Episodic Viral Wheeze Research Articles

Blood eosinophils in managing preschool wheeze: Lessons learnt from a proof-of-concept trial.

Management of preschool wheeze is based predominantly on symptom patterns. To determine whether personalizing therapy using blood eosinophils or airway bacterial infection results in fewer attacks compared with standard care. A proof-of-concept, randomized trial to investigate whether the prescription of inhaled corticosteroids (ICS) guided by blood eosinophils, or targeted antibiotics for airway bacterial infection, results in fewer unscheduled healthcare visits (UHCVs) compared with standard care. Children aged 1-5years with ≥2 wheeze attacks in the previous year were categorized as episodic viral wheeze (EVW) or multiple trigger wheeze (MTW). The intervention group was prescribed ICS if blood eosinophils ≥3%, or targeted antibiotics if there is positive culture on induced sputum/cough swab. The control group received standard care. The primary outcome was UHCV at 4months. 60 children, with a median age of 36.5 (range 14-61) months, were randomized. Median blood eosinophils were 5.2 (range 0-21)%, 27 of 60 (45%) children were atopic, and 8 of 60 (13%) had airway bacterial infection. There was no relationship between EVW, MTW and either blood eosinophils, atopic status or infection. 67% in each group were prescribed ICS. 15 of 30 control subjects and 16 of 30 patients in the intervention group had UHCV over 4months (p=.8). The time to first UHCV was similar. 50% returned adherence monitors; in those, median ICS adherence was 67%. There were no differences in any parameter between those who did and did not have an UHCV. Clinical phenotype was unrelated to allergen sensitization or blood eosinophils. ICS treatment determined by blood eosinophils did not impact UHCV, but ICS adherence was poor.

Intravenous magnesium sulphate in children with acute wheeze: a nationwide survey

Objective Dutch guidelines recommend to consider intravenous magnesium sulfate (iv MgSO4) as a treatment option in case of failure of first line treatment in both children with exacerbations of acute episodic viral wheeze (AEVW) and acute asthma (AA). The implications on the actual use of iv MgSO4 iv in daily practice in both groups are unknown. Therefore, we conducted a cross-sectional nationwide survey to evaluate the use of iv MgSO4 in children with AEVW and AA. Methods A questionnaire was handed out to pediatricians and pediatric residents in one academic and six community teaching hospitals. Results In 111 respondents, 76% reported regular use of iv MgSO4 in children with AEVW and 96% in children with AA. In total 89% and 93% of users were convinced iv MgSO4 was effective in children with AEVW and AA, respectively. Adverse effects, mainly hypotension, were identified by 23% and 17% of users in AEVW and AA, respectively. Most common reasons not to give MgSO4 were lack of evidence and small amount of studies. Conclusions IV MgSO4 is reported to be widely used in Dutch practice in both young children with AEVW and older children with AA by respondents, while the national guidelines advise only to consider this treatment option.

Electronic adherence monitoring identifies severe preschool wheezers who are steroid responsive.

Little is known about adherence to inhaled corticosteroids (ICS) in preschool children with troublesome wheeze. Children with aeroallergen senitization, or those reporting multiple trigger wheeze (MTW), are more likely to respond to ICS. We hypothesized that adherence to ICS and symptom control are only positively related in atopic children, or those reporting MTW. Patients aged 1 to 5 years with recurrent wheeze prescribed ICS were recruited from a tertiary respiratory clinic. Clinical phenotype and aeroallergen senitization were determined, and adherence assessed using an electronic monitoring device (Smartinhaler). Symptom control (test for respiratory and asthma control in kids [TRACK]), quality of life (PACQLQ), airway inflammation (offline exhaled nitric oxide) were assessed at baseline and follow-up. Forty-eight children (mean age 3.7 years; SD, 1.2) were monitored for a median of 112 (interquartile range [IQR], 91-126) days. At baseline n = 29 reported episodic viral wheeze and n = 19 reported MTW. Twenty-four out of 48 (50%) wheezers had suboptimal ICS adherence (<80%). Median adherence was 64% (IQR, 38-84). There was a significant increase in TRACK and PACQLQ in the group as a whole, unrelated to adherence. In subgroup analysis only atopic wheezers with moderate or good adherence ≥ 60% had a significant increase in TRACK. There was no relationship between clinical phenotype, and adherence or TRACK. In this pilot study, overall adherence to ICS was suboptimal and was positively related to symptom control in atopic wheezers only. Assessments of adherence are important in preschool troublesome wheezers before therapy escalation to help identify those with an ICS responsive phenotype.

