Nonatopic Wheezers Research Articles

Microarray-Based Analyses of Rhinovirus Species-Specific Antibody Responses in Exacerbated Pediatric Asthma in a German Pediatric Cohort.

Rhinoviruses (RV) account for a significant number of asthma exacerbations, and RV species C may be associated with a severe course in vulnerable patient groups. Despite important evidence on the role of RV reported by clinicians and life scientists, there are still unanswered questions regarding their influence on asthma exacerbation in young patients. Thus, we measured the RVspecies-specific IgG titers in our German pediatric exacerbation cohort using a microarray-based technology. For this approach, human sera of patients with exacerbated asthma and wheeze, as well as healthy control subjects (n = 136) were included, and correlation analyses were performed. Concordantly with previously published results, we observed significantly higher cumulative levels of RV species A-specific IgG (p = 0.011) and RV-C-specific IgG (p = 0.051) in exacerbated asthma group compared to age-matched controls. Moreover, atopic wheezers had increased RV-specific IgG levels for species A (p = 0.0011) and species C (p = 0.0009) compared to non-atopic wheezers. Hypothesizing that bacterial infection positively correlates with immune memory against RV, we included nasopharyngeal swab results in our analyses and detected limited correlations. Interestingly, the eosinophil blood titer positively correlated with RV-specific IgG levels. With these observations, we add important observations to the existing data regarding exacerbation in pediatric and adolescent medicine. We propose that scientists and clinicians should pay more attention to the relevance of RV species in susceptible pediatric patients.

Reduced Exhaled Breath Condensate pH and Severity of Allergic Sensitization Predict School Age Asthma

We previously reported that deaerated breath condensate pH (dEBC pH) can identify preschool children with recurrent wheezing at high asthma risk. To assess the ability of preschool dEBC pH to predict asthma risk at school age. Children of the baseline cohort were recontacted for follow-up. Asthma diagnosis at school age was evaluated according to Global Initiative for Asthma recommendations in 135 children who at baseline had been classified into the following groups: (asymptomatic) atopic wheezers (n= 30), (asymptomatic) nonatopic wheezers (n= 57), allergic rhinitis only (n= 14), and healthy controls (n= 34). All (100%) former atopic wheezers, 12 (21%) of nonatopic wheezers, 2 (14%) of allergic rhinitis group, and 1 (3%) of healthy controls had developed asthma at follow-up. Among all children with baseline wheezing, baseline dEBC pH predicted asthma at follow-up with an area under the receiver operating characteristic curve (AUC) of 0.72 (sensitivity, 0.67; specificity, 0.76; at pH 7.83). Combining pH and Capacity class (CAP) led to substantial gain in sensitivity (0.96) and negative predictive value (NPV, 0.94). Additional clinical information (Asthma Predictive Index, family atopy, family asthma, and inhaled corticosteroids) further increased the potential to predict asthma (AUC, 0.94) and raised sensitivity (0.98) and NPV (0.97) to nearly perfect values. Our findings suggest (1) that dEBC pH combined with CAP class may serve as highly sensitive, noninvasive marker for the early detection of young asymptomatic preschool children with increased asthma risk, and (2) the need for additional biomarkers with high specificity to optimize early risk stratification in this clinically challenging scenario.

Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze

Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze

Relationship between urine dichlorophenol levels and asthma morbidity

BackgroundChlorinated phenols are associated with atopic conditions, but it is not known whether they are associated with wheeze or asthma and whether atopy is involved in these associations. ObjectivesTo test the association between urine levels of 2 dichlorophenols (2,4- and 2,5-dichlorophenols) and asthma morbidity in atopic and nonatopic wheezers and between total serum immunoglobulin E (IgE) levels. MethodsData from a sample of 2,125 participants at least 6 years old from the US National Health and Nutrition Examination Survey 2005 to 2006 were analyzed. Asthma morbidity data were available for those participants who reported wheezing in the past year (“wheezers”; n = 250). This subsample was categorized as atopic or nonatopic. ResultsAtopic wheezers with higher 2,5-dichlorophenol levels were more frequently diagnosed with asthma by a physician (odds ratio [OR] 4.7 for highest vs lowest tertile, P < .001), required more prescriptions for asthma medications (OR 2.2, P = .046), and reported more exercise-induced wheezing (OR 5.8, P = .045) than atopic wheezers with low dichlorophenol levels. Atopic wheezers with higher 2,5- or 2,4-dichloropheonol levels also were more likely to miss work or school because of wheezing (OR 10.0, P < .001; OR 11.4, P < .01, respectively). In contrast, in nonatopic wheezers, there were no significant associations between dichlorophenol levels and asthma morbidity measurements. The 2 dichlorophenol metabolites were positively associated with increased serum IgE levels in the larger study sample. ConclusionThese findings indicate that in patients with atopy and a history of wheezing, asthma morbidity is associated with high urinary dichlorophenol levels. Increased urine dichlorophenol levels are associated with higher total serum IgE.

