Mastocitosis pediátricas. Factores clínicos y biológicos que predicen el comportamiento clínico al inicio de la enfermedadestudio prospectivo multicéntrico de 132 pacientes

Resum

BACKGROUND: Pediatric mastocytosis comprise a heterogeneous group of diseases with different prognosis and a wide range of clinical symptoms. While some patients only have slight or no symptoms, the others present a severe clinical behavior even whit life-threatening mast cell-mediator related symptoms. The low prevalence of this entity makes very difficult to determine accurately the factors associated to clinical behavior at onset and to provide therapeutic guidelines. LITERATURE REVIEW: Currently, the cutaneous classification of pediatric mastocytosis distinguishes five variants: maculopapular cutaneous mastocytosis (MPCM), plaque-variant mastocytosis, nodular mastocytosis, mastocytoma and diffuse cutaneous mastocytosis (DCM). Current knowledge about the mast cell-mediator related symptoms at onset and the most useful predictors for patient clinical behavior remains rather limited. This is mainly due to the low prevalence of the disease and the lack of prospective studies in large series of patients with a long follow-up. WORK HYPOTHESIS AND OBJECTIVES: In children with mastocytosis, it is well known that symptoms associated to mast-cell mediators release are more frequent during the first months after the appearance of the skin lesions. However, the potential predicting factors of a severe clinical behavior remain unclear. The main objective of this study is to establish clinical (age of onset of skin lesions and type and extension of skin lesions, among others) and biological factors (serum baseline tryptase and histological findings on skin biopsy, among others) that could predict a severe clinical behavior of the disease, and hence to select the patients that would get benefit of a premature intensive therapy. METHODS: A multicentric, prospective-cohort study was performed between January 2001 and December 2009. Children diagnosed of mastocytosis and referred to the REMA in the first 18 months after the appearance of skin lesions were included in the study. For each patient, physical examination, laboratory analyses, abdominal ultrasonography and skin biopsy were performed. Epidemiologic, clinic, diagnostic, therapeutic, evolutive and socio-economic variables were recorded. The patients were classified according to clinical severity and treated following homogeneous criteria. For considering a patient as “severe” all the following criteria should be present: a) Continuous and intense symptoms (including daily itching, flushing, abdominal pain, diarrhea and/or neuropsychiatric symptoms). b) Need for continuous intensive treatment to ameliorate symptoms (including at least oral anti-histamines H1 and H2 and oral sodium cromolyn). c) Outbreaks requiring hospital admission. The variables included in the study were statistically analysed looking for predicting factors of a severe clinical behavior. RESULTS: A total of 132 patients, 75 males (56.8%) and 57 females (43.2%), were included in the study. Age at the inclusion ranged from 0 to 11 years (median 3 years). Clinical forms included were 56 MPCM (42.4%), 22 nodular mastocytosis (16.7%), 21 plaque-type mastocytosis (15.9%), 20 mastocytomas (15.2%) and 13 DCM (9.8%). A total of 18 patients (13.6%) fulfilled the criteria of severity. Stratifying the severe clinical behavior by clinical forms, 12 (92%) patients with DCM (n=13), 3 patients (14%) with plaquevariant (n=21), 3 patients (13%) with nodular mastocytosis (n=22) and no patients with MPCM (n=56) and mastocytoma (n=20) were severe. The relationship between epidemiologic, clinic and diagnostic variables with severity was analysed. The following variables reached statistic significance in the univariate analysis: fever as a trigger (p=0.003), food as a trigger (p=0.016), stress as a trigger (p<0.001), vaccines as a trigger (p=0.013), diffuse clinical form (p<0.001), localization of lesions at the neck (p=0.001), localization of the lesions at the scalp (p<0.001), continuous vesicle-bullous formation (p<0.001), antecedent of anaphylaxis (p<0.001), diffuse mast-cell infiltrate on skin biopsy (p<0.001), tryptase of 10 ng/mL or more (p<0.001) and ferritine below 20 ng/mL (p=0.028). A logistic regression multivariate analysis was performed. The independent predictor variables of a severe clinical behavior were: diffuse clinical form (OR 84, p<0.001) and tryptase of 10 ng/mL or more (OR 14, p=0.002). CONCLUSIONS: 1. The clinical form and the serum baseline tryptase level are the most important predicting factors of a severe clinical behavior in pediatric mastocytosis. 2. Children with diffuse cutaneous mastocytosis are at high risk for presenting a severe clinical behavior. 3. Children with tryptase equal or higher than 10 ng/mL are at high risk for presenting a severe clinical behavior. 4. The clinical form of cutaneous mastocytosis may predict the severity of clinical behavior: diffuse cutaneous mastocytosis would have a very high risk, nodular and plaque-variant mastocytosis would have an intermediate risk and maculopapular mastocytosis and mastocytoma would have a minimum risk. 5. Patients with diffuse cutaneous mastocytosis, tryptase of 10 ng/mL or more, or patients presenting severe and continuous symptoms (including flushing, diarrhea, abdominal pain or neuropsychiatric symptoms) would benefit of an intensive therapy with antihistamines and oral sodium cromolyn.