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Background:
The aim of this study was to analyze the relative frequency, clinical characteristics, disease onset and progression in f-IPF vs. sporadic IPF (s-IPF).
Methods:
Familial IPF index patients and their family members were recruited into the European IPF registry/biobank (eurIPFreg) at the Universities of Giessen and Marburg (UGMLC). Ini...
Context in source publication
Citations
... FPF is a strong risk factor for idiopathic pulmonary fibrosis (IPF), but FPF has also revealed various other forms of ILD [3,4]. Compared with IPF patients without a familial burden, FPF patients are often younger and have worse survival [4,5]. ...
... Thyroid diseases were also found to be common, especially in patients inconsistent with usual interstitial pneumonia (UIP) patterns [19]. Krauss et al. observed pulmonary hypertension in 26% of patients and OSA and pulmonary embolism in 7% of the patients in a study that included 27 FPF patients [5]. ...
... To the best of our knowledge, this study of 68 FPF patients is one of the Our results supported earlier studies showing that disease onset in FPF patients occurred earlier than that usually observed in IPF patients, at least in men [4,19]. In the study of Krauss et al., the FPF patients were 58.3 years old, and in the study of Bennet et al., the men with familial IPF were 58.5 years old at the time of diagnosis [5,19]. In our study, the men were significantly younger than the women (61.7 and 68.6 years, respectively; p<0.003), and the mean age was 64.4 years. ...
Background
In familial pulmonary fibrosis (FPF) at least two biological relatives are affected. Patients with FPF have diverse clinical features.
Research question
We aimed to characterize demographic and clinical features, re-evaluate high-resolution computed tomography (HRCT) scans and histopathology of surgical lung biopsies, assess survival and investigate the suitability of risk prediction models for FPF patients.
Study design
A retrospective cohort study.
Methods
FPF data (n = 68) were collected from the medical records of Oulu University Hospital (OUH) and Oulaskangas District Hospital between 1 Jan 2000 and 11 Jan 2023. The inclusion criterion was pulmonary fibrosis (PF) (ICD 10-code J84.X) and at least one self-reported relative with PF. Clinical information was gathered from hospital medical records. HRCT scans and histology were re-evaluated.
Results
Thirty-seven (54.4%) of the patients were men, and 31 (45.6%) were women. The mean ages of the women and men were 68.6 and 61.7 years, respectively (p = 0.003). Thirty-seven (54.4%) patients were nonsmokers. The most common radiological patterns were usual interstitial pneumonia (UIP) (51/75.0%), unclassifiable (8/11.8%) and nonspecific interstitial pneumonia (NSIP) (3/4.4%). Pleuroparenchymal fibroelastosis (PPFE) was observed as a single or combined pattern in 13.2% of the patients. According to the 2022 guidelines for idiopathic pulmonary fibrosis (IPF), the patients were categorized as UIP (31/45.6%), probable UIP (20/29.4%), indeterminate for UIP (7/10.3%) or alternative diagnosis (10/14.7%). The histopathological patterns were UIP (7/41.2%), probable UIP (1/5.9%), indeterminate for UIP (8/47.2%) and alternative diagnosis (1/5.9%). Rare genetic variants were found in 9 patients; these included telomerase reverse transcriptase (TERT, n = 6), telomerase RNA component (TERC, n = 2) and regulator of telomere elongation helicase 1 (RTEL1, n = 1). Half of the patients died (n = 29) or underwent lung transplantation (n = 5), with a median survival of 39.9 months. The risk prediction models composite physiology index (CPI), hazard ratio (HR) 1.07 (95.0% CI 1.04–1.10), and gender-age-physiology index (GAP) stage I predicted survival statistically significantly (p<0.001) compared to combined stages II and III.
Conclusions
This study confirmed the results of earlier studies showing that FPF patients’ radiological and histopathological patterns are diverse. Moreover, radiological and histological features revealed unusual patterns and their combinations.
... • fILD: fibrotic interstitial lung diseases Among patients with IPF and PPF, it becomes increasingly clear that a significant proportion (10-20%) demonstrates familial aggregation (2 or more relatives affected from the same family), has a pathogenic variant in telomere related genes (TRG) and/or demonstrate significant telomere shortening (2)(3)(4). The currently known FFP-associated TRG variants, which are mostly germline, are in TERT, TERC, RTEL1, PARN, TINF2, DKC1, NOP10, NHP2, ACD, NAF1, RPA, POT1 and ZCCHC8 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). ...
... Both clinical trials and real-world studies in the literature have consistently shown that IPF primarily affects older male individuals with a smoking history (4,5,10,13). However, it has been reported that patients with a positive family history tend to be diagnosed at a younger age (14). Consistent with the existing literature, our study also demonstrated a high proportion of male patients (76.7%) and a significant prevalence of smoking history among the study population (70.9%). ...
