Incident Idiopathic Pulmonary Fibrosis Research Articles

Cluster analysis of blood biomarkers to identify molecular patterns in pulmonary fibrosis: assessment of a multicentre, prospective, observational cohort with independent validation

Pulmonary fibrosis results from alveolar injury, leading to extracellular matrix remodelling and impaired lung function. This study aimed to classify patients with pulmonary fibrosis according to blood biomarkers to differentiate distinct disease patterns, known as endotypes. In this cluster analysis, we first classified patients from the PROFILE study, a multicentre, prospective, observational cohort of individuals with incident idiopathic pulmonary fibrosis or non-specific interstitial pneumonia in the UK (Nottingham University Hospitals, Nottingham; and Royal Brompton Hospital, London). 13 blood biomarkers representing extracellular matrix remodelling, epithelial stress, and thrombosis were measured by ELISA in the PROFILE study. We classified patients by unsupervised consensus clustering. To evaluate generalisability, a machine learning classifier trained on biomarker signatures derived from consensus clustering was applied to a replication dataset from the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR). Biomarker associations with mortality and change in percentage of predicted forced vital capacity (FVC%) were assessed, adjusting for age, gender, baseline FVC%, and antifibrotic treatment and steroid treatment before and after baseline. Mortality risk associated with the clusters in the PROFILE cohort was evaluated with Cox proportional hazards models, and mixed-effects models were used to analyse how clustering was associated with longitudinal FVC% in the PROFILE and AIPFR cohorts. 455 of 580 participants from the PROFILE study (348 [76%] men and 107 [24%] women; mean age 72·4 years [SD 8·3]) were included in the analysis. Within this group, three clusters were identified based on blood biomarkers. A basement membrane collagen (BM) cluster (n=248 [55%]) showed high concentrations of PRO-C4, PRO-C28, C3M, and C6M, whereas an epithelial injury (EI) cluster (n=109 [24%]) showed high concentrations of MMP-7, SP-D, CYFRA211, CA19-9, and CA-125. The third cluster (crosslinked fibrin [XF] cluster; n=98 [22%]) had high concentrations of X-FIB. In the replication dataset (117 of 833 patients from AIPFR; 87 [74%] men and 30 [26%] women; mean age 72·9 years [SD 7·9]), we identified the same three clusters (BM cluster, n=93 [79%]; EI cluster, n=8 [7%]; XF cluster, n=16 [14%]). These clusters showed similarities with clusters in the PROFILE dataset regarding blood biomarkers and phenotypic signatures. In the PROFILE dataset, the EI and XF clusters were associated with increased mortality risk compared with the BM cluster (EI vs BM: adjusted hazard ratio [HR] 1·88 [95% CI 1·42-2·49], p<0·0001; XF vs BM: adjusted HR 1·53 [1·13-2·06], p=0·0058). The EI cluster showed the greatest annual FVC% decline, followed by the BM and XF clusters. A similar FVC% decline pattern was observed in these clusters in the AIPFR replication dataset. Blood biomarker clustering in pulmonary fibrosis identified three distinct blood biomarker signatures associated with lung function and prognosis, suggesting unique pulmonary fibrosis biomarker patterns. These findings support the presence of pulmonary fibrosis endotypes with the potential to guide targeted therapy development. None.

Residential greenness and incident idiopathic pulmonary fibrosis: A prospective study

BackgroundThe impact of residential greenness on incident idiopathic pulmonary fibrosis (IPF) is unknown. We aimed to assess the association between residential greenness and incident IPF, identify underlying pathways, and further evaluate the effect among different genetic subgroups. Methods469,348 participants in the UK Biobank were included and followed until December 2020. Normalized difference vegetation index (NDVI) within 300-, 500-, 1000-, and 1500-m buffers (NDVI300m, NDVI500m, NDVI1000m, and NDVI1500m) were employed as indicators of greenness. The polygenic risk score (PRS) was constructed based on 13 independent SNPs. Cox models were fitted to assess the association of residential greenness with incident IPF. Casual mediation analyses were applied to evaluate potential mediators. FindingsAfter a median follow-up of 11.85 years, 1574 IPF cases were identified. We found residential greenness inversely associated with incident IPF. The HRs (95%CIs) for each interquartile increase of NDVI300m, NDVI500m, NDVI1000m, NDVI1500m were 0.93 (0.87, 0.99), 0.92 (0.86, 0.98), 0.89 (0.83, 0.95), and 0.89 (0.83, 0.95), respectively. The association was stronger among individuals with intermediate or high genetic risk. In mediation analyses, the main mediators identified were PM2.5 and NO2, with proportion mediated estimated to be 31.92% and 40.61% respectively for NDVI300m. InterpretationResidential greenness was associated with reduced risk of incident IPF.

