TOC | Pulm
Clinical Presentation and Diagnostic Evaluation
Karl W. Thomas; Gary W. Hunninghake
JAMA. June 25, 2003;289:3300-3303.
SARCOIDOSIS IS a systemic inflammatory disease that occurs throughout the world and affects people of all races and ages. Despite years of study and many recent advances in diagnostic strategies, the etiology of sarcoidosis remains unknown. The disease is characterized pathologically by the presence of noncaseating granulomas in affected organs. These granulomas can occur with varying rates in any organ system, but most commonly are found in the lung and lymph nodes. Patients with sarcoidosis may be entirely asymptomatic or can have a wide range of constitutional and other nonspecific symptoms. The wide spectrum of affected patients, variability in organ involvement, absence of specific symptoms, and unidentified etiology combine to make sarcoidosis both a diagnostic and a therapeutic challenge.
An expert panel recently proposed adoption of standard diagnostic criteria for sarcoidosis to guide clinical evaluation and to promote standardization of research. 1 These criteria include the presence of typical clinical and radiological findings, histological evidence of noncaseating epithelioid cell granulomas, and exclusion of other known causes of granulomatous disease. This review will discuss the clinical appearance and diagnosis of patients with sarcoidosis, recent advances in research on genetic and clinical testing for sarcoidosis, and a treatment strategy for patients with sarcoidosis.
Clinical Presentation and Diagnostic Evaluation
The reported prevalence and presenting symptoms of sarcoidosis vary significantly by sex, racial group, and country. 2,3 Within the United States, analysis of a racially diverse population demonstrated an age-adjusted annual incidence of 35.5 per 100 000 for blacks in comparison with 10.9 per 100 000 for whites. 4 In this same study, the highest incidence was observed in black females, followed sequentially by black males, white females, and white males. 4 While some cohorts of patients with sarcoidosis have included Hispanic Americans and South Americans, little comparative data are available regarding the specific incidence rates and clinical characteristics in these populations. 5
A range of 30% to 60% of reported cases of sarcoidosis are asymptomatic and have been discovered by the presence of characteristic findings on routine health screening chest radiographs. 2,5,6 However, the true incidence of asymptomatic disease has been difficult to establish and the reported rates depend on participation in organized screening programs for chest disease. For symptomatic patients, the most common presenting problems include respiratory symptoms (eg, dry cough, dyspnea, chest pain), skin rashes (eg, erythema nodosum, papules, nodules, plaques), systemic symptoms (eg, fever, night sweats, fatigue, malaise), ocular symptoms (eg, pain, visual change), and musculoskeletal symptoms (eg, joint pains, myalgias). Uncommon findings of neurologic or cardiac dysfunction may signify life-threatening disease. Encephalopathy, dementia, seizures, headache, or ataxia may be found in patients with central neurologic sarcoid. Syncope, arrhythmias, or congestive heart failure can occur in patients with significant cardiac sarcoid. The symptoms and findings of sarcoidosis may be restricted to a single organ system or can be the result of widespread inflammation with multiple concurrent manifestations. Establishment of the diagnosis of sarcoidosis depends on the clinical correlation of these nonspecific symptoms with supporting biochemical, radiological, and pathological information.
The characteristic granuloma found in sarcoidosis is discrete and compact. It is composed of multinucleated giant cells, mononuclear phagocytes, and lymphocytes surrounded by tightly organized fibroblasts, mast cells, and an extracellular matrix. 1 These granulomas typically do not contain focal areas of necrosis (caseation) and tend to occur in lymph nodes, perivascular sheaths, and connective tissue spaces. The location of the granulomas in the lung is directly related to the most common radiological features that include enlarged hilar and paratracheal lymph nodes, central bronchovascular and interlobular septal thickening, subpleural and bronchovascular nodular opacities, micronodules, and ground-glass attenuation. 7 Any of these abnormal characteristics may be found in asymptomatic individuals, but the typical abnormal radiographic feature in this group of patients is bilateral hilar lymphadenopathy. Symptomatic patients may also have hilar lymphadenopathy as the sole finding, but are more likely to also have parenchymal infiltrates and nodules.
The initial clinical evaluation of patients with sarcoidosis should focus on determining the extent and severity of individual organ system involvement (Box). 1,8,9 Since patients may not have symptoms referable to the presence of granulomas in any single organ, the evaluation should exclude critical organ involvement (ie, heart, eye, and brain) and other major organ involvement (ie, liver, bone marrow, kidney). Given the overlap of clinical findings in sarcoidosis with Wegener granulomatosis, lymphoma, carcinoma, fungal disease, and mycobacterial infections, patients may require additional testing to exclude these possibilities. A thorough ophthalmologic evaluation is recommended in most patients, including those without ocular symptoms. Finally, a complete history of occupational and environmental exposure should be obtained to exclude other known causes of granulomatous disease.
