What’s the role of small droplets or aerosolized particles in the transmission of Covid-19?

Although transmission of SARS-CoV-2 is often considered to occur through large respiratory droplets by coughing or sneezing, emerging data suggests that smaller respiratory particles (5 microns or less) generated by breathing, speaking or singing also account for a sizeable number of infections. Several lines of evidence make a cogent argument for aerosols serving as an important mode of transmission for SARS-CoV-2. 1-9

 First, there are ample accounts of SARS-CoV-2 spreading by being near an infected individual without symptoms.  Since by definition, those without symptoms do not cough or sneeze transmission must have occurred through other means, including breathing, talking or touching surfaces that might have become secondarily contaminated through aerosol.1,2,5  To make matters worse, the peak of contagion in infected individuals occurs on or before symptoms occur.1

Second, aerosolized SARS-CoV-2 has been shown to remain viable in the air for at least 3 hours and viral RNA (not necessarily viable virus) has been found in the air outside patient rooms and inside patient rooms in the absence of cough.2,9 One study found SARS-CoV-2 in outdoor air at a hospital entrance and in front of a department store.7

Third, contaminated air samples and long-range aerosol transport and transmission have been reported by several studies involving a related coronavirus, SARS-CoV-1, the agent of SARS.2

What’s the ramifications of aerosol transmission of Covid-19? The most obvious is the requirement for universal wearing of masks or face covers in public spaces even when 6 feet apart. This practice is particularly important indoors where the amount of ventilation, number of people, duration of stay in the facility, and airflow direction may impact the risk of exposure to SARS-CoV-2.1

The other potential ramification of aerosolized SARS-CoV-2 is that due to their smaller size, these virus-laden particles may bypass the upper respiratory tract and be inhaled directly into the lungs resulting in more severe disease.4  So it really makes sense to routinely wear a mask when out in public places.

Bonus Pearl: Did you know that 1 minute of loud speaking could generate over 1000 virus-containing aerosols in the air with a “super-emitter” generating over 100,000 virus particles in their droplets during the same time?1

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

 References

  1. Prather KA, Wang CC, Schooley RT. Reducing transmission of SARS-CoV-2. Science. May 27, 2020.
  2. Anderson EL, Turnham P, Griffin JR, et al. Consideration of the aerosol transmission for COVID-19 and public health. Risk Analysis 2020;40:902-7.
  3. Hamner L, Dubbel P, Capron I, et al. High SARS-CoV-2 attack rate following exposure at a choir practice-Skagit County, Washington, March 2020. MMWR 2020; 69: 606-10.
  4. Gralton J, Tovey E, McLaws ML, et al. The role of particle size in aerosolized pathogen transmission: a review. J Infect 2011;62:1-13.
  5. Asadi S, Bouvier N, Wexler AS et al. The coronavirus pandemic and aerosols: does COVID-19 transmit via expiratory particles. Aerosol Sci Technol 2020;54:635-38.
  6. Morawska L, Cao J. Airborne transmission of SARS-CoV-2: the world should face the reality. Env International 2020;139:105730.
  7. Liu Y, Ning Z, Chen Y, e al. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature 2020;582:557-60. https://www.nature.com/articles/s41586-020-2271-3.pdf
  8. Somsen GA, van Rijn C, Kooij S, et al. Small droplet aerosols in poorly ventilated spaces and SARS-CoV-2 transmission. Lancet Respir Med 2020; May 27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255254/pdf/main.pdf

9. Santarpia JL, Rivera DN, Herrera V, et al. Transmission potential of SARS-CoV-2 in viral shedding observed at the University of Nebraska Medical Center. 2020 (Preprint) https://www.ehs.ucsb.edu/files/docs/bs/Transmission_potential_of_SARS-CoV-2.pdf

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 role of small droplets or aerosolized particles in the transmission of Covid-19?

How does Covid-19 affect pregnancy?

We still have a long ways to go before fully understanding the potential effects of Covid-19 on pregnant women and their infants but based on data to date the disease severity seems similar to that of non-pregnant people and vertical transmission seems rare.

