Thorax

IntroductionShared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection. MethodsThe UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam. ResultsA total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days from discharge; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants. ConclusionThese interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors.

BackgroundCommunity-based surveys suggest a substantial burden of chronic respiratory diseases (CRDs) in the Malawian population, causing significant morbidity and loss of economic productivity. Pulmonary rehabilitation (PR) is an effective non-pharmacological intervention for people with CRDs, but there is limited data on its feasibility and acceptability in Malawi. ObjectivesTo explore the experiences of patients with CRDs before and after participating in a PR program at Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi, and their suggestions to improve a future program. MethodsFourteen adult patients (eight females and six males) presenting with functionally limiting CRDs to QECH were invited to participate in a six-week PR program. Following program completion, face-to-face semi-structured in-depth interviews with the participants were conducted. Interviews were audio-recorded and transcribed verbatim. The transcripts were anonymised and thematically analysed using a deductive approach. ResultsTen adults (five females and five males) participated in the PR program. Their documented CRD diagnoses included chronic obstructive pulmonary disease (COPD), asthma, post-tuberculosis lung disease, and bronchiectasis. Five key themes emerged: (1) experiences of living with a CRD before PR, (2) experiences of living with a CRD after PR, (3) feedback on the conduct of the completed PR program, (4) suggestions to improve a future PR program, and (5) program continuation/maintenance at home. Participants reported experiencing improvements in physical, psychological, and social health associated with PR program participation. The provision of transport was considered a key facilitator for PR program completion. Realising the gained PR benefits, participants were willing to continue exercising at their homes, albeit with potential barriers including a lack of equipment. ConclusionThe PR program improved the participants perceived health status and was well-accepted. Addressing barriers related to transport facilitated immediate implementation while providing a challenge for the scaling and sustainability of PR beyond the project duration. These findings support the drive for shifting chronic care, including rehabilitation, towards primary care and community. Trial RegistrationProspective; 27/08/2021; ISRCTN13836793

RationaleAsbestos is posited to cause otherwise idiopathic pulmonary fibrosis (IPF); establishing this has important diagnostic and therapeutic implications. ObjectivesTo determine the association between occupational asbestos exposure and IPF; to investigate interaction with MUC5B rs35705950 genotype. MethodsMulti-centre, incident case-control study. Cases (n=494) were men diagnosed with IPF at 21 United Kingdom hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was measured using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs3570950 was investigated using a genetic dominant model. Measurements and Main Results327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls, had cumulative exposure estimates [&ge;] 25 fibre.ml-1.years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1(95%CI 0.8-1.4; p=0.6) and there was no gene-environment interaction (p=0.2). Ever smoking was associated with IPF, OR 1.4 (95%CI 1-1.9; p=0.04). When stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs3570950. ConclusionsOccupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. However, exposure to asbestos and smoking interact to increase IPF risk in carriers of the minor allele of MUC5B rs3570950. Clinical trial registered with www.clinicaltrials.gov (NCT03211507).