Associations of combined phenotypic ageing and genetic risk with incidence of chronic respiratory diseases in the UK Biobank: a prospective cohort study.

Accelerated biological ageing has been associated with an increased risk of several chronic respiratory diseases. However, the associations between phenotypic age, a new biological age indicator based on clinical chemistry biomarkers, and common chronic respiratory diseases have not been evaluated. We analysed data from 308 592 participants at baseline in the UK Biobank. The phenotypic age was calculated from chronological age and nine clinical chemistry biomarkers, including albumin, alkaline phosphatase, creatinine, glucose, C-reactive protein, lymphocyte percent, mean cell volume, red cell distribution width and white blood cell count. Furthermore, phenotypic age acceleration (PhenoAgeAccel) was calculated by regressing phenotypic age on chronological age. The associations of PhenoAgeAccel with incident common chronic respiratory diseases and cross-sectional lung function were investigated. Moreover, we constructed polygenic risk scores and evaluated whether PhenoAgeAccel modified the effect of genetic susceptibility on chronic respiratory diseases and lung function. The results showed significant associations of PhenoAgeAccel with increased risk of idiopathic pulmonary fibrosis (IPF) (hazard ratio (HR) 1.52, 95% CI 1.45-1.59), COPD (HR 1.54, 95% CI 1.51-1.57) and asthma (HR 1.18, 95% CI 1.15-1.20) per 5-year increase and decreased lung function. There was an additive interaction between PhenoAgeAccel and the genetic risk for IPF and COPD. Participants with high genetic risk and who were biologically older had the highest risk of incident IPF (HR 5.24, 95% CI 3.91-7.02), COPD (HR 2.99, 95% CI 2.66-3.36) and asthma (HR 2.07, 95% CI 1.86-2.31). Mediation analysis indicated that PhenoAgeAccel could mediate 10∼20% of the associations between smoking and chronic respiratory diseases, while ∼10% of the associations between particulate matter with aerodynamic diameter <2.5 µm and the disorders were mediated by PhenoAgeAccel. PhenoAgeAccel was significantly associated with incident risk of common chronic respiratory diseases and decreased lung function and could serve as a novel clinical biomarker.

Low-level ambient sulfur dioxide exposure and genetic susceptibility associated with incidence of idiopathic pulmonary fibrosis: A national prospective cohort study

BackgroundThe association between long-term air pollution exposure and the development of idiopathic pulmonary fibrosis (IPF) has been established, but the evidence regarding the effect of low levels of air pollution, especially ambient sulfur dioxide (SO2), is limited. Besides, the combined effect and interaction between genetic susceptibility and ambient SO2 on IPF remain uncertain. MethodsThis study retrieved data from 402,042 participants who were free of IPF at baseline in the UK Biobank. The annual mean concentration of ambient SO2 was estimated for each participant based on their residential addresses using a bilinear interpolation method. Cox proportional hazard models were used to examine the relationship between ambient SO2 and incident IPF. We further generated a polygenic risk score (PRS) for IPF and estimated the combined effects of genetic susceptibility and ambient SO2 on incident IPF. ResultsAfter a median follow-up of 11.78 years, 2562 cases of IPF were identified. The results indicated that each 1 μg/m3 increase in ambient SO2 was associated with a hazard ratio (HR) (95% confidence interval [CI]) of 1.67 (1.58, 1.76) for incident IPF. The study found statistically significant synergistic additive interaction between genetic susceptibility and ambient SO2. Individuals with high genetic risk and high ambient SO2 exposure had a higher risk of developing IPF (HR = 7.48, 95% CI:5.66, 9.90). ConclusionThe study suggests that long-term exposure to ambient SO2, even at concentrations lower than current air quality guidelines set by the Word Health Organization and European Union, may be an important risk factor for IPF. This risk is more pronounced among people with a high genetic risk. Therefore, these findings emphasize the need to consider the potential health effects of SO2 exposure and the necessity for stricter air quality standards.

