Preschool Wheeze Research Articles

Enigma variations: The multi-faceted problems of pre-school wheeze.

Numerous publications on wheezing disorders in children younger than 6 years have appeared in the medical literature over the last decades with the aim of shedding light on the mechanistic pathways (endotypes) and treatment. Nevertheless, there is yet no consensus as to the appropriate way to manage preschool wheeze mainly because of the lack of a clear definition of "preschool asthma" and the paucity of scientific evidence concerning its underlying endotypes. A symptom-based approach is inadequate since the human airway can respond to external stimuli with a limited range of symptoms and signs, including cough and wheeze, and these manifestations represent the final expression of many clinical entities with potentially different pathophysiologies requiring different individualized treatments. Hence, new studies challenge the symptom-based approach and promote the importance of managing the wheezy child based on the "airway phenotype." This will enable the clinician to identify not only the child with a serious underlying pathology (e.g., a structural airway disorder or immunodeficiency) who is in need of prompt and specific treatment but also increase the specificity of treatment for the child with symptoms suggestive of an "asthma" syndrome. In the latter case, focus should be given to the identification of treatable traits. This review summarizes the current understanding in management of preschool wheezing and highlights the unmet need for further research.

How to Choose the Correct Drug in Severe Pediatric Asthma.

When a child with severe asthma (asthma defined clinically for the purposes of this review as wheeze, breathlessness, and chest tightness sometimes with cough) does not respond to treatment, it is important to be sure that an alternative or additional diagnosis is not being missed. In school age children, the next step is a detailed protocolized assessment to determine the nature of the problem, whether within the airway or related to co-morbidities or social/environmental factors, in order to personalize the treatment. For example, those with refractory difficult asthma due to persistent non-adherence may benefit from using budesonide and formoterol combined in a single inhaler [single maintenance and reliever treatment (SMART)] as both a reliever and preventer. For those with steroid-resistant Type 2 airway inflammation, the use of biologicals such as omalizumab and mepolizumab should be considered, but for mepolizumab at least, there is a paucity of pediatric data. Protocols are less well developed in preschool asthma, where steroid insensitive disease is much more common, but the use of two simple measurements, aeroallergen sensitization, and peripheral blood eosinophil count, allows the targeted use of inhaled corticosteroids (ICSs). There is also increasing evidence that chronic airway infection may be important in preschool wheeze, increasing the possibility that targeted antibiotics may be beneficial. Asthma in the first year of life is not driven by Type 2 inflammation, so beyond avoiding prescribing ICSs, no evidence based recommendations can be made. In the future, we urgently need to develop objective biomarkers, especially of risk, so that treatment can be targeted effectively; we need to address the scandal of the lack of data in children compared with adults, precluding making evidence-based therapeutic decisions and move from guiding treatment by phenotypes, which will change as the environment changes, to endotype based therapy.

The Role of Breastfeeding on Respiratory Outcomes Later in Childhood.

BackgroundBreastfeeding is associated with a lower risk of wheezing in early childhood, but its effect later in childhood remains unclear. We investigated the association of breastfeeding and respiratory outcomes in children aged 11 years.Materials and MethodsWe performed an observational longitudinal study including 110 prepubertal children. Information about breastfeeding duration, wheezing and asthma was collected by questionnaires. At 11 years of age, we measured spirometry parameters, lung volumes, diffusing lung capacity, and fractional exhaled nitric oxide. We used logistic and linear regression models to examine the associations of breastfeeding duration with the odds of asthma and lung function measures. All multivariable analyses were adjusted for sex, smoking during pregnancy, gestational age at birth, twins, and mode of delivery (confounder model).ResultsBreastfeeding duration was associated with FEV1 z-score [β = 0.04, CI 95% (0.02–0.09)], FEF75 z-score [β = 0.06, CI 95% (0.03–0.09)] and FEV1/FVC z-score [β = 0.03, CI 95% (0.00–0.07)], but not with diffusing lung capacity and fractional exhaled nitric oxide. No association of breastfeeding duration with preschool wheezing, ever asthma and current asthma was documented.ConclusionWe showed that children breastfed for longer time presented higher FEV1, FEV1/FVC, and FEF75 z-score values at 11 years of age compared to children breastfed for shorter time, suggesting a protective effect of breastfeeding on airways, and not on lung parenchyma (lung volumes and alveolar capillary membrane) or allergic airway inflammation. The positive effect of breastfeeding duration on lung function lays the foundation to promote breastfeeding more and more as effective preventive measure.

