Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in COPDGene.

RATIONALE: Quantitative interstitial abnormalities (QIA) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIA and its role in the QIA-outcome relationship is unknown. OBJECTIVES: To quantify radiographic pulmonary vasculopathy in quantitative interstitial abnormalities (QIA) and determine if this vasculopathy mediates the QIA-outcome relationship. METHODS: Ever-smokers with QIA, outcome, and pulmonary vascular mediator data were identified from the COPDGene cohort. CT-based vascular mediators were: right ventricle-to-left ventricle ratio (RV/LV), pulmonary artery-to-aorta ratio (PA/Ao), and pre-acinar intraparenchymal arterial dilation (PA volume 5-20mm2 in cross-sectional area, normalized to total arterial volume). Outcomes were: six-minute walk distance (6MWD) and modified Medical Council Research Council (mMRC) Dyspnea score ≥2. Adjusted causal mediation analyses were used to determine if the pulmonary vasculature mediated the QIA effect on outcomes. Associations of pre-acinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. MAIN RESULTS: Among 8,200 participants, QIA burden correlated positively with vascular damage measures including pre-acinar arterial dilation. Pre-acinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6MWD (56.2-100%, p<0.001). PA/Ao was a weak mediator and RV/LV was a suppressor. Similar results were observed in the QIA-mMRC relationship. Pre-acinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels including angiopoietin-2 and NT-proBNP. CONCLUSIONS: Parenchymal quantitative interstitial abnormalities (QIA) deleteriously impact outcomes primarily through pulmonary vasculopathy. Pre-acinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIA.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common single nucleotide polymorphisms (SNPs). The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis, clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia (UIP)/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. Additionally, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multi-omic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Thematic analysis to explore patients' experiences with long COVID-19: a conceptual model of symptoms and impacts on daily lives.

OBJECTIVES: There is limited qualitative research on patients' experiences with long COVID-19, and how specific symptoms impact their daily lives. The study aimed to understand patients' lived experiences of long COVID-19 and to develop a conceptual model representing the symptoms and their impact on overall quality of life. SETTING: Qualitative study consisting of a comprehensive literature review, and in-depth clinician and patient semistructured interviews. PARTICIPANTS: Forty-one adult patients with long COVID-19, of whom 18 (44%) were recruited through Regeneron Pharmaceuticals's clinical trials and 23 (56%) through recruitment agencies; 85.4% were female and 73.2% were White. Five independent clinicians treating patients with long COVID-19 were interviewed. Concept saturation was also assessed. PRIMARY AND SECONDARY OUTCOMES: Interview transcripts were analysed thematically to identify concepts of interest spontaneously mentioned by patients, including symptoms and their impacts on daily life, to guide the development of the conceptual model. RESULTS: Findings from the literature review and clinician and patient interviews resulted in the development of a conceptual model comprising two overarching domains: symptoms (upper respiratory tract, lower respiratory tract, smell and taste, systemic, gastrointestinal, neurocognitive and other) and impacts (activities of daily living, instrumental activities of daily living, physical impacts, emotional, social/leisure activities and professional impacts). Saturation was achieved for the reported impacts. The symptoms reported were heterogenic; neurocognitive symptoms, such as numbness, ringing in ears, haziness, confusion, forgetfulness/memory problems, brain fog, concentration, difficulties finding the right word and challenges with fine motor skills, were particularly pertinent for several months. CONCLUSION: The conceptual model, developed based on patient experience data of long COVID-19, highlighted numerous symptoms that impact patients' physical and mental well-being, and suggests humanistic unmet needs. Prospective real-world studies are warranted to understand the pattern of long COVID-19 experienced in larger samples over longer periods of time.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Defining the pathway to timely diagnosis and treatment of interstitial lung disease: a US Delphi survey.

INTRODUCTION: Timely diagnosis of interstitial lung disease (ILD) is limited by obstacles in the current patient pathway. Misdiagnosis and delays are common and may lead to a significant burden of diagnostic procedures and worse outcomes. This Delphi survey aimed to identify consensus on the key steps that facilitate the patient journey to an accurate ILD diagnosis and appropriate management in the US. METHODS: A modified Delphi analysis was conducted, comprising three online surveys based on a comprehensive literature search. The surveys spanned five domains (guidelines, community screening, diagnosis, management and specialist referral) and were completed by a panel of US physicians, including primary care physicians and pulmonologists practising in community or academic settings. A priori definitions of consensus agreement were median scores of 2-3 (agree strongly/agree), with an IQR of 0-1 for questions on a 7-point Likert scale from -3 to 3, or ≥80% agreement for binary questions. RESULTS: Forty-nine panellists completed the surveys and 62 statements reached consensus agreement. There was consensus agreement on what should be included in the primary care evaluation of patients with suspected ILD and the next steps following workup. Regarding diagnosis in community pulmonology care, consensus agreement was reached on the requisition and reporting of high-resolution CT scans and the appropriate circumstances for holding multidisciplinary discussions. Additionally, there was consensus agreement on which symptoms and comorbidities should be monitored, the frequency of consultations and the assessment of disease progression. Regarding specialist referral, consensus agreement was reached on which patients should receive priority access to ILD centres and the contents of the referral package. CONCLUSIONS: These findings clarify the most common issues that should merit further evaluation for ILD and help define the steps for timely, accurate diagnosis and appropriate collaborative specialty management of patients with ILD.

