Multitrigger Wheeze Research Articles

17q12-21 risk-variants influence cord blood immune regulation and multitrigger-wheeze.

Childhood wheeze represents a first symptom of asthma. Early identification of children at risk for wheeze related to 17q12-21 variants and their underlying immunological mechanisms remain unknown. We aimed to assess the influence of 17q12-21 variants and mRNA expression at birth on the development of wheeze. Children were classified as multitrigger/viral/no wheeze until six years of age. The PAULINA/PAULCHEN birth cohorts were genotyped (n=216; GSA-chip). mRNA expression of 17q21 and innate/adaptive genes was measured (qRT-PCR) in cord blood mononuclear cells. Expression quantitative trait loci (eQTL) and mediation analyses were performed. Genetic variation of 17q12-21 asthma-single nucleotide polymorphisms (SNPs) was summarized as the first principal component (PC1) and used to classify single SNP effects on gene expression as (locus)-dependent/independent eQTL SNPs. Core region risk variants (IKZF3, ZPBP2, GSDMB, ORMDL3) were associated with multitrigger wheeze (OR: 3.05-5.43) and were locus-dependent eQTL SNPs with higher GSDMA, TLR2, TLR5, and lower TGFB1 expression. Increased risk of multitrigger wheeze with rs9303277 was in part mediated by TLR2 expression. Risk variants distal to the core region were mainly locus-independent eQTL SNPs with decreased CD209, CD86, TRAF6, RORA, and IL-9 expression. Distinct immune signatures in cord blood were associated either with multitrigger wheeze (increased innate genes, e.g., TLR2, IPS1, LY75) or viral wheeze (decreased NF-κB genes, e.g., TNFAIP3 and TNIP2). Locus-dependent eQTL SNPs (core region) associated with increased inflammatory genes (primarily TLR2) at birth and subsequent multitrigger wheeze indicate that early priming and imbalance may be crucial for asthma pathophysiology. Locus-independent eQTL SNPs (mainly distal region, rs1007654) may be involved in the initiation of dendritic cell activation/maturation (TRAF6) and interaction with T cells (CD209, CD86). Identifying potential mechanistic pathways at birth may point to critical key points during early immune development predisposing to asthma.

Viral origin of wheeze in the under-five population in Pakistan

Background: One of the most common issues arising these days is wheezing that is observed in kids below five year of age accompanied with acute respiratory infections (ARIs). The main etiological causes of ARIs are viruses. Aim: To investigate the viral cause of wheezing in kids below five years of age who were hospitalized in hospital located in Pakistan. Methods: Forty candidates under 5 years of age were admitted complaining wheezing, in this case research. Nasal and throat swaps were taken. For screening purpose, real-time, polymerase chain reaction (PCR) assay was employed in order to rule out rhinovirus, influenza 1 and 2, respiratory para influenza virus (PIV) 1, 2, 3 and 4, syncytial virus (RSV), human meta-pneumovirus, bocavirus (HBoV), Enterovirus Coronavirus, Parechovirus and adenovirus. Results: 30% was regarded as total viral detection rate. Candidates detected with pheumonina viral RNA markers were found from their samples (6 cases), episodic wheeze (1 cases) bronchiolitis (7 cases) and multitrigger wheeze (8 cases). It was discovered that RSV was the most common virus found (30%) which is then followed by PIV1, 2 and 3(18%), HBoV (8%) and rhinovirus (4%). Whereas mixed infection was found in case of in 32 per cent. Conclusions: According to the case research, respiratory viral agents was found to be the culprit in 30 per cent of kids suffering from wheezing; the most common RSV and PIV were responsible for 50 per cent of the total number of cases involved. In case of 30% of cases mixed infections were reported. There was also noteworthy Seasonal variation was noted. Moreover, Further research required to accomplished with a large samples and long duration follow up span in order to clarify results of research. Keywords: Asthma - bronchiolitis - child - incidence - PCR

Role of montelukast in multitrigger wheezers attending chest clinic in Punjab, India.

