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

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

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

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

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

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

Truly a “novel” virus!

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

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References

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

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

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

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  

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 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?

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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

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 References

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

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

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

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

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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

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 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?

What do eyes, nose, and toes have to do with Covid-19?

Increasingly, we are finding out that the clinical manifestations of Covid-19 are not limited to the respiratory tract and that several other areas of the body, including the eyes, nose, and toes, may also be affected.

Eyes: In a study1 of 38 patients with Covid-19, 12 (32%) had eye manifestations consistent with conjunctivitis (or “pink eye”), including conjunctival hyperemia, chemosis, epiphora (watering eyes) and increased secretions; none had blurred vision. Most patients had more severe manifestations of Covid-19. Tears from 2 patients tested positive for Covid-19 virus (SARS-Co-V-2) by PCR.

Nose: Altered sense of smell was reported in 4 of 9 mild Covid-19 cases, 2 without rhinitis.2 Loss of sense of smell or anosmia has been reported in 30% or more of patients as their major presenting symptom of Covid-19 in otherwise mild cases by the British Rhinological Society (unpublished data).3  Another study found a 5% prevalence of hyposmia (unpublished).4 In addition to infecting mucosal surfaces inside the nose, the coronaviruses may infect nerve cells.5 Fortunately, sense of smell alterations appear temporary.

Toes: Findings that may mimic frostbite or chilblains with erythema or bluish/purplish discoloration of toes along with pain, itching or burning have been described in patients with Covid-19.6,7 Anecdotally, many cases been observed in relatively healthy or younger patients.  Whether these changes are due to known coagulation and/or endothelial derangements in Covid-19 or other causes is not clear.8,9

Bonus Pearl: Did you know that ACE2 receptors have reportedly been found in abundance in the testes (not ovaries)10 and testicular pain has also been reported in a Covid-19 patient seen without respiratory symptoms?11

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 References

  1. Wu P, Duan F, Luo C, et al. Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei province, China. JAMA Ophthalmology 2020; March 31. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2764083
  2. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020;April 1. https://www.nature.com/articles/s41586-020-2196-x
  3. Hopkins C, Kumar N. Loss of sense of smell as marker of COVID-19 infection. https://www.entuk.org/sites/default/files/files/Loss%20of%20sense%20of%20smell%20as%20marker%20of%20COVID.pdf
  4. Mao L, Wang M, Chen S, et al. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study. https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1
  5. Perlman S, Jacobsen G, Afifi A. Spread of a neurotropic murine Coronavirus into the CNS via the trigeminal and olfactory nerves. Virology 1989;170:556-560 https://www.sciencedirect.com/science/article/pii/0042682289904467
  6. Mazzotta F, Troccoli T, Bonifazi E. A new vasculitis at the time of COVID-19. Eur J Ped Dermatol 2020. https://www.ejpd.com/images/nuova-vasculite-covid-ENG.pdf
  7. Lee YJ. “Covid toes” might be the latest unusual sign that people are infected with the novel coronavirus. April 23, 2020. https://www.businessinsider.com/covid-toes-frostbite-coronavirus-skin-lesion-discolored-swollen-feet-2020-4
  8. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Eng J Med 2020;382:e38. https://www.nejm.org/doi/full/10.1056/NEJMc2007575
  9. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; April 17. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2930937-5
  10. Kim J, Thomsen T, Sell N, et al. Abdominal and testicular pain: an atypical presentation of COVID-19. Am J Emerg Med 2020 https://doi.org/10.1016/j.ajem.2020.03.052
  11. Fan C, Li K, Ding Y, et al. ACE2 expression in kidney and testis may cause kidney and testis damage. medRxiv 2020. https://doi.org/10.1101/2020.02.12.20022418.t
     

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 do eyes, nose, and toes have to do with Covid-19?

How common are acute kidney abnormalities in patients with Covid-19?

Although early reports suggested a low incidence (3-9%) of AKI among Covid-19 patients, more recent studies have shown higher frequencies of renal abnormalities, including albuminuria and hematuria (1).

 
A study of 59 patients with Covid-19 reported that 34% had “massive albuminuria” on the first day of admission, and 63% developed proteinuria during their hospitalization (2 [unpublished]). BUN was elevated in 27% of patients and in two-thirds of those who died. In another study involving 710 patients with Covid-19, nearly one-half had proteinuria and hematuria and a quarter had hematuria on admission. Overall, around 15% of patients had an elevated serum creatinine and BUN (3).

 
Possible explanations for renal manifestations of Covid-19 include sepsis, cytokine storm, secondary infections, and direct cellular injury due to the virus itself (1, 4). Interestingly, SARS-CoV-2 has been reportedly isolated from the urine sample of a Covid-19 patient (1). This should not be surprising given the presence of ACE2 receptors in the proximal tubules and, at lower concentrations, in the glomeruli (5).

 
An autopsy study of patients with Covid-19 found evidence of diffuse proximal tubule injury with the loss of brush border, vascular degeneration but no vasculitis, interstitial inflammation or hemorrhage. Coronavirus particles were found in the tubular epithelium and podocytes (6).

 
Bonus Pearl: Did you know that proteinuria (2-3+) and hematuria are independent risk factors for in-hospital mortality (3)?

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References
1. Naicker S, Yang CW, Hwang SJ. The novel coronavirus 2019 epidemic and kidneys. Kidney International 2020, May. DOI: https://doi.org/10.1016/j.kint.2020.03.001
2. Li Z, Wu M, Guo J, et al. Caution on kidney dysfunctions of 2019-nCoV patients . medRxiv 2020.02.08.20021212
3. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney International 2020;97:829-38.
4. Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney International 2020, April 9. https://www.sciencedirect.com/science/article/pii/S0085253820303690  
5. Mizuiri S, Ohashi Y. ACE and ACE2 in kidney disease. World J Nephrol 2015;4:74-82. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317630/
6. Cheng N, Zhou M, Dong X, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients. medRxive 2020 .0218.20023242. https://doi.org/10.1101/2020.02.18.20023242.

