Multisystem inflammatory syndrome (MIS): a multicentre retrospective review of adults and adolescents in South Africa

Open AccessPublished:August 21, 2021DOI:https://doi.org/10.1016/j.ijid.2021.08.042

      Highlights

      • This is the largest multicentre review of adults and adolescents with multisystem inflammatory syndrome (MIS) in Africa.
      • Despite heterogeneous presentations, a pattern of disease is discernible.
      • Haemodynamic instability was prominent, requiring acute intensive care.
      • Increased awareness of MIS in adults and adolescents in low- and middle-income countries is important.

      Abstract

      Objectives: The aim of this study was to add to the descriptive data pertaining to the epidemiology, presentation, and clinical course of multisystem inflammatory syndrome (MIS) temporally associated with coronavirus disease 2019 in adults and adolescents from low- and middle-income countries.
      Methods: Patients presenting to the adult wards (14 years and older) of three academic hospitals in South Africa, who were diagnosed with MIS between August 1, 2020 and May 31, 2021, were reviewed retrospectively. The presentation, laboratory and radiographic findings, and clinical course are described.
      Results: Eleven cases of MIS were reported, four in adolescents (14–19 years) and seven in adults (≥19 years). Fever was universal. Gastrointestinal symptoms (90.9%), cardiorespiratory abnormalities (90.9%), and mucocutaneous findings (72.7%) were prominent. Echocardiography in 10/11 patients (90.9%) showed a median left ventricular ejection fraction of 26.3% (interquartile range 21.9–33.6%). All patients required high care admission and 72.7% required inotropic support. Glucocorticoids were initiated in all cases and 72.7% received intravenous immunoglobulin.
      Conclusions: This constitutes the largest multicentre review of adults and adolescents with MIS in Africa. MIS may be overlooked in resource-limited settings, and heightened suspicion is needed in patients with multi-organ dysfunction, especially where repeated investigations for other aetiologies are negative.

