Non-atopic Wheeze Research Articles

Identifying wheezing phenotypes in a pediatric Turkish cohort

Objective Characterization of wheezing phenotypes in children might help to identify the underlying mechanisms through which asthma occurs. In our study, we aimed to describe wheezing phenotypes in Turkish children and to identify risk factors according to phenotypes. Methods 651 wheezy children were evaluated and 5 wheezing phenotypes were described according to age of onset, atopy and persistence at 6 years of age and risk factors were identified. Results Distribution of wheezing phenotypes was transient early wheeze (TEW)(34.9%) non-atopic wheeze (NAW) (18%), atopic wheeze (AW) (22.3%), intermediate onset wheeze (IOW) (11.1%), late onset wheeze (LOW) (11.7%). LOW, AW, and IOW were associated with, father’s, sibling’s and family’s atopy (p:0.001) whereas LOW and AW were associated with mother’s asthma and atopy as well as family’s asthma (p < 0.05). Atopic dermatitis and allergic rhinitis were common of patients with LOW, AW, and IOW (p < 0.05). İnfection was the major trigger for TEW and NAW whereas multiple triggers were common of AW, LOW, and IOW. Allergens were mostly associated with AW, IOW and LOW. Aeroallergen-specific IgE positivity was mostly with AW, IOW, and LOW phenotype. Skin prick tests showed multiple allergen sensitivity in IOW, LOW groups and mostly single allergen in AW phenotype. Modified asthma predictive index (mAPI) positivity was high in all groups except TEW and NAW. Conclusions With this study we classified five wheeze phenotypes and found that atopy and family’s atopy history, maternal asthma were strongly associated with AW, LOW, and IOW phenotypes which were usually effected by allergens or multiple triggers.

Prevalência e fenótipos de sibilância na criança hospitalizada

Wheezing is quite common in childhood. Developed countries report prevalence between 20% and 30%, with high recurrence. The definition of phenotypes and the understanding of etiological factors are fundamental for prevention and treatment strategies. The aim of this study was to evaluate the prevalence and the main wheezing phenotypes in the hospitalized child. Descriptive observational study conducted in a public hospital on the outskirts of São Paulo in 2018. The medical records of children who were hospitalized in pediatric units with wheezing symptoms were excluded, and those whose parents did not consent and who had failures in the medical records were excluded. Approval of the research ethics committee No. 2,913,139. 787 children were hospitalized, 210 (26.7%) with wheezing symptoms. Eighty-six children were excluded, totaling a sample of 124 individuals. The average age was 2.8 ± 3.1 years and most were infants (51.2%). The phenotypes found were: transient wheezing (47.2%), non-atopic wheezing (37.4%) and persistent wheezing (15.4%). It was found that the prevalence of wheezing in 2018 was high and the main phenotypes were transient wheezing and nonatopic wheezing.

The IL-4 rs2070874 polymorphism may be associated with the severity of recurrent viral-induced wheeze.

Childhood recurrent wheezing and consequently asthma corresponds to various phenotypes. Our aim was to link genetic variants of asthma candidate genes to the phenotypes of early onset wheezing. We included very young consecutive children presenting with recurrent wheezing who had been evaluated for the severity of wheezing, associated atopic comorbidities, and tested for biomarkers of atopy and inflammation. All were genotyped for 16 single nucleotide polymorphisms (SNPs) linked with asthma or atopy. An unsupervised hierarchical bottom-up method was used for clustering the phenotypes and a multinomial logistic regression was performed for each individual SNP. We replicated the three phenotypes previously described Trousseau Asthma Program in 317 children aged 21.5 ± 7.9 months: cluster 1 (nonatopic uncontrolled severe wheeze), n = 207, a severe viral-induced wheeze, cluster 2 (atopic multiple trigger wheeze), n = 61, with multiple allergic comorbidities, and cluster 3 (episodic viral wheeze), n = 49, a mild viral-induced wheeze. The TT-genotype of the IL-4 rs2070874 polymorphism was significantly associated with the nonatopic uncontrolled severe wheeze compared to the episodic viral wheeze (OR 7.9; CI95% [2.5-25.3]; P = 0.001). Association between the TT-genotype of IL-4 rs2070874 polymorphism and a severe phenotype of viral-induced wheeze further underlines the role IL-4 plays in the inflammation pathway leading to viral respiratory infections.

