[Paediatric prescribing of anti-asthmatics in primary care in Castilla-León. Geographical variability]. / Prescripción pediátrica de fármacos antiasmáticos en atención primaria en Castilla y León. Variabilidad geográfica.

INTRODUCTION AND OBJECTIVES: Asthma is one of the most prevalent chronic diseases with effective treatment in paediatrics. The aim of this study is to describe the paediatric prescribing of anti-asthmatics in Castilla-León, analyzing its geographic variability and temporal evolution. MATERIAL AND METHODS: An analysis was made of prescriptions dispensed in pharmacies of R03 therapeutic subgroup (anti-asthmatic agents), and the active ingredients mepyramine and ketotifen, prescribed in children less than 14 years of age in the Castilla-León health service from 2005 to 2010 in Primary Care. Data is presented in prescribed daily doses per thousand inhabitants per day (PDHD) for each active ingredient being calculated raw rates and age-adjusted to the variables health area, type of health zone and year of study. RESULTS: A total of 462,354 prescriptions of anti-asthmatic agents were dispensed to a population of 1,580,229 persons/year. There was wide variation between areas in the type and intensity of anti-asthmatic agents used, partly explained by differences in the prevalence of asthma. Montelukast predominated as controller drug in most of them (PDHD 3.1 to 7.7), being similar the consumption intensity in the three types of health zones (PDHD 4.7 to 4.8). The annual variability was low. CONCLUSIONS: The study describes the paediatric prescribing pattern of anti-asthmatic agents in Castilla-León between 2005-2010. It shows wide geographical variation, as well as inadequacies regarding current recommendations of asthma treatment.

Anti-asthmatic prescription variability in children according to age.

INTRODUCTION: There is little research in the Spanish paediatric population about the consumption of anti-asthmatic agents. The aim of this study was to describe the current pattern of anti-asthmatic drug prescription in the paediatric population from a region of Spain, using the prescribed daily dose as a unit of measurement. METHODS: We analysed the requirements of R03 therapeutic subgroup (anti-asthmatic agents) in children less than 14 years of age in the Public Health System of Castilla y León from 2005 to 2010. Consumption data are presented in prescribed daily doses per thousand inhabitants per day (PDHD) and compared with defined daily doses per thousand inhabitants per day (DHD). RESULTS: 394 876 prescriptions of anti-asthmatics were given to a population of 1 580 229 persons/year. Bronchodilators, leukotriene receptor antagonists, single inhaled corticosteroids (ICS) and long-acting ß2-adrenergics associated with inhaled corticosteroids were the most commonly prescribed drugs: 7.5, 5.2, 4.9 and 2.2 PDHD, respectively. The maximum prescription of bronchodilators (15.9 PDHD/9.8 DHD) occurred in children under 12 months, with montelukast (8.9 PDHD/3.6 DHD) and single inhaled corticosteroids (7.9 PDHD/2.9 DHD) at one year of age. CONCLUSIONS: Between 2005 and 2010, children under four years received a high prescription of anti-asthmatic drugs. The use of maintenance therapy was poorly aligned with the recommendations of asthma guidelines. The PDHD was more accurate for measuring consumption than DHD, especially in younger children.

[Prescription of systemic cold and cough drugs to children 0-13 years old. An unresolved problem]. / Prescripción de fármacos anticatarrales de uso sistémico a niños de 0-13 años. Un problema no resuelto.

