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Idiopathic
interstitial pneumonias are interstitial lung diseases of unknown
etiology that share similar clinical features. Classified into 6
histologic subtypes, all are characterized by varying degrees of
inflammation and fibrosis and all cause dyspnea and typical radiographic
abnormalities. Diagnosis is based on history, physical examination, imaging,
pulmonary function tests, and lung biopsy. Treatment varies by subtype
but typically involves corticosteroids, cytotoxic drugs, or both;
treatment is frequently ineffective. Prognosis varies by subtype
and ranges from excellent to nearly always fatal.
The 6 histologic subtypes of idiopathic interstitial pneumonia (IIP) in decreasing order of frequency are usual interstitial pneumonia (UIP), known clinically as idiopathic pulmonary fibrosis; nonspecific interstitial pneumonia; bronchiolitis obliterans organizing pneumonia; respiratory bronchiolitis-associated interstitial lung disease (ILD); desquamative interstitial pneumonia; and acute interstitial pneumonia. Lymphoid interstitial pneumonia, although still considered a subtype of IIP, is now thought to be part of the lymphoproliferative disease spectrum rather than primary ILD (see Interstitial Lung Diseases: Lymphoid Interstitial Pneumonia). These subtypes are characterized by varying degrees of interstitial inflammation and fibrosis, and all cause dyspnea; diffuse, usually reticular opacities on chest x-ray; and inflammation and/or fibrosis on biopsy. The subtypes are important to distinguish, however, because they have different clinical features and responses to treatment (see Table 2: Interstitial Lung Diseases: Key Features of Idiopathic Interstitial Pneumonias ).
Diagnosis
Known causes of ILD must be excluded. Chest x-ray is always obtained as well as pulmonary function tests (see Tests of Pulmonary Function (PFT)) and high-resolution CT (HRCT), which distinguishes airspace from interstitial disease, provides better assessment of the extent and distribution of disease, and is more likely to detect underlying or coexisting disease (eg, occult mediastinal adenopathy, carcinoma, emphysema). HRCT is best performed with the patient prone to reduce dependent lung atelectasis.
Lung biopsy is usually needed to confirm the diagnosis except when HRCT demonstrates a diagnostic pattern. Bronchoscopic transbronchial biopsy can rule out ILD by detecting other diseases but does not yield enough tissue to diagnose ILD. Biopsy of multiple sites with an open or video-assisted thoracoscopic surgery (VATS) procedure is required.
Bronchoalveolar lavage helps narrow the differential diagnosis in selected patients and can provide information about disease progression and response to therapy. The usefulness of this procedure in the initial clinical assessment and follow-up of most patients with these diseases has not been established, however.
Idiopathic
Pulmonary Fibrosis
(Cryptogenic Fibrosing Alveolitis)
Idiopathic
pulmonary fibrosis, the most common form of IIP, causes progressive
pulmonary fibrosis predominantly in male smokers. Symptoms and signs
develop over months to years and include exertional dyspnea, cough,
and fine (Velcro) crackles. Diagnosis is based on history, physical
examination, chest x-ray, and pulmonary function tests and is confirmed
with HRCT, lung biopsy, or both if necessary. No specific treatment has
proven effective, but corticosteroids, cyclophosphamide, azathioprine,
or a combination are often given. Most patients deteriorate even
with treatment; median survival is < 3
yr from diagnosis.
Etiology
and Pathophysiology
Idiopathic pulmonary fibrosis (IPF), identified histologically as UIP, accounts for 50% of cases of IIP. IPF affects men and women in their 50s and 60s in a ratio of 2 : 1. Current or former cigarette smoking is most strongly associated with the disease. There is some genetic predisposition; familial clustering occurs in up to 3% of cases.
Although IPF is called a pneumonia, inflammation seems to play a relatively minor role. Environmental, genetic, or other unknown factors are thought to initially trigger alveolar epithelial cell injury, but self-perpetuating and aberrant interstitial fibroblast and mesenchymal cell proliferation (with collagen deposition and fibrosis) are thought to account for development of clinical disease. The key histologic findings are subpleural fibrosis with sites of fibroblast proliferation (fibroblast foci) and dense scarring, alternating with areas of normal lung tissue (heterogeneity). Scattered interstitial inflammation occurs with lymphocyte, plasma cell, and histiocyte infiltration. Cystic dilatation of peripheral alveoli (honeycombing) is found in all patients and increases with advanced disease. A similar histologic pattern uncommonly occurs in cases of ILD of known etiology (see Table 1: Interstitial Lung Diseases: Causes Of Interstitial Lung Disease*); the term UIP is reserved for idiopathic lesions not associated with known conditions.
