Mast cells are associated with exacerbations and eosinophilia in children with severe asthma.

The role of mast cells in the pathogenesis of childhood asthma is poorly understood. We aimed to estimate the implication of airway mucosal mast cells in severe asthma and their relationship with clinical, functional, inflammatory and remodelling parameters.Bronchial biopsies were performed in 36 children (5-18 years) with severe asthma: 24 had frequent severe exacerbations and/or daily symptoms in the previous year (symptomatic group), and 12 had few symptoms and a persistent obstructive pattern (paucisymptomatic group). Nine children without asthma were included as control subjects. We assessed mast cells in the submucosa and airway smooth muscle using c-kit antibodies and in the entire biopsy area using Giemsa.The number of submucosal mast cells was higher in the symptomatic group than in the paucisymptomatic group (p=0.02). The number of submucosal mast cells correlated with the number of severe exacerbations (p=0.02, r=0.37). There were positive correlations between the number of submucosal mast cells (p<0.01, r=0.44), airway smooth muscle mast cells (p=0.02, r= 0.40), mast cells stained by Giemsa (p<0.01, r=0.44) and submucosal eosinophils.Mast cells are associated with severe exacerbations and submucosal eosinophilic inflammation in children with severe asthma.

New insights into the treatment of severe asthma in children.

Severe asthma accounts for 0.5% of the general paediatric population and 4.5% of children with asthma, representing the major burden of asthma-health-care-associated costs. After ensuring a diagnosis of asthma and excluding difficult-to-treat patients with co-morbidities and non-adherence profiles, there remains children with real therapy-resistant asthma for whom the recommendations are to treat beyond guidelines. We describe new insights into the treatment of severe asthma in children, regarding both "classic drugs" (corticosteroids, bronchodilators) and innovative biological therapies targeting airway inflammation and impaired innate immunity. All of these new avenues remain to be studied and validated in children and will require fine clinical and biological phenotyping.

Beta-lactam hypersensitivity in children with cystic fibrosis: a study in a specialized pediatric center for cystic fibrosis and drug allergy.

BACKGROUND: Beta-lactam hypersensitivity (HS) is suspected in 5-12% of the children, but proven in only 10-15% of those children, based on skin and challenge tests results. In contrast, 30-60% of patients with cystic fibrosis (CF) are diagnosed allergic to beta-lactams, based mainly on the clinical history of the patients. OBJECTIVES: To confirm or rule out a suspected beta-lactam HS in CF children and to determine the prevalences of suspected and confirmed beta-lactam HS in those children. PATIENTS AND METHODS: Children with CF and suspected beta-lactam HS were explored by means of skin and challenge tests with the suspected and alternate beta-lactams. The results in CF children were compared with those reported in the literature in non- CF children. RESULTS: Eight of the 701 CF children followed in our center between 1990 and 2011 (1.14%), and 11 other children from other centers were explored for suspected beta-lactam HS. Beta-lactam HS was diagnosed in nine of these children (47.3%). Based on the results in the children followed in our center, the prevalence of beta-lactam HS was 0.71% (5/701) in CF children vs. a mean estimated prevalence of 1-1.5% in the general pediatric population. CONCLUSION: Our results contrast with those of most previous studies. Although half of the CF children with suspected beta-lactam HS were truly allergic to beta-lactams, the general prevalence of beta-lactam HS in CF children was very low. This may result from tolerance induced by frequent and/or prolonged treatments with beta-lactams.

Asthma control assessed in the EGEA epidemiological survey and health-related quality of life.

BACKGROUND: The aims were to assess 1) the relationship of asthma control assessed by combining epidemiological survey questions and lung function to Health-Related Quality of Life (HRQL) and 2) whether individuals with controlled asthma reach similar generic HRQL levels as individuals without asthma. METHODS: The analysis included 584 individuals without asthma and 498 with asthma who participated in the follow-up of the Epidemiological study on Genetics and Environment of Asthma (EGEA). Asthma control was assessed from survey questions and lung function, closely adapted from the 2006-2009 Global Initiative for Asthma guidelines. The Asthma Quality of Life Questionnaire (AQLQ, scores range:1-7) and the generic SF-36 (scores range: 0-100) were used. RESULTS: Adjusted mean total AQLQ score decreased by 0.5 points for each asthma control steps (6.4, 5.9 and 5.4 for controlled, partly-controlled and uncontrolled asthma respectively, p < 0.0001). The differences in SF-36 scores between individuals with controlled asthma and those without asthma were minor and not significant for the PCS (-1, p = 0.09), borderline significant for the MCS (-1.6, p = 0.05) and small for the 8 domains (<5.1) although statistically significant for 4 domains. CONCLUSION: These results support the discriminative properties of the proposed asthma control grading system and its use in epidemiology.