The most common difficulties encountered in the evaluation of patients with sarcoidosis arise from the nonspecific nature of its symptoms and the absence of a known etiologic agent. The finding of noncaseating granulomas in biopsy specimens requires the presence of a correlating clinical syndrome consistent with sarcoidosis and the exclusion of alternative diseases (eg, tuberculosis) to confidently establish the diagnosis. The sites that most frequently undergo biopsy include skin, lymph nodes, and lung. Both histological and cytologic specimens obtained through needle aspiration are clinically useful. 10
Factors that have been associated with a more rapid establishment of diagnosis have included findings of skin involvement that typically lead to early consultations and to performance of skin biopsies. In contrast, factors associated with delay of diagnosis include nonspecific pulmonary findings such as cough, dyspnea, or airflow obstruction, as patients with these findings may have been initially treated for more common pulmonary diseases, including bronchitis and asthma. 11 In most cases, biopsy specimens of lung, lymph nodes, or skin should be pursued to establish the presence of typical histological features. For the minority of patients, such as those with no symptoms, bilateral hilar lymphadenopathy, and no other worrisome findings, close clinical observation without biopsy may be sufficient.
Natural History and Prognosis
As the result of diverse patterns of organ involvement and the wide range of susceptible patients, individual reports and case series documenting the natural history of sarcoidosis have varied tremendously. However, several common and clinically useful findings about the disease have been recognized. 1 First, the symptoms and clinical findings of sarcoidosis tend to wax and wane spontaneously or in response to therapy. Second, spontaneous complete remissions and resolution of abnormal radiographic findings occur in a significant number of patients who do not receive treatment. Third, fatalities usually occur as the result of progressive respiratory, central nervous system, or cardiac involvement. Finally, unique clinical variables may serve as predictors of outcome. Some of these prognostic variables are age at onset, race, specific patterns of organ involvement, and chest radiograph findings.
While sarcoidosis can occur in a wide age range of patients, it most commonly affects individuals aged 20 years to 40 years. It is often associated with the development of chronic, progressive disease when it occurs in persons older than 40 years. 1 Other negative prognostic indicators include lupus pernio (a chronic rash consisting of papules and plaques usually found on the face), nasal mucosal involvement, chronic uveitis, hypercalcemia, nephrocalcinosis, progressive pulmonary function decline, cystic bone lesions, neurosarcoidosis, and cardiac involvement. 1,6,12 Chronic disease, defined as presence of symptoms or abnormal clinical findings for longer than 2 years, has also been associated with a poor prognosis and lower rates of remission. The appearance of posteroanterior chest radiographs may predict resolution of lung disease. Recent studies have confirmed that patients with a normal radiographic finding or hilar adenopathy alone have the most favorable prognosis and those with significant pulmonary parenchymal involvement or fibrosis have the least favorable prognosis. 13
Finally, Lofgren syndrome, the acute onset of erythema nodosum or periarticular ankle inflammation together with bilateral hilar or right paratracheal lymphadenopathy, is typically associated with a benign course. The disease remits in more than 90% of these cases. 14
Several different serum markers of disease activity and prognosis in sarcoidosis have been proposed. Foremost has been the serum angiotensin-converting enzyme level. Despite early reports of good correlation with disease activity, subsequent studies have not consistently demonstrated an association between serum angiotensin-converting enzyme levels and disease activity or response to treatment. 15 Recent promising studies of serum levels of IL-2, a cytokine, and bronchoalveolar lavage levels of macrophage inflammatory protein 1, a chemokine, demonstrate a correlation with disease stage and activity. 16,17 These results must be confirmed and evaluated in additional clinical investigations before routine clinical use is recommended.
Influence of Racial, Ethnic, and Genetic Factors on Disease Presentation and Prognosis
Comparative epidemiologic studies have demonstrated that geographic, ethnic, and genetic factors are linked to the specific clinical characteristics of patients with sarcoidosis. 5,18 The disease incidence is highest in US black and Scandinavian populations, while it appears to be less common in US white, Japanese, Indian, Spanish, or South American populations. 1,2,4 Within the US population, racial background contributes significantly to the variability in the spectrum of the initial presenting of findings and organ involvement.
