SARS-CoV-2;

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

FA Manian MD, MPH, , , , , , , , Leave a comment

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?

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

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

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?

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

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?

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

FA Manian MD, MPH, , , , , , , , , , , , , , , Leave a comment

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). 6   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?

FA Manian MD, MPH, , , , , , Leave a comment

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?

How effective are the mRNA Covid-19 vaccines in reducing the risk of hospitalization among adults 65 years of age or older?

FA Manian MD, MPH, , , , , , , , Leave a comment

The mRNA vaccines by Pfizer and Moderna seem very effective in not only reducing risk of symptomatic Covid-19 but also risk of hospitalization among adults 65 years of age or older.   A CDC study published on April 28, 2021, showed a vaccine efficacy of 94% among fully immunized and 64% among partially immunized adults ≥ 65 years of age  with approximately one-half of subjects  ≥75 years old.1

This study was carried out in 24 hospitals in 14 states in the U.S. during January 1, 2021-March 26, 2021, and involved 417 patients: 187 case-patients with Covid-19 and 230 controls with negative SARS-CoV-2 PCR test.  Among patients with Covid-19, 10% were partially immunized (vs 27% among controls) and 0.5% were fully immunized (vs. 8% among controls). 1

An Israeli study in a nationwide mass vaccination setting involving persons (28% ≥ 60 y) receiving Pfizer mRNA vaccine similarly found a vaccine efficacy of 74% for hospitalization for partially immunized and 87% for fully immunized persons.2

The high effectiveness of mRNA vaccines against more severe Covid-19 requiring hospitalization is great news, of course, as advanced age is by far the greatest risk factor for death from Covid-19, independent of underlying comorbidities.3   

Bonus Pearl: Did you know that prior to the availability of effective Covid-19 vaccination, adults over 65 years of age represented 80% of hospitalizations and had a 23-fold greater risk of death than those under 65?3

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References

  1. Tenforde MW, Olson SM, Self WH, et al. Effectiveness of Pfizer-BioNTech and Moderna vaccines against COVID-19 among hospitalized adults aged ≥65 years-United States, January-March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7018e1.htm?s_cid=mm7018e1_w
  2. Dagan N, Barda N, Kepten E, et al. BNT162b2mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Engl J Med 2021;384:1412-1423. https://www.nejm.org/doi/10.1056/NEJMoa2101765
  3. Mueller AL, McNamara MS, Sinclair DA. Why does COVID-19 disproportionately affect older people. Aging (Albany NY) 2020;12:9959-9981. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/

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!

How effective are the mRNA Covid-19 vaccines in reducing the risk of hospitalization among adults 65 years of age or older?

How long should my patient recovering from Covid-19 remain on isolation precautions?

FA Manian MD, MPH, , , , , , , , Leave a comment

For the great majority of patients with Covid-19, the risk of shedding viable SARS-CoV2 diminishes considerably as the time from onset of symptoms nears 10 days or more, with the risk higher among those who have severe (eg, sp02 <94%)  or critical disease (eg, in need of ICU care) or who are immunocompromised. 1-4  

For patients with mild-moderate illness who are not immunocompromised, the CDC recommends isolation for “at least 10 days” from onset of symptoms as long as at least 24 hours have passed since last fever without the use of fever-reducing medications and symptoms  (eg, cough, shortness of breath) have improved.  For patients with severe to critical illness or who are severely immunocompromised, “at least 10 days” and up to 20 days since onset of symptoms—with qualifications as above— is recommended. 1

A 2021 meta-analysis found that although SARS-CoV-2 RNA shedding in respiratory and stool samples may be prolonged, duration of viable virus was relatively short with no study detecting live virus beyond day 9 of illness.2

In contrast, another study involving patients with severe or critical illness (23% immunocompromised, 2/3 on mechanical ventilation) found  that the median time of infectious virus shedding was 8 days (range 0-20) and concluded that detection of infectious virus was common after 8 days or more since onset of symptoms; the probability of isolating infectious SARS-CoV-2 was  ≤5% when the duration of symptoms was 15.2 days (95% CI 13.4-17.2). In the same study, a single patient had infectious particles for up to 20 days following onset of symptoms. 3

