Approach to difficult-to-treat asthma in childhood: a narrative review.

ABSTRACT: Asthma is a major chronic disease affecting children, and children with difficult-to-treat asthma account for a disproportionate share of resource utilisation and healthcare costs. This review presents a comprehensive and up-to-date overview of the treatment strategies in difficult-to-treat paediatric asthma. Mimickers of asthma must first be ruled out, and the diagnosis confirmed with objective tests whenever possible. The effect of comorbid conditions such as obesity, smoking, other atopic conditions and psychosocial factors on asthma control and severity should be considered. Treatment can then be optimised by implementing personalised strategies, including the use of appropriate drug delivery devices and adherence monitoring. Biologics can be an alternative treatment option for selected patients but should not be a substitute for addressing poor adherence. Many patients with difficult-to-treat asthma may not have severe asthma, and the physician should work with patients and families to achieve good asthma control via an individualised approach.

Evaluation of Stool Short Chain Fatty Acids Profiles in the First Year of Life With Childhood Atopy-Related Outcomes.

Introduction: Short chain fatty acids (SCFAs) are the main intestinal intermediate and end products of metabolism of dietary fibers/polyphenols by the gut microbiota. The aim of this study was to evaluate the biological implication of stool SCFA profiles determined in the first year of life on the clinical presentation of allergic outcomes in childhood. Methods: From the Growing Up in Singapore Toward healthy Outcomes (GUSTO) cohort, a sub-cohort of 75 participants was recruited. Scheduled questionnaire data was collected for cumulative prevalence of physician-diagnosed eczema, wheezing with the use of nebuliser, and allergen sensitization till the age of 8 years. Stool samples collected at week 3 and months 3, 6 and 12 were quantitated for 9 SCFAs using LC/MS/MS. SCFA data were grouped into lower (below the 25th) and higher (above the 75th percentiles) categories. Generalized Linear Mixed Models was employed to analyse longitudinal association between SCFAs and atopy-related outcomes. Results: Children with lower stool butyric acid levels (≤25th percentile) over the first 3 time points had higher odds ratio (OR) for wheezing (adjOR = 14.6), eczema (adjOR = 13.2), food sensitization (adjOR = 12.3) and combined outcomes of both wheezing and eczema (adjOR = 22.6) till age 8 years, compared to those with higher levels (≥75 percentile). Additionally, lower longitudinal levels of propionic acid (≤25th percentile) over 4 time points in first year of life was associated with recurrent wheezing (≥2 episodes) till 8 years (adjOR = 7.4) (adj p < 0.05). Conclusion: Our results suggest that relatively low levels of gut SCFAs in early life are associated with increased susceptibility to atopic-related outcomes in childhood.

Keeping Pace with Adolescent Asthma: A Practical Approach to Optimizing Care.

Known for their pre-occupation with body image, self-identity creation, peer acceptance, and risk-taking behaviors, adolescents with asthma face unique challenges. Asthma is a heterogeneous disease and accurate diagnosis requires assessment through detailed clinical history, examination, and objective tests. Diagnostic challenges exist as many adolescents can present with asthma-like symptoms but do not respond to asthma treatment and risk being mis-diagnosed. Under-recognition of asthma symptoms and denial of disease severity must also be addressed. The over-reliance on short-acting beta-agonists in the absence of anti-inflammatory therapy for asthma is now deemed unsafe. Adolescents with mild asthma benefit from symptom-driven treatment with combination inhaled corticosteroids (ICS) and long-acting beta-agonist (LABA) on an as-required basis. For those with moderate-to-persistent asthma requiring daily controller therapy, maintenance and reliever therapy using the same ICS-LABA controller simplifies treatment regimes, while serving to reduce exacerbation risk. A developmentally staged approach based on factors affecting asthma control in early, middle, and late adolescence enables better understanding of the individual's therapeutic needs. Biological, psychological, and social factors help formulate a risk assessment profile in adolescents with difficult-to-treat and severe asthma. Smoking increases risks of developing asthma symptoms, lung function deterioration, and asthma exacerbations. Morbidity associated with e-cigarettes or vaping calls for robust efforts towards smoking and vaping cessation and abstinence. As adolescents progress from child-centered to adult-oriented care, coordination and planning are required to improve their self-efficacy to ready them for transition. Frequent flare-ups of asthma can delay academic attainment and adversely affect social and physical development. In tandem with healthcare providers, community and schools can link up to help shoulder this burden, optimizing care for adolescents with asthma.

