Granulomatous Disease

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30 Granulomatous Disease

Scott M. Lieberman, Pamela F. Weiss

Noninfectious granulomatous disease is rare in children, with the exception of Crohn disease (see Chapter 110). This group of diseases includes sarcoidosis, granulomatous vasculitides (Wegener granulomatosis [WG] and Churg-Strauss syndrome [CSS]), and familial juvenile systemic granulomatosis (Blau syndrome).

Sarcoidosis

Sarcoidosis is an uncommon multisystem disorder of uncertain etiology involving granulomatous infiltrates in affected organs. Sarcoidosis occurs in children worldwide without gender predominance. The incidence ranges from 0.22 to 0.9 per 100,000 children in Denmark and Japan, respectively. Race predilection follows the predominant race of the country (e.g., whites in Scandinavian countries and Asians in Japan); however, there is a higher prevalence in 8- to 15-year-old black children of the southeastern United States. The incidence in children in the United States is unclear owing to lack of systematic evaluation.

Etiology and Pathogenesis

Despite considerable research, the cause of sarcoidosis is unknown. Inheritance is multigenic with relatively weak human leukocyte antigen associations varying with populations studied. An infectious cause has been considered but not confirmed. Interestingly, mycobacterial DNA has been detected by polymerase chain reaction in sarcoidosis lesions. A candidate mycobacterial antigen, Mycobacterium tuberculosis catalase-peroxidase protein (mKatG), has been proposed as a trigger for an adaptive immune response that leads to granuloma formation. Other microbes, including Propionibacterium acnes, have been implicated, but not confirmed, by independent studies.

Sarcoidosis is characterized by granulomas consisting of tightly packed epithelioid cells and macrophages surrounded by lymphocytes (Figure 30-1). In the lung, CD4⁺ T cell-mediated alveolitis occurs early followed by granuloma formation. Granulomas may resolve without sequelae or may heal with residual fibrosis.

Figure 30-1 Granulomatous disease in sarcoidosis.

Clinical Presentation

Sarcoidosis in children occurs in two distinct forms. Older children (age 8-15 years) typically present with symptoms resembling the adult form of disease, including lymphadenopathy, lung involvement (often asymptomatic), systemic signs (fever, weight loss), and hypercalcemia, but rarely with joint involvement. In children younger than 5 years, the onset typically consists of the triad of rash, arthritis, and uveitis. Sarcoidosis commonly presents with lymphadenopathy and may affect a wide range of organs (Figure 30-2).

Figure 30-2 Clinical features in sarcoidosis and Wegener granulomatosis.

Lymphoreticular System Manifestations

Lymphadenopathy is the most common presenting sign in childhood sarcoidosis. Enlarged nodes are generally nontender, firm, and mobile. Hepatosplenomegaly occurs less commonly.

Pulmonary Manifestations

Pulmonary involvement is often asymptomatic, consisting of hilar adenopathy and pulmonary infiltrates. Chronic dry cough is the most common pulmonary symptom, but children are often asymptomatic despite having restrictive disease on pulmonary function testing (PFT).

Ocular Manifestations

Uveitis (anterior, posterior, or panuveitis) is the most common ocular manifestation and is typically bilateral and asymptomatic, with occurrence of redness, pain, photophobia, or blurry vision in fewer than 30% of patients with uveitis. Keratic precipitates (tightly packed lymphocytic accumulations) are characteristic and occur at the corneal edge or pupil–iris junction. Synechiae may occur, typically between the lens and iris, resulting in irregular pupils. Conjunctival granulomas (small, pale yellow, translucent nodules), keratitis, glaucoma, or retinitis may also occur.

Skin Manifestations

Typical rashes include yellow-brown erythematous papules on the face or larger violaceous plaques on the trunk, extremities, and buttocks. Other skin involvement includes nodular (e.g., erythema nodosum), papular, macular, or ichthyosiform lesions; hypopigmentation; hyperpigmentation; or ulceration.