Passive and active smoking and exhaled nitric oxide levels according to asthma and atopy in adults.

BACKGROUND: No data are available regarding the utility of fractional exhaled nitric oxide (FeNO) level in guiding therapy in smoking asthmatic patients. Identification of the effect of smoking in a large sample is needed. OBJECTIVE: To study the association between smoking and FeNO level according to current asthma and atopy status in adults from the French EGEA (Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy). METHODS: Levels of FeNO were measured at 50 mL/s in 654 adults (268 asthmatic participants). Active smoking and environmental tobacco smoke (ETS) exposure at home, at work, and during leisure activities were recorded. Participants were categorized as having no exposure to ETS, mild exposure (ETS <2 h/d), and noticeable exposure (ETS > or = 2 h/d). Multivariate analyses were performed, with adjustment for age, sex, height, and center. RESULTS: Mean adjusted FeNO values increased with asthma (15.1 vs 19.5 ppb), atopy (14.2 vs 18.9 ppb), and eosinophilia (15.8 vs 24.8 ppb) (P < .001 for all). Mean FeNO levels decreased with smoking (18.4, 17.5, and 14.5 ppb in nonsmokers, ex-smokers, and current smokers, respectively; P for trend = .001). The association with smoking was observed in nonasthmatic and asthmatic participants, especially in atopic asthmatic participants. Multivariate analyses showed that ETS exposure of at least 2 h/d and active smoking were negatively and significantly associated with FeNO levels independent of age, sex, height, and center in nonasthmatic participants (mean [SE], -0.13 [0.06], P = .03 and -0.10 [0.03], P < .001) and in asthmatic participants (mean [SE], -0.18 [0.07], P = .01 and -0.14 [0.04], P = .02). CONCLUSIONS: Active and passive smoking decreased FeNO levels in adults. Careful consideration of asthma, atopy, and active and passive smoking are needed to interpret FeNO values.

Phenotypic determinants of uncontrolled asthma.

BACKGROUND: Although uncontrolled asthma remains frequent, determinants of asthma control are poorly studied. OBJECTIVES: The aim was to estimate the distribution and the phenotypic characteristics of asthma control in 2 groups of subjects defined by the use of inhaled corticosteroids (ICS) in the past 12 months, in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). METHODS: Five hundred one adult current patients with asthma who participated in the follow-up of the EGEA study were included. Asthma control was assessed from survey questions reflecting asthma control, as defined in the 2006 Global Initiative for Asthma guidelines. The factors analyzed were age, sex, educational level, body mass index, active and passive smoking, sensitization to aeroallergens, total IgE, rhinitis, chronic cough/phlegm, and age at asthma onset. Analyses were stratified according to ICS use. RESULTS: Uncontrolled asthma was more frequent in ICS users (27.6%, 35.0%, and 37.4% with controlled, partly-controlled, and uncontrolled asthma respectively) compared with non-ICS users (60.0%, 23.9%, and 16.1%, respectively). In ICS users, chronic cough or phlegm and female sex were independently and significantly related to uncontrolled asthma. In non-ICS users, high total IgE and sensitization to molds were associated with uncontrolled asthma. Smoking and rhinitis were not associated with asthma control. CONCLUSION: Optimal asthma control remained unachieved in the majority of patients with asthma in this study. Factors associated with uncontrolled asthma were different in ICS users (chronic cough/phlegm, female sex) and non-ICS users (high total IgE and sensitization to molds).

Immunochemical characterisation of structure and allergenicity of peanut 2S albumins using different formats of immunoassays.

