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.

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.

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.

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.

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.

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.

Microbiological diagnosis of empyema in children: comparative evaluations by culture, polymerase chain reaction, and pneumococcal antigen detection in pleural fluids.

BACKGROUND: Pleural empyema is an increasingly reported complication of pneumonia in children. Microbiological diagnostic tests for empyema by culture frequently have false-negative results due to previous administration of antibiotics. Molecular diagnosis by broad-range 16S ribosomal DNA (rDNA) polymerase chain reaction (PCR) and rapid pneumococcal antigen detection are reliable tools, but their diagnostic value has not been clearly established for pleural fluid samples. Pneumococcal antigen detection has only been validated for urine and cerebrospinal fluid samples. METHODS: Over 4 years, pleural fluid specimens were collected from 78 children with pleural empyema. Standard culture, pneumococcal antigen detection by latex agglutination (Pastorex; Bio-Rad) and immunochromatographic testing (Binax NOW Streptococcus pneumoniae), and 16S rDNA PCR were performed on these specimens. Pneumococcal identification by 16S rDNA PCR and sequencing was confirmed by pneumolysin PCR. RESULTS: Of the 78 cases of pleural empyema, 60 (77%) were microbiologically documented by culture or 16S rDNA PCR. Of the 40 pneumococcal empyema cases, 17 (43%) were only diagnosed by PCR and 23 with PCR and culture. The sensitivity and specificity of the latex antigen detection (with the use of culture and/or PCR as the test standard) were 90% and 95%, respectively. The immunochromatographic test detected pneumococcal antigens in 3 additional specimens for which latex agglutination results were negative, thereby increasing the sensitivity of antigen detection. CONCLUSIONS: Pneumococcal antigen detection in pleural fluid specimens from children provides a rapid and sensitive method of diagnosis of pneumococcal empyema, which can be confirmed by specific pneumolysin PCR when culture results are negative. Broad-range 16S rDNA PCR has value in detecting bacterial agents responsible for culture-negative pleural empyema.

Foreign body aspiration: clinical, radiological findings and factors associated with its late removal.

OBJECTIVE: The study was carried out to assess the clinical and radiological findings and factors related to delay in definite diagnosis of foreign body aspiration and its removal. METHODS: Medical charts of 280 bronchoscopic-proven foreign body (FB) inhalators were reviewed. To analyze factors related to late removal, the population studied was divided into two groups according to time elapsed between injury and care-seeking (up to 24h and longer than 24h) followed by FB removal. RESULTS: Most children (69.5%) were under three, most were males (63.1%) and in 47.5%, rigid bronchoscopy was performed 24h after the accident. Organic foreign bodies were found in 63.4% of cases, most frequently peanuts (20.5%). Mortality related to FB aspiration reached 0.7%. In comparison with endoscopic diagnosis, clinical and radiological abnormalities were found in 99.3 and 84.3% (95% CI, 79.5-88.4%) of studied patients, respectively. The number of health services sought until definite diagnosis was the only factor associated with late removal (OR=23.0, 95% CI, 10.7-49.3%, p<0.001). CONCLUSION: The population studied presented a long delay in FB removal, thus demanding actions enhancing parent, physician and health services awareness, aiming at an earlier referral for diagnostic and therapeutic bronchoscopy.

Nitric oxide in children with persistent asthma.

OBJECTIVE: To assess the difference in exhaled nitric oxide levels in atopic and nonatopic asthmatic patients treated with anti-inflammatory drugs, and to compare exhaled nitric oxide measurement with lung function tests. METHODS: Cross-sectional study with 45 consecutively selected patients with moderate and severe persistent asthma, aged between 6 and 17 years, and treated with anti-inflammatory drugs for at least 1 year. The patients were split into two groups: atopic ones (with positive skin tests) and nonatopic ones. The clinical and functional assessments and the measurement of exhaled nitric oxide were carried out concomitantly. RESULTS: There was a male predominance (62.5%), with an age range between 6 and 13 years (mean of 10.4 years) in 85% of the patients. Neither the symptoms associated with asthma (p = 0.07), allergic rhinitis (p = 0.17), food allergy (p = 0.09), necessity of systemic corticosteroids (p = 0.10), antileukotrienes (p = 0.20) and antihistamines (p = 0.70), nor the three parameters used to assess lung function (FEV(1), FEV(1)/FVC and FEF(25-75%), p > or = 0.14) were statistically significant. The frequency of eczema (p < 0.005) and exhaled nitric oxide levels (p < 0.001) were higher among atopic patients. CONCLUSION: Results suggest that clinical and functional stability of asthma among atopic patients does not necessarily reflect an efficient control over the inflammatory process and a higher probability for recurrence after discontinuation of anti-inflammatory therapy.

DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis.

