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Teng Moua, Jay H Ryu Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester MN, USA Abstract: Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic lung disease which has seen new opportunity for drug treatment in the last several years with the approval of nintedanib and pirfenidone, two antifibrotic agents aimed at slowing decline in lung function as defined by FVC on pulmonary function testing. Despite these promising effects, delays in drug initiation have been reported undermining the premise that earlier drug initiation may sustain lung function and prolong survival. This review explores obstacles to earlier treatment, inclusive of defining so-called early idiopathic pulmonary fibrosis, difficulties in achieving a confident diagnosis in that setting, and uncertainties regarding drug-related benefits among specific patient subgroups such as those with no symptoms or advanced disease at presentation. Goals of therapy balanced with the burdens associated with antifibrotic drug therapy are negotiated on an individual basis. We review the evidence for and against earlier initiation of antifibrotic drug therapy along with its role in patient-centered outcomes. Keywords: idiopathic pulmonary fibrosis, nintedanib, pirfenidone, antifibrotics

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.

Background: Birt-Hogg-Dube (BHD) syndrome is a rare genetic condition associated with the development of renal tumors. This study aims to determine typical age ranges for detecting renal abnormalities, risk factors for tumor development, and long-term outcomes based on current surveillance strategies., Methods: A single-center multi-site retrospective cohort study was performed on all patients with BHD diagnosed from 2000 to 2023. Baseline demographics, pulmonary function, laboratory, radiologic, and histopathologic findings were collected. Logistic regression was used to assess predictor variables for the development of renal tumors with survival analysis evaluated from the date of BHD diagnosis to date of death or last known follow-up., Results: The study included 149 patients with BHD, 39 (26%) with diagnosed renal tumors, of which 28 had histopathologic confirmation. Mean age at renal tumor detection was 53.61 years. Older age and male sex were predictive of renal tumor development ((odds ratio 1.05; 95% CI, 1.01-1.08, P = 0.002) and (odds ratio 2.59; 95% CI, 1.17-5.73, P = 0.02), respectively). Time to all-cause mortality appeared shorter in those with renal tumors (Log-rank P = 0.02), though no deaths were from cancer or cancer-related complications., Conclusions: Current screening protocols for renal tumors in BHD suggest the most common presenting age range for presentation is late 40s to early 50s, with older age and male sex as risk factors for tumor development., (© 2024. The Author(s).)

Background: Lung biopsy remains the gold standard in the diagnosis of fibrotic interstitial lung disease (F-ILD), but there is a growing appreciation of the role of pathogenic gene variants in telomere and surfactant protein genes, especially in familial pulmonary fibrosis (FPF). Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that can coexist with different patterns of F-ILD, including FPF. It can be progressive and often leads to respiratory failure and death. This study tested the hypothesis that genetic testing goes beyond radiological and histological findings in PPFE and other F-ILD further informing clinical decision-making for patients and affected family members by identifying pathological gene variants in telomere and surfactant protein genes., Methods: This is a retrospective review of 70 patients with F-ILD in the setting of FPF or premature lung fibrosis. Six out of 70 patients were diagnosed with PPFE based on radiological or histological characteristics. All patients underwent telomere length evaluation in peripheral blood by Flow-FISH or genetic testing using a customized exome-based panel that included telomere and surfactant protein genes associated with lung fibrosis., Results: Herein, we identified six individuals where radiographic or histopathological analyses of PPFE were linked with telomere biology disorders (TBD) or variants in surfactant protein genes. Each case involved individuals with either personal early-onset lung fibrosis or a family history of the disease. Assessments of telomere length and genetic testing offered insights beyond traditional radiological and histopathological evaluations., Conclusion: Detecting anomalies in TBD-related or surfactant protein genes can significantly refine the diagnosis and treatment strategies for individuals with PPFE and other F-ILD., (© 2024. The Author(s).)

Background: Patient-reported outcome measures (PROMs) may provide clinicians and researchers with direct insights into disease impact and patient well-being. We assessed whether selected PROMs and their domains are associated with baseline and longitudinal changes in lung function and can predict mortality in patients with fibrotic interstitial lung disease (f-ILD)., Methods: A single-centre prospective study of adult patients with f-ILD enrolled over 3 years was conducted assessing baseline and short-term changes in PROMs. Three questionnaires, the modified Medical Research Council dyspnoea scale (mMRC), Chronic Respiratory Questionnaire (CRQ) and Self-Management Ability Scale (SMAS-30) were administered at planned intervals and assessed for their association with baseline clinical findings, change in lung function (% predicted forced vital capacity (FVC%) and diffusion capacity of the lung for carbon monoxide ( D LCO %)) and all-cause mortality., Results: 199 patients were enrolled with a mean PROM follow-up of 9.6 months. When stratified by FVC% quartiles at presentation, lower mMRC (less dyspnoea), higher CRQ Physical and Emotional domain (better health-related quality of life) and higher total SMAS-30 scores (better self-management ability) were associated with higher FVC%. Short-term changes in all three PROMs appeared to be associated with changes in FVC% and D LCO %. Adjusted and unadjusted baseline and serial PROM changes were also predictive of mortality., Conclusions: Baseline and serial assessments of PROMs were associated with changes in lung function and predicted death in patients with f-ILD. PROMs may strengthen comprehensive assessments of disease impact in clinical practice as well as support patient-centred outcomes in research., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2024.)

