Identification of connective tissue disease autoantibodies and a novel autoantibody anti-annexin A11 in patients with "idiopathic" interstitial lung disease.

BACKGROUND: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in patients diagnosed with idiopathic ILD. METHODS: 499 patient sera were analysed: 251 idiopathic pulmonary fibrosis (IPF), 206 idiopathic non-specific interstitial pneumonia (iNSIP) and 42 cryptogenic organising pneumonia (COP). Autoantibody status was determined by immunoprecipitation. RESULTS: 2.4% of IPF sera had a CTD-autoantibody compared to 10.2% of iNSIP and 7.3% of COP. 45% of autoantibodies were anti-synthetases. A novel autoantibody targeting an unknown 56 kDa protein was found in seven IPF patients (2.8%) and two NSIP (1%) patients. This was characterised as anti-annexin A11. CONCLUSION: Specific guidance on autoantibody testing and interpretation in patients with ILD could improve diagnostic accuracy. Further work is required to determine the clinical significance of anti-annexin A11.

A Retrospective Analysis of 2-Year Follow-Up of Patients with Incidental Findings of Sarcoidosis.

INTRODUCTION: Sarcoidosis is a multi-system granulomatous disease most commonly involving the lungs. It may be incidentally diagnosed during imaging studies for other conditions or non-specific symptoms. The appropriate follow-up of incidentally diagnosed asymptomatic stage 1 disease has not been well defined. OBJECTIVE: To define the clinical course of incidentally diagnosed asymptomatic stage 1 sarcoidosis and propose an algorithm for the follow-up of these patients. METHODOLOGY: A retrospective case note analysis was performed of all EBUS-TBNA (endobronchial ultrasound-guided transbronchial needle aspiration)-confirmed cases of stage 1 sarcoidosis presenting incidentally to Bristol and Liverpool Interstitial Lung Disease services. Clinical history, serology results, imaging scans, and lung function parameters were examined at baseline, 12, and 24 months. A cost analysis was performed comparing the cost of the current 2-year follow-up guidance to a 1 year follow-up period. RESULTS: Sixty-seven patients were identified as the final cohort. There was no significant change in the pulmonary function tests over the two-year follow-up period. Radiological disease stability was observed in the majority of patients (58%, n = 29), and disease regression was evidenced in 40% (n = 20) at 1 year. Where imaging was performed at 2 years, the majority (69.8%, n = 37) had radiological evidence of disease regression, and 30.2% (n = 16) showed radiological evidence of stability. All patients remained asymptomatic and did not require therapeutic intervention over the study period. CONCLUSIONS: Our results show that asymptomatic patients with incidental findings of thoracic lymph nodal non-caseating granulomas do not progress over a 2-year period. Our results suggest that the prolonged secondary-care follow-up of such patients may not be necessary. We propose that these patients are followed up for 1 year with a further year of patient-initiated follow-up (PIFU) prior to discharge.

The Impact of Integrated Palliative Care on Survival in Idiopathic Pulmonary Fibrosis: A Retrospective Multicenter Comparison.

Background: Early and integrated palliative care is recommended for patients with idiopathic pulmonary fibrosis. Unfortunately, palliative care delivery remains poor due to various barriers in practice. This study describes various palliative care delivery models in a real-world cohort of patients with idiopathic pulmonary fibrosis, examines the predictors of survival in this cohort of patients, and explores the impact of palliative care on survival. Design: Charts were reviewed retrospectively and analyzed. The primary outcome was survival during a 4-year follow-up period. Two multivariable models were created to examine the impact of therapeutic strategies including palliative intervention on survival. Results: 298 patients with idiopathic pulmonary fibrosis were enrolled from 3 interstitial lung disease clinics with different palliative care models in Edmonton, Canada; Bristol, UK; and Kingston, Canada. 200 (67%) patients received palliative care and 119 (40%) died during follow up. Primary palliative care models (Edmonton and Bristol) delivered palliative care to 96% and 100% respectively compared 21% in the referral model (Queens). Palliative care [adjusted hazard ratio (aHR) .28 (.12-.65)] along with the use of antifibrotics [aHR .56 (.37-.84)], and body mass index >30 [aHR .47 (.37-.85)] reduced the risk of death in our idiopathic pulmonary fibrosis cohort. Opioid use was associated with worse survival [aHR 2.11 (1.30-23.43)]. Conclusions: Both palliative care and antifibrotic use were associated with survival benefit in this cohort of patients with idiopathic pulmonary fibrosis after adjusting for covariates. The benefit was seen despite differences in disease severity and different palliative care delivery models.

