Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease.

BACKGROUND: Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD). METHODS: A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure. RESULTS: The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. fHP and uILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26-10.92; p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77; p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (discovery pinteraction=0.013; replication pinteraction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for CTD-ILD. CONCLUSION: Similar to IPF, fHP and uILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

Evaluation of Pulmonary Fibrosis Outcomes by Race and Ethnicity in US Adults.

Importance: Pulmonary fibrosis (PF) is characterized by progressive scarring of lung tissue and poor survival. Racial and ethnic minority populations face the greatest risk of morbidity and mortality from disparities impacting respiratory health, but the pattern of age at clinically relevant outcomes across diverse racial and ethnic populations with PF is unknown. Objective: To compare the age at PF-related outcomes and the heterogeneity in survival patterns among Hispanic, non-Hispanic Black, and non-Hispanic White participants. Design, Setting, and Participants: This cohort study included adult patients with a PF diagnosis and used data from prospective clinical registries: the Pulmonary Fibrosis Foundation Registry (PFFR) for the primary cohort and registries from 4 geographically distinct tertiary hospitals in the US for the external multicenter validation (EMV) cohort. Patients were followed between January 2003 and April 2021. Exposures: Race and ethnicity comparisons between Black, Hispanic, and White participants with PF. Main Outcomes and Measures: Age and sex distribution of participants were measured at the time of study enrollment. All-cause mortality and age at PF diagnosis, hospitalization, lung transplant, and death were assessed in participants over 14 389 person-years. Differences between racial and ethnic groups were compared using Wilcoxon rank sum tests, Bartlett 1-way analysis of variance, and χ2 tests, and crude mortality rates and rate ratios were assessed across racial and ethnic categories using Cox proportional hazards regression models. Results: In total, 4792 participants with PF were assessed (mean [SD] age, 66.1 [11.2] years; 2779 [58.0%] male; 488 [10.2%] Black, 319 [6.7%] Hispanic, and 3985 [83.2%] White); 1904 were in the PFFR and 2888 in the EMV cohort. Black patients with PF were consistently younger than White patients (mean [SD] age at baseline, 57.9 [12.0] vs 68.6 [9.6] years; P < .001). Hispanic and White patients were predominantly male (Hispanic: PFFR, 73 of 124 [58.9%] and EMV, 109 of 195 [55.9%]; and White: PFFR, 1090 of 1675 [65.1%] and EMV, 1373 of 2310 [59.4%]), while Black patients were less likely to be male (PFFR, 32 of 105 [30.5%] and EMV, 102 of 383 [26.6%]). Compared with White patients, Black patients had a lower crude mortality rate ratio (0.57 [95% CI, 0.31-0.97), but for Hispanic patients, the mortality rate ratio was similar to that of White patients (0.89; 95% CI, 0.57-1.35). Mean (SD) hospitalization events per person were highest among Black patients compared with Hispanic and White patients (Black: 3.6 [5.0]; Hispanic, 1.8 [1.4]; and White, 1.7 [1.3]; P < .001). Black patients were consistently younger than Hispanic and White patients at first hospitalization (mean [SD] age: Black, 59.4 [11.7] years; Hispanic, 67.5 [9.8] years; and White, 70.0 [9.3] years; P < .001), lung transplant (Black, 58.6 [8.6] years; Hispanic, 60.5 [6.1] years; and White, 66.9 [6.7] years; P < .001), and death (Black, 68.7 [8.4] years; Hispanic, 72.9 [7.6] years; and White, 73.5 [8.7] years; P < .001). These findings remained consistent in the replication cohort and in sensitivity analyses within prespecified deciles of age groups. Conclusions and Relevance: In this cohort study of participants with PF, racial and ethnic disparities, especially among Black patients, were found in PF-related outcomes, including earlier onset of death. Further research is essential to identify and mitigate the underlying responsible factors.

Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts.

