Search

Background Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILAs are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. Research Question Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? Study Design and Methods Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. Results Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System “S-modifier” [which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of FVC and diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. Interpretation Guidance for identifying clinically relevant ILA, with subsequent referral and follow-up, was established. These results lay the foundation for developing practical guidance on managing patients with ILA.

Background Angiotensin peptides have been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Angiotensin modulators are used to treat arterial hypertension, a frequent comorbidity of IPF. This post hoc analysis evaluated associations of antihypertensive treatments with disease-related outcomes in IPF. Methods All patients randomized to placebo (n = 624) in the CAPACITY and ASCEND studies were categorized by antihypertensive treatment at baseline. Outcomes of disease progression (first occurrence of ≥ 10% absolute decline in % predicted FVC, ≥ 50-m decline in 6-min walk distance, or death) and all-cause mortality were assessed over 52 weeks. Results At baseline, 111 and 121 patients were receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), respectively; 392 were receiving neither. In multivariable analyses adjusted for differences in baseline characteristics compared with the non-ACEi/ARB group, ACEi treatment (hazard ratio [HR], 0.6 [95% CI, 0.4-0.9]; P = .026), but not ARB (HR, 0.9 [95% CI, 0.6-1.2]; P = .413), was associated with slower disease progression. Furthermore, the increase in all-cause mortality associated with cardiovascular disease was not observed in the ACEi group (HR, 1.1 [95% CI, 0.5-2.9]; P = .782), which presented a similar percentage of IPF-related mortality as the non-ACEi/ARB group (3.6% vs 3.6%). In contrast, patients in the ARB group had greater risk of all-cause mortality (HR, 2.5 [95% CI, 1.2-5.2]). These observations were validated in a pooled analysis that included patients from the INSPIRE trial. Conclusions Prospective clinical trials are needed to evaluate whether angiotensin modulators may be beneficial to clinical outcomes in IPF. Trial Registry ClinicalTrials.gov ; Nos.: NCT01366209 , NCT00287716 , NCT00287729 , NCT00075998 ; URL: www.clinicaltrials.gov ).

Fibrotic interstitial lung diseases (ILDs) have a high mortality rate with an unpredictable disease course and clinical features that frequently overlap. Recent data indicate important roles for genomics in the mechanisms underlying susceptibility and progression of pulmonary fibrosis. The impact of these genomic markers on pharmacotherapy and their contribution to outcomes is increasingly recognized. Interstitial lung abnormalities, frequently considered representative of early ILD, have been consistently associated with the MUC5B promoter polymorphism, a common gene variant. Other rare gene variant mutations, including TERT, TERC, SFTPC, and DKC1, may be present in patients with familial interstitial pneumonia and are frequently associated with a usual interstitial pneumonia pattern of fibrosis. The minor allele of the MUC5B rs35705950 genotype is prevalent in several sporadic forms of ILD, including idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. Gene mutations that characterize familial pulmonary fibrosis may be present in patients with connective tissue disease-related ILD, such as rheumatoid arthritis-ILD. Additionally, shorter telomere lengths and mutations in telomere biology-related genes have been demonstrated in both familial and sporadic ILD, with significant implications for disease progression, lung function, and survival. An improved understanding of the impact of genetic and genomic risk factors on disease progression would better guide personalized therapeutic choices in persons with fibrotic ILD.

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease. IPF is a complex disease, with environmental and genetic factors variably contributing to disease susceptibility and outcomes. A host of common gene variants with modest effect size impart disease risk in patients with sporadic IPF, while rare variants with large effect size influence disease risk in those with familial interstitial pneumonia. In this review, we highlight several common and rare variants underpinning IPF risk and call attention to recently published studies informing our understanding of this risk.

© 2016 Elsevier Ltd Background Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. Methods A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. Results Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. Conclusions A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function.

