Pediatric Sarcoidosis

Updated: Feb 01, 2016
  • Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Michael R Bye, MD  more...
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Overview

Background

Sarcoidosis, a systemic, granulomatous disease, can occur in adult and pediatric patients, but it is nonetheless relatively rare in children. The description of sarcoidosis goes back to 1899, when Caesar Boeck described the skin nodules characterized by epithelioid cells with large, pale nuclei and giant cells as "multiple benign sarcoid of skin," due to its resemblance to sarcoma.

Sarcoidosis, the etiology of which is unknown, most commonly affects young adults, who frequently present with hilar lymphadenopathy, pulmonary infiltration, and ocular and cutaneous lesions. Although the lung is most frequently involved, the disease can affect any organ system of the body. Infants and children younger than age 4 years present with the triad of skin, joint, and eye involvement without typical pulmonary disease; in older children, involvement of the lungs, lymph nodes, and eyes predominates (see the image below). (See Clinical and Workup.)

Chest radiograph showing bilateral hilar lymphaden Chest radiograph showing bilateral hilar lymphadenopathy in a 10-year-old girl with sarcoidosis.

Despite various hypotheses regarding causative agents, the cause of sarcoidosis still is unknown. The diagnosis of sarcoidosis is established when histopathologic evidence of noncaseating granulomata in affected organs and reasonable exclusion of other granulomatous diseases support compatible clinical and radiographic findings. (See Etiology, Clinical, and Workup.) [1]

Frequently observed immunologic features include depression of cutaneous delayed-type hypersensitivity and a heightened helper T-cell type 1 (Th1) immune response at sites of disease. Circulating immune complexes, along with signs of B-cell hyperactivity, may also be found. The illness can be self-limited or chronic, with episodic recrudescence and remissions. The course and prognosis may correlate with the mode of onset and the extent of the disease. (See Prognosis and Treatment.)

Complications

Because sarcoidosis can involve any organ in the body, potential complications can include a gamut of abnormalities. Progressive interstitial lung disease with restrictive ventilatory pattern can occur. Untreated ocular disease may result in synechiae, glaucoma, and blindness.

Unusual, but serious, complications described in childhood sarcoidosis include nephrolithiasis, nephrocalcinosis, cranial nerve palsies, and cardiac disease, including vasculitis involving the aortic arch. (See Prognosis.)

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Etiology

Sarcoidosis is a chronic inflammatory disease characterized by a highly focused, exaggerated immune response to an unknown antigen at the target organs. The hallmarks of the disease, sarcoid granulomas, most likely are formed in response to a persistent, poorly degradable, antigenic stimulus. 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.

Iannuzzi et al hypothesized a possible role of infectious, organic and inorganic agents in the immunopathogenesis of sarcoidosis. [1] Any causative microbe, if present, is probably cleared, leaving behind an undegradable product. This process may initiate a cross-reacting immune response to self-antigen. Antigen-presenting cells (APC), in addition to producing high levels of tumor necrosis factor alpha (TNF-α), secrete interleukin (IL)-12, IL-15, and IL-18; macrophage inflammatory protein 1 (MIP-1); monocyte chemotactic protein 1 (MCP-1); and granulocyte macrophage colony-stimulating factor (GM-CSF).

The lung lymphocytes usually consist of CD4 memory T cells. Activated CD4+ T cells interact with APCs to initiate the formation and maintenance of granulomas. CD4+ T cells release IL-2 and interferon-γ. Activated CD4+ cells differentiate into type 1 helper (Th1) ̶ like cells and secrete predominantly IL-2 and interferon-γ. The efficiency of antigen processing, antigen presentation, and cytokine release is probably under genetic control. Evidence supports a role for macrophage human leukocyte antigen (HLA) and BTNL2 alleles in sarcoidosis susceptibility and phenotypic presentation. [2, 3]

Sarcoidal granulomas are organized, structured masses composed of macrophages and their derivatives, epithelioid cells, giant cells, and T cells. Sarcoidal granulomas may persist, resolve, or lead to fibrosis. Alveolar macrophages activated in the context of a predominant type 2 helper (Th2) T-cell response appear to stimulate fibroblast proliferation and collagen production, leading to progressive fibrosis.

The immunopathology has been best studied in lung disease in which early lesions consist of an alveolitis with a high proportion of activated CD4+ Th1 cells, which may precede granuloma formation. Although the lung lymphocytes usually consist of CD4 memory T cells, in some patients they are predominantly CD8 cells. 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.

The appearance of worsening of sarcoidosis in the immune reconstitution inflammatory syndrome after treatment with antiretroviral therapy in patients with human immunodeficiency virus (HIV) infection underscores the central pathogenic role of CD4+ cells in sarcoidosis. [1]

As a result of these various immunologic interactions, an acute and often a chronic cascade of inflammation occurs. 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.

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.

