Viral infections

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

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

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had “massive albuminuria” on the first day of admission, and 63% developed proteinuria during their hospitalization (2 [unpublished]).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?

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

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?

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

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.8  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?

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

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

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?

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

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

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

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

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

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

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

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

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

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 References

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

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

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

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

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

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

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

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

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

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

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

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References

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

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

 

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

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

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

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

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

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

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

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

 

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

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References

 

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

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

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

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

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

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?

Key clinical pearls on the management of patients suspected of or diagnosed with Covid-19 in the outpatient setting

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

Here are some key points to remember when managing patients with Covid-19 symptoms in the outpatient setting.  These points are primarily based on the CDC guidelines and the current literature. They may be particularly useful to primary care providers (PCP) who do not have ready access to Covid-19 test kits or radiographic imaging in the diagnosis of patients suspected of or diagnosed with Covid-19.

  • Isolation precautions. 1,6-7 Minimize chances of exposure by placing a facemask on the patient and placing them in an examination room with the door closed. Use standard and transmission-based precautions including contact and airborne protocols when caring for the patient. Put on an isolation gown and N95 filtering facepiece respirator or higher. Use a facemask if a respirator is not available. Put on face shield or goggles if available. Adhere to strict hand hygiene practices with the use of alcohol-based hand rub with greater than 60% ethanol or 70% isopropanol before and after all patient contact. If there is no access to alcohol-based hand sanitizers, the CDC recommends hand washing with soap and water as the next best practice.

 

  • Risk Factors.2-3 Older patients and patients with severe underlying medical conditions seem to be at higher risk for developing more serious complications from Covid-19 illness. Known risk factors for severe Covid-19 include age over 60 years, hypertension, diabetes, cardiovascular disease, chronic respiratory disease, and immunosuppression.

 

  • Symptoms.2,4,8,9 Reported illnesses have ranged from mild symptoms to severe illness and death. These symptoms may appear after a 2- to 14-day incubation period.
    • Fever at any time 88-99%
    • Cough 59-79%
    • Dyspnea 19-55%
    • Fatigue 23-70%
    • Myalgias 15%-44%
    • Sputum production 23-34%
    • Nausea or vomiting 4%-10%
    • Diarrhea 3%-10%
    • Headache 6%-14%
    • Sore throat 14%
    • Rhinorrhea/nasal congestion (4.8%)
    • Anosmia (undocumented percentage)

 

  • Treatment for mild illness.5 Most patients have mild illness and are able to recover at home. Counsel patients suspected to have Covid-19 to begin a home quarantine staying in one room away from other people as much as possible. Patients should drink lots of fluids to stay hydrated and rest. Over the counter medicines may help with symptoms. There is controversy regarding the safety of NSAIDs in Covid-19 (See related P4P pearl). Generally, symptoms last a few days and  patients get better after a week. There is no official guidance from the CDC or other reliable sources on how often a PCP should check in with a patient confirmed with Covid-19 and in quarantine. Please use good judgement and utilize telehealth capabilities via phone call, video call, etc… if possible.

 

  • Treatment for severe illness.3 Patients should be transferred immediately to the nearest hospital. If there is no transfer service available, a family member with appropriate personal protective equipment (PPE) precautions, should drive patient to nearest hospital for critical care services.

 

  • Ending home isolation. 5
    • Without testing: Patients can stop isolation without access to a test result after 3 things have happened. 1) No fever for at least 72 hours. This is 3 full days of no fever and without the use of medication that reduces fever; 2) Respiratory symptoms have improved.; and 3) At least 7 days have passed since symptoms first appeared.
    • With testing. 5 Home isolation may be ended after all of the following 3 criteria have been met: 1) No fever for at least 72 hours. This is 3 full days of no fever and without the use of medication that reduces fever; 2) Respiratory symptoms have improved; and 3) Negative results from at least 2 consecutive nasopharyngeal swab specimens collected more than 24 hours apart.

To all the healthcare providers out there, please be safe and stay healthy!

 

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Contributed by Erica Barnett, Harvard Medical Student, Boston, MA.

 

References:

  1. CDC. Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19). https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html
  2. CDC. Symptoms and Testing. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/index.html
  3. World Health Organization. Operational Considerations for case management for COVID-19 in health facility and community. https://apps.who.int/iris/bitstream/handle/10665/331492/WHO-2019-nCoV-HCF_operations-2020.1-eng.pdf
  4. Partners in Health. Resource Guide 1: Testing, Tracing, community management. https://www.pih.org/sites/default/files/2020-03/PIH_Guide_COVID_Part_I_Testing_Tracing_Community_Managment_3_28.pdf
  5. CDC. Caring for someone at home. https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/care-for-someone.html
  6. CDC. Using PPE. https://www.cdc.gov/coronavirus/2019-ncov/hcp/using-ppe.html
  7. CDC. Hand Washing. https://www.cdc.gov/coronavirus/2019-ncov/hcp/hand-hygiene.html
  8. Harvard Health Publishing. COVID-19 Basics. https://www.health.harvard.edu/diseases-and-conditions/covid-19-basics
  9. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020, March 6. DOI:10.1056/NEJM022002032 https://www.ncbi.nlm.nih.gov/pubmed/32109013

 

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!

Key clinical pearls on the management of patients suspected of or diagnosed with Covid-19 in the outpatient setting

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

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

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

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

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

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

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

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

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

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

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

 

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

References:

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

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

 

 

 

 

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