Introduction:
The aim of this study was to evaluate the real-life treatment and follow-up data of patients with idiopathic pulmonary fibrosis (IPF) in a singlecenter setting.
Materials and methods:
The study included consecutive patients diagnosed with IPF who were followed up at the Akdeniz University, between January 1, 2014 and December 31, 2022. Patient information was obtained from the hospital automation system.
Result:
A total of 227 patients with a mean age of 72.0 ± 8.2 years were included in the study. One hundred sixty-seven patients (73.6%) received pirfenidone while 60 patients (26.4%) received nintedanib treatment. Radiological findings were used to diagnose IPF in 79.3% (n= 180) of cases. Mean duration of antifibrotic treatment was 26.3 ± 19.9 months. Of the patients, 49.8% experienced hospital admissions during the treatment course, with respiratory reasons accounting for a majority of these admissions (33.6%). Disease exacerbation was detected in 26.6% of the patients during the treatment period. At least one side effect was observed in 126 patients (55.5%), with a significant portion of these side effects being mild to moderate (n= 79, 34.8%). Disease progression was observed in 21.6% of the patients under antifibrotic treatment. Dose reduction was necessary in 22.9% of the patients, with an average duration of dose reduction of 29 months. Antifibrotic treatment was switched to another medication in 24.2% of the patients. There were no statistically significant differences in baseline forced vital capacity (FVC) levels between the two groups (p= 0.314) while the diffusing capacity of the lungs for carbon monoxide (DLCO) level was higher in the nintedanib group (p= 0.024), and the six-minute walk distance was shorter (p= 0.049).
Conclusions:
In this study evaluating patients with IPF under follow-up in our hospital, it was observed that the majority of patients consisted of elderly male individuals, frequent hospitalizations were due to respiratory reasons, and both antifibrotic medications were well tolerated with a similar side effect profile.
... It is important to note that among individuals diagnosed with ILD, those who have a familial history of ILD are typically younger than those without a family history of ILD [12,16]. It is also reported that those with a family history have an earlier age at death than those without familial forms of ILD [12,16]. ...
... It is important to note that among individuals diagnosed with ILD, those who have a familial history of ILD are typically younger than those without a family history of ILD [12,16]. It is also reported that those with a family history have an earlier age at death than those without familial forms of ILD [12,16]. However, the presence of a common variant known as MUC5b promoter polymorphism (MUC5B rs35705950) is paradoxically noted to be associated with increased survival from diagnosis of ILD compared to those without this variant, and the reason for this is unclear [17]. ...
Purpose of Review
This review aims to summarize the recent evidence supporting the role of genetic testing across the spectrum of interstitial lung diseases and identifying barriers and unintended risks of genetic testing.
Recent Findings
There is increasing interest among patients and their relatives in pursuing testing and no significant negative psychological impact of testing has been identified. Specific group of individuals who would most benefit from genetic testing (younger age at diagnosis, familial pulmonary fibrosis, features of short telomere syndrome, Hermansky-Pudlak syndrome, and relatives of individuals with known pathogenic genetic variants) and those who would likely not benefit from testing have been recently addressed. Gene sequencing can be used to identify known pathogenic variants in the surfactant-related genes and telomere-related genes. Peripheral blood leukocyte telomere length measurement may be of prognostic value and evidence for using this to guide clinical decision-making is evolving. Practical aspects like cost and availability of genetic testing are major barriers to genetic testing in the USA.
Summary
Though genetic testing is not currently a part of routine clinical practice, there is a role for testing in specific situations. Future research should focus on how the results of genetic testing can guide clinical decision-making in pulmonary fibrosis.
... There is evidence to suggest that FPF is worse, faster progressing and has higher mortality than sporadic fibrotic ILD, although data is incomplete and at times contradictory (5). In a small study, a 9.9% annual rate of FVC decline was seen in familial IPF patients compared to 4.9% in those with sporadic IPF (not statistically significant, p = 0.12) (49). The average annual rate of FVC decline amongst 115 ILD patients with TRG mutations (46% of whom had IPF) was found to be 300 ml (regardless of gene involved) (16). ...
Within the wide scope of interstitial lung diseases (ILDs), familial pulmonary fibrosis (FPF) is being increasingly recognized as a specific entity, with earlier onset, faster progression, and suboptimal responses to immunosuppression. FPF is linked to heritable pathogenic variants in telomere-related genes (TRGs), surfactant-related genes (SRGs), telomere shortening (TS), and early cellular senescence. Telomere abnormalities have also been identified in some sporadic cases of fibrotic ILD. Air pollution and other environmental exposures carry additive risk to genetic predisposition in pulmonary fibrosis. We provide a perspective on how these features impact on screening strategies for relatives of FPF patients, interstitial lung abnormalities, ILD multidisciplinary team (MDT) discussion, and disparities and barriers to genomic testing. We also describe our experience with establishing a familial interstitial pneumonia (FIP) clinic and provide guidance on how to identify patients with telomere dysfunction who would benefit most from genomic testing.
