Background

The current coronavirus disease (COVID-19) pandemic has brought the recognition of multisystem inflammatory syndrome in adults (MIS-A) as a de novo entity temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection in adults. Hypothesis about its true pathophysiology remains controversial. Its initial presentation, response to empiric therapy, and clinical outcomes are widely variable. We report the case of a 22-year-old female who presented with distributive shock after 3 days of fever, sore throat, and right-sided neck pain. She was diagnosed with MIS-A and successfully treated. We further provided the reader with an in-depth review of the current published case report of MIS-A available in the medical literature, and review the pathophysiology and clinical resemblance and difference to Kawasaki disease.

Case description

A 22-year-old overweight African American female, with a body mass index (BMI) of 29.1 kg/m2, presented to the emergency department (ED) with 3 days of fever, sore throat, right-sided neck pain, and swelling. She denied any respiratory symptoms. She had tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) 4 weeks prior, complaining of fever, chills, cough, headache, and diarrhea for 1 week. At that time, she had visited the ED and had been discharged with acetaminophen. Per the patient, she was not discharged with steroids or antibiotics.

During her initial ED visit, her blood pressure was stable at 110/57 mmHg, temperature of 39.4 °C, and heart rate of 150 beats per minute (BPM). While in the ED, she received broad spectrum antibiotics (vancomycin and ceftriaxone), 30 cc/kg bolus of normal saline, and blood cultures were obtained. Computed tomography (CT) of the neck with intravenous contrast revealed bilateral reactive lymphadenopathy with enlarged adenoids and mildly enlarged tonsillar pillars without abscesses. Initial chest X-ray was negative, without signs of pleural effusions or consolidations. Her electrocardiogram showed sinus tachycardia. She was admitted for persistent tachycardia and otolaryngology evaluation. Originally, the patient was admitted to a telemetry floor. The following night, a rapid response code was called due to hypotension. At that time, her blood pressure was 80/57 mmHg, heart rate was 125 BPM, respiratory rate of 25, and temperature of 103 F. She appeared comfortable, without signs of respiratory distress. She exhibited mild bilateral periorbital and lower extremities edema. Neck examination was notable for bilateral posterior lymphadenopathy with mild decreased range of motion. Her pulmonary and cardiac examinations were unremarkable other than tachycardia. Additionally, the rapid response team noted bilateral conjunctivitis as well as small strawberry rash diffusely. Another electrocardiogram was performed, which showed low voltage and sinus tachycardia. A point of care ultrasound (POCUS) was performed that was negative for pericardial effusion, right ventricular dilation, or signs of obstructive shock. She was fluid resuscitated with an additional 2 L of normal saline, with transient/negligible improvement of blood pressure. She was bolused another liter of lactated Ringer’s, initiated norepinephrine infusion, and admitted to the intensive care unit (ICU) for the management of distributive shock.

Her follow-up studies showed a peak d-dimer of 3557 ng/mL, C-reactive protein (CRP) of 47 mg/dL, and ferritin of 344 ng/mL. Fibrinogen was 460 mg/dL and remained within normal limits. She has a nadir hemoglobin of 10.6 g/dL, 24-hour urinary protein of 560 mg with preserved glomerular filtration rate through her entire hospital admission. Initial white blood cell count was 7000 cells/mm3 and only increased slightly after corticosteroid use. She exhibited a mild elevation of aspartate transaminase (AST) to 46 U/L, alanine transaminase (ALT) of 49 U/L, and alkaline phosphate (ALP) of 51 U/L. Her pro-B-type natriuretic peptide (BNP) was 3590 pg/mL on hospital day 2 and her troponin I peaked at 0.257 ng/m on day 3.

Official transthoracic echocardiography revealed a mild systolic dysfunction, grade 2 diastolic dysfunction and an ejection fraction of 40–45%, and a concentric small pericardial effusion. Coronary angiography revealed normal coronaries without evidence of obstruction or aneurysms. CT angiogram of the chest was negative for pulmonary embolism but notable for moderate-sized pleural effusions bilaterally. Cardiac magnetic resonance imaging (MRI) was not performed.

The patient received supportive treatment with dynamic hemodynamic-driven preload resuscitation and vasopressor support with norepinephrine. Her maximum dose of norepinephrine was 5 mcg/minute. Infectious disease was consulted on hospital day 3, who broadened antibiotic coverage with 3.375 mg piperacillin/tazobactam every 8 hours (q8) for 1 week. Broad infectious and immunologic workup was ordered and is summarized in Table 1. She tested negative for immunoglobulin (Ig)M and positive for IgG SARS-CoV-2 antibody. Dexamethasone 4 mg was initiated in the ED and continued q12 hours until hospital day 5 when it was changed by infectious disease team to hydrocortisone 50 mg q6 hours. Full-dose aspirin was initiated on hospital day 4 and continued until discharge. Intravenous immunoglobulin (IVIG) infusion was initiated and completed on hospital day 5, when she received 80 g over 16 hours. She was weaned off vasopressors by hospital day 6. An MRI of the neck without contrast on day 6 revealed resolution of her prevertebral soft tissue swelling and persistent nonspecific cervical lymphadenopathy bilaterally without any fluid collection. She received intravenous furosemide and albumin 25% intermittently with improvement in her interstitial edema. Blood and urine cultures remained negative during her hospitalization. She was discharged home on day 11.

Table 1 Infectious and immunologic panel
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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%) [4,5,6,7,8] and unilateral cervical pain/swelling in four other cases (6/36; 16%) [8,9,10,11,12]. Some patients had predominant visual symptoms [5, 13,14,15,16,17].

Table 2 MIS-A published case reports
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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%) [5,6,7,8, 10, 12, 15, 17,18,19,20,21,22,23,24]. 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.

Fig. 1
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

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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.

Conclusion

Our case report is an example of the presentation, diagnosis, and management of MIS-A. As we dove into the literature and discovered other documented cases of MIS-A, we created Fig. 1 to illustrate the similarities and differences when compared with Kawasaki-like multisystem inflammatory syndrome. Our research into previous case reports illustrates the wide range of presentations, degree of end-organ damage, and treatment modalities. This diagnosis needs to be considered in the presence of recent COVID infection with new onset end organ failure, as prompt diagnosis and treatment is crucial for better outcomes.