Wheezing Episodes Research Articles

Deciphering the Importance of Host and Environmental Factors that Influence the Genesis of Asthma During Childhood

Deciphering the Importance of Host and Environmental Factors that Influence the Genesis of Asthma During Childhood

Ethical considerations and rationale of the MAKI trial: A multicenter double-blind randomized placebo-controlled trial into the preventive effect of palivizumab on recurrent wheezing associated with respiratory syncytial virus infection in children with a gestational age of 33–35 weeks

BackgroundRespiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is the most frequent cause of bronchiolitis during infancy. Long-term airway morbidity with recurrent post bronchiolitis wheezing (PBW) episodes, which are probably associated with respiratory infections, occurs in 30 to 70% of infants that were hospitalised with RSV LRTI. MethodsWe set up a multicenter, placebo-controlled double-blind randomized clinical trial in healthy preterm infants born between 33 and 35weeks gestational age (WGA). The children received either one-monthly intramuscular palivizumab or placebo injection during the RSV season with a minimum of 2 injections. ResultsThe primary objective was to determine the preventive effect of RSV immunoprophylaxis (palivizumab) on the development of recurrent wheezing during the first year of life. The primary outcome measure was the number of wheezing days during the first year of life as obtained by daily logs. As a secondary outcome nasal swabs were taken for viral analysis in case of respiratory symptoms. We will also examine wheezing at age 1, 3 and 6years both reported by the parents and the general practitioner and quality of life as secondary outcomes. This trial is possible because RSV immunoprophylaxis, although effective in this population, is not completely used in the Netherlands due to its high costs. ConclusionThe Institutional review board (IRB) concluded the study has high clinical relevance because the benefit of 50% chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo.

Exhaled Nitric Oxide in Acute Phase of Bronchiolitis and Its Relation with Episodes of Subsequent Wheezing in Children of Preschool Age

BACKGROUND: Fractional exhaled nitric oxide (FENO) levels are increased in children with asthma and in infants with recurrent wheezing, but the role of FENO in the acute phase of bronchiolitis is still not defined. OBJECTIVE: The aim of this study is to evaluate FENO values in the acute phase of bronchiolitis, compare them with healthy infants, and relate those values with the appearance of other wheezing episodes. METHODS: FENO values were determined in infants between 2 months and 2 years affected with RVS bronchiolitis by offline method. The FENO values collected in the acute phase were related with the respiratory clinical symptoms presented in the 2 years following the episode. RESULTS: A total of 30 patients were recruited: 15 in the bronchiolitis group and 15 in the control group. The average of the FENO values in the acute phase was 18.74 ppb (range 2-88) in the bronchiolitis group, and 8.75 ppb (range 2-24) in the control group. However, these results showed no significant statistical differences (p=0.176). Nevertheless, we found a positive correlation between the FENO values and the clinical score (Downes) of the bronchiolitis episode (p=0.023). In infants that presented other wheezing episodes in the 2 years after, the average of FENO in the acute phase of the first episode was 23.1 ppb (average of 10.25 ppb) versus 8.4 ppb (average 5.4 ppb) in the group of patients with no other episodes. The comparison of averages has no statistical significance. CONCLUSION: We found no differences in FENO between infants with bronchiolitis and healthy ones. The FENO values in the acute phase seems to be related to the severity of the disease but do not predict the appearance of wheezing episodes in the following 2 years.

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.

All that wheezes is not asthma: a case report of a child with a concealed upper airways foreign body