The role of respiratory syncytial virus- and rhinovirus-induced bronchiolitis in recurrent wheeze and asthma-A systematic review and meta-analysis.

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis. RSV-induced bronchiolitis has been associated with preschool wheeze and asthma in cohort studies where the comparison groups consist of healthy infants. However, recent studies identify rhinovirus (RV)-induced bronchiolitis as a potentially stronger risk factor for recurrent wheeze and asthma. This systematic review and meta-analysis aimed to compare the associations of RSV- and RV-induced bronchiolitis with the development of preschool wheeze and childhood asthma. We performed a systematic search of the published literature in five databases by using a MeSH term-based algorithm. Cohort studies that enrolled infants with bronchiolitis were included. The primary outcomes were recurrent wheeze and asthma diagnosis. Wald risk ratios and odds ratios (ORs) were estimated, along with their 95% confidence intervals (CIs). Individual and summary ORs were visualized with forest plots. There were 38 studies included in the meta-analysis. Meta-analysis of eight studies that had data on the association between infant bronchiolitis and recurrent wheeze showed that the RV-bronchiolitis group were more likely to develop recurrent wheeze than the RSV-bronchiolitis group (OR 4.11; 95% CI 2.24-7.56). Similarly, meta-analysis of the nine studies that had data on asthma development showed that the RV-bronchiolitis group were more likely to develop asthma (OR 2.72; 95% CI 1.48-4.99). This is the first meta-analysis that directly compares between-virus differences in the magnitude of virus-recurrent wheeze and virus-childhood asthma outcomes. RV-induced bronchiolitis was more strongly associated with the risk of developing wheeze and childhood asthma.

Wheeze trajectories: Determinants and outcomes in the CHILD Cohort Study

Wheezing in early life is associated with asthma in adulthood; however, the determinants of wheezing trajectories and their associations with asthma and lung function in childhood remain poorly understood. In the CHILD Cohort Study, we aimed to identify wheezing trajectories and examine the associations between these trajectories, risk factors, and clinical outcomes at age 5 years. Wheeze data were collected at 8 time points from 3 months to 5 years of age. We used group-based trajectory models to derive wheeze trajectories among 3154 children. Associations with risk factors and clinical outcomes were analyzed by weighted regression models. We identified 4 trajectories: a never/infrequent trajectory, transient wheeze, intermediate-onset (preschool) wheeze, and persistent wheeze. Higher body mass index was a common risk factor for all wheeze trajectories compared with that in the never/infrequent group. The unique predictors for specific wheeze trajectories included male sex, lower respiratory tract infections, and day care attendance for transient wheeze; paternal history of asthma, atopic sensitization, and child genetic risk score of asthma for intermediate wheeze; and maternal asthma for persistent wheeze. Blood eosinophil counts were higher in children with the intermediate wheeze trajectory than in those children with the other trajectories at the ages of 1 and 5 years. All wheeze trajectories were associated with decreased lung function and increased risk of asthma at age 5 years. We identified 4 distinct trajectories in children from 3 months to 5 years of age, reflecting different phenotypes of early childhood wheeze. These trajectories were characterized by different biologic and physiologic traits and risk factors.

