Early Wheeze Research Articles

Asthma: Differential Diagnosis and Comorbidities.

Childhood asthma remains a multifactorial disease with heterogeneous clinical phenotype and complex genetic inheritance. The primary aim of asthma management is to achieve control of symptoms, in order to reduce the risk of future exacerbations and progressive loss of lung function, which results especially challenging in patients with difficult asthma. When asthma does not respond to maintenance treatment, firstly, the correct diagnosis needs to be confirmed and other diagnosis, such as cystic fibrosis, primary ciliary dyskinesia, immunodeficiency conditions or airway and vascular malformations need to be excluded. If control remains poor after diagnostic confirmation, detailed assessments of the reasons for asthma being difficult-to-control are needed. Moreover, all possible risk factors or comorbidities (gastroesophageal reflux, rhinosinusitis, dysfunctional breathing and/or vocal cord dysfunction, obstructive sleep apnea and obesity) should be investigated. At the same time, the possible reasons for poor symptom control need to be find in all modifiable factors which need to be carefully assessed. Non-adherence to medication or inadequate inhalation technique, persistent environmental exposures and psychosocial factors are, currently, recognized as the more common modifiable factors. Based on these premises, investigation and management of asthma require specialist multidisciplinary expertise and a systematic approach to characterizing patients' asthma phenotypes and delivering individualized care. Moreover, since early wheezers are at higher risk of developing asthma, we speculate that precocious interventions aimed at early diagnosis and prevention of modifiable factors might affect the age at onset of wheezing, reduce the prevalence of persistent later asthma and determine long term benefits for lung health.

Clinical and Pathologic Factors Predicting Future Asthma in Wheezing Children. A Longitudinal Study.

Wheeze is a common symptom in infants, but not all wheezers develop asthma. Indeed, up to 50% of wheezing children outgrow their symptoms by school age. How to predict if early wheeze will become asthma is still a matter of vivid debate. In this work, we sought to assess the clinical and pathological factors that might predict the future development of asthma in children. Eighty children (mean age 3.8 ± 1 yr) who underwent a clinically indicated bronchoscopy were followed prospectively for a median of 5 years. At baseline, clinical characteristics with a particular focus on wheezing and its presentation (episodic or multitrigger) were collected, and structural and inflammatory changes were quantified in bronchial biopsies. Follow-up data were available for 74 of the 80 children. Children who presented with multitrigger wheeze were more likely to have asthma at follow-up than those with episodic wheeze (P = 0.04) or without wheeze (P < 0.0001). Children with asthma also had lower birth weights (P = 0.02), a lower prevalence of breastfeeding (P = 0.02), and a trend for increased IgE (P = 0.07) at baseline than those with no asthma. Basement membrane thickness and airway eosinophils at baseline were increased in children who developed asthma at follow-up (P = 0.001 and P = 0.026, respectively). Multivariate analysis showed that among all clinical and pathological factors, multitrigger wheezing, basement membrane thickening, and reduced birth weight were predictive of future asthma development. We conclude that multitrigger wheeze and reduced birth weight are clinical predictors of asthma development. Basement membrane thickening in early childhood is closely associated with asthma development, highlighting the importance of airway remodeling in early life as a risk factor for future asthma.

Is there a role for inhaled corticosteroids in early life wheeze?

Is there a role for inhaled corticosteroids in early life wheeze?

Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development

Virus-associated febrile lower respiratory tract infections (fLRIs) during infancy have been identified as risk factors for persistent wheeze development. We hypothesized that variations in innate immune defense capacity during this period, as exemplified by production of type 1 and 3 interferons (T1/3IFNs), might be an underlying determinant of risk. We sought to investigate relationships between postnatal development of innate interferon response capacity and susceptibility to early infections and persistent wheeze. We studied a subset of subjects from a birth cohort at high risk for asthma/allergy and determined the capacity of cord blood cells (n=151) to produce any of a panel of 17 T1/3IFNs in response to the viral mimic polyinosinic-polycytidylic acid using a sensitive PCR assay. We investigated relationships between neonatal interferon responses and lower respiratory tract infection history during infancy, wheezing history to 5 age years, and ensuing maturation of innate immune capacity by age 4years (n=160) and 10years (n=125). Although cohort subjects produced an average of 2.6±0.3 of the 17 innate interferons tested at birth, 24% showed no T1/3IFN production. This nonproducer subgroup showed increased risk for infant fLRIs (odds ratio, 2.62; 95% CI, 1.14-6.06; P=.024) and persistent wheeze (odds ratio, 4.24; 95% CI, 1.60-11.24; P=.004) at age 5years relative to those producing 1 or more T1/3IFNs, whereas risk for infant wheezy lower respiratory tract infections or "transient early wheeze" was unaffected. Moreover, infants who experienced fLRIs subsequently demonstrated accelerated development of T1/3IFN response capacity between 1 and 4years of age. T1/3IFN response capacity appears strongly developmentally constrained at birth. Infants in whom this negative regulation is strongest manifest increased risk for severe respiratory tract infections during infancy and subsequent persistent wheeze.