BackgroundAccurate prediction of exacerbation risk enables personalised chronic obstructive pulmonary disease (COPD) care. We developed and validated a generalisable model to predict the individualised rate and severity of COPD exacerbations. MethodsWe pooled data from three COPD trials on patients with a history of exacerbations. We developed a mixed-effect model to predict exacerbations over one-year. Severe exacerbations were those requiring inpatient care. Predictors were a history of exacerbations, age, sex, body mass index, smoking status, domiciliary oxygen therapy, lung function, symptom burden, and current medication use. ECLIPSE, a multicentre cohort study, was used for external validation. ResultsThe development dataset included 2,380 patients (mean 64{middle dot}7 years, 1373 [57{middle dot}7%] men, mean exacerbation rate 1{middle dot}42/year, 0{middle dot}29/year [20{middle dot}5%] severe). When validated against all COPD patients in ECLIPSE (n=1819, mean 63{middle dot}3 years, 1186 [65{middle dot}2%] men, mean exacerbation rate 1{middle dot}20/year, 0{middle dot}27/year [22{middle dot}2%] severe), the area-under-curve was 0{middle dot}81 (95%CI 0{middle dot}79-0{middle dot}83) for [&ge;]2 exacerbations and 0{middle dot}77 (95%CI 0{middle dot}74-0{middle dot}80) for [&ge;]1 severe exacerbation. Predicted rates were 0{middle dot}25/year for severe and 1{middle dot}31/year for all exacerbations, close to the observed rates (0{middle dot}27/year and 1{middle dot}20/year, respectively). In ECLIPSE patients with a prior exacerbation history (n=996, mean 63{middle dot}6 years, 611 (61{middle dot}3%) men, mean exacerbation rate 1{middle dot}82/year, 0{middle dot}40/year [22{middle dot}0%] severe), the area-under-curve was 0{middle dot}73 (95%CI 0{middle dot}70-0{middle dot}76) for [&ge;]2 exacerbations and 0{middle dot}74 (95%CI 0{middle dot}70-0{middle dot}78) for [&ge;]1 severe exacerbation. Calibration was accurate for severe exacerbations (predicted=0{middle dot}37/year, observed=0{middle dot}40/year) and all exacerbations (predicted=1{middle dot}80/year, observed=1{middle dot}82/year). The model is accessible at http://resp.core.ubc.ca/ipress/accept. InterpretationThis model can be used as a decision tool to personalise COPD treatment and prevent exacerbations. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPreventing future exacerbations is a major goal in COPD care. Because of adverse effects, preventative treatments should be reserved for those at a higher risk of future exacerbations. Predicting exacerbation risk in individual patients can guide these clinical decisions. A 2017 systematic review reported that of the 27 identified COPD exacerbation prediction tools, only two had reported external validation and none was ready for clinical implementation. To find the studies that were published afterwards, we searched PubMed for articles on development and validation of COPD exacerbation prediction since 2015, using the search terms "COPD", "exacerbation", "model", and "validation". We included studies that reported prediction of either the risk or the rate of exacerbations and excluded studies that did not report external validation. Our literature search revealed two more prediction models neither of which was deemed generalisable due to lack of methodological rigour, or local and limited nature of the data available to investigators. Added value of this studyWe used data from three randomised trials to develop ACCEPT, a clinical prediction tool based on routinely available predictors for COPD exacerbations. We externally validated ACCEPT in a large, multinational prospective cohort. To our knowledge, ACCEPT is the first COPD exacerbation prediction tool that jointly estimates the individualised rate and severity of exacerbations. Successful external validation of ACCEPT showed that its generalisability can be expanded across geography and beyond the setting of therapeutic trials. ACCEPT is designed to be easily applicable in clinical practice and is readily accessible as a web application. Implications of all the available evidenceCurrent guidelines rely on a history of exacerbations as the sole predictor of future exacerbations. Simple clinical and demographic variables, in aggregate, can be used to predict COPD exacerbations with improved accuracy. ACCEPT enables a more personalised approach to treatment based on routinely collected clinical data by allowing clinicians to objectively differentiate risk profiles of patients with similar exacerbation history. Care providers and patients can use individualised exacerbation risk estimates to decide on preventive therapies based on objectively-established or patient-specific thresholds for treatment benefit and harm. COPD clinical researchers can use this tool to target enriched populations for enrolment in clinical trials.

In a normal year, the fatal lung disease Idiopathic Pulmonary Fibrosis (IPF) accounts for [~]1% of UK deaths. Smoking is a recognised risk factor for IPF but the question of causality remains unanswered. Here, we used data from the UK Biobank (UKBB) and the well-established genetic technique of Mendelian randomisation (MR) methods to investigate whether smoking is causal for IPF compared with COPD, where causality is established. We looked at observational associations in unrelated Europeans, with 871 IPF cases, 11,413 COPD cases and 366,942 controls. We performed analyses using one-sample MR to test for inferred smoking causality in ever smokers using genetic variants that have a previously demonstrated association with smoking heaviness. Strong associations between disease status and ever having smoked were found in both IPF (OR = 1.52; 95%CI:1.32-1.74; P=2.4x10-8) and COPD (OR= 5.77; 95%CI:5.48-6.07; P<1x10-15). Using MR, a one allele increase in smoking volume genetic risk score was associated with higher odds of COPD in ever smokers, (OR = 4.32; 95%CI:3.37-5.54; P<1x10-15), but no association was seen in IPF (OR=0.55; 95%CI: 0.17-1.81; P=0.33). No association was found between the genetic risk score and disease prevalence in never smokers with IPF (OR = 1.00; 95%CI:0.98-1.02; P=1.00) or COPD (OR = 1.00; 95%CI:0.99-1.01; P=0.53). Although both IPF and COPD are observationally associated with smoking, our analysis provides evidence inferring that the association is causal in COPD but there is no such evidence in IPF. This suggests that other environmental exposures also need consideration in IPF.

