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Rationale: Experimental studies and epidemiological data in adults suggest that somatomedin-C (insulin-like growth factor-1, IGF-1) may play a role in asthma by modulating airway inflammation, bronchial hyperreactivity, and airway smooth muscle hyperplasia. However, its role in children with asthma is not well understood., Methods: We established a birth cohort with 339 Chilean pregnant mothers enrolled at the time of delivery from December 2014 to January 2016. We obtained cord blood at birth and followed the offspring every 6 months until 30 months of age, recording data on atopy, wheezing, and other respiratory illnesses. We measured IGF-1 in cord blood and determined the Asthma Predictive Index (API) at 30 months. The cohort was divided according to the API., Results: Complete data were available for 307/339 (91%) dyads, including 44 preschoolers with API+ and 263 with API-. Demographic characteristics were similar between groups, but mothers of API+ children had a higher prevalence of obesity, previous use of oral contraceptives, and higher education than those of API- children. API+ children had higher birth weight and significantly higher IGF-1 in cord blood (37.4 ± 13.2 in API+ vs. 30.5 ± 13.0 ng/ml in API-, p = .01). In the multivariable analysis, IGF-1 in cord blood remained independently associated with a higher risk of asthma (adjusted OR for API+ per ng/ml higher IGF-1 = 1.03 [1.0-1.06], p = .015)., Conclusions: Higher insulin-like growth factor-1 in cord blood is associated with asthma risk in the preschool years., (© 2023 Wiley Periodicals LLC.)

Background: Lung function in children with persistent asthma may be impaired during preschool and school ages. The aim of this study was to describe if some preschool impulse oscillometry (IOS) parameters are related to spirometry alterations on reaching school age., Methods: In 66 diagnosed with persistent asthma, an IOS was performed at entrance and followed-up to school age where a spirometry was done., Results: The mean age was 4.9 years at the first evaluation and 7.9 years at the second evaluation, and 59.1% were male. During preschool, R5, R20, Fres, AX, and D5-20 were found to have diagnostic accuracy (area under the curve > 0.7) for predicting abnormal spirometry during school age (defined as FEV1 and/or FEV/FVC and/or FVC values below the lower limit of normality according to Quanjer predictive values). AX, D5-20, and R5 had the best LR+ to increase the probability of abnormal spirometry (50, 10, and 7.1, respectively). R20, R5, and AX was the best IOS parameters for discriminating bronchodilator response (BDR) in schoolchildren (LR+ = 3.4, 2.9, and 2.8, respectively)., Conclusion: The findings of this study indicate that some IOS parameters between 3 and 5 years of age are useful for predicting abnormal spirometry and BDR at school age., (© 2023 Wiley Periodicals LLC.)

Introduction: High altitude pulmonary edema (HAPE) is a form of acute noncardiogenic pulmonary edema caused by altitude-related hypoxia seen in children as well as in adults. In this systematic review we focus in HAPE occurring in children and adolescents., Methods: A systematic review was conducted including publications in children 0-18 years of age from three databases up to June 2022., Results: Thirty-five studies representing 210 cases were found. The mean age was 9.8 ± 3.6 years with a male/female ratio of 2.6. The peak age incidence was seen in children between 6 and 10 years old. Only two children (0.9%) were ≤2 years old. The mean altitude in 166 cases was 2861 masl. Only 17 cases (8.1%) occurred at altitudes below 2500 masl. Regarding the different HAPE subtypes there was a predominance of re-entry HAPE (R-HAPE) with 58%, followed by classic HAPE (C-HAPE) with 37.6%. The mean time between arrival and onset of symptoms was 16.5 h. The mortality rate was 1.4%. In 10/28 (36%) of C-HAPE cases there was a structural cardiac/pulmonary anomaly compared to 1/19 (5%) in R-HAPE (p < 0.01). HAPE recurrence was found in 46 cases (21.9%). The involvement in the chest X-rays was seen predominantly in the apices and in the right lung., Conclusions: R-HAPE was the most common HAPE subtype; HAPE peak age was found between 6 and 10 years of age; HAPE was more frequent in males and was rare in children under 2 years old; associated HAPE structural abnormalities were more common in C-HAPE than in R-HAPE., (© 2022 Wiley Periodicals LLC.)

Background: Observational studies suggest that asthma/wheezing improves after adenotonsillectomy (AT). However, there is a paucity of randomized clinical trial (RCT) specifically studying the effects of AT in asthma/wheezing. Therefore, we conducted a post-hoc analysis of the Childhood Adenotonsillectomy Trial (CHAT), the largest RCT of AT in children with obstructive sleep apnea (OSA) to test the hypothesis that AT would result in fewer wheezing episodes., Methods: In the CHAT study, 464 children with OSA, aged 5-9 years, were randomized to early AT (n = 226) or watchful waiting with supportive care (WWSC) (n = 227). For this post-hoc analysis, children were categorized as having "any wheezing" versus "no wheezing" at baseline and at 7 months of follow-up. A multivariate analysis was conducted to evaluate the association between "any wheezing" at follow-up and treatment group after controlling for several potential confounders., Results: Children in the "any wheezing" group were predominantly black, had more allergic rhinitis, eczema, second-hand smoke exposure, body mass index, apnea-hypopnea index (AHI), and had lower maternal education and family income than those in the "no wheezing group." In the AT arm, the prevalence of wheezing significantly decreased from baseline to follow-up (at 7 months of the intervention) (47% vs. 21.6%, p < 0.001); while in the WWSC arms did not change (45.2% vs. 43.1%, p = 0.67). In the multivariate analysis, second-hand smoke exposure, wheezing at baseline, and belong to WWSC arm (odds ratio: 3.65 [2.16-6.19]) increase the risk of wheezing at follow-up., Conclusion: This study demonstrated that AT decreased the risk of wheezing at 7 months of follow-up., (© 2022 Wiley Periodicals LLC.)

