Wheezing Preschool Children Research Articles

A meta-analysis of montelukast for recurrent wheeze in preschool children

There is conflicting evidence of the effectiveness of montelukast in preschool wheeze. A recent Cochrane review focused on its use in viral-induced wheeze; however, such subgroups are unlikely to exist in real life and change with time, recently highlighted in an international consensus report. We have therefore sought to investigate the effectiveness of montelukast in all children with preschool wheeze (viral-induced and multiple-trigger wheeze). The PubMed, Cochrane Library, Ovid Medline and Ovid EMBASE were screened for randomised controlled trials (RCTs), examining the efficacy of montelukast compared with placebo in children with the recurrent preschool wheeze. The primary endpoint examined was frequency of wheezing episodes. Five trials containing 3960 patients with a preschool wheezing disorder were analysed. Meta-analyses of studies of intermittent montelukast showed no benefit in preventing episodes of wheeze (mean difference (MD) 0.07, 95% confidence interval (CI) −0.14 to 0.29; mean for montelukast 2.68 vs placebo 2.54 (p = 0.5)), reducing unscheduled medical attendances (MD −0.13, 95% CI −0.33 to 0.07; mean for montelukast 1.62 vs placebo 1.78 (p = 0.21)) and reducing oral corticosteroids (MD −0.06, 95% CI −0.16 to 0.02; mean for montelukast 0.35 vs placebo 0.36 (p = 0.25)). The pooled results of the continuous regimen showed no significant difference in the number of wheezing episodes between the montelukast and placebo groups (MD −0.40, 95% CI −1.00 to 0.19; mean for montelukast 2.05 vs placebo 2.37 (p = 0.18)).Conclusions: This review highlights that the currently available evidence does not support the use of montelukast in preschool children with recurrent wheeze. We recommend further studies to investigate if a ‘montelukast responder’ phenotype exists, and how these can be easily identified in the clinical setting.What is Known:• Current guidelines recommend montelukast use in preschool children with recurrent wheeze.• A recent Cochrane review has found montelukast to be ineffective at reducing courses of oral corticosteroids for viral-induced wheeze.What is New:• This meta-analysis has examined all children with preschool wheeze and found that montelukast was not effective at preventing wheezing episodes or reducing unscheduled medical attendances.• A specific montelukast responder phenotype may exist, but such patients should be sought in larger multicentre RCTs.

Neutrophilic Steroid-Refractory Recurrent Wheeze and Eosinophilic Steroid-Refractory Asthma in Children

Little is known about inflammatory pathways of severe recurrent wheeze in preschool children and severe asthma in children. The aim of the Severe Asthma Molecular Phenotype cohort was to characterize phenotypes of severe recurrent wheeze and severe asthma during childhood in terms of triggers (allergic or not), involved cells (eosinophil or neutrophil), and corticoid responsiveness. Children with moderate-to-severe asthma and preschool children with moderate-to-severe recurrent wheeze were enrolled prospectively. They underwent standardized clinical and blood workup, and bronchoalveolar lavage (BAL) evaluation. Cluster analysis was applied to 350 children with 34 variables. Three clusters were identified: cluster 1, Neutrophilic steroid-refractory recurrent wheeze phenotype, with 138 children uncontrolled despite high-dose inhaled corticosteroids (ICS) (92%, P < .001), with more history of pneumonia (31%, P<.001), more gastroesophageal reflux disease (37%, P < .001), and the highest blood neutrophil count (mean 4.524 cells/mm3, P= .05); cluster 2, Severe recurrent wheeze with sensitization to a single aeroallergen (12%, P= .002), with 104 children controlled with high-dose ICS (63%, P < .001); cluster 3, Eosinophilic steroid-refractory asthma phenotype, with 108 children uncontrolled despite high-dose ICS (76%, P < .001) with more allergic rhinitis, atopic dermatitis, and food allergies (82%, 40%, 31%, P < .001, respectively). They also had a higher blood eosinophil count and a higher percentage of BAL eosinophil (506/mm3, 2.6%, P < .001 respectively). Inflammation pathway of asthma and recurrent wheeze are related to eosinophil cells in older children and neutrophil cells in younger children. These results could improve personalized treatments.

A longitudinal assessment of circulating YKL-40 levels in preschool children with wheeze.