Nintedanib for non-IPF progressive pulmonary fibrosis: 12-month outcome data from a real-world multicentre observational study.

Background: Nintedanib slows lung function decline for patients with non-idiopathic pulmonary fibrosis progressive pulmonary fibrosis (PPF) in clinical trials, but the real-world safety and efficacy are not known. Methods: In this retrospective cohort study, standardised data were collected from patients in whom nintedanib was initiated for PPF between 2019 and 2020 through an early-access programme across eight centres in the United Kingdom. Rate of lung function change in the 12 months pre- and post-nintedanib initiation was the primary analysis. Symptoms, drug safety, tolerability and stratification by interstitial lung disease subtype and computed tomography pattern were secondary analyses. Results: 126 patients were included; 67 (53%) females; mean±sd age 60±13 years. At initiation of nintedanib, mean forced vital capacity (FVC) was 1.87 L (58% predicted) and diffusing capacity of the lung for carbon monoxide (D LCO) was 32.7% predicted. 68% of patients were prescribed prednisolone (median dose 10 mg) and 69% were prescribed a steroid-sparing agent. In the 12 months after nintedanib initiation, lung function decline was significantly lower than in the preceding 12 months: FVC -88.8 mL versus -239.9 mL (p=0.004), and absolute decline in D LCO -2.1% versus -6.1% (p=0.004). Response to nintedanib was consistent in sensitivity and secondary analyses. 89 (71%) out of 126 patients reported side-effects, but 86 (80%) of the surviving 108 patients were still taking nintedanib at 12 months with patients reporting a reduced perception of symptom decline. There were no serious adverse events. Conclusion: In PPF, the real-world efficacy of nintedanib replicated that of clinical trials, significantly attenuating lung function decline. Despite the severity of disease, nintedanib was safe and well tolerated in this real-world multicentre study.

Use of illness severity scores to predict mortality in interstitial lung disease patients hospitalised with acute respiratory deterioration.

INTRODUCTION: Hospitalisations relating to acute respiratory deteriorations (ARD) in Interstitial Lung Disease (ILD) have poor outcomes. Factors predicting adverse outcomes are not fully understood and data addressing the use of illness severity scores in prognostication are limited. OBJECTIVE: To investigate the use of CURB-65 and NEWS-2 severity scores in the prediction of mortality following ARD-ILD hospitalisation, using prospective methodology and to validate previously determined cut-offs, derived from a retrospective study cohort. METHODS: A dual-centre prospective observational cohort study of all adults (≥18y) hospitalised with ARD-ILD in Bristol, UK (n = 179). Gender-Age-Physiology (GAP), CURB-65 and NEWS-2 scores were calculated for each eligible admission. Receiver operating characteristics (ROC) curve analysis was used to quantify the strength of discrimination for NEWS-2 and CURB-65 scores. Univariable and multivariable logistic regression analyses were performed to explore the relationship between baseline severity scores and mortality. RESULTS: GAP showed some merit at predicting 30-day mortality (AUC = 0.64, P = 0.015); whereas CURB-65 showed modest predictive value for in-hospital (AUC = 0.72, P < 0.001) and 90-day mortality (AUC = 0.67, P < 0.001). NEWS-2 showed higher predictive value for in-hospital (AUC = 0.80, P < 0.001) and 90-day mortality (AUC = 0.75, P < 0.001), with an optimal derived cut-off ≥6.5 found to be sensitive and specific for predicting in-hospital (83% and 63%) and 90-day (73% and 72%) mortality. In exploratory analyses, GAP score addition improved the predictive ability of NEWS-2 against 30-day mortality and CURB-65 across all time-periods. CONCLUSION: NEWS-2 has good discriminatory value for predicting in-hospital mortality and moderate discriminatory value for predicting 90-day mortality. The optimal NEWS-2 cut-off value determined was the same as in a previous retrospective cohort, confirming the NEWS-2 score shows promise in predicting mortality following ARD-ILD hospitalisation.

