Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Analytic Morphomics in Myositis-Related Interstitial Lung Disease.

PURPOSE: Interstitial lung disease (ILD) is the most common non-musculoskeletal manifestation of idiopathic inflammatory myopathies (IIM). Identification of body composition change may enable early intervention to improve prognosis. We investigated muscle quantity and quality derived from cross-sectional imaging in IIM, and its relationship to ILD severity. METHODS: A retrospective cohort study assessing IIM of ILD patients (n = 31) was conducted. Two datasets separated in time were collected, containing demographics, biochemical data, pulmonary function testing and thoracic CT data. Morphomic analysis of muscle quantity (cross-sectional area) and quality (density in Hounsfield Units) on thoracic CT were analysed utilising a web-based tool allowing segmentation of muscle and fat. Bilateral erector spinae and pectoralis muscle (ESM&PM) were measured at defined vertebral levels. RESULTS: FVC and DLCO decreased but within acceptable limits of treatment response (FVC: 83.7-78.7%, p < 0.05, DLCO 63.4-60.6%, p < 0.05). The cross-sectional area of the PM and ESM increased (PM: 39.8 to 40.7 cm2, p = 0.491; ESM: 35.2 to 39.5 cm2, p = 0.098). Density significantly fell for both the PM and ESM (PM: 35.3-31 HU, p < 0.05; ESM: 38-33.7, p < 0.05). Subcutaneous fat area increased from 103.9 to 136.1 cm2 (p < 0.05), while the visceral fat area increased but not reaching statistical significance. The change in PM density between time points demonstrated an inverse correlation with DLCO (p < 0.05, R = - 0.49). CONCLUSION: Patients with IIM ILD demonstrated significant body composition changes on CT imaging unlikely to be detected by traditional measurement tools. An increase in muscle area with an inverse decrease in density suggests poor muscle quality.

"Management of myositis associated interstitial lung disease".

Idiopathic inflammatory myopathies (IIM) are rare disorders characterised by the presence of skeletal muscle inflammation, with interstitial lung disease (ILD) being the most frequent pulmonary manifestation. The spectrum of clinical presentations of myositis related ILD (M-ILD) encompasses a chronic process to a rapidly progressive ILD (RP-ILD); which is associated with a high mortality rate. The most effective treatments remain controversial and poses a unique challenge to both rheumatologists and respiratory physicians to manage. Given the rare heterogenous nature of M-ILD, there is a paucity of data to guide treatment. The cornerstone of existing treatments encompasses combinations of immunosuppressive therapies, as well as non-pharmacological therapies. In this review, we aim to summarize the current pharmacological therapies (including its dosing regimens and side effects profiles) and non-pharmacological therapies. Based on the existing literature to date, we propose a treatment algorithm for both chronic M-ILD and RP-ILD.

Single-Use or Disposable Flexible Bronchoscopy in Advanced Bronchoscopy Procedures: Experience in a Quaternary Referral Centre.

BACKGROUND: The development of single-use flexible or disposable bronchoscopes (SUFBs) has accelerated in recent years, with the reduced risk of infectious transmission and reduced need for endoscopy staffing particularly advantageous in the COVID-19 pandemic era. OBJECTIVE: The objective of this study was to assess the performance of a novel single-use bronchoscope in an academic quaternary referral centre with on-site interventional pulmonology programme. METHODS: With ethical approval in a quaternary referral centre, we prospectively collected data on sequential bronchoscopy procedures using The Surgical Company Broncoflex© range of SUFBs. Data collected included demographic, procedural, scope performance, user satisfaction, and complication parameters in a tertiary bronchoscopy service. RESULTS: 139 procedures were performed by five pulmonology faculty from January to July 2021. The majority were carried out for infection (45%) and malignancy (32%). Most were performed in the endoscopy suite and 8% were COVID positive or suspected. Most procedures reported the highest score in satisfaction (85%) with technical limitations reported in 15% (predominately related to scope suction or inadequate image quality) reverting to a reusable scope in 2.8 %. CONCLUSION: In our subset of patients in a bronchoscopy unit, SUFBs are safe, and both routine and advanced bronchoscopy procedures can be performed with high satisfaction reported.