Presence of anti-modified protein antibodies in idiopathic pulmonary fibrosis.

Studies of autoimmunity and anti-citrullinated protein antibodies (ACPA) in idiopathic pulmonary fibrosis (IPF) have been confined to investigations of anti-cyclic citrullinated peptide (anti-CCP) antibodies which utilize synthetic peptides as surrogate markers for in vivo citrullinated antigens. We studied immune activation by analysing the prevalence of in vivo anti-modified protein antibodies (AMPA) in IPF. We included patients with incident and prevalent IPF (N = 120), sex and smoking-matched healthy controls (HC) (N = 120) and patients with RA (N = 104). Serum (median time: 11 months [Q1-Q3: 1-28 months] from diagnosis) was analysed for presence of antibodies towards native and posttranslational modified (citrullinated [Cit, N = 25]; acetylated [Acet, N = 4] and homocitrullinated [Carb, N = 1]) peptides derived from tenascin (TNC, N = 9), fibrinogen (Fib, N = 11), filaggrin (Fil, N = 5), histone (N = 8), cathelicidin (LL37, N = 4) and vimentin (N = 5) using a custom-made peptide microarray. AMPA were more frequent and in increased levels in IPF than in HC (44% vs. 27%, p < 0.01), but less than in RA (44% vs. 79%, p < 0.01). We specifically observed AMPA in IPF towards certain citrullinated, acetylated and carbamylated peptides versus HC: tenascin (Cit(2033) -TNC2025-2040 ; Cit(2197) -TNC2177-2200 ; Cit(2198) -TNC2177-2200 ), fibrinogen (Cit(38,42) -Fibα36-50 ; Cit(72) -Fibβ60-74 ) and filaggrin (Acet-Fil307-324 , Carb-Fil307-324 ). No differences in survival (p = 0.13) or disease progression (p = 0.19) between individuals with or without AMPA was observed in IPF. However, patients with incident IPF had better survival if AMPA were present (p = 0.009). A significant proportion of IPF patients present with specific AMPA in serum. Our results suggest autoimmunity as a possible characteristic for a subgroup of IPF that may affect disease outcome.

Lifestyle, Genetic Susceptibility, and the Risk of Idiopathic Pulmonary Fibrosis: A Large Prospective Cohort Study

Lifestyle is thought to be an important contributor of age-related chronic disease, but the association between lifestyle and the risk of idiopathic pulmonary fibrosis (IPF) remains unknown. Also, the extent to which genetic susceptibility modifies the effects of lifestyle on IPF remains unclear. Whether there is joint effect or interaction of lifestyle and genetic susceptibility on the risk of developing IPF? Our study included 407615 participants from the UK Biobank. We constructed a lifestyle score and a polygenic risk score (PRS) for each participant, separately. Participants were then classified into 3 lifestyle categories and 3 genetic risk categories based on the corresponding score. Cox models were fitted to assess the association of lifestyle and genetic risk with the risk of incident IPF. With favorable lifestyle as the reference group, intermediate lifestyle (hazard ratio (HR): 1.384, 95% confidence interval (CI): 1.218-1.574) and unfavorable lifestyle (HR: 2.271, 95% CI: 1.852-2.785) were significantly associated with increased risk of IPF. For the combined effect of lifestyle and PRS, participants with unfavorable lifestyle and high genetic risk had the highest risk of IPF (HR: 7.796, 95% CI: 5.482-11.086) compared to those with favorable lifestyle and low genetic risk. Moreover, approximately 32.7% (11.3%, 54.1%) of IPF risk could be attributed to the interaction of an unfavorable lifestyle and high genetic risk. Exposure to unfavorable lifestyle significantly increased the risk of IPF, particularly in those with high genetic risk.

Air pollutants, genetic susceptibility and risk of incident idiopathic pulmonary fibrosis.

