Other Interstitial Lung Diseases

Clinical Features

Patients with HP can present with an acute, subacute, or chronic clinical picture. A patient with acute HP may report a history of abrupt onset (4–6 hours after exposure) of a flulike syndrome with fever, malaise, chills, diaphoresis, headache, nonproductive cough, and dyspnea. There is peripheral blood leukocytosis with neutrophilia, but eosinophilia is usually not seen. These symptoms resolve without specific treatment in 1 to 3 days, but can recur with repeated exposures to the triggering agent. The subacute form of the disease is more difficult to define: usually these patients have had a history consistent with HP for several months, with one or more previous acute exacerbations of the disease. Patients with chronic HP present with progressive dyspnea, cough, weight loss, and anorexia, developing over a period of months or years. Some patients will recognize acute symptoms after exposures to the antigen, whereas others may notice a more insidious onset of dyspnea.

Radiologic Features

Plain films of the chest may show parenchymal changes that become better defined on high-resolution computed tomography (HRCT) scan. HRCT during the acute and subacute phases shows bilateral ground-glass opacities and centriacinar nodules. The ground-glass infiltrates can be preferentially located in the centers of the secondary pulmonary lobules with relative sparing of the periphery. If small-airway obstruction is present, air trapping can be seen on expiratory HRCT as a mosaic pattern. Patients with chronic disease show a radiologic appearance that will depend on the degree of interstitial fibrosis, with a reticular pattern.

Pathologic Features

Gross Findings

Only a few cases of acute HP have been described because the disease is usually not fatal during early stages, and the appearance that has been described is that of acute diffuse alveolar damage (DAD). In the subacute stage, there may be irregular areas of consolidation that tend to be centriacinar in distribution. The chronic stage has been well described and consists of interstitial fibrosis with honeycomb change in areas.

Microscopic Findings

Lung biopsies are usually obtained from patients with subacute or chronic disease, whereas acute HP is less often seen in surgical pathology material because the diagnosis may be made clinically. The histopathology of acute farmer’s lung has been described as that of acute DAD. Cases of acute HP or acute exacerbation of HP have been described as having features of subacute HP and acute fibrinous and organizing pneumonia. The histopathology of the subacute and chronic manifestations of HP is well known: there is a typically bronchiolocentric interstitial pneumonitis ( Fig. 17.1 ), with interstitial lymphoplasmacytic infiltrates ( Fig. 17.2 ), cellular bronchiolitis, and poorly formed (loose), nonnecrotizing granulomas. Isolated giant cells ( Fig. 17.2 ) with occasional cholesterol clefts and Schaumann bodies may be found. As a rule, these granulomas are small and poorly defined. Stains for microorganisms (fungi, acid-fast organisms) will usually not reveal these agents. Obliterative bronchiolitis can also be seen in occasional examples.

Although the triad of interstitial pneumonitis, cellular bronchiolitis, and ill-defined granulomas is seen in 80% of the well-documented cases of HP, some cases will demonstrate only one or two of these features, and in these cases, it is particularly important to demonstrate a linkage between exacerbations and exposures to the triggering agent. Occasional areas of organizing pneumonia are commonly seen ( Fig. 17.3 ) in combination with the other findings. In some cases, there are collections of foamy macrophages ( Fig. 17.4 ), which may represent small foci of endogenous lipid pneumonia, although it has been suggested that some antigens (such as those seen in pigeon breeder’s disease) may exist in some of these foamy cells. If exposure to the inciting antigen is avoided, the granulomatous lesions resolve in 4 to 6 months, but persistent exposure results in progression of the disease to interstitial fibrosis that may resemble a nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) pattern.

Cytologic Findings

Bronchoalveolar lavage (BAL) characteristically shows increased CD8+ T-cells.

Prognosis and Therapy

The long-term prognosis of patients with HP depends on several factors, including the type and duration of antigen exposure and the response of the individual to immunologic injury. Acute and subacute cases, in which the offending antigen is identified and avoided and the patient receives adequate treatment, generally show a good prognosis. Corticosteroids are a mainstay of therapy and will produce improvement in most subacute and chronic cases. A subset of patients with chronic HP, however, will have developed significant interstitial fibrosis by the time the diagnosis is made, and these individuals may not respond to either corticosteroids or avoidance of the responsible agent.

Clinical Features

The lung and hilar lymph nodes represent the most common sites of involvement by sarcoidosis. Symptoms resulting from parenchymal lung involvement include dyspnea and cough. Pulmonary function abnormalities are found in nearly all symptomatic patients and in some patients who are asymptomatic. Physiologic abnormalities in patients with symptomatic sarcoidosis typically consist of a reduction in diffusing capacity of the lungs for carbon monoxide (DLCO) and vital capacity without airflow obstruction. The DLCO typically becomes abnormal before the vital capacity becomes abnormal, but both are usually affected in persons with moderate or severe symptoms. Airflow obstruction is relatively uncommon except in patients with advanced disease or with endobronchial involvement of larger airways. In rare instances, diffuse endobronchial granulomas in small airways lead to a predominantly obstructive pattern.

