natural severe acute respiratory syndrome coronavirus 2 infection and coronavirus disease vaccination, Tennessee, USA, 2021. A) Lung...Notable findings on gross internal autopsy examination included a 525-mL pericardial effusion and cardiac enlargement, as well as a 5-L hemoperitoneum and a 20-cm diameter perisplenic hematoma. Microscopic examination of the lungs showed diffuse congestion, increased intra-alveolar macrophages, multifocal hemorrhage, capillaritis, and microthrombi throughout (-, panels A, B). We observed no viral inclusions or diffuse alveolar damage. Trachea and bronchi showed mild tracheobronchitis. Sections of the heart showed multifocal myocarditis with mixed inflammatory infiltrate, myocyte necrosis, and numerous microthrombi. We also identified disseminated microvascular thrombosis in the heart, stomach, kidneys, and liver (-, panels C–F). Gram stain results were negative on lung and heart tissue. SARS-CoV-2 RT-PCR was negative on lungs, trachea, bronchi, and heart. Conclusions This fatal case of MIS-A occurred after full COVID-19 vaccination in a patient with prior natural SARS-CoV-2 infection suspected 6 weeks before MIS-A symptom onset. Serum antibody results before IVIg infusion indicated the patient was previously infected with SARS-CoV-2 and was vaccinated with a COVID-19 vaccine. Antibodies to the nucleocapsid protein are the most sensitive target for serologic diagnosis for natural infection (P.D. Burbelo et al., unpub. data, https://doi.org/10.1101/2020.04.20.20071423External Link), and these antibodies are not present following COVID-19 vaccination alone. In addition, clinical history was compatible with natural infection beginning 6 days before the first mRNA vaccine dose and consistent with negative SARS-CoV-2 nucleocapsid IgM on testing during hospitalization. The patient demonstrated similar clinical findings to previously reported MIS-A cases, including fever for 3 consecutive days, laboratory evidence of inflammation, neurologic and mucocutaneous clinical findings, and severe cardiac illness that included systemic hypotension progressing to cardiogenic shock (1,5). These criteria meet the CDC case definition for MIS-A, as well as a definitive case at level 1 of diagnostic certainty by the Brighton collaboration case definition for MIS-A and MIS-C (10). In addition, the histopathologic findings of capillaritis and multiorgan microvascular thrombosis in association with clinical symptoms and laboratory findings are compatible with MIS-A (1,11). Substantial blood loss on gross examination may represent a diffuse intravascular coagulation–type picture in which diffuse microthrombosis depleted platelets and clotting factors. The etiology for clinical deterioration was likely multifactorial, although considerable cardiac compromise in the setting of high fluid volumes and intraperitoneal hemorrhage may have contributed to multiorgan failure Whether mRNA COVID-19 vaccination contributed to MIS-A onset in this case is unclear, and future epidemiologic studies are needed to understand whether an association exists. The immunopathology leading to hyperinflammation causing MIS-A after SARS-CoV-2 infection remains unknown, although postinfection immune dysregulation is consistent among reported cases. Notably, MIS-A has not been reported among adult participants of COVID-19 vaccine trials (10), and no direct evidence exists to support vaccine alone as the primary etiology in this