infection that generated antibody responses offered protection from reinfection for most people in the six months following infection.”
        25) Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells, Cohen, 2021 “Evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells… most recovered COVID-19 patients mount broad, durable immunity after infection, spike IgG+ memory B cells increase and persist post-infection, durable polyfunctional CD4 and CD8 T cells recognize distinct viral epitope regions.”
        26) Single cell profiling of T and B cell repertoires following SARS-CoV-2 mRNA vaccine, Sureshchandra, 2021 “Used single-cell RNA sequencing and functional assays to compare humoral and cellular responses to two doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease… natural infection induced expansion of larger CD8 T cell clones occupied distinct clusters, likely due to the recognition of a broader set of viral epitopes presented by the virus not seen in the mRNA vaccine.”
        27) SARS-CoV-2 antibody-positivity protects against reinfection for at least seven months with 95% efficacy, Abu-Raddad, 2021 “SARS-CoV-2 antibody-positive persons from April 16 to December 31, 2020 with a PCR-positive swab ≥14 days after the first-positive antibody test were investigated for evidence of reinfection, 43,044 antibody-positive persons who were followed for a median of 16.3 weeks…reinfection is rare in the young and international population of Qatar. Natural infection appears to elicit strong protection against reinfection with an efficacy ~95% for at least seven months.”
        28) Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity, Ripperger, 2020 “Conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein…neutralizing and spike-specific antibody production persists for at least 5–7 months… nucleocapsid antibodies frequently become undetectable by 5–7 months.”
        29) Anti-spike antibody response to natural SARS-CoV-2 infection in the general population, Wei, 2021 “In the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021…we estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.”
        30) Researchers find long-lived immunity to 1918 pandemic virus, CIDRAP, 2008 “A study of the blood of older people who survived the 1918 influenza pandemic reveals that antibodies to the strain have lasted a lifetime and can perhaps be engineered to protect future generations against similar strains…the group collected blood samples from 32 pandemic survivors aged 91 to 101..the people recruited for the study were 2 to 12 years old in 1918 and many recalled sick family members in their households, which suggests they were directly exposed to the virus, the authors report. The group found that 100% of the subjects had serum-neutralizing activity against the 1918 virus and 94% showed serologic reactivity to the 1918 hemagglutinin. The investigators generated B lymphoblastic cell lines from the peripheral blood mononuclear cells of eight subjects. Transformed cells from the blood of 7 of the 8 donors yielded secreting antibodies that bound the 1918 hemagglutinin.”
        and the actual 2008 NATURE journal publication by Yu Yu: “here we show that of the 32 individuals tested that were born in or before 1915, each showed sero-reactivity with the 1918 virus, nearly 90 years after the pandemic. Seven of the eight donor samples tested had circulating B cells that secreted antibodies that bound the 1918 HA. We isolated B cells from subjects and generated five monoclonal antibodies that showed potent neutralizing activity against 1918 virus from three separate donors. These antibodies also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain.”
        31) Live virus neutralisation testing in convalescent patients and subjects vaccinated against 19A, 20B, 20I/501Y.V1 and 20H/501Y.V2 isolates of SARS-CoV-2, Gonzalez, 2021 “No significant difference was observed between the 20B and 19A isolates for HCWs with mild COVID-19 and critical patients. However, a significant decrease in neutralisation ability was found for 20I/501Y.V1 in comparison with 19A isolate for critical patients and HCWs 6-months post infection. Concerning 20H/501Y.V2, all populations had a significant reduction in neutralising antibody titres in comparison with the 19A isolate. Interestingly, a significant difference in neutralisation capacity was observed for vaccinated HCWs between the two variants whereas it was not significant for the convalescent groups…the reduced neutralising response observed towards the 20H/501Y.V2 in comparison with the 19A and 20I/501Y.V1 isolates in fully immunized subjects with the BNT162b2 vaccine is a striking finding of the study.”
        32) Differential effects of the second SARS-CoV-2 mRNA vaccine dose on T cell immunity in naïve and COVID-19 recovered individuals, Camara, 2021 “Characterized SARS-CoV-2 spike-specific humoral and cellular immunity in naïve and previously infected individuals during full BNT162b2 vaccination…results demonstrate that the second dose increases both the humoral and cellular immunity in naïve individuals. On the contrary, the second BNT162b2 vaccine dose results in a reduction of cellular immunity in COVID-19 recovered individuals.”
        33) Op-Ed: Quit Ignoring Natural COVID Immunity, Klausner, 2021 “Epidemiologists estimate over 160 million people worldwide have recovered from COVID-19. Those who have recovered have an astonishingly low frequency of repeat infection, disease, or death.”
        34) Association of SARS-CoV-2 Seropositive Antibody Test With Risk of Future Infection, Harvey, 2021 “To evaluate evidence of SARS-CoV-2 infection based on diagnostic nucleic acid amplification test (NAAT) among patients with positive vs negative test results for antibodies in an observational descriptive cohort study of clinical laboratory and linked claims data…the cohort included 3 257 478 unique patients with an index antibody test…patients with positive antibody test results were initially more likely to have positive NAAT results, consistent with prolonged RNA shedding, but became markedly less likely to have positive NAAT results over time, suggesting that seropositivity is associated with protection from infection.”
        35) SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study, Letizia, 2021 “Investigated the risk of subsequent SARS-CoV-2 infection among young adults (CHARM marine study) seropositive for a previous infection…enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants…Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11–0·28; p<0·001)…infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants (ORF1ab gene cycle threshold difference 3·95 [95% CI 1·23–6·67]; p=0·004).”
        36) Associations of Vaccination and of Prior Infection With Positive PCR Test Results for SARS-CoV-2 in Airline Passengers Arriving in Qatar, Bertollini, 2021 “Of 9,180 individuals with no record of vaccination but with a record of prior infection at least 90 days before the PCR test (group 3), 7694 could be matched to individuals with no record of vaccination or prior infection (group 2), among whom PCR positivity was 1.01% (95% CI, 0.80%-1.26%) and 3.81% (95% CI, 3.39%-4.26%), respectively. The relative risk for PCR positivity was 0.22 (95% CI, 0.17-0.28) for vaccinated individuals and 0.26 (95% CI, 0.21-0.34) for individuals with prior infection compared with no record of vaccination or prior infection.”
