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Short-term outcomes of South African children with multisystem inflammatory syndrome in children: a prospective cohort study

Short-term outcomes of South African children with multisystem inflammatory syndrome in children:... Global child health Global child health Original research Short- term outcomes of South African children with multisystem inflammatory syndrome in children: a prospective cohort study 1,2 1,2 1,2 Juanita Lishman , Deepthi Raju Abraham, Barend Fourie, 1,2 1,2 1,3 Nurea Abdulbari Yunis, Andrew Redfern, Marieke M van der Zalm, 1,2 Helena Rabie ► Additional supplemental ABSTRACT WHAT IS ALREADY KNOWN ON THIS TOPIC material is published online Background Despite the life- threatening presentation only. To view, please visit the ⇒ Despite the life- threatening presentation of of multisystem inflammatory syndrome in children journal online (http:// dx. doi. multisystem inflammatory syndrome in children (MIS- C), the overall prognosis is favourable in centres org/ 10. 1136/ archdischild- (MIS- C), the overall prognosis is favourable in 2022- 325287). with access to appropriate supportive care. In this study, high- income countries. 1 we investigate the short- term outcomes in children with Paediatrics and Child Health, MIS- C in Cape Town, South Africa. Stellenbosch University, Cape WHAT THIS STUDY ADDS Town, South Africa Methods This prospective observational cohort study ⇒ Our study adds to the very limited data of Paediatrics and Child Health, included children <13 years who fulfilled the WHO case Tygerberg Hospital, Cape Town, cardiovascular outcomes of children with MIS-C definition of MIS- C and were admitted to Tygerberg Western Cape, South Africa in Africa. Hospital in Cape Town, South Africa between 1 June Department of Paediatrics ⇒ Outcomes were overall good with no deaths 2020 and 31 October 2021. Clinical features were and Child Health, Faculty of reported. Medicine and Health Sciences, recorded at baseline and at follow- up at the 6- week ⇒ There were persistent abnormal Desmond Tutu TB Centre, cardiology and 3- month rheumatology- immunology Stellenbosch University, Cape echocardiograms at follow- up, suggesting that clinics, respectively. Town, South Africa selected children will need longer follow-up to Findings Fifty- three children with a median age of 7.4 assess effect on their cardiovascular health. years (IQR 4.2–9.9) were included. There was a slight Correspondence to ⇒ Follow- up was challenging with a large male predominance (30/53; 56.6%) and the majority Dr Juanita Lishman, Paediatrics proportion of children being lost despite the and child health, Stellenbosch was of mixed ancestry (28/53; 52.83%) or black African clinical need to see them and strategies to University, Cape Town 7505, ancestry (24/53; 45.3%). Fourteen children (14/53; South Africa; retain them in care. 26.4%) had comorbid disease. The median length of lishman@ sun. ac. za hospital stay was 8 days (IQR 6–10). All children had HOW THIS STUDY MIGHT AFFECT RESEARCH, Received 15 January 2023 an echocardiogram performed at baseline of which PRACTICE OR POLICY Accepted 14 May 2023 39 were abnormal (39/53; 73.6%). All children were ⇒ Further research on the mid- term and long- term discharged alive. The median days from discharge to outcomes of MIS- C in Africa are needed to cardiology follow- up was 39 days (IQR 33.5–41.5) and further characterise morbidity in children from for rheumatology- immunology clinic was 70.5 days Africa and to inform targeted interventions. (IQR 59.5–85.0). Eleven children (11/41; 26.8%) had a persistently abnormal echocardiogram at cardiology follow- up. Systemic inflammation and organ dysfunction resolved in most. 10 care with no deaths reported. A systematic review Interpretation Although the short- term outcomes of of 16 case series including 655 children with MIS- C MIS- C in our cohort were generally good, the cardiac reported a mortality rate of 1.7%. Mortality morbidity needs further characterisation and follow- up. appears to be higher in older children and those with comorbid diseases. In a recent report from KwaZulu Natal, South Africa, the mortality was reported much higher at 20.6%, similar to the 20% BACKGROUND 13 14 mortality in Pakistan. The mortality rate was Multisystem inflammatory syndrome in children 11.2% in a multicentre cohort including 135 chil- (MIS- C) is temporally associated with SARS- CoV- 2 dren from India. © Author(s) (or their infection. The syndrome is characterised by fever, employer(s)) 2023. No There are no randomised data on the manage- mucocutaneous features, hypotension, gastrointes- commercial re- use. See rights ment of children with MIS-C but large observa- tinal symptoms and features of myocardial inflam- and permissions. Published 1–3 tional studies found clinical benefit in giving both mation. MIS- C was first reported in Europe in by BMJ. 4–7 intravenous immunoglobulin (IVIG) and gluco- March 2020. The first case in Cape Town, South 16–18 To cite: Lishman J, corticoids as compared with IVIG alone. The Africa was noted in early May 2020. Abraham DR, Fourie B, et al. Best Available Treatment Study consortium evalu- Forty to 80% of children with MIS- C required Arch Dis Child Epub ahead of ated the use of IVIG, glucocorticoid or combina- print: [please include Day intensive care admission for haemodynamic insta- 6 9 Month Year]. doi:10.1136/ tion therapy in a propensity-weighted cohort study bility. In a cohort from Lagos, Nigeria, only archdischild-2022-325287 including 2101 children from 39 countries. They 10.7% (3/28) of patients were admitted to intensive Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 1 Original research concluded that glucocorticoids appears to be a safe alternative to The laboratory parameters included white blood cell count, IVIG or combined therapy. absolute lymphocyte count, absolute neutrophil count, haemo- The available information on long-term outcomes from globin, platelets, C reactive protein, ferritin, pro- brain natri- North America and Europe suggests good cardiac prognosis, uretic peptide (pro- BNP) and troponin T. with systolic dysfunction recovering in the convalescent phase All data including echocardiograms and blood tests were and most children making a full clinical recovery at 6- month performed as needed for routine care. All echocardiograms 20 21 follow- up. Children with cardiac dysfunction showed were performed by or reviewed by a paediatric cardiologist. We recovery of ventricular function and resolution of coronary classified coronary artery Z- scores as follows: normal <2, dila- 22 23 artery aneurysms. tion 2 to <2.5, aneurysm ≥2.5. Left ventricular (LV) systolic We previously reported that the clinical presentation and dysfunction was defined as an LVEF<55% and graded as mild early outcomes of South African children with MIS-C managed (LVEF 45%–54%), moderate (LVEF 35%–44%) or severe (LVEF at Tygerberg Hospital (TBH) and Red Cross War Memorial <35%) as previously described. Children’s Hospital in Cape Town are similar to European and The WHO weight-for - age Z-scores were calculated for chil- 8 9 24 North American children and adolescents. However, there dren younger than the age of 5 years and the WHO body mass are limited data on postdischarge outcomes of children with index Z- score for children over the age of 5 years using the MIS- C from Africa. We aimed to evaluate the outcomes of chil- AntrhoCalc application V.2.1. dren with MIS-C managed at TBH up to 3 months after diag- nosis and beyond as indicated clinically. Statistical analysis Basic demographic data, clinical features on presentation, management and echocardiogram findings at baseline and METHODS follow- up was described using standard summary statistics. Study design and population Continuous variables are summarised as mean, SD or median This single- centre prospective observational study of children and IQRs where appropriate. Comparative data were analysed and adolescents <13 years diagnosed with MIS-C at TBH using IBM SPSS Statistics, V.27. Fisher’s exact test and χ test between 1 June 2020 and 31 October 2021 describes the clin- were used for dichotomous variables and Mann- Whitney U test ical progress from diagnosis until approximately 3 months after for non- parametric continuous variables. diagnosis. Where children with abnormal echocardiograms were followed beyond 3 months, those data are reported up to 6 RESULTS months after diagnosis. We identified 64 children and adolescents <13 years with Locally, all children and adolescents diagnosed with MIS-C suspected MIS-C between 1 June 2020 and 31 October 2021; are managed with supportive care, IVIG and/or intravenous or we excluded 11 cases that did not meet the case definition oral steroids and low- dose aspirin. All children have echocar- (figure 1). The median age of the 53 patients was 7.4 years (IQR diography on admission and follow- up. The coronary artery 4.3–9.9) and 30/53 (56.6%) were male (table 1). Symptoms on diameter Z-score derived from the Paediatric Heart Network presentation, findings on initial clinical examination, hospital