Managing children with frequent respiratory infections and associated wheezing: a preliminary randomized study with a new multicomponent nasal spray.

BACKGROUND: Preschoolers frequently have respiratory infections (RIs), which may cause wheezing in some subjects. Type 2 polarization may favor increased susceptibility to RIs and associated wheezing. Non-pharmacological remedies are garnering increasing interest as possible add-on therapies. The present preliminary study investigated the efficacy and safety of a new multi-component nasal spray in preschoolers with frequent RIs and associated wheezing. METHODS: Some preschoolers with these characteristics randomly took this product, containing lactoferrin, dipotassium glycyrrhizinate, carboxymethyl-beta-glucan, and vitamins C and D3 (Saflovir), two sprays per nostril twice daily for 3 months. Other children were randomly treated only with standard therapy. Outcomes included the number of RIs and wheezing episodes, use of medications, and severity of clinical manifestations. RESULTS: Preschoolers treated add-on with this multicomponent product experienced fewer RIs and used fewer beta-2 agonists than untreated children (P = 0.01 and 0.029, respectively). CONCLUSIONS: This preliminary study demonstrated that a multicomponent product, administered add-on as a nasal spray, could reduce the incidence of RIs and use of symptomatic drugs for relieving wheezing in children.

Azithromycin therapy in infants hospitalized for respiratory syncytial virus bronchiolitis: Airway matrix metalloproteinase-9 levels and subsequent recurrent wheeze.

BACKGROUND: Early life respiratory syncytial virus (RSV) bronchiolitis is a significant risk factor for childhood asthma. In vitro and in vivo studies suggested that decreasing levels of airway matrix metalloproteinase (MMP)-9 during RSV bronchiolitis may be associated with clinical benefits. OBJECTIVE: To investigate whether azithromycin therapy during severe RSV bronchiolitis reduces upper airway MMP-9 levels, whether upper airway MMP-9 levels correlate with upper airway interleukin IL-8 levels, and whether MMP-9 level reduction is associated with reduced post-RSV recurrent wheeze (RW). METHODS: A total of 200 otherwise healthy 1- to 18-month-old infants hospitalized with RSV bronchiolitis were randomized into a double-blind, placebo-controlled trial of oral azithromycin (10 mg/kg daily for 7 days followed by 5 mg/kg daily for 7 days) or placebo. Infants were followed for 2 to 4 years for the outcome of RW (3 or more wheezing episodes). Nasal lavage samples for MMP-9 levels were obtained at baseline, day 14 (end of the study treatment), and after 6 months. RESULTS: Upper airway MMP-9 levels were highly correlated with IL-8 levels at all 3 time points: randomization, day 14, and 6 months (r = 0.80; P < .0001 for all time points). MMP-9 levels were similar between treatment groups at randomization, were lower on day 14 among children treated with azithromycin (P = .0085), but no longer different after 6 months. MMP-9 levels at baseline and change from baseline to day 14 were not associated with the development of RW (P = .49, .39, respectively). CONCLUSION: Azithromycin therapy in children hospitalized with RSV bronchiolitis had a short-term anti-inflammatory effect in reducing upper airway MMP-9 levels. However, the reduction in MMP-9 levels did not relate to subsequent RW post-RSV. TRIAL REGISTRATION: This study is a secondary analysis of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis-II clinical trial registered at Clinicaltrials.gov (NCT02911935).

Effect of Prophylactic Subcutaneous Scopolamine Butylbromide on Death Rattle in Patients at the End of Life: The SILENCE Randomized Clinical Trial.