INTRODUCTION AND OBJECTIVES: Upper respiratory tract infections are the most common cause of paediatric consultation, generating a high volume of prescriptions of drugs with unfavourable risk-benefit ratio. The aim of this study is to describe the prescription of systemic cough and cold medicines to children under 14 years of age in Castilla y León and analyse its variability. POPULATION AND METHODS: A count was made of the prescriptions for the R05 therapeutic subgroup (antitussives and mucolytics) and the R01B pharmacological therapeutic subgroup (nasal decongestants for systemic use), prescribed for children under the age of 14 in the Public Health System between 2005-2010. The number of prescriptions was analysed as crude and age-adjusted rates, as well as a a multivariate analysis (Poisson regression) of the variability associated with health area, the urban/rural environment, age, and year of prescription. RESULTS: There were 806,785 prescriptions for systemic cough and cold drugs given to an exposed population of 1,580,229 person-years. Prescription rates (per 100 person-years) were 20.7 (antitussives), 7.0 (sympathomimetic) and 23.4 (mucolytics). These drugs were employed more often in children <4 years. The prescription of mucolytics and sympathomimetics was highest at age of 1 year (rates=41.9 and 18.7, respectively) and of antitussives at 3 years (35.7). Multivariate analysis showed that in rural areas the prescription was higher than in urban areas, and that there were also significant differences between health areas. CONCLUSIONS: Between 2005 and 2010 there was a high prescription of systemic cough and cold medicines, especially in children under 2 years old, and often outside the recommended conditions of use, and there was a high geographic variabilty.

[Cerebral sinovenous thrombosis in a girl with acute lymphoblastic leukaemia carrying the prothrombin G20210A variant]. / Trombosis de senos venosos cerebrales en una niña con leucemia linfoblástica, portadora de la variante de la protrombina G20210A.

Although cerebral venous thrombosis is rare, it is more commonly associated with children suffering from acute lymphoblastic leukaemia. We report the case of a 7-year-old girl who developed massive cerebral sinovenous thrombosis on day 22 of induction therapy for high-risk acute lymphoblastic leukaemia. Clinical symptoms were gradual onset of headache, decreasing consciousness, and ensuing left hemiplegia. A subsequent prothrombotic study revealed a heterozygous prothrombin G20210A variant in the child and mother. We analysed the prothrombotic factors found in the case before and after thrombosis. We confirm the importance of early exploration of patients for clinical predisposing risk factors of thrombosis and primary prothrombotic states in children with acute lymphoblastic leukaemia. This might help identify patients at particular risk from thrombosis and so administer thromboprophylaxis.

Ascorbate-dependent decrease of the mucosal immune inflammatory response to gliadin in coeliac disease patients.

BACKGROUND: The IL-15/NF-κB axis has an important role in coeliac disease (CD) and may represent a molecular target for immunomodulation. Ascorbate (vitamin C) is known to show inhibitory effects on NF-κB. Therefore, we studied if ascorbate supplementation to gliadin gliadin-stimulated biopsy culture could down-regulate the mucosal immune response to gliadin in CD. METHODS: Duodenal biopsy explants from treated CD patients were gliadin challenged in vitro (100 µg/ml) with and without 20mM ascorbate. An extra tissue explant in basal culture was used as internal control. Secretion levels of nitrites (3h), and IFNγ, TNFα, IFNα, IL-17, IL-13, and IL-6 (24h) were measured on the supernatants. IL-15 was assayed by western-blot on whole protein duodenal explants. RESULTS: The addition of ascorbate to in vitro culture gliadin-challenged biopsies blocked the secretion of nitrites (p=0.013), IFNγ (p=0.0207), TNFα (p=0.0099), IFNα (p=0.0375), and IL-6 (p=0.0036) compared to samples from non-ascorbate supplemented culture. Cytokine secretion was downregulated by ascorbate even to lower values than those observed in basal cultures (IFNγ: p=0.0312; TNFα: p=0.0312; IFNα: p=0.0312; and IL-6: p=0.0078). Gliadin-challenge induced IL-15 production in biopsies from treated CD patients, while the addition of ascorbate to culture medium completely inhibited IL-15 production. Moreover, the inhibition of IL-15 by ascorbate took place even in the only treated CD-patient who had basal IL-15 production. CONCLUSIONS: Ascorbate decreases the mucosal inflammatory response to gluten in an intestinal biopsy culture model, so it might have a role in future supplementary therapy in CD.

Diet and prevalence of atopic eczema in 6 to 7-year-old schoolchildren in Spain: ISAAC phase III.

