Why is Paxlovid (nirmatrelvir/ritonavir) a promising new drug in our fight against Covid-19?

Based on the manufacturer’s (Pfizer’s) report, there are several reasons why Paxlovid may be a promising drug:1

  • It’s the first oral drug approved by the FDA for Emergency Use Authorization (EUA)
  • It reduces risk of hospitalization or death by ~ 90% (when taken within 3-5 days of symptom onset) in patients at high risk of complications from Covid-19
  • It reduces viral load at day 5 of treatment by 10-fold compared to placebo, theoretically reducing infectivity at least in household settings 2
  • Serious adverse events were comparable to placebo; possible side effects include liver disease, diarrhea, altered sense of taste, hypertension and muscle aches
  • Nirmatrelvir component of Paxlovid has been found to be active against a variety of SARS-CoV-2 variants of concern such as alpha, beta, delta as well as the newer omicron variant. This finding is in contrast to significantly reduced or loss of neutralizing activity of many commercially-available monoclonal antibody products against the omicron variant (eg, Casirivimab/Imdevimab-REGEN-COV, Bamlanivimab/Etesevimab, but not Sotrovimab)  designed to reduce serious Covid-19 complications in mild to moderate disease. 3-4

Few caveats to keep in mind when prescribing Paxlovid at this time:

  • It’s only approved for adults and children 12 years of age or older weighing at least 88 lbs (40kg) who test positive for SARS-CoV-2
  • Patients should be at high risk for progression to severe Covid-19 such as hospitalization or death
  • Per manufacturer (Pfizer), Paxlovid should not be taken if a patient is on certain medications due to the possibility of adverse drug interactions. The list includes colchicine, lovastatin, simvastatin, sildenafil for pulmonary arterial hypertension, some anti-epileptics (eg, carbamazepine, phenytoin), rifampin and St. John’s Wort.
  • There is no experience with treating pregnant women or breastfeeding mothers.
  • Pfizer recommends effective barrier contraception or refraining from sexual activity while taking Paxlovid

Paxlovid comes in a box of blister packs containing 5 days’ worth of medications (two 150 mg tablets of nirmatrelvir plus one 100 mg tablet of ritonavir to be taken 2x/day).  

Bonus Pearl: Another preliminary study of Paxlovid, this time including unvaccinated adults at low risk of hospitalization or death, has found a 70% reduction in hospitalization and no death compared to placebo with marginal statistical significance (P=0.051) but still with a 10-fold drop in viral load. 1

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References

  1. Pfizer announces additional phase 2/3 study results confirming robust efficacy of novel COVID-19 oral antiviral treatment candidate in reducing risk of hospitalization or death. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results . Accessed Dec 23, 2021.
  2. Marc A, kerioui M, Blanquart F, et. al. Quantifying the relationship between SARS-CoV-2 viral load and infectiousness. eLife 2021;10:e69302. https://elifesciences.org/articles/69302#:~:text=Based%20on%20the%20current%20knowledge,24%25%20to%2058%25%20in%20household  
  3. Aggarwal A, Stell AO, Walker G, et al. SARS-CoV-2 Omicron:evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern. MedRxiv 2021. Doi:https://doi.org/10.1101/2021.12.14.21267772. https://www.medrxiv.org/content/10.1101/2021.12.14.21267772v1
  4. Planas D, Saunders N, Maes P, et al. Considerable escape of SARS-CoV-2 variant Omicron to antibody neutralization. MedRxiv 2021. https://www.biorxiv.org/content/10.1101/2021.12.14.472630v1

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, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their 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!

Why is Paxlovid (nirmatrelvir/ritonavir) a promising new drug in our fight against Covid-19?

Who should get tested after a holiday indoor gathering with family members?

Whether you should get tested after holiday gatherings depends a lot on factors such as the level of transmission of Covid-19 within your region, the vaccination status of all the attendees, the likelihood of Covid-19 in any of the attendees, and your threshold for risk of either contracting or transmitting of Covid-19 to others, particularly immunocompromised persons. 

