Paul W Noble Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Duke University Medical Center, Durham, North Carolina 27710, USA , Eric B Meltzer Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Duke University Medical Center, Durham, North Carolina 27710, USA.

Abstract
Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/ 100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness.

Disease name and synonyms
Idiopathic pulmonary fibrosis (IPF).
Synonym: cryptogenic fibrosing alveolitis (CFA) was the preferred term in Europe until terminology was simplified by consensus conference ^[1].

Definition
Idiopathic pulmonary fibrosis (IPF) is a chronic disease that manifests over several years and is characterized by scar tissue within the lungs, in the absence of known provocation. Exerciseinduced breathlessness and chronic dry cough are the prominent symptoms.

IPF belongs to a family of lung disorders known as the interstitial lung diseases (ILD) or, more accurately, the diffuse parenchymal lung diseases (DPLD). Within this broad category of diffuse lung diseases, IPF belongs to the subgroup known as idiopathic interstitial pneumonia (IIP). By definition, the etiology of IIP is unknown. There are seven distinct IIPs, differentiated by specific clinical features and pathological patterns ^[2]. IPF is the most common form of IIP. It is associated with the pathologic pattern known as usual interstitial pneumonia (UIP); for that reason, IPF is often referred to as IPF/UIP. IPF is usually fatal, with an average survival of approximately three years from the time of diagnosis ^[3-5]. Older studies suggested that fiveyear mortality for IPF was only 50%, but this estimate was derived prior to the recognition of nonspecific interstitial pneumonia (NSIP), a pathological subtype of IIP that mimics IPF in its clinical presentation ^[6-8]. NSIP has a more favorable prognosis and the almost certain inclusion of NSIP cases in older studies of IPF mortality accounts for differences in observed outcome ^[9]. By definition, IPF/UIP must be discriminated from NSIP.

Epidemiology
The incidence and prevalence of IPF are difficult to determine because uniform diagnostic criteria have only recently been defined ^[1]. Historical information relating to vital statistics relied on population studies which utilized diagnostic coding data and death certificates to identify cases. The accuracy of this information can be questioned, especially when studies were performed in the era of undefined diagnostic criteria.

The best available data suggests an incidence of approximately 10.7 per 100,000 persons for men; and 7.4 per 100,000 persons for women. The prevalence of IPF is slightly greater at 20.2 men per 100,000 and 13.2 women per 100,000 ^{[10, 11]}. Data from around the world demonstrates that IPF favors no particular race, ethnic group or social environment. It is estimated that IPF affects at least 5 million persons worldwide. It also appears that, during the last decade, the incidence of IPF was on the rise ^[12].

Cigarette smoking is strongly associated with IPF. One study reported a correlation between smoking history (20-40 pack-years) and risk for IPF, with an odds ratio of 2.3 (95% confidence interval, 1.3 to 3.8) for smokers ^[13].

IPF affects men more than women. In addition, the incidence of IPF increases with age. IPF most commonly appears between the fifth and seventh decades of life, with two-thirds of all cases arising in patients over 60 years of age ^[1]. The mean age at presentation is 66 years old ^[1]. IPF occurs infrequently in those younger than 40 and rarely affects children, if at all. A large U.S. population-based study noted a significant difference in prevalence by age ^[10]. This study found that the prevalence of IPF was only 2.7 cases per 100,000 amongst those aged 35 to 44 years-old; meanwhile, 175 cases per 100,000 were found among persons over the age of 75 years.

Familial cohorts of IPF are described in dozens of reports, though sporadic cases constitute the majority of disease. Clinical features of familial IPF are indistinguishable from those of the sporadic form, excepting for an earlier age of onset ^[14]. Familial IPF is defined as two or more verified cases within a group of relatives belonging to a primary family unit (parents, children and siblings). Familial IPF accounts for 0.5 to 2% of all cases of IPF. Lung inflammation has been identified in unaffected members of families with IPF ^[15]. The largest description of familial pulmonary fibrosis identified 111 families with 309 affected family members ^[16]. This study identified an autosomal dominant vertical transmission pattern. Also described were families in which more than one variant of idiopathic interstitial pneumonia was present. This finding in particular suggests that pulmonary fibrosis, independent of specific form, is a common endpoint for genetically-mediated disease-forming pathways. While single gene defects have yet to be identified, a recent and intriguing report described polymorphisms of hTERT and hTR in a cohort of patients with familial IPF ^[17]. These two genes are involved in the regulation of telomere length and thereby play a pivotal role in controlling cell death and aging.