The chitinase-like protein YKL-40 (CHI3L1) is elevated in the circulation of adults and schoolchildren with chronic severe asthma. It is unknown whether YKL-40 is altered in younger, preschool children with wheeze, acute or chronic. We therefore examined YKL-40 in preschool children during an acute episode of wheeze and during remission, in comparison with healthy controls. Blood was obtained from 128 children (aged 6-44 months) at the emergency department during an acute episode of wheeze, and at two follow-up visits (approximately 3 months and 1 year later), as well as from 100 age-matched healthy controls on one occasion. Plasma YKL-40 levels were examined in relation to CHI3L1 rs4950928 genotype and clinical characteristics including Asthma Predictive Index, medication use, time spent with respiratory symptoms, atopic status, and blood leukocytes. Children with wheeze had higher median YKL-40 levels at the acute visit (14.7 (11.5-22.6) ng/ml, p < 0.001) and 3-month follow-up (15.9 (11.5-20.2), p < 0.001) compared to the 1-year follow-up (11.9 (9.5-17.3)). YKL-40 levels in healthy controls (13.6 (11.0-17.0)) tended to be lower than those during acute wheeze (p = 0.07) and 3-month follow-up (p = 0.04), but were no different at the 1-year follow-up. CHI3L1 rs4950928 affected YKL-40 in all subjects, with highest levels present in those with the CC genotype (p < 0.001). Genotype frequency was similar in the two subject groups. YKL-40 levels showed a positive correlation with blood neutrophil counts but no consistent relationships with clinical characteristics of relevance to continuous wheeze. YKL-40 levels were elevated during acute wheeze in preschool children, a finding which may be related to current neutrophilic inflammation, but YKL-40 was not associated with characteristics of persistent wheeze in this young cohort.

Preschool Wheezing Phenotypes

Wheezing in preschool children is very common, with a wide differential diagnosis. It is essential to be sure of the exact sound that parents are describing; the term ‘wheeze‘ is often applied to non-specific sounds. Structural airway disease such as vascular ring should be considered. Thereafter we propose that umbrella terms for preschool wheeze should be abandoned in favour of ‘Hargreave phenotyping’, in which the presence and extent of the components of infection, inflammation, variable airflow obstruction, and fixed airflow obstruction are determined as far as is possible, rather than using a general umbrella term such as ‘asthma’. The justification for this approach is that it leads to a logical approach to treatment in the disparate airway diseases presenting in the preschool years, and should hopefully prevent over-treatment with inhaled corticosteroids. If, despite this approach, doubt remains as to the nature of the airway disease, then a therapeutic trial of treatment is permissible, but it should be for a short defined period only. In any event, such children should be reviewed regularly to see if treatments need to be changed.

Biomarkers to predict asthma in wheezing preschool children

Wheezing in preschool children is a very common symptom. An adequate prediction of asthma in these children is difficult and cannot be reliably assessed with conventional clinical tools. The study of potential predictive biomarkers in various media, ranging from invasive sampling (e.g. bronchoscopy) to non-invasive sampling (lung function testing and exhaled breath analysis), was comprehensively reviewed. The evolution in biomarker discovery has resulted in an 'omics' approach, in which hundreds of biomarkers in the field of genomics, proteomics, metabolomics, and 'breath-omics' can be simultaneously studied. First, results on gene expression and exhaled breath profiles in predicting an early asthma diagnosis are promising. However, many hurdles need to be overcome before clinical implementation is possible. To reliably predict asthma in a wheezing child, probably a holistic approach is needed, combining clinical information with blood sampling, lung function tests, and potentially exhaled breath analysis. The further development of predictive, non-invasive biomarkers may eventually improve an early asthma diagnosis in wheezing preschool children and assist clinicians in early treatment decision-making.

Spirometry and bronchodilator responsiveness in wheezing preschool children

Methods We carried out a retrospective analysis of incentive spirometry tests in recurrent wheezing children, aged 2-5 years, from our center, performed between September 2012 and March 2014. Lung function was assessed before and after 400 mg of inhaled salbutamol using a Jaeger spirometer v.4.65 (CareFusion). Wheezing symptoms, parental asthma, prematurity, passive smoking exposure, atopy and controller medication use were evaluated. Categorical frequency analysis and non-parametric tests were used.

Association of wheezing phenotypes with fractional exhaled nitric oxide in children.