The following discussion assumes a scenario that is common to most indoor holiday gatherings: 1. You are getting together with people outside of your household; 2.  You or your family members don’t wear a face mask at all or certainly not all the time during the gathering; and 3. You find it impossible or don’t wish to socially distance from others during the get-together.1,2

First, let’s start with 2 situations where you should get tested following a holiday get-together, irrespective of your (or the attendees’) vaccination status: 1. if you have symptoms of Covid-19; and 2. If you were in close contact of an infected person (ie, commonly defined as within 6 feet of that person for a minimum of 15 minute during a 24-hour period).3

In the absence of known exposure or symptoms, you should consider getting tested if you are not fully immunized since you will be at higher risk of contracting and transmitting Covid-19 to others as long as there is still significant Covid-19 transmission in the region.  In contrast, if you and other attendees are fully immunized already, routine testing for Covid-19 after the gathering is hard to justify given the effectiveness of FDA-authorized Covid-19 vaccines and the costs and impracticalities associated with routine testing of millions of fully vaccinated persons.  

It goes without saying that holiday gatherings with family members outside of one’s immediate houseshold is not a zero-risk proposition for contracting or transmitting Covid-19 because people can have no symptoms and be infectious and vaccinated individuals can on occasion become infected.   Even the tests are not perfect. However, if you are concerned that you might have been exposed to Covid-19  and knowledge of a negative Covid-19 test (with its inherent limitations) gives you peace of mind, you should consider getting tested. The over-the-counter rapid Covid-19 tests may be particularly useful in assessing the likelihood of being contagious.4

For further recommendations on when you should consider getting tested for Covid-19 in general, I highly recommend an NIH-sponsored online calculator called “When to Test”.  This calculator is based on mathematical modelling that takes into account an individual’s vaccination status, transmission rates in the geographic area, and mitigation behaviors (eg, masks and social distancing).1

Bonus Pearl: Did you know that persons with Covid-19 are considered infectious 2 days before they develop symptoms or 2 days before the date of their positive test if they don’t have symptoms?5

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References:

  1. When to test offers free online tool to help individuals make informed Covid-19 testing decisions. https://www.nih.gov/news-events/news-releases/when-test-offers-free-online-tool-help-individuals-make-informed-covid-19-testing-decisions. Accessed November 26, 2021.
  2. Covid-19 testing overview. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/testing.html. Accessed November 26, 2021.
  3. Covid-19. https://www.cdc.gov/coronavirus/2019-ncov/php/contact-tracing/contact-tracing-plan/appendix.html#contact. Accessed November 26, 2021.
  4. Schuit E, Venekamp RP, Pas SD, et al. Diagnostic accuracy of rapid antigen tests in asymptomatic and presymptomatic close contacts of individuals with confirmed SARS-CoV-2 infection: cross sectional study. BMJ 2021;374:n1676.  https://www.bmj.com/content/374/bmj.n1676
  5. Quarantine and isolation. https://www.cdc.gov/coronavirus/2019-ncov/your-health/quarantine-isolation.html#:~:text=Get%20tested%205%2D7%20days%20after%20their%20first%20exposure.,the%20person%20with%20COVID%2D19. Accessed November 26, 2021.

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, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their 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!

 

Who should get tested after a holiday indoor gathering with family members?

What’s the evidence that a third dose of mRNA Covid-19 vaccine reduces risk of Covid-19 disease?

The strongest evidence to date demonstrating the effectiveness of a third dose of mRNA Covid-19 vaccine comes from an observational study from Israel which reported 93% effectiveness for admission to hospital, 92% for severe disease and 81% for Covid-19 related deaths when compared to those who had received 2 doses of the vaccine (Pfizer, BNT162b2 mRNA) at least 5 months before.1

This was a large population-based study involving over a million people 16 years or older (one-half in each group) who were eligible for the third dose (median age 52 y); those living in long-term facilities, healthcare workers and those medically confined to their homes were excluded. Vaccine effectiveness was evaluated at least 7 days after receipt of the third dose.  Median follow-up period was 13 days for both groups.

Overall effectiveness of the third dose vs 2 vaccine doses was 93% (88-97) for admission to hospital, 92% (82-97) for severe disease and 81% for death (59-97). Effectiveness of the third dose was similar between males and females and between individuals 40-60 years and those at least 70 years of age; effectiveness could not be determined in the younger age group due to small number of adverse outcomes.

What makes this study stand out among the previous works2,3 is that it controlled for important possible confounders, including sociodemographic factors, clinical factors, and behavioral factors related to Covid-19.  Limitations include its observational nature and exclusion of certain at risk groups, such as nursing home residents and healthcare workers.