Endobronchial Balloon Blockers: A Retrospective Analysis of Their Implementation for Use in Transbronchial Cryobiopsy Under Conscious Sedation.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is a promising technique that is evolving as a standard diagnostic procedure in the diagnosis of interstitial lung disease. However, there are a variety of non-standardised techniques adopted for this procedure. We aim to describe our approach to TBLC with balloon blockade under conscious sedation (CS). METHODS: We performed a retrospective analysis of patients undergoing TBLC using flexible bronchoscopy under CS in our institution over the calendar years 2017-2018; before and after a transition to the use of endobronchial balloon blockers (EBB) in 2017. RESULTS: 25 patients underwent transbronchial cryobiopsy during the study period. Of these; 12 procedures used EBB. EBB subjects had significantly less moderate or severe airway bleeding (8.3% vs 38.5%) despite higher biopsy rates in the EBB group, 2.9 (2-4) vs 2.4 (1-4) in the non-EBB group. No severe airway bleeding occurred in the EBB group. A multidisciplinary meeting (MDM) confirmed diagnosis was achieved in 88% of patients. 10/12 subjects (83%) in the EBB group and 12/13 subjects (92%) in the non-EBB group (p = 0.5). CONCLUSION: Our institution is novel in using EBB as standard during TBLC specifically under CS with flexible bronchoscopy in the bronchoscopy suite. This retrospective analysis demonstrates that EBB enhances the safety profile of performing TBLC under CS and did not appear to impact diagnostic yield or patient safety.

Statins versus placebo for people with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable respiratory disease. COPD exacerbations are associated with worse quality of life, increased hospitalisations, and increased mortality. Currently available pharmacological interventions have variable impact on exacerbation frequency. The anti-inflammatory effects of statins may lead to decreased pulmonary and systemic inflammation, resulting in fewer exacerbations of COPD. Several observational studies have shown potential benefits of statins for patients with COPD. OBJECTIVES: This review aims to evaluate available evidence on benefits and harms associated with statin therapy compared with placebo as adjunct therapy for patients with COPD. Primary objectives include the following.• To determine whether statins reduce mortality rates in COPD.• To determine whether statins reduce exacerbation frequency, improve quality of life, or improve lung function in COPD.• To determine whether statins are associated with adverse effects. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted the most recent search on 20 May 2019. SELECTION CRITERIA: Parallel, randomised controlled trials recruiting adults with COPD. DATA COLLECTION AND ANALYSIS: We used standard methods as expected by Cochrane. Prespecified primary outcomes were number of exacerbations, all-cause mortality, and COPD-specific mortality. MAIN RESULTS: Eight studies including 1323 participants with COPD were included in the review. Participants had a mean age of 61.4 to 72 years, and most were male (median 73.4%). Mean baseline forced expiratory volume in one second (FEV1) ranged from 41% to 90% predicted. All studies compared moderate- or high-intensity statin therapy versus placebo. The duration of treatment ranged from 12 weeks to 36 months.We found no statistically significant difference between statins and placebo in our primary outcome of number of exacerbations per person-year (mean difference (MD) -0.03, 95% confidence interval (CI) -0.25 to 0.19, 1 trial, 877 participants), including number of exacerbations requiring hospitalisation per person-year (MD 0.00, 95% CI -0.10 to 0.10, 1 trial, 877 exacerbations). This evidence was of moderate quality after downgrading for unclear risk of bias. Our primary outcomes of all-cause mortality (odds ratio (OR) 1.03, 95% CI 0.61 to 1.74, 2 trials, 952 participants) and COPD-specific mortality (OR 1.25, 95% CI 0.38 to 4.13, 1 trial, 877 participants) showed no significant difference between statins and placebo, with wide confidence intervals suggesting uncertainty about the precision of the results. This evidence was of low quality after downgrading for unclear risk of bias and imprecision.Results of the secondary outcomes analysis showed no clear differences between statins and placebo for FEV1 (% predicted) (MD 1.18, 95% CI -2.6 to 4.97, 6 trials, 325 participants) but did show a statistically significant improvement in FEV1/forced vital capacity (FVC) (MD 2.66, 95% CI 0.12 to 5.2; P = 0.04; 6 trials, 325 participants). A sensitivity analysis excluding two trials at high risk of bias showed no statistically significant difference in FEV1/FVC (MD 2.05, 95% CI -0.87 to -4.97; P = 0.17; 4 trials, 255 participants). We also found no significant differences between the two groups in functional capacity measured by six-minute walk distance in metres (MD 1.79, 95% CI -52.51 to 56.09, 3 trials, 71 participants), with wide confidence intervals suggesting uncertainty about the precision of the results. Results show no clear difference in quality of life, which was reported in three trials, and a slight reduction in C-reactive protein (CRP) in the intervention group, which was statistically significant (MD -1.03, 95% CI -1.95 to -0.11; I² = 0%, P = 0.03; 3 trials, 142 participants). We noted a significant reduction in interleukin (IL)-6 in the intervention group (MD -2.11, 95% CI -2.65 to -1.56; I² = 0%, P ≤ 0.00001; 2 trials, 125 participants). All trials mentioned adverse events and indicated that statins were generally well tolerated. One study reported adverse events in detail and indicated that rates of all non-fatal adverse events (the number of serious adverse events per person-year) were similar in both groups (0.63 ± 1.56 events (intervention group) and 0.62 ± 1.48 events (control group); P > 0.20) for all comparisons, except for non-fatal serious adverse events involving the gastrointestinal tract, which were more frequent in the intervention group (in 30 patients (0.05 events per person-year) vs 17 patients (0.02 events per person-year); P = 0.02). Another trial lists the total numbers and percentages of adverse events in the intervention group (12 (26%)) and in the control group (21 (43%)) and of serious adverse events in the intervention group (4 (9%)) and in the control group (3 (6%)).The other trials stated that researchers found no significant adverse effects of statins but did not report adverse events in detail. AUTHORS' CONCLUSIONS: A small number of trials providing low- or moderate-quality evidence were suitable for inclusion in this review. They showed that use of statins resulted in a reduction in CRP and IL-6, but that this did not translate into clear clinical benefit for people with COPD. Further randomised controlled trials are needed to explore this topic.