Dysfunctional Bronchial Cilia Are a Feature of Chronic Obstructive Pulmonary Disease (COPD).

Impaired mucociliary clearance may increase COPD exacerbation risk. We aimed to compare bronchial ciliary function and epithelial ultrastructure of COPD patients to healthy controls and explore its relationship to exacerbator phenotypes (frequent [FE] and infrequent [IFE] exacerbator). In this cross-sectional study, 16 COPD patients and 12 controls underwent bronchial brushings. Ciliary beat frequency (CBF) and dyskinesia index (DI; % of dyskinetic cilia) were assessed using digital high-speed video microscopy, and epithelial ultrastructure using transmission electron microscopy (TEM). Bronchial epithelium in COPD showed lower CBF and higher DI, compared to controls (median [IQR] CBF: 6.8 (6.1-7.2) Hz vs 8.5 (7.7-8.9) Hz, p<0.001 and DI: 73.8 (60.7-89.8) % vs 14.5 (11.2-16.9) %, p<0.001, respectively). This was true for FE and IFE phenotypes of COPD, which were similar in terms of bronchial CBF or DI. Subgroup analyses demonstrated lower CBF and higher DI in FE and IFE COPD phenotypes compared to controls, irrespective of smoking status. TEM showed more loss of cilia, extrusion of cells, cytoplasmic blebs and dead cells in COPD patients versus controls. Profound dysfunction of bronchial cilia is a feature of COPD irrespective of exacerbation phenotype and smoking status, which is likely to contribute to poor mucus clearance in COPD.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1963695 .

Non-immune hydrops fetalis secondary to congenital chylothorax with diffuse interstitial lung disease: a diagnostic conundrum.

A Chinese male infant was born at 35 weeks weighing 2935 g to a mother with polyhydramnios and prenatal hydrops fetalis. He developed marked respiratory distress secondary to bilateral congenital chylothorax and required pleural drainage, high frequency oscillation and inhaled nitric oxide therapy. He was extubated to non-invasive ventilation by day 14. There was no bacterial or intrauterine infection, haematologic, chromosomal or cardiac disorder. He was exclusively fed medium-chain triglyceride formula. High-resolution CT showed diffuse interstitial lung disease. He received a dexamethasone course for chronic lung disease to facilitate supplemental oxygen weaning. A multidisciplinary team comprising neonatology, pulmonology, haematology, interventional radiology and thoracic surgery considered congenital pulmonary lymphangiectasia as the most likely diagnosis and advised open lung biopsy, lymphangiography or scintigraphy for diagnostic confirmation should symptoms of chylothorax recur. Fortunately, he was weaned off oxygen at 5 months of life, and tolerated human milk challenge at 6 months of life and grew well.

Combination of slide tracheoplasty and side-to-side bronchoplasty for complex congenital tracheobronchial stenosis.

Congenital tracheal stenosis is a rare but serious condition with high mortality and morbidity. We present a 6-month-old patient with complex congenital tracheal stenosis involving the trachea, carina and right bronchus intermedius, which was corrected with a combination of slide tracheoplasty and side-to-side bronchoplasty.

Trajectories of early-onset rhinitis in the Singapore GUSTO mother-offspring cohort.

BACKGROUND: The natural history of childhood rhinitis is not well described. OBJECTIVE: This study aimed to identify different rhinitis trajectories in early childhood and their predictors and allergic associations. METHODS: Rhinitis symptoms were ascertained prospectively from birth until 6 years using standardized questionnaires in 772 participants. Rhinitis was defined as one or more episodes of sneezing, runny and/or blocked nose >2 weeks duration. Latent trajectories were identified using group-based modelling, and their predictive risk factors and allergic associations were examined. RESULTS: Three rhinitis trajectory groups were identified: 7.6% (n = 59) were termed early transient rhinitis, 8.6% (n = 66) late transient rhinitis, and 6.6% (n = 51) persistent rhinitis. The remaining 77.2% (n = 596) were classified as non-rhinitis/reference group. Early transient rhinitis subjects were more likely of Indian ethnicity, had siblings, reported childcare attendance, early wheezing and eczema in the first 3 years of life. Late transient rhinitis was associated with antenatal exposure to smoking, higher maternal education levels, and wheezing at age 36-72 months. Persistent rhinitis was associated with male gender, paternal and maternal history of atopy, eczema, and house dust mite sensitization. CONCLUSIONS & CLINICAL RELEVANCE: Risk factors for early transient rhinitis involve a combination of genetic and early environmental exposures, whereas late transient rhinitis may relate to maternal factors and early respiratory infections independent of atopy. In contrast, persistent rhinitis is strongly associated with atopic risk and likely represents the typical trajectory associated with allergic disorders. Allergic rhinitis symptoms may commence as early as the first year of life and may inform development of early interventive strategies.

