When should I consider systemic corticosteroids in my patient with Covid-19?

As of July 30, 2020, The National Institute of Health (NIH) Coronavirus Disease 2019 (COVID-19) Guidelines Panel recommends using dexamethasone 6 mg per day for up to 10 days for the treatment of Covid-19 in patients who are mechanically ventilated (“Strong” recommendation based on 1 or more randomized trials) with a a less strong recommendation (“Moderate”) in those who require supplemental oxygen but who are not mechanically ventilated.1

These recommendations appear to primarily stem from a multicenter, open label randomized controlled trial of dexamethasone vs standard of care in hospitalized patients in United Kingdom, 2 with treated group receiving dexamethasone 6 mg IV or orally daily for 10 days or until hospital discharge (whichever came first).  Mortality at 28 days was significantly lower among patients on mechanical ventilation who received dexamethasone (29.3% vs 41.4%, rate ratio 0.64, 95% CI, 0.51-0.81) and in those receiving supplemental oxygen without mechanical ventilation (23.3% vs 26.2%). The risk of progression to invasive mechanical ventilation was also lower in the dexamethasone group. No significant difference in mortality was found in patients who did not require supplemental oxygen. 

Retrospective and case series studies have reported conflicting results on the efficacy of corticosteroid for the treatment of covid-19. 3-10 That’s why despite its limitations (open label, wide range of 02 supplementation, few patients receiving remdesvir), the randomized controlled trial discussed above should guide our decision making on the use of corticosteroids in patients with Covid-19.

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References

  1. NIH. The Coronavirus Disease 2019 (COVID-19) Guidelines. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/ Accessed August 6, 2020.
  2. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19—Preliminary report. N Engl J Med 2020; July 17, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
  3. Keller MJ, Kitsis EA, Arora S, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. J Hosp Med 2020;15(8):489-493. https://www.journalofhospitalmedicine.com/jhospmed/article/225402/hospital-medicine/effect-systemic-glucocorticoidsmortalityor-mechanical
  4. Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther. 2020;5(1):57. https://www.ncbi.nlm.nih.gov/pubmed/32341331
  5. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020. https://www.ncbi.nlm.nih.gov/pubmed/32167524
  6. Corral L, Bahamonde A, Arnaiz delas Revillas F, et al. GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv. 2020. https://www.medrxiv.org/content/10.1101/2020.06.17.20133579v1
  7. Fadel R, Morrison AR, Vahia A, et al. Early short course corticosteroids in hospitalized patients with COVID-19. Clin Infect Dis. 2020. https://www.ncbi.nlm.nih.gov/pubmed/32427279
  8. Fernandez Cruz A, Ruiz-Antoran B, Munoz Gomez A, et al. Impact of glucocorticoid treatment in SARS-CoV-2 infection mortality: a retrospective controlled cohort study. Antimicrob Agents Chemother 2020. https://www.ncbi.nlm.nih.gov/pubmed/32571831
  9. Yang Z, Liu J, Zhou Y, Zhao X, Zhao Q, Liu J. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020;81(1):e13-e20. https://www.ncbi.nlm.nih.gov/pubmed/32283144

 10. Lu X, Chen T, Wang Y, Wang J, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. Crit Care. 2020;24(1):241. https://www.ncbi.nlm.nih.gov/pubmed/32430057

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!

 

When should I consider systemic corticosteroids in my patient with 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).

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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?

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?

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!

 
.

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

How often is the liver affected by Covid-19?

Abnormal liver enzymes in patients with Covid-19 are common, particularly in those with severe disease.

 
Elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported in 14-53% of patients in several case series. More severe cases appear to have a higher prevalence of AST elevation (1). As some cases also have elevated creatine kinase (CK), the relative contribution of muscles to these enzyme abnormalities is unclear (2).

 
A small study involving ICU patients with Covid-19 reported a prevalence of elevated AST of 62% compared to 25% in non-ICU patients (3). Other studies have confirmed lower incidence of AST abnormality among patients with mild or subclinical disease (4,5).

 
Although much of the published reports of liver injury in Covid-19 have revolved around AST and ALT abnormalities, gamma-glutamyl transferase (GGT) may also be elevated. GGT was abnormal in 54% of patients with Covid-19 during their hospitalization with alkaline phosphatase elevation reported in ~2.0% (1, unpublished reports). Elevation of total bilirubin has also been reported occasionally (1).

 
Although the exact mechanism(s) of Covid-19-related is unclear, direct viral infection of liver cells is one possibility as viremia has been documented in some cases (1). Of interest, a related coronavirus, SARS-CoV-1 has been shown to infect liver tissue and cholangiocytes may express ACE2 receptors, a prime target for Covid-19 virus (1,6,7, unpublished reports).