Modifiable environmental factors predispose term infants to bronchiolitis but bronchiolitis itself predisposes to respiratory sequelae

Viral bronchiolitis is a common lower respiratory tract infection in infants. Environmental and genetic factors can favor respiratory tract infections. The aim of this study is to analyze risk factors for bronchiolitis and to investigate the predisposing factors for developing transient wheezing and asthma through a 6-year follow-up after hospitalizationfor bronchiolitis compared with a group of healthy controls that belonged to Piccolipiù cohort,who never had bronchiolitis. We enrolled 645 infants hospitalized with bronchiolitis. A structured questionnaire was used to obtain demographic and clinical data. At 6 years of age, 370 cases and 183 controls were investigated for the presence of asthma by the structured questionnaire, for prick test and for spirometry, and were classified to asthmatic, transient wheezing, and no wheezing/no asthma. Breastfeeding was an independent protective factor (odds ratio [OR]: 0.3, 95% confidence interval [95% CI]:0.2-0.4, p < 0.001) and tobacco smoke was a risk factor for the development of bronchiolitis (OR: 2.1, 95% CI: 1.4-3.1, p < 0.001). Analyzing follow-up, bronchiolitis increased the risk of developing transient wheezing by 12.9 (95% CI: 6.3-26.1, p < 0.001) and of developing asthmaby 4.6 (95% CI: 1.9-10.7, p < 0.001). A positive family history of atopy increased the risk of developing asthma by 3.1 (95% CI: 1.4-6.7, p = 0.005). Asthmatic patients had a lower % FEV1, a lower % flow-volume curve (FVC), and a lower FEV1/FVC value, and they had more frequently positive skin prick test. Bronchiolitis is influenced by environmental factors: tobacco smoke increases its risk and breastfeeding is a protective factor. At the end of 6 years of follow-up, bronchiolitis is a significant risk factor to have pre-school wheezing and asthma.

Lung clearance index predicts persistence of preschool wheeze.

The lung clearance index (LCI) is a measure of pulmonary function. Variable feasibility (50->80%) in preschool children has been reported. There are limited studies exploring its relationship to respiratory symptoms and how it predicts persistent wheeze. We aimed to assess the association with respiratory symptoms in preschool-aged children with LCI and determine its utility in predicting persistent wheeze. LCI was measured in a subcohort of the CHILD Cohort Study at age 3years using SF6 multiple breath washout test mass spectrometry. Respiratory symptom phenotypes at age 3 were derived from children's respiratory symptoms reported by their parents. Responses were used to categorize children into 4symptom groups: recurrent wheeze (3RW), recurrent cough (3RC), infrequent symptoms (IS), and no current symptoms (NCS). At age 5years, these children were seen by a specialist clinician and assessed for persistent wheeze (PW). At age 3years, 69% (234/340) had feasible LCI. Excluding two children with missing data, 232 participants were categorized as follows: 33 (14%) 3RW; 28 (12%) 3RC; 17 (7%) IS; and 154 (66%) NCS. LCI z-score at age 3years was highest in children with 3RW compared to 3RC (mean (SD): 1.14 (1.56) vs. 0.09 (0.95), p<.01), IS (mean (SD): -0.14 (0.59), p<.01), and NCS (mean (SD): -0.08 (1.06), p<.01). LCI z-score at age 3 was predictive of persistent wheeze at age 5 (PW) (AUROC: 0.87). LCI at age 3 was strongly associated with recurrent wheeze at age 3, and predictive of its persistence to age 5.

Impact of Oral Corticosteroids on Respiratory Outcomes in Acute Preschool Wheeze: A Randomised Clinical Trial