Symptoms and Signs
Symptoms and signs typically develop over 6 mo to several years and include dyspnea on exertion and nonproductive cough. Constitutional symptoms, such as low-grade fever and myalgias, are uncommon. The classic sign of IPF is fine, dry, bibasilar inspiratory crackles (Velcro crackles). Clubbing is present in about 50% of cases. The remainder of the examination is normal until disease is advanced; in advanced disease, signs of pulmonary hypertension and right ventricular systolic dysfunction may develop.
Diagnosis
Diagnosis is based on history, imaging tests, pulmonary function tests, and biopsy. IPF is commonly overlooked at first because of clinical similarities to other diseases, such as bronchitis, asthma, and heart failure.
Chest x-ray typically shows diffuse reticular opacities in the lower and peripheral lung zones. Small cystic lesions (honeycombing) and dilated airways due to traction bronchiectasis are additional findings.
Pulmonary function tests typically reveal a restrictive pattern (see Tests of Pulmonary Function (PFT)). Diffusing capacity for carbon monoxide (DLco) is also reduced. ABGs show hypoxemia, which is often exaggerated or elicited by exercise and low arterial CO2 levels.
HRCT shows diffuse, patchy, subpleural, reticular opacities with irregularly thickened interlobular septa and intralobular lines; subpleural honeycombing; and traction bronchiectasis. Ground-glass opacities affecting > 30% of the lung suggest an alternative diagnosis.
Laboratory testing plays little role in diagnosis. Elevated ESR, C-reactive protein, and hypergammaglobulinemia are common. Antinuclear antibody or rheumatoid factor is elevated in up to 30% of patients and, depending on the titer, may not imply underlying connective tissue disease.
Prognosis
Most patients have moderate to advanced clinical disease at the time of diagnosis and deteriorate despite treatment. Normal Pao2 at presentation and fewer fibroblastic foci on biopsy improve the prognosis. Prognosis is worse with advanced age, poor pulmonary function at presentation, and severe dyspnea. Median survival is < 3 yr from time of diagnosis. An increase in the frequency of hospitalization for unexpected respiratory infection and insufficiency indicates the approach of the patient's end of life and should prompt discussions about advance care planning (see Medicolegal Issues: Advance Directives). Lung cancer occurs more frequently in patients with IPF, but cause of death is usually respiration failure, respiratory infection, or heart failure with ischemia and arrhythmia.
Treatment
No specific treatment has proven effective. Supportive therapy consists of O2 for hypoxemia and antibiotics for pneumonias. End-stage disease may qualify selected patients for lung transplantation. Corticosteroids and cytotoxic drugs ( cyclophosphamide , azathioprine ) have traditionally been given to IPF patients empirically in an attempt to halt the progression of inflammation, but limited data support their efficacy. Nevertheless, it is common practice to attempt treatment with prednisone (0.5 to 1.0 mg/kg po once/day for 3 mo, tapered to 0.25 mg/kg once/day over the next 3 to 6 mo) combined with cyclophosphamide or azathioprine (1 to 2 mg/kg po once/day). Every 3 mo for 1 yr, clinical, radiographic, and physiologic responses are assessed, and drug doses are increased or decreased accordingly. Therapy is stopped if there is no objective response.
Pirfenidone, an antifibrotic agent, may stabilize pulmonary function and reduce exacerbations. Antifibrotics that inhibit collagen synthesis (relaxin), profibrotic growth factors ( suramin ), and endothelin-1 (an angiotensin receptor blocker) have only been demonstrated effective in vitro.
Interferon-γ-1b has shown promise when combined with prednisone in a small group of patients, but a larger double-blind multinational randomized trial found no effect on progression-free survival time, pulmonary function, or quality of life.
Lung transplantation is successful for otherwise healthy IPF patients < 55 yr with end-stage pulmonary disease (< 40% of all IPF patients).
Desquamative
Interstitial Pneumonia
Desquamative
interstitial pneumonia is chronic lung inflammation characterized
by mononuclear cell infiltration of the airspaces.
Over 90% of patients with desquamative interstitial pneumonia are smokers, who tend to develop the disease in their 30s or 40s. The disease tends to affect the lung parenchyma uniformly. The alveolar walls are lined with plump cuboidal pneumocytes; there is moderate infiltration of the alveolar septum by lymphocytes, plasma cells, and, occasionally, eosinophils, and alveolar septal fibrosis is mild at worst. The most striking feature is the presence of numerous pigmented macrophages within distal airspaces, mistaken as desquamated pneumocytes when the disease was first described. Honeycombing is rare. Similar but much less extensive findings are seen in respiratory bronchiolitis-associated ILD (RBILD), leading to the suggestion that desquamative interstitial pneumonia and RBILD are different manifestations of the same disease caused by cigarette smoking.
