Citations

Abstract Rationale Dyspnea is a prominent symptom of fibrotic hypersensitivity pneumonitis (fHP), limiting patients’ activity and impairing their quality of life. The University of California San Diego Shortness of Breath questionnaire (UCSD-SOBQ) is a 24-item instrument used to assess dyspnea severity in patients with various respiratory conditions. Objectives This study aimed to examine the reliability and responsiveness of the UCSD-SOBQ score, its validity as a measure of dyspnea severity, and its prognostic value in a prospective cohort with fHP. Methods We conducted psychometric analyses on UCSD-SOBQ response data and assessed the association between score changes and survival in patients with fHP who completed the UCSD-SOBQ and other HP severity metrics at baseline, 6 and 12 months. We introduce the reliable change index (RCI) and the likely change index (LCI) to assess the statistical significance of within-individual change in UCSD scores. Results At baseline, internal consistency was high (Cronbach’s alpha = 0.97). Significant moderately strong correlations were observed between UCSD-SOBQ scores and percent predicted forced vital capacity (FVC%), r = -0.46, percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%), r = -0.32, and Borg dyspnea scores r = 0.56. UCSD-SOBQ scores were significantly different between the lowest and highest strata of FVC% (64.9 ± 18.9 vs. 36.2 ± 22.9), DLCO% and Borg scores. The threshold for worsening within-individual change in the UCSD-SOBQ score at 95% confidence was 12 points. A 1-point higher baseline UCSD-SOBQ score was associated with a 2% increase in the risk of death or transplant (HR 1.02, 95% CI 1.00, 1.04). Conclusions In fHP, the UCSD-SOBQ score is a reliable and valid measure of dyspnea severity, is responsive to change, discriminates patients with differing severities, and is associated with transplant free survival. Additional qualitative data and psychometric analyses could tailor the UCSD-SOBQ to fHP and may further improve its measurement properties.

Abstract Rationale Quantitative CT using multiple instance learning (MIL)-usual interstitial pneumonia (UIP) classifier and data-driven textural analysis (DTA) provides objective and reproducible measurements of disease pattern and extent, respectively. However, the understanding of their individual or combined relationships with outcomes in fibrotic hypersensitivity pneumonitis (fHP) remains limited. Objectives To determine whether visual CT patterns of fHP or UIP, a MIL-UIP classifier, baseline and changes in DTA over 12-months and DTA at 12 months are associated with progression-free survival (PFS) in fHP. Methods The primary cohort included 134 participants with fHP. Associations between CT variables and subsequent lung function change, and PFS were assessed using linear mixed models and Cox hazards models. Results were validated in a combined dataset from three independent populations (N = 216). Results Visual patterns of fHP or UIP were not associated with PFS. A baseline MIL-UIP classification and DTA were significantly associated with 24-month PFS. However, the MIL-UIP did not predict PFS after adjusting for DTA fibrosis extent. Over 12 months, a 1-point increase in DTA across and within patients resulted in a significant decline in FVC% and DLCO%. A 12-month change in DTA (HR = 1.07, 95%CI 1.01-1.13) and DTA at 12-months (HR = 1.03, 95%CI 1.01-1.05) were associated with subsequent 12-month PFS. Similar estimates were observed in the validation cohort. Conclusions In fHP, the objectively measured extent of lung fibrosis is more prognostic than either a UIP classifier or visual CT patterns of fHP or UIP. Baseline DTA, DTA at 12 months, and its change over 12-months are associated with PFS.

Interstitial lung abnormalities (ILAs) are incidental nondependent radiologic findings that may portend early or future interstitial lung disease (ILD), but do not meet specific criteria at the time of presentation. They are subclinical by definition and found more commonly in older ever-smokers undergoing computed tomography (CT) imaging for other indications, including cardiac or lung cancer screening programs. As ILA prevalence increases, driven by an aging population and heightened awareness in younger patients, understanding risk factors for their development and progression has gained recent interest, particularly for optimizing subsequent ILD outcomes. This narrative review summarizes current ILA definitions, epidemiology, risk stratification, and management, while highlighting current challenges and knowledge gaps.