        37) Natural immunity against COVID-19 significantly reduces the risk of reinfection: findings from a cohort of sero-survey participants, Mishra, 2021 “Followed up with a subsample of our previous sero-survey participants to assess whether natural immunity against SARS-CoV-2 was associated with a reduced risk of re-infection (India)… out of the 2238 participants, 1170 were sero-positive and 1068 were sero-negative for antibody against COVID-19. Our survey found that only 3 individuals in the sero-positive group got infected with COVID-19 whereas 127 individuals reported contracting the infection the sero-negative group…from the 3 sero-positives re-infected with COVID-19, one had hospitalization, but did not require oxygen support or critical care…development of antibody following natural infection not only protects against re-infection by the virus to a great extent, but also safeguards against progression to severe COVID-19 disease.”
        38) Lasting immunity found after recovery from COVID-19, NIH, 2021 “The researchers found durable immune responses in the majority of people studied. Antibodies against the spike protein of SARS-CoV-2, which the virus uses to get inside cells, were found in 98% of participants one month after symptom onset. As seen in previous studies, the number of antibodies ranged widely between individuals. But, promisingly, their levels remained fairly stable over time, declining only modestly at 6 to 8 months after infection… virus-specific B cells increased over time. People had more memory B cells six months after symptom onset than at one month afterwards… levels of T cells for the virus also remained high after infection. Six months after symptom onset, 92% of participants had CD4+ T cells that recognized the virus… 95% of the people had at least 3 out of 5 immune-system components that could recognize SARS-CoV-2 up to 8 months after infection.”
        39) SARS-CoV-2 Natural Antibody Response Persists for at Least 12 Months in a Nationwide Study From the Faroe Islands, Petersen, 2021 “The seropositive rate in the convalescent individuals was above 95% at all sampling time points for both assays and remained stable over time; that is, almost all convalescent individuals developed antibodies… results show that SARS-CoV-2 antibodies persisted at least 12 months after symptom onset and maybe even longer, indicating that COVID-19-convalescent individuals may be protected from reinfection.”
        40) SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells, Jung, 2021 “ex vivo assays to evaluate SARS-CoV-2-specific CD4+ and CD8+ T cell responses in COVID-19 convalescent patients up to 317 days post-symptom onset (DPSO), and find that memory T cell responses are maintained during the study period regardless of the severity of COVID-19. In particular, we observe sustained polyfunctionality and proliferation capacity of SARS-CoV-2-specific T cells. Among SARS-CoV-2-specific CD4+ and CD8+ T cells detected by activation-induced markers, the proportion of stem cell-like memory T (TSCM) cells is increased, peaking at approximately 120 DPSO.”
        41) Immune Memory in Mild COVID-19 Patients and Unexposed Donors Reveals Persistent T Cell Responses After SARS-CoV-2 Infection, Ansari, 2021 “Analyzed 42 unexposed healthy donors and 28 mild COVID-19 subjects up to 5 months from the recovery for SARS-CoV-2 specific immunological memory. Using HLA class II predicted peptide megapools, we identified SARS-CoV-2 cross-reactive CD4+ T cells in around 66% of the unexposed individuals. Moreover, we found detectable immune memory in mild COVID-19 patients several months after recovery in the crucial arms of protective adaptive immunity; CD4+ T cells and B cells, with a minimal contribution from CD8+ T cells. Interestingly, the persistent immune memory in COVID-19 patients is predominantly targeted towards the Spike glycoprotein of the SARS-CoV-2. This study provides the evidence of both high magnitude pre-existing and persistent immune memory in Indian population.”
        42) COVID-19 natural immunity, WHO, 2021 “Current evidence points to most individuals developing strong protective immune responses following natural infection with SARSCoV-2. Within 4 weeks following infection, 90-99% of individuals infected with the SARS-CoV-2 virus develop detectable neutralizing antibodies. The strength and duration of the immune responses to SARS-CoV-2 are not completely understood and currently available data suggests that it varies by age and the severity of symptoms. Available scientific data suggests that in most people immune responses remain robust and protective against reinfection for at least 6-8 months after infection (the longest follow up with strong scientific evidence is currently approximately 8 months).”
        43) Antibody Evolution after SARS-CoV-2 mRNA Vaccination, Cho, 2021 “We conclude that memory antibodies selected over time by natural infection have greater potency and breadth than antibodies elicited by vaccination…boosting vaccinated individuals with currently available mRNA vaccines would produce a quantitative increase in plasma neutralizing activity but not the qualitative advantage against variants obtained by vaccinating convalescent individuals.”
        44) Humoral Immune Response to SARS-CoV-2 in Iceland, Gudbjartsson, 2020 “Measured antibodies in serum samples from 30,576 persons in Iceland…of the 1797 persons who had recovered from SARS-CoV-2 infection, 1107 of the 1215 who were tested (91.1%) were seropositive…results indicate risk of death from infection was 0.3% and that antiviral antibodies against SARS-CoV-2 did not decline within 4 months after diagnosis (para).”
        45) Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection, Dan, 2021 “Analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection…IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset.”
        46) The prevalence of adaptive immunity to COVID-19 and reinfection after recovery – a comprehensive systematic review and meta-analysis of 12 011 447 individuals, Chivese, 2021 “Fifty-four studies, from 18 countries, with a total of 12 011 447 individuals, followed up to 8 months after recovery, were included. At 6-8 months after recovery, the prevalence of detectable SARS-CoV-2 specific immunological memory remained high; IgG – 90.4%… pooled prevalence of reinfection was 0.2% (95%CI 0.0 – 0.7, I2 = 98.8, 9 studies). Individuals who recovered from COVID-19 had an 81% reduction in odds of a reinfection (OR 0.19, 95% CI 0.1 – 0.3, I2 = 90.5%, 5 studies).”
        47) Reinfection Rates among Patients who Previously Tested Positive for COVID-19: a Retrospective Cohort Study, Sheehan, 2021 “Retrospective cohort study of one multi-hospital health system included 150,325 patients tested for COVID-19 infection…prior infection in patients with COVID-19 was highly protective against reinfection and symptomatic disease. This protection increased over time, suggesting that viral shedding or ongoing immune response may persist beyond 90 days and may not represent true reinfection.”
