Asthma Phenotypes In Children Research Articles

Asthma Phenotypes in Childhood

Asthma Phenotypes in Childhood

Asthma in childhood: a complex, heterogeneous disease

Asthma in childhood is a heterogeneous disease with different phenotypes and variable clinical manifestations, which depend on the age, gender, genetic background, and environmental influences of the patients. Several longitudinal studies have been conducted to classify the phenotypes of childhood asthma, on the basis of the symptoms, triggers of wheezing illness, or pathophysiological features of the disease. These studies have provided us with important information about the different wheezing phenotypes in young children and about potential mechanisms and risk factors for the development of chronic asthma. The goal of these studies was to provide a better insight into the causes and natural course of childhood asthma. It is well-known that complicated interactions between genes and environmental factors contribute to the development of asthma. Because childhood is a period of rapid growth in both the lungs and the immune system, developmental factors should be considered in the pathogenesis of childhood asthma. The pulmonary system continues to grow and develop until linear growth is completed. Longitudinal studies have reported significant age-related immune development during postnatal early life. These observations suggest that the phenotypes of childhood asthma vary among children and also in an individual child over time. Improved classification of heterogeneous conditions of the disease will help determine novel strategies for primary and secondary prevention and for the development of individualized treatment for childhood asthma.

Risk Factors and Asthma Phenotypes in Children and Adults with Seasonal Allergic Rhinitis

Background: There are few data on asthma risk factors and phenotypes in patients with seasonal allergic rhinitis (SAR). Methods: Thirty-three children (mean age, 8.27 ± 1.77 years) and 82 adults (mean age, 34.12 ± 10.59 years) with SAR were evaluated for asthma (history, reversibility of bronchial obstruction, increased inhaled nitric oxide). The following asthma risk factors were considered in the multiple regression analysis: male sex, family history of asthma, breastfeeding < 2 months, passive/active smoking, obesity, pets/molds exposure, high total serum immunoglobulin E (IgE), polysensitization (sensitized to 3 seasonal pollens with different structure), mixed sensitization (seasonal and perennial allergens), severe rhinitis (according to the Allergic Rhinitis and its Impact on Asthma guidelines), and lack of allergen-specific immunotherapy (SIT) for rhinitis preceding asthma diagnosis. Asthma phenotypes were characterized using the k-means clustering (silhouette method for cluster validation). Results: Asthma was diagnosed in 22 (66.7%) children and in 57 (69.5%) adults with SAR. Independent risk factors for asthma were lack of SIT preceding asthma diagnosis, both for children (P = 0.008132) and adults (P = 0.000017), and mixed sensitization for children (P = 0.035694). Asthma phenotypes identified in children according to the associated risk factors were: breastfeeding < 2 months and severe rhinitis in 16 (63.6%) patients; male, polysensitized, and severe rhinitis in 8 (36.4%) patients. Asthma phenotypes in adults were: polysensitization and severe rhinitis in 30 (52.6%) patients; male, exposure to pets, and severe rhinitis in 11 (19.3%) patients; and high total serum IgE and polysensitization in 16 (28.1%) patients. Conclusion: Lack of SIT is an independent risk factor for asthma both in children and adults with SAR, whereas polysensitization is a risk factor only for children. The dominant asthma phenotype in children with SAR is breastfeeding < 2 months and severe rhinitis. In adults with SAR, the dominant asthma phenotype is polysensitization and severe rhinitis.

Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma

Prenatal and infant acetaminophen exposure has been associated with an increased risk of childhood asthma phenotypes. Demonstration of biologically plausible interactions between these exposures and maternal and child antioxidant gene polymorphisms would strengthen causal inference. To explore potential interactions between prenatal and infant acetaminophen exposure and antioxidant genotypes on childhood asthma. In the Avon Longitudinal Study of Parents and Children, we typed a functional nuclear erythroid 2 p45-related factor 2 (Nrf2) polymorphism and glutathione S-transferase (GST) M1, T1, and P1 polymorphisms. Effects of prenatal and infant acetaminophen exposure on asthma phenotypes at 7 years were stratified by genotype in >4000 mothers and >5000 children. Risk of asthma and wheezing associated with early gestation acetaminophen exposure was increased when maternal copies of the minor T allele of Nrf2 were present (Pinteractions, .02 and .04, respectively). Risk of asthma associated with late gestation exposure was higher when maternal GSTT1 genotype was present rather than absent (Pinteraction, .006), and risk of wheezing was increased when maternal GSTM1 was present (P interaction, .04). Although acetaminophen use in infancy was associated with an increased risk of atopy, child antioxidant genotype did not modify associations between infant acetaminophen use and asthma phenotypes. However, the increased risk of asthma and wheezing associated with late gestation acetaminophen exposure in the presence of maternal GSTM1 was further enhanced when GSTM1 was also present in the child. Maternal antioxidant gene polymorphisms may modify the relation between prenatal acetaminophen exposure and childhood asthma, strengthening evidence for a causal association. In contrast, relations between infant acetaminophen use and asthma and atopy were not modified by child genotype and may be confounded by pre-existing wheeze or allergy.