IntroductionHypersensitivity pneumonitis (HP), a common interstitial lung disease (ILD), comprises two distinct but related forms, acute and fibrotic (fHP). HP is classically described as a disease triggered by antigen exposure. However, a wide range of triggers are described and in [~]50% of cases no cause is identified, rendering observational studies challenging. The British Pigeon Fanciers Genetics of ILD (BPF-GILD) study aims to address this by studying a population with a clear history of exposure to a common trigger. MethodsParticipants were recruited from 2019 to 2023 at large UK Pigeon Fancier meetings. Each participant performed spirometry, completed a standardised questionnaire with a doctor, and provided blood samples. We present our baseline data in this manuscript. Results417 subjects were recruited from four shows. The median age of the cohort was 63 years, 95% were male and 94% self-reported white ethnicity. The median number of pigeons kept was 80 [range 4-800], with fanciers spending 14 hours per week [1-100] in their lofts. 52% of participants had occupational dust exposures. 49% of the cohort reported at least one respiratory symptom related to loft exposure. 14% had a history of ILD and these individuals had more loft-related respiratory symptoms, poorer lung function, and appeared more likely to wear a mask with their pigeons than those without (74% vs 57%). 41% of participants had positive responses to questions employed to detect occult connective tissue disease in ILD clinics. DiscussionOur well characterised cohort of pigeon fanciers commonly experience acute HP symptoms and are likely to be at increased risk of fHP. Subsequent work using stored samples will enable us to determine genetic risk factors and pathways relevant to the development of fHP.

IntroductionRadiological change which may be attributed to infection can also be attributable to lung cancer. Patients with SARS-CoV-2 infection can develop groundglass lung opacification which may result in chronic lung changes. Current British Thoracic Society (BTS) guidelines recommend patients with pneumonia and COVID19 undergo repeat chest radiography. MethodsA single-centre audit of patients hospitalised with community-acquired pneumonia or COVID19 over three time periods during the COVID19 pandemic (Aug-Dec 2020, Jun-Aug 2021, Dec-Jan 2022). We assessed whether patients were eligible for radiological follow-up and if repeat radiological investigation occurred. Results1040 adults were hospitalised with infective radiological change (pneumonia=596, COVID19=444). 831/1040 patients (80%) required radiological follow-up under BTS guideline criteria: there was minimal difference between the first two time periods studied. Patients hospitalised with CAP were less likely to have radiological follow-up planned than those admitted with COVID19 disease (49% versus 59% respectively). Following a change in hospital policy, follow-up rates increased to 69% and 71% for pneumonia and COVID19. Overall, only 47% eligible patients received follow-up in line with current guidelines. ConclusionBTS guideline adherence is important to avoid delay in diagnosing underlying malignancy or chronic lung disease. Radiological follow-up following CAP and COVID19 may be suboptimal, with a paucity of data. Follow-up arranged under the hospital team was more likely to occur than when the GP was responsible for instigating repeat radiological imaging. Further investigation into rates of radiological follow-up should be undertaken, including reasons for non-adherence, to ensure patients receive appropriate treatment following respiratory infection.