Multiple modifiable lifestyle factors and the risk of perinatal depression during pregnancy: Findings from the GUSTO cohort.

BACKGROUND: Studies have identified lifestyle risk factors for perinatal depression, but none have examined the cumulative effect of these risk factors in pregnant women. METHODS: We considered the following six factors during pregnancy: poor diet quality (Healthy eating index for Singapore pregnant women 5), physical inactivity (<600 MET-minutes/week), vitamin D insufficiency (<50 nmol/l), smoking before or during pregnancy, and the perceived need for social support. Probable depression was assessed using the Edinburgh postnatal depression scale during pregnancy (>15) and at three months postpartum (≥13). Prevalence risk ratios were calculated with Poisson regressions while adjusting for potential confounders. RESULTS: Of 535 pregnant women, 207 (39%) had zero or one risk factor, 146 (27%) had two, 119 (22%) had three, 48 (9%) had four, and 15 (3%) had ≥5 risk factors at 26-28 weeks' gestation. These six lifestyle habits contributed to 32% of the variance in depressive symptoms during pregnancy. The prevalence of being probably depressed was 6.4 (95% CI 2.1, 19.8; ptrend < 0.001) for expecting women who had ≥4 risk factors compared to women who had ≤1 risk factor. No association was observed between the number of risk factors and depressive symptoms at 3 months postpartum (ptrend = 0.746). CONCLUSION: Pregnant women with ≥4 lifestyle risk factors showed a higher prevalence of depression during pregnancy, while no associations were observed for postpartum depression. CLINICAL TRIAL REGISTRATION: This cohort is registered under the Clinical Trials identifier NCT01174875; http://www.clinicaltrials.gov/ct2/show/NCT01174875?term=GUSTO&rank=2.

Predictive equation for optimal continuous positive airway pressure in children with obstructive sleep apnoea.

AIM: A subgroup of children with obstructive sleep apnoea (OSA) requires treatment with continuous positive airway pressure (CPAP). This study's aims were: 1) to determine if the optimal CPAP for the treatment of OSA in children correlates with body mass index (BMI); 2) to determine the correlation between polysomnographic variables and optimal CPAP in children with OSA; and 3) to develop a CPAP predictive equation for children with OSA. METHODS: This was a retrospective study of children with OSA who underwent CPAP titration studies. Patients with craniofacial abnormalities (except Down syndrome) and neuromuscular diseases were excluded. Polysomnograms were done using Sandman Elite. Correlations between optimal CPAP, clinical and polysomnographic variables were analysed. A multivariable linear regression model for optimal CPAP was developed. RESULTS: 198 children (mean±sd age 13.1±3.6 years) were studied. Optimal CPAP had a significant positive correlation with age (rho=0.216, p=0.002), obstructive apnoea-hypopnoea index (rho=0.421, p<0.001), 3% oxygen desaturation index (rho=0.417, p<0.001), rapid eye movement respiratory disturbance index (rho=0.378, p<0.001) and BMI z-score (rho=0.160, p=0.024); and a significant negative correlation with arterial oxygen saturation measured by pulse oximetry nadir (rho= -0.333, p<0.001). The predictive equation derived was:Optimal CPAP (cmH2O)=6.486+0.273·age (years)-0.664·adenotonsillectomy(no=1, yes=0)+2.120·Down syndrome (yes=1, no=0)+0.280·BMI z-score. CONCLUSION: The equation developed may help to predict optimal CPAP in children with OSA. Further studies are required to validate this equation and to determine its applicability in different populations.

Approach to the snoring child.