Asthma severity in childhood, untangling clinical phenotypes*

Assessment of childhood asthma severity and asthma control encompasses heterogeneous clinical presentations. The relationship between patterns of asthma symptoms and objective measurements is poorly defined in paediatric asthma. This study includes 115 asthmatic schoolchildren, of which 31 were at inclusion defined as Problematic severe asthma because of inadequate asthma control in the presence of high-dose inhaled corticosteroid (HD-ICS) treatment and at least one other asthma controller drug. Two partially overlapping clinical outcomes were defined irrespective of severity classification (Exacerbations and Chronic persistent asthma) in patients with uncontrolled asthma. The same symptom criteria were used as for Problematic severe asthma, but disregarding current medication. Lung function, exhaled nitric oxide (FE(NO)), bronchial hyperresponsiveness, allergic sensitization and Quality of life (QoL) in the symptom subgroups were compared to children with well-controlled asthma. Multifactor analysis was performed to assess the relative explanatory power of clinical asthma presentations and of HD-ICS treatment on objective measurements. Whereas children included in the Exacerbations subgroup had objective features similar to patients with well-controlled asthma, the Chronic persistent asthma subgroup demonstrated significantly reduced lung function, increased immunoglobin E, allergic poly-sensitization and impaired QoL, similar to that in patients pre-defined as Problematic severe asthma. The presence of chronic asthma symptoms was a significant explanatory factor for reduced lung function, QoL and increased FE(NO) in multifactor analysis. Differences in objective measurements suggest that children with Chronic persistent asthma and those who are symptomatic predominantly during exacerbations may represent distinct phenotypes of childhood asthma with different clinical prognoses.

Phenotypes of childhood asthma: are they real?

It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. Childhood wheezing disorders manifest themselves in a range of observable (phenotypic) features such as lung function, bronchial responsiveness, atopy and a highly variable time course (prognosis). The underlying causes are not sufficiently understood to define disease entities based on aetiology. Nevertheless, there is a need for a classification that would (i) facilitate research into aetiology and pathophysiology, (ii) allow targeted treatment and preventive measures and (iii) improve the prediction of long-term outcome. Classical attempts to define phenotypes have been one-dimensional, relying on few or single features such as triggers (exclusive viral wheeze vs. multiple trigger wheeze) or time course (early transient wheeze, persistent and late onset wheeze). These definitions are simple but essentially subjective. Recently, a multi-dimensional approach has been adopted. This approach is based on a wide range of features and relies on multivariate methods such as cluster or latent class analysis. Phenotypes identified in this manner are more complex but arguably more objective. Although phenotypes have an undisputed standing in current research on childhood asthma and wheezing, there is confusion about the meaning of the term 'phenotype' causing much circular debate. If phenotypes are meant to represent 'real' underlying disease entities rather than superficial features, there is a need for validation and harmonization of definitions. The multi-dimensional approach allows validation by replication across different populations and may contribute to a more reliable classification of childhood wheezing disorders and to improved precision of research relying on phenotype recognition, particularly in genetics. Ultimately, the underlying pathophysiology and aetiology will need to be understood to properly characterize the diseases causing recurrent wheeze in children.

Severe Asthma in Children: Insights from the National Heart, Lung, and Blood Institute's Severe Asthma Research Program

Severe asthma in children is a complicated disorder characterized by ongoing symptoms and persistent airway inflammation despite treatment with high doses of inhaled and oral corticosteroids. Although knowledge of asthma and its associated mechanisms has increased substantially over the past decade, significant gaps remain about the determinants of severe asthma in children and the progression of the disorder across the lifespan. This review highlights recent insights into severe asthma in children derived from the National Heart, Lung, and Blood Institute's Severe Asthma Research Program (SARP), with an emphasis on age-specific findings and differences from severe asthma in adults. While the existence of a true severe asthma phenotype in children is subject to some debate, given the results of SARP and other investigators, we conclude that there is indeed a subgroup of children with severe asthma who have extreme morbidity and differentiating clinical features that are identifiable very early in life. However, unlike adults with severe asthma, children with severe asthma are more likely to fall in a more narrow cluster that is characterized by marked atopy and reversible airflow obstruction. While SARP has advanced knowledge of severe asthma in children, considerable gaps remain for which additional studies are needed.