BackgroundWHO Tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited. MethodsWe conducted a prospective cohort study of household TB contacts in South Africa. Participants all underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2-3 induced] sputum investigation and passive and active follow-up for incident TB. CXR were processed comparing 3 CAD softwares (CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT CXR 3.1.4.111). We evaluated their performance to detect routine and enhanced prevalent, and incident TB, comparing the performance to blood-based biomarkers (Xpert MTB host-response, Erythrocyte Sedimentation Rate, C-Reactive Protein, QuantiFERON) in a subgroup. Findings483 participants were followed-up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROC to identify prevalent TB for CAD4TB, qXR and Lunit INSIGHT CXR were 0.87 (95% CI 0.77-0.96), 0.88 (95% CI 0.79-0.97) and 0.91 (95% CI 0.83-0.99) respectively. >30% with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced baseline sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between 0.60-0.65. The diagnostic performance of CAD for prevalent TB was superior to blood-based biomarkers. InterpretationOur findings suggest that the potential of CAD-CXR screening for TB is not maximised as a high proportion of those above current thresholds but with a negative routine confirmatory sputum have true TB disease that may benefit intervention. FundingUKRI-MRC SummaryWe found that the diagnostic accuracy of CAD-CXR to identify prevalent TB cases in household TB contacts was high but >30% with scores above recommended CAD thresholds who were bacteriologically negative on routine testing baseline were subsequently diagnosed suggest that the potential of CAD-CXR screening is not maximised.

BackgroundIt is unclear whether smoking increases the risk of COVID-19 hospitalisation. We examined i) the association of smoking status with hospitalisation for COVID-19 compared with hospitalisation for other respiratory viral infections a year previous; and ii) concordance between smoking status recorded on the electronic health record (EHR) and the contemporaneous medical notes. MethodsThis case-control study enrolled adult patients (446 cases and 211 controls) at a single National Health Service trust in London, UK. The outcome variable was type of hospitalisation (COVID-19 vs. another respiratory virus a year previous). The exposure variable was smoking status (never/former/current smoker). Logistic regression analyses adjusted for age, sex, socioeconomic position and comorbidities were performed. The study protocol and analyses were pre-registered in April 2020 on the Open Science Framework. ResultsCurrent smokers had lower odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (ORadj=0.55, 95% CI=0.31-0.96, p=.04). There was no significant association among former smokers (ORadj=1.08, 95% CI=0.72-1.65, p=.70). Smoking status recorded on the EHR (compared with the contemporaneous medical notes) was incorrectly recorded for 168 (79.6%) controls ({chi}2(3)=256.5, p=<0.001) and 60 cases (13.5%) ({chi}2(3)=34.2, p=<0.001). ConclusionsIn a single UK hospital trust, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous, although it is unclear whether this association is causal. Targeted post-discharge recording of smoking status may account for the greater EHR- medical notes concordance observed in cases compared with controls.

IntroductionAsthma risk is a complex interplay between genetic susceptibility and environment. Despite many significantly-associated common variants, the contribution of rarer variants with potentially greater effect sizes has not been as extensively studied. We present an exome-based study adopting 24,576 cases and 120,530 controls to assess the contribution of rare protein-coding variants to the risk of early-onset or all-comer asthma. MethodsWe performed case-control analyses on three genetic units: variant-, gene- and pathway-level, using sequence data from the Scandinavian Asthma Genetic Study and UK Biobank participants with asthma. Cases were defined as all-comer asthma (n=24,576) and early-onset asthma (n=5,962). Controls were 120,530 UK Biobank participants without reported history of respiratory illness. ResultsVariant-level analyses identified statistically significant variants at moderate-to-common allele frequency, including protein-truncating variants in FLG and IL33. Asthma risk was significantly increased not only by individual, common FLG protein-truncating variants, but also among the collection of rare-to-private FLG protein-truncating variants (p=6.8x10-7). This signal was driven by early-onset asthma and did not correlate with circulating eosinophil levels. In contrast, a single splice variant in IL33 was significantly protective (p=8.0x10-10), while the collection of remaining IL33 protein-truncating variants showed no class effect (p=0.54). A pathway-based analysis identified that protein-truncating variants in loss-of-function intolerant genes were significantly enriched among individuals with asthma. ConclusionsAccess to the full allele frequency spectrum of protein-coding variants provides additional clarity about the potential mechanisms of action for FLG and IL33. Beyond these two significant drivers, we detected a significant enrichment of protein-truncating variants in loss-of-function intolerant genes.