Musculoskeletal Manifestations

The arthritis of sarcoidosis is characterized by boggy tenosynovitis with effusion that is minimally painful or painless. Joint involvement may be oligoarticular (i.e., in few joints) initially but frequently progresses to polyarthritis over time. Associated stiffness and limited range of motion, typical in other forms of chronic arthritis, are generally minimal at diagnosis; however, with increased duration of disease, they become more apparent. Bony involvement is rare, but in the right setting, vertebral sarcoidosis should be considered in a child with back pain. Additionally, the small bones of the hands and feet may be involved. Nodular or inflammatory muscle lesions are rare.

Central Nervous System Manifestations

Central nervous system (CNS) disease includes cranial nerve abnormalities (e.g., optic neuritis or facial nerve palsy), encephalopathy, seizures, and mass lesions.

Other Manifestations

Salivary or lacrimal gland involvement may present similarly to Sjögren syndrome (recurrent parotitis, sicca syndrome, or lacrimal gland enlargement). Pancreatitis is very rare. Renal involvement is usually the result of nephrocalcinosis and nephrolithiasis rather than direct granulomatous inflammation. Heart block, cardiomyopathy, or ventricular arrhythmias may occur but are less common in children. Cytopenias may result from granulomatous infiltrates in bone marrow. Vasculitis affecting any sized vessel has been reported but is rare.

Differential Diagnosis

Sarcoidosis should be considered in any child presenting with nonspecific findings, including fever, weight loss, and lymphadenopathy, especially if accompanied by rash, arthritis, or hilar adenopathy, or in any child with fever of unknown origin (see Chapter 86, Figure 86-1). Other conditions that must be considered in a child suspected of having sarcoidosis include infections, malignancies, and other rheumatic illnesses (vasculitides, systemic lupus erythematosus [SLE], mixed connective tissue disease [MCTD], Sjögren syndrome, juvenile idiopathic arthritis [JIA]). Hilar adenopathy with constitutional symptoms may mimic lymphoma. After granulomatous inflammation has been established, infections must be ruled out before initiation of immunosuppressive medications (Box 30-1).

Evaluation and Management

Blood and Urine Studies

No diagnostic tests specific for sarcoidosis exist. Many children have increased nonspecific inflammatory markers (e.g., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and platelets). Serum angiotensin-converting enzyme (ACE) is elevated in up to 80% of children with sarcoidosis because of production of ACE by granuloma epithelial cells, and levels often correlate with disease activity. Sarcoid granuloma macrophages express 25-hydroxyvitamin D3-1α and are able to synthesize 1,25-dihydroxyvitamin D, resulting in increased intestinal calcium absorption and bone resorption. Calciuria is present in most children with sarcoidosis and commonly occurs in the absence of hypercalcemia. Thus, the urine calcium/creatinine ratio should be obtained. Other common nonspecific findings include leukopenia, anemia, eosinophilia, hypergammaglobulinemia, and positive rheumatoid factor (RF). In early-onset sarcoidosis, genetic tests for NOD2/CARD15 mutations should be performed (see Blau Syndrome below).

Imaging

Chest radiography should be performed to evaluate for hilar adenopathy or other pulmonary involvement suggestive of, but not specific for, sarcoidosis. Chest computed tomography (CT) may be considered to further characterize abnormalities found on chest radiographs. Plain radiographs of the hands and vertebrae may demonstrate characteristic lytic bone lesions in up to 19% of children with sarcoidosis. A gallium scan or ¹⁸F-fluorodesoxyglucose-positron emission tomographic (FDG-PET) scan is useful in determining extent of pulmonary and extrapulmonary involvement. Lacrimal and parotid gland involvement results in the so-called “panda” pattern, in which gallium uptake is noted in the nasopharynx and lacrimal and parotid glands, resulting in a PET image that resembles the face of a panda. Magnetic resonance imaging (MRI) is preferred for evaluation of CNS or bone involvement.

