2. Pediatric Sarcoidosis—Epidemiology
Since 2008, with the Danish series, around 22 manuscripts on pediatric sarcoidosis have been published annually, compared to over 900 for adult sarcoidosis, with more than half being case reports
[6]. Pediatric sarcoidosis is extremely rare, with only three reported cohorts: Danish (Caucasian), French (Afro-Caribbean), and Louisiana (Afro-American) patients. Most patients were aged 11–13 years. The disease seemed severe in children, involving multiple organs, and was often persistent in adulthood
[7]. The diagnosis of sarcoidosis is relatively uncommon in children, and the manifestations of the disease may be different in children compared to adults
[8]. Sarcoidosis is 3–4 times more common and more aggressive in black than in white patients
[9]. Furthermore, the lifetime risk of developing sarcoidosis is higher in African Americans (2.4%) than in whites (0.8%)
[10], although the true incidence and prevalence are unknown due to the limited number of reported cases in children. A recent study among Danish patients estimated an incidence of approximately 0.29 per 100,000 person-years in children under 15 years of age. The incidence of pediatric sarcoidosis ranged from 0.06 per 100,000 person-years for children under 5 years of age to 1.02 per 100,000 person-years for children aged 14 to 15 years
[11]. Most pediatric cases have been reported in children between 13 and 15 years of age. At the onset, the researchers' patient had an age close to the maximum incidence of the disease in children.
3. Sarcoidosis—Etiopathology
Sarcoid granulomas represent an intensely interconnected network of immune cells, including macrophages, dendritic cells, T helper lymphocytes, T regulatory cells, and their mediators. After years of investigations and advances in medical science, the immunopathogenesis of sarcoidosis remains evasive. One or multiple antigens may trigger an exaggerated cell-mediated immune response resulting in granulomatous inflammation. These antigens, possible etiologic agents, vary from occupational or environmental factors to infectious agents, and, of course, genetic contribution may play an important role
[12][13][14]. A multicenter National Institutes of Health (NIH)-funded ACCESS case-control study of over 700 patients and around 30,000 relatives revealed that no single etiologic agent and no genetic locus was clearly implicated in the pathogenesis of sarcoidosis
[15]. Recent findings concerning T cell sensitization to aluminum, beryllium, silica, or zirconium in some cases of sarcoidosis suggest the role of triggers in different clinical phenotypes
[16]. Several proteins, such as vimentin, a major constituent of the intermediate filament family of proteins expressed in normal mesenchymal cells and involved in maintaining cellular integrity and resistance against stress, along with tubulin and alpha-actinin-4, may induce similar patterns of cytokine secretion by sarcoidosis peripheral blood mononuclear cells
[17][18].
4. Sarcoidosis—Laboratory Diagnosis
Sarcoidosis is diagnosed based on clinical and imaging manifestations as well as the histopathological detection of non-caseating granulomas at the level of the affected organs after excluding other diseases. No laboratory marker can be conclusive for the diagnosis of sarcoidosis, although serum angiotensin-converting enzyme is among the most commonly used diagnostic biomarkers for sarcoidosis; however, the test is nonspecific and lacks sensitivity
[19]. Regarding sarcoidosis, vitamin D and its metabolism are noteworthy due to their crucial involvement in immune system regulation and granulomatous inflammation. The expression of 1-α-hydroxylase is present in numerous tissues, but only the kidneys, activated macrophages, and placenta have the ability to affect plasma 1,25(OH)2D3 levels through hydroxylation
[20]. Hypercalciuria, hypercalcemia, and elevated levels of 1,25-dihydroxy vitamin D (1,25(OH)2D) may also occur in patients with sarcoidosis due to the overproduction of 25-hydroxy vitamin D-1 α-hydroxylase
[21][22]. Recent studies involving adult patients have suggested that serum levels of soluble interleukin-2 receptor (sIL-2r) represent a superior and more sensitive biomarker than serum ACE levels in supporting the diagnosis of systemic sarcoidosis
[23][24]. It seems that the level of sIL-2r correlates with the level of disease activity and may indicate multisystem involvement
[25]. However, most studies of sarcoidosis biomarkers have been conducted only among adult patients.