Air pollutants are considered as non-negligible risk factors of idiopathic pulmonary fibrosis (IPF). However, the relationship between long-term air pollution and the incidence of IPF is unknown. Our objective was to explore the associations of air pollutants with IPF risk and further assess the modification effect of genetic susceptibility. We used land-use regression model estimated concentrations of nitrogen dioxide (NO2), nitrogen oxides (NO x ) and particulate matter (fine particulate matter with diameter <2.5 μm (PM2.5) and particulate matter with diameter <10 μm (PM10)). The polygenic risk score (PRS) was constructed using 13 independent single nucleotide polymorphisms. Cox proportional hazard models were used to evaluate the associations of air pollutants with IPF risk and further investigate the modification effect of genetic susceptibility. Additionally, absolute risk was calculated. Among 433 738 participants from the UK Biobank, the incidence of IPF was 27.45 per 100 000 person-years during a median follow-up of 11.78 years. The adjusted hazard ratios of IPF for each interquartile range increase in NO2, NO x and PM2.5 were 1.11 (95% CI 1.03-1.19), 1.07 (95% CI 1.01-1.13) and 1.09 (95% CI 1.02-1.17), respectively. PM2.5 had the highest population attribution risk, followed by NO x and NO2. There were additive interactions between NO2, NO x and PM2.5 and genetic susceptibility. Participants with a high PRS and high air pollution had the highest risk of incident IPF compared with those with a low PRS and low air pollution (adjusted hazard ratio: NO2 3.94 (95% CI 2.77-5.60), NO x 3.08 (95% CI 2.21-4.27), PM2.5 3.65 (95% CI 2.60-5.13) and PM10 3.23 (95% CI 2.32-4.50)). Long-term exposures to air pollutants may elevate the risk of incident IPF. There are additive effects of air pollutants and genetic susceptibility on IPF risk.

Impact of smoking on the development of idiopathic pulmonary fibrosis: results from a nationwide population-based cohort study

BackgroundSmoking has been considered an important risk factor for idiopathic pulmonary fibrosis (IPF) incidence. However, there are no population-based large-scale studies demonstrating the effects of smoking on the development of...

Gender Differences in Idiopathic Pulmonary Fibrosis: Are Men and Women Equal?

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a male predominance. The aim of the study was to explore gender differences in a well-designed French multicentre prospective IPF cohort (COhorte FIbrose, COFI) with a 5-year follow-up.Methods: Between 2007 and 2010, 236 patients with incident IPF were included in COFI. Gender characteristics were compared using a t-test, Chi-squared test and ANOVA, as appropriate. Survival analyses were performed.Results: Fifty-one (22%) females and 185 (78%) males with an average age at diagnosis of 70.1 ± 9.20 and 67.4 ± 10.9 years, respectively, were included in the cohort. Women were significantly less exposed to tobacco smoke [never n = 32 (62.7%) vs. n = 39 (21.1%), p < 0.001] and to occupational exposure [n = 7 (13.7%) vs. n = 63 (34.1%), p = 0.012]. Baseline forced vital capacity, % of predicted (FVC%) was significantly better in women compare to men (83.0% ± 25.0 v. 75.4% ± 18.7 p = 0.046). At presentation honeycombing and emphysema on CT scan were less common in women [n = 40 (78.4%) vs. n = 167 (90.3%) p = 0.041] and [n = 6 (11.8%) vs. n = 48 (25.9%) p = 0.029], respectively. During follow-up fewer women were transplanted compared to men [n = 1 (1.96%) vs. n = 20 (10.8%) p = 0.039]. Medians of survival were comparable by gender [31 months (CI 95%: 28–40) vs. 40 months (CI 95%: 33–72) p = 0.2]. After adjusting for age and FVC at inclusion, being a woman was not associated to a better survival.Conclusions: Women appear to have less advanced disease at diagnosis, maybe due to less exposure history compare to men. Disease progression and overall survival remains comparable regardless gender, but women have less access to lung transplantation.

Gender differences in idiopathic pulmonary fibrosis: Are men and women equal or not?