The authors report the case of a previously fit and well six-year-old girl who presented to paediatric outpatients with a four month history of wheezing associated with intermittent cough. During her first clinic appointment, she was given a trial of salbutamol via a spacer, which appeared to reduce the wheeze and few crepitations which had been heard prior to administration of the drug. She was diagnosed with asthma and prescribed Beclomethasone and Salbutamol at this time. This apparent initial response to salbutamol was later disputed as spirometry showed no reversibility. Also, she did not report any interval symptoms or increased wheezing with exercise or upper respiratory tract infections. Her mother did not feel that the inhalers had made any difference to her symptoms so her medications were stopped. She developed a number of chest infections and was investigated for possible underlying conditions including cystic fibrosis and structural defects, none of which were found to be present. IgE and RAST for specific allergens were negative and a chest X-ray was completely normal. Full blood count and immunoglobulins were also normal. She was found to have low Hib and tetanus antibodies but these returned to normal after she was re-vaccinated. The doctors treating her began to suspect tracheobronchomalacia was responsible for her symptoms and at this point, the wheeze was noted to be musical in character. At this point, she was referred for a bronchoscopy and a small piece of plastic tubing was found in her airway. It was removed successfully and she has been completely well since, with no further episodes of wheeze or cough. In retrospect she could not remember a choking episode or inhaling a foreign body. This case demonstrates that all that wheezes is not asthma. It is important to re-evaluate and re-consider differential diagnoses when the clinical picture does not completely fit. Airway foreign bodies should be considered even with a long history of cough and no signs of respiratory distress and absence of a history of inhalation of a foreign body does not rule it out, even in older children.

Novel severe wheezy young children phenotypes: Boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze

Recurrent wheezing during infancy is a heterogeneous disorder that has been associated with early-onset asthma. To identify phenotypes of severe recurrent wheezing and therapeutic approaches. We performed cluster analysis with 20 variables of 551 children with active asthma, younger than 36 months old, and enrolled in the Trousseau Asthma Program. We identified 3 independent clusters of children with wheezing. Cluster 1, mild episodic viral wheeze (n= 327), consisted of children with wheezing related only to colds (71%), mild disease (76%), and mainly normal chest x-ray results. Cluster 2, nonatopic uncontrolled wheeze (n = 157), was characterized by moderate to severe disease (91%), uncontrolled wheezing despite high doses of inhaled corticosteroids (55%), parents with asthma, and increased levels of ferritine. Cluster 3, atopic multiple-trigger wheeze (n = 67), included more children with multiple-trigger wheeze (68%) than did clusters 1 or 2; eczema (75%); a positive result from the Phadiatop Infant test (90%); increased levels of IgE, IgA, and IgG; and abnormal results from chest x-rays. In separate analysis, 1 parameter for boys (increased total level of IgE) and 2 parameters for girls (wheezing severity and increased total level of IgE) properly classified 90% of boys and 83% of girls in the appropriate cluster. Significant associations were found between overcrowding, molds and cockroaches at home, and atopic multiple-trigger wheeze and between day-care attendance and nonatopic uncontrolled wheeze in other parts. We identified different phenotypes of recurrent wheezing in young children by using cluster analysis with usual variables. These phenotypes require confirmation in longer, follow-up studies.

Effect of adenotonsillectomy on the use of respiratory medication

ObjectiveRecurrent tonsillitis and upper respiratory tract obstruction due to adenotonsillar hypertrophy are the most common indications for (adeno)tonsillectomy ((A)TE). Symptoms of upper respiratory tract infection and obstruction can, however, be attributed to lower airway pathology and thus treated with respiratory medication – this is non-antimicrobial medication used for lower respiratory diseases like bronchitis, bronchiolitis, asthma and episodic wheezing. The aim of this study is to investigate the effect of the current (A)TE practice in Belgium on the use of respiratory medication in subjects aged 0–15. MethodsRetrospective data on 11.114 subjects aged 0–15years old who underwent (A)TE from January 1st 2002 until Sept 30th 2003 were retrieved from the database of the Christelijke Mutualiteit, the largest mutual health insurance society in Belgium. We compared the use of respiratory medication 12months before and 12months after (A)TE. ResultsOut of 11.114 subjects, 4.654 received at least one prescription for respiratory medication in the year before and/or after (A)TE. In this subgroup, the median respiratory medication use reduced with 32% in the year after surgery. ConclusionCompared with the year before surgery, the median use of respiratory medication in subjects aged 0–15 drastically reduces in the year after (A)TE. A possible reason for this reduction is that children with upper airway obstruction and infections are often wrongly diagnosed as having lower airway problems.