 
In one of the larger studies involving 158 obstetric patients with Covid-19 from New York City, ~80% had mild or asymptomatic disease with the rest manifesting moderate or severe disease (1). Cough and fever were common symptoms in both groups. Women with moderate/severe disease were more likely to have comorbidities (eg, asthma) and were also more likely to have dyspnea and chest pain/pressure. Other symptoms included muscle aches, sore throat, congestion, headache, diarrhea, nausea and loss of taste or smell. Two women had pre-term delivery because of clinical status deterioration; there were no reported deaths. The generally favorable course of Covid-19 among pregnant women has been supported by other studies (2,3,4).

 
To date, vertical transmission of SARS-CoV-2, the agent of Covid-19 appears rare (2,3,5,6). In one review, only 1 of 75 newborns tested for SARS-CoV-2 infection were positive; this infant did well clinically but had transient lymphocytopenia and abnormal liver function tests (2). A systematic review found no evidence of intrauterine transmission of SARS-CoV-2 (6).

 
Transmission of SARS-CoV-2 during the first trimester may be unlikely because of expression of ACE2 (a receptor for the virus) in the trophoblasts is very low between 6-14 weeks (7). In a small study examining placenta and fetal membranes in Covid-19 women, 3/11 samples were positive for SARS-CoV-2 but none of the infants tested positive on day 1-5 of life or demonstrated symptoms of Covid-19 (8).

 
Although another source of perinatal infection is exposure to mother’s secretions during vaginal delivery, so far presence of SARS-CoV-2 in vaginal secretions has not been reported (8). Also encouraging is a study of 18 infants born of women testing positive for SARS-CoV-2, all of whom had normal APGAR scores, with the majority (>80%) testing negative (3).

 
So overall, the major threat of Covid-19 to the fetus appears to be the severity of illness in the mother. Pregnant women should be familiar with the early symptoms of Covid-19 and seek medical care as soon as possible.

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References
1. Andrikopoulou M, Madden N, Wen T, et al. Symptoms and critical illness among obstetric patients with coronavirus disease 2019 (COVID-19) infection. OB GYN 2020 https://pubmed.ncbi.nlm.nih.gov/32459701/
2. Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies. Acta Obstet Gynecol Scand 2020;00:1-7. https://pubmed.ncbi.nlm.nih.gov/32259279/
3. Breslin N, Baptiste C, Gyamfi-Bannerman C, et al. Coronavirus disease 2019 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals. Am J Obstet Gynecol MFM 2020;100118. https://www.sciencedirect.com/science/article/pii/S2589933320300483
4. Chen L, Li Q, Zheng D, et al. Clinical characteristics of pregnant women with Covid-19 in Wuhan, China. N Engl J Med 2020, April 17. https://www.nejm.org/doi/full/10.1056/NEJMc2009226?af=R&rss=currentIssue
5. Di Mascio D, Khalil A, Saccone G, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis. Am J OB GYN 2020. https://www.sciencedirect.com/science/article/pii/S0002937820305585
6. Yang Z, Liu Y. Vertical transmission of severe acute respiratory syndrome coronavirus 2: A systematic review. Am J Perinatol 2020;10.1055/s-0040-1712161. https://pubmed.ncbi.nlm.nih.gov/32403141/
7. Amouroux A, Attie-Bitach, Martinovic J, et al. Evidence for and against vertical transmission for SARS-CoV-2 (COVID-19). Am J OB GYN 2020. https://www.sciencedirect.com/science/article/pii/S000293782030524X
8. Penfield CA, Brubaker SG, Lighter J. Detection of severe acute respiratory syndrome coronavirus 2 in placental and fetal membrane samples. Am J OB GYN MFM 2020. https://pubmed.ncbi.nlm.nih.gov/32391518/

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 does Covid-19 affect pregnancy?

What’s the connection between elevated troponins and Covid-19?

