Goal 1.

Briefly describe the clinical characteristics of pulmonary fibrosis.

Goal 2.

Review genetic causes of pulmonary fibrosis.

Goal 3.

Review the differential diagnosis of pulmonary fibrosis.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of pulmonary fibrosis in a proband.

Goal 5.

Inform genetic counseling of family members of an individual with a genetic predisposition to pulmonary fibrosis.

Goal 6.

Review management of pulmonary fibrosis.

Clinical Features of Pulmonary Fibrosis

Individuals with pulmonary fibrosis typically present with shortness of breath with exertion and a dry cough. Disease onset during adulthood is most common, but onset can range over multiple decades. Most individuals with pulmonary fibrosis have had a history of smoking or fibrogenic environmental exposures [Borie et al 2016, Newton et al 2016, Salisbury et al 2020]. The prevalence of fibrotic lung disease increases with age.

Dry rales are identified on pulmonary auscultation. Hypoxemia with exertion is usually one of the earliest signs. With disease progression, hypoxemia occurs at rest. Symptoms worsen over time as lung scarring progresses. Later findings include finger clubbing, signs of pulmonary hypertension, and sequelae of right heart failure.

Degradation of pulmonary function occurs over time, with progressive decline of forced vital capacity and diffusion capacity. Most individuals die of respiratory causes. Transplant-free survival appears to be lower for individuals with TERC or TERT pathogenic variants than for those without identifiable pathogenic variants in these two genes [Borie et al 2016].

Radiographic Features of Pulmonary Fibrosis

The distribution and extent of specific radiographic features of pulmonary fibrosis can vary, but generally pulmonary fibrosis is characterized by reticulations, traction bronchiectasis, and honeycombing. Individual interstitial lung diseases are associated with different radiographic patterns and features. Radiographic patterns of lung involvement in individuals with certain pathogenic variants may be atypical (see Table 1).

Suggestive Features of a Genetic Cause of Pulmonary Fibrosis

The presence of a genetic cause of predisposition to pulmonary fibrosis can be suggested by family history or by clinical features of a known genetic cause of pulmonary fibrosis (see Table 1 and Table 2).

Family history. Familial pulmonary fibrosis (FPF) describes the occurrence of fibrotic interstitial lung disease (ILD) in at least two related family members. The specific ILD diagnosis may vary in affected individuals from the same family [Lee et al 2012, Newton et al 2016]. Individuals with FPF may be clinically diagnosed with any of the following disorders:

• Idiopathic pulmonary fibrosis (~50% of individuals with FPF) [Borie et al 2016, Newton et al 2016]
• Chronic hypersensitivity pneumonitis (~10% of individuals with FPF) [Okamoto et al 2013, Borie et al 2016, Newton et al 2016]
• Progressive pulmonary fibrosis [Newton et al 2016]
• Idiopathic interstitial pneumonia (IIP) (e.g., unclassifiable IIP, nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis, among others) [Reddy et al 2012, Borie et al 2016, Newton et al 2016, Nunes et al 2017]
• Connective tissue disease-associated ILD, including rheumatoid arthritis ILD and scleroderma ILD [Juge et al 2017]
• Drug-induced ILD [Borie et al 2016]
• Pulmonary fibrosis and adenocarcinoma of the lung
• Combined pulmonary fibrosis and emphysema [Nunes et al 2014, Stanley et al 2015, Stanley et al 2016]

Adenocarcinoma of the lung. Individuals with familial pulmonary fibrosis are at a threefold greater risk of developing adenocarcinoma of the lung compared to the general population [Yoon et al 2018]. A variant of non-small cell lung cancer previously described as bronchoalveolar cancer, arising from the alveolar acinar epithelial with a lepidic growth pattern in the presence or absence of minimally invasive disease, suggests an SFTPA1 or SFTPA2 pathogenic variant [Wang et al 2009, van Moorsel et al 2015, Nathan et al 2016].

