Does my patient testing positive for hepatitis A IgM really have acute hepatitis A infection even though he is completely asymptomatic?

Not necessarily! A positive hepatitis A (HA) IgM in a patient without any symptoms could indicate a few different things: 1. Asymptomatic infection; 2. Prior HA infection with prolonged IgM presence; 3. False positive results due to cross-reacting antibodies; and 4. Commercial kits with a falsely low cutoff value.1

A 2013 retrospective study found that of patients testing positive for HA IgM antibody, only 11% could be confirmed to have acute HA infection; 57% had recent and/or resolved hepatitis and 29% had reasons to have elevated hepatic enzymes other than HA infection, at least some likely to be false-positive.1

Other viral illnesses and autoimmune conditions have been associated with false positive HA-IgM.1-3  One case report described a patient with malaise, fever, jaundice, and elevated liver enzymes who tested positive for HA-IgM but ultimately was found to be infected with Epstein-Barr virus (EBV)2. In another case report, a patient was described as having a drug-induced liver injury in the setting of infliximab usage. False positive Hep A IgM was suspected to be due to a polyclonal B-cell autoimmune-mediated response stimulated by the infliximab.3

So, even a positive HA-IgM should always be interpreted in the context of the patient’s history and likelihood of active HA infection based on epidemiological factors.1

Bonus Pearl: Did you know that modes of transmission of HA include person-to-person via saliva or sex, consuming raw/undercooked shellfish, or drinking contaminated drinking water?4

Contributed by Joseph Kinsella, Medical Student, A.T. Still Osteopathic Medical School,  Kirksville, Missouri

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References

  1. Alatoom A., Ansari M. Q, Cuthbert J. (2013). Multiple factors contribute to positive results for hepatitis a virus immunoglobulin M antibody. Arch Pathol Lab Med 2013;137:90–95. https://doi.org/10.5858/arpa.2011-0693-oa
  2. Valota M, Thienemann F, Misselwitz B. False-positive serologies for acute hepatitis A and autoimmune hepatitis in a patient with acute Epstein–Barr virus infection. BMJ Case Reports CP 2019;12: e228356.
  3. Tennant E, Post JJ. Production of false-positive immunoglobulin m antibodies to hepatitis a virus in autoimmune events. J Infect Dis 2016;213: 324–325. https://doi.org/10.1093/infdis/jiv417
  4. Mayo Foundation for Medical Education and Research. (2020, August 28). Hepatitis A. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/hepatitis-a/symptoms-causes/syc-20367007.

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

Does my patient testing positive for hepatitis A IgM really have acute hepatitis A infection even though he is completely asymptomatic?

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?

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

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?