Establishing a telehealth model addressing paediatric sleep health in remote and rural Northern Territory Australia: Overcoming the distance barrier.

AIM: This study examined the outcomes of a telehealth model for sleep health assessment among Indigenous and non-Indigenous children residing in remote and regional communities at the Top End Northern Territory (NT) of Australia. METHODS: Video telehealth consultation, that included clinical history and relevant physical findings assessed virtually with an interstate paediatric sleep physician was conducted remotely. Polysomnography (PSG) and therapeutic interventions were carried out locally at Darwin, NT. The study participants were children referred between 2015 and 2020. RESULTS: Of the total 812 children referred for sleep assessment, 699 underwent a diagnostic PSG. The majority of patients were female (63%), non-Indigenous (81%) and resided in outer regional areas (88%). Indigenous children were significantly older and resided in remote or very remote locations (22% vs. 10%). Referral patterns differed according to locality and Indigenous status - (non-Indigenous via private (53%), Indigenous via public system (35%)). Receipt of referrals to initial consultation was a median of 16 days and 4 weeks from consult to PSG. Remote children had slightly longer time delay between the referral and initial consult (32 vs. 15 days). Fifty one percent were diagnosed to have OSA, 27% underwent adenotonsillectomy and 2% were prescribed with CPAP therapy. CONCLUSIONS: This study has demonstrated that a telehealth model can be an effective way in overcoming logistical barriers and in providing sleep health services to children in remote and regional Australia. Further innovative efforts are needed to improve the service model and expand the reach for vulnerable children in very remote communities.

Molecular Dynamics and Theratyping in Airway and Gut Organoids Reveal R352Q-CFTR Conductance Defect.

A significant challenge to making targeted cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies accessible to all individuals with cystic fibrosis (CF) are many mutations in the CFTR gene that can cause CF, most of which remain uncharacterized. Here, we characterized the structural and functional defects of the rare CFTR mutation R352Q, with a potential role contributing to intrapore chloride ion permeation, in patient-derived cell models of the airway and gut. CFTR function in differentiated nasal epithelial cultures and matched intestinal organoids was assessed using an ion transport assay and forskolin-induced swelling assay, respectively. CFTR potentiators (VX-770, GLPG1837, and VX-445) and correctors (VX-809, VX-445, with or without VX-661) were tested. Data from R352Q-CFTR were compared with data of 20 participants with mutations with known impact on CFTR function. R352Q-CFTR has residual CFTR function that was restored to functional CFTR activity by CFTR potentiators but not the corrector. Molecular dynamics simulations of R352Q-CFTR were carried out, which indicated the presence of a chloride conductance defect, with little evidence supporting a gating defect. The combination approach of in vitro patient-derived cell models and in silico molecular dynamics simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine.

Real-world respiratory and bulbar comorbidities of SMA type 1 children treated with nusinersen: 2-Year single centre Australian experience.

AIM: To describe the respiratory and nutritional supportive care and hospitalisations required in the real-world scenario in children with SMA type 1 treated with nusinersen. METHODS: Single-centre observational cohort study of children with SMA1 commencing nusinersen from November 2016 to September 2018. Motor, respiratory and nutritional clinical characteristics and management are described from initiation of nusinersen for a minimum of two years. RESULTS: Nine children (5 females, 4 males), median age 10.7 months (range 2.7-181.2) commenced treatment with nusinersen and outcomes were assessed over a total of 270.5 patient months and 209 hospital admissions. Supportive care in newly-diagnosed patients (n = 7) included gastrostomy insertion (n = 4) and commencement of noninvasive ventilation (n = 4) at an average of 8.3 and 4.5 months after diagnosis, respectively. The annualised hospitalisation rate was 9.3/patient/year, average length of stay (LOS) of 3.3 days (SD = 5.6). Children with two SMN2 copies required more gastrostomies (p < 0.05) and had more frequent admissions (p < 0.05). Number of total admissions halved from the first to the second year of treatment in all patients (p < 0.005). INTERPRETATION: Children with treated SMA1 experienced considerable respiratory and bulbar comorbidities, necessitating substantial respiratory and nutritional supportive care. Proactive respiratory and nutritional surveillance and management is essential in SMA1 patients treated with nusinersen.

Utility of bronchoscopy in immunocompromised paediatric patients: Systematic review.