Background: The heterogeneity of bronchiolitis may imply or reflect a different predisposition to respiratory sequelae., Objective: Our aim was to investigate whether, among infants hospitalized with bronchiolitis, different clinical profiles extracted by latent class analysis (LCA) are associated with different risks of wheezing., Methods: Over 15 consecutive epidemic seasons (2004-2019), we prospectively enrolled infants <1 year hospitalized for the first episode of bronchiolitis in a single tertiary hospital. A detailed clinical questionnaire was filled for each infant. LCA was applied to differentiate bronchiolitis phenotypes, and after hospital discharge, a phone interview was performed annually to record the presence of wheezing episodes. Adjusted multivariate regression analyses were run to investigate the risk of wheezing during 7 years follow-up according to clinical phenotypes., Results: LCA performed on 1312 infants resulted in a three-class model. Profile 1 (65.5%): moderate bronchiolitis; Profile 2 (6.1%): severe bronchiolitis; and Profile 3(28.4%): bronchiolitis infants with high eosinophils blood count. At 1 year of follow up, about 50% of children presented wheezing in each profile. Compared to Profile 1, the adjusted odds ratio (OR) of having wheezing episodes was significantly higher in Profile 2 at 2, 3, and 4 years of follow-up. At 7 years, Profile 3 had an adjusted OR = 2.58, higher than Profile 2 (adjusted OR = 2.29)., Conclusions: LCA clearly identified a "moderate", "severe," and "high eosinophils blood count" bronchiolitis. During the first 4 years after bronchiolitis, the "severe" profile showed the higher risk of wheezing, but after 7 years this risk seems higher in the "high eosinophils blood count" group., (© 2021 Wiley Periodicals LLC.)

Over the past decade, "omics" approaches have advanced our understanding of the molecular programming of the airways in humans. Several studies have identified potential molecular mechanisms that contribute to early life epigenetic reprogramming, including DNA methylation, histone modifications, microRNAs, and the homeostasis of the respiratory mucosa (epithelial function and microbiota). Current evidence supports the notion that early infancy is characterized by heightened susceptibility to airway genetic reprogramming in response to the first exposures in life, some of which can have life-long consequences. Here, we summarize and analyze the latest insights from studies that support a novel epigenetic paradigm centered on human maturational and developmental programs including three cardinal elements: genes, environment, and developmental timing. The combination of these factors is likely responsible for the functional trajectory of the respiratory system at the molecular, functional, and clinical levels., (© 2021 Wiley Periodicals LLC.)

Diagnosing asthma in preschool children remains an unsolved challenge, at a time when early identification would allow for better education and treatment to prevent morbidity and lung function deterioration., Objective: To evaluate if the asthma predictive index (API) can be used as surrogate for asthma diagnosis in preschoolers., Methods: Birth cohort of 339 pregnant women enrolled at delivery and their offspring, who were followed for atopy, wheezing, and other respiratory illnesses through 30 months of age. The API was determined at 30 months of age by the researchers; and examined its association with physician-diagnosed asthma during the first 30 months, made independently by the primary care physician not involved in the study., Results: Among 307 offspring with complete follow-up, 44 (14.3%) were API+. Maternal body mass index, maternal education, past oral contraceptive use, birthweight, placenta weight, age of daycare at 12 m, gastroesophageal reflux disease at 12 m, acute otitis media at 18 m, bronchiolitis, croup and pneumonia, cord blood adiponectin were all associated with API+. In the multivariable analysis, API+ was associated with almost sixfold odds of asthma diagnosis (adjusted OR = 5.7, 95% CI [2.6-12.3]), after adjusting for the relevant covariates above including respiratory infections like bronchiolitis and pneumonia. The API sensitivity was 48%, specificity 92%, 61% PPV, 88% NPV, 6.4 LR+, 0.56 LR-, 0.84 diagnosis accuracy. The adjusted odds for asthma was 11.4., Conclusions: This longitudinal birth cohort suggests, for first time, that API (a structured definition for asthma), could be used as a diagnostic tool, not only as a prognostic tool, in toddlers and preschoolers., (© 2021 Wiley Periodicals LLC.)

Objectives: Although several randomized clinical trials performed in children 6 years and older with Omalizumab as add-on therapy have reported improvements in diverse clinical outcomes, the evidence regarding its cost effectiveness is not sufficient, especially in less-affluent countries, where the clinical and economic burden of the disease is the greatest. The aim of the present study was to perform a cost-utility analysis of adding omalizumab to standard treatment for treating pediatric patients with uncontrolled severe allergic asthma in Colombia, a middle-income country (MIC)., Methods: A Markov-type model was developed to estimate costs and health outcomes of a simulated cohort of pediatric patients with persistent asthma treated over a 5-year period. The effectiveness data and transition probabilities were obtained from various sources, including systematic reviews with meta-analysis. Cost data were obtained from official databases provided by the Colombian Ministry of Health. The study was carried out from the perspective of the national healthcare system in Colombia. The main outcome was the variable ''quality-adjusted life-years'' (QALYs)., Results: For the base-case analysis, the cost-utility analysis showed that compared with the standard treatment strategy, the omalizumab strategy involved higher costs (US$72,142.3 vs. $20,243.4 average cost per patient) and greater gain in QALYs (0.8718 vs. 0.8222 QALYs on average per patient). The incremental cost-utility ratio (ICUR) of omalizumab compared with standard treatment was US$82,748.1 per QALY CONCLUSIONS: This study shows that in Colombia, an MIC, compared with standard treatment, omalizumab is not a cost-effective strategy for treating pediatric patients with uncontrolled severe allergic asthma., (© 2021 Wiley Periodicals LLC.)