      Graphical abstract

      KEYWORDS

      1. Introduction

      In April 2020,
      • Riphagen S
      • Gomez X
      • Gonzalez-Martinez C
      • Wilkinson N
      • Theocharis P.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      in the United Kingdom described a cluster of cases with a new clinical inflammatory syndrome similar to Kawasaki disease (KD), Kawasaki disease shock syndrome, and toxic shock syndrome that targeted previously healthy children and adolescents, with a temporal relationship to coronavirus disease 2019 (COVID-19). This entity became known as multisystem inflammatory syndrome in children (MIS-C) or paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) (
      • Davies P
      • Evens C
      • Kanthimathinathan HK
      • Lillie J
      • Brierley J
      • Waters G
      • et al.
      Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study.
      ;
      • Feldstein LR
      • Rose EB
      • Horwitz SM
      • Collins JP
      • Newhams MM
      • Son MBF
      • et al.
      Multisystem inflammatory syndrome in U.S. children and adolescents.
      ;
      • Verdoni L
      • Mazza A
      • Gervasoni A
      • Martelli L
      • Ruggeri M
      • Ciuffreda M
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      ). Although MIS-C has been well researched in paediatric populations, including South African children (
      • Salloo A.
      Multisystem inflammatory syndrome in children in South Africa.
      ;
      • Webb K
      • Abraham DR
      • Faleye A
      • McCulloch M
      • Rabie H
      • Scott C
      • et al.
      Multisystem inflammatory syndrome in children in South Africa.
      ), there is significantly less available data for adult populations, especially from African countries.
      MIS-C is a post-infectious multi-organ inflammatory consequence of COVID-19 diagnosed by case definitions set out by the US Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and Royal College of Paediatric and Child Health (RCPCH) (
      Centers for Disease Control and Prevention (CDC)
      Multisystem inflammatory syndrome (MIS).
      ;
      • Royal College of Paediatrics and Child Health (RCPCH)
      Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.
      ;
      WHO
      Multisystem inflammatory syndrome in children and adolescents with COVID-19: scientific brief. Geneva.
      ). These classifications require evidence of inflammation with organ dysfunction, the absence of a plausible alternative diagnosis, and a temporal relationship to COVID-19 (
      • Whittaker E
      • Bamford A
      • Kenny J
      • Kaforou M
      • Jones CE
      • Shah P
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      ). It is now well established that a similar phenomenon occurs in adults (
      • Bastug A
      • Aslaner H
      • Aybar Bilir Y
      • Kemirtlek N
      • Gursoy FM
      • Bastug S
      • et al.
      Multiple system inflammatory syndrome associated with SARS-CoV-2 infection in an adult and an adolescent.
      ;
      • Morris S
      • Schwartz N
      • Patel P
      • Abbo L
      • Beauchamps L
      • Balan S
      • et al.
      Case Series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March–August 2020.
      ;
      • Parker A
      • Louw EH
      • Lalla U
      • Koegelenberg CFN
      • Allwood BW
      • et al.
      Multisystem inflammatory syndrome in adult COVID-19 patients.
      ). Although a working case definition was developed by
      • Morris S
      • Schwartz N
      • Patel P
      • Abbo L
      • Beauchamps L
      • Balan S
      • et al.
      Case Series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March–August 2020.
      , multisystem inflammatory syndrome in adults (MIS-A) is now defined with an official CDC definition released in May 2021 (
      Centers for Disease Control and Prevention (CDC)
      Multisystem inflammatory syndrome (MIS).
      ;
      • Morris S
      • Schwartz N
      • Patel P
      • Abbo L
      • Beauchamps L
      • Balan S
      • et al.
      Case Series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March–August 2020.
      ).
      MIS is a heterogeneous disease entity, and the spectrum of disease may be even broader in adults than in children and, therefore, under-diagnosed (
      • Davogustto GE
      • Clark DE
      • Hardison E
      • Yanis AH
      • Lowery BD
      • Halasa NB
      • et al.
      Characteristics associated with multisystem inflammatory syndrome among adults with SARS-CoV-2 infection.
      ). Consensus-based management recommendations have been published for MIS-C (
      • American Academy of Pediatrics (AAP)
      Multisystem inflammatory syndrome in children (MIS-C) interim guidance.
      ;
      • Harwood R
      • Allin B
      • Jones CE
      • Whittaker E
      • Ramnarayan P
      • Ramanan A
      • et al.
      A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process.
      ;
      • Henderson LA
      • Canna SW
      • Friedman KG
      • Gorelik M
      • Lapidus SK
      • Bassiri H
      • et al.
      American College of Rheumatology Clinical Guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19: Version 1.
      ;
      • Royal College of Paediatrics and Child Health (RCPCH)
      Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.
      ) and treatment protocols extrapolated from MIS-C are used in adults (
      • Bastug A
      • Aslaner H
      • Aybar Bilir Y
      • Kemirtlek N
      • Gursoy FM
      • Bastug S
      • et al.
      Multiple system inflammatory syndrome associated with SARS-CoV-2 infection in an adult and an adolescent.
      ). However, the management of MIS in adults is still being defined, especially in low- and middle-income countries (LMIC).
      In South Africa the case burden of COVID-19 has been high, with more than 2.2 million confirmed cases detected by reverse transcription PCR (RT-PCR), and even higher seroprevalence rates have been reported (
      • Chambers D.
      Covid-19 antibodies as high as 68% in latest Western Cape study.
      ;
      • Hsiao M
      • Davies MA
      • Kalk E
      • Hardie D
      • Naidoo M
      • Centner C
      • et al.
      SARS-CoV-2 seroprevalence in the Cape Town metropolitan sub-districts after the peak of infections.
      ;

      National Department of Health. COVID-19 South Africa dashboard. Pretoria, 2021. Available: https://www.covid19sa.org/(accessed 30 May 2021).