Importance: Death rattle, defined as noisy breathing caused by the presence of mucus in the respiratory tract, is relatively common among dying patients. Although clinical guidelines recommend anticholinergic drugs to reduce the death rattle after nonpharmacological measures fail, evidence regarding their efficacy is lacking. Given that anticholinergics only decrease mucus production, it is unknown whether prophylactic application may be more appropriate. Objective: To determine whether administration of prophylactic scopolamine butylbromide reduces the death rattle. Design, Setting, and Participants: A multicenter, randomized, double-blind, placebo-controlled trial was performed in 6 hospices in the Netherlands. Patients with a life expectancy of 3 or more days who were admitted to the participating hospices were asked to give advance informed consent from April 10, 2017, through December 31, 2019. When the dying phase was recognized, patients fulfilling the eligibility criteria were randomized. Of the 229 patients who provided advance informed consent, 162 were ultimately randomized. The date of final follow-up was January 31, 2020. Interventions: Administration of subcutaneous scopolamine butylbromide, 20 mg four times a day (n = 79), or placebo (n = 78). Main Outcomes and Measures: The primary outcome was the occurrence of a grade 2 or higher death rattle as defined by Back (range, 0-3; 0, no rattle; 3, rattle audible standing in the door opening) measured at 2 consecutive time points with a 4-hour interval. Secondary outcomes included the time between recognizing the dying phase and the onset of a death rattle and anticholinergic adverse events. Results: Among 162 patients who were randomized, 157 patients (97%; median age, 76 years [IQR, 66-84 years]; 56% women) were included in the primary analyses. A death rattle occurred in 10 patients (13%) in the scopolamine group compared with 21 patients (27%) in the placebo group (difference, 14%; 95% CI, 2%-27%, P = .02). Regarding secondary outcomes, an analysis of the time to death rattle yielded a subdistribution hazard ratio (HR) of 0.44 (95% CI, 0.20-0.92; P = .03; cumulative incidence at 48 hours: 8% in the scopolamine group vs 17% in the placebo group). In the scopolamine vs placebo groups, restlessness occurred in 22 of 79 patients (28%) vs 18 of 78 (23%), dry mouth in 8 of 79 (10%) vs 12 of 78 (15%), and urinary retention in 6 of 26 (23%) vs 3 of 18 (17%), respectively. Conclusions and Relevance: Among patients near the end of life, prophylactic subcutaneous scopolamine butylbromide, compared with placebo, significantly reduced the occurrence of the death rattle. Trial Registration: trialregister.nl Identifier: NTR6264.

Inhaled corticosteroids for the prevention of asthma exacerbations.

OBJECTIVE: To provide an overview of the risk factors and mechanisms underlying asthma exacerbations and the role of inhaled corticosteroids (ICSs) in preventing exacerbations. DATA SOURCES: Queries for asthma exacerbations and ICSs were conducted using PubMed, searching for primary articles and reviews. STUDY SELECTIONS: Studies written in English, with a focus on well-designed randomized controlled clinical trials. RESULTS: Asthma exacerbations remain a major source of morbidity, with future exacerbations most likely among patients with previous exacerbations and among those with peripheral blood eosinophilia. Exacerbations are often triggered by viral respiratory tract infections, but recent evidence supports nonviral triggers as well. In terms of exacerbation prevention, several approaches to ICS therapy have been found to be effective, including intermittent high-dose ICS without use of background controller in preschool children with recurrent episodic wheezing, intermittent high-dose ICS without use of background controller in adults with mild asthma, and as-needed ICS dosing whenever rescue treatment is needed among children, adolescents, and adults with mild asthma not receiving daily controller therapy. CONCLUSION: ICSs are highly effective in preventing exacerbations of asthma. Multiple dosing strategies have been found to reduce exacerbation risk, allowing for a personalization of approaches based on individual patient phenotypes and preferences.

Efficacy of inhaled salbutamol with and without prednisolone for first acute rhinovirus-induced wheezing episode.

BACKGROUND: Acute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta2 -agonist in this clinical scenario. OBJECTIVE: To study post hoc the short-term (up to 2 months) efficacy of inhaled beta2 -agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children. METHODS: The study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2-4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences. RESULTS: Median age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group × treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p < .05), but no difference was detected in placebo arm (both p > .26). CONCLUSIONS: In young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.

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

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

Impact of oral corticosteroids on respiratory outcomes in acute preschool wheeze: a randomised clinical trial.

