Background

Multisystem inflammatory syndrome in children (MIS-C) was first reported in mid-April 2020 by Riphagen et al in the UK and Verdoni et al in Italy, when emerging cases of a hyperinflammatory shock syndrome following COVID-19 infection were identified in children.1 2 Since these initial reports, over 4000 cases and 37 deaths have been reported in the USA.3 MIS-C is considered a post-infectious inflammatory condition, given the low or nonexistent viral loads and treatment response to immunomodulation. Based on early case series, approximately 60% of patients with MIS-C have positive serology with negative PCR at the time of diagnosis, 34% are both serology and PCR positive, and 5% have negative results for both tests.2 4–8 MIS-C has specific clinical criteria per the US Centers for Disease Control and Prevention (CDC) including age <21 years, fever ≥24 hours, laboratory markers of inflammation, involvement of two or more organ systems, no alternative plausible diagnosis and a recent or current COVID-19 infection or exposure.9 WHO has similar criteria with minor variations including fever ≥3 days, and no specific timeframe for previous COVID-19 exposure.10

The pathophysiology of MIS-C is still being clarified, but it is distinct from that occurring in acute COVID-19 infection. Patients with acute severe COVID-19 show lymphopenia, T-cell activation and elevated interferon-gamma levels, whereas the summation of interleukin 10 and tumor necrosis factor alpha levels has been found to be predictive of MIS-C over acute COVID-19 infection.11 12 Myocarditis has become a well-recognised immune-mediated vaccine reaction in younger patients. The proposed mechanisms for this include mRNA immune reactivity and antibody cross reactivity as well as hormonal differences due to the male predominant prevalence of myocarditis. Although the clinical diagnosis of MIS-C has significant overlap with Kawasaki disease (KD), the underlying immunological cascades likely differ given the differing cytokine profiles.13

Theoretical concerns have been raised about COVID-19 vaccine triggering MIS-C. Recently, Nune et al described multisystem inflammatory syndrome in an adult after COVID-19 mRNA vaccine (MIS-V) in the absence of acute COVID-19.14 No similar reports of this entity in those younger than 21 years of age have yet been identified to our knowledge. We evaluated a patient in our medical centre with MIS-C who had no evidence of past or recent infection with COVID-19 but had received two doses of the Pfizer BioNTech COVID-19 vaccine 12 weeks prior to hospitalisation, raising the possibility that MIS-C was related to vaccination.

Case presentation

A woman in her late teens presented to our hospital emergency department with fevers up to 40°C for 4 days, chills, sweats, tachycardia, shortness of breath, fatigue and a throbbing headache. Fevers were only briefly responsive to antipyretics. At the time of presentation, she also described mid-sternal chest pressure resolving with ambulation, diffuse myalgias, nausea, one episode of vomiting and four episodes of watery non-bloody diarrhoea.

The patient had a history of dysmenorrhea managed by oral contraceptives (ethinyl estradiol and norgestimate). Her prior surgical history included an appendectomy 6 months prior. SARS-CoV-2 PCR testing done both 3 and 2 days prior to admission were negative. She had received weekly to biweekly PCR testing in the 3-month period prior to presentation, given her employment at a long-term care facility. All PCR tests were negative. The patient received her first dose of the Pfizer BioNTech COVID-19 vaccine approximately 12 weeks prior to her presentation, with her second dose 20 days later. Six weeks prior to her presentation, the patient’s two younger siblings developed febrile illnesses of unclear aetiology that lasted 36 hours and self-resolved. They were seen at an urgent care facility at that time and had negative SARS-CoV-2 PCR testing. They did not have COVID-19 antibody testing performed at that time or subsequently. No one else in the home was sick and the final diagnosis of the siblings at the urgent care facility was an unspecified viral illness. At that time, the patient developed dysuria and haematuria without vaginal discharge, spotting or abdominal pain and was prescribed nitrofurantoin at an urgent care facility for treatment of a urinary tract infection. She had no fever or other symptoms at that time and her symptoms resolved shortly thereafter with antibiotics. The patient had no known contact with COVID-19 positive individuals and no travel, animal or other environmental exposures.