      ;
      • Sykes W
      • Mhlanga L
      • Swanevelder R
      • Glatt TN
      • Grebe E
      • Coleman C
      • et al.
      Prevalence of anti-SARS-CoV-2 antibodies among blood donors in Northern Cape, KwaZulu-Natal, Eastern Cape and Free State provinces of South Africa in January 2021.
      ). Despite this high COVID-19 incidence, data on MIS in South African adults and adolescents are limited to isolated reports (
      • Moodley P
      • Tsitsi JML
      • Reddy DL
      • Debising M
      • Ickinger C.
      A case of multisystem inflammatory syndrome in an African adolescent male: case report.
      ;
      • Parker A
      • Louw EH
      • Lalla U
      • Koegelenberg CFN
      • Allwood BW
      • et al.
      Multisystem inflammatory syndrome in adult COVID-19 patients.
      ), and collaborative South African data are needed. Furthermore, in South Africa, patients over the age of 14 years are managed in the adult wards, and a portion of MIS-C cases may be missed due to lack of familiarity with the entity (
      • Parker A
      • Louw EH
      • Lalla U
      • Koegelenberg CFN
      • Allwood BW
      • et al.
      Multisystem inflammatory syndrome in adult COVID-19 patients.
      ).
      MIS in adults and adolescents has thus far been described mainly in high-income settings. The aim of the present study was to add to the understanding of MIS in LMIC, particularly within an African context, where unique challenges exist. These include the need to exclude a wider differential diagnosis that may mimic the presentation of MIS, such as HIV, HIV-related opportunistic infections, malaria, and tick bite fever, in addition to sepsis and septic shock. Furthermore, diagnostic and treatment options are often limited in resource-constrained centres. Given these challenges, the aim was to describe the clinical course of MIS in a cohort of South African adults and adolescents to improve clinical recognition in these settings.

      2. Methods

      2.1 Study design and inclusion criteria

      A retrospective review was conducted of patients presenting to the adult wards in three tertiary South African hospitals who were diagnosed with MIS temporally associated COVID-19.
      Inclusion criteria for this study were (1) patients admitted to the adult wards (these admit all patients 14 years and older) of Helen Joseph Hospital (HJH), Chris Hani Baragwanath Academic Hospital (CHBAH), and Tygerberg Hospital (TBH); (2) patients diagnosed with MIS by the treating physician according to the US CDC, WHO, or RCPCH criteria for MIS-C (but disregarding the age criterion to include adults); and (3) a temporal relationship to SARS-CoV-2 infection or exposure. This latter criterion could be laboratory proven (preceding SARS-CoV-2 RT-PCR positive or SARS-CoV-2 antibody positive) or noted in the history by a preceding COVID-19 illness or the presence of a close contact.

      2.2 Study setting and period

      The study was conducted at HJH and CHBAH in Johannesburg, Gauteng, and TBH in Cape Town, Western Cape. These are three urban tertiary referral hospitals, including the two largest hospitals in South Africa (CHBAH and TBH). Patients included in the study were diagnosed and treated between August 1, 2020 and May 31, 2021, including the time periods following the first and second COVID-19 peaks in the country, which occurred in July 2020 and January 2021, respectively.

      2.3 Data collection

      Data were collected retrospectively from the existing medical records. The hospital file of each patient was reviewed individually, and data were collected using a standardized case report form. Data concerning epidemiology, clinical presentation, radiological and laboratory investigations, clinical course, treatment, and outcomes were collected for analysis. All radiological findings were recorded as per the patient notes. Laboratory results collected reflected peak values where applicable, and National Health Laboratory Service (NHLS) reference ranges were used to determine abnormal results.
      As the investigations ordered were at the discretion of the treating physicians, not all patients underwent the same investigations. Where data were not available, these variables were excluded from the calculations. Selected variables were described using the median value and interquartile range (IQR) as data were not assumed to be normally distributed. Categorical data were described as frequencies and expressed as percentages.