Practice patterns in reporting interstitial lung abnormality at a tertiary academic medical center.

PURPOSE: Interstitial lung abnormality (ILA) is a common finding on chest CTs and is associated with higher all-cause mortality. The 2020 Fleischner Society position paper standardized the terminology and definition of ILA. Despite these published guidelines, the extent to which radiologists use this term is unknown. We evaluated practice patterns for identification of ILAs among radiologists at a tertiary academic medical center. METHODS: In this retrospective review, we identified 157 radiology reports between January 1, 2010 through December 31, 2021 containing the phrase "interstitial lung abnormality" or "interstitial abnormality". After exclusions, 125 CT scans were reviewed by thoracic-trained radiologists using the sequential reading method. RESULTS: Seventy-seven (62%) patients were found to have ILA (69% subpleural fibrotic, 19% subpleural non-fibrotic, and 6% non-subpleural), nine (7%) were equivocal for ILA and 39 (31%) had no ILA. The term ILA was used exclusively by thoracic-trained radiologists except for two cases. Use of the term ILA has rapidly increased since the position paper publication (none from 2010-2017, one case in 2018, 20 cases in 2019, 41 cases in 2020, and 73 cases in 2021), and cases were typically very mild (1-25% of the lung). CONCLUSION: While there has been increased use of the term ILA among thoracic-trained radiologists, non-thoracic radiologists have essentially not begun to use the term. Almost one-third of cases labeled ILA on clinical reads were re-classified as not having ILA on research reads.

Prevalence, Risk Factors, and Outcomes of Adult Interstitial Lung Abnormalities: A Systematic Review and Meta-Analysis.

Rationale: Incidental parenchymal abnormalities detected on chest computed tomography scans are termed interstitial lung abnormalities (ILAs). ILAs may represent early interstitial lung disease (ILD) and are associated with an increased risk of progressive fibrosis and mortality. The prevalence of ILAs is unknown, with heterogeneity across study populations. Objectives: Estimate the pooled prevalence of ILAs in lung cancer screening, general population-based, and at-risk familial cohorts using meta-analysis; identify variables associated with ILA risk; and characterize ILA-associated mortality. Methods: The study protocol was registered on PROSPERO (CRD42022373203), and Meta-analyses of Observational Studies in Epidemiology recommendations were followed. Relevant studies were searched on Embase and Medline. Study titles were screened and abstracts reviewed for full-text eligibility. Random effect models were used to pool prevalence estimates for specified subgroups and ILA-associated mortality risk. Risk of ILAs was estimated based on age, sex, and FVC. Quality assessment was conducted using an adapted Assessment Tool for Prevalence Studies. Measurements and Main Results: The search identified 9,536 studies, with 22 included, comprising 88,325 participants. The pooled ILA prevalence was 7% (95% confidence interval [CI], 0.01-0.13) in lung cancer screening, 7% (95% CI, 0.04-0.10) in general population, and 26% (95% CI, 0.20-0.32) in familial cohorts. Pooled mortality risk was increased in those with ILAs (odds ratio, 3.56; 95% CI, 2.19-5.81). Older age, male sex, and lower FVC% were associated with greater odds of ILA. Conclusions: Populations undergoing imaging for non-ILD indications demonstrate high ILA prevalence. Standardized reporting and follow-up of ILAs is needed, including defining those at greatest risk of progression to ILD.

Incidence of Interstitial Lung Abnormalities: The MESA Lung Study.