Background/Objectives: Individual and increasing numbers of comorbidities have been associated with worse outcomes in patients with fibrotic interstitial lung disease (f-ILD). The association and impact of medical comorbidities on patient-reported outcome measures (PROMs) in f-ILD have yet to be reported. Methods: Analysis was conducted using data from a single-center prospective cohort involving 199 patients with f-ILD. All f-ILD diagnoses and severities were screened and enrolled over a three-year study period. Baseline demographics, pulmonary function test (PFT) measures, and survival status were collected. PROMs, including the Chronic Respiratory Questionnaire (CRQ) and the Self-Management Ability Scale (SMAS-30), were assessed at baseline and serially. Thirteen medical comorbidities were evaluated for their prevalence and impact on PROMs and all-cause mortality. Results: Mean age was 69 years, with a female-to-male ratio of 61% vs. 39%. Dyslipidemia (74%) and gastroesophageal reflux disease (GERD) (71%) were the most prevalent comorbidities. Hypertension, diabetes, GERD, pulmonary hypertension (PH), depression, congestive heart failure (CHF), and obstructive sleep apnea (OSA), were independently associated with lower PROM scores along with increasing numbers of concomitant comorbidities. Increasing numbers of comorbidities, as well as specifically diabetes, PH, hypertension, CHF, and OSA, were associated with greater all-cause mortality. Conclusions: Medical comorbidities may independently impact respiratory-related PROMs in patients with f-ILD. These findings highlight the importance of comprehensive comorbidity management in improving quality of life and survival outcomes in patients with f-ILD.

Background Antifibrotic (AF) therapy has been shown to potentially reduce the risk of lung cancer (LC) in patients with idiopathic pulmonary fibrosis (IPF). Our study further assesses the impact of AF use and LC incidence in a real-world cohort with patient-level data. Methods A retrospective multisite cohort study involving patients with IPF followed at Mayo Clinic between 2005 and 2022 was conducted. We identified individuals with new diagnoses of LC in the pre-AF and post-AF eras and defined AF use as continuous treatment for 6 months or more before LC diagnosis. Given the inclusion of LC cases prior to the wide availability of AF therapy and potential differences in patients exposed and unexposed to treatment, propensity score analysis with inverse probability of treatment weighting (IPTW) was used to balance comparator groups. Fine and Gray modelling was used to explore risk factors for developing LC, reported as parameter subdistribution HRs (SHR). Results A total of 3313 patients with IPF were included (1161 treated and 2152 non-treated). LC incidence rates were lower for treated patients in the post-AF era (0.34 vs 1.25 per 100 person-years, p<0.001). After IPTW, 2148 treated were compared with 2167 non-treated individuals. AF treatment was independently associated with reduced LC risk (SHR 0.36 (0.16–0.82), p=0.02), while smoking history and higher forced vital capacity were associated with increased risk. Conclusion AF use appears to be associated with a reduced incidence rate and risk of LC in patients with IPF.

Abstract Rationale: Fibrotic interstitial lung diseases (f-ILDs) often lead to increased dyspnea and decreased physical activity, negatively impacting patient quality of life. While center-based pulmonary rehabilitation (PR) provides known benefits, access and adherence may be limited. This study investigates the implementation of a home-based pulmonary rehabilitation program with telephonic health coaching to improve physical activity and respiratory-related quality of life (RR-QOL) over 12 weeks. Methods: This prospective, single-center, non-randomized study enrolled patients with various f-ILD subtypes and severities over two years. Participants engaged in video-based exercises (25 minutes/day, 6 days per week) with weekly telephonic health coaching. Primary outcomes included changes in average daily steps, dyspnea (modified Medical Research Council (mMRC)), and self-reported RR-QOL (Chronic Respiratory Questionnaire (CRQ)- Physical and Emotional Summary domain scores). Minimal Clinically Important Differences (MCID) for study endpoints were defined as ≥600 steps per day, 1-point change in mMRC, and 0.5-point change in CRQ Physical and Emotional Summary scores, used to stratify patient responses to intervention as improved, stable, or worsened. Pre- and post-intervention summary results were compared using paired two-sample t-tests. The percentage of patients reaching MCID thresholds for improvement in primary endpoints was also reported. Results: 88 patients completed the program (mean age 70.2 years, 54% male, and mean FVC 66.9%). Mean CRQ Physical Summary scores improved from baseline 4.09 to 4.35 (mean improvement of 0.26 with 95% CI [0.06, 0.46]). 35% of patients achieved MCID change in the CRQ Physical Summary score, 34% in the CRQ Emotional score, and 22% in mMRC. Although 24% of patients increased their daily steps by 600 or more, average daily steps declined from 7,594 to 7,103 (mean decrease of 492 with 95% CI [101, 883]). When stratified by outcome responses to intervention (improved, stable, or worsened), lower baseline DLCO% was associated with decreased CRQ Physical Summary Scores and daily steps. Conclusion: Home-based PR may improve self-reported quality of life in f-ILD patients, as evidenced by improved CRQ Physical Summary scores. DLCO% may be associated with poorer response to PR intervention, as lower values were associated with declines in CRQ Physical Summary scores and daily steps. These findings support the potential utility of home-based rehabilitation and customizing individual strategies according to baseline characteristics and background disease progression.

