Viral Wheeze Research Articles

Severe episodic viral wheeze in preschool children: High risk of asthma at age 5–10 years

In population studies, most children with episodic viral wheeze (EVW) become symptom free by 6 years. We studied the outcome of children with severe EVW, treated and followed up in hospital. We followed up 78 children <4 years, managed by paediatricians for severe EVW, to the age of 5–10 years. We recorded respiratory symptoms, spirometry and exhaled nitric oxide (FeNO). At follow-up, 42 children (54%) had current wheeze or dyspnoea, and 52 (67%) had current asthma. There was no significant difference between children with and without current asthma in FEV1 (p = 0.420), but FeNO was higher in children with current asthma (median (interquartile range) 14.5 (11.25–21.50) ppb) than in those without (12.0 (10.0–13.8) ppb, p = 0.020). Positive family history of asthma was the only factor associated with current asthma (odds ratio 8.77, 95% CI 2.88–26.69, p < 0.001). This remained significant after adjustment for duration of follow-up, gender and parental smoking. Conclusion. Severe EVW at preschool age has a high risk of asthma at age 5–10 years, and this is reinforced by a positive family history of asthma and to elevated FeNO levels.

Viral wheezing is virus specific and not just host specific

To the Editors: In a recent issue of the European Respiratory Journal , Strippoli et al. [1] reported their interesting findings on exclusive viral wheezing versus allergic wheezing in a large population-based, prospectively followed cohort including 4,102 children at 1 yr and 1,858 children at 9 yrs of age. The parents reported current wheezing in 36, 20, 16 and 16% of the children at age 1, 4, 6 and 9 yrs, respectively. The study showed considerable age-related, parent-reported changes in the relative importance of triggers for wheezing in children. The proportion of infection decreased constantly from 94.1% (at age 1 yr) to 81.0% (at age 9 yrs) and the proportion of allergic wheeze increased constantly from 7.5% (at age 1 yr) to 62.4% (at age 9 yrs). The proportion of exercise as a trigger for wheezing was rather similar at all ages, …

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...

Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life

Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood. To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing. A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model. Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50-1.1). Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.

Ciclesonide in wheezy preschool children with a positive asthma predictive index or atopy

Few large-scale studies have examined inhaled corticosteroid treatment in preschool children with recurrent wheeze. We assessed the effects of ciclesonide in preschool children with recurrent wheeze. We included children 2-6 yrs with recurrent wheeze and a positive asthma predictive index or aeroallergen sensitization to, excluding patients with episodic viral wheezing. After a 2-4-week baseline period, patients with ongoing symptoms or rescue medication use were randomised to once-daily ciclesonide 40, 80, 160 μg or placebo for 24 weeks. The number of wheeze exacerbations requiring systemic corticosteroids was unexpectedly low in all groups: 25 (10.2%) in placebo group, as compared to 11 (4.4%), 18 (7.3%), and 17 (6.7%) in ciclesonide 40, 80, and 160 μg, respectively. The difference in time to first exacerbation was not significantly different between groups (p = 0.786), but the difference in exacerbation rates between placebo and the pooled ciclesonide groups was (p = 0.03). Large and significant (p < 0.0001) improvements in symptom scores and rescue medication use occurred in all groups, including placebo. Improvements in FEV(1) and FEF(25-75) (measured in 284 4-6 yr olds) were larger in the ciclesonide than in the placebo group. No differences in safety parameters (adverse events, height growth, serum and urinary cortisol levels) between ciclesonide and placebo were observed. In preschool children with recurrent wheeze and a positive asthma predictive index, ciclesonide modestly reduces wheeze exacerbation rates and improves lung function. A large placebo response and unexpected selection of patients with mild disease may have affected outcomes, highlighting the heterogeneity of preschool wheezing disorders.