Introduction L’une des caracteristiques de la pathogenie de la fibrose pulmonaire idiopathique (FPI) est l’accumulation excessive de matrice extracellulaire (MEC) dans les poumons. La degradation de la MEC par les metalloproteinases (MMP) genere des fragments proteiques circulant librement (neo-epitopes). Les donnees de l’etude PROFILE ont suggere qu’une augmentation des taux de neo-epitopes sur 6 mois etait predictive de la progression de la maladie (declin absolu de la CVF ≥ 10 % de la valeur predite ou deces avant le mois 12) et que le taux de variation sur 3 mois etait predictif de la mortalite. Methodes INMARK ( NCT02788474 ) est un essai qui evalue l’effet du nintedanib sur les variations des biomarqueurs du renouvellement de la MEC chez les patients presentant une FPI et un declin limite de la CVF (CVF ≥ 80 % de la valeur predite). Au total, 347 patients dans 13 pays ont ete randomises pour recevoir le nintedanib 150 mg 2 fois/jour ou le placebo pendant 12 semaines, suivi d’une periode en ouvert ou tous les patients recevront le nintedanib pendant 40 semaines et d’une visite de suivi 4 semaines plus tard. Resultats Critere d’evaluation principal : taux de variation de la proteine C reactive serique degradee par les MMP-1/8 (CRPM) entre l’inclusion et la semaine 12. Criteres d’evaluation secondaires : taux de variation du collagene de type 3 serique degrade par la MMP-9 (C3M), du collagene de type 1 serique degrade par les MMP-2/9/13 (C1M) entre l’inclusion et la semaine 12, proportion de patients avec une progression de la maladie (declin absolu de la CVF C 10 % de la valeur predite ou deces) sur 52 semaines. L’association entre les variations de la CRPM, du C3M et du C1M sur 12 semaines et la progression de la maladie a la semaine 52 chez les patients recevant le placebo est evaluee afin de confirmer la valeur de ces biomarqueurs comme facteurs predictifs de la progression de la maladie. L’effet du nintedanib sur l’association entre les variations de la CRPM, du C3M et du C1M sur 12 semaines et la progression de la maladie a la semaine 52 est egalement etudie ( Fig. 1 ) Conclusion L’essai INMARK donne des indications sur l’association entre les variations des biomarqueurs du renouvellement de la MEC et la progression de la maladie et sur le fait de savoir si le traitement par le nintedanib a un effet sur le taux de variation de ces biomarqueurs chez les patients presentant une FPI et un declin limite de la CVF.

BACKGROUND The National Heart, Lung, and Blood Institute-sponsored IPF Clinical Research Network (IPFnet) studies enrolled subjects with idiopathic pulmonary fibrosis (IPF) to evaluate drug therapies in treatment trials. An adjudication committee (AC) provided a structured review of cases in which there was uncertainty or disagreement regarding diagnosis or clinical event classification. This article describes the diagnosis and adjudication processes. METHODS The diagnostic process was based on review of clinical data and high-resolution CT scans with central review of lung biopsies when available. The AC worked closely with the data coordinating center to obtain clinical, radiologic, and histologic data and to communicate with the clinical centers. The AC used a multidisciplinary discussion model with four clinicians, one radiologist, and one pathologist to adjudicate diagnosis and outcome measures. RESULTS The IPFnet trials screened 1,015 subjects; of these, 23 cases required review by the AC to establish eligibility. The most common diagnosis for exclusion was suspected chronic hypersensitivity pneumonitis. The AC reviewed 88 suspected acute exacerbations (AExs), 93 nonelective hospitalizations, and 16 cases of bleeding. Determination of AEx presented practical challenges to adjudicators, as necessary clinical data were often not collected, particularly when subjects were evaluated outside of the primary study site. CONCLUSIONS The IPFnet diagnostic process was generally efficient, but a multidisciplinary adjudication committee was critical to assure correct phenotype for study enrollment. The AC was key in adjudicating all adverse outcomes in two IPFnet studies terminated early because of safety issues. Future clinical trials in IPF should consider logistical and cost issues as they incorporate AExs and hospitalizations as outcome measures. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov

Summary Background The role of the lung microbiome in the pathogenesis of idiopathic pulmonary fibrosis is unknown. We investigated whether unique microbial signatures were associated with progression of idiopathic pulmonary fibrosis. Methods Patients (aged 35–80 years) with idiopathic pulmonary fibrosis within 4 years of diagnosis from the Correlating Outcomes with biochemical Markers to Estimate Time-progression (COMET) in idiopathic pulmonary fibrosis study were followed up for a maximum of 80 weeks. Progression-free survival was defined as time to death, acute exacerbation, lung transplant, or decrease in forced vital capacity (FVC) of 10% or greater or decrease in diffusion capacity of the lung (DLCO) of 15% or greater. DNA was isolated from 55 samples of bronchoscopic alveolar lavage. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) to bacteria based on a 3% sequence divergence. Adjusted Cox models were used to identify OTUs that were significantly associated with progression-free survival at a p Findings Mean FVC was 70·1% (SD 17·0) and DLCO 42·3% (14·0) of predicted. Disease progression was significantly associated with increased relative abundance of two OTUs— Streptococcus OTU 1345 (relative risk 1·11, 95% CI 1·04–1·18; p=0·0009) and Staphylococcus OTU 1348 (1·16, 1·03–1·31, p=0·012). Thresholds for relative abundance of each OTU associated with progression-free survival were more than 3·9% for Streptococcus OTU 1345 (10·19, 2·94–35·35; p=0·0002) and more than 1·8% for Staphylococcus OTU 1348 (5·06, 1·71–14·93; p=0·003). Interpretation These preliminary data suggest progression of idiopathic pulmonary fibrosis is associated with the presence of specific members within the Staphylococcus and Streptococcus genera. Additional research will be needed to identify the specific bacterial species and to ascertain whether this is a causal association. Funding National Institutes of Health.