BACKGROUND: The prevalence of atopic dermatitis (AD), a chronic skin disease, has increased substantially in recent decades, and different factors have been implicated in its etiology. Although dietary habits are being investigated, few conclusive findings have been reported. Nevertheless, increased consumption of polyunsaturated fatty acids (PUFA) and a diet poor in antioxidants have been related to AD. OBJECTIVES: The objectives of this study were to investigate the association between AD, the intake of different foods, and the effect of a Mediterranean diet among Spanish schoolchildren aged 6 to 7. METHODS: We performed a cross-sectional study with 20 106 schoolchildren aged 6-7 years from 10 different areas of Spain. The participation rate was 76.50%. The prevalence of AD was assessed using the International Study of Asthma and Allergies in Childhood questionnaire and the criteria of the Spanish Academy of Dermatology. To calculate the Mediterranean diet score, we classified food into 2 groups: Mediterranean food, including fruit, seafood, vegetables, pulses, cereals, pasta, rice, and potatoes; and non-Mediterranean food, including meat, milk, and fast food. RESULTS: Milk was negatively associated with AD. Butter and nuts also were negatively associated, although statistical significance was only reached when these foods were consumed 3 or more times a week. CONCLUSIONS: We found no association between the Mediterranean diet score and AD and a positive association between AD and obesity.

From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome.

The term autoimmune enteropathy (AIE) was applied to a form of "intractable diarrhoea" with serum gut autoantibodies, characterized by male predominance, early onset, poor response to parenteral nutrition and several autoimmune diseases, mainly type 1 diabetes. In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis. The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells (Treg) expressing CD4+ and CD25+ molecules. Mutations of the FOXP3 gene, located in X chromosome, produce a syndrome with Immune dysfunction, Polyendocrinopathy, Enteropathy and X-linked inheritance (IPEX). The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome, even in female patients who may have some autosomal genetic variants. Besides FOXP3, other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes. Meanwhile, the important pathogenic role previously ascribed to gut autoantibodies has vanished, with it remaining as having only certain screening usefulness.

Higher constitutive IL15R alpha expression and lower IL-15 response threshold in coeliac disease patients.

The IL-15 triggering effect of gliadin is not exclusive to coeliac disease (CD) patients, whereas the secondary response is CD specific. We have studied the expression of the IL-15 receptor, and the IL-15 response upon stimulation, in non-CD and CD patients, and the possible existence of a lower immunological threshold in the latter. Forty-two CD patients (20 on a gluten-containing diet, GCD, and 22 on gluten-free diet, GFD) and 24 non-CD healthy individuals were studied. IL15R alpha mRNA expression, and tissue characterization, were assayed in the duodenum. Biopsies from six CD patients on GFD and 10 non-CD individuals were studied in vitro using organ culture in basal conditions, as well as after IL-15 stimulation discarding basal IL-15 production. Secretion of immune mediators was measured in the culture supernatants. IL15R alpha mRNA expression was increased in CD patients, as compared with non-CD controls (on GFD P = 0.0334, on GCD P = 0.0062, respectively), and confirmed also by immunofluorescence. No differences were found between CD patients on GFD and on GCD. After in vitro IL-15 stimulation, IL15R alpha expression was only triggered in non-CD controls (P = 0.0313), though it remained increased in CD patients. Moreover, IL-15 induced a more intense immunological response in CD patients after triggering the production of both nitrites and IFN gamma (P = 0.0313, P = 0.0313, respectively). Gliadin-induced IL15 has a lower response threshold in CD patients, leading to the production of other immune mediators and the development of the intestinal lesion, and thus magnifying its effects within the CD intestine.

How the presence of rhinoconjunctivitis and the severity of asthma modify the relationship between obesity and asthma in children 6-7 years old.