Increased Serum Soluble ST2 In Asthmatic Children and Recurrent Early Wheezers

RationaleSoluble ST2 (sST2) has been reported to regulate Th2 response. In this study, serum levels of sST2, Th1, and Th2 cytokines were measured in recurrent early wheezers and asthmatic children. We aimed to investigate if there is any difference or similarities in immune responses between those two patient groups.MethodsFifty-nine patients admitted with exacerbation of wheezing or asthma were enrolled. Two patient groups were defined: children with atopic asthma (≥6yrs, N=21) and recurrent early wheezers (≤2yrs, N=38). Recurrent early wheezers were divided based on their atopic status: 19 were atopic and 19 were non-atopic. sST2, IL-33, IL-5, and IFN-r were measured in serum samples from two patient groups. sST2 and cytokine levels in both patient groups were compared with their age-matched controls. Their relationships with blood eosinophils, serum IgE levels, and severity of symptom were also evaluated.ResultssST2 and IL-5 were significantly increased both in asthmatic children (P=0.02, P=0.004) and recurrent early wheezers (P=0.01, P=0.001) compared to their age-matched controls. IL-5 was significantly higher in atopic wheezers compared with non-atopic wheezers (P=0.04). Severity score showed a positive correlation with sST2 and IFN-r in asthmatic children, but only with IFN-r in early wheezers. There was an inverse correlation between sST2 and blood eosinophil counts both in asthmatic children and atopic recurrent wheezers.ConclusionsOur study suggests that sST2 might regulate allergic inflammation by suppressing eosinophilia and play an important role in pathophysiology of acute exacerbation of wheezing or asthma both in asthmatic children and early wheezers. RationaleSoluble ST2 (sST2) has been reported to regulate Th2 response. In this study, serum levels of sST2, Th1, and Th2 cytokines were measured in recurrent early wheezers and asthmatic children. We aimed to investigate if there is any difference or similarities in immune responses between those two patient groups. Soluble ST2 (sST2) has been reported to regulate Th2 response. In this study, serum levels of sST2, Th1, and Th2 cytokines were measured in recurrent early wheezers and asthmatic children. We aimed to investigate if there is any difference or similarities in immune responses between those two patient groups. MethodsFifty-nine patients admitted with exacerbation of wheezing or asthma were enrolled. Two patient groups were defined: children with atopic asthma (≥6yrs, N=21) and recurrent early wheezers (≤2yrs, N=38). Recurrent early wheezers were divided based on their atopic status: 19 were atopic and 19 were non-atopic. sST2, IL-33, IL-5, and IFN-r were measured in serum samples from two patient groups. sST2 and cytokine levels in both patient groups were compared with their age-matched controls. Their relationships with blood eosinophils, serum IgE levels, and severity of symptom were also evaluated. Fifty-nine patients admitted with exacerbation of wheezing or asthma were enrolled. Two patient groups were defined: children with atopic asthma (≥6yrs, N=21) and recurrent early wheezers (≤2yrs, N=38). Recurrent early wheezers were divided based on their atopic status: 19 were atopic and 19 were non-atopic. sST2, IL-33, IL-5, and IFN-r were measured in serum samples from two patient groups. sST2 and cytokine levels in both patient groups were compared with their age-matched controls. Their relationships with blood eosinophils, serum IgE levels, and severity of symptom were also evaluated. ResultssST2 and IL-5 were significantly increased both in asthmatic children (P=0.02, P=0.004) and recurrent early wheezers (P=0.01, P=0.001) compared to their age-matched controls. IL-5 was significantly higher in atopic wheezers compared with non-atopic wheezers (P=0.04). Severity score showed a positive correlation with sST2 and IFN-r in asthmatic children, but only with IFN-r in early wheezers. There was an inverse correlation between sST2 and blood eosinophil counts both in asthmatic children and atopic recurrent wheezers. sST2 and IL-5 were significantly increased both in asthmatic children (P=0.02, P=0.004) and recurrent early wheezers (P=0.01, P=0.001) compared to their age-matched controls. IL-5 was significantly higher in atopic wheezers compared with non-atopic wheezers (P=0.04). Severity score showed a positive correlation with sST2 and IFN-r in asthmatic children, but only with IFN-r in early wheezers. There was an inverse correlation between sST2 and blood eosinophil counts both in asthmatic children and atopic recurrent wheezers. ConclusionsOur study suggests that sST2 might regulate allergic inflammation by suppressing eosinophilia and play an important role in pathophysiology of acute exacerbation of wheezing or asthma both in asthmatic children and early wheezers. Our study suggests that sST2 might regulate allergic inflammation by suppressing eosinophilia and play an important role in pathophysiology of acute exacerbation of wheezing or asthma both in asthmatic children and early wheezers.