Severe preschool asthmatics have altered cytokine and anti-viral responses during exacerbation.

Preschool asthma/recurrent wheeze is a heterogeneous condition. Different clinical phenotypes have been described, including episodic viral wheeze (EVW), severe intermittent wheeze (SIW), and multiple-trigger wheeze (MTW). To compare clinical, viral, and inflammatory/immune profiling at exacerbation between MTW, SIW, and EVW phenotypes. Multicenter, prospective, observational cohort (VIRASTHMA-2). Children (1-5years) with preschool asthma were enrolled during hospitalization for a severe exacerbation. History and anamnestic data, plasma, and nasal samples were collected at exacerbation (T1) and at steady state, 8weeks later (T2), and sputum samples were collected at T1. A total of 147 children were enrolled, 37 (25%) had SIW, 18 (12.2%) EVW, and 92 (63%) MTW. They were atopic (47%), exposed to mold (22%) and cigarette smoke (50%), and prone to exacerbations (≥2 in the previous year in 70%). At exacerbation, at least one virus was isolated in 94% and rhinovirus in 75%, with no difference between phenotypes. Children with MTW and SIW phenotypes displayed lower plasma concentrations of IFN-γ (P=.002), IL-5 (P=.020), TNF-α (P=.038), IL-10 (P=.002), IFN-β (P=.036), and CXCL10 (P=.006) and lower levels of IFN-γ (P=.047) in sputum at exacerbation than children with EVW. At T2, they also displayed lower plasma levels of IFN-γ (P=.045) and CXCL10 (P=.013). Among preschool asthmatic children, MTW and SIW, prone to exacerbations, display lower systemic levels of Th1, Th2 cytokines, pro- and anti-inflammatory cytokines, and antiviral responses during severe virus-induced exacerbation.

Clinical Profile of Episodic Wheezing and Multiple Trigger Wheezing in Preschool Children: A Cross-Sectional Study

AbstractThe objectives of our study were to identify the relative frequency of episodic viral wheeze (EVW) and multiple trigger wheeze (MTW) in preschool children of 1 to 5 years of age with recurrent wheezing and to compare the relevant clinical and sociodemographic parameters in the above phenotypes. This cross-sectional study included 165 children aged 1 to 5 years with recurrent wheeze. Participants were categorized into EVW and MTW based on history according to European Respiratory Society Task Force recommendations 2008. Symptom control was assessed by Global Initiative for Asthma guidelines 2015. Of the total participants, EVW was seen in 55% and MTW in 45%. Children with MTW were significantly older than those with EVW, more atopic, and had higher eosinophil counts. The dominant phenotype seen in our study was EVW. The absence of ocular/nasal allergy and exclusive breastfeeding predicted well-controlled symptoms in EVW and in all preschool wheezers, respectively.

Is it time to move on from episodic viral wheeze and multiple trigger wheeze?

Is it time to move on from episodic viral wheeze and multiple trigger wheeze?

Episodic viral wheeze and multiple-trigger wheeze in preschool children are neither distinct nor constant patterns. A prospective multicenter cohort study in secondary care.

To evaluate whether episodic viral wheeze (EVW) and multiple-trigger wheeze (MTW) are clinically distinguishable and stable preschool wheezing phenotypes. Children of age 1 to 4 year with recurrent, pediatrician-confirmed wheeze were recruited from secondary care; 189 were included. Respiratory and viral upper respiratory tract infection (URTI) symptoms were recorded weekly by parents in an electronic diary during 12 months. Every 3 months, diary-based symptoms were classified as EVW or MTW and compared to phenotypes assigned by pediatricians based on clinical history. We collected nasal samples for respiratory virus PCR during URTI, respiratory symptoms and in absence of symptoms. Of 660 3-month periods, the diary-based phenotype was EVW in 11%, MTW in 54% and 35% were free from respiratory episodes. Pediatrician-based classification showed 59% EVW and 26% MTW. The Kappa measure of agreement between diary-based and pediatrician-assigned phenotypes was very low (0.12, 95%CI, 0.07-0.17). Phenotypic instability was observed in 32% of cases. PCR was positive in 71% during URTI symptoms, 66% during respiratory symptoms and 38% in the absence of symptoms. This study shows that EVW and MTW are variable over time within patients. Pediatrician classification of these phenotypes based on clinical history does not correspond to prospectively recorded symptom patterns. The applicability of these phenotypes as a basis for therapeutic decisions and prognosis should be questioned.

