The Lancet Respiratory Medicine

BACKGROUNDInhaled budesonide has shown efficacy for treating COVID-19 in the community but has not yet been tested in effectiveness trials. METHODSWe performed a multicenter, open-label, multi-arm, adaptive platform randomized controlled trial involving people aged [≥]65 years, or [≥]50 years with comorbidities, and unwell [≤]14 days with suspected COVID-19 in the community (PRINCIPLE). Participants were randomized to usual care, usual care plus inhaled budesonide (800{micro}g twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalization/death related to COVID-19, both measured over 28 days from randomisation and analysed using Bayesian models. RESULTSThe trial opened on April 2, 2020. Randomization to inhaled budesonide began on November 27, 2020 and was stopped on March 31, 2021 based on an interim analysis using data from March 4, 2021. Here, we report updated interim analysis data from March 25, 2021, at which point the trial had randomized 4663 participants with suspected COVID-19. Of these, 2617 (56.1%) tested SARS-CoV-2 positive and contributed data to this interim budesonide primary analysis; 751 budesonide, 1028 usual care and 643 to other interventions. Time to first self-reported recovery was shorter in the budesonide group compared to usual care (hazard ratio 1.208 [95% BCI 1.076 - 1.356], probability of superiority 0.999, estimated benefit [95% BCI] of 3.011 [1.134 - 5.41] days). Among those in the interim budesonide primary analysis who had the opportunity to contribute data for 28 days follow up, there were 59/692 (8.5%) COVID-19 related hospitalizations/deaths in the budesonide group vs 100/968 (10.3%) in the usual care group (estimated percentage benefit, 2.1% [95% BCI -0.7% - 4.8%], probability of superiority 0.928). CONCLUSIONSIn this updated interim analysis, inhaled budesonide reduced time to recovery by a median of 3 days in people with COVID-19 with risk factors for adverse outcomes. Once 28 day follow up is complete for all participants randomized to budesonide, final analyses of time to recovery and hospitalization/death will be published. (Funded by the National Institute of Health Research/ United Kingdom Research Innovation [MC_PC_19079]; PRINCIPLE ISRCTN number, ISRCTN86534580.)

IL-6 responses are ubiquitous in Mycobacterium tuberculosis (Mtb) infections, but their role in determining human tuberculosis (TB) disease risk is unknown. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor (IL6R) gene, focusing on the non-synonymous variant, rs2228145, associated with reduced classical IL-6 signalling, to assess the effect of altered IL-6 activity on TB disease risk. We identified 16 genome wide association studies (GWAS) of TB disease collating 17,982 cases of TB disease and 972,389 controls across 4 continents. Meta-analyses and Mendelian randomisation analyses revealed that reduced classical IL-6 signalling was associated with lower odds of TB disease, a finding replicated using multiple, independent SNP instruments and 2 separate exposure variables. Our findings establish a causal relationship between IL-6 signalling and the outcome of Mtb infection, suggesting IL-6 antagonists do not increase the risk of TB disease and should be investigated as adjuncts in treatment.

Pulmonary inflammation drives critical illness in Covid-19, 1;2 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3;4 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1;5 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. 6 In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C 7 and SCOURGE 8 studies, and meta-analysis with previously-reported data. We find an additional 14 new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.

BACKGROUNDThe interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear. METHODSWe evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-{beta}1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility. RESULTSStatistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.20) and 0.97 (95%CrI 0.66, 1.40) for tocilizumab, sarilumab and anakinra respectively, compared to control, yielding 98.8%, 98.8% and 43.6% posterior probabilities of superiority, respectively, compared to control. All treatments appeared safe. CONCLUSIONSIn patients with severe COVID-19 receiving organ support, tocilizumab and sarilumab are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population. (ClinicalTrials.gov number: NCT02735707)