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Multi-center evaluation of baseline neutrophil-to-lymphocyte (NLR) ratio as an independent predictor of mortality and clinical risk stratifier in idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes in IPF. Methods: We adopted a two-stage discovery (n = 71) and validation (n = 134) design using patients from the UCL partners (UCLp) cohort. We then combined discovery and validation cohorts and included an additional 794 people with IPF, using real-life data from 5 other UK centers, to give a combined cohort of 999 patients. Data were collected from patients presenting over a 13-year period (2006-2019) with mean follow up of 3.7 years (censoring: 2018-2020). Findings: In the discovery analysis, we showed that high values of NLR (>/ = 2.9 vs < 2.9) were associated with increased risk of mortality in IPF (HR 2.04, 95% CI 1.09-3.81, n = 71, p = 0.025). This was confirmed in the validation (HR 1.91, 95% CI 1.15-3.18, n = 134, p = 0.0114) and combined cohorts (HR 1.65, n = 999, 95% CI 1.39-1.95; p < 0·0001). NLR correlated with GAP stage and GAP index (p < 0.0001). Stratifying patients by NLR category (low/high) showed significant differences in survival for GAP stage 2 (p < 0.0001), however not for GAP stage 1 or 3. In a multivariate analysis, a high NLR was an independent predictor of mortality/progression after adjustment for individual GAP components and steroid/anti-fibrotic use (p < 0·03). Furthermore, incorporation of baseline NLR in a modified GAP-stage/index, GAP-index/stage-plus, refined prognostic ability as measured by concordance (C)-index. Interpretation: We have identified NLR as a widely available test that significantly correlates with lung function, can predict outcomes in IPF and refines cohort staging with GAP. NLR may allow timely prioritisation of at-risk patients, even in the absence of lung function. Funding: Breathing Matters, GSK, CF Trust, BLF-Asthma, MRC, NIHR Alpha-1 Foundation.

Animal-derived medicinal products: community representatives' views of their use.

In the UK, there are a variety of religious or cultural beliefs and preferences that guide people in a range of lifestyle decisions. This qualitative study aimed to better understand the views of the public around prescribing animal-derived products, in particular low-molecular-weight heparin (LMWH), from a potential patient perspective. A series of quality improvement focus groups with stakeholders were undertaken to understand perceptions and to evaluate and inform an established treatment pathway. Stakeholders discussed finding out about the porcine nature of LMWH asking 'Why don't they tell us?', suggesting that they 'shouldn't have to give out clues' about their personal preferences. Participants' thoughts about 'how' information be provided, by 'whom' and 'when' were gained. The stakeholders indicated that current practice is unacceptable for patients. They require greater knowledge and transparency regarding product components and recommend that healthcare professionals provide more dialogue and choice to patients.

Factoring patients' beliefs and values into decisions around anticoagulation: a community-led multi-cycle quality improvement project.

Low-molecular-weight heparin (LMWH), prescribed for prophylaxis of venous thromboembolism, is derived from porcine animal products. An audit in our Trust showed that most healthcare professionals (95%, n=58/61) did not consider religious or dietary preferences when prescribing LMWH. Focus groups with local stakeholders helped develop project aims. Quality improvement methods were used to develop, test and optimise interventions over two cycles in our medical unit. Interventions included written and audiovisual information for patients, a staff eLearning module, a policy to guide switching from LMWH to a synthetic alternative and a written prompt reminding doctors to consent patients before prescribing LMWH. The proportion of patients being appropriately consented for LMWH prescriptions increased following our interventions (from <5% at baseline to >80%). Patient and staff feedback was positive, with high demand for a non-animal-derived alternative to LMWH. Simple measures, increasing awareness and knowledge among staff and patients, can improve the number of patients being appropriately consented for LMWH prescriptions.

A multidisciplinary approach to the diagnosis of antisynthetase syndrome.

Antisynthetase syndrome is a subtype of idiopathic inflammatory myopathy, strongly associated with the presence of interstitial lung disease. Diagnosis is made by identifying myositis-specific antibodies directed against aminoacyl tRNA synthetase, and relevant clinical and radiologic features. Given the multisystem nature of the disease, diagnosis requires the careful synthesis of subtle clinical and radiological features with the interpretation of specialized autoimmune serological testing. This is provided in a multidisciplinary environment with input from rheumatologists, respiratory physicians, and radiologists. Differentiation from other idiopathic interstitial lung diseases is key; treatment and prognosis differ between patients with antisynthetase syndrome and idiopathic interstitial lung disease. In this review article, we look at the role of the multidisciplinary team and its individual members in the initial diagnosis of the antisynthetase syndrome, including the role of physicians, radiologists, and the wider team.

