Familial Idiopathic Pulmonary Fibrosis Research Articles

Tell me more – telomere biology and understanding telomere defects

Telomeres are DNA-protein structures at the ends of chromosomes that maintain chromosome stability and protects them from damage during mitosis and prevents abnormal fusion with adjacent chromosomes. They are non-coding repeats of the (TTAGGG)n nucleotide sequence. Telomere length affects cell replication potential and cell senescence. There are numerous proteins and enzymes that protect and maintain telomere length. Telomere disorders are a heterogenous group of diseases caused by germline pathogenic variants in genes involved in telomere maintenance. The clinical features are variable but often include bone marrow failure, idiopathic pulmonary fibrosis (IPF), liver cirrhosis, premature greying of hair, and dysplastic nails. However, incomplete penetrance and variable expressivity influence the clinical phenotype in individuals, which results is underdiagnosis or late diagnosis for many patients. At birth, telomere length on average in white blood cells (WBCs) is estimated to be 10Kb and the rate of attrition ranges from 27–41 base pairs each year. There are many factors that affect telomere length but genetics plays a significant role. Also, telomere length can vary in different cells in the same individual based on variable local gene expression. Idiopathic pulmonary fibrosis (IPF) is the most common telomere defect and approximately 30% of patients with sporadic or familial IPF have genetic defects in telomere-related genes. This talk will cover fundamental concepts of telomeres and discuss short and long telomere defects and measurement of telomere length in the clinical laboratory.

Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease; although the recent introduction of two anti-fibrosis drugs, pirfenidone and Nidanib, have resulted in a significant reduction in lung function decline, IPF is still not curable. Approximately 2-20% of patients with IPF have a family history of the disease, which is considered the strongest risk factor for idiopathic interstitial pneumonia. However, the genetic predispositions of familial IPF (f-IPF), a particular type of IPF, remain largely unknown. Genetics affect the susceptibility and progression of f-IPF. Genomic markers are increasingly being recognized for their contribution to disease prognosis and drug therapy outcomes. Existing data suggest that genomics may help identify individuals at risk for f-IPF, accurately classify patients, elucidate key pathways involved in disease pathogenesis, and ultimately develop more effective targeted therapies. Since several genetic variants associated with the disease have been found in f-IPF, this review systematically summarizes the latest progress in the gene spectrum of the f-IPF population and the underlying mechanisms of f-IPF. The genetic susceptibility variation related to the disease phenotype is also illustrated. This review aims to improve the understanding of the IPF pathogenesis and facilitate his early detection.

Evolving Concepts and Controversies in Interstitial Lung diseases: Update in 2023

Recent studies elicited evolving concepts and controversies in interstitial lung diseases and proposed substantial changes in diagnostic and therapeutic approaches to interstitial lung diseases. Dr. Averill A. Liebow first coined the term usual interstitial pneumonia (UIP) in 1960’s as distinct pathologic pattern of fibrosis in idiopathic pulmonary fibrosis (IPF), the prototype of progressive fibrosing interstitial lung disease with poor prognosis. Advances in omics led to a better understanding of molecular pathogenesis of UIP and shed light on various types of familial pulmonary fibrosis as well as familial IPF. The concept of progressive pulmonary fibrosis was introduced to acknowledge additional types of progressive fibrosing interstitial lung diseases with the clinical and pathologic phenotypes very similar to those of UIP/IPF. As such, some authors have proposed a paradigm shift by considering UIP as a stand-alone diagnostic entity to encompass other fibrosing interstitial lung diseases that undergo the same relentless progression as IPF. Cicatricial organizing pneumonia is a variant of organizing pneumonia that can be reminiscent of UIP on histopathology but usually follows a stable clinical course unlike UIP. There has been significant disconnection in fundamental understanding as well as diagnostic criteria of lymphocytic interstitial pneumonia among pathologists, pulmonologists and radiologists, which needs to be resolved. The concept and histopathologic criteria of granulomatous and lymphocytic interstitial lung disease are also elusive and require clarification as well. In this review, these topics will be covered based on current literature.

