Cutaneous exanthema revealing Multisystem-Inflammatory Syndrome in adults (MIS-A) in the course of SARS-CoV-2 infection

Multisystem-inflammatory syndrome in adults (MIS-A) is a newly-described but rare complication of SARS-CoV-2 infection. Case definition criteria include severe cardiac illness as well as rash and non-purulent conjunctivitis [1]. Herein, we present the case of a 30-year-old woman with MIS-A in the aftermath of a SARS-CoV-2 infection.

1. Observation

A 30-year-old woman was admitted to our dermatology department on December 7, 2021, with fever and a spreading rash. Three days prior to admission, the patient had a sore throat, a left sub-mandibular node and a rash spreading from the hands to the rest of the body. The patient had a history of SARS-CoV-2 infection at the beginning of November 2021. There was no record of SARS-CoV-2 vaccination and no history of new drug intake or recent travel.

On examination, body temperature was measured at 39.7 °C, blood pressure at 106/64 mmHg, heart rate at 100/min, respiratory rate at 23/min and oxygen saturation at 100% while breathing ambient air. The patient presented severe fatigue as well as an intermittent chest pain while walking, but without associated symptoms (no headache, no muscle or joint aches). She presented a generalized erythematous maculopapular rash (Fig. 1 ) and non-purulent asymptomatic conjunctivitis. One lymph node was found in the left submandibular area. Examination of the throat revealed no abnormalities. The remainder of the examination was unremarkable. A reverse transcription-polymerase chain reaction test for SARS-CoV-2 performed on nasopharyngeal swabs was negative. Laboratory studies revealed increased levels of high-sensitivity troponin (Tn: 82 ng/L, range: 0–16) and creatine phosphokinase (342 IU/L, range: 29–168). Biologic inflammatory syndrome was observed with elevated C-reactive protein (288 mg/L, N < 5), D-dimer (3.38 µg/ml, N < 0.5) and hyperferritinemia (1002 µg/L, range: 10–200). Liver function tests were abnormal with elevation of aspartate aminotransferase at 94 IU/L (range: 5–34) and of alanine aminotransferase at 92 IU/L (N < 55). The blood count revealed normal platelet (320 G/L) and lymphocyte (2.75 G/L) counts. Blood cultures drawn after admission were negative. Serological testing was negative for human immunodeficiency virus, hepatitis B, hepatitis C, cytomegalovirus, and Epstein-Barr virus. The electrocardiogram was normal with a sinus rhythm of 112 bpm. A computed tomography (CT) scan of the chest and cervical spine showed additional non-necrotizing lymphadenopathy in the jugular-carotid and axillary node chains.

Fig. 1.

(a) Erythematous macules, papules and plaques on the back; (b) erythematous palmar papules; (c) erythematous papules on the thigh.

Twelve hours after admission, her cardiac condition worsened with onset of dyspnea, increased chest pain, low blood pressure (80/50 mmHg), a rise of Tn from 82 ng/L (admission Tn) to 1453 ng/L (11 h after first Tn) and an unmodified electrocardiogram recording. Bedside transthoracic echocardiogram showed normal valves, an estimated left ventricular ejection fraction at 50% and no pericardial effusion. The clinical presentation along with the elevation of myocardiocytolysis markers and creatine phosphokinase were highly suggestive of myocarditis [2]. The patient was transferred to a Coronary Care Unit for 4 days following the onset of low blood pressure. Treatment with norepinephrine was initially needed to maintain blood pressure and was continued for two days. A clinical diagnosis of MIS-A was made after a positive SARS-CoV-2 serology (451 BAU/mL with the Alinity® chemiluminescence method) based on the diagnostic criteria for MIS-A (Table 1 ). The patient received 1 g/kg intravenous immunoglobulin on day 4 and day 7 and corticosteroids at 90 mg/day with progressive dosage reduction over two weeks. The patient’s rash and cardiac symptoms resolved during her hospital stay and she was discharged from hospital on day 10. The patient was subsequently lost to follow-up. Magnetic resonance imaging and CT coronary angiogram were not performed and a definitive diagnosis of myocarditis has not yet been made.

Table 1.

MIS-A case definition criteria – Adapted from the Center for Disease Control and Prevention case definition.

≥ 24 hours prior to hospitalization or within the first 3 days of hospitalization
Clinical Criteria
Subjective fever or documented fever (≥38.0 °C)
1 Primary clinical criteria
•Severe cardiac illness: includes myocarditis, pericarditis, coronary artery dilatation/aneurysm, or new-onset right or left ventricular dysfunction (left ventricular ejection fraction < 50%), 2nd/3rd degree atrioventricular block, or ventricular tachycardia (N.B.: cardiac arrest alone does not meet this criterion). •Rash AND non-purulent conjunctivitis.
2 Secondary clinical criteria
•New-onset neurologic signs and symptoms, including encephalopathy in a patient without prior cognitive impairment, seizures, meningeal signs, or peripheral neuropathy (including Guillain-Barré syndrome). •Shock or hypotension not attributable to medical therapy (e.g., sedation, renal replacement therapy). •Abdominal pain, vomiting, or diarrhea. •Thrombocytopenia (platelet count < 150,000/ microliter).
Laboratory evidence: both criteria
A positive SARS-CoV-2 test for current or recent infection by RT-PCR, serology, or antigen detection.
Elevated levels of at least TWO of the following: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin.