The symptoms, signs, pulmonary function test findings, and approach to diagnosis are otherwise the same as for idiopathic pulmonary fibrosis (IPF).
Chest x-ray abnormalities are less severe than in IPF; findings may be normal in up to 20% of cases. HRCT shows patchy, subpleural ground-glass opacities, usually without reticular opacities.
Treatment with smoking cessation results in clinical improvement in an estimated 75% of patients; those who do not improve may respond to corticosteroid or cytotoxic drugs. Prognosis is good, with about 70% survival at 10 yr.
Respiratory
Bronchiolitis-Associated Interstitial Lung Disease
Respiratory
bronchiolitis-associated ILD is a syndrome of small airway inflammation
and interstitial lung disease occurring in smokers.
Most smokers develop a subclinical bronchiolitis characterized by mild or moderate inflammation of the small airways. The few patients who develop more severe inflammation with clinically significant interstitial disease are said to have respiratory bronchiolitis-associated ILD (RBILD). Male-to-female ratio is 2:1. RBILD is characterized histologically by submucosal inflammation of the membranous and respiratory bronchioles manifested by the presence of tan-brown pigmented macrophages (resulting from increased iron content, as is seen in smokers), mucus stasis, and metaplastic cuboidal epithelium in bronchioles and alveoli. Alveolar septal scarring always occurs. These findings, however, occur in some hypersensitivity reactions, occupational lung exposures (usually due to mineral dusts), viral infections, and drug reactions. RBILD also resembles desquamative interstitial pneumonia histologically, but in RBILD inflammation is patchier and less extensive. The similarity of the 2 conditions has led to the suggestion that they are different manifestations of the same disease caused by cigarette smoking.
Symptoms of cough and breathlessness with exertion resemble those of other ILDs, especially IPF, but are milder. Crackles on examination are the only physical finding.
Diagnosis is based on history, imaging tests, pulmonary function tests, and biopsy. Chest x-ray findings include diffuse, fine reticular or nodular opacities; bronchial wall thickening; prominent peribronchovascular interstitium; small regular and irregular opacities; and small peripheral ring shadows. HRCT scanning often shows hazy ground-glass opacities. A mixed obstructive-restrictive pattern is common on pulmonary function tests, although results may be normal or show an isolated increase in residual volume. ABG measurements show mild hypoxemia. Routine laboratory tests are not helpful.
Treatment of RBILD is smoking cessation; evidence of efficacy of corticosteroids is anecdotal. The natural clinical course of the disease is unknown, but prognosis is good with smoking cessation.
Acute
Interstitial Pneumonia
(Accelerated Interstitial Pneumonia; Hamman-Rich Syndrome)
Acute interstitial
pneumonia is an idiopathic version of the acute respiratory distress
syndrome (ARDS—see Acute Lung Injury and Acute Respiratory Distress Syndrome (ARDS)).Acute interstitial pneumonia (AIP) affects apparently healthy men and women usually > 40 yr equally.
AIP is defined histologically by organizing diffuse alveolar damage, a nonspecific pattern seen in other causes of lung injury unrelated to IIP. The hallmark of organizing diffuse alveolar damage is diffuse, marked alveolar septal edema with inflammatory cell infiltration; fibroblast proliferation; occasional hyaline membranes; and thickening. Septa are lined with atypical, hyperplastic type II pneumocytes, and airspaces are collapsed. Thrombi develop in small arteries but are nonspecific.
Symptoms are abrupt onset of fever, cough, and shortness of breath and last 7 to 14 days, quickly progressing in most patients to respiratory failure.
Diagnosis is based on history, imaging tests, pulmonary function tests, and biopsy. Chest x-ray findings are similar to those in ARDS and show diffuse bilateral airspace opacification. HRCT scan shows bilateral patchy symmetric areas of ground-glass attenuation and sometimes bilateral areas of airspace consolidation in a predominantly subpleural distribution. Mild honeycombing, usually affecting < 10% of the lung, may be seen. Routine laboratory tests are nonspecific and generally not helpful.
Diagnosis is confirmed by biopsy showing diffuse alveolar damage in the absence of known causes of ARDS and diffuse alveolar damage (eg, sepsis, drugs, toxins, radiation, and viral infection). The disease must also be distinguished from diffuse alveolar hemorrhage syndrome, acute eosinophilic pneumonia, and idiopathic bronchiolitis obliterans organizing pneumonia.