... Пневмосклероз відноситься до групи хронічних, незворотних і часто смертельних інтерстиціальних захворювань легень, які виникають переважно у людей середнього та похилого віку [4] за відсутності або при недостатній фармакологічній корекції запальних процесів у легенях. Зрештою це призводить до небезпечних для життя структурних та функціональних змін у легеневій тканині [5]. ...
The purpose of the study was to analyze literary sources on the study of modern views on information about the pathogenetic mechanisms of the formation of pulmonary fibrosis. Materials and methods. Analytical and bibliosemantic methods were used in the research. During the scientific search, 39 sources of modern domestic and foreign literature were reviewed and analyzed. Results and discussion. Pulmonary fibrosis is a heterogeneous group of chronic, progressive and incurable interstitial lung diseases characterized by scar formation and irreversible destruction of the lung parenchyma and is accompanied by disorders of elasticity and gas exchange in pathologically altered areas. The mechanism of development of pulmonary fibrosis is determined by its root causes. There are three distinct pathologic patterns of pulmonary fibrosis: usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway fibrosis. Their morphological differences are based on the distribution of fibrosis (diffuse or spotty) and anatomical location. The development of pulmonary fibrosis in most cases is a consequence of a previous acute inflammation of the lungs caused by various etiological factors, which in the case of untimely started or incorrectly selected treatment causes the deposition of fibrous tissue in the lungs. It is believed that the appearance and subsequent progression of pulmonary fibrosis can be attributed to reparative processes after repeated injuries of alveolar epithelial cells in response to various stimuli, including injuries. Loss of function or reduction in the number of alveolar epithelial cells can lead to improper repair of the lung parenchyma, which can lead to fibrosis. Various cytokines such as transforming growth factor-β1, tumor necrosis factor-α, and platelet-derived growth factor can be released when alveolar epithelial cells are damaged. These cytokines can promote the accumulation of fibroblasts. In addition to the cytokine response, the lung’s response to injury includes the stimulation of myofibroblasts, which when activated serve as the primary collagen-producing cell. This leads to massive deposition of collagen and subsequently affects the normal structure and function of lung tissue. Conclusion. Pulmonary fibrosis is a progressive lung disease that leads to morpho-functional restructuring of lung tissue. In the course of the work, the presence of three models of the development of pulmonary fibrosis were analyzed. Despite the long history of study and good coverage of the problem in the scientific literature, currently the mechanisms of formation of pulmonary fibrosis remain insufficiently studied
... The Mayo Clinic series further concluded that f-IPF and s-IPF share the same clinical, radiological, and pathological features (12), except that the average age of onset of f-IPF (55 years) is lower than that of s-IPF (68 years). In addition, the average age of diagnosis for f-IPF (58 years) is lower than that for s-IPF (65 years) (22). ...
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.
... Familial interstitial pneumonia (FIP) (MIM: 178500) is usually defined as idiopathic interstitial lung disease (ILD) in two or more relatives who share a common ancestry [1][2][3]. Adults with FIP are practically indistinguishable from sporadic ILD patients concerning their clinical presentation, radiographic findings, and histopathology, except that those with FIP tend to present at an earlier age and with a more aggressive natural course of the disease [1,[4][5][6]. ...
Familial interstitial pneumonia (FIP) is defined as idiopathic interstitial lung disease (ILD) in two or more relatives. Genetic studies on familial ILD discovered variants in several genes or associations with genetic polymorphisms. The aim of this study was to describe the clinical features of patients with suspected FIP and to analyze the genetic variants detected through next-generation sequencing (NGS) genetic testing. A retrospective analysis was conducted in patients followed in an ILD outpatient clinic who had ILD and a family history of ILD in at least one first-or second-degree relative and who underwent NGS between 2017 and 2021. Only patients with at least one genetic variant were included. Genetic testing was performed on 20 patients; of these, 13 patients had a variant in at least one gene with a known association with familial ILD. Variants in genes implicated in telomere and surfactant homeostasis and MUC5B variants were detected. Most variants were classified with uncertain clinical significance. Probable usual interstitial pneumonia radiological and histological patterns were the most frequently identified. The most prevalent phenotype was idiopathic pulmonary fibrosis. Pulmonologists should be aware of familial forms of ILD and genetic diagnosis.