Ikimokyklinio amžiaus vaikų bronchų obstrukcijos klinikinio įvertinimo, diagnostikos ir gydymo galimybės

Bronchų obstrukcijos diagnostikos ir gydymo galimybės analizuojamos vadovaujantis Europos respiratologų draugijos ekspertų grupės parengtomis rekomendacijos ikimokyklinio amžiaus vaikų švokštimui įvertinti, diagnozuoti ir gydyti. Straipsnio pabaigoje aprašomas klinikinis sunkios ir blogai kontroliuojamos astmos atvejis.

Les phénotypes de l’asthme de l’enfant

Asthma must no longer be considered simply as a disease but rather as a complex of multiple syndromes which are associated in various ways. Early onset asthma most often has a familial and allergic component, and it is often associated with a risk of persistence during childhood and then into adulthood. Virus-induced asthma (occurring in young infants and preschool children) has a good long-term prognosis. Nevertheless, severe viral infections with asthma requiring hospitalization are at risk of evolving into asthma which persists to adolescence. Severe childhood asthma is often associated with acute attacks, with predominance in males, and with atopy together with cortico-sensitivity. Inversely, in adolescents the severe asthma phenotype resembles asthma in adults, being predominant in females, with an absence of atopy, and with a history of previous episodes of pneumonia. Asthma is a multiform disease whose phenotype can vary throughout a child's life. Regular re-evaluation of the asthma phenotype in children allows better control of the management of this disease over the long term.

Chromosome 17q21 Gene Variants Are Associated with Asthma and Exacerbations but Not Atopy in Early Childhood

An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups. To characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus. The single nucleotide polymorphism (SNP), rs7216389, was genotyped in 376 of 411 children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort born to mothers with asthma together with 305 mothers and 224 fathers. Nineteen additional SNPs in the region were genotyped in the children. Investigator-diagnosed clinical endpoints were based on diary cards and clinic visits every 6 months and at acute symptoms from birth. Lung function, bronchial responsiveness, and sensitization were tested longitudinally from early infancy. rs7216389 was significantly associated with the development of wheeze (hazard ratio 1.64 [1.05-2.59], P value = 0.03), asthma (hazard ratio, 1.88 [1.15-3.07], P = 0.01), and acute severe exacerbations (hazard ratio 2.66 [1.58-4.48], P value = 0.0002). The effect on wheeze and asthma was observed for early onset but not late onset of disease. The increased risk of exacerbations persisted from 1 to 6 years of age (incidence ratio 2.48 [1.42-4.32], P value = 0.001), and increased bronchial responsiveness was present in infancy and at 4 years of age, but not at 6 years. In contrast, rs7216389 conferred no risk of eczema, rhinitis, or allergic sensitization. Variation at the chromosome 17q12-q21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.

IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study

BackgroundTobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13) polymorphisms and tobacco smoke on persistent childhood wheezing and asthma.MethodsIn the Isle of Wight birth cohort (UK, 1989–1999), five IL13 single nucleotide polymorphisms (SNPs): rs1800925 (-1112C/T), rs2066960, rs1295686, rs20541 (R130Q) and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy.ResultsMaternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p < 0.0001); polymorphisms in IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair). However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014). Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02). Comparable results were observed for persistent childhood asthma (p for interaction = 0.03).ConclusionThis is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.

ACE gene polymorphism might disclose why some Taiwanese children with allergic rhinitis develop asthma symptoms but others do not

Although allergic asthma and allergic rhinitis have recently been considered to be a single disease, many questions remain unanswered. Why do some atopic patients develop asthma symptoms and others develop allergic rhinitis symptoms? Which factors play a role in the development of different allergic phenotypes? We hypothesized that angiotensin-converting enzyme (ACE) gene polymorphism might play a role in the development of asthma phenotypes in children with allergic rhinitis. The study sample included 106 children with allergic rhinitis, but no asthma, and 105 age- and gender-matched children with allergic rhinitis and asthma. Subjects of both groups exhibited the same systemic immunologic changes and allergen sensitivities. Controls consisted of 102 healthy children. The ACE genotype was determined by polymerase chain reaction. The serum total immunoglobulin E (IgE) level, allergen-specific IgE sensitivity, and eosinophil count were also measured. The frequencies of the DD genotype were significantly higher in the children with both allergic rhinitis and asthma than in the children with allergic rhinitis but no asthma [p = 0.018; odds ratio (OR) = 3.257; (1.222-8.680)]. Results of this study suggest that ACE gene polymorphism DD genotype might play a role in the development of the asthma phenotype in children with allergic rhinitis.