Z- score system, and left ventricular ejection fraction (LVEF) course and management are summarised in table 1. measured qualitatively and quantitatively and calculated using 25 26 The median length of hospital stay was 8 days (IQR 6–8). the M- mode method are recorded. All children and adoles- Twenty-four (45,3%) patients required intensive care admission, cents are given dates for review approximately at 6 weeks after 22 (41.5%) patients required inotropic support and 7 (13.2%) diagnosis at cardiology and at rheumatology-immunology clinic intubation and ventilation. The majority received both IVIG and within 6 weeks to 3 months after diagnosis. The evaluation at methylprednisolone (56.6%) with 18 patients (34%) receiving follow- up includes a detailed clinical assessment, repeat echocar- IVIG only. diogram and repeating inflammatory markers, COVID-19 serum At baseline, 39 of the 53 children (73.6%) had an abnormal antibody, renal function, liver enzymes and other investigations echocardiogram report (table 2). The majority (29, 54,7%) had as indicated. Data sources and definitions Children and adolescents <13 years who met the WHO case definition of MIS- C were enrolled. We excluded children and adolescents in whom another plausible diagnosis was apparent; we also excluded children with typical and atypical Kawasaki disease with negative SARS COVID-2 PCR and antibody tests. Routine access to SARS-CoV - 2 antibody testing against the nucleocapsid protein only became available in August 2020. Cases with MIS-C prior to A ugust 2020 that were SARS- CoV- 2 PCR negative were included if the full case definition was met and there was a positive history of exposure to a likely source case. None of these children and adolescents was vaccinated against COVID- 19. South Africa only approved the use of two doses of the Pfizer- BioNTech COVID- 19 vaccines for those aged 12–17 years in October 2021. Demographic data and clinical characteristics were reported at admission and follow- up. Care interventions including the Figure 1 Follow- up of children and adolescents <13 years with need for intensive care intervention, IVIG and steroids were confirmed multisystem inflammatory syndrome in children (MIS- C) at documented. cardiology and rheumatology- immunology clinic. KD, Kawasaki disease. 2 Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 Global child health Global child health Original research Table 1 Demographic and clinical characteristics, hospital course Table 1 Continued and management Value Value Any biological 0 Demographic characteristics Numbers are presented with percentages in brackets. Median values are presented Patients, n 53 with IQR. Age, years, median (IQR) 7.4 (4.3–9.9) BMI, body mass index; IVIG, intravenous immunoglobulin; PICU, paediatric intensive care unit; WAZ, weight for age Z- score. Male sex, n (%) 30 (56.6) Ethnicity, n (%) Mixed race 29 (54.7) mitral or tricuspid regurgitation at baseline, 8 of the 15 patients Black African 23 (43.4) with coronary abnormalities had brightness of the artery and White 1 (1.9) although 19 (29,3%) had abnormalities of LV function only, 10 WAZ (<5 years) N=17 of the patients had moderate or severe dysfunction. Median WAZ (IQR) 0.53 (–1.2 to 2.02) In the acute phase, all patients had elevated markers of Possible growth problem (Z- score ≥3), n (%) 1 (5.9) systemic inflammation. The majority had lymphopenia, anaemia, renal impairment, hyponatraemia and elevated cardiac enzymes Possible growth problem (Z- score 2 to <3), n (%) 2 (14.3) on admission. In the convalescent phase, C reactive protein and Normal (Z- score −2 to <2), n (%) 13 (76.5) ferritin remained raised in 33 of 45 (73.3%) of children and Underweight (Z- score <−2), n (%) 1 (5.9) 28/28 (100%) of children, respectively (online supplemental BMI (>5 years) N=36 table 1). Median BMI Z- score (IQR) −0.54 (–1.5 to 0.54) Obesity (Z- score ≥3), n (%) 3 (8.3) Follow-up Overweight (Z- score 2 to <3), n (%) 2 (5.6) By 28 February 2022, follow- up data for at least one cardiology Risk of overweight (Z- score 1 to <2), n (%) 2 (5.6) outpatient review was available for 41/53 (77%) cases and 30/53 Normal (Z- score ≥−2 to <1), n (%) 24 (66.7) (56.6%) cases had at least one rheumatology follow-up ( figure 1). Wasted (Z- score <−2), n (%) 2 (5.6) The median days from discharge to cardiology follow-up was 39 Comorbid disease, n (%) 14 (26.4) days (IQR 33.5–41.5) and for rheumatology-immunology clinic Obesity/WAZ >3 4 (7.5) was 70.5 days (IQR 59.5–85.0). HIV- exposed uninfected 3 (5.7) Acute myeloid leukaemia 2 (3.8) Cardiology follow-up Fetal alcohol syndrome 1 (1.9) Thirty- three patients (33/41, 80.5%) had an initial repeat echo- Gastro- oesophageal reflux disease 1 (1.9) cardiogram within 6 weeks, four patients (4/41, 9.8%) within 3 Tuberculous endocarditis 1 (1.9) months and the remaining four (4/41, 9.8%) patients within 6 Chronic lung disease 1 (1.9) months. Eleven (11/41, 26.8%) patients had persistent abnormal Ventricular septal defect 1 (1.9) findings on echocardiography at follow- up (table 3). In eight Evidence of COVID- 19 exposure, n (%) 53 (100) children, the persistent abnormality was due to an endocardial COVID- 19 contact 21 (39.6) dysfunction manifesting as mitral or tricuspid regurgitation. Positive PCR SARS- CoV- 2 at diagnosis 10 (18.9) Three patients had abnormalities that persisted at 6- month Positive antibody to SARS- CoV- 2 38/40 (95) follow- up (patients 2, 3 and 4, table 3). Patients 2 and 3 had moderate and mild LV dysfunction, respectively and patient Hospitalisation 4 had a dilated coronary artery (Z- score=2). We found that Length of stay, days, median (IQR)* 8 (6–10) PICU admission, n (%) 24 (45.3) Length of stay in PICU, days, median (IQR) 3.5 (1.5–6) Table 2 Echocardiogram report (baseline and first follow- up) Discharged alive, n (%) 53 (100) Management N=53 AcuteFollow- up Echocardiogram findings (n=53) (n=41) Cardiovascular support, n (%) 24 (45.3) Fluid boluses, n (%) 16 (30.2) Normal echo, n (%) 14 (26.4) 30 (73.2) Inotropic support, n (%) 22 (41.5) Any left ventricular systolic dysfunction, n (%) 19 (35.8) 2 (4.9) Duration of inotropic support, days, median (IQR) 3 (1–4) LVEF (mean, SD) 55.2 (±11.6) 62.3 (±8.4) Respiratory support, n (%) 19 (35.8) Mild (LVEF 45%–54%), n (%) 9 (17.0) 1 (2.4) Nasal prong oxygen, n (%) 18 (34) Moderate (LVEF 35%–44%), n (%) 8 (15.1) 0 Non- invasive ventilation, n (%) 11 (20.8) Severe (<35%), n (%) 2 (3.8) 1 (2.4) Invasive ventilation, n (%) 7 (13.2) Any coronary artery abnormality, n (%) 15 (28.3) 1 (2.4) Duration of invasive ventilation, days, median 5 (3–6) Dilated coronary artery (Z- score 2 to <2.5), n (%)* 5 (9.4) 1 (2.4) (IQR) Coronary artery aneurysm (Z- score ≥2.5), n (%) 5 (9.4) 0 Medications 53 (100) Coronary artery echobright, n (%) 8 (15.1) 0 Both IVIG and methylprednisolone, n (%) 30 (56.6) Mitral or tricuspid regurgitation, n (%) 29 (54.7) 8 (19.5) IVIG alone, n (%) 18 (34.0) *Three patients reported to have a ‘dilated coronary artery’ did not have a Z-score Methylprednisolone alone, n (%) 2 (3.8) documented. Acute echocardiogram was performed at presentation and follow-up Oral prednisone alone, n (%) 2 (3.8) echocardiogram at the first cardiac outpatient review. Numbers are presented with percentages in brackets. No immune- modulation, n (%) 1 (1.9) LVEF, left ventricular ejection fraction. Continued Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 3 Original research Table 3 Abnormal echocardiogram on follow- up (n=11) Elevated cardiac PICU and Patient Age enzymes on inotropic SARS- CoV- 2 Abnormal finding number (years) Sex presentation support PCR Acute and follow- up echocardiogram Left ventricular 1 12.7 F Yes (pro- BNP 15 259, Yes Negative Acute: LVEF 51%, dilated RCA systolic dysfunction Trop T 58) 6 weeks: LVEF 53%, mild MR and TR (n=3) 6 months: LTFU 2 7.4 F Yes (pro- BNP 27 731, Yes Negative Acute: LVEF 31%, MR and TR Trop T 303) 6 weeks: LVEF 53% 6 months: LVEF 53%. Reduced exercise recommended by cardiologist 9 months: fatigues with play, echocardiogram not repeated 12 months: LTFU 3 10 M Yes (pro- BNP 1089, No Positive Baseline: LVEF 43%, dilated left ventricle Trop T <3) (multiple follow- up reviews in ward with repeat echocardiograms. Persistent severe left ventricular dysfunction) 6 months: LVEF 39% Patient remained on antifailure treatment with poor LVEF for 15 months Coronary artery 4 7.9 M Yes (pro- BNP >35 Yes Negative Acute: LVEF 44%, moderate MR and TR, dilated LAD dilated (n=1) 000, Trop T 76) 6 weeks: LVEF normal. LAD CA still dilated (Z- score=2), aspirin continued 6 months: moderate TR, LAD CA still dilated (Z- score=2), aspirin continued 12 months: due Mitral regurgitation 5 8.8 M Yes (pro- BNP 7485, No Negative Acute: LVEF 47%, LCA mildly dilated, mild MR and TR (MR) or tricuspid Trop T 25) 6 weeks: LVEF normal. Mild TR regurgitation (TR) 6 months: normal clinical exam (n=7) 12 months: LTFU 6 10.3 M Yes (pro- BNP 3875, No Negative Acute: LVEF normal. Moderate MR and TR Trop T 25) 6 weeks: trivial MR and mild TR 6 months: LTFU 7 8.3 F Yes (pro- BNP 26 620, Yes Negative Acute: LVEF 59% mild- to- moderate MR Trop T 46) 6 weeks: LVEF normal. Mild MR 6 months: mild MR, trivial TR, LVEF normal 8 10.7 M Yes (pro- BNP >35 Yes Negative Acute: LVEF 50%, valvulitis, LCA dilated, MR and TR 000, Trop T 699) 6 weeks: LVEF normal. Mild residual MR and TR 6 months: LTFU 9 5.3 F Yes (pro- BNP 3696, No Negative Acute: LVEF 64%, mild MR and TR Trop T 10) 6 weeks: LVEF normal. TR. 6 months: trivial TR 10 8.8 M Yes (pro- BNP 2441, No Negative Acute: LVEF 73%, mild TR Trop T 21) 6 weeks: LVEF normal. Mild MR and TR 6 months: LTFU 11 8.2 M Yes (pro- BNP 3469, No Negative Acute: LVEF 62%, mild TR Trop T 15) 6 weeks: LVEF normal. Mild TR 6 months: LRFU Echocardiograms were not always performed discretely at 6 weeks and 6 months as indicated in table. The median days from discharge to cardiology follow-up w as 39 days (IQR 33.5–41.5). F, female; LAD CA, left ascending descending coronary artery; LTFU, lost to follow-up; M, male; PICU, paediatric intensive care unit; Pro- BNP, pro- brain natriuretic peptide (pg/mL); RCA, right coronary artery; Trop T, troponin T (ng/L). the median age of children with abnormal echocardiogram diagnosed with myasthenia gravis shortly after admission that at follow- up was higher compared with children with normal was temporally associated with SARS- CoV- 2. She was treated echocardiogram at follow- up (p=0.04) and similarly children with pyridostigmine and methotrexate. Nine months after treated with both methylprednisolone and IVIG frequently had initial diagnosis, she had normal function and muscle strength abnormal echocardiogram at follow-up compared with children and all medication was successfully stopped. The fourth patient with methylprednisolone or IVIG alone (p=0.02) (table 4). complained of headache, ankle pain and stiff legs. She had no objective clinical signs or inflammatory markers suggestive of Rheumatology-immunology follow-up chronic arthritis or impaired mobility. Her symptoms resolved Four patients (4/30, 13.3%) had ongoing clinical concerns. completely at 8- month follow- up. The first patient had an intermittent urticarial rash, derma- Follow-up labora tory parameters are summarised in online tology diagnosed papular urticarial pustulosis, association with supplemental table 1. Of the 32 patients that had repeat SARS- SARS- CoV- 2 infection could not be excluded. On subsequent CoV- 2 antibody test at follow- up, 40.6% (13/32) remained sero- follow- up, the rash had resolved. The second patient had mild conjunctival injection unrelated to MIS- C. The third patient was positive. All patients were discharged alive from hospital. 4 Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 Global child health Global child health Original research degrees of echocardiographic changes at their first follow- up Table 4 Determinants associated with abnormal echocardiogram at postdischarge. Three cases showed a reduction in ejection follow- up fraction, 1 case with persistent coronary artery dilatation and Normal Abnormal 3 of the 11 cases with abnormalities persisting throughout the echocardiogram echocardiogram 6- month follow- up phase. This contrasts the Nigerian cohort Variable N=42 N=11 P value which demonstrated normalisation of cardiovascular manifesta- tions by 6 months in all. Age in months 70 (49.3–125.5) 106 (96.6–125.5) 0.04 (median, IQR) A group that may need further characterisation is the seven Chronic illness (n, %) 8 (19.0%) 3 (27.2%) 0.68 children that had persistent mild mitral or tricuspid regurgi- tation at cardiac follow-up. The significance of this remains Duration of fever in 4 (2–5) 5 (3.5–5) 0.41 days (median, IQR) unclear and it is difficult to attribute the regurgitation to some- Days from symptom 7 (4–8) 6.5 (5.3–8) 0.67 thing specific. Ventricular strain method was not performed on onset to diagnosis our patient population. This might have shown that these chil- (median, IQR) dren had myocardial dysfunction even if it was not evident on Highest C reactive 232 (120.8–294.5) 237 (152–265) 0.94 M mode. Sirico et al evaluated the early and mid- term cardiac protein (median, IQR) outcomes of 32 children with MIS- C by performing standard Highest NT- pro- BNP 5777 (1388–27 386) 7485 (3582.5–27 175.5) 1.00 and speckle- tracking echocardiography, and cardiac magnetic (median, IQR) resonance imaging (CMR). They demonstrated subclinical Highest troponin T 22.5 (9–64.3) 25 (18–67) 0.93 myocardial dysfunction still detectable at 6 months. Thirteen (median, IQR) per cent showed persistent LV global longitudinal strain and on PICU admission (n, %) 20 (47.6%) 4 (36.6%) 1.00 CMR 33.4% had persistence of late gadolinium enhancement. Inotropic support 17 (40.5%) 5 (45.5%) 1.00 It is difficult to speculate what the cause of cardiac regurgitation (n, %) is in our cohort as we did not have capacity to perform cardiac Methylprednisolone 2 (4.8%) 0 (0%) 1.00 MRI to investigate for inflammation. only The median age of those with an abnormal echocardiogram IVIG only 17 (40.5%) 1 (9.1%) 0.08 at follow- up was higher than those with a normal echocardio- Both 20 (47.6%) 10 (90.1%) 0.02 gram. Although other cohorts also report older children having methylprednisolone more severe disease, we should note that we did not include any and IVIG children >13 years. Children who received both methylpred- IVIG, intravenous immunoglobulin; NT- pro- BNP, N- terminal pro- brain natriuretic nisolone and IVIG were also more likely to have an abnormal peptide; PICU, paediatric intensive care unit. echocardiogram at follow- up. This may be a proxy for disease severity that we were unable to demonstrate. However, in our DISCUSSION study we did not find an association between cardiac outcomes This study adds to expanding data on the outcomes of African at follow- up and children who required PICU admission or 10 28 children with MIS- C. As in the cohort from Nigeria and Kenya, inotropic support or those with elevated pro- BNP or troponin T, overall outcomes were good, and no children required a biologic but numbers were small, and this requires further investigation. agent. It is, however, in contrast with data recently published A major concern in our study is the poor follow- up rate of 13 14 29 from KwaZulu Natal, South Africa, Pakistan and Egypt, children possibly related to socio- economic factors. Only 77% where the mortality was reported to be very high (20.6%, 20% of children presented to cardiology clinic at 6 weeks and 57% and 33.3%, respectively). Critical shortage of intensive care beds to the rheumatology-immunology clinic by 3 months. Children is reported from Nigeria and KwaZulu Natal. In KwaZulu Natal, in high- income country (HIC) cohorts had serial echocardio- limited intensive care space and delay in access to specialised care grams and rigorous multidisciplinary follow-up and clinical may have contributed to the high mortality. In addition, African review. This is not always feasible in a resource-limited setting children may have more aggressive inflammation. We note that such as South Africa. It is especially concerning that 5.7% (3/53) children from both the cohorts from Egypt and KwaZulu Natal of children in our cohort had ongoing cardiac abnormalities at had a median age <5 years. It is not clear whether young age 6 months in the context of 22.6% (12/53) not presenting for contributed to the higher mortality. cardiac follow-up at all. Online supplemental table 2 compares the clinical features Emerging data indicate that children and adolescents from and outcomes in children from four African countries. Detailed African countries experience higher COVID-19- related 31 32 information on echocardiographic findings at baseline and morbidity and mortality, when compared with HIC. Kitano follow- up is only provided in the Nigerian cohort and our et al reported on the differential impact of paediatric COVID-19 study. Of interest, in the Kenyan cohort with only 25% (5/20) between HICs and low- income and middle- income countries of patients receiving immune- modulation the outcomes were (LMICs) in a systematic review. The paediatric deaths and case good with no deaths reported, compared with the higher 33.3% fatality rate was significantly higher in LMICs. This is supported mortality in the Egyptian cohort where all patients received by Javalkar et al, who concluded that lower socio-economic immune- modulation. The differences in mortality rates are status, Hispanic ethnicity and black race were independent risk poorly understood and this requires further analysis. factors for worse outcomes in children with MIS- C and advo- In a 6- month follow- up review of 50 children with MIS-C in cated for targeted interventions to improve health equity for New York, all had favourable cardiac outcomes with normali- children. sation of LV systolic function, recovery of coronary abnormal- ities and no inflammation or scarring on cardiac MRI. In a Strengths and limitations systematic review, most children are reported to have complete Follow-up studies of children with MIS- C are limited and our study recovery of LV dysfunction and coronary artery abnormalities at adds to the growing knowledge base. Our cohort had substantial hospital discharge. Of concern are the 11 children with varying loss to follow- up, which limits some of our findings. In addition, Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 5 Original research our cohort did not include children older than 13 years, which is REFERENCES 1 Centers for Disease Control and Prevention Health Alert Network (HAN). Multisystem important, as mortality is reported to be higher in older children. inflammatory syndrome in children (MIS- C) associated with Coronavirus Disease 2019 Most echocardiograms in this cohort were performed and inter- (COVID- 19). Available: https://emergency.cdc.gov/han/2020/han00432.asp [Accessed preted by a single operator and not verified and discussed by a few. 7 Mar 2022]. The preponderance of regurgitation in this cohort could thus be 2 World Health Organization. Multisystem inflammatory syndrome in children and operator- dependent. adolescents with COVID- 19: scientific brief. 