Virus-associated Wheeze Research Articles

Oral prednisolone in preschool children with virus-associated wheeze: a prospective, randomized, double-blind, placebo-controlled trial: Foster SJ, Cooper MN, Oosterhof S, Barland ML. Lancet Respir Med. 2018;6:97-106

Wheezing associated with viral upper respiratory illness is a common cause of emergency department presentation in preschool-aged children and is known to have different pathophysiology than asthma seen in older children and adults. It is therefore unclear whether systemic corticosteroids are of benefit in this population. Previous studies have had conflicting results on this point, and critics have argued that many were confounded by the inclusion of infants and toddlers with bronchiolitis.

Oral prednisolone in preschool children with virus-associated wheeze: a prospective, randomised, double-blind, placebo-controlled trial

Children of preschool age often have episodes of virus-associated wheeze, and research assessing efficacy of corticosteroids for paediatric wheeze exacerbations is inconclusive. This non-inferiority, randomised, double-blind, placebo-controlled trial was to compare the efficacy of placebo versus oral prednisolone in children aged 24-72 months presenting with virus-associated wheeze at the paediatric emergency department of Princess Margaret Hospital in Perth, WA, Australia. Eligible participants were randomly assigned (1:1) using a computer-generated random number program to receive placebo or prednisolone (1 mg/kg per day) for 3 days. The primary outcome was total length of stay in hospital until ready for discharge. Following an analysis to test the hypothesis that placebo is non-inferior to prednisolone, a post-hoc superiority analysis was done to test the hypothesis that prednisolone was superior to placebo. A non-inferiority margin of 10% was used to establish non-inferiority. Efficacy analyses were on a modified intention-to-treat basis, whereby patients were excluded from the final efficacy analysis if consent was withdrawn, two doses of study drug were vomited, or paperwork was lost. All participants were included in safety analyses. This study is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000394842. Between June 11, 2012, and June 10, 2015, we screened 3727 patients for eligibility. 624 eligible patients were randomly assigned to treatment, and 605 patients were included in the modified intention-to-treat analysis (300 patients from the placebo group, 305 patients from the prednisolone group). The median length of stay until ready for discharge was longer in the placebo group (540 min [IQR 124-971]) than in the prednisolone group (370 min [121-709]); placebo was inferior to prednisolone. In the post-hoc superiority analysis of 605 patients, the unadjusted ratio of geometric mean for length of stay was 0·79 (95% CI 0·64-0·97; p=0·0227) for the prednisolone group relative to the placebo group. No serious adverse events were reported during the study or follow-up period. One child in the placebo group had a non-specific maculopapular rash, which resolved spontaneously. Two children (one from each group) were reported to be hyperactive during follow-up assessments. Oral prednisolone had a clear benefit over placebo at reducing the length of stay in children presenting to a paediatric emergency department with virus-associated wheeze and was well tolerated. Western Australian Department of Health.

Oral corticosteroids reduce length of hospital stay for preschool children with virus-associated wheeze

Oral corticosteroids reduce length of hospital stay for preschool children with virus-associated wheeze

Trends in eczema, rhinitis, and rye grass sensitization in a longitudinal asthma cohort

BackgroundAtopic conditions are prevalent in the Western world, with limited long-term data on atopic trends in patients with asthma. ObjectiveTo describe the trends in eczema, rhinitis, and allergic sensitization in a longitudinal childhood asthma cohort. MethodsFour hundred eighty-four patients were recruited at 7 years of age and followed regularly to 50 years of age. Subjects completed an interviewer-administered questionnaire to define current eczema and rhinitis. Skin prick testing to rye grass also was performed. ResultsThe participation rate over the past 4 decades has been maintained at 72% to 91%. There was a decrease in the prevalence of eczema in the past 12 months in groups with viral-associated wheeze (21% to 8%, P = .002), asthma (47% to 18%, P < .001), and severe asthma (69% to 28%, P < .001) from 14 to 21 years of age. Conversely, there was an increase in the prevalence of rhinitis in the previous 12 months in groups without asthma (1% to 6%, P = .04; 1% to 20%, P = .008), with viral-associated wheeze (16% to 28%, P = .006; 16% to 49%, P < .001), and with asthma (45% to 56%, P = .2; 45% to 73%, P = .014) from recruitment to 10 and 14 years of age, respectively. There were 2 peaks in prevalence in the sensitization to rye grass in this cohort from 7 to 10 years of age and from 14 to 21 years of age in all groups. ConclusionThe adolescence phase appears to be an important period in the body's response to allergens whereby eczema decreases in prevalence, whereas rhinitis and rye grass sensitization increase in prevalence.