2. Discussion

Multisystem inflammatory syndrome was first described in the pediatric population at the beginning of the SARS-CoV-2 pandemic in April 2020 [3], [4]. Some weeks after initial SARS-CoV-2 infection, children would present Kawasaki-like Disease (KD). However, in these cases patients were older and had fewer coronary abnormalities and more frequent myocarditis than in KD. The new entity known as multisystem inflammatory syndrome in children (MIS-C) was described. It is interesting to note that MIS-C shares many common features with severe KD, such as a higher frequency of myocarditis, and of digestive and neurological involvement than normal KD. Notably, both have an atypical cutaneous presentation with fewer mucocutaneous signs than non-severe KD. The current hypothesis is that KD, severe KD and MIS-C belong to a common clinical spectrum [5]. Several cases have been described in adults since then, and a recent systematic review in September 2021 identified 221 cases of MIS-A reported in the worldwide literature [6]. Case definition criteria are set out in Table 1. In the review by Patel et al., the median age of patients was 21 years, with the majority being non-Hispanic black men. Onset of MIS-A symptoms occurred on average after 28 days following SARS-CoV-2 infection and generally resulted in fever (197 of 219 cases) associated with hypotension (33 of 219 cases), cardiac dysfunction (114 of 219 cases), shortness of breath (102 of 219 cases), or diarrhea (102 of 219 cases). Rash occurred in 38% (83 of 219 cases) of patients. Other dermatologic symptoms included mucocutaneous lesions and conjunctival injection. The latter, in association with the rash, was one of the primary criteria for diagnosis of MIS-A. MIS-A descriptions of cutaneous manifestations are scarce. Detailed descriptions report polymorphous, maculopapular, morbilliform rashes and erythroderma. Some cases also report urticarial, reticular, petechial, and purpuric skin lesions. Distribution of the rashes does not follow a specific pattern [7], [8]. While the physiopathology has yet to be understood, this state of hyperinflammation seems to be more prevalent in younger patients and in minority groups (Black and/or Hispanic populations) [6], [9]. Confusion could arise from the fact that the first cases of MIS were reported in the pediatric population, while most MIS-A cases in the recent systematic review of September 2021 were reported via the MIS-C surveillance system. Concerning minority prevalence, a probable confusion bias may be attached to the already higher risk of COVID-19 in these populations [10]. Multisystem inflammatory syndrome has also been described following SARS-CoV-2 vaccination (MIS-V). The main difference in relation to MIS-C and MIS-A lies in the shorter time between initial exposure and onset of MIS symptoms [11], [12], [13]. This supports the hypothesis of a hyperinflammatory state leading to immune dysregulation and cytokine storm, even if the exact physiopathology remains unknown. However, sub-clinical SARS-CoV-2 infections around the time of vaccination could lead to wrongly-diagnosed and mislabeled MIS-V [14]. MIS-V should therefore be diagnosed with caution since misattribution of MIS to vaccination could elicit increased hesitation regarding vaccination. General recommendations for MIS-A treatment have been extrapolated from pediatric guidelines due to the small sample size that offers insufficient data [15]. Treatment guidelines include the use of immunomodulatory therapy such as intravenous immunoglobulin and corticosteroids. Intensification therapy is recommended when no improvement has occurred within 24 hours following initiation of immunomodulatory treatment. It involves the use of anakinra, high-dose glucocorticoids or infliximab [16]. Regarding antithrombotic treatment, similarities between KD and MIS-C lead to the recommendation of low-dose aspirin use in patients with no risk factors for bleeding [17]. Prophylactic or therapeutic anticoagulation should be considered on a case-by-case basis as no clear benefit has been shown in patients without large coronary artery aneurysms or moderate-to-severe left ventricular dysfunction [16], [18]. In June 2022, there were an estimated 541 million cases of COVID-19 by the end of the month [19]. With case numbers continuing to increase, MIS-A cases will probably continue to rise as well. Vaccination may offer protection against MIS-A but further investigations are required to allow a proper conclusion to be drawn [20]. In this global context, it is important for the medical community to be able to provide adequate MIS-A diagnosis, care and follow-up. Dermatologic symptoms may be among the first symptoms for which patients consult their physician. It therefore appears worthwhile to bear this diagnosis in mind as one of the multiple etiologies of maculopapular rash.

Disclosure of interest

The authors declare that they have no conflicts of interest.