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Rôle des facteurs socio-économiques et environnementaux dans l’histoire naturelle de la fibrose pulmonaire idiopathique
Abstract
La fibrose pulmonaire idiopathique (FPI), est la plus fréquente et la plus grave des pneumopathies interstitielles idiopathiques. Son pronostic est sombre, avec une médiane de survie d'environ 3 à 5 ans. Bien que de cause inconnue, certaines expositions sont associées à un risque accru de FPI : tabac, expositions professionnelles (poussière de bois, métaux, silice, milieu agricole). Une première étude en Corée a suggéré le rôle de certains polluants ozone (O3) et dioxyde d’azote (NO2) sur la survenue d’exacerbation aiguë (EA) de FPI. Les niveaux et types d’expositions aux polluants aériens sont fortement liés au niveau socioéconomique. Or, les données disponibles sur les facteurs socioéconomiques dans la FPI sont rares. Nous faisons les hypothèses que, la pollution atmosphérique en France ainsi que le revenu puissent influencer l’histoire naturelle de la FPI. A partir de la cohorte multicentrique prospective française de FPI (COhorte FIbrose, COFI), nous avons étudié le rôle de la pollution atmosphérique (O3, NO2, PM10, PM2.5) sur la survenue d’EA, de la progression et du décès). Le second travail a porté l’impact du revenu, sur la survie des patients. Les résultats montrent qu’une exposition accrue à l’O3 est un facteur de risque d’EA-FPI et qu’une exposition cumulée élevée aux particules fines (PM10, PM2.5) est un facteur de mauvais pronostic et qu’un revenu faible est un facteur de mauvais pronostic pour la survie globale et sans progression. La pollution de l’air et précarité pourraient influencer le pronostic de la FPI. Une approche de type « exposome » nous permettrait de mieux étudier le rôle des facteurs sociaux et environnementaux dans la progression de la FPI.
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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.
Objective
We aimed to assess the relationship between major air pollutants and the natural history and mortality of idiopathic pulmonary fibrosis (IPF).
Methods
We conducted a retrospective cohort study from 2013 to 2019 among 52 patients with IPF from the pneumology department of a tertiary hospital. According to their geocoded residential address, each patient was assigned a mean concentration of carbon monoxide (CO), nitrogen dioxide, particulate matter 2.5 and 10, ozone, and sulfur dioxide, as measured at a single surveillance station in central Madrid, Spain. We analyzed forced vital capacity (FVC), CO diffusing capacity, 6-minute walking test, degree of dyspnea, radiologic pattern, and signs of pulmonary hypertension in all patients.
Results
Patients’ mean age was 66 ± 10 years, and 79% were men. The mean predicted FVC was 78.9 ± 0.5%. Forty-two patients met the criteria for severe disease, and 18 patients died. Mortality was significantly associated with increased CO exposure (for each 0.1 mg/m ² increase: odds ratio 2.45, 95% confidence interval 1.39–4.56). We observed no association between any of the other investigated contaminants and IPF mortality or severity.
Conclusions
Air pollution, specifically that caused by carbon monoxide, can increase mortality in patients with IPF.
Background
Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease with considerable morbidity. Heterogeneity in epidemiologic studies means the full impact of the disease is unclear.
Methods
A targeted literature search for population-based, observational studies reporting incidence and/or prevalence of IPF from January 2009 to April 2020 was conducted. Identified studies were aggregated by country. For countries with multiple publications, a weighted average was determined. Incidence and prevalence data were adjusted for between-study differences where possible. The final model included adjusted estimates of incidence and prevalence per 10,000 of the population with 95% confidence intervals. As prevalence estimates vary depending on the definitions used, estimates were based on a specific case definition of IPF.
Results
Overall, 22 studies covering 12 countries met the inclusion criteria, with 15 reporting incidence and 18 reporting prevalence estimates. The adjusted incidence estimates (per 10,000 of the population) ranged from 0.35 to 1.30 in Asia–Pacific countries, 0.09 to 0.49 in Europe, and 0.75 to 0.93 in North America. Unadjusted and adjusted incidence estimates were consistent. The adjusted prevalence estimates ranged from 0.57 to 4.51 in Asia–Pacific countries, 0.33 to 2.51 in Europe, and 2.40 to 2.98 in North America. South Korea had the highest incidence and prevalence estimates. When prevalence estimates were compared to country-specific rare disease thresholds, IPF met the definition of a rare disease in all countries except South Korea. There were notable geographic gaps for IPF epidemiologic data.
Conclusions
Due to differences in study methodologies, there is worldwide variability in the reported incidence and prevalence of IPF. Based on the countries included in our analysis, we estimated the adjusted incidence and prevalence of IPF to be in the range of 0.09–1.30 and 0.33–4.51 per 10,000 persons, respectively. According to these prevalence estimates, IPF remains a rare disease. For consistency, future epidemiologic studies of IPF should take age, sex, smoking status, and the specificity of case definitions into consideration.
Abstract Background Short-term exposure to ozone and nitrogen dioxide is a risk factor for acute exacerbation (AE) of idiopathic pulmonary fibrosis (AE-IPF). The comprehensive roles of exposure to fine particulate matter in AE-IPF remain unclear. We aim to investigate the association of short-term exposure to fine particulate matter with the incidence of AE-IPF and to determine the exposure-risk time window during 3 months before the diagnosis of AE-IPF. Methods IPF patients were retrospectively identified from the nationwide registry in Japan. We conducted a case–control study to assess the correlation between AE-IPF incidence and short-term exposure to eight air pollutants, including particulate matter
Purpose
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [¹⁸F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [¹⁸F]FDG.
Methods
Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [¹⁸F]FDG and [¹⁸F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23.
Results
We demonstrate that mean lung density on CT as well as [¹⁸F]FDG and [¹⁸F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [¹⁸F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [¹⁸F]FDG and [¹⁸F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [¹⁸F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy.
Conclusion
[¹⁸F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.
Idiopathic pulmonary fibrosis (IPF) is characterised by an important remodelling of lung parenchyma. Current evidence indicates that the disease is triggered by alveolar epithelium activation following chronic lung injury, resulting in alveolar epithelial type 2 cell hyperplasia and bronchiolisation of alveoli. Signals are then delivered to fibroblasts that undergo differentiation into myofibroblasts. These changes in lung architecture require the activation of developmental pathways that are important regulators of cell transformation, growth and migration. Among others, aberrant expression of profibrotic Wnt-β-catenin, transforming growth factor-β and Sonic hedgehog pathways in IPF fibroblasts has been assessed. In the present review, we will discuss the transcriptional integration of these different pathways during IPF as compared with lung early ontogeny. We will challenge the hypothesis that aberrant transcriptional integration of these pathways might be under the control of a chaotic dynamic, meaning that a small change in baseline conditions could be sufficient to trigger fibrosis rather than repair in a chronically injured lung. Finally, we will discuss some potential opportunities for treatment, either by suppressing deleterious mechanisms or by enhancing the expression of pathways involved in lung repair. Whether developmental mechanisms are involved in repair processes induced by stem cell therapy will also be discussed.