2020. Available: https://www.who.int/ publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents- with-covid-19 [Accessed 7 Mar 2022]. 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Multisystem inflammatory syndrome in U.S. needed to inform targeted interventions and ensure adequate long- children and adolescents. N Engl J Med 2020;383:334–46. 7 Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a term follow- up services. pediatric inflammatory multisystem syndrome temporally associated with SARS- Cov- 2. JAMA 2020;324:259–69. Twitter Andrew Redfern @PaedCapeTown 8 Webb K, Abraham DR, Faleye A, et al. Multisystem inflammatory syndrome in children Contributors JL: joint first author. Responsible for conceptualisation, project in South Africa. Lancet Child Adolesc Health 2020;4:e38. administration and methodology of study. Responsible for data collection. 9 Butters C, Abraham DR, Stander R, et al. The clinical features and estimated incidence Responsible for data curation and analysis. Had access to data and were responsible of MIS- C in Cape Town, South Africa. BMC Pediatr 2022;22:241. for writing the original draft. Responsible for draft review and editing. DRA: joint first 10 Sokunbi O, Akinbolagbe Y, Akintan P, et al. Clinical presentation and short- term author. Responsible for conceptualisation, project administration and methodology outcomes of multisystemic inflammatory syndrome in children in Lagos, Nigeria during of study. Responsible for data collection and rheumatology-immunology follow- up the COVID- 19 pandemic: a case series. EClinicalMedicine 2022;49:101475. of patients. Had access to data and were responsible for writing the original draft. 11 Kaushik A, Gupta S, Sood M, et al. A systematic review of multisystem inflammatory Responsible for draft review and editing. BF: responsible for data collection and syndrome in children associated with SARS- Cov- 2 infection. Pediatr Infect Dis J performing echocardiograms and cardiac follow- up of patients. Responsible for 2020;39:e340–6. draft review and editing. NAY: responsible for data collection and rheumatology- 12 Bowen A, Miller AD, Zambrano LD, et al. Demographic and clinical factors associated immunology follow- up. Responsible for draft review and editing. AR: responsible with death among persons <21 years old with Multisystem inflammatory syndrome for draft review and editing. MMVdZ: responsible for data curation and analysis. in children- United States, February 2020-March 2021. Open Forum Infect Dis Responsible for draft review and editing. HR: responsible for conceptualisation, 2021;8:ofab388. project administration and methodology of study. Had access to data and were 13 Chinniah K, Bhimma R, Naidoo KL, et al. Multisystem inflammatory syndrome in responsible for writing the original draft. Responsible for draft review and editing. JL children associated with SARS- CoV-2 infection in Kwazulu- Natal, South Africa. Pediatr is guarantor. Infect Dis J 2023;42:e9–14. 14 Mohsin SS, Abbas Q, Chowdhary D, et al. Multisystem inflammatory syndrome Funding DRA and MMVDZ are supported by the South African Medical Research (MIS- C) in Pakistani children: a description of the phenotypes and comparison with Council (SAMRC) with researcher initiated grants. MMVDZ is supported by a historical cohorts of children with Kawasaki disease and myocarditis. PLoS One career development grant from the EDCTP2 program supported by the European Union (TMA2019SFP- 2836 TB lung- FACT2), the Fogarty International Center of 2021;16:e0253625. the National Institutes of Health (NIH) under Award Number K43TW011028. 15 Nayak S, Panda PC, Biswal B, et al. Eastern India collaboration on Multisystem Stellenbosch University supplied SEED funding for the start of the project. inflammatory syndrome in children (EICOMISC): a multicenter observational study of 134 cases. Front Pediatr 2022;10:834039. Disclaimer The content and findings reported/illustrated are the sole deduction, 16 Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children view and responsibility of the researcher and do not reflect the official position and - initial therapy and outcomes. N Engl J Med 2021;385:23–34. sentiments of the SAMRC, NIH or National Treasury. 17 McArdle AJ, Vito O, Patel H, et al. Treatment of multisystem inflammatory syndrome in Competing interests None declared. children. N Engl J Med 2021;385:11–22. 18 Ouldali N, Toubiana J, Antona D, et al. Association of intravenous Immunoglobulins Patient consent for publication Not applicable. plus methylprednisolone vs Immunoglobulins alone with course of fever in Ethics approval The study was approved under Stellenbosch University Health Multisystem inflammatory syndrome in children. JAMA 2021;325:855–64. Research Ethics Committee (HREC number N20/04/013_COVID- 019; N20/07/041). 19 Channon- Wells S, Vito O, McArdle AJ, et al. Immunoglobulin, glucocorticoid, The aim of the study was to describe standard practice without any additional or combination therapy for Multisystem inflammatory syndrome in children: a intervention. Data were obtained from patient records, the laboratory system and the propensity- weighted cohort study. Lancet Rheumatol 2023;5:e184–99. PACS system. There is minimal risk for breach of patient confidentiality. 20 Capone CA, Misra N, Ganigara M, et al. Six month follow- up of patients with multi- system inflammatory syndrome in children. Pediatrics 2021;148:e2021050973. Provenance and peer review Not commissioned; externally peer reviewed. 21 Penner J, Abdel- Mannan O, Grant K, et al. 6- month multidisciplinary follow- up and Data availability statement Data may be obtained from a third party and are outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS- TS) not publicly available. at a UK tertiary paediatric hospital: a retrospective cohort study. Lancet Child Adolesc Supplemental material This content has been supplied by the author(s). It Health 2021;5:473–82. has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have 22 Capone CA, Subramony A, Sweberg T, et al. Characteristics, cardiac involvement, been peer- reviewed. Any opinions or recommendations discussed are solely those and outcomes of multisystem inflammatory syndrome of childhood associated of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and with severe acute respiratory syndrome coronavirus 2 infection. J Pediatr responsibility arising from any reliance placed on the content. Where the content 2020;224:141–5. includes any translated material, BMJ does not warrant the accuracy and reliability 23 Theocharis P, Wong J, Pushparajah K, et al. Multimodality cardiac evaluation in of the translations (including but not limited to local regulations, clinical guidelines, children and young adults with multisystem inflammation associated with COVID- 19. terminology, drug names and drug dosages), and is not responsible for any error Eur Heart J Cardiovasc Imaging 2021;22:896–903. and/or omissions arising from translation and adaptation or otherwise. 24 Abraham DR, Butters C, Abdulbari Yunis N, et al. The impact of SARS- Cov- 2 variants on the clinical phenotype and severity of multisystem inflammatory syndrome in This article is made freely available for personal use in accordance with BMJ’s children in South Africa. Pediatr Infect Dis J 2022;41:e510–2. website terms and conditions for the duration of the covid- 19 pandemic or until 25 Lopez L, Colan S, Stylianou M, et al. Relationship of echocardiographic Z scores otherwise determined by BMJ. You may download and print the article for any lawful, adjusted for body surface area to age, sex, race, and ethnicity: the pediatric non- commercial purpose (including text and data mining) provided that all copyright heart network normal echocardiogram database. Circ Cardiovasc Imaging notices and trade marks are retained. 2017;10:e006979. 26 Tissot C, Singh Y, Sekarski N. Echocardiographic evaluation of ventricular function- for ORCID iD the neonatologist and pediatric Intensivist. Front Pediatr 2018;6:79. Juanita Lishman http://orcid.org/0000-0003-0743-6766 6 Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 Global child health Global child health Original research 27 Govender K, Nyamaruze P, McKerrow N, et al. COVID- 19 vaccines for children and 31 Van der Zalm MM, Lishman J, Verhagen LM, et al. Clinical experience with SARS adolescents in Africa: aligning our priorities to situational realities BMJ global health. Cov- 2 related illness in children - hospital experience in Cape town, South Africa. Clin BMJ Glob Health 2022;7:e007839. Infect Dis 2020;72:e945–7. 