BackgroundThere is concerted effort to reduce the burden of 6 months antimicrobial treatment for tuberculosis (TB). Early treatment cessation at 8 weeks is effective for most but incurs increased risk of disease relapse. We tested the hypothesis that blood RNA signatures of TB disease or C-reactive protein (CRP) measurements discriminate microbiological cure after 8 weeks of treatment, as a pre-requisite for a biomarker to stratify risk of relapse. MethodsWe identified blood RNA signatures of TB disease or cure by systematic review. We evaluated CRP measurements and blood RNA signatures that could be reproduced in genome-wide transcriptomic data from a previously reported longitudinal dataset in pulmonary TB, spanning samples collected pre-treatment, at 2 and 8 weeks of treatment, and after 2 years of follow up. In our primary analysis, we tested discrimination of sputum culture positivity at 8 weeks by contemporary blood RNA and CRP measurements using area under the receiver operating characteristic curve (AUROC) analysis. In secondary analyses, we tested the relationship between biomarker measurements and time to culture positivity as a surrogate for bacterial load in sputum culture positive cases at 8 weeks, and discrimination of sputum culture status at 8 weeks by biomarker measurements at any other time point. FindingsWe evaluated 12 blood RNA signatures. Blood RNA signature scores normalised over time from TB treatment initiation. 11/44 cases with available blood RNA, CRP and sputum culture results, were sputum culture positive at 8 weeks of treatment. None of the 12 blood RNA signature scores tested achieved statistically significant discrimination between sputum culture-positive vs. negative patients at this time point, with AUROC point estimates of 0.48-0.61. CRP achieved the best AUROC of 0.69 (95% confidence interval 0.52-0.87). None of the contemporary biomarker measurements correlated with bacterial load, and no measurements pre-treatment or at 2 weeks discriminated sputum culture status at 8 weeks. InterpretationThe current repertoire of blood RNA signatures of TB and CRP will not provide host response surrogates of microbiological cure to support cessation of TB treatment at 8 weeks. Decoupling of blood transcriptional host-response from the presence of viable bacteria is indicative of subpopulations of Mycobacterium tuberculosis able to colonise the respiratory tract without triggering a detectable immune response. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe performed a systematic review, using comprehensive terms for "tuberculosis", "transcriptional" and "biomarker" with no language or date restrictions in Medline on October 4, 2023. Many studies have described normalisation of blood RNA signatures during the course of tuberculosis treatment. Five studies have evaluated blood RNA signatures as a test of microbiological cure after completion of 6 months of treatment. However, there is growing interest in their application as a test of cure to support shortened treatment regimens. The performance of one blood RNA signature has been reported to provide modest discrimination of contemporary sputum culture status at 8 weeks of treatment among HIV co-infected patients with recurrent tuberculosis. We found no reports of whether these findings are generalisable to other blood RNA signatures or to HIV negative patients with their first episode of tuberculosis, who are most likely to be candidates for shortened treatment regimens. Added value of this studyTo our knowledge, we provide the first evaluation and comparison of multiple blood RNA signatures of tuberculosis for discrimination of microbiological cure after 8 weeks of tuberculosis therapy among HIV negative patients. 12 previously validated blood RNA signatures of tuberculosis identified by systematic review underwent head-to-head evaluation, alongside blood C-reactive protein measurement as an alternative biomarker of disease, to determine whether they discriminated contemporary sputum culture status after 8 weeks of treatment among 44 HIV negative patients with smear-positive drug-sensitive tuberculosis enrolled to a previously reported randomised controlled trial of adjunctive vitamin D therapy. None of the blood RNA signatures showed statistically significant discrimination of contemporary sputum culture status after 8 weeks tuberculosis treatment, or quantitative relationships with sputum bacterial load among sputum culture positive cases. Importantly, most sputum culture positive cases at this time point, showed contemporary blood RNA signature scores within the normal range. Implications of all the available evidenceAssuming that microbiological cure is a pre-requisite for early cessation of antimicrobial treatment for tuberculosis, the current repertoire of blood RNA signatures of tuberculosis does not provide host response surrogates of microbiological cure to support introduction of 8-week treatment regimens. Therefore, there is a need for further discovery and validation of new biomarkers to support risk stratification for truncated therapy both for research and clinical practice applications. The lack of association between blood transcriptomic signatures and sputum culture status after 8 weeks of treatment suggests the existence of microbial sub-populations that do not trigger a host response. Whether this reflects a state of latency or bacterial persistence in immune privileged compartments requires further investigation.

