Should patients previously immunized against Covid-19 receive selected monoclonal antibodies when diagnosed with a breakthrough infection?

Although published studies supporting monoclonal antibody therapy in mild to moderate Covid-19 preceded availability of Covid-19 vaccines and the emergence of new variants of concern,1,2 given the possibility of severe breakthrough Covid-19 in high risk vaccinated patients with suboptimal immunity and the retained activity of certain monoclonal antibody products (ie, casirivimab and imdevimab-Regeneron-Cov and sotrovimab) against common variants of SARS-CoV-2 , their use is recommended even in vaccinated individuals with mild to moderate Covid-19.3-5

In fact, the CDC states that “For people who have received one or more doses of Covid-19 vaccine and subsequently experience SARS-CoV-2 infection, prior receipt of a Covid-19 vaccine should not affect treatment decisions (including use of monoclonal antibodies, convalescent plasma, antiviral treatment, or corticosteroid administration) or timing of such treatment.”3

In its July 30, 2021 Emergency Authorization Use (EUA) letter regarding use of casirivimab and imdevimab – REGEN-COV), the FDA does not distinguish between vaccinated and unvaccinated individuals for its indications,4 similar to those of guidelines posted by the Department of Health and Human Services and the NIH.5-6

When indicated, high risk vaccinated individuals with Covid-19 should be offered  an FDA approved (under EUA currently) monoclonal antibody product (such as  casirivimab and imdevimab antibody cocktail or sotrovimab) soon after diagnosis and certainly no later than 10 days.

Vaccinated individuals with mild to moderate Covid-19 not requiring hospitalization and for whom monoclonal antibody treatment may be indicated include older patients and those with risk factors for severe disease, such as obesity, pregnancy, chronic kidney disease, chronic lung disease (including COPD), immunocompromised state, serious heart conditions (eg, heart failure, coronary artery disease, cardiomyopathies), sickle cell disease and type 2 diabetes.7

Of note, casirivimab and imdevimab is indicated for adults (weighing at least 40 kg) and children 12 years or older and is administered by IV infusion or subcutaneously, if IV infusion is not feasible and would lead to delay in treatment.4

Bonus Pearl: Did you know that in phase III trials, casirivimab and imdevimab  antibody cocktail reduced hospitalization or death by 70% in non-hospitalized patients with Covid-19?2

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References

  1. Interim clinical considerations for use of Covid-19 vaccines currently authorized in the United States. 2021. Available at https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html. Accessed August 22, 2021.
  2. March 23, 2021 https://www.roche.com/media/releases/med-cor-2021-03-23.htm
  3. Dougan M, Nirula A, Azizad M, et al. Bamlanivimab plus Etesevimab in mild or moderate Covid-19. N Engl J Med, July 14, 2021. https://www.nejm.org/doi/10.1056/NEJMoa2102685
  4. Letter, EUA REGEN-COV, July 30, 2021. https://www.fda.gov/media/145610/download
  5. Department of Health and Human Services. High risk Covid-19 outpatients may avoid hospitalization with monoclonal antibody treatment. July 16, 2021. https://combatcovid.hhs.gov/sites/default/files/documents/High-Risk-COVID-19-Outpatients-072021.pdf
  6. Anti-SARS Cov-2 monoclonal antibodies. Accessed August 22, 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/
  7. Science brief: evidence used to update the list of underlying medical conditions that increase a person’s risk of severe illness from Covid-19. Accessed August 22, 2021. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/underlying-evidence-table.html

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should patients previously immunized against Covid-19 receive selected monoclonal antibodies when diagnosed with a breakthrough infection?

What’s the evidence that immunocompromised patients need a 3rd booster mRNA Covid vaccine shot?

At this time, the Centers for Disease Control and Prevention (CDC) recommendation for a booster shot of an mRNA vaccine in patients with moderate to severe immunocompromised state (1,2) is based primarily on the concern for waning immunity following the initial series—including a decline in neutralizing antibodies— in this patient population, and the finding that at least some immunocompromised patients may have a significant improvement in certain laboratory measurements of immunity following their booster shot. 

Although there are no randomized-controlled trials of the efficacy of the 3rd shot in protecting against Covid-19 in immunocompromised patients, the recent surge in the highly transmissible SARS-CoV-2 variants in many parts of the world (including the U.S.)  as well as immunocompromised patient population accounting for nearly one-half of all breakthrough Covid-19 cases requiring hospitalization (1) make it urgent to adopt these recommendations. 

A randomized trial involving 120 solid organ transplant patients (median age 67 y) found higher neutralizing antibody levels and SARS CoV-2 specific T-cell counts after the mRNA-1273 (Moderna) vaccine booster dose compared to placebo (3).

In another study involving 101 solid organ transplant patients, of 59 subjects who were seronegative before the 3rd dose, 44% became seropositive 4 weeks after the 3rd vaccine dose ( BNT162b2-Pfizer vaccine administered 2 months after the second dose). Patients who did not have an antibody response were older, had higher degree of immunosuppression and had a lower estimated glomerular filtration rate than those with antibody response (4).