The incidence of newly developed interstitial lung abnormalities (ILA) and fibrotic ILA have not been previously reported.Trained thoracic radiologists evaluated 13 944 cardiac CT scans for the presence of ILA in 6197 Multi-Ethnic Study of Atherosclerosis longitudinal cohort study participants >45 years of age from 2000 to 2012. 5% of the scans were re-read by the same or a different observer in a blinded fashion. After exclusion of participants with ILA at baseline, incidence rates and incidence rate ratios for ILA and fibrotic ILA were calculated.The intra-reader agreement of ILA was 92.0% (Gwet AC1=0.912, ICC=0.982) and the inter-reader agreement of ILA was 83.5% (Gwet AC1=0.814; ICC=0.969). Incidence of ILA and fibrotic ILA was estimated to be 13.1 cases/1000 person-years and 3.5/1000 person-years, respectively. In multivariable analyses, age (HR 1.06 (1.05, 1.08), p <0.001; HR 1.08 (1.06, 1.11), p <0.001), high attenuation area (HAA) at baseline (HR 1.05 (1.03, 1.07), p <0.001; HR 1.06 (1.02, 1.10), p=0.002), and the MUC5B promoter SNP (HR 1.73 (1.17, 2.56) p=0.01; HR 4.96 (2.68, 9.15), p <0.001) were associated with incident ILA and fibrotic ILA, respectively. Ever smoking (HR 2.31 (1.34, 3.96), p= 0.002) and an IPF polygenic risk score (HR 2.09 (1.61-2.71), p<0.001) were associated only with incident fibrotic ILA.Incident ILA and fibrotic ILA were estimated by review of cardiac imaging studies. These findings may lead to wider application of a screening tool for atherosclerosis to identify preclinical lung disease.

Validity and Reliability of the Fatigue Severity Scale in a Real-World Interstitial Lung Disease Cohort.

Rationale: Fatigue is a common and debilitating symptom for people living with interstitial lung disease (ILD). Studies on fatigue in ILD are limited, and little headway has been made toward developing interventions targeting the alleviation of fatigue. A barrier to progress is a lack of knowledge around the performance characteristics of a patient-reported outcome measure to assess fatigue in patients with ILD. Objectives: To assess the validity and reliability of the Fatigue Severity Scale (FSS) for measuring fatigue in a national cohort of patients with ILD. Methods: FSS scores and several anchors were measured in 1,881 patients from the Pulmonary Fibrosis Foundation Patient Registry. Anchors included the Short Form 6D Health Utility Index (SF-6D) score and a single vitality question from the SF-6D; the University of California, San Diego, Shortness of Breath Questionnaire; FVC; DlCO; and 6-minute-walk distance. Internal consistency reliability, concurrent validity, and known-groups validity were assessed. Structural validity was assessed using confirmatory factor analysis. Measurements and Main Results: The FSS demonstrated high internal consistency (Cronbach's α = 0.96). There were moderate to strong correlations between FSS score and patient-reported anchors (vitality question from the SF-6D [r = 0.55] and University of California, San Diego, Shortness of Breath Questionnaire total score [r = 0.70]) and weak correlations between FSS score and physiological measures (FVC [r = -0.24], percentage predicted DlCO [r = -0.23], and 6-minute-walk distance [r = -0.29]). Higher mean FSS scores, indicating greater fatigue, were observed among patients using supplemental oxygen, those prescribed steroids, and those with lower percentage predicted FVC and percentage predicted DlCO. The confirmatory factor analysis results suggest that the nine questions of the FSS reflect one dimension of fatigue. Conclusions: Fatigue is an important patient-centered outcome in ILD that is poorly correlated with physiological measures of disease severity, including lung function and walk distance. These findings further support the need for a reliable and valid measure of patient-reported fatigue in ILD. The FSS possesses acceptable performance characteristics for assessing fatigue and distinguishing different degrees of fatigue among patients with ILD.

A Narrative Review of Real-World Data on the Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis.

Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases. Placebo-controlled trials showed that the adverse event profile of nintedanib was characterised mainly by gastrointestinal events, particularly diarrhoea. We review the data from all published real-world studies of the safety of nintedanib in patients with IPF. These real-world data were consistent with the safety profile observed in clinical trials and described in the product label. The most common adverse events were diarrhoea, nausea and vomiting, but these infrequently led to permanent treatment discontinuation. Liver enzyme elevations were observed, supporting the recommendation for regular monitoring of liver enzymes, particularly in the first few months of treatment. Bleeding and cardiovascular adverse events were rarely reported. As in clinical trials, in real-world studies, reductions of the nintedanib dose, treatment interruptions and use of anti-diarrhoeal medications were frequently employed to manage adverse events. Few data are available on the use of nintedanib in patients who are elderly or have advanced disease, but there are some data to suggest a greater rate of treatment discontinuation in these patients. Effective management of adverse events associated with nintedanib is important to minimise their impact.

Obstructive Sleep Apnea and Longitudinal Changes in Interstitial Lung Imaging and Lung Function: The MESA Study.