The take home point is that although 10 days of isolation since onset of symptoms should be sufficient for mild to moderate Covid-19, for those with severe or critical disease or immunocompromised state, a longer duration up to 20 days may be needed.  The setting and status of the potential contacts (eg, an immunocompromised person in household setting) should also be considered in our decision making. 4

Bonus Pearl: Did you know that infectious particles are unlikely to be isolated from respiratory tract samples once patients develop a serum neutralizing antibody titer of at least 1:80, potentially useful information in deciding when a patient may come off isolation? 3

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References

  1. Discontinuation of transmission-based precautions and disposition of patients with SARS-CoV-2 infection in healthcare settings. https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html#definitions. Accessed March 24, 2021
  2. Cevik M, Tate M, Lloyd O, et al. Sars-Cov-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe 2021;2:e13-22. https://www.thelancet.com/pdfs/journals/lanmic/PIIS2666-5247(20)30172-5.pdf
  3. Van Kampen JJA, van de Vijver DAMC, Fraaij PLA, et al. Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19). Nature Communications 2021;12:267. https://www.nature.com/articles/s41467-020-20568-4
  4. Kadire SR, Fabre V, Wenzel RP. Doctor, how long should I isolate? NEJM, March 2021 https://www.nejm.org/doi/pdf/10.1056/NEJMclde2100910?articleTools=true

 

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. 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 long should my patient recovering from Covid-19 remain on isolation precautions?

Should I treat my patient with Covid-19 with ivermectin?

FA Manian MD, MPH, , , , , , , , , Leave a comment

Despite its potential antiviral activity,1 there is insufficient data at this time to recommend either for or against the use of ivermectin for the treatment of Covid-19, per NIH Covid-19 guidelines.2 This conclusion is based on lack of robust, adequately powered and designed clinical trials.2  The Infectious Diseases Society of America (IDSA) recommends against its use in ambulatory or hospitalized patients with Covid-19 (mild to moderate or severe, respectively) except in clinical trials.

Although some studies (published or preprint) have reported benefits of ivermectin (eg, shorter time to resolution of disease or viral clearance, greater reduction in inflammatory markers, and lower mortality rates) in Covid-19, others have found either no benefit or worsening of disease with ivermectin therapy.2-6

Unfortunately, methodological problems have plagued many of these studies.1 For example, a randomized-controlled preprint study from Egypt reported clinical improvement and decreased mortality in Covid-19 patients treated with ivermectin.  Noteworthy,  the ivermectin group also received hydroxychloroquine plus a “standard therapy”, defined in the study as azithromycin, vitamin C, zinc, lactoferrin and acetylcysteine.3  This preprint article has since been withdrawn due to allegations of plagiarism and data manipulation, including duplicate patient records and patients whose records indicated that they had died before the study’s start date (Nature, 12 Aug 2021).

A retrospective study from Bangladesh involving hospitalized patients with Covid-19,  reported lower mortality in those receiving only 1 dose of ivermectin (12 mg) within 24 h of admission.  However, 60% of the non-ivermectin group also received antibiotics, often for undefined “secondary infection” (vs 15% of ivermectin group)4, making it difficult to interpret the results.

In contrast, a randomized double-blind trial in mild Covid-19 failed to find any improvement in time to resolution of symptoms  after a 5-day course of Ivermectin. In a retrospective preprint study from Peru found significantly higher rates of death and/or ICU transfer among hospitalized patients treated with ivermectin or hydroxychloroquine+azithromycin.7

The plausibility of studies supporting treatment of Covid-19 with ivermectin has been further questioned because, despite its apparent antiviral activity in vitro,1 pharmacokinetic and pharmacodynamic studies suggest that doses up to 100 times higher than those approved for use in humans would be needed to achieve potentially effective plasma concentrations.2,8

Bonus Pearl: Did you know that ivermectin enhances the activity of GABA receptors, resulting in paralysis of somatic muscles, poor pharyngeal function and starvation of parasites and worms? 9 Fortunately, ivermectin’s affinity for parasite is 100 times more than for brain of mammals because of the blood brain barrier.

