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Idiopathic
interstitial pneumonias are interstitial lung diseases of unknown
etiology that share similar clinical and radiologic features and
are distinguished primarily by the histopathologic patterns on lung
biopsy. Classified into 6 histologic subtypes, all are characterized
by varying degrees of inflammation and fibrosis and all cause dyspnea.
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
Lymphoid interstitial pneumonia, although still considered a subtype of IIP, is now thought to be part of the lymphoproliferative disease spectrum rather than a primary interstitial lung disease (see Interstitial Lung Diseases: Lymphoid Interstitial Pneumonia). These subtypes are characterized by varying degrees of interstitial inflammation and fibrosis. All cause dyspnea, diffuse usually reticular opacities on chest x-ray, and inflammation, fibrosis, or both on biopsy. The subtypes are important to distinguish, however, because they have different clinical features (see Table 2: Interstitial Lung Diseases: Key Features Of Idiopathic Interstitial Pneumonias ) and respond differently to treatment.
Symptoms and Signs
Symptoms and signs are usually nonspecific. Cough and dyspnea on exertion are typical, with variable onset and progression. Common signs include tachypnea, reduced chest expansion, and bibasilar end-inspiratory dry crackles.
Diagnosis
IIP should be suspected in any patient with unexplained interstitial lung disease. Clinicians, radiologists, and pathologists should exchange information to determine the diagnosis in individual patients. Potential causes (see Table 1: Interstitial Lung Diseases: Causes of Interstitial Lung Disease) are assessed systematically. For maximum diagnostic yield, history should address the following criteria:
Chest x-rays are always done as are pulmonary function tests (see Tests of Pulmonary Function (PFT)). 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, cancer, emphysema). HRCT is best done with the patient prone to reduce dependent lung atelectasis.
The initial laboratory evaluation includes liver and renal function tests and CBC to check for anemia, polycythemia, and leukocytosis. Other tests are obtained for patients who have clinical features suggesting a connective tissue disorder, vasculitis, or environmental exposure. Such tests include ESR, antinuclear antibodies, rheumatoid factor, hypersensitivity panel (a collection of tests for antibodies to common antigens from microbial, fungal, and animal sources), antineutrophil cytoplasmic antibodies, and anti-basement membrane antibody.
Bronchoscopic transbronchial biopsy can exclude interstitial lung disease, establishing a diagnosis of another disorder, but the biopsy does not yield enough tissue to diagnose one of the IIPs. Bronchoalveolar lavage helps narrow the differential diagnosis in some 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.
Surgical lung biopsy is usually needed to confirm the diagnosis except when HRCT demonstrates a pattern consistent with idiopathic pulmonary fibrosis. Biopsy of multiple sites with an open or video-assisted thoracoscopic surgery (VATS) procedure is required.
Treatment
Treatment may vary by disorder (see Table 3: Interstitial Lung Diseases: Treatment and Prognosis of Idiopathic Interstitial Pneumonias*). Smoking cessation is always recommended to avoid accelerating disease progression. Corticosteroids are recommended for cryptogenic organizing pneumonia, lymphoid interstitial pneumonia, and nonspecific interstitial pneumonia. Lung transplantation may be recommended for end-stage disorders.
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Table 3
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Treatment and Prognosis
of Idiopathic Interstitial Pneumonias*
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Disorder
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Treatment
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Prognosis
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Idiopathic pulmonary fibrosis
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Possibly lung transplantation (most other treatments appear ineffective)
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Mortality rate: 50–70% in 5 yr
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Nonspecific interstitial pneumonia
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Corticosteroids
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Mortality rate: < 10% in 5 yr
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Cryptogenic organizing pneumonia
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Corticosteroids
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Complete recovery rate: > 65%
Relapses: In many
Mortality rate: Rare
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Respiratory bronchiolitis–associated interstitial lung disease
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Smoking cessation
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Mortality rate: Rare
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Desquamative interstitial pneumonia
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Smoking cessation
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Mortality rate: 5% in 5 yr
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Acute interstitial pneumonia
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Best treatment unknown
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Mortality rate: 60% in < 6 mo
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Lymphoid interstitial pneumonia†
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Corticosteroids
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Not well defined
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* Listed in order of decreasing frequency.
† Lymphoid interstitial pneumonia, once considered a subtype of idiopathic interstitial pneumonia, is now thought to be a lymphoproliferative disease rather than primary interstitial lung disease.
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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 proved effective. Most patients deteriorate; median survival
is < 3 yr from diagnosis.