Pulmonary fibrosis (PF) is characterized by profound scarring and poor survival. We investigated the association of leukocyte telomere length (LTL) with chronological age and mortality across racially diverse PF cohorts. LTL measurements among participants with PF stratified by race/ethnicity were assessed in relation to age and all-cause mortality, and compared to controls. Generalized linear models were used to evaluate the age-LTL relationship, Cox proportional hazards models were used for hazard ratio estimation, and the Cochran-Armitage test was used to assess quartiles of LTL. Standardized LTL shortened with increasing chronological age; this association in controls was strengthened in PF (R = -0.28; P < 0.0001). In PF, age- and sex-adjusted LTL below the median consistently predicted worse mortality across all racial groups (White, HR = 2.21, 95% CI = 1.79-2.72; Black, HR = 2.22, 95% CI = 1.05-4.66; Hispanic, HR = 3.40, 95% CI = 1.88-6.14; and Asian, HR = 2.11, 95% CI = 0.55-8.23). LTL associates uniformly with chronological age and is a biomarker predictive of mortality in PF across racial groups.

Validation of Proposed Criteria for Progressive Pulmonary Fibrosis.

Rationale: Criteria for progressive pulmonary fibrosis (PPF) have been proposed, but their prognostic value beyond categorical decline in FVC remains unclear. Objectives: To determine whether proposed PPF criteria predict transplant-free survival (TFS) in patients with non-idiopathic pulmonary fibrosis (IPF) forms of interstitial lung disease (ILD). Methods: A retrospective, multicenter cohort analysis was performed. Patients with diagnoses of fibrotic connective tissue disease-associated ILD, fibrotic hypersensitivity pneumonitis, and non-IPF idiopathic interstitial pneumonia from three U.S. centers and one UK center constituted the test and validation cohorts, respectively. Cox proportional hazards regression was used to test the association between 5-year TFS and ⩾10% FVC decline, followed by 13 additional PPF criteria satisfied in the absence of ⩾10% FVC decline. Measurements and Main Results: One thousand three hundred forty-one patients met the inclusion criteria. A ⩾10% relative FVC decline was the strongest predictor of reduced TFS and showed consistent TFS association across cohorts, ILD subtypes, and treatment groups, resulting in a phenotype that closely resembled IPF. Ten additional PPF criteria satisfied in the absence of 10% relative FVC decline were also associated with reduced TFS in the U.S. test cohort, with 6 maintaining TFS associations in the UK validation cohort. Validated PPF criteria requiring a combination of physiologic, radiologic, and symptomatic worsening performed similarly to their stand-alone components but captured a smaller number of patients. Conclusions: An FVC decline of ⩾10% and six additional PPF criteria satisfied in the absence of such decline identify patients with non-IPF ILD at increased risk for death or lung transplantation.

Utility of whole genome sequencing in assessing risk and clinically relevant outcomes for pulmonary fibrosis.

BACKGROUND: Whole genome sequencing (WGS) can detect variants and estimate telomere length. The clinical utility of WGS in estimating risk, progression and survival of pulmonary fibrosis patients is unknown. METHODS: In this observational cohort study, we performed WGS on 949 patients with idiopathic pulmonary fibrosis or familial pulmonary fibrosis to determine rare and common variant genotypes, estimate telomere length and assess the association of genomic factors with clinical outcomes. RESULTS: WGS estimates of telomere length correlated with quantitative PCR (R=0.65) and Southern blot (R=0.71) measurements. Rare deleterious qualifying variants were found in 14% of the total cohort, with a five-fold increase in those with a family history of disease versus those without (25% versus 5%). Most rare qualifying variants (85%) were found in telomere-related genes and were associated with shorter telomere lengths. Rare qualifying variants had a greater effect on telomere length than a polygenic risk score calculated using 20 common variants previously associated with telomere length. The common variant polygenic risk score predicted telomere length only in sporadic disease. Reduced transplant-free survival was associated with rare qualifying variants, shorter quantitative PCR-measured telomere lengths and absence of the MUC5B promoter (rs35705950) single nucleotide polymorphism, but not with WGS-estimated telomere length or the common variant polygenic risk score. Disease progression was associated with both measures of telomere length (quantitative PCR measured and WGS estimated), rare qualifying variants and the common variant polygenic risk score. CONCLUSION: As a single test, WGS can inform pulmonary fibrosis genetic-mediated risk, evaluate the functional effect of telomere-related variants by estimating telomere length, and prognosticate clinically relevant disease outcomes.

