Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications.

BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. METHODS: We actively searched for cases by contacting all Brazilian referral centers. RESULTS: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). CONCLUSIONS: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.

Comparative performance for immediate hypersensitivity skin testing using two skin prick test devices.

Fifty-five patients were skin-tested by Multi-Test (M) and needle prick test (NPT) to compare the reproducibility of the methods. We used 6 allergenic extracts: Dermatophagoides pteronyssinus, Dermatophagoides farinae, dog epithelium, cat pelt, American cockroach and mixed molds. A glycerosaline and a positive control (histamine 1 mg/ml) were performed in both methods. Statistically significant differences in histamine and Dermatophagoides farinae wheal reactions between the two methods (M > NPT) were found, with no differences with the other allergenic extracts. We concluded that the two methods are similar with respect to determining the immediate hypersensitivity, but the Multi-Test is better accepted by children.

IgE antibodies to aeroallergens in allergic children in São Paulo, Brazil.

The sensitization to inhaled allergens was studied in 80 Brazilian children and 12 controls, aged 6 to 16 years. We performed skin tests with Alternaria alternata, cat, dog, Lolium perenne, grasses and the following domestic mites: Blomia tropicalis, Dermatophagoides pteronyssinus, Dermatophagoides farinae, Lepidoglyphus destructor, Chortoglyphus arcutus and Aleuroglyphus ovatus. The frequencies of positive skin tests (mean diameter > or = 23 mm) were respectively 15%, 11%, 11%, 6%, 7%, 95%, 92%, 88%, 76%, 75% and 71%. The mean diameter of the wheal to domestic mites was higher to D. pteronyssinus than to B. tropicalis, L. destructor, A. ovatus and C. arcuatus (p < 0.05). The skin test results to domestic mites by regression analysis revealed highly significant correlation (p < 0.0001), suggesting considerable cross-reactivity between them. Specific IgE to each mite was determined and the results expressed as the mean of the percentage of total counts bound (% TCB). We had the highest levels of % TCB to D. farinae, followed by D. pteronyssinus, E. maynei, B. tropicalis, C. arcuatus, L. destructor and A. ovatus. The Brazilian children with asthma had more positive skin tests to domestic mites than to other inhalant allergens, and based on previous studies performed in São Paulo that have shown D. pteronyssinus and B. tropicalis as the most prevalent mite species in house dust, we assumed that IgE Ab to D. farinae reflects cross-reactivity with D. pteronyssinus in most cases. The observed high levels of IgE Ab to domestic mites stress the importance of environmental avoidance measures, decreasing the rate of sensitization or perhaps the development of symptoms of asthma in genetically predisposed children.

Nasal provocation test (NPT) with isolated and associated dermatophagoides pteronyssinus (Dp) and endotoxin lipopolysaccharide (LPS) in children with allergic rhinitis (AR) and nonallergic controls.

BACKGROUND: Inhalation of endotoxin may enhance inflammatory airway response in sensitized asthmatics persons after allergen(s) inhalation. OBJECTIVE: To evaluate nasal response to intranasal instillation of Dermatophagoides pteronyssinus (Dp), endotoxin (LPS), and to Dp+LPS in children with perennial allergic rhinitis (PAR). METHODS: 10 PAR children (positive skin prick test to Dp) and 10 nonallergic controls (C) undergoing nasal provocation test (NPT), who were quantified by active anterior rhinomanometry and measurement of Total Nasal Resistance (TNR). The NPTs were initially performed with histamine (H; 0.03 to 16.0 mg/mL), and then, at least at weekly intervals, the NPTs were done with Dp (1/100,000 to 1/2.5), LPS (1 to 500 mg/mL) and to Dp+LPS. During NPT with Dp+LPS, Dp concentration was kept constant (1/100,000; 1/10,000; 1/1,000) and was combined with different concentrations of LPS (1, 5, 10, 20 mg/mL). The NPT was considered positive when TNR reached twice the basal TNR. RESULTS: H and Dp NPTs were positive in all AR children. In group C, H NPT was positive in 60% and Dp NPT was negative in all children. NPT with LPS was positive only in 30% of the AR children. NPT with Dp+LPS was positive in 90% of the AR patients in Dp concentration of 1/1,000 and in LPS concentrations of 5, 10, and 20 mcg/ mL. This positive association was observed with Dp concentrations lower than those obtained during NPT with Dp in 60% of AR patients. There were no changes in pulmonary function tests in all children after NPT. CONCLUSIONS: This study suggests that LPS enhances the effects of allergen challenges on nasal airflow. The daily inhalation of allergens plus endotoxin in AR patients does increase the nasal responsiveness.