BackgroundDrug-resistant tuberculosis (TB) remains a formidable global health challenge. Host-directed therapies (HDTs) offer the potential to mitigate tissue damage, reduce treatment duration, and improve clinical outcomes by modulating immune responses. We assessed the safety and potential efficacy of adjunctive ibuprofen--an inexpensive, well-tolerated non-steroidal anti-inflammatory drug--in patients with pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) TB. MethodsIn this prospective, open-label, randomized pilot study (NCT02781909) conducted in Georgia, 28 adults with bacteriologically confirmed pulmonary pre-XDR or XDR-TB were randomized 1:1 to receive either standard-of-care (SoC) TB treatment alone (n=14) or SoC plus 400 mg ibuprofen daily during the first 2 months (n=14). Participants were followed for 6 months. The primary endpoints were early sputum culture conversion and radiological improvement. Secondary endpoints included WHO-defined final treatment outcomes, safety, health-related quality of life (HQoL), and changes in inflammatory markers. FindingsBy week 2, culture negativity was achieved in 27% of control participants versus 9% in the ibuprofen group (risk difference 18%, 95% CI -13 to 50). The median time to culture conversion was 4 months in both groups. At month 2, favourable X-ray evolution was observed in 64% of controls compared with 54% of the ibuprofen group (risk difference 9%, 95% CI -32 to 50), with 90% of participants in each group showing improvement by month 6. Final treatment outcomes were comparable ({approx}71% cured) and the incidence of safety-related events did not differ significantly. Notably, the ibuprofen group exhibited greater proportional reductions in inflammatory markers--including a statistically significant decrease in the monocyte-to-lymphocyte ratio at months 2 and 5, along with reductions in interferon gamma levels and the enrichment score for Thompson_FAIL_13 gene signature at month 6. InterpretationAlthough adjunctive ibuprofen did not improve primary microbiological or radiological endpoints, its excellent safety profile and significant anti-inflammatory effects support its potential role as an immune-modulating adjunct in the treatment of drug-resistant TB. These findings warrant further investigation in larger studies to optimize dosing and evaluate clinical benefits. FundingCatalan Government (2021 SGR 00920), Spanish Government-FEDER Funds (CPII18/00031, PI20/01424 and CB06/06/0031, and European Unions Horizon 2020 research and innovation program under grant agreement No. 847762 (SMA-TB project). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDrug-resistant tuberculosis (TB) remains a major global health challenge. Host-directed therapies (HDTs) have emerged as a means to shorten treatment, improve outcomes and limit tissue damage from excessive inflammation. In preclinical models of active TB, non-steroidal anti-inflammatory drugs (NSAIDs) enhanced bacterial control and reduced lung pathology. Clinical data on NSAIDs as HDTs are scarce, confined to small studies in tuberculous meningitis and TB patients with diabetes, which reported encouraging but preliminary benefits. Added value of this studyThis is the first randomized trial of adjunctive ibuprofen in patients with pre-XDR and XDR-TB. Whilst ibuprofen did not confer microbiological or clinical benefit at two and six months, it was safe, well tolerated and significantly lowered systemic inflammatory markers. Baseline imbalances in disease severity and high inter-patient variability likely obscured any clinical effect despite reduced inflammation. Implications of all the available evidenceOur findings demonstrate that ibuprofen is a safe adjunct in drug-resistant TB and can mitigate harmful inflammation. Future work should explore optimised dosing regimens, alternative HDT candidates and more sensitive or tailored endpoints--potentially focusing on patient subgroups most likely to benefit. Such refinements will be essential to reveal the true clinical value of HDTs across diverse TB populations.

