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...