Influenza

What’s the latest on second Covid vaccine boosters and should I recommend them to my adult patients?

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

On March 29, 2022, the CDC and the FDA approved second booster shots of Pfizer and Moderna Covid vaccines for everyone 50 years of age or older as well as people 12 years of age or older with moderate to severe immune deficiencies to be given at least 4 months following the first booster.1-3  This means a 4th dose of an mRNA vaccine for many adults and a 5th dose for those with moderate to severe immune deficiencies. 

Admittedly, these recommendations are made in the context of many uncertainties, including when the next Covid surge will arrive, what will be the predominant variant, and how will our immunity hold up if a surge occurs. 

Nevertheless, in discussing the merits of a 2nd booster, I would emphasize several “talking points”:

  • Covid hasn’t gone away with new cases still diagnosed daily, some still  requiring hospitalization, albeit at lower frequency than recent past. 
  • Our immunity against Covid wanes in the absence of boosters or natural infection.
  • SARS-CoV-2 has been unpredictable in its surges, as well as emergence of new variants with frequent changes in its virulence and ease of transmission. This means we don’t know when the next surge will hit us (summer, fall or later) and how the predominant variant will behave.
  • But let’s not get too hung up on surges! The fact is that as long as Covid is circulating around, maintaining a robust immunity against infection is the best way to avoid getting infected and the best way to do this is through boosters!
  • As more people go around without masks, the risk of unprotected exposure to SARS-CoV-2 is also likely to increase, particularly in indoor public gatherings.  Boosters may allow us the freedom to go maskless more often!
  • The risk of Long Covid even following mild infection is still real even between surges. This means even if we don’t get very sick from Covid, we are placing ourselves at risk of Long Covid. Remember, no Covid, no Long Covid!
  • Irrespective of whether it’s mild or even asymptomatic, Covid infection  can cause significant disruption in our lives, whether it be isolation at home, not being allowed to return to work or just the anxiety of having it or having passed it to others. This means that, at least currently, it’s premature to consider this virus as “just another respiratory virus.”  It’s impact on our everyday lives is still a lot different than typical respiratory viruses. 
  • mRNA vaccine boosters have been proven to be as safe as primary series. 
  • Last, but not the least, a preprint Israeli study involving volunteers 60 to 100 years old found a 78% reduction in mortality from Covid following a 2nd booster dose of Pfizer mRNA vaccine compared to those who only had 1 booster.4  This study has several limitations including self-selected volunteers who may already be at lower risk of Covid mortality due to their healthier lifestyle. Nevertheless, the data is very encouraging!

Ultimately, the decision to get a second booster, particularly during non-surge periods, will depend a lot on not only available facts but the individual’s threshold for acceptable risk of even mild disease, concern over transmission to others and more recently the cost of the vaccine, among other factors.  

Bonus Pearl: Did you know that each year there are plenty of uncertainties around which influenza A or B subtypes will be the predominant seasonal strain or what month they may surge but these questions never keep us from recommending the annual flu vaccine to the public as a means of reducing influenza cases and saving lives?   

 

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References

  1. D.A. Allows Second Covid Boosters for Everyone 50 and Older – The New York Times (nytimes.com)
  2. Coronavirus (COVID-19) Update: FDA Authorizes Second Booster Dose of Two COVID-19 Vaccines for Older and Immunocompromised Individuals | FDA
  3. CDC Recommends Additional Boosters for Certain Individuals | CDC Online Newsroom | CDC
  4. Arbel R, Sergienko R, Friger M, et al. Second booster vaccine and Covid-19 mortality in adults 60-100 years old. Preprint, posted March 24, 2022. 24514bba-2c9d-4add-9d8f-321f610ed199.pdf (researchsquare.com)

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 latest on second Covid vaccine boosters and should I recommend them to my adult patients?

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?

My elderly patient developed a flare-up of her gout few days after receiving Covid-19 vaccine. Is there a connection between immunization and gout flare?