BackgroundThe Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial evaluated the effects of sixteen potential treatments for patients hospitalised with COVID-19. Dexamethasone (at a dose of 6mg daily), tocilizumab, baricitinib, and the monoclonal antibodies casirivimab-imdevimab and sotrovimab were shown to reduce 28-day mortality in all or specific groups of patients. Here we report the long-term efficacy and safety of all sixteen therapies. MethodsPatients hospitalised with COVID-19 were potentially eligible to join this randomised, controlled, open-label, platform trial. Participants were randomly allocated to receive each trial treatment, or not, on top of usual care. Analyses were by intention to treat comparing each treatment with its own usual care control group. The pre-specified primary long-term follow-up outcome was 6-month all-cause mortality, presented as mortality rate ratios adjusted for baseline age and ventilation status. The key safety outcomes were major non-COVID infection and non-COVID death at 6 months. ISRCTN50189673 and NCT04381936. FindingsBetween 19 March 2020 and 19 March 2024, 48,402 patients were included in RECOVERY COVID-19 treatment comparisons. For each of the treatments previously demonstrated to be effective at 28 days, the early mortality benefit was preserved up to 6 months. Among 6425 patients in the dexamethasone (6mg daily) comparison, 6-month mortality was 34.3% vs 44.4% in the invasive mechanical ventilation group (rate ratio [RR] 0.68; 95% confidence interval [CI] 0.55-0.85; p=0.0006); 27.7% vs 29.2% in the oxygen or non-invasive ventilation group (RR 0.87; 95% CI 0.77-0.99; p=0.034); and 26.1% vs 22.5% in the no oxygen group (RR 1.10; 95% CI 0.89-1.36; p=0.39); test for trend p=0.0024. Among 4116 patients in the tocilizumab comparison, 34.3% vs 38.9% died within 6 months (RR 0.87; 95% CI 0.79-0.96; p=0.0077). Among 8156 patients in the baricitinib comparison, 15.7% vs. 16.6% died (RR 0.89; 95% CI 0.80-0.99; p=0.032). Among 3153 anti-SARS-CoV-2 serum antibody negative patients (the primary analysis population) in the casirivimab-imdevimab comparison, 29.3% vs. 34.7% died (RR 0.87; 95% CI 0.77-0.98; p=0.024). Among 720 patients with high serum nucleocapsid antigen concentration (the primary analysis population) in the sotrovimab comparison, 33.0% vs. 38.6% died (RR 0.78; 95% CI 0.61-1.00; p=0.050). In line with the 28-day results, aspirin, azithromycin, colchicine, convalescent plasma, dimethyl fumarate, empagliflozin, lopinavir-ritonavir, molnupiravir, and nirmatrelvir-ritonavir did not reduce 6-month mortality. Mortality at 6 months was higher with hydroxychloroquine therapy (33.3% vs. 30.2%; RR 1.14; 95% CI 1.02-1.27; p=0.018) and, among hypoxic patients not requiring ventilatory support, with higher dose dexamethasone (initial dose 20mg daily, 22.0% vs. 17.6%, RR 1.34; 95% CI 1.04-1.72; p=0.021). Allocation to dexamethasone 6mg once daily resulted in a small increase in major non-COVID infection within 6 months compared with usual care (21.4% vs. 19.1%; absolute difference 2.2%; 95% CI 0.2-4.5%). We found no evidence that any other treatments increased the risk of major non-COVID infection. InterpretationIn patients hospitalised with COVID-19, dexamethasone (at a dose of 6mg daily in hypoxic patients), tocilizumab (in hypoxic patients with CRP [≥]75 mg/L), baricitinib, casirivimab-imdevimab (in seronegative patients), and sotrovimab (in high antigen patients) reduced 6-month mortality. Dexamethasone at a dose of 6mg daily was associated with an increase in major non-COVID infection but there was no evidence of other later emerging harms. Other treatments tested in RECOVERY did not reduce 6-month mortality. FundingUK Research and Innovation (Medical Research Council) and National Institute for Health and Care Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

BackgroundAs novel strategies are needed to improve tuberculosis (TB) outcomes and shorten treatment; we evaluated whether host-directed therapy with non-steroidal anti-inflammatory drugs (NSAIDs) could enhance treatment response when added to standard therapy. MethodsWe conducted a phase 2b, double-blind, placebo-controlled, randomized trial in South Africa and Georgia. Adults with microbiologically confirmed pulmonary TB were randomized to receive standard therapy plus acetylsalicylic acid (ASA) (300 mg), ibuprofen (IBU) (400 mg), or placebo twice daily for 4 weeks and once daily for 4 weeks. Primary end points were time to a 67% reduction in the clinical symptom/sign-based TB score (TBS) and time to stable sputum culture conversion (SCC). Safety and clinical, radiological and microbiological assessments were performed up to 24 weeks after treatment completion. ResultsOf 221 randomized participants, 204 were included in the analysis. No significant differences were observed in the primary end points; median time to 67% TBS reduction was 4.5 weeks (ASA) and 5.0 weeks (IBU and placebo), and median time to stable SCC was 8 weeks in all groups. Both NSAIDs were associated with earlier cavity resolution at week 8, sustained at week 24 for ASA. IBU was associated with greater clinical improvement in multidrug-resistant-TB. Adverse event rates were similar across arms. ConclusionsAdjunctive ASA and IBU did not shorten the time to clinical or microbiologic response but were associated with earlier cavity resolution and improved TBS in specific subgroups, with similar safety to standard therapy alone. Funded by the European Unions Horizon 2020; ClinicalTrials.gov number, NCT04575519.