Maternal status of vitamin D and risk of childhood wheeze: a systematic review and meta-analysis

Objective To assess the association between vitamin D levels during pregnancy and the risk of offspring’s wheeze. Methods We searched electronic databases of PubMed and EMbasefrom published studies until July 2017.A random-effects meta-analysis was conducted among 11 birth cohort studies. Results Eleven studies on the association between maternal vitamin D status and childhood wheeze met our inclusion criteria.Maternal vitamin D status during pregnancy was associated with childhood wheeze(OR=0.97, 95%CI: 0.96~0.99). Maternal intake of vitamin D(pooled OR=0.51, 95%CI: 0.37~0.64), cord blood 25(OH)D levels at birth (pooled OR=0.94, 95%CI: 0.9~0.98) were associated with childhood wheeze.Furthermore, maternal vitamin D stasus were only associated with childhood early wheeze(OR=0.92, 95%CI: 0.89~0.96), but not with late-onset or persistent wheeze. Conclusion High levels of vitamin D during pregnancy are inversely associated with the risk of wheeze during childhood. Key words: Vitamin D; Wheeze; Pregnancy

Paths of causal influence from prenatal inflammation and preterm gestation to childhood asthma symptoms

Introduction: Long-lasting respiratory symptoms have a huge impact on the quality of life in prematurely born children. The aim was to investigate paths of assumed causality leading from foetal inflammatory response syndrome (FIRS) to asthma symptoms in preterms. Methods: Demographic, antenatal, delivery and outcome data were collected from 262 infants with less than 32 completed weeks of gestational age over a 10-year period in a prospective cohort study. The presence of symptoms of asthma beyond the age of 5 years was the primary outcome measure. The causal effect of FIRS on childhood asthma was tested with three different logistic regression models and two structural equation models (SEM). Results: FIRS (OR = 4.7) and subsequent chronic lung disease of prematurity (OR = 7.7) and early childhood wheezing (OR = 9.5) are the most important risk factors for development of asthma symptoms in children born with less than 32 weeks of gestational age. The path analysis showed that FIRS has a large direct (0.59), medium indirect (0.11) and large overall (0.70) effect on CLD; large negative direct effect on ECW (−0.34) and a large positive indirect effect (0.74), mediated by CLD. On the occurrence of asthma symptoms, FIRS has a medium negative direct effect (−0.18) and a medium positive indirect effect (0.26), mediated by CLD and ECW. Conclusion: Prenatal inflammation plays an important role in the development of chronic respiratory disturbances in preterm infants. This influence is mainly related to structural and developmental lung abnormalities initiated in utero as consequences of FIRS, resulting in CLD of prematurity, and overcoming the protective mechanisms of chorioamnionitis.

Day-care center attendance and risk of Asthma—A systematic review

Introduction and ObjectivesAsthma and other wheezing disorders are common chronic health problems in childhood. We aim to evaluate whether the attendance by children under three years of age to day-care centers is a protector or risk factor in the development of recurrent wheezing or asthma in the following years of their lives. MethodsSystematic review of published cohort or cross-sectional studies, without any time limitation. We searched in PubMed, Cinhal, Cuiden and Scopus (EMBASE included). The quality of the studies was evaluated using the Newcastle-Ottawa Scale. Disagreements were solved by mutual consensus. Weighted odds ratio (ORs) were estimated using RevMan 5.3, following random effects models. ResultsWe selected 18 studies for qualitative analysis, nine cohort studies and nine cross-sectional studies. Day-care center attendance is associated with an increased risk of early recurrent wheezing (four studies; 50,619 subjects; adjusted OR 1.87 [1.21 to 2.88]; I2 91%) and asthma before the age of six (five studies; 5412 subjects; adjusted OR 1.59 [1.26 to 2.01]; I2 0%), but not later (five studies; 5538 subjects; adjusted OR 0.86 [0.55 to 1.32]; I2 76%). ConclusionsChildren attending day-care center during the first years of life have a higher risk of recurrent wheezing during the first three years and asthma before the age of six, but not later. This risk must be taken into account to inform parents in order to choose what kind of care children should have throughout infancy and to implement preventive measures to reduce its impact.