Asthma comprises a heterogeneous group of disorders characterized by airway inflammation, airway obstruction, and airway hyperresponsiveness (AHR). Airway inflammation, which induces AHR and recurrence of asthma, is the main pathophysiology of asthma. The fractional exhaled nitric oxide (FeNO) level is a noninvasive, reproducible measurement of eosinophilic airway inflammation that is easy to perform in young children. As airway inflammation precedes asthma attacks and airway obstruction, elevated FeNO levels may be useful as predictive markers for risk of recurrence of asthma. This review discusses FeNO measurements among early-childhood wheezing phenotypes that have been identified in large-scale longitudinal studies. These wheezing phenotypes are classified into three to six categories based on the onset and persistence of wheezing from birth to later childhood. Each phenotype has characteristic findings for atopic sensitization, lung function, AHR, or FeNO. For example, in one birth cohort study, children with asthma and persistent wheezing at 7 years had higher FeNO levels at 4 years compared to children without wheezing, which suggested that FeNO could be a predictive marker for later development of asthma. Preschool-aged children with recurrent wheezing and stringent asthma predictive indices also had higher FeNO levels in the first 4 years of life compared to children with wheezing and loose indices or children with no wheeze, suggesting that FeNO measurements may provide an additional parameter for predicting persistent wheezing in preschool children. Additional large-scale longitudinal studies are required to establish cutoff levels for FeNO as a risk factor for persistent asthma.

Hypertonic Saline and Acute Wheezing in Preschool Children

D Ater, H Shai, BE Bar. Pediatrics. 2012;129(6):e1397–e1403 To determine the effect of inhalation of hypertonic saline in children presenting to the emergency department (ED) with acute wheezing, on length of stay (LOS), admission rate (AR), and clinical severity score (CS). Included in the study were 41 children presenting to 1 medical center in Israel. In a randomized, controlled, double-blinded study, 41 children aged 1 to 6 years old (mean age 31.9 months), presenting to the ED with acute …

Wheezing in preschool children

Wheezing is a common condition in pediatric practice, it can be defined as a musical sound, high-pitched and continuous, emitting from the chest during breath exhalation.Although almost 50% of children experiences wheeze in the first 6years of life, only 40% of them will report continued wheezing symptoms after childhood. The classification of wheeze in preschool children is more difficult compared to school aged children. It is based on the onset and duration of symptoms and divided children in three categories: transient early wheezing, non-atopic wheezing and atopic wheezing/asthma.History and physical examination, skin prick test, exhaled nitric oxide, lung function test are the parameter to evaluate children with wheezing.The aim of management of wheezing is to finalize the control of symptoms, reduce exacerbations and improve the quality of life. All guidelines underline the complexity in making a diagnosis of asthma under five years and the need to identify phenotypes that may help paediatricians in the therapeutic choices.

Impact of bacterial colonization on exhaled inflammatory markers in wheezing preschool children

Wheeze is a common symptom in preschool children. The role of bacteria, regulatory T (Treg) cells and their association with airway inflammation in preschool wheeze is largely unknown. We evaluated inflammatory markers in exhaled breath condensate (EBC), bacterial colonization and circulating Treg cells in preschool children with and without recurrent wheeze. We recruited 252 children (aged two to four years) with (N = 202) and without (N = 50) recurrent wheeze. EBC was collected using an efficient closed glass condenser. Inflammatory markers in EBC (Interleukin(IL)-2, IL-4, IL-8, IL-10, IL-13) were assessed using multiplex immunoassay. Nasal and throat swabs were analysed for presence of Streptococcus pneumoniae, Haemophilus (para)influenzae and Staphylococcus aureus. Proportions of Treg cells (CD4+CD25highCD127−) were quantified by flow cytometry. Recurrent wheezing children had elevated EBC levels of IL-2, IL-4, IL-10 and IL-13 compared to non-wheezers (odds ratio (95% confidence interval): 1.67 (1.23–2.27): 1.58 (1.15–2.18): 1.47 (1.14–1.90): 1.55 (1.16–2.06), p <0.05, respectively). Bacteria were frequently present in children with and without wheeze, with no difference in prevalence (16–52% versus 16–50%, respectively). Moreover, the proportion of Treg cells did not differ between both groups. Wheezing children with bacterial colonization did not significantly differ in exhaled levels of inflammatory markers or proportion of Treg cells compared to wheezing children without colonization. The analysis of EBC might serve as a helpful non-invasive tool to early assess airway inflammation in wheezing children. The various elevated exhaled inflammatory markers indicate increased airway inflammation in wheezing preschool children. In the presence of wheeze, we found no evidence for bacterial induced airway inflammation.