Objectives: Although recent evidence suggests that management of viral bronchiolitis requires something other than guidelines-guided therapy, there is a lack of evidence supporting the economic benefits of phenotypic-guided bronchodilator therapy for treating this disease. The aim of the present study was to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis., Methods: A decision analysis model was developed to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. Phenotypic-guided bronchodilator therapy was defined as the administration of albuterol in infants exhibiting a profile of increased likelihood of response to bronchodilators. The effectiveness parameters and costs of the model were obtained from systematic reviews of the literature with meta-analyses and electronic medical records. The main outcome was the avoidance of hospital admission after initial care in the emergency department., Results: Compared to guidelines-guided strategy, treating patients with viral bronchiolitis with the phenotypic-guided bronchodilator therapy strategy was associated with lower total costs (US$250.99; 95% uncertainty interval [UI]: US$184.37 to $336.51 vs. US$263.46; 95% UI: US$189.81 to $349.19 average cost per patient) and a higher probability of avoidance of hospital admission (0.7902; 95% UI: 0.7315-0.8356 vs. 0.7638; 95% UI: 0.7062-0.8201), thus leading to dominance. Results were robust to deterministic and probabilistic sensitivity analyses., Conclusions: Compared to guidelines-guided strategy, treating infants with viral bronchiolitis using the phenotypic-guided bronchodilator therapy strategy is a more cost-effective strategy, because it involves a lower probability of hospital admission at lower total treatment costs., (© 2020 Wiley Periodicals LLC.)

International guidelines have recommended the use of inhaled beta-2 agonists and systemic corticosteroids (SCs) as the first-line treatment for acute asthma., Objective: To evaluate the evidence for the efficacy of inhaled corticosteroids (ICSs) in addition to SCs compared to SCs alone in children with acute asthma in the emergency department (ED) or during hospitalization., Data Sources: Five electronic databases were searched., Study Selection: All randomized clinical trials that compared ICS (via nebulizer or metered dose inhaler) plus SC (oral or parenteral) with placebo (or standard care) plus SC were included without language restriction., Data Extraction: Two reviewers independently reviewed all the studies. The primary outcomes were hospital admission and hospital length of stay (LOS), and secondary outcomes were readmissions during follow-up, ED-LOS, lung function, asthma clinical score, oxygen saturation, and heart and respiratory rates., Results: Nine studies (n = 1473) met the inclusion criteria. In all the studies, the ICS was budesonide. Compared to SC alone, adding budesonide to SC did not affect hospitalization rate, but decreased hospital LOS by more than 1 day (MD = -29.08 hours [-39.9 to -18.3]; I 2  = 0%, P = < .00001). Moreover, adding budesonide significantly improved the acute asthma severity score among patients at ED., Conclusions: Compared to SC alone, adding budesonide to SC does not affect the hospitalization rate, but decreases the LOS and improves the acute asthma score in children in an ED setting., (© 2020 Wiley Periodicals LLC.)

Rationale: Whether asthma constitutes a risk factor for coronavirus disease-2019 (COVID-19) is unclear. Here, we aimed to assess whether asthma, the most common chronic disease in children, is associated with higher COVID-19 risk or severity in pediatric populations., Methods: We performed a systematic literature search in three stages: first, we reviewed PubMed, EMBASE, and CINAHL for systematic reviews of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 in pediatric populations, and reviewed their primary articles; second, we searched PubMed for studies on COVID-19 or SARS-CoV-2 and asthma/wheeze, and evaluated whether the resulting studies included pediatric populations; third, we repeated the second search in BioRxiv.org and MedRxiv.org to find pre-prints that may have information on pediatric asthma., Results: In the first search, eight systematic reviews were found, of which five were done in pediatric populations; none of the 67 primary studies included data on pediatric asthma as a comorbidity for COVID-19. In the second search, we found 34 results in PubMed, of which five reported asthma in adults, but none included data on children. In the third search, 25 pre-prints in MedRxiv included data on asthma, but none on children. We found one report by the US Centers for Disease Control and Prevention stating that 40/345 (~11.5%) children with data on chronic conditions had "chronic lung diseases including asthma," and one from a tertiary hospital in New York that reported asthma in 11/46 (~23.9%) children hospitalized for COVID-19., Conclusion: There is scarcely any data on whether childhood asthma (or other pediatric respiratory diseases) constitute risk factors for SARS-CoV-2 infection or COVID-19 severity. Studies are needed that go beyond counting the number of cases in the pediatric age range., (© 2020 Wiley Periodicals LLC.)