Phenotypes of childhood wheeze in Japanese children: A group-based trajectory analysis.

Exploring patterns of childhood wheeze may help to clarify the etiology and prognosis of respiratory diseases. The purpose of this study was to classify phenotypes of wheezing in children up to 9years of age in Japan and to evaluate the individual and environmental risk factors for these phenotypes. Wheeze was evaluated at approximately 1-year intervals based on the mothers' recollection of their child's wheezing or whistling in the chest during the preceding 12months. The children were aged 1-9years. In total, 1116 children who had at least five measures of wheezing at all nine time points were used for identifying trajectories. Trajectories were identified with group-based trajectory analysis. A multinomial logit model was built to evaluate the relationships between phenotypes and risk factors. Five typical trajectories were identified. The probability of group membership was 43.7%, 32.2%, 6.2%, 8.6%, and 9.2% for the never/infrequent wheeze, transient early wheeze, school-age-onset wheeze, early-childhood-onset remitting wheeze, and persistent wheeze trajectories, respectively. Infant tobacco exposure increased the odds of membership in the transient early wheeze trajectory compared to the never/infrequent wheeze trajectory. Using the group-based trajectory modeling approach, we identified five trajectories of childhood wheeze development in a Japanese population. The trajectories shown here are based on formal statistical modeling rather than on subjective classification, and an assessment of its precision suggested that the model has high assignment accuracy.

Prevalence estimates and risk factors for early childhood wheeze across Europe: the EuroPrevall birth cohort

BackgroundPreschool wheeze is an important problem worldwide. No comparative population-based studies covering different countries have previously been undertaken.ObjectiveTo assess the prevalence of early childhood wheeze across Europe and evaluate risk...

Breastfeeding and Childhood Wheeze: Age-Specific Analyses and Longitudinal Wheezing Phenotypes as Complementary Approaches to the Analysis of Cohort Data

Systematic reviews suggest that breastfeeding is associated with a lower risk of asthma, although marked heterogeneity exists. Using UK Millennium Cohort Study data (n = 10,126 children, born 2000–2002), we examined the association between breastfeeding duration and wheezing in the previous year, first for each age group separately (ages 9 months, 3 years, 5 years, 7 years, and 11 years) and then in terms of a longitudinal wheezing phenotype: “early transient” (wheezing any time up to age 5 years but not thereafter), “late onset” (any time from age 7 years but not beforehand), and “persistent” (any time up to age 5 years and any time from age 7 years). The association between breastfeeding and wheeze varied by age (2-sided P for interaction = 0.0003). For example, breastfeeding for 6–9 months was associated with lower odds of wheezing at ages 9 months, 3 years, and 5 years but less so at ages 7 years and 11 years (adjusted odds ratios = 0.73, 0.78, 0.79, 0.84, 1.06, respectively). There was a strong dose-response relationship for breastfeeding per month and early transient wheeze (adjusted odds ratio for linear trend = 0.961, 95% confidence interval: 0.942, 0.980) but no clear trend for late-onset or persistent wheeze. Our results identified heterogeneity in the association between breastfeeding and wheezing according to age at wheezing and wheezing phenotype.

