Diagnosis: Usual interstitial pneumonia (clinical idiopathic pulmonary fibrosis)

Comment: No explanation for the sudden pulseless electrical activity was found at autopsy.

Idiopathic Pulmonary Fibrosis (IPF)/Usual Interstitial Pneumonia (UIP)

Introduction: IPF/UIP is one of the idiopathic interstitial pneumonias [1]. It has long been separated from desquamative interstitial pneumonia (DIP), and more recently, from nonspecific interstitial pneumonia (NSIP) [2,3]. NSIP may be further divided into cellular and fibrotic forms with different prognostic significance [4]. The usefulness of this subclassification is in the better response to current therapy of patients with DIP or NSIP compared to UIP. Both DIP and NSIP have known causes besides being idiopathic (Table 1). Here, UIP will be discussed, but with the understanding that some cases of DIP or NSIP may be included in previous clinical or radiologic studies that were not based on current histopathologic criteria [5].

Table 1. Histologic Patterns in Diffuse Chronic Interstitial Pulmonary Fibrosis and Idiopathic Interstitial Pneumonia

Diffuse Interstitial Pulmonary Fibrosis--Known Cause (Dusts, Drug reactions, Collagen-vascular diseases, etc.) [6]

Idiopathic Interstitial Pneumonias






Definition: UIP is a chronic, progressive, non-infectious inflammation of alveolar structures (alveolitis) that converts the lungs into shrunken, firm, dense, or honeycombed structures. Clinically, patients present with gradual progression of dyspnea over a period of months. The radiograph shows reticular infiltrates in the lower zones, but CT findings are more specific. The course is variable, and therapeutic options are very limited at present. Diagnosis is based on the correlation of clinical features and CT and histologic patterns by the clinician, radiologist, and pathologist working together.

Epidemiology: An estimate of the prevalence of IPF of 16.7 cases/100,000 persons in Bernalillo Co, NM from 1988 to 1990 was based on cases identified by an interstitial lung disease registry. The annual incidence rate was 10.7/100,000 for men and 7.4/100,000 for women, but few diagnoses were based on open lung biopsies. IPF accounted for about one quarter of the prevalence of interstitial lung diseases [7].

Causes: Whereas causes of diffuse interstitial pulmonary fibrosis include dusts, fumes, drugs, radiation, infections, chronic aspiration, and collagen vascular diseases, the cause of IPF is unknown [6]. A small study produced evidence that asymptomatic gastroesophageal reflux occurs more frequently in patients with UIP than in patients with other interstitial lung diseases and thus deserves to be considered as a possible etiologic or complicating feature of IPF [8]. Further, cigarette smoking, especially for those with 21-40 pack-yrs of smoking, increases the risk of IPF [9]. Epstein-Barr virus has recently been associated with IPF, but its causal significance is unknown [10]. Familial cases also occur [11].

Clinical features of UIP: Typically, there is a history of gradual progression of dyspnea and cough over a period of months to years. It can begin at any age, but the usual age is between 50 and 60, and males predominate slightly. The symptoms and pulmonary signs are the same in patients with the idiopathic form of the disease as in those with a known cause or associated disease. Findings on physical examination can include finger clubbing and fine end-inspiratory rales over the lower lobes.

Pulmonary function tests show restriction, reduced DLCO, and hypoxemia that is made worse by exercise. Pulmonary hypertension develops in somewhat less than 1/2 of cases. Laboratory abnormalities may include an increased erythrocyte sedimentation rate, hypergammaglobulinemia, and the presence of antinuclear antibodies or rheumatoid factor. Sometimes symptoms typical of IPF precede the diagnosis of a connective tissue disease, at which time the diagnosis should be changed from IPF. Median survival is about 5 years from onset of symptoms [12]. Therapy includes corticosteroids, cytotoxic drugs, and colchicine. A new anti-fibrotic agent--pirfenidone--has undergone a compassionate use trial in patients who had already survived a mean time of 3.2 y after open lung biopsy. Survival on the drug was 78% at one year and 63% at 2 years [13]. An accelerated phase of disease, which sometimes responds to steroids, has been described [14,15].

In a small study of the effectiveness of interferon gamma-1b along with prednisolone in the treatment of IPF, improvement occurred in the test group compared to the control group that was treated with prednisolone alone [15a,15b].

Radiographic changes: HRCT has become routine in the diagnosis of IPF. Increasing experience in diagnosis gives the radiologist who sees many examples confidence in separating it from other diseases, especially when the pre-test clinical probability is high. When the diagnostic certainty is high, open lung biopsies are believed to be unnecessary by some. However, biopsy is important when the clinical story and CT are discordant. On the other hand, the histologic subclassification of IPF is still undergoing change, and histologic and CT correlations are still needed [16].

