Idiopathic pulmonary fibrosis

In many people, symptoms are present for a considerable time before diagnosis. • Age over 50 years • Dry, non-productive cough on exertion • Progressive exertional dyspnea (shortness of breath with exercise) • Dry, inspiratory bilateral basal crackles on auscultation (a crackling or popping sound in the lungs during inhalation). • Clubbing of the digits, a disfigurement of the finger tips or toes (see image) • Abnormal pulmonary function test results, with evidence of restriction and impaired gas exchange. Some of these features are due to chronic hypoxemia (oxygen deficiency in the blood), and are not specific for IPF, they can occur in other pulmonary disorders. IPF should be considered in all patients with unexplained chronic exertional dyspnea who present with cough, inspiratory bilateral basal crackles, or finger clubbing. If bilateral fine crackles are present throughout the inspiratory time and are persisting after several deep breaths, and if remaining present on several occasions several weeks apart in a subject aged ≥60 years, this should raise the suspicion of IPF and lead to consideration of an HRCT scan of the chest which is more sensitive than a chest X-ray. As crackles are not specific for IPF, they must prompt a thorough diagnostic process. ==Causes==

The cause of IPF is unknown but certain environmental factors and exposures have been shown to increase the risk of getting IPF. Cigarette smoking is the best recognized and most accepted risk factor for IPF, and increases the risk of IPF by about twofold. ==Pathogenesis==

Despite extensive investigation, the cause of IPF remains unknown. IPF is believed to be the result of an aberrant wound healing process including/involving abnormal and excessive deposition of collagen (fibrosis) in the pulmonary interstitium with minimal associated inflammation. Cellular senescence is suspected to be a central contributing cause, a belief which is supported by benefits seen in patients given senolytic therapy. It is hypothesized that the initial or repetitive injury in IPF occurs to the lung alveolar epithelial cells (pneumocytes), the type I and type II cells, which line the majority of the alveolar surface. When type I cells are damaged or lost, it is thought that type II cells undergo proliferation to cover the exposed basement membranes. In normal repair, the hyperplastic type II cells die and the remaining cells spread and undergo a differentiation process to become type I cells. Under pathologic conditions and in the presence of transforming growth factor beta (TGF-β), fibroblasts accumulate in these areas of damage and differentiate into myofibroblasts that secrete collagen and other proteins. Other proposed repeated injury mechanisms indicate that IPF may result not just from a UIP lesion, but also from NSIP and DAD (nonspecific interstitial pneumonia and diffuse alveolar damage) lesions, or a combination of several. In the past, it was thought that inflammation was the first event in initiating lung tissue scarring. Later findings showed that the development of fibroblastic foci precedes the accumulation of inflammatory cells and the consequent deposition of collagen. This pathogenetic model is indirectly supported by the clinical features of IPF, including an insidious onset over several years, relatively infrequent acute exacerbations, and failure to respond to immunosuppressive therapy. However, it is the belief of some researchers that the disease is a multi-mechanistic one, wherein the trigger for the disease may stem from abnormalities in any number of wound healing pathways, including the inflammatory response. A remarkable aspect of the MUC5B variant is its high frequency of detection, as it is found in approximately 20% of individuals with Northern and Western European ancestry and in 19% of the Framingham Heart Study population. Mutations in human telomerase genes are also associated with familial pulmonary fibrosis and in some patients with sporadic IPF (e.g. the TERT, TERC genes). ==Diagnosis==