      3. Results

      Thirteen patients were diagnosed with MIS between August 2020 and May 2021. Two patients were later excluded from the study, as alternative diagnoses (sarcoidosis and lymphoma) were subsequently made on histological samples. The 11 patients with MIS had a median age of 20 years (range 14–51 years) and seven (63.6%) were older than 19 years (Table 1). Ten patients (90.9%) were of Black African race. Five of the 11 patients (45.5%) had no known comorbidities. In the remaining cases, comorbidities included obesity (2/11, 18.2%) and HIV (1/11, 9.1%).
      Table 1Epidemiological features and COVID-19 exposure for 11 cases of multisystem inflammatory syndrome (MIS) in South African adults and adolescents
      Variablen (%)
      Unless otherwise specified.
      Age (years)Median (range)20 (14–51)
      <19 years old
      The World Health Organization definition defines the age criterion for multisystem inflammatory syndrome in children (MIS-C) as 0–19 years and the US Centers for Disease Control and Prevention use the age criterion of <21 years.
      4 (36.4)
      ≥19 years old7 (63.6)
      SexFemale6 (54.5)
      Male5 (45.5)
      EthnicityBlack African10 (90.9)
      Mixed race1 (9.1)
      Region within South AfricaGauteng6 (54.5)
      Western Cape5 (45.5)
      ComorbiditiesNone5 (45.5)
      Obesity
      Noted by the treating physician.
      2 (18.2)
      HIV1 (9.1)
      Previous TB1 (9.1)
      Type 1 diabetes mellitus1 (9.1)
      COVID-19 exposurePreceding COVID-19 illness4 (36.4)
      Known contact with COVID-192 (18.2)
      COVID-19, coronavirus disease 2019; n, number; TB, tuberculosis.
      a Unless otherwise specified.
      b The World Health Organization definition defines the age criterion for multisystem inflammatory syndrome in children (MIS-C) as 019 years and the US Centers for Disease Control and Prevention use the age criterion of <21 years.
      c Noted by the treating physician.
      Despite a wide range of presentations (Table 2), fever (subjective or recorded) was universal and gastrointestinal disturbance (at least one of abdominal pain, vomiting, or diarrhoea) (10/11, 90.9%) was commonly documented. At presentation, cardiorespiratory findings featured predominantly. Mucocutaneous lesions described included a generalized erythematous maculopapular rash, non-exudative conjunctivitis, oral mucositis, desquamation of the lips, and pharyngitis.
      Table 2Clinical presentation of 11 cases of multisystem inflammatory syndrome (MIS) in South African adults and adolescents
      Variable (units)Median (IQR)
      Vital signsHeart rate (bpm)124 (118.5–131.5)
      Blood pressure (MAP) (mmHg)93/52 (68.3)
      Temperature (°C)38 (36.7–38.3)
      Oxygen saturation (%)97 (94.5–98)
      Respiratory rate (breaths/min)24.5 (20.5–40)
      Clinical symptomatologyn (%)Clinical signn (%)
      GeneralHistory of fever
      One patient did not have a documented history of subjective fever, but fever (temperature >38°C) was recorded in hospital.
      10 (90.9)Dehydration8 (72.7)
      Myalgia2 (18.2)Oedema5 (45.5)
      Arthralgia2 (18.2)Lymphadenopathy2 (18.2)
      GastrointestinalAbdominal pain9 (81.8)Abdominal guarding4 (36.4)
      Vomiting8 (72.7)Hepatomegaly1 (9.1)
      Diarrhoea6 (54.5)Jaundice1 (9.1)
      RespiratoryShortness of breath5 (45.5)Respiratory crackles7 (63.6)
      Cough2 (18.2)Respiratory distress6 (54.5)
      CardiovascularChest pain5 (45.5)S3 gallop5 (45.5)
      Orthopnoea1 (9.1)Displaced apex beat4 (36.4)
      Reduced effort tolerance1 (9.1)Raised JVP1 (9.1)
      MucocutaneousHistory of rash7 (63.6)Generalized rash8 (72.7)
      Sore throat6 (54.5)Mucous membrane changes7 (63.6)
