RATIONALE:Fibrotic interstitial lung diseases (ILDs) cause loss of forced vital capacity (FVC) and increased risk of death over time. Most clinical trials aim to slow FVC decline and reduce mortality. However, the association of lower FVC with higher mortality will bias simple estimates of differences in FVC progression between groups. Therefore, both the time-dependent decline in FVC and increase in mortality should be jointly modeled. METHODS:We developed a Bayesian, joint mixed-effects disease progression model (DPM), using minimally informative prior distributions, for FVC trajectory and the hazard for ILD-related mortality over time. This model minimizes bias due to mortality in estimating differences in the rate of FVC decline and is suitable for use when characterizing populations or in estimating a treatment effect in a clinical trial. The DPM was applied to individual patient data from prospective cohort studies of fibrotic ILD. MEASUREMENTS AND MAIN RESULTS:The DPM yields a higher estimated rate of FVC decline (6.0% vs 4.7%/year) and a more precise fit than a linear mixed model of FVC alone, and replicates the nonlinear pattern in the observed data. By modeling the full FVC trajectory rather than only the change from baseline at a given time point, the DPM increases the information from each patient and reduces both the time to information and the effect of variability in baseline FVC measurements on the estimation of treatment effects. CONCLUSIONS:The joint DPM provides an integrated approach to minimizing bias in the estimation of treatment effects in clinical trials in fibrotic ILDs.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease triggered by inhalation of a variety of environmental antigens. HP ranges from acute manifestations to progressive fibrosis and can be classified as nonfibrotic or fibrotic based on imaging and histopathological features. The pathophysiological mechanism of HP involves an exaggerated immune cell response and, in chronic stages, fibroblast activation leading to fibrosis. Diagnosis requires integrated assessment of exposure history, HRCT findings, BAL findings, and histopathological findings, as well as multidisciplinary discussion. In nonfibrotic HP patients, HRCT typically shows ground-glass opacities, centrilobular nodules, and mosaic attenuation, whereas, in fibrotic HP patients, HRCT often shows reticulation, traction bronchiectasis, and honeycombing. Typical histological features include cellular bronchiolitis, poorly formed granulomas, and interstitial fibrosis. Recent advances in imaging—including artificial intelligence–based pattern recognition—and investigation of biomarkers are improving precision and will likely contribute to the diagnostic investigation of HP. Management strategies depend on disease phenotype and severity, with antigen avoidance remaining the cornerstone of therapy. Immunomodulators such as corticosteroids, azathioprine, and mycophenolate may be used when there is evidence or suspicion of active inflammatory disease, whereas nintedanib is indicated for progressive fibrotic forms. Emerging phosphodiesterase 4B inhibitors have shown promise based on recent evidence. A greater number of comorbidities are observed in patients with fibrotic HP and are associated with worse survival, particularly pulmonary hypertension. Understanding genetic predisposition, comorbidities, and the transition from inflammation to fibrosis is essential to guide personalized treatment and improve outcomes. This review provides an update of pathophysiology, current diagnostic approaches, and therapeutic options, including emerging strategies.

Background:Hypersensitivity pneumonitis (HP) is an immune-mediated condition triggered by inhaled antigens in susceptible individuals. Patients with HP often present with exercise limitation due to multiple mechanisms, including ventilatory and cardiocirculatory impairments, particularly pulmonary hypertension (PH). Methods:In this cross-sectional study, patients with HP of varying severity underwent clinical assessment, including quality-of-life questionnaires, incremental treadmill cardiopulmonary exercise testing (CPET), pulmonary function testing, 6-min walk test and transthoracic echocardiography (TTE). Patients with a diffusing capacity of the lung for carbon monoxide (D LCO) below 40% of predicted and/or a tricuspid regurgitation velocity >2.5 m·s-1 or pulmonary artery systolic pressure >35 mmHg on TTE were referred for right heart catheterisation. Results:Among 90 patients, 65% were female, with a median age of 65.5 years, and 85% had fibrotic HP. CPET was performed in 51 patients (56%), with a mean peak oxygen consumption of 58±13% of predicted. Exercise capacity was reduced in 98% of patients, with multifactorial limitation in 88%, primarily due to cardiocirculatory impairment (76%) and impaired gas exchange (66%). The mean 6-min walk distance was 334±116 m. Mean forced vital capacity and D LCO were 56±20% and 42±22% predicted, respectively. PH was identified in 59% of patients (95% CI 48-72%), predominantly with combined post- and pre-capillary involvement. Conclusions:Reduced exercise capacity is highly prevalent in patients with HP and is typically multifactorial. PH is also common, with a predominance of combined post- and pre-capillary patterns. These findings underscore the need for a comprehensive evaluation strategy in symptomatic HP patients.

