Distinct asthma phenotypes with low maximal attainment of lung function on cluster analysis.

OBJECTIVE: Asthma is a heterogeneous disease with varying clinical presentations, severity and ability to achieve asthma control. The present study aimed to characterize clinical phenotypes of asthma in an Indian cohort of subjects using a cluster analysis approach. METHODS: Patients with confirmed asthma (N = 100) and at least 6-months of follow-up data, identified by retrospective chart review, were included in this study. Demographics, age at disease onset, disease duration, body mass index, serial spirometry and allergen sensitization were assessed. Asthma control was assessed prospectively using Global Initiative for Asthma and Asthma Control Test. R version 3.4.3 was used for statistical analysis. Ward's minimum-variance hierarchical clustering method was performed using an agglomerative (bottom-up) approach. To compare differences between clusters, analysis of variance using Kruskal-Wallis test (continuous variables) and chi-square test (categorical variables) was used. RESULTS: Cluster analysis of 100 treatment-naive patients with asthma identified four clusters. Cluster 1, (N = 40), childhood onset of disease, normal body weight, equal gender distribution and achieved normal lung function. Cluster 2 (N = 16) included adolescent disease-onset, obese, majority males and had poor attainment of maximum lung functions. Cluster 3 (N = 20) were older, late-onset of disease, obese, majority male and had poor attainment of maximum lung function. Cluster 4 (N = 24) had adult-onset of disease, obese, predominantly female and achieved normal lung function. CONCLUSIONS: In an Indian cohort of well-characterized patients with asthma, cluster analysis identified four distinct clinical phenotypes of asthma, two of which had poor attainment of maximum lung functions.

Haplotype analysis of ADAM33 polymorphisms in asthma: A pilot study.

Background & objectives: ADAM33 is implicated as a potentially strong candidate gene for asthma and bronchial hyper-responsiveness. Many polymorphisms of ADAM33 have been studied along with ADAM33 expression in various cells of the lungs. Haplotype analysis also showed association with asthma in different populations across the world. Therefore, the aim of this study was to perform a comprehensive screening of ADAM33 polymorphisms in adult patients with asthma. Methods: Thirty five polymorphisms of ADAM33 were genotyped in 55 patients with asthma and 53 controls. The association of single nucleotide polymorphisms (SNPs) and haplotypes with phenotypes of asthma was analysed. Results: The genotype, minor allele frequency, odds ratio and Hardy-Weinberg equilibrium did not show any significant difference among cases and controls. No association was found between SNPs of ADAM33 with the severity of asthma. Correlation analysis of ADAM33 SNPs to the phenotypes, based on clinical variables and allergen sensitization, did not show significant difference. Haplotype analysis showed that rs2280090 and rs2280091 were associated with asthma in the patient group. Interpretation & conclusions: Haplotype analysis showed an association of the two SNP variations with asthma. These SNPs lead to amino acid change and are prone to phosphorylation, which may affect expression levels and protein function of ADAM33 and asthma susceptibility.

Prevalence of food sensitization and probable food allergy among adults in India: the EuroPrevall INCO study.

BACKGROUND: Data are lacking regarding the prevalence of food sensitization and probable food allergy among general population in India. We report the prevalence of sensitization and probable food allergy to 24 common foods among adults from general population in Karnataka, South India. METHODOLOGY: The study was conducted in two stages: a screening study and a case-control study. A total of 11 791 adults in age group 20-54 were randomly sampled from general population in South India and answered a screening questionnaire. A total of 588 subjects (236 cases and 352 controls) participated in the case-control study involving a detailed questionnaire and specific IgE estimation for 24 common foods. RESULTS: A high level of sensitization (26.5%) was observed for most of the foods in the general population, higher than that observed among adults in Europe, except for those foods that cross-react with birch pollen. Most of the sensitization was observed in subjects who had total IgE above the median IgE level. A high level of cross-reactivity was observed among different pollens and foods and among foods. The prevalence of probable food allergy (self-reports of adverse symptoms after the consumption of food and specific IgE to the same food) was 1.2%, which was mainly accounted for cow's milk (0.5%) and apple (0.5%). CONCLUSION: Very high levels of sensitization were observed for most foods, including those not commonly consumed in the general population. For the levels of sensitization, the prevalence of probable food allergy was low. This disassociation needs to be further explored in future studies.

IL-10 and IL-17F Promoter Single Nucleotide Polymorphism and Asthma: A Case-Control Study in South India.