Objectives: Although a short course (ie, 3 to 5 days) of orally administered prednisolone is a common and widely accepted practice among clinicians for administering systemic corticosteroids in pediatric acute asthma, oral dexamethasone for 1 to 2 days is an attractive alternative to prednisolone due to its better palatability and compliance. However, a cost-effectiveness analysis regarding the use of dexamethasone compared to prednisolone is not sufficient, especially in lower- and middle-income countries. The objective of this study was to analyze the cost-effectiveness of prednisolone vs oral dexamethasone for treating pediatric asthma exacerbations., Methods: Using a decision-analysis model, we analyzed the cost-effectiveness of prednisolone vs oral dexamethasone for treating acute pediatric asthma. Effectiveness parameters were derived from a systematic review of the published literature. Data for costs were acquired from hospital accounts and from an official national database, the national manual of drug prices in Colombia. The study was carried out from a Colombian third-party payer perspective. The principal outcome of the model was the avoidance of hospitalization., Results: The base-case analysis showed that compared to dexamethasone, administering prednisolone was associated with lower overall treatment costs (US$93.97 vs US$104.91 mean cost per patient) without a significant difference in the probability of hospitalization avoided (.9108 vs .9108)., Conclusions: The present study shows that in Colombia, a middle-income country, compared with oral dexamethasone, the use of prednisolone for treating acute pediatric asthma is cost-effective, yielding a similar probability of hospitalization at lesser overall costs., (© 2020 Wiley Periodicals LLC.)

Objectives: There has been no systematic review of studies aimed to predict differential responses to medication regimens for asthma controller therapies in pediatric patients. The aim of the present study was to summarize those identifying biomarkers for the different asthma controller therapies., Methods: Studies published by June 2019 that report phenotypic or genotypic characteristics or biomarkers that could potentially serve as response predictors to asthma controller therapies in pediatric patients were included. The quality of studies was assessed using the Cochrane Risk of Bias tool and the Newcastle-Ottawa Scale tool., Results: Of 385 trials identified, 30 studies were included. Children with asthma and a positive family history of asthma, with more severe disease, of the white race, with allergy biomarkers, nonobese, with lower lung function, high bronchial hyperresponsiveness to methacholine, or having variants in the FCER2 and CRHR1 gene respond better to inhaled corticosteroids (ICS). Younger age (<10 years), short disease duration (<4 years), high cotinine and urinary leukotriene E4 (LTE4) levels, and 5/5 ALOX5 were associated with a better response to leukotriene receptor antagonist (LTRA). For patients that remain symptomatic, white Hispanics were more likely to respond to LTRA, blacks to ICS, white non-Hispanics to LTRA or LABA, and children without a history of eczema, regardless of race or ethnicity to LABA set-up therapy. In severe persistent asthma, those with atopy and body mass index greater than or equal 25 were more likely to benefit from omalizumab., Conclusion: Several phenotypic characteristics, biomarkers, or pharmacogenomics markers could be useful for predicting the best drug for asthma treatment., (© 2020 Wiley Periodicals, Inc.)

Objectives: Although the benefits of albuterol delivered via metered-dose inhalers with a spacer (MDI+S) have been increasingly recognized, the evidence regarding the cost-effectiveness of MDI+S compared to nebulization (NEB) is not sufficient, especially in less-affluent countries, where the clinical and economic burden of the disease is the greatest. The aim of the present study was to evaluate the cost-effectiveness of MDI+S vs NEB for delivering albuterol for the treatment of pediatric asthma exacerbations., Methods: A decision-analysis model was developed to estimate the cost-effectiveness of MDI+S vs NEB for delivering albuterol for the treatment of pediatric asthma exacerbations. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from hospital bills and from the national manual of drug prices in Colombia. The study was carried out from the perspective of the national healthcare system in Colombia, a middle-income country (MIC). The main outcome of the model was the avoidance of hospital admission., Results: For the base-case analysis, the model showed that compared to NEB, using MDI+S for the delivery of albuterol was associated with lower total costs (US$96.68 vs US$121.41 average cost per patient) and a higher probability of hospital admission avoided (0.9219 vs 0.8900), thus leading to dominance., Conclusions: This study shows that in Colombia, an MIC, compared with NEB, the use of MDI+S for delivering albuterol for the treatment of pediatric asthma exacerbations is the preferred strategy because it is associated with a lower probability of hospital admission at lower total treatment costs., (© 2020 Wiley Periodicals, Inc.)

Objective: To evaluate trends and geographic distribution of infant bronchiolitis hospitalizations in Chile, a country with large variation in solar radiation (SR) and high rates of urban air pollution., Methods: We performed a nationwide ecological study of bronchiolitis hospitalizations from 2001 to 2014. We investigated the associations of regional SR (a proxy of vitamin D status) and regional fine particulate matter (PM2.5) air pollution with bronchiolitis hospitalizations. We also evaluated the role of sociodemographic factors, including regional poverty, education, indigenous population, and rurality rates., Results: During the study period, 119 479 infants were hospitalized for bronchiolitis in Chile; 59% were boys. The mean bronchiolitis hospitalization rate increased from 29 to 41 per 1000 infants per year (P = .02). There was an inverse correlation between regional SR and incidence of hospital admissions for bronchiolitis (r = -0.52, P = .049), accounting for 27% of these hospitalizations. There was also a significant direct correlation between regional ambient PM2.5 and bronchiolitis hospitalizations (R = 0.68, P = .006), accounting for 42% of the variation in admission rate. High firewood and/or coal residential use for heating, high regional poverty, lower years of education, and high rurality rates were also significantly correlated with bronchiolitis hospitalization rates. None of the environmental or sociodemographic factors evaluated were correlated with regional case fatality rates or length of stay at the hospital., Conclusions: This ecological study revealed significant associations between regional SR, air pollution, and sociodemographic factors with infant bronchiolitis hospitalizations in Chile, suggesting that these factors play a major role in the incidence and severity of respiratory infections in early childhood., (© 2019 Wiley Periodicals, Inc.)