Asthma prevalence and severity in low-resource communities

The prevalence of asthma was thought to be low in most low-income countries, but several reports have indicated this is not always true. This is a narrative review of recent publications on the burden of asthma in low and middle-income countries (LMIC) and underprivileged communities from developed countries. Several studies have reported a low prevalence of asthma is LMIC, but indicate it is increasing. In the last few years, however, many surveys demonstrated this may not always be true. An analysis of the International Study for Asthma and Allergy in Childhood phase III database indicated although the prevalence of asthma among children and adolescents is higher in the developed countries, symptoms of asthma are often more severe in less affluent nations. The rate of uncontrolled asthma is also higher among underprivileged communities of developed countries. Secondary analysis of data generated by the WHO's world health survey performed among adults of 70 countries indicate symptoms of asthma are less frequent in middle-income countries and more frequent in the extremes, low income and high income. This sort of U shaped distribution suggests the disease (or syndrome) comprise more than one major phenotype related to diverse underlying mechanisms. In fact, recent reports show symptoms of asthma among the poor are associated with unhygienic living conditions, which may reduce the risk of atopy but increase the risk of nonatopic wheezing. Urbanization and exposure to air pollution also seem to contribute to an increasing prevalence severity of asthma in LMIC. Access to proper diagnosis and treatment with controller medications for asthma, specially with inhaled corticosteroids is feasible and cost-effective, reduce symptoms, health resource utilization, improves quality of life, and reduce mortality in low-resource settings. Prevalence of asthma was thought to be low in low-income countries, but several reports have indicated this is not always true. Under diagnosis, under treatment, exposure to air pollution, and unhygienic living conditions may contribute to a higher frequency and severity of symptoms of asthma among the poor. Proper diagnosis and treatment with controller medications for asthma is feasible and cost-effective in low-resource settings.

What lessons can be learned about asthma phenotypes in children from cohort studies?

'Phenotyping' asthma by multivariate analyses and more recently by unsupervised analysis has been performed in children cohorts. We describe the key findings that have emerged from these cohorts. It would appear that there are three wheeze phenotypes in children of preschool age: the mild episodic viral wheeze phenotype; the multitrigger atopic wheeze; and, less often encountered, the severe non-atopic wheeze. Early onset of allergy in asthma (more prevalent in boys) is associated with poor prognosis unlike the severe non-atopic wheeze phenotype which has a female predominance. The prognosis of the severe non-atopic wheeze depends on time of onset (early or late) of allergic expression. At school age, the risk of severe asthmatic exacerbations is associated with eosinophil predominant inflammation frequently related to allergic asthma, whereas neutrophil inflammation is associated with moderate-to-severe asthma with poorer lung function. Nevertheless, allergic asthma is also a heterogeneous disease with a severe allergic phenotype strongly associated with atopic dermatitis and very high eosinophil-driven inflammatory markers. Further studies are required to find non-invasive biological markers in very young children to better define wheezing phenotypes associated with an elevated risk of developing severe asthma with a view to personalizing treatment.

Circulating TSLP associates with decreased wheezing in non‐atopic preschool children: data from the URECA birth cohort

Mouse models of atopic march suggest that systemic, skin-derived thymic stromal lymphopoietin (TSLP) mediates progression from eczema to asthma. We investigated whether circulating TSLP is associated with eczema, allergic sensitization, or recurrent wheezing in young children. A prospective analysis of the relationship between plasma levels of TSLP to allergic sensitization and recurrent wheezing was conducted in the birth cohort from the Urban Environment and Childhood Asthma (URECA) study. Plasma TSLP levels were measured at 1, 2, and 3years of age and analysed for correlation with clinical parameters in each of the three years. Only those children with consecutive samples for all three years were included in this analysis. We detected TSLP in 33% of 236 children for whom plasma samples were available for all three years. Overall, a consistently significant association was not found between TSLP and eczema or allergic sensitization. With regard to recurrent wheezing, children with detectable TSLP at one year of age were significantly less likely to experience recurrent wheezing by 3years compared with those children without detectable TSLP, but this was only seen in children without aeroallergen sensitization at 3years (P<0.01). Contrary to our expectations, circulating TSLP was not significantly associated with eczema, allergen sensitization, or recurrent wheezing during the first three years of life. Early presence of circulating TSLP was significantly associated with reduced incidence of recurrent wheeze in those children not sensitized to aeroallergen. These findings suggest a possible underlying distinction between pathogenesis of developing atopic vs. non-atopic recurrent wheeze.

