Idiopathic interstitial pneumonias are a group of interstitial lung diseases that lead to progressive scarring of the alveolar interstitium, respiratory insufficiency, and, in many cases, death. In 2002, the American Thoracic Society and European Respiratory Society published a joint statement with the goals of standardizing classification as well as providing definitions and criteria for the diagnosis of the idiopathic interstitial pneumonias (1). This statement defined a group of seven clinical, radiographic, and histopathologic patterns of unknown etiology, which were “sufficiently different from one another to be designated as separate disease entities” (1). Idiopathic pulmonary fibrosis, the most common of the idiopathic interstitial pneumonias, is defined as a chronic fibrosing interstitial process of unknown cause limited to the lungs and associated with a surgical lung biopsy showing a histologic pattern of usual interstitial pneumonia. Many nonidiopathic clinical conditions can be associated with a histologic pattern of usual interstitial pneumonia, such collagen vascular disease, drug toxicity, asbestos exposure, chronic hypersensitivity pneumonitis, and familial idiopathic pulmonary fibrosis. Although these clinical conditions are technically not idiopathic interstitial pneumonias, they can provide useful insights into the pathobiology of these disorders.

In this issue of the Journal (pp. 1146–1152), Steele and coworkers present data from a large cohort of subjects with familial interstitial pneumonia as defined by the presence of two or more cases of probable or definite idiopathic interstitial pneumonia in related individuals within three decades (2). They identified 111 families and were able to obtain data from 708 of 945 (75%) subjects. Subjects were asked to complete a questionnaire, obtain a chest radiograph, and undergo measurement of carbon monoxide diffusing capacity. A high-resolution computed tomography scan was requested in subjects with self-reported interstitial pneumonia, significant dyspnea, or abnormal pulmonary function/chest radiograph. A surgical lung biopsy was recommended in individuals with a high-resolution computed tomography scan suggestive of idiopathic interstitial pneumonia. Older age, male sex, and a history of ever smoking were identified as significant risk factors for the development of interstitial pneumonia.

Although the cause of pulmonary fibrosis is unknown, it is plausible to speculate that the pathogenesis involves both an injury to the pulmonary epithelium and an abnormal host response to healing (3). Previous case-control studies have identified smoking as a risk factor for the development of idiopathic pulmonary fibrosis, particularly in association with environmental exposures (4–6). The clinical series from Steel and colleagues adds additional evidence that smoking is associated with the development of interstitial pneumonia, even though correlation between sibling pairs was lacking.

Given the complexities of fibrotic pathways, we can speculate that defects in any number of regulatory systems can result in a predisposition to fibrosis. Cigarette smoke may prime the lung toward a fibrotic response when other injuries are encountered (7). The lack of correlation within sibling pairs in this study could be explained by the presence of multiple recessive mutations with incongruent distribution among siblings or perhaps a differential response to “second” injuries, environmental or infectious. Indeed, only a minority of families in this study appeared to demonstrate an autosomal dominant pattern of inheritance. A very important point of this study, which has also been suggested by other clinical series, is that cigarette smoking participates in the etiology of a spectrum of lung diseases, including fibrotic lung disease. This association between cigarette smoking and fibrotic lung disease appears to be true for both the sporadic and inherited forms of the disease.

Using clinical, radiographic, and pathologic tools, it is possible to separate the idiopathic interstitial pneumonias into separate “diseases” with varied phenotypes and prognoses (1). A surprising feature in this study, at least at face value, is that 45% of families had more than one type of interstitial pneumonia. The presence of multiple genes, interacting with each other, could explain why varying clinical phenotypes (1) can be seen within families where the genetics would be expected to be similar (2) and in families where only a single genetic mutation, such as surfactant protein C (8), was identified.

A weakness of this study is that only a minority (78/713, 11%) of patients had their diagnosis confirmed by surgical lung biopsy. Surprisingly, despite being younger than patients without a surgical lung biopsy, their mortality was higher! As a group, 67 patients had idiopathic pulmonary fibrosis at biopsy; 181 patients had idiopathic pulmonary fibrosis on the basis of clinical features and high-resolution computed tomography. Numerous studies have highlighted the diagnostic value of high-resolution computed tomography in the diagnosis of pulmonary fibrosis (9–12), so it is likely that the diagnostic classification of these patients was accurate. What is not known are the radiographic characteristics (i.e., presence of honeycombing) for the patients with a surgical lung biopsy. It is plausible to speculate that the patients undergoing surgical lung biopsy had atypical radiographic features for idiopathic pulmonary fibrosis and likely lacked honeycombing. What is puzzling is that patients with radiographically demonstrated honeycomb change are known to have increased mortality (10, 12, 13). Even if the patients with and without a surgical lung biopsy had similar radiographic features, we would at least expect a similar mortality. Perhaps genetic anticipation or the accumulation of multiple genetic mutations resulted in an earlier and more aggressive manifestation of disease in these patients.

A practical point for our day-to-day practice is the need for a heightened suspicion for idiopathic interstitial pneumonias in patients with a positive family history. Approximately 8% of subjects participating in this survey who reported their clinical status as “unaffected” had definite or probable interstitial pneumonia when they were evaluated. Although, there is currently no effective therapy for idiopathic pulmonary fibrosis, many therapeutic trials are underway (14) and others are in the design phase. Most investigators believe these interventions are more likely to work in patients with mild or moderate disease. Maintaining a high level of suspicion for interstitial pneumonia, especially in patients with a pertinent family history, should help identify patients with an early stage of disease who could be eligible for participation in research trials.

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