Asthma, from childhood to adulthood: a prospective 20-year longitudinal study of a cohort of asthmatics.

Ladeira S.

Center of Allergy and Immunology of Algarve, Portugal. cn imunoalergologia.com

This study analyzes the evolution of a group of children under 10 years of age with asthma over a period of 20 years. We selected a random group of 32 children with asthma and compared it with a control group composed of 33 children without asthma, similar in age, sex, and socio-economic characteristics. Throughout the 20 years we analyzed the number of ambulatory visits, morbidity, environmental tobacco smoke (ETS) as well as social and economic characteristics. The results after 20 years of evaluation showed that inflammatory and infectious processes in the airways (upper and lower) were more frequent among asthmatics than in the control group. ENT infections were more predominant in the group with inadequate sanitary conditions. There were no significant differences for the other pathologies. We studied the frequency of asthmatic crises requiring emergency care according to age and sex. Clinical ambulatory visits in asthmatic children were 2.8 times more frequent than in the control group. We found no differences between males and females, either in terms of global morbidity or the worsening of their asthmatic disease e.g., crises, going to emergency services and hospitalization. In the asthmatic group, the frequency of asthma crises, visits to emergency services and hospitalization were analyzed, with no differences being found between the sexes. We measured the PEFR, FEV1, and FEF25-75 in both groups for 20 years and compared those values to age, weight, height, and sex. We found that the parameters of lung function were lower in the asthmatic group than in the control group. We used as statistical method the chi 2 test, and regression analyses were made to relate the PEFR, FEV1, and FEF25-75 values to age and gender. A paired t-test was used to compare ambulatory visits, morbidity, emergency care, ETS, and sanitary housing conditions to age and sex in both groups. A p value < or = 0.05 was taken as indicating statistical significance.

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Gastroesophageal reflux in asthmatic children not responding to asthma medication: a scintigraphic study in 126 patients with correlation between scintigraphic and clinical findings of reflux.

Malhothra A.

Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India.

Gastroesophageal reflux (GER) is frequently found in association with asthma. Successful control of GER in these patients may improve in their asthma symptoms. The present retrospective analysis was undertaken to find out the incidence of GER in asthmatic children not responding to routine antiasthmatic medications and to find out if there is a clinical correlation between the symptoms of GER and scintigraphic evidence of GER in these patients. A total of 126 children with a mean age of 2.31 years and range 6 months to 6 years were evaluated. The children were divided into two groups. Group I (n = 100) consisted of children with asthma but no clinical symptoms of GER. Group II (n = 26) consisted of those children with asthma and clinical symptoms of GER. Radionuclide scintigraphy was performed with 100-200 microCi (3.7-7.4 MBq) of Tc99m-sulphur colloid. All 33 out of 126 (26%) children had GER on scintigraphy. In Group I, only 23 (23%) had reflux while in Group II, 10 (38.5%) had reflux. In conclusion, esophageal scintiscanning can be used to detect GER in asthmatic children refractory to routine antiasthmatic medication irrespective of the presence or absence of symptoms suggestive of GER.

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[Study of cellular inflammatory response with bronchoalveolar lavage in allergic asthma, aspirin asthma and in extrinsic infiltrating alveolitis.]

[Article in Spanish]

Romero-Piffiguer M.

