We report 20 MIS-C patients cross 3 centers in Kenya. The median age was 3·98 years (range 1·71 − 7·44) and 70% of the children were male. Our colleagues in South Africa had a cohort of 68 patients with a much higher median age of 7 years (range 3·6–9·9) (15). The majority of our patients were African, reflecting the demographics of our nation.
In our cohort, MIS-C was distinguished by certain demographic features and clinical presentations including being aged 6 to 12 years, fever (90%), tachycardia (80%), prolonged capillary refill (80%), vomiting (75%), oral mucosal changes (65%) and peripheral cutaneous inflammation (50%). Similarly, in the South African study by Webb and co-workers, the most common clinical features in children with MIS-C were fever (100%), tachycardia (98·5%), rash (85·3%), conjunctivitis (77·9%), abdominal pain (60·3%) and hypotension (60·3%) (15). Eighty five percent of the children in the South African cohort had gastrointestinal symptoms, including abdominal pain (60·3%), diarrhea (58·8%) and vomiting (10/41) (15).
In the cohort studied by Webb and colleagues, twenty-three percent of children with MIS-C (14/61) had a confirmed SARS-CoV-2 contact, 18% (11/61) had a suspected contact and 59% (36/61) had no contact reported (15). In our cohort only 10% of the patients (2 of 20) reported a confirmed history of COVID-19, 2 (10%) had household members with confirmed COVID-19 infection, six (30%) had household members with suspected COVID 19 infection. The other 10 participants (50%) did not have COVID 19 test done or any known history of COVID 19 infection nor contact. It is thus important to highlight children exposed to COVID-19 infection can be severely ill with negative COVID-19 tests and hence a high index of suspicion is key in detecting MIS-C cases. In addition, lack of diagnostics in our context might have contributed to the low testing and positivity rate.
There are few reports of MIS-C is sub-Saharan Africa, which may lead to a presumption that this syndrome is not identified in these populations yet low and middle-income countries (LMICs) have the challenge of delayed vaccination, poor vaccine coverage, inadequate diagnostics, sub-optimal management options despite a relatively larger proportion of younger people in their population (15).
In every cohort reported to date, black children are disproportionately affected by MIS-C (1, 2, 13, 14) with an estimation of a nearly six times higher risk of developing MIS-C as compared to white children (15). In the case series from South Africa by Webb and colleagues for example, they found that black children were over-represented in the MIS-C group (62% vs 37%, p = 0·002) (15). Kenya is a low-middle income country (LMIC), but the centers reporting cases had the resources to identify, treat and document these cases. In rural areas, it is possible that more children remain undiagnosed due to lack of resources and this may explain the low or no detection rate in other county referral hospitals across Kenya further highlighting inequities in resources available to manage these patients.
Work by Feldstein revealed presenting symptoms and signs were similar among patients with MIS-C and COVID-19 with the exception of muco-cutaneous findings (66·8% [95%CI, 63%-71%] vs 10·2% [95%CI, 8%-13%]; p < .001), which were uncommon in patients with COVID-19 and prevalent in those with MIS-C (16). One fifth of the patients in their cohort required critical care support (16). Similar findings were found by Odisha and colleagues in eastern state of India that analyzed a cohort of 21 children the majority of whom were male (76·2%) and the predominant age group was 6–10 years (16). However, unlike our cohort which had no mortality reported, Odisha and co-workers reported a mortality of 9% in their cohort which is higher than that reported in western literature (16). Majority of their cases were positive for severe acute respiratory syndrome coronavirus antibody (16). Solanki and co-workers in eastern India studied a cohort of 10 children and there was no mortality; findings which are similar to our cohort (17). Further studies are required to help predict which category of children are likely to develop MIS-C and progress on to have the risk of mortality (17). This will help us prioritize resources for the paediatric population that truly need it.
As regards laboratory investigations, our cohort revealed patients with MIS-C had markedly elevated inflammatory markers. It is important to note that less than 50% of our cases had the laboratory investigations of interest such as inflammatory markers, white cell count, platelet count, INR, ferritin and electrolytes. In the cohort studied by Webb and colleagues in South Africa, the laboratory tests that were most frequently abnormal as compared to the local normal range were CRP (100%), sodium (98%), ferritin (98%), D-Dimer (98%), haemoglobin (88%) and neutrophil count (88%)(15). In the work by Feldstein and colleagues, patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6·4 vs 2·7, p < .001), higher C-reactive protein level (median, 152mg/L), and lower platelet count (16).
As regards cardiac evaluation in our cohort, 4 patients had myocardial dysfunction, 3 had valvulitis and 1 had pericarditis. There was no documentation of any further follow up except for 1 child who had normal cardiac evaluation at six weeks post discharge. On the contrary, in the South African cohort, 71% had cardiac involvement which included pericardial effusions (17·6%), mitral regurgitation (36·8%) and coronary artery aneurysms (5·9%) (15). The estimated median ejection fraction was 47% (IQR 39,60)(15). Children with MIS-C and hypotension had a lower EF compared to non-hypotensive patients(15). In the cohort studied by Fieldstein and co-workers, the most severe cardiovascular involvement from MIS-C, included left ventricular dysfunction and coronary artery aneurysms which resolved within 30 days (16).