Rationale: Obstructive sleep apnea (OSA) has been hypothesized to be a risk factor in interstitial lung disease (ILD) and is associated with radiological markers that may represent the earlier stages of ILD. Prior studies have been limited by their cross-sectional design and potential confounding by body habitus. Objectives: To test the hypothesis that OSA severity is associated with more high-attenuation areas (HAAs) on computed tomography and worse lung function over time among older community-dwelling adults. Methods: We used data from participants in the MESA (Multi-Ethnic Study of Atherosclerosis) who had apnea-hypopnea index (AHI) measured from polysomnography (2010-2013), high attenuation areas (HAAs, -600 to -250 Hounsfield units, n = 784), assessments from exams 5 (2010-2012) and 6 (2016-2018) full-lung computed tomography scans, and spirometry assessments (n = 677). Linear mixed-effects models with random intercept were used to examine associations of OSA severity (i.e., AHI and hypoxic burden) with changes in HAAs, total lung volumes, and forced vital capacity (FVC) between exams 5 and 6. Potential confounders were adjusted for in the model, including age, sex, smoking history, height, and weight. Results: Among those with a higher AHI there were more men and a higher body mass index. Participants with AHI ⩾ 15 events/h and in the highest hypoxic burden quartile each had increases in HAAs of 11.30% (95% confidence interval [CI], 3.74-19.35%) and 9.85% (95% CI, 1.40-19.01%) per 10 years, respectively. There was a more rapid decline in total lung volumes imaged and FVC among those with AHI ⩾ 15 events/h of 220.2 ml (95% CI, 47.8-392.5 ml) and 3.63% (95% CI, 0.43-6.83%) per 10 years, respectively. Conclusions: A greater burden of hypoxia related to obstructive events during sleep was associated with increased lung densities over time and a more rapid decline in lung volumes regardless of body habitus. Our findings suggest OSA may be a contributing factor in the early stages of ILD.

MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study.

BACKGROUND: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown. METHODS: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD). RESULTS: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs. CONCLUSIONS: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

Idiopathic pulmonary fibrosis: state of the art for 2023.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterised by worsening respiratory symptoms and physiological impairment. Increasing awareness of the clinical manifestations of IPF, more widespread use of computed tomography scans and other potential factors have contributed to a rising prevalence of IPF over the last two decades, especially among people over the age of 65 years. Significant advances in the understanding of the pathobiology of IPF have emerged, and multiple genetic and nongenetic contributors have been identified. The individual patient course and the rate of disease progression in IPF are often unpredictable and heterogeneous. The rate of lung function decline is further modified by treatment with antifibrotic therapies, which have been shown to slow down disease progression. The presence of comorbid conditions may increase symptom burden and impact survival. Clinical monitoring at regular intervals to assess for disease progression by worsening symptoms, physiological parameters and/or radiological features is essential to assess the natural disease course and to guide further management, including prompt detection of complications and comorbid conditions that warrant additional treatment considerations, and timely consideration of referral to palliative care and lung transplantation for the appropriate patient. More studies are needed to determine whether early detection of IPF might improve patient outcomes. The purpose of this concise clinical review is to provide an update on IPF diagnosis, epidemiology, natural history and treatment in the context of new knowledge and latest clinical practice guidelines.

Associations of hiatus hernia with CT-based interstitial lung changes: the MESA Lung Study.

BACKGROUND: Hiatus hernia (HH) is prevalent in adults with pulmonary fibrosis. We hypothesised that HH would be associated with markers of lung inflammation and fibrosis among community-dwelling adults and stronger among MUC5B (rs35705950) risk allele carriers. METHODS: In the Multi-Ethnic Study of Atherosclerosis, HH was assessed from cardiac and full-lung computed tomography (CT) scans performed at Exam 1 (2000-2002, n=3342) and Exam 5 (2010-2012, n=3091), respectively. Percentage of high attenuation areas (HAAs; percentage of voxels with attenuation between -600 and -250 HU) was measured from cardiac and lung scans. Interstitial lung abnormalities (ILAs) were examined from Exam 5 scans (n=2380). Regression models were used to examine the associations of HH with HAAs, ILAs and serum matrix metalloproteinase-7 (MMP-7), and adjusted for age, sex, race/ethnicity, educational attainment, smoking, height, weight and scanner parameters for HAA analysis. RESULTS: HH detected from Exam 5 scans was associated with a mean percentage difference in HAAs of 2.23% (95% CI 0.57-3.93%) and an increase of 0.48% (95% CI 0.07-0.89%) per year, particularly in MUC5B risk allele carriers (p-value for interaction=0.02). HH was associated with ILAs among those <80 years of age (OR for ILAs 1.78, 95% CI 1.14-2.80) and higher serum MMP-7 level among smokers (p-value for smoking interaction=0.04). CONCLUSIONS: HH was associated with more HAAs over time, particularly among MUC5B risk allele carriers, and ILAs in younger adults, and may be a risk factor in the early stages of interstitial lung disease.