Tissue and Bronchoalveolar Lavage Biomarkers in Idiopathic Pulmonary Fibrosis Patients on Pirfenidone.

BACKGROUND: Pirfenidone is a novel anti-fibrotic agent in idiopathic pulmonary fibrosis with proven clinical benefit. Better human tissue models to demonstrate the immunomodulatory and anti-fibrotic effect of pirfenidone are required. OBJECTIVES: The purpose of the study was to use transbronchial lung cryobiopsy (TBLC), a novel technique which provides substantial tissue samples, and a large panel of biomarkers to temporally assess disease activity and response to pirfenidone therapy. METHODS: Thirteen patients with confirmed idiopathic pulmonary fibrosis (IPF) underwent full physiological and radiological assessment at diagnosis and after 6-month pirfenidone therapy. They underwent assessment for a wide range of potential serum and bronchoalveolar lavage biomarkers of disease activity. Finally, they underwent TBLC before and after treatment. Tissue samples were assessed for numbers of fibroblast foci, for Ki-67, a marker of tissue proliferation and caspase-3, a marker of tissue apoptosis. RESULTS: All patients completed treatment and investigations without significant incident. There was no significant fall in number of fibroblast foci per unit tissue volume after treatment (pre-treatment: 0.14/mm2 vs. post-treatment 0.08/mm2, p = 0.1). Likewise, there was no significant change in other markers of tissue proliferation, Ki-67 or Caspase-3 with pirfenidone treatment. We found an increase in three bronchoalveolar lavage angiogenesis cytokines, Placental Growth Factor, Vascular Endothelial Growth Factor-A, and basic Fibroblast Growth Factor, two anti-inflammatory cytokines Interleukin-10 and Interleukin-4 and Surfactant Protein-D. CONCLUSIONS: TBLC offers a unique opportunity to potentially assess the course of disease activity and response to novel anti-fibrotic activity in IPF.

Nebulized hypertonic saline via positive expiratory pressure versus via jet nebulizer in patients with severe cystic fibrosis.