Introduction: In moderate-severe asthma exacerbation, salbutamol by inhaler (MDI) is superior to salbutamol delivered by nebulizer (NEB); however, to our knowledge, no studies in children with exclusively severe exacerbations were performed., Objective: To compare the efficacy of salbutamol and ipratropium bromide by MDI versus by NEB in severe asthma exacerbations., Methods: We performed a clinical trial enrolling 103 children (2-14 years of age) with severe asthma exacerbations (defined by the Pulmonary Score ≥ 7) seen at the emergency room in Asuncion, Paraguay. One group received salbutamol and ipratropium (two puff every 10 min for 2 h and then every 30 min for 2 h more) by MDI with a valved-holding chamber and mask along with oxygen by a cannula separately (MDI-SIB); and the other received nebulization with oxygen (NEB-SIB) of salbutamol and ipratropium (1 every 20 min for 2 h and then every 30 min for 2 h more). Primary outcome was the rate of hospitalization (Pulmonary Score ≥ 7) after 4 h and secondary outcome was oxygen saturation., Results: Fifty two children received MDI-SIB and 51 NEB-SIB. After the 4th hour, children on MDI-SIB had significantly (P = 0.003) lower rate of hospital admission than on NEB-SIB (5.8% vs 27.5%, RR: 0.21 [0.06-0.69], respectively). Similarly, a significant improved clinical score after 60 min and increase in oxygen saturation after 90 min of treatment was observed in MDI-SIB versus NEB-SIB group (4.46 ± 0.7 vs 5.76 ± 0.65, P < 0.00001; and 90.5 ± 1.7 vs 88.43 1 ± 1, P < 0.00001, respectively)., Conclusion: Even in severe asthma exacerbations administration of salbutamol and ipratropium by MDI with valved-holding chamber and mask along with oxygen by a cannula separately was more effective than by a nebulizer., (© 2019 Wiley Periodicals, Inc.)

Background: Most international asthma guidelines recommend that children ≤5 years with asthma or recurrent wheezing be treated with daily low- moderate dose inhaled corticosteroids (ICS) as the preferred controller and leukotriene receptor antagonists (LTRA) as alternative therapy. There is no systematic review comparing the efficacy of ICS versus LTRA monotherapy in this age group., Objective: To compare the efficacy of daily ICS versus LTRA in preschoolers with asthma or recurrent wheezing., Methods: Randomized, prospective, controlled trials published by December 2017, with a minimum of 3-month therapy with daily ICS versus LTRA were identified. The co-primary outcomes were the number of wheezing episodes and daily symptom score. Secondary outcomes included unscheduled emergency visits, need of rescue systemic corticosteroids (SC), hospitalization for exacerbations, lung function, and adverse effects., Results: Of 29 trials identified, six studies (n = 3204 patients, 62% males, age range: 6-54 months) met the inclusion criteria; two were at low risk of bias. Five pertained to children with asthma; one to those with recurrent wheezing. No outcomes were similarly reported in the six studies, preventing meta-analysis. Based on trials at lowest risk of bias and the largest open-labelled studies, ICS was associated with better control of symptoms and less exacerbations than LTRA. And also less need for rescue SC. Insufficient data of high quality prevented firm conclusions on other secondary outcomes., Conclusions: In preschoolers with asthma or recurrent wheezing, daily ICS appears more effective than daily LTRA for improving symptom control and decreasing exacerbations, particularly those requiring rescue SC, although the magnitude of benefit remains to be quantified., (© 2018 Wiley Periodicals, Inc.)

Objectives: We aimed to perform a systematic review of all studies with direct measurements of both airway inflammation and remodeling in the subgroup of children with repeated wheezing and/or persistent asthma severe enough to warrant bronchoscopy, to address whether airway inflammation precedes remodeling or is a parallel process, and also to assess the impact of remodeling on lung function., Methods: Four databases were searched up to June 2017. Two independent reviewers screened the literature and extracted relevant data., Results: We found 526 references, and 39 studies (2390 children under 18 years old) were included. Airway inflammation (eosinophilic/neutrophilic) and remodeling were not present in wheezers at a mean age of 12 months, but in older pre-school children (mean 2.5 years), remodeling (mainly increased reticular basement membrane [RBM] thickness and increased area of airway smooth muscle) and also airway eosinophilia was reported. This was worse in school-age children. RBM thickness was similar in atopic and non-atopic preschool wheezers. Airway remodeling was correlated with lung function in seven studies, with FeNO in three, and with HRCT-scan in one. Eosinophilic inflammation was not seen in patients without remodeling. There were no invasive longitudinal or intervention studies., Conclusion: The relationship between inflammation and remodeling in children cannot be determined. Failure to demonstrate eosinophilic inflammation in the absence of remodeling is contrary to the hypothesis that inflammation causes these changes. We need reliable, non-invasive markers of remodeling in particular if this is to be addressed., (© 2018 Wiley Periodicals, Inc.)