BackgroundColchicine has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory actions. MethodsIn this randomised, controlled, open-label trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus colchicine twice daily for 10 days or until discharge (or one of the other treatment arms) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 27 November 2020 and 4 March 2021, 5610 patients were randomly allocated to receive colchicine and 5730 patients to receive usual care alone. Overall, 1173 (21%) patients allocated to colchicine and 1190 (21%) patients allocated to usual care died within 28 days (rate ratio 1.01; 95% confidence interval [CI] 0.93-1.10; p=0.77). Consistent results were seen in all pre-specified subgroups of patients. There was no significant difference in duration of hospitalisation (median 10 days vs. 10 days) or the proportion of patients discharged from hospital alive within 28 days (70% vs. 70%; rate ratio 0.98; 95% CI 0.94-1.03; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (25% vs. 25%; risk ratio 1.02; 95% CI 0.96-1.09; p=0.47). InterpretationIn adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056). Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator.

BackgroundThe evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood. Methods250 HIV-uninfected, adult household contacts of rifampicin-resistant TB with a negative symptom screen underwent baseline 18F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum sampling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease. ResultsAt baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p<0.001]). ConclusionsThese findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.

IntroductionRecent trials have demonstrated that shortened four-month treatment durations are effective for the majority of people with tuberculosis (TB). However, there is a population of TB patients who require longer treatment durations. Prospectively identifying those who require shorter versus longer treatment durations would support evaluation and implementation of optimized regimens. MethodsWe analysed data from the RIFASHORT TB treatment-shortening non-inferiority trial to define a TB phenotype classification. The RIFASHORT trial primary outcome was reanalysed using the protocol-defined non-inferiority criterion of eight percentage points, stratifying by those classified as having limited or extensive disease. ResultsXpert MTB/RIF(R) semiquantitative bacterial burden in combination with TB disease involvement grading on chest X-ray achieved the strongest differentiation between relapse and non-relapse. The extensive disease TB phenotype (high semiquantitative bacterial burden and extensive TB disease on X-ray) accounted for one quarter of the RIFASHORT trial population and more than half of all post-treatment TB relapses (13/23). For the limited TB disease phenotype (<high semiquantitative bacterial burden or no extensive TB disease on X-ray), the experimental 4-month 1200mg rifampicin-containing regimen met the protocol-defined non-inferiority criterion in both modified-intention-to-treat (adjusted risk difference: -1.3% (95% confidence interval: -6.7% to 4.0%)) and per protocol analyses (1.7% (95% CI: -3.8% to 7.1%)). ConclusionA four-month treatment duration, with a widely available, tolerable, rifampicin-based TB treatment regimen, was non-inferior to the standard of care for three-quarters of people with TB in the RIFASHORT trial. This finding justifies definitive evaluation of disease-stratified rifampicin-based TB treatment in a phase III randomised trial. summaryXpert MTB/RIF(R) and chest radiography at TB treatment initiation identify a majority of patients for whom a 4-month treatment duration is non-inferior to the standard of care. These widely available measures may facilitate personalised TB treatment durations.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF. MethodsWe performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females. FindingsThree independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results. InterpretationWe prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females. Research in context Evidence before this studyThe prevalence of IPF is higher in males than females. IPF risk has a genetic component, but analyses have only been performed in studies where males and females have been combined. One previous study reported sex-specific differences in association for the MUC5B promoter variant, rs35705950, however the finding was not replicated in an independent study. No genome-wide association studies assessing for different genetic risk factors between males and females have been conducted for IPF. It is not known whether approaches to predict individuals at risk of IPF should take sex- specific genetic risk into consideration. Added value of this studyThis was the largest study to test whether there are genetic variants whose effects on IPF susceptibility are different in males and females. The MUC5B promotor variant rs35705950 did not show a different magnitude of effect in males vs females. We identified three genetic variants with opposite directions of effect on IPF risk in males vs females. Our polygenic risk score analyses suggested that genetic prediction based on data from males and females separately did not perform better than when males and females were combined. Implications of all available evidenceAlthough we found some preliminary evidence of genetic variants with sex-specific effects on IPF risk, our analyses suggest that genome-wide genetic risk from common single nucleotide polymorphisms is similar in males and females. This is important when considering integration of polygenic risk scores into clinical prediction models for IPF. There may be other forms of genetic variation, such as complex structural variation or rare variants, not captured in this analysis, that may improve risk prediction for males and females separately.

BackgroundImmune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. MethodsWe conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. ResultsA total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. ConclusionsInfliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registrationClinicalTrials.gov (NCT04593940).

