Sarcoidosis: Granulomatous Disease Overview PDF

## Granulomatous Diseases ### Sarcoidosis Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granulomatous inflammation in many tissues and organs. ### Sarcoidosis as a Restrictive Lung Disease - Sarcoidosis is discussed in this chapter because one presentation o...

## Granulomatous Diseases ### Sarcoidosis Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granulomatous inflammation in many tissues and organs. ### Sarcoidosis as a Restrictive Lung Disease - Sarcoidosis is discussed in this chapter because one presentation of the disease is as a restrictive lung disease. - Other diseases, such as mycobacterial and fungal infections and berylliosis, can produce noncaseating granulomas making the histologic diagnosis of sarcoidosis one of exclusion. - In most cases, the major finding at presentation is bilateral hilar lymphadenopathy or lung involvement (or both) visible on chest radiographs. - Eye and skin involvement also occur in about 25% of cases, and are occasionally the presenting feature of the disease. ### Epidemiology - Sarcoidosis occurs throughout the world, affecting both genders and all age groups. - Certain interesting epidemiologic trends are consistent, such as: - a predilection for adults younger than 40 years of age - a high incidence in Danish and Swedish populations and in the United States among people of African descent (frequency is 2 to 3 times higher than in those of European descent) - a higher prevalence among nonsmokers (virtually unique to sarcoidosis among pulmonary diseases) ### Pathogenesis - The etiology of sarcoidosis remains unknown. - Several lines of evidence suggest that it is a disease of disordered immune regulation in genetically predisposed individuals exposed to undefined environmental agents. - The role of each of these contributory influences is summarized below. #### Immunologic Abnormalities - Several immunologic abnormalities in sarcoidosis suggest the development of a cell-mediated response to an unidentified antigen. - This process is driven by CD4+ helper T cells. - Immunologic "clues" include: - Intraalveolar and interstitial accumulation of CD4+ Th1 cells. - Oligoclonal expansion of CD4+ Th1 T cells within the lung as determined by analysis of T-cell receptor rearrangements. - Increases in Th1 cytokines such as IL-2 and IFN-γ, resulting in T-cell proliferation and macrophage activation, respectively. - Increases in several cytokines in the local environment (IL-8, TNF, macrophage inflammatory protein-12) that favor recruitment of additional T cells and monocytes and contribute to the formation of granulomas. - Interestingly, levels of CD4+ helper T cells in the blood are often low, a finding associated with anergy to common skin test antigens such as Candida or purified protein derivative (PPD), an M. tuberculosis antigen. #### Lung Transplantation - After lung transplantation, sarcoidosis recurs in the new lungs in at least one-third of patients. - Several putative "antigens" have been proposed as the inciting agent for sarcoidosis, but there is no concrete evidence linking sarcoidosis to any specific antigen or infectious agent. - ## Morphology - The cardinal histopathologic feature of sarcoidosis is the nonnecrotizing epithelioid granuloma. - This is a discrete, compact collection of epithelioid macrophages rimmed by an outer zone rich in CD4+ T cells. - Intermixed multinucleate giant cells, formed by fusion of macrophages, are not uncommon. - Early on, a thin layer of laminated fibroblasts is found peripheral to the granuloma. - Over time, these proliferate and lay down collagen that replaces the entire granuloma with a hyalinized scar. - Two other microscopic features are sometimes seen in the granulomas: - Schaumann bodies: laminated concretions composed of calcium and proteins. - Asteroid bodies: stellate inclusions enclosed within giant cells. - The presence of these bodies is not required for diagnosis of sarcoidosis, and they may be found in granulomas seen in other disorders. - Rarely, foci of central necrosis may be present in sarcoid granulomas, especially in the nodular form. ### Lung Involvement - The lungs are involved at some stage of the disease in 90% of patients. - The granulomas predominantly involve the interstitium rather than air spaces and have a tendency to localize in the connective tissue around bronchioles and pulmonary venules and in the pleura ("lymphangitic" distribution). - Bronchoalveolar lavage fluid contains abundant CD4+ T cells. - In 5 to 15% of patients, the granulomas are eventually replaced by diffuse interstitial fibrosis, resulting in a so-called "honeycomb lung." ### Lymph Node Involvement - Intrathoracic hilar and paratracheal lymph nodes are enlarged in 75% to 90% of patients, while one-third present with peripheral lymphadenopathy. - The nodes are characteristically painless and have a firm, rubbery texture. - Unlike in tuberculosis, lymph nodes in sarcoidosis are "nonmatted" (nonadherent) and do not undergo necrosis. ### Skin Involvement - Skin lesions are encountered in approximately 25% of patients. - Erythema nodosum, a hallmark of acute sarcoidosis, presents as bilateral raised, red, tender nodules on the anterior aspects of the legs. - It is a form of panniculitis marked by infiltrates of chronic inflammatory cells and fibrosis; classic sarcoidal granulomas are uncommon in these lesions. - Alternatively, sarcoid may involve the skin as discrete painless subcutaneous nodules; these lesions usually contain typical noncaseating granulomas. ### Eye and Lacrimal Gland Involvement - Involvement of the eye and lacrimal glands occurs in about one-fifth to one-half of patients. - The ocular involvement takes the form of iritis or iridocyclitis and may be unilateral or bilateral.  - As a consequence, corneal opacities, glaucoma, and (less commonly) total loss of vision may develop. - The posterior uveal tract is also affected, with resultant choroiditis, retinitis, and optic nerve involvement. - These ocular lesions are frequently accompanied by inflammation in the lacrimal glands, with suppression of lacrimation (sicca syndrome). - Unilateral or bilateral parotitis with painful enlargement of the parotid glands occurs in fewer than 10% of patients with sarcoidosis; some develop xerostomia (dry mouth). - Combined uveoparotid involvement is designated Mikulicz syndrome. ### Spleen Involvement - The spleen may appear unaffected grossly, but in about three-fourths of cases, it contains granulomas. - In approximately 10%, it becomes clinically enlarged. ### Liver Involvement - The liver demonstrates microscopic granulomas, usually in the portal triads, about as often as the spleen, but only about one-third of patients demonstrate hepatomegaly or abnormal liver function. ### Bone Marrow Involvement - Involvement of bone marrow is reported in as many as 40% of patients, although it rarely causes severe manifestations. ## Clinical Features - In many affected individuals, the disease is entirely asymptomatic, discovered on routine chest films as bilateral hilar adenopathy or as an incidental finding at autopsy. - In others, peripheral lymphadenopathy, cutaneous lesions, eye involvement, splenomegaly, or hepatomegaly may be presenting manifestations. - In about two-thirds of symptomatic cases, there is gradual appearance of respiratory symptoms (e.g., shortness of breath, dry cough, or vague substernal discomfort) or constitutional signs and symptoms (e.g., fever, fatigue, weight loss, anorexia, night sweats). - Laboratory findings may include hypercalcemia and hypercalciuria, both related to production of biologically active vitamin D by the macrophages that form the granulomas. ### Diagnosis - A definitive test for sarcoidosis does not exist. - Establishing the diagnosis requires the presence of clinical and radiologic findings that are consistent with the disease, the exclusion of other disorders with similar presentations, and the identification of noncaseating granulomas in involved tissues. - In particular, tuberculosis must be excluded. ### Course - Sarcoidosis follows an unpredictable course characterized by either chronic progressive disease or periods of activity interspersed with remissions. - Remissions may be spontaneous or initiated by steroid therapy and are often permanent. - Overall, 65% to 70% of affected individuals recover with minimal or no residual manifestations. - Another 20% develop permanent lung dysfunction or visual impairment. - Of the remaining 10% to 15%, most succumb to progressive pulmonary fibrosis and cor pulmonale. ## Hypersensitivity Pneumonitis - Hypersensitivity pneumonitis is an immunologically mediated lung disease that primarily affects the alveoli and is therefore often called allergic alveolitis. - It is associated with diverse occupational and household exposures. - Most often it results