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?

How effective are face masks in reducing transmission of Covid-19?

Overall, review of data to date suggests that face masks are quite effective in reducing the transmission of coronaviruses, including SARS-CoV-2, the cause of Covid-19. A Lancet 2020 meta-analysis involving over 12,000 subjects, found that transmission of coronaviruses (SARS-CoV-2, SARS and MERS) was reduced with face masks by 85% (adjusted O.R. 0.15, 95%CI 0.07-0.34).1

More specific to Covid-19, a study from Mass General Brigham hospitals found a significant drop in healthcare worker (HCW) SARS-CoV-2 PCR positivity rate from 21.3% to 11.5% following adoption of universal masking of HCWs and patients.2

An U.S. epidemiologic survey of 2,930 unique counties plus New York City found mandating face mask use in public was associated with a significant decline in the daily Covid-19 growth rate. 3 It was estimated that more than 200,000 Covid-19 cases were averted by May 22, 2020 as a result of the implementation of these mandates.

Another 2020 meta-analysis involving 21 studies reported an overall efficacy of masks (including surgical and N-95 masks) of 80% in healthcare workers and 47% in non-healthcare workers for respiratory virus transmission (including SARS, SARS-CoV-2 and influenza).4

A criticism of above reports has been their primarily retrospective nature. A randomized-controlled Danish study found a statistically insignificant 20% reduction in incident SARS-CoV-2 infection among mask wearers (5,6).    Despite its randomized-controlled design, this study had several limitations, including relatively low transmission rate in the community and lack of universal mask wearing in public during the study period. In addition, less than one-half of participants in the mask group reported adherence to wearing masks, and there was no assurance that masks were worn correctly when they did wear them. 

At most, this study suggests that it’s not enough for the uninfected to wear masks; the infected—often with little or no symptoms— should also wear them to help curb the pandemic.

So please do your part and tell your friends and family members to do the same by masking up while we are at war with Covid-19!

Bonus Pearl: Did you know that universal wearing of masks in the public in response to a respiratory virus pandemic is nothing new?  It was adopted as far back as 100 years ago during the 1918 Spanish influenza pandemic!

References

  1. Chu DK, Akl EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet 2020;395: 1973-87. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31142-9.pdf
  2. Wang X, Ferro EG, Zhou G, et al. Association between universal masking in a health care system and SARS-CoV-2 positivity among health care workers. JAMA 2020;324:703-4. https://jamanetwork.com/journals/jama/fullarticle/2768533
  3. Lyu W, Wehby GL. Community use of face masks and COVID-19: evidence from a natural experiment of state mandates in the US. Health Affairs 2020;39: July 16. https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2020.00818
  4. Liang M, Gao L, Cheng Ce, et al. Efficacy of face mask in preventing respiratory virus transmission: A systematic review and meta-analysis. Travel Med Infect Dis 2020;36:1-8. https://pubmed.ncbi.nlm.nih.gov/32473312/ 
  5. Bundgaard H, Bundgaard JS, Tadeusz DE, et al. Effectiveness of adding a mask recommendation to other public health measures to prevent SARS-CoV-2 infection in Danish mask wearers. Ann Intern Med 2020; November 18. https://pubmed.ncbi.nlm.nih.gov/33205991/
  6. Frieden TR Cash-Goldwasser S. Of masks and methods. Ann Intern Med 2020; November 18. https://www.acpjournals.org/doi/10.7326/m20-7499

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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 effective are face masks in reducing transmission of Covid-19?

Why is Covid-19 more contagious than SARS or MERS?

From the beginning of the Covid-19 pandemic, it was evident that SARS-CoV2, the agent of Covid-19, was more contagious than other well-known coronaviruses that cause SARS or MERS. Based on a fascinating “shell disorder model, the reason may lie in the “odd” combination of “hardiness” of its membrane protein (M) (outer shell) making it more likely to survive in body fluids and environment, and resilience of its nuclear protein (N) (inner shell) making it more likely to rapidly replicate even before the immune system detects it.1

Outer shell hardiness of the M protein of SARS-CoV2 contributes to its persistence in the environment and resistance to digestive enzymes in saliva, mucus, stool, and other bodily fluids. Inner shell resilience of the N protein can lead to greater virulence through more rapid replication of viral proteins and particles. The latter is also an efficient way of evading the host immune system ie, by the time the immune system finds out there is a problem, the virus has already reproduced in high numbers in the absence of symptoms!