Exclusive viral wheeze and allergic wheeze: evidence for discrete phenotypes

To the Editors: There is a broad consensus that childhood wheezing illness consists of several distinct disease entities, but there is no agreement on their number or underlying mechanisms [1]. Commonly used phenotypic classifications are based on clinical or epidemiological criteria [2–6], and there has been little work focusing on causal mechanisms [1, 6, 7]. Trigger factors for wheezing episodes might be indicators of such mechanisms. In young children, wheeze is commonly triggered by respiratory viral infections (colds), physical factors associated with increased breathing (exercise, laughing, crying and excitement) or allergens (aeroallergens and food allergens). These triggers are increasingly used to define asthma phenotypes in young children [3, 5]. Despite this, there are few data on the way in which these triggers change in importance with age or whether different classes of triggers are independent. A close association between different classes of triggers in the same children would suggest a common underlying mechanism while a lack of association might reflect independent causal mechanisms. In this analysis, we describe changes in the prevalence of different parent-reported triggers of wheeze by age in 1–9 yr olds and report statistical associations between different classes of triggers (exercise, allergens and infection). We used data from the …

Prenatal paracetamol exposure and risk of wheeze at preschool age*

To analyse the association between prenatal paracetamol exposure and preschool wheeze. Data were obtained from a prospective, longitudinal study of a cohort of children born in the region of western Sweden in 2003; 8176 families were randomly selected. The parents answered questionnaires at 6 and 12 months and at 4.5 years of age. The response rate was 55%, i.e. 4496 of the 5398 questionnaires distributed at 4.5 years (83%). Inhaled corticosteroid (ICS) treated wheeze during the last year was regarded as a proxy for doctor-diagnosed asthma. Episodic viral wheeze was defined as wheezing only with viral infections and multiple-trigger wheeze as wheezing also in between infections. In the multivariate analysis, the risk of ICS-treated wheeze was increased by paracetamol (OR 1.6; 95% CI 1.01-2.6). Within the ICS-treated group, the effect was significant for multiple-trigger wheeze (OR 2.4; 1.2-4.8) but not for episodic viral wheeze (OR 1.1; 0.5-2.3). Prenatal paracetamol exposure was an independent risk factor for ICS-treated wheeze at preschool age, especially among children with ICS-treated multiple-trigger wheeze. Although the analysis adjusted for e.g. maternal asthma and antibiotic use, the possibility of residual confounding by maternal indication (respiratory illness) should be acknowledged.

Advancement of wheezing disorders in preschool children

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The latest study found that frequent wheezing was associated with humid living environment, nutritional status (including vitamin D intake during pregnancy and serum vitamin A levels) and gene cellular level. Based on the limited evidence available, inhaled short-acting β2-agonists are recommended for symptomatic relief. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze. Montelukast is recommended for the treatment of episodic (viral) wheeze. Key words: Infant wheezing; Related factors; Phenotype; Treatment

Do migrant studies help to identify causes of asthma?

Do migrant studies help to identify causes of asthma?

Episodic Viral Wheeze and Multiple Trigger Wheeze in preschool children: A useful distinction for clinicians?

Accumulating evidence suggest that splitting preschool recurrent wheezing disorders into Episodic (Viral) Wheeze (EVW) and Multiple Trigger Wheeze (MTW) is an oversimplification. There is little evidence that the EVW and MTW phenotypes are related to the longitudinal patterns of wheeze, or to different underlying pathological processes. As the clinical response to inhaled corticosteroids and montelukast varies considerably between individual children with EVW, and between individual patients with MTW, the clinical usefulness of the EVW-MTW approach is doubtful. Based on the currently available evidence, we propose to describe preschool wheeze symptoms not only in terms of temporal pattern, but also in terms of frequency and severity, and age of onset. Relevant associated clinical parameters like atopy and eczema should be described with recognition of age of onset, pattern, and severity. Comparing these data to biomarkers and histopathology may help to improve our understanding of preschool wheezing disorders in the future. Until phenotypes can be described that are associated with different pathobiological process, are related to different longitudinal outcomes, or are clearly different in terms of response to therapy, clinicians are encouraged to take a trial and error approach of different therapeutic agents in preschool children with troublesome recurrent wheeze.

Allergic sensitization is associated with rhinovirus-, but not other virus-, induced wheezing in children