Given the increasing number of Covid-19 cases in many communities at this writing, the news that a booster shot of an mRNA vaccine provides further protection in preventing Covid-19 is very welcome!

Bonus Pearl: Did you know that in a study measuring the immune response after the third dose of an mRNA vaccine (Moderna) in those 60 years of age or older, the median antibody titer rose 50-fold!4

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References

  1. Barda N, Dagan N, Cohen C, et al. Effectiveness of a third dose of the BNT162b2 mRNA Covid-19 vaccine for preventing severe outcomes in Israel: an observational study. Lancet, published online October 29, 2021. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2902249-2
  2. Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 vaccine.N Engl J Med 2021; published online Sept 15, https://doi.org/10.1056/nejmoa21114255.
  3. Patalon T, Gazit S, Pitzer VE, et al. Short term reduction in the odds of testing positive for SARS-CoV-2; a comparison between two doses and three doses of the BNT162b2 vaccine. medRxive 2021;published online Aug 31. https://doi.org/10.1101/2021.008.29.21262792 (preprint).
  4.  Eliakim-Raz N, Liebovici-Weisman Y, Stemmer A, et al. Antibody titers before and aftera third dose of SARS-CoV-2 BNT162b2 vaccine in adults ages ≥60 years. JAMA. Published online November 5, 2021. doi:10.1001/jama.2021.19885 https://jamanetwork.com/journals/jama/fullarticle/2786096

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, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their 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!

What’s the evidence that a third dose of mRNA Covid-19 vaccine reduces risk of Covid-19 disease?

What’s the evidence that REGEN-COV (casirivimab and imdevimab) monoclonal antibody cocktail is effective in the post-exposure prophylaxis of Covid-19?

The U.S. FDA has issued an Emergency Use Authorization (EUA) for the emergency use of REGEN-COV in adult and pediatric populations (≥12 years of age and older weighing> 40 kg) who are at high risk* of progression to severe COVID-19— including hospitalization or death— and who are not fully vaccinated or are not expected to mount an adequate immune response to the vaccine (eg, immunocompromised state).1  This recommendation is based on a randomized controlled trial involving individuals enrolled within 96 hours of exposure to a known Covid-19 case (Covid-10 Phase 3 Prevention Trial).2

In this trial, the primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28  in participants who did not have SARS-CoV-2 infection  by PCR or serology at the time of enrollment. Symptomatic SARS-CoV-2 infection developed in 1.5% of treatment group (vs 7.8% in placebo group) with 81.4% relative risk reduction (P<0.001); 66% reduction was observed when symptomatic and asymptomatic infections were combined.  Duration of symptoms and the magnitude and duration of detectable RNA were also lower in the REGEN-COV group compared to placebo. Therapy was well tolerated.2

In the same study, in a subgroup analysis of those who were seropositive at the time of enrollment REGEN-COV lowered the risk of symptomatic disease (0.4% vs 2.3% in the placebo group) with relative risk reduction of 81%, though not statistically significant (P=0.14).  This may be why the FDA EUA extended to certain vaccinated groups as well since to date there are no published trials on the use of REGEN-COV as post-exposure prophylaxis in vaccinated individuals.

*High risk group included ≥65 years of age, BMI≥25 kg/m2, diabetes, immunocompromised state, cardiovascular disease or hypertension, chronic lung disease, sickle cell disease and neurodevelopment disorders.

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References

  1. Fact sheet for health care providers emergency use authorization (EUA) of REGEN-COV. https://www.fda.gov/media/145611/download. Accessed September 15, 2021.
  2. O’Brien MP. Forleo-Neto E, Musser BJ et al. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med 2021, August 4, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2109682

 

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, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their 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!

What’s the evidence that REGEN-COV (casirivimab and imdevimab) monoclonal antibody cocktail is effective in the post-exposure prophylaxis of Covid-19?

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?

What’s the effectiveness of Covid-19 vaccination in patients with multiple sclerosis (MS) treated with high-efficacy disease-modifying therapies?