Long before Covid-19 pandemic, a group of scientists proposed categorization of coronaviruses into 3 major “shell disorder” categories (based on the features of the M and N proteins), correlating with their primary modes of transmission. Category A: higher levels of respiratory transmission, lower levels of fecal-oral transmission (eg. HCoV-229E, common cold coronavirus); category B: intermediate levels of respiratory and fecal-oral transmission (eg, SARS-CoV); and category C: lower levels of respiratory transmission with higher levels of fecal-oral transmission (eg, MERS).1,2  

It turns out that Covid-19 falls into category B which means that it has the potential for transmission not only through respiratory route but also through fecal-oral route and the environment. What’s “odd” about SARS-CoV2 though is that it seems to have the hardiest outer shell compared to SARS-CoV and other coronaviruses in its category.

So not only is Covid-19 more likely to be transmitted due to high viral loads in the respiratory tract even before symptoms develop, it may have an advantage over other respiratory coronaviruses by persisting in the environment when contaminated by respiratory secretions, feces or other body fluids.

Truly a “novel” virus!

Bonus Pearl: Did you know that despite being more contagious, Covid-19 is fortunately less fatal than SARS or MERS?

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References

  1. Goh GKM, Dunker AK, Foster JA, Uversy VN. Shell disorder analysis predicts greater resilience of the SARS-CoV-2 (COVID-19) outside the body and in body fluids. Microbial pathogenesis 2020;144:104177. https://pubmed.ncbi.nlm.nih.gov/32244041/
  2. Goh GKM, Dunker AK, Uversky VN. Understanding viral transmission behavior via protein intrinsic disorder prediction: Coronaviruses. J Pathol 2012;2012:738590. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477565/

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!

Why is Covid-19 more contagious than SARS or MERS?

What’s antibody-dependent enhancement and does it play a role in Covid-19?

Antibody-dependent enhancement (ADE) is an intriguing mechanism by which certain antibodies actually enhance viral replication by promoting entry of the pathogen into immune cells (eg, macrophages) resulting in worsening of the infection.1-4 Although these antibodies are pathogen-specific, they are commonly not neutralizing or only sub-neutralizing.4  So aside from not being able to protect the host from infection, they actually help the virus attack host cells!

Fortunately, there is no evidence that ADE contributes to pathogenesis of Covid-19 or SARS. 2,3 In fact, in contrast to the dengue virus, a classic cause of ADE,  SARS-CoV-2 does not seem to target or grow in macrophages; a related coronavirus, SARS-CoV is also unable to grow in macrophages infected through ADE.2,3

ADE was initially proposed as an explanation for severe Covid-19 cases in China.1 More specifically, it was thought that prior infection due to other coronaviruses (eg, common cold, SARS-CoV) in these patients was predisposing them to the development of severe Covid-19 following.   This hypothesis never panned out, however.  

Bonus Pearl: Did you know that in experimental studies, cats and ferrets have been found to be highly susceptible to  SARS-CoV-2, while dogs had low susceptibility and livestock, including pigs and chickens were not susceptible at all? 5

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 References

  1. Francesco N. Is antibody-dependent enhancement playing a role in COVID-19 pathogenesis. Swiss Med Wkly 2020;150:w20249. https://smw.ch/article/doi/smw.2020.20249
  2. Iwasaki A, Yang Y. The potential danger of suboptimal antibody responses in COVID-19. https://www.nature.com/articles/s41577-020-0321-6.pdf
  3. Peeples L. New feature: avoiding pitfalls in thepursuit of a COVID-19 vaccine. PNAS 2020:117:8218-8221. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165470/
  4. Wan Y, Shang J, Sun S, et al. Molecular mechanism for antibody-dependent enhancement of coronavirus entry. J Virol 2020; 94:e02015 https://jvi.asm.org/content/jvi/94/5/e02015-19.full.pdf 
  5. Shi J, Wen Z , Zhong G, et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2.  Science 2020;10.1126/science.abb7015 https://pubmed.ncbi.nlm.nih.gov/32269068/

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!

What’s antibody-dependent enhancement and does it play a role in Covid-19?