Treatment is supportive and usually requires mechanical ventilation. Corticosteroid therapy is generally used, but efficacy has not been established.
Mortality is > 60%; most patients die within 6 mo of presentation, and death is usually due to respiratory failure. In patients who survive the initial acute episode, recovery of pulmonary function is complete, although the disease may recur.
Bronchiolitis
Obliterans Organizing Pneumonia (BOOP)
(Cryptogenic Organizing Pneumonia)
Bronchiolitis
obliterans organizing pneumonia is an idiopathic condition in which
granulation tissue obstructs bronchioles and alveolar ducts with chronic
inflammation and organizing pneumonia in adjacent alveoli.
Idiopathic bronchiolitis obliterans organizing pneumonia (BOOP) affects men and women equally, usually in their 40s or 50s. Cigarette smoking does not appear to be a risk factor.
About 1⁄2 the patients recall having a community-acquired pneumonia-like syndrome (ie, a nonresolving flu-like illness characterized by cough, fever, malaise, fatigue, and weight loss). Progressive cough and exertional dyspnea are what usually prompt the patient to seek medical attention. Examination demonstrates inspiratory crackles.
Diagnosis is based on history, physical examination, imaging tests, pulmonary function tests, and biopsy. Chest x-ray shows bilateral, diffuse, peripherally distributed alveolar opacities with normal lung volumes; a peripheral distribution similar to that seen in chronic eosinophilic pneumonia may occur. Rarely, alveolar opacities are unilateral. Recurrent and migratory pulmonary opacities are common. Rarely, irregular linear or nodular interstitial opacities or honeycombing are seen at presentation. HRCT scans of the lung show patchy airspace consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening and dilatation. The patchy opacities are more common in the periphery of the lung, often in the lower lung zone. CT scans may show much more extensive disease than is expected from review of the chest x-ray.
Pulmonary function tests usually show a restrictive defect, although an obstructive defect ([FEV1/FVC] < 70%) is found in 21% of patients, and pulmonary function is occasionally normal.
Routine laboratory tests are nonspecific. Leukocytosis without an increase in eosinophils occurs in about 1⁄2 of patients. The initial ESR often is elevated. Rest and exercise hypoxemia is common.
Lung biopsy shows excessive proliferation of granulation tissue within small airways and alveolar ducts, with chronic inflammation in the surrounding alveoli. Foci of organizing pneumonia (ie, a BOOP pattern) are nonspecific and can occur secondary to other pathologic processes, including infections, Wegener's granulomatosis, lymphoma, hypersensitivity pneumonitis, and eosinophilic pneumonia.
Treatment is similar to that for idiopathic pulmonary fibrosis. Clinical recovery occurs in 2⁄3 of treated patients, often within 2 wk. Relapses occur in up to 50% of patients, but these patients are responsive to additional courses of corticosteroids.
Nonspecific
Interstitial Pneumonia
Nonspecific
interstitial pneumonia refers to a histologic appearance in ILD
that does not conform to the other more specific histologic patterns.
Nonspecific interstitial pneumonia appears to be a discrete entity. Its incidence and prevalence are unknown, but it appears to be the 2nd most common form of IIP (14 to 36% of reported cases). Most cases occur in patients who have connective-tissue disease, drug-induced ILD, or chronic hypersensitivity pneumonitis as an underlying feature. Some cases have no identified etiology and are not associated with another disease.
Clinical presentation is similar to that of IPF. Most patients are between 40 and 60 yr. Cough and dyspnea are present for months to years.
Chest x-ray primarily demonstrates lower-zone reticular opacities. Bilateral patchy opacities can also be seen. HRCT scan findings include bilateral patchy ground-glass attenuation, bilateral areas of consolidation, irregular lines, and bronchial dilatation. Ground-glass attenuation is the predominant finding in most cases and is the sole abnormality in about 1⁄3 of cases.
The main histologic feature of nonspecific interstitial pneumonia is homogenous inflammation and fibrosis, as opposed to the heterogeneity in usual interstitial pneumonia. The changes are temporally uniform, but the process may be patchy, with intervening areas of unaffected lung. Honeycomb areas are rare.
Most patients have a good prognosis after treatment with corticosteroids. Relapse may occur. The disease progresses in a few patients, who die 5 to 10 yr after diagnosis. The estimated 10-yr mortality is < 15 to 20%.
Last full review/revision November 2005
Content last modified November 2005
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