To determine if oral prednisolones given to acutely wheezing preschool-aged children alter respiratory outcomes.A total of 3247 children (aged 24–59 months) with acute wheezing episodes between August 2014 and September 2016 in 3 New Zealand emergency departments (EDs) were potentially eligible. A total of 493 were randomly assigned, and 477 patients were included in the intention-to-treat analysis (238 in the prednisolone group and 239 in the placebo group). Primary outcome data were available on 393 patients (82% overall; 195 (79%) in the prednisolone group and 198 (83%) in the placebo group). Children <24 months of age were purposely excluded, ensuring that those with bronchiolitis were not included.In this double-blind placebo-controlled trial, preschool-aged children with viral-induced wheeze who presented to the ED were randomly assigned to receive 3 days of prednisolone (2 mg/kg) or a placebo. The primary outcome measure was a change in the validated Preschool Respiratory Assessment Measure (PRAM) score 24 hours after the intervention. Secondary outcomes included PRAM score at 4 hours, admission rate, length of ED and inpatient stay, amount of albuterol given in 48 hours, additional treatment with open-label prednisolone, time to return to normal activity, and adverse events, including the need for intravenous (IV) medication, ICU admission, and representation to the ED or primary care provider within 7 days. Pediatric Respiratory Assessment Measure (PRAM) scores (ranging from 0–12) were calculated on the basis of suprasternal retractions, scalene retractions, wheezing, and oxygen saturation in room air. The study was designed as an equivalence trial and powered (power: 95%) to detect the minimal difference in PRAM scores that would disprove the null hypothesis that corticosteroids and placebo are equivalent treatments. In a pilot study (n = 137), researchers determined a SD of 2.3 for change in PRAM score at 24 hours was significant. Therefore, analysis was by intention to treat.Between groups, there was no difference in the primary outcome, the change in PRAM score at 24 hours (difference between means: −0.39; 95% confidence interval [CI]: −0.84 to 0.06, P = .09). The median PRAM score at 24 hours for both groups was 0, with only approximately one-third in either group showing mild disease (PRAM score 1–4) and few with PRAM scores >4 (2.0% and 3.6% in treatment and control groups, respectively). Change in PRAM score at 4 hours was significantly different in the treatment group (−0.67; 95% CI: −1.18 to −0.16; P = .01). No difference in length of ED stay was observed (−0.57; 95% CI: −1.15 to 0.02; P = .06), although admission to the hospital occurred more often in the placebo group (0.67; 95% CI: 0.45 to 1.01; P = .05) as well as additional corticosteroid (0.22; 95% CI: 0.06 to 0.79; P = .01) and IV medication use (0.27; 95% CI: 0.07 to 0.96; P = .03). No difference was observed in representation to the hospital or the primary care provider within 7 days (P = .33 and P = .22, respectively) or ICU admission (undefined P value because only 2 total children went to the ICU) as well as the amount of albuterol given in 48 hours (P = .27).Oral prednisolone does not alter respiratory outcomes at 24 hours or beyond in preschool-aged children presenting with acute wheezing to the ED because most children improved after 24 hours regardless of initial treatment. Subgroup analyses revealed no evidence that the 24-hour treatment effect differed for albuterol responsive children, those with a positive Asthma Predictive Index, or more severe disease at presentation (higher PRAM score). However, those who received prednisolone had less respiratory distress 4 hours after medication administration and a reduced requirement for hospital admission, additional corticosteroid, or IV treatment. These findings suggest that early in-hospital administration of oral prednisolone to preschoolers with wheeze may prevent further deterioration and requirement for escalation of therapy. Additionally, considering the lack of significant difference at 24 hours, oral prednisolone may improve short-term respiratory outcomes for preschoolers presenting with wheeze. However, subsequent doses of oral prednisolone may provide no additional therapeutic benefit.With this robustly designed randomized controlled trial, we are reminded that wheezing preschoolers are a heterogeneous group with numerous factors contributing to a wheezy phenotype. We should consider that they should not be treated the same as older asthmatics, with regards to corticosteroids. With this study, the authors question oral steroid dosing dogma and demonstrate that oral prednisolone may improve short-term respiratory outcomes for wheezing preschoolers but subsequent doses of oral prednisolone may provide no additional therapeutic benefit. Further studies are needed in this population to understand the timing and dosing of corticosteroids.

Blood eosinophils in managing preschool wheeze: Lessons learnt from a proof-of-concept trial.