Sleep is an important component in a child's growth and development. Snoring is common in children and often perceived as benign, but habitual snoring may be an indication of obstructive sleep apnoea (OSA). OSA can have health, developmental and cognitive consequences. The three common risk factors for paediatric OSA are tonsillar and/or adenoidal hypertrophy, obesity and allergic rhinitis. Primary care providers are well-placed to identify children at risk by screening for habitual snoring and associated OSA risk factors during routine consultations. Physician awareness of OSA symptoms/signs facilitates diagnosis, management and referral decisions. A trial of medical treatment may be considered for habitual snoring with mild symptoms/signs before referral. Overnight polysomnography is the gold standard investigation utilised by paediatric sleep specialists to diagnose OSA. Adenotonsillectomy is the first-line management for OSA with adenotonsillar hypertrophy, but residual/recurrent OSA may occur, so follow-up by primary care providers is important after surgery.

Personal level exposure and hazard potential of particulate matter during haze and non-haze periods in Singapore.

Severe haze episodes originating from biomass burning are common in Southeast Asia. However, there is a paucity of data on the personal exposure and characteristics of Particulate Matter (PM) present in ambient air during haze and non-haze periods. Aims of this study were to monitor 24 h ambulatory exposure to PM among school children in Singapore; characterize haze and non-haze PM for their physicochemical properties, cytotoxicity and inflammatory potential, using bronchial epithelial cell culture model (BEAS-2B). Forty-six children had ambulatory PM exposure monitored using portable Aethalometer and their hourly activity recorded. The mean (±SE) PM exposure on a typical school day was 3343 (±174.4) ng/m3/min. Higher PM exposure was observed during haze periods and during commuting to and from the school. Characterization of PM collected showed a drastic increase in the proportion of ultrafine particle (UFP) in haze PM. These PM fraction showed higher level of sulphur, potassium and trace metals in comparison to those collected during non-haze periods. Dose dependent increases in abiotic reactive oxygen species generation, activation of NF-κB and cytotoxicity were observed for both haze and non-haze PM. Generally, haze PM induced significantly higher release of IL-6, IL-8 and TNFα by BEAS-2B cells in comparison to non-haze PM. In summary, this study provides experimental evidence for higher PM exposure during haze period which has the potential to elicit oxidative stress and pro-inflammatory cytokine release from airway epithelial cells.

Primary spontaneous pneumothorax in children: factors predicting recurrence and contralateral occurrence.

BACKGROUND: The risk factors for recurrence in primary spontaneous pneumothorax (PSP) in children are not well known. We aimed to identify possible risk factors, and to evaluate the utility of computerised tomography (CT) scans in predicting future episodes. METHODS: We reviewed children aged < 18 years admitted to our institution for PSP from 2008 to 2017, excluding those with malignancies. Basic demographic data were extracted. Clinical data collected include pneumothorax laterality, CT results, treatment protocols and recurrences. RESULTS: 63 patients were included, 19 (30.2%) of whom had CT scans. A total of 41 surgeries were performed. The median (interquartile range) age was 15.4 years (14.9-15.9), and body-mass index was 17.9 kg/m2 (15.8-19.3). 56 (88.9%) patients were male. Median follow-up duration was 19.8 months (11.6-35.9). Multivariate logistic regression analyses identified surgery in the first episode as a predictor for a subsequent contralateral occurrence (odds ratio [95% confidence interval] 32.026 [1.685-608.518], p = 0.021). No predictors for ipsilateral recurrence were found. CT scans were 76.5% sensitive for bleb detection, and predicted poorly for occurrence (positive predictive value 14.3%, likelihood ratio 1.1). CONCLUSION: This is the first study demonstrating that surgery at first presentation appears to predict for occurrence of PSP on the contralateral lung. CT appears to be ineffective in detecting blebs and predicting PSP occurrence.

Epidemiology of Pediatric Tracheostomy and Risk Factors for Poor Outcomes: An 11-Year Single-Center Experience.

