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Background: Risks associated with video-assisted surgical lung biopsy (VASLB) for interstitial lung disease (ILD) with endotracheal intubation and mechanical ventilation are not nil. Awake video-assisted surgical lung biopsy (Awake-VASLB) has been proposed as a method to obtain a precise diagnosis in several different thoracic diseases., Objectives: To compare clinical outcomes of Awake-VASLB and Intubated-VASLB in patients with suspected ILDs., Methods: From June 2016 to February 2020, all patients submitted to elective VASLB for suspected ILD were included. Differences in outcomes between Awake-VASLB and Intubated-VASLB were assessed through univariable, multivariable-adjusted, and a propensity score-matched analysis., Results: Awake-VASLB was performed in 66 out of 100 patients, while 34 underwent Intubated-VASLB. The Awake-VASLB resulted in a lower post-operative morbidity (OR 0.025; 95% CI 0.001-0.35; p=0.006), less unexpected intensive care unit admission, less need for rescue therapy for pain, a reduced surgical and anaesthesiologic time, a reduced chest drain duration, and a lower post-operative length of stay., Conclusion: Awake-VASLB in patients affected by ILD is feasible and seems safer than Intubated-VASLB., Competing Interests: Conflict of interest: F. Guerrera has nothing to disclose. Conflict of interest: L. Costardi has nothing to disclose. Conflict of interest: G.L. Rosboch has nothing to disclose. Conflict of interest: P. Lyberis has nothing to disclose. Conflict of interest: E. Ceraolo has nothing to disclose. Conflict of interest: P. Solidoro has served as investigator in clinical trials, consultant or speaker for Alfasigma, AstraZeneca, Boehringer Ingelheim, GSK, Menarini, Novartis, Chiesi, Guidotti & Malesci and ABC Farmaceutici outside this work. Conflict of interest: C. Filippini has nothing to disclose. Conflict of interest: G. Verri has nothing to disclose. Conflict of interest: L. Brazzi has nothing to disclose. Conflict of interest: C. Albera has nothing to disclose regarding this work, but has served as investigator in clinical trials, consultant, speaker, steering committee or scientific advisory board member for Bayer, Boehringer Ingelheim, FibroGen, Gilead, Grifols, GSK, Roche, MSD, Sanofi Aventis outside this work. Conflict of interest: E. Ruffini has nothing to disclose., (Copyright ©The authors 2021.)

Real-world studies include a broader patient population for a longer duration than randomised controlled trials (RCTs) and can provide relevant insights for clinical practice. PASSPORT was a multicentre, prospective, post-authorisation study of patients who were newly prescribed pirfenidone and followed for 2 years after initiating treatment. Physicians collected data on adverse drug reactions (ADRs), serious ADRs (SADRs) and ADRs of special interest (ADRSI) at baseline and then every 3 months. Post hoc stepwise logistic regression models were used to identify baseline characteristics associated with discontinuing treatment due to an ADR. Patients (n=1009, 99.7% with idiopathic pulmonary fibrosis) had a median pirfenidone exposure of 442.0 days. Overall, 741 (73.4%) patients experienced ADRs, most commonly nausea (20.6%) and fatigue (18.5%). ADRs led to treatment discontinuation in 290 (28.7%) patients after a median of 99.5 days. Overall, 55 (5.5%) patients experienced SADRs, with a fatal outcome in six patients. ADRSI were reported in 693 patients, most commonly gastrointestinal symptoms (38.3%) and photosensitivity reactions/skin rashes (29.0%). Older age and female sex were associated with early treatment discontinuation due to an ADR. Findings were consistent with the known safety profile of pirfenidone, based on RCT data and other post-marketing experience, with no new safety signals observed., Competing Interests: Conflict of interest: V. Cottin has received consultancy and lectures fees, and support for travel to medical meetings from Actelion and Roche; has received personal fees for development of educational presentations, consultancy and lectures fees, and support for travel to medical meetings from Boehringer Ingelheim; has received consultancy fees from Bayer and Galapagos; has received personal fees from service on an adjudication committee from Gilead; consultancy fees from GlaxoSmithKline (in 2015) and MSD; has received consultancy and lecture fees from Novartis and Sanofi; is the chair of the data and safety monitoring board (DSMB) of Promedior; and serves on the DSMB of Celgene, all outside the submitted work. Conflict of interest: D. Koschel has received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Grifols, Novartis, Roche/Intermune, Sanofi-Aventis and Teva. Conflict of interest: A. Günther has received research funding from Sanofi, Inventiva and Roche; and consultancy or speaker fees from Boehringer Ingelheim, Roche and Teva. Conflict of interest: C. Albera has received fees from Roche (formerly InterMune), Boehringer Ingelheim, Fibrogen, MSD, GlaxoSmithKline, Bayer and Sanofi for activity as an advisor, consultant or steering committee member; he has also received unrestricted grants from Boehringer Ingelheim. Conflict of interest: A. Azuma has received personal fees from AFT Pharma, Boehringer Ingelheim, InterMune/Roche and Shionogi Co. Conflict of interest: C.M. Sköld has received research funding from Boehringer Ingelheim, Roche and Sandoz; and consultancy or speaker fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, InterMune, Meda, Mundipharma, Novartis, Roche, Sandoz and Vicore Pharma. Conflict of interest: S. Tomassetti has received speaker fees from Boehringer Ingelheim and Roche. Conflict of interest: P. Hormel is an employee of Roche-Genentech and holds shares in that company. Conflict of interest: J.L. Stauffer is an employee of Roche-Genentech and holds shares in that company. Conflict of interest: I. Strombom is an employee of Roche-Genentech and holds shares in that company. Conflict of interest: K-U. Kirchgaessler is an employee of Roche-Genentech and holds shares in that company. Conflict of interest: T.M. Maher has received industry academic research funding from GlaxoSmithKline R&D and UCB Pharma; and consultancy or speaker fees from Apellis, AstraZeneca, aTyr Pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, ProMetic, Roche (and previously InterMune), Sanumed and UCB Pharma.

Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com, (Copyright ©ERS 2017.)

This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage.Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC ≥80% versus <80% or GAP stage I versus II-III. Treatment-by-subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term.Patients with both more preserved (FVC ≥80% or GAP stage I) and less preserved (FVC <80% or GAP stage II-III) lung function at baseline demonstrated clinically significant disease progression at 12 months in terms of categorical decline in FVC, 6MWD and UCSD SOBQ. The magnitude of pirfenidone treatment effect was comparable between subgroups, regardless of whether lung function was classified using FVC or GAP index stage.These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population., (Copyright ©ERS 2016.)

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF., (Copyright ©ERS 2016.)

Sarcoidosis is characterised by non-caseating granulomas that secrete pro-inflammatory cytokines, including interleukin (IL)-12, IL-23, and tumour necrosis factor (TNF)-α. Ustekinumab and golimumab are monoclonal antibodies that specifically inhibit IL-12/IL-23 and TNF-α, respectively. Patients with chronic pulmonary sarcoidosis (lung group) and/or skin sarcoidosis (skin group) received either 180 mg ustekinumab at week 0 followed by 90 mg every 8 weeks, 200 mg golimumab at week 0 followed by 100 mg every 4 weeks, or placebo. Patients underwent corticosteroid tapering between weeks 16 and 28. The primary end-point was week 16 change in percentage predicted forced vital capacity (ΔFVC % pred) in the lung group. Major secondary end-points were: week 28 for ΔFVC % pred, 6-min walking distance, St George's Respiratory Questionnaire (lung group), and Skin Physician Global Assessment response (skin group). At week 16, no significant differences were observed in ΔFVC % pred with ustekinumab (-0.15, p = 0.13) or golimumab (1.15, p = 0.54) compared with placebo (2.02). At week 28, there were no significant improvements in the major secondary end-points, although a nonsignificant numerically greater Skin Physician Global Assessment response was observed following golimumab treatment (53%) when compared with the placebo (30%). Serious adverse events were similar in all treatment groups. Although treatment was well tolerated, neither ustekinumab nor golimumab demonstrated efficacy in pulmonary sarcoidosis. However, trends towards improvement were observed with golimumab in some dermatological end-points., (©ERS 2014.)

6-min walk distance (6MWD) has recently been shown to be associated with the risk of mortality in patients with idiopathic pulmonary fibrosis (IPF); however, the independent contribution of 6MWD to the prediction of mortality risk has not been evaluated in a large, well-defined population of patients with IPF. A Cox proportional hazards model was used to characterise the relationship between risk factors of interest and all-cause mortality in IPF patients who completed a week 24 study visit in a clinical trial evaluating interferon γ-1b (n=748). Risk factors of interest included the independent predictors of mortality in the previously published clinical prediction model together with 6MWD and 24-week change in 6MWD. Baseline 6MWD <250 m was associated with a two-fold increase in the risk of mortality (hazard ratio 2.12, 95% CI 1.15-3.92) and a 24-week decline in 6MWD >50 m was associated with a nearly three-fold increase in mortality risk (hazard ratio 2.73; 95% CI 1.60-4.66). Inclusion of 6MWD data improved model discrimination compared with the original model (C-statistic 0.80 (95% CI 0.76-0.85) versus 0.75 (0.71-0.79)). Both 6MWD and change in 6MWD are independent predictors of mortality in patients with IPF. The addition of 6MWD to the clinical prediction model improves model discrimination compared with the original model.

