Sarcoidosis is a multisystem systemic granulomatous disease of unknown etiology that most commonly affects young adults, who frequently present with hilar lymphadenopathy, pulmonary infiltration, and ocular and cutaneous lesions 1. Although the lung is most frequently involved, the disease can affect any organ system of the body 2. The disease is relatively rare in the pediatric population 34. Infants and children younger than 5 years usually present with the triad of skin, joint, and eye involvement, without typical lung disease. However, older children have involvement of the lungs, lymph nodes, and eyes more frequently, as seen in adult 56.

Despite a variety of hypotheses regarding causative agents, the cause of sarcoidosis is unknown 7. The definitive diagnosis of sarcoidosis is made when compatible clinical findings are associated with histopathological evidence of noncaseating granulomata in affected organs and other granulomatous disorders are excluded 8. The illness can be self-limited or chronic, and the disease characteristics vary among various populations 1. The course and prognosis of sarcoidosis in children is different compared to adults, and may correlate with the mode of onset and the extent of the disease 1910.

In this review, we discuss the epidemiology, pathogenesis, etiology, and clinical features of sarcoidosis in children, and examine the current approaches to diagnosis and treatment of this enigmatic disease.

The prevalence of sarcoidosis in the adult population ranges from 10 to 40 per 100,000 in the United States and Europe 1. The true incidence and prevalence of childhood sarcoidosis is unknown because of the rarity of the disease and the small number of reported cases in childhood. A recent review reported that the approximate incidence of clinically recognized sarcoidosis in Danish children younger than 15 years was 0.22–0.27 per 100,000 children per year, corresponding to approximately 3 new cases in Denmark each year 4. As in adults, many children with sarcoidosis may be asymptomatic and the disease may remain undiagnosed.

Most reported childhood cases have occurred in patients aged 13–15 years 1112. In a recent international registry study of childhood sarcoidosis associated with joint involvement, the mean age at onset was 10.6 years (range, 0.1–16 years) 13. Early-onset childhood sarcoidosis (ie, with onset in the first 4 y of life) is rare but well described 56.

Adult studies have reported a slightly higher disease rate for women. A population-based study of incidence and survival in adults with sarcoidosis reported incidence rates of 5.9 per 100,000 person-years for men and 6.3 per 100,000 person-years for women. No clear sex predominance exists in childhood sarcoidosis. In a recent study from Denmark, the male/female gender ratio was close to one 4.

The racial distribution of sarcoidosis varies with geographic location. In the US adult population, sarcoidosis occurs in about 35.5 per 100,000 blacks and 11 per 100,000 whites. Studies in military and veteran populations showed that blacks are 10–17 times more commonly affected with sarcoidosis than are whites 1. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among African Americans 1114. In children aged 4 years and younger with sarcoidosis, 7–28% are African Americans, whereas in children aged 8–15 years, the percentage of African Americans increases to 72–81% 51114. Outside the United States, sarcoidosis most frequently occurs in the predominant race of the country. Thus, in Scandinavian countries where sarcoidosis is common, almost all cases occur in white people, while in Japan, most patients are Asian 115.

Within the US, approximately 80% of childhood cases have been reported primarily in Virginia, North Carolina, South Carolina, and Arkansas, and Louisiana, suggesting that the southeastern and south central states are an endemic area for childhood sarcoidosis 11141617.

Familial aggregation and the striking racial variation in sarcoidosis incidence suggest a genetic predisposition to develop sarcoidosis 18. The strongest support for a genetic susceptibility to sarcoidosis comes from numerous reports of familial clustering of cases 1920. In the United States, familial clusters more frequently are observed in African Americans, with a rate of at least 19% in affected African American families as compared to 5% in white families. When sarcoidosis has been observed in twins, monozygotic twins are 2–4 times more concordant for disease than dizygotic twins 19. The most common familial relationship is sibling pairs, followed by parent-offspring 19. The hereditary differences in candidate genes that promote susceptibility may reside in loci that influence regulation of antigen presentation or recognition, T cell function, or the regulation of matrix deposition that favors granuloma formation and progressive fibrosis.