Should Preschool Wheezers Ever Be Treated with Inhaled Corticosteroids?

The syndrome of preschool wheeze commonly regresses completely in the preschool years, but it may lead to prolonged symptoms and established asthma. Although epidemiological studies have established that there are several different phenotypes, it is currently impossible to assign the majority of wheezing preschool children to a phenotype prospectively. Bronchoalveolar lavage studies have shown an increase in total cellular inflammation in the youngest, symptomatic children, and that in older preschool children the neutrophil is the predominant inflammatory cell in the airway. Endobronchial biopsy studies have shown that eosinophilic inflammation and structural airway wall changes are absent in symptomatic infants but appear in severe wheezers by the age of 3 years. Treatment guidelines are not evidence based in this age group and frequently do not appear to consider either the likely pathology or the different patterns of symptoms. Pure virus-associated symptoms may be treated with intermittent beta-2 agonist or anticholinergics by inhalation. If this fails, intermittent oral leukotriene receptor antagonists or short courses of very high dose inhaled corticosteroids could be considered. The role of oral corticosteroids is highly debatable in young children with virus-associated wheeze. Prophylactic therapy may be considered for chronic intermittent symptoms (interval symptoms between acute episodes). The choices are oral leukotriene receptor antagonists, or inhaled corticosteroids, which should be introduced in a three-stage protocol to avoid overtreating the child with evanescent symptoms. Because the natural history of preschool wheeze is one of improvement, treatment should be tapered after a period of stability. Unfortunately, neither corticosteroids nor any other currently available therapy modifies the long-term outcome of preschool wheeze. In conclusion, corticosteroid treatment may have a small role in preschool wheeze, in particular for those thought to have early asthma, but the uncritical application of recommendations that are appropriate for older children and adults with asthma has led to widespread overuse of these medications. There is an urgent need for better treatment of preschool wheeze.

Parent‐initiated oral corticosteroid therapy for intermittent wheezing illnesses in children: Systematic review

Intermittent wheezing illnesses, which include viral-associated wheeze and asthma, are among the most common reasons for children to present urgently to a doctor. The objectives of this systematic review were to assess the benefits and harmful effects of parent-initiated oral corticosteroids (PIOCS) in the management of intermittent wheezing illness in children. The Cochrane Airways Group Specialised Register, The Cochrane Controlled Trials Register (CENTRAL), MEDLINE, EMBASE, LILACS, Web of Science and Dissertation Abstracts were searched. Only randomised clinical trials studying patients aged between 1 and 18 years, with an intermittent wheezing illness were included. From 572 original citations, a total of two randomised clinical trials (303 randomised participants) were included. The quality of the included trials was high; however, marked clinical heterogeneity precluded a meta-analysis. The two trials did not find evidence that PIOCS are associated with a benefit in terms of hospital admissions, unscheduled medical reviews, symptoms scores, or bronchodilator use. Limited current evidence is available and it is inconclusive regarding the benefit from PIOCS therapy in the treatment of intermittent wheezing illnesses in children. Oral corticosteroids have a clearly defined role in the management of acute asthma in the hospital setting. Therefore, it is reasonable for clinicians to recommend PIOCS when (i) the child has a history of severe acute asthma; and (ii) the parents are able to assess asthma status. However, widespread use of PIOCS cannot be recommended until the benefits and harms can be clarified further.

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.

Exhaled Carbon Monoxide Levels in Children with Bronchial Asthma

Exhaled carbon monoxide (eCO) has been proposed as a potential marker of oxidative stress in the asthmatic airways. This study was conducted to investigate eCO levels in different asthma groups in children. Exhaled CO was measured electrochemically in 117 asthmatic and 45 non-asthmatic, non-atopic healthy children between the ages of 6 to 16 years. Exhaled CO levels in viral associated wheeze were similar to healthy controls. However, all symptomatic patients with either persistent or seasonal asthma had higher eCO values (mean ± SD) (2.05 ± 0.9 parts per million (ppm) and 2.30 ± 0.8 ppm) as compared to controls (0.94 ± 0.5 ppm, p < 0.001, p < 0.001, respectively), viral associated wheeze (1.19 ± 0.4 ppm, p < 0.001, p < 0.001, respectively), and symptom-free seasonal asthmatics (1.45 ± 0.6 ppm, p < 0.01, p < 0.001, respectively). In symptom-free seasonal asthmatics eCO levels that were measured at the specific pollen season, were higher than the controls (p < 0.001) and the viral associated wheeze (p < 0.01). However, all these groups were symptom-free and clinically stable, and there were no significant differences between the forced expiratory volume in one second values. In atopic persistent asthmatics eCO levels were 1.5-fold higher than non-atopic ones (p = 0.007, Mann-Whitney U). But there were only nine non-atopic persistent asthmatics, while atopics were 27. No correlation was found between forced expiratory volume in 1 sec and eCO values measured in all asthma groups regardless of inhaled corticosteroid therapy. In conclusion, the measurements of CO in exhaled air may be useful in the evaluation of children with asthma in clinical setting.