Hypertonic Saline and Acute Wheezing in Preschool Children

Most acute wheezing episodes in preschool children are associated with rhinovirus. Rhinovirus decreases extracellular adenosine triphosphate levels, leading to airway surface liquid dehydration. This, along with submucosal edema, mucus plaques, and inflammation, causes failure of mucus clearance. These preschool children do not respond well to available treatments, even oral steroids. This calls for pro-mucus clearance and prohydration treatments such as hypertonic saline in wheezing preschool children. Randomized, controlled, double-blind study. Forty-one children (mean age 31.9 ± 17.4 months, range 1-6 years) presented with wheezing to the emergency department were randomized after 1 albuterol inhalation to receive either 4 mL of hypertonic saline 5% (HS) (n = 16) or 4 mL of normal saline (NS) (n = 25), both with 0.5 mL albuterol, twice every 20 minutes in the emergency department and 4 times a day thereafter if hospitalized. The primary outcome measured was length of stay (LOS) and the secondary outcomes were admission rate (AR) and clinical severity score. The LOS was significantly shorter in the HS than in the NS group: median 2 days (range 0-6) versus 3 days (range 0-5) days (P = .027). The AR was significantly lower in the HS than the NS group: 62.2% versus 92%. Clinical severity score improved significantly in both groups but did not reach significance between them. Using HS inhalations significantly shortens LOS and lowers AR in preschool children presenting with an acute wheezing episode to the emergency department.

Hypertonic Saline and Acute Wheezing in Preschool Children

Background: Most acute wheezing episodes in preschool children are associated with viral respiratory tract infections, most commonly rhinovirus. Rhinovirus, like RSV, decreases extra-cellular ATP, leading to airway surface liquid dehydration. This, along with sub-mucosal edema, mucus plaques and inflammation cause failure of mucus clearance (MC). Such preschool children do not respond well to available treatments, including oral steroids. This calls for pro-MC and pro-hydration treatment like hypertonic saline. Methods: Randomized, controlled, double-blind study. Forty one children (mean age 31.9±17.4 months, range 1-6 years) presented with wheezing to the emergency department (ED) were randomized after one albuterol inhalation to receive either 4 ml of Hypertonic Saline 5% (HS), (n=16) or 4 ml of Normal saline (NS), (n=25) both with 0.5 ml albuterol, twice every 20 minutes in the ED and four times a day thereafter if hospitalized. Primary outcome measured was length of stay (LOS) and secondary outcomes were admission rate (AR) and clinical severity score (CS). Results: LOS was significantly shorter in the HS than in the NS group: median (range) 2 (0-6) days, versus 3 (0-5) days (P=0.027). AR was significantly lower in the HS than the NS group: 62.2% versus 92%. CS improved significantly in both groups but did not reach significance between them. View this table: Hospitalization rate Conclusions: Using HS inhalations significantly shortens LOS and lowers AR in preschool children presenting with acute wheezing episode to the ED.

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.

Can exhaled inflammatory markers predict a steroid response in wheezing preschool children?

The efficacy of inhaled corticosteroids (ICS) varies among wheezing preschool children. Currently, it is not possible to predict which fraction of wheezing children will benefit from an ICS treatment. We explored whether fractional exhaled nitric oxide (FeNO) and inflammatory markers in exhaled breath condensate (EBC) can predict an ICS response in preschool wheezers. An 8-week ICS study (registered at Clinicaltrial.gov: NCT 00422747; 200 μg; beclomethasone extra-fine daily) was performed in 93 wheezing children (age range 2.0-4.4 years). At baseline, FeNO was determined off-line. EBC was collected using a closed glass-condenser. The acidity of EBC was determined and other EBC markers [interleukin (IL)-1α, IL-2, IL-4, IL-5, IL-10, soluble intercellular adhesion molecule, interferon-γ, eotaxin] were measured using a multiplex immunoassay. The change in airway resistance (Rint) and symptom score following ICS treatment was related to atopy (positive Phadiatop Infant test), FeNO and EBC markers. Airway resistance and symptoms mildly improved after ICS treatment [median (IQR): 1.4 (1.2-1.7) to 1.3 (1.1-1.5) kPa s/L, symptom score: 26 (23-28) to 28 (24-29), P < 0.01, respectively]. Only IL-10 and atopy had limited predictive value regarding a change in symptoms [β (SE) =-0.13 (0.07), P = 0.08, β (SE) = 2.05 (1.17), P = 0.08, respectively]. We did not find convincing evidence that FeNO and EBC markers could predict an ICS response in preschool wheezers. Recommendations for future studies on this topic are given.

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.

Should Inhaled Corticosteroids Be Used to Treat Recurrent Wheeze in Preschool Children?

Wheeze in preschool children is common. In a small proportion of children, it can be very troublesome, requiring repeated visits for medical attention. Response to treatment is variable and often disappointing. Children with frequent wheeze, particularly if they have a family history of asthma, are likely to benefit from inhaled corticosteroids, in terms of both improved symptom control and reduced number and severity of exacerbations. Children with infrequent episodic wheeze do not benefit from regular inhaled corticosteroids, and their use should be avoided in children with this pattern of wheeze.