Increased serum soluble ST2 in asthmatic children and recurrent early wheezers

Purpose: Soluble ST2 (sST2) has been reported to regulate Th2 response. In this study, serum levels of sST2 and other cytokines were measured in recurrent early wheezers and asthmatic children. We aimed to investigate if there are any differences or similarities in Th1 or Th2 response between those two patient groups. Methods: Fifty-nine patients admitted with exacerbation of wheezing or asthma were enrolled. Two patient groups were defined: children with atopic asthma (≥6 years, n=21) and recurrent early wheezers (≤2 years, n=38). Recurrent early wheezers were divided based on their atopic status: 19 were atopic and 19 were nonatopic. sST2, interleukin (IL) 33, IL-5, and interferon (IFN)-γ were measured in serum samples collected on admission. Cytokine levels in both patient groups were compared with their age-matched controls and evaluated the relationship with blood eosinophils, serum IgE levels, and also with the severity of symptom. Results: sST2 and IL-5 were significantly increased both in asthmatic children (P=0.02, P=0.004) and recurrent early wheezers (P=0.01, P=0.001) compared to their age-matched controls. IL-5 was significantly higher in atopic wheezers compared with nonatopic wheezers (P=0.04). Severity score showed a positive correlation with sST2 and IFN-γ in asthmatic children, but only with IFN-γ in early wheezers. There was an inverse correlation between sST2 and blood eosinophil counts both in asthmatic children and atopic recurrent wheezers. Conclusion: Our study suggests that sST2 might regulate allergic inflammation by suppressing eosinophilia and play an important role in pathophysiology of acute exacerbation of wheezing or asthma both in asthmatic children and early wheezers. (Allergy Asthma Respir Dis 2013;1:314-320)

Chapter 11: The infant and toddler with wheezing

Recurrent wheezing is common in young infants and toddlers with 27% of all children having at least one wheezing episode by the age of 9 years. The initial wheezing episodes in young children often are linked to respiratory infections due to viral pathogens such as respiratory syncytial virus, rhinovirus, human metapneumovirus, and influenza virus. Bacterial colonization of the neonatal airway also may be significant in the late development of recurrent wheeze and asthma. Some 60% of children who wheeze in the first 3 years of life will have resolution of wheezing by age 6 years ("transient early wheezers"). Children who are "transient early wheezers" have reduced lung function, which remains low at age 6 years, although wheezing has ceased when compared with children who have never wheezed. In contrast, "nonatopic wheezers" represent 20% of wheezing toddlers <3 years of age. These children have more frequent symptoms during the 1st year of life and may continue to wheeze through childhood, but, typically, episodes become less frequent by early adolescence. Lung function in "nonatopic wheezers" is slightly lower than in control subjects from birth to 11 years of age, but they do not have bronchial hyperreactivity on methacholine challenge. The third phenotype refers to "atopic wheezing" or wheezing associated with IgE sensitization. This phenotype accounts for the last 20% of wheezing children <3 years of age. These "atopic wheezers" have normal lung function in infancy; however, lung function is reduced by age 6 years and bronchial hyperreactivity typically is observed.

Maternal mental health and social support: effect on childhood atopic and non-atopic asthma symptoms

BackgroundAtopic and non-atopic asthma have distinct risk factors and immunological mechanisms, and few studies differentiate between the impacts of psychosocial factors on the prevalence of these disease phenotypes. The authors...

P2-198 Overweight associated with non-atopic wheeze in rural tropics

IntroductionThe parallel rise in prevalence of asthma and overweight/obesity in some Latin American countries has led to suggestions of a link between the two epidemics. The aim of this study...