BACKGROUND: Nebulized hypertonic saline is a highly effective therapy for patients with cystic fibrosis (CF), yet 10% of patients are intolerant of hypertonic saline administered via jet nebulizer. Positive expiratory pressure (PEP) nebulizers splint open the airways and offers a more controlled rate of nebulization. METHODS: In 4 consecutive adult CF patients who were intolerant of hypertonic saline via jet nebulizer, we nebulized 6% hypertonic saline via a PEP nebulizer. We measured the number of days the patients required intravenous antibiotics from enrollment to study end, compared to an equal period before PEP, and the mean time between the patients' 3 most recent infective pulmonary exacerbation episodes before PEP to their next exacerbation after PEP. Patients also completed a Likert-scale adverse-effects questionnaire on hypertonic saline via PEP versus jet nebulizer. RESULTS: The 4 patients had severe CF pulmonary disease and all fully tolerated hypertonic saline via PEP, for 77, 92, 128, and 137 days, respectively until the study end date. There were fewer days of antibiotics in 3 of the 4 patients, from 45 to 20 days, 66 to 14 days, and 28 to 0 days (mean relative risk reduction 53%, P = .11). The other patient had 63 days of antibiotics during both the PEP and the jet nebulizer periods. There was a mean 3.6-fold longer time to next infective pulmonary exacerbation during the PEP period (P = .07). Adverse effects were less with PEP: chest tightness 68% (P = .04), bad taste 62% (P = .06), cough 47% (P = .10), and sore throat 50% (P = .20). CONCLUSIONS: Hypertonic saline via PEP nebulizer benefits CF patients who do not tolerate hypertonic saline via jet nebulizer.

Transbronchial lung cryobiopsy (TBLC) in the diagnosis of interstitial lung disease: experience of first 100 cases performed under conscious sedation with flexible bronchoscope.

BACKGROUND: Diagnosing the aetiology of interstitial lung disease (ILD) may require histology via a surgical lung biopsy (SLB). SLB is associated with significant complications. Transbronchial lung cryobiopsy (TBLC) can provide large, adequate biopsies with fewer complications offering a potential alternative to SLB. AIMS: This study evaluated the safety, diagnostic yield and impact of TBLC on diagnostic certainty in the multidisciplinary diagnosis (MDD) of ILD within routine clinical practice. METHODS: A retrospective study of all TBLC performed in a tertiary institute from March 2014 to December 2016 was performed. Procedures were performed using a flexible bronchoscope and cryoprobe without fluoroscopic guidance. RESULTS: One hundred procedures were performed on 85 patients. A total of 272 cryobiopsies were obtained with a mean biopsy diameter of 5.9 ± 3.2 mm. Ninety-seven percent contained alveolated lung tissue. Diagnosis based against MDD gold standard was confirmed using TBLC in 67.1% of patients and in 72/100 procedures. Three patients proceeded to SLB. The addition of histological information changed the clinic-radiological diagnosis in twelve patients. The most common diagnosis based on clinical-radiologic-pathologic correlation at MDD was idiopathic pulmonary fibrosis (IPF) (51.2%) and hypersensitivity pneumonitis (15.9%). Moderate bleeding occurred in 18% of cases and five patients (5%) developed pneumothorax requiring intervention. Eleven patients required admission, with a mean length of stay of 1.3 ± 0.9 days. CONCLUSION: TBLC aids the diagnosis of ILD in the appropriate patient and may be an acceptable alternative to SLB with fewer complications. Further work on standardizing the procedure is required.

Disease Behaviour During the Peri-Diagnostic Period in Patients with Suspected Interstitial Lung Disease: The STARLINER Study.

INTRODUCTION: Disease behaviour may guide diagnosis and treatment decisions in patients with interstitial lung disease (ILD). STARLINER aimed to characterise disease behaviour in patients with suspected ILD during the peri-diagnostic period using real-time home-based assessments. METHODS: STARLINER (NCT03261037) was an international, multicentre study. Patients ≥ 50 years old with suspected ILD were followed throughout the peri-diagnostic period, consisting of a pre-diagnostic period (from enrolment to diagnosis) and a post-diagnostic period (from diagnosis to treatment initiation). Study length was variable (≤ 18 months). The primary endpoint was time-adjusted semi-annual forced vital capacity (FVC) change measured during the peri-diagnostic period using daily home spirometry in patients with idiopathic pulmonary fibrosis (IPF). Secondary outcomes included changes in FVC (home spirometry) in patients with non-IPF ILD, changes in FVC (site spirometry), changes in physical functional capacity measured by daily home accelerometry and site 6-min walk distance (6MWD), and changes in patient-reported outcomes (PROs) in IPF or non-IPF ILD. RESULTS: Of the 178 patients enrolled in the study, 68 patients were diagnosed with IPF, 62 patients were diagnosed with non-IPF ILD, 9 patients received a non-ILD diagnosis and 39 patients did not receive a diagnosis. Technical and analytical issues led to problems in applying the prespecified linear regression model to analyse the home FVC data. Time-adjusted median (quartile [Q]1, Q3) semi-annual FVC change during the peri-diagnostic period measured using home and site spirometry, respectively, was - 147.7 (- 723.8, 376.2) ml and - 149.0 (- 314.6, 163.9) ml for IPF and 19.1 (- 194.9, 519.0) ml and - 23.4 (- 117.9, 133.5) ml in non-IPF ILD. A greater decline in steps per day was observed for IPF versus non-IPF ILD, whereas an increase in 6MWD was observed for patients with IPF versus a decline in 6MWD for patients with non-IPF ILD. No clear patterns of disease behaviour were observed for IPF versus non-IPF ILD for PROs. CONCLUSIONS: Despite home spirometry being feasible for most patients and centres, technical and analytical challenges in the home-based assessments prevented firm conclusions regarding disease behaviour. This highlights that further optimisation of the technology and analysis methods is required before widespread implementation. TRIAL REGISTRATION: NCT03261037.