BACKGROUND: Several studies have assessed the association between IL-17F and IL-10 promoter polymorphisms and asthma, but the results were conflicting. Furthermore, few studies have evaluated the association of cytokine polymorphisms with asthma and its clinical phenotypes. OBJECTIVE: This study was conducted to evaluate the association of IL-10 (interleukin 10) and IL-17F (interleukin 17F) promoter polymorphisms (rs1800871, rs1800896 and rs1889570) with asthma and its clinical phenotypes including severity, atopic status, spirometric parameters, and response to treatment in south Indian population. A sub-study was conducted to assess cytokine levels in subjects with different gene variants. METHODS: IL-10 and IL-17F polymorphisms were genotyped in 419 asthmatic patients and 393 controls using Mass ARRAY. RESULTS: Our results showed an association between IL-10 SNPs and mild asthma. No association was found with any of three SNPs in moderate to severe asthma. Comparison of genotype distribution of IL-17F rs1887570 AA variant among atopic and non-atopic patients showed significant difference (p = 0.024). Correlation analysis of IL-10 and IL-17F SNPs to clinical variables showed a positive correlation between IL-17F rs1887570 AA and number of allergen sensitized (rs = 0.142, p = 0.004). Significant improvement in lung function was observed after 2 months of ICS (Inhaled corticosteroids) and LABA (long acting ß2 agonist) treatment in all subjects with no statistically significant difference among SNPs variants. Cytokines levels were similar in different SNP variants. CONCLUSION: We observed an association between IL-10 rs1800871 and rs1800896 SNPs and mild asthma, as well as IL-17F rs1887570 AA variant and number of allergens sensitized.

A preliminary study on the association of single nucleotide polymorphisms of interleukin 4 (IL4), IL13, IL4 receptor alpha (IL4Rα) & Toll-like receptor 4 (TLR4) genes with asthma in Indian adults.

BACKGROUND & OBJECTIVES: Interleukin 4 (IL4) and IL13 genes are believed to be responsible for inflammation of the airways in asthmatics. These share a common receptor component called IL4Rα which is another potentially important candidate gene linked to asthma phenotypes. Another gene Toll-like receptor 4 (TLR4) might affect the incidence or progression of asthma through the expression of proinflammatory genes. Several single nucleotide polymorphisms (SNPs) in IL4, IL13, IL4Rα and TLR4 have been reported to be linked to asthma or related phenotypes in several ethnic populations using linkage studies and association studies. However, the results have not been consistent. We investigated five SNPs (C-589T and C-33T of IL4, G+2044A of IL13, A+1902G of IL4Rα, and A+896G of TLR4) in patients with adult onset asthma to evaluate their role in manifestation and severity of asthma. METHODS: Adult (>18 yr of age) patients with asthma (n=100) and healthy controls (n=50) were included in the study. Genotyping was performed using sequenom MassARRAY technology. RESULTS: The mutant alleles of the C-589T and C-33T SNPs in the promoter region of IL4 were present in 4 per cent patients with asthma but absent from the control group suggesting that the variations in IL4 may contribute to asthma occurrence. The SNPs of other genes were seen in both controls and patients. INTERPRETATION & CONCLUSIONS: The results suggest the possible association between the genetic distribution of C-589T and C-33T SNPs of IL4 with asthma in Indian adults.

Serum levels of IL-10, IL-17F and IL-33 in patients with asthma: a case-control study.

OBJECTIVES: The development of inflammation in asthma involves an intricate network of cytokines that recruit and activate numerous immune cells. This study was aimed to compare serum levels of IL-10, IL-17F, and IL-33 in asthmatic patients and non-asthmatic controls and correlate cytokine levels to asthma severity and various clinical, spirometric, and laboratory variables. METHODS: Using ELISA, serum levels of IL-10, IL-17F, and IL-33 were evaluated in 44 asthmatics (14 mild persistent, 15 moderate persistent, and 15 severe persistent) and 44 controls. RESULTS: This is one of the first reports showing a significant difference in serum levels of asthma-associated cytokines, anti-inflammatory IL-10, and pro-inflammatory IL-17F and IL-33, in the same subset of asthmatic patients. Our results showed diminished level of IL-10 and elevated levels of IL-17F and IL-33 in asthmatics than in controls (p < 0.001). Assessment of cytokine levels between subjects of different gender, age group, and BMI showed non-significant differences. Correlation analysis of cytokine levels to clinical variables showed that IL-17F is associated negatively to FVC % predicted (forced vital capacity) and FEV1% predicted (forced expiratory volume in one second) and positively to number of allergens sensitized and FEV1 reversibility. A strong negative correlation was found between IL-10 and IL-33 levels (p = 0.001). CONCLUSIONS: Negative correlation between IL-10 and IL-33 levels may reflect a converse relationship between anti-inflammatory and pro-inflammatory cytokines in an individually balanced pattern. The association between IL-17F level and asthmatic phenotypes such as reduced FVC and FEV1, higher degree of sensitization, and post-bronchodilator reversibility needs further assessments.

Association of socio-economic status with family history in adult patients with asthma.