‘We can’t diagnose asthma until ’

The use of low-dose inhaled corticosteroids (ICS) to treat children with asthma can be life-transforming, and this is confirmed repeatedly when they are made widely available for the first time...

Strategies for treatment of pre-schoolers with episodic viral wheeze.

Strategies for treatment of pre-schoolers with episodic viral wheeze.

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.

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.

Age-related changes in childhood wheezing characteristics: A whole population study.

Wheezing illnesses are characterized by phenotypic variability, which changes with age, but few studies report on a wide age range of children. We studied how prevalence, severity, and triggers of wheeze vary throughout childhood. We analyzed data from a large population-based cohort of children from Leicestershire, UK, who were followed from infancy through late adolescence using postal questionnaires. We used generalized estimating equations to describe age-related changes in prevalence of any wheeze: episodic viral and multiple trigger wheeze; wheeze triggered by exercise, aeroallergens, food/drinks, laughing/crying; and of severe wheeze (frequent attacks, shortness of breath, sleep disturbance, disturbance of daily activities) from age 1-18 years. We analyzed this in the entire cohort (absolute prevalence) and separately among children with wheeze (relative prevalence). This study included 7670 children. Current wheeze was most common in 1-year-olds (36%) and then decreased in prevalence to reach 17% in children aged 14-17 years. Absolute prevalence of episodic viral wheeze (EVW) decreased with age (from 24% to 7%), while multiple trigger wheeze (MTW) remained relatively constant throughout childhood (8-12%). Among children with wheeze, the proportion with EVW decreased, and the proportion with MTW increased with age. In older children, wheeze triggered by exercise or aeroallergens, and wheeze accompanied by shortness of breath became more frequent, while wheeze triggered by food or laughter, and sleep disturbance decreased in prevalence. Knowledge of these age-related changes in wheezing illness is informative for health care planning and the design of future research projects and questionnaires.

Stability and predictiveness of multiple trigger and episodic viral wheeze in preschoolers.

In 2008, the European Respiratory Society Task Force proposed the terms multiple-trigger wheeze (MTW) and episodic (viral) wheeze (EVW) for children with wheezing episodes. We determined MTW and EVW prevalence, their 24-month stability and predictiveness for asthma. In total, 565 preschoolers (1-, 2- and 3-year-olds) in primary care with respiratory symptoms were followed until the age of 6years when asthma was diagnosed. MTW status and EVW status were determined using questionnaire data collected at baseline and after one and 2years. We distinguished 3 phenotypes and determined their 24-month stability, also accounting for treatment with inhaled corticosteroids (ICS). Logistic regression was used to analyse the phenotypes' associations with asthma. Two hundred and eighty-one children had complete information. MTW and EVW were stable in 10 of 281 (3.6%) and 24 of 281 (8.5%), respectively. The odds of developing asthma for children with stable MTW and stable EVW were 14.4 (1.7-119) and 3.6 (1.2-11.3) times greater than those for children free of wheeze (for at least 1year). ICS was associated with increased stability of MTW and EVW. Stable multiple-trigger and stable episodic viral wheeze are relatively uncommon. However, 1- to 3-year-olds with stable MTW are at much increased risk of asthma.

Leukotriene receptor antagonists as maintenance or intermittent treatment in pre-school children with episodic viral wheeze

Malcolm Brodlie *, Atul Gupta , Carlos E. Rodriguez-Martinez , Jose A. Castro-Rodriguez , Francine M. Ducharme , Michael C. McKean 2 1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 2 Paediatric Respiratory Medicine, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 3 Paediatric Respiratory Medicine, King’s College Hospital, London, UK Department of Pediatrics, School of Medicine, Universidad Nacional de Colombia, Bogota, Colombia Research Unit, Military Hospital of Colombia, Bogota, Colombia Departments of Paediatric and Family Medicine, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile Department of Paediatrics, University of Montreal, Montreal, Canada Research Centre, CHU Sainte-Justine, Montreal, Canada

Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children.