28 Migowa A, Samia P, Del Rossi S, et al. Management of Multisystem inflammatory 32 Sam- Agudu NA, Quakyi NK, Masekela R, et al. Children and adolescents in syndrome in children (MIS- C) in resource limited settings: the Kenyan experience. African countries should also be vaccinated for COVID- 19. BMJ Glob Health Pediatr Rheumatol Online J 2022;20:110. 2022;7:e008315. 29 Abdelaziz TA, Abdulrahman DA, Baz EG, et al. Clinical and laboratory characteristics of 33 Kitano T, Kitano M, Krueger C, et al. The differential impact of pediatric COVID- 19 multisystem inflammatory syndrome in children associated with COVID-19 in Egypt: a between high- income countries and low- and middle- income countries: a tertiary care hospital experience. J Paediatr Child Health 2023;59:445–52. systematic review of fatality and ICU admission in children worldwide. PLoS One 30 Sirico D, Basso A, Sabatino J, et al. Evolution of echocardiographic and cardiac 2021;16:e0246326. magnetic resonance imaging abnormalities during follow-up in patients with Multisystem inflammatory syndrome in children. Eur Heart J Cardiovasc Imaging 34 Javalkar K, Robson VK, Gaffney L, et al. Socioeconomic and racial and/or ethnic 2022;23:1066–74. disparities in multisystem inflammatory syndrome. Pediatrics 2021;147:e2020039933. Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 7 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Disease in Childhood British Medical Journal

Short-term outcomes of South African children with multisystem inflammatory syndrome in children: a prospective cohort study

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10.1136/archdischild-2022-325287
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Abstract

Global child health Global child health Original research Short- term outcomes of South African children with multisystem inflammatory syndrome in children: a prospective cohort study 1,2 1,2 1,2 Juanita Lishman , Deepthi Raju Abraham, Barend Fourie, 1,2 1,2 1,3 Nurea Abdulbari Yunis, Andrew Redfern, Marieke M van der Zalm, 1,2 Helena Rabie ► Additional supplemental ABSTRACT WHAT IS ALREADY KNOWN ON THIS TOPIC material is published online Background Despite the life- threatening presentation only. To view, please visit the ⇒ Despite the life- threatening presentation of of multisystem inflammatory syndrome in children journal online (http:// dx. doi. multisystem inflammatory syndrome in children (MIS- C), the overall prognosis is favourable in centres org/ 10. 1136/ archdischild- (MIS- C), the overall prognosis is favourable in 2022- 325287). with access to appropriate supportive care. In this study, high- income countries. 1 we investigate the short- term outcomes in children with Paediatrics and Child Health, MIS- C in Cape Town, South Africa. Stellenbosch University, Cape WHAT THIS STUDY ADDS Town, South Africa Methods This prospective observational cohort study ⇒ Our study adds to the very limited data of Paediatrics and Child Health, included children <13 years who fulfilled the WHO case Tygerberg Hospital, Cape Town, cardiovascular outcomes of children with MIS-C definition of MIS- C and were admitted to Tygerberg Western Cape, South Africa in Africa. Hospital in Cape Town, South Africa between 1 June Department of Paediatrics ⇒ Outcomes were overall good with no deaths 2020 and 31 October 2021. Clinical features were and Child Health, Faculty of reported. Medicine and Health Sciences, recorded at baseline and at follow- up at the 6- week ⇒ There were persistent abnormal Desmond Tutu TB Centre, cardiology and 3- month rheumatology- immunology Stellenbosch University, Cape echocardiograms at follow- up, suggesting that clinics, respectively. Town, South Africa selected children will need longer follow-up to Findings Fifty- three children with a median age of 7.4 assess effect on their cardiovascular health. years (IQR 4.2–9.9) were included. There was a slight Correspondence to ⇒ Follow- up was challenging with a large male predominance (30/53; 56.6%) and the majority Dr Juanita Lishman, Paediatrics proportion of children being lost despite the and child health, Stellenbosch was of mixed ancestry (28/53; 52.83%) or black African clinical need to see them and strategies to University, Cape Town 7505, ancestry (24/53; 45.3%). Fourteen children (14/53; South Africa; retain them in care. 26.4%) had comorbid disease. The median length of lishman@ sun. ac. za hospital stay was 8 days (IQR 6–10). All children had HOW THIS STUDY MIGHT AFFECT RESEARCH, Received 15 January 2023 an echocardiogram performed at baseline of which PRACTICE OR POLICY Accepted 14 May 2023 39 were abnormal (39/53; 73.6%). All children were ⇒ Further research on the mid- term and long- term discharged alive. The median days from discharge to outcomes of MIS- C in Africa are needed to cardiology follow- up was 39 days (IQR 33.5–41.5) and further characterise morbidity in children from for rheumatology- immunology clinic was 70.5 days Africa and to inform targeted interventions. (IQR 59.5–85.0). Eleven children (11/41; 26.8%) had a persistently abnormal echocardiogram at cardiology follow- up. Systemic inflammation and organ dysfunction resolved in most. 10 care with no deaths reported. A systematic review Interpretation Although the short- term outcomes of of 16 case series including 655 children with MIS- C MIS- C in our cohort were generally good, the cardiac reported a mortality rate of 1.7%. Mortality morbidity needs further characterisation and follow- up. appears to be higher in older children and those with comorbid diseases. In a recent report from KwaZulu Natal, South Africa, the mortality was reported much higher at 20.6%, similar to the 20% BACKGROUND 13 14 mortality in Pakistan. The mortality rate was Multisystem inflammatory syndrome in children 11.2% in a multicentre cohort including 135 chil- (MIS- C) is temporally associated with SARS- CoV- 2 dren from India. © Author(s) (or their infection. The syndrome is characterised by fever, employer(s)) 2023. No There are no randomised data on the manage- mucocutaneous features, hypotension, gastrointes- commercial re- use. See rights ment of children with MIS-C but large observa- tinal symptoms and features of myocardial inflam- and permissions. Published 1–3 tional studies found clinical benefit in giving both mation. MIS- C was first reported in Europe in by BMJ. 4–7 intravenous immunoglobulin (IVIG) and gluco- March 2020. The first case in Cape Town, South 16–18 To cite: Lishman J, corticoids as compared with IVIG alone. The Africa was noted in early May 2020. Abraham DR, Fourie B, et al. Best Available Treatment Study consortium evalu- Forty to 80% of children with MIS- C required Arch Dis Child Epub ahead of ated the use of IVIG, glucocorticoid or combina- print: [please include Day intensive care admission for haemodynamic insta- 6 9 Month Year]. doi:10.1136/ tion therapy in a propensity-weighted cohort study bility. In a cohort from Lagos, Nigeria, only archdischild-2022-325287 including 2101 children from 39 countries. They 10.7% (3/28) of patients were admitted to intensive Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 1 Original research concluded that glucocorticoids appears to be a safe alternative to The laboratory parameters included white blood cell count, IVIG or combined therapy. absolute lymphocyte count, absolute neutrophil count, haemo- The available information on long-term outcomes from globin, platelets, C reactive protein, ferritin, pro- brain natri- North America and Europe suggests good cardiac prognosis, uretic peptide (pro- BNP) and troponin T. with systolic dysfunction recovering in the convalescent phase All data including echocardiograms and blood tests were and most children making a full clinical recovery at 6- month performed as needed for routine care. All echocardiograms 20 21 follow- up. Children with cardiac dysfunction showed were performed by or reviewed by a paediatric cardiologist. We recovery of ventricular function and resolution of coronary classified coronary artery Z- scores as follows: normal <2, dila- 22 23 artery aneurysms. tion 2 to <2.5, aneurysm ≥2.5. Left ventricular (LV) systolic We previously reported that the clinical presentation and dysfunction was defined as an LVEF<55% and graded as mild early outcomes of South African children with MIS-C managed (LVEF 45%–54%), moderate (LVEF 35%–44%) or severe (LVEF at Tygerberg Hospital (TBH) and Red Cross War Memorial <35%) as previously described. Children’s Hospital in Cape Town are similar to European and The WHO weight-for - age Z-scores were calculated for chil- 8 9 24 North American children and adolescents. However, there dren younger than the age of 5 years and the WHO body mass are limited data on postdischarge outcomes of children with index Z- score for children over