Elevated cardiac troponins or myocardial injury (defined as troponin levels above the 99th percentile upper reference range) are not uncommon in Covid-19, having been reported in ~10-30% of hospitalized patient and usually observed in the absence of acute coronary syndrome (ACS) (1-4).

 
Elevated troponins have been associated with increased risk of in-hospital mortality in Covid-19. The prevalence of elevated troponins among patients who died was 76% compared to 10% among survivors in 1 Chinese study (3). Another study from China found increasing troponin levels over a 22 day period among those who died while troponin levels remained low in those who survived (5).

 
Risk factors for elevated troponins in Covid-19 include older age, cardiovascular comorbidities (eg, hypertension, coronary heart disease, heart failure), diabetes, chronic obstructive pulmonary disease, chronic renal failure, and the presence of a high inflammatory state, as indicated by elevated inflammatory markers such as C-reactive protein (CRP) (3).

 
Several mechanisms have been proposed to explain elevated troponins in Covid-19, including cytokine-induced myocardial injury, microangiopathy due to prothrombotic state, myocardial infarction (type I due to plaque rupture or type II due to oxygen supply/demand imbalance), and myocarditis either due to direct viral invasion or indirectly through immune-mediated mechanisms (1,2).

 
Patients with Covid-19 and modest troponin elevation with rapid fall in the absence of signs or symptoms of ACS, may have type II myocardial infarction due to demand ischemia, particularly in the setting of coronary disease. In contrast, more protracted elevation of troponins associated with high inflammatory markers such as CRP is suggestive of hyperinflammatory myocardial injury (1).

 

It will be interesting to see if trials of anti-inflammatory agents, such as colchicine and anti-interleukin-I, will have an impact on the troponin levels in Covid-19 patients (1).

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References
1. Cremer PC. SARS-CoV-2 and myocardial injury: few answers, many questions. Clev Clin J Med. Posted April 8, 2020. Doi:10.3949/ccjm.87a.ccc001 https://www.ccjm.org/content/early/2020/05/12/ccjm.87a.ccc001
2. Tersalvi G, Vicenzi M, Calabretta D, et al. Elevated troponin in patients with coronavirus disease 2019:possible mechanisms. J Card Failure 2020; https://pubmed.ncbi.nlm.nih.gov/32315733/
3. Shi S, Qin M, Cai Y, et al. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J 2020. https://pubmed.ncbi.nlm.nih.gov/32391877/
4. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052-59. https://jamanetwork.com/journals/jama/fullarticle/2765184
5. Zhou F, YU T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext

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 connection between elevated troponins and Covid-19?

What role does obesity play in severe Covid-19?

Obesity has been shown to be a strong independent predictor of not only Covid-19-related hospitalization but also critical illness requiring invasive mechanical ventilation (IMV) or ICU support (1-3).

 
A large New York City study involving over 4,000 Covid-19 patients found obesity ( BMI≥30 kg/m2) to be an independent risk factor for hospitalization; BMI 30-40 kg/m2 was associated with ~4-fold and >40 kg/m2 with ~6-fold increased risk. Obesity was also strongly associated with increased risk of critical illness, stronger than other common preexisting conditions such as heart disease, hypertension or diabetes (1, preprint).

 
Another New York City study found that among Covid-19 patients younger than 60 years of age, obese patients were twice as likely to be hospitalized or have critical illness (2). Similarly, a French study found severe obesity (BMI >35 kg/m2) to be strongly associated with IMV compared to those with BMI <25 kg/m2 (O.R. 7.4, 1.7-33) (3).

 
Many factors likely play a role in making obese patients particularly susceptive to severe Covid-19. Obesity is a well-recognized inflammatory state and is associated with abnormal secretion of cytokines and adipokines which may have an effect on lung parenchyma and bronchi (1,3,4). Somewhat paradoxically, obese patients may also have an impaired adaptive immune response to certain infections, including influenza (4). Abdominal obesity is also associated with impaired ventilation of the base of the lungs resulting in reduced oxygenation (1).