Proteins of the 2S albumin family, such as Ara h2 and Ara h6, are most frequently involved in peanut allergy. We have developed a reverse enzyme allergo-sorbent test (EAST) in which total serum IgE antibodies are first captured by immobilised anti-human IgE monoclonal antibodies, and then the binding of the anti-Ara h2 and anti-Ara h6 specific IgE to the corresponding labelled allergens is measured. This reverse immunoassay was used either as a direct EAST or as an EAST inhibition assay to study the interactions of whole peanut protein extract and purified Ara h2 and Ara h6 with IgE antibodies from peanut-allergic patients. Finally, we identified some IgE-binding epitopes on Ara h6 using a format of EAST in which the protein is immobilised in a particular, well defined, manner through interactions with specific monoclonal antibodies (mAbs) coated on the micro-plates. The fine specificity of those mAbs has been characterised at the epitope level, and their binding to the allergen thus masks a known particular epitope and makes it unavailable for recognition by IgE antibodies. The reverse EAST increased the ratio specific signal/background. It avoids interferences with competitors such as anti-peanut protein IgG antibodies and allows the study of the specificity and/or affinity of the interactions between IgE antibodies and Ara h2 or Ara h6 with a higher sensitivity and accuracy than the conventional EAST. The EAST results obtained when the allergens are presented by specific mAbs suggest that the homologous molecular domain(s) in peanut 2S albumins encompass major IgE epitope(s) and are strongly involved in peanut allergenicity.

Temporal dynamics of interferon gamma responses in children evaluated for tuberculosis.

BACKGROUND: Development of T-cells based-Interferon gamma (IFNgamma) assays has offered new possibilities for the diagnosis of latent tuberculosis infection (LTBI) and active disease in adults. Few studies have been performed in children, none in France. With reference to the published data on childhood TB epidemiology in the Paris and Ile de France Region, we considered it important to evaluate the performance of IGRA (QuantiFERON TB Gold In Tube(R), QF-TB-IT) in the diagnosis and the follow-up through treatment of LTBI and active TB in a cohort of French children. METHODOLOGY/PRINCIPAL FINDINGS: 131 children were recruited during a prospective and multicentre study (October 2005 and May 2007; Ethical Committee St Louis Hospital, Paris, study number 2005/32). Children were sampled at day 0, 10, 30, 60 (except Healthy Contacts, HC) and 90 for LTBI and HC, and a further day 120, and day 180 for active TB children. Median age was 7.4 years, with 91% of the children BCG vaccinated. LTBI and active TB children undergoing therapy produced significant higher IFNgamma values after 10 days of treatment (p = 0.035). In addition, IFNgamma values were significantly lower at the end of treatment compared to IFNgamma values at day 0, although the number of positive patients was not significantly different between day 0 and end of treatment. CONCLUSIONS/ SIGNIFICANCE: By following quantitative IFNgamma values in each enrolled child with LTBI or active TB and receiving treatment, we were able to detect an increase in the IFNgamma response at day 10 of treatment which might allow the confirmation of a diagnosis. In addition, a decline in IFNgamma values during treatment makes it possible for clinicians to monitor the effect of preventive or curative therapy.

Familial interstitial disease with I73T mutation: A mid- and long-term study.

OBJECTIVES: To describe the long-term course and the management in children of chronic interstitial lung disease associated with I73T mutation. MATERIALS AND METHODS: Clinical, radiological, and histological data from one family including five children and two adults were analyzed retrospectively for three patients and prospectively for the others. RESULTS: Mean age of onset of respiratory symptoms for children was 6 months (2-15 months). The follow up was 14 months to 15 years (mean 55 months). The children were treated by intravenous high dose methylprednisolone pulses (6-15, mean 12). Four received oral prednisolone (mean 16 months) and hydroxychloroquine, one of these had additional mycophenolate mofetil. One adult with mild respiratory symptoms in infancy and another who was symptom free were also diagnosed. Both of them received no treatment. BAL fluids were obtained in all children: pro-SPC and SPB were positive in all. Lung biopsies were performed in two children respectively at 7 months, showing interstitial pneumonia features with endoluminal macrophage and type II alveolar cells hyperplasia, and at 33 months, showing subpleural microbullae, areas of interstitial pneumonia and type II alveolar cells hyperplasia. Immunohistochemistry showed for both an increased SPB and TTF1 staining in type II cells nuclei and a faint staining for pro-SPC and for ABCA3. Genetic diagnosis obviated the need for biopsy in other cases. The clinical status progressively improved and oxygen supplementation could be stopped after 3-14 months (mean 9 months). The CT scans initially showed ground glass opacities, then reduction in the ground glass pattern associated with clinical improvement and development of cysts. CONCLUSION: This kindred illustrates the variability of respiratory involvement and prognosis. It confirms the value of genetic screening for surfactant protein genes mutations.