Hyponatremia and hypercalcemia: a study of a large cohort of patients with lung cancer.

BACKGROUND: Hyponatremia and hypercalcemia are reported to be associated with poorer prognosis in lung cancer. Our study assessed the incidence of hyponatremia and hypercalcemia in a recent large cohort of patients diagnosed with lung cancer in an academic institution and correlated incidence with patient and tumour parameters. METHODS: All patients presented at our regional lung cancer multidisciplinary team meeting between January 2011 and December 2016 were included. The incidence of hyponatremia (serum sodium ≤135 mEq/L) and hypercalcemia (serum calcium >2.62 mmol/L), including severity (mild, moderate or severe) was evaluated and stratified by tumour subtype and stage, and correlated with patient parameters. RESULTS: A total of 624 patients (mean age, 67.4 years; 59.3% male) diagnosed with tissue-proven lung cancer were included. Hyponatremia and hypercalcemia were present in 31.6% (n=197) and 7.1% (n=44) at time of diagnosis. Hyponatremia occurred most commonly in patients with small cell lung carcinoma (SCLC) (n=42; 41.2%; P=0.001). Hypercalcemia occurred most commonly in patients with non-small cell lung carcinoma (NSCLC) squamous subtype (n=27; 12.2%; P=0.003). The incidence of hyponatremia and hypercalcemia were significantly higher in the advanced stages (P<0.041), except in SCLC where no difference in hypercalcemia incidence across the stages was observed (P=0.573). The Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was positively correlated with severity of hyponatremia at the early stage of NSCLC (Spearman correlation coefficient =0.325; P=0.003). CONCLUSIONS: Hyponatremia is a common association in lung cancer, especially in SCLC. Hypercalcemia is an uncommon but significant association in the NSCLC squamous subtype. Hyponatremia might contribute to poorer ECOG-PS scores at the early stage of NSCLC.

Lung cancer in young patients: tumour characteristics and treatment in an Irish population.

BACKGROUND: Lung cancer is the leading cause of cancer death in both sexes in Ireland. Studies suggest that lung cancer in younger patients has distinct characteristics. The aim of this study is to define the characteristics of lung cancer in patients 55-year-old or younger in an Irish population. METHODS: Data was collected retrospectively from local medical records and the hospital electronic database regarding all patients diagnosed with lung cancer aged 55-year-old and younger, from 2010-2016. Information regarding patient demographics, smoking status, tumour histology, molecular analysis, stage and location, diagnostic modality and initial treatment choice was collected. In all cases the diagnosis of lung cancer was confirmed at the regional lung cancer multidisciplinary team (MDT) meeting. RESULTS: In total, 8% (n=130) of all cases of lung cancer diagnosed from 2010 to 2016 in our center occurred in patients aged 55 years old or younger; 83% (n=108) were 45 to 55-year-old, 15% (n=19) were 35 to 44-year-old and 2% (n=3) were younger than 35-year-old; 88% (n=115) of patients reported a smoking history. There was a female preponderance (58%, n=76), higher rates of NSCLC non-squamous subtype (53%, n=69) and an upper lobe predominance (42%, n=54); 53% (n=68) of patients had IV or extensive disease at presentation. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and Kirsten rat sarcoma oncogene (KRAS) mutation rates were 9% (n=4) and 3% (n=1) and 80% (n=4) respectively. CONCLUSIONS: Lung cancer in younger patients has distinct characteristics. This study suggests a female preponderance, high smoking rates and a predilection for the upper lobes. Further large-scale multicenter studies are required to verify these results and to clarify the responsible mechanisms.