Genetic factors may also be important in defining the pattern of disease presentation, its severity, and prognosis. Several investigators have searched for associations with human leukocyte antigen (HLA)-related genes that may confer susceptibility to sarcoidosis 21. A genome-wide linkage analysis performed in German families with follow-up fine mapping studies has revealed a unique candidate gene, BTNL2 in the MHC II region on chromosome 6 22. A follow-up study found that sarcoidosis is associated with a truncating splice site mutation in BTNL2 23. The BTNL2-conferred sarcoidosis risk has been noted in both Caucasians and African-Americans 24. A genome-wide scan performed in African-American families with follow-up fine mapping studies has indicated chromosome 5 as potentially harboring candidate genes 25.

Despite the global occurrence of sarcoidosis, the etiology of sarcoidosis is unknown. Most experts think that sarcoidosis results from exposure of genetically susceptible hosts to specific environmental, occupational or infectious agents that trigger an exaggerated cellular immune response, leading to granuloma formation 2026. Despite extensive research, no defined cause has been demonstrated to account for the granulomata that characterize the disease 262728.

Case clustering, and immunologic and clinical similarities of sarcoidosis to infectious granulomatous diseases suggests that an infectious agent may be responsible. Mycobacteria, including Mycobacterium tuberculosis and other atypical species have received the greatest amount of attention 29303132. The detection of mycobacterial DNA in sarcoid lesions by polymerase chain reaction (PCR) lends support to that association 32. A recent molecular study identified a novel candidate tissue antigen of mycobacterial origin, the Mycobacterium tuberculosis catalase-peroxidase protein (mKatG) in sarcoid granulomas as a potential target of the adaptive immune response in sarcoidosis 31.

Besides Mycobacteria, many different antigens are under suspicion, including other bacteria such as Proprionibacterium acnes 32. However, results from different studies have varied considerably and have failed in their attempts to fulfill the Koch postulates. Therefore the role of mycobacteria and proprionibacteria in the pathogenesis of sarcoidosis remains a controversial issue 33. Recent report by Izbicki and colleagues revealed increase incidence of sarcoidosis among fire fighters in NY City that were involved in the 2001 disaster. This suggests that exposure to world trade center "dust" may play a role in sarcoidosis etiology 34.

Sarcoidosis is a chronic inflammatory disease characterized by a highly focused exaggerated immune response to an unknown antigen(s) at the target organs. The hallmarks of the disease, sarcoid granulomas, most likely are formed in response to a persistent, poorly degradable, antigenic stimulus 1. Macrophages, bearing increased expression of major histocompatibility class (MHC) II molecules, most likely initiate the inflammatory response of sarcoidosis by presenting an unidentified antigen to CD4⁺ Th (helper-inducer) lymphocytes. This results in proliferation and activation of the T cell 35.

The immunopathology has been best studied in bronchoalveolar lavage fluid and lung disease in which early lesions consist of an alveolitis with a high proportion of activated CD4+ Th1 cells, which may precede granuloma formation 136. CD4⁺ and CD8⁺ T-lymphocytes, as well as a few B-lymphocytes, form a characteristic ring at granuloma periphery 37. Most granuloma-associated lymphocytes have a Th1 phenotype, secreting cytokines, including interferon gamma, interleukin (IL) -2, IL-12, and tumor necrosis factor-alpha (TNF-α), which is likely to favor the granulomatous response at sites of disease activity 38. Additionally, alveolar macrophages release a variety of cytokines, including TNF-alpha, IL-1, IL-6, IL-12, IL-15, and growth factors in patients with sarcoidosis and pulmonary disease 3537. IL-18, a monocyte/macrophage-derived cytokine has been recently identified as an IFN-gamma-inducing factor and plays an important role in the induction of Th1 response and sarcoid granuloma formation 39.

Chemokines may play an important role in the pathogenesis of sarcoidosis 35. Chemokine receptors, CXCR3 and CXCR6 are co-expressed by Th1 cells infiltrating the lung and the granuloma of patients with sarcoidosis 40. Recent data show that T cells expressing CCR6, CXCR3, and CXCR6 act coordinately with respective ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease 41.

The CD4+ lymphocytes, in association with other immune effector cells, such as macrophages, mast cells, and natural killer cells, perpetuate the inflammatory response by release of cytokines, monocyte chemotactic factors, macrophage migration inhibitory factor, leukocyte inhibitory factor, adhesion molecules (CD49a, CD54, CD102), and growth factors 3536.