A “spectacular increase” in anti-spike antibodies with levels close to the general population has also been reported among hemodialysis patients receiving a third dose of Pfizer mRNA vaccine (5). 

Until further data from larger studies become available,  these studies support administration of a 3rd dose booster mRNA vaccine in moderate to severely immunosuppressed individuals.

Bonus Pearl: Did you know that although immunocompromised patients have significantly worse influenza outcome, the data on the impact of immunocompromised status on the outcome of Covid-19 is less clear with published evidence that both supports and refutes this association (6)?  

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References

  1. CDC. Data and clinical considerations for additional doses in immunocompromised people: ACIP Meeting, July 22, 2021. ACIP Data and Clinical Considerations for Additional Doses in Immunocompromised People (cdc.gov)
  2. CDC. Interim clinical considerations for use of Covid-19 vaccines currently authorized in the United States. August 13, 2021. Interim Clinical Considerations for Use of COVID-19 Vaccines | CDC
  3. Hall VG, Ferreira VH, Ku T, et al. Randomized trial of a third dose of mRNA-1273 vaccine recipients. N Engl J Med 2021, Aug 11. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients | NEJM
  4. Kamar N, Abravanel F, Marion O. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipient. N Engl J Med 2021, Aug 12.Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients | NEJM
  5. Frantzen L, Thibeaut S, Moussi-Frances J, et al. Covid-19 vaccination in haemodialysis patients: Good things come in threes… Neph Dial Transplant, 20 July 2023. COVID-19 Vaccination in Haemodialysis Patients: Good things come in threes… – PubMed (nih.gov)
  6. Parisi C. An opportunity to better understand the impact of coronavirus on immunocompromised patients. J Infect Dis 2021;224:372-3. Opportunity to Better Understand the Impact of Coronaviruses on Immunocompromised Patients | The Journal of Infectious Diseases | Oxford Academic (oup.com)

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the evidence that immunocompromised patients need a 3rd booster mRNA Covid vaccine shot?

Are women at higher risk of Covid-19 vaccine-related adverse events?

Data to date shows a preponderance of Covid-19 vaccine-related adverse events (AEs) among women compared to men. This finding may be due to the generally more robust immunological response to infections and vaccines among women, increased reporting of AEs by women, genetic factors, microbiome differences as well as other factors.1-3

A CDC study involving mRNA vaccines (Pfizer and Moderna) during the 1st month of vaccination roll out in the US, found that nearly 80% of adverse events were reported by women.  The great majority (>90%) of these AEs were not serious and included symptoms such as headache, dizziness and fatigue.1

A JAMA study involving individuals receiving one of the mRNA vaccines found that 94% (Pfizer) and 100% (Moderna) of anaphylaxis events occurred among women. Of note, the median age was ~40 years  with the majority of anaphylaxis events were reported after the first dose. 2

Higher incidence of AEs following Covid-19 vaccination is not surprising and may be explained biologically. Women typically have a more robust immune response to infections and vaccination, both at the level of innate and adaptive immunity with higher antibody responses.  

These findings may be in part due to hormones such as estrogen which is known to enhance differentiation of dendritic cells and proinflammatory cytokine production. Other proposed mechanisms include differences in microbiome between sexes and sex-based genetic influences on humoral immune profile with the X chromosome expressing 10 times more genes than the Y chromosome, including genes that influence immunity.3

Bonus Pearl: Did you know that anaphylactic reaction to the mRNA Covid-19 vaccines is extremely rare, occurring in only 2-5 cases/ million!2

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References

  1. Gee J, Marquez P, Su J, et al. First month of Covid-19 vaccine safety monitoring—United States, December 14, 2020—January 13, 2021. MMWR 2021;70:283-88. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008e3.htm
  2. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA Covid-19 vaccines in the US—December 14, 2020-January 18, 2021. JAMA 20201;325:1101-1102. https://jamanetwork.com/journals/jama/fullarticle/2776557
  3. Fischinger S, Boudreau CM, Butler AL, et al. Sex differences in vaccine-induced humoral immunity. Semin Immunopath 2019;41:239-49. https://pubmed.ncbi.nlm.nih.gov/30547182/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Are women at higher risk of Covid-19 vaccine-related adverse events?

Is there any evidence that routinely wearing gowns and gloves upon entry into the rooms of patients on contact precautions for MRSA or VRE really works?

Although routine gowning and gloving in the care of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE)—also known as contact precautions (CP)— is considered a standard of care (1), the evidence supporting its effectiveness in preventing endemic hospital-associated multidrug-resistant organism (MDROs) infections is not robust and is often conflicting. In fact, this practice is increasingly being questioned (including by some hospital epidemiologists) as means of preventing endemic transmission of MDROs in hospitals (1-7).

Critics often point out that studies supporting the use of CP in MDROs are observational, involving only outbreak situations where they were instituted as part of a bundled approach (eg, improved hand hygiene), making it difficult to determine its relative contribution to infection prevention (2,6).

In fact, recent cluster-randomized trials have largely failed to demonstrate clear benefit of CP over usual care for the prevention of acquiring MRSA or VRE in hospitalized patients (2,4). Furthermore, a meta-analysis of studies in which CP were eliminated failed to find an increase in the subsequent rates of transmission of MRSA, VRE, or other MDROs (2,7).