Although sarcoidosis most commonly involves the lungs, it can affect nearly any organ system; products injure local tissues, and elaborating growth factors cause fibrosis. Sarcoid granulomas either resolve or heal by fibrosis. This fibrotic response can be severe and include the lymph nodes, [4] ears, [5] eyes, [6] skin, liver, spleen, kidneys, bone, joints, nervous system, and heart. Granulomas mediate disease by compressing tissues, secreting cytokines that provoke constitutional symptoms, and recruiting inflammatory cells that cause often irreversible organ damage and physiologic dysfunction.

Causes

Despite the world occurrence of sarcoidosis, the cause of the disease is still unknown. Attempts to elucidate the cause of sarcoidosis have been disappointingly thwarted by lack of an animal model and the failure to identify the antigen.

Despite extensive research, no identifiable agent has been demonstrated to account for the granulomata that characterize the disease. Infectious agents, chemicals, drugs, autoimmunity, and genetic factors have all been explored as potential causes. Most experts think that sarcoidosis results from exposure of genetically susceptible hosts to specific environmental agents that trigger an exaggerated cellular immune response, leading to granuloma formation. Case clustering suggests that an infectious agent may be responsible.

Mycobacteria, including Mycobacterium tuberculosis and other atypical species, have received the greatest amount of attention. The detection of mycobacterial deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in sarcoid lesions by polymerase chain reaction (PCR) assay, demonstration of components of the mycobacterial cell wall (eg, tuberculostearic acid, muramyl dipeptide) in sarcoid nodules, and the growth of acid-fast L-forms from the blood of patients with sarcoidosis lend support to that association. However, several investigators have fiercely contested the results obtained by PCR assay. Furthermore, attempts to fulfill the Koch postulates have failed, and the role of mycobacteria in sarcoidosis remains a controversial issue.

Besides M tuberculosis, many other antigens are under suspicion, including other bacteria, such as Propionibacterium acnes, Streptococcus species, Borrelia burgdorferi, Mycoplasma species, and Nocardia species. Viruses (eg, Epstein-Barr virus, herpesvirus, Coxsackie B virus, cytomegalovirus, retrovirus) and noninfectious environmental chemicals (eg, beryllium, aluminum, zirconium, titanium, pine pollen, peanut dust, clay ingestion) are also under suspicion.

Case reports from Scandinavia suggesting that rickettsiae may contribute to a granulomatous process as seen in sarcoidosis [7] were not supported by a prospective study in Danish patients with sarcoidosis. [8]

Variant human herpesvirus 8 (HHV-8) DNA sequences were detected from multiple sample sites in all patients with sarcoidosis. The significance of this finding is not clear and further studies are necessary to determine whether the association between HHV-8 and sarcoidosis is causal.

The striking racial variation in sarcoidosis incidence suggests a genetic predisposition to develop sarcoidosis. The strongest support for a genetic susceptibility to sarcoidosis comes from numerous reports of familial clustering of cases. In the United States, familial clusters more frequently are observed in blacks, with a rate of at least 19% in affected black families, compared with 5% in white families. Segregation and linkage analyses have not been performed.

When sarcoidosis has been observed in twins, monozygotic twins have been 2-4 times more concordant for disease than have dizygotic twins. The most common familial relationship is sibling pairs, followed by parent-offspring.

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 the prognosis.

Several investigators have searched for associations with human leukocyte antigen (HLA)–related genes that may confer susceptibility to sarcoidosis. HLA analyses of affected families suggest a polygenic mode of inheritance of risk for sarcoidosis; the most commonly found alleles include class I HLA-A1 and B8 and class II HLA-DR3 in whites. Reports have demonstrated that association studies may be performed best with families in whom the ethnic background can be controlled.

HLA-DRB1*1101 is a significant risk factor for sarcoidosis in blacks. The rates for HLA DRB1 are reported to be 16% in blacks and 9% whites. In African American population, DQB1*0201 has no effect, while DQB1*0602 is associated with radiographic disease progression. [9] A 2011 study reports that HLA-DRB1*04 is associated with symptoms of Heerfordt syndrome (uveitis, parotid or salivary gland enlargement, and cranial nerve palsy) in a Scandinavian sarcoidosis population. [10]

Examination of other genetic loci, such as those encoding polymorphisms for immunoregulatory cytokines, growth factors, and angiotensin-converting enzyme (ACE), may prove equally important. A recent review article highlights recently performed genome-wide association studies (GWAS) and influence of genetic factors on phenotypic presentation of sarcoidosis; for example, HLA-DRB1*03 is both a risk factor for sarcoidosis and a determinant of good prognosis. [11]

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Epidemiology

Occurrence in the United States

The prevalence of sarcoidosis in the adult population ranges from less than 1 case to 40 cases per 100,000 population, with an age-adjusted annual incidence rate of 10.9 per 100,000 for white people and 35.5 per 100,000 in black people. True incidence and prevalence is unknown because of the rarity of the disease and the small number of reported cases in childhood. As in adults, many children with sarcoidosis may be asymptomatic and the disease may remain undiagnosed.