International Study of Asthma and Allergies in Childhood (ISAAC) written questionnaire: validation of the asthma component among Brazilian children.

Written questionnaires have been widely used in epidemiological studies of asthma. However, when translated to another language, they must be validated. The International Study of Asthma and Allergies in Childhood (ISAAC) written questionnaire had been previously validated by a comprehensive study, but this had not been done in Brazil. Our objective was to validate the asthma component of the ISAAC self-applicable written questionnaire following its translation to Portuguese. A group of 10 pediatricians and 10 pediatric allergists graded the questions from 0 to 2, and established a maximum score for each question. The questionnaire was answered by parents or guardians of asthmatic children, aged 6 to 7 years old (n = 26) and of nonasthmatic control children of the same age (n = 26); and by asthmatic (n = 33) and nonasthmatic (n = 33) adolescents, aged 13 to 14 years. Half of these individuals responded to the same questionnaire after 2 to 4 weeks. This second response allowed the evaluation of the reproducibility of the ISAAC questionnaire. The maximum global score possible was 14, and cut-off levels of 5 and 6 were found for the groups of 6 to 7 and 13 to 14 year olds, respectively. There was significant agreement between the adolescents' responses to the questionnaire and those from their parents or guardians (74.3%); however, significant discordance was observed for individual questions including "wheezing with exercise." In both age periods the questionnaire was significantly reproducible (Kappa test) (6 to 7 year olds Kw = 1; 13 to 14 year olds Kw = 0.89). In conclusion, the asthma component of the ISAAC written questionnaire was proven to be reproducible, adequate and able to differentiate between asthmatics and controls. Adolescents answered the questionnaire appropriately, however the results suggest that adolescents' parents or guardians underestimate asthma symptoms which interfere little with the adolescent's daily activities.

In vitro evaluation of cumulative release of valproic acid and vitamin E from hexadecanol microspheres. Part 2: Antiepileptic agents.

Hexadecanol microspheres were investigated as a vehicle for the controlled release of valproic acid. Microsphere of the antiepileptic agent were prepared by the meltable dispersion method in water using wetting agents. To prevent hepatotoxicity, microspheres containing both the drug and vitamin E were also prepared. The method in simple, inexpensive, rapid and reproducible. The drug release was evaluated in vitro. Kinetic results were analyzed to distinguish between the first-order release model and the square root of time relationship. More than 99% of the isolated microspheres were particle size range 200-710 microns. The average drug content was 24%. Drug bioavailability was greatly affected as a result of microspheres formation.

[Effect of inhaled terbutaline sulphate (dry powder, Turbuhaler and nebulizer solution) in children with acute asthma]. / Estudo dos efeitos do sulfato de terbutalino inalado, sob a forma de pó seco (TurbuhalerR) e solução para nebulização em crianças com asma aguda.

Forty seven children (6-14 years), with an acute mild or moderate attack of asthma (clinical score 3 or FEV1 > 50% of the predicted), were treated with terbutaline sulphate, by inhalation route with a dry powder inhaler (Turbuhaler - 0,5 mg - group T; N=27, or by a nebulizer 1% solution-in saline-compressed air (6 l/min.) group S; N=20. The children were evaluated at 5, 15, 25 and 30 minutes after the initial treatment. In both groups a significant fall of the clinical score (starting at 15 minutes) (p < 0.05) and a significant improvement of the FEV(1), VC and FEF25-75% (starting at 5 minutes), were observed (p < 0.05). There were no significant changes in heart rates, respiratory rates and blood pressure (p > 0.05). At the end of the first treatment, the number of patients with a FEV(1) < 80% was similar in both groups (T = 13/27 and S = 10/20). The same treatment was repeated, and all the children showed a marked improvement, except for one boy of the group T was hospitalized. In conclusion, children with mild or moderate acute attacks of asthma can be treated up to a week with an inhalation of dry powder, resulting in adequate bronchodilatation without important side effects.

[Atopic diseases in Brazilian children--etiologic multicentric study]. / Etiologia da doença atópica em crianças brasileiras--Estudo multicêntrico.