Effect of 17q21 variants and smoking exposure in early-onset asthma.

BACKGROUND: A genomewide association study has shown an association between variants at chromosome 17q21 and an increased risk of asthma. To elucidate the relationship between this locus and disease, we examined a large, family-based data set that included extensive phenotypic and environmental data from the Epidemiological Study on the Genetics and Environment of Asthma. METHODS: We tested 36 single-nucleotide polymorphisms (SNPs) in the 17q21 region in 1511 subjects from 372 families for an association with asthma. We also tested for genetic heterogeneity according to the age at the onset of asthma and exposure to environmental tobacco smoke in early life. RESULTS: Eleven SNPs were significantly associated with asthma (P<0.01), of which three (rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001). Ordered-subset regression analysis led us to select an onset at 4 years of age or younger to classify patients as having early-onset asthma. Association with early-onset asthma was highly significant (P<10(-5) for four SNPs), whereas no association was found with late-onset asthma. With respect to exposure to environmental tobacco smoke in early life, we observed a significant association with early-onset asthma only in exposed subjects (P<5x10(-5) for six SNPs). Under the best-fitting recessive model, homozygous status (GG) at the most strongly associated SNP (rs8069176) conferred an increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA) in the group exposed to environmental tobacco smoke (P=2.8x10(-6); P=0.006 for the test for heterogeneity of the SNP effect on early-onset asthma between groups with tobacco exposure and those without such exposure). CONCLUSIONS: This study shows that the increased risk of asthma conferred by 17q21 genetic variants is restricted to early-onset asthma and that the risk is further increased by early-life exposure to environmental tobacco smoke. These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma.

Diagnostic value of high-resolution CT in the evaluation of chronic infiltrative lung disease in children.

OBJECTIVE: The purpose of this study was to evaluate the accuracy of CT in the diagnosis of chronic infiltrative lung disease in children. MATERIALS AND METHODS: Fifty-nine patients selected over a 14-year period (29 girls, 30 boys; mean age, 6 +/- 4.9 years; range, 2 months-18 years) had nine disorders. CT scans were evaluated independently by two experienced chest radiologists, who were unaware of pathologic or clinical data. The radiologists recorded specific CT findings of infiltrative lung disease and were asked to give the most likely diagnosis and up to two differential diagnoses. Descriptive statistic analysis was followed by logistic regression analysis for each elementary lesion on the grid of abnormalities. RESULTS: A correct first-choice diagnosis was made in 38% of CT observations. The correct diagnosis was among the three main choices in 59% of CT observations. Pulmonary alveolar proteinosis (n = 18) was most frequently correctly diagnosed; it was the first-choice diagnosis 47% of the time and among the three main choices 72% of the time. The correct first-choice diagnosis of idiopathic pulmonary fibrosis (n = 16) was made 43% of the time; of hypersensitivity pneumonitis (n = 4), 37% of the time; of sarcoidosis (n = 7), 28% of the time; of idiopathic pulmonary hemosiderosis (n = 6), 16% of the time; and of connective tissue diseases (n = 5), 10% of the time. All single cases of pulmonary fibrosis with calcification, lymphangiectasia, and Langerhans' cell histiocytosis were correctly diagnosed. CONCLUSION: Our results showed there are limitations to diagnosing chronic infiltrative lung disease in children on the basis of CT data alone. We suppose that these differences are explained by the technical difficulties of high-resolution CT in children, the insufficient number of cases of and data on high-resolution CT of children, and the heterogeneity of lesions of a given cause.

Hypersensitivity to cyclooxygenase inhibitory drugs in children: a study of 164 cases.