        48) Assessment of SARS-CoV-2 Reinfection 1 Year After Primary Infection in a Population in Lombardy, Italy, Vitale, 2020 “The study results suggest that reinfections are rare events and patients who have recovered from COVID-19 have a lower risk of reinfection. Natural immunity to SARS-CoV-2 appears to confer a protective effect for at least a year, which is similar to the protection reported in recent vaccine studies.”
        49) Prior SARS-CoV-2 infection is associated with protection against symptomatic reinfection, Hanrath, 2021 “We observed no symptomatic reinfections in a cohort of healthcare workers…this apparent immunity to re-infection was maintained for at least 6 months…test positivity rates were 0% (0/128 [95% CI: 0–2.9]) in those with previous infection compared to 13.7% (290/2115 [95% CI: 12.3–15.2]) in those without (P<0.0001 χ2 test).”
        50) Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals, Grifoni, 2020 “Using HLA class I and II predicted peptide “megapools,” circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%–27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted.”
        51) NIH Director’s Blog: Immune T Cells May Offer Lasting Protection Against COVID-19, Collins, 2021 “Much of the study on the immune response to SARS-CoV-2, the novel coronavirus that causes COVID-19, has focused on the production of antibodies. But, in fact, immune cells known as memory T cells also play an important role in the ability of our immune systems to protect us against many viral infections, including—it now appears—COVID-19.An intriguing new study of these memory T cells suggests they might protect some people newly infected with SARS-CoV-2 by remembering past encounters with other human coronaviruses. This might potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill with COVID-19.”
        52) Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants, Wang, 2021 “Our study demonstrates that convalescent subjects previously infected with ancestral variant SARS-CoV-2 produce antibodies that cross-neutralize emerging VOCs with high potency…potent against 23 variants, including variants of concern.”
        53) Why COVID-19 Vaccines Should Not Be Required for All Americans, Makary, 2021 “Requiring the vaccine in people who are already immune with natural immunity has no scientific support. While vaccinating those people may be beneficial – and it’s a reasonable hypothesis that vaccination may bolster the longevity of their immunity – to argue dogmatically that they must get vaccinated has zero clinical outcome data to back it. As a matter of fact, we have data to the contrary: A Cleveland Clinic study found that vaccinating people with natural immunity did not add to their level of protection.”
        54) Protracted yet coordinated differentiation of long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence, Ma, 2021 “Screened 21 well-characterized, longitudinally-sampled convalescent donors that recovered from mild COVID-19…following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence, into a state characteristic of long-lived, self-renewing memory.”
        55) Decrease in Measles Virus-Specific CD4 T Cell Memory in Vaccinated Subjects, Naniche, 2004 “Characterized the profiles of measles vaccine (MV) vaccine-induced antigen-specific T cells over time since vaccination. In a cross-sectional study of healthy subjects with a history of MV vaccination, we found that MV-specific CD4 and CD8 T cells could be detected up to 34 years after vaccination. The levels of MV-specific CD8 T cells and MV-specific IgG remained stable, whereas the level of MV-specific CD4 T cells decreased significantly in subjects who had been vaccinated >21 years earlier.”
        56) Remembrance of Things Past: Long-Term B Cell Memory After Infection and Vaccination, Palm, 2019 “The success of vaccines is dependent on the generation and maintenance of immunological memory. The immune system can remember previously encountered pathogens, and memory B and T cells are critical in secondary responses to infection. Studies in mice have helped to understand how different memory B cell populations are generated following antigen exposure and how affinity for the antigen is determinant to B cell fate… upon re-exposure to an antigen the memory recall response will be faster, stronger, and more specific than a naïve response. Protective memory depends first on circulating antibodies secreted by LLPCs. When these are not sufficient for immediate pathogen neutralization and elimination, memory B cells are recalled.”
        57) SARS-CoV-2 specific memory B-cells from individuals with diverse disease severities recognize SARS-CoV-2 variants of concern, Lyski, 2021 “Examined the magnitude, breadth, and durability of SARS-CoV-2 specific antibodies in two distinct B-cell compartments: long-lived plasma cell-derived antibodies in the plasma, and peripheral memory B-cells along with their associated antibody profiles elicited after in vitro stimulation. We found that magnitude varied amongst individuals, but was the highest in hospitalized subjects. Variants of concern (VoC) -RBD-reactive antibodies were found in the plasma of 72% of samples in this investigation, and VoC-RBD-reactive memory B-cells were found in all but 1 subject at a single time-point. This finding, that VoC-RBD-reactive MBCs are present in the peripheral blood of all subjects including those that experienced asymptomatic or mild disease, provides a reason for optimism regarding the capacity of vaccination, prior infection, and/or both, to limit disease severity and transmission of variants of concern as they continue to arise and circulate.”
        58) Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection, Wang, 2021 “T-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed individuals…report virus-specific CD4+ and CD8+ T-cell memory in recovered COVID-19 patients and close contacts…close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection.”
        59) CD8+ T-Cell Responses in COVID-19 Convalescent Individuals Target Conserved Epitopes From Multiple Prominent SARS-CoV-2 Circulating Variants, Redd, 2021and Lee, 2021 “The CD4 and CD8 responses generated after natural infection are equally robust, showing activity against multiple “epitopes” (little segments) of the spike protein of the virus. For instance, CD8 cells responds to 52 epitopes and CD4 cells respond to 57 epitopes across the spike protein, so that a few mutations in the variants cannot knock out such a robust and in-breadth T cell response…only 1 mutation found in Beta variant-spike overlapped with a previously identified epitope (1/52), suggesting that virtually all anti-SARS-CoV-2 CD8+ T-cell responses should recognize these newly described variants.”