BACKGROUND & OBJECTIVES: Socio-economic status is associated with increased morbidity in patients with asthma. The aim of the present study was to assess the association between socio-economic status and family history of asthma in adult asthma patients. METHODS: The study included 200 adults with asthma and 400 non-asthmatic controls. Socio-economic status was determined based on income. Regression analysis was used to estimate odd ratios in relation to socio-economic class, using age, gender, family history of asthma and smoking habits. RESULTS: The highest occurrence of having any family history of asthma was observed in the high class group (88.2%), followed by upper middle class (79.5%), lower middle class (60%) and the lowest in the low class group (34%). Having any family history of asthma was an important risk factor in both univariate and multivariate analyses in lower middle class, upper middle class and high class, but not in the low class group. INTERPRETATION AND CONCLUSIONS: The results indicated a positive association between having a family history of asthma and higher socio-economic status. Further studies on a large representative sample need to be conducted to confirm these findings.

Association between ADAM33 Single-Nucleotide Polymorphisms and Treatment Response to Inhaled Corticosteroids and a Long-Acting Beta-Agonist in Asthma.

ADAM33 has been linked to airway structural changes in patients with asthma, leading to airway hyperresponsiveness, narrowing, and ultimately poor treatment responsiveness. This study aimed to evaluate the genetic association of ADAM33 SNPs with asthma, disease severity, and treatment responsiveness to ICS+LABA in the South Indian population. In this case-control study (486 controls and 503 cases), we performed genotyping using MassArray for six SNPs of ADAM33, namely rs2280091, rs2787094, rs3918396, rs67044, rs2853209, and rs3918392. We studied the association with asthma and treatment responsiveness to ICS+LABA, using genotype, allele frequency distribution, and haplotype analysis. A significant clinical finding of the study was that certain patients in the disease severity group (moderate and mild) showed poor or no improvement after a three-month follow-up of regular ICS+LABA therapy. Of the studied ADAM33 SNPs, rs2853209 showed an association with asthma. The further analysis of asthma patients according to disease severity suggested an association between moderate disease and the minor allele "T" for rs2853209. The homozygous minor allele of SNP rs2787094 was found to be associated with poorer lung function and the least lung-function improvement after three months of ICS+LABA therapy. The haplotype analysis of six SNPs showed a significant association between the rs2853209 and rs3918396 blocks and asthma. ADAM33 gene polymorphism has clinical relevance in terms of disease association and response to treatment. SNP rs2853209 seemed most relevant to asthma, and SNP rs2787094 could be a genetic marker for predicting response to ICS+LABA therapy in the study population.

Serum levels of interleukin-13 and interferon-gamma from adult patients with asthma in Mysore.

Serum protein analysis for noninvasive quantification of airway inflammation in asthma is a promising research tool in the field of lung diseases. Cytokines are believed to have major role in inflammatory process of the airways of the lung. There is an imbalance between T-helper (Th)-2 cells, which secrete interleukin (IL)-4 and interleukin (IL)-13, and Th1 cells, which secrete interferon (IFN)-gamma in asthma. To test the hypothesis that serum IL-13 and IL-4 levels may be elevated whereas IFN-gamma would be decreased in this cohort of patients, a property that could make them possible candidate biomarkers in determining asthma occurrence and severity, we measured concentrations of IL-4, IL-13 and IFN-gamma in serum samples of 88 subjects (44 normal, 12 with mild asthma, 16 with moderate asthma, and 16 with severe asthma). Serum Levels of IL-4, IL-13, and IFN-gamma were determined by an enzyme-linked immune-sorbent assay (ELISA). Median serum level of IFN-gamma in asthmatic patients was 8.0 pg/ml, while it was 11.4 pg/ml in healthy controls. However, the difference was not significant. Among the different age groups in whom IFN-gamma was assessed, the highest median value in both cases and controls was observed in the age group of 31-40 years. The median serum level of IL-13 was 40.0 pg/ml in asthmatic patients and 58.25 pg/ml in healthy controls. The difference was not significant. On subgroup analysis, no significant difference of IFN-gamma and IL-13 between asthma of different severities was observed. The study also revealed nonsignificant difference of serum cytokines with the duration of asthma, number of allergens, and severity of sensitization. Normal serum levels of IFN-gamma and IL-13 in asthmatic patients suggest their neutral role in the inflammatory process; however, more studies are required to establish the effect of these cytokines in adulthood asthma in different ethnic populations.

Time interval and the factors associated with the development of asthma in patients with allergic rhinitis.