Background
Nintedanib is an approved therapy for idiopathic pulmonary fibrosis (IPF). Some patients treated with nintedanib experience weight loss. Exploratory data suggest that low body mass index or weight loss are associated with worse outcomes in patients with IPF. We investigated whether BMI at baseline or weight loss over 52 weeks was associated with FVC decline, or influenced the effect of nintedanib, in patients with IPF.
Methods
Using pooled data from the two INPULSIS trials, we analysed the rate of decline in FVC (mL/yr) over 52 weeks in patients treated with nintedanib and placebo in subgroups by baseline BMI (< 25; ≥25 to < 30; ≥30 kg/m²) and by weight loss over 52 weeks (≤5; > 5%) using random coefficient regression.
Results
In the placebo group, the mean rate of FVC decline over 52 weeks was numerically greater in patients with lower baseline BMI (− 283.3 [SE 22.4], − 207.9 [20.9] and − 104.5 [21.4] in patients with BMI < 25 kg/m², ≥25 to < 30 kg/m² and ≥ 30 kg/m², respectively). Nintedanib reduced the rate of FVC decline versus placebo in all subgroups by BMI, with a consistent treatment effect across subgroups (interaction p = 0.31). In the placebo group, the mean rate of FVC decline was numerically greater in patients with > 5% than ≤5% weight loss over 52 weeks (− 312.7 [SE 32.2] versus − 199.5 [SE 14.4] mL/year). Nintedanib reduced the rate of FVC decline versus placebo in both subgroups by weight loss, with a greater treatment effect in patients with > 5% weight loss (interaction p = 0.0008). The adverse event profile of nintedanib was similar across subgroups.
Conclusions
In patients with IPF, lower BMI and weight loss may be associated with faster decline in FVC. Nintedanib reduces the rate of FVC decline both in patients who lose weight on treatment and those who do not.
Trial registration
ClinicalTrials.gov; Nos. NCT01335464 and NCT01335477; URL: www.clinicaltrials.gov.
In patients with idiopathic pulmonary fibrosis (IPF), the effects of antifibrotic agents on the prognosis remain unclear. This study aimed to investigate the impact of antifibrotic treatment on the risks of mortality, hospitalisation, and acute exacerbation in real-world patients with IPF. A total of 1213 IPF patients (biopsy-proven cases: 405) were included in this retrospective study. Propensity score matching was used to adjust for differences in baseline characteristics between patients who received antifibrotic treatment and who did not. A Cox proportional hazard model was used to compare the risks of all-cause mortality, hospitalisation, acute exacerbation, and mortality following acute exacerbation between the two groups. From the 1213 patients, 474 matched pairs were generated. The mean age of the patients in the matched cohort was 65.8 years and 82.8% were men. The median follow-up duration was 27 months. Antifibrotic treatment significantly reduced the risks of mortality [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.48-0.72; p < 0.001], all-cause hospitalisation (HR 0.71), respiratory-related hospitalisation (HR 0.67), acute exacerbation (HR 0.69), and mortality after acute exacerbation (HR 0.60). Our results suggest that antifibrotic treatment may reduce the risks of all-cause mortality, hospitalisation, acute exacerbation, and mortality after acute exacerbation in patients with IPF.
Background and objectives:
Evidence of mediastinal Lymph Node Enlargement (LNE) on CT scan is a common finding in idiopathic pulmonary fibrosis (IPF). We sought to investigate whether the involvement of mediastinal lymph nodes is associated with accelerated disease progression, and explored the changes occurring in mediastinal lymph nodes during the radiological follow up of these patients.
Methods:
This retrospective study included IPF patients referred to a single ILD centre in Italy. A consensus-based assessment of mediastinal LNE on chest CT scan was performed by two thoracic radiologists. Kaplan-Meier curves and multivariate Cox proportional hazards regression were used to assess hazard ratios for mortality and disease progression (defined as categorical FVC decline ≥10%). The annualized rates of change in functional parameters for each patient were calculated using mixed linear models.
Results:
The study population consisted of 152 IPF patients, of whom 135 (89%) received antifibrotic treatment for IPF during the study follow up. Patients having evidence of 3 or more enlarged mediastinal lymph nodes on baseline CT scan showed increased rates of mortality (HR 5.03, 95% CI 1.86-13.62, p ≤ 0.001) and significant disease progression (HR 2.99, 95% CI 1.22-7.33, p = 0.17) as compared to patients without LNE, after adjusting for GAP stage. Among 62 patients with LNE who underwent a follow up CT scan of the chest and received antifibrotic treatment, 57 (92%) maintained evidence mediastinal LNE over time.
Conclusions:
Diffuse mediastinal lymph node involvement predicts clinically meaningful functional deterioration in patients with IPF.
Evidence regarding the impact of air pollution on acute respiratory distress syndrome (ARDS) is limited, and most studies focus on ARDS onset. Our study aimed to evaluate whether exposure to fine particulate matter interferes with lung recovery and remodeling in a murine model of acute lung injury. Forty-eight mice received nebulized LPS or the vehicle (controls). Blood, BALF, lungs and spleen were collected after 5 weeks of exposure to either PM2.5 (PM and LPS + PM group) or filtered air (control and LPS5w groups). Inflammatory cells and cytokines were assessed in the blood, BALF, lungs and spleen. Stereological analyses and remodeling assessments were performed by histology. The LPS + PM group showed increased BALF leukocytes, characterized by increased macrophages, increased IL-1β and IL-6 levels, anemia and thrombocytopenia. Moreover, we also observed septal thickening, decreased alveolar air space total volume and, septa surface density. Finally, regarding tissue remodeling, we observed elastosis of the lung parenchyma, and unlike in the LPS5w group, we did not observe fibrosis in the LPS + PM group. In conclusion, the delayed inflammation resolution due to subchronic exposure to PM2.5 could be influenced by low systemic and local lymphocyte counts, which lead to impaired lung injury recovery and tissue remodeling.
Rationale:
Chronic hypersensitivity pneumonitis (CHP) is a condition that arises following repeated exposure and sensitisation to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease but to date, no study has investigated the composition of microbial communities in the lower airways in CHP.
Objective:
To characterise and compare the airway microbiome in subjects with CHP, idiopathic pulmonary fibrosis (IPF) and controls.
Methods:
We prospectively recruited individuals diagnosed with CHP (n=110), IPF (n=45) and controls (n=28). Subjects underwent bronchoalveolar lavage and bacterial DNA was isolated, quantified by qPCR and the 16S rRNA gene was sequenced to characterise the bacterial communities in the lower airways.
Main measurements and results:
Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both IPF and CHP subjects included Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. However, in IPF, Firmicutes dominated while the percentage of reads assigned to Proteobacteria in the same group was significantly lower compared to CHP subjects. At the genus level, Staphylococcus was increased in CHP and Actinomyces and Veillonella in IPF. The lower airway bacterial burden in CHP subjects was higher than controls but lower than those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP.