INTRODUCTION:The main diffuse cystic lung diseases (DCLD) include lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), Birt-Hogg-Dubé syndrome, and lymphocytic interstitial pneumonia. Exercise limitation is frequent and secondary to multiple mechanisms in DCLD. Some studies addressed mechanisms for exercise limitation, field tests, and pulmonary rehabilitation (PR) in DCLD. AREAS COVERED:This review aims to present the main mechanisms that determine exercise limitation, the responses of patients in field tests, and the details regarding the safety and efficacy of PR in DCLD, with emphasis on LAM and PLCH. A search on the issue was performed in the MEDLINE and SciELO databases between 27 November 2024 and 20 February 2025. Manuscripts were reviewed and important topics were included in this review. EXPERT OPINION:Reduced exercise capacity is common and multifactorial, including ventilatory, cardiocirculatory, and peripheral limitations, pulmonary hypertension (PH), and impaired gas exchange in LAM and PLCH. Variables from field tests are correlated with pulmonary function tests, and PR is safe and beneficial in LAM. Further studies are necessary to evaluate exercise in other DCLDs, the impact of other therapeutic modalities on DH, hypoxemia, and exercise-induced PH in LAM and PLCH, and the safety and benefits of PR mostly in PLCH.

Objective: To evaluate clinical, functional, and CT characteristics, as well as disease progression, in patients with idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) treated at a referral center in Brazil. Methods: This was a retrospective cohort study analyzing demographic characteristics, clinical variables, pulmonary function test results, HRCT findings, serological profiles, treatments, and outcomes. Results: Seventy-nine IIM-ILD patients were included in the present study. The mean follow-up period was 8.7 ± 4.7 years. The most common diagnosis was antisynthetase syndrome, observed in 51 (64.5%) of the 79 patients. The most common symptoms were dyspnea (in 94.9%), arthralgia (in 82.2%), and muscle weakness (in 75.9%). Mean baseline FVC was 2.19 ± 0.75 L, corresponding to 62.5% of the predicted value. During follow-up, FVC showed significant improvement. The most common CT patterns were indeterminate (in 44.4%) and nonspecific interstitial pneumonia (in 35.4%). Treatment most frequently included prednisone (in 98.7%), azathioprine (in 92.3%), or methotrexate (in 57.7%). Overall survival was 84.8%. Mortality was higher among patients who developed pulmonary hypertension and those who required intravenous methylprednisolone pulse therapy. Conclusions: Most patients with IIM-ILD progress well with immunosuppressive therapy. Pulmonary hypertension and the need for methylprednisolone pulse therapy appear to be associated with higher mortality.