Definir asma para estudos epidemiológicos: essa meta pode ser alcançada?

However, these differences may simplyresult in the use of distinct definitions for asthma orin the application of various instruments to measureit (e.g. questionnaires). In addition, there is nouniversally accepted definition that encompasses thevarious asthma phenotypes in children and adults.Defining asthma has always been a subject fordiscussion. More recently, several establishedguidelines have defined asthma in a careful, elaborateway, although the result is still unsatisfactory.

Beyond our pages

Beyond our pages

Are There Different Phenotypes of Childhood Asthma?

Are There Different Phenotypes of Childhood Asthma?

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.

Does environment mediate earlier onset of the persistent childhood asthma phenotype?

We investigated the role of environmental and hereditary factors in determining whether persistent childhood wheezing phenotypes had an early or late onset. In a whole population birth cohort (n = 1456), children were seen at birth and at 1, 2, 4, and 10 years. At each visit, information was collected prospectively regarding wheeze prevalence and used to classify subjects into wheezing phenotypes. Information on genetic and environmental risk factors in early life was also obtained prospectively, and skin-prick testing to common allergens was performed at 4 years. Early-onset persistent wheezers (n = 125) had wheeze onset in the first 4 years, still present at age 10, whereas late-onset persistent wheezers (n = 81) had wheeze onset after age 4 years that was still present at 10 years. Multivariate logistic regression analysis identified independent significance only for inherited factors (parental asthma, family history of rhinitis, eczema at 4 years, and atopic status at 4 years) in the development of late-onset persistent wheeze. However, low social class at birth, recurrent chest infections at 2 years, and parental smoking at 2 years plus inherited factors (eczema at 2 years; food allergy at 4 years; maternal asthma, sibling asthma, maternal urticaria, and atopic status at 4 years) demonstrated independent significance for early-onset persistent wheeze. Inheritance seems to be of prime significance in the cause of persistent childhood wheeze. Environmental exposure in early life may combine with this tendency to produce an early onset of persistent wheeze. Absence of these environmental factors might delay but not prevent the onset of wheeze in children with atopic heredity.

IL10 gene polymorphisms are associated with asthma phenotypes in children.

IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3' UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3' UTR SNP was significantly associated with FEV(1) as a percent of predicted (FEV(1)PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV(1)PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC(20) and FEV(1)PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.

The association of maternal but not paternal genetic variation in GSTP1 with asthma phenotypes in children

Maternal factors including atopy and smoking during pregnancy are associated with asthma risk during childhood. Suggested mechanisms include transmission of specific maternal alleles and maternal influences on the intrauterine environment. We have previously shown that polymorphism in glutathione S-transferase, GSTP1 is associated with airway hyperresponsiveness (AHR) and atopy in adults. We now hypothesise that GSTP1 genotypes in the mother and child, but not the father, mediate asthma phenotypes in the child. One hundred and forty-five Caucasian families were recruited via an asthmatic proband aged 7–18 years. Atopy and asthma were assessed using a questionnaire, skin prick testing, serum IgE, spirometry and methacholine challenge (PC 20, dose–response slope—DRS). GSTP1 genotyping was determined using PCR. GSTP1 Val 105/Val 105 genotype in the child was associated with a reduced risk of atopy ( P=0.038) and AHR (PC 20, P=0.046; DRS, P=0.032). In mothers ( P=0.014) but not fathers ( P=0.623), Val 105/Val 105 was associated with a reduced risk of AHR in the child. We have identified, for the first time, an association between maternal genotype and the child's asthma phenotype that appears not to be due to transmission of specific maternal alleles. This preliminary data supports the view of in utero effects of maternal genotype and adds new insights into the possible mechanisms by which maternal factors may influence development of childhood asthma.

Long-term outcome of childhood asthma.

What we know: The outcome of childhood asthma is dependent on the pattern of asthma through childhood. Episodic asthma in childhood tends to resolve in adolescence and through mid-adult years, with no impairment of lung function. Persistent asthma in childhood is more likely to persist into adult years, with modest impairment of lung function. The impairment of lung function occurs early in the disease process and is not progressive, despite continuing symptoms. What we need to know: Are there clearly identifiable phenotypes of childhood asthma that have different aetiologies, response to treatment, genotypes and natural history? Does early treatment with anti-inflammatory agents prevent impairment of lung function? Can an algorithm be developed to predict the likelihood of persistent asthma on first presentation?