      Odynophagia4 (36.4)Conjunctivitis6 (54.5)
      NeurologicalConfusion5 (45.5)Altered consciousness4 (36.4)
      Headache2 (18.2)Neck stiffness3 (27.3)
      OtherGeneralized body weakness1 (9.1)Joint effusion1 (9.1)
      IQR, interquartile range; JVP, jugular venous pressure; MAP, mean arterial pressure; n, number.
      a One patient did not have a documented history of subjective fever, but fever (temperature >38°C) was recorded in hospital.
      Radiological investigations are summarized in Table 3. Echocardiography at presentation was abnormal in 90% of cases when performed, with a median left ventricular ejection fraction (LVEF) of 26.3% (IQR 21.9–33.6). Cardiac magnetic resonance imaging (MRI), performed in two cases, showed myocardial oedema, mild hypokinesis, and subtle to marked late gadolinium enhancement. A myocardial biopsy, done in one patient, demonstrated lymphocyte aggregates without significant myocyte necrosis, reported as borderline myocarditis, not meeting the Dallas criteria for active myocarditis.
      Table 3Radiological features of 11 cases of multisystem inflammatory syndrome (MIS) in South African adults and adolescents
      Radiological featuresn/N (%)
      Unless otherwise specified.
      Chest radiography (n = 11)Normal5/11 (45.5)
      Increased cardiothoracic ratio5/11 (45.5)
      Alveolar opacifications3/11 (27.3)
      Other (Kerley B lines, upper lobe diversion)2/11 (18.2)
      Electrocardiography (n = 11)Sinus tachycardia10/11 (90.9)
      T wave abnormalities4/11 (36.4)
      ST segment changes3/11 (27.3)
      Saddle-shaped ST elevation2/11 (18.2)
      Poor R wave progression2/11 (18.2)
      PR depression2/11 (18.2)
      Arrhythmia1/11 (9.1)
      Echocardiography (n = 10)LVEF (%), median (IQR)26.3 (21.9–33.6)
      LV dilated6/10 (60)
      LV or global hypokinesis5/10 (50)
      Mild/moderate/severe MR or TR4/10 (40)
      Small pericardial effusion3/10 (30)
      Pericarditis1/10 (10)
      Abdominal ultrasound (n = 7)Pleural effusions3/7 (42.9)
      Normal2/7 (28.6)
      Bilateral enlarged kidneys2/7 (28.6)
      Ascites1/7 (14.3)
      Cardiac MRI (n = 2)Myocardial oedema2/2 (100)
      Late gadolinium enhancement2/2 (100)
      EEG (n = 1)Encephalopathy1/1 (100)
      EEG, electroencephalography; IQR, interquartile range; LV, left ventricle; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MRI, magnetic resonance imaging; n, number; N, number of cases with investigation performed; TR, tricuspid regurgitation.
      a Unless otherwise specified.
      The laboratory results (Table 4) reflected the heightened immune response. Deranged cardiovascular markers were prominent, and 10/11 (90.9%) patients had derangement of at least one cardiac biomarker. The laboratory investigations performed to exclude alternative diagnoses differed between cases and included microbiological investigations on cerebrospinal fluid (CSF), urine, and stool; viral serology; respiratory viral panel testing; malaria investigations and bone marrow aspiration biopsy. Blood cultures were universally performed and were negative in all cases.
      Table 4Laboratory findings of 11 cases of multisystem inflammatory syndrome (MIS) in South African adults and adolescents
      Variable (units)Median (IQR); (+/−)
      (−) indicates a negative test result and (+) indicates a positive test result.
      Abnormal, n/N
      National Health Laboratory Service reference ranges were used: (↑) indicates higher than the reference range, (↓) indicates lower than the reference range.
      (%)
      C-reactive protein (mg/l)317 (176.5–345)11/11 (100) (↑)
      Procalcitonin (μg/l)12.8 (3–33.6)10/11 (90.9) (↑)
      Ferritin (μg/l)1432 (473–2713.5)10/11 (90.9) (↑)