OBJECTIVE: To determine if administration of oral prednisolone to preschool children with acute wheeze alters respiratory outcomes. DESIGN: Double-blind, randomised, placebo-controlled equivalence trial. SETTING: Three hospitals in New Zealand. PATIENTS: 477 children aged 24-59 months with acute wheeze associated with respiratory illness. INTERVENTIONS: 2 mg/kg (maximum 40 mg) oral prednisolone or similar placebo, once daily for 3 days. MAIN OUTCOME MEASURES: Primary outcome was change in Preschool Respiratory Assessment Measure (PRAM) score 24 hours after intervention. Secondary outcomes included PRAM score at 4 hours, length of emergency department and inpatient stays, admission and representation rates, time to return to normal activities and use of additional oral prednisolone or intravenous medications. Analysis was by intention-to-treat. RESULTS: There was no difference between groups for change in PRAM score at 24 hours (difference between means -0.39, 95% CI -0.84 to 0.06, p=0.09). Absolute PRAM score was lower in the prednisolone group at 4 hours (median (IQR) 1 (0-2) vs 2 (0-3), p=0.01) and 24 hours (0 (0-1) vs 0 (0-1), p=0.01), when symptoms had resolved for most children regardless of initial treatment. Admission rate, requirement for additional oral prednisolone and use of intravenous medication were lower in the prednisolone group, although there were no differences between groups for time taken to return to normal activities or rates of representation within 7 days. CONCLUSION: Oral prednisolone does not alter respiratory outcomes at 24 hours or beyond in preschool children presenting with acute wheeze.

Cross-Sectional Association of Lifetime Electronic Cigarette Use with Wheezing and Related Respiratory Symptoms in U.S. Adults.

INTRODUCTION: Electronic cigarette use (vaping) has been found to be associated with respiratory symptoms like wheezing or whistling in the chest. Whether or not lifetime vaping occurrences are associated with wheezing has not yet been investigated. METHODS: Population Assessment of Tobacco and Health (PATH) Study Wave 4 data with 22,233 adults collected from December 2016 to January 2018 were used. The cross-sectional association of lifetime vaping occurrences with wheezing and related respiratory symptoms was examined using multivariable weighted logistic regression models considering the complex sampling design. RESULTS: According to the weighted PATH Wave 4 data, about 89.9% adults never vaped, 3.2% adults vaped one time, 3.2% vaped 2-10 times, 1.3% vaped 11-20 times, 1.1% vaped 21-50 times, 0.4% vaped 51-99 times, and 0.9% vaped 100 or more times in their entire life. Compared to adults who never vaped, adults who vaped 2-10 times had a significantly higher association with ever wheezing (aOR = 1.4, 95% CI: 1.1 to 1.6), past 12-month wheezing (aOR = 1.5, 95% CI: 1.2 to 1.9) and the number of wheezing attacks in the past 12 months (aOR = 1.5, 95% CI: 1.2 to 1.8). Adults who vaped 11-20 times and 100 or more times had similar associations with wheezing as that for adults who vaped 2-10 times. Controlling other tobacco use attenuated the associations. CONCLUSIONS: Lifetime vaping occurrences were found to be associated with some definitions of self-reported wheezing in cross-sectional analyses adjusted for other tobacco use. IMPLICATIONS: Using the cross-sectional PATH Wave 4 data with 22,233 adults, we found significant associations between lifetime vaping occurrences and ever wheezing or whistling in the chest, past 12 months wheezing or whistling in the chest, as well as the number of wheezing attacks in the past 12 months. The study results suggest that larger studies with more precise time frames and measures are needed to further understand possible connections between vaping experimentation and wheezing symptoms that could inform our understanding of the health effects of electronic cigarettes and resultant policy decisions.

Cross-Sectional Association Between Exclusive and Concurrent Use of Cigarettes, ENDS, and Cigars, the Three Most Popular Tobacco Products, and Wheezing Symptoms Among U.S. Adults.