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias and is associated with both a variable clinical course and a poor prognosis. Investigators involved in clinical trials and clinicians reviewing the IPF literature are confronted with daunting challenges in selecting reliable outcome measures, interpreting the clinical and statistical importance of these findings, and applying this knowledge to the clinical care of their patients. In order to evaluate the efficacy of new treatment regimens, a number of studies have been performed, employing a range of clinical and surrogate end-points. In most studies, the primary end-point consists of a single outcome measure. A desirable single clinical end-point for IPF should be reliable, valid, responsive to changes in disease status, clinically meaningful, predictive of clinical outcome and responsive to treatment effect of a given intervention. Proper consideration and effective choice of outcome measures used in IPF studies will help establish effective and achievable drug development programmes and will enable clinicians and investigators to make informed critical decisions in recommending a treatment regimen to their IPF patients.

Tuberculosis (TB) serological testing with antigen complexes, although very sensitive, is not always as specific due to reactive serum antibodies in patients with inactive TB or nontuberculous infections. Since the use of recombinant M. tuberculosis proteins may enhance specificity, this study was designed to evaluate a novel 34 kDa tuberculosis complex-specific protein as a component of an antigen panel of recombinant proteins. Seventy patients with active TB (41 positive and 29 negative for acid-fast bacilli (AFB) in sputum) were evaluated, in comparison with 30 tuberculin purified protein derivative skin test positive (PPD+) and 30 PPD- normals, 20 subjects with inactive TB and 20 PPD+ subjects with nontuberculous pneumonia as controls. Serum antibody levels were quantified using enzyme linked immunosorbent assay (ELISA) tests with MS2-34, a fusion protein comprising the NH2-terminal 16 kDa of the 34 kDa protein, a recombinant 38 kDa protein (p38), and PPD. Using MS2-34 and p38 as an antigen panel in active TB patients yielded higher sensitivity and negative predictive value (sensitivity 86%; negative predictive value 91%) than using PPD (sensitivity 66%; negative predictive value 81%). Importantly, the MS2-34+p38 panel yielded a higher sensitivity (83%) than PPD (66%) in the subset of AFB- active TB patients. Thus, this novel protein increases sensitivity and specificity of serological testing for TB when used in panels of recombinant proteins.

To investigate the possible involvement of T-lymphocytes in the immunopathogenesis of idiopathic eosinophilic pneumonia (IEP), we have evaluated the phenotypic characteristics both of peripheral blood and alveolar lymphocytes in six patients with symptomatic IEP, and in 24 healthy nonsmokers as controls, by employing bronchoalveolar lavage (BAL), monoclonal antibodies, and flow-cytometry. In IEP, total and differential cell counts showed a mild alveolitis with an increase of eosinophil percentage and number; the alveolar lymphocyte count was also increased. In BAL, the total number both of CD4+ and CD8+ lymphocytes was significantly raised; CD4+ cells expressed early (CD25) activation antigens. The analysis of CD45R0, CD45RA and CD62L coexpression in IEP patients, when compared to healthy controls, revealed an accumulation of alveolar CD4+ cells showing phenotypic repertoire usually expressed by memory T-cells (CD45R0+, CD45RA-, CD62L-). CD8+ alveolar lymphocytes did not show any significant increase of activation antigen coexpression. Circulating lymphocytes were not significantly increased and showed only a significantly higher CD25 expression. These data suggest that a pivotal role is played by activated and memory CD4+ alveolar lymphocytes in IEP patients.

Pretreatment serum neuron specific enolase (NSE) and plasma bombesin/gastrin releasing peptide (BN/GRP) were measured in 92 lung cancer patients and 17 controls. The mean level of NSE (p less than 0.001) and BN/GRP (p less than 0.05) was significantly raised in patients with small cell lung cancer (SCLC, n = 62) compared to non-SCLC (n = 30) and controls. The mean concentration of NSE in extensive SCLC was significantly greater (p less than 0.005) than in limited stage but with a substantial overlap of values. Forty-seven out of 62 SCLC patients had at least one of the two markers raised (sensitivity 76%, specificity 83%), 44 had raised NSE (sensitivity 71%, specificity 89%) but only 24 had BN/GRP raised (sensitivity 42%, specificity 91%). At restaging, 16 of 19 patients with SCLC responsive to chemotherapy showed a significant fall of NSE; on the other hand, BN/GRP fell significantly in only 3 patients, remaining unchanged in the majority of responding patients. In conclusion, the combined determination of NSE and BN/GRP in SCLC, at diagnosis and during the follow-up, was not found to be superior to NSE determination alone.