FA Manian MD, MPH, , , , , , , , , , , , , , , 1 Comment

Although the connection between Covid-19 vaccination and gout flare has yet to be established, higher rates of gout/gout flare following the administration of several other vaccines (eg, influenza, tetatnus, recombinant zoster) have been reported.1  Thus, it is conceivable that Covid-19 vaccine may also be associated with gout flare as more and more people are immunized.  

A 2019 prospective study of over 500 patients with gout found that vaccination was associated with 2-fold higher odds of gout flare (aO.R. 1.99; 95% ci 1.01-3.89) during the 2 day period following immunization; no information on the type of vaccines administered was provided, however.1  Similarly,  higher risk of gout (3.6-fold) has been reported in recipients of recombinant zoster vaccine following immunization.1

An intriguing mechanism explaining the association of vaccination and gout flare is the activation of the Nlrp3 inflammasome, a multiprotein complex produced in response to diverse stimuli such as uric acid crystals and ATP released from tissue injury/necrotic cells.2 Of interest, ~25% of patients with asymptomatic hyperuricemia have been found to have evidence of monosodium urate crystals in and around their joints by advanced imaging, such that vaccination may potentially bring out more inflammatory response and gout flare. 3 

Although aluminum adjuvants intended to increase the immunogenicity of one-half of all routine adult vaccines (eg, tetanus, diphteria, pertussis) have been shown to activate the Nlrp3 inflammasome in vitro, neither currently available mRNA vaccines (Pfizer, Moderna) nor the Johnson&Johnson vaccine contains aluminum as an adjuvant. 4  

Despite the potential for gout flare following adult vaccination, it should be emphasized that the absolute risk is still low and pales compared to the overwhelming benefits of vaccination in general.1

Bonus Pearl: Did you know that, in addition to the usual uric acid lowering drugs, losartan, fenofibrate and some non-steroidal anti-inflammatory drugs, such as indomethacin, also lower serum uric acid levels? 5,6

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References

  1. Yokose C, McCormick N, Chen C, et al. Risk of gout flares after vaccination: a prospective case-crossoverstudy. Ann Rheum Dis 2019;78:1601-1604. https://ard.bmj.com/content/early/2019/07/31/annrheumdis-2019-215724.info?versioned=true
  2. Lyer SS, Pulskens WP, Sadler JJ, et al. Necrotic cells trigger a sterile inflammatory response throught the Nlrp3 inflammasome. PNAS 2009;106:20388-20393. https://pubmed.ncbi.nlm.nih.gov/19918053/
  3. Yokose C, Choi H. Response to “Clarification regarding the statement of the association between the recombinant zoster vaccine (RZV) and gout flares’ by Didierlaurent etal. Ann Rheum Dis Month, December 2019. https://ard.bmj.com/content/annrheumdis/early/2019/12/18/annrheumdis-2019-216670.full.pdf
  4. Covid-19 vaccine information. https://covidvaccine.mo.gov/ Accessed March 16, 2021.
  5. Daskalopoulou SS, Tzovaras V, Mikhailidis DP, et al. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Current Pharmaceutical Design 2005;11:4161-75. https://www.eurekaselect.com/60510/article
  6. Tiitinen S, Nissila M, Ruutsalo HM, et al. Effect of nonsteroidal anti-inflammatory drugs on the renal excretion of uric acid. Clin Rheumatol 1983;2:233-6. https://pubmed.ncbi.nlm.nih.gov/6678696/#:~:text=The%20effect%20of%209%20nonsteroidal,studied%20had%20no%20significant%20influence.

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!

My elderly patient developed a flare-up of her gout few days after receiving Covid-19 vaccine. Is there a connection between immunization and gout flare?

What’s the connection between Covid-19 and persistent fatigue?

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

Fatigue is one of the most common symptoms in patients with Covid-19, both during the acute illness as well during the weeks or months that follows it. Depending on the study, fatigue has been reported in around 30%-80% of patients at 2-3 weeks to 6 months or longer after the onset of illness (1-4).