Lymphangioleiomyomatosis (LAM) is a rare disease, characterized as a low-grade neoplasm with metastatic potential that mainly affects women of reproductive age, in which there is proliferation of atypical smooth muscle cells (LAM cells) and formation of diffuse pulmonary cysts. It can occur in a sporadic form or in combination with tuberous sclerosis complex. In recent decades, a number of advances have been made in the understanding of the pathophysiology and management of LAM, leading to improvements in its prognosis: identification of the main genetic aspects and the role of the mechanistic target of rapamycin (mTOR) pathway; relationship with hormonal factors, mainly estrogen; characterization of pulmonary and extrapulmonary manifestations in imaging studies; identification and importance in the diagnosis of VEGF-D; a systematic diagnostic approach, often without the need for lung biopsy; use of and indications for the use of mTOR inhibitors, mainly sirolimus, for pulmonary and extrapulmonary manifestations; pulmonary rehabilitation and the management of complications such as pneumothorax and chylothorax; and the role of and indications for lung transplantation. To date, no Brazilian recommendations for a comprehensive approach to the disease have been published. This document is the result of a non-systematic review of the literature, carried out by 12 pulmonologists, a radiologist, and a pathologist, which aims to provide an update of the most important topics related to LAM, mainly to its diagnosis, treatment, and follow-up, including practical and multidisciplinary aspects of its management.

Background: Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm that can lead to progressive diffuse cystic lung disease. Pregnancy has been associated with accelerated disease progression and increased risk of spontaneous pneumothoraces in women with LAM. Sirolimus is the current first line treatment for LAM and has demonstrated benefit in stabilizing lung function decline and reducing the risk of spontaneous pneumothoraces; however, there is unclear evidence regarding the risk benefit ratio of the use of sirolimus during pregnancy. Methods: We queried physicians across the LAM Clinic Network and obtained information regarding demographics, baseline characteristics, LAM related complications, lung function, sirolimus dosing, and pregnancy outcomes in women with LAM who took sirolimus during pregnancy. Results: We identified 9 women with LAM who had used sirolimus during pregnancy for a total of 12 pregnancies. All women had sporadic LAM with moderate lung function impairment prior to pregnancy: median FEV1 56% predicted, median DLCO 43% predicted, and 2 patients on supplemental oxygen. Sirolimus was used throughout pregnancy in most instances (10/12 (83.3%)). Sirolimus was held prior to pregnancy in 2 patients; both these patients experienced a spontaneous pneumothorax in the first trimester and resumed sirolimus in the second trimester with no further pneumothoraces during the rest of the pregnancy. The median sirolimus dose during pregnancy was 1 (range 1-2) mg daily with a median trough level of 2.95 (range: 1 – 6.7) ng/ml. Ten pregnancies (83.3%) resulted in live births, 1 pregnancy was terminated due to molar pregnancy, and 1 pregnancy resulted in miscarriage. Spirometry and DLCO were available in 8 pregnancies and tended to be stable (Figure 1). None of the 10 pregnancies that resulted in live births reported any fetal health issues. Seven out of these 10 children (70%) were breastfed with continued sirolimus use. At the time of submission of this report, the median age of these children is 3.5 years (range: 1 – 6.5 years) with no reported adverse health outcomes from sirolimus exposure during pregnancy. Conclusions: The use of sirolimus during pregnancy in women with LAM appears to be safe for both mother and fetus and might help reduce the pregnancy associated risks of accelerated lung function decline and spontaneous pneumothoraces.

Background Lymphangioleiomyomatosis (LAM) is a rare disease that can occur sporadically (S-LAM) or associated with the tuberous sclerosis complex (TSC-LAM). The natural history of LAM is not completely understood, including whether there is a difference between the clinical courses of the two forms. This study aimed to compare the clinical, functional and tomographic features between S-LAM and TSC-LAM, and evaluate the annual rates of change in lung function. Methods This retrospective cohort study included patients with LAM followed up between 1994 and 2019. Clinical, functional and imaging variables were evaluated, and the lung cysts were automatically quantified. Quality of life and predictors of lung function impairment were accessed, and the annual rate of lung function decline was compared between S-LAM and TSC-LAM. Results Of the 107 patients included, 77 had S-LAM and 30 had TSC-LAM. Although patients with TSCLAM had a higher prevalence of renal angiomyolipomas and neurological and dermatological manifestations, pulmonary function tests were similar. Patients with S-LAM had a greater rate of forced expiratory volume in 1 s decline and a higher extent of cysts. Pneumothorax, desaturation in the 6-minute walking test and a higher extent of lung cysts were predictors of functional impairment. A greater impact on vitality and emotional health was observed in the TSC-LAM. Conclusion Greater functional decline and a higher cystic extension were found in patients with S-LAM. Our study provides a broad clinical, functional and tomographic characterisation of patients with LAM, adding valuable information to the existing evidence to better understand the two forms of the disease.

