Inhaled dexamethasone differentially attenuates disease relapse and established allergic asthma in mice

Inhaled glucocorticoids are effective in patients with chronic allergic asthma. We examined the effects of inhaled glucocorticoids on relapse (allergen challenge after disease remission) and established/overt allergic asthma (repeated allergen challenge in weekly intervals) in mice to establish a reference standard for novel treatments. BALB/c mice were treated before relapse or during overt disease with 1 h of nebulized PBS or 10 mg% dexamethasone twice daily for 5 days. Dexamethasone eliminated airway hyperresponsiveness before relapse and during overt disease. They more efficiently reduced airway inflammation, mucus production, and OVA-specific IgG1 and IgE during relapse compared to overt disease. However, during overt disease, parenchymal inflammatory infiltrates were more effectively eliminated compared to relapse, suggesting that activated infiltrating leukocytes have increased sensitivity to steroids. These data demonstrate that inhaled corticosteroids attenuate relapse and overt disease differentially and suggest that both airway and parenchymal inflammation need to be evaluated for treatment efficacy.     

Asthma severity and child quality of life in pediatric asthma: A systematic review

Objective

To systematically review evidence of asthma severity as a correlate of child quality of life (QOL) in pediatric asthma.

Methods

Online bibliographic databases (PsycINFO, PsycARTICLES, and MEDLINE) were used to identify relevant studies that specifically considered the relationship between asthma severity and child QOL.

Results

Fourteen studies matching inclusion and exclusion criteria were reviewed. Asthma severity was significantly related to child QOL in nine of these studies. Informant of QOL and type of QOL measure were found to influence the strength of the relationship between severity and child QOL in pediatric asthma.

Conclusions

Findings suggest that asthma severity is a correlate of child QOL. Children whose asthma symptoms are not well-managed are likely to experience an impaired level of QOL. Findings also suggest the need to utilize asthma-specific QOL measures and an informant of QOL other than the child's parent in order to receive the most accurate information about the child's level of functioning.

Practice implications

Researchers and healthcare providers basing clinical outcomes on QOL assessments should consider asthma severity in their evaluations. Further, researchers and healthcare providers should recognize the continued need to reduce asthma severity and improve asthma symptom control in their attempts to improve the QOL of children with asthma.     

Exhaled nitric oxide is associated with allergic inflammation in children

Exhaled nitric oxide (eNO) has been proposed as a noninvasive marker of airway inflammation in asthma. In asthmatic patients, exhaled NO levels have been shown to relate with other markers of eosinophilic recruitment, which are detected in blood, sputum, bronchoalveolar lavage fluid and bronchial biopsy samples. The purpose of this study was to assess the possible relationship between eNO and allergic inflammation or sensitization in childhood asthma and allergic rhinitis. Subjects consisted of 118 asthmatic children, 79 patients with allergic rhinitis, and 74 controls. Their age ranged from 6 to 15 yr old. eNO level, peripheral blood eosinophil count, eosinophil cationic protein (ECP), serum total IgE level and specific IgE levels were measured. Methacholine challenge test and allergic skin prick test for common allergens were performed in all subjects. Atopic group (n = 206, 44.48 ± 30.45 ppb) had higher eNO values than non-atopic group (n = 65, 20.54 ± 16.57 ppb, P < 0.001). eNO level was significantly higher in patients with asthma (42.84 ± 31.92 ppb) and in those with allergic rhinitis (43.59 ± 29.84 ppb) than in healthy controls (27.01 ± 21.34 ppb, P < 0.001) but there was no difference between asthma and allergic rhinitis group. eNO also had significant positive correlations with Dermatophagoides pteronyssinus IgE level (r = 0.348, P < 0.001), Dermatophagoides farinae IgE level (r = 0.376, P < 0.001), and the number of positive allergens in skin prick test (r = 0.329, P = 0.001). eNO had significant positive correlations with peripheral blood eosinophil count (r = 0.356, P < 0.001), serum total IgE level (r = 0.221, P < 0.001), and ECP (r = 0.436, P < 0.001). This study reveals that eNO level is associated with allergic inflammation and the degree of allergic sensitization.     