As a result of these various immunologic interactions, an acute and often a chronic cascade of inflammation occur. This is characterized by changes in tissue permeability, cellular influx, and local cell proliferation, resulting in a granuloma. Persistent antigenic stimulation is believed to maintain the pathogenic processes. Sarcoid granulomas either resolve or heal by fibrosis. Genetic polymorphisms may influence the clinical expression of sarcoid granuloma and disease outcome 35.

Other immunologic abnormalities observed in patients with sarcoidosis include circulating immune complexes, B-cell hyperactivity, spontaneous in situ production of immunoglobulins, and depression of cutaneous delayed-type hypersensitivity reactions 1.

Because sarcoidosis is a multisystem disease and affects most organs, the clinical presentation can vary greatly. In most children, the disease frequently involves the lungs, lymph nodes, eyes, skin, liver, and spleen 479. Most of the reported cases of childhood sarcoidosis are accompanied by nonspecific constitutional symptoms, such as fever, fatigue, malaise, and weight loss, as well as symptoms from particular organs such as lungs, eyes, skin, and lymph nodes. 491415. The disease can be asymptomatic in children and remain undiagnosed 4.

Two distinct forms of childhood sarcoidosis appear to exist. Older children usually present with a multisystem disease similar to the adult manifestation with frequent lymphadenopathy and pulmonary involvement, as well as generalized signs and symptoms, such as fever, malaise, and weight loss 4131415. In contrast, early-onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in children who are younger than 5 years 5610.

Early-onset childhood sarcoidosis, i.e., with onset in the first 5 years of life differs from sarcoidosis in older children and adults and often poses a diagnostic challenge to the clinician 561015. Typically presenting in the first year of life 10, patients with early-onset disease exhibit unique clinical features characterized by the triad of arthritis, rash, and uveitis. 56 Hilar lymphadenopathy, the leading feature of late-onset forms 15, is rare in early-onset sarcoidosis 5. Uveitis, which occurs in about in more than half the children with early-onset sarcodiosis, is relatively less common in patients with later onset 6.

In 1985, Edward Blau described families with autosomal dominant granulomatous disease demonstrating the classic triad of arthritis, dermatitis, and uveitis, an identical phenotype to early-onset sarcoidosis 53. Recent data suggests that early-onset sarcoidosis and Blau syndrome likely represent the same disease since both entities share genetic mutations in the NOD2 (nucleotide binding oligomerization domain 2), also referred to as capsule recruitment domain family member 15 (CARD15) in 50–90% of cases 54. This finding has led some experts to propose the term "pediatric granulomatous arthritis" to describe both disorders 55. Although clinical similarities between Blau syndrome and sarcoidosis suggest genetic homogeneity between them, a study by Rybicki and colleagues 56 found no linkage of sarcoidosis to the Blau syndrome locus. Therefore, Blau gene has no major effect on sarcoidosis susceptibility.

Early-onset sarcoidosis may be overlooked due to its similarity to systemic-onset JRA 45. Both entities may be associated with systemic manifestations such as fever, weight loss, and fatigue. Skin changes, however, may help to distinguish between the two diseases at the onset. The rash of JRA is pink, evanescent, and macular, whereas the rash of sarcoidosis is classically a papule or a plaque with scaling 5. Arthritis of sarcoidosis is characterized by painless boggy effusions of the synovium without limitation of range of movement 546. However, painful, destructive polyarthritis with functional impairment indistinguishable from that associated with JRA has been described in early-onset sarcoidosis 6.

There is no laboratory test diagnostic of sarcoidosis. Laboratory evaluation may reveal elevated erythrocyte sedimentation rate (ESR) or other acute phase reactants. Anemia, leukopenia, and eosinophilia are commonly seen on blood counts 4. Immunological abnormalities include hypergammaglobulinemia and impaired delayed hypersensitivity on skin testing 1. Hypercalcemia and/or hypercalciuria may be found 9111547. The serum level of angiotensin-converting enzyme (ACE) is elevated in over 50% of children with late-onset sarcoidosis 45758, but the test is not specific for sarcoidosis, and many other disorders may be similarly associated with increased serum ACE activity 3.

