Multisystem Inflammatory Syndrome in Adults

Discussion

Multisystem inflammatory syndrome in adults (MIS-A) was first mentioned in 2020 following the initial description of this syndrome in the pediatric population (multi-inflammatory syndrome in children) during the COVID-19 pandemic. Since its first recognition, several case reports have been published in the literature, with a wide range of clinical manifestations and therapeutic interventions. MIS-A is suspected to be caused by an abnormal immune response to SARS-CoV-2 infection and is commonly associated with clinical features such as fever, systemic inflammation, and shock with end-organ damage.^[1,2] Many of these features have been proposed to resemble Kawasaki-like manifestations.^[1,2] According to the Centers of Disease Control (CDC), five criteria should be fulfilled to diagnosed MIS-A: (1) concurrent or previous (within the past 12 weeks) COVID-19 diagnosed by either PCR or antigen/antibody testing, (2) severe sickness necessitating hospitalization in those aged 21 years or more, (3) marked involvement or dysfunction of single or multiple extrapulmonary organs (acute kidney injury, acute liver injury, neurological involvement, cardiac insult, shock, hypotension, and so on), (4) absence of severe respiratory affection (respiratory signs and symptoms), and (5) exhibiting severe inflammation as per laboratory findings: elevated CRP, D-dimer, serum ferritin, erythrocyte sedimentation rate (ESR), fibrinogen, interleukin-6 (IL-6).^[3] In our case, the patient fulfilled all five criteria to make the diagnosis.

Thirty-six documented cases of MIS-A were reviewed and are summarized in Table 2. The mean age of patients was 33 years, with male predominance (23/36; 63%). Most of the patients had no past medical history of significance (23/36; 63%), while 17/36 (47%) contracted SARS-CoV-2 infection, suggested by PCR, antibody testing, or clinically. Fever was recorded in 31/36 cases (86%). Gastrointestinal symptoms were less frequently reported: nausea (7/36, 19%), abdominal pain (11/36; 30%), vomiting (5/36; 13%), and diarrhea (7/36; 19%). Like our case report, sore throat was present in five patients (5/36; 14%)^[4–8] and unilateral cervical pain/swelling in four other cases (6/36; 16%).^[8–12] Some patients had predominant visual symptoms.^[5,13–17]

Cardiovascular impairment was also noted in the literature. Specifically, tachycardia (22/36; 61%) and hypotension/cardiogenic shock with documented impaired ejection fraction (23/36; 64%).^{[5–8,10,12,15,17–24]} The left ventricular function/ejection fraction normalized with treatment in 15 patients,^{[6,7,12,17,21,23,24]} of whom 7 patients received IVIG with or without aspirin.^{[10,12,17,23,24]} Overall, 28/36 (78%) patients recovered and were safely discharged. Cardiac MRI has been discussed in the literature in terms of assessing for myocarditis. It can confirm signs of diffuse myocardial inflammation while ruling out ischemic or stress-induced cardiomyopathy.^[12]

There is no consensus on the mechanism causing MIS-A during or post-CoVID-19 infection. MIS-A is viewed as an atypical immune response causing systemic vasculitis and multiple acute organ injury. The dramatic response to IVIG and high-dose aspirin supports the occurrence of vasculitis, which was demonstrated in our patient. She was successfully weaned off vasopressors following the IVIG treatment, and discharged without any complications in her hospital course. Target management of MIS-A with immunomodulatory therapy has reversed acute kidney injury^[25] and heart failure, with normalization of cardiac function in many patients.^{[6,7,12,17,21,23,24]} Many theories were proposed to uncover the linkage between vasculitis and SARS-CoV-2 infection. For example, IL-6 increases markedly during CoVID-19 infection, and it is the same cytokine that mediates vasculitis in Kawasaki syndrome. IL-6 enhances the adhesion of lymphocytes to endothelial cells causing their damage.^[26] Another theory points toward complement activation and capillary deposition of immune complexes as initial insult, which could be suggested in our case based on her low complement C3 and C4 levels.^[27]

MIS-A of CoVID-19 shares many similarities with Kawasaki-like multisystem inflammatory syndrome, a syndrome which has been linked to other viral infections. Diagnosis of Kawasaki disease requires (1) fever for ^> 5 days and (2) at least four signs of conjunctivitis, involvement of the oropharyngeal mucosa or IgA infiltration of the upper respiratory tract, cervical lymphadenopathy, rash, and extremity changes (edema or erythema).^[28] Furthermore, Kawasaki may present with acute kidney injury or aneurysms, especially in coronaries and abdominal aorta.

COVID-19 Kawasaki-like syndrome is diagnosed by (1) fever for ^> 3 days, (2) at least two signs of rash, hypotension/shock, or acute cardiac injury (infarction, pericarditis, left ventricle dysfunction, right ventricular dysfunction, or coronary syndrome), (3) coagulopathy, or (4) acute gastrointestinal (GI) symptoms in the setting of elevated inflammatory markers (CRP, D-dimer, and/or ferritin) during or after COVID-19 infection, after excluding other infections.^[29] This description was consistently seen with our patient. She exhibited fever, strawberry-like rash, hypotension requiring vasopressors, decreased ejection fraction, nephropathy, and significant elevations in her CRP and D-dimer.

Figure 1 illustrates the clinical features and possible pathophysiology basis of MIS-A and classic Kawasaki syndromes. Our patient did not fulfill the criteria of classic Kawasaki. Furthermore, the acute cardiac injury and hypotension, acute renal injury, fever, sore throat, unilateral lymphadenopathy, and elevated inflammatory markers in the setting of positive SARS-CoV-2 IgG antibody support a diagnosis of MIS-A.

(Enlarge Image)

Figure 1.

Clinical manifestations and possible mechanism of injury in COVID MIS-A and Kawasaki disease. A MIS-A. B Kawasaki Disease. MIS-A multisystem inflammatory syndrome in adults, RVD right ventricular dysfunction, LVD left ventricular dysfunction, GI gastrointestinal, CRP C-reactive protein, IgG immunoglobulin G, IgA immunoglobulin A, IL interleukin. This figure was created by Fardad Behzadi for the purposes of this publication

In terms of management, there was considerable variation in treatment modalities when reviewing the literature. In our case, the patient was aggressively fluid resuscitated and started on broad spectrum antibiotics, steroids, and ultimately vasopressors. In conjunction with the infectious disease team, full-dose aspirin and IVIG was initiated, with resolution of her symptoms and ultimate discharge. To demonstrate the variability in treatments, we reviewed previously documented cases of MIS-A. Summarizing Table 2, 44% of patients were given IVIG, 56% given steroids, 39% antibiotics, 13% given immunomodulators (tocilizumab, anakinra, cyclophosphamide, rituximab), 11% given aspirin, 22% anticoagulation, and 36% requiring vasopressors. Despite the differences in management, recent literature studying the treatment modalities of MIS-C concluded that were was no evidence that IVIG alone or IVIG with steroids or immunomodulators leads to higher rates of recovery.^[30] These findings may not be generalizable to the adult population who experience MIS-A, but it gives insight into the challenges of choosing a treatment modality.

J Med Case Reports. 2022;16(102) © 2022 BioMed Central, Ltd.