Idiopathic pulmonary fibrosis (IPF) is a lung disorder where there is scarring of the lungs from an unknown cause. It is usually a progressive disease with a poor long-term prognosis. The classic features of the disorder include progressive dyspnea and a nonproductive cough. Pulmonary function tests usually reveal restrictive impairment and diminished carbon monoxide diffusing capacity. The diagnosis is clinically aided with imaging tests and a biopsy.
The exact etiology for the development of IPF is unknown, but risk factors like exposure to tobacco smoke, metal, wood, or dust as well as gastroesophageal reflux have been implicated. While the majority of cases are idiopathic, some genetic factors that contribute to familial cases have been identified. Mutations in the telomerase genes (eg., TERT), surfactant genes (eg., SFTPA2), and mucin genes (eg., MUC5B) have been known to lead to pulmonary fibrosis. Hermansky Pudlak syndrome is another rare autosomal recessive condition with defects in lysosome-related organelles that lead to albinism, platelet defects, and, in many of the affected individuals, pulmonary fibrosis.
IPF usually presents after the fifth or sixth decade of life and is more common with older age. There is a slight male predominance. Prevalence is estimated to range from 14 to 42 cases per 100,000.
Environmental factors like smoking, chronic aspiration, or viral infections along with advancing age can lead to respiratory alveolar epithelial injury and are thought to be the likely driving factors for the pathogenesis of IPF. With an epithelial injury, there is activation of fibroblasts and dysregulated repair of the alveolar epithelium. When this leads to increased matrix deposition in the lung interstitium and scarring, there is a destruction of lung architecture that results in pulmonary fibrosis. 
The histology usually is non-specific and reveals heterogeneous zones of the normal and affected lung. Interstitial inflammation, honeycomb change, and fibrosis are common. To make the diagnosis histologically, the following should be present:
Most common presenting symptoms of IPF are dyspnea on exertion and cough. Most patients are diagnosed more than a year after symptom onset. Since symptoms are nonspecific and the disease is idiopathic, other conditions must be excluded before diagnosis. History of exposure to inhaled dust, metals, asbestos, mold, or birds, should be elicited to exclude conditions like asbestosis, pneumoconiosis, and hypersensitivity pneumonitis. Medication and drug history to exclude drug toxicities should also be performed. History to exclude autoimmune conditions like rheumatoid arthritis, scleroderma, Sjogren disease, or poly/dermatomyositis should also be elicited since these conditions can also lead to interstitial lung disease.
The physical exam should be focused on evaluating for lung involvement, extent and severity of disease and excluding another diagnosis.The pulmonary exam usually reveals fine bibasilar “velcro” crackles during inspiration. Clubbing may also be present. To exclude autoimmune conditions, skin rashes, joint swelling, synovitis, or sclerodactyly, Raynaud phenomenon, and muscle weakness should be assessed. In advanced cases of IPF, patients may be tachypneic with minimal exertion and have resting hypoxemia.
Pulmonary function tests should be performed to assess for restrictive lung disease which is characterized by decreased lung volumes (especially decreased forced vital capacity, total lung capacity and functional residual capacity) and decreased diffusion capacity. When IPF is suspected, laboratory tests to exclude autoimmune disease should be performed. Antinuclear antibodies and rheumatoid factor are commonly indicated, but if there is a high suspicion, then antisynthetase antibodies, aldolase, Sjogren and scleroderma antibodies should also be sent.
Chest imaging is essential for diagnosis, but chest x-rays are not helpful if IPF is suspected. High-resolution CT (HRCT) of the chest should be performed. The characteristic feature on HRCT is a “usual interstitial pneumonia” (UIP) pattern, which on imaging consists of bilateral subpleural basal predominant honeycombing or traction bronchiectasis or bronchiectasis. Peripheral reticular opacities are usually most notable in the lower lobes. Ground glass opacities and consolidation are atypical for a UIP pattern and when present on imaging should lead to suspicion for conditions other than IPF.