the age of 5 years using the MIS- C from Africa. We aimed to evaluate the outcomes of chil- AntrhoCalc application V.2.1. dren with MIS-C managed at TBH up to 3 months after diag- nosis and beyond as indicated clinically. Statistical analysis Basic demographic data, clinical features on presentation, management and echocardiogram findings at baseline and METHODS follow- up was described using standard summary statistics. Study design and population Continuous variables are summarised as mean, SD or median This single- centre prospective observational study of children and IQRs where appropriate. Comparative data were analysed and adolescents <13 years diagnosed with MIS-C at TBH using IBM SPSS Statistics, V.27. Fisher’s exact test and χ test between 1 June 2020 and 31 October 2021 describes the clin- were used for dichotomous variables and Mann- Whitney U test ical progress from diagnosis until approximately 3 months after for non- parametric continuous variables. diagnosis. Where children with abnormal echocardiograms were followed beyond 3 months, those data are reported up to 6 RESULTS months after diagnosis. We identified 64 children and adolescents <13 years with Locally, all children and adolescents diagnosed with MIS-C suspected MIS-C between 1 June 2020 and 31 October 2021; are managed with supportive care, IVIG and/or intravenous or we excluded 11 cases that did not meet the case definition oral steroids and low- dose aspirin. All children have echocar- (figure 1). The median age of the 53 patients was 7.4 years (IQR diography on admission and follow- up. The coronary artery 4.3–9.9) and 30/53 (56.6%) were male (table 1). Symptoms on diameter Z-score derived from the Paediatric Heart Network presentation, findings on initial clinical examination, hospital Z- score system, and left ventricular ejection fraction (LVEF) course and management are summarised in table 1. measured qualitatively and quantitatively and calculated using 25 26 The median length of hospital stay was 8 days (IQR 6–8). the M- mode method are recorded. All children and adoles- Twenty-four (45,3%) patients required intensive care admission, cents are given dates for review approximately at 6 weeks after 22 (41.5%) patients required inotropic support and 7 (13.2%) diagnosis at cardiology and at rheumatology-immunology clinic intubation and ventilation. The majority received both IVIG and within 6 weeks to 3 months after diagnosis. The evaluation at methylprednisolone (56.6%) with 18 patients (34%) receiving follow- up includes a detailed clinical assessment, repeat echocar- IVIG only. diogram and repeating inflammatory markers, COVID-19 serum At baseline, 39 of the 53 children (73.6%) had an abnormal antibody, renal function, liver enzymes and other investigations echocardiogram report (table 2). The majority (29, 54,7%) had as indicated. Data sources and definitions Children and adolescents <13 years who met the WHO case definition of MIS- C were enrolled. We excluded children and adolescents in whom another plausible diagnosis was apparent; we also excluded children with typical and atypical Kawasaki disease with negative SARS COVID-2 PCR and antibody tests. Routine access to SARS-CoV - 2 antibody testing against the nucleocapsid protein only became available in August 2020. Cases with MIS-C prior to A ugust 2020 that were SARS- CoV- 2 PCR negative were included if the full case definition was met and there was a positive history of exposure to a likely source case. None of these children and adolescents was vaccinated against COVID- 19. South Africa only approved the use of two doses of the Pfizer- BioNTech COVID- 19 vaccines for those aged 12–17 years in October 2021. Demographic data and clinical characteristics were reported at admission and follow- up. Care interventions including the Figure 1 Follow- up of children and adolescents <13 years with need for intensive care intervention, IVIG and steroids were confirmed multisystem inflammatory syndrome in children (MIS- C) at documented. cardiology and rheumatology- immunology clinic. KD, Kawasaki disease. 2 Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 Global child health Global child health Original research Table 1 Demographic and clinical characteristics, hospital course Table 1 Continued and management Value Value Any biological 0 Demographic characteristics Numbers are presented with percentages in brackets. Median values are presented Patients, n 53 with IQR. Age, years, median (IQR) 7.4 (4.3–9.9) BMI, body mass index; IVIG, intravenous immunoglobulin; PICU, paediatric intensive care unit; WAZ, weight for age Z- score. Male sex, n (%) 30 (56.6) Ethnicity, n (%) Mixed race 29 (54.7) mitral or tricuspid regurgitation at baseline, 8 of the 15 patients Black African 23 (43.4) with coronary abnormalities had brightness of the artery and White 1 (1.9) although 19 (29,3%) had abnormalities of LV function only, 10 WAZ (<5 years) N=17 of the patients had moderate or severe dysfunction. Median WAZ (IQR) 0.53 (–1.2 to 2.02) In the acute phase, all patients had elevated markers of Possible growth problem (Z- score ≥3), n (%) 1 (5.9) systemic inflammation. The majority had lymphopenia, anaemia, renal impairment, hyponatraemia and elevated cardiac enzymes Possible growth problem (Z- score 2 to <3), n (%) 2 (14.3) on admission. In the convalescent phase, C reactive protein and Normal (Z- score −2 to <2), n (%) 13 (76.5) ferritin remained raised in 33 of 45 (73.3%) of children and Underweight (Z- score <−2), n (%) 1 (5.9) 28/28 (100%) of children, respectively (online supplemental BMI (>5 years) N=36 table 1). Median BMI Z- score (IQR) −0.54 (–1.5 to 0.54) Obesity (Z- score ≥3), n (%) 3 (8.3) Follow-up Overweight (Z- score 2 to <3), n (%) 2 (5.6) By 28 February 2022, follow- up data for at least one cardiology Risk of overweight (Z- score 1 to <2), n (%) 2 (5.6) outpatient review was available for 41/53 (77%) cases and 30/53 Normal (Z- score ≥−2 to <1), n (%) 24 (66.7) (56.6%) cases had at least one rheumatology follow-up ( figure 1). Wasted (Z- score <−2), n (%) 2 (5.6) The median days from discharge to cardiology follow-up was 39 Comorbid disease, n (%) 14 (26.4) days (IQR 33.5–41.5) and for rheumatology-immunology clinic Obesity/WAZ >3 4 (7.5) was 70.5 days (IQR 59.5–85.0). HIV- exposed uninfected 3 (5.7) Acute myeloid leukaemia 2 (3.8) Cardiology follow-up Fetal alcohol syndrome 1 (1.9) Thirty- three patients (33/41, 80.5%) had an initial repeat echo- Gastro- oesophageal reflux disease 1 (1.9) cardiogram within 6 weeks, four patients (4/41, 9.8%) within 3 Tuberculous endocarditis 1 (1.9) months and the remaining four (4/41, 9.8%) patients within 6 Chronic lung disease 1 (1.9) months. Eleven (11/41, 26.8%) patients had persistent abnormal Ventricular septal defect 1 (1.9) findings on echocardiography at follow- up (table 3). In eight Evidence of COVID- 19 exposure, n (%) 53 (100) children, the persistent abnormality was due to an endocardial COVID- 19 contact 21 (39.6) dysfunction manifesting as mitral or tricuspid regurgitation. Positive PCR SARS- CoV- 2 at diagnosis 10 (18.9) Three patients had abnormalities that persisted at 6- month Positive antibody to SARS- CoV- 2 38/40 (95) follow- up (patients 2, 3 and 4, table 3). Patients 2 and 3 had moderate and mild LV dysfunction, respectively and patient Hospitalisation 4 had a dilated coronary artery (Z- score=2). We found that Length of stay, days, median (IQR)* 8 (6–10) PICU admission, n (%) 24 (45.3) Length of stay in PICU, days, median (IQR) 3.5 (1.5–6) Table 2 Echocardiogram report (baseline and first follow- up) Discharged alive, n (%) 53 (100) Management N=53 AcuteFollow- up Echocardiogram findings (n=53) (n=41) Cardiovascular support, n (%) 24 (45.3) Fluid boluses, n (%) 16 (30.2) Normal echo, n (%) 14 (26.4) 30 (73.2) Inotropic support, n (%) 22 (41.5) Any left ventricular systolic dysfunction, n (%) 19 (35.8) 2 (4.9) Duration of inotropic support, days, median (IQR) 3 (1–4) LVEF (mean, SD) 55.2 (±11.6) 62.3 (±8.4) Respiratory support, n (%) 19 (35.8) Mild (LVEF 45%–54%), n (%) 9 (17.0) 1 (2.4) Nasal prong oxygen, n (%) 18 (34) Moderate (LVEF 35%–44%), n (%) 8 (15.1) 0 Non- invasive ventilation, n (%) 11 (20.8) Severe (<35%), n (%) 2 (3.8) 1 (2.4) Invasive ventilation, n (%) 7 (13.2) Any coronary artery abnormality, n (%) 15 (28.3) 1 (2.4) Duration of invasive ventilation, days, median 5 (3–6) Dilated coronary artery (Z- score 2 to <2.5), n (%)* 5 (9.4) 1 (2.4) (IQR) Coronary artery aneurysm (Z- score ≥2.5), n (%) 5 (9.4) 0 Medications 53 (100) Coronary artery echobright, n (%) 8 (15.1) 0 Both IVIG and methylprednisolone, n (%) 30 (56.6) Mitral or tricuspid regurgitation, n (%) 29 (54.7) 8 (19.5) IVIG alone, n (%) 18 (34.0) *Three patients reported to have a ‘dilated coronary artery’ did not have a Z-score Methylprednisolone alone, n (%) 2 (3.8) documented. Acute echocardiogram was performed at presentation and follow-up Oral prednisone alone, n (%) 2 (3.8) echocardiogram at the first cardiac outpatient review. Numbers are presented with percentages in brackets. No immune- modulation, n (%) 1 (1.9) LVEF, left ventricular ejection