Abstract RATIONALE: Pulmonary fibrosis is recognized as the end result of multiple and recurrent pathways of lung injury. However, the role of chronic inflammation in non-idiopathic pulmonary fibrosis fibrotic interstitial lung disease (non-IPF f-ILD) remains inconclusive, as acute responses to anti-inflammatory treatment may vary. A reliable predictor for identifying patients who stand to benefit from treatment may be helpful for improving or sustaining lung function and avoiding adverse treatment effects. Our study aims to assess whether initial serum inflammatory markers, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), in the absence of clinically suspected infection or other causes of inflammation, are predictive of therapeutic response to anti-inflammatory medications in non-IPF f-ILD. METHODS: We performed a retrospective study comparing treatment response to anti-inflammatory therapy in non-IPF f-ILD stratified by initial CRP or ESR levels. Treatment was defined as corticosteroid or steroid-sparing agent for three months or more with lung function response defined as: 1) relative increase in percent predicted forced vital capacity (FVC%) &gt; 5% in 6 months or &gt; 10% or greater in 12 months; or 2) no change or any increase in FVC% if FVC% was declining prior to treatment initiation (relative decline in FVC% &gt; 5% in the prior 6 months or &gt; 10% in the prior 12 months). Logistic regression was used to predict treatment response as stratified by high vs low-to-normal inflammatory markers, with a mixed model for repeated measures for comparing FVC% change while treated. RESULTS: One hundred sixty-seven non-IPF f-ILD pts received anti-inflammatory therapy with baseline inflammatory markers stratified by high (N = 104) vs low-to-normal (N = 63) prior to treatment. Median age was 64 years with systemic rheumatic disease diagnosed in 58%. Treatment response was higher in patients with elevated inflammatory markers (55.77% vs. 34.92%, P = 0.011), even after adjustment for age, sex, baseline FVC%, and treatment duration (OR 2.45 [1.243-4.828], P = 0.010). FVC% slope from treatment initiation to discontinuation appeared to be increasing in patients with higher baseline inflammatory markers compared to those with low to normal marker levels (P = 0.003) (Figure1). CONCLUSION: Patients with non-IPF f-ILD and high initial inflammatory markers appear to be more acutely responsive to anti-inflammatory therapy with slower FVC decline or improvement over time while on treatment. These findings suggest baseline serum CRP and ESR may be reliable predictors of treatment response and direct treatment duration and intensity for efficacy or reducing adverse effects.

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease most commonly encountered in older individuals. Several decades of research have contributed to a better understanding of its pathogenesis, though only two drugs thus far have shown treatment efficacy, i.e., by slowing the decline of lung function. The pathogenesis of IPF remains incompletely understood and involves multiple complex interactions and mechanisms working in tandem or separately to result in unchecked deposition of extracellular matrix components and collagen characteristic of the disease. These mechanisms include aberrant response to injury in the alveolar epithelium, inappropriate communication between epithelial cells and mesenchymal cells, imbalances between oxidative injury and tissue repair, recruitment of inflammatory pathways that induce fibrosis, and cell senescence leading to sustained activation and proliferation of fibroblasts and myofibroblasts. Targeted approaches to each of these mechanistic pathways have led to recent clinical studies evaluating the safety and efficacy of several agents. This review highlights selected concepts in the pathogenesis of IPF as a rationale for understanding current or future therapeutic approaches, followed by a review of several selected agents and their recent or active clinical studies. Current novel therapies include approaches to attenuating or modifying specific cellular or signaling processes in the fibrotic pathway, modifying inflammatory and metabolic derangements, and minimizing inappropriate cell senescence.