Conclusions:
The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF and, notably, bacterial burden in individuals with CHP fails to predict survival.
As global awareness of air pollution rises, so does the imperative to provide evidence-based recommendations for strategies to mitigate its impact. While public policy has a central role in reducing air pollution, exposure can also be reduced by personal choices. Qualified evidence supports limiting physical exertion outdoors on high air pollution days and near air pollution sources, reducing near-roadway exposure while commuting, utilising air quality alert systems to plan activities, and wearing facemasks in prescribed circumstances. Other strategies include avoiding cooking with solid fuels, ventilating and isolating cooking areas, and using portable air cleaners fitted with high efficiency particulate air filters. We detail recommendations to assist providers and public health officials when advising patients and the public regarding personal-level strategies to mitigate risk imposed by air pollution, while recognising that well-designed prospective studies are urgently needed to better establish and validate interventions that benefit respiratory health in this context.
Although it is well accepted that air pollution exposure exacerbates preexisting airway disease, it has not been firmly established that long-term pollution exposure increases the risk of new-onset asthma or chronic obstruction pulmonary disease (COPD). This Workshop brought together experts on mechanistic, epidemiological, and clinical aspects of airway disease to review current knowledge regarding whether air pollution is a causal factor in the development of asthma and/or COPD. Speakers presented recent evidence in their respective areas of expertise related to air pollution and new airway disease incidence, followed by interactive discussions. A writing committee summarized their collective findings. The Epidemiology Group found that long-term exposure to air pollution, especially metrics of traffic-related air pollution such as nitrogen dioxide and black carbon, is associated with onset of childhood asthma. However, the evidence for a causal role in adult-onset asthma or COPD remains insufficient. The Mechanistic Group concluded that air pollution exposure can cause airway remodeling, which can lead to asthma or COPD, as well as asthma-like phenotypes that worsen with long-term exposure to air pollution, especially fine particulate matter and ozone. The Clinical Group concluded that air pollution is a plausible contributor to the onset of both asthma and COPD. Available evidence indicates that long-term exposure to air pollution is a cause of childhood asthma, but the evidence for a similar determination for adult asthma or COPD remains insufficient. Further research is needed to elucidate the exact biological mechanism underlying incident childhood asthma, and the specific air pollutant that causes it.
Ultrafine particles (PM0.1), which are present in the air in large numbers, pose a health risk. They generally enter the body through the lungs but translocate to essentially all organs. Compared to fine particles (PM2.5), they cause more pulmonary inflammation and are retained longer in the lung. Their toxicity is increased with smaller size, larger surface area, adsorbed surface material, and the physical characteristics of the particles. Exposure to PM0.1 induces cough and worsens asthma. Metal fume fever is a systemic disease of lung inflammation most likely caused by PM0.1. The disease is manifested by systemic symptoms hours after exposure to metal fumes, usually through welding. PM0.1 cause systemic inflammation, endothelial dysfunction, and coagulation changes that predispose individuals to ischemic cardiovascular disease and hypertension. PM0.1 are also linked to diabetes and cancer. PM0.1 can travel up the olfactory nerves to the brain and cause cerebral and autonomic dysfunction. Moreover, in utero exposure increases the risk of low birthweight. Although exposure is commonly attributed to traffic exhaust, monitored students in Ghana showed the highest exposures in a home near a trash burning site, in a bedroom with burning coils employed to abate mosquitos, in a home of an adult smoker, and in home kitchens during domestic cooking. The high point-source production and rapid redistribution make incidental exposure common, confound general population studies and are compounded by the lack of global standards and national reporting. The potential for PM0.1 to cause harm to health is great, but their precise role in many illnesses is still unknown and calls for more research.
The field of small air quality sensors is of growing interest within the scientific community, especially because this new technology is liable to improve air pollutant monitoring as well as be used for personal exposure quantification. Amongst the myriad existing devices, the performances are highly variable; this is why the sensors must be rigorously assessed before deployment, according to the intended use. This study is included in the Polluscope project; its purpose is to quantify personal exposure to air pollutants by using portable sensors. This paper designs and applies a methodology for the evaluation of portable air quality sensors to eight devices measuring PM, BC, NO2 and O3. The dedicated testing protocol includes static ambient air measurements compared with reference instruments, controlled chamber and mobility tests, as well as reproducibility evaluation. Three sensors (AE51, Cairclip and Canarin) were retained to be used for the field campaigns. The reliability of their performances were robustly quantified by using several metrics. These three devices (for a total of 36 units) were deployed to be worn by volunteers for a week. The results show the ability of sensors to discriminate between different environments (i.e., cooking, commuting or in an office). This work demonstrates, first, the ability of the three selected sensors to deliver data reliable enough to enable personal exposure estimations, and second, the robustness of this testing methodology.
Cet article examine la qualité des réponses individuelles aux enquêtes Emploi de l'INSEE. Nous rappelons tout d'abord les conséquences possibles de l'existence d'erreurs de mesure pour l'analyse économétrique et présentons les principales statistiques permettant d'évaluer la qualité des données déclarées. Nous procédons ensuite à une évaluation de la qualité des déclarations salariales fournies en réponse à l'enquête Emploi à partir de données appariant une partie des enquêtes Emploi et les déclarations fiscales de revenus d'activité contenues dans les enquêtes Revenus Fiscaux. Nous examinons successivement la qualité des déclarations de niveaux de salaire et de variation interannuelles de salaire et discutons la contribution des comportements d'arrondi aux erreurs de mesure observées.
Rationale:
Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.
Objectives:
To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.
Methods and measurements:
We conducted genome-wide analyses across three independent studies and meta-analysed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.
Main results:
We identified and replicated three new genome-wide significant (P<5×10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1 and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF susceptibility variants contribute to IPF susceptibility.
Conclusions:
The observation that decreased DEPTOR expression associates with increased susceptibility to IPF, supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
Interstitial lung diseases (ILDs) are a set of heterogeneous lung diseases characterised by inflammation and, in some cases, fibrosis. These lung conditions lead to dyspnoea, cough, abnormalities in gas exchange, restrictive physiology (characterised by decreased lung volumes), hypoxaemia and, if progressive, respiratory failure. In some cases, ILDs can be caused by systemic diseases or environmental exposures. The ability to treat or cure these ILDs varies based on the subtype and in many cases lung transplantation remains the only curative therapy. There is a growing body of evidence that both common and rare genetic variants contribute to the development and clinical manifestation of many of the ILDs. Here, we review the current understanding of genetic risk and ILD.