Clinical features of a short telomere syndrome (e.g., dyskeratosis congenita) include skin reticular pigmentation, nail dystrophy, oral mucosal leukoplakia, premature graying of hair (age <30 years), thrombocytopenia, macrocytosis, aplastic anemia, bone marrow failure, immunodeficiency, myelodysplasia, acute leukemia, elevated liver enzymes, liver cirrhosis, gastrointestinal disease, radiation sensitivity, and infertility [Newton et al 2016]. Hepatopulmonary syndrome and the development of pulmonary fibrosis after liver transplantation have been reported in individuals with short telomere syndrome [Gorgy et al 2015]. Features of short telomere syndrome are more common in individuals with pathogenic variants in DKC1, TINF2, and TERC than TERT, RTEL1, or PARN.

Prognosis for Those with a Predisposition to Pulmonary Fibrosis

Median survival for those with TERT- or TERC-related pulmonary fibrosis was 3.7 years in a European cohort; this was shorter than the life expectancy of the entire cohort of individuals with a suspected genetic cause of pulmonary fibrosis (6.3 years) [Borie et al 2016]. Median life expectancy for a United States cohort with pulmonary fibrosis due to pathogenic variants in TERT, TERC, RTEL1, and PARN was 2.9 years.

Influence of Environmental Exposures

Cigarette smoking and exposures to inhaled agents are frequently reported by individuals with an identified genetic predisposition to pulmonary fibrosis, suggesting that the combination of genetic predisposition and environmental exposures are particularly injurious [Diaz de Leon et al 2010, Borie et al 2016, Newton et al 2016, Salisbury et al 2020].

Pulmonary Fibrosis – Associated Genes and Syndromes

See Table 1 and Table 2.

Mode of Inheritance

Almost all germline pathogenic variants known to be associated with predisposition to pulmonary fibrosis (see Table 1) are associated with autosomal dominant inheritance. Less commonly, predisposition to pulmonary fibrosis is inherited in an autosomal recessive manner (ABCA3-related pulmonary fibrosis) or an X-linked manner (DKC1-related pulmonary fibrosis).

Genetic counseling for pulmonary fibrosis associated with a pathogenic variant(s) in a gene involved in telomere maintenance (see Table 1) may be complicated by factors such as anticipation and clinical phenocopies (see Related Genetic Counseling Issues); it is recommended that individuals and their families undergo genetic counseling with a healthcare provider who has experience with monogenic short telomere syndromes.

Note: Individuals with germline pathogenic variants in genes associated with short telomere syndrome, especially those older than age 60 years, may acquire somatic TERT promoter pathogenic variants in circulating leukocytes [Maryoung et al 2017, Gutierrez-Rodrigues et al 2019]. Somatic TERT promoter pathogenic variants are not transmitted to offspring.

Syndromic pulmonary fibrosis. If a proband has syndromic pulmonary fibrosis (e.g., dyskeratosis congenita or features suggestive of a syndrome listed in Table 2), genetic counseling for the specific syndrome is appropriate.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Some individuals diagnosed with predisposition to pulmonary fibrosis inherited a pathogenic variant from an affected parent. Because some genetic causes of pulmonary fibrosis can be associated with anticipation, an affected parent may have a later age of onset than the proband.
• Alternatively, a proband with predisposition to pulmonary fibrosis may have a de novo pathogenic variant. The overall proportion of individuals with predisposition to pulmonary fibrosis caused by a de novo pathogenic variant is unknown.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for both parents to ascertain their genetic status and to allow reliable recurrence risk counseling. (Note: Because individuals with predisposition to pulmonary fibrosis are often diagnosed late in the adult years, parental genetic testing is not feasible in many families.)
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with predisposition to pulmonary fibrosis may appear to be negative because of failure to recognize the disorder in affected family members (due to lack of appropriate radiographic imaging) and/or reduced, age-related penetrance (i.e., late onset of the disease in the affected parent or early death of the parent before onset of symptoms). Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (including radiographic imaging) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected or is known to have a pulmonary fibrosis-related pathogenic variant, the risk to the sibs of inheriting the pulmonary fibrosis-related pathogenic variant is 50%. Because predisposition to pulmonary fibrosis is associated with reduced penetrance and intrafamilial clinical variability, the age of onset and clinical manifestations in a sib who inherits a familial pathogenic variant cannot be predicted.
• In families segregating a pathogenic variant in a gene associated with telomere maintenance (see Table 1), sibs of a proband are at risk of inheriting the familial pathogenic variant and are at risk for epigenetic inheritance of shortened telomere length. The inheritance of shortened telomere length (with or without the familial pathogenic variant) can result in manifestations of a short telomere syndrome (including pulmonary fibrosis) (see Related Genetic Counseling Issues).
• If the proband has a known pulmonary fibrosis pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with a germline pathogenic variant associated with predisposition to pulmonary fibrosis has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on their biological relationship with the proband and the genetic status of the proband’s parents.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one ABCA3 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for one ABCA3 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an ABCA3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with ABCA3-related nonsyndromic pulmonary fibrosis are obligate heterozygotes (carriers) for a pathogenic variant in ABCA3.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a ABCA3 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the ABCA3 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management of Pulmonary Fibrosis, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment

Genetic counseling for short telomere syndrome. It is recommended that individuals with a pathogenic variant(s) in a gene associated with telomere maintenance (see Table 1) and their families undergo genetic counseling with a healthcare provider who has experience with monogenic short telomere syndromes and complicating factors including the following:

• Epigenetic inheritance. Shortened telomere length is transmitted from parent to offspring independently of the familial short telomere syndrome-causing pathogenic variant (i.e., the offspring of a heterozygous individual may inherit shortened telomere length but not the pathogenic variant).
• Clinical phenocopies. An individual who inherits a shortened telomere length but not the familial pathogenic variant may have manifestations of a short telomere syndrome (i.e., a clinical phenocopy) because of epigenetic inheritance of shortened telomere length [Alder et al 2011]. Consequently, assessment of recurrence risk based on family history (rather than molecular genetic testing and telomere length measurement) is unreliable.
• Anticipation. Anticipation (the occurrence of increasing disease severity and decreasing age of onset in successive generations) may be observed in pulmonary fibrosis caused by a pathogenic variant(s) in a gene associated with telomere maintenance (see Table 1). This phenomenon is the result of epigenetic transmission of progressively shorter telomere lengths in conjunction with autosomal dominant transmission of the familial pathogenic variant (i.e., offspring of an affected individual who inherit both the familial pathogenic variant and a shorter telomere length than that in their transmitting parent) [Armanios et al 2005, Armanios 2009, Newton et al 2016, Borie et al 2017].
• Variant interpretation. The lack of cosegregation of a familial genetic variant and clinical manifestations (resulting from epigenetic inheritance and phenocopies) raises the possibility that the variant is not pathogenic (see Evaluation Strategies to Identify the Genetic Cause of Pulmonary Fibrosis in a Proband, Molecular genetic testing).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the pulmonary fibrosis-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Age of onset, severity of disease, specific symptoms, and rate of disease progression are variable and cannot be accurately predicted by the family history or prenatal molecular genetic testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a predisposition to pulmonary fibrosis, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) should be considered.

Treatment

Clinical management of pulmonary fibrosis due to a genetic cause is similar to that for individuals with other causes of fibrotic interstitial lung disease and depends on the subtype of interstitial lung disease. It is recommended that individuals be evaluated by a pulmonologist, preferably one with experience in treating familial pulmonary fibrosis.

Surveillance

Agents/Circumstances to Avoid

Environmental exposures. Every effort should be made to remove and avoid environmental exposures linked to the development of pulmonary fibrosis. Deleterious environmental exposures include but are not limited to: smoking, metal fumes/dust, wood dust, stone and sand particulates, certain agricultural, farming and livestock exposures, bird feather and droppings, aerosolized molds, as well as certain medications including chemotherapeutics, antiarrhythmia agents, and nitrofurantoin.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from avoidance of environmental risks and initiation of antifibrotic medications to slow down the rate of progression of disease in those with early findings of lung fibrosis. Evaluations can include the following:

• Molecular genetic testing if a molecular diagnosis has been established in the proband
• If a molecular diagnosis has not been established in the proband but there is a family history of pulmonary fibrosis, the following evaluations are recommended:
  • Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members
  • If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see Table 6).
  • Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome.