Histopathologic confirmation for IPF is not always necessary but should be considered if there are other conflicting factors like absence of a typical UIP imaging pattern and suspicion for connective tissue disease or if the patient is young. Patient factors also should be considered since a surgical lung biopsy is usually indicated, and transbronchial biopsies are not usually helpful to diagnose IPF unless it is to exclude granulomatous disease like sarcoid. More recently, cryobiopsies have provided adequate tissue for pathologic diagnosis. If the patient has advanced disease with functional impairment and respiratory failure, the risks of lung biopsy may be significant. Characteristic histopathologic features for IPF is a UIP pattern which indicates the presence of temporal and spatial heterogeneity, the presence of fibroblastic foci, areas of subpleural honeycombing, and interstitial inflammation. There should also be an absence of other features like granulomas or giant cells.
Pulmonary function tests every 3 to 6 months should be performed based on symptoms and the disease's progression. However, serial chest imaging is not always necessary. Tools like GAP (gender, age physiology) score issue points for the male gender, advanced age, forced vital capacity, and diffusing capacity or transfer factor of the lung for carbon monoxide) and can be used to assess long-term prognosis, with a high GAP score indicating worse mortality. This is mainly used when considering a patient for a lung transplant referral.
There are two antifibrotic agents approved for use in IPF. These are pirfenidone and nintedanib (tyrosine kinase inhibitor). Both drugs are mostly recommended for mild to moderate disease and have shown to slow the disease progression but not significantly benefit mortality. Further studies also have shown decreased exacerbations of IPF with these drugs. While on treatment with these agents, serial monitoring of liver function tests is recommended. Common side effects reported with nintedanib is diarrhea and with pirfenidone side effects noted commonly are rash, photosensitivity, and gastrointestinal discomfort.
Recommended supportive measures include tobacco cessation, oxygen supplementation, and control of gastroesophageal reflux with proton pump inhibitors. Influenza and pneumococcal vaccination are recommended. Corticosteroids, immunosuppressants like azathioprine and N acetyl cysteine, have been used in the past but now the recommendation is against the use of these agents in IPF.
Referral for a lung transplant is recommended early in the course of the disease, especially in a patient with a progressive decline in lung function. Survival benefit has been shown for patients with IPF who undergo a lung transplant.
IPF is mainly confined to the lungs, and other organ involvement is not known. Progression of the disease is variable in patients. Some patients remain stable for several years after diagnosis, some patients decline rapidly after diagnosis, and some patients have periodic exacerbations during their course which leads to declining lung function and increased mortality. Baseline lung function at diagnosis, the presence of comorbidities (especially co-existing emphysema and pulmonary hypertension), smoking history, low body mass index, and older age are associated with a worse prognosis.
Acute exacerbations can occur in IPF which lead to rapid decline. Factors like heart failure must be excluded, and potential infections and thromboembolic disease must also be considered and promptly treated when an acute exacerbation is suspected. Imaging during acute exacerbations may show ground-glass opacities and consolidations.
Since IPF is a challenging disease with a poor prognosis, early diagnosis is essential. Multidisciplinary management with involvement of a pulmonologist, radiologist, pathologist, and, if necessary, a thoracic surgeon and rheumatologist is useful for the approach to IPF, especially for consistent and accurate diagnosis and optimizing patient outcomes.