Phototherapy for neonatal hyperbilirubinemia and childhood eczema, rhinitis and wheeze

The pathogenesis of allergic diseases in childhood may be attributed to influences of early environmental stimuli on fetal and neonatal immune regulation. Neonatal hyperbilirubinemia is common in the Asian population and up to 20% of infants require phototherapy. We examined the hypothesis that phototherapy for neonatal hyperbilirubinemia modulates the infant's risk of developing eczema, rhinitis and wheeze in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort. Interviewers collected information on demographics, lifestyle, birth data andallergic outcomes. Atopic sensitization was assessed through skin prick testing (SPT) to aeroallergens and food allergens. A total of 135 (12.8%) children underwent phototherapy for neonatal hyperbilirubinemia. Infants who underwent phototherapy were of a significantly lower mean (SD) gestational age [37.5 (2.5) weeks] compared to those who did not [38.5 (1.2) weeks p<0.01]. A higher proportion of infants born by Caesarean section underwent phototherapy compared to those who were born vaginally (17.5% vs 10.7%, p<0.01). There were no differences in prevalence of allergen sensitization, eczema, rhinitis and early onset wheeze with use of nebulizer in the first 5 years of life between subjects that underwent phototherapy and those that did not. There were also no associations between mean bilirubin peak levels within the phototherapy group with development of eczema, rhinitis and early onset wheeze in the first 5 years of life. We found no evidence for a link between phototherapy for neonatal hyperbilirubinemia and childhood allergic outcomes in this prospective mother-offspring cohort. NCT01174875 Registered 1 July 2010, retrospectively registered.

Maternal vegetable intake in early pregnancy and wheeze in offspring at the age of 2 years.

Vegetable intake during childhood may reduce the risk of subsequent asthma. We verified the effect of maternal intake during pregnancy on asthma risk in offspring, which has rarely been studied. In a hospital-based birth cohort study conducted in Tokyo, we administered a food frequency questionnaire at two periods during the respondents' pregnancy: early and mid to late periods. In addition, a questionnaire including the International Study of Asthma and Allergies in Childhood questionnaire was conducted when the offspring were 2 years old. Multivariate Poisson regression adjusting for maternal baseline demographics was used to elucidate the association between maternal vegetable intake and the incidence of wheeze in the offspring. Among 310 singletons, 82 (26.5%) experienced wheeze at 2 years of age. Women with the highest intake of cruciferous, and folate-rich vegetables during early pregnancy reported a significantly lower prevalence of wheeze in their child at 2 years of age in comparison with those who reported the lowest intake (adjusted risk ratio: 0.48 and 0.47, 95% confidence interval: 0.26-0.89, and 0.25-0.87, respectively). In trend analysis, a higher maternal intake of cruciferous, folate-rich vegetables, and total vegetables during early pregnancy was less likely to be associated with wheeze in the offspring at 2 years old (p for trend: 0.038, <0.001, and 0.028, respectively). Maternal vegetable intake during mid to late pregnancy was not associated with wheeze in the offspring. Maternal vegetable intake during early pregnancy may have a protective effect against asthma in offspring at 2 years of age.

Dysbiosis of the Newborn Upper Airway is Associated with Early Wheeze

Dysbiosis of the Newborn Upper Airway is Associated with Early Wheeze

Association of prenatal folate status with early childhood wheeze and atopic dermatitis.

Prenatal folic acid supplementation is recommended to prevent birth defects. Some foods are fortified in the USA to ensure sufficient intake among reproductive-aged women. However, high prenatal folate exposure may be a risk factor for childhood atopic diseases. We investigated associations between prenatal folate and early childhood wheeze and atopic dermatitis in a US cohort. We studied 858 mother-child dyads, enrolled prenatally. Folate was measured in 2nd and 3rd trimester maternal plasma. Parents reported current wheeze (previous 12months) and healthcare provider diagnosis of atopic dermatitis at 3years. We examined associations using logistic regression, modeling folate continuously and dichotomously (< or ≥20ng/mL), a level often considered supraphysiologic. Over half of women were African American and on Medicaid. Median (interquartile range) folate levels were 22.6 (15.9-30.0) and 23.1 (16.1-30.0) ng/mL for 2nd and 3rd trimesters, respectively. Current wheeze and atopic dermatitis were reported for 20.4% and 26.8% of children, respectively. Second trimester folate as a continuous exposure was not significantly associated with outcomes. Decreased odds of current wheeze were observed in children born to mothers who had 2nd trimester folate ≥20ng/mL (adjusted odds ratios=0.67, 95% confidence interval=0.46, 0.97) compared to children with maternal levels <20ng/mL. Third trimester folate was not associated with outcomes. High plasma folate in mid-pregnancy was associated with decreased odds of current wheeze at age 3. Our findings do not support harmful effects of high prenatal folate levels on childhood atopic diseases in this setting.