Is my patient with Covid-19 immune to future infections due to the same virus?

Since Covid-19 is a new disease, it is unclear if our body’s immune response can protect us from future infections, and if so, for how long.

In a MedRxiv study involving 175 Covid-19 recovered patients (median age 50 y) with mild symptoms, the production of neutralizing antibodies (Nab) varied, with ~30% of patients considered to have “very low level” titers. So at least a subset of patients with mild symptoms may not produce adequate antibodies against Covid-19 despite seemingly uncomplicated recovery.  Whether these patients are at risk of re-infection with Covid-19 virus remains to be seen.1

In a study involving patients with Covid-19 (median age 62 y) of variable severity, the rate of seropositivity at 2-4 weeks was 88% or higher. However, despite development of antibodies against surface spike protein and internal nucleoproteins of SARS-CoV-2, the Covid-19 virus, viral RNA could be detected in the throat samples from a third of patients for 20 days or longer.2

In another study involving mild Covid-19 cases, despite seroconversion after 7 days in 50% of patients and after 14 days in 100% of patients, no rapid decline in pharyngeal viral load was noted. These findings raised doubts about the role of antibodies in clearing the virus.3

Somewhat more encouraging is the finding that experimentally infected monkeys rechallenged with Covid-19 virus after full recovery 28 days following initial infection seem to be protected against Covid-19.4 So there may be some protection for couple of weeks at least! 

Ultimately, whether immunity to Covid-19 will be like seasonal coronaviruses that cause common colds with unpredictable protection after 1 year, or more similar to that of SARS virus with persistence of antibodies for ~2-3 years, only time will tell. 4,5

Stay tuned!

 

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References

  1. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. MedRxiv preprint doi: https://doi.org/10.1101/2020.03.30.20047365
  2. To KKW, Tsang OWTY, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet 2020; March 23. https://doi.org/10.1016/S1473-3099 (20)30196-1
  3. Wolfel R, Corman VM, Gugggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature https://doi.org/10.1038/s42586-020-2196-x (2020) .
  4. Bao L, Deng W, Gao H, et al. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv doi: https://dli.org/10.1101/2020.03.13.990226.
  5. Callow KA, Parry HF, Sergeant M. et al. The time course of the immune response to experimental coronavirus infection of man. Epidemiol Infect 1990;105:435-46. https://www.ncbi.nlm.nih.gov/pubmed/2170159
  6. McKenna S. What immunity to COVID-19 really means? Scientific American, April 10, 2020. https://www.scientificamerican.com/article/what-immunity-to-covid-19-really-means/

 

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!

Is my patient with Covid-19 immune to future infections due to the same virus?

What’s the evidence that people without symptoms can transmit Covid-19 to those around them?

Rapid spread of Covid-19 virus has been attributed in large part to its ease of transmission from person to person even before symptoms develop, particularly since an estimated 18% to 75% of patients testing positive for Covid-19 have no symptoms. 1-4

Transmission before onset of symptoms (presymptomatic): Modeled estimates for the percentage of transmissions that occur from presymptomatic patients range from 37% to as high as 62% based on studies of patients in the cities of Tianjin and Guangzhou in China, as well as Singapore.5-7 Infectiousness appears to begin within 1-3 days prior to symptoms.8-10

Transmission when symptoms never develop (asymptomatic): Asymptomatic transmission was invoked in a familial cluster in Anyang, China where 5 patients developed Covid-19 after a 6th asymptomatic family member returned home from Wuhan, China. The asymptomatic patient never developed symptoms—such as fever or respiratory symptom— and had a normal chest CT, but briefly tested positive for Covid-19 by RT-PCR before testing negative later.11

It’s important to point out that up to ~75% of patients who are initially “asymptomatic” later develop symptoms. 12-14 So what we often call “asymptomatic” may actually be “presymptomatic.”

Transmission of Covid-19 before onset of symptoms is in distinct contrast to SARS, another coronavirus disease, which was transmitted only when a person was symptomatic and was easier to control. This unique property among coronaviruses may be explained by the high tropism of Covid-19 virus not only for the lungs (as in case of SARS virus) but also for the upper respiratory tract.15,16 As such, Covid-19 behaves more like influenza viruses whose upper respiratory tract binding is thought to promote their rapid transmission even before symptoms develop.17  No wonder, Covid-19 spread like wild fire!

