TOC | Pulm

Idiopathic Pulmonary Fibrosis

The term pulmonary fibrosis describes a heterogeneous group of pulmonary diseases characterized by interstitial inflammation (alveolitis), thickening of the alveolar walls, and varying degrees of parenchymal destruction and fibrosis. More than 160 individual diseases associated with pulmonary fibrosis have been identified.  Despite this long list, an underlying etiology is not found in more than 50% of patients even after intensive investigation. These cases are referred to as idiopathic pulmonary fibrosis (IPF), also called Hamman-Rich syndrome, diffuse interstitial fibrosis, diffuse or cryptogenic fibrosing alveolitis. The exact incidence is unknown, but is estimated to be 3 to 5 cases per 100,000 population. Patients are often middle-aged, usually between 40 and 70 years of age. Familial cases do exist and follow a simple autosomal dominant pattern of transmission.

I. Clinical presentation

A. Symptoms and signs

The insidious and progressive development of shortness of breath, initially during exercise, and a nonproductive cough are the most common complaints (80-100%) and are often present 12-24 months before presentation. A small percentage of patients may present with abnormal chest x-rays without respiratory symptoms but invariably develop symptoms as the disease progresses. Up to 50% of patients develop systemic or constitutional symptoms (e.g., fatigue, weight loss, fever, myalgias, and arthralgias). Examination of the chest reveals late respiratory fine dry crackles ("Velcro rales") at the bases. Late in the course of disease, clubbing of the fingers and evidence of cor pulmonale and pulmonary hypertension (augmented P2, S3 gallop, right ventricular heave) are often found.

B. Laboratory findings

Hypergammaglobulinemia (80%), an elevated erythrocyte sedimentation rate (50%), positive rheumatoid factor (30%), positive antinuclear antibodies (15%-20%), and circulating immune complexes are all relatively common with IPF but are nonspecific. Polycythemia rarely occurs even with hypoxemia.

C. Radiographic and nuclear medicine findings

Initially, the chest x-ray reveals a nonspecific, bilateral, fine reticular or reticulonodular pattern, which is most apparent in the lung bases. Serial chest x-rays show progressive coarse reticulation, 5- to 10-mm thin-walled cysts (honeycomb lung), and loss of lung volume. Pleural involvement is not a part of IPF. The correlation between plain chest x-ray and clinical or histopathologic stage is poor, and up to 10% of patients with IPF have normal chest x-rays. High-resolution computed tomography (HRCT) is very sensitive in detecting IPF and is especially useful in patients with normal chest x-rays. HRCT reveals the peripheral predominance of the interstitial densities, and the patchy nature of the involvement with areas of normal tissue. Gallium-67 lung scintigraphy does suggest active alveolitis when positive, but is nonspecific, correlates poorly with clinical or histopathologic stage, and if negative, does not exclude disease. The utility of gallium scintigraphy is therefore unclear.

D. Physiologic tests

Pulmonary function studies invariably reveal a restrictive ventilatory defect, with reduction in vital capacity, total lung capacity, and diffusing capacity. Arterial blood gas analysis reveals hypoxemia at rest secondary to ventilation/perfusion mismatch and respiratory alkalosis (hyperventilation) induced by stimulation of intrapulmonary stretch-receptors. With exercise the alveolar-arterial oxygen gradient increases and oxygen saturation falls in part because of diffusion impairment and ventilation/perfusion mismatch. 

Pathologic Features:
A. Desquamative interstitial pneumonia (DIP)

Desquamative interstitial pneumonia (DIP) is characterized by a relatively uniform appearance with intra-alveolar collections of macrophages and lymphocytes and concurrent hyperplasia of type II alveolar cells. Alveolar-wall thickening and interstitial inflammatory cell infiltration are present, but fibrosis is minimal.

B. Usual interstitial pneumonia (UIP)

Usual interstitial pneumonia (UIP) is characterized by varying degrees of parenchymal edema, fibrinous exudates, mononuclear cell infiltration, and fibroblast proliferation. Areas of dense fibrosis and destruction of normal lung architecture are common.

