Poor outcomes in COVID‐19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID‐19.

BACKGROUND. Pediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail. METHODS.We retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS). RESULTS.Twenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort. CONCLUSION. MIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.

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ObjectiveMacrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS.MethodsWe established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis.ResultsADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes.ConclusionsThese findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.

Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children; yet, the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk and single-cell RNA sequencing, DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4 + , CD8 + , and gd T cells expressed Th1-related markers, while Th17 cells were not enriched. Th1 skewing was prominent in CD4 + T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4 + T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. While synovial fluid CD4 + T cells displayed an overall Th1 phenotype, scRNA-seq uncovered heterogeneous effector and regulatory sub-populations, including interferoninduced Tregs, peripheral helper T cells, and cytotoxic CD4 + T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

Background The relationship between malnutrition and tuberculosis (TB) severity is understudied. We investigated the effect of malnutrition on radiographic findings and mycobacterial burden. Methods Subjects included newly diagnosed, smear-positive, culture-confirmed, pulmonary TB cases enrolled in the Regional Prospective Observational Research for TB (RePORT) cohort. Multivariate regression models were used to evaluate the relationship at start of treatment between body mass index (BMI) and chest radiograph (CXR) findings of cavitation and percentage of lung affected and mycobacterial growth indicator tube (MGIT) time to positive (TTP). Severe malnutrition was defined as BMI<16 kg/m 2 , moderate malnutrition as 16–18.4kg/m 2 , and “normal”/overweight as ≥18.5 kg/m 2 . Results Of 173 TB cases with chest x-ray data, 131 (76%) were male. The median age was 45 years (range 16–82); 42 (24%) had severe malnutrition and 58 (34%) moderate malnutrition. Median percentage of lung affected was 32% (range 0–95), and 132 (76%) had cavitation. Individuals with severe malnutrition had, on average, 11.1% [95% CI: 4.0–13.3] more lung affected, compared to those with normal BMI, controlling for diabetes and cavitation. In multivariable analyses, cases with severe malnutrition had a 4.6-fold [95% CI, 1.5–14.1] increased odds of cavitation compared to those with normal BMI, controlling for smoking. Median MGIT TTP was 194.5 hours. Neither severe (aRR 0.99; 95% CI, 0.9–1.2) nor moderate (aRR 0.97; 95% CI, 0.8–1.1) malnutrition was associated with MGIT TTP. Conclusion We found that malnutrition was associated with increased extent of disease and cavitation on CXR. These findings may reflect the immunomodulatory effect of malnutrition on pulmonary pathology.

Inflammatory conditions are increasingly described in patients with primary immunodeficiencies; however, little is known about the prevalence of immune defects in patients who present first with autoimmunity. We describe the immunologic features of children with early-onset/ polyautoimmunity followed in the Multiple Autoimmunity and Immunodeficiency (MAID) Clinic, where patients are co-managed by rheumatologists and immunologists. The most common autoimmune manifestations were cytopenias, lymphoproliferation, and colitis. Recurrent infections were noted in 65% of patients. Abnormalities in lymphocyte subsets and immunoglobulins were common. A pathogenic variant was identified in 19% of patients, and 2 novel inherited disorders were discovered. Additionally, 42% of patients had treatment changes implemented in the MAID clinic. By evaluating this unique cohort of patients, we report on the immunologic underpinning of early-onset/polyautoimmunity. The high rate of genetic diagnoses and treatment interventions in this population highlights the value of collaboration between rheumatologists and immunologists in the care of these complex patients.

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