Trichophyton sensitivity in allergic and nonallergic asthma

BACKGROUND: Although the role of inhaled fungi in inducing asthma has been repeatedly confirmed, there are few reports about the association of asthma with dermatophyte sensitivity and the causal role of Trichophyton allergy in asthma. The objective was to investigate the presence of Trichophyton sensitivity among patients with allergic and nonallergic asthma in combination with tinea, and to compare the situation with several control groups in order to evaluate the factors determining Trichophyton sensitivity. METHODS: A total of 86 subjects (55 female, 31 male) with a mean age of 38.6 +/- 11.1 years were included in the study. The patients were divided into five groups: 1) nonallergic asthma plus tinea (n = 19) 2) allergic asthma plus tinea (n = 15) 3) asthma without tinea (n = 22) 4) tinea without asthma (n = 17) 5) healthy controls (n = 13). Skin tests with standardized extracts of T. rubrum and specific IgE measurements were performed in all subjects. All patients were also subjected to microscopic evaluation and fungal culture for dermatophyte infection. RESULTS: The skin test positivity rate to Trichophyton extract of groups 1 (63.1%), 2 (46.7%), and 4 (47.1%) was higher than that in groups 3 (4.4%) and 5 (7.7%) (P < 0.05). Although not significant, the rates of sensitivity to T. rubrum (63.1%) and of severe asthma (31.6%) were higher in the group with nonallergic asthma with tinea (group 1) than in other groups. Among 51 patients in whom direct microscopic evaluation revealed dermatophyte infection, 60.8% had positive fungal cultures for T. rubrum (58.1%), T. mentagrophytes (35.5%), and Candida (6.4%). CONCLUSION: According to our data, the presence of fungal infection seems to be an important determinant in hypersensitivity to Trichophyton whether or not the subject is asthmatic and/or allergic. Since a greater proportion of patients with nonallergic asthma--in whom the rate of severe asthma was also higher - showed positive skin tests to Trichophyton extracts in this study, we believe that patients with severe, intrinsic asthma should be examined for signs of fungal infection and tested to determine immediate hypersensitivity to dermatophyte antigens.     

Mechanisms of climate change and related air pollution on the immune system leading to allergic disease and asthma

Climate change is considered the greatest threat to global health. Greenhouse gases as well as global surface temperatures have increased causing more frequent and intense heat and cold waves, wildfires, floods, drought, altered rainfall patterns, hurricanes, thunderstorms, air pollution, and windstorms. These extreme weather events have direct and indirect effects on the immune system, leading to allergic disease due to exposure to pollen, molds, and other environmental pollutants. In this review, we will focus on immune mechanisms associated with allergy and asthma-related health risks induced by climate change events. We will review current understanding of the molecular and cellular mechanisms by which the changing environment mediates these effects.     

Adenylyl cyclase type 9 gene polymorphisms are associated with asthma and allergy in Brazilian children

Asthma is a chronic inflammatory disease of the respiratory tract. This heterogeneous disease is caused by the interaction of interindividual genetic variability and environmental factors. The gene adenylyl cyclase type 9 (ADCY9) encodes a protein called adenylyl cyclase (AC), responsible for producing the second messenger cyclic AMP (cAMP). cAMP is produced by T regulatory cells and is involved in the down-regulation of T effector cells. Failures in cAMP production may be related to an imbalance in the regulatory immune response, leading to immune-mediated diseases, such as allergic disorders. The aim of this study was to investigate how polymorphisms in the ADCY9 are associated with asthma and allergic markers. The study comprised 1309 subjects from the SCAALA (Social Changes Asthma and Allergy in Latin America) program. Genotyping was accomplished using the Illumina 2.5 Human Omni bead chip. Logistic regression was used to assess the association between allergy markers and ADCY9 variation in PLINK 1.07 software with adjustments for sex, age, helminth infection and ancestry markers. The ADCY9 candidate gene was associated with different phenotypes, such as asthma, specific IgE, skin prick test, and cytokine production. Among 133 markers analyzed, 29 SNPs where associated with asthma and allergic markers in silico analysis revealed the functional impact of the 6 SNPs on ADCY9 expression. It can be concluded that polymorphisms in the ADCY9 gene are significantly associated with asthma and/or allergy markers. We believe that such polymorphisms may lead to increased expression of adenylyl cyclase with a consequent increase in immunoregulatory activity. Therefore, these SNPs may offer an impact on the occurrence of these conditions in admixture population from countries such as Brazil.     