C. End-stage fibrosis

End-stage fibrosis is associated with marked connective tissue alterations and derangement of parenchymal structures. Cystic spaces (honeycomb lung) lined with metaplastic bronchial epithelium and evidence of pulmonary hypertension (cholesterol-ester clefts, smooth-muscle proliferation, pulmonary arteriolar fibrointimal thickening, and obliteration) are late findings.


Diagnostic Approach

A. Criteria

  1. A compatible clinical and radiographic presentation.
  2. Histologic evidence of DIP, UIP, or radiologic evidence of diffuse honeycomb lung.
  3. Careful exclusion of other causes of diffuse interstitial fibrosis

B. Bronchoscopy
Transbronchial biopsy and bronchoalveolar lavage (BAL) using the fiberoptic bronchoscope may be useful in excluding alternative diagnoses, especially sarcoidosis and infection. However, the small sample size of the biopsy is often insufficient to make an accurate diagnosis of IPF, and the cellularity observed on the BAL is a poor indicator of the interstitial inflammatory response. Bronchoscopy, therefore, rarely gives a definitive diagnosis of IPF or an accurate assessment of its level of activity.

C. Lung biopsy
A definite determination of the cause and activity state of diffuse interstitial fibrosis can only be made by examining tissue obtained by lung biopsy. Both thoracoscopic and open lung biopsy provide adequate tissue samples. At least two lobes (avoiding the dependent portions of the right middle lobe and lingula) should be biopsied to sample both an area of obvious abnormality and an apparently uninvolved area, since histologic activity can vary from one area to another and since the changes of end-stage pulmonary fibrosis are nonspecific.

D. Differential diagnosis
IPF is a diagnosis of exclusion but can be diagnosed with a high degree of accuracy on clinical and laboratory grounds. Since the injured lung responds to many diseases with similar clinical and histologic changes, determination of the etiology and pathogenesis is difficult unless there is historic or physical evidence of infection, occupational or environmental exposure, or multisystem involvement (e.g., collagen vascular disease). The many diseases that should be considered are listed in Table 8-2 Table 8-2. Many of these diseases are serious, and management and prognosis will be influenced by the specific diagnosis. Every effort should be made to identify treatable diseases such as tuberculosis and other infections, collagen vascular diseases, sarcoidosis, and hypersensitivity pneumonitis.


V. Treatment

A. Oral corticosteroids

Prednisone, beginning at 1.5-2 mg/kg/day (not to exceed 100 mg/day), is the preferred treatment. The initial dose is continued for 6 weeks and then reduced to 1 mg/kg/day for an additional 6 weeks and then 0.5 mg/kg/day for 3 months. If the patient responds (stabilized or improved) the dose is slowly tapered (1-2 mg/week) to 0.25 mg/kg/day. After approximately 1 year, it may be possible to taper the prednisone further, but immediate or late relapses are common and repeat therapy with prednisone may be required. No well-controlled studies demonstrate the superiority of any particular regimen of corticosteroids, and many other regimens may be equally effective. Precise guidelines are not available.

B. Immunosuppressive therapy

In patients who have failed or cannot tolerate corticosteroid therapy, therapy with cyclophosphamide may be initiated at 2 mg/kg/day (not to exceed 200 mg/day) with prednisone 0.25 mg/kg/day. The dose of cyclophosphamide should be adjusted to maintain the neutrophil count > 1500 cells/mm3. Therapy should be continued for at least 3 months and, if stabilization or clinical improvement are documented, then continued for 9-12 months. Azathioprine may be less effective than cyclophosphamide but may have more manageable side effects. Azathioprine may be initiated at 2 mg/kg/day (not to exceed 200 mg/day) with prednisone 0.25 mg/kg/day. It too should be continued for at least 3 months and, if stabilization or clinical improvement are documented, then continued for 9-12 months.