Rationale: Workplace inhalational hazards remain common worldwide, even though they are ameliorable. Previous American Thoracic Society documents have assessed the contribution of workplace exposures to asthma and chronic obstructive pulmonary disease on a population level, but not to other chronic respiratory diseases. The goal of this document is to report an in-depth literature review and data synthesis of the occupational contribution to the burden of the major nonmalignant respiratory diseases, including airway diseases; interstitial fibrosis; hypersensitivity pneumonitis; other noninfectious granulomatous lung diseases, including sarcoidosis; and selected respiratory infections. Methods: Relevant literature was identified for each respiratory condition. The occupational population attributable fraction (PAF) was estimated for those conditions for which there were sufficient population-based studies to allow pooled estimates. For the other conditions, the occupational burden of disease was estimated on the basis of attribution in case series, incidence rate ratios, or attributable fraction within an exposed group. Results: Workplace exposures contribute substantially to the burden of multiple chronic respiratory diseases, including asthma (PAF, 16%); chronic obstructive pulmonary disease (PAF, 14%); chronic bronchitis (PAF, 13%); idiopathic pulmonary fibrosis (PAF, 26%); hypersensitivity pneumonitis (occupational burden, 19%); other granulomatous diseases, including sarcoidosis (occupational burden, 30%); pulmonary alveolar proteinosis (occupational burden, 29%); tuberculosis (occupational burden, 2.3% in silica-exposed workers and 1% in healthcare workers); and community-acquired pneumonia in working-age adults (PAF, 10%). Conclusions: Workplace exposures contribute to the burden of disease across a range of nonmalignant lung conditions in adults (in addition to the 100% burden for the classic occupational pneumoconioses). This burden has important clinical, research, and policy implications. There is a pressing need to improve clinical recognition and public health awareness of the contribution of occupational factors across a range of nonmalignant respiratory diseases.
Background
Surveys 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.
Methods
Dates 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.
Results
The 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.
Conclusion
Despite 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 registration
This study was registered at http://clinicaltrials.gov (NCT02772549) on May 10, 2016.
Electronic supplementary material
The online version of this article (10.1186/s12931-019-1076-0) contains supplementary material, which is available to authorized users.
Over the past decade, several large registries of patients with idiopathic pulmonary fibrosis (IPF) have been established. These registries are collecting a wealth of longitudinal data on thousands of patients with this rare disease. The data collected in these registries will be complementary to data collected in clinical trials because the patient populations studied in registries have a broader spectrum of disease severity and comorbidities and can be followed for a longer period of time. Maintaining the quality and completeness of registry databases presents administrative and resourcing challenges, but it is important to ensuring the robustness of the analyses. Data from patient registries have already helped improve understanding of the clinical characteristics of patients with IPF, the impact that the disease has on their quality of life and survival, and current practices in diagnosis and management. In the future, analyses of biospecimens linked to detailed patient profiles will provide the opportunity to identify biomarkers linked to disease progression, facilitating the development of precision medicine approaches for prognosis and therapy in patients with IPF.
Rationale: Characteristics and outcomes of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) in the United States remain understudied.Objectives: To determine the tumor characteristics and survival of patients with IPF with non-small cell lung cancer (NSCLC) using U.S. population-based data.Methods: We selected Medicare beneficiaries from the Surveillance, Epidemiology, and End Results registry with histologically confirmed NSCLC diagnosed between 2007 and 2011. IPF was identified using two validated claims-based algorithms. We compared tumor characteristics and used logistic and Cox regression to compare rates of stage-appropriate therapy and of overall and lung cancer-specific survival in those with IPF and without IPF.Results: A total of 54,453 patients with NSCLC were included. Those with IPF were more likely to be diagnosed at an earlier stage (P < 0.01) and to have squamous histology (46% vs. 35%; P < 0.01) and lower-lobe tumors (38% vs. 28%; P < 0.01) than those without IPF. Patients with IPF and stages I-II disease had odds of receiving stage-appropriate therapy similar to patients without IPF who had stages I-II disease (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.89-1.43); however, those with advanced disease were less likely to be treated (OR, 0.82; 95% CI, 0.68-0.99). Overall and lung cancer-specific survival were worse in patients with IPF (respectively, hazard ratio [HR], 1.35; 95% CI, 1.26-1.45; and HR, 1.21; 95% CI, 1.10-1.32).Conclusions: NSCLC has a unique presentation in patients with IPF and is associated with poorer prognosis. Further research is needed to identify optimal treatment strategies in this population.
Objective:
The aim of this study is to evaluate the efficacy and safety of pulmonary rehabilitation (PR) in patients with idiopathic pulmonary fibrosis (IPF). Methods. Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and Chinese Biomedical Literature Database (SinoMed) were comprehensively searched. Randomized controlled trials (RCTs) that investigated the effects of PR for IPF patients were included. Literature selection and data extraction were conducted by two review authors independently. The Cochrane Collaboration's Risk of Bias tool and RevMan software (version 5.3) were used to evaluate the quality of studies and conduct statistical analysis, respectively. Results. Seven studies (190 participants) were included. PR had a significant effect on six-minute walk distance (6MWD) (MD:48.60; 95%CI: 29.03 to 68.18; Z=4.87, P<0.00001), and 6MWD was improved more in subgroup analysis including studies conducted in Asia (MD: 53.62; 95%CI: 30.48 to 76.66; Z=4.54, P<0.00001) and Europe (MD:54.10; 95% CI: 26.65 to 101.56; Z=2.23, P=0.03). Forced vital capacity (FVC%) was higher (MD: 3.69; 95%CI: 0.16 to 7.23; Z=2.05, P=0.04). St. George's Respiratory Questionnaire (SGRQ)/IPF-specific SGRQ (SGRQ-I) total score was lower (MD: -7.87; 95% CI: -11.44 to -4.30; Z=4.32, P<0.0001). No significant effects were found for lung diffusing capacity determined by the single-breath technique (DLCO%) (MD: 3.02; 95%CI: -0.38 to 6.42; Z=1.74, P=0.08).
Conclusions:
This study suggests that PR may enhance exercise capacity and improve quality of life in IPF patients. Besides, PR may also delay the decline of lung function of patients with IPF. However, further research should more fully assess the efficacy and safety of PR for IPF.
Background:
Several single-exposure studies have documented possible effects of environmental factors on lung function, but none has relied on an exposome approach. We aimed to evaluate the association between a broad range of prenatal and postnatal lifestyle and environmental exposures and lung function in children.
Methods:
In this analysis, we used data from 1033 mother-child pairs from the European Human Early-Life Exposome (HELIX) cohort (consisting of six existing longitudinal birth cohorts in France, Greece, Lithuania, Norway, Spain, and the UK of children born between 2003 and 2009) for whom a valid spirometry test was recorded for the child. 85 prenatal and 125 postnatal exposures relating to outdoor, indoor, chemical, and lifestyle factors were assessed, and lung function was measured by spirometry in children at age 6-12 years. Two agnostic linear regression methods, a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering exposures independently, were applied to test the association with forced expiratory volume in 1 s percent predicted values (FEV1%). We tested for two-way interaction between exposures and corrected for confounding by co-exposures.
