key: cord-0024999-w8b0u9ye
authors: Belay, Ermias D; Godfred Cato, Shana; Rao, Agam K; Abrams, Joseph; Wyatt Wilson, W; Lim, Sarah; Newton-Cheh, Christopher; Melgar, Michael; DeCuir, Jennifer; Webb, Brandon; Marquez, Paige; Su, John R; Meng, Lu; Grome, Heather N; Schlaudecker, Elizabeth; Talaat, Kawsar; Edwards, Kathryn; Barnett, Elizabeth; Campbell, Angela P; Broder, Karen R; Bamrah Morris, Sapna
title: Multisystem Inflammatory Syndrome in Adults After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and Coronavirus Disease 2019 (COVID-19) Vaccination
date: 2021-11-28
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab936
sha: 1f2c479c0949baf9d35009c1abe3cc41f8ba271b
doc_id: 24999
cord_uid: w8b0u9ye

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) was reported in association with the coronavirus disease 2019 (COVID-19) pandemic. MIS-A was included in the list of adverse events to be monitored as part of the emergency use authorizations issued for COVID-19 vaccines. METHODS: Reports of MIS-A patients received by the Centers for Disease Control and Prevention (CDC) after COVID-19 vaccines became available were assessed. Data collected on the patients included clinical and demographic characteristics and their vaccine status. The Vaccine Adverse Events Reporting System (VAERS) was also reviewed for possible cases of MIS-A. RESULTS: From 14 December 2020 to 30 April 2021, 20 patients who met the case definition for MIS-A were reported to CDC. Their median age was 35 years (range, 21–66 years), and 13 (65%) were male. Overall, 16 (80%) patients had a preceding COVID-19-like illness a median of 26 days (range 11–78 days) before MIS-A onset. All 20 patients had laboratory evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Seven MIS-A patients (35%) received COVID-19 vaccine a median of 10 days (range, 6–45 days) before MIS-A onset; 3 patients received a second dose of COVID-19 vaccine 4, 17, and 22 days before MIS-A onset. Patients with MIS-A predominantly had gastrointestinal and cardiac manifestations and hypotension or shock. CONCLUSIONS: Although 7 patients were reported to have received COVID-19 vaccine, all had evidence of prior SARS-CoV-2 infection. Given the widespread use of COVID-19 vaccines, the lack of reporting of MIS-A associated with vaccination alone, without evidence of underlying SARS-CoV-2 infection, is reassuring.

A novel multisystem inflammatory syndrome in children (MIS-C) temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was first described in April 2020, initially in the United Kingdom and subsequently in other countries [1] [2] [3] [4] [5] . Almost all patients reported in the United States had evidence of SARS-CoV-2 infection, with a delayed occurrence in most patients of 2-6 weeks after acute infection [5, 6] . A similar multisystem inflammatory syndrome was identified in adults (MIS-A) beginning in June 2020 [7] . The clinical course of both MIS-C and MIS-A predominantly includes fever, elevated inflammatory markers, gastrointestinal symptoms such as vomiting and diarrhea, shock or hypotension, cardiac dysfunction, and in some cases rash and bilateral conjunctivitis [5, 7] . Similar to MIS-C, patients with MIS-A typically have evidence of prior SARS-CoV-2 infection by serologic testing [5, 7] .

As the coronavirus disease 2019 (COVID-19) pandemic spread in multiple waves throughout the United States, the occurrence of MIS-C peaks followed COVID-19 peaks by 2-5 weeks [5] . As of June 2021, 4018 MIS-C cases have been reported to the Centers for Disease Control and Prevention's (CDC's) national surveillance system [8] . In contrast, during the same period, fewer than 150 MIS-A cases have been reported to CDC or published in the scientific literature [7] . The temporal association of both MIS-C and MIS-A with the COVID-19 pandemic, their delayed occurrence by 2-6 weeks after acute SARS-CoV-2 infection, evidence of generalized inflammation, and multi-organ involvement suggest that both syndromes result from a dysregulated immune response to SARS-CoV-2 infection [9, 10] . However, the mechanisms driving this immune dysregulation and any potential predisposing environmental or host factors are unknown.

Data on patients with MIS-A published in the scientific literature and spontaneously reported to CDC by health departments and clinicians across the United States were previously analyzed to learn more about the clinical phenotype of the illness [7] . Due to the theoretical risk of MIS-A after exposure to any SARS-CoV-2-derived antigen, MIS-A was included in the list of potential adverse events following COVID-19 vaccination to be monitored as part of the Food and Drug Administration (FDA) emergency use authorization (EUA) [11] . In the present analysis, we assessed the clinical characteristics of MIS-A patients reported to CDC after COVID-19 vaccines were authorized for use among adults in the United States and we compared the demographic and clinical features of patients with and without a vaccination history. For patients who received a COVID-19 vaccine, we evaluated timing of vaccine receipt in relation to the onset of MIS-A and presence or absence of evidence of natural SARS-CoV-2 infection.