Pregnancy in a Patient with Idiopathic Pulmonary Fibrosis: A Case Report

Idiopathic pulmonary fibrosis (IPF) is a progressive restrictive lung disease. Data on the impact of pregnancy on IPF and maternal outcome is extremely limited. We present the case of a 35-year-old woman, gravida 1 para 0 with familial IPF with no oxygen requirement prior to pregnancy. The patient demonstrated significant deterioration in her lung function beginning at 22 weeks' gestation and underwent hospitalization at 27 2/7 weeks gestation due to acute on chronic hypoxic respiratory failure, ultimately requiring delivery at 28 weeks' gestation. The patient has not regained her baseline pulmonary function and remains oxygen dependent at 5 months postpartum. Based on limited available data, significant maternal morbidity and mortality is reported for women with IPF who become pregnant. Key Points Pregnancy outcomes in IPF are more severe than chronic interstitial lung disease due to connective tissue disorders.Deterioration in lung function amongst pregnant women with IPF occurs predominantly in the late second trimester, and lung function does not appear to recover postpartum.Significant maternal morbidity and mortality (40% at 1 year postpartum) is reported for women with IPF who become pregnant.

Radiological Assessment in Idiopathic Pulmonary Fibrosis (IPF) Patients According to MUC5B Polymorphism.

The MUC5B rs35705950 mutant T allele is the strongest genetic risk factor for familial and sporadic IPF. We sought to determine whether MUC5B genotype influences radiological patterns of IPF at diagnosis, as well as their change over time, in patients on antifibrotic therapy. Among eighty-eight IPF patients, previously genotyped for MUC5B rs35705950, we considered seventy-eight patients who were evaluated for radiological quantification of the following features both at treatment initiation (HRCT1) and after 1 year (HRCT2): ground glass opacities (AS), reticulations (IS) and honeycombing (HC). Of the evaluated patients, 69% carried at least one copy of the T allele (TT/TG). Carriers of the T allele displayed similar FVC loss in the first year of treatment as GG carriers, but overall survival at the end of follow-up was longer in the TT/TG group, compared to the GG group. In the GG group, both the AS and HC increased significantly, whereas in the TT/TG group only HC increased over the first year of treatment. MUC5B rs35705950 GG carriers are associated with increased ground glass and honeycombing extent over time and worse survival than T allele carriers. Longitudinal HRCT may help define the prognostic role of the MUC5B rs35705950 genotype.

Utility of Telomerase Gene Mutation Testing in Patients with Idiopathic Pulmonary Fibrosis in Routine Practice.

Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which is not directly translatable to routine practice. To validate the prevalence results and to establish the individual level, routine clinical practice, and utility of those results we performed next generation sequencing of TCGs on a cohort of well-characterized consecutive individuals with IPF (diagnosis established according to ATS/ERS/JRS/ALAT guidelines). Of 27 IPF patients, three had a family history of idiopathic interstitial pneumonia (familial IPF) and 24 did not (sporadic IPF). Pathogenic/likely-pathogenic variants (according to American College of Medical Genetics criteria) in TCG were found in three individuals (11.1%) of the whole cohort; specifically, they were present in 2 out of 24 (8.3%) of the sporadic and in 1 out of 3 (33.3%) of the patients with familial IPF. Our results, which were established on an individual-patient level study design and in routine clinical practice (as opposed to the case-control study design), are roughly in line with the around 10% prevalence of causative TCG variants in patients with IPF.