In a study of hospitalized patients with Covid-19, ~80% of patients complained of fatigue during the acute illness, with ~50% having persistent fatigue at a mean follow-up of 60 days following onset of illness (1). Persistent fatigue was the most common symptom during the post-Covid-19 period, followed by dyspnea, joint pain, chest pain and cough.

In another study, 52.3% of patients with Covid-19 complained of persistent debilitating fatigue at a median of 10 weeks after initial onset of symptoms, despite a negative test for the virus (2). Of interest, there was no association between severity of Covid-19 illness/need for hospitalization and post-covid fatigue.  No association was found between routine laboratory markers of inflammation, WBC profile, LDH, C-reactive protein or interleukin-6 levels and persistent fatigue.

A CDC survey of outpatients with Covid-19 patients at 14-21 days from test date found persistent fatigue in one-third of patients (3).   

A MedRxive study (pending peer review) of over 3700 patients with definite (27%) or probable diagnosis of Covid-19 from 56 countries (>90% not hospitalized) reported fatigue in 78% of patients after 6 months (4).

Although the true nature or course of persistent fatigue following Covid-19 has yet to be clearly defined, In some respects, it’s reminiscent of chronic fatigue syndrome associated with many acute viral infections, such as SARS, EBV, and enteroviruses (5-7).

Bonus pearl: Did you know that persistent fatigue following Covid-19 may be more frequent than that following influenza in which >90% of outpatients recover within about 2 weeks (3)?

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References

  1. Carfi A, Bernabei R, Landi. Persistent symptoms in patients after acute COVID-19.JAMA 2020;324:603-605. https://pubmed.ncbi.nlm.nih.gov/32644129/
  2. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLOS ONE 2020. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240784   
  3. Tenforde MW, Kim SS, Lindsell CJ, et al. Duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March—June 2020. MMWR 2020;69:993-98. https://www.cdc.gov/mmwr/volumes/69/wr/mm6930e1.htm
  4. Davis HE, Assaf GS, MCorkell L, et al. Characterizing long COVID in an international cohort:7 months of symptoms and their impact. MedRxive 2020. https://www.medrxiv.org/content/10.1101/2020.12.24.20248802v2.full.pdf
  5. Chia JKS, Chia AY. Chronic fatigue syndrome is associated with chronic infection of the stomach. Clin Pathol 2008;61:43-48. https://jcp.bmj.com/content/61/1/43
  6. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case control study. BMC Neurol 2011;11:37. https://pubmed.ncbi.nlm.nih.gov/21435231/
  7. Hickie I, Davenport T, Whitfield D, et al. Post-infective and chronic fatigue syndrome precipitated by pathogens: prospective cohort study. BMJ 2006;333:575. https://jcp.bmj.com/content/61/1/43

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

What’s the connection between Covid-19 and persistent fatigue?

How can people with a respiratory virus such as Covid-19 be contagious even when they don’t cough or sneeze?

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

Couple of factors likely play a role in the transmission of respiratory viruses such as Covid-19 even in the absence of respiratory symptoms: 1. Generation of small droplets through everyday activities such as talking and breathing; 2. Presence of infectious virus in the respiratory tract before onset of symptoms.1-4

Small droplet generation during every day activity: Normal human speech and breathing can yield small particles or droplets that are too small to see by naked eye but are perfectly capable of serving as vehicles for aerial transport (more like hot air balloons than 737’s!) of a variety of communicable respiratory pathogens. 1  These small particles are believed to originate from the mucosal layers coating the respiratory tract as well as from vocal cord adduction and vibration within the larynx.1

In some cool experiments involving normal volunteers,1 the rate of particle emission during normal human speech positively correlated with the loudness of voice, ranging from 1-50 particles/second, irrespective of the language spoken (English, Spanish, Mandarin, or Arabic).  Perhaps, equally intriguing was identification of “speech superemitters”, consistently releasing an order of magnitude more particles than other participants.

Simply counting out loud has been associated with around 2-10 times as many total particles emitted as a single cough, 2 and the percentage of airborne droplet nuclei generated by singing is several times more than that emitted during normal talking and more like that of coughing! 3 Given, these observations, perhaps, the unfortunate outbreak of Covid-19 among members of a church choir in state of Washington 5 is not totally unexpected.