BackgroundWe evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19. MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0{middle dot}87; 95% CI 0{middle dot}77-0{middle dot}98; p=0{middle dot}026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes. InterpretationIn patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

BackgroundThe effectiveness of inhaled corticosteroids to shorten time to symptom resolution or prevent hospitalization or death among outpatients with mild-to-moderate coronavirus 2019 (Covid-19) is unclear. MethodsACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial testing repurposed medications in outpatients with confirmed SARS-CoV-2 infection. Non-hospitalized adults aged [&ge;]30 years, experiencing [&ge;]2 symptoms of acute infection for [&le;]7 days were randomized to inhaled fluticasone furoate 200 g once daily for 14 days or placebo. The primary outcome was time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Secondary outcomes included composites of hospitalization or death with or without urgent care or emergency department visit by day 28. ResultsOf those eligible for the fluticasone arm, 656 were randomized to and received inhaled fluticasone; 621 received concurrent placebo. There was no evidence of improvement in time to recovery with fluticasone compared with placebo (hazard ratio [HR] 1.01, 95% credible interval [CrI] 0.91-1.12; posterior probability for benefit [HR>1]=0.56). Twenty-four participants (3.7%) in the fluticasone arm had urgent care or emergency department visits or were hospitalized compared with 13 (2.1%) in the pooled, concurrent placebo arm (HR 1.9, 95% CrI 0.8-3.5; posterior probability for benefit [HR<1]=0.03). Three participants in each arm were hospitalized, and no deaths occurred. Adverse events were uncommon in both arms. ConclusionsTreatment with inhaled fluticasone furoate for 14 days did not result in improved time to recovery among outpatients with Covid-19 in the United States during the delta and omicron variant surges. Trial RegistrationClinicalTrials.gov (NCT04885530).

BackgroundThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. MethodsWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility. ResultsTocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] -1, 16), 11 (IQR 0, 16) and 0 (IQR -1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists. ConclusionsIn critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.gov number: NCT02735707)

BackgroundLow-dose corticosteroids (e.g. 6 mg dexamethasone) have been shown to reduce mortality for hypoxic COVID-19 patients. We have previously reported that higher dose corticosteroids cause harm in patients with hypoxia but not receiving ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation), but the balance of efficacy and safety in patients receiving ventilatory support is uncertain. MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) assessed multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients receiving ventilatory support were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. Recruitment closed on 31 March 2024 when funding for the trial ended. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 25 May 2021 and 9 January 2024, 477 COVID-19 patients receiving ventilatory support were randomly allocated to receive usual care plus higher dose corticosteroids versus usual care alone (of whom 99% received corticosteroids during the follow-up period). Of those randomised, 221 (46%) were in Asia, 245 (51%) in the UK and 11 (2%) in Africa. 143 (30%) had diabetes mellitus. Overall, 86 (35%) of 246 patients allocated to higher dose corticosteroids versus 86 (37%) of 231 patients allocated to usual care died within 28 days (rate ratio [RR] 0.87; 95% CI 0.64-1.18; p=0.37). There was no significant difference in the proportion of patients discharged from hospital alive within 28 days (128 [52%] in the higher dose corticosteroids group vs 120 [52%] in the usual care group; RR 1.04, 0.81-1.33]; p=0.78). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (76 [37%] of 206 vs 93 [45%] of 205; RR 0.79 [95% CI 0.63-1.00]; p=0.05). InterpretationIn patients hospitalised for COVID-19 receiving ventilatory support, we found no evidence that higher dose corticosteroids reduced the risk of death compared to usual care, which included low dose corticosteroids. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

BackgroundAn estimated 40% of people who developed tuberculosis in 2021 were not diagnosed or treated. Pre-chemotherapy era data are a rich resource on survival for people with untreated TB. We aimed to identify heterogeneities in these data to inform more precise use of them. MethodsWe extracted survival data from pre-chemotherapy era papers reporting TB specific mortality and/or natural recovery data. We used Bayesian parametric survival analysis to model the survival distribution, stratifying by geography (North America versus Europe), time (pre-1930 versus post-1930), and setting (sanitoria versus non-sanitoria). ResultsWe found 12 studies with TB-specific mortality data. Ten-year survival was 69% in North America (95 CI: 54%-81%) and 36% in Europe (95% CI: 10%-71%). Only 38% (95% CI: 18%-63%) of non-sanitorium individuals survived to 10 years compared to 69% (95% CI: 41%-87%) of sanitoria/hospitalized patients. There were no significant differences between people diagnosed pre-1930 and post-1930 (five-year survival pre-1930: 65%; 95% CI: 44%-88% versus post-1930: 72%; 95% CI: 41%-94%). ConclusionsMortality and natural recovery risks vary substantially by location and setting. These heterogeneities need to be considered when using pre-chemotherapy data to make inferences about expected survival of people with undiagnosed TB.

