Abstract
Pediatric granulomatous diseases constitute a heterogenous group of conditions in terms of clinical phenotypes, pathogenic mechanisms, and outcomes. The common link is the presence of multinucleated giant cells in the inflammatory infiltrate. The clinical scenario in which a tissue biopsy shows granulomatous inflammation is not an uncommon one for practicing adult and pediatric rheumatologists. Our role as rheumatologists is to develop a diagnostic plan based on a rational differential diagnostic exercise tailored to the individual patient and based mainly on a detailed clinical assessment.
This chapter presents a comprehensive differential diagnosis associated with a classification developed by the authors. We describe with some detail extrapulmonary sarcoidosis, Blau syndrome, and immunodeficiency associated granulomatous inflammation, which in our view are the paradigmatic primary forms of granulomatous diseases in childhood. The other entities are presented only as differential diagnoses listing their most relevant clinical features.
This chapter shows that almost all granulomatous diseases seen in adults can be found in children and that there are some entities that are essentially pediatric at onset, namely Blau syndrome and most forms of immunodeficiency associated granulomatous diseases.
Introduction
Granulomas are organized inflammatory infiltrates characterized by a core of macrophages, epithelioid, and multinucleated giant cells and a corona of lymphocytes and a few to many fibroblasts. Giant cell formation in turn is the result of macrophage fusion via a mechanism that is highly dependent on membrane-bound signaling and which is not completely understood . Formation of granulomas is observed across most multicellular organisms; it occurs within a diverse myriad of clinical conditions and is the result of a highly orchestrated process involving numerous cellular types, cytokines, chemokines, and cell surface receptors .
Antigen persistence in tissue resulting from inability of individual phagocytes to carry on antigen digestion and processing is a time-honored notion that provides a rationale to the biologic function of granuloma formation; in fact, data suggest that multinucleated giant cell formation may enhance degradative activity perhaps at the expense of phagocytic capacity . Lipid-rich mycobacterium, large multicellular parasites, or inert non-digestible inorganic material like silica and beryllium are well-known inducers of macrophage fusion and granuloma formation, in both in vivo and ex vivo experimental conditions . Yet, no antigen has been identified in many human granulomatous diseases, and these are likely the result of deregulation of the immune system ultimately leading to macrophage fusion and giant cell formation. Blau syndrome and a number of immunodeficiency syndromes are inheritable monogenic diseases with prominent granulomatous inflammation. Sarcoidosis, primary biliary cirrhosis, Crohn’s disease, and granulomatous necrotizing vasculitis are also examples of immune deregulation, yet their genetic mechanisms remain less defined.
The purpose of this chapter is to provide the consulting pediatric rheumatologist with a tool to assist in the differential diagnosis when a granulomatous disease is found on a biopsy material or is suspected on clinical bases. We will review the classification of granulomatous diseases (in broad categories) and focus our attention on clinically definable forms of granulomatous disease, namely granuloma associated with immunodeficiency, sarcoidosis, and Blau syndrome, limiting our description to the main and defining features. The reader is referred to specific reviews for a comprehensive account of the clinical entities . We will also briefly review the mechanism of granuloma formation and discuss possible pathogenic mechanisms in selected diseases. There are several ways in which granulomatous diseases can be classified. We prefer to follow a combination of pathologic findings and etiologic factors, recognizing that this is still a work in progress ( Table 1 ).