Once a diagnosis of Idiopathic pulmonary fibrosis is made, the management is an interprofessional. The goal is to improve the quality of life. A physical therapy consult is recommended because evidence shows that regular physical activity or an exercise program can result in a marked improvement in the symptoms and the quality of life. Nursing will chart and assess the patient's condition along with the pulmonologist. The pharmacist should educate the patient on refraining from smoking and alcohol. The patient may benefit from the use of bronchodilators. To improve nutrition, a dietary consult should be sought. The nurse should educate the patient on the benefits of vaccination as many patients with pulmonary fibrosis do not tolerate lung infections well.  Interprofessional coordination of this type can increase patient quality of life. [Level 5]
Idiopathic pulmonary fibrosis has a poor prognosis with a mean survival of 24-30 months. Most patients have continued dyspnea and no exercise tolerance and the quality of life is poor. Deaths are most common in the winter even in the absence of any lung infection. Many of these patients develop pulmonary hypertension and are at an increased risk of pulmonary embolism and sudden cardiac death. The prognosis is usually worse for those with severe changes on imaging studies, unresponsiveness to oxygen and steroids. (Level V)
|||Njock MS,Guiot J,Henket MA,Nivelles O,Thiry M,Dequiedt F,Corhay JL,Louis RE,Struman I, Sputum exosomes: promising biomarkers for idiopathic pulmonary fibrosis. Thorax. 2018 Sep 22 [PubMed PMID: 30244194]|
|||Walsh SLF,Calandriello L,Silva M,Sverzellati N, Deep learning for classifying fibrotic lung disease on high-resolution computed tomography: a case-cohort study. The Lancet. Respiratory medicine. 2018 Sep 14 [PubMed PMID: 30232049]|
|||Wells AU, Efficacy data in treatment extension studies of idiopathic pulmonary fibrosis: interpret with caution. The Lancet. Respiratory medicine. 2018 Sep 14 [PubMed PMID: 30224324]|
|||Zhang L,Wang Y,Wu G,Xiong W,Gu W,Wang CY, Macrophages: friend or foe in idiopathic pulmonary fibrosis? Respiratory research. 2018 Sep 6 [PubMed PMID: 30189872]|
|||Shioya M,Otsuka M,Yamada G,Umeda Y,Ikeda K,Nishikiori H,Kuronuma K,Chiba H,Takahashi H, Poorer Prognosis of Idiopathic Pleuroparenchymal Fibroelastosis Compared with Idiopathic Pulmonary Fibrosis in Advanced Stage. Canadian respiratory journal. 2018 [PubMed PMID: 30186537]|
|||Raghu G,Remy-Jardin M,Myers JL,Richeldi L,Ryerson CJ,Lederer DJ,Behr J,Cottin V,Danoff SK,Morell F,Flaherty KR,Wells A,Martinez FJ,Azuma A,Bice TJ,Bouros D,Brown KK,Collard HR,Duggal A,Galvin L,Inoue Y,Jenkins RG,Johkoh T,Kazerooni EA,Kitaichi M,Knight SL,Mansour G,Nicholson AG,Pipavath SNJ,Buendía-Roldán I,Selman M,Travis WD,Walsh S,Wilson KC, Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. American journal of respiratory and critical care medicine. 2018 Sep 1 [PubMed PMID: 30168753]|
|||Nakatsuka Y,Handa T,Kokosi M,Tanizawa K,Puglisi S,Jacob J,Sokai A,Ikezoe K,Kanatani KT,Kubo T,Tomioka H,Taguchi Y,Nagai S,Chin K,Mishima M,Wells AU,Hirai T, The Clinical Significance of Body Weight Loss in Idiopathic Pulmonary Fibrosis Patients. Respiration; international review of thoracic diseases. 2018 Aug 21 [PubMed PMID: 30130749]|
|||Walsh SLF, Imaging biomarkers and staging in IPF. Current opinion in pulmonary medicine. 2018 Sep [PubMed PMID: 30015679]|
|||Homma S,Bando M,Azuma A,Sakamoto S,Sugino K,Ishii Y,Izumi S,Inase N,Inoue Y,Ebina M,Ogura T,Kishi K,Kishaba T,Kido T,Gemma A,Goto Y,Sasaki S,Johkoh T,Suda T,Takahashi K,Takahashi H,Taguchi Y,Date H,Taniguchi H,Nakayama T,Nishioka Y,Hasegawa Y,Hattori N,Fukuoka J,Miyamoto A,Mukae H,Yokoyama A,Yoshino I,Watanabe K, Japanese guideline for the treatment of idiopathic pulmonary fibrosis. Respiratory investigation. 2018 Jul [PubMed PMID: 29980444]|
