Epidemiologic and clinical characteristics of multisystem inflammatory syndrome in adults: a rapid review

Multisystem inflammatory disease in children (MIS-C) is one of the severe presentations of the coronavirus disease 2019 (COVID-19) that has been described in the literature since the beginning of the pandemic. Although MIS-C refers to children, cases with similar clinical characteristics have been recently described in adults. A description of the epidemiologic and clinical characteristics of multisystem inflammatory disease in adults (MIS-A) is a starting point for better knowledge and understanding of this emerging disease. We identified nine case reports of MIS-A in the literature, five from the United States, two from France and two from the United Kingdom. The case descriptions revealed similarities in clinical features, including occurrence during post-acute disease phase, fever, digestive symptoms, cardiac involvement and elevated inflammatory markers. All the patients were hospitalized, three required admission to the intensive care unit and one died. The most common treatments were intravenous immunoglobulin, prednisolone and aspirin. These findings suggest that MIS-A is a severe complication of COVID-19 disease that can lead to death. Further studies to improve our understanding of the pathogenesis of MIS-A, which will help improve treatment decisions and prevent sequelae or death. lymphopenia) gastrointestinal neurologic 38.5°C of oxygen requirement, hypotension and features. must show abnormal fibrinogen, of potential causative organisms (other SARS-CoV-2), CRP, D-dimers, ferritin, hypoalbuminemia lymphopenia. full partial criteria for disease. microbial cause, sepsis, staphylococcal streptococcal


Introduction
The coronavirus disease 2019 (COVID-19) is a novel disease resulting from infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). As of May 29, 2021, the virus has infected more than 170 million people and caused more than 3.5 million deaths worldwide (2).
The clinical characteristics of COVID-19 disease vary from asymptomatic to severe. The most common symptoms are fever, cough, diarrhea and dyspnea (3). There are three clinical stages (4). The first stage is characterized by infection with SARS-CoV-2, with flu-like symptoms in certain cases. The second stage, characterized by viral pneumonia, possibly combined with pulmonary inflammation and coagulopathy, can require hospitalization and even mechanical ventilation. The third stage of the disease is characterized by fibrosis.
Multisystem inflammatory syndrome has been widely reported in children (5) and, more recently, in adults (6). In children, multisystem inflammatory syndrome (MIS-C) is a severe presentation that has been described in the literature since the beginning of the pandemic. Although MIS-C is defined as restricted to children, similar clinical characteristics have been described in adults. Knowing the epidemiologic and clinical characteristics of multisystem inflammatory syndrome cases in adults (MIS-A) provides a starting point to a better understanding of this emerging disease.
Our search through the Public Health Agency of Canada database included studies published in English since the start of the pandemic until November 13, 2020. We gathered details about COVID-19-related studies in a RefWorks database and an Excel spreadsheet that are searchable by topic. Search terms used to retrieve the MIS-A literature from titles and abstracts in the Excel spreadsheet included "MIS-A," "Kawasaki," "multisystem inflam*," "multi-system inflam*," "inflammatory multisystem," "inflammatory multi-system," "inflammatory disease," "Kawasaki-like" and "COVID-19 linked disease." We screened articles (n=314) for relevance and included those that described MIS-A with a COVID-19 link (see Appendix A and Appendix B). We excluded paediatric cases and studies with cases similar to a MIS-A, but not formally diagnosed as MIS-A as per the authors. Since MIS-A is an emerging disease, a case definition does not yet exist. Authors of studies included in this review based case selection on the definition of MIS-C, while excluding the age criteria (see Appendix C).