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References

  1. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In vivo 2020;34:3023-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652439/pdf/in_vivo-34-3023.pdf
  2. NIH. The Covid-19 treatment guidelines panel’s statement on the use of ivermectin for the treatment of COVID-19. Last updated Jan 14, 2021. https://www.covid19treatmentguidelines.nih.gov/statement-on-ivermectin/. Accessed January 18, 2021.
  3. Elgazzar A, Hany B, Abo Youssef S, et al. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Research Square Preprint 2020. https://assets.researchsquare.com/files/rs-100956/v2/39b225ad-5df4-4da7-9cbd-233bf26a0eb4.pdf
  4. Ahmed S, karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. International J Infect Dis 2021;103:214-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709596/
  5. Soto-Becerra P, Culquichicon C, Hurtado-Roca Y, et al. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru. MedRxive 2020. https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.full.pdf
  6. Chachar AZ, Khan KA, Asif M, et al. Effectiveness of ivermetctin in SARS-CoV-1/COVID-19 patients. International J Sciences 2020; 9:31-35. https://c19ivermectin.com/chachar.html
  7. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolutoin of symptoms among adults with mild COVID-19. JAMA 202;325:1426-35.  https://jamanetwork.com/journals/jama/fullarticle/2777389
  8. Chaccour C, hammann F, Ramon-Garcia S, et al. Ivermectin and COVID-19: Keeping rigor in times of urgency. Am J Trop med hyg 2020;102:1156-7. https://pubmed.ncbi.nlm.nih.gov/32314704/  
  9. Kaur H, Shekhar N, Sharma S, et al. Ivermectin as a potential drug for treatment of COVID-19:an in-sync review with clinical and computational attributes. Pharmacological Reports. Published online January 3, 2021. Great review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778723/pdf/43440_2020_Article_195.pdf

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. 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 I treat my patient with Covid-19 with ivermectin?

Beyond masks and hand hygiene, what factors impact transmission of Covid-19 in indoor gatherings?

FA Manian MD, MPH, , , , , , , , , , , , , , , Leave a comment

Aside from factors specific to the source individual (eg, viral load in exhaled air, “superspreader” features, etc…) and host characteristics (eg, older age, obesity, immunocompromised state), transmission of SARS-CoV-2 in indoor settings may be impacted by several factors, including social distancing, ventilation of rooms/ direction of airflow, room occupancy, exposure time and higher risk activities, such as eating, talking loud, heavy breathing during exercise, laughing, coughing and sneezing. 1-4

  1. Physical distance from infected individuals. Although a “safe” distance of 6 feet has often been cited, increasing evidence suggests that SARS-CoV-2 may be spread not only by larger droplets but also by airborne route (ie, beyond 6 feet or shortly after an infected person leaves the area). In fact, 8 of 10 studies on horizontal droplet distance have reported droplets traveling more than 6 feet (2 meters), some cases up to 26 feet (8 meters), and 1 study documented virus at 13 feet (4 meters). Transmission beyond 6 feet is not surprising since even as early as 1948 beta streptococci were found 9.5 feet from 10% of people who were infected!1
  2. Quality of ventilation and direction of airflow in the room. Poorly ventilated rooms would be expected to have more potentially infectious droplets in the air for longer periods of time, even after an infected person leaves the area.
  3. Room occupancy. The higher the occupancy the more likely to have exhaled contaminated air from 1 or more infected persons (symptomatic or asymptomatic) with exposure of susceptible hosts.
  4. Exposure time. Exposure to contaminated air in the room even for a relatively short period of time (ie, >5-15 minutes) is likely to increase the risk of transmission.
  5. Activity of infected individual. Many activities such as singing, speaking loudly, eating, laughing, breathing heavily during exercise, coughing and sneezing may increase risk of Covid-19 transmission in indoor settings.

Recall that over one-half of Covid-19 transmissions are due to asymptomatic individuals.5 In this setting and in the presence of factors discussed above, it’s easy to see how transmission of Covid-19 in indoor settings can occur readily, possibly explaining cases without apparent source.