Histology

Biopsy-proven granulomatous inflammation is vital to the diagnosis of sarcoidosis. Tissue should be sampled from the most accessible site (preferably superficial lymph nodes), which may be determined by imaging (e.g., FDG-PET) if not clinically apparent. Typical histology includes noncaseating epithelioid cell granulomas; however, this is not specific and does not distinguish sarcoidosis from other granulomatous diseases, including infections. Specific stains and cultures for granulomatous infections should be performed (see Box 30-1).

Pulmonary Function Testing

PFTs should be performed to evaluate for subclinical pulmonary involvement.

Ophthalmologic Evaluation

Ophthalmologic evaluation, including a slit-lamp examination, should be sought early in the diagnostic workup because ocular lesions typical of sarcoidosis are not common in infections or malignancy.

Management

Sarcoidosis is often quite responsive to corticosteroid therapy and may be controlled on low daily doses. For cases in which low-dose corticosteroids are not adequately effective because of persistent disease or side effects, immunomodulatory therapies, such as methotrexate or anti–TNF-α (tumor necrosis factor-α) monoclonal antibodies (infliximab or adalimumab), may be used. Other immunomodulatory agents that have been used include azathioprine, cyclophosphamide, chlorambucil, and cyclosporine.

Wegener Granulomatosis

WG is a systemic disease characterized by granulomatous inflammation and necrotizing vasculitis predominantly involving small vessels. A rare disease, the incidence is approximately 0.1 in 100,000 children, with a female predominance (4 : 1) and a median age at onset of 14.5 years (range, 9-17 years).

Etiology and Pathogenesis

The cause of WG is unknown, but a pathogenic role for antineutrophil cytoplasmic antibodies (ANCAs), specifically antiproteinase 3 (anti-PR3, the main component of cytoplasmic ANCA or c-ANCA), has been proposed in the mechanism of initial endothelial cell damage. A correlation with Staphylococcus aureus infections and WG flares suggests that extrinsic factors play a role.

Clinical Presentation

The triad of pulmonary, renal, and sinus involvement characterizes classic WG; however, the most common presentation is nonspecific constitutional symptoms (fever, weight loss) and arthralgias. Limited WG involves the upper airway and spares the kidneys.

Pulmonary Manifestations

Pulmonary involvement ranges from asymptomatic pulmonary nodules to hemorrhage and respiratory failure. Common symptoms include cough, dyspnea, and hemoptysis.

Renal Manifestations

Necrotizing glomerulonephritis is a serious manifestation and may initially be asymptomatic with progression to renal failure necessitating hemodialysis or transplantation.

Ear, Nose, and Throat Manifestations

Upper airway manifestations typically involve sinusitis or recurrent epistaxis but may also include oral or nasal ulcers, recurrent otitis media, hearing loss (conductive or sensorineural), subglottic stenosis, or granulomatous inflammation of nasal cartilage resulting in nasal septal perforation or saddle nose deformity.

Ocular Manifestations

Ocular involvement includes scleritis, episcleritis, conjunctivitis, or uveitis and may present as blurry vision, eye pain, or without symptoms. Before establishment of the diagnosis, the eye involvement is frequently misdiagnosed as allergic conjunctivitis.

Musculoskeletal Manifestations

Arthritis may occur with active disease but is usually not chronic. Myalgias and arthralgias are common.

Skin Manifestations

The rash of WG most commonly presents as palpable purpura (often misdiagnosed as Henoch-Schönlein purpura) or erythematous nodules, but necrotizing vasculitic lesions and ulcerations may occur.

CNS Manifestations

Cerebral vasculitis, seizures, optic neuritis, and cranial nerve palsies are rare.

Other Manifestations

Less common manifestations include cardiac involvement (infarction, arrhythmia, or valvulitis), gastrointestinal tract involvement (nausea, vomiting, or pain), and venous thromboembolism.

Differential Diagnosis

The differential diagnosis depends on presentation and often requires evaluating for other causes of nonspecific systemic symptoms, such as fever and malaise or fever of unknown origin (see Chapter 86, Figure 86-1). Infectious causes of granulomatous vasculitis must be considered (see Box 30-1). Other rheumatologic illnesses (sarcoidosis, CSS, microscopic polyangiitis, SLE, MCTD, Sjögren syndrome, and Goodpasture syndrome) and chronic granulomatous disease (especially in young children) should be considered.