Wheeze is seen in 40% of preschool children, one-third of these may develop recurrent wheeze. Montelukast is an oral, once a day, easy to give therapy but there is no definite evidence to support its use in a recent meta-analysis. Present study was done to evaluate role of daily montelukast and various factors affecting the outcome after therapy in multitrigger wheeze (MTW). A prospective study conducted in Pediatric chest clinic over 18 months at DMCH, Ludhiana. Children from 6 months to 5 years, diagnosed cases of MTW were started on montelukast. Diagnosis based on symptoms of recurrent wheeze triggered by various allergens/precipitants was made by pediatrician in charge of chest clinic. Children were followed up at 1 and 3 months. They were labeled as controlled, partially controlled, or uncontrolled as per global initiative for asthma guidelines. Data were used to compare the outcome related to various factors. Total 139 out of 150 children came for regular follow-up. At the end of 3 months, 94 (67.7%) were controlled, 8 (5.7%) partially controlled, and 37 (26.6%) children remained uncontrolled on montelukast. Factors associated with poor control were onset of symptoms at younger age (<6 months of age), family history of allergies, prior multiple visits or hospitalizations due to MTW, use of MDI in the past. No significant side effects were reported by parents. Symptomatically two-third of children became better after starting montelukast. There were few factors which resulted in poorer control in subset of patients.

Wheezing in children: Approaches to diagnosis and management.

Wheezing in children: Approaches to diagnosis and management.

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.

Temporal stability of multitrigger and episodic viral wheeze in early childhood.

The distinction between episodic viral wheeze (EVW) and multitrigger wheeze (MTW) is used to guide management of preschool wheeze. It has been questioned whether these phenotypes are stable over time. We examined the temporal stability of MTW and EVW in two large population-based cohorts.We classified children from the Avon Longitudinal Study of Parents and Children (n=10 970) and the Leicester Respiratory Cohorts ((LRCs), n=3263) into EVW, MTW and no wheeze at ages 2, 4 and 6 years based on parent-reported symptoms. Using multinomial regression, we estimated relative risk ratios for EVW and MTW at follow-up (no wheeze as reference category) with and without adjusting for wheeze severity.Although large proportions of children with EVW and MTW became asymptomatic, those that continued to wheeze showed a tendency to remain in the same phenotype: among children with MTW at 4 years in the LRCs, the adjusted relative risk ratio was 15.6 (95% CI 8.3-29.2) for MTW (stable phenotype) compared to 7.0 (95% CI 2.6-18.9) for EVW (phenotype switching) at 6 years. The tendency to persist was weaker for EVW and from 2-4 years. Results were similar across cohorts.This suggests that MTW, and to a lesser extent EVW, tend to persist regardless of wheeze severity.

Viral aetiology of wheezing in children under five.

Background & objectives:Wheezing is a common problem in children under five with acute respiratory infections (ARIs). Viruses are known to be responsible for a considerable proportion of ARIs in children. This study was undertaken to know the viral aetiology of wheezing among the children less than five years of age, admitted to a tertiary care hospital in eastern India.Methods:Seventy five children, under the age of five years admitted with wheezing, were included in the study. Throat and nasal swabs were collected, and real-time multiplex polymerase chain reaction (PCR) assay was used to screen for influenza 1 and 2, respiratory syncytial virus (RSV), parainfluenza virus (PIV) 1, 2, 3 and 4, rhinovirus, human meta-pneumovirus, bocavirus (HBoV), Coronavirus, adenovirus, Enterovirus and Parechovirus.Results:The total viral detection rate was 28.57 per cent. Viral RNA markers were detected from children diagnosed to be having pneumonia (3 cases), bronchiolitis (9 cases), episodic wheeze (2 cases) and multitrigger wheeze (6 cases). RSV was the most common virus (35%) followed by PIV1, 2 and 3 (20%), HBoV (10%) and rhinovirus (5%). However, mixed infection was observed in 30 per cent of cases.Interpretation & conclusions:The study reported the presence of respiratory viral agents in 28.57 per cent of children with wheezing; RSV and PIV were most common, accounting to 55 per cent of the total cases. Mixed infection was reported in 30 per cent of cases. Seasonal variation in the occurrence of these viruses was also noted. Further studies need to be done with a large sample and longer follow up period to verify these findings.