Interstitial Pneumonia with Autoimmune Features: What the Rheumatologist Needs to Know.

PURPOSE OF REVIEW: This narrative review will focus on the role of the rheumatologist in evaluating patients with interstitial lung disease (ILD) without a defined rheumatic disease and will outline the current classification criteria for interstitial pneumonia with autoimmune features (IPAF) and describe what is known regarding IPAF pathobiology, natural history, prognosis, and treatment. Lastly, knowledge gaps and opportunities for future research will be discussed. RECENT FINDINGS: IPAF is a recently defined classification of ILD patients who have features suggesting an autoimmune-mediated process, but do not fulfill current rheumatic disease criteria. The goal of the IPAF criteria is to provide a uniform case definition for the study of autoimmune ILD patients who do not currently fit within standard ILD diagnostic categories, ultimately improving diagnosis and therapy. Many of these patients are referred for rheumatologic evaluation to aid the diagnostic process. The care of the IPAF patient is complex and is multidisciplinary with pulmonology, rheumatology, pathology, radiology, physical therapy, primary care, pulmonary transplant providers all serving vital roles. The rheumatologist has several roles which include classification, disease monitoring, and management.

Time-limited trials in the ICU: a mixed-methods sequential explanatory study of intensivists at two academic centres.

OBJECTIVE: To understand intensivist perceptions of the appropriateness of time-limited trials (TLTs)-a strategy to align life-sustaining care with patient goals and values in the midst of clinical uncertainty. DESIGN: We conducted a mixed-methods sequential explanatory study of intensive care unit (ICU) intensivists regarding appropriateness of utilising TLTs in three vignettes centred on invasive mechanical ventilation (IMV); continuous renal replacement therapy (CRRT); and heated high-flow nasal cannula (HHFNC). Semistructured interviews were conducted using the Tailored Implementation of Chronic Diseases framework. Data were analysed using thematic and matrix analysis. SETTING: Two academic medical centres in the USA participated in the randomised surveys and one centre participated in the semistructured interviews. PARTICIPANTS: Pulmonary and critical care intensivists and fellows. PRIMARY AND SECONDARY OUTCOMES: To understand intensivists perceptions of the appropriateness in using TLTs. RESULTS: Of 115 physicians surveyed, 71 initiated the survey and 44 completed the entire survey with a response rate of 38% (N=44/115) and a completion rate of 62% (N=44/71). While 35% (N=23/66) of intensivists had never heard of a TLT, of the intensivists who had heard of a TLT, 77% (N=33/43) had participated in one. In response to the vignettes, appropriateness of using a TLT varied (IMV: 74% (N=46/62); CRRT 78% (N=49/63); HHFNC 92% (N=56/61) as did the durations of the TLT. Semistructured interviews with 11 intensivists revealed having clarity about patient goals and clinical endpoints facilitated successful TLTs while lack of an evidenced-based framework was a barrier. CONCLUSION: More than half of the physicians who responded had conducted or participated in a TLT. To increase the use of TLTs in the ICU, clinicians desire a more robust, evidence-based framework on how to conduct TLTs.

Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Genetic studies of idiopathic pulmonary fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. Objectives: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. Methods: We performed gene burden analysis of whole-exome data, tested single variants for disease association, conducted KIF15 (kinesin family member 15) functional studies, and examined human lung single-cell RNA sequencing data. Measurements and Main Results: Gene burden analysis of 1,725 cases and 23,509 control subjects identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT [telomerase reverse transcriptase], RTEL1 [regulator of telomere elongation helicase 1], and PARN [poly(A)-specific ribonuclease]). KIF15 was implicated in autosomal-dominant models of rare deleterious variants (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.7-8.8; P = 2.55 × 10-7) and rare protein-truncating variants (OR, 7.6; 95% CI, 3.3-17.1; P = 8.12 × 10-7). Meta-analyses of the discovery and replication cohorts, including 2,966 cases and 29,817 control subjects, confirm the involvement of KIF15 plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405; OR, 1.6; 95% CI, 1.4-1.9; P = 5.63 × 10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells and shows diminished expression in replicating epithelial cells of patients with IPF. Conclusions: Both rare deleterious variants and common variants in KIF15 link a nontelomerase pathway of cell proliferation with IPF susceptibility.