IntroductionThe spring 2023 COVID-19 booster vaccination programme in England used both Pfizer BA.4-5 and Sanofi vaccines. All people aged 75 years or over and the clinically vulnerable were eligible to receive a booster dose. Direct comparisons of the effectiveness of these two vaccines in boosting protection against severe COVID-19 events have not been made in trials or observational data. MethodsWith the approval of NHS England, we used the OpenSAFELY-TPP database to compare effectiveness of the Pfizer BA.4-5 and Sanofi vaccines during the spring 2023 booster programme, between 1 April and 30 June 2023. We investigated two cohorts separately: those aged 75 or over (75+); and those aged 50 or over and clinically vulnerable (CV). In each cohort, vaccine recipients were matched on date of vaccination, COVID-19 vaccine history, age, and other characteristics. Effectiveness outcomes were COVID-19 hospital admission, COVID-19 critical care admission, and COVID-19 death up to 16 weeks after vaccination. Safety outcomes were pericarditis and myocarditis up to 4 weeks after vaccination. We report the cumulative incidence of each outcome, and compare safety and effectiveness using risk differences (RD), relative risks (RR), and incidence rate ratios (IRRs). Results492,642 people were 1-1 matched in the CV cohort, and 673,926 in the 75+ cohort, contributing a total of 7,423,251 and 10,173,230 person-weeks of follow-up, respectively. The incidence of COVID-19 hospital admission was higher for Sanofi than for Pfizer BA.4-5. In the CV cohort, 16-week risks per 10,000 people were 22.3 (95%CI 20.4 to 24.3) for Pfizer BA.4-5 and 26.4 (24.4 to 28.7) for Sanofi, with an IRR of 1.19 (95%CI 1.06 to 1.34). In the 75+ cohort, these were 17.5 (16.1 to 19.1) for Pfizer BA.4-5 and 20.4 (18.9 to 22.1) for Sanofi, with an IRR of 1.18 (1.05-1.32). These findings were similar across all pre-specified subgroups. More severe COVID-19 related outcomes (critical care admission and death), and safety outcomes at 4 weeks, were rare in both vaccines so we could not reliably compare effectiveness of the two vaccines. ConclusionThis observational study comparing effectiveness of Pfizer BA.4-5 and Sanofi vaccine during the spring 2023 programme in England in the two main eligible cohorts - people aged 75 and over and in clinically vulnerable people - found some evidence of superior effectiveness against COVID-19 hospital admission for Pfizer BA.4-5 compared with Sanofi within 16 weeks after vaccination.

BackgroundAzithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We evaluated the efficacy and safety of azithromycin in hospitalised patients with COVID-19. MethodsIn this randomised, controlled, open-label, adaptive platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge (or one of the other treatment arms). Patients were twice as likely to be randomised to usual care as to any of the active treatment groups. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 7 April and 27 November 2020, 2582 patients were randomly allocated to receive azithromycin and 5182 patients to receive usual care alone. Overall, 496 (19%) patients allocated to azithromycin and 997 (19%) patients allocated to usual care died within 28 days (rate ratio 1{middle dot}00; 95% confidence interval [CI] 0{middle dot}90-1{middle dot}12; p=0{middle dot}99). Consistent results were seen in all pre-specified subgroups of patients. There was no difference in duration of hospitalisation (median 12 days vs. 13 days) or the proportion of patients discharged from hospital alive within 28 days (60% vs. 59%; rate ratio 1{middle dot}03; 95% CI 0{middle dot}97-1{middle dot}10; p=0{middle dot}29). Among those not on invasive mechanical ventilation at baseline, there was no difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0{middle dot}97; 95% CI 0{middle dot}89-1{middle dot}07; p=0{middle dot}54). InterpretationIn patients hospitalised with COVID-19, azithromycin did not provide any clinical benefit. Azithromycin use in patients hospitalised with COVID-19 should be restricted to patients where there is a clear antimicrobial indication. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).