Rationale: Systemic corticosteroids (SCS) are used for treat preschoolers with acute asthma or wheezing exacerbations, with conflicting results., Objective: To evaluate the effectiveness of oral corticosteroids (OCS) compared to placebo in preschoolers presenting with acute asthma/wheezing exacerbations., Methods: Five electronic databases were searched for all placebo-controlled, randomized clinical trials of OCS in children <6 years of age presenting with recurrent wheezing/asthma exacerbations of any severity. Primary outcomes were hospitalizations, unscheduled emergency department (ED) visits in following month, need of additional OCS courses, and length of stay (ED or hospital)., Results: Eleven studies met inclusion criteria (n = 1,733); four were conducted on an outpatient basis, five in inpatients, and two in the ED. Significant heterogeneity was found when pooling all studies, and thus analysis was stratified by trial setting. Among the outpatient studies, children who received OCS had a higher hospitalization rate (RR: 2.15 [95%CI = 1.08-4.29], I(2)  = 0%) compared to those to received placebo. Among the ED studies, children who received OCS had a lower risk of hospitalization (RR: 0.58 [0.37-0.92], I(2)  = 0%). Among the inpatient studies, children who received OCS needed fewer additional OCS courses than those on placebo (RR: 0.57 [0.40-0.81], I(2)  = 0%)., Conclusions: Treatment with OCS in the ED or hospital may be beneficial in toddlers and preschoolers with frequent asthma/wheezing exacerbations. However, more studies are needed before OCS can be broadly recommended for this age group. Future trials should be carefully designed to avoid bias and according to our findings regarding administration setting. Pediatr Pulmonol. 2016;51:868-876. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Introduction: Despite the many benefits that have been demonstrated by the continuous administration of inhaled corticosteroids (ICS) in persistent asthma, a new strategy for mild-asthma is emerging, consisting of using intermittent or as-needed ICS treatment in conjunction with short-acting beta2 agonists in response to symptoms. However, no previous studies have reported an economic evaluation comparing these two therapeutic strategies., Methods: A Markov-type model was developed in order to estimate costs and health outcomes of a simulated cohort of pediatric patients with persistent asthma treated over a 12-month period. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from official databases provided by the Colombian Ministry of Health. The main outcome was the variable "quality-adjusted life-years" (QALYs)., Results: For the base-case analysis, the model showed that compared to intermittent ICS, daily therapy with ICS had lower costs (US$437.02 vs. 585.03 and US$704.62 vs. 749.81 average cost per patient over 12 months for school children and preschoolers, respectively), and the greatest gain in QALYs (0.9629 vs. 0.9392 QALYs and 0.9238 vs. 0.9130 QALYS for school children and preschoolers, respectively), resulting in daily therapy being considered dominant., Conclusions: The present analysis shows that compared to intermittent therapy, daily therapy with ICS for treating pediatric patients with recurrent wheezing and mild persistent asthma is a dominant strategy (more cost effective), because it showed a greater gain in QALYs with lower total treatment costs., (© 2014 Wiley Periodicals, Inc.)

Introduction: Although hospital admissions for pediatric asthma constitute a significant problem in high-income countries, they are an even greater health problem in low- and middle-income countries (LMIC). However, previous studies that aimed to identify predictors of hospital admission for asthma in children have mainly been conducted in high-income countries, and these findings might not be applicable to LMIC., Methods: In a prospective cohort study, we aimed to identify predictors of hospital admission for asthma, including measures of parental knowledge about asthma and maternal depression level, in a population of children aged 1-18 years living in urban Bogota, Colombia hospitalized for acute asthma symptoms, over a 6-month period., Results: Out of the total of 101 included patients, 37 (36.6%) had at least one hospital admission for asthma during the year following admission. After controlling for the age of the patients, dog ownership in the previous 12 months, asthma severity variables in the previous 6 months, maternal allergic rhinitis, level of maternal education, and measures of parental knowledge about asthma and maternal depression level, we found that maternal smoking (IRR, 3.12; 95% confidence interval [95% CI], 1.12-8.68; P = 0.029) was the only independent predictor of hospital admissions due to asthma exacerbations in the year following admission to the study., Conclusions: In a population of asthmatic Latino children admitted to hospital for an asthma exacerbation, approximately one-third of the patients had at least one hospital admission for asthma during the year following admission, and maternal smoking was the only independent predictor of these hospitalizations., (© 2013 Wiley Periodicals, Inc.)

Objective: To compare the effects of inhaled corticosteroids (ICS) against systemic corticosteroids (SC) in children consulting in emergency department (ED) or equivalent for asthma exacerbation., Methods: Electronic search in MEDLINE, CENTRAL, CINAHL, and LILACS databases and other sources. Study selection criteria: children 2-18 years of age, consulting in ED or equivalent for asthma exacerbation, comparison between ICS and SC, randomized controlled trials., Primary Outcomes: hospital admission rate, unscheduled visits for asthma symptoms, need of additional course of SC., Secondary Outcomes: improvement of lung function, length of stay in ED, clinical scores, and adverse effects., Results: Eight studies met inclusion criteria (N = 797), published between 1995 and 2006. All used prednisolone as SC and budesonide, fluticasone, dexamethasone, and flunisolide were administered as ICS. No significant difference between ICS versus SC was found in terms of hospital admission (RR: 1.02; 95% CI: 0.41-2.57), unscheduled visits for asthma symptoms (RR: 9.55; 95% CI: 0.53-170.52) nor for need of additional course of SC (RR: 1.45; 95% CI: 0.28-7.62). The change in % of predicted FEV1 at fourth hour was significantly higher for SC group, but there was no significant difference between both groups after this time. There was insufficient data to perform meta-analysis of length of stay during first consult in ED and of symptom scores. Vomiting was similar among both groups., Conclusions: There is no evidence of a difference between ICS and SC in terms of hospital admission rates, unscheduled visits for asthma symptoms and need of additional course of SC in children consulting for asthma exacerbations., (© 2013 Wiley Periodicals, Inc.)