Jartti T, Kuusipalo H, Vuorinen T, Söderlund‐Venermo M, Allander T, Waris M, Hartiala J, Ruuskanen O. Allergic sensitization is associated with rhinovirus‐, but not other virus‐, induced wheezing in children. Pediatr Allergy Immunol 2010: 21: 1008–1014. © 2010 John Wiley & Sons A/S Background: Data on the link between atopy and viral wheeze are limited. Aim: To evaluate the association between IgE sensitization and viral infection in wheezing children. Methods: This is an observational study in hospitalized wheezing children (n = 247; median age 1.6 ; interquartile range 1.1, 2.9). Eighteen respiratory viral infections were studied using all available methods. A specific immunoglobulin E (IgE) sensitization for common food and aeroallergens and other atopy‐related variables including total IgE, blood and nasal eosinophils, exhaled nitric oxide, eczema and atopic eczema, parental allergy and asthma, number of wheezing episodes, positive asthma predictive index or asthma and use of inhaled corticosteroid were correlated with specific viral etiology. Results: Atopy was closely associated with sole rhinovirus etiology (n = 58) but not with sole respiratory syncytial virus, sole enterovirus, sole human bocavirus, sole other virus, mixed viral, or virus negative etiology. The number of sensitizations was particularly associated with sole rhinovirus etiology (odds ratio 4.59; 95% confidence interval 1.78, 11.8; adjusted to age and sex), followed by aeroallergen sensitization (respectively; 4.18; 2.00, 8.72), total IgE level (2.06; 1.32, 3.21), food allergen sensitization (2.02; 1.08, 3.78), and nasal eosinophil count (1.52; 1.08, 2.13). Conclusions: According to our data, allergic sensitization is positively linked to rhinovirus‐, but not other virus‐, associated wheezing and calls attention for studies to test rhinovirus‐associated wheezing as a part of asthma risk indices.

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.

Inhaled corticosteroids in childhood asthma: the story continues.

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic–pituitary–adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses.

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.

Paediatric asthma: everything that seemed to be certain no longer is

'Paediatric asthma: everything that seemed to be certain no longer is', holds the promise of leaving you with more questions than answers at the end of this review of paediatric asthma 2008-2009. This has often been true for asthma research, in particular over the past few years. Research with direct consequences for a clinician managing children with wheezing or asthma is discussed such as limitations in the characterisation of asthma phenotypes and the influence of early viral infections on asthma and the development of atopic sensitisation. It appears that wheezing in preschool children with specific viral pathogens confers differential rates of asthma risk. Viruses and day-care shift respiratory morbidity to an early age when it is more troublesome than at a later age but are not protective for sensitisation or asthma. What needs to be further explored is the relationship between viruses and recurrent wheeze or asthma in studies with stringently defined phenotypes including personal atopic status, timing of infection, and severity of infection. A modification of preschool wheeze phenotypes or replacement by other phenotypes that have been defined with the application of different methods is needed. Oral corticosteroids should not be prescribed in preschool children with acute mild to moderate viral wheeze, unless a severe outcome is anticipated or if the child has a classic atopic phenotype. Despite initial high expectations, FeNO was proven not to be beneficial for routine monitoring of asthma treatment.

Properdin in childhood and its association with wheezing and atopy

Properdin, a serum glycoprotein, is an important component of innate immunity, the only known positive regulator of complement, acting as an initiation point for alternative pathway activation. As an X-linked protein, we hypothesized that properdin may play a modulatory role in the pathogenesis of viral wheeze in children, which tends to be more common and more severe in boys. We aimed to determine properdin levels in a community-based paediatric sample, and to assess whether levels of properdin were associated with childhood wheeze phenotypes and atopy. We studied 137 school-children aged 8-12 yrs, a nested sample from a cohort study. Properdin was measured by a commercial enzyme-linked immunoabsorbant assay. We assessed wheeze by questionnaire, validated it by a nurse-led interview and performed skin prick tests and a methacholine challenge in all children. Forty children (29%) reported current wheeze. Serum properdin levels ranged between 18 and 40 microg/ml. Properdin was not associated with age, gender, atopy, bronchial responsiveness, current wheeze (neither the viral wheeze nor multiple-trigger wheeze phenotype) or severity of wheeze, but was slightly lower in south Asian (median 21.8 microg/ml) compared with white children (23.3 microg/ml; p = 0.006). Our data make it unlikely that properdin deficiency is common in healthy children or that levels of properdin are a major risk factor for wheeze or atopy.