Use of peripheral neutrophil to lymphocyte ratio and peripheral monocyte levels to predict survival in fibrotic hypersensitivity pneumonitis (fHP): a multicentre retrospective cohort study.

The factors determining disease course and survival in fibrotic hypersensitivity pneumonitis (fHP) have not been fully elucidated.The aim of this study was to describe the characteristics of patients with fHP in a real-world cohort and investigate factors associated with worse outcomes. We aimed to explore the use of neutrophil to lymphocyte ratio (NLR) and peripheral blood monocyte levels in predicting mortality. METHODS: A retrospective, multicentre, observational UK cohort study. RESULTS: Patients with fHP were significantly younger than those with idiopathic pulmonary fibrosis (IPF) (median age fHP 73 vs IPF 75 years) and were much more likely to be woman (fHP 61% vs IPF 26%). In almost half of all fHP cases (49%, n=104/211), no causative antigen was identified from either the history or specific antigen testing. Overall, fHP was associated with a better survival than IPF, although median survival of both groups was poor (fHP 62 months vs IPF 52 months).IPF survival in patients with a high NLR was significantly lower than those with a low NLR (44 vs 83 months). A monocyte count ≥0.95 K/uL also predicted significantly poorer outcomes for patients with IPF compared with <0.95 K/uL (33 vs 57 months). In contrast, NLR and monocyte count did not predict survival in the fHP cohort. CONCLUSIONS: Although fHP has a statistically lower mortality than IPF, absolute survival time of both conditions is poor. High baseline NLR and absolute monocyte counts predict worse survival in IPF but not in fHP, highlighting the potential for divergence in their pathogenic mechanisms.

Diagnostic test accuracy of artificial intelligence analysis of cross-sectional imaging in pulmonary hypertension: a systematic literature review.

OBJECTIVES: To undertake the first systematic review examining the performance of artificial intelligence (AI) applied to cross-sectional imaging for the diagnosis of acquired pulmonary arterial hypertension (PAH). METHODS: Searches of Medline, Embase and Web of Science were undertaken on 1 July 2020. Original publications studying AI applied to cross-sectional imaging for the diagnosis of acquired PAH in adults were identified through two-staged double-blinded review. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies and Checklist for Artificial Intelligence in Medicine frameworks. Narrative synthesis was undertaken following Synthesis Without Meta-Analysis guidelines. This review received no funding and was registered in the International Prospective Register of Systematic Reviews (ID:CRD42020196295). RESULTS: Searches returned 476 citations. Three retrospective observational studies, published between 2016 and 2020, were selected for data-extraction. Two methods applied to cardiac-MRI demonstrated high diagnostic accuracy, with the best model achieving AUC=0.90 (95% CI: 0.85-0.93), 89% sensitivity and 81% specificity. Stronger results were achieved using cardiac-MRI for classification of idiopathic PAH, achieving AUC=0.97 (95% CI: 0.89-1.0), 96% sensitivity and 87% specificity. One study reporting CT-based AI demonstrated lower accuracy, with 64.6% sensitivity and 97.0% specificity. CONCLUSIONS: Automated methods for identifying PAH on cardiac-MRI are emerging with high diagnostic accuracy. AI applied to cross-sectional imaging may provide non-invasive support to reduce diagnostic delay in PAH. This would be helped by stronger solutions in other modalities. ADVANCES IN KNOWLEDGE: There is a significant shortage of research in this important area. Early detection of PAH would be supported by further research advances on the promising emerging technologies identified.