Introduction Le nintedanib est un inhibiteur intracellulaire de tyrosines kinases (TKI). La classe des TKI peut etre associee a un risque accru d’evenements thromboemboliques arteriels. L’efficacite et la securite d’un traitement de 52 semaines (S52) par nintedanib versus placebo chez des patients atteints de FPI ont ete evaluees lors de l’essai de phase II TOMORROW et des essais de phase III INPULSIS. Les patients ayant eu un infarctus du myocarde (IDM) au cours des 6 mois precedents, un angor instable au cours du mois precedent, ou un accident vasculaire cerebral (AVC) au cours de l’annee precedente ont ete exclus de ces essais. Nous avons evalue l’effet du risque CV initial sur la securite CV du nintedanib a la dose de 150 mg deux fois par jour (bid). Methodes Analyse des taux d’incidence des evenements cardiovasculaires majeurs (ECVM*) a l’aide des donnees groupees des essais TOMORROW et INPULSIS chez les patients avec antecedents de cardiopathie atherosclereuse et/ou ≥ 1 facteur de risque (FDR) CV** a l’inclusion (risque CV plus eleve) vs les patients sans antecedents de cardiopathie atherosclereuse et sans FDR CV a l’inclusion (risque CV plus faible). Resultats A l’inclusion, 1107 (89,9 %) patients (656 sous nintedanib, 451 sous placebo) avaient un risque CV plus eleve et 124 (10,1 %) patients (67 sous nintedanib, 57 sous placebo) avaient un risque CV plus faible. Chez les patients a risque CV plus eleve, les taux d’incidence (IC a 95 %) d’ECVM etaient de 3,88 (2,58, 5,84) et de 3,49 (2,10, 5,79) pour 100 patients–annee dans les groupes nintedanib et placebo, respectivement ( Tableau 1 ). Chez les patients a risque CV plus faible, les taux d’incidence (IC a 95 %) d’ECVM etaient de 4,78 (1,54, 14,82) et 5,37 (1,73, 16,65) pour 100 patients–annee dans les groupes nintedanib et placebo, respectivement ( Tableau 1 ). Conclusion Dans les donnees groupees des essais TOMORROW et INPULSIS, l’incidence des ECVM etaient similaires entre les groupes nintedanib et placebo aussi bien chez les patients ayant un risque CV initial plus eleve (qui representaient 90 % des patients de ces essais) que chez les patients ayant un risque CV initial plus faible.

Summary Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF. Methods First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p −8 ) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes. Findings In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [ r 2 =0·07], rs5743894 [ r 2 =0·16], and rs5743890 [ r 2 =0·01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1·72 [95% CI 1·24–2·38]; p=0·0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0·097), 40% in those with the minor allele of rs111521887 (p=3·0 × 10 −4 ), and 50% in those with the minor allele of rs5743894 (p=2·93 × 10 −5 ) compared with homozygous carriers of common alleles for these SNPs. Interpretation Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP , rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease. Funding National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.

SummaryBackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that often causes disabling dyspnea. In IPF and other lung diseases, patient-reported outcomes (PROs)—questionnaires designed to gather information from the patient's perspective—can determine whether therapies affect dyspnea or other outcomes meaningful to patients. Before a PRO can be used confidently as an outcome measure in a longitudinal trial, studies must demonstrate the PRO's ability to capture change over time in the target population. Our goal in this study was to examine whether the UCSD Shortness of Breath Questionnaire does so in patients with IPF.MethodsWe used data from the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP-IPF) to perform analyses that examined associations between UCSD scores and five external measures (anchors) at baseline and over time. Anchors included the Activity domain from St. George's Respiratory Questionnaire (SGRQ-A), the Physical Functioning domain from the SF-36 (SF36-PF), forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and distance walked during a timed walk test (6MWD). Linear regression models were used to examine relationships between UCSD scores and anchors over time.ResultsAt baseline, UCSD scores were weakly correlated with percent predicted FVC (−0.21, p = 0.005) and percent predicted DLCO (−0.20, p = 0.008), moderately correlated with 6MWD (−0.39, p

Background Patients with interstitial lung disease (ILD) may have features of an autoimmune disorder that do not meet the diagnostic criteria for connective tissue diseases. We determined the prevalence and characteristics of autoimmune-featured ILD (AIF-ILD) and compared these with those of idiopathic pulmonary fibrosis (IPF) and known connective tissue disease-related ILD (CTD-ILD). Methods Patients with ILD who did not meet the criteria for a connective tissue disease were defined as having AIF-ILD if they had a sign or symptom suggestive of a connective tissue disease and a serologic test reflective of an autoimmune process. Clinical characteristics, high-resolution CT images, and lung biopsy specimens were analyzed and compared with those of patients with IPF and CTD-ILD. Survival was evaluated using a Kaplan-Meier curve. Results Two hundred subjects completed the questionnaire and serologic testing. AIF-ILD was identified in 32%, IPF in 29%, and CTD-ILD in 19%. Gender, age, and race differed among groups (P Conclusions Systematic evaluation of symptoms and serologic tests in ILD can identify AIF-ILD. A UIP pattern on CT images and histopathology is common in AIF-ILD. Although survival for patients with AIF-ILD is poor, ANA titers ≥ 1:1280 are associated with improved survival.