Intrathoracic sarcoidosis is diagnosed most easily by bronchoscopy with lung biopsy. The yield of bronchoscopic biopsy depends on the radiographic stage. In patients with pulmonary infiltrates, bronchoscopic lung biopsy demonstrates nonnecrotizing granulomas in approximately 90% of cases. In stage I disease, the yield is 60% to 70%. If a diagnosis is not established by bronchoscopy and lung biopsy, mediastinoscopy is indicated and will provide a diagnosis in over 95% of cases in which mediastinal adenopathy is present. Fine-needle aspiration procedures can also be useful for retrieving granulomas and when used with either endobronchial or transbronchial biopsies can improve the yield to over 90%. Biopsy of extrapulmonary tissues can be performed for diagnosis when clinically indicated (eg, in patients with peripheral lymph node enlargement or skin lesions).

Radiologic Features

Sarcoidosis is characterized by bilateral hilar lymphadenopathy and diffuse infiltrative lung disease. The changes have been classified according to a five-stage system as follows: stage 0, normal chest radiograph (8% of cases at presentation); stage I, bilateral hilar lymphadenopathy alone (40% of cases); stage II, bilateral hilar lymphadenopathy and diffuse infiltrative lung disease (37% of cases); stage III, diffuse infiltrative lung disease alone (10% of cases); and stage IV, lung fibrosis, often with upper lobe cystic disease (5% of cases).

Pathologic Features

Gross Findings

The gross findings depend on the stage of the disease. Yellowish nodules corresponding to granulomas can be seen along the interlobular septa and bronchovascular areas of the lung, as well as on a cut section of involved lymph nodes. In advanced stages, interstitial fibrosis and honeycomb changes can develop. When the granulomas cluster and form clinical masses in the lung, the term nodular sarcoidosis is often used. These masses, which may be as large as 5 to 7 cm, can be multiple and bilateral and mimic neoplasms on imaging studies. This entity is considered a type of sarcoidosis and has no prognostic or therapeutic significance.

Microscopic Findings

The classical histopathologic lesion in sarcoidosis is the nonnecrotizing granuloma. Granulomas are usually small, compact, well circumscribed ( Fig. 17.5 ), generally unassociated with diffuse interstitial pneumonitis (unlike HP), and often follow lymphatic and bronchovascular routes ( Figs. 17.6 and 17.7 ). Granulomas can often be found in the bronchial mucosa, accounting for the high percentage of cases that can be diagnosed by bronchoscopic lung biopsy ( Fig. 17.8 ). Granulomatous angiitis is another occasional manifestation of sarcoidosis ( Fig. 17.9 ). When granulomatous angiitis and ischemic-type necrosis are present in a nodular sarcoidosis, a diagnosis of necrotizing sarcoid granulomatosis should be considered (see Chapter 8 ).

Although the granulomas in sarcoidosis are usually described as nonnecrotizing, small foci of necrosis have been reported in 6% to 39% of cases. Schaumann bodies, also known as conchoidal bodies, are lamellated calcifications that are often seen in giant cells in the sarcoidal granulomas, as well as other types of granulomatous lesions. Asteroid bodies are seen in 2% to 9% of granulomas from patients with sarcoidosis; these structures are seen within giant cells and consist of 5- to 30-μm stellate inclusions with numerous rays radiating from a central core. Oxalate crystals, which are birefringent under polarized light, may also be found. Over time, the granulomas become hyalinized ( Fig. 17.10 ), and dense interstitial fibrosis can develop. Stains for acid-fast organisms and fungi should be performed, and the lack of organisms visible on these stains forms a key component of the diagnosis.

Cytologic Findings

Cytology samples, especially needle aspirates, may yield nonnecrotizing granulomas ( Fig. 17.11 ).

Prognosis and Therapy

The natural history of sarcoidosis is highly variable. In 60% to 70% of all cases, spontaneous remission will occur, and in 10% to 30%, the disease will follow a progressive course. The mortality rate is up to 10%, and death usually results from progressive lung disease, neurosarcoidosis, or cardiac disease. Other adverse prognostic features include chronic uveitis, onset after 40 years of age, hypercalcemia or nephrocalcinosis, nasal mucosal involvement, and cystic bone disease.

The treatment of patients with sarcoidosis has been a controversial issue. Many patients have mild disease that does not require systemic treatment. Clinical trials have clearly shown some differences in steroid treated versus untreated groups, but overall, corticosteroids do not seem to induce significant long-term durable benefits when used as routine therapy. Methotrexate, leflunomide, azathioprine, mycophenolate, infliximab, adalimumab, and hydroxychloroquine, among others, are used as second-line agents for symptomatic sarcoidosis.