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.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

Background Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. Methods In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov , NCT04421027 . Findings Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of −2·7 percentage points (95% CI −7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47–0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Interpretation Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition t...