OBJECTIVE: Children with long-term tracheostomies are at higher risk of complications. This study aims to describe the epidemiology, outcomes, and factors associated with successful decannulation in children undergoing tracheostomy. STUDY DESIGN: Case series with chart review. SETTING: Tertiary hospital. SUBJECTS AND METHODS: A retrospective analysis was conducted on pediatric tracheostomies performed from 2006 to 2016. Demographics, preexisting comorbidities, indications for tracheostomy, and pretracheostomy ventilatory requirements were collected. A multivariate regression model with covariates of age, failure to thrive (FTT), and comorbidities was used to identify factors associated with successful decannulation. Secondary outcomes were ventilation and oxygen requirements at hospital discharge, hospital and intensive care unit length of stay, and complications. RESULTS: In total, 105 patients received a tracheostomy at a median age of 8.0 months (interquartile range, 2.0-45.0). The most common indication was anatomic airway obstruction (55 of 105, 52.5%). Forty-four (41.9%) patients had preexisting FTT. In-hospital mortality was 14 of 105 (13.3%). None were directly related to tracheostomy. At discharge, 40 of 91 (44.0%) and 12 of 91 (13.2%) required home mechanical ventilation and supplemental oxygen, respectively. Forty-one (39%) patients underwent successful decannulation at a median 408 days (interquartile range, 170-1153) posttracheostomy. On adjusted analysis, unsuccessful decannulation was more common in patients with FTT and neurologic comorbidities. Postoperative complications were more common in younger patients and those with a longer time to decannulation. CONCLUSION: Neurologic comorbidities and FTT were risk factors for unsuccessful decannulation after pediatric tracheostomy. Nutritional interventions may have a role in improving long-term outcomes following pediatric tracheostomies and should be investigated in future studies.

High Maternal Circulating Cotinine During Pregnancy is Associated With Persistently Shorter Stature From Birth to Five Years in an Asian Cohort.

BACKGROUND: Self-reported maternal active smoking has been associated with reduced offspring birth length and shorter stature in early and late childhood. OBJECTIVE: To use circulating cotinine as an objective biomarker to investigate the association between smoking and environmental tobacco smoke (ETS) exposure in pregnancy and longitudinal measures of offspring length/height from birth to 60 months. METHODS: In 969 maternal-offspring dyads from the GUSTO cohort, maternal plasma cotinine at 26-28 weeks' gestation was measured by LC/MS/MS and categorized into four groups: Group 1: cotinine <0.17 ng/mL (the assay's detection limit) and no ETS exposure; Group 2: cotinine <0.17 ng/mL but self-reported ETS; Group 3: cotinine 0.17-13.99 ng/mL (ETS or light smoking); Group 4: cotinine ≥14 ng/mL (active smoking). RESULTS: Adjusting for infant sex, gestational age at birth, ethnicity, maternal age, education, parity, BMI, and height, Group 4 offspring were shorter at birth [z-score ß = -0.42 SD units (SDs) (95% CI = -0.77 to -0.06)] than Group 1 offspring. Group 4 offspring continued to be shorter at older ages, with similar effect sizes at 3 months [-0.57 SDs (-0.95 to -0.20)], 36 months [-0.53 SDs (-0.92 to -0.15)], 48 months [-0.43 SDs (-0.81 to -0.04)], and 60 months [-0.57 SDs (-0.96 to -0.17)]. Associations were particularly marked in boys. No significant differences in stature were observed in Groups 2 or 3 compared with Group 1. CONCLUSIONS: This Asian longitudinal study associated high prenatal cotinine with persistently shorter stature in offspring from birth and into early childhood, whilst low prenatal cotinine levels and ETS exposure showed no such association. IMPLICATIONS: Little is known about the long-term effects of prenatal tobacco exposure on offspring stature in Asia where passive smoking is common. This study has used an objective biomarker to reveal that the association of prenatal tobacco exposure with offspring length/height mainly occurs at a high maternal cotinine level of greater than 14 ng/mL in pregnancy, consistent with active smoking, but no significant associations were found with lower cotinine levels, consistent with passive smoking. Encouraging women to quit smoking prior to or during pregnancy may avert the long-term negative impact on their child's height despite appreciable prenatal ETS exposure.

Exercise testing in children with lung diseases.

Exercise is an important aspect of health and development in children. By placing the pulmonary system under stress, exercise testing may reveal subtle dynamic abnormalities that are not apparent on conventional static pulmonary function tests. Furthermore, exercise testing assesses the functional impact of respiratory disease on children. Exercise testing has been used in children with a variety of respiratory diseases such as exercise induced bronchoconstriction, asthma, cystic fibrosis and bronchopulmonary dysplasia to assess the severity of disease as well as response to various interventions. Furthermore, there is good evidence that exercise testing is a useful tool to help determine prognosis in patients with cystic fibrosis. In addition to the clinical utility, exercise testing is also becoming an increasingly important outcome measure in research studies.