Telomere Dysfunction in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is an age-dependent progressive and fatal lung disease of unknown etiology, which is characterized by the excessive accumulation of extracellular matrix inside the interstitial layer of the lung parenchyma that leads to abnormal scar architecture and compromised lung function capacity. Recent genetic studies have attributed the pathological genes or genetic mutations associated with familial idiopathic pulmonary fibrosis (IPF) and sporadic IPF to telomere-related components, suggesting that telomere dysfunction is an important determinant of this disease. In this study, we summarized recent advances in our understanding of how telomere dysfunction drives IPF genesis. We highlighted the key role of alveolar stem cell dysfunction caused by telomere shortening or telomere uncapping, which bridged the gap between telomere abnormalities and fibrotic lung pathology. We emphasized that senescence-associated secretory phenotypes, innate immune cell infiltration, and/or inflammation downstream of lung stem cell dysfunction influenced the native microenvironment and local cell signals, including increased transforming growth factor-beta (TGF-β) signaling in the lung, to induce pro-fibrotic conditions. In addition, the failed regeneration of new alveoli due to alveolar stem cell dysfunction might expose lung cells to elevated mechanical tension, which could activate the TGF-β signaling loop to promote the fibrotic process, especially in a periphery-to-center pattern as seen in IPF patients. Understanding the telomere-related molecular and pathophysiological mechanisms of IPF would provide new insights into IPF etiology and therapeutic strategies for this fatal disease.

Pathogenetic bases of the use of antifibrotic therapy with Bovhyaluronidazum azoximerum in patients with new coronavirus infection COVID-19

One of the most likely and serious complications of the novel coronavirus infection (COVID-19) is pneumofibrosis, which can negatively affect the duration and quality of life of patients who have suffered from this disease. The appearance of fibrotic changes in COVID-19 is due to a number of pathological processes that occur in the lungs after the pathogen, the SARS- CoV-2 virus, enters there. First of all, an inflammatory response is triggered, which is mediated by macrophages and granulocytes, due to which the synthesis of pro-inflammatory cytokines, incl. IL-1, TNF, which are potent inducers of hyaluronic acid synthetase. There is a decrease in the content of fibrinolysis activators in the pulmonary endothelium, which contributes to the accumulation of fibrin in the vessels of the lungs. Fibrin can escape into the interstitial space and cause the formation of sclerosing alveolitis. The increasing defeat of pneumocytes favors the release of fibrin into the lumen of the alveoli, which causes the formation of hyaline membranes. The regulation of the fibrotic process involves immunocompetent cells, primarily CD4 + T-lymphocytes, which are capable of producing cytokines, chemokines and growth factors, and these, in turn, stimulate the proliferation and differentiation of fibroblasts, as well as their production of collagen. The more severe forms of infectious process can lead to the greater risk of developing fibrotic changes. Risk factors are a large area of lung damage, the use of artificial pulmonary ventilation, ARDS, fibrosis in anamnesis. An additional role in the pathomorphogenesis of pneumofibrosis is played by smoking, external inhalation effects (inhalation of organic and inorganic dust), gastroesophageal reflux, type II diabetes mellitus, genetic factors (familial idiopathic pulmonary fibrosis). The pathogenetic features of COVID-19 require administration of anti-fibrotic treatment. Bovhyaluronidazum azoximerum, a drug that is a conjugate of the proteolytic enzyme hyaluronidase, is considered as an antifibrotic agent. The treatment regimens with this drug recommended in the period of convalescence for patients who have undergone COVID-19 are given.

Evaluation of Correlations between Genetic Variants and High-Resolution Computed Tomography Patterns in Idiopathic Pulmonary Fibrosis.

Background. Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD). This prospective observational study aimed at the evaluation of any correlation between genetic variants associated with IPF susceptibility and high-resolution computed tomography (HRCT) patterns. It also aimed at evidencing any differences in the HRTC pattern between the familial and sporadic form at diagnosis and after two years. Methods. A total of 65 IPF patients (mean age at diagnosis 65 ± 10) were enrolled after having given written informed consent. HRCT and genetic evaluations were performed. Results. A total of 19 familial (mean age 62 ± 15) and 46 sporadic (mean age 70 ± 9) IPF patients were enrolled. A statistically significant difference was evidenced in the HRTC pattern at diagnosis between the two groups. Sporadic IPF patients had a predominantly usual interstitial pneumonia (UIP) pattern compared with those patients with familial IPF (60.0% vs. 21.1%, respectively). Moreover, familial IPF patients had more alternative diagnoses than those with sporadic IPF (31.6% vs. 2.2%, respectively). Furthermore, there was a slight increase in the typical UIP pattern in the familial IPF group at two years from diagnosis. Conclusions. Genetic factors play a pivotal role in the risk of developing IPF. However, further studies are required to clarify how these genetic factors may guide clinical treatment decisions.