Hypersensitivity to cyclooxygenase (COX) inhibitors is rare in children. We studied 164 children reporting 213 reactions to paracetamol, ibuprofen and/or acetylsalicylic acid (ASA). Most reactions were cutaneous, either isolated or associated with respiratory symptoms and/or anaphylaxis. Based on a convincing clinical history or positive responses in challenges with the drug(s), hypersensitivity to one or several drug(s) was diagnosed in 49.4% of the children (60, 76.5 and 23.2% of the children reporting reactions to ASA, ibuprofen and paracetamol respectively). Cross-reactivity between nonsteroidal anti-inflammatory drugs (NSAIDs) was frequent (69.1%), but only 10.6% of the NSAID-sensitive children reacted to paracetamol. In contrast, all paracetamol-sensitive children reacted to NSAIDs. Anaphylaxis, immediate and accelerated reactions, atopy, older age and chronic/recurrent urticaria were risk factors for hypersensitivity and/or cross-reactivity between ASA, ibuprofen and paracetamol. In conclusion, hypersensitivity to COX inhibitors was frequent, especially in children reporting severe and/or immediate and accelerated reactions, and in older and atopic children. Cross-reactivity was frequent, suggesting that most reactions resulted from a non allergic hypersensitivity linked to the pharmacological properties of the drugs. However, in a few children, the reactions may result from allergic hypersensitivity to selective (families of) drugs, with tolerance to other drugs.

Lung resection in cystic fibrosis: a survival analysis.

Lung resection may be considered for cystic fibrosis (CF) patients showing localized severe chronic atelectasis and/or bronchiectasis. Nonetheless, literature on survival after surgery is scarce. This study was carried out to assess survival time after partial lung resection. Twenty-one CF patients were operated from 1988 to 2003 and were followed until November 30th, 2004. Survival analysis was performed through Kaplan-Meier method. Mean age at resection was 8.09 years (SD 4.40 years) and two-thirds were females. Z-scores for height, weight, and body mass index as well as FEV1 values showed no statistical significance when comparing values obtained from 2 years before to 2 years after resection. Eleven years after resection, survival probability was 93.8%. Our results suggest that lobectomy or segmentectomy are safe procedures and should be considered in carefully selected patients with unilateral severe symptomatic localized and chronic persistent atelectasis and/or bronchiectasis refractory to conservative management.

Relationship between bronchial hyperresponsiveness and impaired lung function after infantile asthma.

Wheezing during infancy has been linked to early loss of pulmonary function. We prospectively investigated the relation between bronchial hyperresponsiveness (BHR) and progressive impairment of pulmonary function in a cohort of asthmatic infants followed until age 9 years. We studied 129 infants who had had at least three episodes of wheezing. Physical examinations, baseline lung function tests and methacholine challenge tests were scheduled at ages 16 months and 5, 7 and 9 years. Eighty-three children completed follow-up. Twenty-four (29%) infants had wheezing that persisted at 9 years of age. Clinical outcome at age 9 years was significantly predicted by symptoms at 5 years of age and by parental atopy. Specific airway resistance (sRaw) was altered in persistent wheezers as early as 5 years of age, and did not change thereafter. Ninety-five per cent of the children still responded to methacholine at the end of follow-up. The degree of BHR at 9 years was significantly related to current clinical status, baseline lung function, and parental atopy. BHR at 16 months and 5 years of age did not predict persistent wheezing between 5 and 9 years of age, or the final degree of BHR, but it did predict altered lung function. Wheezing that persists from infancy to 9 years of age is associated with BHR and to impaired lung function. BHR itself is predictive of impaired lung function in children, strongly pointing to early airway remodeling in infantile asthma.

The use of imaging techniques for assessing severe childhood asthma.

Computed tomography (CT) scans are usually performed in children with asthma to exclude alternative diagnoses. Technical improvements of high-resolution CT (HRCT) scans have increased the spatial resolution sufficiently for the theoretical quantification of bronchial wall thickening of the proximal airways and the assessment of small airway disease by the extent and degree of low attenuation areas, which are believed to represent air trapping. In contrast with adults, very few studies have been performed in children. The results suggest that the HRCT scan might be useful as a noninvasive technique for airway inflammation and airway remodeling. In the future, the potential use of HRCT scans for determining optimal treatment should be evaluated. However, several issues remain to be resolved, including the validity of algorithm reconstruction, the imaging parameters to be used, and the application of this technique to young children. Furthermore, because of its cost and the irradiation involved, this examination is highly unlikely to be used routinely for the management and follow-up of all children with asthma but will likely be restricted to patients with severe asthma.