Complex relationships between vitamin D and allergic sensitization among Puerto Rican 2-year-old children

BackgroundIn the United States, Puerto Ricans have a higher prevalence of asthma than other Latino ethnicities. Low vitamin D levels for children living in northern climates could be a factor. ObjectiveTo assess serum 25-hydroxyvitamin D [25(OH)D] distributions (a marker of vitamin D) and associations among vitamin D, allergic sensitization, early wheeze, and home/demographic factors. MethodsPuerto Rican infants born in New York City, with a maternal history of atopy, were enrolled in a birth cohort. Blood was collected at age 2 years (n = 154; 82 males and 72 females). Serum 25(OH)D and immunoglobulin E (IgE) (indoor allergen-specific and total) were determined using immunoassays. Home/demographic characteristics and respiratory symptoms were assessed by questionnaire. ResultsThe median concentration of 25(OH)D was 22.6 ng/mL; 32% were at risk of deficiency or inadequacy (<12 or 12–19 ng/mL). Serum 25(OH)D levels were lower in the heating (a surrogate for less sun exposure in colder months) compared with nonheating (26.1 vs 22.7 ng/mL, P = .02) season, but were not associated with allergen-specific IgE levels or with level of acculturation (measured by maternal birthplace). However, low 25(OH)D levels (below median) were associated with high total IgE >100 IU/mL (P = .01). Also, 25(OH)D concentrations differed between children who attended daycare and those who did not (21.8 vs 24.5 ng/mL; t test, P = .02). Serum 25(OH)D was not associated with wheeze or asthma by 2 years of age (P = .43). ConclusionVitamin D deficiency, possibly linked with allergic pathways, may partially explain the trajectory for disproportionate asthma burden among Puerto Ricans, especially those born and raised in colder climates.

The Independent Role of Prenatal and Postnatal Exposure to Active and Passive Smoking on the Development of Early Wheeze in Children

CI Vardavas, C Hohmann, E Patelarou. Eur Respir J. 2016;48(1):115–124 To examine the association of maternal passive smoking during pregnancy and wheezing in children up to 2 years. The authors of this study included 15 cohorts in the European project Environmental Health Risks in European Birth Cohorts. The cohorts were recruited from 1990 to 2008. A total of 37 459 mother-child pairs were available, and 27 993 had complete data on secondhand smoke exposure and wheeze. Active and passive smoke exposure was obtained from questionnaire data submitted by each cohort. Four exposure definitions were created: prenatal active smoking, prenatal passive smoking, …

Pro-inflammatory mediator responses from neonatal airway epithelial cells and early childhood wheeze.

Airway epithelial cell (AEC) function differs between children with and without asthma. Here, we associated neonatal AEC function with asthma symptoms at 4 years of age. Nasal AEC were collected from neonates within 48 h of birth. Cells were cultured and stimulated with tumor necrosis factor alpha/interleukin-1 beta (TNFα/IL-1β), lipopolysaccharide (LPS), or house dust mite (HDM). Absolute concentrations of pro-inflammatory mediators in the culture supernatant were quantified and expressed as median [interquartile range] in pg/mg protein. A parent-completed respiratory questionnaire was returned when the child was 4 years old. AEC were successfully cultured in 139 neonates, of whom 120 were contacted at 4 years and 91 (76%) questionnaires were returned. Sixteen children had wheezed ever and 11 had recent wheeze. At birth, when compared to those with no recent wheeze, supernatants from cultured neonatal AEC from the children with recent wheeze had reduced median IL-8 (CXCL8) release after treatment with culture medium alone (P = 0.049), with TNFα/IL-1β (P < 0.001) and LPS (P = 0.004). Additionally, and when compared to those with no recent wheeze, 4 year olds with recent wheeze had reduced neonatal AEC release of IL-6 (P = 0.013), GMCSF (P = 0.012), and ICAM-1 (P = 0.017) after treatment with TNFα/IL-1β and reduced release of ICAM-1 (P = 0.038) and RANTES (P = 0.042) after treatment with HDM. Abnormalities in AEC function are present at birth before the onset of childhood wheeze. The relationship between reduced AEC function at birth and wheeze at 4 years was not exclusive, suggesting that post-natal factors are required for the AEC abnormality to translate into symptoms.