Vital signs in the emergency department were notable for: temperature 39.6°C, heart rate 121 beats/min, blood pressure 122/70 mm Hg and oxygen saturation 100% in room air. Anthropometrics included: weight 77 kg, height 165.1 cm and body mass index 28.3 kg/m². The patient was ill appearing with persistent tachycardia despite normal saline boluses (2 L in total) and maintenance fluids. Her blood pressure remained normal. Her initial examination was otherwise unremarkable apart from bilateral non-exudative conjunctivitis.

Investigations

See table 1 for pertinent laboratory values from the patient’s admission, which were notable for absolute lymphocytopenia and elevated inflammatory markers, troponin, fibrinogen, D-dimer and soluble IL-2 receptor. Complete metabolic panel and complete blood count (CBC) with differential were unremarkable. Infectious workup including SARS-CoV-2 PCR, qualitative nucleic acid testing for influenza A/B, respiratory syncytial virus, and human metapneumovirus, as well as Lyme antibody were all negative. Blood and urine cultures were without growth. She had a normal chest x-ray; ECG showed normal sinus rhythm with rsR’ pattern which was considered a likely normal variant in the setting of normal QRS duration and no significant increase in voltages. Echocardiogram showed normal biventricular function, valvular function and coronary artery dimensions. The patient was admitted to the paediatric intensive care unit for telemetry monitoring. Paediatric infectious diseases and immunology and cardiology services were consulted. Her troponin, initially elevated at 0.23 ng/mL, subsequently normalised by day 1 of hospitalisation.

Differential diagnosis

The patient fulfilled clinical and laboratory criteria for MIS-C including ≥24 hours of fever, evidence of systemic inflammation with at least two organ systems involved (gastrointestinal, haematological, dermatological/mucocutaneous, neurocognitive and cardiac) and illness requiring hospitalisation. She had a positive COVID-19 IgG (Beckman Coulter Access SARS-CoV-2 IgG), although this could certainly have been secondary to receipt of vaccine. Stool studies were not performed as her diarrhoea resolved. The patient did not fulfil criteria for KD, acute COVID-19, bacterial sepsis or toxic shock syndrome. As above, viral aetiologies were explored but molecular testing for additional viruses (such as enterovirus/rhinovirus, adenovirus and parainfluenza) was not sent as extended viral testing at our centre has a multiday turnaround time. Given expanded viral testing was not sent, it remains possible that another viral aetiology, not specified, could have caused this patient’s presentation. Viral aetiologies known to cause multisystem involvement are listed in box 1. This patient was immunocompetent and was not expected to present with serious illness secondary to these other viruses, however, it remains possible that another viral illness was present. She had no evidence of excessive immune activation (such as haemophagocytic lymphohistiocytosis or macrophage activation syndrome) or rheumatological disease such as systemic lupus erythematosus or vasculitis. In the absence of an alternative plausible diagnosis, the decision was made to treat her for MIS-C.

Treatment

Treatment for MIS-C was initiated with intravenous immune globulin 2 g/kg ×1 dose, as well as medium dose aspirin 650 mg every 6 hours for anti-inflammatory effect,15 and methylprednisolone 1 mg/kg every 12 hours. She was also given enoxaparin secondary to concern for risk of coagulopathy as she was taking combined oral contraceptives. By 24 hours after treatment initiation, the patient defervesced and reported that all of her symptoms had resolved. Her physical examination was normal including resolution of conjunctivitis. She was discharged 48 hours from admission in good condition on aspirin 81 mg daily and oral prednisone taper over 3 weeks.

Outcome and follow-up

At the time of outpatient follow-up 2 weeks from hospital discharge, the patient reported she was back to her baseline. Follow-up echocardiogram remained normal. Labs showed slight increase in white cell count to 11×10⁹/L and neutrophilia (absolute neutrophil count 8.99×10⁹/L), likely secondary to neutrophil demargination related to corticosteroid therapy. C reactive protein (CRP) had normalised to <1.0 mg/L. Given the previously noted IgG titre may have been from vaccination, antinucleocapsid IgG testing (Abbott ARCHITECT SARS-CoV-2 IgG) was performed (this testing was not available at the time of hospitalisation). Testing was negative, suggesting she had not had prior COVID-19 disease. Due to the onset of a multisystem inflammatory process potentially consistent with MIS-C occurring 12 weeks postvaccination, this case was reported to the Massachusetts Department of Public Health and the US Vaccine Adverse Event Reporting System.