Pediatric Sarcoidosis Workup

No definitive laboratory test diagnostic of sarcoidosis has been identified. In the absence of a known etiologic agent, sarcoidosis often remains a diagnosis of exclusion, although a typical presentation may strongly suggest the diagnosis. The diagnosis of sarcoidosis is established when a compatible clinical and radiographic picture is supported by histologic evidence of noncaseating granulomas in affected tissues and exclusion of other granulomatous diseases capable of producing a similar histologic or clinical picture.

Other tests that may provide supportive evidence for sarcoidosis include measurement of serum ACE level, gallium-67 (⁶⁷ Ga) scan, ^[22] bronchoalveolar lavage (BAL) lymphocyte count, and CD4⁺/CD8⁺ T-lymphocyte ratio; however, tissue biopsy is required for a definitive diagnosis.

Laboratory evaluation may reveal an elevated erythrocyte sedimentation rate (ESR) or other acute-phase reactants. Anemia, leukopenia, and eosinophilia are commonly observed on blood cell counts. Hypergammaglobulinemia can occur in 75% of children with sarcoidosis. The presence of impaired delayed hypersensitivity on skin testing is typical, but not diagnostic, of sarcoidosis. Hypercalcemia and/or hypercalciuria may be found in as many as 30% of cases.

Renal and endocrine systems

In a review, decreased creatinine clearance was found in more than 60% of children with sarcoidosis, although other evidence of renal dysfunction, such as abnormal urinalysis results, elevated blood urea nitrogen (BUN) levels, and elevated serum creatinine values were found in less than 40% of children.

Histopathologic studies have revealed epithelioid granuloma formation, interstitial infiltration by mononuclear cells, interstitial fibrosis, tubulitis, tubular atrophy, mesangial hyperplasia, glomerular fibrosis, membranous nephropathy, and vascular involvement.

Granulomas have been found in the kidneys in 15-40% of adult patients with sarcoidosis. Incidence in children is unknown but is believed to be lower. Children who have a partial response to corticosteroid therapy and who develop arterial hypertension have a poor prognosis.

Derangement in calcium metabolism manifesting as hypercalcemia and/or hypercalciuria occurs in up to 30% of children. In vitro experiments of cultured alveolar macrophages from patients with sarcoidosis and of homogenized sarcoid lymph node tissue have demonstrated that the sarcoid macrophage is able to synthesize 1,25-dihydroxyvitamin D via 25-hydroxyvitamin D3-1-alpha hydroxylating activity. The excess circulating 1,25-dihydroxyvitamin D produced extrarenally causes increased intestinal absorption of calcium, enhanced bone resorption, and resultant hypercalciuria with or without hypercalcemia.

Additionally, granulomatous production of parathyroid hormone–related protein may also play a role. This process can ultimately result in nephrocalcinosis and renal failure. Nephrolithiasis and nephrocalcinosis have been reported in several cases of childhood sarcoidosis with hypercalcemia and hypercalciuria.

Hypercalcemia of sarcoidosis often becomes clinically manifest during the summer months, because the production of provitamin D in the skin is accelerated by exposure to sunlight. Intense sunlight exposure, as occurs during prolonged sunbathing in subtropical or tropical countries, may induce severe hypercalcemia in some patients with sarcoidosis. Hypercalcemic crisis has been reported as the presenting sign in childhood sarcoidosis.

Heart

Half of the patients with cardiac sarcoidosis have electrocardiographic abnormalities of rhythm, conduction, and repolarization, warranting 24-hour Holter monitoring. A high index of suspicion and early diagnosis is crucial, because aggressive treatment with prolonged steroids may result in decreased mortality rates.

Other manifestations of cardiac sarcoidosis include infiltrative cardiomyopathy with congestive heart failure, valvular disease, pericardial effusion, and papillary-muscle dysfunction. A combination of myocardial scintigraphy with thallium-201 (²⁰¹ Tl) and⁶⁷ Ga is recommended to evaluate disease status and predict possible response to corticosteroids.

Hematologic manifestations

Sarcoidosis can affect the bone marrow. The toxicity may result from mechanical disruption of the marrow by granulomas as well as from an indirect effect from the variety of cytokines released. Several studies of adult patients with sarcoidosis have shown 1 or more hematologic abnormalities in over half of the cases. Anemia occurs in 4-20% of patients with sarcoidosis. Leukopenia occurs in as many as 40% of patients but rarely is severe. In the absence of splenomegaly, leukopenia may reflect bone marrow involvement. Other hematologic abnormalities, such as leukemoid reaction, eosinophilia, autoimmune hemolytic anemia, and thrombocytopenia, are rare.