The analysis included clinical data from patients with suspected MIS-A identified from different sources, including spontaneous reporting by treating clinicians and state health departments, during the period 14 December 2020 to 30 April 2021. Clinical information was evaluated using the criteria in the CDC case definition for MIS-A (Table 1 ) [12] . The case definition included hospitalized patients with fever, primary and secondary clinical criteria, and laboratory evidence of inflammation and SARS-CoV-2 infection. Only patients who met the CDC case definition for MIS-A were included in the analysis. In addition to the clinical data, information about the COVID-19 vaccine type, timing, and the number of doses administered was reviewed. Available laboratory evidence of natural SARS-CoV-2 infection by molecular testing and serology for antinucleocapsid antibody, which is not induced by spike-based vaccines, was also evaluated. All COVID-19 vaccines currently available in the United States are based on SARS-CoV-2 spike protein. Some cases following COVID-19 vaccine were reviewed by infectious disease specialists and other medical experts in CDC's Clinical Immunization Safety Assessment Project which is established to review adverse events for vaccines used in the United States [13] . Information from MIS-A patients was obtained using a case report form developed to collect demographic, clinical, laboratory, imaging and treatment data or by using information from the Vaccine Adverse Event Reporting System (VAERS) and available medical records. VAERS is the national passive surveillance system for adverse events after immunization, which is jointly operated by CDC and FDA [14] .

Cases of MIS-A among vaccine recipients are required to be reported to VAERS as part of the COVID-19 vaccine EUAs [11] . A VAERS search was completed for reports received from 14 December 2020 to 30 April 2021, using text and automated coding searches for key terms from the MIS-A case definition. Cases were identified if one of the following three search strategies were fulfilled: (1) search for "systemic inflammatory response syndrome" which is the designated term by medical dictionary for regulatory activities (MedDRA) for the suspected diagnosis of multisystem inflammatory syndrome in adults; (2) text string search of "multi-system inflammatory syndrome, " "MIS-A, " "MISA, " or "MIS-C" found in symptoms text, laboratory data, illness at time of vaccination, preexisting illness, and Table 1 

A patient aged ≥21 years hospitalized for ≥24 hours, or with an illness resulting in death, who meets the following clinical and laboratory criteria. The patient should not have a more likely alternative diagnosis for the illness (eg, bacterial sepsis, exacerbation of achronic medical condition).

Subjective fever or documented fever (≥38.0 C) for ≥24 hours prior to hospitalization or within the first 3 days of hospitalization a and at least 3 of the following clinical criteria occurring prior to hospitalization or within the first 3 days of hospitalization. a At least 1 must be a primary clinical criterion. 

The presence of laboratory evidence of inflammation AND SARS-CoV-2 infection.

A. Elevated levels of at least 2 of the following: C-reactive protein, ferritin, IL-6, erythrocyte sedimentation rate, procalcitonin B. A positive SARS-CoV-2 test for current or recent infection by RT-PCR, serology, or antigen detection Abbreviations: IL-6, interleukin 6; RT-PCR, reverse transcription polymerase chain reaction; SARS-CoV-2, sever acute respiratory syndrome coronavirus 2. a These criteria must be met by the end of hospital day 3, where the date of hospital admission is hospital day 0. The case definition is available at https://www.cdc.gov/mis-c/mis-a/hcp.html.

allergies on the initial VAERS report form; or (3) combinations of the following preferred terms: (a) "pyrexia" and (b) "myocarditis, " or "conjunctivitis" or "rash"; and (c) "abdominal pain upper" or "thrombocytopenia" or "shock" or "encephalopathy"; and (d) "ESR increased" or "C-reactive protein increased" or "serum ferritin increased" or "procalcitonin increased. " Demographic and clinical data of MIS-A patients who received the COVID-19 vaccine were compared with those of MIS-A patients who did not receive the vaccine. Fisher exact tests were used to assess differences in categorical variables, and Mann-Whitney U tests were used to assess differences in continuous variables. When available, the timing of preceding COVID-19 illness onset, SARS-CoV-2 laboratory testing, and/ or COVID-19 vaccination dates were assessed and described in relation to MIS-A onset. The activity was determined to meet criteria for public health surveillance as defined in 45 CFR 46.102(l) [2] at the CDC.