The puzzle of immune phenotypes of childhood asthma.

Asthma represents the most common chronic childhood disease worldwide. Whereas preschool children present with wheezing triggered by different factors (multitrigger and viral wheeze), clinical asthma manifestation in school children has previously been classified as allergic and non-allergic asthma. For both, the underlying immunological mechanisms are not yet understood in depth in children. Treatment is still prescribed regardless of underlying mechanisms, and children are not always treated successfully. This review summarizes recent key findings on the complex mechanisms of the development and manifestation of childhood asthma. Whereas traditional classification of childhood asthma is primarily based on clinical symptoms like wheezing and atopy, novel approaches to specify asthma phenotypes are under way and face challenges such as including the stability of phenotypes over time and transition into adulthood. Epidemiological studies enclose more information on the patient’s disease history and environmental influences. Latest studies define endotypes based on molecular and cellular mechanisms, for example defining risk and protective single nucleotide polymorphisms (SNPs) and new immune phenotypes, showing promising results. Also, regulatory T cells and recently discovered T helper cell subtypes such as Th9 and Th17 cells were shown to be important for the development of asthma. Innate lymphoid cells (ILC) could play a critical role in asthma patients as they produce different cytokines associated with asthma. Epigenetic findings showed different acetylation and methylation patterns for children with allergic and non-allergic asthma. On a posttranscriptional level, miRNAs are regulating factors identified to differ between asthma patients and healthy controls and also indicate differences within asthma phenotypes. Metabolomics is another exciting chapter important for endotyping asthmatic children. Despite the development of new biomarkers and the discovery of new immunological molecules, the complex puzzle of childhood asthma is still far from being completed. Addressing the current challenges of distinct clinical asthma and wheeze phenotypes, including their stability and underlying endotypes, involves addressing the interplay of innate and adaptive immune regulatory mechanisms in large, interdisciplinary cohorts.

Preschool wheeze is not asthma: a clinical dilemma.

Recurrent wheezing is common in preschool children and often gets labelled as asthma. It is important to differentiate preschool wheeze from asthma through focused history, examination and exclusion of other serious conditions that may present as wheeze. Two different pragmatic clinical phenotypes viz. episodic viral wheeze (EVW) and multi-trigger wheeze (MTW) have been described although categories do not remain fixed and cross over is often seen in clinical practice. Episodic use of inhaled bronchodilators such as salbutamol when wheezy, is the mainstay of treatment along with non-pharmacological measures such as avoidance of environmental tobacco smoke and parental education. Inhaled corticosteroids are the first choice for maintenance therapy in MTW whereas montelukast may be useful when maintenance therapy is considered in EVW. Any maintenance therapy should be viewed as a trial and need to be discontinued in cases where no benefit has been demonstrated. Short term systemic steroid therapy should be reserved for excaerbation of wheezy symptoms where hospitalization is necessary. Prognosis is good in recurrent mild EVW although remission in atopic MTW is often not achieved and the children in the latter group go on to develop asthma.

P82 Episodic viral wheeze and multitrigger wheeze: are they really different phenotypes?

IntroductionEpisodic viral wheeze (EVW) and multitrigger wheeze (MTW) are thought to be distinct recurrent wheezing phenotypes in preschool children. Here we tested the hypothesis that there are detectable physiological differences...

Do migrant studies help to identify causes of asthma?

Do migrant studies help to identify causes of asthma?