 

Coauthor, Bruce Tiu, Harvard Medical Student, Boston, MA

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References

 

  1. Mizumoto K, Kagaya K, Zarebski A, et al. Estimating the asymptomatic proportion of coronavirus diseae 2019 (COID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill.2020;25(10):pii=2000180 https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.10.2000180?ftag=MSF0951a18
  2. Kimaball, A, Hatfield KM, Arons M, et al. Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing facility—King County, Washington, March 2020. MMWR 2020;69:377-381. https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm
  3. Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci 2020 Mar 4. https://www.ncbi.nlm.nih.gov/pubmed/32146694
  4. Day M. Covid-19: identifying and isolating asymptomatic people helped eliminate virus in Italian village. BMJ 2020;368 https://www.bmj.com/content/368/bmj.m1165
  5. He X, Lau E, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.15.20036707v2
  6. Ferretti L, Wymant C, Kendall M, et al. Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing [published online ahead of print, 2020 Mar 31]. Science. 2020; eabb6936. https://science.sciencemag.org/content/early/2020/03/30/science.abb6936
  7. Ganyani T, Kremer C, Chen D, et al. Estimating the generation interval for COVID-19 based on symptom onset data. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.05.20031815v1
  8. Wei WE, Li ZB, Chiew CJ, et al. Presymptomatic transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 1 April 2020. https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e1.htm
  9. He X, Lau E, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.15.20036707v2
  10. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med. 2020;382(10):970–971. https://www.nejm.org/doi/full/10.1056/NEJMc2001468
  11. Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19 [published online ahead of print, 2020 Feb 21]. JAMA. 2020;e202565. https://jamanetwork.com/journals/jama/fullarticle/2762028
  12. Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility — King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69:377–381 https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm
  13. Chen, C. “What We Need to Understand About Asymptomatic Carriers if We’re Going to Beat Coronavirus”. ProPublica. 2020. https://www.propublica.org/article/what-we-need-to-understand-about-asymptomatic-carriers-if-were-going-to-beat-coronavirus
  14. WHO. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 2020. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
  15. Woelfel R, Corman VM, Guggemos W, et al. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.05.20030502v1
  16. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361(9371):1767–1772. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)13412-5/fulltext
  17. van Riel D, den Bakker MA, Leijten LM, et al. Seasonal and pandemic human influenza viruses attach better to human upper respiratory tract epithelium than avian influenza viruses. Am J Pathol. 2010;176(4):1614–1618. https://wwwnc.cdc.gov/eid/article/26/6/20-0357_article

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!

What’s the evidence that people without symptoms can transmit Covid-19 to those around them?

Why might convalescent sera or plasma transfusion therapy be effective in the treatment of patients with Covid-19?

Of the myriad therapeutic approaches currently under consideration in our fight against Covid-19, convalescent sera/plasma therapy (CSPT) is particularly promising. The principle behind CSPT is to provide immediate immunity to susceptible people by administering the serum or plasma—therefore antibodies—of individuals who have successfully recovered from Covid-19.1

The theory behind using antibody-containing blood products to treat infections is by no means new and goes back to the 1890s when serum from exposed animals who recovered from disease was used to protect healthy animals against tetanus and diphtheria.2

Historically, CSPT has been used against poliomyelitis, measles, mumps, and influenza, and more recently in a smaller number of patients with SARS, H5N1 and H7N9 avian influenza and Ebola.1,3-8 A 2015 systematic review and exploratory meta-analysis of 32 studies involving severe acute respiratory infections of viral etiology (including influenza and SARS) found a reduction in mortality (odds ratio, 0.25, 95% C.I. 0.14-0.45), particularly when CSPT was administered early into the illness.3

Experience with 1918 Spanish influenza pandemic: A meta-analysis of 1703 hospitalized patients (Yes, scientists performed wonderful studies back then too despite a pandemic!) during the 1918 Spanish influenza pandemic demonstrated decreased mortality with administration of convalescent blood products with crude case-fatality rates dropping by one-half (16% vs 37% in controls)! Notably, patients who were treated within 4 days of pneumonia had one-third the case-fatality rate compared to those treated later.3