Granulomatous inflammation with known triggers
Infections
Rheumatologists may be involved with the care of patients who are eventually diagnosed with an infection. Two distinct scenarios are likely. (1) The finding on histology of granulomas due to infection of lymph node, liver, bone, or bone marrow in the setting of a systemic illness or (2) inflammatory syndromes ‘reactive’ to a granulomatous infection commonly characterized by arthritis, erythema nodosum, uveitis, and constitutional symptoms. Examples of the latter infections are caused by Mycobacterium tuberculosis , Mycobacterium leprae , Yersinia enterocolitica , and Coccidioides immitis (valley fever, desert rheumatism, or San Joaquin valley fever). Clinically, granulomatous infections can present in the context of skin and mucosal lesions, pulmonary and mediastinal disease, bone marrow dysfunction, or hepatic granulomas. Adenitis is still the most frequent presentation in children for all granulomatous infections and the location of the inflamed lymph node will determine the clinical features (cervical, abdominal, or inguinal adenitis). Although infectious disease specialists are more likely to be consulted in these cases, occasionally the histology may be unclear because of lack of obvious necrosis or caseation and a suspicion for a primary inflammatory disease will be raised. Bacterial and fungal staining and a good epidemiologic history are crucial to avoid the catastrophic consequences of initiating corticosteroid or anti-tumor necrosis factor (TNF) therapy in a child with an ongoing granulomatous infection. Table 1 lists some of the infections associated with granuloma formation. It will be after an exhaustive, yet systematic, assessment of infections that one could comfortably begin to consider idiopathic inflammation. Excellent reviews on infection and granuloma are available.
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Granulomatous reaction to inert materials
Most granulomatous disorders associated with inhalation of inert material result from occupational exposure and, as such, are very rare in children. Peri-prosthetic granulomatous inflammation around aseptic loosening following cemented joint replacement, although occasionally seen in children, signifies no diagnostic challenge. One interesting scenario, in turn very relevant to pediatrics, is foreign body synovitis, a form of granulomatous synovitis resulting from a penetrating injury with foreign material. Because the puncture can be rather small, the antecedent trauma may have not been noticed. Between 1 and 7 days from the injury, an acute arthritis sometimes mimicking septic arthritis may ensue although it can also be indolent and resemble oligoarticular juvenile idiopathic arthritis (JIA). The ankles, knees, and small joints of the hands are common locations. It can also affect tendon sheaths and bursae. The biopsy reveals typical foreign body-type multinucleated giant cells within an inflammatory infiltrate. A number of sources have been described; the best known is the spine of the sea urchin, fiberglass, yucca, and rose-thorn .
Drugs
Drug-induced liver injury is a common occurrence in clinical medicine. When liver biopsies are performed, the most common histological feature is acute hepatitis with or without cholestasis. Occasionally, drug-induced granulomatous hepatitis will be reported raising the question of sarcoidosis. Drugs including nitrofurantoin and antimalarials have been associated with this histological pattern; resolution with discontinuation of the drug is the rule .
Closer to rheumatology practice is the reported association between TNF blockers and induction of granulomatous disease, mimicking sarcoidosis. It is rather paradoxical that these agents are commonly used to treat granulomatous disorders such as Crohn’s disease, sarcoidosis, and Blau syndrome. This type of observation proves how complex and diverse the mechanisms behind granuloma formation are. Clinically, the most common phenotypes are pulmonary and subcutaneous nodules. In some cases, the histology is typical of a rheumatoid nodule while in others, aseptic necrotizing granulomas have been documented in biopsy. These lesions have been mostly associated with etanercept . One of us has cared for a child with JIA who developed pancytopenia while on etanercept and exhibited non-caseating aseptic granuloma on bone marrow biopsy (unpublished observation).