Findings:
In the 1033 children (median age 8·1 years, IQR 6·5-9·0), mean FEV1% was 98·8% (SD 13·2). In the ExWAS, prenatal perfluorononanoate (p=0·034) and perfluorooctanoate (p=0·030) exposures were associated with lower FEV1%, and inverse distance to nearest road during pregnancy (p=0·030) was associated with higher FEV1%. Nine postnatal exposures were associated with lower FEV1%: copper (p=0·041), ethyl-paraben (p=0·029), five phthalate metabolites (mono-2-ethyl 5-carboxypentyl phthalate [p=0·016], mono-2-ethyl-5-hydroxyhexyl phthalate [p=0·023], mono-2-ethyl-5-oxohexyl phthalate [p=0·0085], mono-4-methyl-7-oxooctyl phthalate [p=0·040], and the sum of di-ethylhexyl phthalate metabolites [p=0·014]), house crowding (p=0·015), and facility density around schools (p=0·027). However, no exposure passed the significance threshold when corrected for multiple testing in ExWAS, and none was selected with the DSA algorithm, including when testing for exposure interactions.
Interpretation:
Our systematic exposome approach identified several environmental exposures, mainly chemicals, that might be associated with lung function. Reducing exposure to these ubiquitous chemicals could help to prevent the development of chronic respiratory disease.
Funding:
European Community's Seventh Framework Programme (HELIX project).
Background:
There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes.
Objectives:
We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort - Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences.
Methods:
Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender.
Results:
The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George's Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females.
Conclusions:
This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females.
Background
Low income, a known prognostic indicator of various chronic respiratory diseases, has not been properly studied in idiopathic pulmonary fibrosis (IPF). We hypothesize that a low income has an adverse prognostic impact on IPF.
Methods
Patients were selected from the French national prospective cohort COFI. Patients’ income was assessed through the median city-level income provided by the French National Institute of Statistics and Economic Studies according to their residential address. Patients were classified in two groups as "low income" vs. "higher income" depending on whether their annual income was estimated to be < or ≥ 18 170 €/year (the first quartile of the income distribution in the study population). The survival and progression-free survival (PFS) of the groups were compared by a log-rank test and a Cox model in multivariate analysis.
Results
200 patients were included. The average follow-up was 33.8±22.7 months. Patients in the low income group were significantly more likely to be of non-European origin (p<0.006), and to have at least one occupational exposure (p<0.0001), and they tended to have a higher cumulative exposure to fine particles PM2.5 (p=0.057). After adjusting for age, gender, forced vital capacity at inclusion, geographical origin, and occupational exposure having a low-income level was a factor associated with a worse PFS (HR: 1.81; CI95%: 1.24 - 2.62, p=0.001) and overall survival (HR: 1.49; CI95%: 1.0006 - 2.23, p=0.049).
Conclusions
Low income appears to be a prognostic factor in IPF. IPF patients with low incomes may also be exposed more frequently to occupational exposures.
Background:
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with unknown etiology. A limited number of small studies showed an effect of tobacco smoking on risk for IPF, but second-hand smoking has not been examined.
Research question:
Are smoking-related exposures associated with risk for IPF, and is there any interaction between them?
Study design and methods:
We designed a prospective cohort study in UK Biobank, including 437,453 non-related men and women of white ethnic background (aged 40 to 69 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 for potential additive and multiplicative interaction between these exposures. Multiple imputation with chained equations was used to deal with missing data.
Results:
We identified 802 incident IPF cases. We showed an association between smoking status (HR, 2.12; 95% CI, 1.81-2.47), maternal smoking (HR, 1.38; 95% CI, 1.18-1.62) and smoking in household (HR, 1.26; 95% CI, 1.02-1.57) with risk for IPF in the multivariable model. 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 HR of 1.50 (95% CI, 1.05-2.14).
Interpretation:
Active and passive 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.
Ambient air pollution is associated with prognosis of idiopathic pulmonary fibrosis (IPF) patients. We aimed to identify the impacts of individual exposure to particulate matter with aerodynamic diameter ≤10 μm (PM 10 ) and nitrogen dioxide (NO 2 ) on IPF patients' mortality.
Total 1114 patients (mean age, 65.7 years; male, 80.5%) diagnosed with IPF between 1995 and 2016 were included in this study. Individual-level long-term concentrations of PM 10 and NO 2 at residential addresses of patients were estimated using a national-scale exposure prediction model. The effect of PM 10 and NO 2 on mortality was estimated using a Cox proportional hazards model adjusted for individual- and area-level covariates.
The median follow-up period was 3.8 years, and 69.5% of all the patients died or underwent lung transplantation. When adjusted for individual- and area-level covariates, a 10-ppb increase in NO 2 concentration was associated with a 17% increase in mortality (hazard ratio [HR], 1.172 [95% CI: 1.030–1.344, p=0.016]). When IPF patients were stratified by age (≥65 years versus <65 years) or by sex, NO 2 was a significant prognostic factor for mortality in the elderly (HR, 1.331 [95% CI: 1.010–1.598, p=0.010]). When stratified by age and sex jointly, NO 2 showed the stronger association with mortality in elderly male (HR, 1.305 [95% CI: 1.072–1.598, p=0.008]) than in other groups. PM 10 was not associated with IPF mortality in all patients and in subgroups stratified by age or sex.
Our findings suggest that increased exposure to NO 2 can increase risk of mortality in patients with IPF, specifically in elderly men.
Background and objective
The relationship between IPF development and environmental factors has not been completely elucidated. Analysing geographic regions of idiopathic pulmonary fibrosis (IPF) cases could help identify those areas with higher aggregation and investigate potential triggers. We hypothesize that cross‐analysing location of IPF cases and areas of consistently high air pollution concentration could lead to recognition of environmental risk factors for IPF development.
Methods
This retrospective study analysed epidemiological and clinical data from 503 patients registered in the Observatory IPF.cat from January 2017 to June 2019. Incident and prevalent IPF cases from the Catalan region of Spain were graphed based on their postal address. We generated maps of the most relevant air pollutant PM2.5 from the last 10 years using data from the CALIOPE air quality forecast system and observational data.
Results
In 2018, the prevalence of IPF differed across provinces; from 8.1 cases per 100 000 habitants in Barcelona to 2.0 cases per 100 000 in Girona. The ratio of IPF was higher in some areas. Mapping PM2.5 levels illustrated that certain areas with more industry, traffic and shipping maintained markedly higher PM2.5 concentrations. Most of these locations correlated with higher aggregation of IPF cases. Compared with other risk factors, PM2.5 exposure was the most frequent.
Conclusion
In this retrospective study, prevalence of IPF is higher in areas of elevated PM2.5 concentration. Prospective studies with targeted pollution mapping need to be done in specific geographies to compile a broader profile of environmental factors involved in the development of pulmonary fibrosis.
Rationale:
Current evidence on the relationship between long-term exposure to air pollution and new onset of chronic lung disease is inconclusive.
Objective:
To examine associations of incident chronic obstructive pulmonary disease (COPD) and adult-onset asthma with past exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3), and the redox-weighted average of NO2 and O3 (Ox), and characterize the concentration-response relationship.