Bonus Pearl: Did you know that the odds of Covid-19 transmission may be 18.7 times greater indoors compared to open-air environment and the odds of superspreading event in closed environments may be 32.6 times higher?4

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References

  1. Bahl P, Doolan C, de Silva C, et al. Airborne or droplet precautions for health workers treating coronavirus disease 2019? J Infect Dis 2020. Published online April 16, 2020. https://pubmed.ncbi.nlm.nih.gov/32301491/
  2. Jones NR, Quereshi Z, Temple RJ, et al. Two metres or one: what is the evidence for physical distancing in covid-19? BMJ 2020;370:m3223. https://www.bmj.com/content/370/bmj.m3223/rr-18
  3. Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 transmission from people without COVID-19 symptoms. JAMA Network open. 2021;4():e2035057. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2774707?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=010721
  4. Nishiura H, Oshitani H, Kobayashi T, et al. Closed environments facilitate secondary transmission of coronavirus disease 2019 (COVID-19). MedRxiv 2020. https://www.medrxiv.org/content/10.1101/2020.02.28.20029272v2.full.pdf
  5. Leclerc QJ, Fuller NM, Knight LE,e tal. What settings have been linked to SARS-CoV-2 transmission clusters? Wellcome Open Research October, 2020. https://wellcomeopenresearch.org/articles/5-83    

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. 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!

Beyond masks and hand hygiene, what factors impact transmission of Covid-19 in indoor gatherings?

Is the discovery of new variants of SARS-CoV-2 expected to impact the transmissibility, clinical course or vaccine efficacy in Covid-19?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

To date, the discovery of new variants of SARS-CoV-2 has raised concerns primarily around their association with higher than expected transmission rates, not increased severity, risk of death or impairment in vaccine efficacy. 1-5

The new variants of SARS-CoV-2—first recognized in the U.K (strain B.1.1.7), then South Africa (B.1.351), and now many parts of the world, including US and Canada—seem to be associated with higher rates of transmission without any evidence for more severe disease or hospitalization.3 Based on mathematical models, it is suggested that the new variant may be up to 70% more transmissible than the original virus.1 However, it is important to point out that, to date, there are no published studies that corroborates this finding in laboratory animals and some have questioned whether these new strains are truly more transmissible.1

The B.1.1.7 strain has several mutations involving the spike protein (the surface  protein that attaches to host cells) at least 1 of which (N501Y) seems to improve the virus’s ability to bind to cells.1 Preliminary laboratory studies have also found higher viral replication rates in upper respiratory tract of hamsters when challenged with another SARS-CoV-2 variant with spike protein mutation (D614G) compared to the lungs.4  Both “stickiness” to cells and high replication rates in upper respiratory tract alone may explain more rapid spread of the virus without increased severity of disease.

Preliminary reports also suggest that that antibodies against the original strain  neutralize the B.1.1.7 strain, supporting the efficacy of the current Covid-19 vaccine in protecting against this strain.1

A theoretical concern, however, based on a preprint publication, is the suboptimal binding and neutralization of new strains by commercially available monoclonal antibodies.2

The potential increased transmissibility of new SARS-CoV-2 variants only underscores the importance of public health measure such as masks, social distancing and hand hygiene, now more than ever before!

Bonus Pearl: Did you know that despite lack of clear increase in the severity of disease associated with new variants of SARS-CoV-2, increased rate of transmission will lead to more people getting infected and therefore die from its complications. That’s why, more than ever before, we should double down our efforts to stick to public health measures to mask, social distance and exercise hand hygiene during this critical period of the pandemic. Please spread the word, again!

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References

  1. Reardon S. The U.K. coronavirus mutation is worrying but not terrifying. Scientific American. December 24, 2020. https://www.scientificamerican.com/article/the-u-k-coronavirus-mutation-is-worrying-but-not-terrifying/
  2. Starr TN, Greaney AJ, Addetia A, et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Bio Rxiv 2020. https://www.biorxiv.org/content/10.1101/2020.11.30.405472v1
  3. CDC. Interim: Implications of the emerging SARS-CoV-2 variant VOC 202012/01. Accessed Jan 12, 2020. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-emerging-variant.html
  4. Plante JA, Liu Y, Liu J, et al. Spike mutation D614G alters SARS-CoV-2 fitness. Nature. Published online 26, 2020. https://pubmed.ncbi.nlm.nih.gov/33106671/
  5. Baric RS. Emergence of a highly fit SARS-CoV-2 variant. N Engl J Med 2020; 383;2684-2686. https://www.nejm.org/doi/full/10.1056/NEJMcibr2032888

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. 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 the discovery of new variants of SARS-CoV-2 expected to impact the transmissibility, clinical course or vaccine efficacy in Covid-19?