Based on these and other studies, some have suggested that in the presence of other infection prevention measures (eg, hand hygiene monitoring), CP be implemented only in select circumstances such as open or draining wounds, severe diarrhea or outbreak situations (3).

 

The United States Centers for Disease Control and Prevention (CDC), along with the Infectious Diseases Society of America (IDSA) and the Society of Healthcare Epidemiologists of America (SHEA), however, continue to recommend implementation of CP in the care of patients with MDROs.  

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References

1. Maragakis LL, Jernigan JA. Things we do for good reasons: contact precautions for multidrug-resistant organisms, including MRSA and VRE. J Hosp Med 2019;14:194-6. https://www.ncbi.nlm.nih.gov/pubmed/30811332
2. Young K, Doernberg SB, Snedcor RF, et al. Things we do for no reason:contact precautions for MRSA and VRE. J Hosp Med 2019;14:178-80. https://www.ncbi.nlm.nih.gov/pubmed/30811326
3. Bearman G, Abbas S, Masroor N, et al. Impact of discontinuing contact precautions for methicillin-resistant Staphylococcus aureus and vancomyin-resistant Enerococcus: an interrupted time series analysis. Infect Control Hosp Epidemiol 2018;39: 676-82. https://www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/impact-of-discontinuing-contact-precautions-for-methicillinresistant-staphylococcus-aureus-and-vancomycinresistant-enterococcus-an-interrupted-time-series-analysis/869CD5E44B339770AC771BC06049B98F
4. Harris AD, Pineles L, Belton B, et al. Universal glove and gown use and acquisition of antibiotic-resistant bacteria in the ICU. A randomized trial. JAMA 2013;310:1571-80. https://www.ncbi.nlm.nih.gov/pubmed/24097234
5. Morgan DJ, Murthy R, Munoz-Price LS, et al. Reconsidering contact precautions for endemic methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Infect Control Hosp Epidemiol 2015;36:1163-72. https://www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/reconsidering-contact-precautions-for-endemic-methicillinresistant-staphylococcus-aureus-and-vancomycinresistant-enterococcus/CCB41BF48CEC2185CC4D69AF3730584C
6. Morgan DJ, Wenzel RP, Bearman G. Contact precautions for endemic MRSA and VRE. Time to retire legal mandates. JAMA 2017;318:329-30. https://jamanetwork.com/journals/jama/article-abstract/2635333
7. Marra AR, Edmond MB, Schweizer ML, et al. Discontinuing contact precautions for multidrug-resistant organisms: a systematic literature review and meta-analysis. Am J Infect Control 208;46:333-340. https://www.ncbi.nlm.nih.gov/pubmed/29031432

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Is there any evidence that routinely wearing gowns and gloves upon entry into the rooms of patients on contact precautions for MRSA or VRE really works?

How can I be sure that my patient truly has orthostatic hypotension (OH)?

 

OH is a sustained reduction of systolic blood pressure (SBP) of ≥ 20 mm Hg or diastolic BP ≥ 10 mm Hg within 3 min of standing or head-up tilt to at least 60° on a tilt table (1); symptoms are not part of the criteria. In patients with supine hypertension, a reduction in SBP of 30 mm Hg has been suggested (1).  

The Centers for Disease Control and Prevention (CDC) recommends BP measurements when patient is supine for 5 min, and after standing for 1 and 3 min (2).  In some patients symptomatic OH occurs beyond 3 minutes of standing (1). Preference for mercury column sphygmomanometer due to its reliability and simplicity, with arm at the level of the heart has been stressed (3). 

A 2017 report involving over 11,000 middle-aged participants (Atherosclerosis Risk in Communities Study) has challenged the notion of waiting 3 minutes before OH is measured (4).  This prospective study  found a significant association between participant-reported history of dizziness on standing and OH but only at 1st measurement (mean of 28.0 seconds after standing), not at subsequent ones over a 2 minute period. It was concluded that measuring OH during the first minute “not only makes a lot of sense” but it’s more appropriate “because it’s more predictive of future falls”.

Keep in mind that OH is more common and more severe during mornings and after meals, and is exacerbated by large meals, meals high in carbohydrate, and alcohol intake (1).

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 References

 

  1. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Autonomic Neuroscience: Basic and Clinical 2011;161: 46–48. https://www.ncbi.nlm.nih.gov/pubmed/21431947
  2. http://www.cdc.gov/steadi/pdf/measuring_orthostatic_blood_pressure-a.pdf , accessed Dec 13, 2015.
  3. Naschitz J, Rosner I. Orthostatic hypotension: framework of the syndrome . Postgrad Med J 2007; 83:568-574. http://pmj.bmj.com/content/83/983/568
  4. Juraschek SP, Daya N, Rawlings AM, et al. Comparison of early versus late orthostatic hypotension assessment times in middle-age adults. JAMA Intern Med 2017;1177:1316-1323. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661881/

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

How can I be sure that my patient truly has orthostatic hypotension (OH)?