Objective: To determine if nitrites (nitric oxide metabolites) measured in induced sputum decrease and correlate with improvement of clinical asthma symptoms after treatment, we performed a prospective longitudinal study in a tertiary care hospital in Arequipa, Peru., Methods: In 95 schoolchildren with mild and moderate persistent asthma we determined nitrites in induced sputum samples (measured using the Griess assay). Clinical parameters and exercise bronchial challenge (EBC) test were performed twice, at baseline and after 3 months of beclomethasone-dipropionate treatment (median doses: 300 mcg/day, IQR: 300-450)., Results: Sixty out of 95 children completed the study (median age of 9-year [IQR: 7-13]). A significant change in sputum nitrites levels between admission and the end of the study was observed (34.4 nmol/ml [IQR:18.2-58.4] and 11.2 nmol/ml [6-20.1], respectively, P = < 0.0001). Also a significant correlation between decrease of sputum nitrites levels and improvement of clinical parameters (acute exacerbations [r = 0.361, P = 0.005]; use of salbutamol [r = 0.322, P = 0.013]; emergency visits [r = 0.275, P = 0.033]; and school absence [r = 0.41, P = 0.001]) from admission to the end of the study was found. However, sputum nitrites levels did not correlated with peripherical blood eosinophils or serum IgE levels or with EBC test at any point of the study. The decrease of sputum nitrites levels after the treatment was significant in each asthma group (mild and moderate), but not between groups., Conclusion: This study showed that measured nitrite in induced sputum (a simple and cheap non-invasive method) is a good alternative for monitoring asthmatic treatment in schoolchildren., (© 2013 Wiley Periodicals, Inc.)

Background: The association between obesity and bronchial hyperreactivity (BHR) in children has not been fully demonstrated in cross-sectional or longitudinal studies, and no study has specifically addressed Latino children., Methods: A cross-sectional study of 450 children (10-18 years) from public schools was conducted in Mexico city. Among this group, 260 met the study criteria (no chronic respiratory illnesses, including asthma and rhinitis; no acute respiratory infections; and no tobacco-exposure or endocrine or body dysmorphic disorders), and 229 performed reproducible pulmonary function and methacholine challenge tests and were fully analyzed., Results: According to BMI percentiles, 40 were normal weight, 116 were obese, and 73 morbidly obese. Children in the morbidly obese group had significantly higher % FVC than those in the normal-weight group, and obese children had higher % PEF those in the morbidly obese and normal-weight groups. In the BHR methacholine challenge test, baseline FEV1 values among obese children were significantly lower than in the morbidly obese group. Using adjusted percentages for FEV1 , values were significantly lower among obese compared to morbidly obese children at metacholine concentrations of 0.25, 1, and 4 mg/ml. The proportion of positive BHR (PC20  ≤ 16 mg/ml) was higher in these two groups compared to normal-weight children (28.4%, 17.8%, and 12.5%, respectively), although differences were not significant., Conclusion: Our findings show that obesity by itself is not a sufficient condition to alter airway responsiveness to methacholine in a group of adolescents., (© 2013 Wiley Periodicals, Inc.)

Introduction: It is important to predict if preschool children with recurrent wheezing will suffer from asthma in future years. To aid in this early identification, a number of asthma predictive scores have been reported, such as the asthma predictive index (API) and the PIAMA risk score. However, to the best of our knowledge, their predictive properties have not been evaluated in any lower- to middle-income country., Materials and Methods: A prospective cohort study was carried out including preschoolers aged 1-3 years with recurrent wheezing who came to our Pediatric Pulmonary Unit in Bogota, Colombia. We collected the information required to complete the API index and the PIAMA risk score. At 5-6 years of age, the patients were contacted in order to determine if they were suffering from active asthma. We calculated the sensitivity, specificity, predictive values, and likelihood ratios (LR) of the API and PIAMA risk scores for the presence of active asthma at 5-6 years old., Results: The mean age at recruitment of the 130 included patients was 27.2 ± 5.9 months. The loose API yielded a sensitivity of 71.4% (95% CI: 50.0-86.2), specificity of 33.3% (95% CI 23.5-44.8), and positive predictive value of 23.8% (95% CI: 15.0-35.6). The stringent API yielded a sensitivity of 42.9% (95% CI: 24.5-63.5), specificity of 79.2% (95% CI 68.4-86.9), positive predictive value of 37.5% (95% CI: 21.2-57.3), and positive LR of 2.06. The PIAMA risk score yielded a sensitivity of 54.5% (95% CI: 42.6-66.0), specificity of 78.9 (95% CI: 66.7-87.5), positive predictive value of 75.0 (95% CI: 61.2-85.1), and positive LR of 2.59., Conclusions: Our results suggest that both indices can be used to predict asthma in preschoolers with recurrent wheezing in the context of a referral hospital., (Copyright © 2011 Wiley Periodicals, Inc.)

Objective: To test the hypothesis that consuming Mediterranean diet and using olive oil for cooking/dressing salads during pregnancy might be associated with less wheezing during the first year of the offspring's life., Methods: A study was conducted in 1,409 infants (mean age, 16.6 +/- 2.5 months) attending healthy infant clinics in Spain. Dietary data of mothers' intake during pregnancy was collected by means of a parental food frequency questionnaire. Demographic information and data on wheezing during the first year of the offspring's life were also recorded. Infants were stratified according to any wheezing (42.2%) during the first year of life., Results: In the univariate analysis, adherence to a Mediterranean diet and using olive oil for cooking/dressing salads during pregnancy were both significantly associated with less wheezing during the first year of life. However, after multivariate analysis, only olive oil consumption during pregnancy remained associated with less wheezing in the studied period (aOR = 0.57 [95% CI = 0.4-0.9]); whereas male gender (1.8 [1.4-2.3]), day care attendance (2.15 [1.5-3.1]), maternal asthma (2.16 [1.3-3.6]), maternal smoking during pregnancy (1.83 [1.3-2.2]), infant eczema (1.95 [1.3-2.9]), and mould stains on the household walls (1.72 [1.2-2.5]) remained associated with wheezing., Conclusion: Our findings suggest a protective effect (primary prevention) of olive oil use during pregnancy on wheezing during the first year of the offspring's life.