There's limited evidence of the potential benefits of cardiopulmonary and metabolic rehabilitation (CPMR) in patients with heart failure with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) and coronary artery disease (CAD). The aim of this study was to investigate the impact of CPMR on the myocardial ischemia response (MIR), exercise-induced arrhythmias (EIA), New York Heart Association (NYHA) functional class, heart rate recovery (HRR), Borg CR10 perceived symptoms, and the SF-36 physical and mental health summary scores. A prospective cohort study was conducted with 106 patients undergoing 12 weeks of CPMR who completed two exercise tests pre- and post-CPMR: 1) maximum incremental test (CPX) and 2) submaximal constant load test (SUB). After CPMR, the effects on MIR, EIA, NYHA functional class, and HRR during both tests were analyzed. There was a significant change in NYHA functional classes after CPMR, with 96% of the patients in class I (vs 62% pre-CPMR, P<0.0001), 4% in class II (vs 32%), and none in class III (vs 6%). There was a significant reduction in the frequency of EIA (P<0.05) and MIR (P<0.001) and a significantly improved performance on both CPX and SUB tests (P<0.0001). Lastly, there was significant progress in the recovery metrics like HRR (P<0.0001), the Borg CR10 (P<0.0001), and the SF-36 summary scores (P<0.0001). The CPMR resulted in a significant decrease in EIA, delayed ischemia threshold in CPX and SUB tests, increased functional capacity, and improved quality of life.

Lymphangioleiomyomatosis (LAM) is a rare (twenty-one per million female inhabitants) neoplastic cystic lung disease that impairs health-related quality of life (HRQoL). However, the factors associated with impaired quality of life in patients with LAM are poorly understood. To assess the clinical, psychosocial, and functional characteristics associated with impaired quality of life in patients with LAM. This was a cross-sectional study performed on two nonconsecutive days. HRQoL (SF-36 and CRQ), lung function tests, anxiety and depression symptoms (HADS), maximal (CPET and ISWT), and submaximal exercise capacity (6MWT) were assessed. Linear associations among outcomes were assessed using Pearson's correlation and multivariate tests. Forty-five women with LAM (46 ± 10.years; FEV1,74