 

 

Bonus Pearl: Did you know among pre-existing conditions commonly found in the population (eg, hypertension, diabetes, COPD), obesity has been found to be the only condition independently associated with pulmonary embolism in Covid-19 (O.R. 2.7, 1.3-5.5) (5).

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References
1. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospitalization and critical illness among 4, 103 patients with Covid-19 disease in New York City. MedRxiv preprint doi: https://doi.org/10.1101/2020.04.0820057794
2. Lighter J, Phillips M, Hochman S, et al. Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission. Clin Infect Dis 2020. https://pubmed.ncbi.nlm.nih.gov/32271368/
3. Simonnet A, Chetboun M, Poissy J, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. https://pubmed.ncbi.nlm.nih.gov/32271993/
4. Sattar N, BcInnes IB, McMurray JJV. Obesity a risk factor for severe COVID-19 infection:multiple potential mechanisms. Circulation 2020. https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047659
5. Poyiadji N, Cormier P, Patel PY, et al. Acute pulmonary embolism and COVID-19. Radiology 2020; https://pubmed.ncbi.nlm.nih.gov/32407256/

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 role does obesity play in severe 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?

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

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?

How does older people’s immune system place them at high risk of sepsis and death?

Increased risk of sepsis and death from infectious causes among the elderly is a well-known phenomenon—particularly as witnessed in the Covid-19 era— and is in part due to 2 major age-related alterations of their immune system: 1. Defective T and B cell functions in response to acute infections; and 2. Once infection sets in, inadequate control of sepsis-induced pro-inflammatory response and its attendant procoagulant state. Interestingly, the essential elements of the innate immunity (eg, neutrophils, dendritic cells, complements) are generally spared from the effects of aging.1,2

Increased susceptibility of the elderly to acute infections is in part caused by poorer T helper cell function and suboptimal B cell humoral response to neoantigens. Despite this, serum levels of pro-inflammatory cytokines such as IL-1, IL-6,TNF-alpha, and IFN-gamma are intact.  In fact, production of IL-6 and its duration of response is actually increased in the elderly.1,2

Poor control of the inflammatory state due to sepsis in older patients may be related to the difficulty in clearing a pathogen or dysfunction in the signaling by counter-regulatory cytokines, such as IL-10.2 Either way, unchecked inflammatory response is deleterious to the patient and is associated with increased risk of thrombosis and thromboembolism, multiorgan system failure, septic shock and death. 

Bonus Pearl: Did you know that even in the absence of infection, older people are more prone to thrombosis and thromboembolism , in part related to elevated plasma levels of fibrinogen, as well as factor VII, VIII, and IX, among others?2,3  

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

 References

  1. Ticinesi A, Lauretani F, Nouvenne A, et al. C-reactive protein (CRP) measurement in geriatric patients hospitalized for acute infection. Eur J Intern Med 2017;37:7-12. https://pubmed.ncbi.nlm.nih.gov/27594414/
  2. Opal SM, Girard TD, Ely EW. The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis 2005;41: (Suppl 7) S504-12. https://pubmed.ncbi.nlm.nih.gov/16237654/
  3. Mari D, Coppola R, Provenzano R. Hemostasis factors and aging. Experimental Gerontology 2008;43:66-73. https://www.sciencedirect.com/science/article/abs/pii/S0531556507001404?via%3Dihub

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 does older people’s immune system place them at high risk of sepsis and death?

What’s the connection between Covid-19 and cytokine release syndrome?