The source of serum ACE in sarcoidosis is believed to be epitheloid cells in granulomata. ACE serum levels have been shown to be useful in diagnosing sarcoidosis and following disease activity and the effect of therapy in older children with sarcoidosis 5758. Reference values for serum ACE is age-dependent and healthy children have ACE levels that are 40–50% higher than in adults 58.

Chest radiograph is very useful and may reveal bilateral hilar adenopathy 442. Because alveolitis precedes granuloma formation in the lungs and is the earliest sign of activity in pulmonary sarcoidosis, bronchoalveolar lavage (BAL) performed through a flexible fiberoptic bronchoscope has been used to assess that activity. 12 BAL typically demonstrates an increased number of lymphocytes, most of which are activated helper-inducer T lymphocytes, which can cause the CD4/CD8 ratio to be high 12. However, in children BAL lymphocytosis does not correlate with disease activity, treatment response or prognosis 59. Therefore, serial BAL is not routinely recommended in pulmonary sarcoidosis in children 9. High-resolution chest computed tomography (CT) can be helpful in delineating the extent of parenchymal disease and hilar adenopathy. Although fibrotic lung disease is a rare consequence of childhood sarcoidosis, follow-up with pulmonary function tests (PFTs) is useful in detecting it. Other studies such as gallium-scan, have not proven to have clear prognostic benefits 3. Another emerging tool that is been used mainly in detecting metastatic cancer is positron emession tomography (PET scan). A recent study determined that PET scan does not allow differentiation of interstitial pulmonary fibrosis (IPF) from a non-IPF pulmonary diseases including sarcoidosis 60.

The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating epithelioid cell granuloma on a biopsy specimen 61 (Figure 4). To further support the diagnosis of sarcoidosis, infectious granulomatous conditions (such as histoplasmosis, blastomycosis, and tuberculosis) must be excluded by special stains and cultures 13. The preferred non-invasive sites of biopsy in children include peripheral lymph node, skin lesion, enlarged salivary glands or lacrimal gland and conjunctival nodule. Other potential sites for tissue biopsy include the bone, bone marrow, liver, and lungs. The histopathological findings noted in sarcoidosis have been observed in a number of other disorders, such as tuberculosis, leprosy, Sjogren syndrome, Behcet disease and berylliosis 1961.

Occasionally, sarcoidosis may present initially as fever of unknown origin (FUO) and localized bone pains, mimicking a number of infectious, inflammatory, and neoplastic processes. In such cases, magnetic resonance imaging (MRI) may reveal multifocal small nodular lesions within the marrow and help localize lesions for diagnostic exploration 62.

The differential diagnosis depends largely on the clinical presentation of sarcoidosis 15. It is critical to exclude granulomatous pulmonary infections, especially those caused by mycobacteria and fungi 3. Exclude neoplastic diseases, such as lymphoma, in cases with hilar adenopathy. Hypercalcemia in sarcoidosis may mimic metabolic disorders, such as primary hyperparathyroidism 315. Early-onset sarcoidosis is often misdiagnosed as systemic-onset JRA 45. Rarely, severe symptomatic bone marrow involvement may mimic a number of infectious and neoplastic disorders 62.

The current therapy of choice for childhood sarcoidosis with multisystem involvement is corticosteroids 4791563. Dose and duration of therapy must often be individualized. Oral prednisone or prednisolone is usually initiated at 1–2 mg/kg/d for 4–8 weeks as induction treatment 1563. This treatment is continued until the clinical manifestations of the disease resolve or show significant improvement. The steroid dosage is slowly tapered in treatment responders over a period of 2–3 months to an appropriate maintenance dose (i.e., the lowest dose that controls activity of the disease, typically 10–15 mg per day as a once daily regimen) 63. Depending on which organs are involved and on the activity of the disease, maintenance treatment is usually required for at least 6 months for most age groups and then tapered if possible 64. Asymptomatic patients with isolated bilateral hilar adenopathy may not need systemic steroid therapy 64.