In order to determine the etiologic agents involved in atopic diseases in Brazilian children, we have performed this multicentric study in 8 areas in Brazil. We have done prick tests with inhalants and food antigens and analyzed skin tests results, considering positive the wheal mean diameter 3 mm. 22,2% of skin tests were negative and the majority were positive to inhalants: D.pteronyssinus(Dpt) (66.6%) and D. farinae(Df) (66.0%), house dust extract (29.0%), dogs epithelium (19.2%), cat's epithelium (8.8%), feather (5.5%), molds (4.2%), Penicillium sp (2.2%) and Lollium perene (0.6%). We have had 9,1% of food positive tests: cow milk (5.2%), peanut (3.5%), corn (3.2%), cocoa and soya (2.2%), eggs and wheat (1.9%). We have concluded that the domestic mites are the most important agents involved in the etiology of atopic diseases in Brazilian children, and the extracts involved, in line with the sensitization of each geographical area.

[Duration of bronchodilator effect of inhaled Salmeterol (dry powder x metered dose inhaler) in children with acute asthma attack]. / Duração do efeito broncodilatador do Salmeterol inalado (pó seco e aerossol dosificador) em crianças com asma aguda.

Patients during a mild to moderate acute attack of asthma (FEV1: 50 - 80% of predicted) were treated with Salmeterol MDI - 50mcg or Rotadisk - 50mcg or Salbutamol (MDI -200mcg). The children were followed by Spirometry, measuring FEV1 (basal) and after treatment: at 30 minutes, 60 minutes and thereafter every 60 minutes until 780 minutes, if the patients maintained the FEV1 above 80% of the predicted value and/or an increment of 20% in the VEF1 basal value. The Salmeterol group showed a significant bronchodilation at 60 minutes which was maintained in half of the patients up to 9 hours. This was not observed in the Salbutamol group: the peak bronchodilatation was observed at 30 minutes and the bronchodilation effect was observed in half of the patients up to 6 hours. There were no significant differences between both presentations of Salmeterol. This drug allowed a prolonged bronchodilator effect and is, according to the several consensus on management of asthma, an adequate option in the treatment of moderate to severe asthma.

Corticosteroids (inhaled and/or intranasal) in the treatment of respiratory allergy in children: safety vs. efficacy.

BACKGROUND: Topical administration of Corticosteroids (CS) can reduce the total dose of CS required to treat the patient and minimize side effects. Topical CS is extremely effective and has an excellent safety profile. Nonetheless, care must be taken when multiple sites such as lungs, nose and skin are being treated. CS mechanisms of action on the inflammatory process are complex. The aim of this study is to review such mechanisms and the adverse events secondary to it. METHODS: Review English database (Embase, PubMed, Scielo) searching words: CS, adverse events, inhaled CS, intranasal CS, and children. RESULTS: There is a classic mechanism involving a genomic effect of CS and a non-genomic effect, independently of gene transcription process. This mechanism acts by reducing mucosal blood flow in the asthmatic airways. Second-generation topical CS is the treatment of choice in allergic diseases control because of their good anti-inflammatory activity, poor absorption and first-pass hepatic metabolism. When comparing different CS, it is important to compare therapeutically equivalent doses. Although topical CS reduces systemic side effects, local and even systemic side effects can occur. Many factors affect the amount of drug that reaches the lung, including inhaler technique and inhaler type, fine particle dose and particle distribution. CONCLUSION: Most patients with allergic diseases respond to CS treatment, but there is a small subset of them whose response is unsatisfactory even with high doses of CS. They are classified as corticosteroid-resistant asthmatics. Pro-inflammatory cytokines appear to up regulate the expression of GRb that has been associated with CS resistance.

[The impact of the environment upon the respiratory tract] / O impacto do meio ambiente no trato respiratório.

OBJECTIVES: Air pollution has been a significant worldwide problem with repercussions in the respiratory tract, along the years. The main objectives of this review are to present results from studies on the harmful effects of allergens as well as of pollutants over the respiratory tract.METHOD: Published studies were analyzed in respect to each agent involved, either environmental pollutants or allergens.RESULTS: There has been a remarkable increase in the prevalence of asthma and allergies in Western countries children, during the last decades, which involves participation of many environmental factors. The house dust mites allergens followed by pet allergens have been classified as one of the most important causes of early sensitization, in genetically susceptible individuals. It became of utmost importance to determine the action of pollutants in the airways of asthmatic patients, once asthma is an inflammatory disease with an outstanding surge of inflammatory cells, affecting airway mucosal. Among the environmental agents, tobacco smoke, NO(2), O(3) and the CO are associated to the increase in morbidity, with specific harmfulness.CONCLUSION: There are evidences that the higher exposure to indoor allergens, to pollutants and irritants, associated to changes in diets, changes in the exposure pattern to infectious agents and the use of antibiotics are leading to an increase in respiratory diseases over the last 30 years.