        60) Exposure to common cold coronaviruses can teach the immune system to recognize SARS-CoV-2,La Jolla, Crotty and Sette, 2020 “Exposure to common cold coronaviruses can teach the immune system to recognize SARS-CoV-2”
        61) Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans, Mateus, 2020 “Found that the pre-existing reactivity against SARS-CoV-2 comes from memory T cells and that cross-reactive T cells can specifically recognize a SARS-CoV-2 epitope as well as the homologous epitope from a common cold coronavirus. These findings underline the importance of determining the impacts of pre-existing immune memory in COVID-19 disease severity.”
        62) Longitudinal observation of antibody responses for 14 months after SARS-CoV-2 infection, Dehgani-Mobaraki, 2021 “Better understanding of antibody responses against SARS-CoV-2 after natural infection might provide valuable insights into the future implementation of vaccination policies. Longitudinal analysis of IgG antibody titers was carried out in 32 recovered COVID-19 patients based in the Umbria region of Italy for 14 months after Mild and Moderately-Severe infection…study findings are consistent with recent studies reporting antibody persistency suggesting that induced SARS-CoV-2 immunity through natural infection, might be very efficacious against re-infection (>90%) and could persist for more than six months. Our study followed up patients up to 14 months demonstrating the presence of anti-S-RBD IgG in 96.8% of recovered COVID-19 subjects.”
        63) Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19, Juno, 2020 “Characterized humoral and circulating follicular helper T cell (cTFH) immunity against spike in recovered patients with coronavirus disease 2019 (COVID-19). We found that S-specific antibodies, memory B cells and cTFH are consistently elicited after SARS-CoV-2 infection, demarking robust humoral immunity and positively associated with plasma neutralizing activity.”
        64) Convergent antibody responses to SARS-CoV-2 in convalescent individuals, Robbiani, 2020 “149 COVID-19-convalescent individuals…antibody sequencing revealed the expansion of clones of RBD-specific memory B cells that expressed closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on the RBD neutralized the virus with half-maximal inhibitory concentrations (IC50 values) as low as 2 ng ml−1.”
        65) Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence, Hartley, 2020 “COVID-19 patients rapidly generate B cell memory to both the spike and nucleocapsid antigens following SARS-CoV-2 infection…RBD- and NCP-specific IgG and Bmem cells were detected in all 25 patients with a history of COVID-19.”
        66) Had COVID? You’ll probably make antibodies for a lifetime, Callaway, 2021 “People who recover from mild COVID-19 have bone-marrow cells that can churn out antibodies for decades…the study provides evidence that immunity triggered by SARS-CoV-2 infection will be extraordinarily long-lasting.”
        67) A majority of uninfected adults show preexisting antibody reactivity against SARS-CoV-2, Majdoubi, 2021 In greater Vancouver Canada, “using a highly sensitive multiplex assay and positive/negative thresholds established in infants in whom maternal antibodies have waned, we determined that more than 90% of uninfected adults showed antibody reactivity against the spike protein, receptor-binding domain (RBD), N-terminal domain (NTD), or the nucleocapsid (N) protein from SARS-CoV-2.”
        68) SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19, Braun, 2020 “The results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses.”
        Presence of SARS-CoV-2-reactive T cells in COVID-19 patients and healthy donors, Braun, 2020 “The presence of pre-existing SARS-CoV-2-reactive T cells in a subset of SARS-CoV-2 naïve HD is of high interest.”
        69) Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection, Wang, 2021 “A cohort of 63 individuals who have recovered from COVID-19 assessed at 1.3, 6.2 and 12 months after SARS-CoV-2 infection…the data suggest that immunity in convalescent individuals will be very long lasting.”
        70) One Year after Mild COVID-19: The Majority of Patients Maintain Specific Immunity, But One in Four Still Suffer from Long-Term Symptoms, Rank, 2021 “Long-lasting immunological memory against SARS-CoV-2 after mild COVID-19… activation-induced marker assays identified specific T-helper cells and central memory T-cells in 80% of participants at a 12-month follow-up.”
        71) IDSA, 2021 “Immune responses to SARS-CoV-2 following natural infection can persist for at least 11 months… natural infection (as determined by a prior positive antibody or PCR-test result) can confer protection against SARS-CoV-2 infection.”
        72) Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study, Holm Hansen, 2021 Denmark, “during the first surge (ie, before June, 2020), 533 381 people were tested, of whom 11 727 (2·20%) were PCR positive, and 525 339 were eligible for follow-up in the second surge, of whom 11 068 (2·11%) had tested positive during the first surge. Among eligible PCR-positive individuals from the first surge of the epidemic, 72 (0·65% [95% CI 0·51–0·82]) tested positive again during the second surge compared with 16 819 (3·27% [3·22–3·32]) of 514 271 who tested negative during the first surge (adjusted RR 0·195 [95% CI 0·155–0·246]).”
        73) Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity, Moderbacher, 2020 “Adaptive immune responses limit COVID-19 disease severity…multiple coordinated arms of adaptive immunity control better than partial responses…completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19.”
        74) Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals, Ni, 2020 “Collected blood from COVID-19 patients who have recently become virus-free, and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in eight newly discharged patients. Follow-up analysis on another cohort of six patients 2 weeks post discharge also revealed high titers of immunoglobulin G (IgG) antibodies. In all 14 patients tested, 13 displayed serum-neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells.”
        75) Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection, Zuo, 2020 “Analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT and/or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression… functional SARS-CoV-2-specific T-cell responses are retained at six months following infection.”
        76) Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees, Tarke, 2021 “Performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines… the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations.”
        77) A 1 to 1000 SARS-CoV-2 reinfection proportion in members of a large healthcare provider in Israel: a preliminary report, Perez, 2021 Israel, “out of 149,735 individuals with a documented positive PCR test between March 2020 and January 2021, 154 had two positive PCR tests at least 100 days apart, reflecting a reinfection proportion of 1 per 1000.”
        78) Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients, Iyer, 2020 “Measured plasma and/or serum antibody responses to the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 in 343 North American patients infected with SARS-CoV-2 (of which 93% required hospitalization) up to 122 days after symptom onset and compared them to responses in 1548 individuals whose blood samples were obtained prior to the pandemic…IgG antibodies persisted at detectable levels in patients beyond 90 days after symptom onset, and seroreversion was only observed in a small percentage of individuals. The concentration of these anti-RBD IgG antibodies was also highly correlated with pseudovirus NAb titers, which also demonstrated minimal decay. The observation that IgG and neutralizing antibody responses persist is encouraging, and suggests the development of robust systemic immune memory in individuals with severe infection.”