fraction. Continued Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 3 Original research Table 3 Abnormal echocardiogram on follow- up (n=11) Elevated cardiac PICU and Patient Age enzymes on inotropic SARS- CoV- 2 Abnormal finding number (years) Sex presentation support PCR Acute and follow- up echocardiogram Left ventricular 1 12.7 F Yes (pro- BNP 15 259, Yes Negative Acute: LVEF 51%, dilated RCA systolic dysfunction Trop T 58) 6 weeks: LVEF 53%, mild MR and TR (n=3) 6 months: LTFU 2 7.4 F Yes (pro- BNP 27 731, Yes Negative Acute: LVEF 31%, MR and TR Trop T 303) 6 weeks: LVEF 53% 6 months: LVEF 53%. Reduced exercise recommended by cardiologist 9 months: fatigues with play, echocardiogram not repeated 12 months: LTFU 3 10 M Yes (pro- BNP 1089, No Positive Baseline: LVEF 43%, dilated left ventricle Trop T <3) (multiple follow- up reviews in ward with repeat echocardiograms. Persistent severe left ventricular dysfunction) 6 months: LVEF 39% Patient remained on antifailure treatment with poor LVEF for 15 months Coronary artery 4 7.9 M Yes (pro- BNP >35 Yes Negative Acute: LVEF 44%, moderate MR and TR, dilated LAD dilated (n=1) 000, Trop T 76) 6 weeks: LVEF normal. LAD CA still dilated (Z- score=2), aspirin continued 6 months: moderate TR, LAD CA still dilated (Z- score=2), aspirin continued 12 months: due Mitral regurgitation 5 8.8 M Yes (pro- BNP 7485, No Negative Acute: LVEF 47%, LCA mildly dilated, mild MR and TR (MR) or tricuspid Trop T 25) 6 weeks: LVEF normal. Mild TR regurgitation (TR) 6 months: normal clinical exam (n=7) 12 months: LTFU 6 10.3 M Yes (pro- BNP 3875, No Negative Acute: LVEF normal. Moderate MR and TR Trop T 25) 6 weeks: trivial MR and mild TR 6 months: LTFU 7 8.3 F Yes (pro- BNP 26 620, Yes Negative Acute: LVEF 59% mild- to- moderate MR Trop T 46) 6 weeks: LVEF normal. Mild MR 6 months: mild MR, trivial TR, LVEF normal 8 10.7 M Yes (pro- BNP >35 Yes Negative Acute: LVEF 50%, valvulitis, LCA dilated, MR and TR 000, Trop T 699) 6 weeks: LVEF normal. Mild residual MR and TR 6 months: LTFU 9 5.3 F Yes (pro- BNP 3696, No Negative Acute: LVEF 64%, mild MR and TR Trop T 10) 6 weeks: LVEF normal. TR. 6 months: trivial TR 10 8.8 M Yes (pro- BNP 2441, No Negative Acute: LVEF 73%, mild TR Trop T 21) 6 weeks: LVEF normal. Mild MR and TR 6 months: LTFU 11 8.2 M Yes (pro- BNP 3469, No Negative Acute: LVEF 62%, mild TR Trop T 15) 6 weeks: LVEF normal. Mild TR 6 months: LRFU Echocardiograms were not always performed discretely at 6 weeks and 6 months as indicated in table. The median days from discharge to cardiology follow-up w as 39 days (IQR 33.5–41.5). F, female; LAD CA, left ascending descending coronary artery; LTFU, lost to follow-up; M, male; PICU, paediatric intensive care unit; Pro- BNP, pro- brain natriuretic peptide (pg/mL); RCA, right coronary artery; Trop T, troponin T (ng/L). the median age of children with abnormal echocardiogram diagnosed with myasthenia gravis shortly after admission that at follow- up was higher compared with children with normal was temporally associated with SARS- CoV- 2. She was treated echocardiogram at follow- up (p=0.04) and similarly children with pyridostigmine and methotrexate. Nine months after treated with both methylprednisolone and IVIG frequently had initial diagnosis, she had normal function and muscle strength abnormal echocardiogram at follow-up compared with children and all medication was successfully stopped. The fourth patient with methylprednisolone or IVIG alone (p=0.02) (table 4). complained of headache, ankle pain and stiff legs. She had no objective clinical signs or inflammatory markers suggestive of Rheumatology-immunology follow-up chronic arthritis or impaired mobility. Her symptoms resolved Four patients (4/30, 13.3%) had ongoing clinical concerns. completely at 8- month follow- up. The first patient had an intermittent urticarial rash, derma- Follow-up labora tory parameters are summarised in online tology diagnosed papular urticarial pustulosis, association with supplemental table 1. Of the 32 patients that had repeat SARS- SARS- CoV- 2 infection could not be excluded. On subsequent CoV- 2 antibody test at follow- up, 40.6% (13/32) remained sero- follow- up, the rash had resolved. The second patient had mild conjunctival injection unrelated to MIS- C. The third patient was positive. All patients were discharged alive from hospital. 4 Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 Global child health Global child health Original research degrees of echocardiographic changes at their first follow- up Table 4 Determinants associated with abnormal echocardiogram at postdischarge. Three cases showed a reduction in ejection follow- up fraction, 1 case with persistent coronary artery dilatation and Normal Abnormal 3 of the 11 cases with abnormalities persisting throughout the echocardiogram echocardiogram 6- month follow- up phase. This contrasts the Nigerian cohort Variable N=42 N=11 P value which demonstrated normalisation of cardiovascular manifesta- tions by 6 months in all. Age in months 70 (49.3–125.5) 106 (96.6–125.5) 0.04 (median, IQR) A group that may need further characterisation is the seven Chronic illness (n, %) 8 (19.0%) 3 (27.2%) 0.68 children that had persistent mild mitral or tricuspid regurgi- tation at cardiac follow-up. The significance of this remains Duration of fever in 4 (2–5) 5 (3.5–5) 0.41 days (median, IQR) unclear and it is difficult to attribute the regurgitation to some- Days from symptom 7 (4–8) 6.5 (5.3–8) 0.67 thing specific. Ventricular strain method was not performed on onset to diagnosis our patient population. This might have shown that these chil- (median, IQR) dren had myocardial dysfunction even if it was not evident on Highest C reactive 232 (120.8–294.5) 237 (152–265) 0.94 M mode. Sirico et al evaluated the early and mid- term cardiac protein (median, IQR) outcomes of 32 children with MIS- C by performing standard Highest NT- pro- BNP 5777 (1388–27 386) 7485 (3582.5–27 175.5) 1.00 and speckle- tracking echocardiography, and cardiac magnetic (median, IQR) resonance imaging (CMR). They demonstrated subclinical Highest troponin T 22.5 (9–64.3) 25 (18–67) 0.93 myocardial dysfunction still detectable at 6 months. Thirteen (median, IQR) per cent showed persistent LV global longitudinal strain and on PICU admission (n, %) 20 (47.6%) 4 (36.6%) 1.00 CMR 33.4% had persistence of late gadolinium enhancement. Inotropic support 17 (40.5%) 5 (45.5%) 1.00 It is difficult to speculate what the cause of cardiac regurgitation (n, %) is in our cohort as we did not have capacity to perform cardiac Methylprednisolone 2 (4.8%) 0 (0%) 1.00 MRI to investigate for inflammation. only The median age of those with an abnormal echocardiogram IVIG only 17 (40.5%) 1 (9.1%) 0.08 at follow- up was higher than those with a normal echocardio- Both 20 (47.6%) 10 (90.1%) 0.02 gram. Although other cohorts also report older children having methylprednisolone more severe disease, we should note that we did not include any and IVIG children >13 years. Children who received both methylpred- IVIG, intravenous immunoglobulin; NT- pro- BNP, N- terminal pro- brain natriuretic nisolone and IVIG were also more likely to have an abnormal peptide; PICU, paediatric intensive care unit. echocardiogram at follow- up. This may be a proxy for disease severity that we were unable to demonstrate. However, in our DISCUSSION study we did not find an association between cardiac outcomes This study adds to expanding data on the outcomes of African at follow- up and children who required PICU admission or 10 28 children with MIS- C. As in the cohort from Nigeria and Kenya, inotropic support or those with elevated pro- BNP or troponin T, overall outcomes were good, and no children required a biologic but numbers were small, and this requires further investigation. agent. It is, however, in contrast with data recently published A major concern in our study is the poor follow- up rate of 13 14 29 from KwaZulu Natal, South Africa, Pakistan and Egypt, children possibly related to socio- economic factors. Only 77% where the mortality was reported to be very high (20.6%, 20% of children presented to cardiology clinic at 6 weeks and 57% and 33.3%, respectively). Critical shortage of intensive care beds to the rheumatology-immunology clinic by 3 months. Children is reported from Nigeria and KwaZulu Natal. In KwaZulu Natal, in high- income country (HIC) cohorts had serial echocardio- limited intensive care space and delay in access to specialised care grams and rigorous multidisciplinary follow-up and clinical may have contributed to the high mortality. In addition, African review. This is not always feasible in a resource-limited setting children may have more aggressive inflammation. We note that such as South Africa. It is especially concerning that 5.7% (3/53) children from both the cohorts from Egypt and KwaZulu Natal of children in our cohort had ongoing cardiac abnormalities at had a median age <5 years. It is not clear whether young age 6 months in the context of 22.6% (12/53) not presenting for contributed to the higher mortality. cardiac follow-up at all. Online supplemental table 2 compares the