Idiopathic pulmonary fibrosis (IPF), identified histologically as usual interstitial pneumonia, accounts for about 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.
Etiology
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.
Pathophysiology
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) occurs in all patients and increases with advanced disease. A similar histologic pattern uncommonly occurs in cases of interstitial lung diseases of known etiology (see Table 2: Interstitial Lung Diseases: Key Features Of Idiopathic Interstitial Pneumonias).
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, at which time signs of pulmonary hypertension and right ventricular systolic dysfunction may develop.
Diagnosis
Diagnosis is suspected in patients with subacute dyspnea, nonproductive cough, and Velcro crackles on chest examination. However, IPF is commonly overlooked initially because of clinical similarities to other more common diseases, such as bronchitis, asthma, and heart failure. Diagnosis requires HRCT, pulmonary function tests, and often surgical lung biopsy.
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.
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 predict a better prognosis. Prognosis is worse with advanced age, poor pulmonary function at presentation (forced vital capacity [FVC] < 55% of predicted or DLco < 35% of predicted), and severe dyspnea. Median survival is < 3 yr from time of diagnosis.
Causes of acute deterioration include infections, pulmonary embolism, pneumothorax, and heart failure. Also, acute exacerbations without an identifiable cause are common and have a high morbidity. Lung cancer occurs more frequently in patients with IPF, but cause of death is usually respiratory failure, respiratory infection, or heart failure with ischemia and arrhythmia. Because of the poor prognosis of IPF, discussions with the patient and family about advance care planning and end-of-life management are important at the early stages of diagnosis and management (see Medicolegal Issues: Advance Directives).
Treatment
No specific treatment has proved effective. Supportive therapy consists of O2 for hypoxemia, pulmonary rehabilitation, and antibiotics for pneumonias. Smoking must be stopped. Joining a support group may help reduce the stress of the illness. Treatment of IPF with corticosteroids and cytotoxic agents is of unproved benefit and causes substantial morbidity; thus, combined therapy should not be routinely prescribed. Drugs such as Nacetylcysteine, bosentan , pirfenidone, warfarin , and etanercept show promise, but there is insufficient evidence to recommend their general use.
Lung transplantation is successful for otherwise healthy IPF patients < 55 yr with end-stage pulmonary disease (< 40% of all IPF patients). Otherwise healthy IPF patients should be evaluated for lung transplantation at the time of diagnosis.
Nonspecific
Interstitial Pneumonia
Nonspecific
interstitial pneumonia is an idiopathic interstitial pneumonia that
occurs mainly in women, nonsmokers, and patients < 50
yr.
Idiopathic nonspecific interstitial pneumonia is the second most common idiopathic interstitial pneumonia. Most patients are between the ages of 40 and 50 and have no known cause or association; however, a similar pathologic process can occur in patients with a connective tissue disorder (in particular, systemic sclerosis or polymyositis/dermatomyositis), in some forms of drug-induced lung injury, and in patients with hypersensitivity pneumonitis.
Clinical presentation is similar to that of IPF. Cough and dyspnea are present for months to years. Constitutional symptoms are unusual, although a low-grade fever and malaise are possible.
Diagnosis
The diagnosis should be considered in patients with unexplained subacute or chronic cough and dyspnea. Diagnosis usually requires chest x-ray, HRCT, pulmonary function tests, and biopsy. In contrast to IPF, antinuclear antibodies and rheumatoid factor may be positive in low titer.
Pulmonary function tests usually show a restrictive pattern. Hypoxemia is often present at rest and is even more prominent with exercise.
Chest x-ray primarily demonstrates lower-zone reticular opacities. Bilateral patchy opacities are also possible. HRCT 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. More than half of the patients have an increased percentage of lymphocytes in bronchoalveolar lavage fluid.
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.
Treatment
Most patients respond to corticosteroids. Relapse may occur. The disease progresses in a small percentage of patients and these die 5 to 10 yr after diagnosis. The estimated overall 10-yr mortality is < 15 to 20%.
Cryptogenic
Organizing Pneumonia
(Bronchiolitis obliterans Organizing Pneumonia)
Cryptogenic
organizing pneumonia is an idiopathic condition in which granulation
tissue obstructs alveolar ducts and alveolar spaces with chronic
inflammation occurring in adjacent alveoli.
Cryptogenic organizing pneumonia (COP) affects men and women equally, usually in their 40s or 50s. Cigarette smoking does not appear to be a risk factor.