Bone marrow involvement in sarcoidosis often is asymptomatic. In severe cases, children may present with fever of unknown origin, localized bone pains, anemia, and leukopenia, mimicking a number of infectious, inflammatory, and neoplastic processes. In such cases, MRI may reveal multiple small, nodular lesions within the marrow, even in the presence of normal findings on plain radiographs and normal findings on bone scan. MRI can help to localize sarcoid lesions for diagnostic marrow biopsy.

ACE is produced by the epithelioid cells of granulomas and, thus, may be elevated in the serum of sarcoid patients. ACE serum level is typically elevated in as many as 80% of older children and in 60% of adults with sarcoidosis. Healthy children have higher ACE levels than adults, and, thus, results must be compared with age-matched controls.

ACE is found in many organs and body fluids, especially in the lungs, kidneys, and seminal fluid. At the cellular level, serum ACE is secreted by pulmonary capillary endothelial cells, alveolar macrophages, and epithelial cells of the renal proximal tubule. However, the test is not specific for sarcoidosis, and a wide variety of disorders, including tuberculosis, leprosy, primary biliary cirrhosis, diabetes mellitus, pulmonary neoplasm, lymphoma, Gaucher disease, and hyperthyroidism, may be associated with increased serum ACE activity, making it a supportive test rather than a diagnostic one.

ACE serum level is often associated with active disease and routinely decreases with corticosteroid therapy in pediatric and adult sarcoidosis patients. Although proven not to be very sensitive in early onset sarcoidosis, one report found serum ACE levels to correlate well with disease activity and effects of therapy in older children with sarcoidosis. However, in adult patients with sarcoidosis, serum ACE levels generally have not been a useful guide to predict the clinical course and the response to therapy, because ACE measurements do not necessarily correlate with symptoms, findings on pulmonary function testing, or findings on chest radiographs and they do not assist in determining prognosis.

The most helpful noninvasive test to support the diagnosis of sarcoidosis is chest radiography, which typically shows bilateral hilar lymph node enlargement, frequently with right paratracheal enlargement but normal lungs. (See the images below.)

Pulmonary disease and abnormal findings on chest radiography are more common in children with sarcoidosis who are aged 8-15 years, occurring in 94-100% of patients. In contrast, approximately 22% of children with sarcoidosis who are younger than age 4 years have pulmonary involvement.

Bilateral hilar adenopathy is the most common chest radiographic finding in children and occurs in almost all cases. Other radiographic findings include paratracheal adenopathy (75-88%) and subcarinal adenopathy (42%). The hilar lymphadenopathy is typically symmetrical, although it may appear unilateral in rare instances.

Pulmonary parenchymal involvement is common and predominantly appears radiographically as an interstitial pattern, although nodular, alveolar, and fibrotic patterns have also been described. Uncommon manifestations include pleural effusion, pneumothorax, pleural thickening, calcification, atelectasis, and cor pulmonale.

Exclude other diseases, including tuberculosis, histoplasmosis or other fungal infection, or lymphoma, that can also demonstrate hilar adenopathy similar to sarcoidosis. In one series of consecutive cases of bilateral hilar adenopathy, sarcoidosis accounted for 74% of cases and lymphoma accounted for 20% of cases.

Staging

Traditionally, pulmonary involvement in sarcoidosis has been classified into 5 stages based on chest radiography findings; however, the prognostic value of this classification in children is uncertain.

• Stage 0 - Normal findings on chest radiograph

• Stage I - Bilateral hilar lymphadenopathy, which may be accompanied by paratracheal adenopathy

• Stage II - Bilateral hilar adenopathy with pulmonary infiltrates

• Stage III - Parenchymal infiltrates without hilar adenopathy

• Stage IV - Advanced fibrosis with evidence of honey-combing, hilar retraction, bullae, cysts, and emphysema

High-resolution CT scanning

High-resolution computed tomography (HRCT) scanning of the chest may be helpful in delineating the distribution of the parenchymal lung lesions and of hilar adenopathy. Characteristic HRCT scan findings include smooth or nodular peribronchovascular interstitial thickening; small, well-defined nodules in relation to the pleural surfaces; interlobular septa or centrilobular structures; and peribronchovascular distribution of nodules in the central lung and upper lobes. ^[23] . A recent study found no correlation between HRCT and pulmonary function tests; forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV₁), forced expiratory flow during mid half of the FVC (FEF_25-75) and specific dynamic compliance (SpecC_Ldyn) at the time of diagnosis, however use of linear mixed models showed a significant association between HRCT and pulmonary function tests thus reducing the needs of HRCT during follow up. ^[24]

Gallium-67 scanning

⁶⁷ Ga scanning shows increased isotope uptake in the affected organ; however, increased uptake can occur with any inflammatory disease. These findings are present in a small number of cases. Furthermore, because of its expense, nonspecificity, and significant radiation exposure, gallium scanning is not recommended as a diagnostic tool. Several adult studies have shown a poor correlation between gallium scans and clinical course and other objective measures.