Granulomatous inflammation with known triggers
Infections
Rheumatologists may be involved with the care of patients who are eventually diagnosed with an infection. Two distinct scenarios are likely. (1) The finding on histology of granulomas due to infection of lymph node, liver, bone, or bone marrow in the setting of a systemic illness or (2) inflammatory syndromes ‘reactive’ to a granulomatous infection commonly characterized by arthritis, erythema nodosum, uveitis, and constitutional symptoms. Examples of the latter infections are caused by Mycobacterium tuberculosis , Mycobacterium leprae , Yersinia enterocolitica , and Coccidioides immitis (valley fever, desert rheumatism, or San Joaquin valley fever). Clinically, granulomatous infections can present in the context of skin and mucosal lesions, pulmonary and mediastinal disease, bone marrow dysfunction, or hepatic granulomas. Adenitis is still the most frequent presentation in children for all granulomatous infections and the location of the inflamed lymph node will determine the clinical features (cervical, abdominal, or inguinal adenitis). Although infectious disease specialists are more likely to be consulted in these cases, occasionally the histology may be unclear because of lack of obvious necrosis or caseation and a suspicion for a primary inflammatory disease will be raised. Bacterial and fungal staining and a good epidemiologic history are crucial to avoid the catastrophic consequences of initiating corticosteroid or anti-tumor necrosis factor (TNF) therapy in a child with an ongoing granulomatous infection. Table 1 lists some of the infections associated with granuloma formation. It will be after an exhaustive, yet systematic, assessment of infections that one could comfortably begin to consider idiopathic inflammation. Excellent reviews on infection and granuloma are available.
|
Granulomatous reaction to inert materials
Most granulomatous disorders associated with inhalation of inert material result from occupational exposure and, as such, are very rare in children. Peri-prosthetic granulomatous inflammation around aseptic loosening following cemented joint replacement, although occasionally seen in children, signifies no diagnostic challenge. One interesting scenario, in turn very relevant to pediatrics, is foreign body synovitis, a form of granulomatous synovitis resulting from a penetrating injury with foreign material. Because the puncture can be rather small, the antecedent trauma may have not been noticed. Between 1 and 7 days from the injury, an acute arthritis sometimes mimicking septic arthritis may ensue although it can also be indolent and resemble oligoarticular juvenile idiopathic arthritis (JIA). The ankles, knees, and small joints of the hands are common locations. It can also affect tendon sheaths and bursae. The biopsy reveals typical foreign body-type multinucleated giant cells within an inflammatory infiltrate. A number of sources have been described; the best known is the spine of the sea urchin, fiberglass, yucca, and rose-thorn .
Drugs
Drug-induced liver injury is a common occurrence in clinical medicine. When liver biopsies are performed, the most common histological feature is acute hepatitis with or without cholestasis. Occasionally, drug-induced granulomatous hepatitis will be reported raising the question of sarcoidosis. Drugs including nitrofurantoin and antimalarials have been associated with this histological pattern; resolution with discontinuation of the drug is the rule .
Closer to rheumatology practice is the reported association between TNF blockers and induction of granulomatous disease, mimicking sarcoidosis. It is rather paradoxical that these agents are commonly used to treat granulomatous disorders such as Crohn’s disease, sarcoidosis, and Blau syndrome. This type of observation proves how complex and diverse the mechanisms behind granuloma formation are. Clinically, the most common phenotypes are pulmonary and subcutaneous nodules. In some cases, the histology is typical of a rheumatoid nodule while in others, aseptic necrotizing granulomas have been documented in biopsy. These lesions have been mostly associated with etanercept . One of us has cared for a child with JIA who developed pancytopenia while on etanercept and exhibited non-caseating aseptic granuloma on bone marrow biopsy (unpublished observation).
Granulomatous inflammation without a known trigger
Largely non-vasculitic
Systemic granulomatous disorders
Adult-type sarcoidosis in children
Similar to adult, pediatric-onset adult sarcoidosis is a pulmonary disease in about 90% with extrapulmonary disease either concurrent or in the absence of lung/hilar involvement showing a variable frequency depending on the organ system . About 1% of sarcoidosis begin at or before age 15 as shown in the Danish sarcoidosis registry . This chapter will focus on extrapulmonary manifestations, which are more likely to lead to a rheumatology consult. The name ‘adult-type sarcoidosis of childhood onset’ was proposed by the authors to differentiate it from early-onset or infantile sarcoidosis that characteristically appears before age 4 and is known as Blau syndrome. The latter will be discussed separately. Table 2 provides a summary of the frequency of the main extrapulmonary manifestations from three pediatric series ( Table 2 ) . When the adult form of childhood-onset sarcoidosis presents in the pediatric population, it tends to affect older children with a median age of 13 in the Danish registry . In the USA, individuals of African ancestry are three times more frequently affected compared with non-Blacks .