Presence of infectious virus in persons without symptoms:  An estimated 18% to 75% of patients testing positive for Covid-19 have no symptoms. This of course means that irrespective of whether symptoms ever develop, persons with Covid-19 may serve as a source of infection, by just breathing, talking, or singing when around susceptible people.

For these reasons, social distancing and wearing of masks during a pandemic makes sense!

Bonus Pearl: Did you know that infectious viral particles can be recovered from 40% of breath samples of patients with influenza? 6

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 References

  1. Asadi S, Wexler AS, Cappa CD, et al. Aerosol emission and superemission during human speech increase with voice loudness. Scientific Reports 2019;9:2348. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382806/
  2. Loudon RG, Roberts RM. Droplet expulsion from the respiratory tract. Am Rev Resp Dis 1967;435-42. https://doi.org/10.1164/arrd.1967.95.3.435
  3. Loudon RG, Roberts MR. Singing and the dissemination of tuberculosis. Am Rev Resp Dis 1968;98:297-300. DOI: 10.1164/arrd.1968.98.2.297 https://www.atsjournals.org/doi/abs/10.1164/arrd.1968.98.2.297?journalCode=arrd
  4. Lai KM, Bottomley C, McNerney. Propagation of respiratory aerosols by the Vuvuzela. PLoS One 2011;6:e20086. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100331/
  5. Read R. A choir decided to go ahead with rehearsal. Now dozens of members have COVID-19 and two are dead. Los Angeles Times March 29, 2020. https://www.latimes.com/world-nation/story/2020-03-29/coronavirus-choir-outbreak
  6. Yan J, Grantham M, Pantelic J, et al. Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community. PNAS 2018;115:1081-1086 https://www.pnas.org/content/115/5/1081

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

How can people with a respiratory virus such as Covid-19 be contagious even when they don’t cough or sneeze?

Does a positive routine PCR test for Covid-19 virus mean the person is infectious?

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

Not necessarily! Although a positive routine PCR test for Covid-19 indicates the presence of the virus in a clinical specimen, it does not mean that the virus is still viable or transmissible, particularly as the patient may be recovering from Covid-19. Viral cultures are often needed to help answer this question. 1-5

In a study of 9 hospitalized patients with Covid-19, no viable Covid-19 virus could be found by culture in any specimen beyond 8 days following onset of symptoms despite a positive routine PCR for up to 13 days. Successful growth of the virus was dependent in part on viral load, with samples containing <106 copies/mL never yielding any viable virus.1  

In the same study, none of stools that were positive for Covid-19 virus by PCR were positive by culture.  The authors concluded that there is “little residual risk of infectivity” beyond day 10 of symptoms when sputum contains less than 100,000 viral RNA copies /ml.  Of note, the patients in this study were young- to middle-aged without significant underlying disease and had milder disease, so the results may not necessarily be generalizable to other patients with Covid-19. 1

The discrepancy between a positive PCR and negative culture has been seen with other respiratory pathogens,  such as respiratory syncytial virus (RSV) and influenza. In a study involving experimentally infected subjects with RSV, the average duration of viral shedding was 9.2 days by PCR compared to 7.2 days by viral culture.2 In another study involving patients with symptomatic influenza, virus could be detected for up to 7 days with PCR compared to 1-2 days by viral culture.3

Factors that may explain this discrepancy include suboptimal sample transport, low viral titers,  and the presence of neutralizing antibody in the clinical specimen.2,3

So, despite our incomplete knowledge, don’t assume that PCR positivity means the presence of live virus capable of transmitting Covid-19!

