Case Reports and Clinical Images

Multisystem Inflammatory Syndrome in an Adult After COVID-19 Vaccination

Kevin GW Chien, MD1, Lisa Duffett, MD2, Dimitrios Scarvelis, MDCM2*

1Department of Medicine, University of Ottawa, Ottawa, ON, Canada;

2Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada


Multisystem inflammatory syndrome in adults (MIS-A) is a hyperinflammatory syndrome associated with COVID-19, for which our understanding of diagnosis and treatment continues to evolve. We present a case of a 62-year-old woman with fever, fatigue, and general malaise with pancytopenia and significantly elevated inflammatory markers 3½ weeks after the first dose of her Pfizer-BioNTech COVID-19 vaccine consistent with MIS-A post-vaccination. Most cases of MIS-A have been associated with previous COVID-19 infection, but our case highlights that MIS-A is a potentially rare adverse event post-vaccination, even in individuals without previous COVID-19 infection.


Le syndrome inflammatoire multisystémique chez les adultes (SIM-A) est un syndrome hyperinflammatoire associé à la COVID-19 pour lequel notre compréhension du diagnostic et du traitement ne cesse d’évoluer. Nous rapportons le cas d’une femme de 62 ans éprouvant de la fièvre, de la fatigue et un malaise général qui a présenté une pancytopénie et une élévation considérable des marqueurs inflammatoires trois semaines et demie après avoir reçu sa première dose du vaccin contre la COVID-19 de Pfizer-BioNTech, ce qui correspond à un SIM-A post-vaccination. La plupart des cas de SIM-A sont associés à une infection antérieure à la COVID-19, mais ce cas précis met en évidence que le SIM-A est un événement indésirable potentiel rare qui survient après la vaccination, même chez les personnes qui n’ont jamais contracté la COVID-19.

Key words: vaccine, COVID-19, Multisystem inflammatory syndrome

Corresponding Author: Dimitrios Scarvelis:

Submitted: 24 November 2021; Accepted: 7 February 2022; Published: 21 June 2022


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Case Report

A 62-year-old woman presented to hospital with a 5-day history of fever of up to 40°C, fatigue, general malaise, and weakness. She felt lethargic but was otherwise oriented. She had mild shortness of breath but no cough or chest pain. She had nausea and vomiting but no diarrhea or abdominal pain. She had no headache, vision changes, myalgias, or arthralgias. She had no recent travel or exposure to ticks or insects. She had no night sweats or unintentional weight loss. Her past medical history was significant for BRCA2 positive breast cancer treated with bilateral mastectomy and oophorectomy and was stable on adjuvant letrozole. She received her first dose of the Pfizer-BioNTech COVID-19 vaccine 3½ weeks prior to presentation.

Her vitals on admission were as follows: temperature, 39.1°C, blood pressure, 90/57 mmHg, heart rate, 74 beats per minute, respiratory rate, 22 breaths per minute, and oxygen saturation, 95% at room air. She had bilateral nonpurulent conjunctivitis. She had no nuchal rigidity. Her cardiac examination was normal. Her respiratory examination revealed clear breath sounds bilaterally. Her abdomen was soft and nontender, without hepatosplenomegaly. She had no palpable cervical, axillary, or inguinal lymphadenopathy. She had no joint effusions or tenderness. Her skin was normal with no rashes, erythema, or desquamation of her fingers or toes.

Initial laboratory findings revealed pancytopenia, significantly elevated inflammatory markers, elevated troponins, and hypertriglyceridemia (Table 1). Blood culture, urine culture, and respiratory virus panel were negative. She had two COVID-19 nasopharyngeal polymerase chain reaction (PCR) tests, both of which were negative. Her chest x-ray was normal. Her electrocardiogram (ECG) indicated normal sinus rhythm. She also had extensive rheumatologic and infectious disease investigations, which eventually were negative (Table 1).

