IDIOPATHIC INTERSTITIAL PNEUMONIAS
The idiopathic interstitial pneumonias (IIPs) are a subset of the acute and chronic lung disorders collectively referred to as interstitial lung diseases (ILDs) or diffuse parenchymal lung diseases. In 2002, the American Thoracic Society/European Respiratory Society consensus classiﬁcation separated the IIPs into seven clinical-radiologic-pathologic entities: idiopathic pulmonary ﬁbrosis (IPF), idiopathic nonspeciﬁc interstitial pneumonia (NSIP), respiratory bronchiolitis–associated ILD/desquamative interstitial pneumonia (RB-ILD/DIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), and lymphoid interstitial pneumonia (LIP). The various sub-groups of the IIPs are often clinically indistinguishable (with the exception of COP and AIP).
IDIOPATHIC PULMONARY FIBROSIS
IPF is a speciﬁc form of chronic ﬁbrosing interstitial pneumonia limited to the lung and associated with the histologic appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. IPF mainly affects people older than 50 years of age. The incidence of IPF is estimated at 6.8 cases per 100,000, and the prevalence is estimated to be 14.0 per 100,000. Cigarette smoking has been identiﬁed as a risk factor for developing IPF. The clinical manifestations of IPF include dyspnea on exertion, nonproductive cough, and inspiratory crackles on physical examination. Digital clubbing and signs of cor pulmonale may be present in advanced disease.
The chest radiographs typically reveal diffuse bibasilar reticular opacities. However, the chest radiograph lacks diagnostic speciﬁcity. High-resolution computed tomography (HRCT) scanning is more sensitive and speciﬁc for the diagnosis of IPF. The characteristic HRCT features of IPF include patchy, predominantly basilar, subpleural reticular opacities; traction bronchiectasis and bronchiolectasis; and subpleural honeycombing. The presence of extensive ground-glass opacities, nodules, upper lobe or mid-zone predominance of ﬁndings, and signiﬁcant hilar or mediastinal lymphadenopathy should question the radiographic diagnosis of IPF.
Pulmonary function tests often reveal restrictive impairment (decreased static lung volumes), reduced diffusing capacity for carbon monoxide (DLCO), and arterial hypoxemia exaggerated or elicited by exercise. The histologic appearance of the UIP pattern is essential to conﬁrm this diagnosis. UIP is characterized by a heterogeneous, predominantly subpleural distribution of involvement (often distinguishable even on low- power magniﬁcation). There is temporal heterogeneity, with areas of end-stage ﬁbrosis and “honeycombing” (thickened collagenous septa surrounding airspaces lined by bronchial epithelium) abutting areas of active proliferation of ﬁbroblasts and myoﬁbroblasts (termed ﬁbroblastic foci). There is generally minimal interstitial inﬂammation, and if this is present in signiﬁcant amounts, the histopathologic diagnosis should be reconsidered.
IPF patients have a distinctly poor prognosis with only a 20% to 30% survival at 5 years after the time of diagnosis. Acute deterioration in IPF—“acute exacerbations” with an abrupt and unexpected worsening of the underlying lung disease in the absence of any identiﬁable cause may occur and portends a poor prognosis (mortality rate, 20%-86%). Lung transplantation is the only measure shown to prolong survival.
No speciﬁc drug treatment recommendations can be made. Treatment of patients with IPF with corticosteroids alone or with cytotoxic agents is of unproven beneﬁt and causes substantial morbidity. N-acetyl-cysteine, pirfenidone, or bosentan show promise, but there is insufﬁcient evidence to recommend their general use. Improved management of acute exacerbations may improve survival in patients with IPF.
Pulmonary rehabilitation and oxygen therapy are useful adjuncts in treatment. In addition, where available, lung transplant should be recommended to qualiﬁed patients.
NONSPECIFIC INTERSTITIAL PNEUMONIA
NSIP is a histopathologic pattern commonly found in the context of another disorder, such as a connective tissue disease, chronic hypersensitivity pneumonitis, or drug-induced ILD. Idiopathic NSIP is a distinct clinical entity that occurs mostly in middle-aged women who have never smoked. It has been suggested that idiopathic NSIP may be the lung manifestation of “undifferentiated connective tissue disease.”
Dyspnea and cough are the most common symptoms. Serologic abnormalities (i.e., positive antinuclear anti-bodies or rheumatoid factor) are common. A restrictive pattern of pulmonary function abnormality is common. Chest radiographic ﬁndings show primarily lower-zone reticular or hazy opacities. HRCT shows bilateral symmetric ground-glass opacities or bilateral airspace consolidation. A reticular pattern with traction bronchiectasis and volume loss is also common. Honey-combing is uncommon and when present should suggest another diagnosis.
Surgical lung biopsy is required to conﬁrm the diagnosis of NSIP. The main histologic feature of NSIP is the homogeneous appearance of either inﬂammation or ﬁbrosis. The lung injury pattern is characterized by varying degrees of inﬂammation and ﬁbrosis (“ﬁbrotic NSIP”). There is less temporal and spatial heterogeneity than in UIP and little honeycombing.
Patients with NSIP have a good prognosis, with most showing improvement after treatment with corticosteroids (often with a cytotoxic agent such as azathioprine). The 5-year mortality rate is estimated at 10% to 20%.
RESPIRATORY BRONCHIOLITIS–ASSOCIATED INTERSTITIAL LUNG DISEASES
RB-ILD is a clinical syndrome found in young adults (30-40 years old). Most are current or former cigarette smokers with a history of more than 30 pack-years of smoking. The clinical presentation is with cough and breathlessness on exertion, and crackles are found on chest examination.