Few studies analyzed gender-related outcomes and characteristics differences of patients with idiopathic pulmonary fibrosis (IPF). The aim of the study was to explore gender differences in a French IPF cohort. 236 patients with incident IPF were included in the multicentric longitudinal prospective cohort COhorte FIbrose (COFI), and followed for 5 years. Men and women were compared for characteristics atinclusion ( t -test, Chi 2 or ANOVA) and survival (Log rank, Cox model). The population consisted of 51 (22%) women and 185(78%) men. At inclusion women significantly differed from men for an older age (> 65 years, 78 vs. 61%, P = 0.028), a lower proportion of smokers ( P < 0.001) and lower frequency of occupational exposure ( P = 0.012). At baseline forced vital capacity (FVC) was significantly better in women (83 ± 25 vs. 75 ± 19%, P = 0.046); honeycombing (78.4 vs. 90.3%, P = 0.041) and emphysema (11.8 vs. 25.9%, P = 0.029) on CT scan were less common in women. Comorbidities such as osteoporosis (9.8 vs. 2.2%, P = 0.025) and thromboembolic events (11.8 vs. 2.2%, P = 0.008) were more frequently reported among women. Women were less likely to be transplanted (2 vs. 11%, P = 0.039). Survival median was comparable between men and women (31months vs. 40 months, P = 0.2). After adjusting for age and FVC at inclusion, being a woman was not associated to a better survival. At diagnosis women appear to have a distinct imaging pattern and a better FVC, which may be due to less exposure history compared to men. However, outcomes remain comparable in both sexes. Less access to lung transplantation in women may be due to age and comorbidities.

Association between influenza vaccination and the occurrence of acute exacerbation inidiopathic pulmonary fibrosis

International guidelines recommend that annual influenza vaccination be performed in patients with idiopathic pulmonary fibrosis (IPF). Viral infections are recognized to be triggers of acute exacerbation (AE). The purpose of this study was to investigate the role of annual influenza vaccination on AE occurrence. 236 patients with incident IPF were included in the multicentric longitudinal prospective cohort COhorte FIbrose (COFI), and followed for 5 years. Influenza vaccination status was requested annually. We have defined aone-year vaccination coverage from September the first to August the 30th of the following year. 638 annual observations were available with an informed vaccination status. To evaluate the association between annual influenza vaccination and AE occurrence, two mixed-effect Cox regression was used. For the second model we divided patients in 3 groups: – patients vaccinated every year; – patients vaccinated at least half of the years of follow-up; – patients vaccinated less than half the years of follow-up. Only the first AE was considered. The definition of AE was that of Akira et al. Mean follow-up was 33.2 ± 23.6 months. 36 AEs occurred in 33 patients. Of the 33 patients, only 27 had an informed vaccination status in the year of their AE. Nine (33%) patients who experienced an AE weren’t vaccinated. For 141 (22%) annual observations, the patient didn’t receive the vaccine. In this model, influenza vaccination was associated with a decreased occurrence of AE but this did not reach the level of significance in this small population (HR:0.58 CI95%0.23-1.46, P = 0.25). In the first group patients were vaccinated every year and consisted of hundred and thirty-three individuals. The second group was composed of patients vaccinated at least half of the years of follow-up, with 35 patients. And 36 patients were vaccinated less than half the years of follow-up in the last group. In the second model, patients vaccinated less than half the years of follow-up were significantly more at risk to present AE compared to patients who were vaccinated every year (HR:2.77 CI95%1.11-6.93, P = 0.03). In our IPF cohort, only about half of the patients had influenza vaccination coverage throughout the follow-up period. Annual influenza vaccination seems to reduce the risk of AE but due to a lack of power this association was not significant. However patients vaccinated less than half the years of follow-up were significantly more at risk to present AE compared to patients who were vaccinated every year. A study with a larger number of patients is highly desirable to confirm this association.

Tobacco Smoking and Risk for Pulmonary Fibrosis: A Prospective Cohort Study From the UK Biobank