INTRODUCTION: This study assessed the association of exclusive and concurrent use of cigarettes, electronic nicotine delivery systems (ENDS), and cigars with ever and past 12-month wheezing symptoms among a nationally representative sample of US adult current tobacco users. METHODS: Cross-sectional data from the Population Assessment of Tobacco and Health (PATH) Study Wave 3 (W3) were used. The weighted prevalence of self-reported ever and past 12-month wheezing symptoms for noncurrent users compared with users of cigarettes, ENDS, cigars, and any combination of these products (polytobacco use of these tobacco products) were presented for 28 082 adults. The cross-sectional association of tobacco use with self-reported wheezing symptoms was assessed using weighted multivariable and ordinal logistic regression with consideration of complex sampling design. RESULTS: Significantly higher odds of ever had wheezing or whistling in the chest at any time in the past were observed among current cigarette (adjusted odds ratio: 2.62, 95% confidence intervals [CI]: 2.35, 2.91), ENDS (1.49, 95% CI: 1.14, 1.95), and polytobacco users (2.67, 95% CI: 2.26, 3.16) compared with noncurrent users. No associations were seen for cigar use. Polytobacco use was associated with a higher odds of ever wheezing when compared with exclusive ENDS (1.61, 95% CI: 1.19, 2.17) and exclusive cigar use (2.87, 95% CI: 1.93, 4.26), but not exclusive use of cigarettes. CONCLUSIONS: Ever wheezing is associated with the use of cigarettes, ENDS, and polytobacco use of cigarettes, ENDS, and/or cigars, but not cigar use. The association of polytobacco use and wheezing appears to be driven by cigarette use. IMPLICATIONS: Cross-sectional associations with ever and past 12-month wheezing symptoms were found to be the strongest among cigarette users, exclusively or in combination. Future longitudinal research is needed to better understand how cigarette use interacts with other tobacco and nicotine products and contributes to respiratory symptoms.

Metered-dose inhalers versus nebulization for the delivery of albuterol for acute exacerbations of wheezing or asthma in children: A systematic review with meta-analysis.

OBJECTIVES: The benefits of metered-dose inhalers with a spacer (MDI+S) have increasingly been recognized as an alternative method of albuterol administration for treating pediatric asthma exacerbations. The aim of this systematic review was to compare the response to albuterol delivered through nebulization (NEB) with albuterol delivered through MDI+S in pediatric patients with asthma exacerbations. METHODS: We conducted an electronic search in MEDLINE/PubMed, EMBASE, Ovid, and ClinicalTrials. To be included in the review, a study had to a randomized clinical trial comparing albuterol delivered via NEB versus MDI+S; and had to report the rate of hospital admission (primary outcome), or any of the following secondary outcomes: oxygen arterial saturation, heart rate (HR), respiratory rate (RR), the pulmonary index score (PIS), adverse effects, and need for additional treatment. RESULTS: Fifteen studies (n = 2057) met inclusion criteria. No significant differences were found between the two albuterol delivery methods in terms of hospital admission (relative risk, 0.89; 95% confidence interval [CI], 0.55-1.46; I2 = 32%; p = .65). There was a significant reduction in the PIS score (mean difference [MD], -0.63; 95% CI, -0.91 to -0.35; I2 = 0%; p < .00001), and a significantly smaller increase in HR (better; MD -6.47; 95% CI, -11.69 to -1.25; I2 = 0%; p = .02) when albuterol was delivered through MDI+S than when it was delivered through NEB. CONCLUSIONS: This review, an update of a previously-published meta-analysis, showed a significant reduction in the PIS and a significantly smaller increase in HR when albuterol was delivered through MDI+S than when it was delivered through NEB.

[Asthma and cannabis, cocaine or heroin use]. / Asthme et usage de cannabis, de cocaïne ou d'héroïne.

