Idiopathic Pulmonary Fibrosis: Current Concepts

doi:10.4065/73.11.1085

Mayo Clinic Proceedings

Volume 73, Issue 11, November 1998, Pages 1085-1101

https://doi.org/10.4065/73.11.1085 Get rights and content

Idiopathic pulmonary fibrosis (IPF) is generally defined as a progressive, fibrosing inflammatory disease of the lung parenchyma of unknown cause. It is characterized by slowly increasing dyspnea, diffuse interstitial lung infiltrates, restrictive lung dysfunction, and impaired gas exchange. Ultimately, it is fatal in most patients, and treatment options remain unsatisfactory. The advent of high-resolution computed tomography of the chest and modifications in the histopathologic classification of interstitial pneumonias have reshaped the concept of IPF. Although initially thought to be a relatively specific clinicopathologic entity, it seems likely that IPF as previously defined is a heterogeneous disorder consisting of several clinicopathologic entities with differing histopathologic patterns, clinical course, response to therapy, and prognosis. The most common histologic pattern in cases previously defined as IPF is usual interstitial pneumonia, which is associated with a median survival of less than 3 years. For accurate prognosis and optimal management of patients, the clinician should attempt to be as precise as possible in distinguishing various clinicopathologic entities that have been included under the clinical heading of IPF. In the future, we recommend that the use of the term “idiopathic pulmonary fibrosis” be restricted to patients with usual interstitial pneumonia and that clinicians recognize the fact that other idiopathic interstitial pneumonias do not have the same prognostic effect traditionally ascribed to IPF.

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DEFINITION

Currently, a universally accepted definition of IPF is lacking. The clinician, the radiologist, the physiologist, and the pathologist all have different points of view and frames of reference. IPF is generally considered a pulmonary disease of unknown cause, characterized by parenchymal inflammation (“alveolitis”) and progressive interstitial fibrosis.8, 9, 18, 19 Usually, it affects middle-aged and older persons.6, 7, 20 In most patients, IPF is slowly progressive and results in death.6, 7, 20

HISTORICAL PERSPECTIVE

More than 50 years ago, Hamman and Rich30, 31 described four patients dying of diffuse interstitial fibrosis of the lungs of unknown cause. The duration of illness ranged from 4 to 24 weeks.30, 31 These investigators referred to this condition as “interstitial fibrosis” and described “the remarkable proliferation of connective tissue that occurs within the alveolar walls.”³¹ Although this report is frequently referred to as the initial description of IPF, the rapidly fatal course of their

EPIDEMIOLOGY

The prevalence of IPF is not precisely known but has been estimated to be 3 to 29 cases per 100,000 population.5, 6, 7 The wide range of this estimate is likely explained by the lack of uniform definition used in identifying cases of IPF, the differences in study designs and populations, and the fact that the incidence may be increasing (see subsequent discussion). The most recent prevalence estimates are from a population-based registry of patients with ILDs from 1988 to 1990 in Bernalillo

PATHOGENESIS

The cause of IPF remains unknown. A general theory is that a triggering agent or event induces an inflammatory reaction in the lung that perpetuates itself and causes progressive parenchymal fibrosis.9, 18, 37 Reports have described familial cases of IPF for which an autosomal dominant pattern of inheritance has been suggested.51, 52 No clear evidence exists for a viral cause.⁵⁹ A few cases of IPF have been described after viral or mycoplasmal infections, but some of these probably represented

PATHOLOGY

Although most investigators currently consider IPF synonymous with idiopathic UIP, IPF (and CFA) has historically been used to refer to a heterogeneous group of disorders in patients with various histologic pattems.10, 12, 21, 25 The histologic modifications in the classification of idiopathic interstitial pneumonias have occurred in recent years and have confused clinicians, radiologists, and pathologists. The results of reclassification of a series of cases diagnosed as IPF during the 1970s

CLINICAL FEATURES

Most patients with a clinical diagnosis of IPF have increasing exertional breathlessness and a chronic cough, which may produce sputum but often is dry.19, 21, 25 These symptoms may be preceded by an influenza-like illness.19, 21, 25 About 5% of patients are asymptomatic at the time of diagnosis.²⁰ Almost all patients have bibasilar crackles, and about one-half to two-thirds have digital clubing20, 21, 25, 26, 44, 71 Additional symptoms can include chest pain or constitutional symptoms such as