About ½ 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) at the onset of the illness. Progressive cough and exertional dyspnea are what usually prompt the patient to seek medical attention. Chest examination demonstrates Velcro crackles.
Diagnosis
Diagnosis requires imaging tests, pulmonary function tests, and, if the diagnosis is not clear from these tests, biopsy. Chest x-ray shows bilateral, diffuse, peripherally distributed alveolar opacities with normal lung volumes; a peripheral distribution similar to 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 visible at presentation. HRCT scans of the lung show patchy airspace consolidation (present in 90% of patients), 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 (ratio of forced expiratory volume in 1 sec to forced vital capacity [FEV1/FVC] < 70%) is found in 21% of patients, and pulmonary function is occasionally normal. Hypoxemia during rest and exercise is common.
Routine laboratory test results are nonspecific. Leukocytosis without an increase in eosinophils occurs in about ½ of patients. The initial ESR often is elevated.
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 are nonspecific and can occur secondary to other pathologic processes, including infections, Wegener's granulomatosis, lymphoma, hypersensitivity pneumonitis, and eosinophilic pneumonia.
Treatment
Clinical recovery follows treatment with corticosteroids in 2/3 of patients, often within 2 wk. Relapses occur in up to 50% of patients, but these patients are responsive to additional courses of corticosteroids. Recovery following treatment is common when COP appears on HRCT as parenchymal consolidation, ground-glass opacity, or nodules. In contrast, recovery is less common when COP appears on HRCT as linear and reticular opacities.
Respiratory
Bronchiolitis-Associated Interstitial Lung Disease
Respiratory
bronchiolitis-associated interstitial lung disease 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 occurs in smokers), mucus stasis, and metaplastic cuboidal epithelium in bronchioles and alveoli. Alveolar septal scarring always occurs. Similar 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 interstitial lung diseases, especially IPF, but are milder. Crackles on examination are the only physical finding.
Diagnosis
Diagnosis is considered in patients being evaluated for interstitial lung disease. Diagnostic testing includes imaging tests, pulmonary function tests, and biopsy. Chest x-ray findings include the following:
HRCT scanning often shows attenuation nodules and patchy areas of 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
Treatment is smoking cessation and avoidance of even passive cigarette smoke exposure, which may prevent improvement or lead to recurrence of the illness. There is only anecdotal evidence of the efficacy of corticosteroids. The natural clinical course of the disease is unknown, but prognosis is good with smoking cessation.
Desquamative
Interstitial Pneumonia
Desquamative
interstitial pneumonia is chronic lung inflammation characterized
by mononuclear cell infiltration of the airspaces; it occurs almost
exclusively in current or former cigarette smokers.
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. Alveolar septal fibrosis, if present, is mild. 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 occur in RBILD, leading to the suggestion that desquamative interstitial pneumonia and RBILD are different manifestations of the same disease caused by cigarette smoking.
Diagnosis
Chest x-ray abnormalities include bibasilar hazy opacities without honeycombing; findings may be normal in up to 20% of cases. HRCT shows multifocal or diffuse, basilar, subpleural ground-glass opacities. Irregular linear and reticular opacities are common but are not usually the dominant features. Honeycombing may be visible occur in the minority of patients and is usually limited.
Treatment
Smoking cessation results in clinical improvement in an estimated 75% of patients. Patients who do not improve may respond to corticosteroids or cytotoxic drugs. Prognosis is good, with about 70% survival at 10 yr.
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 that occurs 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 of the alveolar walls. Septa are lined with atypical, hyperplastic type II pneumocytes, and airspaces are collapsed. Thrombi develop in small arteries but are nonspecific.
Symptoms consist of the abrupt onset of fever, cough, and shortness of breath, which in most patients increase in severity over 7 to 14 days, progressing to respiratory failure.
Diagnosis is suspected in patients with symptoms, signs, and chest x-ray findings of ARDS (eg, diffuse bilateral airspace opacification). Diagnosis is supported by HRCT but usually requires biopsy. 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 present. Routine laboratory tests are nonspecific and generally not helpful.
Diagnosis is confirmed by surgical lung 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). Biopsy is often required to distinguish AIP from diffuse alveolar hemorrhage syndrome, acute eosinophilic pneumonia, and cryptogenic 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. Patients who survive the initial acute episode may recover complete pulmonary function, although the disease may recur.
Last full review/revision May 2008 by Talmadge E. King, Jr., MD
Content last modified May 2008
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