Methods:
We conducted a population-based cohort study of all Ontarians, aged 35 to 85 years, from 2001 to 2015. 3-year moving average of residential exposures to selected pollutants with 1-year lag were estimated during follow-up. We used Cox proportional and Aalen's additive hazards models to quantify the pollution-disease associations, and characterized the shape of these relationships using newly developed non-linear risk models.
Measurements and main results:
Among 5.1 million adults, we identified 340,733 and 218,005 incident cases of COPD and asthma, respectively. We found positive associations of COPD with PM2.5 per interquartile-range (IQR) increase of 3.4µg/m3 (hazard ratio, 1.07; 95% confidence interval, 1.06-1.08), NO2 per 13.9ppb (1.04; 1.02-1.05), O3 per 6.3ppb (1.04; 1.03-1.04), and Ox per 4.4ppb (1.03; 1.03-1.03). By contrast, we did not find strong evidence linking these pollutants to adult-onset asthma. Additionally, we quantified that each IQR increase in pollution exposure yielded 3.0 (2.4-3.6) excess cases of COPD per 100,000 adults for PM2.5, 3.2 (2.0-4.3) for NO2, 1.9 (1.3-2.5) for O3, 2.3 (1.7-2.9) for Ox. Furthermore, most pollutant-COPD relationships exhibited supralinear shapes.
Conclusions:
Air pollution was associated with higher incidence of COPD, but not adult-onset asthma.
Résumé
Les maladies allergiques sont le résultat d’interactions entre de multiples facteurs génétiques et environnementaux et seuls des changements environnementaux récents peuvent expliquer leur augmentation au cours des dernières décennies. Le concept d’exposome englobe l’ensemble des facteurs d’exposition à l’environnement extérieur, spécifiques et non spécifiques, auxquels un sujet donné est soumis dès la préconception et les conséquences de ces expositions au niveau des cellules et des organes (exposome interne) à l’origine des processus pathologiques. L’étude de l’exposome contribue de manière significative à la compréhension de l’établissement, du développement et de l’exacerbation de l’asthme et des maladies allergiques qui sont des maladies complexes. Un nombre croissant de preuves scientifiques confirme que les polluants atmosphériques interagissent avec les aéroallergènes, augmentant le risque de sensibilisation allergique et l’apparition et le développement d’une allergopathie chez les sujets sensibilisés. Les facteurs socioéconomiques et le mode de vie sont également des aspects cruciaux dans le développement de l’exposition extérieure et dans l’identification des individus à risque. L’hypothèse de la perte de la biodiversité affirme que le contact avec la nature enrichit le microbiome humain et favorise le bon équilibre du système immunitaire, protégeant ainsi contre le développement de problèmes inflammatoires ; au contraire, la perte de biodiversité en termes de plantes, d’animaux et de microorganismes entraîne des phénomènes d’immuno-dérégulation et d’inflammation chronique avec une augmentation conséquente des maladies chroniques, y compris de l’asthme et des maladies allergiques.
This review covers fibrotic pulmonary diseases. Although idiopathic pulmonary fibrosis is very common, the review focuses mainly on fibrotic diseases other than IPF. The biology, clinical presentation, and treatment of the more common disorders are discussed.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a lung disease of unknown cause characterised by progressive scarring, with limited effective treatment and a median survival of only 2–3 years. Our aim was to identify potential occupational and environmental exposures associated with IPF in Australia.
Methods
Cases were recruited by the Australian IPF registry. Population-based controls were recruited by random digit dialling, frequency matched on age, sex and state. Participants completed a questionnaire on demographics, smoking, family history, environmental and occupational exposures. Occupational exposure assessment was undertaken with the Finnish Job Exposure Matrix and Australian asbestos JEM. Multivariable logistic regression was used to describe associations with IPF as ORs and 95% CIs, adjusted for age, sex, state and smoking.
Results
We recruited 503 cases (mean±SD age 71±9 years, 69% male) and 902 controls (71±8 years, 69% male). Ever smoking tobacco was associated with increased risk of IPF: OR 2.20 (95% CI 1.74 to 2.79), but ever using marijuana with reduced risk after adjusting for tobacco: 0.51 (0.33 to 0.78). A family history of pulmonary fibrosis was associated with 12.6-fold (6.52 to 24.2) increased risk of IPF. Occupational exposures to secondhand smoke (OR 2.1; 1.2 to 3.7), respirable dust (OR 1.38; 1.04 to 1.82) and asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF. However occupational exposures to other specific organic, mineral or metal dusts were not associated with IPF.
Conclusion
The burden of IPF could be reduced by intensified tobacco control, occupational dust control measures and elimination of asbestos at work.
Background:
Idiopathic pulmonary fibrosis (IPF) is a disease with a male predominance. Prior data suggest that male sex is associated with disease progression and survival. The basis for this sex difference is unknown.
Research question:
Are there differences in clinical disease characteristics and outcomes between men and women with idiopathic pulmonary fibrosis?
Study design:
and Methods: Two tertiary care center IPF cohorts were pooled to analyze sex differences in outcomes of time to lung transplantation or death. Predictors of outcome that were analyzed included age, forced vital capacity percent predicted (FVC%), diffusion capacity for carbon monoxide percent predicted (DLCO%), body mass index, smoking history, and respiratory variables of cough, phlegm, and need for supplemental oxygen. These associations of these factors with mortality were estimated by sex, then compared using tests for interaction.
Results:
There were a total of 1,263 patients in the pooled cohort with follow-up data, approximately 71% of whom were men. Male sex was independently associated with higher risk for death or lung transplantation after adjusting for age, FVC%, and DLCO% (HR for men 1.4, 95% CI [1.2, 1.7], p<0.001). Older age, lower DLCO%, and presence of cough or phlegm were negatively associated with transplant-free survival in men but not in women, but only the association for cough differed statistically by sex (interaction p=0.007).
Interpretation:
Male sex is associated with worse transplant-free survival in IPF. Cough may be a sex-specific predictor of survival in this population.
Rationale:
The pre-clinical natural history of progressive lung fibrosis is poorly understood.
Objectives:
Our goal was to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans, and determine progression towards clinical interstitial lung disease (ILD) among participants in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia.
Methods:
Enrollment evaluation included health/exposure questionnaire and HRCT, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study-time to complete a 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated.
Measurements and main results:
Among 336 subjects, the mean age was 53.1 (SD 9.9) years. Those with ILA [early/mild (n=74) or extensive (n=3)] were older, more likely ever-smokers, had shorter peripheral-blood mononuclear cell telomeres, and more likely carried the MUC5B risk allele. Self-reported environmental/occupational exposures, including aluminum smelting, lead, birds, and mold were independently associated with ILA. Among 129 subjects with sufficient study-time, 25 (19.4%) had an ILD event by 5 years post-enrollment [12 met the study endpoint and another 13 had radiologic progression of ILA]. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs 6.1%, p<0.0001).