Invasive monitoring of airway inflammation.

What we know: Ethical concerns have limited research involving invasive bronchoscopy techniques in young children. No longitudinal studies have been conducted to compare the findings of bronchial biopsy or bronchoalveolar lavage in young children with transient episodic wheeze versus asthma. Children with atopic asthma have more airway eosinophils and mast cells than children with viral-associated wheeze. Both neutrophilic and eosinophilic patterns of inflammation are present in asthma. What we need to know: Can we establish robust normal values for tissue and fluid samples obtained at bronchoscopy or bronchoalveolar lavage? Do biopsy specimens taken at the carina tell us about the pathological processes occurring in asthma? Can we use invasive procedures to predict which children with wheeze will continue to wheeze and develop a classical asthma phenotype? Can we use invasive procedures to guide asthma therapy? Can we expect airway inflammation to resolve with anti-inflammatory medication? Can we correlate invasive with non-invasive measures of inflammation? Can we use our understanding of pro- and anti-inflammatory pathways to develop new therapeutic interventions? Is there a presymptomatic phase of inflammation?

Genetic/environmental determinants of adult chronic obstructive pulmonary disease and possible links with childhood wheezing.

Epidemiological evidence and similarities in underlying inflammatory mechanisms suggest that childhood respiratory conditions and adult onset chronic obstructive pulmonary disease (COPD) may have a common aetiology. The prevalence of COPD in the UK has been estimated to be 10% in males and 11% in females, and like asthma, is thought to have a polygenic contribution with a complex interplay between genetic and environmental factors. The only proven genetic factor so far identified in its pathogenesis is alpha1-antitrypsin deficiency, although this accounts for less than 1% of individuals with disease. Environmental exposures are significant but the observation that only 15% of smokers develop COPD and only some young children exposed in utero develop recurrent wheezing points to as yet undefined contributory genetic factors. The similarity in response to medication also suggests some features in common and a central question must be whether those adults who develop COPD had transient viral-associated wheeze (VAW) or non-specific bronchial hyperresponsiveness (BHR) in childhood? Similarities between some of the childhood wheezing syndromes and adult onset COPD invites a re-examination of possible links between the two conditions.

Early use of inhaled corticosteroids in infancy

The inability to accurately predict the outcome of infants with recurrent wheezy bronchitis makes the early use of inhaled corticosteroids (ICS) controversial. Data from bronchoalveolar lavages and epidemiological surveys suggest a persistent inflammation of the airways in the more severe cases. Prospective studies, mostly with nebulized corticosteroids, have demonstrated clinical efficacy on daytime and nightime symptoms, reduced requirements for rescue bronchodilators and a real steroid sparing effect. In infants with episodic viral-associated wheeze with or without interval symptoms, ICS use carries the risk of overtreatment and of adverse effects. Long-term prospective studies are urgently required to assess the efficacy and safety of ICS and their possible effects on the natural history of infantile asthma.

Clinical implications of inflammation in young children.