Stress and allergic diseases

Allergy describes a constellation of clinical diseases that affect up to 30% of the world's population. It is characterized by production of allergen-specific IgE, which binds to mast cells and initiates a cascade of molecular and cellular events that affect the respiratory tract (rhinitis and asthma), skin (dermatitis, urticaria), and multiple systems (anaphylaxis) in response to a variety of allergens including pollens, mold spores, animal danders, insect stings, foods, and drugs. The underlying pathophysiology involves immunoregulatory dysfunctions similar to those noted in highly stressed populations. The relationships in terms of potential for intervention are discussed.     

母亲过敏性哮喘病史对新生儿调节性T细胞的影响

目的:研究母亲过敏性哮喘病史对新生儿调节性T细胞的影响。方法:收集62例胎儿脐带血[40例健康母亲(对照组),22例母亲有过敏性哮喘病史(哮喘组)],分离单个核细胞进行体外培养,每例样品均分别给予以下4种刺激:类脂A(LpA)-Toll样受体4的配体,肽多糖(Ppg)-Toll样受体2的配体,植物血凝素(PHA),屋尘螨提取物。培养3天后,应用流式细胞技术检测CD4+CD25+Foxp3+调节性T细胞数量;Luminex流式荧光仪检测特异性细胞因子分泌浓度;体外分离CD4+CD25+调节性T细胞与CD4+CD25-效应T细胞共同培养,检测调节性T细胞对效应细胞的增殖和分泌细胞因子的抑制功能。结果:在Ppg诱导的免疫反应中,与对照组相比,过敏组脐带血中调节性T细胞数量(CD4+CD25+Foxp3+T细胞)减少;相关细胞因子IL-10分泌降低,差异具有统计学意义。在PHA诱导的免疫反应中,与对照组相比,调节性T细胞对效应细胞增值的抑制功能下降,差异具有统计学意义;对于效应细胞分泌IL-13的抑制功能也趋向于降低。结论:母亲有过敏性哮喘病史的新生儿脐带血中,调节性T细胞的数量和功能存在缺陷,可能与其易患过敏性疾病有关。     

哮喘豚鼠IL-5、IL-3、GM-CSF mRNA表达及雷公藤内酯醇的影响

目的研究ＩＬ－５、ＩＬ－３、ＧＭ－ＣＳＦ在哮喘发病中的作用及雷公藤的干预。方法将实验豚鼠随机分为：①哮喘组（ｎ＝８）：用卵蛋白雾化吸入诱导哮喘模型；②处理组（ｎ＝８）：用雷公藤内酯醇腹腔注射处理哮喘模型；③正常对照组（ｎ＝８）。制备ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｃＤＮＡ探针，用斑点印迹杂交法检测以上三组豚鼠支气管肺组织ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ的表达。结果哮喘豚鼠支气管肺组织ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ表达显著高于对照组（Ｐ＜０．０５～０．００１）；雷公藤处理组ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ表达低于哮喘组（Ｐ＜０．０５～０．００１），与对照组无显著差异（Ｐ＞０．０５）。结论哮喘豚鼠肺组织中有明显的ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ表达增加。雷公藤内酯醇能抑制体内ＩＬ－５、ＩＬ－３和ＧＭ－ＣＳＦｍＲＮＡ的表达，可能在哮喘抗炎中具有潜在的临床价值。     