Background: Patients with fibrotic hypersensitivity pneumonitis (f-HP) have varied clinical and radiologic presentations whose associated phenotypic outcomes have not been previously described. We conducted a study to evaluate mortality and lung transplant (LT) outcomes among clinical clusters of f-HP as characterized by an unsupervised machine learning approach., Methods: Consensus cluster analysis was performed on a retrospective cohort of f-HP patients diagnosed according to recent international guideline. Demographics, antigen exposure, radiologic, histopathologic, and pulmonary function findings along with comorbidities were included in the cluster analysis. Cox proportional-hazards regression was used to assess mortality or LT risk as a combined outcome for each cluster., Results: Three distinct clusters were identified among 336 f-HP patients. Cluster 1 (n = 158, 47%) was characterized by mild restriction on pulmonary function testing (PFT). Cluster 2 (n = 46, 14%) was characterized by younger age, lower BMI, and a higher proportion of identifiable causative antigens with baseline obstructive physiology. Cluster 3 (n = 132, 39%) was characterized by moderate to severe restriction. When compared to cluster 1, mortality or LT risk was lower in cluster 2 (hazard ratio (HR) of 0.42; 95% CI, 0.21-0.82; P = 0.01) and higher in cluster 3 (HR of 1.76; 95% CI, 1.24-2.48; P = 0.001)., Conclusions: Three distinct phenotypes of f-HP with unique mortality or transplant outcomes were found using unsupervised cluster analysis, highlighting improved mortality in fibrotic patients with obstructive physiology and identifiable antigens., (© 2024. The Author(s).)

Purpose: Pulmonary rehabilitation is a behavioral modification intervention shown to improve exercise tolerance and patient-reported quality of life in patients with fibrotic interstitial lung disease. Home-based rehabilitation may provide easier access for those who struggle to complete center-based rehabilitation programs due to increased symptom burden or frailty., Methods: We present the quantitative and qualitative findings of a pilot study of 21 patients with fibrotic interstitial lung disease who participated in a 12-wk home-based pulmonary rehabilitation program with activity monitoring and health coaching., Results: Pre- and post-intervention patient-reported outcome questionnaires suggested improvements in dyspnea and respiratory-related quality of life but were underpowered to meet statistical significance. Half had increases in mean daily step counts while a quarter declined because of disease progression. Qualitative analysis of semistructured participant interviews suggested a significant baseline disease burden with related secondary impacts, including anxiety regarding disease progression and prognosis. Many who participated had no specific program expectations or self-determined goals but still found the program impactful, particularly on their abilities to adapt and cope with the disease., Conclusion: Our study suggests feasibility in a diverse set of patients with varying severity and diagnostic subtypes. We also provide quantitative and qualitative aspects of program impact on patient well-being and highlight the complex interaction between measured physical and self-reported outcomes and disease experience., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is common in patients with RA and leads to significant morbidity and mortality. No randomized, placebo-controlled data are available that support the role of immunosuppression to treat RA-associated ILD, despite being widely used in clinical practice., Research Question: How does immunosuppression impact pulmonary function trajectory in a multisite retrospective cohort of patients with RA-associated ILD?, Study Design and Methods: Patients with RA who started treatment for ILD with mycophenolate, azathioprine, or rituximab were identified retrospectively from five ILD centers. Change in lung function before and after treatment was analyzed using a linear spline mixed-effect model with random intercept. Prespecified secondary analyses examined the impact of radiologic pattern of ILD (ie, usual interstitial pneumonia [UIP] vs non-UIP) on treatment trajectory., Results: Two hundred twelve patients were included in the analysis: 92 patients (43.4%) were treated with azathioprine, 77 patients (36.3%) were treated with mycophenolate mofetil, and 43 patients (20.3%) were treated with rituximab. In the combined analysis of all three agents, an improvement in FVC % predicted was found after 12 months of treatment compared with the potential 12-month response without treatment (+3.90%; P ≤ .001; 95% CI, 1.95-5.84). Diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted also improved at 12 months (+4.53%; P ≤ .001; 95% CI, 2.12-6.94). Neither the UIP pattern of ILD nor choice of immunosuppressive agent significantly impacted the pulmonary function trajectory on immunosuppression., Interpretation: Immunosuppression was associated with an improved trajectory in FVC and Dlco compared with the pretreatment pulmonary function trajectory. Prospective, randomized trials are required to validate these findings., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Antifibrotic treatment has been approved for reducing disease progression in fibrotic interstitial lung disease (ILD). As a result of increased bleeding risk, some experts suggest cessation of antifibrotics prior to lung transplantation (LT). However, extensive knowledge regarding the impact of antifibrotic treatment on postoperative complications remains unclear. We performed a comprehensive search of several databases from their inception through to 30 September 2021. Original studies were included in the final analysis if they compared postoperative complications, including surgical wound dehiscence, anastomosis complication, bleeding complications, and primary graft dysfunction, between those with and without antifibrotic treatment undergoing LT. Of 563 retrieved studies, 6 studies were included in the final analysis. A total of 543 ILD patients completing LT were included, with 161 patients continuing antifibrotic treatment up to the time of LT and 382 without prior treatment. Antifibrotic treatment was not significantly associated with surgical wound dehiscence (RR 1.05; 95% CI, 0.31-3.60; I 2 = 0%), anastomotic complications (RR 0.88; 95% CI, 0.37-2.12; I 2 = 31%), bleeding complications (RR 0.76; 95% CI, 0.33-1.76; I 2 = 0%), or primary graft dysfunction (RR 0.87; 95% CI, 0.59-1.29; I 2 = 0%). Finally, continuing antifibrotic treatment prior to LT was not significantly associated with decreased 1-year mortality (RR 0.80; 95% CI, 0.41-1.58; I 2 = 0%). Our study suggests a similar risk of postoperative complications in ILD patients undergoing LT who received antifibrotic treatment compared to those not on antifibrotic therapy.

Background: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD., Methods: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤  - 2.5 or ≥  + 2.5 with a standard deviation not crossing zero., Results: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants., Conclusions: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need., (© 2023. The Author(s).)