HRCT patterns in IPF, which include ground-glass opacities, reticular opacities, traction bronchiectasis/bronchiolectasis, and honeycombing, are useful for predicting prognosis and for following the patient after treatment [16]. In one study, those with ground-glass opacities predominating over reticular opacities (8 of 76) all survived >50 mo, whereas the others had a median survival of about 2 y [17]. HRCT is also useful for detecting emphysema and carcinoma in these patients. Further, in another type of study, it was found that in comparison with patients with systemic sclerosis, patients with IPF had more functional impairment in gas exchange and higher dyspnea scores after controlling for extent of disease on HRCT [18].

Serial changes on HRCT: In 12 patients with biopsy-proven UIP, quantification of ground-glass opacities, irregular lines, and honeycombing at the time of diagnosis and at a median of 10 mo later showed the changes indicated in Table 2. In contrast, 11 patients with DIP showed initially more ground-glass opacities, but honeycombing occurred in only one, and after a median of 10 mo, honeycombing occurred in only one other. Thus, progression of disease depends on the underlying histologic diagnosis and not the presence of ground-glass opacities alone. The authors concluded that in UIP, ground-glass opacities become honeycombed more frequently than do similar opacities in DIP [19].

Table 2. Temporal Changes in HRCT in 12 Patients with UIP [19]

Initial % Involvement of HRCT (Mean ± SD)

10 mo later (median) (progression in 9 overall)

Ground-glass opacities 30 ± 16% (N=12)

Progression in 6

Irregular lines 17 ± 7% (N=12)

Progression in 2

Honeycombing 10 ± 6% (N=10)

Progression in 4

Histopathologic diagnosis: Although transbronchial or endobronchial biopsies are useful for diagnosing tumor, sarcoidosis, infection, and a few other unusual lung diseases, a diagnosis of UIP cannot be made because of the small size: open or thoracoscopic biopsies are necessary [20]. The main use of open/thoracoscopic lung biopsy is to provide a specific diagnosis when the clinical or radiographic findings are not typical. A biopsy also helps to justify therapy, which is associated with its own adverse effects. It can be used to justify lung transplantation [5].

Gross changes: In end-stage disease, the lungs are moderately heavy and symmetrically shrunken. Pleural surfaces are coarsely nodular or cobblestoned. Pleural thickening is unusual, and adhesions are usually absent. Slices of lung show enlargement of air spaces with slightly thickened walls that remain upright when fixative runs out--honeycombing. This change first occurs subpleurally in the lower lobes and is associated with a grey network of fibrosis that contrasts with the normal, soft parenchyma more centrally. With time, grey fibrosis encroaches on the normal central parenchyma. Close examination of the honeycombed spaces shows that many of them represent dilated respiratory bronchioles and alveolar ducts; the intervening fibrosis represents the collapsed and fibrotic alveolar parenchyma. Secondarily, with severe disease, there may be right ventricular cardiac hypertrophy and dilation in addition to atherosclerosis of the main pulmonary arteries.

Tissue preparation: A properly expanded specimen and sections stained with H&E, an elastic-van Gieson stain (or pentachrome stain), and a stain for iron are necessary for diagnosis of fibrosing lung diseases. Preferably, biopsies should be taken from two sites chosen radiographically to show active disease (ground-glass). Specific features must be present to make a diagnosis of UIP. These are described below and summarized in Table 3.

Microscopic changes--low power: Architecture is distorted in a patchy fashion by granulation tissue (fibroblast foci), interstitial fibrosis, and honeycombing. Despite these changes, patches of normal lung remain in biopsies that are selected properly. The presence of old fibrosis and granulation tissue (indicating temporal heterogeneity) signifies a progressive process.

High power features--evolution of alveolitis: The initial lesion--an alveolitis--consists of a focus of inflammatory thickening of alveolar walls with lymphocytes and hyperplastic type II cells; an alveolar exudate of macrophages and PMNs is present. This alveolitis does not resolve. It results in both alveolar collapse and the process of organization and reepithelialization of alveolar exudate (mural incorporation) to form thick, fibrous walls. This alveolar collapse and fibrosis causes honeycombing by traction on small bronchi, bronchioles, and alveolar ducts. The fibrotic walls of the cystic spaces distinguish honeycombing from emphysema, which has thin-walled spaces. In honeycombing, the spaces often become lined by hyperplastic or metaplastic epithelium, which can be atypical. When the epithelium resembles respiratory epithelium with ciliated cells, the process is called bronchiolization. Because clearance from these spaces can be impaired, they are sometimes filled with mucus or collections of neutrophils. Bony metaplasia and smooth muscle metaplasia may be striking features in areas of fibrosis.