The asthmatic inflammatory responses present different type of cells involved in this process, such as: Lymphocytes and Eosinophils. In experienced hands the bronchoalveolar lavage (BAL) is a well-tolerated and valuable tool for investigation of basic mechanisms in asthma and other immunological respiratory diseases. The purpose of this work was to study the different cells involved in asthmatic inflammatory responses in allergic and aspirin sensitivity patients and compared with Extrinsic Allergic Alveolitis patients (EAA) by BAL procedure. We studied 27 asthmatic patients. This group was divided by etiological conditions in: allergic asthmatic patients (a) (n: 19), (9 male and 10 female) demonstrated by reversible fall of FEV 1 (3) 20% and 2 or more positive skin test for common aeroallergens. The aspirin asthmatic patients (b) (n: 8) (5 male and 3 female) demonstrated by progressive challenge with aspirin and fall of FEV 1 (3) 20%. The third group with compatible symptoms and signs of EAA, demonstrated by lung biopsy, (n: 9) (8 male and 1 female) (c). We determined in all patients: Total IgE serum level by ELISA test. BAL was performed by standard procedure in all patients. The cells count were performed in BAL and were separated in Eosinophils, T lymphocytes defined by monoclonal anti CD 3 antibody, Lymphocytes CD 4 and CD 8 by monoclonal anti CD 4 and CD 8 antibodies respectively. The B lymphocytes defined by surface immunoglobulin isotypes IgG, IgM, IgA and IgE. The IgE level was in (a) 630 +/- 350 kU/L, in (b) it was 85 +/- 62 kU/L and in EAA (c) 55 +/- 23 kU/L, p < .0005. Eosinophil percentage in (a) was 25 +/- 13% of cells, in (b) was 28 +/- 15% of cells, NS, and 0 in (c), p < .0005. Lymphocytes T level was 43 +/- 15% of cells in (a), it was 32 +/- 15% of cells in (b) and it was 54 +/- 19% of cells in (c), NS. Lymphocytes CD 4 (+) level was 30 +/- 10% of cells in (a), it was 24 +/- 11% of cells in (b) and it was 8 +/- 6% of cells in (c), p < .005. Lymphocytes CD8 level was 8 +/- 6% of cells in (a), it was 7 +/- 4% of cells in (b) and it was 44 +/- 15% of cells in EAA (c), p < .005. Lymphocytes B level was 8 +/- 4% cells in (a), it was 2.9 +/- 2.5% cells in (b) and it was 3 +/- 2.7% of cells in (c), p < .025. The features described here suggest the importance of the Eosinophils and CD 4 +/- Lymphocytes in asthmatic response of allergic asthmatic patients as well as in aspirin sensitivity asthmatic patients. The LBA cellular profile of E.AA patients presented eosinophilia and CE8+ Lymphocite predominance when compared with both asthmatic cellular profile.

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Food and nutrient intakes and asthma risk in young adults.

Abramson MJ.

Department of Epidemiology & Preventive Medicine, Central and Eastern Clinical School, Monash University, and The Alfred Hospital, Melbourne, Victoria, Australia.

BACKGROUND: Some aspects of diet are relatively newly recognized potential risk factors for asthma, but the evidence to date is conflicting. OBJECTIVE: The goal was to determine whether the food and nutrient intakes of adults with asthma differ from those of adults without asthma. DESIGN: This was a community-based, cross-sectional study of 1601 young adults ( +/- SD age: 34.6 +/- 7.1 y) who were initially recruited by random selection from the federal electoral rolls in Melbourne in 1999. Subjects completed a detailed respiratory questionnaire, a validated semiquantitative food-frequency questionnaire, skin-prick testing, and lung function tests, including a methacholine challenge test for bronchial hyperreactivity (BHR). A total of 25 nutrients and 47 food groups were analyzed by using multiple logistic regression with alternate definitions of asthma and atopy as the outcomes. RESULTS: Whole milk appeared to protect against current asthma (odds ratio: 0.66; 95% CI: 0.46, 0.97), doctor-diagnosed asthma (0.73; 0.54, 0.99), BHR (0.68; 0.48, 0.92), and atopy (0.71; 0.54, 0.94). Conversely, soy beverage was associated with an increased risk of current asthma (2.05; 1.19, 3.53), doctor-diagnosed asthma (1.69; 1.04, 2.77), and BHR (1.65; 1.00, 2.71). Apples and pears appeared to protect against current asthma (0.83; 0.71, 0.98), asthma (0.88; 0.78, 1.00), and BHR (0.88; 0.77, 1.00). CONCLUSIONS: The consumption of dairy products, soy beverages, and apples and pears, but not of nutrients per se, was associated with a range of asthma definitions. Dietary modification after diagnosis is one possible explanation for this finding. Intervention studies using whole foods are required to ascertain whether such modifications of food intake could be beneficial in the prevention or amelioration of asthma.