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) presents with a high prevalence of pulmonary fibrosis. Pulmonary fibrosis confers a worse prognosis to RA-ILD. There are no well stablished serum biomarkers for the identification of fibrotic versus non-fibrotic RA-ILD. This study reports the baseline plasma biomarkers analysed in RA-ILD individuals, both with and without pulmonary fibrosis, who are being closely monitored for two years as part of the BERTHA study (NCT04136223). Objectives: Investigate whether exploratory plasma biomarkers differ between RA-ILD with and without pulmonary fibrosis. Methods: All consecutive adult RA-ILD participants seen in five Brazilian rheumatologic centers between March 2021 – July 2022 were included in the study (ethical approval n.3.799.253). Patients with mMRC dyspnea score 5, use of long-term oxygen supplementation, significant pulmonary hypertension, and comorbidities with an impact in the respiratory system were excluded. At baseline, participants underwent high resolution computed tomography (HRCT) of the chest and blood draw. HRCTs were visually assessed by two independent radiologists and quantitatively analyzed by lung densitometry (Chest Imaging Platform software). Pulmonary fibrosis was defined on visual assessment of HRCT by the unequivocal presence of traction bronchiectasis and/or honeycombing. Plasma was analyzed for known biomarkers associated with pulmonary fibrosis, namely anti-CCP, MMP-7, SP-D, CCL-8, CA125, and CA19.9. The novel biological markers, tetrahydrobiopterin (BH4) and neopterin, associated with inflammation and oxidative stress, were also assessed. All laboratory analyses were performed in a central laboratory (LABOX, Federal University of Santa Catarina). Mean differences between participants with and without pulmonary fibrosis were evaluated using a two-sample T-test or Mann-Whitney U test. Results: 95 RA-ILD participants were included (Table 1). Articular disease activity did not differ between groups. Pulmonary fibrosis was present in 84 % of participants [kappa radiologists: 0.65 (95CI 0.45-0.84)]. Patients with pulmonary fibrosis were older with worse pulmonary function (FVC % predicted 75±16 vs. 83±16, p=0.038, and DLCO %predicted 68±21 vs. 93±5, p=0.014), worse 6-minute walking distance (361±61m vs. 419±116m, p=0.023), and with more extensive disease in the HRCT (% HAA 12.3±6.8 vs. 6.6±3.8, p=0.004). No difference was observed in baseline plasma biomarkers between participants with or without pulmonary fibrosis (Table 1). Conclusion: At baseline, participants with RA-ILD and pulmonary fibrosis did not differ from RA-ILD participants without pulmonary fibrosis in terms of MMP-7, SP-D, CCL-8, CA125, and CA19.9. New plasma biomarkers, BH4 and neopterin, also did not differ between groups. As per BERTHA protocol, participants will be followed for more two years and the prognostic value of these plasma biomarkers will be assessed. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Leticia Kawano-Dourado For Boehringer Ingelheim and Roche, From Boehringer Ingelheim and Bristol-Myers-Squibb, Karina Bonfiglioli For Roche, Lilly, BMS, Ana Cristina Medeiros-Ribeiro To Roche, Lilly and BMS, Licia Mota Boehringer Ingelheim, Lilly, BMS, Alisson Pugliesi Roche, Lilly, BMS, Luciana Muniz Boehringer Ingelheim, Roche, Lilly, Daniel Strabelli: None declared, Marcio Sawamura: None declared, Andrea Shimabuco: None declared, Sandra Pasoto: None declared, Luciana Teófilo Lourenconi: None declared, Fernanda L F B Riscado: None declared, Cleandro Albuquerque: None declared, Tassiane R C M Morais: None declared, Clemilda C da Silva: None declared, Ana Carolina Londe: None declared, Luciana C Palhares: None declared, Romuel Barros: None declared, Luis F Marqueze: None declared, Juliana D R Lindenau: None declared, Yara C N Muniz: None declared, Rachel H V Machado: None declared, Thabata S Veiga: None declared, Viviane B Bezerra: None declared, Leila O Silva: None declared, Jackeline O Gomes: None declared, Debora H K Miyada: None declared, Samira M Tokunaga: None declared, Tiago Mendonça: None declared, Bruno G Baldi Boehringer and Roche, Alexandra Latini: None declared.

Drug-induced lung disease (DILD) encompasses a broad, highly heterogeneous group of conditions that may occur as a result of exposure to numerous agents, such as antineoplastic drugs, conventional or biological disease-modifying antirheumatic drugs, antiarrhythmics, and antibiotics. Between 3% and 5% of prevalent cases of interstitial lung diseases are reported as DILDs. The pathogenesis of lung injury in DILD is variable, multifactorial, and often unknown. Acute presentation is the most common, can occur from days to months after the start of treatment, and ranges from asymptomatic to acute respiratory failure. The CT patterns are varied and include ground-glass opacities, organizing pneumonia, and diffuse alveolar damage. Notably, there are no clinical manifestations or CT patterns specific to DILD, which makes the diagnosis quite challenging and necessitates a high index of suspicion, as well as the exclusion of alternative causes such as infection, cardiac-related pulmonary edema, exacerbation of a preexisting ILD, and neoplastic lung involvement. Discontinuation of the offending medication constitutes the cornerstone of treatment, and corticosteroid treatment is usually necessary after the onset of clinical manifestations. The prognosis varies widely, with high mortality rates in severe cases. A history of medications related to pulmonary toxicity in patients with new-onset respiratory symptoms should prompt consideration of DILD as a potential underlying cause.