from heightened sensitivity to inhaled antigens such as those found in moldy hay. - Because the damage occurs at the level of alveoli, it manifests predominantly as a restrictive lung disease associated with variable decreases in diffusion capacity, lung compliance, and total lung volume. ### Evidence for Hypersensitivity Pneumonitis as an Immunologically Mediated Disease - Bronchoalveolar lavage specimens show increased numbers of CD4+ and CD8+ T lymphocytes. - Most affected patients have specific antibodies against the offending antigen in their serum. - Deposits of complement and immunoglobulins have been demonstrated within pulmonary vessel walls. - Noncaseating granulomas are found in the lungs of two-thirds of affected patients. ## Table: Sources of Antigens Causing Hypersensitivity Pneumonitis | Source of Antigen | Types of Exposures | |:--:|:--:| | Mushrooms, fungi, yeasts | Contaminated wood, humidifiers, central hot air heating ducts, peat moss plants | | Bacteria (Thermophilic actinomycetes) | Dairy barns (farmer's lung) | | M. avium complex (MAC) | Metalworking fluids, sauna, hot tub | | Birds | Pigeons, dove feathers, ducks, parakeets  | | Chemicals | Isocyanates (auto painters), zinc, dyes | ## Morphology - The histopathologic picture in both acute and chronic forms of hypersensitivity pneumonitis includes patchy mononuclear cell infiltrates in the pulmonary interstitium, particularly around bronchioles. - Lymphocytes predominate, but plasma cells and epithelioid macrophages are also present. - In acute forms of the disease, variable numbers of neutrophils may also be seen. - Poorly formed (noncohesive) granulomas, without necrosis, are present in more than two-thirds of cases, usually in a peribronchiolar location. - In advanced chronic cases, bilateral, upper-lobe-dominant interstitial fibrosis (UIP pattern) occurs. ## Clinical Features - Hypersensitivity pneumonitis may manifest either as an acute reaction, with fever, cough, dyspnea, and constitutional signs and symptoms arising 4 to 8 hours after exposure, or as a chronic disease characterized by insidious onset of cough, dyspnea, malaise, and weight loss. - With the acute form, the diagnosis is usually obvious because of the temporal relationship of symptom onset and exposure to the inciting antigen. - When antigenic exposure is eliminated after acute attacks of the disease, complete resolution of pulmonary symptoms occurs within days. - Failure to remove the inciting agent from the environment eventually results in irreversible chronic interstitial pulmonary disease. ## Pulmonary Eosinophilia - A number of disorders are characterized by pulmonary infiltrates rich in eosinophils, which are recruited to the lung by local release of chemotactic factors. - These diverse diseases generally are of immunologic origin, but their etiology is not understood. - They sometimes have known associations such as with helminth infections, drugs such as Allopurinol, and vasculits, but most often are idiopathic. - Their clinical course is varied, but when chronic they may culminate in interstitial fibrosis. ## Smoking-Related Interstitial Diseases - In addition to obstructive lung disease (COPD), smoking is also associated with restrictive or interstitial lung diseases. - Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis are two related examples of smoking-associated interstitial lung disease. ### Desquamative Interstitial Pneumonia - The most striking histologic feature of DIP is the accumulation of large numbers of macrophages containing dusty-brown pigment (smokers' macrophages) in the air spaces. - The alveolar septa are thickened by a sparse inflammatory infiltrate (usually lymphocytes); interstitial fibrosis, when present, is mild. - Pulmonary function tests usually show a mild restrictive abnormality. - Overall, patients with DIP have a good prognosis and an excellent response to steroids and smoking cessation; however, some patients progress despite therapy. ### Respiratory Bronchiolitis - Respiratory bronchiolitis is a common disorder of people who smoke that is characterized by the presence of pigmented intraluminal macrophages similar to those in DIP, but in a "bronchiolocentric" distribution (first- and second-order respiratory bronchioles). - Mild peribronchiolar fibrosis is also seen. - As with DIP, affected patients present with gradual onset of dyspnea and dry cough, symptoms that recede with smoking cessation.