An earlier diagnosis of IPF is a prerequisite for earlier treatment and, potentially, improvement of the long-term clinical outcome of this progressive and ultimately fatal disease. A Multidisciplinary Consensus Statement on the Idiopathic Interstitial Pneumonias published by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 2000 proposed specific major and minor criteria for establishing the diagnosis of IPF. Various technologies using artificial intelligence have been developed to help with diagnosis. A deep learning algorithm for categorizing high-resolution CT images reported high accuracy and a research project led by Nagoya University Graduate School of Medicine and Riken used a combination of deep learning and machine learning algorithm to accurately diagnose the disease. Recent developments indicate a potential benefit of positron emission tomography (PET) for diagnosis of IPF if suitable radiotracers are applied. Since IPF is driven by transforming growth factor beta (TGF-β), cellular mechanisms that enhance the interstitial TGF-β concentration are also a key factor for IPF development. The likely most important activator of TGF-β is αvβ6-integrin, which releases TGF-β from its latent form. Hence, αvβ6-integrin has been recognized earlier as a potential prognostic biomarker for IPF. Radiopharmaceuticals targeting αvβ6-integrin have thus been proposed for diagnosis of IPF by means of PET/CT imaging. The tracer 68Ga-Trivehexin showed an uptake of SUVmax = 5.53 in fibrotic lung tissue and enabled a differentiation between fibrotic and non-fibrotic lung areas in PET/CT images. 68Ga-Trivehexin yielded clear PET signals in IPF lesions which were PET-negative using the standard metabolic PET tracer 18F-FDG. Differential diagnosis Recognizing IPF in clinical practice can be challenging as symptoms often appear similar to those of more common diseases, such as asthma, chronic obstructive pulmonary disease (COPD) and congestive heart failure. The key issue facing clinicians is whether the presenting history, symptoms (or signs), radiology, and pulmonary function testing are collectively in keeping with the diagnosis of IPF or whether the findings are due to another process. It has long been recognized that patients with ILD related to asbestos exposure, drugs (such as chemotherapeutic agents or nitrofurantoin), rheumatoid arthritis and scleroderma/systemic sclerosis may be difficult to distinguish from IPF. Other differential diagnostic considerations include interstitial lung disease related to mixed connective tissue disease, advanced sarcoidosis, chronic hypersensitivity pneumonitis, pulmonary Langerhan's cell histiocytosis and radiation-induced lung injury. Pulmonary function tests Spirometry classically reveals a reduction in the vital capacity (VC) with either a proportionate reduction in airflows, or increased airflows for the observed vital capacity. The latter finding reflects the increased lung stiffness (reduced lung compliance) associated with pulmonary fibrosis, which leads to increased lung elastic recoil. Measurement of static lung volumes using body plethysmography or other techniques typically reveals reduced lung volumes (restriction). This reflects the difficulty encountered in inflating the fibrotic lungs. The diffusing capacity for carbon monoxide (DLCO) is invariably reduced in IPF and may be the only abnormality in mild or early disease. Its impairment underlies the propensity of patients with IPF to exhibit oxygen desaturation with exercise which can also be evaluated using the 6-minute walk test (6MWT). • Forced vital capacity (FVC) of ≥50% • DLCO of ≥30% • 6MWT distance ≥150 meters. ==Treatment==