The effect of cigarette smoking on allergic conditions in Maltese children (ISAAC)

Maltese children are frequently exposed to tobacco smoke through passive and personal smoking. In the phase 3 ISAAC study questionnaire, we enquired about passive smoking to the parents of 3816 (80% response rate) 5- to 8-yr-old children and about passive and personal smoking to 4139 (90% response rate) 13- to 15-yr-old participating children. Thirty-one percent of 5- to 8-yr olds were passive smokers with their father more likely to be the smoker (p < 0.0001). Maternal smoking in the first year of the child's life resulted in the children having an increased chance of wheezing 'ever' (p < 0.001), exercise-induced wheezing (p < 0.05) and being diagnosed with asthma (p < 0.0001). Current smoking by the mother also led to the child having current rhinitis (p < 0.001). Fifty-one percent of 13- to 15-yr olds were passive smokers again with the father more likely to be the smoker (p < 0.0001). Maternal (p < 0.0001) and paternal smoking (p < 0.05) resulted in the children having an increased chance of wheezing sometime in their life, exercise-induced wheezing, nocturnal cough, and being diagnosed with asthma. Current smoking by the mother was more common in children having current rhinitis (p < 0.05), while current smoking by both mother and/or father led to itchy/watery eyes accompanying rhinitis (p < 0.05). Recurrent itchy rashes were also more likely in passive smokers (p < 0.001). Personal smoking by the 13- to 15-yr olds (8.15% boys vs. 8.8% girls ns ) resulted in a higher cumulative prevalence of wheezing (p < 0.0001), rhinitis (p < 0.05), and recurrent itchy rash (p < 0.001) but only affected current prevalence of wheezing (p < 0.0001). These smokers were more likely to experience exercise-induced wheezing (p < 0.0001), nocturnal cough (p < 0.0001), and being diagnosed with asthma (p < 0.05) and eczema (p < 0.001). Children smoking more than 10 cigarettes/day persisted with wheezing (p = 0.04) had more frequent episodes of exercise-induced wheeze (p = 0.04), nocturnal cough (p < 0.0001), and rhinoconjunctivitis (p = 0.02) than milder smokers. Smoking seems to be affecting childhood allergies in Maltese children quite significantly.

Childhood respiratory cohort studies: do they generate useful outcomes?

<h3>Educational aims</h3> To describe the strengths and limitations of cohort studies. To give insight into the likely magnitude of effect of exposures on asthma causation. To summarise the relative weight of predictors of asthma prognosis. To describe results from cohort studies where interventions were made. <h3>Summary</h3> Cohort studies give insight into the evolution of respiratory disease over time and provide a low level of evidence for causation. The initial pioneering cohort studies in which symptoms and/or exposures were captured in early life and related to respiratory outcome in later life are now part of a large family which is diverse in age and exposures; however, asthma remains a fairly constant outcome. This article aims to first describe the strengths and weaknesses of the various asthma cohort studies. Thereafter, the article aims to describe the insight that cohort studies have given into asthma causation, with a focus on relative magnitude of effect, and also to describe the relative weight of factors identified in cohort studies as predictors of persisting asthma symptoms. It is clear that many factors are implicated in asthma causation; in isolation, each exerts a rather modest positive of negative effect on causation, but are likely to be acting in combination and modifying each other9s relative risk. There is no single “good” predictor of asthma outcome, but the coexistence of parental asthma/atopy in a child with at least three episodes of wheeze by their third birthday indicates a high relative risk for asthma at 11–13 years of age. There remains no cure for asthma and the next step needs to apply what cohort studies have taught us to intervention studies where several exposures are modified in at risk individuals during the first year of life.

Maternal smoking during pregnancy, prematurity and recurrent wheezing in early childhood

Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood. We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing. We evaluated 1,448 children with smoke exposure data from a prospective urban birth cohort in Boston. Maternal antenatal and postnatal exposure was determined from standardized questionnaires. Gestational age was assessed by the first day of the last menstrual period and early prenatal ultrasound (preterm < 37 weeks gestation). Wheezing episodes were determined from medical record extraction of well and ill/unscheduled visits. The primary outcome was recurrent wheezing, defined as ≥ 4 episodes of physician documented wheezing. Logistic regression models and zero inflated negative binomial regression (for number of episodes of wheeze) assessed the independent and joint association of prematurity and maternal antenatal smoking on recurrent wheeze, controlling for relevant covariates. In the cohort, 90 (6%) children had recurrent wheezing, 147 (10%) were exposed to in utero maternal smoke and 419 (29%) were premature. Prematurity (odds ratio [OR] 2.0; 95% confidence interval [CI], 1.3-3.1) was associated with an increased risk of recurrent wheezing, but in utero maternal smoking was not (OR 1.1, 95% CI 0.5-2.4). Jointly, maternal smoke exposure and prematurity caused an increased risk of recurrent wheezing (OR 3.8, 95% CI 1.8-8.0). There was an interaction between prematurity and maternal smoking upon episodes of wheezing (P = 0.049). We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.