C. Monitoring of response

In general, responsive patients report a decrease in symptoms, demonstrate clearing of chest x-ray findings, and experience improvement or no further decline of physiologic tests. A 25% increase in vital capacity, a 40% increase in diffusing capacity, and reduction or normalization of oxygen desaturation during exercise are all significant. Any therapeutic trial should continue at least 3 months (if not prevented by side effects) before a decision is reached as to its ineffectiveness.

VI. Prognosis

The course of idiopathic pulmonary fibrosis is variable and frequently chronic and slowly progressive, ultimately ending in death. Recent studies have shown a mean survival of 12 years in patients with predominantly a DIP pattern, as compared with 6 years in patients with predominantly a UIP pattern. Without treatment, 22% with DIP but none with UIP improved. With corticosteroid therapy, 62% with DIP and only 12% with UIP improved. The main causes of death are respiratory failure, cor pulmonale, infection, and lung carcinoma.

NEJM  October 21, 1999 -- Vol. 341, No. 17

A Preliminary Study of Long-Term Treatment with
Interferon Gamma-1b and Low-Dose Prednisolone in Patients with Idiopathic Pulmonary Fibrosis

Rolf Ziesche, Elisabeth Hofbauer, Karin Wittmann, Ventzislav Petkov, Lutz-Henning Block

Patients with idiopathic pulmonary fibrosis have progressive scarring of the lung and usually die within four to five years after symptoms develop. Treatment with oral glucocorticoids is often ineffective. We conducted an open, randomized trial of treatment with a combination of interferon gamma-1b, which has antifibrotic properties, and an oral glucocorticoid.

We studied 18 patients with idiopathic pulmonary fibrosis who had not had responses to glucocorticoids or other immunosuppressive agents. Nine patients were treated for 12 months with oral prednisolone alone (7.5 mg daily, which could be increased to 25 to 50 mg daily), and nine with a combination of 200 µg of interferon gamma-1b (given three times per week subcutaneously) and 7.5 mg of prednisolone (given once a day).

All the patients completed the study. Lung function deteriorated in all nine patients in the group given prednisolone alone: total lung capacity decreased from a mean (±SD) of 66±8 percent of the predicted value at base line to 62±6 percent at 12 months. In contrast, in the group receiving interferon gamma-1b plus prednisolone, total lung capacity increased (from 70±6 percent of the predicted value at base line to 79±12 percent at 12 months, P<0.001 for the difference between the groups). In the group that received interferon gamma-1b plus prednisolone, the partial pressure of arterial oxygen at rest increased from 65±9 mm Hg at base line to 76±8 mm Hg at 12 months, whereas in the group that received prednisolone alone it decreased from 65±6 to 62±4 mm Hg (P<0.001 for the difference in the change from base-line values between the two groups); on maximal exertion, the value increased from 55±6 to 65±8 mm Hg in the group that received combined treatment and decreased from 55±6 mm Hg to 52±5 mm Hg in the group given prednisolone alone (P<0.001). The side effects of interferon gamma-1b, such as fever, chills, and muscle pain, subsided within the first 9 to 12 weeks.

In a preliminary study, 12 months of treatment with interferon gamma-1b plus prednisolone was associated with substantial improvements in the condition of patients with idiopathic pulmonary fibrosis who had had no response to glucocorticoids alone. (N Engl J Med 1999;341:1264-9.)   see the Editorial

Manual of Allergy & Immunology - Glenn Lawlor, etc.



Medical Progress: Idiopathic Pulmonary Fibrosis  
Gross T. J., Hunninghake G. W.
N Engl J Med 2001; 345:517-525, Aug 16, 2001. Review Articles

Diagnostic Approach to the Patient With Diffuse Lung Disease -  
Jay H. Ryu, Eric J. Olson, David E. Midthun, and Stephen J. Swensen
Mayo Clinic Proceedings November 2002 Volume 77 Number 11