High-resolution CT can play an essential role Idiopathic pulmonary fibrosis, part 1: Presentation and diagnosis key words: Interstitial lung disease, Idiopathic pulmonary fibrosis, Usual interstitial pneumonia

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia (IIP). This disease continues to represent a diagnosis that is devastating to patients and extremely frustrating for their physicians. Although an understanding of the pathogenesis of IPF and the development of effective therapies have been vigorously pursued in recent years, we have yet to identify the cause of this disorder or discover pharmacological agents that can prevent its progression to end-stage lung fibrosis and death. Numerous clinical trials are currently evaluating new agents that have been developed to target various aspects of fibrogenesis.

In this article, I will review the epidemiology, clinical presentation, and diagnosis of this disease. In part 2, to be published in a coming issue of The Journal of Respiratory Diseases, I will review the management of IPF.

Background

In 1944, Hamman and Rich¹ described a syndrome of rapidly progressive pulmonary fibrosis that we now recognize as acute interstitial pneumonia (AIP). As more cases of pulmonary fibrosis were reported in the medical literature over the next half-century, the term "IPF" gradually became used for cases of pulmonary fibrosis of unknown cause with subacute or chronic onset and usual interstitial pneumonia (UIP) was thought to be a subset of IPF.

The literature on IPF published before the mid-1990s typically included other forms of IIP, such as nonspecific interstitial pneumonia (NSIP) and desquamative interstitial pneumonia (DIP), that were labeled IPF. The term "IPF" was essentially synonymous with the term "cryptogenic pulmonary fibrosis," which was used in the literature from Europe. However, current recommendations made on the basis of a consensus statement on IIP published in 2002 now limit the use of the term "IPF" to patients with UIP that lacks a known cause (such as collagen-vascular disease, drug exposures, or occupational exposures) of the histopathological pattern.²

^{IPF, or idiopathic UIP, is now recognized as the most common form of IIP. Other forms of IIP include AIP, NSIP, DIP, respiratory bronchiolitis with interstitial lung disease (ILD), cryptogenic organizing pneumonia (COP), and lymphoid interstitial pneumonia.}2 In contrast to AIP, IPF typically has a chronic onset. Key features that distinguish IPF from other forms of IIP, such as AIP, NSIP, or DIP, are its temporal heterogeneity and patchy involvement of lung tissue. In contrast to IPF, the other forms of IIP are characterized by a uniform, temporally homogeneous involvement of lung tissue.² As experience with high-resolution CT (HRCT) scanning of the thorax has evolved, it has become acceptable to make a clinical diagnosis of IPF in patients who have typical clinical presentations and an HRCT pattern that is consistent with UIP (Table 1).

Epidemiology and risk factors

The epidemiology of IPF has been difficult to assess because of the lack of population-based screening and the lack of uniform diagnostic criteria. Nonetheless, IPF does not appear to have a significantly biased expression by race or ethnic background; however, males are more commonly affected than females. Estimates of the incidence and prevalence of IPF have ranged considerably, and many of the studies were done before the currently accepted definition of IPF was adopted.

Coultas and associates³ conducted a population-based assessment of ILD incidence in the des- ert southwestern region of the United States and found that the incidence and prevalence of IPF in men were, respectively, 11 and 20 per 100,000/year and 7 and 13 per 100,000/year in women. Raghu and associates⁴ recently estimated the incidence and prevalence of IPF in the United States to be 6.8 and 14 per 100,000, respectively, using narrow criteria (diagnostic code for IPF plus a procedure code for surgical lung biopsy, transbronchial lung biopsy, or thoracic CT scan). Us- ing broad criteria (diagnostic code only), the incidence and prevalence estimates were 16.3 and 42.7 per 100,000, respectively.

Both studies demonstrated that the incidence and prevalence of IPF increased dramatically with advancing age. Coultas and associates³ estimated the incidence and prevalence of IPF in persons aged 75 years and older were, respectively, 102 and 175 per 100,000 for men and 57 and 73 per 100,000 for women. The corresponding estimates (using broad criteria) by Raghu and associates⁴ were, respectively, 71 and 271 per 100,000/year for men and 67 and 266 per 100,000/year for women.

Gribbin and colleagues⁵ analyzed data from a longitudinal computerized general practice database and estimated an incidence of 4.6 per 100,000 person-years for IPF in the United Kingdom, and they observed a progressive increase in incidence from 1991-1995 to 2000-2003. In contrast, the incidence of colorectal cancer is about 15 to 18 cases per 100,000/year.⁶ In elderly persons, the incidence of IPF approaches that of primary lung cancer.^3,4,7

Various risk factors have been linked to IPF. Epidemiological studies have shown that IPF occurs more commonly in workers exposed to metal or wood dust, fumes, or livestock,^3,8-10 and men are more likely to have occupations that expose them to such dust and fumes. One study found that the risk of IPF as a cause of death was correlated with the duration of exposure to metal fumes.⁹ IPF is more prevalent in industrialized areas than in rural areas.¹¹