BACKGROUND: The association between asthma and obesity in children, and the effect modification of allergy on this association have not been fully established. Aims The objective of the study was to know the effect modification of the severity of asthma and of the coexistence of rhinoconjunctivitis (RC) in the relationship between obesity and asthma. METHODS: A cross-sectional study of 17 145 schoolchildren 6-7 years old from eight Spanish cities who had completed information on height and weight of the ISAAC phase III questionnaire, which also included questions about asthma and RC symptoms and on various risk factors. Body mass index (BMI) was used to define obesity according to international standards. Two different logistic regressions, using current occasional asthma (COA) and current severe asthma (CSA) as dependent variables, were made stratifying for gender and for the coexistence of RC and controlling for age, older and younger siblings, exercise, mother's education, truck traffic, cat/dog during the first year of life and smoking father or mother. RESULTS: Obesity was a risk factor of CSA without RC, both for boys (1.92, CI 95% 1.13-3.25) and for girls (2.99, CI 95% 1.68-5.32). Every BMI unit increment increased by 6.7% the risk of CSA without RC in boys and by 12.4% in girls. Obesity was not a risk factor for CSA with RC. The association between COA and obesity was weaker and the coexistence of RC did not modify it greatly. CONCLUSIONS: Obese schoolchildren are more at risk of suffering from non-allergic asthma than the non-obese subjects.

Parents' smoking habit and prevalence of atopic eczema in 6-7 and 13-14 year-old schoolchildren in Spain. ISAAC phase III.

BACKGROUND AND AIMS: Atopic eczema (AE) is the most frequent inflammatory skin disease in childhood in the western world. Several studies have reported a significant increase of prevalence in recent decades and the environmental factors implicated in its aetiology, including environmental tobacco smoke. This study aims to investigate the possible association of AE prevalence in Spanish schoolchildren aged 6-7 and 13-14 years in relation to their parents' smoking habits. METHODS: We conducted a cross-sectional population-based study with 6-7 year-old (n = 27805) and 13-14 year-old (n = 31235) schoolchildren from 10 Spanish centres. AE prevalence was assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, and the Spanish Academy of Dermatology criteria, used in Spain to diagnose AE. RESULTS: An association was found in school-children aged 6-7 (adjusted for gender, presence of asthma, presence of rhinitis, siblings and mother's level of education) between AE being clinically diagnosed with the mother's smoking habit (RPRa 1.40, 1.10-1.78) and there being more than 2 smokers at home (RPRa 1.34, 1.01-1.78). Regarding the presence of itchy rash, an association was observed with fathers who smoke (RPRa 1.40, 1.13-1.72). Among the 13-14 year-olds, no association was observed in relation to either clinically diagnosed AE or the appearance of itchy rash with parents' smoking habit. CONCLUSIONS: Our results indicate the risk for children of being exposed to environmental tobacco smoke in terms of AE, especially when they are younger.

[Interleukin 18 (IL-18) and other immunological parameters as markers of severity in acute pancreatitis]. / Interleucina-18 (IL-18) y otros parámetros inmunológicos como marcadores de gravedad en la pancreatitis aguda.

OBJECTIVE: Our aim was to prospectively compare the behavior of interleukin 18 (IL-18) levels and other immunological parameters during the first week of hospitalization between acute pancreatitis patients with and without severity criteria, as well as between patients with and without late pseudocyst development. PATIENTS AND METHODS: In 36 patients with acute pancreatis we compared sTNF-RI, IL-1Ra, IL-6, and IL-18 levels at days 1, 2, 3 and 7 after hospitalization between mild pancreatitis, severe pancreatitis, and a "control" group (13 patients) with uncomplicated biliary colic, as well as between patients with and without pseudocyst. RESULTS: On comparing mild to severe pancreatitis, IL-18 was significantly higher only the first day in severe pancreatitis, while the other parameters were steadily higher after the second day. In patients developing pseudocyst, IL-18 was also noticeably higher the first day. CONCLUSIONS: IL-18 appears to be the earliest marker of complications and severity in acute pancreatitis at both the systemic and local level (pseudocyst).

Common variable immunodeficiency. Old questions are getting clearer.