Chest Radiograph

Most symptomatic patients have abnormal findings on chest radiographs. Rarely, patients may have abnormal findings on chest radiographs in the absence of respiratory symptoms.²⁰ A previous chest radiograph (if available) for comparison is extremely helpful in the assessment of the activity of the disease. The most common chest radiographic abnormalities are bilateral reticular (linear) interstitial infiltrates with a predilection for the lower lung zones.9, 19, 21, 26 As the disease advances,

MEDIASTINAL IMAGING

Mediastinal lymph nodes are commonly detected by CT in patients with UIP.83, 84 Usually, only a few nodes are enlarged; maximal diameter is less than 15 mm.⁸⁴ In late disease, pneumomediastinum may be detected by CT.⁸⁵

GALLIUM SCANNING

Ga⁶⁷ lung scanning previously had been recommended as a noninvasive method of distinguishing active cellular disease from fibrotic disease by assessment of the degree of active inflammation in the lung of patients with IPF and other ILDs.⁸⁶⁶⁷Ga citrate is taken up by activated macro-phages. Unfortunately, the validity of this test has not been adequately demonstrated, and interpretation has been difficult. Subjective visual index is generally used and is not always reproducible.⁶⁷Ga lung

PULMONARY FUNCTION TESTING

As with most types of ILDs, pulmonary function testing in patients with IPF usually shows a restrictive impairment, with reduced lung volumes and decreased diffusing capacity.87, 88 In early stages, an isolated reduction in diffusing capacity may be seen with normal lung volumes. The ratio of the forced expiratory volume in 1 second to the forced vital capacity is normal or increased, a finding consistent with a restrictive dysfunction. Gas exchange is usually impaired with an increased

DIAGNOSIS

During the initial assessment of a patient with suspected IPF, elicitation of the history is the most important step in identifying clues to possible occupational and environmental causes (Table 4). The history should include a review of not only previous occupations but also the home environment, including presence of birds, pets, humidifiers, air conditioners, and hot tubs. A review of the family history and the list of medications may also yield the cause of lung disease. Known causes of

TREATMENT

The traditional mainstay of treatment of patients with IPF has been corticosteroids, but this type of therapy is unproved in prospective and randomized studies. Corticosteroid therapy is based on current knowledge of the pathogenic mechanisms of this disease—that is, chronic active inflammation leading to progressive, irreversible fibrosis. Thus, the attempt is made to control the inflammatory and immune cell response with corticosteroid therapy in conjunction with other immunosuppressive

PROGNOSIS

The median survival for patients with IPF has been estimated to be 3 to 6 years, but the clinical course of IPF has been noted to vary considerably.21, 24, 26, 27, 42, 43, 71 This variability in clinical course and prognosis is likely due, in part, to the heterogeneity of patients included in earlier series of IPF. For example, in a recent study by Bjoraker and associates,¹² patients with an initial diagnosis of IPF based on open-lung biopsy were shown to have various histologic lesions,

SUMMARY

1.
IPF (or CFA) as originally defined was a clinical concept. Cases previously classified as IPF are currently heterogeneous and include several clinicopathologic entities.
2.
The most common histologic pattern in cases previously diagnosed as IPF is UIP. UIP is associated with a worse prognosis (median survival of less than 3 years) and response to corticosteroid therapy in comparison with other types of chronic interstitial pneumonia including DIP, NSIP, RB-ILD, and BOOP.
3.
Inclusion of several

CONCLUSION

Assessment and management of patients with IPF remain challenging. A need exists for a consensus on the defining diagnostic criteria of IPF. Many of the currently available studies describe patient populations that have been inadequately characterized and are not entirely comparable. Thus, we recommend that, in the future, the term “idiopathic pulmonary fibrosis” be used only in reference to patients with known or suspected UIP histology.

Treatment options remain limited and unsatisfactory for

Acknowledgment

We thank Drs. William W. Douglas and David E. Midthun for their critique and thoughtful suggestions regarding the submitted manuscript.

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