clinical features Emerging data indicate that children and adolescents from and outcomes in children from four African countries. Detailed African countries experience higher COVID-19- related 31 32 information on echocardiographic findings at baseline and morbidity and mortality, when compared with HIC. Kitano follow- up is only provided in the Nigerian cohort and our et al reported on the differential impact of paediatric COVID-19 study. Of interest, in the Kenyan cohort with only 25% (5/20) between HICs and low- income and middle- income countries of patients receiving immune- modulation the outcomes were (LMICs) in a systematic review. The paediatric deaths and case good with no deaths reported, compared with the higher 33.3% fatality rate was significantly higher in LMICs. This is supported mortality in the Egyptian cohort where all patients received by Javalkar et al, who concluded that lower socio-economic immune- modulation. The differences in mortality rates are status, Hispanic ethnicity and black race were independent risk poorly understood and this requires further analysis. factors for worse outcomes in children with MIS- C and advo- In a 6- month follow- up review of 50 children with MIS-C in cated for targeted interventions to improve health equity for New York, all had favourable cardiac outcomes with normali- children. sation of LV systolic function, recovery of coronary abnormal- ities and no inflammation or scarring on cardiac MRI. In a Strengths and limitations systematic review, most children are reported to have complete Follow-up studies of children with MIS- C are limited and our study recovery of LV dysfunction and coronary artery abnormalities at adds to the growing knowledge base. Our cohort had substantial hospital discharge. Of concern are the 11 children with varying loss to follow- up, which limits some of our findings. In addition, Lishman J, et al. 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Responsible for draft review and editing. DRA: joint first 10 Sokunbi O, Akinbolagbe Y, Akintan P, et al. Clinical presentation and short- term author. Responsible for conceptualisation, project administration and methodology outcomes of multisystemic inflammatory syndrome in children in Lagos, Nigeria during of study. Responsible for data collection and rheumatology-immunology follow- up the COVID- 19 pandemic: a case series. EClinicalMedicine 2022;49:101475. of patients. Had access to data and were responsible for writing the original draft. 11 Kaushik A, Gupta S, Sood M, et al. A systematic review of multisystem inflammatory Responsible for draft review and editing. BF: responsible for data collection and syndrome in children associated with SARS- Cov- 2 infection. Pediatr Infect Dis J performing echocardiograms and cardiac follow- up of patients. Responsible for 2020;39:e340–6. draft review and editing. NAY: responsible for data collection and rheumatology- 12 Bowen A, Miller AD, Zambrano LD, et al. Demographic and clinical factors associated immunology follow- up. Responsible for draft review and editing. AR: responsible with death among persons <21 years old with Multisystem inflammatory syndrome for draft review and editing. MMVdZ: responsible for data curation and analysis. in children- United States, February 2020-March 2021. Open Forum Infect Dis Responsible for draft review and editing. HR: responsible for conceptualisation, 2021;8:ofab388. project administration and methodology of study. Had access to data and were 13 Chinniah K, Bhimma R, Naidoo KL, et al. Multisystem inflammatory syndrome in responsible for writing the original draft. Responsible for draft review and editing. JL children associated with SARS- CoV-2 infection in Kwazulu- Natal, South Africa. Pediatr is guarantor. Infect Dis J 2023;42:e9–14. 14 Mohsin SS, Abbas Q, Chowdhary D, et al. Multisystem inflammatory syndrome Funding DRA and MMVDZ are supported by the South African Medical Research (MIS- C) in Pakistani children: a description of the phenotypes and comparison with Council (SAMRC) with researcher initiated grants. MMVDZ is supported by a historical cohorts of children with Kawasaki disease and myocarditis. PLoS One career development grant from the EDCTP2 program supported by the European Union (TMA2019SFP- 2836 TB lung- FACT2), the Fogarty International Center of 2021;16:e0253625. the National Institutes of Health (NIH) under Award Number K43TW011028. 15 Nayak S, Panda PC, Biswal B, et al. Eastern India collaboration on Multisystem Stellenbosch University supplied SEED funding for the start of the project. inflammatory syndrome in children (EICOMISC): a multicenter observational study of 134 cases. Front Pediatr 2022;10:834039. Disclaimer The content and findings reported/illustrated are the sole deduction, 16 Son MBF, Murray N, Friedman K, et al. 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Immunoglobulin, glucocorticoid, The aim of the study was to describe standard practice without any additional or combination therapy for Multisystem inflammatory syndrome in children: a intervention. Data were obtained from patient records, the laboratory system and the propensity- weighted cohort study. Lancet Rheumatol 2023;5:e184–99. PACS system. There is minimal risk for breach of patient confidentiality. 20 Capone CA, Misra N, Ganigara M, et al. Six month follow- up of patients with multi- system inflammatory syndrome in children. Pediatrics 2021;148:e2021050973. Provenance and peer review Not commissioned; externally peer reviewed. 21 Penner J, Abdel- Mannan O, Grant K, et al. 6- month multidisciplinary follow- up and Data availability statement Data may be obtained from a third party and are outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS- TS) not publicly available. at a UK tertiary paediatric hospital: a retrospective cohort study. Lancet Child Adolesc Supplemental material This content has been supplied by the author(s). It Health 2021;5:473–82. has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have 22 Capone CA, Subramony A, Sweberg T, et al. Characteristics, cardiac involvement, been peer- reviewed. Any opinions or recommendations discussed are solely those and outcomes of multisystem inflammatory syndrome of childhood associated of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and with severe acute respiratory syndrome coronavirus 2 infection. J Pediatr responsibility arising from any reliance placed on the content. Where the content 2020;224:141–5. includes any translated material, BMJ does not warrant the accuracy and reliability 23 Theocharis P, Wong J, Pushparajah K, et al. Multimodality cardiac evaluation in of the translations (including but not limited to local regulations, clinical guidelines, children and young adults with multisystem inflammation associated with COVID- 19. terminology, drug names and drug dosages), and is not responsible for any error Eur Heart J Cardiovasc Imaging 2021;22:896–903. and/or omissions arising from translation and adaptation or otherwise. 24 Abraham DR, Butters C, Abdulbari Yunis N, et al. The impact of SARS- Cov- 2 variants on the clinical phenotype and severity of multisystem inflammatory syndrome in This article is made freely available for personal use in accordance with BMJ’s children in South Africa. Pediatr Infect Dis J 2022;41:e510–2. website terms and conditions for the duration of the covid- 19 pandemic or until 25 Lopez L, Colan S, Stylianou M, et al. Relationship of echocardiographic Z scores otherwise determined by BMJ. You may download and print the article for any lawful, adjusted for body surface area to age, sex, race, and ethnicity: the pediatric non- commercial purpose (including text and data mining) provided that all copyright heart network normal echocardiogram database. Circ Cardiovasc Imaging notices and trade marks are retained. 2017;10:e006979. 26 Tissot C, Singh Y, Sekarski N. Echocardiographic evaluation of ventricular function- for ORCID iD the neonatologist and pediatric Intensivist. Front Pediatr 2018;6:79. Juanita Lishman http://orcid.org/0000-0003-0743-6766 6 Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 Global child health Global child health Original research 27 Govender K, Nyamaruze P, McKerrow N, et al. COVID- 19 vaccines for children and 31 Van der Zalm MM, Lishman J, Verhagen LM, et al. Clinical experience with SARS adolescents in Africa: aligning our priorities to situational realities BMJ global health. 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PLoS One 30 Sirico D, Basso A, Sabatino J, et al. Evolution of echocardiographic and cardiac 2021;16:e0246326. magnetic resonance imaging abnormalities during follow-up in patients with Multisystem inflammatory syndrome in children. Eur Heart J Cardiovasc Imaging 34 Javalkar K, Robson VK, Gaffney L, et al. Socioeconomic and racial and/or ethnic 2022;23:1066–74. disparities in multisystem inflammatory syndrome. Pediatrics 2021;147:e2020039933. Lishman J, et al. Arch Dis Child 2023;0:1–7. doi:10.1136/archdischild-2022-325287 7

Journal

Archives of Disease in ChildhoodBritish Medical Journal

Published: Oct 26, 2023

Keywords: child health; COVID-19

References