The goals of treatment in IPF are essentially to reduce the symptoms, stop disease progression, prevent acute exacerbations, and prolong survival. Preventive care (e.g. vaccinations) and symptom-based treatment should be started early in every patient. Oxygen therapy In the 2011 IPF guidelines, oxygen therapy, or supplementary oxygen for home use, became a strong recommendation for use in those patients with significantly low oxygen levels at rest. Although oxygen therapy has not been shown to improve survival in IPF, some data indicate an improvement in exercise capacity. Pulmonary rehabilitation Fatigue and loss of muscular mass are common and disabling problems for patients with IPF. Pulmonary rehabilitation may alleviate the overt symptoms of IPF and improve functional status by stabilizing and/or reversing the extrapulmonary features of the disease. Typical programs of rehabilitation include exercise training, nutritional modulation, occupational therapy, education and psychosocial counseling. In the late phase of disease, IPF patients tend to discontinue physical activity due to increasing dyspnea. Whenever possible, this should be discouraged. Medications A number of treatments have been investigated in the past for IPF, including interferon gamma-1β, bosentan, ambrisentan, and anticoagulants, but these are no longer considered effective treatment options. Many of these earlier studies were based on the hypothesis that IPF is an inflammatory disorder. Pirfenidone A Cochrane review comparing pirfenidone with placebo, found a reduced risk of disease progression by 30%. FVC or VC was also improved, even if a mild slowing in FVC decline could be demonstrated only in one of the two CAPACITY trials. A large randomized, controlled trial (PANTHER-IPF) was undertaken by the National Institutes of Health (NIH) in the US to evaluate triple therapy and NAC monotherapy in IPF patients. This study found that the combination of prednisone, azathioprine, and NAC increased the risk of death and hospitalizations and the NIH announced in 2012 that the triple-therapy arm of the PANTHER-IPF study had been terminated early. This study also evaluated NAC alone and the results for this arm of the study were published in May 2014, concluding that "as compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function". Nintedanib Nintedanib is a triple angiokinase inhibitor that targets receptor tyrosine kinases involved in the regulation of angiogenesis: fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), which have also been implicated in the pathogenesis of fibrosis and IPF. In both phase III trials, nintedanib reduced the decline in lung function by approximately 50% over one year. and authorised in Europe in January 2015. Nerandomilast Nerandomilast (Jascayd) was approved for medical use in the United States in October 2025. Rentosertib Rentosertib is an investigational new drug that targets TNIK (TRAF2 and NCK-interacting protein kinase). It is asserted to be the first drug generated entirely by generative artificial intelligence to reach mid-stage human clinical trials, and the first to target a novel AI-discovered biological pathway. A multicenter, double-blind, placebo-controlled, randomized phase 2a trial was conducted in China, testing the drug in 71 IPF patients from July 2023 to June 2024, encompassing an administration period of 12 weeks. Participants were randomly assigned to receive 30 mg once daily (QD), 30 mg twice daily (BID), 60 mg QD, or placebo. Since the introduction of the lung allocation score (LAS), which prioritizes transplant candidates based on survival probability, IPF has become the most common indication for lung transplantation in the USA. Symptomatic patients with IPF younger than 65 years of age and with a body mass index (BMI) ≤26 kg/m2 should be referred for lung transplantation, but there are no clear data to guide the precise timing for LTx. Although controversial, the most recent data suggest that bilateral lung transplantation is superior to single lung transplantation in patients with IPF. Five-year survival rates after lung transplantation in IPF are estimated at between 50 and 56%. Palliative care Palliative care focuses on reducing symptoms and improving the comfort of patients rather than treating the disease. This may include treatment of worsening symptoms with the use of chronic opioids for severe dyspnea and cough. Further, oxygen therapy may be useful for palliation of dyspnea in hypoxemic patients. Palliative care also includes relief of physical and emotional suffering and psychosocial support for patients and caregivers. In selected cases of particularly severe dyspnea morphine could be considered. It can reduce dyspnea, anxiety and cough without significant decrease in oxygen saturation. Follow-up IPF is often misdiagnosed, at least until physiological and/or imaging data suggest the presence of an ILD leading to delay in accessing appropriate care. a routine evaluation every 3 to 6 months, including spirometry (body plethysmography), diffusion capacity testing, chest X-rays, 6MWT, assessment of dyspnea, quality of life, oxygen requirement is mandatory. In addition, the increasing awareness of complications and common concomitant conditions frequently associated with IPF requires a routinely evaluation of comorbidities, most of them simply reflecting concurrent diseases of aging, and medications with their interaction and side effects. Acute exacerbations Acute exacerbations of IPF (AE-IPF) are defined as an unexplained worsening or development of dyspnea within 30 days with new radiological infiltrates at HRCT abnormality often superimposed on a background consistent with UIP pattern. The yearly incidence of AE-IPF is between 10 and 15% of all patients. The prognosis of AE-IPF is poor, with mortality ranging from 78% to 96%. Other causes of AE-IPF such as pulmonary embolism, congestive heart failure, pneumothorax, or infection need to be excluded. Pulmonary infection have to be ruled out by endotracheal aspirate or BAL. Many patients experiencing acute deterioration require intensive care treatment, particularly when respiratory failure is associated with hemodynamic instability, significant comorbidities or severe hypoxemia. However, mortality during hospitalization is high. Mechanical ventilation should be introduced only after carefully weighing the person's long-term prognosis and, whenever possible, the person's wishes. However, current guidelines discourage the use of mechanical ventilation in patients with respiratory failure secondary to IPF. ==Prognosis==