Inflammatory infiltrate: Mild to moderate interstitial inflammation with lymphocytes, scattered plasma cells, and a few PMNs and eosinophils persists in areas of granulation tissue and fibrosis. This inflammation includes occasional lymphoid aggregates. Alveolar macrophages mixed with a few PMNs are present to a variable degree.

Vascular bed: As a result of the alveolar collapse, portions of the capillary bed disappear. Arteries and veins in inflamed and fibrotic areas become narrowed by myointimal thickening and adventitial fibrosis. When the process is extensive, pulmonary hypertension occurs.

Pleura: The pleura typically shows little fibrosis or inflammation.

Table 3: Summary of Histologic Criteria for Usual Interstitial Pneumonia [21]

* Caution should be used in diagnosing carcinoma in histologic or cytologic preparations obtained from fibrotic lungs because of the marked atypia that can occur [22].

Assessment of the biopsy: In addition to H&E-stained sections, use of the elastic van Gieson stain that colors elastic tissue black and collagenous tissue red helps to identify acinar landmarks, shows the difference between recent (pink) and old (red) fibrosis, and helps delineate vascular sclerosis, all features that help with the differential diagnosis. In all cases, an iron stain should be scanned serially for ferruginous bodies. Ferruginous bodies with a thin, transparent core in a person with a history of asbestos exposure can be designated asbestos bodies. The number of bodies found can be expressed as bodies/cm2 if the area of the section is measured by laying the section on graph paper ruled 100/cm2 and counting the squares covered by the section. A concentration of 1 body/2 cm2 indicates heavy exposure [23]. Observation of the section with polarized light can identify birefringent dusts like talc acquired by either inhalational or intravenous routes.

Structure-function correlations: There is interest in quantification of features in the lung biopsy for correlation with aspects of pulmonary function [24, 25]. In 96 patients with biopsy-proven UIP and no prior therapy, a significant inverse correlation was found between DLCO and total pathology score and score for cells in air spaces. Also, FVC and TLC declined with increasing interstitial cellular infiltrates. It was disappointing that no significant relation was found between fibrosis or connective tissue/granulation tissue scores and any physiologic parameter. However, when patients were divided into never smokers and ever smokers, correlations emerged. It was found that in never smokers, gas exchange during exercise worsened as fibrosis increased, and decreases in FVC were related to increasing degree of cellularity in the interstitium and air spaces. In ever smokers, the DLCO was inversely related to both the extent of overall cellularity and total pathology score [26].

Association with lung cancer: IPF is associated with lung cancer. Compared with age, sex, and smoking matched controls, men with IPF had a risk of lung cancer 14 times, and women 7 times that in controls [27]. In another study, the actual number of lung cancers (7) among 31 persons who died with pulmonary fibrosis was 8.5 times that expected for men and 16 times that expected for women [28]. Histologic types of tumor were the same as in the general population.

Familial disease: Although familial pulmonary fibrosis has been described, only a few series have good documentation of the pathologic changes [11,29,30]. Defined as disease in an index case and 2 or more relatives, it is likely to have an autosomal dominant transmission.

Prognosis of UIP: Clinical markers of progression include severe dyspnea, requirement of cytoxan therapy, and cigarette smoking [12]. Survival is less for men and for those with poor lung function, but, as death in these patients has multiple other causes--cardiovascular problems, lung cancer, and infection--respiratory failure, which occurs in about 40%, is not the only determinant [31,32]. In one study, median survival of 74 patients from onset of symptoms was >5 y [32]. In another study, median survival for 63 patients who had biopsy-proven UIP was a median of 2.8 y from diagnosis [33]. In a recent study of response to therapy and survival in biopsy-proven IPF, the following were found to indicate a response to therapy: lower age, high pretreatment "clinical, radiographic, and physiologic" scores, high cellular infiltration scores on biopsy, and high CT ground-glass and low CT fibrosis scores. Death was related to increasing fibrosis shown by CT or histology. Non-responders to an initial 3-month course of steroid therapy had a higher risk of decreasing pulmonary function and a poorer long-term survival than responders [34].

The British Thoracic Society has published its recommendations for diagnosis, assessment, and treatment of diffuse parenchymal lung disease [35], as has an international group under the auspices of the American Thoracic Society [1].


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Clinical summary

Comments: mw6825@itsa.ucsf.edu

Table of Contents

Last revised 8/29/00

Copyright 1999 by Martha L. Warnock. All rights reserved.