Probiotics and allergic diseases

The prevalence of allergic diseases including atopic dermatitis, asthma, allergic rhinitis (AR) and food allergy is increasing worldwide and they cause a big economic and social burden. Understanding of reasons that contribute to the etiology of allergic diseases as well as new treatment approaches are very important for the follow-up and prevention of these diseases. In recent years, probiotics seem to be promising for allergic diseases. The effect of probiotics in the prevention and treatment of eczema is more extensively studied, but little is known about the association of the microbial flora of the host and allergic airway diseases and the efficacy of probiotics in decreasing the symptoms of patients with asthma and rhinitis. Hitherto, there is no strong evidence for use of probiotics in the treatment of eczema; however, administration of probiotics in breastfeeding mothers in the prenatal period and infants in the postnatal period can be accepted as a safe and helpful option in the prevention of eczema. In contrast, there is not yet reliable evidence or recommendations on use of probiotics for the prevention or treatment of asthma, AR, food allergy, and anaphylaxis currently. More standardized studies should be performed with different strains of probiotics to evaluate the protective and therapeutic effects of probiotics on other allergic diseases as well as eczema. In this review, the relationship between allergy and probiotics is handled in the light of current literature.     

Antigen-binding characteristics of circulating IgG autoantibodies to cytokeratin 18 protein in patients with nonallergic asthma

Cytokeratin 18 (CK18) protein was identified as an airway epithelial cell autoantigen associated with nonallergic asthma. Cleavage of CK18 protein by caspase-3 is a marker of early apoptosis in epithelial cells. It has been shown that the expression of active caspase-3 was increased in bronchial epithelial cells of asthmatic patients, when compared with healthy controls. To investigate the antigen-binding characteristics of IgG autoantibodies to CK18 protein in nonallergic asthma, the bindings of IgG autoantibodies to the fragments of CK18 protein cleaved by caspase-3 were analyzed by Western blot using serum samples from three patients with nonallergic asthma. Recombinant human CK18 protein was treated by caspase-3 and cleaved into N-terminal fragment (1-397 amino acids) and C-terminal fragment (398-430 amino acids). The binding capacity of IgG autoantibodies to N-terminal fragment of CK18 was maintained in one patient and reduced in other two patients. IgG autoantibodies from all three patients did not bind to C-terminal fragment of CK 18. In conclusion, IgG autoantibodies to CK18 protein from patients with nonallergic asthma seems to preferentially bind to the whole molecule of CK18 protein and their antigen-binding characteristics were heterogeneous among the patients with nonallergic asthma.     

Mast cells in allergic asthma and beyond

Mast cells have been regarded for a long time as effector cells in IgE mediated type I reactions and in host defence against parasites. However, they are resident in all environmental exposed tissues and express a wide variety of receptors, suggesting that these cells can also function as sentinels in innate immune responses. Indeed, studies have demonstrated an important role of mast cells during the induction of life-saving antibacterial responses. Furthermore, recent findings have shown that mast cells promote and modulate the development of adaptive immune responses, making them an important hinge of innate and acquired immunity. In addition, mast cells and several mast cell-produced mediators have been shown to be important during the development of allergic airway diseases. In the present review, we will summarize findings on the role of mast cells during the development of adaptive immune responses and highlight their function, especially during the development of allergic asthma.     

Both allergic and nonallergic asthma are associated with increased FENO levels, but only in never-smokers

Background:  Allergic asthma is consistently associated with increased FE_NO levels whereas divergence exists regarding the use of exhaled nitric oxide (NO) as marker of inflammation in nonallergic asthma and in asthmatic smokers. The aim of this study is to analyze the effect of having allergic or nonallergic asthma on exhaled nitric oxide levels, with special regard to smoking history.
Methods:  Exhaled NO measurements were performed in 695 subjects from Turin (Italy), Gothenburg and Uppsala (both Sweden). Current asthma was defined as self-reported physician-diagnosed asthma with at least one asthma symptom or attack recorded during the last year. Allergic status was defined by using measurements of specific immunoglobulin E (IgE). Smoking history was questionnaire-assessed.
Results:  Allergic asthma was associated with 91 (60, 128) % [mean (95% CI)] increase of FE_NO while no significant association was found for nonallergic asthma [6 (–17, 35) %] in univariate analysis, when compared to nonatopic healthy subjects. In a multivariate analysis for never-smokers, subjects with allergic asthma had 77 (27, 145) % higher FE_NO levels than atopic healthy subjects while subjects with nonallergic asthma had 97 (46, 166) % higher FE_NO levels than nonatopic healthy subjects. No significant asthma-related FE_NO increases were noted for ex- and current smokers in multivariate analysis.
Conclusions:  Both allergic and nonallergic asthma are related to increased FE_NO levels, but only in never-smoking subjects. The limited value of FE_NO to detect subjects with asthma among ex- and current smokers suggests the predominance of a noneosinophilic inflammatory phenotype of asthma among ever-smokers.     