INTRODUCTION: The use of cannabis, cocaine or heroin can be responsible for many respiratory complications including asthma. OBJECTIVES: The aim of this systematic literature review of data was to expose the relations between cannabis, cocaine or heroin use and asthma. RESULTS: Cannabis, cocaine or heroin use by inhalation may be responsible for respiratory symptoms (cough, wheezing), asthma onset, acute asthma exacerbations (which may require intubation and invasive ventilation) or deaths related to asthma. Lower adherence to asthma treatment is also observed. Cannabis induces a rapid bronchodilator effect. In contrast, its chronic use may induce a decrease in specific airway conductance. Studies on forced expiratory volume in one second (FEV1) reduction or decline are discordant. CONCLUSION: Cannabis, cocaine or heroin use must be considered in cases of acute respiratory symptoms or asthma exacerbation in young persons and practitioners must help illicit substance users to stop their consumption.

A Randomized, Doubled-Blind Clinical Trial on the Effect of Zataria multiflora on Clinical Symptoms, Oxidative Stress, and C-Reactive Protein in COPD Patients.

The effects of Zataria multiflora on clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein levels in chronic obstructive pulmonary disease (COPD) patients were evaluated. Forty-five patients were allocated to 3 groups: placebo group and 2 groups that received 3 and 6 mg/kg/day Z. multiflora extract (Z3 and Z6) for 2 months. Clinical symptoms, pulmonary function tests, oxidative stress, and serum C-reactive protein levels were evaluated pretreatment (step 0) and 1 (step I) and 2 (step II) months after treatment. Clinical symptoms including breathlessness and chest wheeze in Z3- and Z6-treated groups and sputum production only in the Z6-treated group were significantly improved 1 and 2 months after treatment compared with baseline values (P < .01 to P < .001). The FEV1 was significantly increased after 2 months of treatment with Z3 and Z6 (P < .05 to P < .01). Malondialdehyde and nitrite levels were significantly decreased after a 2-month treatment with Z6 compared with step 0 (P < .05 to P < .01). The thiol contents in the Z6 group as well as superoxide dismutase and catalase activities in both groups treated with the extract were significantly increased in step II compared with step 0 (P < .05 to P < .01). The C-reactive protein level at the end of the study was significantly reduced compared with the step 0 in both treated groups (P < .05 for both cases). Two-month treatment with Z. multiflora improved clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein in COPD patients. The results suggest that this herbal medicine could be of therapeutic value as a preventive drug for the treatment of COPD.

A multi-center randomized prospective study on the treatment of infant bronchiolitis with interferon α1b nebulization.

BACKGROUND: The respiratory syncytial virus (RSV) is the main cause of bronchiolitis in infants and interferon (IFN) α is a commercial antiviral drug. The nebulization of IFN α1b could be a viable treatment method. In this study, the therapeutic effects and safety of IFN α1b delivery via nebulization in infant bronchiolitis were investigated in this multi-center prospective study. METHODS AND FINDINGS: Bronchiolitis patients admitted to 22 hospitals who met the inclusion criteria were enrolled and randomly allocated to four groups: control, IFN Intramuscular Injection, IFN Nebulization 1 (1 µg/kg), and IFN Nebulization 2 (2 µg/kg) groups. All patients were observed for 7 days. The therapeutic effects and safety of different IFN delivery doses and delivery modes were evaluated. Coughing severity change, as scored by the researchers and parents, between days 1 and 3 was significantly different between the IFN Nebulization 2 and control groups. Lowell wheezing score change between days 3 and 5 was significantly different between IFN Nebulization 1 and control groups. There were no significant differences among the four groups regarding the number of consecutive days with fever, three-concave sign, fatigue and sleepiness, and loss of appetite. There were no cases of severe complications, no recurrence of fever, and no regression of mental status. CONCLUSIONS: IFN-α1b could more effectively alleviate coughing and wheezing in bronchiolitis. IFN-α1b nebulization had significant advantages in shortening the duration of wheezing and alleviating coughing.

Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction.

BACKGROUND: We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze. METHODS: In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children's sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D3 per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D3 per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups. RESULTS: There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance. CONCLUSIONS: Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.).

Change in the symptom profile treated as asthma - two cross-sectional studies twenty years apart.