Conclusions:
Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.
Air quality data from satellites and low-cost sensor systems, together with output from air quality models, have the potential to augment high-quality, regulatory-grade data in countries with in situ monitoring networks and provide much-needed air quality information in countries without them. Each of these technologies has strengths and limitations that need to be considered when integrating them to develop a robust and diverse global air quality monitoring network. To address these issues, the American Thoracic Society, the U.S. Environmental Protection Agency, the National Aeronautics and Space Administration, and the National Institute of Environmental Health Sciences convened a workshop in May 2017 to bring together global experts from across multiple disciplines and agencies to discuss current and near-term capabilities to monitor global air pollution. The participants focused on four topics: 1) current and near-term capabilities in air pollution monitoring, 2) data assimilation from multiple technology platforms, 3) critical issues for air pollution monitoring in regions without a regulatory-quality stationary monitoring network, and 4) risk communication and health messaging. Recommendations for research and improved use were identified during the workshop, including a recognition that the integration of data across monitoring technology groups is critical to maximizing the effectiveness (e.g., data accuracy, as well as spatial and temporal coverage) of these monitoring technologies. Taken together, these recommendations will advance the development of a global air quality monitoring network that takes advantage of emerging technologies to ensure the availability of free, accessible, and reliable air pollution data and forecasts to health professionals, as well as to all global citizens.
Background:
Connective tissue growth factor (CTGF) is a secreted glycoprotein that has a central role in the process of fibrosis. This study was designed to assess the safety, tolerability, and efficacy of pamrevlumab (FG-3019), a fully recombinant human monoclonal antibody against CTGF, in idiopathic pulmonary fibrosis. The aim was to establish whether pamrevlumab could slow, stop, or reverse progression of idiopathic pulmonary fibrosis.
Methods:
The phase 2, randomised, double-blind, placebo-controlled PRAISE trial was done at 39 medical centres in seven countries (Australia, Bulgaria, Canada, India, New Zealand, South Africa, and the USA). Patients with idiopathic pulmonary fibrosis and percentage of predicted forced vital capacity (FVC) of 55% or greater were enrolled and randomly assigned (1:1) by use of interactive responsive technology to intravenous infusion of pamrevlumab 30 mg/kg or placebo every 3 weeks over 48 weeks (16 infusions). The primary efficacy outcome was change from baseline in percentage of predicted FVC at week 48. Disease progression (defined as a decline from baseline in percentage of predicted FVC of ≥10%, or death) at week 48 was a key secondary efficacy outcome. All patients in the pamrevlumab group received at least one dose of the study drug and were analysed for safety. Two patients in the placebo group were excluded from the intention-to-treat population for the efficacy analyses because of enrolment error. This trial is registered with ClinicalTrials.gov, NCT01890265.
Findings:
Between Aug 17, 2013, and July 21, 2017, 103 patients were randomly assigned (50 to pamrevlumab and 53 to placebo). Pamrevlumab reduced the decline in percentage of predicted FVC by 60·3% at week 48 (mean change from baseline -2·9% with pamrevlumab vs -7·2% with placebo; between-group difference 4·3% [95% CI 0·4-8·3]; p=0·033). The proportion of patients with disease progression was lower in the pamrevlumab group than in the placebo group at week 48 (10·0% vs 31·4%; p=0·013). Pamrevlumab was well tolerated, with a safety profile similar to that of placebo. Treatment-emergent serious adverse events were observed in 12 (24%) patients in the pamrevlumab group and eight (15%) in the placebo group, with three patients on pamrevlumab and seven on placebo discontinuing treatment. Of the three (6%) deaths in the pamrevlumab group and six (11%) in the placebo group, none was considered treatment related.
Interpretation:
Pamrevlumab attenuated progression of idiopathic pulmonary fibrosis and was well tolerated. Now in phase 3 development, pamrevlumab shows promise as a novel, safe, and effective treatment for idiopathic pulmonary fibrosis.
Funding:
FibroGen.
Background:
The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias.
Methods:
We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration-response curves from each city were pooled to allow global estimates to be derived.
Results:
On average, an increase of 10 μg per cubic meter in the 2-day moving average of PM10 concentration, which represents the average over the current and previous day, was associated with increases of 0.44% (95% confidence interval [CI], 0.39 to 0.50) in daily all-cause mortality, 0.36% (95% CI, 0.30 to 0.43) in daily cardiovascular mortality, and 0.47% (95% CI, 0.35 to 0.58) in daily respiratory mortality. The corresponding increases in daily mortality for the same change in PM2.5 concentration were 0.68% (95% CI, 0.59 to 0.77), 0.55% (95% CI, 0.45 to 0.66), and 0.74% (95% CI, 0.53 to 0.95). These associations remained significant after adjustment for gaseous pollutants. Associations were stronger in locations with lower annual mean PM concentrations and higher annual mean temperatures. The pooled concentration-response curves showed a consistent increase in daily mortality with increasing PM concentration, with steeper slopes at lower PM concentrations.
Conclusions:
Our data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe. These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies. (Funded by the National Natural Science Foundation of China and others.).
Rationale:
Real-world data on pirfenidone treatment of patients with idiopathic pulmonary fibrosis (IPF) are limited. This study assessed the effectiveness of pirfenidone in a large real-life Italian IPF cohort.
Methods:
IRENE was an observational, retrospective study of patients with IPF treated with pirfenidone in routine clinical practice (18 centres). At Month 6, a mandatory re-evaluation of forced vital capacity (FVC) decline (absolute change < 10%) was required to continue pirfenidone. The primary effectiveness outcomes were absolute change from baseline in FVC and the percentage of patients with ≥ 10% absolute decline in % predicted FVC at Month 12. Safety was described by adverse event (AE) occurrence. Prespecified subgroups included sex, age, presence/absence of emphysema, usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography, and baseline lung function.
Results:
The study included 379 patients (mean age, 67.6 years; 78.1% male). Mean change from baseline in FVC and the percentage of patients with ≥ 10% absolute decline in % predicted FVC at Month 12 were -81.8 mL (SD, 419.6 mL; P = 0.002) and 16.0% (95% CI, 12.2-20.9%), respectively. Disease progression was similar across prespecified subgroups, including patients with definite vs possible UIP. Overall, 211 AEs occurred in 149 patients (39.3%), with serious AEs in 31 patients (8.2%) and 9 discontinuations due to AEs. Skin and gastrointestinal AEs were most frequent. Fifteen patients (4.0%) died.
Conclusions:
The decline in FVC and the safety profile observed in this real-world IPF cohort were consistent with the findings of the Phase III pirfenidone trials.
Background
Ambient air pollution accelerates lung function decline among adults, however, there are limited data about its role in the development and progression of early stages of interstitial lung disease.
Aims
To evaluate associations of long-term exposure to traffic and ambient pollutants with odds of interstitial lung abnormalities (ILA) and progression of ILA on repeated imaging.