Rhinitis and asthma commonly coexist and studies have shown a positive association between rhinitis and asthma in both atopic and nonatopic adults. Longitudinal studies have shown that in many cases rhinitis precedes the onset of asthma. The aims of this study were to study the time interval for the development of asthma after the onset of rhinitis, to determine the proportion of patients in whom rhinitis precedes asthma, and to study the factors associated with the development of asthma in patients with allergic rhinitis compared to patients who continue to have allergic rhinitis alone. This was a cross-sectional study done at a tertiary care allergy center in Mysore, South India. It included consecutive patients between 2004 and 2006 with allergic rhinitis and/or asthma. We used a structured questionnaire, clinical evaluation, spirometry, and skin-prick testing. A total of 1,141 subjects were included in the study. Among them, 700 had allergic rhinitis for varying intervals before developing asthma and 355 had rhinitis without asthma. In subjects aged 20 years or younger, logistic regression analysis confirmed an independent association with a family history of allergic rhinitis and sensitization to house dust mites as risk factors and ever-used nasal steroids as protective against developing asthma in subjects with allergic rhinitis. In subjects older than 20 years, a family history of allergic rhinitis, atopy, and sensitization to house dust mites and trees were risk factors and ever-user of nasal steroids was protective. Rhinitis often preceded asthma and a high proportion of patients, both children and adults, developed asthma within 2 years after the onset of rhinitis. A family history of allergic rhinitis, atopy, and sensitization to house dust mites and trees are associated with the development of asthma in patients with allergic rhinitis.

House dust mite sensitivity is a factor in chronic urticaria.

BACKGROUND: Chronic urticaria is one of the perplexing problems faced by clinicians. There are a few reports associating house dust mite sensitivity with chronic urticaria, based upon the patient's history as well as intradermal skin testing and in vitro analysis. AIMS: To investigate the possible association between house dust mite sensitivity and chronic urticaria. METHODS: In this case control study three groups of patients were enrolled. Group I: Chronic urticaria (73 subjects). Group II: Chronic urticaria with collateral allergic disorders (49 subjects). Group III: Normal subjects without chronic urticaria or other allergies (25 subjects). All the patients underwent skin prick testing with antigens of the house dust mite, Dermatophagoides pteronyssinus (DP) and Dermatophagoides farinae (DF), with positive and negative controls. RESULTS: Among the patients with chronic urticaria, 78/122 (64%) patients had skin sensitivity to house dust mites. Out of these, 39/73 (53%) had chronic urticaria alone and 39/49 (79%) had chronic urticaria with other associated allergies. Among the normal control subjects, 7/25(28%) reacted positively to house dust mites. CONCLUSION: This study suggests a possible association of house dust mite sensitivity with chronic urticaria.

Endotoxin, atopy and asthma.

Endotoxin is infamous for its ability to exacerbate existing allergy and asthma symptoms. Current research supports this phenomenon, demonstrating its significance in the home, as well as in the workplace. At the same time, evidence is emerging that exposure to endotoxin may drive immune development away from the T-helper lymphocyte type 2-mediated allergy and asthma profile. This fits in nicely with the 'hygiene hypothesis', which attributes the past century's rise in allergy and asthma to a reduction in microbial burden. Indeed, infections have been associated with less atopy and asthma. Recent investigations have suggested that naturally-occurring non-infectious exposure to microbial components such as endotoxin might mitigate atopy and asthma as well.

Effect of animal contact and microbial exposures on the prevalence of atopy and asthma in urban vs rural children in India.

BACKGROUND: Environmental factors, including microbial exposures and close animal contact, are implicated in the lower prevalence of asthma and allergy in rural vs urban children. OBJECTIVES: To determine (1) the prevalence of asthma, rhinitis, eczema, and atopic sensitization in rural and urban children in India; (2) differences in microbial and animal exposures in these locales; and (3) whether differences in environmental exposures account for the different rates of asthma and atopy in these locales. METHODS: One child from each of 50 urban (Mysore) and 50 rural (Vinobha) households in southern India was randomly selected for data analysis. Allergy, asthma, health, environment, and lifestyle information was obtained using a questionnaire and household inspections. Atopy was determined via skin prick testing for common allergens. Endotoxin content was measured in house dust samples. RESULTS: Children from rural vs urban areas had lower prevalences of self-reported asthma (8% vs 30%; P = .005), rhinitis (22% vs 42%; P = .03), and atopic sensitization (36% vs 58%; P = .03). Higher median dust endotoxin loads were found in rural vs urban households (6.50 x 10(4) EU/m2 vs 1.27 x 10(4) EU/m2; P < .001). In multivariate analysis, close indoor animal contact (adjusted odds ratio [OR] 0.2; 90% confidence interval [CI], 0.05-0.9), outdoor animal contact (OR, 0.3; 90% CI, 0.1-0.8), and exclusive breastfeeding for at least 6 months (OR, 0.2; 90% CI, 0.1-0.5) were associated with lower atopic sensitization; mud flooring was associated with lower self-reported wheezing (OR, 0.1; 90% CI, 0.02-1.0). CONCLUSION: Children in India who live with close animal contact and mud flooring and who were exclusively breastfed in infancy are less likely to develop asthma, rhinitis, and atopic sensitization.