Outcome measurement instrument selection for lung physiology in systemic sclerosis associated interstitial lung disease: A systematic review using the OMERACT filter 2.1 process.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) is a research organization focused on improving health care outcomes for patients with autoimmune and musculoskeletal diseases. The Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) Working Group on Lung Physiology is a group within OMERACT charged with identifying outcome measures that should be implemented in studies of patients with CTD-ILD. The OMERACT Filter 2.1 is an evidence-based algorithm used to identify outcome measures that are truthful, feasible, and able to discriminate between groups of interest. Our objective was to summate evidence (published literature, key opinion leader input, patient perspectives) that would influence the CTD-ILD Working Group's vote to accept or reject the use of two measures of lung physiology, the forced vital capacity (FVC) and the diffusion capacity of carbon monoxide (DLco) for use in randomized controlled trials (RTCs) and longitudinal observational studies (LOSs) involving patients with systemic sclerosis associated ILD (SSc-ILD). METHODS: Patient Research Partners (those afflicted with SSc-ILD) and the CTD-ILD Working Group on Lung Physiology were polled to assess their opinion on the FVC and DLco in terms of feasibility; the CTD-ILD Working Group was also queried on these instruments' face and content validity. We then conducted a systematic literature review to identify articles in the SSc-ILD population that assessed the following measurement properties of FVC and DLco: (1) construct validity, (2) test-retest reliability, (3) longitudinal construct validity, (4) clinical trial discrimination/sensitivity to detect change in clinical trials, and (5) thresholds of meaning. Results were summarized in a Summary of Measurement Properties (SOMP) table for each instrument. OMERACT CTD-ILD Working Group members discussed and voted on the strength of evidence supporting these two instruments and voted to endorse, provisionally endorse, or not endorse either instrument. RESULTS: Forty Patient Research Partners reported these two measures are feasible (are not an unnecessary burden or represent an infeasible longitudinal assessment of their disease). A majority of the 18 CTD-ILD Working Group members voted that both the FVC and DLco are feasible and have face and content validity. The systematic literature review returned 1,447 non-duplicated articles, of which 177 met eligibility for full text review. Forty-eight studies (13 RCTs, 35 LOSs) were included in the qualitative analysis. The FVC SOMP table revealed high quality, consistent data with evidence of good performance for all five measurement properties, suggesting requisite published evidence to proceed with endorsement. The DLco SOMP table showed a lack of data to support test-retest reliability and inadequate evidence to support clinical trial discrimination. There was unanimous agreement (15 [100%]) among voting CTD-ILD Working Group members to endorse the FVC as an instrument for lung physiology in RCTs and LOSs in SSc-ILD. Based on currently available evidence, DLco did not meet the OMERACT criteria and is not recommended for use in RCTs to represent lung physiology of SSc-ILD. The OMERACT Technical Advisory Group agreed with these decisions. CONCLUSION: The OMERACT Filter 2.1 was successfully applied to the domain of lung physiology in patients with SSc-ILD. The FVC was endorsed for use in RCTs and LOSs based on the Working Group's vote; DLco was not endorsed.

Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID).

INTRODUCTION: The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). METHODS AND ANALYSIS: The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. ETHICS AND DISSEMINATION: All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. CONCLUSION: This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD.

Krebs von den Lungen 6 (KL-6) as a marker for disease severity and persistent radiological abnormalities following COVID-19 infection at 12 weeks.

INTRODUCTION: Acute presentations of COVID-19 infection vary, ranging from asymptomatic carriage through to severe clinical manifestations including acute respiratory distress syndrome (ARDS). Longer term sequelae of COVID-19 infection includes lung fibrosis in a proportion of patients. Krebs von den Lungen 6 (KL-6) is a mucin like glycoprotein that has been proposed as a marker of pulmonary epithelial cell injury. We sought to determine whether KL-6 was a marker of 1) the severity of acute COVID-19 infection, or 2) the persistence of symptoms/radiological abnormalities at medium term follow up. METHODS: Prospective single centre observational study. RESULTS: Convalescent KL-6 levels were available for 93 patients (male 63%, mean age 55.8 years) who attended an 12-week follow up appointment after being admitted to hospital with COVID-19. For 67 patients a baseline KL-6 result was available for comparison. There was no significant correlations between baseline KL-6 and the admission CXR severity score or clinical severity NEWS score. Furthermore, there was no significant difference in the baseline KL-6 level and an initial requirement for oxygen on admission or the severity of acute infection as measured at 28 days. There was no significant difference in the 12-week KL-6 level and the presence or absence of subjective breathlessness but patients with abnormal CT scans at 12 weeks had significantly higher convalescent KL-6 levels compared to the remainder of the cohort (median 1101 IU/ml vs 409 IU/ml). CONCLUSIONS: The association between high KL-6 levels at 12 weeks and persisting CT abnormalities (GGO/fibrosis), is a finding that requires further exploration. Whether KL-6 may help differentiate those patients with persisting dyspnoea due to complications rather than deconditioning or dysfunctional breathing alone, is an important future research question.