Evaluation and Management

Blood and Urine Studies

No diagnostic laboratory tests exist for WG, though 90-95% of children are ANCA positive, with cANCA (cytoplasmic antineutrophil cytoplasmic antibodies) occurring more frequently than pANCA (perinuclear antineutrophil cytoplasmic antibodies) (87% vs. 13%, respectively). Anti-PR3 antibodies should also be evaluated. RF is positive in up to 63% of children with WG. Inflammatory markers (ESR and CRP) and other acute-phase reactants (e.g., platelets) are typically elevated, and a mild anemia is often present. Elevated serum creatinine occurs in up to 44% and abnormal urine analysis (proteinuria, microscopic hematuria, and red blood cell casts) in up to 50%.

Imaging

Chest radiograph abnormalities, typically nodular infiltrates, are present in up to two-thirds of children, half of whom are asymptomatic. Pleural effusions and pneumothoraces may occur. Chest and sinus CTs should be obtained to characterize the extent of pulmonary and sinus involvement. FDG-PET scan may help to characterize the extent of extrapulmonary involvement and to determine the least invasive biopsy site.

Pulmonary Function Tests

Decreased diffusion capacity of the lung for carbon monoxide (DLCO) suggests early pulmonary hemorrhage.

Ophthalmologic Evaluation

Because ophthalmologic manifestations are common in WG, ophthalmologic evaluation should be sought early in the diagnostic workup.

Histology

Classic granulomas include central necrosis, histiocytes, lymphocytes, and giant cells. The pathology varies by biopsy site. Typical kidney lesions include pauciimmune crescentic necrotizing glomerulonephritis, with granulomas or vasculitis rarely noted. Biopsies from the upper respiratory tract (sinus or nasal septum) may reveal granulomas with giant cells or necrotizing vasculitis. Whereas lung nodules typically show granulomas, other air-space disease may reveal vasculitis or posthemorrhage changes.

Management

Corticosteroids are the mainstay of management of patients with WG. Other immunomodulatory therapy choices depend on the extent of organ involvement. For life-threatening disease, cyclophosphamide is warranted; for more limited disease, azathioprine or mycophenolic acid have been used. Trimethoprim–sulfamethoxazole is often used as adjunct treatment; whether the benefit is attributable to antimicrobial properties (i.e., in limiting S. aureus–associated WG flares) or to other antiinflammatory properties is unclear. Newer biologic agents, such as anti–TNF-α monoclonal antibodies, provide a promising alternative, but large-scale studies of these agents have not been performed in children. Plasmapheresis has been used for severe, life-threatening disease. WG is generally well controlled with therapy; however, relapse is common, especially as medication is weaned or discontinued. Notably, approximately one-third of children with WG develop irreversible renal insufficiency.

Churg-Strauss Syndrome

CSS, also known as allergic granulomatosis, is a granulomatous small vessel vasculitis associated with asthma, eosinophilia, and allergic rhinitis. Classification criteria include asthma, eosinophilia (>10% of white blood cells), allergy history, peripheral neuropathies (mono-, poly-, or mononeuritis multiplex), transient pulmonary infiltrates, paranasal sinus abnormalities, and extravascular eosinophils. The presence of four of these criteria achieves 85% sensitivity and 99.7% specificity. CSS is extremely rare in children, with 33 cases reported in the literature between 1951 and 2007. The mean age of onset is 12 years, ranging from 2 to 18 years, with a slight female predominance (1.35 : 1). The cause and pathogenesis are currently unknown.

Clinical Presentation

At diagnosis, there is a history of asthma in 91% of children and of sinusitis in 77%. Nonfixed pulmonary infiltrates occur in 85% and pleural effusions in 12%. Skin involvement occurs in 66%, typically with leukocytoclastic vasculitis manifesting as purpura, but other rashes (maculopapular, cutaneous nodules, livedo reticularis, ulcers, and bullae) occur as well. Pericardial effusion occurs in 27% and cardiomyopathy in 42%. Other manifestations include peripheral neuropathy (39%), gastrointestinal (40%) or musculoskeletal (20%) involvement, and mild nonprogressive renal disease (20%). Involvement of the lymph nodes, mammary glands, orbits, salivary glands, testes, and thymus has also been noted.