To describe clinical, pulmonary function, and chest tomography profiles in a 5-year follow-up of infants with adenovirus pneumonia and determine the factors that potentially contributed to the development of bronchiolitis obliterans (BO). We prospectively assessed 45 hospitalized infants with adenovirus pneumonia with additional follow-up for 5 years. At the end of the study, pulmonary function by impulse oscillometry technique (IOS) and chest tomography were performed in the 38 surviving patients (mean 5.7 years of age). We divided the population between those who developed chest tomography evidence of BO and those who did not. Most of the children developed adenovirus infection before 2 years of age. During the 5 years of follow-up, almost half (47.4%) developed BO. Children who developed BO had significantly more respiratory compromise (intensive care admission, need for mechanical ventilation and for oxygen therapy, and systemic corticosteroid and beta agonist use) during their adenovirus pneumonia episode than those who did not develop BO. Only 33.3% of children with BO had normal impedance compared with 85% in the no BO group. Children who developed BO had significantly higher levels of Zrs, R5, X5 and predicted Zrs, R5, and X5 and frequency. However, there were no differences in the beta 2 agonist response between the children with and without BO (94% vs. 80%, respectively). This study represents the spectra of adenovirus pneumonia ranging from relatively mild to severe and fatal cases. Children with severe pulmonary compromise are usually more prone to develop BO., ((c) 2006 Wiley-Liss, Inc.)

Our objective was to compare the clinical efficacy of azithromycin vs. erythromycin and amoxicillin in the treatment of presumed bacterial community-acquired pneumonia in ambulatory children, and to evaluate the etiologies of these illnesses. One hundred and ten children, aged 1 month to 14 years, were enrolled between January 1996-January 1999. Children were distributed into two groups according to clinical and radiological patterns: classic or atypical pneumonia. Patients with classic pneumonia were randomly assigned to receive oral amoxicillin 75 mg/kg/day for 7 days, or azithromycin 10 mg/kg/day for 3 days; patients with atypical pneumonia received azithromycin 10 mg/kg/day for 3 days, or erythromycin 50 mg/kg/day for 14 days. Chest X-ray, clinical, and laboratory parameters were obtained on enrollment. Clinic visits were performed on days 3, 7, and 14, and chest X-ray follow-up on days 7 and 14. Microbiological diagnosis of classic pathogens was based on blood and bronchial secretion cultures. The diagnosis of atypical pathogens C. pneumoniae, C. trachomatis, and M. pneumoniae was based on PCR and serologic tests.Forty-seven children met the criteria for classic pneumonia (23 children received azithromycin, and 24 received amoxicillin), and 59 children had atypical pneumonia (33 children were treated with azithromycin, and 26 with erythromycin). Demographic characteristics at enrollment were similar between children with classic pneumonia treated with azithromycin and erythromycin and children treated with azithromycin and erythromycin for atypical pneumonia. However, on day 7, children with classic pneumonia who received azithromycin normalized their chest X-ray more often than those who received amoxicillin (81.0% vs. 60.9%, respectively, P = 0.009). The same was true for children with atypical pneumonia; their chest X-rays had normalized by day 14 (100% in those with azithromycin vs. 81% in those with erythromycin, P = 0.059). Also, children with atypical pneumonia treated with azithromycin had earlier cessation of cough than children treated with erythromycin (3.6 +/- 1.9 vs. 5.5 +/- 3.6 days respectively, P = 0.02). There were only three children with side effects (mild diarrhea, all in the erythromycin group). Etiological agents were identified in 41% of children. In conclusion, azithromycin is an effective therapeutic option for the treatment of community-acquired classic and atypical pneumonia in children., (Copyright 2003 Wiley-Liss, Inc.)

The aim of this study was to compare the efficacy of salbutamol delivered via a metered-dose inhaler with a spacer and facial mask (MDI-S) vs. a nebulizer (NEB) for the treatment of acute exacerbations of wheezing in children. In a single-blind, prospective, randomized clinical trial, 123 outpatients (1-24 months of age), presenting with "moderate to severe" wheezing, were seen in the emergency department. Children were randomly assigned to one of two salbutamol treatment groups. In the first hour, the MDI-S group received 2 puffs (100 microg/puff) every 10 min for 5 doses, and the NEB group received 0.25 mg/kg every 13 min for 3 doses. If the clinical score was >5 at the end of the first hour, the patients received another hour of the same treatment and also betamethasone (0.5 mg/kg intramuscular). On enrollment and after the first and the second hour of treatment each child had a validated clinical score assigned by a blinded investigator. There were no differences at the time of admission to the emergency department between groups in clinical score or demographic data. Success (clinical score 0.05). We conclude that in this study population, children less than 2 years of age with moderate-severe exacerbations of wheezing responded faster to salbutamol delivered by MDI with a spacer and facial mask than to salbutamol delivered by nebulizer., (Copyright 2000 Wiley-Liss, Inc.)