Preschool Wheeze: Phenotypes and Beyond

Wheezing in preschool children is mostly associated with viral upper respiratory tract infections, can recur frequently and is not usually associated with any underlying inflammation between episodes of wheeze. While spontaneous resolution of wheezing occurs in some of these children, in others wheeze persists, and these children are at risk of developing asthma. A number of birth cohort studies have improved our understanding of the natural history of preschool wheeze disorders but many gaps in our knowledge still remain. This article summarizes existing knowledge regarding preschool wheeze phenotypes including clinical relevance, natural history of preschool wheeze disorders, pathophysiology and treatment strategies. This article will focus on preschool children with recurrent wheeze with or without viral respiratory tract infections.

Association of nutrient intake and wheeze or asthma in a Greek pre‐school population

The rise of asthma prevalence in children observed the last years might be related to several dietary factors/components as suggested by several researchers. We aimed to evaluate the potential relationship between certain nutrients intake and asthma occurrence in a population of pre-school children. In the framework of the cross-sectional study 'Growth, Exercise and Nutrition Epidemiological Study In pre-schoolers', data were collected from 1964 children, aged 24-72 months, living in five different counties in Greece. The International Study of Asthma and Allergies in Childhood questionnaire was used to assess asthma related outcomes. Dietary intake was assessed with 3 days diet records. The prevalence of ever wheeze, current wheeze and diagnosed asthma was 37.7%, 27.5% and 10.5% respectively. Dietary intake of magnesium had a 0.5% and 0.6% increase in the reported risk of current wheeze and diagnosed asthma respectively. On the contrary a decrease in the prevalence of ever (OR: 0.997, 95% CI: 0.995-1.000) and current wheeze (OR: 0.996, 95% CI: 0.993-0.999) was associated with vitamin C intake. Calcium intake slightly decreased the risk of current wheeze (OR: 0.999, 95% CI: 0.998-0.999). An increase of 2% of the risk of reporting ever or current wheeze was associated with mono-unsaturated fatty acid intake. Magnesium intake was the only independent predictor for doctor's diagnosed asthma. We conclude that dietary intake of vitamin C and calcium seem to have a protective effect on the incidence of wheeze in pre-school children, whereas magnesium and mono-unsaturated fatty acid may have a harmful role.

Regular vs prn nebulized treatment in wheeze preschool children

International guidelines recommend regular treatment with inhaled glucocorticoids for children with frequent wheezing; however, prn inhaled bronchodilator alone or in combination with glucocorticoid is also often used in practice. We aimed to evaluate whether regular nebulized glucocorticoid plus a prn bronchodilator or a prn nebulized bronchodilator/glucocorticoid combination is more effective than prn bronchodilator alone in preschool children with frequent wheeze. Double-blind, double-dummy, randomized, parallel-group trial. After a 2-week run-in period, 276 symptomatic children with frequent wheeze, aged 1-4 years, were randomly assigned to three groups for a 3-month nebulized treatment: (1) 400 microg beclomethasone bid plus 2500 microg salbutamol prn; (2) placebo bid plus 800 microg beclomethasone/1600 microg salbutamol combination prn; (3) placebo bid plus 2500 microg salbutamol prn. The percentage of symptom-free days was the primary outcome measure. Secondary outcomes included symptom scores, use of relief medication and exacerbation frequency. As compared with prn salbutamol (61.0 +/- 24.83 [SD]), the percentage of symptom-free days was higher with regular beclomethasone (69.6%, SD 20.89; P = 0.034) but not with prn combination (64.9%, SD 24.74). Results were no different in children with or without risk factors for developing persistent asthma. The effect of prn combination was no different from that of regular beclomethasone on the primary and on several important secondary outcomes. Regular inhaled glucocorticoid is the most effective treatment for frequent wheezing in preschool children. However, prn bronchodilator/glucocorticoid combination might be an alternative option, but it requires further study.

Episodic Viral Wheezing in Preschool Children: What Works?

Pediatric Asthma, Allergy & ImmunologyVol. 22, No. 1 Pharmacotherapy UpdateEpisodic Viral Wheezing in Preschool Children: What Works?H. William KellyPharm.D.H. William KellyPharm.D.Search for more papers by this authorPublished Online:1 May 2009https://doi.org/10.1089/pai.2009.2201.phAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetails Volume 22Issue 1Mar 2009 Information© Mary Ann Liebert, Inc.To cite this article:H. William KellyPharm.D..Episodic Viral Wheezing in Preschool Children: What Works?.Pediatric Asthma, Allergy & Immunology.Mar 2009.39-42.http://doi.org/10.1089/pai.2009.2201.phPublished in Volume: 22 Issue 1: May 1, 2009Online Ahead of Print:April 8, 2009PDF download