        79) A population-based analysis of the longevity of SARS-CoV-2 antibody seropositivity in the United States, Alfego, 2021 “To track population-based SARS-CoV-2 antibody seropositivity duration across the United States using observational data from a national clinical laboratory registry of patients tested by nucleic acid amplification (NAAT) and serologic assays… specimens from 39,086 individuals with confirmed positive COVID-19…both S and N SARS-CoV-2 antibody results offer an encouraging view of how long humans may have protective antibodies against COVID-19, with curve smoothing showing population seropositivity reaching 90% within three weeks, regardless of whether the assay detects N or S-antibodies. Most importantly, this level of seropositivity was sustained with little decay through ten months after initial positive PCR.”
        80) What are the roles of antibodies versus a durable, high- quality T-cell response in protective immunity against SARS-CoV-2? Hellerstein, 2020 “Progress in laboratory markers for SARS-CoV2 has been made with identification of epitopes on CD4 and CD8 T-cells in convalescent blood. These are much less dominated by spike protein than in previous coronavirus infections. Although most vaccine candidates are focusing on spike protein as antigen, natural infection by SARS-CoV-2 induces broad epitope coverage, cross-reactive with other betacoronviruses.”
        81) Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients, Peng, 2020 “Study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors…found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins…total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre…furthermore showed a higher ratio of SARS-CoV-2-specific CD8+ to CD4+ T cell responses…immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections.”
        82) Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19, Sekine, 2020 “SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19…mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19…collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.”
        83) Potent SARS-CoV-2-Specific T Cell Immunity and Low Anaphylatoxin Levels Correlate With Mild Disease Progression in COVID-19 Patients, Lafron, 2021 “Provide a full picture of cellular and humoral immune responses of COVID-19 patients and prove that robust polyfunctional CD8+ T cell responses concomitant with low anaphylatoxin levels correlate with mild infections.”
        84) SARS-CoV-2 T-cell epitopes define heterologous and COVID-19 induced T-cell recognition, Nelde, 2020 “The first work identifying and characterizing SARS-CoV-2-specific and cross-reactive HLA class I and HLA-DR T-cell epitopes in SARS-CoV-2 convalescents (n = 180) as well as unexposed individuals (n = 185) and confirming their relevance for immunity and COVID-19 disease course…cross-reactive SARS-CoV-2 T-cell epitopes revealed pre-existing T-cell responses in 81% of unexposed individuals, and validation of similarity to common cold human coronaviruses provided a functional basis for postulated heterologous immunity in SARS-CoV-2 infection…intensity of T-cell responses and recognition rate of T-cell epitopes was significantly higher in the convalescent donors compared to unexposed individuals, suggesting that not only expansion, but also diversity spread of SARS-CoV-2 T-cell responses occur upon active infection.”
        85) Karl Friston: up to 80% not even susceptible to Covid-19, Sayers, 2020 “Results have just been published of a study suggesting that 40%-60% of people who have not been exposed to coronavirus have resistance at the T-cell level from other similar coronaviruses like the common cold…the true portion of people who are not even susceptible to Covid-19 may be as high as 80%.”
        86) CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses, Lineburg, 2021 “Screening of SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7+ COVID-19-recovered individuals that was also detectable in unexposed donors…the basis of selective T cell cross-reactivity for an immunodominant SARS-CoV-2 epitope and its homologs from seasonal coronaviruses, suggesting long-lasting protective immunity.”
        87) SARS-CoV-2 genome-wide mapping of CD8 T cell recognition reveals strong immunodominance and substantial CD8 T cell activation in COVID-19 patients, Saini, 2020 “COVID-19 patients showed strong T cell responses, with up to 25% of all CD8+ lymphocytes specific to SARS-CoV-2-derived immunodominant epitopes, derived from ORF1 (open reading frame 1), ORF3, and Nucleocapsid (N) protein. A strong signature of T cell activation was observed in COVID-19 patients, while no T cell activation was seen in the ‘non-exposed’ and ‘high exposure risk’ healthy donors.”
        88) Equivalency of Protection from Natural Immunity in COVID-19 Recovered Versus Fully Vaccinated Persons: A Systematic Review and Pooled Analysis, Shenai, 2021 “Systematic review and pooled analysis of clinical studies to date, that (1) specifically compare the protection of natural immunity in the COVID-recovered versus the efficacy of full vaccination in the COVID-naive, and (2) the added benefit of vaccination in the COVID-recovered, for prevention of subsequent SARS-CoV-2 infection…review demonstrates that natural immunity in COVID-recovered individuals is, at least, equivalent to the protection afforded by full vaccination of COVID-naïve populations. There is a modest and incremental relative benefit to vaccination in COVID-recovered individuals; however, the net benefit is marginal on an absolute basis.”
        89) ChAdOx1nCoV-19 effectiveness during an unprecedented surge in SARS CoV-2 infections, Satwik, 2021 “The third key finding is that previous infections with SARS-CoV-2 were significantly protective against all studied outcomes, with an effectiveness of 93% (87 to 96%) seen against symptomatic infections, 89% (57 to 97%) against moderate to severe disease and 85% (-9 to 98%) against supplemental oxygen therapy. All deaths occurred in previously uninfected individuals. This was higher protection than that offered by single or double dose vaccine.”
        90) SARS-CoV-2 specific T cells and antibodies in COVID-19 protection: a prospective study, Molodtsov, 2021 “Explore the impact of T cells and to quantify the protective levels of the immune responses…5,340 Moscow residents were evaluated for the antibody and cellular immune responses to SARS-CoV-2 and monitored for COVID-19 up to 300 days. The antibody and cellular responses were tightly interconnected, their magnitude inversely correlated with infection probability. Similar maximal level of protection was reached by individuals positive for both types of responses and by individuals with antibodies alone…T cells in the absence of antibodies provided an intermediate level of protection.”