Experience with 2002-2004 SARS epidemic: A retrospective study from Hong Kong involving 80 patients with SARS (caused by another coronavirus, SARS-CoV-1) not responding to antibiotics/steroids/interferon but receiving CSPT reported a lower mortality rate with near significant (P=0.08) improvement in outcome and reduced mortality in the group that received CSPT before day 14 of the illness (6.3% vs 21.9%).4

What about Covid-19? A very preliminary report out of China involving 5 mechanically-ventilated patients with ARDS and rapid progression despite corticosteroids and antivirals found clinical improvement in all 5 patients. More specifically, body temperature normalized within 3 days in 4 of 5 patients and ARDS resolved in 4 patients at 12 days following transfusion, 2 patients were in stable condition and 3 patients were eventually discharged from the hospital.9

Of course, we should be mindful of potential adverse reactions due to CSP as well, such as allergic reactions, infections, transfusion-related acute lung injury (TRALI), and theoretical risk of antibody-dependent enhancement of infection (ADE).1 Only properly designed clinical studies can shed light on the safety and efficacy of CSPT in Covid-19.

Nevertheless, the historical data on the use of CSPT in serious viral infections is encouraging. In fact, the first US studies of CSPT in Covid-19 have already been approved by the FDA!10 Stay tuned!

Bonus pearl: Did you know that serum and plasma both refer to the noncellular fluid part of blood, but serum is collected after coagulation factors (fibrinogen) have been removed. Fortunately, both contain antibodies!

 

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Contributed by Bruce Tiu, Harvard Medical Student, Boston, MA.

References:

  1. Casadevall A, Pirofski L. The convalescent sera for containing COVID-19. J Clin Invest. 2020;130(4):1545-1548. doi: 10.1172/JCI138003 https://www.jci.org/articles/view/138003
  2. Eibl MM. History of immunoglobulin replacement. Immunol Allergy Clin North Am. 2008;28(4):737–viii. doi:10.1016/j.iac.2008.06.004 https://www.sciencedirect.com/science/article/abs/pii/S0889856108000702
  3. Mair-Jenkins J, Saavedra-Campos M, Baillie K, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. J Infect Dis 2015; 211: 80-90. https://academic.oup.com/jid/article/211/1/80/799341
  4. Luke TC, Kilbane EM, Jackson JL, et al. Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment?. Ann Intern Med. 2006;145:599–609. doi: 10.7326/0003-4819-145-8-200610170-00139 https://annals.org/aim/article-abstract/729754/meta-analysis-convalescent-blood-products-spanish-influenza-pneumonia-future-h5n1
  5. Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44–46. doi:10.1007/s10096-004-1271-9 https://link.springer.com/article/10.1007/s10096-004-1271-9
  6. Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007;357:1450–1. doi: 10.1056/NEJMc070359 https://www.nejm.org/doi/full/10.1056/NEJMc070359
  7. Chen L, Xiong J, Bao L, et al. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis 2020;20: 398-400. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30141-9/fulltext
  8. Wu XX, Gao HN, Wu HB, Peng XM, Ou HL, Li LJ. Successful treatment of avian-origin influenza A (H7N9) infection using convalescent plasma. Int J Infect Dis. 2015;41:3–5. doi: 10.1016/j.ijid.2015.10.009 https://www.ncbi.nlm.nih.gov/pubmed/26482389
  9. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783 https://jamanetwork.com/journals/jama/fullarticle/2763983
  10. https://thehill.com/regulation/healthcare/490768-first-us-coronavirus-patients-being-treated-with-plasma-therapy.

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!

 

 

 

 

Why might convalescent sera or plasma transfusion therapy be effective in the treatment of patients with Covid-19?

5 Covid-19 facts worth keeping in mind as we deal with our pandemic anxiety

As an infectious disease physician who had the privilege of caring for many patients during the unsettling times of the early HIV epidemic and the more recent H1N1 pandemic influenza, I fully understand the widespread anxiety the current Covid-19 pandemic has inflicted on our society.

Here are 5 scientific facts that may be worth remembering as we try to deal with our pandemic anxiety.