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.

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...

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Short term efficacy of nebulized beclomethasone in mild-to-moderate wheezing episodes in pre-school children

BackgroundFew data are available on the usefulness of short term treatment with low-medium dose of inhaled corticosteroids (ICS) in pre-school children with wheezing exacerbations.MethodsTo compare the efficacy of one week treatment with 400 μg b.i.d. nebulized beclomethasone dipropionate (BDP), plus nebulized 2500 μg prn salbutamol (BDP group), versus nebulized b.i.d. placebo, plus nebulized prn 2500 μg salbutamol (placebo group), a post-hoc analysis was performed on data obtained in 166 pre-school children with multiple-trigger wheezing, recruited during an acute wheezing episode.ResultsThe percentage of symptom-free days (SFDs) was significantly higher in the BDP group (54.7%) than in the placebo group (40.5%; p = 0.012), with a 35% relative difference. Day-by-day analysis showed that the percentage of SFDs was already higher in the BDP group after 2 days (7.4%), the difference reaching statistical significance at day 6 (12.3%; p = 0.035). Cough score was also reduced in the BDP group (0.11) as compared with the placebo group (0.39; p = 0.048), the difference reaching statistical significance after 5 days of treatment (0.18 and 0.47 respectively; p = 0.047). The mean number of nebulizations per day of prn salbutamol was lower in the BDP group as compared to the placebo group (0.26 and 0.34, respectively), but the difference was not significant (p = 0.366). There were no differences in positive effects of BDP treatment between children with and without risk factors for asthma.ConclusionsA 1-week treatment with nebulized BDP and prn salbutamol is effective in increasing SFDs and improving cough in children with wheezing, providing a clinical rationale for the short term use of ICS in episodic wheeze exacerbations in pre-school children.Trial RegistrationClinicalTrials.gov (NCT00497523)

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.

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

Comparison of clinical presentation of respiratory tract infections in H1N1/09-positive and H1N1/09-negative patients

The true burden of influenza in children is difficult to assess and is probably underestimated as clinical signs are usually nonspecific, and formal viral identification is rarely searched. In this study, we compare the clinical features of infections related to the new H1N1/09 influenza virus with infections due to other respiratory viruses in children consulting in a tertiary care pediatric hospital in Geneva. Between October 1, 2009 and February 10, 2010, 109 patients were recruited, with a median of age of 7 years (range 0.1-18). There were 75 H1N1/09-positive patients (69%), and 32 (43%) had identified risk factors such as asthma or a history of wheezing. Fever (87%), cough (92%), and rhinitis (85%) were the most frequent reported presenting symptoms in both patient groups. H1N1/09-positive patients were significantly older (median of 8.2 vs. 4.6 years) and were more likely to have risk factors (43% vs. 24%) and myalgias (41% vs. 20%). H1N1/09-negative patients had more wheezing episodes (29% vs. 9%), higher rates of dyspnea (28% vs. 20%) and of hospital admissions (35% vs. 16%). Clinical signs cannot reliably differentiate H1N1/09-positive and H1N1/09-negative patients, although we found a higher proportion of myalgias in H1N1/09-positive patients. Severity of disease was lower in H1N1/09-positive than in H1N1/09-negative patients, mostly because of a higher proportion of asthma/wheezing episodes among H1N1/09-negative patients.

Feather bedding and childhood asthma associated with house dust mite sensitisation: a randomised controlled trial

IntroductionObservational studies report inverse associations between the use of feather upper bedding (pillow and/or quilt) and asthma symptoms but there is no randomised controlled trial (RCT) evidence assessing the role...