The clinical course of IPF can be unpredictable. IPF progression is associated with an estimated median survival time of 2 to 5 years following diagnosis. The name of the index is GAP and is based on gender [G], age [A], and two lung physiology variables [P] (FVC and DLCO) that are commonly measured in clinical practice to predict mortality in IPF. The highest stage of GAP (stage III) has been found to be associated with a 39% risk of mortality at 1 year. In IPF patients, the overall mortality at 5 years rate is high but the annual rate of all-cause mortality in patients with mild to moderate lung impairment is relatively low. This is the reason why change in lung function (FVC) is usually measured in 1-year clinical trials of IPF treatments rather than survival. In addition to clinical and physiological parameters to predict how rapidly patients with IPF might progress, genetic and molecular features are also associated with IPF mortality. For example, it has been shown that IPF patients who have a specific genotype in the mucin MUC5B gene polymorphism (see above) experience slower decline in FVC and significantly improved survival. Even if such data are interesting from a scientific point of view, the application in the clinical routine of a prognostic model based on specific genotypes is still not possible. ==Epidemiology==

Although rare, IPF is the most common form of IIP. IPF is more common in men than in women and is usually diagnosed in people over 50 years of age. suggesting that approximately 30,000–35,000 new patients will be diagnosed with IPF each year. A recent single-centre, retrospective, observational cohort study including incident patients diagnosed with ILD at Aarhus University Hospital (Denmark) between 2003 and 2009 revealed an incidence of 4.1 per 100,000 inhabitants/year for ILD. IPF was the most common diagnosis (28%) followed by connective tissue disease-related ILD (14%), hypersensitivity pneumonitis (7%) and non-specific interstitial pneumonia (NSIP) (7%). IPF incidence was 1.3 per 100,000 inhabitants/year. Due to a heterogeneous distribution of the disease across European countries, epidemiological data needs to be updated through a Europe-wide registry for ILD and IPF. ==Other animals==

IPF has been recognized in several breeds of both dogs and cats, and has been best characterized in West Highland White Terriers. Veterinary patients with the condition share many of the same clinical signs as their human counterparts, including progressive exercise intolerance, increased respiratory rate, and eventual respiratory distress. Prognosis is generally poor. ==Research==

A number of agents are currently being investigated in Phase II clinical trials for IPF, including the monoclonal antibodies simtuzumab, tralokinumab, lebrikizumab and FG-3019, a lysophosphatidic acid receptor antagonist (BMS-986020). A Phase II study of STX-100 is also ongoing. These molecules are directed against several growth factors and cytokines that are known to play a role in the proliferation, activation, differentiation or inappropriate survival of fibroblasts. mir-29 microRNA precursor investigations in mice have produced reversal of induced IPF. MRG-201 is currently being tested as-of 2016, but not in IPF patients yet, and no human trials for IPF use have been scheduled . Stem cell therapies for IPF are an area of research. A machine learning algorithm has been proposed that discovers subtle patterns in individual history of medical encounters to reliably estimate the risk of a future IPF diagnosis, up to four years before current medical practice. The algorithm outputs a score (ZCoR) using medical history on file with no new tests, and might be deployable as a universal IPF screening tool in primary care. ZCoR has been trained and validated on nearly 3 million patients across multiple databases, achieving high predictive performance in out-of-sample data (positive likelihood ratio > 30 with 99% specificity). The authors conclude that past respiratory disorders maximally contribute to IPF risk, followed by known IPF comorbidities, metabolic diseases, cardiovascular abnormalities, and diseases of the eye, with the overall pattern of the importance ranking substantially invariant across the sexes. ==References==