Severe Covid-19 is associated with a high inflammatory state similar to that seen in cytokine release syndrome (CRS) in adults with secondary hemophagocytic lymphohistiocytosis (sHLH) which is often due to viral infections.1,2

sHLH is characterized by unremitting fever, pulmonary involvement (including ARDS), pancytopenias, and high serum levels of ferritin, C-reactive protein (CRP) and many inflammatory cytokines, such as Interleukin (IL)-6. These features are also often seen in severe Covid-19 disease. In fact, elevated serum IL-6 has been shown to be associated with respiratory failure, ARDS, adverse clinical outcomes, and death in Covid-19.1,2  

Why CRS in Covid-19? It all begins with SARS-CoV2 activation of monocytes, macrophages and dendritic cells leading to IL-6 release. IL-6 in turn activates B and T lymphocytes as well as the innate immune system. In addition, IL-6 has a profound effect on endothelial cells resulting in vascular permeability, neutrophil recruitment and further increase in IL-6 production, setting the stage for a “perfect  cytokine storm.”  IL-6 also induces the liver to synthesize CRP and ferritin.

The importance of IL-6 in severe Covid-19 is further highlighted by the excitement surrounding drugs that block its action, potentially improving morbidity and mortality in this disease. Tocilizumab, a monoclonal antibody against IL-6 receptor used in the treatment of certain rheumatological diseases and CRS in CAR T cell therapy, looks promising.3

Bonus Pearl: Did you know that IL-6 was formally called B-cell stimulatory factor-2 because it induced B cells to produce immunoglobulins?

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

 

References

 

  1. Moore JB, June CH. Cytokine release syndrome in severe Covid-19. Science 2020;368:473-4. doi:10.1126/science.abb8925
  2. Mehta P, McAuley DF, Brown M, et al. Covid-19:consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
  3. Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19. J Transl Med 2020;18:164. https://translational-medicine.biomedcentral.com/track/pdf/10.1186/s12967-020-02339-3
  4. Kishimoto T. IL-6: From its discovery to clinical applications. Int Immunol 2010;22:347-52. https://pubmed.ncbi.nlm.nih.gov/20410258/

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 connection between Covid-19 and cytokine release syndrome?

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

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

 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?

What’s the evidence that patients with Covid-19 are at high risk of blood clots?

Although we often think of it as a respiratory disease, emerging evidence suggests that Covid-19, particularly when severe,  is also associated with high risk of thrombotic events, including pulmonary embolism, venous thrombosis, and arterial thrombotic events.1

A Chinese study found that ICU patients with severe Covid-19 had a venous thromboembolism (VTE) incidence of 25%, with disseminated intravascular coagulopathy (DIC) found in the majority of fatal cases.2

A prospective Dutch study involving critically ill ICU patients with Covid-19 reported VTE in 27% and arterial thrombotic events in another 3.7%, despite standard VTE prophylaxis.3 The authors suggested the use of “high prophylactic doses” of anticoagulants in these patients due to concern over hypercoagulability.

An ICU French study also found high frequency of thrombotic complications in Covid-19 patients with ARDS, with 11.7% of patients having pulmonary embolism vs 2.1% in non-Covid-19 patients with ARDS. As with the Dutch study, thrombotic complications occurred despite standard prophylactic anticoagulation.4

Postmortem studies have also shown marked changes in lung microvasculature with the presence of microthrombi, with some calling it “pulmonary intravascular coagulopathy” to distinguish it from DIC.1

A NEJM letter reported 5 Covid-19 patients less than 50 years of age who presented with large vessel stroke symptoms without an alternative explanation.5 Of interest, 2 of these patients had no other symptoms suggestive of Covid-19.  A pre-print article from China reported an acute stroke incidence of 5% in hospitalized patients with Covid-19.6

The finding of a hypercoagulable state in patients with severe Covid-19 is not surprising given the frequent association of this infection with a high inflammatory state and the well-known capability of SARS-CoV-2 to attack the endothelial surfaces of blood vessels. High inflammatory state can promote activation of blood coagulation through release of inflammatory cytokines (eg, IL-6, IL-8, and TNF-alpha).1

Perhaps even more intriguing is the finding of extremely high levels of factor VIII found in some Covid-19 patients which could make them hypercoagulable.7 This phenomenon should be suspected when a patient appears to be resistant to anticoagulation by heparin based on aPTT but not based on anti-Xa assay.7