Table 1. Laboratory investigations

Reference range Day 0 Day 1 Day 2 Day 3 Day 6 Day 10 (discharge) 1 month after discharge
Leukocytes (×109/L) 3.5–10.5 2.6 2.1 5 8 9 4.3 5.7
Hemoglobin (g/L) 115–155 114 109 100 102 103 94 110
Platelets (×109/L) 130–380 36 31 30 37 155 375 263
Neutrophils (×109/L) 2–7.5 2.5 1.9 8 8.1 1.9 4.3
Lymphocytes (×109/L) 0.8–3.3 0.1 0.1   0.6 1.6 1.1
D-dimer <500 36,571 >44,000 44,000 34,387 12,888 2565 439
Fibrinogen (g/L) 1.9–4.5 2.9 2.5 1.8 1.8 1.3 1.6 3
Ferritin (µg/L) 13–240 42,826 50,491 44,585 36,273 7635 3185 290
C-reactive protein (mg/L) <10 243.8 202.6 169.7 161.5 48.1 15.4 0.7
Erythrocyte sedimentation rate (mm/h) 0–28 29 8
Lactate (mmol/L) 0.5–2.5 1.7
Na (mmol/L) 136–144 130 135 137 133 138 140
K (mmol/L) 3.5–5.1 3.5 3.5 3 3 3.2 4
Cl (mmol/L) 98–107 93 100 104 100 101 103
Creatinine (umol/L) 49–84 90 71 67 62 61 60
Total bilirubin (umol/L) <12 12 13 9 11 11 8 5
AST (U/L) 12–29 184 174 153 186 343 127 24
ALT (U/L) 8–33 60 48 42 58 180 127 26
LDH (U/L) 99–186 1298 1456 1305 1185 628 455 220
ALP (U/L) 46–118 86 79 74 90 122 100 86
GGT (U/L) 8–51 64 60 54 63 96 79 28
CK (U/L) 39–192 1086 1100 776 458 123 64
Troponin T (ng/L) <14 41 51 74 46 20
Triglyceride (mmol/L) <1.7 4.61
Cryoglobulin Absent
C3 (g/L) 0.9–1.8 1.12
C4 (g/L) 0.1–0.4 0.24
Rheumatoid factor (kIU/L) <14 <10
ANA Negative Negative
ENA Negative Negative
ANCA Negative Negative
Anti-GBM <20 <3
HIV Negative
Hepatitis B Surface Ag Nonreactive
Hepatitis B surface Ab 1
Hepatitis C Ab Nonreactive
Mycoplasma pneumoniae PCR (throat) Negative
Chlamydophilia pneumoniae PCR (throat) Negative
Fungus blood culture Negative
Mycobacteria blood culture Negative
Arbovirus Nonreactive
EBV IgG Ab Nonreactive
EBV viral capsid IgM Nonreactive
CMV IgM Nonreactive
Histoplasma serology Nonreactive
Leptospira serology Nonreactive
Borrelia burgdorferi serology Nonreactive
Rickettsia serology Nonreactive
Syphilis serology Nonreactive
Parvovirus serology Nonreactive
Respiratory virus panela Negative

Notes: AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; CK, creatine kinase; ANA, anti-nuclear antibodies; ENA, extractable nuclear antigen antibodies; ANCA, antineutrophil cytoplasmic antibodies; Anti-GBM, anti-glomerular basement membrane antibodies; EBV, Epstein–Barr virus; CMV, cytomegalovirus; HIV, human immunodeficiency virus.

aTests for influenza A, influenza B, respiratory syncytial virus, parainfluenza virus 1, 2, 3, and 4, human metapneumovirus, adenovirus, enterovirus, bocavirus Hbov, rhinovirus, coronavirus Oc43, coronavirus 229e, and coronavirus Nl63.

Her initial clinical presentation prompted a clinical suspicion for hemophagocytic lymphohistiocytosis. A bone marrow biopsy revealed full spectrum trilineage hematopoiesis with very rare hemophagocytic cells. However, a small population of CD4–CD8 double negative T cells were identified. Furthermore, a soluble interleukin-2 receptor (sCD25) level was drawn, which later returned normal.

As there was no clear source of fever, she had computed tomography (CT) scans of the head, chest, abdomen, and pelvis, which revealed pulmonary edema, a stable thyroid nodule, a right adnexal mass, and trace pelvis ascites. Follow-up pelvic magnetic resonance imaging (MRI) confirmed that the adnexal mass was a pedunculated fibroid. MRI of the brain was conducted to assess for encephalitis, and nonspecific smooth dural thickening and enhancement without leptomeningeal changes were observed with no evidence of leptomeningeal meningitis or encephalitis.

Given these findings, a lumbar puncture was done, which revealed a total nucleated count of 9 (0–5 × 106/L), red blood cell count of 7 (0–5 × 106/L), normal glucose, and mildly elevated protein at 0.63 (0.17–0.61 g/L). Cerebrospinal fluid (CSF) culture was negative and flow cytometry on CSF revealed no abnormalities.