| Pediatric Sarcoid cohorts (%) | Adult series (%) | |
|---|---|---|
| Systemic | 56–98 | 12 |
| Lung | 90–100 | 95 |
| Lymph nodes | 40–67 | 13–15 |
| Hilar adenopathy | 71–76 | |
| Skin | 25–42 | 16–18 |
| Eye | 23–51 | 11–16 |
| Uveitis | 25 | |
| Neurological | 10–25 | 5 |
| CNS | 23 | |
| Peripheral | 2 | |
| Liver/spleen | 4–43 | 7–11 |
| Arthritis | 2–5 | 0.5–14 |
Extrapulmonary manifestations of sarcoidosis in children
Dermatologic manifestations
Skin lesions associated with sarcoidosis can be histologically classified as granulomatous or non-granulomatous. Among the latter, erythema nodosum is the classical example, commonly seen at presentation, located in the lower extremities and showing the typical features of septal panniculitis. Sometimes it presents in the context of a triad with hilar adenopathy and acute lower extremity arthritis known as Lofgren syndrome . Lesions associated with granuloma on biopsy are usually papular or plaque like ( Fig. 1 ) and appear as fleshy skin-colored lesions or reddish brown papules and plaques commonly in the face. Lupus pernio, a violaceous indurated lesion affects mainly the nasal alar process and can be destructive and deep-seated; it is extremely rare in children. Non-erythematous subcutaneous nodules distinct from erythema nodosum can be observed as well. Patients with sarcoidosis also experience transient macular rashes with serpiginous border and fine superficial scaling, hyper or hypopigmented maculae and ulcers sometimes associated with vasculitis. The tendency to develop granulomatous inflammation can be seen in traumatic scars or tattoos as small papules around the scar. All these lesions are commonly observed simultaneously with hilar or lung disease, hence chest imaging is recommended when there is histological confirmation of granulomatous dermatitis .
Neurosarcoidosis
In the long-term Danish study by Milman and Hoffmann, five of 36 children developed this complication. Of the cranial nerves, the most commonly affected is the facial nerve followed by optic and oculomotor nerves in one large literature-based pediatric series of neurosarcoidosis . In older children and in adults, peripheral neuropathy, both sensory and sensorimotor, disease has been well described. Involvement of the brain parenchyma entails poor prognosis and it tends to be recurrent and difficult to treat. Clinically, it presents with intractable headaches, seizures, cognitive dysfunction, focal motor deficit, and ataxia depending upon the location of the lesions. Seizures are the most common presenting symptom in pediatric neurosarcoidosis in the cited series . Myelopathy can also be observed. Involvement of the leptomeninges is responsible for severe headaches and it clinically resembles recurrent aseptic meningitis. In general, neurosarcoidosis can mimic a brain tumor.
The cerebrospinal fluid may reveal increased intracranial pressure and fluid analysis reveals increase protein and cells, mainly lymphocytes. Elevation of angiotensin-converting enzyme (ACE) levels in the fluid may contribute to the diagnostic accuracy although its sensitivity is low . Imaging with magnetic resonance may show gadolinium enhancement of leptomeninges and lesions sometimes with a mass appearance although more frequently as hyperintense gadolinium enhancing lesions on both subcortical and periventricular white matter distribution ( Fig. 2 ). The most valuable tool for confirmation is documentation of concurrent disease in the lung or other tissue amenable to histological diagnosis. In the authors’ experience, neurosarcoidosis enters in the differential diagnosis of inflammatory disorders affecting the central nervous system (CNS) frequently, given that the combination of white matter disease and meningitis is associated with a number of inflammatory conditions including, but not limited to, systemic lupus erythematosus (SLE), Behcet’s syndrome, primary angiitis of the CNS, and neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, and arthritis (NOMID/CINCA).