December 2020 to 30 April 2021, 26 patients with suspected MIS-A were reported to CDC. Of these, 20 (77%) patients met the case definition for MIS-A and are included in the present analysis. The demographic and clinical characteristics of these MIS-A patients are summarized in Tables 2 and 3. The median age of the patients was 35 years (range, 21-66 years), and 13 (65%) patients were male (Table 2 ). Eight (40%) patients were non-Hispanic White, 7 (35%) were non-Hispanic Black, 2 (10%) were Hispanic, 2 (10%) were non-Hispanic Asian, and 1 (5%) was listed as multiple races. Overall, 16 (80%) of the 20 patients had a preceding COVID-19-like illness, 3 of the 4 patients without preceding COVID-19-like illness had a history of COVID-19 exposure, and previous exposure or illness status was unknown for 1 patient. All 20 patients had a positive viral or antibody test for SARS-CoV-2 confirming past or current infection: 15 (80%) patients tested positive by serology, 15 (80%) patients by reverse transcription polymerase chain reaction (RT-PCR), and 10 (50%) by both serology and RT-PCR. Previous COVID-19 illness was reported a median of 26 days (range 11-78 days) before MIS-A onset.

Seven MIS-A patients (35%) received COVID-19 vaccine before MIS-A onset. Demographic and clinical characteristics of these 7 patients were generally similar to the 13 MIS-A patients who had not received a COVID-19 vaccine (Table 2) , although a greater proportion of the vaccinated MIS-A patients (71%) were female. All 7 were reported to CDC and were found on the retrospective VAERS search. No additional MIS-A patient was identified by VAERS search alone. Four patients received the Pfizer-BioNTech vaccine, and 3 patients received the Moderna vaccine. Six of the patients had a history of prior COVID-19 illness and 1 patient had a history of exposure to patients with COVID-19 before MIS-A onset. Six of the 7 patients tested positive for SARS-CoV-2 by RT-PCR; the seventh patient that was negative by RT-PCR tested positive by anti-nucleocapsid serology (Table 3) . Among the 7 patients who received a COVID-19 vaccine, the first dose was given a median of 10 days (range, 6-45 days) before MIS-A onset ( Figure 1 ). Three of those 7 patients received the second dose of COVID-19 vaccine prior to MIS-A onset (4, 17, and 22 days before MIS-A onset). One patient received the second dose 18 days after MIS-A onset or 4 days after hospital discharge and had no reported complications following the second dose.

Almost all MIS-A patients developed gastrointestinal and cardiovascular manifestations. The predominant signs and symptoms included diarrhea (80%), abdominal pain (60%), vomiting (60%), rash (55%), headache (55%), and shortness of breath (45%) ( Table 2 ). Cough and conjunctival injection were reported in less than one-third of patients. The most common clinical findings reported in at least half of the patients included hypotension (80%), shock (75%), cardiac dysfunction (75%), myocarditis (70%), and acute kidney injury (60%). Almost all patients (95%) were treated with corticosteroids, and 65% of patients received at least 1 dose of intravenous immunoglobulin (IVIG). Six (46%) of the 13 patients treated with IVIG were given a second dose. The median number of days of hospitalization among MIS-A patients was 6 days (range, 2-41 days); 14 (70%) of the patients were admitted to the intensive care unit (ICU). Overall, 2 (10%) of the MIS-A patients died, of whom 1 had received COVID-19 vaccine.