Her treatment consisted of intravenous crystalloids for hypotension on admission and piperacillin-tazobactam and vancomycin for empiric treatment of bacterial infections, although none were ultimately identified. She also received a dose of furosemide as she developed clinical findings consistent with mild pulmonary edema. At the time of discharge, her leukopenia and thrombocytopenia had normalized, and she had improvement, but not complete normalization, of her inflammatory markers. Her provisional diagnosis at the time of discharge was multisystem inflammatory syndrome in adults (MIS-A).


Reports of a multisystem inflammatory syndrome in children (MIS-C) following COVID-19 infection with similarities to Kawasaki disease were first reported in April 2020.1,2 Subsequently, cases of a similar entity in adults who had COVID-19 began to surface, prompting the Centers for Disease Control and Prevention (CDC) to release a case series on MIS-A in October 2020.3 Their initial case definition consisted of five criteria (Table 2). The CDC subsequently updated their case definition in May 2021 following the publication of additional case reports of MIS-A (Table 2).4

Table 2. Case definitions for Multisystem Inflammatory Syndrome in Adults (MIS-A)3,4,10

CDC (October 2020) CDC (May 2021) Brighton Collaboration Case Definition (definitive case)
1. Severe illness requiring hospitalization in case of person aged ≥21 years
2. Positive test for current or previous SARS-CoV-2 infection (nucleic acid, antigen, or antibody) during admission or in the previous 12 weeks
3. Severe dysfunction of one or more extrapulmonary organ systemsa
4. Laboratory evidence of severe inflammation (elevated CRP, ferritin, D-dimer, or IL-6)
5. Absence of severe respiratory illness
1. Person aged ≥21 years hospitalized for ≥24 h, or with an illness resulting in death
2. Subjective or documented fever (≥38°C) for ≥24 h
3. At least three of the following with at least one being a primary clinical criterion:
Primary clinical criteria
• Severe cardiac illnessb
• Rashes and nonpurulent conjunctivitis
Secondary clinical criteria
• New-onset neurologic signs and symptomsc
• Shock or hypotension
• Abdominal pain, vomiting, or diarrhea
• Thrombocytopenia
4. Elevated levels of at least two of the following: CRP, ferritin, IL-6, ESR, procalcitonin
5. Positive SARS-CoV-2 test (RT-PCR, serology, or antigen) during the current illness
1. Age ≥21 years
2. Fever for ≥3 consecutive days
3. At least two of the following:
o Mucocutaneous featuresd
o Abdominal pain, vomiting, or diarrhea
o Shock or hypotension
o Neurologic symptomse
4. Elevated levels of any of the following: CRP, ESR, ferritin, or procalcitonin
5. At least two of the following:
o Elevated BNP, NT-pro-BNP, or troponin
o Neutrophilia, lymphopenia, or thrombocytopenia
o Evidence of cardiac involvement by echocardiography or physical stigmata of heart failure
o Changes in EKG consistent with myocarditis or myopericarditis
6. Any of the following:
o Laboratory confirmed SARS-CoV-2 infection (RT-PCR, serology, or antigen)
o Personal history of confirmed COVID-19 within 12 weeks
o Close contact with the known COVID-19 patient within 12 weeks
o Following SARS-CoV-2 vaccination if a known or suspected COVID-19 infection has not occurred in the preceding 12 weeks

Notes: CDC, Centers for Disease Control and Prevention; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin-6; EKG, electrocardiogram.

aIncludes hypotension or shock, cardiac dysfunction, arterial or venous thrombosis or thromboembolism, or acute liver injury.

bIncludes myocarditis, pericarditis, coronary artery dilatation/aneurysm, or new onset right or left ventricular dysfunction, 2nd/3rd degree AV block, or ventricular tachycardia.

cIncludes encephalopathy, seizures, meningeal signs, or peripheral neuropathy.

dIncludes rashes, erythema, or cracking of the lips/mouth/pharynx, bilateral nonexudative conjunctivitis, or erythema/edema of the hands and feet.

eIncludes altered mental status, headache, weakness, paresthesias, or lethargy.

The initial clinical trials for messenger RNA (mRNA)-based COVID-19 vaccines did not report MIS-A post--vaccination.5,6 Since then, the majority of individuals developing MIS-A post-vaccination had previous COVID-19 infection.7 However, there have been recent case reports of patients without previous COVID-19 infection developing MIS-A following the COVID-19 vaccination, the first one following the Pfizer-BioNTech vaccine and another following the Astra-Zeneca vaccine.8,9 Although the current CDC case definition of MIS-A does not account for this possibility, it is accounted for by the Brighton Collaboration Case Definition for MIS-C/A released in February 2021 (Table 2).10 Our patient fulfilled the criteria for Level 1 of diagnostic certainty to be considered a definitive case of MIS-A post-vaccination.