Results
We identified nine case reports of MIS-A in the literature, five in the United States, two in France and two in the United Kingdom.
All nine patients underwent a reverse transcription polymerase chain reaction (RT-PCR) test for COVID-19. Five had negative RT-PCR results but positive serology tests (6-8,10,13). One had a negative RT-PCR result despite having had a positive RT-PCR result a few days earlier (12). The results of RT-PCR swab test and serology were both positive in one case (14). The two remaining patients had a positive RT-PCR test but did not have serology tests (9,11). These findings suggested that MIS-A probably occurred during the post-acute phase of the disease.
There was multi-organ effect in all cases. Involvement of the cardiovascular system was the most common (n=7) (6,7,10,(12)(13)(14)(15) and was documented via echocardiography in four cases. The four cases had an acute myocardial dysfunction with left ventricular systolic dysfunction and pericardial effusion. Two had ventricular fibrillation (11,12) and two other a dilated inferior vena cava (10,14). One of these patients also had overloaded right ventricular pressure and mild enlargement of the main pulmonary artery and hyperkinetic left ventricle (14).
Of the nine patients, one died (12) and the outcome of another was not reported (9). Three patients had severe symptoms, requiring admission to the intensive care unit (ICU), but recovered (6,7,14). Two patients presented with hypotension and tachycardia upon admission but did not require admission to ICU and recovered (11,13). One patient presented with vasoplegic shock upon admission, had a length of stay in hospital of eight days and recovered under treatment (8). One case did not demonstrate shock-like signs and recovered under treatment (9). The case that died had been previously hospitalized for COVID-19 and discharged 12 days earlier; upon readmission she presented with rapid onset of fever and developed hemodynamic instability and ventricular fibrillation and could not be resuscitated.

Discussion
MIS-A appears to be a rare complication of COVID-19 disease. The RT-PCR and serology results and the absence of pulmonary involvement in most cases are consistent with MIS-A occurring during the post-acute phase of COVID-19 disease.
The clinical characteristics of MIS-A share similarities with MIS-C. The pathogenesis of MIS-C involves immune dysregulation similar to Kawasaki disease, macrophage activation syndrome (MAS) and cytokine release syndrome (16,17). Kawasaki disease is theorized to be from an aberrant immune response to a possible infectious trigger; it is described in children and less often in adults (15,18). In the case of MIS-A, the pathogenesis is not fully understood (19). Endothelial damage seems to have led to serious complications with multi-organ involvement in the reported cases (12). This process probably occurs post-infection based on the timing of the rise of MIS-C cases and peak of COVID-19 in the communities in which these cases were found (16,17).
While we identified some common features, the clinical presentations in the case reports of the MIS-A patients varied. For example, ophthalmologic signs (9) were predominant in one case and cardiac signs in another (6). Further studies are required on MIS-C pathophysiology and how it contributes to MIS-A pathogenesis.
The approach to management of children with MIS-C is evolving; management does require multidisciplinary care and a caseby-case approach. Since MIS-C is most likely a post-infectious complication rather than an active infection, the role of antivirals is not clear (20). Those that meet the criteria for Kawasaki disease may benefit from IVIG, as might those with moderate to severe MIS-C (20). Patients who may benefit from this treatment may include those with cardiac involvement or in shock states. Steroids might be considered for those who have severe or refractory shock (20). Other adjunctive therapies (IL-1 inhibitors or convalescent plasma) and their place in the treatment of MIS-C is uncertain (20). How these treatment options can be applied to MIS-A patients is also currently unknown. We need further studies outside of controlled clinical trials to ascertain the role of IVIG, steroids and other immunomodulatory agents in treating suspected cases of MIS-A (21).

Limitations
We based this current review on nine case reports from three countries. Although case reports can help in identifying new trends or diseases, there are limitations. Information from the case reports is difficult to generalize because patients have different backgrounds and are not representative of the population.
Currently, there is no case definition for MIS-A. Using the MIS-C case definition (minus age) has its challenges, as there are at least four definitions (see Appendix C). In addition, how each case met the definition was not always clear. For example, authors of the case reports did not always specify how they excluded all other potential causes of the multisystem inflammatory syndrome or report the duration of fever or presence of comorbidities. There was also a lack of information about ethnicity and severity of the disease. For example, when hypotension was identified, the presence or absence of shock-like syndrome was not always specified.
These are preliminary findings; additional studies will lead to a better understanding of common epidemiologic and clinical characteristics of this condition.

Conclusion
The case descriptions revealed similarities in clinical features such as fever, digestive symptoms, cardiac involvement and elevated inflammatory markers. The RT-PCR and serology results and the absence of pulmonary involvement suggest that MIS-A occurred during the post-acute phase of COVID-19 disease. All patients were hospitalized, three required admission to the ICU and one died. The most common treatments were IVIG, prednisolone and aspirin.
The findings suggest that MIS-A is a severe complication of COVID-19 disease that can lead to death. Early recognition of MIS-A may improve outcomes. A case definition for MIS-A is needed to help standardize reporting and facilitate disease recognition. Further studies to improve our understanding of pathogenesis of MIS-A will help improve treatment decisions and prevent sequelae and death.
Authors' statement NA -Methodology, investigation, writing-original draft RE -Conceptualization, writing-review and editing, supervision MS -Writing-review and editing LW -Writing-review and editing NB -Writing-review and editing TD -Writing-review and editing   The patient was a 46-year-old male of African descent with a history of hypertension and obesity Fever and other signs and symptoms:

Exclusion of other infective and inflammatory conditions
• Admitted for hypertensive emergency (189/123 mmHg) and fever (duration not reported) Evidence of coagulopathy and renal involvement: • Acute kidney injury: Serum creatinine (sCr) level was 169 µmol/L associated with 1 g/day proteinuria, aseptic pyuria, no hematuria and low natriuresis (<20 mmol/L) • Renal biopsy light microscopy revealed typical lesions of thrombotic microangiopathy (TMA) including fibrin thrombi within glomeruli and myxoid intimal alterations of arterioles and small to medium-sized renal arteries • On Day 4, the patient presented evanescent facial erythema and developed acute myocardial dysfunction with reduced left ventricular ejection fraction to 40%, pericardial effusion • On Day 5, the patient presented with neurologic impairment. Abnormal supratentorial periventricular magnetic resonance imaging (MRI) signals responsible for a restriction of the diffusion due to an acute vasculitis PCR and serology for SARS-CoV-2: • RT-PCR negative, IgM negative and IgG positive (no previous COVID-19 symptoms were reported)    The date the study was conducted was not reported September 2020 The patient was a 21-year-old male of African descent The presence or absence of comorbidity was not reported Fever and other signs or symptoms: • Six days of fever • Admitted for abdominal pain associated with constipation, anorexia • Transient maculopapular palmar rash four days into illness • Non-exudative conjunctivitis • Cervical lymphadenopathy • Cracked lips and prominent lingual papillae PCR and serology for SARS-CoV-2: • RT-PCR negative and serology was strongly positive, suggesting recent exposure to SARS-CoV-2 One or more organs involved: United States The date the study was conducted was not reported September 2020 The patient was a 25-year-old female; her ethnicity was not reported She was a nonsmoker, did not use drugs, was not taking any prescription medications and had no known allergies She had taken ibuprofen and acetaminophen over the previous week for symptom relief Fever and other signs and symptoms: • One week of low grade fever, weakness, dyspnea, fatigue • Also developed mild cough, sore throat, vomiting, diarrhea and lymph node swelling Upon admission: • She was afebrile, with mild hypotension (blood pressure 98/56 mmHg) • Oxygen saturation was normal on room air • She appeared ill, with tender cervical lymphadenopathy • Significant conjunctival injection without perilimbal sparing; injected, erythematous and cracked lips • Tenderness to palpation in the left lower abdominal quadrant United States The date the study was conducted was not reported July 2020 The case was a 45-year-old Hispanic male He had no known comorbidity Fever and other signs and symptoms: • Six days of fever, sore throat, diarrhea, bilateral lower extremity pain, conjunctivitis and diffuse exanthema • Exposure to SARS-CoV-2 infection two weeks earlier • Respiratory rate was 25-33 breaths per min • Hypotension (systolic blood pressure 80-90 mmHg) • Tachycardia with episodes of atrial fibrillation with rapid ventricular response • Bilateral, nonexudative conjunctival injection • Tender left neck swelling with palpable lymphadenopathy, periorbital edema with overlying erythema, lip cheilitis and targetoid erythematous papules and plaques with central duskiness involving the back, palms, neck, scalp, anterior trunk and upper thighs One or more organs involved (renal, cardiac, digestive, ophthalmologic): • CT of the neck revealed inflammation and edema involving the bilateral lower eyelid and pre-septal space, as well as sub-occipital reactive lymphadenopathy • Electrocardiogram demonstrated: °ST elevations in the anterolateral leads °Global hypokinesis of the left ventricular wall with a mild to moderately reduced ejection fraction of 40% • Diffuse conjunctivitis with chemosis as well as the presence of inflammatory cells within the anterior chamber, indicative of uveitis °A 4-mm punch biopsy of the skin was performed on a papule on the back, with histology revealing rare intraepithelial collections of neutrophils with necrotic keratinocytes and a sparse interstitial, mixed-cell dermal infiltrate with vacuolar interface changes PCR and serology for SARS-CoV-2: • Positive RT-PCR