Family History of Pulmonary Fibrosis Predicts Worse Survival in Patients With Interstitial Lung Disease

A number of genetic markers linked to familial pulmonary fibrosis predict differential survival in interstitial lung disease (ILD) patients. Although genetic testing is not performed routinely for ILD, family history commonly is obtained and may inform outcome risk. Does survival vary between patients with and without self-reported familial pulmonary fibrosis? Family history was acquired systematically for consecutive ILD patients who consented to clinical registry enrollment at the University of Texas Southwestern and the University of California at Davis. Patients were stratified by idiopathic pulmonary fibrosis (IPF) and non-IPF ILD diagnosis and were substratified by presence or absence of familial pulmonary fibrosis, defined as one or more additional affected family members. Transplant-free survival was compared using multilevel, mixed-effects Cox proportional hazards regression. Of the 1,262 patients included, 534 (42%) had IPF ILD and 728 (58%) had non-IPF ILD. Of those with non-IPF ILD, 18.5%had connective tissue disease, 15.6%had chronic hypersensitivity pneumonitis, and 23.5%had unclassifiable ILD. Familial pulmonary fibrosis was reported in 134 IPF ILD patients (25.1%) and 90 non-IPF ILD patients (12.4%). Those with familial IPF showed an 80%increased risk of death or transplantation compared with those with sporadic IPF (hazard ratio [HR], 1.8; 95%CI, 1.37-2.37; P< .001), whereas those with familial non-IPF ILD showed a twofold increased risk compared with their counterparts with sporadic disease (HR, 2.08; 95%CI, 1.46-2.96; P< .001). Outcome risk among those with familial non-IPF ILD was no different than for those with sporadic IPF ILD (HR, 1.27; 95%CI, 0.89-1.84; P= .19). Patient-reported familial pulmonary fibrosis is predictive of reduced transplant-free survival in IPF and non-IPF ILD patients. Because survival among patients with familial non-IPF ILD approximates that of sporadic IPF ILD, early intervention should be considered for such patients. Until clinical genetic testing is widely available and provides actionable results, family history should be ascertained and considered in risk stratification.