Management of preschool wheeze is based predominantly on symptom patterns. To determine whether personalizing therapy using blood eosinophils or airway bacterial infection results in fewer attacks compared with standard care. A proof-of-concept, randomized trial to investigate whether the prescription of inhaled corticosteroids (ICS) guided by blood eosinophils, or targeted antibiotics for airway bacterial infection, results in fewer unscheduled healthcare visits (UHCVs) compared with standard care. Children aged 1-5years with ≥2 wheeze attacks in the previous year were categorized as episodic viral wheeze (EVW) or multiple trigger wheeze (MTW). The intervention group was prescribed ICS if blood eosinophils ≥3%, or targeted antibiotics if there is positive culture on induced sputum/cough swab. The control group received standard care. The primary outcome was UHCV at 4months. 60 children, with a median age of 36.5 (range 14-61) months, were randomized. Median blood eosinophils were 5.2 (range 0-21)%, 27 of 60 (45%) children were atopic, and 8 of 60 (13%) had airway bacterial infection. There was no relationship between EVW, MTW and either blood eosinophils, atopic status or infection. 67% in each group were prescribed ICS. 15 of 30 control subjects and 16 of 30 patients in the intervention group had UHCV over 4months (p=.8). The time to first UHCV was similar. 50% returned adherence monitors; in those, median ICS adherence was 67%. There were no differences in any parameter between those who did and did not have an UHCV. Clinical phenotype was unrelated to allergen sensitization or blood eosinophils. ICS treatment determined by blood eosinophils did not impact UHCV, but ICS adherence was poor.

Maternal diet in pregnancy and child's respiratory outcomes: an individual participant data meta-analysis of 18 000 children.

RationaleSevere fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health.MethodsWe performed an individual participant meta-analysis among 18 326 mother–child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diets were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured using questionnaires and lung function by spirometry.ResultsAfter adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower forced vital capacity (FVC) in children (z-score difference −0.05, 95% CI −0.08– −0.02, per interquartile range increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. In an exploratory examination of the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low forced expiratory volume in 1 s/FVC (z-score <−1.64) (OR 1.20, 95% CI 1.06–1.36 and z-score difference 1.40, 95% CI 1.06–1.85, compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%, respectively.ConclusionThe main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.

Assessing the feasibility and acceptability of online measurements of exhaled volatile organic compounds (VOCs) in children with preschool wheeze: a pilot study

BackgroundInvestigating airway inflammation and pathology in wheezy preschool children is both technically and ethically challenging. Identifying and validating non-invasive tests would be a huge clinical advance. Real-time analysis of exhaled...

Early Life Factors Associated with Preschool Wheezing in Preterm Infants.

Advanced neonatal care has increased the survival of neonates born prematurely, and prematurity is a well-known risk factor for asthma/wheezing disorders. Thus, this prospective study aimed to determine the early life factors associated with preschool wheezing in premature neonates. Preterm neonates born between 2012 and 2017 were recruited, excluding those with bacterial infection within 7 days of life, maternal sepsis, and maternal chorioamnionitis. Birth and admission history, comorbidities, and maternal history were documented. Respiratory problems were followed-up at the neonatal outpatient department. Patients were divided into wheezing and non-wheezing groups. Data were analyzed using the Mann–Whitney test and Fisher’s exact test, and multivariable logistic regression was used to define the risk factors of preschool wheezing/asthma. A total of 125 preterm infants were enrolled, including 19 in the wheezing group and 106 in the non-wheezing group. Patients in the wheezing group had longer duration of intubation (p = 0.025), higher rates for exclusive breast milk feeding (p = 0.012), and higher re-hospitalization rates for respiratory tract infections (p < 0.001), especially for respiratory syncytial virus (RSV) bronchiolitis (p = 0.045). The incidence of allergic rhinitis was also higher in the wheezing group (p = 0.005). After multivariable logistic regression, allergic rhinitis and re-hospitalization for respiratory tract infections were two significant risk factors for preschool wheezing/asthma in premature neonates. Close follow-up of premature infants at high risk for asthma susceptibility is recommended.

The First 1000 Days: Impact of Prenatal Tobacco Smoke Exposure on Hospitalization Due to Preschool Wheezing.

Preschool wheezing and related hospitalization rates are increasing. Prenatal tobacco smoke exposure (PTSE) increases the risk of wheezing, yet >20% of French women smoke during pregnancy. In this observational retrospective monocentric study, we assessed the link between PTSE and hospital admissions. We included infants <2 years of age admitted for acute wheezing. A phone interview with mothers was completed by electronic records. The primary endpoint was the ratio of cumulative duration of the hospitalization stays (days)/age (months). 129 children were included (36.4% exposed to PTSE vs. 63.6% unexposed). There was a significant difference in the duration of hospitalization/age: 0.9 days/month (exposed) vs. 0.58 days/month (unexposed) (p = 0.008). Smoking one cigarette/day during pregnancy was associated with an increase in hospitalization duration of 0.055 days/month (r = 0.238, p = 0.006). In the multi-variable analysis, this positive association persisted (β = 0.04, p = 0.04; standardized β = 0.27, p = 0.03). There was a trend towards a dose-effect relationship between PTSE and other important parameters associated with hospital admissions. We have demonstrated a dose-effect relationship, without a threshold effect, between PTSE and duration of hospitalization for wheezing in non-premature infants during the first 2 years of life. Prevention campaigns for future mothers should be enforced.