... In that case, first-degree relatives of FPF patients have a 50% chance of also carrying the disease-causing mutation and are therefore at high risk of developing FPF [3][4][5]. Disease course, including decline in forced vital capacity (FVC) [6] and mortality [2,4,7,8] in FPF patients, is comparable with sporadic IPF. While there is no specific treatment for adult FPF patients, retrospective analyses suggest that antifibrotic treatment has similar safety and effectivity as in patients with IPF or progressive PF [9][10][11]. ...
... While there is no specific treatment for adult FPF patients, retrospective analyses suggest that antifibrotic treatment has similar safety and effectivity as in patients with IPF or progressive PF [9][10][11]. In studies of patients with FPF, diffusing capacity for carbon monoxide (DLCO) and FVC are often already impaired at diagnosis, with values around 50% and 70% of normal, respectively [6,12,13]. Timely diagnosis is thus important to fully benefit from therapeutic intervention. ...
... Current clinical screening involves a high-resolution computed tomography (HRCT) of the chest with a five-year interval and an annual medical examination consisting of anamnesis, pulmonary function test, blood tests, and physical examination. This screening protocol was based on parameters that are used for the detection of PF in symptomatic persons, as well as information gathered from studies investigating patients with FPF or asymptomatic family members [6,[15][16][17]. However, evidence on the diagnostic value of these markers, notably in early disease, is scarce and the intervals were chosen arbitrarily. ...
Background: Familial pulmonary fibrosis (FPF) can be defined as pulmonary fibrosis in two or more first-degree family members. The first-degree family members of FPF patients are at high risk of developing FPF and are eligible for screening. Reproducible studies investigating risk factors for disease are much needed. Methods: Description of the screening study protocol for a single-center, prospective cohort study; the study will include 200 asymptomatic, first-degree family members of patients with FPF who will undergo three study visits in two years. The primary objective is determining the diagnostic value of parameters for detection of early FPF; the secondary objectives are determining the optimal timing of the screening interval and gaining insight into the natural history of early FPF. The presence of interstitial lung disease (ILD) changes on high-resolution computed tomography of the chest is indicative of preclinical ILD; the changes are determined at baseline. The comparison between the group with and without ILD changes is made for clinical parameters (pulmonary function, presence of digital clubbing, presence of Velcro-like crackles, blood count, liver- and kidney-function testing, patient-reported cough and dyspnea score) and exploratory parameters. Discussion: This study will be the first large-size, prospective, longitudinal cohort study for yearly screening of asymptomatic family members of FPF patients investigating the diagnostic value of parameters, including lung function, to detect early FPF. More effective screening strategies could advance early disease detection.
... Adults with FPF are essentially indistinguishable from sporadic patients in terms of clinical presentation, radiographic findings and histopathology [2,[26][27][28]. However, they are usually younger and disease evolves towards progressive fibrosing ILD with limited survival [2,[26][27][28]. ...
... Adults with FPF are essentially indistinguishable from sporadic patients in terms of clinical presentation, radiographic findings and histopathology [2,[26][27][28]. However, they are usually younger and disease evolves towards progressive fibrosing ILD with limited survival [2,[26][27][28]. A common genetic background in idiopathic and non-idiopathic ILD has been reported [5][6][7]29]. ...
... The dominant phenotype in FPF is a chronic and progressive fibrotic ILD [2,[26][27][28]45]. The clinical presentation of patients carrying causal mutations for adult and paediatric ILD is similar to sporadic ILD, with dyspnoea, cough, inspiratory crackles and, in a minority, clubbing. ...
Genetic predisposition to pulmonary fibrosis has been confirmed by the discovery of several gene mutations that cause pulmonary fibrosis. Although genetic sequencing of familial pulmonary fibrosis (FPF) cases is embedded in routine clinical practice in several countries, many centers have yet to incorporate genetic sequencing within ILD services, and proper international consensus has not yet been established.
An international and multidisciplinary expert taskforce (pulmonologists, geneticists, pediatrician, pathologist, genetic counselor, patient representative, and librarian) reviewed the literature between 1945 and 2022, and reached consensus for all of the following questions: 1) Which patients may benefit from genetic sequencing and clinical counseling? 2) What is known of the natural history of familial disease? 3) Which genes are usually tested? 4) What is the evidence for telomere length measurement? 5) What is the role of common genetic variants (polymorphisms) in the diagnostic workup? 6) What are the optimal treatment options for FPF? 7) Which family members are eligible for genetic sequencing? 8) Which clinical screening and follow-up parameters may be considered in family members?
Through a robust review of the literature, the panel offers a statement on genetic sequencing, clinical management and screening of patients with FPF and their relatives. This proposal may serve as a basis for a prospective evaluation and future international recommendations.
