Medium-vessel and large-vessel vasculitis in children.

PURPOSE OF REVIEW: This article serves as an up-to-date examination of the latest findings in the field of paediatric large-vessel and medium-vessel vasculitis. RECENT FINDINGS: Over the last 2 years and in the wake of SARS-CoV2 pandemic, a multitude of studies have increased our insight into these conditions. Although large-vessel and medium-vessel vasculitis are uncommon amongst children, they are a complex and multisystem with a constantly evolving landscape. Increasing numbers of reports from low-income and middle-income countries are shaping our understanding of the epidemiology of vasculitis in children. The influence of infectious disease and the microbiome are of particular interest in unravelling pathogenetic aspects. Improved understanding of the genetics and immunology offer opportunities for better diagnostic options and biomarkers of disease as well as targeted therapies. SUMMARY: In this review, we address recent findings in epidemiology, pathophysiology, clinical findings, bio-markers, imaging and treatment that have the potential to offer better management solutions for these uncommon conditions.

The clinical features and estimated incidence of MIS-C in Cape Town, South Africa.

BACKGROUND: Multisystem inflammatory syndrome is a severe manifestation of SARS-CoV-2 in children. The incidence of MIS-C after infection is poorly understood. There are very few cohorts describing MIS-C in Africa despite MIS-C being more common in Black children worldwide. METHODS: A cohort of children with MIS-C and healthy children was recruited from May 2020 until May 2021 from the two main paediatric hospitals in Cape Town, South Africa. Clinical and demographic data were collected, and serum was tested for SARS-CoV-2 antibodies. The incidence of MIS-C was calculated using an estimation of population exposure from seroprevalence in the healthy group. Summary data, non-parametric comparisons and logistic regression analyses were performed. RESULTS: Sixty eight children with MIS-C were recruited with a median age of 7 years (3.6, 9.9). Ninety seven healthy children were recruited with a 30% seroprevalence. The estimated incidence of MIS-C was 22/100 000 exposures in the city in this time. Black children were over-represented in the MIS-C group (62% vs 37%, p = 0.002). The most common clinical features in MIS-C were fever (100%), tachycardia (98.5%), rash (85.3%), conjunctivitis (77.9%), abdominal pain (60.3%) and hypotension (60.3%). The median haemoglobin, sodium, neutrophil count, white cell count, CRP, ferritin, cardiac (pro-BNP, trop-T) and coagulation markers (D-dimer and fibrinogen) were markedly deranged in MIS-C. Cardiac, pulmonary, central nervous and renal organ systems were involved in 71%, 29.4%, 27.9% and 27.9% respectively. Ninety four percent received intravenous immune globulin, 64.7% received methylprednisolone and 61.7% received both. Forty percent required ICU admission, 38.2% required inotropic support, 38.2% required oxygen therapy, 11.8% required invasive ventilation and 6% required peritoneal dialysis. Older age was an independent predictor for the requirement for ionotropic support (OR = 1.523, CI 1.074, 2.16, p = 0.018). The median hospital stay duration was 7 days with no deaths. CONCLUSION: The lack of reports from Southern Africa does not reflect a lack of cases of MIS-C. MIS-C poses a significant burden to children in the region as long as the pandemic continues. MIS-C disproportionately affects black children. The clinical manifestations and outcomes of MIS-C in this region highlight the need for improved surveillance, reporting and data to inform diagnosis and treatment.

IL27 gene expression distinguishes multisystem inflammatory syndrome in children from febrile illness in a South African cohort.

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a severe acute inflammatory reaction to SARS-CoV-2 infection in children. There is a lack of data describing differential expression of immune genes in MIS-C compared to healthy children or those with other inflammatory conditions and how expression changes over time. In this study, we investigated expression of immune-related genes in South African MIS-C patients and controls. Methods: The cohort included 30 pre-treatment MIS-C cases and 54 healthy non-inflammatory paediatric controls. Other controls included 34 patients with juvenile systemic lupus erythematosus, Kawasaki disease or other inflammatory conditions. Longitudinal post-treatment MIS-C specimens were available at various timepoints. Expression of 80 immune-related genes was determined by real-time quantitative PCR. Results: A total of 29 differentially expressed genes were identified in pre-treatment MIS-C compared to healthy controls. Up-regulated genes were found to be overrepresented in innate immune pathways including interleukin-1 processing and pyroptosis. Post-treatment follow-up data were available for up to 1,200 hours after first treatment. All down-regulated genes and 17/18 up-regulated genes resolved to normal levels in the timeframe, and all patients clinically recovered. When comparing MIS-C to other febrile conditions, only IL27 expression could differentiate these two groups with high sensitivity and specificity. Conclusions: These data indicate a unique 29-gene signature of MIS-C in South African children. The up-regulation of interleukin-1 and pyroptosis pathway genes highlights the role of the innate immune system in MIS-C. IL-27 is a potent anti-inflammatory and antiviral cytokine that may distinguish MIS-C from other conditions in our setting.

Genetic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies.

BACKGROUND: Acute rheumatic fever is considered to be a heritable condition, but the magnitude of the genetic effect is unknown. The objective of this study was to conduct a systematic review and meta-analysis of twin studies of concordance of acute rheumatic fever in order to derive quantitative estimates of the size of the genetic effect. METHODS: We searched PubMed/MEDLINE, ISI Web of Science, EMBASE, and Google Scholar from their inception to 31 January 2011, and bibliographies of retrieved articles, for twin studies of the concordance for acute rheumatic fever or rheumatic heart disease in monozygotic versus dizygotic twins that used accepted diagnostic criteria for acute rheumatic fever and zygosity without age, gender or language restrictions. Twin similarity was measured by probandwise concordance rate and odds ratio (OR), and aggregate probandwise concordance risk was calculated by combining raw data from each study. ORs from separate studies were combined by random-effects meta-analysis to evaluate association between zygosity status and concordance. Heritability was estimated by fitting a variance components model to the data. RESULTS: 435 twin pairs from six independent studies met the inclusion criteria. The pooled probandwise concordance risk for acute rheumatic fever was 44% in monozygotic twins and 12% in dizygotic twins, and the association between zygosity and concordance was strong (OR 6.39; 95% confidence interval, 3.39 to 12.06; P<0.001), with no significant study heterogeneity (P = 0.768). The estimated heritability across all the studies was 60%. CONCLUSIONS: Acute rheumatic fever is an autoimmune disorder with a high heritability. The discovery of all genetic susceptibility loci through whole genome scanning may provide a clinically useful genetic risk prediction tool for acute rheumatic fever and its sequel, rheumatic heart disease.