Neuroendocrine manifestations
Children with sarcoidosis experience hypothalamic and pituitary involvement more commonly compared with adults. Although rarely will this be a reason to consult a rheumatologist, the finding of electrolyte abnormalities due to diabetes insipidus or evidence of hypopituitarism from hypothalamic involvement should evoke sarcoidosis during the diagnostic workup of inflammatory disorders .
Renal disease
There are two patterns of renal involvement associated with pediatric sarcoidosis, namely interstitial nephritis and nephrocalcinosis. Interstitial nephritis with granulomatous infiltration is characterized by non-oliguric renal failure, proximal tubulopathy, leukocyturia, hematuria, granular casts, and proteinuria. Nephrocalcinosis with or without nephrolithiasis is associated with hypercalciuria, in turn the result of vitamin D 3 overproduction by the inflammatory cells. In a review of 15 pediatric series, Coutant reported decreased renal function in 26–45% of patients and hypercalciuria in 47%. Interstitial involvement with granulomas was the most consistent severe finding while glomerular disease was less severe. Evolution to chronic renal failure was observed in four of 11 cases despite medical treatment .
Ocular disease
It is not unusual for sarcoidosis to be diagnosed by an ophthalmologist who will consult rheumatology in order to both confirm and determine the extent of involvement of the disease. Patients with sarcoidosis seek ophthalmology care due to either ocular or orbital symptoms . Overall, about one of three of children with sarcoidosis will experience eye disease at some point in the course as shown in the Danish national registry . This frequency may be somewhat overestimated by the inclusion in these series of children with Blau syndrome, a disease with a high frequency of eye disease. Uveitis in sarcoidosis can affect the anterior and posterior compartments. Criteria have been established for ocular sarcoidosis ( Table 2 ) and they include seven biomicroscopic findings on ophthalmologic exam . Many times, the uveitis of sarcoidosis has no specific findings, and in children, it commonly may be indistinguishable from other causes, particularly the uveitis associated with JIA, yet, the appearance and the distribution of corneal involvement could offer a diagnostic clue . Extraocular disease including pulmonary nodules or hilar adenopathy will help in confirming the diagnosis in those patients who present with eye involvement. A conjunctival or lachrymal biopsy may help by exhibiting non-caseating granulomas. Occasionally, the uveitis will be accompanied by parotitis and facial nerve palsy (Heerfordt syndrome) but that triad has not been reported in children. Conversely, the combination of parotitis and uveitis (Mikulicz’s syndrome), a clinical scenario highly suggestive of sarcoidosis, is more frequently seen ( Fig. 3 ). Orbital disease usually presents in the form of an orbital pseudotumor. The three main areas of involvement are the lachrymal gland, the eyelid, and the periocular soft tissue. Granulomatous dacryocystitis appears as a large reddish congested enlargement of the lachrymal gland on gentle palpebral eversion. Eyelid involvement will appear reddish brown with edema. A variable degree of periocular soft tissue inflammation may lead to proptosis mostly with preserved eye movements. With recurrent episodes of lachrymal disease, the child or young adult may develop sicca syndrome, leading to potential confusion with Sjögren’s syndrome. The absence of antinuclear antibodies (ANAs) and the severe involvement of the lachrymal gland are helpful findings in favor of sarcoidosis ( Table 3 ).
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Parotitis
In fact, any salivary gland can be affected in sarcoidosis. It is a granulomatous inflammation commonly bilateral, although one side could predominate. The parotid glands may be involved in both Heerfordt syndrome and Mikulicz’s syndrome ( Fig. 3 ), mentioned above. The combination of parotitis and dacryocystitis can been seen in association with hyper-immunoglobulin G4 (IgG4) as part of the spectrum of IgG4-associated diseases. Mikulicz’s syndrome can also be seen in Sjögren’s syndrome. In the absence of increased IgG4 levels and ANAs, sarcoidosis has to be considered. As in other extrapulmonary manifestations, the most expeditious way of confirming the diagnosis is a search for asymptomatic pulmonary involvement. Alternatively, a biopsy of the tail of the parotid or the lachrymal gland could confirm the granulomatous nature of the disease in the case of sarcoidosis.
