Fatal multisystem inflammatory syndrome; This case has been considered invalid due to lack of clear reporter's causality assessment between the event and the suspect drug.  This is a literature report for the following literature source(s): PRIVACY  An adult patient received COVID-19 Vaccine - Manufacturer Unknown, (Batch/Lot number: unknown) as dose number unknown, single for covid-19 immunisation. The patient's relevant medical history and concomitant medications were not reported. The following information was reported: MULTISYSTEM INFLAMMATORY SYNDROME IN ADULTS (death, medically significant), outcome "fatal", described as "Fatal multisystem inflammatory syndrome"; DRUG INEFFECTIVE (death, medically significant), COVID-19 (death, medically significant), outcome "fatal" and all described as "SARS-CoV-2 natural infection". The patient date of death was unknown. The reported cause of death was multisystem inflammatory syndrome. It was not reported if an autopsy was performed.  Additional information: Withheld. Fatal multisystem inflammatory syndrome in adult after SARS-CoV-2 natural infection and COVID-19 vaccination.    Follow-up (19Jan2022): This is a literature report for the following literature source(s): "Fatal multisystem inflammatory syndrome in adult after SARS-CoV-2 natural infection and COVID-19 vaccination", 2021; Vol: 27, pgs: privacy  Updated Information Included: Dosage Regimens (dose number), Event information (new event added, event details, outcome)  Additional Information: Fatal Multisystem Inflammatory Syndrome in Adult after SARS-CoV-2 Natural Infection and COVID-19 Vaccination: A multisystem inflammatory syndrome in children  and adults occurring after coronavirus disease (COVID-19) has been identified; onset is 4-6 week after severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) infection (1-3). A case definition for adult has been developed by Centers for Disease Control and Prevention (CDC) (4); after vaccination is rear and remains of great clinical and public health interest (5). We report a case study and histopathologic finding from a MIS-A case after SARAS-COV-2 infection and subsequent complete COVID-19 vaccination. The Patient: The patient was a healthcare worker in his 30s with no notable medical history. In Dec2020, he experienced mild COVID-19 like illness symptoms, including fatigue and loss of taste and smell. He did not undergo testing for SARS-COV-2 at that time and was unaware of need for isolation. Six days after onset of COVID-19 like symptoms, and when fully recovered, the patient received the first dose of Pfizer/ Biontech mRNA COVID-19 vaccine. He received the second dose 20 days later. After the second dose, he reported fatigue and malaise, which resolved within 2 days. Twenty-two days after receiving the second dose of the COVID-19 vaccine, he had onset of new fever, malaise, headache, and odynophagia. He was examined by an outpatient medical provider. Diagnostic testing was notable for negative COVID-19 test by reverse transcription PCR (RT-PCR), negative rapid influenza antigen, and negative rapid antigen detection for group A Streptococcus. Four day later, the patient visited an emergency department because of worsening symptoms. Assessment of vital signs revealed a temperature of 37.2 C, heartrate 113beats/min, and blood pressure of 117/66 mmHg. Physical examination identified right sided cervical lymphadenopathy, marked bilateral conjunction erythema, and a faint popular rash on the pelvis and left flank. Laboratory testing revealed a peripheral-blood leukocyte count pf 11000 cells/ul, 93.5% segmented neutrophils, and thrombocytopenia with a platelet count 110,000 / U (Table). Portable chest radiograph result were without no-table findings.  On hospital day 2, the patient remained febrile and tachycardia (heart rate 90-135 beats/min) and had blood pressure of 92/56 mmHg. Diagnostic evaluation related a negative SARS-CoV-2 RT-PCR test but positive serologic negative SARS-Cov-2 nucleocapsid IgG. Additional diagnostic tests were conduce (Table). Inflammatory markers showed elevated C-reactive protein at 284.0 mg/L, serum ferritin at 1434.9 ng/mL, and troponin-I at 18.0 ng/ml. On the evening of hospital day 2, the patient received 75g of intravenous immune globulin (IVIG). Early morning on hospital day 3, the patient had an acute change in mental- status, including confusion and global aphasia. An emergent computed tomography scan of head was negative for cerebrovascular accident and showed normal brain parenchyma and no evidence of acute infarction, mass, or hemorrhage. On completion of the scan, the patient was found nonresponsive and without a pulse. He underwent multiple round of advance cardiac life support, resulting in return of spontaneous circulation. A chest radiograph showed an enlarge cardiac silhouette, and an echocardiogram showed severe biventricular dysfunction, severe global hypokinesis of the left ventricle, and left ventricular ejection fraction of 20 %. The patient received a second dose of IVIg and intravenous steroids and extracorporeal membrane oxygen action support was initiated. On hospital day 4, severe multiple organs failure continue to progress. The patient died on hospital day 4. Figure: Histopathologic findings in a fatal case of