Environmental exposures. Development and progression of interstitial lung abnormalities in family members have been associated with environmental exposures. Progression of radiographic abnormalities occurred in most individuals who had detectable early radiographic abnormalities [Salisbury et al 2020].

Every effort should be made to remove and avoid environmental exposures linked to the development of pulmonary fibrosis. Deleterious environmental exposures include but are not limited to: smoking, metal fumes/dust, wood dust, stone and sand particulates, certain agricultural, farming and livestock exposures, bird feather and droppings, aerosolized molds, as well as certain medications including chemotherapeutics, antiarrhythmia agents, and nitrofurantoin.

Note: It is recommended that individuals with a pathogenic variant(s) in a gene associated with telomere maintenance (see Table 1) and their families undergo genetic counseling with a healthcare provider who has experience with monogenic short telomere syndromes and related complications (see Related Genetic Counseling Issues).

Therapies under Investigation

Many therapies are under investigation for the treatment of pulmonary fibrosis. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Author Notes

Dr Garcia is the Frode-Jensen Professor of Medicine at Columbia University Irving Medical Center, as well as the Chief of the Division of Pulmonary, Allergy, and Critical Care Medicine, and the Acting Director of the Interstitial Lung Disease Program. She obtained her MD and PhD degrees, as well as completed residency in Internal Medicine and fellowship in Pulmonary and Critical Care Medicine, at the University of Texas Southwestern Medical Center in Dallas. Her laboratory has discovered rare pathogenic variants in several genes (TERT, TERC, SFTPA2, PARN, RTEL1) in patients with familial pulmonary fibrosis. These discoveries have linked the telomere and surfactant pathways to adult-onset fibrotic interstitial lung diseases. She and her colleagues have shown that leukocyte telomere length is a biomarker that predicts clinical outcomes for patients, including survival, rate of progression, and response to immunosuppressive medications. Dr Garcia holds appointments in the Department of Medicine, the Institute for Genomic Medicine, and the Center for Precision Medicine and Genomics.

Janet Talbert earned her Master of Science (MS) in Biophysics and Genetics at the University of Colorado Medical Campus. She became a Diplomate of the American Board of Genetic Counselors (ABGC) in 2009. She is a member of the National Society of Genetic Counselors (NSGC) and the American Board of Genetic Counselors (ABGC). She worked in the Interstitial Lung Disease Program at National Jewish Health from 2003 to 2020 in roles that included oversight of a national familial pulmonary fibrosis genetic study that lead to discovery of several SNPs associated with IPF/FPF, providing genetic counseling services for the institution at large and to patients and families with FPF, genetic services manager (molecular laboratory report writing, provider-to-provider genetic services, and genetic test development) and a genetic advisor to the institution. She was the director of the Familial Pulmonary Fibrosis Genetic Counseling telephone line at National Jewish Health from 2008 to 2020. She serves on the Medical Advisory Board of the Pulmonary Fibrosis Foundation (PFF) and is part of an education outreach Ambassador Program for the PFF. From 2014 to 2015 she worked as faculty at the University of Colorado in the Hereditary Cancer clinic and from 2015 to 2020 at InformedDNA as a Senior Genetic Counselor performing genetic counseling via telehealth to patients nationwide with personal or family histories of cancer, inherited retinal disease, neurologic disorders, and FPF. As of 2021 she is an Associate Faculty member in Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University and Vanderbilt University Medical Center.

Author History

Christine Kim Garcia, MD, PhD (2021-present)
David Schwartz, MD; National Jewish Health (2005-2021)
Janet Talbert, MS, CGC (2010-present)
Anastasia Wise, PhD; National Jewish Health (2005-2010)

Revision History

• 12 May 2022 (aa) Revision: edited information on DC/TBD in Table 2
• 11 February 2021 (sw) Comprehensive update posted live; scope changed to overview
• 19 March 2015 (me) Comprehensive update posted live
• 19 October 2010 (me) Comprehensive update posted live
• 11 June 2007 (me) Comprehensive update posted live
• 21 January 2005 (me) Review posted live
• 8 April 2004 (ds) Original submission

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