Assessment of sublingual immunotherapy efficacy in children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment and mite-avoidance measures.

Although several studies have demonstrated the efficacy of subcutaneous immunotherapy in allergic asthma, few have shown the same benefit using sublingual immunotherapy (SLIT) in asthmatic patients. This study was conducted to assess the efficacy of house dust mite (HDM) SLIT in addition to allergen avoidance and standard pharmacologic treatment. A double-blind, placebo-controlled trial was performed in 111 children (aged 5-15 yr) with HDM-induced mild-to-moderate asthma. After a 4-week baseline phase, patients were randomly assigned to receive SLIT with tablets of HDM extract (n = 55) or placebo (n = 56) for 18 months. Pharmacologic treatment was adjusted every 3 months following a step-down approach. Asthma symptom scores, reduction in use of inhaled corticosteroids and inhaled beta(2)-agonists, rhinitis symptoms, lung function tests, skin sensitivity to HDM, dust mite-specific immunoglobulin (Ig) E and IgG(4), and quality of life (QoL) were assessed during the study. After 18 months of treatment, diurnal and nocturnal asthma symptoms scores did not show significant differences between SLIT and placebo groups. Inhaled corticosteroids and inhaled beta(2)-agonists use was reduced in both groups without significant differences between groups. There were no significant differences in lung function (forced expiratory volume in 1 s and peak flow rate variations) between groups. Rhinitis symptom score decreased in both groups, with no difference between the two groups. The severity dimension of QoL was significantly improved in the SLIT group (age 6-12 yr). SLIT induced a significant reduction of skin sensitivity to HDM (p < 0.01) and a significant increase in HDM-specific IgE and IgG(4) antibodies (p < 0.001) in the SLIT group compared with the placebo group. SLIT was well tolerated with mild/moderate local adverse events. No severe systemic reactions were reported. This study indicates that, when mild-moderate asthmatic children are optimally controlled by pharmacologic treatment and HDM avoidance, SLIT does not provide additional benefit, despite a significant reduction in allergic response to HDM. Under such conditions, only a complete, but ethically unfeasible, discontinuation of inhaled corticosteroid would have demonstrated a possible benefit of SLIT.

Oxido nítrico em criança com asma persistente / Nitric oxide in children with persistent asthma

OBJETIVO: Verificar as diferenças nos valores da fração exalada de óxido nítrico (FeNO) em asmáticos atópicos e não-atópicos em uso de tratamento antiinflamatório e comparar a FeNO com a função pulmonar MÉTODOS: Estudo transversal com 45 asmáticos persistentes moderados e graves, de 6 a 17 anos, selecionados consecutivamente, em uso de medicação antiinflamatória há pelo menos 1 ano. Os pacientes foram divididos em dois grupos: atópicos, isto é, com testes cutâneos positivos, e não-atópicos. As avaliações clínico-funcionais e a mensuração da FeNO foram realizadas concomitantemente. RESULTADOS: Houve predomínio do sexo masculino (62,5 por cento),sendo que cerca de 85 por cento pertenciam à faixa etária de 6 até 13 anos (média, 10,4 anos). Não foi encontrada, nos dois grupos, significância estatística para a presença de sintomas associados à asma (p = 0,07), rinite alérgica (p = 0,17), alergia alimentar (p = 0,09), necessidade de corticóide sistêmico (p = 0,10), antileucotrieno (p = 0,20) e anti-histamínico (p = 0,70), nem para os três parâmetros usados para avaliar a função pulmonar (VEF1, VEF1/CVF e FEF25-75 por cento, p > 0,14). A freqüência de eczema (p < 0,005) e a FeNO (p < 0,001) foram mais elevadas entre os atópicos. CONCLUSÃO: Os resultados sugerem que, entre atópicos, a estabilidade clínica e funcional da asma não reflete, necessariamente, o efetivo controle do processo inflamatório, e que haja, talvez, maior chance de recidiva após a suspensão da medicação anti-inflamatória.