The answer appears to be dependent on which high-efficacy disease-modifying agent is being used to treat MS.  Limited data suggest that cladribine treatment does not impair humoral response to Covid-19 vaccine in patients with MS, while ocrelizumab and fingolimod have a major negative impact on vaccine responsiveness based on humoral antibody measurements.1

A study involving 125 Covid-19 MS vaccine (mRNA, Pfizer BNT162b2) recipients  (58% females, 61% relapse-remitting, 19% primary-progressive, 14% secondary-progressive, 3% clinically isolated syndrome and 2% radiologically isolated syndrome), found high levels of SARS-CoV-2 anti-spike IgG in all subjects (n=23) receiving cladribine as early as 4.4 months from last treatment dose.1

In contrast only 4% of patients with MS treated with fingolimod had a post-vaccination humoral response (time-interval from last treatment dose to vaccination not reported).  Similarly, most patients under treatment with ocrelizumab failed to develop a post-vaccination humoral response, with only 23% demonstrating a protective antibody titer (time-interval from last treatment dose 3.1-8.9 months).

These results may not be totally surprising given the attenuated humoral response to several common vaccines in patients with MS treated with ocrelizumab or fingolimod.2,3

Given the potential suboptimal response to Covid-19 vaccine in patients with MS treated with fingolimod or ocrelizumab, until further data become available, it’s fair to state that patients treated with these agents should NOT depend on vaccination to protect them from Covid-19 and that they may need to still take extra precautions during the pandemic.   

 

Bonus Pearl: Did you know that fingolimod prevents lymphocyte egression from secondary lymphoid tissue and ocrelizumab is an anti-CD20 monoclonal antibody that depletes B lymphocytes?1

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Reference

  1. Achiron A, Mandel M, Dreyer-Alster S, et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Therapeutic Adances in Neurological Disorders 2021;14:1-8. https://journals.sagepub.com/doi/full/10.1177/17562864211012835
  2. Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis. Neurology 2020; 95:e1999-22008. https://pubmed.ncbi.nlm.nih.gov/32727835/
  3. Kappos L, Mehling M, Arroyo R, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology 2015;84:872-9. https://pubmed.ncbi.nlm.nih.gov/25636714/  

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!

What’s the effectiveness of Covid-19 vaccination in patients with multiple sclerosis (MS) treated with high-efficacy disease-modifying therapies?

Why is the Delta variant of SARS-CoV-2 increasingly becoming a “variant of concern” in the current Covid-19 pandemic?

The Delta variant (B.1.617.2, formerly India variant) has become an increasingly prevalent strain of SARS-Cov-2 causing Covid-19 in many countries outside of India, including the United States and United Kingdom, particularly affecting younger unvaccinated persons.  Several features of the Delta variant are of particular concern. 1-7

  1. Delta virus appears to be more transmissible when compared to previously emerged variant viruses. Data from new Public Health England (PHE) research suggests that the Delta variant is associated with a 64% increased risk of household transmission compared with the Alpha variant (B.,1.1.7, UK variant) and 40% more transmissibility in outdoors. 1,8  
  2. Delta virus is also associated with a higher rate of severe disease, doubling the risk of hospitalization based on preliminary data from Scotland. In vitro, it replicates more efficiently than the Alpha variant with higher respiratory viral loads.5
  3. Delta virus may also be associated with reduced vaccine effectiveness with increased vaccine breakthroughs. One study found that Delta variant is 6.8-fold more resistant to neutralization by sera from Covid-19 convalescent and mRNA vaccinated individuals.5 Fortunately, a pre-print study released by PHE in May 2021 found that 2 doses of the Pfizer vaccine were still 88% effective against symptomatic infection with Delta variant  (vs 93% for the Alpha variant) and 96% effective against hospitalization; 1 dose was only 33% effective against symptomatic disease (vs 50% for the Alpha variant).  Two doses of Astra Zeneca vaccine were 60% effective against symptomatic disease from the Delta variant.8 
  4. Aside from its somewhat unique epidemiologic features, Covid-19 caused by Delta variant seems to be behaving differently (starting out as a “bad cold” or “off feeling”), with top symptoms of headache, followed by runny nose and sore throat with less frequent fever and cough; loss of sense of smell was not common at all based on reported data to date.1

What the Delta variant reminds us is, again, the importance of vaccination, masks and social distancing. The pandemic is still with us!