In our study treatments offered to the MIS-C patients included; antibiotics n = 16 (80·0%), intravenous immunoglobulin (IVIG) n = 2 (10·0%), systemic steroids n = 3 (15·0%) and non-steroidal anti-inflammatory drugs (NSAIDS) n = 5 (25·0%). Among the patients in the South African cohort, IVIG was the most frequently used medication given to 94·1% of the children (15). Other medications given were intravenous methylprednisolone given to 64·7% of the children and 6% (4/68) of the children received an IL-6 inhibitor (tocilizumab) (15). In our cohort, patients responded well to IVIG and steroid therapy with no requirement of biological therapies. Nonetheless, these therapies are till beyond the reach of many children who need it due to cost and the monitoring required during their administration.
Some of the challenges faced in management and conducting research among MIS-C cases in our context is lack of resources for diagnostics and management. One in every 2 children did not have any COVID test done. In our cohort a quarter of the participants had a COVID-19 PCR test done. This low proportion could be attributed to low index of suspicion of COVID, lack of availability of the investigations or the high cost of the tests. Similarly, Webb et al summarized the first 23 cases of MIS-C treated at The Red Cross War Memorial Children’s Hospital and Tygerberg Children’s Hospital, Cape Town, South Africa, from June 4 to July 24, 2020(13). Proving previous COVID-19 disease (or SARS-CoV-2 infection), or likely contact with someone who has had COVID-19, was a limitation in their data because of poor access to SARS-CoV-2 antibody testing and restricted community testing in the region (13). Most of this cohort had no confirmed or suspected infection or no contact with COVID-19, and no access to antibody tests, but all met clinical diagnostic criteria and had likely community contact with the disease (13). A high level of suspicion was required during diagnosis because the presenting features of MIS-C were nonspecific (persistent fever, rash, and abdominal pain) (13). Our case series found that none of our patients had any known potential risk factor other than COVID-19 contact.
In our cohort, among the patients admitted to the critical care unit, compensated cardio-respiratory failure was a common feature. Webb et al found 12 (52%) of the 23 children required admission to an intensive care unit, most commonly due to myocardial dysfunction (13). Work done by Feldstein and colleagues illustrated that compared to patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40·8%vs 19·4%) and non-Hispanic Black (32·3%vs 21·5%)(17). This features are similar to the demographic characteristics of our cohort. It is postulated that the cardiovascular dysfunction is likely due to severe systemic inflammation and acute stress more often than from ischemia or direct virus-mediated myocardial damage(18). On the contrary, Matsubara et al demonstrated persistent abnormalities in strain and diastolic function in patients with MIS-C and normal ejection fraction (19). These data, together with literature in adult patients with COVID-19, suggest that subclinical myocardial injury may persist even when traditional measures of left ventricular systolic function are normal (18). Despite this, only 30% (6 of 20) of our cases had a cardiac assessment further highlighting the gap in clinical are for these patients.
In order to understand the long-term implications for myocardial health, including risk for myocardial fibrosis and diastolic dysfunction, it is critical to have comprehensive assessment of left ventricular systolic and diastolic function in a large, multicenter cohort followed up longitudinally with centralized review of cardiac imaging (18). Cardiac magnetic resonance imaging and the rare endomyocardial biopsy or postmortem specimen may further help to clarify the underlying pathology and mechanisms of myocardial involvement in MIS-C (18). Feldstein and colleagues showed among patients with MIS-C with reduced left ventricular systolic function (172/503, 34·2%) and coronary artery aneurysm (57/424, 13·4%), an estimated 91·0% (95%CI, 86·0%-94·7%) and 79·1% (95%CI, 67·1%-89·1%), respectively, normalized within 30 days (16). Future studies using standardized protocols and core laboratory interpretation will build on the results of this study. In our study, only 1 patient had a repeat cardiac evaluation 6 weeks after diagnosis.
Most patients in our case series did not experience severe respiratory symptoms. It is most likely that most patients may have had COVID-19 several weeks’ prior or were completely asymptomatic in the respiratory system. Due to the various cycles of the pandemic surge, it is postulated that we shall see more cases of MIS-C. We encourage child health professionals to collaborate locally, regionally and internationally in carrying out comparative effectiveness research to determine the most appropriate and feasible treatment modalities and seek biomarkers and other predictors to identify children at high risk of MIS-C and intervene promptly and appropriately to mitigate against premature morbidity and mortality.
Our study had several limitations. First, data collection was retrospective thus there were cases of missing data or incomplete reporting. We mitigated this by training the research personnel at each site that participated in data collection and recording. Second, missing data were not imputed and might be non-random. Third, participating hospitals may not be generalizable and likely overrepresented patients seeking care at tertiary care centers. Fourth, only 20% of patients had echocardiograms, most patients did not have detailed cardiac assessments. Consequently, left ventricular dysfunction and coronary aneurysms could have been underappreciated. Fifth, the efficacies of different immunomodulatory regimens on recovery of cardiac function in the current study were not examined. Sixth, because MIS-C is thought to be delayed in onset after SARS-CoV-2 infection, its distinction from acute COVID-19 could be improved by elucidating the temporal progression from viral exposure to disease onset which we were unable to ascertain given the retrospective nature of the study. Lastly, due to lack of availability of resources, we did not have the capacity to follow up diligently the 47 county referral hospitals to encourage them to enroll participants.
In conclusion, we provide a detailed clinical description of a cohort of children with confirmed and suspected MIS-C cases in Kenya. These data demonstrate that MIS-C occurs in our setting, and can cause serious disease in the paediatric population in our region. Lack of access to care means that the rates in this study are likely lower than the cases nationally. Further studies should be done to discover true case ascertainment, and highlights the case for equity in vaccination efforts for children and adolescents.