Perennial Allergen Sensitization Early in Life and Chronic Asthma in Children: A Birth Cohort Study

PURPOSE OF THE STUDY. To evaluate the effect of allergic sensitization and allergen exposure early in life on subsequent loss of pulmonary function in atopic wheezers, nonatopic wheezers, and control children. STUDY POPULATION. There were 1314 healthy, term infants enrolled onto the German Multicenter Allergy Study who were followed from birth to 13 years of age. METHODS. Parental reports of wheezing, medication usage, and respiratory tract infections were collected by standardized questionnaire and interviews at regular intervals. Specific immunoglobulin E (IgE) antibodies to food and inhalant allergens and measurements of carpet dust for dust-mite and cat-allergen content were serially obtained, and atopy was defined as a specific IgE level of &amp;gt;0.35 kU/L for ≥1 allergen. Lung-function measurements were obtained at ages 7, 10, and 13 years, and a bronchial challenge was performed at age 7 years. RESULTS. Lung function at 7 years of age was significantly reduced in atopic wheezers sensitized to perennial allergens (ie, dust mite, cat, and dog) and exposed to high levels of the respective allergens in the first 3 years of life. This reduction in lung function at 7 years of age persisted at ages 10 and 13 years, whereas nonatopic wheezers and control children experienced no change in lung function after early exposure to perennial allergens. Atopic wheezers also demonstrated more frequent asthma exacerbations, and a greater proportion had airway hyperresponsiveness compared with nonatopic wheezers. Furthermore, 45% of atopic wheezers continued to have symptoms past 13 years of age, whereas 90% of nonatopic wheezers lost all asthmatic symptoms by the same age. Early sensitization to seasonal allergens and food allergens had no significant effect on subsequent lung function in the 3 study groups. CONCLUSIONS. Early sensitization and exposure to perennial allergens in the first 3 years of life in atopic wheezers predicts chronic asthma characterized by more frequent symptoms and lower lung function by 7 years of age. REVIEWER COMMENTS. Halting the progression toward development of chronic asthma symptoms has been a major goal of pediatric asthma research. Recent studies on daily inhaled corticosteroid therapy in wheezy infants have shown an improvement in symptom-free days while the infants were taking the inhaled corticosteroid but no sustained difference in preservation of lung function or ultimate progression to chronic asthma symptoms after cessation of daily steroid therapy. Thus, the mechanisms that cause asthma disease progression and loss of lung function may be different from those that determine acute symptoms and the frequency of asthma exacerbations. Because none of the previous studies have stratified patients into atopic and nonatopic wheezers, future studies aimed at preventing airway remodeling and the development of chronic asthma in children may need to focus more closely on the early wheezers with perennial allergen sensitization and exposure. It may be that early atopy control may affect the subsequent clinical expression of asthma in children.

Bronchial responsiveness to methacholine and adenosine 5′‐monophosphate in atopic and non‐atopic preschool children with recurrent wheezing

It is well known that atopy is a major determinant of bronchial hyper-responsiveness (BHR) in both asymptomatic and asthmatic children. However, the relationship between atopy and BHR has not been well studied in preschool children with wheezing. BHR is usually measured by bronchial challenges using direct and indirect stimuli. The aim of this study was to investigate whether atopic and non-atopic preschool wheezers display similar or different BHR profiles for direct and indirect stimuli. Methacholine and adenosine 5'-monophosphate (AMP) bronchial challenges were performed in 4 to 6-year-old children with recurrent wheezing, using a modified auscultation method. The end-point was defined as the appearance of wheezing and/or oxygen desaturation. Atopy was determined to be present when a child had at least one positive reaction to a panel of 13 common airborne allergens in the presence of positive and negative controls. A positive response to methacholine (an end-point concentration < or =8 mg/mL) was observed in 89.3% (50/56) of atopic wheezers and in 83.8% (31/37) of non-atopic wheezers (P=0.44) for the difference. By contrast, the frequency of a positive response to AMP (an end-point concentration < or =200 mg/mL) was significantly higher in the atopic group (47/56, 83.9%) compared with the non-atopic group (12/37, 32.4%; P<0.01). While a majority of both atopic and non-atopic preschool wheezers were hyper-responsive to methacholine, atopic subjects were more hyper-responsive to AMP than non-atopic subjects. These findings suggest that atopic and non-atopic wheeze in preschool children are related to distinctive pathophysiologic pathways.

Exhaled Nitric Oxide Differentiates Airway Diseases in the First Two Years of Life