 
1. On transmission in the community: For sure, Covid-19 is transmitted in the community but I am glad that it behaves more like influenza which is primarily contracted through close personal contact and droplets, and less like measles or chickenpox which are considered airborne with viral particles travelling lingering in the air for long periods of time. On average, a patient with Covid-19 may infect 2-3 susceptible contacts vs as many as 12 or more in the case of patients with measles or chickenpox (1, 2).

 
2. On transmission in healthcare settings: For sure, Covid-19 can be transmitted in the healthcare settings, just like other coronaviruses, such severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) coronaviruses. But the good news is that, in the absence of aerosol-producing procedures (eg, intubation, nebulizer therapy) it doesn’t seem to behave like an airborne virus (see above) and adherence to droplet and contact precautions, including donning of masks, gowns, eye protection and hand hygiene has been effective (3, 4).

 
3. On surface viability after cleaning/disinfection: For sure, the novel 2019 coronavirus SARS-CoV-2, the cause of Covid-19, can be found on surfaces outside of the body. But the good news is that, in contrast to hardy viruses such as norovirus, it succumbs to common disinfection and environmental cleaning procedures. That’s because  coronaviruses have a lipid envelope that easily falls apart under usual cleaning and disinfection of surfaces. That means that simple handwashing with soap and water (minimum 20 seconds), alcohol containing hand hygiene products, detergents and diluted bleach should easily inactivate it (5-9) and that’s good!

 
4. On the course of Covid-19: For sure, Covid-19 can make people very sick and, tragically, may be fatal on occasion. But compared to diseases caused by other recent respiratory coronaviruses such as MERS or SARS, the overall mortality associated with Covid-19 is much lower (often ~ 2.0-3.0% or lower vs 36.0% for MERS and ~10.0% for SARS) (1). In fact, the majority of patients (~80%) may have no symptoms or only have mild disease (10). I am thankful that we are not dealing with a transmissible respiratory virus that has mortality rates like that of MERS.

 
5. On the timing of this pandemic: We are fortunate that this is 2020 not 1918-19 when a particularly virulent form of influenza, dubbed as “the mother of all pandemics” infected some 500 million people (a third of the world’s population at the time) and accounted for an estimated 50 million deaths (11). Imagine fighting a pandemic without the technology to identify its cause. Imagine fighting a pandemic without access to the miracles of modern science and medicine, including antibiotics for secondary bacterial pneumonia, artificial ventilation, dialysis, ICU support, and capability to screen for an infectious agent.  Imagine fighting a pandemic without scientific tools to develop effective antimicrobials or vaccines. Imagine fighting a pandemic without the luxury of the internet.

 
As unprepared as we all feel in combatting Covid-19, I take solace in the fact that our armamentarium and collective determination to mount an effective response to this pandemic has never been better. Even during these uncertain times, I reflect on what could have been and remain optimistic. Be safe!

 

 

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References:
1. Fauci AS, Lane HC, Redfield RR. Covid-19—Navigating the uncharted. N Eng J Med 2020. DOI:10.1056/NEJMe2002387. https://www.nejm.org/doi/full/10.1056/NEJMe2002387
2. Delamater PL, Street EJ, Leslie TF, et al. Complexity of the basic reproduction number (R0). Emerg infect Dis 2019;25:1-4. https://wwwnc.cdc.gov/eid/article/25/1/17-1901_article
3. Seto WH, Tsang D, Yung RWH, et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS). Lancet 2003;361:1519-20. https://www.sciencedirect.com/science/article/pii/S0140673603131686
4. Ng K, Poon BH, Puar THK, et al. COVID-19 and the risk to health care workers: a case report. Ann Intern Med. 2020, March 16. https://annals.org/aim/fullarticle/2763329/covid-19-risk-health-care-workers-case-report
5. van Doremalen N, Bushmaker, Morris DH, et al. Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1. N Engl J Med 2020. https://doi.org/10.1101/2020.03.09.20033217
6. Kampf G. Efficacy of ethanol against viruses in hand disinfection. J Hosp Infect 2018;98:331-38. https://www.sciencedirect.com/science/article/pii/S0195670117304693
7. Grayson ML, Melvani S, Druce J, et al. Efficacy of soap and water and alcohol-based hand-rub preparations against live H1N1 influenza virus on the hands of human volunteers Clin Infect Dis 2009;48:285-91. https://www.ncbi.nlm.nih.gov/pubmed/19115974/
8. Service RF. Does disinfecting surfaces really prevent the spread of coronavirus? Science 2020, March 12. https://www.sciencemag.org/news/2020/03/does-disinfecting-surfaces-really-prevent-spread-coronavirus
9. CDC. Norovirus. https://www.cdc.gov/vitalsigns/norovirus/index.html
10. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020. First published Feb 28, 220, last updated March 6, 2020. https://www.nejm.org/doi/10.1056/NEJMoa2002032
11. Taubenberger JK, Morens DM. 1918 influenza: the mother of all pandemics. Emerg Infect Dis 2006;12:15-22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291398/

 

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!