[Asthma in children: classification and treatment] / A asma na criança: classificação e tratamento.

OBJECTIVES: To review concepts, classification based on severity, and long term treatment for children with asthma. METHODS: To identify precipitating factors of acute asthma attacks and classify the disease in order to establish long term treatment. RESULTS: Different plans of management according to its classification: mild, moderate and severe asthma. Antiinflammatory therapy is reserved to moderate and severe asthma. CONCLUSIONS: The identification and control of the etiologic and precipitating factors are important tasks in the management of asthma. The inhalatory route is the most appropriate to treat patients suffering from asthma. The usual drugs indicated in asthma treatment are reviewed. Precocious treatment with inhaled glucocorticosteroids is recommended by several authors.

Endotoxin exposure and symptoms in asthmatic children.

Endotoxins (ET) are pro-inflammatory substances present in house dust which may increase non-specific bronchial reactivity in asthmatic patients. Endotoxins (EU/g) and Der p 1 levels were compared in the homes of ten asthmatic and ten control children, aged 6-16 years, living in São Paulo, Brazil. The houses were visited once a month from February 1993 to February 1994 and dust samples were collected from the bedding and floor of each subject's house. No significant differences were observed in ET and Der p 1 levels in the homes of asthmatics and controls. The highest ET levels were detected in January and November, whereas the lowest levels were detected in April and August (p < 0.05), demonstrating a distinct seasonal distribution. The highest Der p 1 levels in bedding were observed in July and the lowest in February (p < 0.05), while Der p 1 levels in floor did not show significant differences throughout the year. Symptom and medication scores were evaluated monthly in the group of asthmatic children. There was a significant correlation (p < 0.05, r = 0.63) between clinical symptom scores and ET exposure, however no significant correlation was found for mite exposure (p > 0.05, r = 0.19). The results suggest that ET exposure exacerbates asthmatic symptoms in mite allergic, asthmatic children.

Exposure and sensitization to dust mite allergens among asthmatic children in São Paulo, Brazil.

A group of 20 mite allergic asthmatic children aged 6-12 years old, living in São Paulo, Brazil, was studied regarding their degree of sensitization to house dust mites and exposure to mite allergens in their homes. In 18 out of 20 houses at least one dust sample was obtained which contained greater than 10 micrograms Der p I/g of dust. The highest levels of Dermatophagoides pteronyssinus allergens, Der p I and Group II, were measured in bedding samples (geometric mean 38.4 and 36.6 micrograms/g, respectively), followed by bedroom floor, TV room and kitchen. Mite allergen levels in Brazilian houses were as high as those reported to be associated with sensitization and acute attacks of asthma in other parts of the world. In keeping with previous reports that D. farinae is rarely found in Brazil, Der f I was undetectable or found in very low levels (less than 0.5 micrograms/g). Levels of cat allergen Fel d I of greater than 8 micrograms/g of dust were obtained only in 2 houses only. Cockroach allergen Bla g I was detected in five out of 20 houses. Levels of IgE antibodies to D. pteronyssinus were greater than 200 RAST U/ml in 19 out of 20 children (geometric mean 1588 RAST U/ml). IgE antibodies to cat, cockroach, A. fumigatus, ragweed and rye grass pollens were undetectable or less than 80 RAST U/ml. IgE antibodies to the mite Blomia tropicalis were also measured, and levels greater than 200 RAST U/ml were observed in 13 out of 20 sera.(ABSTRACT TRUNCATED AT 250 WORDS)

IgG and IgE antibody responses to dust mite allergens among children with asthma in Brazil.