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown origin. A limited number of small studies show an effect of tobacco smoking on risk of IPF, but second-hand smoking has not been examined. Are smoking-related exposures associated with risk of IPF and does interaction between them exist? We designed a prospective cohort study using UK Biobank data, including 437,453 nonrelated men and women of White ethnic background (40-69 years of age at baseline). We assessed the effect of tobacco smoking-related exposures on risk for IPF using Cox regression adjusted for age, sex, Townsend deprivation index, and home area population density. We also examined potential additive and multiplicative interaction between these exposures. Multiple imputation with chained equations was used to address missing data. We identified 802 incident IPF cases. We showed an association between smoking status (hazard ratio [HR], 2.12; 95%CI, 1.81-2.47), and maternal smoking (HR, 1.38; 95%CI, 1.18-1.62) with risk of IPF. In ever smokers, a dose-response relationship was observed between pack-years of smoking and risk of IPF (HR per 1-pack-year increase, 1.013; 95%CI, 1.009-1.016). Furthermore, an additive and multiplicative interaction was observed between maternal smoking and smoking status, with a relative excess risk due to interaction of 1.00 (95%CI, 0.45-1.54) and a ratio of HRs of 1.50 (95%CI, 1.05-2.14). Active and maternal tobacco smoking have an independent detrimental effect on risk of IPF and work synergistically. Also, intensity of smoking presents a dose-response association with IPF, strengthening the hypothesis for a potentially causal association.

The natural history of idiopathic pulmonary fibrosis in a large European population: the role of age, sex and comorbidities.

Placebo arms of clinical trials provide an opportunity to investigate the natural history of idiopathic pulmonary fibrosis (IPF) but these patients are not representative of the real life IPF population. Objective of this article is to evaluate patients' characteristics of incident IPF cases and their impact on mortality and hospitalizations risk. We conducted a retrospective cohort study using data from administrative databases from 2000 to 2010. Based on different algorithms reported in literature, incident IPF cases were identified. We applied Cox proportional hazards models to assess relationship between patients' characteristics, mortality and hospitalization. According to three case definitions, we identified 2338, 460 and 1704 incident IPF cases. Mean age at diagnosis was about 72years, the proportion of male varied between 59 and 62% and patients with at least one chronic disease were between 70 and 74%. Age, male sex and comorbidities were associated to worse outcomes. Congestive heart failure (CHF), diabetes and cancer were conditions associated to mortality, while those associated to hospitalization were CHF and chronic obstructive pulmonary disease. Our data source provided one of the largest samples of unselected patients with a long follow-up period. Using different algorithms proposed and validated in literature, we observed that mortality and hospitalization rate are high in patients with IPF and age, sex and comorbidities significantly affect clinical outcomes. Females show a significant survival advantage over males, even after adjusting for age and comorbidities. Patients with pre-existing diseases, especially those with pulmonary and cardiovascular diseases are at higher risk.

Incidence and predictors of idiopathic pulmonary fibrosis complicating Type 2 diabetes: the Fremantle Diabetes Study Phase I.

During 106 865 person-years of follow up, 17 (1.3%) Fremantle Diabetes Study Phase I participants with Type 2 diabetes and 57 (1.1%) matched individuals without diabetes developed idiopathic pulmonary fibrosis (IPF), an incidence rate ratio (95% confidence interval) of 1.40 (0.76-2.44) (P = 0.22). In the diabetes cohort, age at diabetes diagnosis and total serum cholesterol (inversely) predicted incident IPF in competing risk multivariable models. The incidence of IPF was low in community-based cohorts, regardless of Type 2 diabetes status.

Impact of Idiopathic Pulmonary Fibrosis on Longitudinal Health-care Utilization in a Community-Based Cohort of Patients

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic lung disease associated with substantial symptom burden, morbidity, and cost. Delivery of high-quality effective care in IPF requires understanding health-care resource utilization (HRU) patterns; however, longitudinal data from real-world populations are limited. This study aimed to define HRU attributable to IPF by evaluating a longitudinal cohort of community patients with IPF compared with matched control subjects. Incident IPF cases were identified in the Kaiser Permanente Northern California electronic health records (2000-2015) using case-validated code-based algorithms. IPF cases were compared with matched control subjects by age, sex, and length of enrollment. Annual rates of HRU measures were assessed during the 5 years pre- and postdiagnosis. Poisson generalized estimating equations were used to estimate adjusted case-control differences in HRU. IPF treatment trends were assessed before and after the availability of IPF-specific medications. A total of 691 IPF cases were identified and matched with 3,452 control subjects. Adjusted rates of all diagnostic procedures were significantly increased (P< .001) for IPF cases compared with control subjects in both the pre- and postindex periods, including chest CT scans (pre-relative risk [RR], 80.35; post-RR, 32.79), 6-min walk tests (pre-RR, 20.81; post-RR, 34.49), and pulmonary function tests (pre-RR, 9.50; post-RR, 13.24). All-cause hospitalizations (pre-RR, 1.42; post-RR, 2.33) and outpatient visits (pre-RR, 1.22; post-RR, 1.80) were significantly higher among cases compared with control subjects during both the preindex (P< .05) and postindex (P< .001) periods. We observed use of immunosuppressive and IPF-specific therapies prior to diagnosis, and high rates of corticosteroid use before and after diagnosis. This study defines a marked increase in HRU in patients with IPF compared with control subjects, with accelerated use beginning at least 1 year prediagnosis and elevated use sustained over the following 5 years. To our knowledge, this is the first study to evaluate longitudinal medication trends in IPF. Collectively, this information is foundational to advancing IPF care delivery models and supporting clinical decision-making.