BACKGROUND: Interplays between Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) in human and host professional phagocytes, namely macrophages (Mphis) and dendritic cells (DCs), are central to immune protection against TB and to TB pathogenesis. We and others have recently shown that the C-type lectin dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN; CD209) mediates important interactions between mycobacteria and human monocyte-derived DCs (MoDCs) in vitro. METHODS AND FINDINGS: In order to explore the possible role of DC-SIGN in M. tuberculosis infection in vivo, we have analysed DC-SIGN expression in broncho-alveolar lavage (BAL) cells from patients with TB (n = 40) or with other non-mycobacterial lung pathologies, namely asthma (n = 14) and sarcoidosis (n = 11), as well as from control individuals (n = 9). We show that in patients with TB, up to 70% of alveolar Mphis express DC-SIGN. By contrast, the lectin is barely detected in alveolar Mphis from all other individuals. Flow cytometry, RT-PCR, and enzyme-linked immunosorbent assay analyses of BAL-derived fluids and cells indicated that M. tuberculosis infection induces DC-SIGN expression in alveolar Mphis by a mechanism that is independent of Toll-like receptor-4, interleukin (IL)-4, and IL-13. This mechanism most likely relies on the secretion of soluble host and/or mycobacterial factors that have yet to be identified, as both infected and uninfected bystander Mphis were found to express DC-SIGN in the presence of M. tuberculosis. Immunohistochemical examination of lung biopsy samples from patients with TB showed that the bacilli concentrate in pulmonary regions enriched in DC-SIGN-expressing alveolar Mphis in vivo. Ex vivo binding and inhibition of binding experiments further revealed that DC-SIGN-expressing alveolar Mphis constitute preferential target cells for M. tuberculosis, as compared to their DC-SIGN- counterparts. In contrast with what has been reported previously in MoDCs in vitro, ex vivo DC-SIGN ligation by mycobacterial products failed to induce IL-10 secretion by alveolar Mphis, and IL-10 was not detected in BALs from patients with TB. CONCLUSION: Altogether, our results provide further evidence for an important role of DC-SIGN during TB in humans. DC-SIGN induction in alveolar Mphis may have important consequences on lung colonization by the tubercle bacillus, and on pulmonary inflammatory and immune responses in the infected host.

Bronchoalveolar cells in children < 3 years old with severe recurrent wheezing.

STUDY OBJECTIVE: To determine the cell profile of BAL from infants with severe recurrent wheezing who were not acutely ill at the time of investigation, suggesting an ongoing inflammation. DESIGN AND PATIENTS: In a retrospective study, we determined BAL cell profiles for 83 children with wheezing aged 4 to 32 months (mean +/- SD, 11.3 +/- 5.5 months). Fiberoptic bronchoscopy was performed in children with severe recurrent wheezy bronchitis unresponsive to inhaled steroids. These children were compared with 17 children aged 6 to 36 months (mean, 15.1 +/- 7.5 months) with various nonwheezing pulmonary diseases. Children were included as control subjects if they had no endobronchial inflammation and no atopy. RESULTS: The BAL cell profile of young children with wheezing typically includes a significantly higher cell count (mean, 644.4 +/- 956.8 x 10(3)/mL vs 313 +/- 203.2 x 10(3)/mL, p = 0.008), a significantly higher percentage of neutrophils (mean, 9 +/- 12.1% vs 2.1 +/- 2.2%, p = 0.003), and a higher neutrophil count (mean, 43.2 +/- 81.6 x 10(3)/mL vs 7.9 +/- 11.8 x 10(3)/mL, p = 0.003), as compared with control subjects. The larger number of neutrophils in children with wheezing was not correlated with bacterial or viral infection, or with age, sex, or atopic status. In contrast to the situation in asthmatic adults, eosinophil levels were not higher in children with wheezing than in control subjects (mean, 0.09 +/- 0.27% vs 0.08 +/- 0.25%). CONCLUSION: Neutrophil-mediated inflammation in the airways appears to better characterize severe recurrent wheezing in children < 3 years old.

Vaccine allergy and pseudo-allergy.

Allergic and pseudo-allergic reactions to vaccines frequently involve the skin, and can be generalized systemic symptoms (urticaria/angioedema, serum sickness, flares of eczema) or localized at the sites of vaccination (persistent nodules, abcesses, granulomas). Diagnosis of Arthus-type reactions is based on clinical history and specific IgM/IgG anti-toxoid determination. For other local reactions, diagnostic value of non-immediate responses in skin tests varies with clinical symptoms and substances involved. Immediate responses in skin tests and specific IgE determination have good diagnostic and/or predictive value in anaphylaxis and immediate/accelerated urticaria/angioedema to toxoid-, pneumococcus-, and egg- and gelatin-containing vaccines. Diagnosis of reactions to dextran in BCG is based on specific IgM/IgG determination. Most non-immediate generalized reactions result from non-specific inflammation, except for gelatin-containing vaccines, but the diagnostic value of immuno-allergological tests with the vaccines and gelatin are controversial. Withholding booster injections is advised if specific IgM/IgG levels are high. If the levels are low, sequential injections of vaccines containing a single vaccinating agent are usually tolerated. However, injections of the vaccine should be performed using a " desensitization " procedure in patients reporting anaphylaxis and immediate/accelerated urticaria/angioedema.

[Asthma and allergic rhinitis as symptoms of the same disease: a paradigm under construction]. / Asma e rinite alérgica como expressão de uma única doença: um paradigma em construção.

OBJECTIVE: To describe current ideas about the relation between upper and lower respiratory tract and to review the epidemiological, immunological, and pathological aspects that support the paradigm of united airways disease. SOURCES: Literature review using the Medline, MD Consult, HighWire, Medscape and Lilacs databases. We used allergic rhinitis and asthma as keywords, and searched articles published in the past 20 years. SUMMARY OF THE FINDINGS: Epidemiological evidence includes prevalence of allergic rhinitis in asthmatic patients and vice-versa, results of cross-sectional studies, bronchial hyperresponsiveness in patients with allergic rhinitis, importance of genetic and environmental factors, and the age of onset of atopic disease. Morphological and physiological aspects show structural differences between the nasal and bronchial mucosa, and the mechanisms that could explain the effect of rhinitis on asthma. Immunological aspects including the participation of bone marrow in the production of inflammatory cells and allergic reactions after allergen challenge are the same in allergic rhinitis and asthma. Finally, the results of the therapy for allergic rhinitis in bronchial hyperresponsiveness and in clinical and functional control of asthma are also reported. CONCLUSIONS: Epidemiological evidence and immunological and pathological aspects suggest that there is a relation between allergic rhinitis and asthma. The paradigm of united airways disease suggests the implementation of an integrated therapeutic approach.

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.