The problem of preschool wheeze: new developments, new questions

Preschool wheeze is a common and often difficult to treat symptom. It may rarely be the first presentation of a severe underlying condition. Preschool wheeze is clearly a syndrome, not a single entity, and thus ripe for phenotyping. A number of approaches to phenotyping have been adopted. Epidemiology, based on the temporal patterns of symptoms, has taught us a lot about the medium and long-term implications of early life events, but is not useful for treatment planning. Atopic status is also not useful. Instead, symptom pattern (episodic (viral) and multiple trigger) should be used to decide on treatment. Reduced lung function at birth is associated with a number of maternal factors, including smoking (both by direct and epigenetic mechanisms), atopic status, and pregnancy complications; these children tend to have transient wheeze. Children whose symptoms persist into mid-childhood are born with normal lung function, but have evidence of airflow obstruction at 4–6 years of age. Early atopic sensitization is important in this group. Treatment of pre-school wheeze should be based on relief of present symptoms; there is no known therapy which prevents progression from episodic to multiple trigger symptoms and asthma. Episodic (viral) wheeze is a neutrophilic disease and should be treated with intermittent therapy. Options include inhaled anticholinergics or short-acting β-2 agonists, oral leukotriene receptor antagonists and short-course, high-dose inhaled corticosteroids. Prophylactic inhaled corticosteroids are not useful. Neither prophylactic nor inhaled corticosteroids are effective in preventing progression from an episodic viral to a multiple-trigger pattern. Multipletrigger wheeze may merit a three-step trial (trial period, stop if apparent response, restart only if symptoms return) of prophylactic inhaled corticosteroids or leukotriene receptor antagonists. Recent data have shown that prednisolone should not be a routine treatment for acute exacerbations of episodic (viral) wheeze, but should only be used for really severe excacerbations, defined as being more severe than a routine admission and likely needing high dependency care. This is especially true in the setting of multiple trigger wheeze. Keywords: asthma, inhaled corticosteroid, leukotriene, neutrophil, prednisolone

Phenotypic Differences between Pediatric and Adult Asthma

The goal of asthma phenotyping is to understand disease mechanisms or optimize management. Phenotypes show age-related variation. The phenotypes of wheezing in the first year of life are little studied; many remit in the second year of life, and the children who remit do not have later-onset wheeze, as far as is known. Preschool wheeze is optimally phenotyped by symptom pattern, defined as either episodic viral or multiple-trigger wheeze, which allows rational treatment planning. In school age and adult life, most patients with mild asthma can be managed adequately without phenotyping, but severe asthma clearly falls into several phenotypic groups. Children with severe asthma have no gender bias and are highly atopic with relatively well-preserved lung function, in contrast to the female-preponderant, non-atopic bias seen in adults. Phenotyping has been mainly by proximal luminal cellularity. However, this does not take account of any variation of cellularity over time, distal airway changes, or the relative contribution of mucosal and luminal inflammatory changes. There may be a separate exacerbating phenotype, characterized by airway eosinophilia. Particular adult phenotypes include late-onset asthma and a phenotype characterized by progressive loss of lung function, but critical review suggests that these phenotypes may also have childhood roots. Longitudinal data are needed to determine the stability of phenotypes and their prognoses. Retrospective recall of childhood events is of limited value. In conclusion, a full understanding the multifaceted phenotypes of asthma requires a thorough knowledge of early life events and their consequences over many decades.

The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze

A recently proposed method for classifying preschool wheeze is to describe it as either episodic (viral) wheeze or multiple trigger wheeze. In research studies, phenotype is generally determined by retrospective questionnaire. To determine whether recently proposed phenotypes of preschool wheeze are stable over time. In all, 132 two to six-year-old children with doctor diagnosed asthma on maintenance inhaled corticosteroids were classified as having episodic (viral) wheeze or multiple trigger wheeze at a screening visit and then followed up at three-monthly intervals for a year. At each follow-up visit, standardized questionnaires were used to determine whether the subjects wheezed only with, or also in the absence of colds. Stability of the phenotypes was assessed at the end of the study. Phenotype as determined by retrospective parental report at the start of the study was not predictive of phenotype during the study year. Phenotypic classification remained the same in 45.9% of children and altered in 54.1% of children. When children with preschool wheeze are classified into episodic (viral) wheeze or multiple trigger wheeze based on retrospective questionnaire, the classification is likely to change significantly within a 1-year period.

Wheezing Rhinovirus Illnesses in Early Life Predict Asthma Development in High-Risk Children

Jackson DJ, Gangnon RE, Evans MD, et al. Am J Respir Crit Care Med. 2008;178(7):667–672 PURPOSE OF THE STUDY. Childhood asthma is often preceded by episodes of viral wheezing. Whether specific viral infections confer more risk for future development of asthma is incompletely understood. Associations between the timing and cause of early viral infections and the subsequent risk of childhood asthma were assessed in a cohort of children at high risk. STUDY POPULATION. A total of 259 children were …