Methods
We ascertained ILA on chest CT obtained from 2618 Framingham participants from 2008 to 2011. Among 1846 participants who also completed a cardiac CT from 2002 to 2005, we determined interval ILA progression. We assigned distance from home address to major roadway, and the 5-year average of fine particulate matter (PM 2.5 ), elemental carbon (EC, a traffic-related PM 2.5 constituent) and ozone using spatio-temporal prediction models. Logistic regression models were adjusted for age, sex, body mass index, smoking status, packyears of smoking, household tobacco exposure, neighbourhood household value, primary occupation, cohort and date.
Results
Among 2618 participants with a chest CT, 176 (6.7%) had ILA, 1361 (52.0%) had no ILA, and the remainder were indeterminate. Among 1846 with a preceding cardiac CT, 118 (6.4%) had ILA with interval progression. In adjusted logistic regression models, an IQR difference in 5-year EC exposure of 0.14 µg/m ³ was associated with a 1.27 (95% CI 1.04 to 1.55) times greater odds of ILA, and a 1.33 (95% CI 1.00 to 1.76) times greater odds of ILA progression. PM 2.5 and O 3 were not associated with ILA or ILA progression.
Conclusions
Exposure to EC may increase risk of progressive ILA, however, associations with other measures of ambient pollution were inconclusive.
Fine particulate matter (PM2.5) from livestock houses is harmful not only to the health and welfare of animals but also to the farmers working inside. As an important pollution source in the atmosphere environment, PM2.5 can threaten public health. PM2.5 collected from nursery pig house was studied. It included particulates of various morphologies, and the concentration of endotoxin was as high as to 681.80 EU/mg. To investigate the ability of PM2.5 from the nursery pig house to induce an immune response, porcine alveolar macrophages 3D4/21 cells were studied. The results showed that PM2.5 can induce cell death, ROS production and inflammatory cytokines release (IL-1β, IL-18, TNF-α and COX-2) by activating TLR4/MyD88 pathway and NLRP3 inflammasome. Furthermore, the downstream signaling pathways of TLR4/MyD88, MAPK and NF-κB, participated in NLRP3 inflammasome activation. To further study the role of endotoxin present in PM2.5 and the oxidative stress induced by PM2.5, polymyxin B (PMB) and N-acetylcysteine (NAC) were used to neutralize the effect of the endotoxin and inhibit the production of ROS, respectively. The results showed endotoxin and ROS played important roles in PM2.5-induced immune response. This study suggests that PM2.5 from pig house is a significant risk for immune response in alveolar macrophages.
Background
Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study.
Methods
Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24.
Findings
Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of −3·6% per year and in 6-min walking distance of −10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from −8·7% per year in weeks 0–28 to −0·9% per year in weeks 28–52, p<0·0001) and 6-min walking distance (from −54·9 m per year to −3·5 m per year, p=0·0224).
Interpretation
Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF.
Funding
Promedior.
Collis and Yule 1 stated in 1933, that “silica is such a body poison as is lead, even though it exerts its maleficent influence, especially with regard to tuberculosis, mainly on the respiratory organs, through which it gains access to the body”. This statement invites us to question the editorial 2 entitled “The world is failing on silicosis” in The Lancet Respiratory Medicine. As clinicians, radiologists, toxicologists, and social scientists working on health hazards related to crystalline silica exposure, we delve beyond silicosis, to learn of other dangers associated with silica.
Background:
The European observational, prospective PASSPORT study evaluated the long-term safety of pirfenidone under real-world conditions in idiopathic pulmonary fibrosis (IPF), over up to 2 years following its initiation.
Objectives:
The FAS (French Ancillary Study) assessed the clinical outcomes of IPF patients participating in PASSPORT (n = 192).
Methods:
Efficacy data were collected retrospectively and prospectively. The primary efficacy endpoints were: change in percent predicted forced vital capacity (FVC) and change in the distance travelled during the 6-min walk test (6MWD).
Results:
The mean baseline FVC was 71.7% of predicted value. The mean absolute change in the percentage of predicted FVC was -2.4% and -3.8% at months 12 and 24. The mean change in 6MWD was 8.6 and 3.1 m at months 12 and 24, with a range of 23.4-51.7 m. Acute IPF exacerbation and pulmonary hypertension occurred in 20.0 and 8.4% of patients, respectively. The most common reasons for prematurely discontinuing PASSPORT were adverse drug reactions (ADRs) related to pirfenidone (31.3%), death (11.5%), and disease progression (10.9%). The median progression-free survival was 18.4 months (95% CI 12.9, not estimable). The median exposure was 16.3 months (0.5-28.5). The most frequently reported ADRs leading to pirfenidone discontinuation were decreased weight (4.2%), rash (4.2%), and photosensitivity reactions (3.1%).
Conclusions:
The efficacy data of FAS are consistent with the efficacy results of published phase III clinical trials in IPF. Approximately one third of IPF patients treated with pirfenidone in real-life settings were still under treatment 2 years after initiation. Safety data are consistent with the known safety profile of pirfenidone.
Background and objective
Sleep‐disordered breathing (SDB) has been reported as highly prevalent in idiopathic pulmonary fibrosis (IPF) and other interstitial lung disease (ILD) populations. Nocturnal oxygen desaturation (NOD), or the total sleep time spent with SpoO2 < 90% (TST < 90), can occur both with and without associated apnoeas, and is common in ILD. This study aimed to characterize abnormal SDB and extent of TST < 90 in ILD patients and evaluate relationships between TST < 90 and markers of disease severity, development of pulmonary hypertension (PH) and mortality.
Methods
Consecutive, newly referred ILD patients attending a specialist clinic underwent polysomnography (PSG). Serial lung function tests, echocardiography and other clinical variables were recorded. Predictors of PH and mortality were evaluated using logistic regression and Cox proportional hazards regression analyses.
Results
A total of 92 ILD patients (including 44 with IPF) underwent PSG. At least mild obstructive sleep apnoea (OSA) was observed in 65.2%, with rapid eye movement (REM)‐related events occurring frequently. At least 10% TST < 90 (designated ‘significant NOD’) was present in 35.9% of patients, and was associated with PH at baseline echocardiography. Multiple indices of hypoxaemia during sleep, including significant NOD, predicted the development of new or worsening PH. TST < 90 predicted overall and progression‐free survival.
Conclusion
Nocturnal oxygen saturation is associated with poorer prognosis in ILD patients and may contribute towards the pathogenesis of pulmonary vascular disease.
In idiopathic pulmonary fibrosis (IPF), the role of gastro-oesophageal reflux (GOR) and its treatment remain unclear [1]. Both acid and non-acid components of GOR contribute to lung inflammation and fibrosis [2, 3]. There are conflicting data on the use of proton-pump inhibitors (PPIs) in IPF, which do not act on the non-acid component of GOR and may be associated with higher rates of respiratory infection [4, 5]. Hiatus hernia (HH) is strongly linked to GOR [6] and is common in IPF patients [7].