Common variable immunodeficiency (CVID) is a heterogeneous entity characterized by an impaired ability to produce antibodies. The failure is localized in partially mature B lymphocytes, though T lymphocyte abnormalities are occasionally present. This deficiency affects antibody synthesis and class switch from IgD and IgM, to IgG and IgA. CVID is related to selective IgA deficiency, and both abnormalities may coincide in one same family, and evolve from one to another in the same patient. The symptoms generally manifest in adults, but can occur at any age, even in infancy. Recurrent bacterial infections or pneumonias are frequent, and may be complicated by gastrointestinal problems, granulomas, autoimmune disorders or malignancies. A defect in memory B cells seems to condition the clinical severity. Recently, several mutations in genes encoding for molecules (CD19, TACI, ICOS) involved in B cell survival and isotype switch have been identified in patients with CVID. Nevertheless, genetic abnormalities have been found in less than 25 % of cases with CVID; the underlying mechanism thus remains unknown in the majority of CVID patients, and research in this field must continue.

Interleukin 18 maintains a long-standing inflammation in coeliac disease patients.

Dietary gluten induces an early response in the intestine of coeliac disease patients (CD), within a few hours, and this is driven by high levels of proinflammatory cytokines, including IFNgamma and IL-15, as has been thoroughly shown by gluten stimulation of biopsy explants. Our aim was to identify the immune mediators involved in the long-standing inflammation in untreated CD patients at diagnosis. mRNA and protein levels of TNFalpha, IL-12(p35), IL-12(p40), IL-15, IL-18 and IL-23(p19) were quantified in biopsies from active CD patients, CD patients on a gluten-free diet (GFD), healthy controls, and patients with non-CD inflammation and mild histological changes in the intestine. Biopsies from CD patients on a GFD were also stimulated in vitro with gliadin, and protein expression of IL-15 and IL-18 was analysed. Levels of IL-12 and IL-23 mRNA are nearly absent, and TNFalpha levels remain unchanged among different groups. Both the active and inactive forms of IL-18 protein have been found in all samples from active CD, and protein expression was only localized within the crypts. Levels of IL-15 mRNA remain unchanged, and protein expression, localized within the lamina propria, is found in a small number of samples. In vitro stimulation with gluten induces the expression of IL-15 and IL-18. In active CD, the early response following gluten intake characterized by high IFNgamma levels is driven by IL-18, and probably IL-15, and this alternates with periods of long-standing inflammation with moderate IFNgamma levels, maintained by IL-18 alone.

[Risk factors for atopic dermatitis and familial prevalence in Spain (ELIHO study)]. / Factores de riesgo y prevalencia familiar de la dermatitis atópica en España (estudio ELIHO).

INTRODUCTION: Atopic dermatitis (AD) is a cutaneous disease of unknown etiology. It shows a clear genetic predisposition with probable environmental modulation. This study evaluated risk factors associated with diagnosis and flares of AD in Spanish children. PATIENTS AND METHODS: We performed an observational, multicenter, retrospective case-control study that included 4243 children aged less than 14 years old with AD and 978 controls matched for age and sex. Family history of disease and environmental variables were collected in both groups and clinical history of AD was recorded in the case group. RESULTS: Significant risk factors for AD were: a family history of the disease and concomitant cutaneous infections. The prevalence of AD in first degree relatives was 39 % and that in second degree relatives was 19 % (higher in maternal than paternal lines). The mean age of children with AD was 4.2 (SD 3.4) years and the mean age at diagnosis was 1.5 (SD 2.2) years, with a mean of 2.9 (SD 2.6) flares during the previous year. Cold weather (Cantabrian and Continental Iberian Peninsula areas) was related to a greater number of flares. Children with AD had a greater number of concomitant cutaneous diseases and infections than children in the control group. CONCLUSIONS: AD is mainly a genetic disease, with climatic factors involved in severity modulation, and with important immunological alterations. In contrast, this study found no domestic environmental factors that were associated with disease onset.