5. Pediatric Sarcoidosis—Clinical Findings
Regarding the clinical presentation, extrapulmonary manifestations were observed more frequently in symptomatic children and adolescents than in adults
[10]. Liver involvement in sarcoidosis is relatively common, with an estimated prevalence of 11.5 to 30% of patients with sarcoidosis
[26]. Little is known about the natural course of hepatic sarcoidosis, as most patients remain asymptomatic for a long time. However, some patients may develop severe complications such as cirrhosis and portal hypertension
[27][28]. The researchers' patient developed liver damage simultaneously with kidney damage, manifested by portal hypertension syndrome. The liver biopsy performed on admission revealed chronic granulomatous hepatitis with giant cells, which is highly suggestive of sarcoidosis. Very few pediatric series with prolonged follow-ups have been reported. In a series of 52 patients (34 followed prospectively from childhood and 18 retrospectively in adulthood), Chauveau et al., found that the age at onset was 12 (±2.7), and the relapses occurred mainly during the de-escalation of therapy or in the first three years after the interruption of the treatment; rarely is the disease in remission for more than three years. Sarcoidosis was more severe in adulthood
[25].
6. Pediatric Sarcoidosis—Renal Involvement
The reported prevalence of kidney involvement in sarcoidosis varies widely due to the study design and enrolled patient populations, but also due to the heterogeneity and asymptomatic nature of renal disease. Kidney lesions associated with sarcoidosis are represented by specific histological changes in the disease or by abnormal calcium metabolism, nephrolithiasis, and nephrocalcinosis. The renal manifestations in sarcoidosis are represented by hypercalcemia and hypercalciuria, nephrolithiasis and nephrocalcinosis, granulomatous or non-granulomatous interstitial nephritis, glomerular and tubular disease, and ureteral obstruction
[29]. A variety of glomerular lesions, including membranous nephropathy, focal segmental sclerosis, mesangioproliferative glomerulonephritis, IgA nephropathy, or crescentic glomerulonephritis, are described as glomerular damage in sarcoidosis, without being able to distinguish it from the primary form of these entities. Tubular dysfunctions can affect the isolated proximal or distal renal tubule, but also in the context of tubulopathy Fanconi syndrome. Polyuria is a common clinical feature, mostly due to hypercalcemia
[30]. The researchers' patient had the same types of manifestations at the onset. Initially, the researchers considered the case to be end-stage kidney disease (ESRD) because he had a chronic evolution over one year. First, the researchers thought of a glomerular pathology, such as focal segmental glomerulosclerosis (FSGS), because of proteinuria, hematuria, and kidney failure. The diagnosis of FSGS is exclusively bioptic because there are no distinctive clinical features that differentiate it from other types of chronic glomerulopathy. FSGS in children is often coupled with the risk of progression toward end-stage renal disease
[31], similar to the researchers' patient, with one-year evolution of hypercalcemia and elevated serum urea and creatinine levels. Thus, the researchers reconsidered the approach because the patient had normal kidney sizes and a good response to corticosteroid therapy, reducing the need for hemodialysis until this therapy was stopped. Therefore, the researchers determined that the patient had acute decompensation of chronic kidney disease (CKD) secondary to sarcoidosis. Prolonged hypercalcemia is responsible for a decrease in the glomerular filtration rate by vasoconstriction of the afferent arteriole. Intracellular calcium overload and tubular obstruction by calcium precipitates lead to acute tubular necrosis. In the absence of adequate treatment, hypercalcemia and hypercalciuria are not reversible, leading to fibrosis, and the damage becomes irreversible
[32][33].
Nephrocalcinosis is a result of chronic hypercalciuria and is a rare finding in sarcoidosis
[34]. It is present in less than 5% of patients with sarcoidosis but in a higher rate of patients with renal insufficiency
[35]. Nephrocalcinosis is a significant cause of chronic kidney disease
[36]. Hypercalcemic nephropathy is the main cause that leads to ESRD in renal sarcoidosis, with some cases requiring some form of kidney replacement therapy. Mahevas et al., conducted a study among 46 patients with sarcoidosis-related interstitial nephritis, and only two progressed to ESKD
[37]. Nephrolithiasis was reported in about 10% of patients with sarcoidosis, with a prevalence range between 3 and 14%
[32]. More recently, Klaus et al., performed a literature review and found a total of 36 cases of renal involvement in pediatric sarcoidosis. The study showed that AKI is a common feature (86%) in pediatric sarcoidosis with renal involvement. Granulomatous interstitial nephritis (GIN) was the predominant histology (66%), and 47% had hypercalcemia. The patients with hypercalcemia showed a trend toward a better prognosis. The negative predictor factors toward CKD are represented by GIN, concentration impairment, and the intensity of GFR impairment at presentation
[38].