Some patients may relapse, either during steroid taper or after discontinuation of the drug. In such cases, steroid treatment should be restarted with a dosage similar to that used in the induction treatment 65. Few patients are steroid-dependent and need long-term treatment with relatively high doses to achieve satisfactory responses. In such cases, serious complications due to chronic corticosteroid therapy, such as growth failure and bone disease, may occur 3. Moreover, a subset of patients with persistent active or progressive sarcoidosis may be unresponsive to corticosteroids; therefore, alternative agents are needed 3566061.

Other immunosuppressive agents, especially low-dose methotrexate (MTX) have been used to treat adult patients with sarcoidosis who have steroid-resistant disease or in those with unacceptable adverse effects from glucocorticoids with good success 64. In 1997, Gedalia and colleagues 65 described their experience with 6 months of low-dose oral MTX following a strict protocol in 7 children with biopsy-proven sarcoidosis. Corticosteroids were used for the first 6 weeks only in 6 of 7 cases. They were treated with low-dose MTX for 1 year, and the clinical response was scored using a composite of the various symptoms encountered. MTX therapy resulted in improvement in clinical symptom score and decreased mean daily steroid dosage. Additionally, parallel decreases in the ESR and the mean serum ACE concentrations were observed. No adverse effects occurred in these patients, all of whom received folate supplementation. In this study, MTX administered orally in low doses in childhood sarcoidosis was effective, safe, and had steroid-sparing properties 65. However, because of significant concerns regarding the risk of long-term adverse effects of MTX therapy and lack of a randomized controlled trial, some experts have questioned the therapeutic index of MTX for corticosteroid-resistant sarcoidosis in children. Liver biopsy performed after a cumulative MTX dose of 1–1.5 g has been proposed to monitor liver toxicity. 3 MTX toxicity can be minimized by the use of folic or folinic acid. More recently a randomized trial of MTX in 24 adult patients with sarcoidosis by Baughman and colleagues had shown that MTX has steroid sparing property 66.

Alternative immunosuppressive agents, such as azathioprine, cyclophosphamide, chlorambucil, and cyclosporine, have been tried in adult cases of sarcoidosis with questionable efficacy 67. The high toxicity profile of these agents, including an increased risk of lymphoproliferative disorders and carcinomas, has limited their use to patients with severe disease refractory to other agents. Successful steroid-sparing treatment with mycophenolate mofetil was described in an adolescent with renal-limited sarcoidosis complicated by renal failure 67. Novel treatment strategies for sarcoidosis have been developed including the use of TNF-alpha inhibitors, such as infliximab 67. Anecdotal case reports about the use of infliximab in renal sarcoidosis exist in the pediatric literature 68.

The prognosis and natural history of sarcoidosis in children is unclear because of the rarity of the disease and the small number of reported series. 4116970 However, the overall prognosis of childhood sarcoidosis is reported as good compared with the prognosis for adults, with most children experiencing considerable improvement in clinical manifestations, chest radiograph findings, and pulmonary function test results 11.

In one series, Marcille et al 70 performed a follow-up study on 19 patients in whom sarcoidosis had been diagnosed in childhood. The mean follow-up period was 21 years (range 8–35 y). Seven patients (37%) had persistent abnormalities on chest radiograph, 68% had impaired lung function, and 63% had abnormal findings on echocardiography 70. In another series from the University of North Carolina, most patients improved; however, 40% still were symptomatic and 35% had physical abnormalities after an average follow-up of 5 years 11.

Sarcoidosis in very young children with involvement of the eyes, joints and skin have a guarded prognosis with the likelihood of a chronic progressive course 56; 80–100% of these children develop residua of uveitis, polyarthritis, and other organ involvement 6. Another case series comprising 6 patients with early-onset sarcoidosis and a long follow-up with a mean of 14 years (range 0–23 y) reported on the severe outcome of the disease, including blindness (4 patients), growth retardation (3 patients), cardiac involvement (2 patients), renal failure (1 patient), and even death (1 patient) 10. Progressive ocular disease may produce severe disability with secondary glaucoma resulting in blindness. Currently, longitudinal clinical assessment focusing on the severity of the disease in affected organs remains the best approach to prognosis. Large follow-up studies are needed to better understand long-term prognosis in childhood sarcoidosis.

The authors declare that they have no competing interests.

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