Passive tobacco smoke in children and young people during the COVID-19 pandemic

Second-hand smoke (SHS) exposure is harmful to children and young people. They inhale double the amount of dust compared with adults, thus inhaling more smoke containing dust particles. They also have faster respiratory rates and narrower airways, meaning their SHS exposure is higher. SHS causes an increased incidence of respiratory infection, cough, increased sputum load, preschool wheeze, and asthma, and is also associated with significantly decreased lung function. It worsens pre-existing chronic respiratory conditions, including being a trigger for asthma attacks and contributing to the pathogenesis of asthma and pre-school wheeze.

Postdischarge Recovery after Acute Pediatric Lung Disease Can Be Quantified with Digital Biomarkers

Background: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery, but little is known regarding the time to full recovery after hospital discharge. Technological innovations have led to increased interest in home-monitoring and digital biomarkers. The aim of this study was to describe at-home recovery of 3 common pediatric respiratory diseases using a questionnaire and wearable device. Methods: In this study, patients admitted due to pneumonia (n = 30), preschool wheezing (n = 30), and asthma exacerbation (AE; n = 11) were included. Patients were monitored with a smartwatch and a questionnaire during admission, with a 14-day recovery period and a 10-day “healthy” period. Median compliance was calculated, and a mixed-effects model was fitted for physical activity and heart rate (HR) to describe the recovery period, and the physical activity recovery trajectory was correlated to respiratory symptom scores. Results: Median compliance was 47% (interquartile range [IQR] 33–81%) during the entire study period, 68% (IQR 54–91%) during the recovery period, and 28% (IQR 0–74%) during the healthy period. Patients with pneumonia reached normal physical activity 12 days postdischarge, while subjects with wheezing and AE reached this level after 5 and 6 days, respectively. Estimated mean physical activity was closely correlated with the estimated mean symptom score. HR measured by the smartwatch showed a similar recovery trajectory for subjects with wheezing and asthma, but not for subjects with pneumonia. Conclusions: The digital biomarkers, physical activity, and HR obtained via smartwatch show promise for quantifying postdischarge recovery in a noninvasive manner, which can be useful in pediatric clinical trials and clinical care.

Inter-society consensus for the use of inhaled corticosteroids in infants, children and adolescents with airway diseases

BackgroundIn 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine.MethodsClinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published.ResultsThe expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm.ConclusionsWe provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research.

Effects of the COVID-19 pandemic and lockdown on symptom control in preschool children with recurrent wheezing.

IntroductionPreschool wheezers are at high risk of recurrent attacks triggered by respiratory viruses, sometimes exacerbated by exposure to allergens and pollution. Because of the COVID‐19 infection, the lockdown was introduced, but the effects on preschool wheezers are unknown. We hypothesized that there would be an improvement in outcomes during the lockdown, and these would be lost when the lockdown was eased.Materials and MethodsPatients underwent medical visits before and after the COVID‐19 lockdown. We recorded the childhood Asthma Control Test (cACT) and a clinical questionnaire. Data on symptoms, the need for medications and the use of healthcare resources were recorded. We compared these data with retrospective reports from the preceding year and prospectively acquired questionnaires after lockdown.ResultsWe studied 85 preschool wheezers, mean age 4.9 years. During the lockdown, cACT score was significantly higher (median 25 vs. 23); families reported a dramatic drop in wheezing episodes (51 vs. none), significant reductions in the day and nighttime symptoms, including episodes of shortness of breath (p < .0001); the use of salbutamol and oral corticosteroids (OCS) dropped significantly (p < .0001) and 79 (95%) patients needed no OCS bursts during the lockdown. Finally, patients had significantly fewer extra medical examinations, as well as fewer Emergency Room visits (p < .0001). All were improved compared with the same time period from the previous year, but outcomes worsened significantly again after lockdown (cACT median: 22).ConclusionsDuring the national lockdown, children with persistent preschool wheeze showed a significant clinical improvement with reduction of respiratory symptoms, medication use for exacerbations, and use of healthcare resources. This trend reversed when lockdown restrictions were eased.