The Management of Pre-School Wheeze

SummaryWheeze, a common symptom in pre-school children, is a continuous high-pitched sound, with a musical quality, emitting from the chest during expiration. A pragmatic clinical classification is episodic (viral) wheeze and multiple-trigger wheeze. Diagnostic difficulties include other conditions that give rise to noisy breathing which could be misinterpreted as wheeze. Most preschool children with wheeze do not need rigorous investigations. Primary prevention is not possible but avoidance of environmental tobacco smoke exposure should be strongly encouraged. Bronchodilators provide symptomatic relief in acute wheezy episodes but the evidence for using oral steroids is conflicting for children presenting to the Emergency Department [ED]. Parent initiated oral steroid courses cannot be recommended. High dose inhaled corticosteroids [ICS] used intermittently are effective in children with frequent episodes of moderately severe episodic (viral) wheeze or multiple-trigger wheeze, but this associated with short term effects on growth and cannot be recommended as a routine. Maintenance treatment with low to moderate continuous ICS in pure episodic (viral) wheeze is ineffective. Whilst low to moderate dose regular ICS work in multi-trigger wheeze, the medication does not modify the natural history of the condition. Even if there is a successful trial of treatment with ICS, a break in treatment should be given to see if the symptoms have resolved or continuous therapy is still required. Maintenance as well as intermittent Montelukast has a role in both episodic and multi trigger wheeze. Good multidisciplinary support and education is essential in managing this common condition.

Danger of using an unreliable classification system for preschool wheeze

To the Editors: The management of preschool children with wheezing disorders remains challenging. Clinicians should, therefore, welcome the decision by the European Respiratory Society to establish a Task Force to address this problem. The Task Force recommends that the terms episodic (viral) wheeze and multi-trigger wheeze should be used to describe different clinical phenotypes of preschool wheeze 1. However, the report acknowledges that there is large …

Role of corticosteroids in preschool wheeze: going, going, but not gone

Inhaled and oral steroids are widely and benefi cially used in older children and adults, but their place in preschool and episodic (viral) wheeze is less clear. This paper reviews recommendations in the light of new clinical trials evidence. Inhaled corticosteroids do not prevent the progression from episodic wheeze to multitrigger wheeze and asthma later in childhood. They may be benefi cial to treat current symptoms in a small minority of atopic preschool children with multitrigger wheeze, especially those over 3 years old. Some in this group may benefi t from regular treatment; for the majority, there will be no benefi t. If a therapeutic trial is contemplated, then a three-stage protocol is advised, with a trial of discontinuing the medication. Oral steroids have been shown not to be useful for home or hospital treatment of episodic wheeze, but may be useful in very severe episodes needing high dependency care. There are safety issues with the use of steroids, including a possible effect on the developing alveoli. In summary, any form of steroid therapy should be used sparingly and on an individualized basis in preschool and episodic viral wheeze.

Nonatopic Children with Multitrigger Wheezing Have Airway Pathology Comparable to Atopic Asthma

Epidemiologic studies have shown that, in atopic children, wheezing is more likely to persist into adulthood, eventually becoming asthma, whereas it appears to resolve by adolescence in nonatopic children. To investigate whether among children with multitrigger wheeze responsive to bronchodilators the airway pathology would be different in nonatopic wheezers, who are often considered nonasthmatic, compared with atopic wheezers, who are more frequently diagnosed as having asthma. Bronchial biopsies were obtained from 55 children undergoing bronchoscopy for appropriate clinical indications: 18 nonatopic children with multitrigger wheeze (median age, 5 yr; range, 2-10 yr), 20 atopic children with multitrigger wheeze (medan age, 5 yr; range, 2-15 yr), and 17 control children with no atopy or wheeze (median age, 4; range, 2-14 yr). By histochemistry and immunohistochemistry, we quantified epithelial loss, basement membrane thickness, angiogenesis, inflammatory cells, IL-4(+,) and IL-5(+) cells in subepithelium. Unexpectedly, all pathologic features examined were similar in atopic and nonatopic wheezing children. Compared with control subjects, both nonatopic and atopic wheezing children had increased epithelial loss (P = 0.03 and P = 0.002, respectively), thickened basement membrane (both P < 0.0001), and increased number of vessels (P = 0.003 and P = 0.03, respectively) and eosinophils (P < 0.0001 and P = 0.002, respectively). Moreover, they had increased cytokine expression, which was highly significant for IL-4 (P = 0.002 and P = 0.0001, respectively) and marginal for IL-5 (P = 0.02 and P = 0.08, respectively). This study shows that the airway pathology typical of asthma is present in nonatopic wheezing children just as in atopic wheezing children. These results suggest that, when multitrigger wheezing responsive to bronchodilators is present, it is associated with pathologic features of asthma even in nonatopic children.