Design of a Study Assessing Disease Behaviour During the Peri-Diagnostic Period in Patients with Interstitial Lung Disease: The STARLINER Study.

BACKGROUND/OBJECTIVES: This study will aim to characterise disease behaviour during the peri-diagnostic period in patients with suspected interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF), using daily home spirometry and accelerometry. Additionally, this study will aim to increase collaboration between secondary and tertiary centres using a digital collaboration platform. METHODS: The STARLINER study (NCT03261037) will enrol approximately 180 symptomatic patients aged 50 years or more with radiological evidence of ILD/IPF from community and tertiary centres in Canada and Europe. Approximately two-thirds of sites will be community centres. Patients will be followed during pre-diagnosis (inclusion to diagnosis; up to a maximum of 12 months) and post-diagnosis (diagnosis to treatment initiation; up to a maximum of 6 months). The study will be facilitated by a digital ecosystem consisting of the devices used for home-based assessments and a digital collaboration platform enabling communication between community and tertiary centres, and between clinicians and patients. PLANNED OUTCOMES: The primary endpoint will be time-adjusted semi-annual change in forced vital capacity (FVC; in millilitres) during the peri-diagnostic period. Physical functional capacity and patient-reported outcomes (PROs) will also be assessed. FVC and physical functional capacity will be measured using daily home spirometry and accelerometry, and at site visits using spirometry and the 6-min walk test. PROs will be assessed prior to, or during, site visits and will always be completed in the same order. CONCLUSIONS: Findings from this study may help to facilitate the early and accurate diagnosis of ILDs by increasing knowledge about disease progression, enabling collaboration between community and tertiary centres and improving communication between clinicians and patients. TRIAL REGISTRATION NUMBER: NCT03261037. FUNDING: F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Plain language summary available for this article.

Bronchoscopy in the investigation of outpatients with hemoptysis at a lung cancer clinic.

BACKGROUND: In the investigation of lung cancer, current practice in many healthcare systems would support bronchoscopy regardless of CT findings in patients with hemoptysis. We sought to identify the cause, the diagnostic yield of CT and bronchoscopy and the requirement for bronchoscopy in at risk patients with hemoptysis with a normal CT scan through our rapid access lung cancer clinic (RALC). METHODS: Initially, a chart review was performed on all patients with hemoptysis (2011-2012) and thereafter a prospective analysis was performed (2013-2016). RESULTS: Our analysis represents the largest study to date in outpatients with hemoptysis. In our retrospective study, 155 patients reported hemoptysis. Causes were lower respiratory tract infections (RTIs) (47%) and lung cancer (16%). Our prospective study included 182 patients. The causes of hemoptysis were RTIs (50%) and lung cancer (18%). There were no false negative CT-scans for lung cancer. 47/57 present with lung cancer underwent bronchoscopy and 43/47 were positive for lung cancer (92%). Patients with hemoptysis and lung cancer have a higher stage of malignancy with a predominance of squamous cell lung carcinoma. Smoking status, the duration of hemoptysis or description of hemoptysis were not predictive of lung cancer however lung cancer was not identified in patients age <50. CONCLUSIONS: One sixth of patients presenting with hemoptysis to our lung cancer clinic had lung cancer. No patient identified with cancer related haemoptysis had a CT negative for lung cancer and a combination of bronchoscopy plus endobronchial ultrasound trans-bronchial needle aspiration (EBUS-TBNA) in those patients with a CT suspicious of lung cancer is 92% sensitive for lung cancer causing hemoptysis.

Investigating Idiopathic Inflammatory Myopathy; Initial Cross Speciality Experience with Use of the Extended Myositis Antibody Panel.

The discovery of unique autoantibodies has informed and altered our approach to the diagnosis and management of the inflammatory myopathies. This study reports the initial clinical experience of use of the Extended Myositis Antibody (EMA) panel in the largest university teaching hospital in Ireland. We conducted a retrospective review of all patients who had serum samples tested for myositis specific antibodies and myositis associated antibodies from April 2014 to March 2015. A positive EMA panel was of significant clinical utility in facilitating decisions on appropriate investigations, and need for onward referral to other physicians. Furthermore, this paper highlights the diversity of possible presentations of idiopathic inflammatory myopathy with subsequent need for multi-speciality involvement, and serves to heighten awareness among clinicians of the diagnostic use of extended myositis antibody testing in these cases.