THE CASE OF ASCENDING PARAPARESIS FOLLOWING NINTEDANIB

SESSION TITLE: Fellows Diffuse Lung Disease SESSION TYPE: Fellow Case Reports PRESENTED ON: October 18-21, 2020 INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an incurable, progressive fibrosing interstitial lung disease reflected by a decline in lung function, worsening dyspnea, exercise capacity, and overall poor prognosis. Nintedanib is one of two anti-fibrotic therapies approved for the treatment of IPF. We present the case of a patient who presented with ascending paraparesis following Nintedanib and here by hope to shed light on treatment of IPF and potential but unproven side effects of Nintedanib. CASE PRESENTATION: 39-year-old male with history of familial IPF secondary to short telomere syndrome who presented with bilateral progressive upper and lower extremity paresthesia and weakness which started shortly after he was commenced on Nintedanib for pulmonary fibrosis. This progressed to numbness and weakness till he could barely walk or lift his arms against gravity by day 5. He denied any preceding upper respiratory tract or gastrointestinal symptoms. Physical exam was significant for bibasilar fine velcro crackles in the lungs, hyporeflexia and flaccid tone with power of 3/5 in all extremities. He had negative autoimmune work up. Cerebro-spinal fluid analysis, Pan spinal MRI and MRI of the brain were unrevealing. Electromyogram was significant for motor polyneuropathy with limited demyelinating features. Management was mainly supportive with physical therapy and patient gradually regained his strength back to baseline. DISCUSSION: Nintedanib inhibits multiple tyrosine kinases and targets growth factors like vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor which have been implicated in the pathogenesis of idiopathic pulmonary fibrosis. It is important to monitor potential adverse effects aside from what was noted in the relevant trials of which diarrhea was the commonest. Other side effects were bronchitis, upper respiratory tract symptoms, nausea, vomiting, cough weight loss and back ache. Our patient presented with paresthesias and ascending paresis after taking Nintadenib. He had negative extensive work up for other causes of ascending paralysis and his weakness gradually improved after stopping the medication and with Physical therapy. He was initially offered Intravenous immunoglobulin but was already improving clinically with supportive therapy and physical therapy, so after weighing risk to benefit, decided against it. CONCLUSIONS: With the widening use of Nintedanib, more patients will undoubtedly be exposed to it, and providers should be aware of this unlikely, but serious, potential side effect of Guillain-Barre like presentation which has been associated with other tyrosine kinase inhibitors. To the best of our knowledge, this is the first reported case of ascending paresis following the use of Nintedanib in particular. Reference #1: Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. (2015). New England Journal Of Medicine, 373(8), 782-782. doi: 10.1056/nejmx150012 Reference #2: "Human Medicines European Public Assessment Report (EPAR): Ofev, Nintedanib, Idiopathic Pulmonary Fibrosis, Date Of Authorisation: 14/01/2015, Revision: 10, Status: Authorised". 2019. Case Journals, doi:10.31525/cmr-587247. Reference #3: Lehky, T. J. et al. "Neuromuscular Junction Toxicity With Tandutinib Induces A Myasthenic-Like Syndrome". Neurology, vol 76, no. 3, 2011, pp. 236-241. Ovid Technologies (Wolters Kluwer Health), doi:10.1212/wnl.0b013e3182074a69. DISCLOSURES: No relevant relationships by Shehabaldin Alqalyoobi, source=Web Response No relevant relationships by Afua Kunadu, source=Web Response No relevant relationships by Ogugua Obi, source=Web Response

Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.

Interstitial Lung Disease in Relatives of Patients with Pulmonary Fibrosis.

Rationale: Although relatives of patients with familial pulmonary fibrosis (FPF) are at an increased risk for interstitial lung disease (ILD), the risk among relatives of sporadic idiopathic pulmonary fibrosis (IPF) is not known.Objectives: To identify the prevalence of interstitial lung abnormalities (ILA) and ILD among relatives of patients with FPF and sporadic IPF.Methods: Undiagnosed first-degree relatives of patients with pulmonary fibrosis (PF) consented to participate in a screening study that included the completion of questionnaires, pulmonary function testing, chest computed tomography, a blood sample collection for immunophenotyping, telomere length assessments, and genetic testing.Measurements and Main Results: Of the 105 relatives in the study, 33 (31%) had ILA, whereas 72 (69%) were either indeterminate or had no ILA. Of the 33 relatives with ILA, 19 (58%) had further evidence for ILD (defined by the combination of imaging findings and pulmonary function testing decrements). There was no evidence in multivariable analyses that the prevalence of either ILA or ILD differed between the 46 relatives with FPF and the 59 relatives with sporadic IPF. Relatives with decrements in either total lung or diffusion capacity had a greater than 9-fold increase in their odds of having ILA (odds ratio, 9.6; 95% confidence interval, 3.1-29.8; P < 0.001).Conclusions: An undiagnosed form of ILD may be present in greater than 1 in 6 older first-degree relatives of patients with PF. First-degree relatives of patients with both familial and sporadic IPF appear to be at similar risk. Our findings suggest that screening for PF in relatives might be warranted.

ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation

Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature TR, consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8-null mice and found that heterozygotes, similar to human mutation carriers, had TR insufficiency but an otherwise preserved transcriptome. In contrast, Zcchc8-/- mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The Zcchc8-/- brain transcriptome was highly dysregulated, showing accumulation and 3' end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3' end maturation mechanism that vertebrate TR shares with replication-dependent histones.

Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f-IPF)

BackgroundThe aim of this study was to analyze the relative frequency, clinical characteristics, disease onset and progression in f-IPF vs. sporadic IPF (s-IPF).MethodsFamilial IPF index patients and their family members were recruited into the European IPF registry/biobank (eurIPFreg) at the Universities of Giessen and Marburg (UGMLC). Initially, we employed wide range criteria of f-IPF (e.g. relatives who presumably died of some kind of parenchymal lung disease). After narrowing down the search to occurrence of idiopathic interstitial pneumonia (IIP) in at least one first grade relative, 28 index patients were finally identified, prospectively interviewed and examined. Their family members were phenotyped with establishment of pedigree charts.ResultsWithin the 28 IPF families, overall 79 patients with f-IPF were identified. In the same observation period, 286 f-IIP and s-IIP patients were recruited into the eurIPFreg at our UGMLC sites, corresponding to a familial versus s-IPF of 9.8%. The both groups showed no difference in demographics (61 vs. 79% males), smoking history, and exposure to any environmental triggers known to cause lung fibrosis. The f-IPF group differed by an earlier age at the onset of the disease (55.4 vs. 63.2 years; p < 0.001). On average, the f-IPF patients presented a significantly milder extent of functional impairment at the time point of inclusion vs. the s-IPF group (FVC 75% pred. vs. FVC 62% pred., p = 0.011). In contrast, the decline in FVC was found to be faster in the f-IPF vs. the s-IPF group (4.94% decline in 6 months in f-IPF vs. 2.48% in s-IPF, p = 0.12). The average age of death in f-IPF group was 67 years vs. 71.8 years in s-IPF group (p = 0.059). The f-IIP group displayed diverse inheritance patterns, mostly autosomal-dominant with variable penetrance. In the f-IPF, the younger generations showed a tendency for earlier manifestation of IPF vs. the older generation (58 vs. 66 years, p = 0.013).ConclusionsThe 28 f-IPF index patients presented an earlier onset and more aggressive natural course of the disease. The disease seems to affect consecutive generations at a younger age.Trial registrationNr. NCT02951416http://www.www.clinicaltrials.gov

Lung Transplantation for Familial Pulmonary Fibrosis

Purpose Up to 20% of idiopathic interstitial pneumonia (IIP) cases cluster in families, and familial pulmonary fibrosis (FPF) may require lung transplantation similar to sporadic idiopathic pulmonary fibrosis (IPF). However, transplant outcomes for FPF are not well characterized. We compared lung transplant for FPF versus IPF in a single center. Methods We identified all lung transplant recipients at UCLA between January 2006 and July 2017 with a UNOS lung diagnosis code of IIP: Idiopathic pulmonary fibrosis. After review of medical records and explant pathology, alternative diagnoses were excluded. Among the remaining cohort, we defined FPF as IIP with at least 1 reported first-degree relative with IIP, or those with a pathogenic variant identified on molecular genetic testing in a gene known to be associated with FPF. The remaining patients were considered IPF. The demographics, clinical parameters, and outcomes were compared between FPF and IPF groups. Results The final cohort included 288 patients, 37 (12.8%) FPF and 251 (87.2%) IPF. Demographic and baseline clinical parameters including laboratory tests were not significantly different between FPF and IPF groups. At 6-months post-transplant, FPF patients had lower WBC (4.1 vs. 5.1, p=0.02) and lower hemoglobin (11.5 vs 12.3, p=0.002). At 12-months, FPF patients had lower hemoglobin (11.5 vs 12.2, p=0.01). There was no significant difference in freedom from CLAD, CLAD free survival, or overall survival between FPF and IPF. Most FPF patients did not have genetic testing, but a subset of FPF patients with established short telomere syndrome (n=6) were more likely to develop severe neutropenia (50% vs 15.5%, p=0.02) and had worse survival (p=0.045) than patients transplanted for sporadic IPF. Conclusion Transplant for familial IPF has outcomes similar to sporadic IPF, but is associated with more cytopenia post-transplant. A subset of FPF with short telomere syndrome may have increased incidence of marrow failure and worse post-transplant survival than sporadic IPF.