Demographics and survival of patients with idiopathic pulmonary fibrosis in the FinnishIPF registry

Idiopathic pulmonary fibrosis (IPF) is characterised by unpredictable disease course and poor survival. After the introduction of novel antifibrotic drugs, the prognosis of patients with IPF is probably changing.FinnishIPF, a nationwide registry of carefully characterised patients, was initiated in Finland in 2011. For the data analysis, we included 453 incident IPF patients diagnosed during 2011–2015. In this study, we describe the demographics and prognosis of these real-life patients.The median overall survival time of registered IPF patients was 4.5 years. The transplant-free survival at 1, 2, 3, 4 and 5 years was 95%, 83%, 70%, 58% and 45%, respectively. Smoking did not have any effect on survival. 117 (26%) patients received pirfenidone or nintedanib. Patients who received ≥6 months of treatment had better survival compared with those who did not receive treatment but this difference disappeared after age adjustment. The transplantation rate was 3%.Although IPF is diagnosed in Finland at a older age, the prognosis is better than expected due to a relatively well preserved lung function at diagnosis. Age and pulmonary function were identified as independent predictors of survival in the entire IPF patient population as well as in patients who had received antifibrotic treatment.

Risk factors for diagnostic delay in idiopathic pulmonary fibrosis

BackgroundSurveys and retrospective studies of patients with idiopathic pulmonary fibrosis (IPF) have shown a significant diagnostic delay. However, the causes and risk factors for this delay are not known.MethodsDates at six time points before the IPF diagnosis (onset of symptoms, first contact to a general practitioner, first hospital contact, referral to an interstitial lung disease (ILD) centre, first visit at an ILD centre, and final diagnosis) were recorded in a multicentre cohort of 204 incident IPF patients. Based on these dates, the delay was divided into specific patient-related and healthcare-related delays. Demographic and clinical data were used to determine risk factors for a prolonged delay, using multivariate negative binomial regression analysis.ResultsThe median diagnostic delay was 2.1 years (IQR: 0.9–5.0), mainly attributable to the patients, general practitioners and community hospitals. Male sex was a risk factor for patient delay (IRR: 3.84, 95% CI: 1.17–11.36, p = 0.006) and old age was a risk factor for healthcare delay (IRR: 1.03, 95% CI: 1.01–1.06, p = 0.004). The total delay was prolonged in previous users of inhalation therapy (IRR: 1.99, 95% CI: 1.40–2.88, p < 0.0001) but not in patients with airway obstruction. Misdiagnosis of respiratory symptoms was reported by 41% of all patients.ConclusionDespite increased awareness of IPF, the diagnostic delay is still 2.1 years. Male sex, older age and treatment attempts for alternative diagnoses are risk factors for a delayed diagnosis of IPF. Efforts to reduce the diagnostic delay should focus on these risk factors.Trial registrationThis study was registered at http://clinicaltrials.gov (NCT02772549) on May 10, 2016.

Clinical and economic burden of idiopathic pulmonary fibrosis in Quebec, Canada.