The historic Kveim-Siltzbach skin anergy test is performed by the intradermal injection of homogenized spleen or lymph node obtained from a patient with sarcoidosis. Biopsy of the skin site 4-6 weeks later shows typical sarcoid granulomas in a high percentage of affected patients, especially those with lymphadenopathy and skin lesions. The Kveim-Siltzbach test is not approved for general use by the US Food and Drug Administration (FDA) because of difficulty in obtaining standardized test material and reports of varying sensitivity and specificity of the test.

Tissue biopsy findings that confirm the diagnosis of childhood sarcoidosis have been documented in 90% of cases reported in the literature. Obtain biopsy specimens from the most readily accessible organ with the least invasive method. Preferred sites of biopsy in children include palpable peripheral lymph nodes, superficial skin lesions, and, occasionally, the conjunctiva, because performing biopsy on these tissue sites is easy and biopsies performed on these sites have a high sensitivity rate.

Other potential biopsy sites include enlarged lacrimal or parotid glands, lung tissue (by transbronchial biopsy), mediastinal lymph nodes (by mediastinoscopy), and lung tissue (by open or thoracoscopic lung biopsy). A diagnostic liver biopsy may be useful if no peripheral lymphadenopathy is present and hepatomegaly or abnormal liver function test findings occur. Bone marrow biopsy specimen may reveal sarcoid granulomas in some cases. Do not perform biopsy on erythema nodosum lesions, because they do not show granulomas.

In adult patients, transbronchial lung biopsy is the recommended procedure, yielding positive results in 40-90% of cases when 4-5 biopsy specimens are obtained from different sites. Transbronchial lung biopsy may be performed in adolescents, but it is technically difficult in younger children. If bronchoscopic findings are negative and mediastinal adenopathy is documented on the conventional CT scan, perform mediastinoscopy.

Data suggest that CT scan ̶ guided transthoracic biopsy can be helpful in the diagnostic evaluation of children who present with nonmalignant pulmonary disease. Some investigators have demonstrated that multidetector CT scan ̶ guided transthoracic lung biopsy may be helpful in evaluating pulmonary manifestations of childhood sarcoidosis, enabling accurate diagnosis and prompt initiation of appropriate therapy. ^[25]

Chiu et al report that the use of endoscopic bronchial ultrasound guided transbronchial sampling of intrathoracic lymph nodes, coupled with transbronchial needle aspiration lung biopsy and cytopathologic study, provides a fair diagnostic yield and has an excellent safety profile in children. ^[26]

Thoracoscopic lung biopsy or open lung biopsy is indicated in rare cases, that is, when bronchial or transbronchial biopsy results are nondiagnostic, no other accessible sites for biopsy are identified, and parenchymal involvement is observed on the chest radiograph or lung CT scan.

BAL performed through a flexible fiberoptic bronchoscope has proven to be a safe and well-tolerated procedure to assess the intensity of alveolitis in children, as measured by the BAL lymphocyte count and CD4⁺/CD8⁺ T cell ratio. However, defining the normal cellular and noncellular components of BAL fluid in children has been difficult.

Lymphocytic alveolitis precedes granuloma formation in the lungs and is the earliest sign of disease activity in pulmonary sarcoidosis in older children, as reported in adults. BAL fluid typically demonstrates an increased number of T lymphocytes (ranging from 20-70%), most of which are activated helper-inducer T lymphocytes that can cause the CD4⁺/CD8⁺ T lymphocyte ratio to be markedly increased (in the range of 2-13). The increased CD4⁺/CD8⁺ ratio may help in differentiating sarcoidosis from tuberculosis, as well as from Hodgkin lymphoma and non-Hodgkin lymphoma.

Other investigators have studied BAL fluid variables, such as yield, cell count, and proportions of cellular components, to differentiate sarcoidosis from other interstitial lung disorders. However, none of the BAL fluid findings are specific for sarcoidosis, including the CD4⁺/CD8⁺ cell ratio, and, although BAL is a useful research tool, its usefulness as a diagnostic test is limited, especially in children.

Histologic findings

The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. Very active disease may be accompanied by some fibrinoid necrosis. To further support the diagnosis of sarcoidosis, exclude infectious granulomatous conditions (eg, histoplasmosis, blastomycosis, tuberculosis) by special stains and cultures.

An experienced pathologist must review characteristic pathologic changes. Clinical history, system review, and detailed physical examination should guide the clinician to choose the biopsy site that can be reached in the least invasive fashion.