Fractional exhaled nitric oxide (FE(NO)) levels are increased in children and adults with asthma, whereas low levels have been found in cystic fibrosis and primary ciliary dyskinesia. The aim of this study was to investigate whether FE(NO) measurements could distinguish between children below the age of 2 with different airway diseases. FE(NO) measurements were performed in 118 infants aged between 4.6 and 25.2 mo: 74 infants with recurrent wheezing (RW), 24 with bronchopulmonary dysplasia (BPD), and 20 with cystic fibrosis (CF). FE(NO) was measured also in 100 healthy controls aged between 1.1 and 7.7 mo. Geometric mean (95% confidence interval) FE(NO) values were 10.4 (9.1-12.0) parts per billion (ppb) in healthy infants, 18.6 (15.6-22.2) ppb in wheezy infants, 11.7 (8.2-16.8) ppb in BPD infants and 5.9 (3.4-10.1) ppb in CF infants. FE(NO) in wheezers was higher than in controls, BPD, and CF (p = 0.009, p = 0.038, and p < 0.001, respectively). Atopic wheezers showed higher FE(NO) than nonatopic wheezers (p = 0.04). CF infants had lower FE(NO) than healthy controls and BPD infants (p = 0.003 and p = 0.043, respectively). FE(NO) values in BPD and control infants were not different. We conclude that FE(NO) is helpful to differentiate various airway diseases already in the first 2 y of life.

The many faces of the hygiene hypothesis

About 15 years have gone by since Strachan first proposed the idea that infections and unhygienic contact might confer protection against the development of allergic illnesses. The so-called hygiene hypothesis has ever since undergone numerous more or less subtle modifications by various researchers in the fields of epidemiology, clinical science, and immunology. Three major tracts have developed exploring the role of overt viral and bacterial infections, the significance of environmental exposure to microbial compounds, and the effect of both on underlying responses of the innate and adaptive immunity. To date, a truly unifying concept has not yet emerged, but various pieces of a complex interplay between immune responses of the host, characteristics of the invading microorganism, the level and variety of the environmental exposure, and the interactions between a genetic background and a range of exposures becomes apparent. These influences are discussed as determinants for a number of complex allergic illnesses in this review, while we attempt to pay attention to the importance of different phenotypes, namely of the asthma syndrome. Even if today practical implications cannot directly be deduced from these findings, there is great potential for the development of novel preventive and therapeutic strategies in the future.

Reduced Interferon γ Production and Soluble CD14 Levels in Early Life Predict Recurrent Wheezing by 1 Year of Age

Guerra S, Lohman IC, Halonen M, Martinez FD, Wright AL. Am J Respir Crit Care Med . 2004;169:70–76 To determine if interferon γ (IFNγ) production and soluble CD14 (sCD14) levels correlate longitudinally with the risk of developing recurrent wheezing in the first year of life. Both environmental risk factors and variation in the maturation of the immune system seem to have a role in the development of asthma. Previous studies have demonstrated reduced IFNγ production in atopic and nonatopic wheezers. IFNγ production correlates positively with endotoxin exposure and with sCD14 levels, and CD14 functions as a receptor for endotoxin. Thus, …

Does bronchiolitis caused by RSV predispose to atopic asthma?

Based on results from the Tucson Children's Respiratory Study, three different forms of wheezing in children have been proposed: transient infant wheezers, non-atopic wheezers, and atopic wheezers (i.e. children with atopic asthma with IgE antibodies to environmental allergens). All controlled studies of children with RSV bronchiolitis in infancy have revealed that wheezing can continue for varying lengths of time after the infection has subsided. The pathophysiology of this disorder remains to be clarified. Is this wheezing a transient and benign condition, or is it non-atopic, in which case the long-term prognosis is good, or is it a marker for atopic asthma? We have followed prospectively 47 children hospitalised with RSV bronchiolitis and 93 non-bronchiolitis matched controls. The results of follow-up examinations at age 3 and 7 years showed that the incidence of asthma—in children with or without IgE antibodies—was significantly increased in the RSV bronchiolitis group compared to the control group. We observed similar results in a recent follow-up study of these same children at age 13. Our results suggest that infants with RSV bronchiolitis severe enough to cause hospitalisation are at risk for atopic asthma at age 13.

Asthma phenotypes in childhood: lessons from an epidemiological approach.

Asthma is a heterogenous disease with variable signs and symptoms among patients. It also presents significant individual variability over time. Recently, some important population-based studies that followed children from birth or from early childhood into adulthood have shed new light on how we understand this syndrome. Three phenotypes have been identified in children with asthma: transient wheezing, non-atopic wheezing of the toddler and pre-school-aged child and IgE-mediated wheezing. Transient wheezing is associated with symptoms that are limited to the first 3-5 years of life, decreased lung function, maternal smoking during pregnancy and exposure to other siblings or children at daycare centres. There is no association between transient wheezing and family history of asthma or allergic sensitisation. Children wheezing with respiratory syncytial virus in the first years of life are more likely to be wheezing up to 13 years of age; this is independent of atopy (non-atopic wheezers) and is not related to atopic sensitisation. Wheezing associated with evidence of allergic sensitisation has been identified as the 'classic' asthma phenotype. Early allergic sensitisation is a major risk factor for persistent asthma.