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.

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Ghrelin has orexigenic effects. It is present in umbilical cord plasma in full-term neonates, raising the prospect that ghrelin plays a role in fetal and neonatal energy balance. We measured ghrelin in small (SGA), appropriate (AGA), and large (LGA) for gestational age neonates and evaluated whether ghrelin levels are modulated by neonatal insulin and glucose concentrations. Plasma concentrations of ghrelin, insulin, and glucose were measured in cord blood sampled at birth in 123 SGA, AGA, and LGA neonates (gestational age, 24-41 wk) born to mothers with and without diabetes. Ghrelin was detected in samples from all infants. Its concentration was 40% higher in SGA neonates (mean +/- SD, 2436 +/- 657 pg/ml) compared with AGA (1738 +/- 380) and LGA (1723 +/- 269) neonates. There was a positive correlation between ghrelin and gestational age in AGA/LGA (r = 0.23; P < 0.05) and a negative correlation in SGA (r = -0.67; P < 0.005) neonates. Therefore, the difference in ghrelin between SGA and AGA/LGA neonates decreases with advancing gestational age. Birth weight z-score, maternal hypertension, and glucose concentrations were significant determinants of ghrelin concentrations. In conclusion, SGA neonates present with higher umbilical cord ghrelin plasma concentrations than AGA/LGA neonates. Ghrelin may play a physiological role in fetal adaptation to intrauterine malnutrition.

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