      NT-Pro BNP (ng/l)11 309 (2901.5–32 069.5)7/7 (100) (↑)
      Troponin I (ng/l)3581.5 (1405–6000.3)4/4 (100) (↑)
      Troponin T (ng/l)478 (254–701)6/7 (85.7) (↑)
      Platelet count (× 109/l)172 (142.5–348)4/11 (36.4) (↓)
      Haemoglobin (g/dl)11.7 (10.1–13.2)9/11 (81.8) (↓)
      White cell count (× 109/l)22.7 (18.9–27)10/11 (90.9) (↑)
      Absolute lymphocyte count (× 109/l)1.02 (0.7–1.4)7/11 (63.6) (↓)
      Absolute neutrophil count (× 109/l)17.1 (12–19)9/11 (81.8) (↑)
      INR1.3 (1.3–1.4)9/11 (81.8) (↑)
      D-dimer (mg/l)3.6 (1.7–3.9)10/10 (100) (↑)
      Fibrinogen (g/l)6 (5.5–7.7)4/5 (80) (↑)
      Sodium (mmol/l)133 (131–136)8/11 (81.8) (↓)
      Urea (mmol/l)16 (9.7–26.6)10/11 (90.9) (↑)
      Creatinine (μmol/l)166 (117–367)9/11 (81.8) (↑)
      ALT (U/l)46 (34–69.5)9/11 (81.8) (↑)
      Albumin (g/l)24 (23–32)8/11 (72.7) (↓)
      LDH (U/l)602.5 (543–648.3)10/10 (100) (↑)
      Complement C3 (g/l)1.1 (0.69–1.51)3/7 (42.9) (↓)
      Complement C4 (g/l)0.2 (0.08–0.45)2/7 (28.6) (↓)
      Bacterial blood culture(−)11/11 (100)
      HIV(−)10/11 (90.9)
      SARS-CoV-2 Serology (IgG, IgM or IgA)(+)10/11 (90.9)
      SARS-CoV-2 RT-PCR(+)1/11 (9.1)
      ALT, alanine aminotransferase; Ig, immunoglobulin; INR, international normalized ratio; IQR, interquartile range; LDH, lactate dehydrogenase; n, number; N, number of cases with investigation performed; NT-Pro BNP, N-terminal prohormone of brain natriuretic peptide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
      a (−) indicates a negative test result and (+) indicates a positive test result.
      b National Health Laboratory Service reference ranges were used: (↑) indicates higher than the reference range, (↓) indicates lower than the reference range.
      One patient in the cohort was living with HIV and had a suppressed HIV viral load on antiretroviral therapy. This patient presented with encephalopathy (confirmed on electroencephalography) and a persistently elevated fever despite appropriate antibiotics. Additional features included a rash with mucous membrane changes and non-exudative conjunctivitis, dilated cardiac chambers on echocardiography, a Coombs positive haemolytic anaemia, and renal dysfunction. Plausible alternative aetiologies were excluded. All blood, urine, and CSF cultures were negative and there were no abnormalities noted on brain computed tomography. Additionally, a good response to glucocorticoids was noted. HIV testing was negative in all other patients, although one patient initially had equivocal results on ELISA.
      A temporal relationship to COVID-19 was established in all patients; however, only four patients reported a previous symptomatic SARS-CoV-2 infection. All patients underwent SARS-CoV-2 serology testing, which was positive in 10/11 (90.9%) cases. Positive immunoglobulin G (IgG) antibodies were demonstrated in eight of these cases and IgA antibodies were found in the remaining cases. SARS-CoV-2 RT-PCR testing yielded one (9.1%) positive result.
      All patients in the study required high care unit admission, and supportive management included invasive ventilation (3/11, 27.3%), haemodialysis (1/11, 9.1%), and inotropic support (8/11, 72.7%). All patients received glucocorticoids, including a methylprednisolone ‘pulse’ in 9/11 cases (81.8%). Intravenous immunoglobulin (IVIG) was prescribed in 8/11 cases (72.7%), with a dosage range of 1.4 to 2.1 g/kg. Biological therapies were not initiated in any cases. All patients survived, and where repeat echocardiography was performed before discharge or at 1 month of follow-up (6/11, 54.5%), there was normalization of the LVEF in all cases, with a median value of 56% (IQR 53.5–60.8%).