|||Cheng L,Tan B,Yin Y,Wang S,Jia L,Warner G,Jia G,Jiang W, Short- and long-term effects of pulmonary rehabilitation for idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Clinical rehabilitation. 2018 Oct [PubMed PMID: 29843523]|
|||Tolle LB,Southern BD,Culver DA,Horowitz JC, Idiopathic pulmonary fibrosis: What primary care physicians need to know. Cleveland Clinic journal of medicine. 2018 May [PubMed PMID: 29733782]|
|||Chung JH,Oldham JM,Montner SM,Vij R,Adegunsoye A,Husain AN,Noth I,Lynch DA,Strek ME, CT-Pathologic Correlation of Major Types of Pulmonary Fibrosis: Insights for Revisions to Current Guidelines. AJR. American journal of roentgenology. 2018 May [PubMed PMID: 29547052]|
|||Jeong SO,Uh ST,Park S,Kim HS, Effects of patient satisfaction and confidence on the success of treatment of combined rheumatic disease and interstitial lung disease in a multidisciplinary outpatient clinic. International journal of rheumatic diseases. 2018 Aug [PubMed PMID: 30146740]|
|||Ahmad K,Nathan SD, Novel management strategies for idiopathic pulmonary fibrosis. Expert review of respiratory medicine. 2018 Aug 30 [PubMed PMID: 30136607]|
|||Serajeddini H,Rogliani P,Mura M, Multi-dimensional Assessment of IPF Across a Wide Range of Disease Severity. Lung. 2018 Aug 27 [PubMed PMID: 30151723]|
|||Barratt SL,Creamer A,Hayton C,Chaudhuri N, Idiopathic Pulmonary Fibrosis (IPF): An Overview. Journal of clinical medicine. 2018 Aug 6 [PubMed PMID: 30082599]|
|||Martinez FJ,Collard HR,Pardo A,Raghu G,Richeldi L,Selman M,Swigris JJ,Taniguchi H,Wells AU, Idiopathic pulmonary fibrosis. Nature reviews. Disease primers. 2017 Oct 20; [PubMed PMID: 29052582]|
|||Lederer DJ,Martinez FJ, Idiopathic Pulmonary Fibrosis. The New England journal of medicine. 2018 May 10; [PubMed PMID: 29742380]|
|||Esposito DB,Lanes S,Donneyong M,Holick CN,Lasky JA,Lederer D,Nathan SD,O'Quinn S,Parker J,Tran TN, Idiopathic Pulmonary Fibrosis in United States Automated Claims. Incidence, Prevalence, and Algorithm Validation. American journal of respiratory and critical care medicine. 2015 Nov 15; [PubMed PMID: 26241562]|
|||Heukels P,Moor CC,von der Thüsen JH,Wijsenbeek MS,Kool M, Inflammation and immunity in IPF pathogenesis and treatment. Respiratory medicine. 2019 Feb; [PubMed PMID: 30704705]|
|||Wolters PJ,Collard HR,Jones KD, Pathogenesis of idiopathic pulmonary fibrosis. Annual review of pathology. 2014; [PubMed PMID: 24050627]|
|||Guenther A,Krauss E,Tello S,Wagner J,Paul B,Kuhn S,Maurer O,Heinemann S,Costabel U,Barbero MAN,Müller V,Bonniaud P,Vancheri C,Wells A,Vasakova M,Pesci A,Sofia M,Klepetko W,Seeger W,Drakopanagiotakis F,Crestani B, The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis. Respiratory research. 2018 Jul 28; [PubMed PMID: 30055613]|
|||Romagnoli M,Colby TV,Berthet JP,Gamez AS,Mallet JP,Serre I,Cancellieri A,Cavazza A,Solovei L,Dell'Amore A,Dolci G,Guerrieri A,Reynaud P,Bommart S,Zompatori M,Dalpiaz G,Nava S,Trisolini R,Suehs CM,Vachier I,Molinari N,Bourdin A, Poor Concordance between Sequential Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy in the Diagnosis of Diffuse Interstitial Lung Diseases. American journal of respiratory and critical care medicine. 2019 May 15; [PubMed PMID: 30864813]|
|||Maher TM,Strek ME, Antifibrotic therapy for idiopathic pulmonary fibrosis: time to treat. Respiratory research. 2019 Sep 6; [PubMed PMID: 31492155]|
|||Raghu G,Anstrom KJ,King TE Jr,Lasky JA,Martinez FJ, Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. The New England journal of medicine. 2012 May 24; [PubMed PMID: 22607134]|
|||Somogyi V,Chaudhuri N,Torrisi SE,Kahn N,Müller V,Kreuter M, The therapy of idiopathic pulmonary fibrosis: what is next? European respiratory review : an official journal of the European Respiratory Society. 2019 Sep 30; [PubMed PMID: 31484664]|