Clinical description

History and physical
IPF patients experience breathlessness upon exertion. They are often bothered by a dry cough which interferes with daily activities. The onset of symptoms is slow, but symptoms become progressively worse over time. The initial presentation of breathlessness is commonly attributed to aging, cardiac disease, or emphysema which results in typical delays of diagnosis. Retrospective analysis of IPF patients suggests that symptoms precede diagnosis by a period of 6 months to 2 years ^[18]. Symptoms such as weight loss, fever, and arthralgias are unusual in IPF and should prompt an investigation for secondary causes of pulmonary fibrosis. Gastroesophageal acid reflux is present in close to 90% of patients with IPF but often occurs without symptoms ^[19].

Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. These rales have a fine acoustic character reminiscent of the sound made by Velcro.

Clubbing is found in approximately 50% of patients with IPF. There are no other physical manifestations, unless cor pulmonale has developed in association with end-stage disease. In that case, classic signs of right heart failure may be present.

The examination of patients with IPF should attempt to identify those signs suggesting an alternative diagnosis such as systemic sclerosis or polymyositis that can be associated with secondary pulmonary fibrosis. To that end, the examiner should look for sclerodactily, scleroderma, proximal muscle weakness and telangiectasias. The history should exclude Raynaud’s phenomenon.

Diagnostic laboratory findings
There are no specific laboratory abnormalities in IPF. However, mild elevation of the erythrocyte sedimentation rate, a low-positive titer of anti-nuclear antibody (ANA) and/or low-positive rheumatoid factor can be seen and are thought to represent a general state of inflammation. In advanced disease, blood counts may reveal polycythemia.

A high titer of autoantibodies suggests an alternative diagnosis such as connective tissue disease. In order to exclude secondary causes of pulmonary fibrosis, a broad panel of autoantibodies should be ordered during the initial evaluation.

Physiologic changes
Routine spirometry reveals decreased measures of forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁). The ratio of FEV1/FVC remains normal (or increased) in IPF, consistent with restrictive physiology. Lung volume measurements confirm restrictive physiology, usually manifest in reduction of total lung capacity (TLC). Restrictive physiology is the consequence of reduced pulmonary compliance. Changes in compliance can be attributed to the accumulation of parenchymal scar tissue and the subsequent distortion of normal lung architecture.

Gas exchange is impaired in IPF which can be demonstrated by measurement of the diffusion capacity. Declining diffusion capacity can sometimes precede changes in lung volume. Isolated impairment of diffusion capacity can be found during the early stages of IPF. The resting arterial blood gas is usually normal. Mild hypoxemia and mild respiratory alkalosis can occur in end-stage disease. Although resting arterial oxygen saturation remains normal, oxygen desaturation is commonly found during exercise. The main cause for exerciseinduced hypoxemia is ventilation-perfusion (V/Q) mismatching, as opposed to anatomic shunting or reduced diffusion capacity [20].

Natural history and prognosis
The natural history of IPF is incompletely known. IPF usually assumes a course of relentless physiologic deterioration. However, some patients remain stable for extended periods and individual outcomes can be highly variable ^[18]. Still, long-term survival with biopsy proven IPF is not expected. The median survival time demonstrated in recent studies using the modern definition of IPF is between 2 and 5 years, counting from the time of diagnosis ^{[3-5, 9]}. New insight into the natural history of IPF has been gleaned from secondary analysis of the placebo groups assembled for recent multi-center clinical trials ^[21-23]. It appears that three potential clinical courses exist: a) slowly progressive disease (the most common); b) disease marked by episodic acute exacerbations; and c) rapidly progressive disease ^[18]. At present, there are no means for accurately predicting the clinical course. Nevertheless, acute exacerbations deserve special attention.