More than 70% of childhood cases in the United States have been reported primarily in Virginia, North Carolina, South Carolina, and Arkansas, suggesting that the southeastern and south central states are an endemic area for childhood sarcoidosis.

International occurrence

In the United Kingdom, the overall prevalence of sarcoidosis is approximately 20 per 100,000 population. In Europe, the prevalence ranges from 3-50 cases per 100,000 population, with the disease most frequently affecting persons aged 20-40 years. Sweden has the highest reported incidence of sarcoidosis in Europe, ranging from 64 cases per 100,000 population using mass radiographic screening to 641 cases per 100,000 population using autopsy studies.

One review reported that the approximate incidence of clinically recognized sarcoidosis in Danish children younger than age 15 years was 0.22-0.27 per 100,000 children per year, corresponding to approximately 3 new cases in Denmark each year. In many other countries, such as Spain, Portugal, India, Saudi Arabia, or South America, the prevalence of sarcoidosis is low, possibly because of the absence of mass chest radiographic screening and also because of the presence of other more commonly recognized granulomatous diseases, especially tuberculosis, that mimic sarcoidosis.

Race-related demographics

In the United States, the lifetime risk of sarcoidosis on the basis of cumulative incidence estimates is 2.4% for black people and 0.85% for white people. The racial distribution of sarcoidosis varies with geographic location. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among blacks.

In children aged 4 years or younger with sarcoidosis, 7-28% are black, whereas in children aged 8-15 years, the percentage of blacks increases to 72-81%. Studies in military and veteran populations showed that black people are 10-17 times more commonly affected by sarcoidosis than are white people. 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.

Sex-related demographics

No clear sex predominance is recognized in childhood sarcoidosis, although a Japanese study reported a higher incidence of sarcoidosis in males than in females. In a study from Denmark, the male/female gender ratio was close to 1. 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.

Age-related demographics

Most reported childhood cases have occurred in patients aged 13-15 years. The disease has also been reported in very young children. A recent report describes sarcoidlike granulomatous disease in an 11-month-old girl. [12] The prevalence increases until adulthood, when the disease most frequently is found in patients aged 20-30 years. A bimodal distribution has been reported in Scandinavian countries and Japan, with a secondary peak occurring primarily in females older than age 50 years.

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Prognosis

Very few studies of the prognosis and natural history of sarcoidosis in children are available because of the rarity of the disease and the small number of reported cases. Thus, long-term prognosis is only speculative. [13] However, the overall prognosis of childhood sarcoidosis is reported to be good, with most children demonstrating considerable improvement in clinical manifestations and in findings on chest radiographs and pulmonary function tests. [14]

Although most children apparently improve, a significant number of patients have sequelae or experience major complications; however, the mortality rate is low. A review of 5 large series of childhood cases of sarcoidosis showed that 6 of 176 patients died, for an overall mortality rate of 3%. Asymptomatic cases usually have a favorable outcome, with spontaneous regression in many patients. Symptomatic patients with multisystemic involvement often experience chronic disease, with residua in about 20%, mainly involving the eyes and lungs.

Early onset sarcoidosis with involvement of the eyes, joints, and skin suggests a guarded prognosis, with the likelihood existing of a chronic, progressive course and even life-threatening complications; 80-100% of these children develop residua of uveitis, polyarthritis, and other organ involvement. Progressive ocular disease may produce severe disability, with the occurrence of secondary glaucoma resulting in blindness. Periodic ophthalmologic evaluations are essential in all cases of childhood sarcoidosis to identify ocular disease and prevent further morbidity.

Currently, longitudinal clinical assessment focusing on the severity of the disease in affected organs remains the best approach to prognosis. An acute onset with erythema nodosum indicates a good prognosis and spontaneous resolution, whereas an insidious onset may be followed by relentless, progressive fibrosis. [15]

A study by Nathan et al collected information on a large cohort of pediatric thoracic sarcoidosis to provide information on disease presentation, management and outcome. The study found that common prognosis factors are not suitable in pediatric patients, and a young age at diagnosis does not seem to be associated with a poorer prognosis; the study found that patients diagnosed before 10 years of age had lower frequency of relapses and were more likely to recover. [16]

Morbidity

Marcille et al performed a follow-up study on 19 individuals in whom sarcoidosis had been diagnosed in childhood, with a mean follow-up period of 21 years (range 8-35 y), and found that 7 patients (37%) had persistent abnormalities on chest radiograph, 68% had impaired lung function, and 63% had abnormal findings on echocardiography. [14]

Although most older children appear to improve, a significant number have sequelae or experience major complications; however, the mortality rate is low. Asymptomatic cases with hilar adenopathy have a very favorable outcome, with spontaneous resolution in many patients, whereas those with stage IV disease have a poor prognosis. Symptomatic patients with multisystemic involvement often experience chronic disease, with residua in about 20%, mainly involving the eyes and lungs.

As stated above, early onset sarcoidosis with involvement of the eyes, joints, and skin suggests a guarded prognosis. A series of 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).

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