We compared exposure and levels of IgE and IgG antibodies to inhalant allergens in 20 children with asthma and positive skin tests to Dermatophagoides pteronyssinus, living in São Paulo, to 20 control children without history of asthma or allergy and negative skin tests to D. pteronyssinus, D. farinae, and Blomia tropicalis. In 16/20 and 17/20 houses of asthmatic and control children, respectively, at least one sample was obtained which contained > 10 micrograms Der p I/g of dust. Serum IgE antibodies to D. pteronyssinus and Blomia tropicalis were > 200 RAST U/mL in 19/20 and in 16/20 asthmatic children, respectively. In the control group, IgE antibodies to either mite species were < 40 RAST U/mL in most cases. IgG anti-Der p I and anti-Der f I antibodies were detected in 17/20 asthmatics, as opposed to 3/20 controls. Neither cat nor cockroach allergens caused significant sensitization among asthmatic or control children. Although exposure to high levels of mite allergens was common in São Paulo, significant IgE and IgG antibody responses were detected only in children with asthma.

Sensitization to Blomia tropicalis in patients with asthma and identification of allergen Blo t 5.

In tropical and subtropical regions of the world, allergens produced by Blomia tropicalis are an important cause of IgE-mediated sensitization among patients with asthma. We compared the relative importance of sensitization to the two mite species among asthma patients from Florida, Puerto Rico, and Brazil (n = 83), who were concurrently exposed to B. tropicalis and D. pteronyssinus, with patients from the United States and from the United Kingdom (n = 56) exposed to D. pteronyssinus. In addition, molecular cloning techniques were used to clone and express a major B. tropicalis allergen. There were significant differences between IgE antibody responses to B. tropicalis and D. pteronyssinus that were related to exposure: only 22% of patients exposed to both species had a high ratio (> 10) of IgE D. pteronyssinus:B. tropicalis, whereas 68% of patients exposed only to D. pteronyssinus had a ratio of > 10 (p < 0.001). A major 14-kD allergen (Blo t 5), cloned from a B. tropicalis cDNA library, showed 43% sequence homology to D. pteronyssinus Der p 5. Recombinant Blo t 5 produced in E. coli reacted with 45 to 69% of sera from B. tropicalis-allergic asthmatics and induced positive immediate skin tests at 10(-3) to 1 microg/ml. In vivo and in vitro comparisons of IgE responses to B. tropicalis, D. pteronyssinus, rBlo t 5, and rDer p 5, showed that B. tropicalis has unique allergens that cause specific IgE responses. The results suggest that B. tropicalis is an independent cause of sensitization and that use of recombinant Blo t 5 should lead to a better understanding of the role of B. tropicalis in causing asthma in tropical environments.

Cockroach allergens and asthma in Brazil: identification of tropomyosin as a major allergen with potential cross-reactivity with mite and shrimp allergens.

BACKGROUND: Cockroaches produce several proteins that induce IgE antibody responses. Although cockroaches are abundant in warm and humid areas, sensitization to cockroach allergens has not been investigated in Brazil. OBJECTIVE: The aims of this study were to investigate the frequency of cockroach allergy among patients with asthma, rhinitis, or both in Brazil and to identify American cockroach allergens. METHODS: Skin tests using cockroach extracts were performed on children and young adults with asthma, rhinitis, or both. A Periplaneta americana complementary (c)DNA library was screened by using IgE antibodies from Brazilian patients allergic to cockroaches. Reactivity of an mAb directed to Dermatophagoides pteronyssinus tropomyosin against cockroach tissue was examined by immunofluorescence. RESULTS: Cockroach allergy was present in 55% and 79% of the patients, as determined by using skin prick tests alone or combined prick and intradermal tests, respectively. Five cDNA clones reacted with IgE antibody and contained the same sequence. A representative clone (1300 bp), pa 12, coded for a protein that reacted with 50% of the sera from patients allergic to cockroaches on plaque immunoassay and showed a high degree of homology to tropomyosins, particularly those from invertebrates. P americana tropomyosin showed 80%, 81%, and 82% sequence identity to tropomyosins from D pteronyssinus, D farinae, and shrimp, respectively, which have been previously defined as important allergens. An mAb directed against D pteronyssinus tropomyosin, which also recognizes shrimp tropomyosin, showed binding to cockroach striated muscle. CONCLUSION: Our results support the recommendation that cockroach extracts should be routinely used for the evaluation of patients with asthma, rhinitis, or both in Brazil. The identification of P americana tropomyosin as an important allergen will make it possible to investigate cross-reactivity among cockroaches, mites, and food derived from invertebrates.