A randomized controlled trial to assess the optimal dose and effect of nebulized albuterol in acute exacerbations of COPD.

STUDY OBJECTIVES: Despite the widespread use of short-acting, inhaled beta(2)-agonists in acute exacerbations of COPD (AECOPDs), little is known about their optimal dose. The aims of this study are to compare the bronchodilator response to incremental doses of inhaled albuterol during and after recovery from an AECOPD, and to compare the effects of regular nebulized albuterol, 2.5 mg and 5 mg, on the speed of recovery. METHODS: Eighty-six patients admitted with an AECOPD were recruited. Each patient was administered incremental doses of inhaled albuterol on hospital admission and following recovery. Dose-response curves were constructed based on FEV(1) and peak expiratory flow rate (PEFR) recorded after each incremental dose. Patients were then randomized in a double-blind fashion to receive 2.5 mg or 5 mg of nebulized albuterol q4h until recovery. Twice-daily PEFR, the number of extra doses of bronchodilators, and side effects reported were recorded. RESULTS: Maximal bronchodilation (Emax) FEV(1) (maximal bronchodilatory response to albuterol) increased from 0.64 +/- 0.27 L/min during the exacerbation to 0.94 +/- 0.38 L/min during recovery (p < 0.001). The Emax PEFR increased from 147.53 +/- 62.46 L/min to 222.94 +/- 73.82 L/min after recovery (p = < 0.001). There was no significant difference in rate of recovery of PEFR (p = 0.684), duration of hospital stay (p = 0.084), or side effects (p = 0.506) between the groups receiving 2.5 mg or 5 mg of nebulized albuterol. CONCLUSIONS: There was significant improvement in Emax to inhaled albuterol as the COPD exacerbation resolved. There was no significant difference in outcomes including length of hospital stay or recovery of lung function between patients treated with regular 2.5 mg vs 5 mg of nebulized albuterol during an AECOPD.

Efficacy and Safety of Rituximab in Connective Tissue Disease related Interstitial Lung Disease.

BACKGROUND: Pulmonary complications of connective tissue disease are being identified more frequently with the advent of more sophisticated radiological investigations. Limited previous studies have suggested Rituximab (RTX), a chimeric monoclonal antibody with activity against CD-20, may benefit connective tissue disease patients with pulmonary complications. We performed a retrospective analysis of the efficacy and safety of RTX in patients attending a tertiary referral centre. METHODS: Ten patients treated with RTX for pulmonary complications of CTD in our institution were identified. Baseline demographics, pre- and post-treatment investigations and adverse events were documented with an average follow up time-frame of 12.3 months (range: 3 - 27). Statistical analysis was performed using the Wilcoxan Signed-Rank test in SPSS. RESULTS: There was a statistically significant improvement in pulmonary function, with a mean increase of 19% in DLCO (median DLCO (ml/min/mmHg) pre-treatment vs. post-treatment: 13.94 vs. 19.34, p=0.028) and a mean increase of 13% in FVC (median FVC (L) pre-treatment vs. post-treatment: 3.47 vs.3.6, p=0.28). For patients with pulmonary fibrosis (n=7), CT severity was improved on post-treatment scan, though this did not reach statistical significance. There was a reduction in the number of nodules seen on the follow-up scans of two patients without fibrosis. No patient had a severe adverse reaction to RTX. CONCLUSIONS: Treatment with RTX resulted in an objective, measurable improvement in pulmonary function and/or radiological severity for the majority of patients included in the series. This was statistically significant despite the small numbers included. These results indicate a positive response to RTX with few complications of treatment.

Biomarkers to identify ILD and predict lung function decline in scleroderma lung disease or idiopathic pulmonary fibrosis.

