On Saturday, the World Health Organization released a scientific brief on the multisystem inflammatory syndrome seen in children and adolescents with COVID-19. Today in Science Speaks two guest posts respond to findings around the syndrome.
The following is a guest post Daniel R. Lucey M.D., MPH and Kristen R. Kent, MPhil.
Since April 26 England, and then Italy and the United States have begun to report a multisystem inflammatory syndrome in children, associated temporally with SARS-CoV-2/COVID-19 1-3. In the past week, both the United States Centers for Disease Control and Prevention* and the United Kingdom Royal College of Paediatrics and Child Health, and the World Health Organization have issued guidelines for the diagnosis of these patients 4-5.
Similarities to a Kawasaki-like disease, a rare blood vessel inflammation mostly in children, have been described in these young patients with laboratory confirmation of having been infected with of SARS-CoV-2. A notable difference in these patients, however, is the unusually high prevalence of shock.
We note that in the past 53 years since Kawasaki’s disease was first described, some adults have also been reported and have responded to traditional treatment with intravenous immunoglobulin and aspirin 6. Thus, this syndrome should also be searched for in adults with COVID-19.
China and other Asian nations, as well as Iran and Middle East nations hard-hit by the pandemic have not yet reported cases. The reason for this (apparent) geographical difference is unclear at this time.
The pathogenesis of this rare multisystem inflammatory syndrome in children (“MIS-C”) is unknown. In a small proportion of adults with COVID-19 a distinct multisystem inflammatory process, often termed “cytokine storm” also occurs.
Preliminary evidence in adults of the pathogenesis has emphasized a macrophage activation syndrome or hemophagocytic syndrome, in the setting of CD4+ and CD8+ T-cell lymphocytopenia. One study from China has reported “T-cell exhaustion”; however, few studies have reported detailed studies of T-cell subsets and activation markers7-8.
Adults have been reported in Europe and the U.S. much more so than in China, of widespread clotting abnormalities including in the lung, and some evidence of a vasculitis. How different is the multisystem inflammatory syndrome in children from that in adults associated with COVID-19, other than in relative prevalence? Is the pathogenesis different in children compared with adults?
Looking ahead to vaccine candidate testing, we advocate for enhanced prospective surveillance and monitoring for potential vaccine-associated multisystem inflammatory syndromes. Although unlikely, a temporal-versus-causal relationship after vaccination must be rapidly identified, distinguished, and understood. In theory, any such potential vaccine-associated reactions could be due to antibody-mediated enhancement (antibody-dependent enhancement), with precedents seen with an investigational respiratory syncytial virus (RSV) vaccine and possibly with both sequential Dengue virus infection with different serotypes and also recently with a licensed dengue vaccine.
In addition to a B-cell antibody-mediated immune reaction, T-cell mediated Human Leukocute Antigen (HLA) mechanism might contribute to severe COVID-19 illness or to a severe reaction to a COVID-19 vaccine. For example, one vaccine against the 2009 pandemic H1N1 influenza virus in some European countries, initially Finland and Sweden, was reported to increase the occurrence of narcolepsy, especially in persons with a specific HLA type 9. Of note, these persons with vaccine-associated narcolepsy were primarily in children and adolescents 9-12. This vaccine was not used in the United States12.
Daniel Lucey, M.D. MPH, FIDSA, FACP, is an infectious diseases physician and adjunct professor of infectious diseases at Georgetown University Medical Center, a senior scholar at the Georgetown University O’Neil Institute, Anthropology Research Associate, Smithsonian Museum of Natural History and a member of the Infectious Diseases Society of America Global Health Committee.He has served as a volunteer medical responder to outbreaks that included the West Africa Ebola crisis. He has collected information on outbreaks starting in 2001 with cases of anthrax in 2001, and including smallpox vaccination 2002, SARS 2003, H5N1 Flu 2004, MERS in 2013, and Ebola in April, 2014, He has gathered, and updated information on the spread of the coronavirus here since Jan. 6.
Kristen Kent, MPhil, is a medical student at Georgetown University School of Medicine.
*US CDC: Case Definition for Multisystem Inflammatory Syndrome in Children (MIS-C)
- An individual aged <21 years presenting with feveri, laboratory evidence of inflammationii, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
- No alternative plausible diagnoses; AND
- Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms
“As of May 12, 2020, the New York State Department of Health identified 102 patients” (5).
- Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet May 6, 2020; 1-2 https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31094-1.pdf
- Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, Bonanomi E, D’Antiga L. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. The Lancet May 13, 2020; 1-8 https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31103-X.pdf
- Viner R, Whittaker E. Kawasaki-like disease: emerging complications during the Covid-19 epidemic. Lancet 2020; May 13 (online). https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31129-6/fulltext
- Royal College of Paediatrics and Child Health. Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf
- CDC. Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-2019). 2020 (May 14). https://emergency.cdc.gov/han/2020/han00432.asp
- Kogulan P, Mbualungu E, Villanueva E, Coe M, Lucey D. Kawasaki’s disease in an adult: Case report and review of the literature in adolescents and adults. J Clin Rheumatol 2001(June); 7(3):194-198.
- Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, Yuan Z, Feng Z, Wu Y, Chen Y. Reduction and functional exhaustion of T cells in patients with Coronavirus Disease 2019 (COVID-19). Frontiers in Immunology May 1, 2020; 11(827): 1-7 https://www.frontiersin.org/articles/10.3389/fimmu.2020.00827/full
- Maggi E, Canonica GW, Moretta L. COVID-19: Unanswered questions on immune response and pathogenesis. Journal of Allergy and Clinical Immunology May 1, 2020; 1-10 https://www.jacionline.org/article/S0091-6749(20)30631-X/pdf
- Ahmed S, Steinman L. Narcolepsy and influenza-vaccination induced autoimmunity. Annals Translational Medicine 2017; 5(1) 25. : http://dx.doi.org/10.21037/atm.2016.12.63
- European Centre for Disease Prevention and Control. Narcolepsy in association with pandemic influenza vaccination (a multi-country European epidemiological investigation) Stockholm: ECDC; September 2012.
- Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finlandexternal icon. PLoS One. 2012;7(3):e33536.
- CDC. Narcolepsy following Pandemrix influenza vaccination. https://www.cdc.gov/vaccinesafety/concerns/history/narcolepsy-flu.html. This online CDC Vaccine Safety original page last reviewed January 29, 2020.