BackgroundSocial deprivation impacts chronic disease and acute admission outcomes. In interstitial lung disease (ILD), prior British Thoracic Society registry data for idiopathic pulmonary fibrosis has shown high deprivation was associated with poorer long-term outcomes. However, its impact on acute admissions in ILD is not known. MethodsWe undertook a multicentre, retrospective study of ILD-related admissions between 1st January 2017 and 31st December 2019 across 11 hospitals in the North West of England, utilising available real-world data. We determined social deprivation geographically by the 2019 English Indices of Deprivation deciles. The primary outcome was 90-day all-cause mortality. Results999 admissions met the inclusion criteria. 327/999 (32.7%) of admissions came from individuals geographically in the most deprived 20%. Across 999 admissions, in unadjusted survival analysis we observed a non-linear relationship between deprivation and 90-day all-cause mortality. In complete case multivariate modelling, deprivation demonstrated borderline significant association with all-cause mortality (HR 1.038, 95% CI 1.00 - 1.077, p = 0.050). However, this effect was lost in pooled analysis using multiple imputation (HR 1.001, 95% CI 0.971 - 1.033, p = 0.928). Male sex and pre-admission long-term oxygen were consistently associated with increased 90-day all-cause mortality across both models. Lower TLCO values were significantly associated with increased 90-day mortality in pooled analysis. ConclusionWe observe a high burden of acute ILD-related hospital admission amongst the most deprived 20%, suggesting geographical deprivation may impact acute healthcare seeking behaviours. Once admitted, the impact of deprivation appears more complex and multifactorial. Further studies which assess geographical and individual-level deprivation are needed to validate our findings. Key Messages What is already known on the topic?The British Thoracic Society idiopathic pulmonary fibrosis registry has previously demonstrated that higher social deprivation is associated with worse long-term outcomes. In other respiratory diseases, social deprivation impacts acute admission patterns and outcomes. What this study addsTo the best of our knowledge, this is the first study examining the relationship between social deprivation and acute ILD-related admission outcomes. This study demonstrates high acute admission burden from the geographically most deprived 20%. Once admitted, the association between geographical social deprivation and mortality outcomes appears complex and multifactorial in our modelling. How this may affect research, practice or policyThis study highlights the acute admission burden from highly deprived communities and the need for additional research to further understand the individual-level and geographical-level deprivation patients with ILD experience. We suggest the need for community outreach to build trust with deprived communities, alongside increasing awareness amongst patients, caregivers and primary care physicians in such communities. Deprivation must remain an important consideration in any new service or intervention to prevent worsening of health inequalities.

BackgroundSpirometry measures lung function by selecting the best of multiple efforts meeting pre-specified quality control (QC), and reporting two key metrics: forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). We hypothesize that discarded submaximal and QC-failing data meaningfully contribute to the prediction of airflow obstruction and all-cause mortality. MethodsWe evaluated volume-time spirometry data from the UK Biobank. We identified "best" spirometry efforts as those passing QC with the maximum FVC. "Discarded" efforts were either submaximal or failed QC. To create a combined representation of lung function we implemented a contrastive learning approach, Spirogram-based Contrastive Learning Framework (Spiro-CLF), which utilized all recorded volume-time curves per participant and applied different transformations (e.g. flow-volume, flow-time). In a held-out 20% testing subset we applied the Spiro-CLF representation of a participants overall lung function to 1) binary predictions of FEV1/FVC < 0.7 and FEV1 Percent Predicted (FEV1PP) < 80%, indicative of airflow obstruction, and 2) Cox regression for all-cause mortality. FindingsWe included 940,705 volume-time curves from 352,684 UK Biobank participants with 2-3 spirometry efforts per individual (66.7% with 3 efforts) and at least one QC-passing spirometry effort. Of all spirometry efforts, 24.1% failed QC and 37.5% were submaximal. Spiro-CLF prediction of FEV1/FVC < 0.7 utilizing discarded spirometry efforts had an Area under the Receiver Operating Characteristics (AUROC) of 0.981 (0.863 for FEV1PP prediction). Incorporating discarded spirometry efforts in all-cause mortality prediction was associated with a concordance index (c-index) of 0.654, which exceeded the c-indices from FEV1 (0.590), FVC (0.559), or FEV1/FVC (0.599) from each participants single best effort. InterpretationA contrastive learning model using raw spirometry curves can accurately predict lung function using submaximal and QC-failing efforts. This model also has superior prediction of all-cause mortality compared to standard lung function measurements. FundingMHC is supported by NIH R01HL137927, R01HL135142, HL147148, and HL089856. BDH is supported by NIH K08HL136928, U01 HL089856, and an Alpha-1 Foundation Research Grant. DH is supported by NIH 2T32HL007427-41 EKS is supported by NIH R01 HL152728, R01 HL147148, U01 HL089856, R01 HL133135, P01 HL132825, and P01 HL114501. PJC is supported by NIH R01HL124233 and R01HL147326. SPB is supported by NIH R01HL151421 and UH3HL155806. TY, FH, and CYM are employees of Google LLC