BACKGROUND: SSc-ILD and IPF demonstrate significant morbidity and mortality. Predicting disease progression is challenging in both diseases. OBJECTIVES: We sought a serum biomarker that could identify patients with SSc-ILD or IPF and prospectively predict short-term decline in lung function in these patients. METHODS: 10 healthy controls, 5 SSc w/o ILD, 6 SSc-ILD and 13 IPF patients underwent venesection. An array of cytokines including KL-6, SP-D and MMP7 were measured. PFTs were obtained at baseline and six months. Cytokine measurements were correlated with PFTs. RESULTS: KL-6 in IPF patients (633 ng/ml, IQR 492-1675) was significantly elevated compared to controls (198 ng/ml, IQR 52-360, p<0.01) and SSc w/o ILD patients (192 ng/ml, IQR 0-524, p<0.05); KL-6 in SSc-ILD patients (836 ng/ml, IQR 431-1303) was significantly higher than in controls (p<0.05). SP-D was significantly higher in IPF patients (542 ng/ml, IQR 305-577) compared to controls (137 ng/ml, IQR 97-284, p<0.01) or to SSc w/o ILD patients (169 ng/ml, IQR 137-219, p<0.05). In comparison with controls (0.0 ng/ml, IQR 0.0-0.6), MMP7 was significantly higher in both IPF patients (2.85 ng/ml, IQR 1.5-3.6, p<0.05) and SSc-ILD patients (5.41 ng/ml, IQR 2.6-7.2, p<0.001). Using a cut-off level of 459ng/ml for KL-6 and of 1.28 ng/ml for MMP7, 18 out of 19 patients with ILD had a serum value of either KL-6 or MMP7 above these thresholds. For all ILD patients, baseline serum SP-D correlated with ΔFVC %pred over six months (r=-0.63, p=0.005, 95% CI -0.85 to -0.24). CONCLUSIONS: Combining KL-6 with MMP7 may be a useful screening tool for patients at risk of ILD. SP-D may predict short-term decline in lung function.

A comparison of standard and novel bronchoscopic endobronchial biopsy retrieval methods.

BACKGROUND: The targets of bronchoscopic biopsy now include not only adequate tissue for histologic diagnosis but also tissue for further analysis. We prospectively compared standard and novel bronchoscopic endobronchial biopsy (EBB) retrieval methods attempting to increase tissue yield. METHODS: EBB samples were retrieved using techniques A, B, and C using a standard forceps. Method A is routinely performed conventional method, where as in method B, biopsy forceps was left protruded from the bronchoscope and in method C, both valve and forceps were removed to prevent the loss of specimen. At least 6 EBB were retrieved per patient. Results were compared with gold standard composite of confirmatory pathological or clinic-radiologic follow up. RESULTS: A total of 42 of 43 patients completed the study. The final gold standard diagnosis was cancer [non-small cell lung cancer, metastatic, carcinoid, carcinoma in situ (24)], benign disease [sarcoid, amyloid, hamartoma, and chondroid tumor (4)], and benign/nonspecific inflammation (14). EBB retrieved using standard method A were smaller than novel methods B and C (P=0.03). However, the percentage of cases where blood was the predominant component (>50%) was less by standard methods A (4/42) than B (16/42) and C (20/42) (P=0.001). There was no difference in mean viable tumor area (n=23, sensitivity for EBB for cancer 96%) between groups A compared with B and C (P 0.27) and adequacy in benign cases by subepithelial depth (>0.3 mm) (P=0.38). CONCLUSION: Standard retrieval of endobronchial biopsies through the bronchoscope and cap does not reduce the size of viable tissue and reduces contaminating blood and necrotic material.

Communication of unexpected and significant findings on chest radiographs with an automated PACS alert system.

PURPOSE: An integral part of realizing the enormous potential of imaging in patient care is close communication between radiologists and referring physicians. One key element of this process is the communication of unexpected significant findings. The authors examined the performance of a PACS-based alert system in the appropriate communication of reports containing unexpected significant findings to referring physicians. METHODS: A PACS-integrated key word system was developed such that an e-mail was sent to the referring clinician if a radiologist detected a significant unexpected finding. The number, source, and outcome of chest radiographic unexpected findings over a 14-month period were analyzed. The time for response of the referring physician plus time for follow-up were also examined. RESULTS: Key words were applied to 158 of the 39,665 chest radiographs (0.4%) obtained during the study period. The emergency department was the most frequent referral location (46.2%). Final diagnostic categories included malignancy (13.9%), benign lesion (49.4%), and no abnormality (20.2%). The average time to acknowledgment by clinicians of notification was 3.1 days, although 57.6% were acknowledged within 24 hours. The mean time interval to the next relevant radiologic investigation was 26 days among the 77.8% of findings that underwent radiologic follow-up. CONCLUSIONS: The development of electronic alert systems, which are integrated into PACS, can aid greatly in report communication and eliminate the risk associated with unread reports that contain significant or unexpected findings.