Smoking appears to play a role in IPF pathogenesis and has been identified as an independent risk factor for pulmonary fibrosis in both sporadic and familial IPF.^12,13 Viral infections, such as Epstein-Barr viral infection,^14,15 and gastroesophageal reflux disease (GERD)^16,17 have also been linked to IPF. The prevalence of GERD is quite high (greater than 80%) in patients with IPF.¹⁸ The association of IPF with exposure to environmental agents, infection, or GERD suggests lung injury combined with an aberrant wound healing and tissue repair response as the cause of IPF (see "The pathobiology of IPF"on pages 289-291).^19-29

Making a confident diagnosis

Patients with IPF typically present in their sixth to seventh decade of life with the insidious onset of progressive dyspnea and cough, and the diagnosis is usually made in the advanced stages of disease.^30,31 A detailed clinical history should be taken to identify important environmental exposures, the presence of a collagen-vascular disease, and drug exposures. About half of the patients have digital clubbing on physical examination, and most have bilateral rales on chest auscultation.

Patients typically have reduced lung volumes (forced vital capacity [FVC] and total lung capacity) and normal or increased expiratory flow rates with normal to increased ratios of forced expiratory volume in 1 second to FVC. These values may be preserved, however, if pulmonary fibrosis is superimposed on emphysema. Carbon monoxide-diffusing capacity (DlCO) is typically reduced, and patients with low DlCO commonly have pulmonary hypertension.³² Cardiopulmonary exercise testing typically reveals arterial hypoxemia or a widened alveolar-arterial oxygen gradient.³³

Chest radiographs typically reveal diffuse, bilateral interstitial opacities that are most prominent at the lung bases and in subpleural peripheral lung region.³⁴ However, these changes also can be seen with other entities, such as chronic hypersensitivity pneumonitis, asbestosis, other IIP, or pulmonary fibrosis associated with collagen-vascular disease. Although chest radiographic findings are nonspecific and have limited prognostic value, obtaining old radiographs (when available) may assist in gauging the tempo of the progression of the disease and in estimating the time of its onset.

HRCT with its thin-section collimation (1 to 2 mm) is a key tool for evaluating patients with interstitial infiltrates of unknown etiology and provides a detailed depiction of parenchymal abnormalities as well as an indication of the severity of disease.³⁴ Changes on HRCT scans that are typical for UIP include a predilection for peripheral and basilar lung zones with patchy involvement and sparing of more central areas, especially in upper lung zones. Linear opacities (thickened intralobular and interlobular septa)--reticular lines--are present, and more advanced disease is characterized by traction bronchiectasis as well as honeycomb cysts resulting from bronchiolectasis (Figure 1). Ground-glass opacities, which are indistinct, hazy areas of increased alveolar attenuation, are usually minimal in patients with UIP, and the presence of extensive ground-glass opacities suggests an alternative diagnosis, such as another IIP (NSIP, DIP, COP) or hypersensitivity pneumonitis.

HRCT findings that are typical for UIP combined with a compatible clinical presentation can provide a confident diagnosis in more than half of patients with IPF and obvi-ate the need to proceed to a surgi- cal lung biopsy, which is relatively safe but can be associated with significant morbidity and mortality (Figure 2).^35,36 Expert opinion published as a consensus statement³⁷ suggested that if various criteria (including bronchoscopy that does not indicate an alternative diagnosis) are present, a confident clinical diagnosis of IPF can often be made without proceeding to a surgical lung biopsy (Table 2).

Bronchoalveolar lavage (BAL) can provide information that contributes significantly to the differential diagnosis of ILD.³⁸A BAL differential cell count pattern that shows a modest increase in neutrophils and/or eosinophils is typical for IPF. However, evidence of significant lymphocytosis (BAL lymphocyte differential count 25% or higher) is inconsistent with a diagnosis of IPF and suggests the presence of another form of ILD, such as granulomatous lung disease (hypersensitivity pneumonitis or sarcoidosis) or drug-induced pneumonitis. Similarly, the finding of marked BAL eosinophilia (25% or higher) suggests a form of eosinophilic lung disease as an alternative diagnosis.

Transbronchial biopsy may provide diagnostic tissue and may even retrieve tissue that is diagnostic of UIP when analyzed by expert lung pathologists.³⁹ However, neither procedure can reliably diagnose IPF. The rationale for including bronchoscopy with BAL or transbronchial lung biopsy is that one of these procedures will detect abnormalities that are inconsistent with IPF. However, the evolving view of many authorities is that the classic HRCT findings combined with a consistent clinical presentation can provide a diagnosis without performing bronchoscopy.⁴⁰

Therefore, findings from HRCT combined with those from a thorough clinical evaluation may provide a confident clinical diagnosis of IPF; however, surgical lung biopsy may be required if HRCT scans show indeterminate changes. In addition, the interaction of the clinician, radiologist, and pathologist has been shown to enhance diagnostic accuracy,⁴¹ especially when cases are challenging and HRCT findings and/or histopathological findings are not straightforward.

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