BackgroundInterstitial lung diseases (ILD) are a heterogenous group of often progressive, unpredictable diseases. They frequently result in hospitalisations secondary to respiratory decompensation, termed ILD-related admissions. A proportion of these are due to acute exacerbations (AEILD). All are associated with high mortality but poorly characterised in real-world populations. AimTo evaluate mortality outcomes and associated risk factors following ILD-related hospital admissions, including AEILD. MethodsWe conducted a multicentre retrospective cohort study of primary ICD10 coded admissions for ILD between 01.01.2017 and 31.12.2019 across 11 NHS hospitals in the North West of England. AEILD events were classified using clinical criteria: a <30-day respiratory deterioration not secondary to cardiac failure, pulmonary embolism or pneumothorax. The AEILD sub-group was subsequently divided into those with CT confirmation (definite AEILD) and without CT confirmation (suspected AEILD). Primary outcome was time from admission to death. Statistical analyses included Kaplan-Meier survival and multivariate cox proportional hazards modelling. ResultsOf 938 admissions ILD-related admissions, 54.5% met study AEILD criteria. Overall, 90-day all-cause mortality was 40.2%. Median survival of the AEILD cohort was 107 days (95% CI 87.0 - 141.0 days) and other ILD-related admission cohort 241.0 days (95% CI 208.0 - 308.0 days), with a statistically significant difference in survival (p <0.0001). 37.6% (192/511) of AEILD events had CT confirmation. Within the AEILD sub-group, median survival was higher in the CT group (144 days vs. 100 days, p = 0.027). AEILD was independently associated with mortality in a multivariate model, and pre-admission oxygen, age and neutrophilia were associated with mortality in both ILD-admission and AEILD 90-day all-cause mortality models. Only 13.9% of admissions had documented palliative care input. ConclusionMortality associated with ILD-related admissions is high, with AEILD events independently associated with high mortality. Findings highlight the need for improved education, improved access to palliative care and targeted AEILD research. Key MessagesO_ST_ABSWhat is already known on this topic.C_ST_ABSHospital admissions in interstitial lung disease (ILD) carry a high risk of mortality, particularly when precipitated by an acute exacerbation (AEILD). Prior international surveys have highlighted clinician heterogeneity in the approach to AEILD, but there is very limited real-world data describing admission outcomes, diagnostic and treatment patterns from the UK. What this study adds.This study adds to the understanding that AEILD conveys poor survival outcomes and highlights age, pre-admission oxygen use and neutrophilia as poor prognostic indicators. It highlights underuse of CT for diagnostic confirmation and demonstrates that a lack of CT confirmation is associated with shorter survival in simple modelling. It also demonstrates low palliative care inpatient service utilisation. How this study might affect research, practice or policy.These findings highlight the urgent need for consistent diagnostic pathways, equitable access to CT imaging and early multidisciplinary input for AEILD. Improved education of the non-specialist, patients and their relatives could improve recognition and outcomes in this high-risk population - including timeline access to palliative care and acute admission burden.

RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. ObjectivesTo assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population. MethodsAn international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. Measurements and Main ResultsData from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and comorbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC [&ge;]80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 1.98, 1.13-3.46). ConclusionsPatients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

COVIDTrach is a UK multidisciplinary collaborative project that aims to evaluate the outcomes of tracheostomy in COVID-19 patients. An invitation to participate in an online survey tool (REDCap) was disseminated to all UK NHS departments involved in tracheostomy in mechanically ventilated COVID-19 patients. Fifty-two percent (n=219/465) of patients who had undergone tracheostomy and were still alive, had been successfully weaned from mechanical ventilation at the point of completing the survey. The all cause in-hospital mortality following tracheostomy was 12% (n=62/530), with 3% of these (n=2/62) due to tracheostomy related complications and the remaining deaths due to COVID-19 related complications. Amongst 400 cases submitting data two weeks after the tracheostomy, no instance of COVID-19 infection amongst operators was recorded. This interim report highlights early outcomes following tracheostomy in mechanically ventilated COVID-19 patients. Future reporting from COVIDTrach will include more detailed analysis at later timepoints using comparator groups in order to provide a more comprehensive assessment of tracheostomy in COVID-19.

BackgroundThose with Chronic Obstructive Pulmonary Disease (COPD) were at a higher risk of experiencing severe illness in the event of contracting COVID-19. Did they therefore act more cautiously? AimThe aim was to determine whether the condition of COPD incurred significant change in social distancing behavior compared to the general public. Design and SettingData was used from the Imperial COVID-19 Behavioural Tracker, which details results of regular public surveying on attitudes surrounding COVID-19 guidance. MethodsResponses by U.K. participants to twenty questions reflecting willingness to adhere to social distancing guidance were compared in those reporting COPD and non-COPD status. ResultsThose with COPD stated a significantly greater willingness to wear face masks during early stages of pandemic. There was greater reluctance to go out and go shopping. There was no apparent or significant difference in willingness to use public transport, suggesting that this was an unavoidable necessity for all. The relationship between level of adherence and COVID-19 case numbers was weak both for those of both COPD and non-COPD status. DiscussionThese results suggest that those with COPD were more cautious and followed guidance more willingly. Advice provided by GPs and healthcare professionals is likely to be beneficial in guiding patient behaviour.

ObjectiveCirculating fibrocytes are elevated in idiopathic pulmonary fibrosis, but the relationship between fibrocyte level with lung function decline and outcomes is lacking replication in prospective clinical study. We aim to validate the utility of circulating fibrocyte levels as a prognostic biomarker in idiopathic pulmonary fibrosis. MethodsWe tested associations between circulating fibrocyte levels, mortality, disease progression and longitudinal lung function in a well-defined prospective observational study of pulmonary fibrosis (PROFILE; NCT01134822). A subset of recruited participants had blood samples processed for fibrocyte measurement, with flow cytometry based on CD45 and collagen-I gating. Associations were tested using univariable and multivariable generalised linear models. Mortality data were subsequently combined with an independent cohort in a mixed-effect multilevel analysis. ResultsIn 102 participants with idiopathic pulmonary fibrosis, an empirically defined cutpoint of 2.22% was associated with a greater risk of overall mortality in adjusted analysis (Hazard Ratio 2.24 95% CI 1.06-4.72). A 2.5 fold greater risk of mortality was supported in a pooled analysis with a historic cohort for a larger sample of 162 participants of idiopathic pulmonary fibrosis, specifically (Hazard Ratio 2.49 95% CI 2.41-2.56). A previously defined mortality risk threshold of 5% circulating fibrocytes was not reproducible in this cohort, circulating fibrocytes were not significantly elevated above non-specific interstitial pneumonia or healthy controls.. We found no association of fibrocytes with lung function or disease progression. ConclusionsIn a prospective clinical cohort of idiopathic pulmonary fibrosis, circulating fibrocytes of 2.22% or above are associated with greater mortality, but do not associate with disease related decline in lung function. What is the key question?Can circulating fibrocytes provide reproducible prognostic biomarker value in fibrotic lung disease? What is the bottom line?Greater proportions of fibrocytes isolated from circulating leukocyte populations are associated with an increase risk of mortality in idiopathic pulmonary fibrosis, but no association was observed with disease related decline in lung function. Why read on?We present associations and limitations of circulating fibrocytes in the largest sample of individuals with pulmonary fibrosis, recruited into a prospective observational study, and replicate prognositic insights from a historic cohort.