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Interleukin-10 gene -627 allele variants, not interleukin-I beta gene and receptor antagonist gene polymorphisms, are associated with atopic bronchial asthma.

Tsai FJ.

Department of Chest, China Medical College Hospital, Taichung, Taiwan.

Asthma is an airway hyperresponsive disease characterized by the expression of multiple inflammatory genes, including cytokines. Interleukin-I and interleukin-10 (IL-1 and IL-10) are cytokines that might play a role in the process of inflammation and are therefore considered to be involved in the pathogenesis of bronchial asthma. The aim of this study was to test whether the polymorphisms of the promoter region and exon 5 of the IL-1 gene, intron 2 of the IL-1Ra gene, and -627 nucleotide (C/A) of the IL-10 gene could be genetic markers for the susceptibility of bronchial asthma. A normal control group made up of 47 healthy volunteers and 117 patients with bronchial asthma were examined in this study. We analyzed the variable number of tandem repeats at intron 2 of the IL-1Ra gene for the polymorphisms by polymerase chain reaction (PCR). PCR-based restriction analysis of the IL-1 gene polymorphisms of the promoter region and exon 5 was carried out by the endonucleases Ava I and Taq I, respectively. The IL-10 gene -627 C/A polymorphisms were investigated by PCR-based restriction analysis. The distribution of CC homozygotes in the IL-10 gene was significantly lower in asthma patients than in controls (P=0.013, OR=3.599, 95% CI=1.240 approximately 10.441). The polymorphisms studied in the IL-1 genes did not reveal any significant association with bronchial asthma when compared with the control group (promoter region by chi-square test, P=0.627; exon 5 region by Fisher's exact test, P=0.403). Only two alleles of the IL-1Ra gene corresponding to one and two copies of an 86-base pair sequence repeat were identified by PCR in the control group. There were three alleles found in the asthmatic patient group. The results revealed no significant differences between normal individuals and asthma patients (P=0.454, Fisher's exact test). The IL-10 gene -627 "A" allele is an associated risk factor of developing atopic asthma. Copyright 2003 Wiley-Liss, Inc.

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ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics.

Shin HD.

Asthma Genome Research Center, Soonchunhyang University Hospital, Bucheon, Korea.

BACKGROUND: A disintegrin and metalloprotease 33 (ADAM33) is expressed in the lung by fibroblasts and bronchial smooth muscle cells. Given its structure and cellular provenance, ADAM33 may be associated with airway remodelling and bronchial hyper-responsiveness. Single nucleotide polymorphisms (SNPs) and haplotypes of the ADAM33 gene have previously been associated with asthma susceptibility in the Caucasian population. OBJECTIVE AND METHODS: To assess whether genetic variants of ADAM33 are related to asthma in a Korean population, we conducted an association study of the ADAM33 gene with asthma susceptibility, bronchial hyper-reactivity and serum IgE in Korean asthmatics (n=326) and normal controls (n=151). Five of the 14 polymorphisms originally reported to be associated with asthma development (S1 G>A, T1 T>C, V-1 C>A, V1 T>A, V4 C>G) were genotyped using single base extension and electrophoresis. Haplotypes and their frequencies were inferred using the algorithm implemented by the software Arlequin. Allele frequencies of each SNP and haplotypes were compared between the patients and the normal controls using logistic regression analysis. RESULTS: There was no significant difference in the distribution of SNPs and the six haplotypes between asthmatics and normal controls. All single SNPs and six haplotypes in ADAM33 were also analysed for the association with level of PC(20) using general linear models. The distribution of the T1 T>C SNP and one haplotype (ht4: GCGG) showed significant association with log-transformed PC(20) methacholine level in the asthma patients (P=0.03 and 0.0007, respectively, using a co-dominant model). CONCLUSION: Polymorphism of ADAM33 may contribute to development of BHR in asthma.