 Bonus pearl: Did you know that the overall incidence of VTE is lowest among Asians-Pacific islanders, followed by Hispanics and Caucasians, with highest rate among African-Americans? 1 ,8

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References

  1. Fogarty H, Townsend L, Cheallaigh CN, et al. COVID-19 coagulopathy in Caucasian patients. Br J Haematol 2020, https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16749
  2. Cui S, Chen S, Li X, et al. Huang C, Wang Y, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haematol 2020, April 9. https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14830
  3. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020. https://www.sciencedirect.com/science/article/pii/S0049384820301201?via%3Dihub
  4. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf
  5. Oxley TJ, Mocco J, Majidie S, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020, April 28. https://www.nejm.org/doi/full/10.1056/NEJMc2009787?query=featured_home
  6. Li Y, Wang M. Acute cerebrovascular disease following COVID-19: A single center, retrospective, observational study. 2020. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3550025
  7. Beun R, Kusadasi N, Sikma M, et al. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol 2020, April 20. https://onlinelibrary.wiley.com/doi/abs/10.1111/ijlh.13230
  8. White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res 2009;123 Suppl 4:S11-S17. doi:10.1016/S0049-3848(09)70136-7

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 patients with Covid-19 are at high risk of blood clots?

Does Covid-19 affect males more than females?

Although there is no clear gender pattern in terms of susceptibility to Covid-19, once infected, men have consistently been shown to have higher fatality rates when compared to women.1

In an earlier study involving over 1000 Covid-19 patients, males accounted for 58% of cases.2  However, a review of over 72,000 patients reported by the Chinese CDC found nearly equivalent male to female ratio (~1:1).3 Among Covid-19 patients who have died, male to female ratio has frequently been found to be between 1.5-3.8:1, depending on the reporting country.1  

In a case series from New York City, males accounted for 55% of Covid-19 patients not on invasive mechanical ventilation but 71% of those who required invasive mechanical ventilation.4 Chinese CDC reported case fatality rates of 2.8% for males and 1.7% for females.3 Higher case-fatality rates among males with 2 other coronavirus-related diseases, SARS and MERS, have also been reported.5

Potential explanations for more fatal outcomes among males with Covid-19 include more robust innate and humoral immune responses to infections among females.6 Immune suppressive activity of testosterone and potential immune enhancing effects of estrogens, such as increased expression of the anti-viral cytokine interferon (IFN)-gamma, have long been recognized.6 Life style differences between men and women such as higher prevalence of smoking in men are often mentioned as well.7 Interestingly, circulating ACE2, a receptor for SARS-CoV-2, has also been reported to be higher in men.8

Bonus pearl: Did you know that testosterone is associated with decreased production of pro-inflammatory cytokines such as IFN-gamma, TNF-alpha and may suppress immunoglobulin production?6

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

 References

  1. Global Health 5050. Towards gender equality in global health. http://globalhealth5050.org/covid19/ , accessed April 27, 2020.
  2. Guan WJ, Ni AY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;Feb 28, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
  3. Chinese CDC. Vital surveillances: the epidemiological charcteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)-China, 2020; 2:113-22. http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
  4. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020, April 17. https://www.nejm.org/doi/full/10.1056/NEJMc2010419
  5. Channappanavar R, Fett C, Mack M, et al. Sex-based differences in susceptibility to SARS-CoV infection. J Immunol 2017;198:4046-4053. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450662/#!po=3.84615
  6. Ysrraelit MC, Correale J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology 2018;156:9-22. https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13004
  7. Wenham C, Smith J, Morgan R. COVID-19: the gendered impacts of the outbreak. Lancet 2020:395:846-7. https://www.ncbi.nlm.nih.gov/pubmed/32151325
  8. Patel SK, Velkoska E, Burrell LM. Emerging markers in cardiovascular disease: Where does angiotensin-converting enzyme 2 fit in? Clin Exp Pharmacol Physiol 2013;40:551-9. https://www.ncbi.nlm.nih.gov/pubmed/23432153/

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 Covid-19 affect males more than females?