The definition of asthma has changed from that of a clinical disease (wheeze and/or cough in a setting where asthma is likely and other, rarer conditions have been excluded) (1) to a combination of clinical symptoms and pathology, usually describing airway inflammation (2). The concept of including inflammation in the definition has been questioned (3). In young children it is impractical to include inflammation as a requirement for the diagnosis. We know that a large part of the asthma phenotype in young adults at least is related to helper T type 2 (Th2) lymphocyteand eosinophil-mediated airway inflammation, but even in atopic adult asthma other important mechanisms may be involved (4, 5). These may include noneosinophilic inflammation (neutrophils or other cells, chemical mediators acting directly on the airway, neurogenic inflammation, plasma extravasation) and the effect of a possible reduction in baseline airway caliber, either for developmental reasons or secondary to acquired remodeling (6). In the context of other childhood wheezing illness, both bronchoscopic (7) and blind (8) lavage studies suggest that pure virus-associated wheeze is not an eosinophilic disease and is not even due to or associated with chronic airway inflammation. Other evidence suggests that the eosinophil may not always be the main cell involved in airway inflammation. The neutrophil is an important component of the late-phase response (9) and of endotoxin-induced asthma (10). Furthermore, a subgroup of patients with asthma without elevated sputum eosinophil levels and who were poorly responsive to corticosteroids has been described (11). Finally, there may be significant differences in the pathology of severe and mild to moderate asthma (12). We also know that the treatment with inhaled or oral corticosteroids of what is presumed to be airway inflammation in children reduces blood markers of T cell activation and cytokine levels (13) and reduces sputum eosinophilia (14) and nitric oxide (NO) levels (15). This suggests that antiinflammatory treatment reduces some forms of airway inflammation. There is a poor correlation between these markers when they are used to measure the response to antiinflammatory therapy (16). Uncontrolled trials in children (17) and controlled studies in adults (18) indicate that a delay in the initiation of inhaled corticosteroid therapy for the treatment of chronic asthma results in poorer long-term lung function. This suggests that untreated inflammation leads to secondary airway remodeling, which becomes irreversible. However, there are few data on the relationship between early inflammatory processes and structural changes in the airways of patients with asthma. We also know that corticosteroids are not disease modifying in chronic childhood asthma, at least when started at the conventional time. Even after 2 yr, the plateau for bronchial hyperreactivity is not reached and relapse occurs if treatment is stopped (19).

The role of inflammation in childhood asthma

The role of inflammation in adult asthma is well known, involving a cascade of immunological stimulation in which mast cells and eosinophils play pivotal roles. However, the assessment of airway...

Inflammatory mediators in bronchoalveolar lavage samples from children with and without asthma.

We investigated whether eosinophils and mast cells, found in the airways of children with wheeze, were activated during relatively asymptomatic periods. A nonbronchoscopic bronchoalveolar lavage (BAL) procedure was performed on children presenting for an elective surgical procedure. Eosinophil-derived (eosinophil cationic protein, ECP) and mast cell-derived (histamine/tryptase) mediator concentrations were measured in the BAL fluid. A detailed history and serum immunoglobulin E were used to classify the children into four groups: atopic with and without asthma, viral-associated wheeze and normal controls. The ECP concentrations in BAL from atopic asthmatic subjects were significantly higher than those measured in BAL from normal controls (P < 0.01), no other groups differed significantly. Histamine concentrations were elevated in both the atopic asthmatic and viral-associated wheeze groups compared with controls (P < 0.02) and additionally higher concentrations were obtained in atopics with asthma compared with atopics without asthma (P < 0.03). Tryptase concentrations did not differ between groups, although the tryptase and histamine concentrations correlated significantly (r = 0.78, P < 0.0001). Elevated histamine concentrations were found in children with wheeze regardless of the aetiology, whereas ECP was only elevated in those asthmatics with atopy. This suggests that even in relatively quiescent periods, there is some on going activation of airway eosinophils in children with atopic asthma.

Bronchoalveolar lavage findings suggest two different forms of childhood asthma.

It seems plausible that children with atopy and persistent asthma symptoms will, like their adult counterparts, have chronic airways inflammation. However, many young children with no other atopic features have episodic wheezing that is triggered solely by viral respiratory infections. Little is known as to whether airways inflammation occurs in these two asthma patterns during relatively asymptomatic periods. Using a non-bronchoscopic bronchoalveolar lavage (BAL) procedure on children presenting for an elective surgical procedure, this study has investigated the cellular constituents of BAL fluid in children with a history of atopic asthma (AA) non-asthmatic atopic children (NAA) or viral associated wheeze (VAW). A total of 95 children was studied: 52 with atopic asthma (8.0 years, range 1.1-15.3, 36 male), 23 with non-asthmatic atopy (median age 8.3 years, range 1.7-13.6, 11 male) and 20 with VAW (3.1 years, range 1.0-8.2, 13 male). No complications were observed during the lavage procedure and no adverse events were noted post-operatively. Total lavage fluid recovered was similar in all groups and the total cell numbers were higher in the VAW group. Eosinophil (P < or = 0.005) and mast cell (P < or = 0.05) numbers were significantly elevated in the group with atopic asthma. During relatively asymptomatic periods there is on-going airways inflammation, as demonstrated by eosinophil and mast cell recruitment, in children with asthma and atopy but not in children with viral associated wheeze or atopy alone. This strongly suggests that there are different underlying pathophysiological mechanisms in these two groups of children who wheeze.