AIMS: The aims of the study were to investigate prevalence trends of respiratory symptoms, asthma and asthma treatment among young adults in Estonia and to estimate changes in symptom profile among subjects who self-report asthma attacks or use asthma medications. METHODS: Two similar questionnaires on respiratory health were sent to subjects in Tartu, Estonia, aged between 20 and 44 years; first in 1993/94, and then in 2014/15. To study the impact of different respiratory symptoms on asthma diagnosis and treatment, the log-binomial regression was used to estimate the association between 'attack of asthma' (as a proxy for current asthma) and respiratory symptoms as well as asthma treatment and respiratory symptoms, adjusted for age, sex and smoking history. RESULTS: Self-reported prevalence of asthma attack, asthma medication use and nasal allergies increased over the twenty years between studies, whereas there was no change in prevalence of asthma-related symptoms, and the prevalence of most respiratory symptoms either decreased, or remained unchanged. For women experiencing asthma attacks, the prevalence of nasal allergies increased and waking with chest tightness decreased. For men using asthma medication, the prevalence of a wheeze without a cold decreased. Women using asthma medication reported decreased prevalence of waking with chest tightness. CONCLUSION: Self-reported asthma attacks and asthma medication use has increased in last 20 years, while the prevalence of most respiratory symptoms either decreased or did not change. It is likely that changes in asthma symptom profile have had an impact on the prevalence of asthma and asthma treatment.

Efficacy of Macrolides on Acute Asthma or Wheezing Exacerbations in Children with Recurrent Wheezing: A Systematic Review and Meta-analysis.

INTRODUCTION: The role of macrolides for treatment of children with acute asthma or wheezing exacerbations is unclear. OBJECTIVE: The aim of this systematic review was to evaluate the effectiveness of macrolides in children with recurrent wheezing presenting with acute asthma or wheezing exacerbation. METHODS: We conducted an electronic search in MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL, and ClinicalTrials.gov. STUDY SELECTION CRITERIA: Randomized controlled trials of macrolides (any macrolide) compared with placebo or standard treatment in children up to 18 years with recurrent wheezing/asthma presenting with an acute exacerbation. OUTCOMES: Primary outcomes were need for hospitalization and/or time of acute asthma/wheezing symptoms resolution; secondary outcomes were duration of stay in the emergency department (ED)/clinic, severity of symptoms of the index episode, use of additional systemic corticosteroids or short active ß-2 agonists, changes in lung function measures, ED visit/hospitalization during first week after index episode, time to next exacerbation, or adverse effects (AEs). RESULTS: Only three studies met the inclusion criteria (n = 334 children, 410 treated episodes); two studies included recurrent wheezers and the third included asthmatic children. There was no difference in hospitalization between groups, but children treated with macrolides had a significantly lower time to symptoms resolution than controls, although the magnitude of benefit remains to be quantified due to no normal distribution data presented. There was no difference in time to next episode of exacerbation (HR 0.96; 95% CI 0.71-1.28; I2 = 0%; p = 0.77). In one study, children receiving macrolides had a significant decrease in the severity of symptoms, decrease use of salbutamol, and another study showed improved lung function. No study evaluated antibiotic resistance development. CONCLUSIONS: Limited evidence support that a macrolide trial could be considered in children with acute asthma or recurrent wheezing exacerbation.

Considerations for the Child with Nonatopic Asthma.

Asthma guidelines provide clinicians with evidence-based management strategies for this chronic condition. The preferred therapy for patient with persistent asthma is inhaled corticosteroids. However, ∼40% of the patients with persistent asthma continue to present with symptoms while treated according to the guidelines. Multiple factors are being explored to explain the variability in response to inhaled corticosteroids including asthma phenotype and genetic predisposition among others. The nonatopic asthma phenotype has been described in the literature. These patients tend to have milder symptoms of asthma and typically outgrow their asthma by adolescence. They present with chronic asthma symptoms in the absence of a positive allergy test, either skin prick test or specific immunoglobulin E blood test. Although patients with nonatopic asthma share many characteristics with patients with atopic asthma, there are several studies that suggest a different inflammatory pathway may be involved in their pathophysiology. Therefore, it is possible that children with nonatopic asthma could respond differently to inhaled corticosteroids compared with those with atopic asthma. Currently there is a variable definition of this phenotype. Furthermore, there is a paucity of therapeutic trial directed toward the patients with nonatopic asthma specifically. Future research should be guided toward identifying the inflammatory pathways in nonatopic asthma and potential phenotype-guided therapies.