Sibilancias recurrentes: prevalencia y factores asociados en lactantes de Buenos Aires, Argentina

BackgroundThe episodes of bronchial obstruction at early age constitute a frequent problem in Pediatrics. The aim of this study was to evaluate the prevalence of recurrent wheezing in infants in Buenos Aires City, as well as to identify any associated factors. MethodsCross-sectional study performed from 2011 to 2012 in the Children Hospital Ricardo Gutiérrez, Buenos Aires City, as part of the International Study of Wheezing in Infants. A validated questionnaire was applied to parents of infants aged between 12 and 15 months. The prevalence of wheezing, mostly the recurrent episodes (three or more), and their probable associated factors were evaluated. Data were statistically analyzed with χ2, Fisher's test, binary and logistics multiple regression analysis. The significance level was 0.05. ResultsOver 1063 infants, 58.9% (confidence interval (CI) 95% 55.9-61.9) presented at least one episode of wheezing and 26.3% (CI95% 23.8-29.9) three or more episodes (recurrent wheezing). Risk factors associated to wheezing were male gender (p=0.001), six or more episodes of cold during the first year of life (p <0.0001), age at first cold <4 months (p <0.0001); pneumonia (p <0.0001) and smoking during pregnancy (tobacco) (p=0.01). For recurrent wheezing, risk factors we considered as six or more episodes of cold during the first year of life (p <0.0001), early (< 4 month of age) onset wheezing (p <0.0001) and nocturnal wheezing (p <0.0001). ConclusionsThe prevalence of recurrent wheezing among infants in Buenos Aires Ciy was high (26.3%). Some identified associated factors can be preventable.

Vitamin D, high-sensitivity C-reactive protein, and airway hyperresponsiveness in infants with recurrent respiratory symptoms

BackgroundVitamin D insufficiency might be associated with biased T-cell responses resulting in inflammatory conditions such as atopy and asthma. Little is known about the role of vitamin D in low-grade systemic inflammation and airway hyperresponsiveness (AHR) in young children. ObjectiveTo evaluate whether vitamin D insufficiency and increased serum high-sensitivity C-reactive protein (hs-CRP) are linked to AHR in symptomatic infants. MethodsSeventy-nine infants with recurrent or persistent lower respiratory tract symptoms underwent comprehensive lung function testing and a bronchial methacholine challenge test. In addition, skin prick tests were performed and serum 25-hydroxyvitamin D (S-25-OHD), hs-CRP, total immunoglobulin E, and blood eosinophil levels were determined. ResultsS-25-OHD was lowest in infants with blood eosinophilia and AHR (n = 10) compared with those with eosinophilia only (n = 6) or AHR only (n = 50) or those with neither (n = 13; P = .035). Moreover, vitamin D insufficiency (S-25-OHD <50 nmol/L) was most common in infants with blood eosinophilia and AHR (P = .041). Serum hs-CRP was lower in infants with recurrent physician-diagnosed wheezing (P = .048) and in those with blood eosinophilia (P = .015) than in infants without these characteristics and was not associated with S-25-OHD or AHR. S-25-OHD levels were significantly lower (median 54 nmol/L) during the autumn-winter season than in the spring-summer season (median 63 nmol/L; P = .026). ConclusionVitamin D insufficiency could underlie eosinophilia and AHR in infants with troublesome lung symptoms, whereas hs-CRP–mediated low-grade systemic inflammation is rare in early childhood wheezing.

Rhinovirus and preschool wheeze.

Rhinovirus (RV) known as the common cold virus generally only causes a mild upper respiratory infection, but severe lower respiratory symptoms have been associated with RV infections especially in asthmatic individuals. Wheezing is a symptom of airway obstruction, and preschool children wheezing with RV have been associated with increased risk of asthma at school age. There are, however, conflicting opinions as to whether there are differences in response to RV infection or whether wheezing with RV reveals a preexisting impairment that promotes asthma mainly in predisposed children. The advent of molecular diagnostics to detect respiratory viruses has led to new insights into the role of RV infections. This review will discuss recent information concerning the role of RV as an important respiratory pathogen related to early onset wheeze and exacerbation of established asthma in preschool children.