Multisystem inflammatory syndrome in adults associated with COVID‐19: A rare life‐threatening complication

Herein, we report a case of a 49-year-old Caucasian man with a medical history of gastroesophageal reflux disease, occasional premature ventricular contractions, and unvaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented with myalgias, fevers, and right-sided neck swelling approximately 26 days after he had tested positive for SARS-CoV-2 and 21 days after receiving the casirivimab–imdevimab (REGEN-COV) infusion. His initial workup showed leukocytosis and thrombocytopenia (platelets: 108 × 109/L, reference range [RR]: 150−328 × 109/L). The SARS-CoV-2 rapid antigen-detection test was negative. The patient was started on intravenous antibiotics for presumed lymphadenitis; however, his fevers persisted, with subsequent development of worsening thrombocytopenia at 91 × 109/L and increasing C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), with peak values at 13.4 mg/dL (RR: < 0.8 mg/dL) and 35 mm/1 h (RR: 0−10 mm/1 h), respectively. A few days later, he developed polymorphic ventricular tachycardia causing cardiac arrest. Return of spontaneous circulation was achieved after 5 min. The patient was subsequently admitted to the critical care unit for acute respiratory failure requiring mechanical ventilation, shock requiring multiple pressors, and acute renal failure requiring continuous renal replacement therapy (CRRT). Transthoracic echocardiogram showed severely reduced left ventricular ejection fraction (LVEF) of 20%–25% with multiple regional wall abnormalities. Coronary angiography of the left and right heart showed patent coronaries, increased left ventricular filling pressures, and moderate pulmonary hypertension. A physical exam showed a new erythematous, punctate rash on the right medial thigh (Figure 1A). An extensive infectious workup—including human immunodeficiency virus, syphilis, cytomegalovirus, toxoplasma, respiratory syncytial virus, influenza, hepatitis B virus, hepatitis C virus, typhus, Bartonella serologies, and Histoplasma—was negative. Given the high suspicion for multisystem inflammatory syndrome in adults (MIS-A), as the patient fulfilled the Centers for Disease Control and Prevention (CDC) case definition (unexplained fever unresponsive to antibiotics, neck lymphadenopathy, cardiac dysfunction, lymphopenia, worsening rash, high inflammatory markers 2–6 weeks after initial coronavirus disease 2019 (COVID-19), the patient was started on a 4-day course of intravenous immunoglobulin (IVIG) infusion and methylprednisone. After completion of the first round of IVIG, the patient improved clinically and his fractional inspired oxygen (FiO2) requirement decreased from 100% to 50%, pressors were weaned off, repeat echo showed recovered ejection fraction (EF) > 65%, urine output improved off CRRT, the rash started clearing up (Figure 1B), fever resolved, and inflammatory biomarkers including white blood cell count, CRP, procalcitonin, and interleukin (IL)-6 improved. However, he remained unresponsive off sedation. Head computed tomography (CT) showed diffuse edema suggestive of hypoxic-ischemic injury. Lumbar puncture was performed, and cerebrospinal fluid analysis was negative for central nervous system infection. As MIS-A with extrapulmonary multiorgan involvement is difficult to distinguish with acute biphasic COVID-19 and postacute sequelae of COVID-19 infection,1 repeat COVID-19 polymerase chain reaction was done to rule out biphasic SARS-CoV-2 infection, which was negative. The patient received the second round of IVIG with intravenous methylprednisone. On Day 21, he was started on anakinra (IL-1 inhibitor), with improvement in inflammatory markers, as ESR improved from 91 to 48 mm/1 h, CRP decreased from 1.7 to 1.1 mg/dL, and ferritin decreased from 4360 to 1500 ng/mL (RR: 18.0–464.0 ng/mL). Given worsening platelet counts, we discontinued anakinra after 5 days and it was unclear whether thrombocytopenia was secondary to anakinra or worsening of MIS-A. Clinically, the patient's prognosis remained guarded secondary to hypoxic brain injury and he continued to require intermittent pressor, mechanical ventilation, and CRRT support. The family opted for comfort care and the patient died on hospital Day 28, with presumed cause of death as multiorgan failure secondary to MIS-A. MIS-A is a rare and fatal complication of SARS-CoV-2 infection. The MIS-A is more complex and could be detrimental, as reported in case series by CDC where 37% (10/27) of patients required critical care during hospitalization.2 A systematic review including 221 patients with MIS-A reported 57% of patients (115 of 201) requiring admission to the intensive care unit and death in 7% (15/220) of patients.1 Although the pathophysiology of MIS-A is still poorly understood, it is proposed to be hyperinflammatory response attributed to disrupted immunity1 secondary to autoantibody formation, persistent viral antigen recognition, and viral super antigens.3 Most of the MIS-A cases are reported in unvaccinated patients. A PubMed search for “adult multisystem inflammatory disease, REGEN-COV” only yielded one report.4 There is not enough evidence to support the possibility of aggravation of systemic response in susceptible patients' status post-REGEN-COV infusion. Regardless, our case report reinforces that REGEN-COV infusion does not prevent patients from developing MIS-A in the post-COVID-19 condition. A systemic review concluded fever and rash as the most common presenting symptoms and cardiovascular, gastroenterology, and mucocutaneous as the most commonly involved systems.3 Our patient fulfilled the primary clinical criteria of CDC5 as he developed documented fever before and within his first 3 days of hospitalization, severe cardiac illness, new-onset reduced left ventricular dysfunction (LVEF < 50%), ventricular tachycardia causing cardiac arrest, and rash. He fulfilled the secondary clinical criteria, including diarrhea, thrombocytopenia, and shock, not secondary to medical therapy. Also, he fulfilled the laboratory criteria of a recent positive SARS-CoV-2 test and elevation of inflammatory markers including CRP, procalcitonin, and IL-6. Since no specific guidelines are available regarding definitive treatment of MIS-A, a variety of modalities are used including IVIG, steroids, antibiotics, immunomodulator therapies, aspirin, and anticoagulants as discussed in a systemic review.3 Although our patient showed objective evidence of improvement in symptoms and laboratory markers in response to MIS-A-specific therapies, including IVIG, steroids, and anakinra, his prognosis remained guarded as he was treated with MIS-A-specific therapies later during the disease course after he had cardiac arrest causing hypoxic brain injury. Our patient died on hospital Day 28, with presumed cause of death as multiorgan failure secondary to MIS-A. Mildly elevated D-dimer with normal levels of fibrinogen and prothrombin time (PT)—international normalized ratio (INR) did not meet the laboratory criteria of disseminated intravascular coagulation. In conclusion, this case emphasizes the necessity of keeping MIS-A in differentials during early assessment when evaluating patients with systemic symptoms after a recent SARS-CoV-2 infection despite treatment with monoclonal antibody infusions, so that diagnosis and treatment can be done in a timely manner. Sameen Zafar: Conceptualization; writing—original draft; writing—review and editing. Daniel Gonzalez: writing—original draft; writing—review and editing. Leonard Kuan-Pei Wang: writing—original draft; writing—review and editing. Alexandria Soybel: writing—original draft; writing—review and editing. Emilio B. Gonzalez: Writing—review and editing. Vijaya Murthy: Writing—review and editing. The authors have nothing to report. The authors declare no conflict of interest. All images are obtained with the permission of the patient and family. Written consent was obtained from the patient for participation in research and publication.