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References

  1. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-19. Nature 2020; April 1. https://www.nature.com/articles/s41586-020-2196-x
  2. Falsey AR, Formica MA, Treanor JJ, et al. Comparison of quantitative reverse transcriptase-PCR to viral culture for assessment of respiratory syncytial virus shedding. J Clin Microbiol 2003;41:4160-65. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC193781/pdf/0106.pdf
  3. Van Elden LJR, Nijhuis M, Schipper P, et al . Simultaneous detection of influenza viruses A and B using real-time quantitative PCR. J Clin Microbiol 2001;39:196-200. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC87701/
  4. Cangelosi GA, Meschke JS. Dead or alive:molecular assessment of microbial viability. App Environ Microbiol 2014;80:5884-91.
  5. European Centre for Disease Prevention and Control. Novel coronavirus (SARS-CoV-2). https://www.ecdc.europa.eu/en/publications-data/novel-coronavirus-sars-cov-2-discharge-criteria-confirmed-covid-19-cases

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!

 

Does a positive routine PCR test for Covid-19 virus mean the person is infectious?

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

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

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?

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

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

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , 1 Comment

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

Do statins have a role in treating novel Coronavirus infection, COVID-19?

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

There is currently no firm clinical evidence that statins improve the outcome of COVID-19. However, there are some theoretical reasons for believing that statins may have a role in the treatment of COVID-19.  That’s because beyond their cholesterol lowering action, statins may also have clinically relevant anti-inflammatory and antiviral (pleotropic) properties.  

Anti-inflammatory: Anti-inflammatory effect of statins is well known and is thought to occur through a variety of molecular pathways of the innate and adaptive immune systems as well as attenuation of several circulating proinflammatory cytokines.1 Although observational studies have suggested that statins lower hospitalization and mortality among outpatients hospitalized with infection, pneumonia or sepsis, several randomized controlled trials (RCTs) have failed to show any mortality benefit among ICU patients with sepsis and ARDS treated with statins.2

In contrast, an RCT involving patients with sepsis (majority with pneumonia, mean CRP 195 mg/dL) reported significant reduction in progression to severe sepsis among statin-naïve patients  placed on atorvastatin 40 mg/day at the time of hospitalization.3 So, perhaps timing of statin therapy before florid sepsis and ARDS is an important factor.  

Some have suggested that statins may decrease the fatality rate of a related Coronavirus, Middle East Respiratory Syndrome (MERS) virus, by blunting exuberant inflammatory response that may result in a fatal outcome. 4

Antiviral: Statins may also have antiviral properties, including activity against influenza, hepatitis C virus, Zika and dengue viruses.2,5 Whether statins have activity against coronaviruses such as the agent of COVID-19 is unclear at this time.

It’s interesting to note that cholesterol may have an important role in the membrane attachment, fusion and replication of many enveloped viruses, including influenza.5 Covid-19 is also an enveloped virus.

So what do we do? Based on the current data, it makes sense to continue statins in patients who have known clinical indications for their use and no obvious contraindications because of COVID-19 (eg. rhabdomyolysis).6 As for statin-naïve patients, particularly those in early stages of sepsis and increased risk of cardiovascular events, benefit may outweigh the risk.  Only proper clinical studies will give us more definitive answers.

Bonus Pearl: Did you know that lipids make up a major component of the envelope in enveloped viruses and that cholesterol makes up nearly one-half of total lipid and over 10% the total mass of influenza viruses?

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References

  1. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular diseae: The emerging role of statins. J Am Coll Cardiol 2014;63:2491-2502. https://www.sciencedirect.com/science/article/pii/S0735109714011553?via%3Dihub
  2. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124618/pdf/atm-04-21-421.pdf
  3. Patel JM, Snaith C, Thickette DR. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) Critical Care 2012;16:R231. https://ccforum.biomedcentral.com/track/pdf/10.1186/cc11895
  4. Espano E, Nam JH, Song EJ, et al. Lipophilic statins inhibit Zika virus production in Vero cells. Scientific Reports 2019;9:11461. https://www.nature.com/articles/s41598-019-47956-1
  5. Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543-12551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC262566/
  6. Virani SS. Is there a role for statin therapy in acute viral infections. Am Coll Cardiol March 18, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19

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!

Do statins have a role in treating novel Coronavirus infection, COVID-19?