      4. Discussion

      This study describes 11 patients with MIS presenting to the adult wards of three South African hospitals. A prominence of fever, gastrointestinal, and mucocutaneous features at presentation, coupled with evidence of cardiovascular dysfunction, were found. All patients were critically ill, but complete recovery was observed with supportive care, glucocorticoids, and IVIG when appropriate.
      In keeping with the global literature, the majority of patients in this study were Black Africans (
      • Hoste L
      • Van Paemel R
      • Haerynck F
      Multisystem inflammatory syndrome in children related to COVID-19: a systematic review.
      ;
      • Morris S
      • Schwartz N
      • Patel P
      • Abbo L
      • Beauchamps L
      • Balan S
      • et al.
      Case Series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March–August 2020.
      ). The predilection for certain ethnic groups may suggest a specific genetic predisposition for MIS (
      • Sood M
      • Sharma S
      • Sood I
      • Sharma K
      • Kaushik A.
      Emerging evidence on multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection: a systematic review with meta-analysis.
      ). Since adolescents (14 years and older) are admitted to the adult wards in South Africa, the median age in this study was younger than that found in international data for MIS in adults (
      • Bastug A
      • Aslaner H
      • Aybar Bilir Y
      • Kemirtlek N
      • Gursoy FM
      • Bastug S
      • et al.
      Multiple system inflammatory syndrome associated with SARS-CoV-2 infection in an adult and an adolescent.
      ;
      • Davogustto GE
      • Clark DE
      • Hardison E
      • Yanis AH
      • Lowery BD
      • Halasa NB
      • et al.
      Characteristics associated with multisystem inflammatory syndrome among adults with SARS-CoV-2 infection.
      ). The study cohort therefore comprised both MIS-A and MIS-C cases. This unique situation emphasizes the need for physicians to be aware of the overlap between MIS-C and MIS-A within a South African setting. Younger children are more likely to meet the disease criteria for KD, with prominent mucocutaneous symptoms, while adolescents have a higher incidence of shock, myocarditis, and neurological symptoms (
      • Dufort EM
      • Koumans EH
      • Chow EJ
      • Rosenthal EM
      • Muse A
      • Rowlands J
      • et al.
      Multisystem inflammatory syndrome in children in New York State.
      ;
      • Vogel T
      • Top KA
      • Karatzios C
      • Hilmers DC
      • Tapia LI
      • Moceri P
      • et al.
      Multisystem inflammatory syndrome in children and adults (MIS-C/A): Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.
      ). Adults with MIS are more likely to have comorbidities, have a higher incidence of thrombosis, and present with more severe cardiac dysfunction (
      • Vogel T
      • Top KA
      • Karatzios C
      • Hilmers DC
      • Tapia LI
      • Moceri P
      • et al.
      Multisystem inflammatory syndrome in children and adults (MIS-C/A): Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.
      ).
      The first description of MIS in an adult living with HIV is reported here. This patient's clinical presentation differed from those of the other patients, with a predominance of neurological system involvement. Further research is needed to determine whether HIV infection affects the incidence and presentation of MIS. Interestingly, another patient had equivocal HIV ELISA results, but was subsequently determined to be HIV-negative by Western blot analysis. The initially equivocal results may indicate cross-reaction of high concentrations of circulating antibodies associated with MIS that interfered with the immunoassay.
      The small number of patients with a preceding symptomatic episode of COVID-19 indicates the necessity for serological testing. However, in areas of high COVID-19 seroprevalence, this finding lacks specificity (
      Centers for Disease Control and Prevention (CDC)
      Interim guidelines for COVID-19 antibody testing: interim guidelines for COVID-19 antibody testing in clinical and public health settings.
      ;
      • Rostad C
      • Chahroudi A
      • Mantus G
      • Lapp S
      • Teherani M
      • Macoy L
      • et al.
      Serology in children with multisystem inflammatory syndrome (MIS-C) associated with COVID-19.
      ). Although MIS appears to be a post-infectious manifestation, in some situations the current SARS-CoV-2 nucleic acid test may be positive, likely due to persistence of the SARS-CoV-2 antigen (
      • Rostad C
      • Chahroudi A
      • Mantus G
      • Lapp S
      • Teherani M
      • Macoy L
      • et al.
      Serology in children with multisystem inflammatory syndrome (MIS-C) associated with COVID-19.
      ;
      • Yonker LM
      • Gilboa T
      • Ogata AF
      • Senussi Y
      • Lazarovits R
      • Boribong BP
      • et al.
      Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.
      ).
      Clinical presentations within this study corresponded with those reported in the literature. Haemodynamic instability with evidence of myocardial dysfunction on echocardiography was notable and is characteristic of MIS in adults and adolescents (
      • Bastug A
      • Aslaner H
      • Aybar Bilir Y
      • Kemirtlek N
      • Gursoy FM
      • Bastug S
      • et al.
      Multiple system inflammatory syndrome associated with SARS-CoV-2 infection in an adult and an adolescent.
      ). Cardiac MRI is a novel area of interest in MIS, and diffuse myocardial oedema has been reported in other studies, suggesting underlying myocardial inflammation (
      • Hékimian G
      • Kerneis M
      • Zeitouni M
      • Cohen-Aubart F
      • Chommeloux J
      • Bréchot N
      • et al.
      Coronavirus disease 2019 acute myocarditis and multisystem inflammatory syndrome in adult intensive and cardiac care units.
      ).
      All patients received glucocorticoids and most received IVIG with dosages between 1.4 g/kg and 2.1 g/kg. The American College of Rheumatology (ACR) paediatric guidelines for MIS-C advise high-dose IVIG (2 g/kg), but suggest caution in cases with depressed cardiac function (
      • Henderson LA
      • Canna SW
      • Friedman KG
      • Gorelik M
      • Lapidus SK
      • Bassiri H
      • et al.
      American College of Rheumatology Clinical Guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19: Version 1.
      ). Large doses of IVIG alone may be less appropriate in adults and adolescents where cardiac dysfunction is often profound (
      • Son MBF
      • Murray N
      • Friedman K
      • Young CC
      • Newhams MM
      • Feldstein LR
      • et al.
      Multisystem inflammatory syndrome in children — initial therapy and outcomes.
      ); moreover, in LMIC, the dosage required in adults may be unaffordable. Glucocorticoids are a viable alternative and outcomes are comparable when MIS-C is treated with glucocorticoids alone compared to IVIG (alone or with glucocorticoids) (
      • McArdle AJ
      • Vito O
      • Patel H
      • Seaby EG
      • Shah P
      • Wilson C
      • et al.
      Treatment of multisystem inflammatory syndrome in children.
      ;
      • Ouldali N
      • Toubiana J
      • Antona D
      • Javouhey E
      • Madhi F
      • Lorrot M
      • et al.
      Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children.
      ). This finding has significant potential benefits within LMIC. Although biological agents, such as tocilizumab, have been used in a few refractory cases of MIS-C in South African children, these agents are not widely available within many LMIC (
      • Sood M
      • Sharma S
      • Sood I
      • Sharma K
      • Kaushik A.
      Emerging evidence on multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection: a systematic review with meta-analysis.
      ;
      • Webb K
      • Abraham DR
      • Faleye A
      • McCulloch M
      • Rabie H
      • Scott C
      • et al.
      Multisystem inflammatory syndrome in children in South Africa.
      ).