Clinicoserological features of antisynthetase syndrome (ASyS)-associated interstitial lung disease presenting to respiratory services: comparison with idiopathic pulmonary fibrosis and ASyS diagnosed in rheumatology services.

INTRODUCTION: Antisynthetase syndrome (ASyS) is a rare autoimmune connective tissue disease (CTD), associated with autoantibodies targeting tRNA synthetase enzymes, that can present to respiratory (interstitial lung disease (ILD)) or rheumatology (myositis, inflammatory arthritis and systemic features) services. The therapeutic management of CTD-associated ILD and idiopathic pulmonary fibrosis (IPF) differs widely, thus accurate diagnosis is essential. METHODS: We undertook a retrospective, multicentre observational cohort study designed to (1) evaluate differences between ASyS-associated ILD with IPF, (2) phenotypic differences in patients with ASyS-ILD presenting to respiratory versus rheumatology services, (3) differences in outcomes between ASySassociated with Jo-1 versus non-Jo-1 autoantibodies and (4) compare long-term outcomes between these groups. RESULTS: We identified 76 patients with ASyS-ILD and 78 with IPF. Patients with ASyS were younger at presentation (57 vs 77 years, p<0.001) with a female predominance (57% vs 33%, p=0.006) compared with IPF. Cytoplasmic staining on indirect immunofluorescence was a differentiating factor between ASyS and IPF (71% vs 0%, p<0.0001). Patients with ASyS presenting initially to respiratory services (n=52) had a higher prevalence of ASyS non-Jo-1 antibodies and significantly fewer musculoskeletal symptoms/biochemical evidence of myositis, compared with those presenting to rheumatology services (p<0.05), although lung physiology was similar in both groups. There were no differences in high-resolution CT appearances or outcomes in those with Jo-1 versus non-Jo-1 ASyS-ILD. CONCLUSIONS: Extended autoimmune serology is needed to evaluate for ASyS autoantibodies in patients presenting with ILD, particularly in younger female patients. Musculoskeletal involvement is common in ASyS (typically Jo-1 autoantibodies) presenting to rheumatology but the burden of ILD is similar to those presenting to respiratory medicine.

The not so innocent bystander: an unusual cause of progressive breathlessness.

This case report discusses a 76-year-old man who presented with symptomatic diffuse alveolar-septal and tracheobronchial amyloidosis with a low-grade monoclonal gammopathy. This patient had a combination of both symptomatic diffuse alveolar-septal interstitial disease and tracheobronchial amyloidosis, features that contradict the widely accepted presentations seen in this disease. First, tracheobronchial amyloidosis has been documented as localised disease without systemic involvement. Second, diffuse alveolar-septal interstitial disease is rarely identified with clinical symptoms unless there is significant cardiac involvement. This case highlights a number learning points in the diagnosis and management of systemic amyloid light chain amyloidosis;(1) There is a need for a high index of suspicion for diagnosis due to the potential subtlety of a plasma cell clone underlying AL amyloidosis, requiring serum-free light chain assays to increase sensitivity; (2) Haematological response and recovery of organ dysfunction are not a linear relationship due to the slower reversal of amyloid deposition; therefore, ongoing monitoring is required to identify those in need of repeated therapy. However, haematological response is a marker of overall survival and (3) Multisystem assessment and multidisciplinary collaboration are critical in optimising the care of patients with systemic AL amyloidosis.

Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort.

The longer-term consequences of SARS-CoV-2 infection are uncertain. Consecutive patients hospitalised with COVID-19 were prospectively recruited to this observational study (n=163). At 8-12 weeks postadmission, survivors were invited to a systematic clinical follow-up. Of 131 participants, 110 attended the follow-up clinic. Most (74%) had persistent symptoms (notably breathlessness and excessive fatigue) and limitations in reported physical ability. However, clinically significant abnormalities in chest radiograph, exercise tests, blood tests and spirometry were less frequent (35%), especially in patients not requiring supplementary oxygen during their acute infection (7%). Results suggest that a holistic approach focusing on rehabilitation and general well-being is paramount.