The impact of emotions on symptom perception in patients with asthma and healthy controls

Accurate perception of respiratory symptoms is highly important for course and treatment of asthma. Recent findings suggest that emotions can greatly impact respiratory symptom perception. This study compared the impact of emotions on respiratory symptom perception between patients with asthma and matched healthy controls. Pleasant and unpleasant emotional states were elicited by viewing emotional picture series while symptom reports and respiratory parameters were measured. Greater symptom report was observed for the unpleasant compared to the pleasant emotional state that was not related to respiratory parameters. Notably, this effect was comparable between patients with asthma and healthy controls. The present results suggest that the impact of emotions on respiratory symptom perception is a rather general phenomenon and not dependent upon previous experiences with asthma symptoms.     

Immunobiology of toll-like receptors in allergic disease

Allergic diseases prevalence rates have increased dramatically over the last 50 years in developed countries and one explanation might be that modern practices in public health lead to a decreased exposure towards pathogens resulting in a misguided immune response. Recently, it has become evident that immune responses against pathogens are initiated by Toll-like receptors (TLRs) that recognize a variety of structures derived from viruses, bacteria, fungi or protozoa. In this review we will discuss TLR ligands, TLR signaling in regard to Th1 and Th2 immune responses, their involvement in the development and their therapeutic potential in treatment of allergic disease.     

Association between perfluoroalkyl substance exposure and asthma and allergic disease in children as modified by MMR vaccination

Perfluoroalkyl substances (PFASs) are highly persistent chemicals that might be associated with asthma and allergy, but the associations remain unclear. Therefore, this study examined whether pre- and postnatal PFAS exposure was associated with childhood asthma and allergy. Measles, mumps, and rubella (MMR) vaccination in early life may have a protective effect against asthma and allergy, and MMR vaccination is therefore taken into account when evaluating these associations. In a cohort of Faroese children whose mothers were recruited during pregnancy, serum concentrations of five PFASs – Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) – were measured at three timepoints (maternal serum in pregnancy week 34–36 and child serum at ages 5 and 13 years) and their association with immunoglobulin E (IgE) (cord blood and at age 7 years) and asthma/allergic diseases (questionnaires at ages 5 and 13 years and skin prick test at age 13 years) was determined. A total of 559 children were included in the analyses. Interactions with MMR vaccination were evaluated. Among 22 MMR-unvaccinated children, higher levels of the five PFASs at age 5 years were associated with increased odds of asthma at ages 5 and 13. The associations were reversed among MMR-vaccinated children. Prenatal PFAS exposure was not associated with childhood asthma or allergic diseases regardless of MMR vaccination status. In conclusion, PFAS exposure at age 5 was associated with increased risk of asthma among a small subgroup of MMR-unvaccinated children but not among MMR-vaccinated children. While PFAS exposure may impact immune system functions, this study suggests that MMR vaccination might be a potential effect-modifier.     

The migration of granulocytes from allergic and nonallergic infiltrations in patients with atopic asthma.

The granulocyte migration inhibition tests both in vivo and in vitro from allergic skin infiltrations were carried out in 30 patients with atopic asthma and in 20 healthy people used as a control. It was found that the migration of leukocytes from allergic skin infiltrations was defective with the lowest ability to migrate. Neutrophils comprised about 80% cells found in the cutaneous allergic infiltrations.