multisystem inflammatory syndrome in adult after natural severe acute respiratory syndrome coronavirus 2 infection and coronavirus disease vaccination, (withheld), 2021, A) Lung tissue shows capillaritis characterized by neutrophilic inflammation and necrosis within interalveolar septa (arrowhead). Fibrin and organizing intraluminal microthrombi in small arteries are also seen (arrows). Original magnification 20x. B) Higher magnification of fibrin microthrombus within a lung vessel (arrow). Original magnification 63x. C) Heart tissue shows myocarditis with myocyte necrosis and mixed inflammatory infiltrate. Original magnification 20x D) Higher magnification cardiac vessel showing microthrombus and perivascular mononuclear inflammatory infiltrate (arrow). Original magnification 40x. E) Stomach tissue shows submucosal microthrombi with perivascular lymphocytic infiltrate. Original magnification 63x. F) Kidney tissue shows multiple fibrin thrombi in glomerular (arrow) and interstitial capillaries (arrow). Original magnification 40x. We reviewed the patient medical history and clinical chart. We assessed serum sample collected during the hospital course before and after IVIg, and we determined endpoint titers to SARS-CoV-2 nucleocapsid (IgM and IgC) and spike receptor binding domain with neutralization function against spike protein (6,7). The endpoint titer was a modified protocol based on Stadlbauer at al. (8). We completed an autopsy and sent formalin-fixed, paraffin-embedded tissues to CDC. Microscopic examination of lung, node, liver, heart, spleen, kidney and stomach tissue samples was performed and lungs and heart. An RT-PCR away for SARS-CoV-2 was performed on RNA extracted from formalin-fixed, paraffin-embedded tissues from lungs, airway, and heart by methods previously published (9). This activity was review by CDC and was conducted consistent with applicable federal law and policy. Serum antibody results drawn before IvIg infusion were negative for SARS-CoV-2 IgM but positive were negative for SARS-CoV-2 IgM but positive for IgM. Serum result had a high titer of anti-spike receptor binding domain antibody both before and after IVIg (1:7500) compared with a naturally infected SARS-CoV-2-positive control (1:4000). In addition, the pre-IVIG sample serum result demonstrated neutralizing function. 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, increase intra-alveolar macrophages, multifocal hemorrhage, capillaritis, and microthrombi through out (Figure, panels A, B). We observed no viral inclusions or diffuse alveolar damage. Trachea and bronchi showed mild tracheobronchitis. Sections of the heart 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, kidney, and liver,. Gram stain result were negative on lung and heart tissue. SARS-CoV-2 RT-PCR was negative on lungs, trachea, bronchi, and heart.  Conclusion: This 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 symptoms 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. Antibody to the nucleocapsid protein are the most sensitive target for serologic diagnosis for natural infection amd these antibodies are not present following COVID-19 vaccination alone. In addition, clinical history was compatible with natural infection beginning 6days 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, neurological and mucocutaneous clinical finding, 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 definitive case at level 1 diagnostic certainty by the collaboration case definition for MIS-A and MIS-C. In addition, the histopathologic finding of capillaritis and multiorgan microvascular thrombosis in associated with clinical symptoms and laboratory findings are compatible with MIS-A (1,11). Substantial blood loss on gross examination may represent a diffuse micro thrombosis depleted platelets and clotting factors. The etiology for clinical deterioration was likely multifactorial, although considerable cardiac compromised in the setting of high fluid volume and intraperitoneal hemorrhage may have contributed to multiorgan failure. Weather mRNA COVID-19 vaccination contributed to MIS-A onset in this case in unclear, and future epidemiologic studies are needed to understand wheather an association exists. The immunopathology leading to hyper inflammation causing MIS-A after SARS-CoV-2 infection remains unknown, although post infection immune dysregulation is consistent among reported case. Notably, MIS-A has not been reported among adult participants of COVID-19 vaccine trials (10), and no direct evidence exist to support vaccine along as the primary etiology in this case. This article further emphasize the importance of COVID-19 prevention, for which infection prevention strategies and vaccination remain our greatest defense. This work was supported by (withheld)   No follow-up attempts are possible; information about lot/batch number cannot be obtained.; Sender's Comments: Based on temporal relationship the possibility of causal association between the reported events multisystem inflammatory syndrome and the suspect drug BNT162B2 cannot be excluded.   The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to regulatory authorities, Ethics Committees, and Investigators, as appropriate.; Reported Cause(s) of Death: Fatal multisystem inflammatory syndrome