The Role of Genetic Testing in Pulmonary Fibrosis: A Perspective From the Pulmonary Fibrosis Foundation Genetic Testing Work Group.

Patients with familial pulmonary fibrosis represent a subset of patients with pulmonary fibrosis in whom inherited gene variation predisposes them to disease development. In the appropriate setting, genetic testing allows for personalized assessment of disease, recognition of clinically relevant extrapulmonary manifestations, and assessing susceptibility in unaffected relatives. However currently, the use of genetic testing is inconsistent, partly because of the lack of guidance regarding high-yield scenarios in which the results of genetic testing can inform clinical decision-making. To address this, the Pulmonary Fibrosis Foundation commissioned a genetic testing work group comprising pulmonologists, geneticists, and genetic counselors from the United States to provide guidance on genetic testing in patients with pulmonary fibrosis. This CHEST special feature presents a concise review of these proceedings and reviews pulmonary fibrosis susceptibility, clinically available genetic testing methods, and clinical scenarios in which genetic testing should be considered.

Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis.

BACKGROUND: Progressive fibrosing interstitial lung disease (ILD) is characterised by parenchymal scar formation, leading to high morbidity and mortality. The ability to predict this phenotype remains elusive. We conducted a proteomic analysis to identify novel plasma biomarkers of progressive fibrosing ILD and developed a proteomic signature to predict this phenotype. METHODS: Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform in patients with connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, or unclassifiable ILD who provided research blood draws at the University of California (discovery cohort) and the University of Texas (validation cohort). Univariable logistic regression was used to identify individual biomarkers associated with 1-year ILD progression, defined as death, lung transplant, or 10% or greater relative forced vital capacity (FVC) decline. A proteomic signature of progressive fibrosing ILD was then derived with use of machine learning in the University of California cohort and validated in the University of Texas cohort. FINDINGS: The discovery cohort comprised 385 patients (mean age 63·6 years, 59% female) and the validation cohort comprised 204 patients (mean age 60·7 years, 61% female). 31 biomarkers were associated with progressive fibrosing ILD in the discovery cohort, with 17 maintaining an association in the validation cohort. Validated biomarkers showed a consistent association with progressive fibrosing ILD irrespective of ILD clinical diagnosis. A proteomic signature comprising 12 biomarkers was derived by machine learning and validated in the University of Texas cohort, in which it had a sensitivity of 0·90 and corresponding negative predictive value of 0·91, suggesting that approximately 10% of patients with a low-risk proteomic signature would experience ILD progression in the year after blood draw. Those with a low-risk proteomic signature experienced an FVC change of +85·7 mL (95% CI 6·9 to 164·4) and those with a high-risk signature experienced an FVC change of -227·1 mL (-286·7 to -167·5). A theoretical clinical trial restricted to patients with a high-risk proteomic signature would require 80% fewer patients than one designed without regard to proteomic signature. INTERPRETATION: 17 plasma biomarkers of progressive fibrosing ILD were identified and showed consistent associations across ILD subtypes. A proteomic signature of progressive fibrosing ILD could enrich clinical trial cohorts and avoid the need for antecedent progression when defining progressive fibrosing ILD for clinical trial enrolment. FUNDING: National Heart Lung and Blood Institute.

Lung function trajectory in progressive fibrosing interstitial lung disease.

BACKGROUND: Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criteria remains unknown. Because survival is rarely employed as the primary end-point in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design. METHODS: A retrospective, multicentre longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centres (test cohort) and one UK centre (validation cohort). 1-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modelling. Subgroup analyses were performed to determine whether results varied across key subgroups. RESULTS: 1227 patients were included, with CTD-ILD predominating. Six out of nine PF-ILD criteria were associated with differential 1-year change in FVC, with radiological progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiological pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype. CONCLUSIONS: These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria.

Variables Associated With Response to Therapy in Patients With Interstitial Pneumonia With Autoimmune Features.