Sarcoid vasculitis
The differential diagnosis of granulomatous vasculitis will be briefly discussed below; here we will refer to vasculitic syndromes involving both small and large vessels in the context of sarcoidosis, where it can be a presenting feature. The association of bilateral ankle arthritis and palpable purpura is rare but typical of adolescents and young adults. Large vessels are rarely involved except in the setting of severe interstitial lung disease with involvement of the pulmonary and bronchial arteries by the granulomatous inflammation of the lung parenchyma .
Musculoskeletal disease
Unlike Blau syndrome, where polyarthritis is prominent and frequent, the arthritis of adult-type sarcoidosis is both rare and mild. Older children and young adults can present with acute arthritis with the bilateral ankles as the most common distribution. When erythema nodosum and hilar adenopathy are also present, we use the term Löfgren syndrome to identify this triad . Recognizing this condition is useful since the prognosis is usually benign and it responds to a short course of anti-inflammatory therapy. The granulomatous chronic synovitis of adult-type sarcoidosis is extremely rare in children, but when it does occur, it tends to affect the lower extremities, exhibits a recurrent course, and is predominantly oligoarticular. Enthesopathy and tenosynovitis are rare . Granulomas are rarely found on synovial biopsy .
The typical cystic osteitis associated with dactylitis and overlying skin disease (lupus pernio) has not been seen in children.
There are three patterns of sarcoid myositis namely acute, chronic, and focal (nodular), none of which is common particularly in children .
Reticuloendothelial system
In sarcoidosis, lymphadenopathy usually generalized, and the lymph node feels rubbery, mobile and is prominently enlarged. Histologically one expects that most of those lymph nodes will show non-caseating granulomas. However, granulomatous inflammation in a single lymph node may be found in patients with infection or lymphoma. Patients with sarcoidosis who are receiving anti-TNF therapy and develop lymphadenopathy may be challenging and a biopsy may be necessary because of the concerns for lymphoproliferative disorders. Hepatosplenomegaly with none or minimal hepatic dysfunction, and almost never associated with portal hypertension, is common and found during autopsies of adults with sarcoidosis in up to 80% of the cases . In a large series of 60 children, mild liver enzyme elevation was common while severe sarcoid hepatitis extremely rare. Asymptomatic hepatomegaly was seen in up to 43% of patients while splenomegaly was less common. In 80% of those who underwent liver biopsy, granulomas were found . The finding of granuloma in a liver biopsy of a child without other features of sarcoidosis entails a wide differential diagnosis that is beyond the scope of this chapter. Suffice to say here that the presence of significant liver disease with cirrhosis or severe cholestasis should lead the physician to consider other granulomatous conditions including primary biliary cirrhosis, a disease that is extremely rare in pediatrics.
Gastrointestinal involvement
In children, the finding of intestinal granuloma is likely the result of Crohn’s disease, since luminal involvement in sarcoidosis is rare. Extrinsic compression of the stomach outlet by sarcoid adenopathy could cause obstructive symptoms, but is once again extremely rare.
Cardiac involvement
Rare but sometimes fatal in adults (sudden death, conduction abnormalities, cardiomyopathy), this complication has not been described in children to our knowledge.
Blau syndrome
Blau syndrome is an autosomic dominant monogenic disease characterized by a triad of boggy polyarthritis with tenosynovitis, panuveitis and erythematous, scaly tan-colored icthyosiform rash as well as multiple visceral manifestations known as expanded features . The disease is caused by a gain-of-function mutation in or near the NACHT domain of the NOD2 gene and histologically is characterized by well-defined multinucleated giant cell granulomas ( Fig. 4 ). Blau syndrome is the only known monogenic disease associated with gain-of-function mutations and granulomatous inflammation.
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