MIS-A is a rare, poorly understood complication of SARS-CoV-2 infection believed to result from a delayed dysregulated immune response to the virus [9, 10] . The patients summarized in the present article have evidence of hyperinflammation, including fever, elevated laboratory markers of inflammation, and multisystem organ involvement. Onset of MIS-A occurred a median of about 1 month after initial SARS-CoV-2 infection, consistent with findings from other reports describing patients with MIS-A and MIS-C [5, 7] . The clinical manifestations of MIS-A are generally similar to those of MIS-C with both involving fever, gastrointestinal and cardiovascular involvement, and elevated laboratory markers of inflammation [5, 7] . As described in Table 1 , before diagnosing MIS-A other more likely alternative diagnosis such as bacterial sepsis should be excluded. Based on patients reported to CDC and published in the literature, MIS-A appears to occur much less frequently than MIS-C. As of May 2021, the total number of MIS-A patients reported to CDC and in the published literature are below 150, whereas over 3700 MIS-C cases have been reported to CDC as of the same month [7, 8] . Patients with MIS-A reported to date typically have a more severe illness course with higher rates b The 2nd dose in 1 patient was administered after recovery from MIS-A illness (Figure 1 ). [5] . The higher rate of cardiac complications in MIS-A may be due to increased recognition, diagnosis, and reporting of patients with a more severe illness course. Seven of the MIS-A patients in the present report received COVID-19 vaccine within 45 days (median 10 days) before MIS-A onset. However, all 7 patients also had evidence of prior SARS-CoV-2 infection. To date, no patient with MIS-A following COVID-19 vaccination without evidence of prior SARS-CoV-2 infection has been reported to CDC. Nune et al reported a 44-year-old woman who was hospitalized in the United Kingdom 2 days after receiving her first COVID-19 vaccination with arm pain. which progressed to fever, diarrhea, abdominal pain, rash, and hypotension [15] . The patient was reported to have tested negative for SARS-CoV-2 by serology and nasopharyngeal swabs. Two other publications reported similar patients who developed multisystem inflammatory syndrome after prior SARS-CoV-2 infection and receiving COVID-19 vaccine. Uwaydah et al reported a 22-year-old man from United Arab Emirates who was diagnosed with MIS-A 6 weeks after a mild COVID-19 illness [16] . The patient received the first dose of an inactivated SARS-CoV-2 vaccine about 30 days and second dose within hours before symptom onset of an illness that led him to visit the emergency department 4 days after vaccination; he was later diagnosed with MIS-A. Salzman et al reported 3 patients in the United States who were diagnosed with multisystem inflammatory syndrome after receiving COVID-19 vaccine [17] . Although patients with MIS-A commonly reported prior COVID-19 illness, in some patients the only evidence of SARS-CoV-2 infection was a positive serology. All current COVID-19 vaccines elicit an immune response to the spike protein, and vaccinated patients are expected to be seropositive for anti-spike protein antibodies but not for anti-nucleocapsid antibodies. In contrast, natural infection with SARS-CoV-2 results in humoral responses to both the spike and nucleocapsid proteins, providing a plausible laboratory method to distinguish the immune response to vaccination from that resulting from natural infection [19] . However, anti-nucleocapsid antibody is not uniformly detectable following COVID-19 illness, so its absence does not necessarily rule out natural infection with SARS-CoV-2. In particular, younger patients with mild illnesses during acute infection with SARS-CoV-2 may be less likely to mount a humoral immune response to nucleocapsid protein [19] .

The present analysis has several limitations. The MIS-A patients were spontaneously reported by health departments, but comprehensive surveillance for MIS-A does not currently exist, leading to potential underreporting of patients with MIS-A. Because VAERS is a passive surveillance system, underreporting of patients with MIS-A among vaccine recipients is also likely. Underreporting may particularly be true for MIS-A patients who have milder illness. Complications such as myocarditis were diagnosed by clinicians managing the patients and the methods used in the diagnosis were not standardized. Absence of imaging details may have limited our assessment of some findings such as pneumonia diagnosed on computed tomography. The treatment for MIS-A is generally adopted from treatment guidelines developed for MIS-C and primarily consists of administration of corticosteroid and IVIG either alone or in combination. These interventions, with possible addition of other adjunctive immunomodulatory treatment for patients not responding to IVIG and/or corticosteroids, were developed by expert opinion based on currently available evidence [20] [21] [22] . Additional treatment with vasopressors and antiplatelet and anticoagulation therapy may be required in some patients. Clinicians who identify patients with an illness similar to MIS-A in temporal association with the COVID-19 vaccine are encouraged to report such cases through VAERS; COVID-19 vaccine providers are required to report suspected MIS-A to VAERS as part of the EUAs. A case definition for MIS-A developed by CDC summarized in Table 1 can be used to assess patients suspected of having the illness [12] . CONCLUSION MIS-A is a rare complication of SARS-CoV-2 infection. Patients developing MIS-A in temporal association with COVID-19 vaccination have been reported, although all patients reported to date also had evidence of prior SARS-CoV-2 infection. The potential contribution of vaccination to the pathogenesis of MIS-A in these patients is unclear. It is reassuring that, to date, no cases of MIS-A have been reported among vaccine recipients in the United States without evidence of prior SARS-CoV-2 infection despite the administration of COVID-19 vaccines to millions of recipients. Clinicians should maintain a high index of suspicion for the occurrence of similar patients and report suspected cases of MIS-A and other serious adverse events following vaccination to VAERS.

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outside of the submitted work; consulting fees from Goddard systems for consultation to day care centers about COVID response; honoraria paid to self as Associate Editor, American Academy of Pediatrics Red Book; unpaid position as ex officio member of Committee on Infectious Diseases, American Academy of Pediatrics. K.T. reports being Hopkins Site PI for the Pfizer COVID-19 vaccine study in adults and children; serving on a number of Data and Safety Monitoring boards for non-COVID related studies for Merck, Takeda, Intralytix, PATH, and NIH and serving on 2 NIH Safety Monitoring committees related to vaccines of therapeutics for COVID-19. E. S. reports payments made to the institution for research studies on which they are investigator from the NIH outside of the submitted work and serving on the Data Safety Monitoring Board for an NIH-funding study (NIH Comparison of High vs Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.