BackgroundPulmonary fibrosis (PF) is an incurable fibrotic lung disease with limited treatment options and a high mortality. Evidence is growing that short telomeres cause both heritable and idiopathic pulmonary fibrosis (IPF). Based on survival data, we hypothesised that sex hormones are protective against premature telomere attrition and could influence PF disease onset and/or progression. MethodsAssociations between IPF, sex hormone concentrations and measured leukocyte telomere length (LTL) were examined for unrelated UK Biobank participants of European ancestry with a diagnosis of IPF (415 females, 718 males) against controls (204,321 females, 174,254 males). Polygenic risk scores were used to explore causality between sex hormone indices, LTL and disease. FindingsStrong associations were found between IPF and LTL. For females, higher odds of having IPF was associated with early menopause and premature ovarian failure. Menopause age correlated positively with both age of IPF diagnosis and age of death. For males, IPF prevalence and stages of disease were associated with serum bioavailable testosterone concentrations. For both sexes, evidence of lower concentrations of sex hormones was associated with shorter LTL. Genetic analysis also inferred bi-directional causal links between sex hormone binding globulin concentration, which impacts free testosterone concentration, and LTL in males. InterpretationOur findings suggest that higher sex hormone concentrations protect against IPF onset and progression, possibly by slowing telomere shortening. Hormonal supplementation may delay or prevent disease onset for those with telomere-associated PF risk and improve disease prognosis. This warrants further exploration in a randomised controlled trial. FundingMedical Research Council.

BackgroundIdentification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status. MethodsWe prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC) and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis, benchmarked against WHO recommendations. ResultsOf 932 included individuals, 255 (27%) had culture-confirmed TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0.80 (95% confidence interval 0.77-0.83), with sensitivity 93% (89-95%) and specificity 54% (50-58%) using a primary cut-off of [&ge;]10mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive TB case diagnosed. ConclusionsCRP approached the WHO-defined minimum performance for a TB triage test and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status.

BackgroundSARS-CoV-2 nosocomial transmission to patients and healthcare workers (HCWs) has occurred throughout the COVID-19 pandemic. Aerosol generating procedures (AGPs) seemed particularly risky, and policies have restricted their use in all settings. We examined the prevalence of aerosolized SARS-CoV-2 in the rooms of COVID-19 patients requiring AGP or supplemental oxygen compared to those on room air. MethodsSamples were collected prospectively near to adults hospitalised with COVID-19 at two tertiary care hospitals in the UK from November 2020 - October 2021. The Sartorius MD8 AirPort air sampler was used to collect air samples at a minimum distance of 1.5 meters from patients. RT-qPCR was used following overnight incubation of membranes in culture media and extraction. ResultsWe collected 219 samples from patients rooms: individuals on room air (n=67), receiving oxygen (n=65) or AGP (n=67). Of these, 54 (24.6%) samples were positive for SARS-CoV-2 viral RNA. The highest prevalence was identified in the air around patients receiving oxygen (32.3%, n=21, CI95% 22.2 to 44.3%) with AGP and room air recording prevalence of (20.7%, n=18, CI95% 14.1 - 33.7%) and (22.3%, n=15, CI95% 13.5 - 30.4%) respectively. We did not detect a significant difference in the observed frequency of viral RNA between interventions. InterpretationSARS-CoV-2 viral RNA was detected in the air of hospital rooms of COVID-19 patients, and AGPs did not appear to impact the likelihood of viral RNA. Enhanced respiratory protection and appropriate infection prevention and control measures are required to be fully and carefully implemented for all COVID-19 patients to reduce risk of aerosol transmission.