      4.1 Strengths and limitations

      This constitutes the most extensive multicentre review of cases of MIS in adults and adolescents in Africa. The admission of adolescents to the adult wards in South Africa means that this cohort represents both MIS-C and MIS-A cases. The small sample size and somewhat heterogeneous investigations and management are acknowledged limitations, as well as the potential for severity bias, given that all patients required intensive care. As the data are retrospective, conclusions about the efficacy of IVIG and glucocorticoids cannot be inferred. However, by increasing the recognition and reporting of MIS in adults we can expect more robust evidence. The setting of this study within a LMIC provides important data that may be extrapolated to other LMIC.

      4.2 Recommendations

      In South Africa, clinical recognition with pre-emptive diagnosis may be necessary in some cases due to resource limitations. In light of this, and considering the overlap of adolescent and adult patients in South African adult wards, a collaborative case definition of MIS-C/A with varied levels of diagnostic certainty similar to that set out by the Brighton Collaboration may be appropriate (
      • Vogel T
      • Top KA
      • Karatzios C
      • Hilmers DC
      • Tapia LI
      • Moceri P
      • et al.
      Multisystem inflammatory syndrome in children and adults (MIS-C/A): Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.
      ). The treatment protocols used varied between hospitals, as well as between patients within the same hospital. This emphasizes the need for adult-based treatment guidelines and, in particular, the need for these within LMIC.

      4.3 Conclusions

      Multisystem inflammatory syndrome associated with COVID-19 in adults and adolescents is a rare but important clinical entity. Despite the need for intensive care, observed outcomes were good. Randomized data are required to assess whether early recognition, supportive care, or specific immunomodulation correlate with improved outcomes.
      In LMIC, where resources are limited, MIS may be overlooked, and a high index of suspicion is needed in patients presenting with multi-organ dysfunction where repeated investigations for alternative aetiologies are negative.

      Author contributions

      JVH, JN, and AP conceived the study. All authors edited and approved the study protocol. Data collection was done by JVH, JH, PG, PM, CI, EL, and AP. JVH drafted the original manuscript. JN and AP provided input to the background, methods, and interpretation of the results of the study. All authors revised the manuscript and approved the final version.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      Ethical approval was granted by the University of Witwatersrand Human Research Ethics Committee (Medical) (protocol number M201141) and the Stellenbosch Health Research Ethics Committee (HREC reference number N20/04/002_COVID-19).

      Conflicts of interest

      None.

      Acknowledgements

      We acknowledge the patients and the dedicated staff of all three hospitals.

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