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Increased circulating 92 kDa matrix metalloproteinase (MMP-9) activity in exacerbations of asthma.

Aizawa H.

First Department of Internal Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan.

BACKGROUND: The 72 kDa matrix metalloproteinase 2 (MMP-2) and the 92 kDa matrix metalloproteinase 9 (MMP-9) are type IV collagenases implicated in various aspects of inflammation including accumulation of inflammatory cells, tissue injury, and development of remodelling. The role of these enzymes in the pathogenesis of asthma exacerbations is unknown. METHODS: Circulating levels of MMP-2 and MMP-9 proteins and the expression of their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP-1), were measured in 21 patients experiencing an asthma exacerbation and 21 age matched patients with stable asthma. Circulating gelatinolytic activity was compared during the asthma exacerbation and during subsequent convalescence by gelatin zymography in the same individuals. In addition, MMP-9 specific activity was quantified with a colorimetric assay which uses an artificial proenzyme containing a specific domain recognised by MMP-9 in the same paired samples. RESULTS: A significant increase in the circulating level of MMP-9 was seen in patients with an asthma exacerbation compared with patients with stable asthma (202.9 (22.0) v 107.7 (9.9) ng/ml, p=0.0003). There were no significant differences in the circulating levels of MMP-2 or TIMP-1. Gelatin zymography identified two major circulating gelatinolytic activities corresponding to MMP-2 and MMP-9, and showed that asthma exacerbations are characterised by markedly increased MMP-9 activity with no significant change in MMP-2 activity compared with the activities during convalescence in the same individuals. Direct measurement showed that MMP-9 specific activity is significantly increased during asthma exacerbations compared with subsequent convalescence (269.6 (31.7) v 170.4 (12.6) ng/ml, p=0.0099). CONCLUSIONS: Asthma exacerbations are characterised by increased circulating MMP-9 activity. This increased activity may be related to exaggerated airway inflammation and airway remodelling.

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Exhaled nitric oxide corresponds with office evaluation of asthma control.

De Boeck K.

Pediatric Pulmonology Department, University Hospital Gasthuisberg Leuven, Herestraat 49, 3000 Leuven, Belgium.

Exhaled NO (ENO) has been studied as a noninvasive marker of airway inflammation, and has been shown to be elevated in asthma patients. The aim of this study was to investigate whether ENO measurements differ significantly between groups of asthmatic children with different disease control and to compare ENO measurements with the clinical assessment of asthma control. Seventy-three children between 5-18 years old with a diagnosis of asthma were recruited. ENO was measured online during a slow vital capacity maneuver. The mean of three plateau NO levels was used for analysis. Baseline and postbronchodilator spirometry were performed. The assessment of disease control was based on the frequency of use of beta2-agonists, occurrence of day- and nighttime asthma symptoms, and spirometry results. Twenty-one children (group 1) had good asthma control. In 31 patients (group 2), asthma control was acceptable. In 21 patients (group 3), asthma was insufficiently controlled. ENO levels were (median (quartiles)): group 1, 11 ppb (9-21); group 2, 15 ppb (11-26); and group 3, 28 ppb (19-33). Measurements were significantly different between all three groups (P = 0.009, Kruskal-Wallis), between groups 1 and 3 (P = 0.01, Mann-Whitney U test), and between groups 2 and 3 (P = 0.01, Mann-Whitney-U test). The same was true for reversibility testing. We found significantly different ENO levels between a group of pediatric asthma patients with insufficient and good/sufficient control, as defined by clinical assessment. These results suggest that ENO measurements may be useful for monitoring asthma patients. Copyright 2003 Wiley-Liss, Inc.

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