Bonus Pearl: Did you know that, on average, a Delta variant-infected person may transmit it to 6 other contacts (Ro~6.0) compared to 3 others (Ro~3) for the original SARS-CoV-2 strains found during the early part of the pandemic?1

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References

  1. https://www.bbc.com/news/health-57467051
  2. Knodell R. Health Advisory: Emergence of Delta variant of coronavirus causing Covid-19 in USA. Missouri Department of Health & Senior Services. 23 June, 2021. https://health.mo.gov/emergencies/ert/alertsadvisories/pdf/update62321.pdf
  3. Kupferschmidt K, Wadman M. Delta variant triggers new phase in the pandemic. Science 25 June 2021; 372:1375-76. https://science.sciencemag.org/content/sci/372/6549/1375.full.pdf
  4. Sheikh A, McMenamin J, Taylor B, et al. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet 2021; 397:2461-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201647/
  5. Mlcochova P, Kemp S, Dhar MS, et al. Sars-Cov-2 B.1.617.2 Delta variant emergence and vaccine breakthrough. In Review Nature portfolio, posted 22 June, 2021. https://www.researchsquare.com/article/rs-637724/v1
  6. Bernal JL, Andrews N, Gower C, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 variant. MedRxiv, posted May 24, 2021. https://www.medrxiv.org/content/10.1101/2021.05.22.21257658v1 vaccine efficacy
  7. Allen H, Vusirikala A, Flannagan J, et al. Increased household transmission of Covid-19 cases associatd with SARS-Cov-2 variant of concern B.1.617.2: a national case control study. Public Health England. 2021. https://khub.net/documents/135939561/405676950/Increased+Household+Transmission+of+COVID-19+Cases+-+national+case+study.pdf/7f7764fb-ecb0-da31-77b3-b1a8ef7be9aa  Accessed June 27, 2021.
  8. Callaway E. Delta coronavirus variant: scientists brace for impact. Nature. 22 June 2021. https://www.nature.com/articles/d41586-021-01696-3 

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.

Why is the Delta variant of SARS-CoV-2 increasingly becoming a “variant of concern” in the current Covid-19 pandemic?

My patient with Covid-19 and abdominal pain has an elevated lipase. Is there a connection between Covid-19 and acute pancreatitis?

Acute pancreatitis as a complication of Covid-19 is infrequent.1 Despite reports of elevated amylase/lipase and/or acute pancreatitis in some patients with Covid-19,2 the exact role that SARS-CoV-2 plays in causing acute pancreatitis is unclear at this time.

A retrospective study of over 11,000 hospitalized patients with Covid-19 in the U.S. found a point prevalence of acute pancreatitis of only 0.27%,3 while another retrospective study of Covid-19 patients seen in Spanish emergency rooms reported acute pancreatitis in only 0.07% of cases.4 Of interest, in the latter study, Covid-19 was associated with lower frequency of acute pancreatitis. Further adding to the controversy on the causative role of Covid-19 is lack of an observed increase in the incidence of acute pancreatitis during Covid-19 pandemic. 1

An earlier study from China reported mild elevation (<3x upper limits of normal) of amylase and/or lipase in 17% of patients with Covid-19 pneumonia, none of whom had abdominal pain. 5

The temporal relationship between Covid-19 and acute pancreatitis has varied from abdominal symptoms at the onset of Covid-19 symptoms to days after diagnosis of Covid-19? 1

Despite these disparate findings, Covid-19 related acute pancreatitis or pancreatic injury is plausible. Pancreatic ductal, acinar and islet cells express ACE2, an important receptor for SARS-CoV-2.1 Infection in the GI tract (virus can easily be found in the stool) may potentially spread from the duodenal epithelium to the pancreatic duct and the pancreatic parenchyma itself. Immune-mediated inflammatory response or endotheliitis caused by SARS-CoV-2 may also potentially explain reports of pancreatic injury in Covid-19. 1,2

Bonus Pearl: Did you know that SARS-CoV-2 has been found in pancreatic tissue of some patients who succumbed to Covid-19 and has been shown to infect human pancreatic beta cells in-vitro.6  Perhaps we should be on the lookout for diabetes as a consequence of Covid-19 as well!