The Evaluation of Changes in the Breath Sound Spectrum with Bronchoconstriction and Bronchodilatation in Asthmatic Children.

OBJECTIVE: Focusing on the relative-middle sound area of the breath sound spectrum, the relationship between airway changes and breath sounds in asthmatic children was investigated. METHODS: In Study 1, 77 children (6-16 years old) were included. The breath sound parameters, the ratio of the second area to the third area of the power spectrum (A2/A3) and the ratio of the third area to the fourth area (B3/B4) were evaluated 3 times, before and just after methacholine inhalation and after ß2 agonist inhalation. Other breath sound parameters, the frequency limiting 99% of the power spectrum (F99), the rolloff from 600-1200 Hz (Slope) and the ratio of the third and fourth area to the total area under the curve (A3/AT and B4/AT), and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF75 and RPF50), were also evaluated. In Study 2, 91 children (6-16 years old) were included, with evaluations performed twice: before and after ß2 a gonist inhalation. Spirography a nd forced o scillation technique were also performed. RESULTS: In Study 1, A2/A3 and B3/B4 were significantly increased after methacholine inhalation and decreased after ß2 agonist inhalation (p < 0.001, P < 0.001, respectively). In Study 2, A2/A3 and B3/B4 were significantly decreased after ß2 agonist inhalation. These changes in A3/AT and B4/AT were the inverse of those in other spectrum curve indices. CONCLUSIONS: A2/A3 and B3/B4, indicate the breath sound changes after bronchoconstriction and bronchodilatation. These parameters may be useful for assessing bronchial reversibility in asthmatic children.

Vitamin D for secondary prevention of acute wheeze attacks in preschool and school-age children.

INTRODUCTION: Vitamin D is best known for its role in bone health; however, the discovery of the vitamin D receptor and the expression of the gene encoding the vitamin D 1α-hydroxylase (CYP27B1) enzyme in a wide variety of tissues including immune cells and respiratory epithelium has led to the discovery of potential roles for vitamin D in the prevention of acute wheeze. METHODS: We review here the literature concerning the relationships between circulating 25-hydroxyvitamin D (25(OH)D) concentration and secondary prevention of acute wheeze attacks in preschool and school-age children. RESULTS: Epidemiological data suggest that vitamin D insufficiency (25(OH)D <75 nmol/L) is highly prevalent in preschool and school-age children with wheeze. Preschool age children with a history of wheeze attacks and circulating 25(OH)D <75 nmol/L are at increased risk and frequency of future acute wheeze. However, no consistent association between low vitamin D status and risk of acute wheeze is reported in school-age children. Seven randomised controlled trials (RCTs) with relatively small sample sizes (30-430) and variable quality showed inconsistent results regarding the effect of oral vitamin D supplementation during childhood on the risk of asthma attacks, asthma symptom control, inhaled corticosteroid requirements, spirometry and unscheduled healthcare attendances for wheeze. A RCT showed that vitamin D supplementation had no effect on the frequency of unplanned healthcare attendances due to acute wheeze in 22 preschool children. DISCUSSION: An evidence-based recommendation for the use of vitamin D as a preventive therapy for wheeze attacks cannot be made until results of further trials are available. The assessment of circulating 25(OH)D concentration and the optimisation of vitamin D status to prevent acute respiratory tract infections, and to maintain skeletal and general health in preschool and school-age children with acute wheeze is worthwhile in its own right, but whether this will reduce the risk of acute wheeze attacks is unclear.