Routine laboratory studies are not helpful. A mixed obstructive-restrictive pattern is found on lung function testing, and arterial hypoxemia is common.
The chest radiograph shows diffuse, ﬁne reticular or nodular interstitial opacities, usually with normalappearing lung volumes. HRCT scanning often reveals centrilobular nodules, ground-glass opacity, thickening of central and peripheral airways with associated centrilobular emphysema, and air trapping.
Pathologic criteria for the diagnosis of RB-ILD include the accumulation of pigmented alveolar macrophages within the lumina of respiratory bronchioles and alveolar ducts accompanied by chronic inﬂammation of the respiratory bronchiolar walls and both bronchiolar and peribronchiolar alveolar ﬁbrosis causing architectural distortion. These features, at low magniﬁcation, are commonly patchy and conﬁned to the peribronchiolar region.
Prolonged survival is common in patients with RB-ILD. However, symptomatic and physiologic improvement occurs in only a minority of patients (28% and 11% of cases, respectively). Neither smoking cessation nor immunosuppressive therapy is regularly associated with clinically signiﬁcant beneﬁt.
LYMPHOID INTERSTITIAL PNEUMONITIS
LIP is common in children but uncommon in adults. LIP is frequently associated with infection (HIV, Epstein-Barr virus, and human T-cell leukemia virus type 1), a serum protein abnormality (variable immunodeﬁciency and dysproteinemia), or autoimmune disorders (Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus, polymyositis). LIP may occur before or after the diagnosis of the underlying process. LIP is part of a spectrum of pulmonary lymphoid proliferations that includes follicular bronchiolitis, nodular lymphoid hyperplasia, and low-grade malignant lymphoma. In fact, idiopathic LIP is rare, and many experts question if this entity should be a part of the IIPs.
The insidious onset of cough and dyspnea are the most common presenting symptoms of LIP. Weight loss, fevers, arthralgias, and pleuritic chest pain are other common ﬁndings. Physical examination may reveal crackles on chest examination.
Pulmonary function testing shows reduced lung volumes and diffusing capacity with preserved airﬂow. Marked hypoxemia may occur. Bronchoalveola lavage may reveal increased numbers of lymphocytes.
LIP has a varied and nonspeciﬁc radiographic appearance. HRCT scanning is characterized by the presence of ground-glass attenuation, poorly deﬁned centrilobular nodules, and thickening of the interstitium along the lymphatic vessels. Thin-walled cystic lesions have been described. Lymph node enlargement is more common.
The natural history and prognosis of LIP are poorly understood and highly variable. Corticosteroid therapy alone or in combination with other agents has been used to treat symptomatic patients with LIP, although its efﬁcacy has not been established in a controlled trial.
ACUTE INTERSTITIAL PNEUMONIA
AIP is an uncommon fulminant form of lung injury that presents acutely (days to weeks from onset of symptoms). The clinicopathologic term is synonymous with the histopathologic pattern of idiopathic diffuse alveolar damage (DAD). Most patients have been previously healthy before the onset of the illness. There is no gender predilection.
A high index of suspicion is required to make this diagnosis. The onset is usually abrupt, although a prodromal illness lasting usually 7 to 14 days before presentation is common. Fever, cough, and shortness of breath are common clinical signs and symptoms. Tachypnea is present, and chest examination reveals crackles on auscultation. Routine laboratory studies are nonspeciﬁc and generally not helpful. Most patients have moderate to severe hypoxemia and develop respiratory failure.
The chest radiograph shows diffuse, bilateral, airspace opacities. CT scans show bilateral, patchy, symmetric areas of ground-glass opacities or occasionally airspace consolidation. A predominantly subpleural distribution may be seen.
Surgical lung biopsy is required to conﬁrm the diagnosis, and the histologic presence of organizing DAD is usually present. The mortality rate is high, with the majority of patients dying within 6 months of presentation. If the patient recovers, substantial improvement in lung function and radiographic clearing may be seen. It is not clear whether corticosteroid therapy is effective in AIP. Mechanical ventilation is often required. The main treatment is supportive care.
DESQUAMATIVE INTERSTITIAL PNEUMONIA
DIP is a rare process that affects cigarette smokers in their fourth or ﬁfth decades of life. Many cases previously called DIP are actually cases of RB-ILD. Clear evidence of cigarette smoke exposure is not always present in patients with DIP.
Most patients present with dyspnea. Lung function testing shows a restrictive pattern with reduced DLCO and hypoxemia on arterial blood gas analysis.
The chest radiographs may be normal in up to 20% of cases. HRCT commonly shows bilateral symmetric areas of ground-glass opaciﬁcation involving mainly the lower lung zones. Reticular opacities can be seen on CT in approximately 50% of patients.
The dominant histologic feature is intraalveolar macrophage accumulation. At low magniﬁcation, the process typically seems to affect the lung diffusely and appears uniform from ﬁeld to ﬁeld. There is often interstitial ﬁbrosis present. Prussian blue staining for iron may reveal a ﬁnely granular hemosiderin pigment. Alveolar pneumocyte proliferation may be prominent along the thickened alveolar septa, but ﬁbroblastic foci do not occur. Several histopathologic ﬁndings appear more often in patients with
DIP compared with RB extent of interstitial ﬁbrosis, presence of lymphoid follicles, and eosinophilic inﬁltration.
Smoking cessation results in clinical improvement. The 5- and 10-year survival rates are 95% and 70%, respectively. Corticosteroid therapy appears to be associated with modest clinical beneﬁt but usually not with resolution of disease. Progressive disease with eventual death may occur in subjects with DIP, especially with continued cigarette smoking.