 

Despite these observations, to date, viral inclusions have not been demonstrated in the liver. Other possible causes of liver injury in Covid-19 include innate immune dysregulation, cytokine storm, hypoxia and drugs (1,2).

 

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References
1. Zhang C, Shi L, Wang FS. Liver injury in COVID-19:management and challenges. Lancet Gastroenterol Hepatol 2020; March 4. https://doi.org/10.1016/S2468-1253(20)30057-1
2. Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. Lancet Gastroenterol Hepatol 2020;March 20. https://doi.org/10.1016/52468-1253(20)30084-4
3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://pubmed.ncbi.nlm.nih.gov/31986264/
4. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. N Engl J Med 2020;published online Feb 28. DOI:10.1056/NEJMoa2003032
5. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020; published onlineFeb 24. DOI:10.1016/S1473-3099(20)30086-4 (lancet 8)
6. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 209-nCoV infection. bioRxiv 2020;published online Feb 4. https://doi.org/10.1101/2020.02.03.931766.
7. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; published online Feb 18. DOI:10.1016/S2213-2600(20)30076-X

 

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 often is the liver affected by Covid-19?

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

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

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

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

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

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

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

Stay tuned!

 

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References

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

 

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

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

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

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?

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?

How common are neurological symptoms in patients with Covid-19 infection?

Although we usually think of it as primarily a respiratory tract disease, neurological manifestations with Covid-19 are not at all uncommon,1-6 occurring in over one-third of hospitalized patients with Covid-19 according to one medRxiv report.1

In a Chinese study1 involving 214 hospitalized patients with Covid-19, 36.4% had 1 or more neurological symptoms, with the majority involving the central nervous system (CNS) (25.0%), of which the most common complaints were dizziness (17%) and headache (13.0%). Some patients (9.0%) had cranial nerve/peripheral nerve complaints of which the most common were difficulty with taste (hypogeusia) (6.0%) and sense of smell (hyposmia) (5.0%).  A fewer number of patients had impaired consciousness, acute cerebrovascular disease (including ischemic stroke and cerebral hemorrhage). Although not strictly-speaking a neurological manifestation, the study also reported “muscle injury” in ~20.0% of patients     (defined as myalgia plus CK >200 IU/L).

Descriptions of Covid-19 encephalopathy, including one associated with acute hemorrhagic necrotizing process, are also beginning to appear in the literature.3-5 Reports of “Neuro-Covid-19 units” in Italy further underlines the common occurrence of neurological symptoms in these patients.6

More than one mechanism for neurological complications in Covid-19 are likely,  including:1-2

  1. Direct viral invasion into the CNS which could explain the associated headache, high fever, vomiting, convulsions, and consciousness disorders. Some have reported normal CSF parameters but a report of PCR positive CSF suggests direct injury from the virus itself.2 Covid-19 virus may gain access to the CNS through direct invasion of neuronal pathways (eg. olfactory nerve given recent reports of difficulty with sense of smell) or through blood circulation.
  2. Indirect CNS injury through extreme systemic derangements such as hypoxia, or immune/inflammatory response-related injury (eg, through cytokines, hypercoagulability related to infection). Some have also posited that binding of Covid-19 virus to ACE2 may cause abnormally elevated blood pressure and increase the risk of cerebral hemorrhage.2

The fact that Covid-19 is so versatile and affects the nervous system as well shouldn’t surprise us. Neurological complications have been reported with couple of other related respiratory Coronaviruses such as those of SARS and MERS.2

 

Bonus pearl: Did you know that as early 1970-80s some coronaviruses were shown to cause “nasoencephalopathy” when injected intranasally in mice with subsequent spread to the CNS through the olfactory nerve?7 Maybe we shouldn’t be too surprised that sense of smell is impaired in some Covid-19 patients. If we could only stop the virus at the nose!

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References

  1. 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
  2. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity 2020, March 30. https://www.sciencedirect.com/science/article/pii/S0889159120303573
  3. Xiang et al. 2020. First case of 2019 novel Coronavirus disease with encephalitis. ChinaXiv, T202003 (2020), p. 00015 (obtained from reference 2).
  4. Poyiadji N, Shain G, Noujaim D, et al. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020 https://pubs.rsna.org/doi/10.1148/radiol.2020201187
  5. Filatov A, Sharma P, Hindi F, et al. Neurological complications of coronavirus (COVID-19): encephalopathy. Cureus 12(3): e7352. DOI 10.7759/cureus.7352 https://www.cureus.com/articles/29414-neurological-complications-of-coronavirus-disease-covid-19-encephalopathy
  6. Talan J. COVID-19: Neurologists in Italy to Colleagues in US: Look for poorly-defined neurologic conditions in patients with the Coronavirus. Neurology Today 2020, March 27. https://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=920
  7. 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

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 neurological symptoms in patients with Covid-19 infection?