        91) Anti- SARS-CoV-2 Receptor Binding Domain Antibody Evolution after mRNA Vaccination, Cho, 2021 “SARS-CoV-2 infection produces B-cell responses that continue to evolve for at least one year. During that time, memory B cells express increasingly broad and potent antibodies that are resistant to mutations found in variants of concern.”
        92) Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses, Ortega, 2021 “Impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies…after the peak response, anti-spike antibody levels increase from ~150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. IgG and IgA to HCoV are significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.”
        93) Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals, Mahajan, 2021 “Findings suggest that SARS-CoV-2 reactive T-cells are likely to be present in many individuals because of prior exposure to flu and CMV viruses.”
        94) Neutralizing Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 in Coronavirus Disease 2019 Inpatients and Convalescent Patients, Wang, 2020 “117 blood samples were collected from 70 COVID-19 inpatients and convalescent patients…the neutralizing antibodies were detected even at the early stage of disease, and a significant response was shown in convalescent patients.”
        95) Not just antibodies: B cells and T cells mediate immunity to COVID-19, Cox, 2020 “Reports that antibodies to SARS-CoV-2 are not maintained in the serum following recovery from the virus have caused alarm…the absence of specific antibodies in the serum does not necessarily mean an absence of immune memory.”
        96) T cell immunity to SARS-CoV-2 following natural infection and vaccination, DiPiazza, 2020 “Although T cell durability to SARS-CoV-2 remains to be determined, current data and past experience from human infection with other CoVs demonstrate the potential for persistence and the capacity to control viral replication and host disease, and importance in vaccine-induced protection.”
        97) Durable SARS-CoV-2 B cell immunity after mild or severe disease, Ogega, 2021 “Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2-specific (SARS-CoV-2-specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline… data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched rMBCs that resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after mild or severe disease.”
        98) Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection., Ng, 2016 “All memory T cell responses detected target the SARS-Co-V structural proteins… these responses were found to persist up to 11 years post-infection… knowledge of the persistence of SARS-specific cellular immunity targeting the viral structural proteins in SARS-recovered individuals is important.”
        99) Adaptive immunity to SARS-CoV-2 and COVID-19, Sette, 2021 “The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells…a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19.”
        100) Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients, Tan, 2021 “These findings provide support for the prognostic value of early functional SARS-CoV-2-specific T cells with important implications in vaccine design and immune monitoring.”
        101) SARS-CoV-2–specific CD8+ T cell responses in convalescent COVID-19 individuals, Kared, 2021 “A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 coronavirus disease 2019 convalescent individuals…Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem cell and transitional memory states (subsets), which may be key to developing durable protection.”
        102) S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit, Nguyen-Contant, 2021 “Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study results also suggest that SARS-CoV-2 infection strengthens pre-existing broad coronavirus protection through S2-reactive antibody and MBC formation.”
        103) Persistence of Antibody and Cellular Immune Responses in Coronavirus Disease 2019 Patients Over Nine Months After Infection, Yao, 2021 “A cross-sectional study to assess the virus-specific antibody and memory T and B cell responses in coronavirus disease 2019 (COVID-19) patients up to 343 days after infection…found that approximately 90% of patients still have detectable immunoglobulin (Ig)G antibodies against spike and nucleocapsid proteins and neutralizing antibodies against pseudovirus, whereas ~60% of patients had detectable IgG antibodies against receptor-binding domain and surrogate virus-neutralizing antibodies…SARS-CoV-2-specific IgG+ memory B cell and interferon-γ-secreting T cell responses were detectable in more than 70% of patients…coronavirus 2-specific immune memory response persists in most patients approximately 1 year after infection, which provides a promising sign for prevention from reinfection and vaccination strategy.”
        104) Naturally Acquired SARS-CoV-2 Immunity Persists for Up to 11 Months Following Infection, De Giorgi, 2021 “A prospective, longitudinal analysis of COVID-19 convalescent plasma donors at multiple time points over an 11-month period to determine how circulating antibody levels change over time following natural infection… data suggest that immunological memory is acquired in most individuals infected with SARS-CoV-2 and is sustained in a majority of patients.”
        105) Decreasing Seroprevalence of Measles Antibodies after Vaccination – Possible Gap in Measles Protection in Adults in the Czech Republic, Smetana, 2017 “A long-term high rate of seropositivity persists after natural measles infection. By contrast, it decreases over time after vaccination. Similarly, the concentrations of antibodies in persons with measles history persist for a longer time at a higher level than in vaccinated persons.”
        106) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection, Wrammert, 2011 “The expansion of these rare types of memory B cells may explain why most people did not become severely ill, even in the absence of pre-existing protective antibody titers”…found “extraordinarily” powerful antibodies in the blood of nine people who caught the swine flu naturally and recovered from it.”…unlike antibodies elicited by annual influenza vaccinations, most neutralizing antibodies induced by pandemic H1N1 infection were broadly cross-reactive against epitopes in the hemagglutinin (HA) stalk and head domain of multiple influenza strains. The antibodies were from cells that had undergone extensive affinity maturation.”
        107) Reinfection With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Patients Undergoing Serial Laboratory Testing, Qureshi, 2021 “Reinfection was identified in 0.7% (n = 63, 95% confidence interval [CI]: .5%–.9%) during follow-up of 9119 patients with SARS-CoV-2 infection.”
        108) Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination, Goel, 2021 “Interrogated antibody and antigen-specific memory B cells over time in 33 SARS-CoV-2 naïve and 11 SARS-CoV-2 recovered subjects… In SARS-CoV-2 recovered individuals, antibody and memory B cell responses were significantly boosted after the first vaccine dose; however, there was no increase in circulating antibodies, neutralizing titers, or antigen-specific memory B cells after the second dose. This robust boosting after the first vaccine dose strongly correlated with levels of pre-existing memory B cells in recovered individuals, identifying a key role for memory B cells in mounting recall responses to SARS-CoV-2 antigens.”
        109) Covid-19: Do many people have pre-existing immunity? Doshi, 2020 “Six studies have reported T cell reactivity against SARS-CoV-2 in 20% to 50% of people with no known exposure to the virus… in a study of donor blood specimens obtained in the US between 2015 and 2018, 50% displayed various forms of T cell reactivity to SARS-CoV-2… Researchers are also confident that they have made solid inroads into ascertaining the origins of the immune responses. “Our hypothesis, of course, was that it’s so called ‘common cold’ coronaviruses, because they’re closely related…we have really shown that this is a true immune memory and it is derived in part from common cold viruses.”