A Rare Missense Variant in Telomerase Reverse Transcriptase is Associated with Idiopathic Pulmonary Fibrosis in a Chinese Han Family.

Background:Idiopathic pulmonary fibrosis (IPF) is an age-related and progressive interstitial lung disease. Up to 20% of cases of IPF cluster in families, genetic factors contribute significantly to the pathogenesis of the disease. This study aimed to explore the association between rare genetic variants and IPF in Chinese Han families.Methods:A Han family, comprising three IPF patients and five unaffected their first-degree relatives, and 100 ethnically matched control individuals from North China were enrolled in this study. Peripheral blood was collected, and genomic DNA was extracted. To elucidate if rare genetic variants are associated with the familial IPF, we performed whole-exome sequencing of affected members from a Chinese Han IPF family. Candidate rare variants were then confirmed by Sanger sequencing.Results:We identified a potentially damaging rare variant-a heterozygous mutation c.2146G>A in exon 6 of the gene encoding for telomerase reverse transcriptase (TERT), which results in an amino acid substitution (p.Ala716Thr). We confirmed the missense mutation by Sanger sequencing in all the affected family members but did not detect this mutation in 100 ethnically matched healthy controls. Patients carried this mutation were characterized by the frequently acute exacerbation of IPF phenotype, with poor prognosis. The mean time to death was 2.8 years after diagnosis.Conclusion:Using next-generation sequencing technology in familial IPF patients, we identified the heterozygous rare variant in TERT gene, and strengthened the importance of genetic variants in telomere-related pathogenesis in Chinese IPF patients.

Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis.

Epithelial cell dysfunction is postulated as an important component in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell-restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knockin mouse model capable of regulated expression of an IPF-associated isoleucine-to-threonine substitution at codon 73 (I73T) in Sftpc (SP-CI73T). Tamoxifen-treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased early mortality (days 7-14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA content of select inflammatory cytokines. Resolution of alveolitis (2-4 weeks), commensurate with a rise in TGF-β1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, α-smooth muscle actin-positive (α-SMA-positive) cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis, strengthening the role of AT2 cell dysfunction as a key upstream driver of IPF pathogenesis.

Pulmonary phenotypes associated with genetic variation in telomere-related genes.

Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes. Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause. Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere-related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors.

Familial interstitial pulmonary fibrosis in two different families in India: A case series.

Introduction:Idiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial lung disease (ILD), Occasionally, IPF occurs in families. Familial interstitial lung disease has been reported worldwide, limited information is available on the disease among Indian patients.Case Presentation:A 59-year-old woman presented with a 2-year history of progressive dyspnoea. Based on clinical and radiological features, our patient was diagnosed with idiopathic pulmonary fibrosis. Several family members of her first and second generations had died from respiratory failure. Her sister also diagnosed as IPF based on typical High resolution computed tomography (HRCT) finding though she was asymptomatic and came for screening. In addition, another male patient also had similar history and diagnosed as familial IPF based on HRCT and genetic testing in spite of significant occupational exposure. Genetic study revealed SFTPA1 gene was associated with susceptibility to idiopathic pulmonary fibrosis.Conclusion:Our report illustrates that asymptomatic screening of family member can uncover such a serious disease in patients with familial interstitial fibrosis. Otherwise, clinical, radiological, and histological features are indistinguishable from those of sporadic cases. Furthermore, our work highlights the importance of compiling a thorough family history in individuals presenting with cough and dyspnoea, particularly in younger patients identified with idiopathic pulmonary fibrosis.