Evaluation and Management

No tests are diagnostic, but eosinophilia, high immunoglobulin E (IgE), and elevated inflammatory markers are common. ANCAs are detected in 25%, with one-third having cANCA and two-thirds having pANCA. On histology, affected tissues demonstrate vasculitis of small arteries, veins, or both with associated extravascular eosinophilic infiltrates and necrotizing granulomas. High-dose corticosteroids in combination with other immunomodulatory therapies, such as cyclophosphamide or azathioprine, are the mainstays of treatment. Overall prognosis is guarded, with relapse common (≈50%) and mortality from disease manifestations (intestinal perforation, cardiac failure, and respiratory insufficiency) occurring in 18% within 1 to 2 years of diagnosis.

Familial Juvenile Systemic Granulomatosis (Blau Syndrome)

Blau syndrome is an autosomal dominant disease characterized by the triad of arthritis, uveitis, and dermatitis along with evidence of noncaseating granulomas and mutations in NOD2/CARD15. This disease is rare, typically occurs in infants and young children (median age, 2 years; range, 2 months–14 years), and is more common among whites. The cause and pathogenesis are unknown. Arthritis is polyarticular in 96% and oligoarticular in 4%. Similar to sarcoidosis, the arthritis is boggy in the majority (74%), but tenosynovitis is less common. Dermatitis consists of nonerythematous, scaly, ichthyosiform rash. Erythema nodosum, liver granulomas, and large vessel vasculitis have also been reported. The lungs are not affected.

Diagnostic and management considerations for Blau syndrome are similar to those for sarcoidosis (with the addition of genetic testing for NOD2/CARD15 mutations), and some regard Blau syndrome and early onset sarcoidosis as a single entity. Ocular outcomes in children with Blau syndrome are frequently worse than in sarcoidosis.

Future Directions

Noninfectious granulomatous diseases are rare in children but should be considered in any child with multisystem manifestations or unexplained constitutional symptoms (e.g., fever of unknown origin). If undiagnosed and untreated, these conditions result in serious disabilities or death. Newer immunomodulatory agents are promising in the treatment of patients with these diseases. The greatest hurdle in determining optimal therapy for noninfectious granulomatous disease in children is the lack of systematic evaluation owing to the low incidence of these diseases. Establishment of registries for these rare conditions will allow for a more systematic and comprehensive evaluation of their characteristics, pathogenesis, genetics, and outcomes, which are prerequisites for improving therapeutic management.

Suggested Readings

Lindsley CB, Laxer RM. Granulomatous vasculitis, giant cell arteritis, and sarcoidosis. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB, editors. Textbook of Pediatric Rheumatology. ed 5. Philadelphia: Elsevier; 2005:539-560.

O’Neil KM. Progress in pediatric vasculitis. Curr Opin Rheumatol. 2009;21(5):538-546.

Ianuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357:2153-2165.

Shetty AK, Gedalia A. Childhood sarcoidosis: a rare but fascinating disorder. Pediatr Rheumatol Online J. 2008;6:16-25.

Wegener Granulomatosis

Akikusa JD, Schneider R, Harvey EA, et al. Clinical features and outcome of pediatric Wegener’s granulomatosis. Arthritis Rheum. 2007;57:837-844.

Frosch M, Foell D. Wegener granulomatosis in childhood and adolescence. Eur J Pediatr. 2004;163:425-434.

Churg-Strauss Syndrome

Zwerina J, Eger G, Englbrecht M, et al. Churg-Strauss syndrome in childhood: a systematic literature review and clinical comparison with adult patients. Semin Arthritis Rheum. 2009;39(2):108-115.

Rose CD, Wouters CH, Meiorin S, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum. 2006;54:3337-3344.

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