        110) Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans, Ng, 2020 “We demonstrate the presence of pre-existing humoral immunity in uninfected and unexposed humans to the new coronavirus. SARS-CoV-2 S-reactive antibodies were readily detectable by a sensitive flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents.”
        111) Phenotype of SARS-CoV-2-specific T-cells in COVID-19 patients with acute respiratory distress syndrome, Weiskopf, 2020 “We detected SARS-CoV-2-specific CD4+ and CD8+ T cells in 100% and 80% of COVID-19 patients, respectively. We also detected low levels of SARS-CoV-2-reactive T-cells in 20% of the healthy controls, not previously exposed to SARS-CoV-2 and indicative of cross-reactivity due to infection with ‘common cold’ coronaviruses.”
        112) Pre-existing immunity to SARS-CoV-2: the knowns and unknowns, Sette, 2020 “T cell reactivity against SARS-CoV-2 was observed in unexposed people…it is speculated that this reflects T cell memory to circulating ‘common cold’ coronaviruses.”
        113) Pre-existing immunity against swine-origin H1N1 influenza viruses in the general human population, Greenbaum, 2009 “Memory T-cell immunity against S-OIV is present in the adult population and that such memory is of similar magnitude as the pre-existing memory against seasonal H1N1 influenza…the conservation of a large fraction of T-cell epitopes suggests that the severity of an S-OIV infection, as far as it is determined by susceptibility of the virus to immune attack, would not differ much from that of seasonal flu.”
        114) Cellular immune correlates of protection against symptomatic pandemic influenza, Sridhar, 2013 “The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether cross-reactive cellular immunity limits symptomatic illness in antibody-naive individuals… Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)() interleukin-2 (IL-2)(-) CD8() T cells (r = -0.6, P = 0.004)… CD8(+) T cells specific to conserved viral epitopes correlated with cross-protection against symptomatic influenza.”
        115) Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans, Wilkinson, 2012 “Precise role of T cells in human influenza immunity is uncertain. We conducted influenza infection studies in healthy volunteers with no detectable antibodies to the challenge viruses H3N2 or H1N1…mapped T cell responses to influenza before and during infection…found a large increase in influenza-specific T cell responses by day 7, when virus was completely cleared from nasal samples and serum antibodies were still undetectable. Pre-existing CD4+, but not CD8+, T cells responding to influenza internal proteins were associated with lower virus shedding and less severe illness. These CD4+ cells also responded to pandemic H1N1 (A/CA/07/2009) peptides and showed evidence of cytotoxic activity.”
        116) Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine, CDC, MMWR, 2009 “No increase in cross-reactive antibody response to the novel influenza A (H1N1) virus was observed among adults aged >60 years. These data suggest that receipt of recent (2005–2009) seasonal influenza vaccines is unlikely to elicit a protective antibody response to the novel influenza A (H1N1) virus.”
        117) No one is naive: the significance of heterologous T-cell immunity, Welsh, 2002 “Memory T cells that are specific for one virus can become activated during infection with an unrelated heterologous virus, and might have roles in protective immunity and immunopathology. The course of each infection is influenced by the T-cell memory pool that has been laid down by a host’s history of previous infections, and with each successive infection, T-cell memory to previously encountered agents is modified.”
        118) Intrafamilial Exposure to SARS-CoV-2 Induces Cellular Immune Response without Seroconversion, Gallais, 2020 “Individuals belonging to households with an index COVID-19 patient, reported symptoms of COVID-19 but discrepant serology results… All index patients recovered from a mild COVID-19. They all developed anti-SARS-CoV-2 antibodies and a significant T cell response detectable up to 69 days after symptom onset. Six of the eight contacts reported COVID-19 symptoms within 1 to 7 days after the index patients but all were SARS-CoV-2 seronegative… exposure to SARS-CoV-2 can induce virus-specific T cell responses without seroconversion. T cell responses may be more sensitive indicators of SARS-Co-V-2 exposure than antibodies…results indicate that epidemiological data relying only on the detection of SARS-CoV-2 antibodies may lead to a substantial underestimation of prior exposure to the virus.”
        119) Protective immunity after recovery from SARS-CoV-2 infection, Kojima, 2021 “It important to note that antibodies are incomplete predictors of protection. After vaccination or infection, many mechanisms of immunity exist within an individual not only at the antibody level, but also at the level of cellular immunity. It is known that SARS-CoV-2 infection induces specific and durable T-cell immunity, which has multiple SARS-CoV-2 spike protein targets (or epitopes) as well as other SARS-CoV-2 protein targets. The broad diversity of T-cell viral recognition serves to enhance protection to SARS-CoV-2 variants, with recognition of at least the alpha (B.1.1.7), beta (B.1.351), and gamma (P.1) variants of SARS-CoV-2. Researchers have also found that people who recovered from SARS-CoV infection in 2002–03 continue to have memory T cells that are reactive to SARS-CoV proteins 17 years after that outbreak. Additionally, a memory B-cell response to SARS-CoV-2 evolves between 1·3 and 6·2 months after infection, which is consistent with longer-term protection.”
        120) This ‘super antibody’ for COVID fights off multiple coronaviruses, Kwon, 2021 “This ‘super antibody’ for COVID fights off multiple coronaviruses…12 antibodies…that was involved in the study, isolated from people who had been infected with either SARS-CoV-2 or its close relative SARS-CoV.”
        121) SARS-CoV-2 infection induces sustained humoral immune responses in convalescent patients following symptomatic COVID-19, Wu, 2020 “Taken together, our data indicate sustained humoral immunity in recovered patients who suffer from symptomatic COVID-19, suggesting prolonged immunity.”
        122) Evidence for sustained mucosal and systemic antibody responses to SARS-CoV-2 antigens in COVID-19 patients, Isho, 2020 “Whereas anti-CoV-2 IgA antibodies rapidly decayed, IgG antibodies remained relatively stable up to 115 days PSO in both biofluids. Importantly, IgG responses in saliva and serum were correlated, suggesting that antibodies in the saliva may serve as a surrogate measure of systemic immunity.”