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 References

  1. De-Madaria E, Capurso G. Covid-19 and acute pancreatitis: examining the causality. Nature Reviews Gastroenterol Hepatol 2021;18: 3-4. https://www.nature.com/articles/s41575-020-00389-y
  2. Kandasamy S. An unusual presentation of Covid-19: acute pancreatitis. Ann Hepatobiliary Pancreat Surg 2020;24:539-41. https://synapse.koreamed.org/upload/SynapseXML/2110ahbps/pdf/AHBPS-24-539.pdf
  3. Inamdar S, Benias PC, Liu Y, et al. Prevalence, risk factors, and outcomes of hospitalized patients with coronavirus disease 2019 presenting as acute pancreatitis. Gastroenterol 2020;159:2226-28. https://www.gastrojournal.org/article/S0016-5085(20)35115-5/pdf
  4. Miro O, Llorens P, Jimenez S, et al. Frequency of five unusual presentations in patients with Covid-19: results of the UMC-19-S. Epidemiol Infect 2020;148:e189. https://pubmed.ncbi.nlm.nih.gov/32843127/
  5. Wang F, Wang H, Fan J, et al. Pancreatic injury patterns in patients with coronavirus disease 19 pneumonia. Gastroenterology 2020;159:367-70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118654/
  6. Wu C-T, Lidsky PV, Xiao Y, et al. SARS-CoV-2 infects human pancreatic beta cells and elicits beta cell impairment. Cell Metab 2021 May 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130512/

 

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!

My patient with Covid-19 and abdominal pain has an elevated lipase. Is there a connection between Covid-19 and acute pancreatitis?

Can Covid-19 exacerbate seizures in patients with epilepsy?

There have been several reports of seizure exacerbation in epileptic patients after Covid-19 infection. Seizure exacerbations have been observed in epileptic patients with uncontrolled epilepsy, as well as patients who were previously controlled with antiepileptic drugs (AEDs).1,2

In a survey of 362 epileptic patients in Wuhan, China, the site of the initial outbreak, 31 (8.6%) patients reported an increased number of seizures in the month after the public lockdown began; 16 (51.6%) of the 31 patients with seizure exacerbation had prior exposure to Covid-19.1

In a study of 439 patients with Covid-19 infection in Egypt, 19 (4.3%) patients presented with acute seizures.2  Two of the 19 seizure patients had a previous diagnosis of epilepsy, which had been controlled for up to 2 years. Interestingly, the other 17 patients had new onset seizures without a previous epilepsy diagnosis.

Covid-19 has been proposed to induce seizures by eliciting inflammatory cytokines in the central nervous system, leading to neuronal necrosis and increased glutamate levels in the cerebral cortex and hippocampus.3

Covid-19 infection may have also indirectly caused seizure exacerbations in a number of epileptic patients. Interestingly, stress related to worrying about the effect of the outbreak on a patient’s seizure activity was associated with seizure exacerbations (odds ratio: 2.5, 95% CI: 1.1-6.1)2. It is also possible that some seizure exacerbations may have been due to fear of visiting the hospital and AED withdrawal, as was demonstrated during the 2003 SARS outbreak.4

Bonus Pearl: Did you know that Guillain–Barré Syndrome has also been observed in patients with Covid-19 infection?5

Contributed by Luke Vest, Medical Student, St. Louis University Medical School

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References:

  1. Huang, S., Wu, C., Jia, Y., et al. (2020). COVID-19 outbreak: The impact of stress on seizures in patients with epilepsy. Epilepsia, 61(9), 1884-1893. https://doi.org/10.1111/epi.16635  
  2. Khedr, E. M., Shoyb, A., Mohammaden, M., & Saber, M. (2021). Acute symptomatic seizures and COVID-19: Hospital-based study. Epilepsy Res, 174, 106650. https://doi.org/10.1016/j.eplepsyres.2021.106650
  1. Nikbakht, F., Mohammadkhanizadeh, A., & Mohammadi, E. (2020). How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Multiple sclerosis and related disorders, 46, 102535. https://doi.org/10.1016/j.msard.2020.102535
  2. Lai, S. L., Hsu, M. T., & Chen, S. S. (2005). The impact of SARS on epilepsy: the experience of drug withdrawal in epileptic patients. Seizure, 14(8), 557–561. https://doi.org/10.1016/j.seizure.2005.08.010
  3.  Abu-Rumeileh, S., Abdelhak, A., Foschi, M., Tumani, H., & Otto, M. (2021). Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases. Journal of neurology, 268(4), 1133–1170. https://doi.org/10.1007/s00415-020-10124-x   

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, or St. Louis University Medical School. 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!

Can Covid-19 exacerbate seizures in patients with epilepsy?