Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a new phenomenon reported worldwide with temporal association with Covid-19. The objective of this paper is to evaluate reported cases in children and adolescents. From 1726 papers, 35 documented papers related to MIS-C cases identified 783 individual cases of MIS-C between March-June 2020; with 55% being male ( n = 435) and a median age of 8.6 years (IQR, 7–10 years; range 3 months–20 years). Patients with MIS-C were noted to have a high frequency of gastrointestinal symptoms (71%) including abdominal pain (34%) and diarrhea (27%). Cough and respiratory distress were reported in 4.5% and 9.6% cases respectively. Blood parameters showed neutrophilia in 345/418 (83%) of cases and a high CRP in 587/626 (94%). 362/619 (59%) cases were SARS-CoV-2 infection positive (serology or PCR) however only 41% demonstrated pulmonary changes on chest imaging. Severity of illness was high with 68% cases requiring intensive care admission; 63% requiring inotropic support; 244/783 (28%) cases needing some form of respiratory support (138 mechanically ventilated), and 31 required extra-corporeal membrane oxygenation. Treatment strategies included intravenous immunoglobulin (63%) and intravenous steroids (44%). 29 cases received Infliximab, 47 received IL1 (interleukin) receptor antagonist, and 47 received IL6-receptor antagonist. 12/783 (1.5%) children died. In summary, a higher incidence of gastrointestinal symptoms were noted in MIS-C. In contrast to acute Covid-19 infection in children, MIS-C appears to be a condition of higher severity with 68% of cases having required critical care support.

Rationale-Little is known about vitamin D status and its effect on asthma pathophysiology in children with severe, therapy-resistant asthma (STRA).Objectives-Relationships between serum vitamin D, lung function, and pathology were investigated in pediatric STRA. Methods-Serum 25-hydroxyvitamin D [25(OH)D3 ] was measured in 86 children (mean age, 11.7 yr): 36 with STRA, 26 with moderate asthma (MA), and 24 without asthma (control subjects). Relationships between 25(OH)D 3 , the asthma control test (ACT), spirometry, corticosteroid use, and exacerbations were assessed. Twenty-two of 36 children with STRA underwent fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy with assessment of airway inflammation and remodeling. Measurements and Main Results-25(OH)D 3 levels (median [IQR]) were significantly lower in nmol/L) than in nmol/L) and control subjects (56.5 [45-67] nmol/L) (P < 0.001). There was a positive relationship between 25(OH)D 3 levels and percent predicted FEV 1 (r = 0.4, P < 0.001) and FVC (r = 0.3, P = 0.002) in all subjects. 25(OH)D 3 levels were positively associated with ACT (r = 0.6, P < 0.001), and inversely associated with exacerbations (r=−0.6, P < 0.001) and inhaled steroid dose (r=−0.39, P = 0.001) in MA and and STRA. Airway smooth muscle (ASM) mass, but not epithelial shedding or reticular basement membrane thickness, was inversely related to 25(OH)D 3 levels (r=−0.6, P = 0.008). Copyright © 2011 by the American Thoracic SocietyCorrespondence and requests for reprints should be addressed to Atul Gupta, M.D., Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. atulgupta@doctors.org.uk. Author Contributions: A.G. recruited the majority of the patients, collected patient samples, conducted the majority of the experiments, analyzed the data, and took the lead on writing the manuscript. A.S. performed some of the experimental work. A.G., A.B., C.H., and S.S. conceptualized, delineated the hypotheses, and designed the experiments A.B., C.H., D.R., and S.S. contributed to the interpretation of the analyses, supervised the project, and helped with revising the manuscript. A.B. and S.S. also performed bronchoscopies and obtained samples. W.B. performed some of the statistical analyses. There was a positive correlation between ASM mass and bronchodilator reversibility (r = 0.6, P = 0.009) and an inverse correlation between ASM mass and ACT (r = −0.7, P < 0.001). Author DisclosuresConclusions-Lower vitamin D levels in children with STRA were associated with increased ASM mass and worse asthma control and lung function. The link between vitamin D, airway structure, and function suggests vitamin D supplementation may be useful in pediatric STRA. Keywordsvitamin D; asthma; remodeling; airway smooth muscle; pediatrics For most children with ready access to healthcare, asthma can be controlled with low doses of inhaled steroids. There remains, however, a significant number of individuals with asthma who, despite apparentl...

Background-The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood.

1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4 + T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3 + regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3 + and IL-10 + CD4 + T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3 + and IL-10 + T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3 + Treg cells over their Foxp3 − T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3 + expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4 + Foxp3 + T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10 + and Foxp3 + Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.Keywords: 1α,25-Dihydroxyvitamin D3 r Asthma r Immune regulation r Regulatory T cells Supporting Information available online IntroductionConsiderable interest exists in the therapeutic potential of regulatory T (Treg) cells to treat a range of immune-mediated patholoCorrespondence: Dr. Catherine M. Hawrylowicz e-mail: catherine.hawrylowicz@kcl.ac.uk gies in humans. This is partly based on evidence obtained from animal models of human disease demonstrating the capacity of Treg cells to control transplant rejection, and to successfully treat autoimmune and allergic disease [1]. Two broad therapeutic * These authors contributed equally to this work. [11]. These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4 + CD25 + T cells, IL-10, TGF-β, and CTLA-4.Our earlier studies have highlighted the capacity of 1α25VitD3 to promote human CD4 + IL-10 secreting Treg cells (IL-10-Treg) in culture both alone [12] and in concert with glucocorticoids such as dexamethasone [13,14]. Furthermore, treatment of severe steroid refractory asthma patients with 1α25VitD3 in vivo directly increased IL-10 gene expression in CD3 + CD4 + T cells [12], and restored the impaired steroid-induced IL-10 response in CD4 + cells in vitro [14,15].The present study was designed to further investigate the mechanisms underlying the therapeutic potential of 1α25VitD3 in the context of asthmatic disease, and to determine effects on the induction of both IL-10 + and Foxp3 + T cells. Specifically, we have examined the effects of 1α25VitD3 on total, unfractionated CD4 + T-cell populations, r...

Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.

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BackgroundThe mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored.ObjectiveWe sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33.MethodsEighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model.ResultsChildren with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2−/− mice lacking a functional receptor for IL-33.ConclusionPediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33–mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.