Blacks are more likely to have severe musculoskeletal or constitutional symptoms on presentation and have been observed to have higher rates of liver, bone marrow, extrathoracic lymph node, and skin involvement (other than erythema nodosum). 1,3 In comparison, whites appear to have higher rates of asymptomatic disease, disease limited to the chest, and erythema nodosum. 1,3,19 Other important differences in rate of disease manifestations include a higher risk of chronic uveitis in US blacks, lupus pernio in Puerto Ricans, erythema nodosum in Europeans, and cardiac involvement in Japanese. 1,20 Although there appear to be links between specific manifestations of sarcoidosis and ethnicity or racial background, a recent meta-analysis did not demonstrate a specific association between mortality and ethnicity. 21
In addition to differences of disease rates and clinical findings in different ethnic groups, evidence for a genetic component of sarcoidosis comes from findings of familial sarcoidosis clustering and of disease correlation with specific gene polymorphisms. Recently, a large, multicenter, case-control study in the United States has demonstrated an almost 5-fold increased familial relative risk for sarcoidosis using a multivariate model. 22 Results from a linkage analysis study in families with a member affected by sarcoidosis strongly suggest that genes associated with sarcoidosis occur within the major histocompatability complex region of chromosome 6. 23 Analysis of HLA genes located within the major histocompatability complex also suggests that unique HLA genes can be linked to disease susceptibility and prognosis. 24,25
Etiology of Sarcoidosis
Despite advances, including the identification of sarcoidosis genetic factors, a specific etiologic agent has not yet been identified. Multiple lines of evidence suggest that sarcoidosis results from the complex interaction of multiple genes with environmental exposures or infection. The inciting antigen then triggers a type 1 T-lymphocyte response that is dependent on host susceptibility and characterized by chronic inflammation, monocyte recruitment, and granuloma formation. 26,27 Intriguing descriptions of space and time clustering and geographic variability of disease support the hypothesis of an external agent. In 1987, Parkes et al 28 reported a cluster of 96 patients on the Isle of Man in which approximately 40% of patients reported a history of close contact with another person who had the disease. Other investigations have demonstrated a higher incidence of disease in patients living or working within particular environments, including individuals living in rural locations, firefighters, and aircraft carrier personnel. 2931 Unfortunately, investigations to identify specific agents, including mycobacteria, viruses, and environmental organic and inorganic antigens, have not consistently demonstrated an association with sarcoidosis. Given this present level of evidence, sarcoidosis can be viewed as a disease in which both host and environmental factors contribute to the phenotype.
Approach to Treatment
A recent systematic review of the effects of corticosteroid treatment in patients with sarcoidosis provides evidence that these agents in oral or inhaled forms may lead to improvement in radiographic appearance and pulmonary function. 32 The same analysis, however, could not demonstrate a significant effect on long-term rates of disease progression. This review and ample evidence from prior studies provide the rationale for a treatment plan that should minimize the frequency, dose, and duration of corticosteroid use. Methotrexate, azothioprine, hydroxychloroquine, and infliximab have been successfully used in conjunction with corticosteroids. 33 However, since definitive evidence of the efficacy of these agents has not yet been established, their use should be restricted to patients requiring long-term treatment or those with central nervous system, cardiac, or other progressive disease refractory to use of systemic corticosteroids.
Treatment decision making for a patient with sarcoidosis should encompass an individual assessment of the extent and severity of organ involvement, presence of disease stability during observation, and the likelihood of therapeutic benefit. 1 Patients who are not symptomatic, have clinically mild disease, or are at low risk for disease progression (eg, those with Lofgren syndrome) generally can be observed or treated with topical corticosteroids or nonsteroidal anti-inflammatory drugs. Conversely, patients with severe symptoms, cardiac or central nervous system involvement, or progressive organ dysfunction require corticosteroid therapy. Once initiated, corticosteroids should be continued for the duration of time commensurate with vital organ involvement or the presence of continued clinical decline (Figure 1). Patients who do not experience clinical decline or disease progression in any organ system may not benefit from corticosteroid treatment. 34
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Figure. General Approach to Therapy of Sarcoidosis
This treatment approach relies on the ability of the treating clinician to both recognize critical organ involvement and provide consistent and regular follow-up to evaluate for disease progression. In many cases, this requires serial diagnostic tests, including radiographs, electrocardiograms, laboratory analysis, and pulmonary function studies. For patients with progressive decline, severe organ dysfunction, or significant ophthalmologic, neurologic, or cardiac involvement, close collaboration among the patient, the primary care physician, and subspecialists will be required.
Although there have been many recent advances in the understanding of clinical, genetic, and environmental factors in sarcoidosis, the underlying etiology and pathogenesis of the disease remain obscure. Research must continue to identify more accurate disease predictors, mechanisms of genetic susceptibility, and potential etiologic factors.
Initial Evaluation of Patients With Sarcoidosis 1,8,9
Exclude Critical Organ Involvement
Exclude Other Diseases
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