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!

 
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How common are acute kidney abnormalities in patients with Covid-19?

How common are cardiac complications in Covid-19?

Although we often think of Covid-19 as a respiratory disease, cardiovascular complications are not uncommon.

Myocardial injury based on elevated cardiac troponin levels have been reported in ~20% of patients with Covid-19.1,2 Among deceased patients with Covid-19 without underlying cardiovascular disease, ~12.0% have been reported to have “substantial heart damage” based on elevated levels of troponins or cardiac arrest.1  

Arrythmias have also been reported in a significant number of patients (~20.0% in those on invasive mechanical ventilation). 3,4

Reports of Covid-19-associated acute onset heart failure, myocardial infarction, myocarditis and pericarditis have also appeared in the literature. 4-6

Proposed mechanisms of acute myocardial injury include direct binding of the virus to ACE2 receptors which are present not only in the lungs but also cardiac endothelial and smooth muscle cells of myocardial vessels as well as in cardiac myocytes. 1,7,8 Myocardial injury may also be a consequence of Covid-19-related cytokine storm or respiratory insufficiency.1

Interestingly, patient with heart failure have increased expression of ACE2 which may make them particularly vulnerable to myocardial injury and failure after Covid-19 infection. 8

Bonus Pearl: Did you know that a type of perivascular mural cell called “pericyte” makes up a significant part of the myocardium and—in contrast to relatively low expression of ACE2 in cardiac myocytes— expresses ACE2 at high levels, potentially serving as an important target for Covid-19 virus? 8

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 References

  1. Zheng YY, Ma YT, Zhang JY, et al. Covid-19 and the cardiovascular system. Nature Rev 2020, May. https://www.nature.com/articles/s41569-020-0360-5
  2. Yang xz, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020, Feb 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102538/
  3. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of Covid-19 in New York City 2010. N Engl J Med 2020. DOI: 10.1056/NEJMc2010419 https://www.nejm.org/doi/full/10.1056/NEJMc2010419
  4. Covid-19 clinical guidance for the cardiovascular care team. American College of cardiology 2020. https://www.acc.org/~/media/665AFA1E710B4B3293138D14BE8D1213.pdf
  5. Hu H, Ma F, Wei X, et al. Coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin. Eur Heart J 2020. https://pubmed.ncbi.nlm.nih.gov/32176300/
  6. Hua A, O’Gallaher KO, Sado D. Life-threatening cardiac tamponade complicating myo-pericarditis in Covid-19. Eur Heart J 2020. https://academic.oup.com/eurheartj/article/doi/10.1093/eurheartj/ehaa253/5813280
  7. Gallager PE, Ferrario CM, Tallant EA. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol heart Circ Physiol 2008;295:H2373-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614534/
  8. Chen L, Li X, Chen M, et al. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 2020, March 13. https://academic.oup.com/cardiovascres/article/doi/10.1093/cvr/cvaa078/5813131

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 common are cardiac complications in Covid-19?

How common are gastrointestinal symptoms in Covid-19?

Although GI symptoms such as diarrhea or nausea were initially thought to be uncommon among Covid-19 patients,1,2 more recent reports suggest that GI symptoms are relatively common.3-8

A review article found that as many as 50.0% of Covid-19 patients had diarrhea, ~30.0% had nausea, ~14.0% had gastrointestinal bleed, and 6.0% had abdominal pain. In a case series from New York City, ~25.0% of patients presented with diarrhea, while ~20.0% had nausea and vomiting. 9 

Some patients may have GI symptoms in the absence of any respiratory complaints.  Fecal tests for RNA  have found nearly one-third to a half of patients with Covid-19 shedding the virus, with some patients testing positive even after  respiratory specimens test negative.8 How often these patients harbor viable or infectious virus is not known, however.

Some have reported that as the severity of the disease worsens so do the GI symptoms.3 GI symptoms have also been associated with later presentation of Covid-19, higher liver enzymes and longer prothrombin time.3

Although the exact mechanism of GI symptoms in Covid-19 is unclear, direct invasion of virus is a plausible explanation. Indeed, potential targets for SARS-CoV-2 virus, the ACE2-expressing cells, have been identified in the GI tract, including the esophagus, gastric, intestinal and colonic epithelial cells.5,8  

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 References

 

  1. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Eng J Med 2020, Feb 28. https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
  2. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA. March 3, 2020. (17% diarrhea) https://jamanetwork.com/journals/jama/fullarticle/2762688
  3. Pan L, Mu M, Yang P, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am j Gastroenterol 2020. https://journals.lww.com/ajg/Documents/COVID_Digestive_Symptoms_AJG_Preproof.pdf
  4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novle coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
  5. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. J Gastroenterol https://www.gastrojournal.org/article/S0016-5085(20)30281-X/pdf
  6. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with Covid-2019. Nature, April 1, 2020. https://doi.org/10.1038/a41586-020-2196-x
  7. Xiao F, Tang M, Zheng X, et al. Evidence of gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020, March 3. https://www.sciencedirect.com/science/article/pii/S0016508520302821?via%3Dihub
  8. Tian Y, Rong L, Nian W, et al. Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther 2020;March 29. https://doi.org/10.1111/apt.15731
  9. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020.  https://www.nejm.org/doi/full/10.1056/NEJMc2010419

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 common are gastrointestinal symptoms in Covid-19?