BACKGROUND/OBJECTIVE: We have limited knowledge regarding characteristics of patients with interstitial pneumonia with autoimmune features (IPAF) that are associated with response to immunosuppression. In this study, we used published IPAF criteria to characterize features associated with response to treatment. METHODS: We conducted a single-center medical records review study of 63 IPAF patients to evaluate for serological, clinical, and morphological characteristics that are associated with response to immunosuppression. Response was defined as % relative functional vital capacity decline of less than 10% and absence of death or lung transplant within the first year of continuous immunosuppressive therapy. Nonparametric measures of association and multivariate logistic regression were used to evaluate the relationship between baseline characteristics and immunosuppressive response. RESULTS: There was a trend of greater progression among men, ever smokers, those negative for antisynthetase antibodies, and those with usual interstitial pneumonia radiographic pattern, but no statistically significant relationship was found between baseline serological, clinical, or morphological features and response to immunosuppression. Patients on combination therapy with mycophenolate mofetil and prednisone had less disease progression (p = 0.018) than those on regimens that did not include both of these medications. CONCLUSIONS: In our cohort, baseline clinical assessment did not identify which patients with IPAF will respond to immunosuppressive therapy. Combination therapy with mycophenolate mofetil and prednisone was associated with lack of disease progression in our IPAF patients, including in IPAF-usual interstitial pneumonia. Further studies are needed to evaluate which IPAF patients would benefit from immunosuppressive therapy, antifibrotic therapy, or a combination of both.

Addition of antifibrotic therapy to immunosuppression in hypersensitivity pneumonitis: A case series.

Hypersensitivity pneumonitis has historically been treated with immunosuppression, but recently nintedanib was approved for the treatment of progressive fibrotic HP. One limitation of INBUILD is that the only immunosuppression (IS) permitted at the time of enrollment was glucocorticoids at a dose of less than 20mg per day, so the additive effect of antifibrotic (AF) therapy to IS in HP remains unclear. We present 5 cases of patients with HP for whom AF therapy was added to IS. Trends observed in the cohort include reduced decline in FVC, oxygen requirement, and symptoms in the year after adding AF to IS in 4 of the 5 patients. All 5 patients (100%) in our series demonstrated progression in the year prior to initiation of antifibrotic based on criteria outlined in the INBUILD trial, but only 1 of 5 (20%) progressed in the year after AF. There was a significant decrease in the rate of relative decline in % predicted FVC in the 12 months after initiation of antifibrotic compared to the 12 months prior to antifibrotic (0.4% ±7.6 vs -17.5% ±7.6, p = 0.0495). Compared to the 12 months prior to antifibrotic therapy, fewer patients met criteria for progression in the 12 months after initiating antifibrotic therapy (p = 0.048). Similarly, fewer patients met criteria for progression in the 6 months after initiating antifibrotic therapy compared to the 6 months prior (p = 0.048). A larger study with control groups on IS alone and AF alone is needed to confirm the role of AF therapy in combination with IS in patients with HP.

Familial Pulmonary Fibrosis: Genetic Features and Clinical Implications.

Pulmonary fibrosis comprises a wide range of fibrotic lung diseases with unknown pathogenesis and poor prognosis. Familial pulmonary fibrosis (FPF) represents a unique subgroup of patients in which at least one other relative is also affected. Patients with FPF exhibit a wide range of pulmonary fibrosis phenotypes, although idiopathic pulmonary fibrosis is the most common subtype. Despite variable disease manifestations, patients with FPF experience worse survival compared with their counterparts with the sporadic disease form. Therefore, ascertaining a positive family history not only provides prognostic value but should also raise suspicion for the inheritance of an underlying causative genetic variant within kindreds. By focusing on FPF kindreds, rare variants within surfactant metabolism and telomere maintenance genes have been discovered. However, such genetic variation is not solely restricted to FPF, as similar rare variants are found in patients with seemingly sporadic pulmonary fibrosis, further supporting the idea of genetic susceptibility underlying pulmonary fibrosis as a whole. Researchers are beginning to show how the presence of rare variants may inform clinical management, such as informing predisposition risk for yet unaffected relatives as well as informing prognosis and therapeutic strategy for those already affected. Despite these advances, rare variants in surfactant and telomere-related genes only explain the genetic basis in about one-quarter of FPF kindreds. Therefore, research is needed to identify the missing genetic contributors of pulmonary fibrosis, which would not only improve our understanding of disease pathobiology but may offer additional opportunities to improve the health of patients.