Pulmonary Sarcoidosis Sarcoidosis is a sometimes-lethal disease affecting primarily the lungs and thoracic lymphatic system, and its hallmark feature is noncaseating granulomas in multiple tissues and organs (Hoang and Nguyen, 2010, p. 36; American Thoracic Society, 1999, p. 736). Over 90% of all sufferers have pulmonary involvement, but granulomas are frequently found in other organs and tissues, including the skin, eyes, liver, spleen, parotid glands, central nervous system, muscles, bones, and genitourinary tract (Hoang and Nguyen, 2010, p. 36). When death does result, it is typically due to pulmonary fibrosis. What follows is a review of pulmonary sarcoidosis from a clinical perspective.

Causes and Risk Factors

The cause of sarcoidosis is unknown, but research into the nature of the resulting granulomas suggests immune dysregulation in genetically susceptible individuals is the primary causative factor (American Thoracic Society, 1999, p. 738-740). The genetic contribution appears to be significant, as evidenced by an ethnic, gender, and familial bias in the patient population. African-Americans, Caucasians of northern European descent, Asians, and Puerto Ricans have a higher risk for developing sarcoidosis than the general population (American Lung Association, 2010, p. 81, 83). There is a slightly higher prevalence in women, and although incidence peaks for most patients between 20 and 29 years of age, women over 50 experience a second peak (American Thoracic Society, 1999, p. 737). Patients were also five times more likely to report that the disease had been diagnosed in a parent or sibling (reviewed by Yeager, Gopalan, Matthew, Lawless, and Bellanti, 2012, p. 36). Genetics therefore plays a significant role in sarcoidosis risk.

Granuloma formation is the result of an unknown etiological agent or agents precipitating macrophages and T. helper cells to a localized area (Drent, Mansour, and Linssen, 2011, p. 487). This inflammatory response produces an epithelial cell core surrounded by phagocytic macrophages and type 1 T. helper cells. The presence of type 1 T. helper cells and the resultant cytokine profile in the affected tissues is consistent with an intracellular pathogen precipitating disease development, but the actual causative agent or agents remain controversial (Veltkamp, van Moorsel, Rijkers, Ruven, and Grutters, 2011, p. 25). However, most research efforts have focused on the causative role of mycobacteria, especially Mycobacterium tuberculosis, because the symptoms of tuberculosis and sarcoidosis are so similar. Consistent with this possibility, genetic mutations in genes involved in mediating an intracellular pathogen immune response are associated with increased susceptibility to sarcoidosis (Veltkamp, van Moorsel, Rijkers, Ruven, and Grutters, 2011; Yeager, Gopalan, Matthew, Lawless, and Bellanti, 2012).

Mycobacteria may not be the only causative agent. Sarcoidosis seasonal clusters have been reported in several different countries around the world, with most occurring during spring and early summer (reviewed by Baughman, Lower, and du Bois, 2003, p. 1111). Clustering has also been observed in such diverse occupations as health care workers, military personnel servicing Navy aircraft, and firefighters. This seasonal and occupational clustering suggests that in addition to mycobacteria, environmental allergens and pollutants may also be contributing to sarcoidosis prevalence in genetically susceptible individuals by eliciting a type 1 T. helper response.

Signs and Symptoms

Individuals with sarcoidosis who initially seek medical care can present with diverse symptoms, because the disease typically involves multiple organs and tissues (American Thoracic Society, 1999, p. 741-742). Patients may also find their way to different specialists, depending on the constellation of symptoms experienced, but about one third to one half of patients with pulmonary sarcoidosis will present with labored breathing (dyspnea), dry cough, and chest pain. Non-specific symptoms may also include fatigue, weight loss, fever, and night sweats. The chest pain generally consists of a vague tightness retrosternal in location, but in some patients, the pain may be severe and experienced as cardiac pain. Blood rarely appears in the sputum (hemoptysis) and only 20% of patients present with lung crackles. Fingertip swelling (clubbing) is also rare.

Diagnosis

Granuloma biopsy is the preferred method for diagnosing sarcoidosis and specimens are typically taken from accessible locations, such as the skin, lungs, or lymph nodes (Hoang and Nguyen, 2010; Drent,...