        123) The T-cell response to SARS-CoV-2: kinetic and quantitative aspects and the case for their protective role, Bertoletti, 2021 “Early appearance, multi-specificity and functionality of SARS-CoV-2-specific T cells are associated with accelerated viral clearance and with protection from severe COVID-19.”
        124) The longitudinal kinetics of antibodies in COVID-19 recovered patients over 14 months, Eyran, 2020 “Found a significantly faster decay in naïve vaccinees compared to recovered patients suggesting that the serological memory following natural infection is more robust compared to vaccination. Our data highlights the differences between serological memory induced by natural infection vs. vaccination.”
        125) Continued Effectiveness of COVID-19 Vaccination among Urban Healthcare Workers during Delta Variant Predominance, Lan, 2021 “Followed a population of urban Massachusetts HCWs…we found no re-infection among those with prior COVID-19, contributing to 74,557 re-infection-free person-days, adding to the evidence base for the robustness of naturally acquired immunity.”
        126) Immunity to COVID-19 in India through vaccination and natural infection, Sarraf, 2021 “Compared the vaccination induced immune response profile with that of natural infection, evaluating thereby if individuals infected during the first wave retained virus specific immunity…the overall immune response resulting from natural infection in and around Kolkata is not only to a certain degree better than that generated by vaccination, especially in the case of the Delta variant, but cell mediated immunity to SARS-CoV-2 also lasts for at least ten months after the viral infection.”
        127) Asymptomatic or mild symptomatic SARS-CoV-2 infection elicits durable neutralizing antibody responses in children and adolescents, Garrido, 2021 “Evaluated humoral immune responses in 69 children and adolescents with asymptomatic or mild symptomatic SARS-CoV-2 infection. We detected robust IgM, IgG, and IgA antibody responses to a broad array of SARS-CoV-2 antigens at the time of acute infection and 2 and 4 months after acute infection in all participants. Notably, these antibody responses were associated with virus-neutralizing activity that was still detectable 4 months after acute infection in 94% of children. Moreover, antibody responses and neutralizing activity in sera from children and adolescents were comparable or superior to those observed in sera from 24 adults with mild symptomatic infection. Taken together, these findings indicate that children and adolescents with mild or asymptomatic SARS-CoV-2 infection generate robust and durable humoral immune responses that can likely contribute to protection from reinfection.”
        128) T cell response to SARS-CoV-2 infection in humans: A systematic review, Shrotri, 2021 “Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear.”
        129) Severity of SARS-CoV-2 Reinfections as Compared with Primary Infections, Abu-Raddad, 2021 “Reinfections had 90% lower odds of resulting in hospitalization or death than primary infections. Four reinfections were severe enough to lead to acute care hospitalization. None led to hospitalization in an ICU, and none ended in death. Reinfections were rare and were generally mild, perhaps because of the primed immune system after primary infection.”
        130) Assessment of the Risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reinfection in an Intense Re-exposure Setting, Abu-Raddad, 2021 “SARS-CoV-2 reinfection can occur but is a rare phenomenon suggestive of protective immunity against reinfection that lasts for at least a few months post primary infection.”
        131) Increased risk of infection with SARS-CoV-2 Beta, Gamma, and Delta variant compared to Alpha variant in vaccinated individuals, Andeweg, 2021 “Analyzed 28,578 sequenced SARS-CoV-2 samples from individuals with known immune status obtained through national community testing in the Netherlands from March to August 2021. They found evidence for an “increased risk of infection by the Beta (B.1.351), Gamma (P.1), or Delta (B.1.617.2) variants compared to the Alpha (B.1.1.7) variant after vaccination. No clear differences were found between vaccines. However, the effect was larger in the first 14-59 days after complete vaccination compared to 60 days and longer. In contrast to vaccine-induced immunity, no increased risk for reinfection with Beta, Gamma or Delta variants relative to Alpha variant was found in individuals with infection-induced immunity.”
        132) Prior COVID-19 protects against reinfection, even in the absence of detectable antibodies, Breathnach, 2021 “Studies did not address whether prior infection is protective in the absence of a detectable humoral immune response. Patients with primary or secondary antibody deficiency syndrome and reduced or absent B cells can recover from COVID-19…Although there have been few mechanistic studies, preliminary data show that such individuals generate striking T-cell immune responses against SARS-CoV-2 peptide pools…SARS-CoV-2 specific T cell immune responses but not neutralising antibodies are associated with reduced disease severity suggesting the immune system may have considerable redundancy or compensation following COVID-19…our results add to the emerging evidence that detectable serum antibody may be an incomplete marker of protection against reinfection. This could have implications for public health and policy-making, for example if using seroprevalence data to assess population immunity, or if serum antibody levels were to be taken as official evidence of immunity – a minority of truly immune patients have no detectable antibody and could be disadvantaged as a result. Our findings highlight the need for further studies of immune correlates of protection from infection with SARS-CoV-2, which may in turn enhance development of effective vaccines and treatments.”
        133) Natural infection vs vaccination: Which gives more protection?, Rosenberg, 2021 “With a total of 835,792 Israelis known to have recovered from the virus, the 72 instances of reinfection amount to 0.0086% of people who were already infected with COVID…By contrast, Israelis who were vaccinated were 6.72 times more likely to get infected after the shot than after natural infection, with over 3,000 of the 5,193,499, or 0.0578%, of Israelis who were vaccinated getting infected in the latest wave.”
        134) Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study, Singanayagam, 2021 “Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts.”
        135) Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection, Greaney, 2021 “The neutralizing activity of vaccine-elicited antibodies was more targeted to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein compared to antibodies elicited by natural infection. However, within the RBD, binding of vaccine-elicited antibodies was more broadly distributed across epitopes compared to infection-elicited antibodies. This greater binding breadth means that single RBD mutations have less impact on neutralization by vaccine sera compared to convalescent sera. Therefore, antibody immunity acquired by natural infection or different modes of vaccination may have a differing susceptibility to erosion by SARS-CoV-2 evolution.”
        136) Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity, Mo