Two main subtypes of wheezing illness? Evidence from the 2004 Aberdeen schools asthma survey

To compare risk factors for wheezy bronchitis (WB) and multi-trigger wheeze (MTW) in pre-pubertal children along the spectrum of disease severity. Cross-sectional survey of children aged 7-12 yr in Aberdeen city primary schools in 2004 using parent-completed questionnaires as used in surveys in 1964, 1989, 1994, and 1999. Children were grouped into five categories: no wheeze in the past three years, non-severe wheeze triggered only by a cold (non-severe WB), non-severe wheeze triggered by other factors (non-severe MTW), severe WB, or severe MTW. Severe wheeze was defined as greater than four wheezing attacks, greater than or equal to one disturbed night per week, or speech limitation in the last 12 months. Questionnaires were returned by 3271 children (57.3%), of whom 7.4% had WB (6.1% non-severe and 1.3% severe) and 17.2% had MTW (9.4% non-severe and 7.8% severe). Severe disease was more frequent in children with MTW (31.8%) than in those with WB (5.1%). Whereas the prevalence of MTW had increased since 1964, the prevalence of WB had remained stable over this period. After adjustment for confounders, age had no influence on either wheeze type, and male sex was only associated with non-severe WB [OR 1.44, 95% confidence intervals (1.03-2.02)]. In the WB group eczema or/and hay fever in the child were more strongly associated with severe wheeze [OR 3.28(1.49-7.23) vs. OR 1.84(1.31-2.60)]. In the MTW group, this association was noticeably higher than in the WB group, but did not differ much between non-severe and severe wheeze [OR 5.46(3.70-7.20) and OR 6.01(4.1-8.75) respectively]. The presence of any allergic diseases in either parent increased the odds for non-severe and severe MTW at the same level of magnitude [OR 1.92(1.38-2.68) and OR 1.92(1.34-2.76) respectively], and statistically non-significantly for severe WB [OR 1.75(0.78-3.94)]. Living in a deprived area increased both severe WB and severe MTW, reaching statistical significance only for severe MTW [OR 1.96(1.39-2.78)]. Smoking in the house was associated with increased risk of WB and MTW of any severity. WB and MTW differ in prevalence trends and severity. Within severity levels, the influence of age, allergic diseases in children and parents also differed between these two wheezing subtypes.

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.

A Comparison of Virus-Associated and Multi-Trigger Wheeze in School Children

To examine differences between virus-associated wheeze and wheeze associated with other triggers (multi-trigger wheeze) in elementary school children, we performed a cross-sectional school-based questionnaire study of 5,998 children mainly 7 to 12 years of age, with outliers 6 and 13 years of age. Using parent-completed questionnaires, we identified 522 children who wheezed only during upper respiratory tract infections (virus-associated wheeze), 1,186 children who wheezed on other occasions (multi-trigger wheeze), and 4,290 children with no wheeze. In comparison with children who had multi-trigger wheeze, children with virus-associated wheeze were more likely to be male, to be younger, and to have less frequent wheezy episodes. They were less likely to have night cough, shortness of breath or chest tightness, to have a personal or parental history of atopic disorders, to have a diagnosis of asthma, or to be receiving asthma treatment. Both types of wheeze were associated with social deprivation, a relationship that persisted after controlling for family smoking. Virus-associated wheeze is a common but diminishing problem in this age group, and the differences between virus-associated wheeze and multi-trigger wheeze already noted in pre-school children persist in this older age group.