 

 

5 Covid-19 facts worth keeping in mind as we deal with our pandemic anxiety

Should I continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?

The original reports of an association between hypertension and increased risk of mortality in hospitalized patients with Covid-19 infection raised concern over the potential deleterious role of ACEIs or ARBs in such patients.1-4 However, as stated by a joint statement of several cardiology societies, including the American Heart Association, American College of Cardiology and the European Society of Cardiology on March 13, 2020, there is no clinical or scientific evidence that ACEI or ARBS should be routinely discontinued in patients with Covid-19 infection.5

In fact, some have argued for the opposite ie, consideration for the use of ARBs, such as losartan (an angiotensin receptor 1 [AT1R] antagonist), in patients with Covid-19.6,7  Although it is true that Covid-19 appears to use ACE2 as a binding site to infect cells (just as in SARS) and that ACE2 may be upregulated in patients on chronic ACEI or ARBs,8,9 ACE2 may also potentially protect against severe lung injury associated with infections.10,11  

Two complementary mechanisms have been posited for the potential protective effect of ARBs in Covid-19 infection-related lung injury: 1. Blocking the excessive AT1R activation caused by the viral infection; and 2. Upregulation of ACE2, thereby reducing production of angiotensin II and increasing the production of the vasodilator angiotensin 1-7.7

In the absence of proper clinical studies, it is premature, however, to recommend use of losartan or other AT1R antagonists as a means of reducing the likelihood of ARDS in patients with Covid-19 at this time.

Bonus Pearl: Did you know that ARDS is a major cause of death in Covid-19 infection?12

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References

  1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020, March 6. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032?articleTools=true
  2. O’Mara GJ. Could ACE inhibitors, and particularly ARBs, increase susceptibility to COVID-19 infection? BMJ 2020;368:m406 ARTICLE
  3. Sommerstein R, Grani C. Preventing a Covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ2020;368:m810. https://www.bmj.com/content/368/bmj.m810/rr-2
  4. Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis 2020, doi htps://doi.org/10.106/j.jpha.2020.03.001. https://www.sciencedirect.com/science/article/pii/S2095177920302045
  5. Cardiology societies recommend patients taking ACE inhibitors, ARBs who contract COVID-19 should continue treatment. March 17, 2020. https://www.healio.com/cardiology/vascular-medicine/news/online/%7Bfe7f0842-aecb-417b-9ecf-3fe7e0ddd991%7D/cardiology-societies-recommend-patients-taking-ace-inhibitors-arbs-who-contract-covid-19-should-continue-treatment
  6. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020;1-4. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  7. Phadke M, Saunik S. Response to the emerging novel coronavirus outbreak. BMJ 2020;368:m406. https://www.bmj.com/content/368/bmj.m406/rr-2
  8. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nature Reviews/Cardiology 2020; https://doi.org/10.1038/s41569-020-0360-5 .
  9. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111:2605-2610. https://www.ahajournals.org/doi/full/10.1161/circulationaha.104.510461
  10. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Medicine 2005;11:875-79. Doi:10.1038/nm1267 https://www.nature.com/articles/nm1267?v=1
  11. Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. International Journal of Peptides. Volume 2012, Article ID 256294, 8 pages. Doi:10.1155/2012/256294. https://research.monash.edu/en/publications/angiotensin-converting-enzyme-2-ace2-is-a-key-modulator-of-the-re

12 . Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. https://doi.org/10.1016/S0140-6736(20)30183-5

 

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!

Should I continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?

What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?