The evolving case definition of MIS-A has made it challenging to classify cases. Although our patient was a definitive case according to the Brighton Collaboration,10 she did not fulfill the current CDC case definition because she did not have laboratory evidence of a SARS-CoV-2 infection and she did not fulfill either of their primary clinical criteria (she did not have severe cardiac illness and she only had non--purulent conjunctivitis with no rash). Of note, her CT chest indicated evidence of pulmonary edema, raising the possibility that she might have had new onset of left ventricular dysfunction; however, she did not have a transthoracic echocardiogram during her admission.

The diagnosis of MIS-A post-vaccination was further supported by the lack of alternative diagnosis to explain her presentation. Her elevated ferritin initially prompted a work-up for hemophagocytic lymphohistiocytosis (HLH), but bone marrow biopsy and sCD25 did not support this. Furthermore, she did not have any lymphadenopathy or organomegaly to support a diagnosis of HLH. Her broad rheumatologic and infectious disease investigations were also negative. The only notable finding in her investigations was nonspecific smooth dural thickening and enhancement, for which the differential includes pachymeningeal neoplastic infiltration, idiopathic dural thickening, and infectious etiologies. There was no evidence of metastatic disease, and her CSF was almost normal with normal flow cytometry and no evidence of infection.

Cases of MIS-A tend to have more severe cardiac involvement, sometimes requiring intensive care admission.3 It is interesting that our patient’s presentation was milder; however, we appreciate that there is a spectrum of presentations of MIS-A. Owing to our patient’s milder presentation, she did not require targeted treatment, unlike other cases. Most cases of MIS-A have been treated with a combination of intravenous (IV) immunoglobulin and steroids.3 Although there is no established treatment regimen for MIS-A, the American College of Rheumatology has provided guidance for the management of MIS-C, and recommend IV immunoglobulin and/or steroids as first line of treatment, and anakinra for refractory cases.11

Although many suspect MIS-C and MIS-A exist on a continuum because of their clinical and laboratory similarities, it remains unclear whether they occur through the same underlying mechanism. Many believe the syndromes are post-infectious phenomena because of immune dysregulation as opposed to being directly caused by viral infection.10 This would support the argument that MIS-A can occur post-vaccination in a susceptible individual. Flow cytometry from our patient’s bone marrow biopsy interestingly noted a small population of CD4/CD8 double negative T cells. Previous studies have suggested that these double negative T cells play an important role in autoimmune and inflammatory conditions.12 Patients with autoimmune conditions, such as systemic lupus erythematosus and Sjogren’s disease, have been noted to have higher levels of double negative T cells in their circulation.13 Although our patient did not have any history of autoimmune disease, it raises the possibility that these double negative T cells played a role in her hyperinflammatory response to her COVID-19 vaccine.

The possibility of MIS-A post-vaccination has ramifications for subsequent vaccine doses. Our patient experienced MIS-A after her first dose of the Pfizer-BioNTech vaccine. Given the severity of her presentation, she was recommended not to receive the second dose of an mRNA-based vaccine. Notably, she had SARS-CoV-2 antibody testing done 2 months after her presentation to hospital. She had no antibodies to the SARS-CoV-2 nucleocapsid protein, which develop following exposure to the virus but not through vaccination. Therefore, this adds support to the theory that she had no previous infection with COVID-19, with a caveat that a negative result does not rule out previous infection. She also had antibodies to the spike protein of SARS-CoV-2 (203.3 U/mL; positive > 0.79 U/mL), but it is unclear what threshold provides immunity. Further investigations are required to determine whether all COVID-19 vaccines can precipitate MIS-A, or if this is specific to certain vaccines. As MIS-C and MIS-A are considered adverse events of special interest following the COVID-19 vaccination, her case was reported to Public Health for post-marketing surveillance.

In conclusion, this case highlights that MIS-A can occur post-vaccination in individuals without previous COVID-19 infection and contributes to the growing literature on MIS-C and MIS-A. Furthermore, the incidental finding of our patient’s population of CD4/CD8 double negative T cells may provide further clues to the pathophysiology of this syndrome. Lastly, MIS-C and MIS-A are considered adverse events of special interest following the COVID-19 vaccination and must be reported to Public Health to allow the medical community to better understand this new syndrome.


The patient provided informed consent for publication of this case report.

Author Contributions

All authors contributed to the conception and design of the work. Kevin Chien drafted the manuscript and all authors revised it critically and gave final approval to the version for publication.


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