Mitochondria are involved in bronchial smooth muscle remodeling in severe preschool wheezers

Bronchial remodeling is a key feature of asthma that is already present in preschoolers with wheezing. Moreover, bronchial smooth muscle (BSM) remodeling at preschool age is predictive of asthma at school age. However, the mechanism responsible for BSM remodeling in preschoolers with wheezing remains totally unknown. In contrast, in adult asthma, BSM remodeling has been associated with an increase in BSM cell proliferation related to increased mitochondrial mass and biogenesis triggered by an altered calcium homeostasis. Indeed, BSM cell proliferation was decreased invitro by the calcium channel blocker gallopamil. Our aim was to investigate the mechanisms involved in BSM cell proliferation in preschoolers with severe wheezing, with special attention to the role of mitochondria and calcium signaling. Bronchial tissue samples obtained from 12 preschool controls without wheezing and 10 preschoolers with severe wheezing were used to measure BSM mass and establish primary BSM cell cultures. BSM cell proliferation was assessed by manual counting and flow cytometry, ATP content was assessed by bioluminescence, mitochondrial respiration was assessed by using either the Seahorse or Oroboros technique, mitochondrial mass and biogenesis were assessed by immunoblotting, and calcium response to carbachol was assessed by confocal microscopy. The effect of gallopamil was also evaluated. BSM mass, cell proliferation, ATP content, mitochondrial respiration, mass and biogenesis, and calcium response were all increased in preschoolers with severe wheezing compared with in the controls. Gallopamil significantly decreased BSM mitochondrial biogenesis and mass, as well as cell proliferation. Mitochondria are key players in BSM cell proliferation in preschoolers with severe wheezing and could represent a potential target to treat BSM remodeling at an early stage of the disease.

Novel Treatment-Refractory Preschool Wheeze Phenotypes Identified by Cluster Analysis of Lung Lavage Constituents

Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids. Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective. To apply unsupervised analysis of lung lavage (bronchoalveolar lavage [BAL]) variables to identify clusters of preschool children with treatment-refractory wheeze. A total of 155 children 6 years or younger underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis and sorted into clusters by Ward's method, and membership was confirmed by discriminant analysis. The model was repeatable in a 48-case validation sample and accurately classified 86% of cases. Cluster 1 (n= 60) had early-onset wheeze, 85% with structural abnormalities, mostly tracheamalacia, with low total IgE and agranulocytic BAL. Cluster 2 (n= 42) had later-onset wheeze, the highest prevalence of gastroesophageal reflux, little atopy, and two-third had increased BAL lipid-laden macrophages. Cluster 3 (n= 46) had mid-onset wheeze, low total IgE, and two-third had BAL viral transcripts, predominately human rhinovirus, with BAL neutrophilia. Cluster 4 (n= 7) was older, with high total IgE, blood eosinophilia, and mixed BAL eosinophils and neutrophils. Preschool children with recurrent wheeze refractory to inhaled corticosteroid treatment include 4 clusters: airway malacia, gastroesophageal reflux, indolent human rhinovirus bronchoalveolitis, and type-2high inflammation. The results support the risk and cost of invasive bronchoscopy to diagnose causes of treatment-refractory wheeze and develop novel therapies targeting airway malacia, human rhinovirus infection, and BAL neutrophilia in preschool children.

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

ObjectiveTo determine if administration of oral prednisolone to preschool children with acute wheeze alters respiratory outcomes.DesignDouble-blind, randomised, placebo-controlled equivalence trial.SettingThree hospitals in New Zealand.Patients477 children aged 24–59 months with acute...