BackgroundIdiopathic pulmonary fibrosis (IPF), although rare, is a severe and costly disease.ObjectiveTo estimate the clinical and economic burden of IPF over multiple years before and after diagnosis using comprehensive administrative databases for the province of Quebec, Canada.MethodsSeveral administrative databases from Quebec, providing information on hospital care, community care, and pharmaceuticals, were linked over a 5-year period ending March 31, 2011, which was before approval of antifibrotic drugs in Canada. Prevalent and incident IPF cases were defined using International Classification Disease-10-CA codes and International Classification Disease-9-CM codes. We used a broad definition that excluded cases with subsequent diagnosis of other interstitial lung diseases and a narrow definition that required further diagnostic testing to confirm IPF diagnosis. Incident cases had an IPF code in a particular year without any IPF code in the 2 previous years. Health care resource utilization before and after the index diagnosis date was determined and costs calculated. Costs were expressed in 2016 Canadian dollars.ResultsOver 5-years, 10,579 (mean age: 76.4; 58% male) satisfied the broad definition of IPF and 8,683 (mean age: 74.5; 57% male) satisfied the narrow definition (82% of broad). Incidences of IPF overall were 25.8 and 21.7/100,000 population for broad and narrow definitions, respectively. Three-year survival was 40% and 37% in broad and narrow cohorts, respectively. For both cohorts, health care resource utilization and costs increased several years before diagnosis ($2,721 and $7,049/patient 5 years and 2 years prior to diagnosis using a broad definition, respectively) and remained elevated for multiple years post diagnosis ($12,978 and $8,267 at 2 and 3 years postdiagnosis).ConclusionHealth care resource utilization and costs of IPF increase many years prior to diagnosis. Incorporating multiyear annual costs before and after diagnosis results in a higher estimate of the economic burden of IPF than previous studies using a 1-year time frame.

Obstructive sleep apnoea and related comorbidities in incident idiopathic pulmonary fibrosis.

The objectives of this prospective study were: 1) to determine the prevalence and determinants of obstructive sleep apnoea (OSA) in patients with newly diagnosed idiopathic pulmonary fibrosis (IPF); 2) to determine whether OSA was associated with cardiovascular disease (CVD) as well as increased oxidative stress and levels of IPF biomarkers in the blood.A group of 45 patients with newly diagnosed IPF attended polysomnography. The prevalence of CVD and the severity of coronary artery calcification were investigated by high-resolution computed tomography. The levels of 8-hydroxydeoxyguanosine (8-OH-DG) and various IPF biomarkers in the blood were compared between patients with no or mild OSA (apnoea-hypopnoea index (AHI) <15 events·h-1), with moderate OSA (15 ≤AHI <30 events·h-1) and with severe OSA (AHI ≥30 events·h-1).The prevalence of moderate-to-severe OSA and severe OSA was 62% and 40%, respectively. AHI did not correlate with demographic or physiological data. All patients with severe OSA had a medical history of CVD, versus 41.2% and 40% of those with no or mild OSA, or with moderate OSA, respectively (p<0.0001). Ischaemic heart disease (IHD) and moderate-to-severe coronary artery calcifications were strongly associated with severe OSA. The 8-OH-DG and matrix metalloproteinase-7 serum levels were significantly increased in the severe OSA group.Moderate-to-severe OSA is highly prevalent in incident IPF and severe OSA is strongly associated with the presence of CVD, particularly IHD.

Occupational exposure and idiopathic pulmonary fibrosis: a multicentre case-control study in Korea.

Multicentred hospital-based cases and control subjects in Korea. To evaluate the association between idiopathic pulmonary fibrosis (IPF) and hazardous materials to which people are occupationally exposed. A multicentre, hospital-based, matched case-control study was performed. The ratio of IPF cases to controls was 1:1 (n = 78 in each group). IPF cases and controls were matched in terms of age group, sex and place of residence. Conditional logistic regression analysis was performed. In simple logistic regression analysis, exposure to metal dust and any exposure for >1 year in an occupational setting were significantly associated with IPF (metal dust OR 4.00, 95%CI 1.34-11.97; any exposure OR 3.67, 95%CI 1.02-13.14). After adjustment for environmental and military exposures and smoking history, the OR for metal dust exposure was 4.97 (95%CI 1.36-18.17) in multiple logistic regression analysis. Metal dust was associated with incident IPF in Seoul and Gyeonggi Provinces in Korea. This information will be used to support a tailored preventive strategy in specific industries or occupations.