7. Pediatric Extrapulmonary Sarcoidosis—Treatment
Depending on the involvement, extrapulmonary sarcoidosis may benefit from local treatment, escalation of systemic treatment, or multimodal interventions
[39]. The majority of studies regarding the treatment of symptomatic sarcoidosis have focused on pulmonary disease
[40]. The goals of treatment in sarcoidosis are to prevent permanent end-organ dysfunction, reduce mortality, and preserve the quality of life. Studies in this area are limited. In previously reported cases, the duration of treatment varied from 1 month to 23 years
[3][4][5][6][41][42][43]. Treatment should target the granulomatous process (anti-inflammatory drugs) as well as organ-targeted and supportive treatments. The treatment of organ dysfunction can improve the outcome of sarcoidosis and includes non-pharmacological therapies (pacemakers, CSF diversion for hydrocephalus management, and heart, kidney, and liver transplantation) or pharmacological therapies (hormone replacement, antiepileptic drugs, or psychiatric drugs, etc.)
[44][45]. Corticosteroids remain the first-line treatment, although they have significant cumulative side effects. Therapies such as alkylating agents, immunosuppressive medication, calcineurin inhibitors, and TNF-α inhibitors can be used in refractory or relapsing diseases or when corticosteroids cause unacceptable toxicity. Methotrexate and infliximab have demonstrated significant efficacy and an acceptable safety profile in cardiac sarcoidosis, for example,
[46]. Chronic kidney disease is a contraindication for treatment with methotrexate. Thiopurine S-methyltransferase (TPMT) deficiency is a contraindication for the use of azathioprine
[47]. Renal sarcoidosis after kidney transplantation is rare, usually follows a mild clinical course and is responsive to increased immunosuppression. It has been recently reported that it is safe to perform renal transplantation in sarcoidosis with close clinical and histological monitoring
[48].
8. Pediatric Extrapulmonary Sarcoidosis—Evolution
Advanced sarcoidosis refers to manifestations of the disease with high mortality (pulmonary fibrosis, pulmonary hypertension, cardiac sarcoidosis, renal sarcoidosis, and neurosarcoidosis) and requires treatment in the stage of disease activity, with long-term maintenance therapy being controversial
[49]. Treatment protocols for pediatric renal sarcoidosis are not yet well established. In all reported cases, prednisolone was the standard treatment. Several immunosuppressants, including mycophenolate mofetil, cyclophosphamide, and methotrexate, were added in refractory cases or to spare steroids, and also TNF-α inhibitors (Infliximab) were used after steroid-resistant/refractory disease
[50][51]. The outcome of kidney transplantation is not well known, and the recurrence of renal sarcoidosis has been described in adults
[52][53]. For children, the outcome is variable for sarcoidosis, ranging from spontaneous remission to end-stage renal disease. Early diagnosis and prompt treatment with corticosteroids can improve prognosis
[54]. Hypercalcemia can be responsible for acute kidney injury (AKI) caused by vasoconstriction of afferent arterioles
[55], as in the case presented, but which, in the context of persistent hypercalcemia, was complicated by nephrocalcinosis. In patients with ESRD, dialysis and transplantation can provide results comparable to those observed in patients with other causes of renal failure.
9. Pediatric Extrapulmonary Sarcoidosis—Prognosis
The prognosis of the disease is generally good, with the exception of patients with severe cerebral deterioration or those with frequent relapses
[56]. The presence of hydrocephalus implies a mortality of up to 75%
[57]. Classically, the prognosis of sarcoidosis in children depends on the age of onset, the extent of the disease, and the response to corticosteroids. However, the prognostic factors still remain unclear in children
[42]. In children, studies on the natural history of sarcoidosis are rare. In the Danish cohort with a median follow-up of 15 years, 78% of patients recovered completely, 11% still had active disease, 4% had remission with organ involvement, and 7% died
[4][43][58]. Being a complex systemic disease, sarcoidosis can present itself with a wide range of signs and symptoms, being often considered one of the important “imitators” in pathology. In this context, a multidisciplinary approach to the patient is necessary. Early identification and establishment of the therapeutic strategy influences the morbidity and mortality of the disease. Mortality in sarcoidosis is affected by factors such as age, gender, race, organ involvement, care, and treatment and is estimated to be 1–8%
[59]. The treatment of sarcoidosis can also lead to complications (infections, malignancy), which can influence the prognosis of the disease. Immunosuppressive drugs have been shown to increase the risk of infection in sarcoidosis
[60]. In the literature, the relationship between sarcoidosis and malignancy is well known. According to the results of various studies, sarcoidosis has been considered a risk factor for the development of cancer, especially lymphoproliferative cancer
[61]. In general, diseases can be classified according to their activity or severity, but in sarcoidosis, disease activity does not necessarily indicate a fatal prognosis or the need for treatment. This is a challenge for the clinician, who faces many difficulties when trying to classify late-onset pediatric sarcoidosis.