486-487). Bronchial biopsies are 70-85% reliable in this regard. Histological examination should reveal noncaseating granulomas with a core consisting of epithelioid and multinucleated giant cells. The utility of pulmonary radiological findings depend on disease stage and is highly predictive for stage I and II only. Laboratory tests may also show an increased CD4:CD8 ratio and hypercalcemia in blood samples. Other recommended tests include a complete physical examination, electrocardiography, and eye exam, since both cardiac and ocular tissue may be involved.
Lung function tests are also useful, but mainly for patients with more advanced disease. Decreased lung function is observed in about 20% of patients with stage I disease and 40-70% with stage II or higher (American Thoracic Society, 1999, p. 744). The common methods for testing lung function include spirometry, lung volume, bronchodilator response, and carbon monoxide diffusing capacity (DL, CO) (Pelligrino et al., 2005, p. 948, 962).

A direct comparison of high resolution computed tomography (HRCT) and lung function tests revealed good agreement in their ability to stage disease (Drent et al., 2003). Predictive radiological findings in terms of lung function were bronchovascular bundle thickening, intraparenchymal nodules, septal and nonseptal lines, and focal pleural thickening. The lung function tests with predictive power were forced expiratory volume (FEV), forced vital capacity (FCV), DL, CO, arterial oxygen tension at maximal exercise, and alveolar-arterial oxygen difference at maximal exercise. The arterial and alveolar oxygen tension readings at rest were not useful.

Treatment and Disease Course

The primary treatment for sarcoidosis is corticosteroids and most patients stabilize or improve as a result (American Thoracic Society, 1999, p. 745-748). Cytotoxic agents, mainly methotrexate and azathiprine, may also be used alone or in combination with corticosteroids to suppress the immune system. Birth control for both partners to avoid pregnancy and a 6-month waiting period following cessation of cytotoxic drug treatment is typically recommended to avoid serious birth defects.

Approximately two thirds of patients will experience a spontaneous remission, but the rest will develop chronic or progressive disease. Death results in less than 5% of patients due to lung fibrosis, or cardiac or central nervous system involvement. There are significant differences between different geographic locations or ethnicities in terms of prognosis, suggesting genetics and/or environment may be a modifier of disease severity and progression.

Case Studies

Rarely does sarcoidosis present as acute respiratory failure, yet a 40-year-old male presented with fever, elevated heart and respiratory rate, bluish skin (cyanosis), bilateral crackles, 80% peripheral oxygen saturation, arterial oxygen of 63 mm Hg, and sinus tachycardia (Gupta, Agarwal, Paul, and Joshi, 2011). A chest radiograph revealed bilateral peripheral reticulonodular shadows and a bronchial biopsy revealed noncaseating granulomas. Biopsy staining for bacilli or fungi were negative, as was skin testing for tuberculin reactivity. HRCT revealed bronchovascular thickening, septal nodules, and interlobular septal thickening. Glucocorticoid treatment was successful in resolving the patient's condition and within a week was discharged. It was uncertain whether a history of cigarette smoking contributed to his presenting symptoms.

One possible side effect of pulmonary sarcoidosis is cardiac arrhythmia. A 42-year-old woman with a history of pulmonary sarcoidosis presented with palpitations (Mohsen, 2011). Paroxysmal atrial fibrillation, without ventricular involvement, was confirmed by 24-hr Holter monitoring. CT scan of chest and an echocardiogram revealed no cardiac abnormalities. Over the next year and a half, several anti-arrhythmic agents and radio frequency ablation were tried, but they failed to bring the arrhythmia under control. However, when the patient was treated with glucocorticoid the arrhythmia resolved.

Cardiac arrhythmia was also one of the presenting symptoms for a 63-year-old man with labored breathing (Srichai, Addrizzo-Harris, and Friedman, 2011). Despite treatment bringing about a normal sinus rhythm, the patient remained symptomatic. Heart structure appeared normal by echocardiogram, but a chest radiograph revealed pulmonary nodules. These nodules displayed abnormal fluorodeoxyglucose uptake as revealed by positron emission tomography/CT imaging, as did several areas on the heart.…