Episodic viral wheeze (EVW) associated with viral respiratory tract infections is a common reason for pre-school children to utilise health care resources and for carers to take time away from employment. About a third of children experience a wheezing episode before the age of five years. EVW therefore represents a significant public health problem. Many pre-school children only wheeze in association with viral infections and in such cases EVW appears to be a separate entity from atopic asthma. Some trials have explored the effectiveness of leukotriene receptor antagonists (LTRAs) as regular (maintenance) or episodic (intermittent) treatment in this context. To evaluate the evidence for the efficacy and safety of maintenance and intermittent LTRAs in the management of EVW in children aged one to six years. We searched the Cochrane Airways Group register of trials with pre-specified terms. We performed additional searches by consulting the authors of identified trials, online trial registries of manufacturers' web sites, and reference lists of identified primary papers and reviews. Search results are current to June 2015. We included randomised controlled trials with a parallel-group or cross-over (for intermittent LTRA only) design. Maintenance was considered as treatment for more than two months and intermittent as less than 14 days. EVW was defined as a history of at least one previous episode of wheezing in association with a viral respiratory tract infection in the absence of symptoms between episodes. As far as possible, relevant specific data were obtained from authors of studies that included children of a wider age group or phenotype. Two authors independently assessed studies for inclusion in the review and assessed risk of bias. The primary outcome was number of children with one or more viral-induced episodes requiring one or more treatments with rescue oral corticosteroids. We analysed combined continuous data outcomes with the mean difference and dichotomous data outcomes with an odds ratio (OR). We identified five studies eligible for inclusion in the review (one investigated maintenance treatment, three intermittent therapy and one had both maintenance and intermittent treatment arms) these included 3741 participants. Each study involved oral montelukast and was of good methodological quality, but differed in choice of outcome measures thus limiting our ability to aggregate data across studies. Only primary outcome and adverse event data are reported in this abstract.For maintenance treatment, specific data obtained from a single study, pertaining to children with only an EVW phenotype, showed no statistically significant group reduction in the number of episodes requiring rescue oral corticosteroids associated with daily montelukast versus placebo (OR 1.20, 95% CI 0.70 to 2.06, moderate quality evidence).For intermittent LTRA, pooled data showed no statistically significant reduction in the number of episodes requiring rescue oral steroids in children treated with LTRA versus placebo (OR 0.77, 95% CI 0.48 to 1.25, moderate quality evidence). Specific data for children with an EVW phenotype obtained from a single study of intermittent montelukast treatment showed a small, but statistically significant reduction in unscheduled medical attendances due to wheeze (RR 0.83, 95% CI 0.71 to 0.98).For maintenance compared to intermittent LTRA treatment no data relating to the primary outcome of the review were identified.There were no other significant group differences identified in other secondary efficacy outcomes for maintenance or intermittent LTRA treatment versus placebo, or maintenance versus intermittent LTRA treatment. We collected descriptive data on adverse events as reported by four of the five included studies, and rates were similar between treatment and placebo groups.Potential heterogeneity in the phenotype of participants within and across trials is a limitation of the evidence. In pre-school children with EVW, there is no evidence of benefit associated with maintenance or intermittent LTRA treatment, compared to placebo, for reducing the number of children with one or more viral-induced episodes requiring rescue oral corticosteroids, and little evidence of significant clinical benefit for other secondary outcomes. Therefore until further data are available, LTRA should be used with caution in individual children. When used, we suggest a therapeutic trial is undertaken, during which efficacy should be carefully monitored. It is likely that children with an apparent EVW phenotype are not a homogeneous group and that subgroups may respond to LTRA treatment depending on the exact patho-physiological mechanisms involved.

Easing the wheeze.

Easing the wheeze.

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.

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.

Classification and pharmacological treatment of preschool wheezing: changes since 2008

Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. In this report, an international consensus group reviews this new evidence and proposes some modifications to the recommendations made in 2008. Specifically, the consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported. Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. Oral corticosteroids are not indicated in mild-to-moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients. Future research should focus on better clinical and genetic markers, as well as biomarkers, of disease severity.

The role of inhaled corticosteroids in management of asthma in infants and preschoolers

This review analyses published data on the treatment of wheezing in infants and preschoolers with inhaled corticosteroids (ICS), including the effect in subgroups of patients such as 'multiple trigger wheeze' and 'episodic viral wheeze'. Therapy with ICS at daily doses of 100-200 μg results in significant clinical improvements in several outcomes in preschoolers and infants suspected of having asthma (multiple trigger wheeze). Such treatment is normally considered well tolerated. Although not well studied, higher daily doses may be associated with measurable effects on growth, which are not cumulative with continued treatment. In children who only wheeze in association with viral infections (episodic viral wheeze), preemptive treatment with high doses of ICS has demonstrated significant clinical effects on several outcomes, whereas lower doses seem to have little effect. Intermittent use of high doses of ICS has been associated with significant reductions in height and weight gain over 1 year. The review illustrates the complexity of treating wheezing in infants and preschoolers and interpreting the study results. It emphasizes the need for more studies in clinical subgroups, more long-term studies and dose-response studies to assess the optimal doses and safety of intermittent as well as regular ICS treatment.