The diversity of young adult wheeze: a cluster analysis in a longitudinal birth cohort

Cluster analyses have enhanced understanding of the heterogeneity of both paediatric and adult wheezing. However, while adolescence represents an important transitional phase, the nature of young adult wheeze has yet to be clearly characterised. To use cluster analysis to define, for the first time, clinically relevant young adult wheeze clusters in a longitudinal birth cohort. K-means cluster analysis was undertaken among 309 currently wheezing subjects at 18 years in the Isle of Wight birth cohort (N=1456). Thirteen disease-characterising clustering variables at 18 years were used. Resulting clusters were then further characterised by severity indices plus potential risk factors for wheeze development throughout the 1st 18 years of life. Six wheeze clusters were identified. Cluster 1 (12.3%) male-early-childhood-onset-atopic-wheeze-with-normal-lung-function had male predominance, normal spirometry, low bronchodilator reversibility (BDR), intermediate bronchial hyper-responsiveness (BHR), high atopy prevalence and more admissions. Cluster 2 (24.2%) early-childhood-onset-wheeze-with-intermediate-lung-function had no specific sex association, intermediate spirometry, BDR, BHR, more significant BTS step therapy and admissions. Cluster 3 (9.7%) female-early-childhood-onset-atopic-wheeze-with-impaired-lung-function showed female predominance, high allergic disease comorbidity, more severe BDR and BHR, greatest airflow obstruction, high smoking prevalence, higher symptom severity and admissions. Cluster 4 (19.4%) female-undiagnosed-wheezers had adolescent-onset non-atopic wheeze, low BDR and BHR, impaired but non-obstructed spirometry, high symptom frequency and highest smoking prevalence. Cluster 5 (24.6%) female-late-childhood-onset-wheeze-with-normal-lung-function showed no specific atopy association, normal spirometry, low BDR, BHR and symptom severity. Cluster 6 (9.7%) male-late-childhood-onset-atopic-wheeze-with-impaired-lung-function had high atopy and rhinitis prevalence, increased BDR and BHR, moderately impaired spirometry, high symptom severity and higher BTS step therapy. Young adult wheeze is diverse and can be classified into distinct clusters. More severe clusters merit attention and are associated with childhood onset, atopy, impaired lung function and in some, smoking. Smoking-associated undiagnosed wheezers also merit recognition. Better understanding of young adult wheeze could facilitate better later adult respiratory health.

The association of the ‘additional height index’ with atopic diseases, non-atopic asthma, ischaemic heart disease and mortality: a population-based study

ObjectiveIntrauterine growth has been associated with atopic conditions. Growth and adult height have been associated with cardiovascular disease, cancers and mortality but are highly genetic traits. The objectives of the...

Wheezing in preschool children

Wheezing is a common condition in pediatric practice, it can be defined as a musical sound, high-pitched and continuous, emitting from the chest during breath exhalation.Although almost 50% of children experiences wheeze in the first 6years of life, only 40% of them will report continued wheezing symptoms after childhood. The classification of wheeze in preschool children is more difficult compared to school aged children. It is based on the onset and duration of symptoms and divided children in three categories: transient early wheezing, non-atopic wheezing and atopic wheezing/asthma.History and physical examination, skin prick test, exhaled nitric oxide, lung function test are the parameter to evaluate children with wheezing.The aim of management of wheezing is to finalize the control of symptoms, reduce exacerbations and improve the quality of life. All guidelines underline the complexity in making a diagnosis of asthma under five years and the need to identify phenotypes that may help paediatricians in the therapeutic choices.

Wheeze phenotypes in young children have different courses during the preschool period

BackgroundRules for predicting the course of asthma in wheezy infants have low specificity. ObjectiveTo determine if the novel phenotypes—mild early viral wheeze (EVW), atopic multiple-trigger wheeze (MTW), and nonatopic uncontrolled wheeze (NAUW)—have different courses during the preschool period. MethodsPart of the prospectively followed Trousseau Asthma Program cohort was phenotyped using cluster analysis with 12 parameters (sex, asthma severity and control with inhaled corticosteroid [ICS], parental asthma, allergic rhinitis, eczema, food allergy, EVW or MTW, and allergen exposure trigger). Wheezing trajectories were assessed by crossing the original phenotypes with the phenotypes obtained at 5 years. ResultsFour clusters were identified at 5 years of age: asymptomatic children (n = 47) with no wheezing (98%), children with mild EVW (n = 40, 87% with EVW, 50% with EVW controlled with low-dose ICS), those with atopic MTW (n = 30, 100% with MTW, only 17% with MTW controlled with low-dose ICS, more significant for pollen asthmatic trigger), and those with atopic severe UW (n = 33, 63% with UW uncontrolled despite high doses of ICS, more significant for allergic rhinitis and dust as asthmatic trigger). Those with mild EVW became asymptomatic or remained with mild EVW. Those with atopic MTW remained with atopic MTW and those with NAUW developed severe UW in most cases. ConclusionThese results show that remission is most frequently observed in mild EVW and that no remission is observed in atopic MTW.

Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide

Previous studies have demonstrated that children raised on farms are protected from asthma and allergies. It is unknown whether the farming effect is solely mediated by atopy or also affects nonatopic wheeze phenotypes. We sought to study the farm effect on wheeze phenotypes and objective markers, such as lung function and exhaled nitric oxide, and their interrelation with atopy in children. The GABRIEL Advanced Studies are cross-sectional, multiphase, population-based surveys of the farm effect on asthma and allergic disease in children aged 6 to 12 years. Detailed data on wheeze, farming exposure, and IgE levels were collected from a random sample of 8023 children stratified for farm exposure. Of those, another random subsample of 858 children was invited for spirometry, including bronchodilator tests and exhaled nitric oxide measurements. We found effects of exposure to farming environments on the prevalence and degree of atopy, on the prevalence of transient wheeze (adjusted odds ratio, 0.78; 95% CI, 0.64-0.96), and on the prevalence of current wheeze among nonatopic subjects (adjusted odds ratio, 0.45; 95% CI, 0.32-0.63). There was no farm effect on lung function and exhaled nitric oxide levels in the general study population. Children living on farms are protected against wheeze independently of atopy. This farm effect is not attributable to improved airway size and lung mechanics. These findings imply as yet unknown protective mechanisms. They might include alterations of immune response and susceptibility to triggers of wheeze, such as viral infections.

Novel severe wheezy young children phenotypes: Boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze

Recurrent wheezing during infancy is a heterogeneous disorder that has been associated with early-onset asthma. To identify phenotypes of severe recurrent wheezing and therapeutic approaches. We performed cluster analysis with 20 variables of 551 children with active asthma, younger than 36 months old, and enrolled in the Trousseau Asthma Program. We identified 3 independent clusters of children with wheezing. Cluster 1, mild episodic viral wheeze (n= 327), consisted of children with wheezing related only to colds (71%), mild disease (76%), and mainly normal chest x-ray results. Cluster 2, nonatopic uncontrolled wheeze (n = 157), was characterized by moderate to severe disease (91%), uncontrolled wheezing despite high doses of inhaled corticosteroids (55%), parents with asthma, and increased levels of ferritine. Cluster 3, atopic multiple-trigger wheeze (n = 67), included more children with multiple-trigger wheeze (68%) than did clusters 1 or 2; eczema (75%); a positive result from the Phadiatop Infant test (90%); increased levels of IgE, IgA, and IgG; and abnormal results from chest x-rays. In separate analysis, 1 parameter for boys (increased total level of IgE) and 2 parameters for girls (wheezing severity and increased total level of IgE) properly classified 90% of boys and 83% of girls in the appropriate cluster. Significant associations were found between overcrowding, molds and cockroaches at home, and atopic multiple-trigger wheeze and between day-care attendance and nonatopic uncontrolled wheeze in other parts. We identified different phenotypes of recurrent wheezing in young children by using cluster analysis with usual variables. These phenotypes require confirmation in longer, follow-up studies.

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...

The effect of single and multiple infections on atopy and wheezing in children

The current epidemic of asthma and atopy has been explained by alterations in immune responses related to reduction in childhood infections. However, the findings of epidemiologic studies investigating the association between infection with atopy and asthma have been inconsistent. We sought to investigate the effect of single or multiple infections (pathogen burden) on atopy and wheeze in urban children from Latin America. Specific IgE against aeroallergens (sIgE) and skin prick test (SPT) reactivity for the most common local allergens were measured in 1128 children aged 4 to 11 years. Data on wheezing and potential confounders were collected by questionnaire. Infections by 8 pathogens were assessed by using serology and stool examination. Associations of wheeze and atopic outcomes with single and multiple infections were analyzed by means of logistic regression. Negative results for Toxoplasma gondii were associated with a higher prevalence of sIgE (≥0.70 kU/L), whereas negative results for Ascaris lumbricoides, T gondii, herpes simplex virus, and EBV were associated with a higher prevalence of SPT reactivity. Children with 3 or fewer infection markers had a higher prevalence of sIgE and SPT reactivity compared with those with 4 or more infection markers. However, isolated infections or pathogen burden were not associated with the prevalence of atopic or nonatopic wheeze. The findings provide support for the idea that the hygiene hypothesis is operating in an urban Latin American context, but its expression is thus far restricted to the atopic status of patients and not the perceived asthma symptoms.

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...

Do migrant studies help to identify causes of asthma?

Do migrant studies help to identify causes of asthma?