There are currently no drugs specifically approved for treatment of Covid-19 infections. However, there are legions of therapies that are being considered, tried, and/or evaluated in clinical trials. Many experts believe a combination of drugs may be necessary for optimal therapy. Here is my select list of potentially promising drugs from gleaning the literature and online resources to date.1-16

  • Remdisivir: A broad spectrum investigational nucleoside analogue, originally developed to treat a variety of viruses, including Ebola, SARS and MERS. Active in vitro against Covid-19. Favorable results have been reported in some cases, including the first reported patient in the U.S.
  • Chloroquine: An old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. Has also been found to be active in mice against a variety of viruses, including certain enteroviruses, Zika virus, influenza A H5N1.  Active in vitro against Covid-19, though hydroxychloroquine may be more effective. Evidence for its efficacy in treating acute viral infections in humans is currently lacking.
  • Lopinavir/ritonavir: Protease inhibitor combo used in HIV infection with possibly some benefit in the treatment of SARS. Recent study showed no significant efficacy in severe Covid-19 disease. 
  • Interferon-alpha: An antiviral cytokine used against hepatitis B and C viruses. May be more effective for prophylaxis than post-exposure, based on experimental animal studies involving SARS.
  • Ribavirin: Another nucleoside analogue approved for hepatitis C (in combination with other drugs) and respiratory syncytial virus (RSV) infections but also evaluated in SARS and MERS. Has been reported to be active in vitro against Covid-19.
  • Sofosbuvir: Inhibits RNA-dependent RNA polymerase. Approved for treatment of hepatitis C, but also with in vitro activity against Covid-19.
  • Tocilizumab: Anti-interleukin-6 monoclonal antibody used in rheumatoid and giant cell arthritis. Theoretically, may mitigate cytokine storm observed in some patients during the later stages of Covid-19 disease.

Of course, there are many more drugs some of which would not be expected to be effective against Covid-19, based on what we so far know this virus. These include darunavir/cobicistat, oseltamivir, immunoglobulins, arbidol (an antiviral used in Russia and China vs influenza), angiotensin receptor blockers, stem cell therapy, convalescent plasma, and traditional Chinese medicine.

Remember corticosteroids are currently not recommended in the absence of other indications for their use (see related PEARL).

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References

  1. US National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=2019nCoV&term=&cntry=&state=&city=&dist
  2. Li Guangdi, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery 2020; Feb 19, 2010. https://www.nature.com/articles/d41573-020-00016-0
  3. Harrison C. Coronavirus puts drug repurposing on the fast track. Nature Biotechnology 020, Feb 27. https://www.nature.com/articles/d41587-020-00003-1
  4. Velavan TP, Meyer CG. The COVID-19 epidemic. Tropical Medicine and International Health 2020;25:278-280. https://onlinelibrary.wiley.com/doi/full/10.1111/tmi.13383
  5. Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sciences 2020;248. 11747. https://www.sciencedirect.com/science/article/pii/S0024320520302253
  6. Wang Y, Wang Y, Chen Y, et al. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020;March 5. https://www.ncbi.nlm.nih.gov/pubmed/32134116
  7. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2029 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://www.ncbi.nlm.nih.gov/pubmed/31986264
  8. Paules CI, Marston HD, Fauci AS. Coronavirus infections—More than just the common cold. JAMA 2020;323:707-78. https://jamanetwork.com/journals/jama/fullarticle/2759815
  9. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.sciencedirect.com/science/article/pii/S0166354220301145
  10. Gurwitz D. Angiotensin receptor blockers as tentavie SARS-CoV-2 therapeutics. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  11. Wang M, Cao R, Zhang L, et al. Remdesivir and chlorquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020;30:269-71. https://www.nature.com/articles/s41422-020-0282-0
  12. Roques P, Thiberville SD, Dupuis-Maguirara L, et al. Paradoxical effect of chloroquine treatment in enhancing Chikungunya virus infection. Viruses 2018;10, 268. https://www.ncbi.nlm.nih.gov/pubmed/29772762
  13. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020;March 3. https://jamanetwork.com/journals/jama/fullarticle/2762688
  14. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; March 5. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  15. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020. March 9. https://www.ncbi.nlm.nih.gov/pubmed?term=32150618
  16. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl M Med 2020, March18. DOI:10.1056/NEJMoa2001282. https://www.nejm.org/doi/full/10.1056/NEJMoa2001282

 

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!

What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?