Poverty, dirt, infections and non-atopic wheezing in children from a Brazilian urban center

BackgroundThe causation of asthma is poorly understood. Risk factors for atopic and non-atopic asthma may be different. This study aimed to analyze the associations between markers of poverty, dirt and infections and wheezing in atopic and non-atopic children.Methods1445 children were recruited from a population-based cohort in Salvador, Brazil. Wheezing was assessed using the ISAAC questionnaire and atopy defined as allergen-specific IgE ≥0.70 kU/L. Relevant social factors, environmental exposures and serological markers for childhood infections were investigated as risk factors using multivariate multinomial logistic regression.ResultsCommon risk factors for wheezing in atopic and non-atopic children, respectively, were parental asthma and respiratory infection in early childhood. No other factor was associated with wheezing in atopic children. Factors associated with wheezing in non-atopics were low maternal educational level (OR 1.49, 95% CI 0.98-2.38), low frequency of room cleaning (OR 2.49, 95% CI 1.27-4.90), presence of rodents in the house (OR 1.48, 95% CI 1.06-2.09), and day care attendance (OR 1.52, 95% CI 1.01-2.29).ConclusionsNon-atopic wheezing was associated with risk factors indicative of poverty, dirt and infections. Further research is required to more precisely define the mediating exposures and the mechanisms by which they may cause non-atopic wheeze.

Risk factors for current wheezing and its phenotypes among elementary school children

Accumulating evidence suggests, asthma includes many phenotypes with varying clinical and prognostic features. Epidemiological surveys documented a number of environmental risk factors for the development of asthma and interestingly these differ between and within countries, suggesting that the differences may be related with the different distribution of asthma phenotypes. This study aimed to investigate risk factors of current wheezing (CW) and different wheezing phenotypes in elementary school children. Six thousand nine hundred sixty-three 9- to 11-year-old children of a previous multicenter survey where the methodology of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase-II was used were analyzed. Wheezing phenotypes were defined as wheezing with rhinitis (RW), wheezing with rhinoconjunctivitis (RCW), atopic wheezing (AW), non-atopic wheezing (NAW), and frequent wheezing (FW) (≥4/year wheezing episodes). The prevalence of CW was 15.8% and among these, 22.4%, 67.3%, 45.9%, 20.5%, and 79.5% were classified as FW, RW, RCW, AW, and NAW, respectively. History of parental asthma/allergic rhinitis, coexistence of other allergic diseases, presence of mold and dampness in the house lived during the first year of life and maternal smoking in pregnancy were found to be risk factors for most phenotypes (odds ratio (OR) ranged from 1.43 to 3.56). Number of household in the last year (OR = 1.14), prematurity (OR = 2.08), and duration of breastfeeding (OR = 1.02) per additional month were found to be risk factor for FW, AW, and RCW, respectively. Beside common risk factors for the development of asthma and its phenotypes, certain risk factors appeared to play a role in the development of phenotypic characteristics of asthma. These findings support our hypothesis that each phenotype has not only different clinical characteristics but also has different roots.

Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years

BackgroundLittle is known about whether patterns of early growth are associated with altered respiratory and immune development. This study relates prenatal and infant growth patterns to wheeze and atopy at...

The relationship between infant lung function and the risk of wheeze in the preschool years

There is evidence that perinatal lung development predicts childhood wheeze. However, very few studies have examined whether preschool wheeze is associated with lower premorbid lung function in early infancy, and as yet there is no information relating atopic and non-atopic preschool wheeze to early lung development. To examine the association between premorbid infant lung function and preschool wheeze, and to explore associations with atopic and non-atopic wheeze phenotypes. Infant lung function was measured in 147 healthy term infants aged 5-14 weeks. Rapid thoracoabdominal compression was performed during tidal breathing and at raised volume to measure maximal expiratory flow at functional residual capacity (V' max FRC) and forced expiratory volume in 0.4 sec (FEV(0.4)). Atopic status was determined by skin prick testing at 3 years and wheeze ascertained from parental questionnaires (1 and 3 years). Lower early infancy V' max FRC was associated with wheeze in both the first and third years of life (P=0.002 and 0.006, respectively). Lower early infancy FEV(0.4) was associated with wheeze in the first year (P=0.03). Compared to non-atopic children who did not wheeze, non-atopic children who wheezed in their third year of life had lower FEV(0.4) (P=0.02), while FEV(0.4) values of atopic children who wheezed were not significantly different (P=0.4). Lower premorbid infant lung function was present in infants who subsequently wheezed during the first and third years of life. Lower FEV(0.4) in early infancy was associated with non-atopic wheeze but not atopic wheeze at 3 years of age.