PURPOSE: The objective of this study was to describe the diagnostic yield and safety of bronchoalveolar lavage (BAL) in the evaluation of pulmonary lesions in immunocompromised children. METHODS: We conducted a systematic review of literature published during the past 20 years, searching Medline, Medline EPub, EMBASE, and Scopus. Studies included involved paediatric patients (<18 years) on treatment for an oncological diagnosis or other immune compromise who underwent BAL for evaluation of pulmonary lesions. Only English language publications were included. RESULTS: In all, 272 studies were screened and 19 included. All were observational studies with moderate (11/19) or serious (8/19) risk of bias. BAL yielded a potential pathogen in 43% of cases (496/1156). Two papers reported improved diagnostic yield with early BAL (less than 3 days of presentation). A change in patient management after BAL was reported in 53% of cases (275/519). Adverse events were reported in 19% of cases following BAL (193/993) but were generally mild with no procedure-related mortality reported. CONCLUSION: BAL appears to be useful for evaluation of pulmonary lesions in immunocompromised children with generally acceptable safety, though included studies had at least moderate risk of bias. Future prospective studies may provide more definitive estimates of benefit, timing and risk of BAL in this population.

Case report: Cholecystoduodenostomy for cholestatic liver disease in a premature infant with cystic fibrosis and short gut syndrome.

BACKGROUND: Cholecystoduodenostomy is a surgical procedure that bypasses the extrahepatic biliary tree and connects the gallbladder directly to the duodenum. This case describes the successful use of this procedure in a novel situation. CASE PRESENTATION: A premature (34 weeks gestation) female infant with cystic fibrosis required a laparotomy on day 1 of life due to an intrauterine small bowel perforation. Resection of small bowel and ileostomy formation resulted in short gut syndrome, with 82 cm residual small bowel and intact ileocaecal valve. Post-ileostomy reversal at 2 months old, she developed conjugated hyperbilirubinaemia. Despite conservative management including increased enteral feeding, ursodeoxycholic acid, cholecystostomy drain insertion and flushes, her cholestatic jaundice persisted. A liver biopsy revealed an "obstructive/cholestatic" picture with fibrosis. To avoid further shortening her gut with an hepatoportoenterostomy, cholecystoduodenostomy was performed at 3 months of age with subsequent post-operative improvement and eventual normalisation of her clinical jaundice and liver biochemistry. CONCLUSIONS: This is the first reported case of a cholecystoduodenostomy being used successfully to treat an infant with persistent conjugated hyperbilirubinemia, cystic fibrosis and short gut syndrome. Cholecystoduodenostomy is a treatment option that with further study, may be considered for obstruction of the common bile duct in patients with short gut and/or where a shorter operating time with minimal intervention is preferred.

Sleep studies in children on long-term non-invasive respiratory support.

PURPOSE: The aim of this study was to assess the impact of changes in respiratory support (RS) settings recommended after a titration polysomnography (PSG), in terms of daytime symptoms and quality of life. METHODS: A retrospective chart review of all RS (CPAP and bi-level ventilation) titration studies was carried out at our tertiary paediatric sleep laboratory in the past 5 years. All patients with at least two studies in the past 5 years were included in the analysis. Parents completed the obstructive sleep apnoea (OSA)-18 and Paediatric Daytime Sleepiness Scale (PDSS) questionnaires on the night of each PSG. Results are presented as means (SD). RESULTS: A total of 42 patients (25 on CPAP and 17 on bi-level ventilation, age 11 (6) years) had 71 pairs of titration studies (41 CPAP and 30 bi-level). Changes in RS settings were recommended in 27 of 41 (65%) CPAP studies and 11 of 30 (36%) bi-level studies. Overall, changes were fully implemented by the treating physician in 55% of cases. There was an improvement in total OSA-18 score between studies in 48% of the paired CPAP studies and 65% of bi-level studies. OSA-18 scores improved in 47% of the studies where any recommended change had been implemented versus 0% of those where none of the recommended changes had been made (p=0.1). CONCLUSIONS: Titration studies frequently led to recommendations for a change in RS settings in these patients on long-term RS. Symptom scores were more likely to improve if recommendations for change were implemented by the time of the follow-up study.

Social deprivation and spatial clustering of childhood asthma in Australia.

BACKGROUND: Asthma is the most common chronic respiratory illness among children in Australia. While childhood asthma prevalence varies by region, little is known about variations at the small geographic area level. Identifying small geographic area variations in asthma is critical for highlighting hotspots for targeted interventions. This study aimed to investigate small area-level variation, spatial clustering, and sociodemographic risk factors associated with childhood asthma prevalence in Australia. METHODS: Data on self-reported (by parent/carer) asthma prevalence in children aged 0-14 years at statistical area level 2 (SA2, small geographic area) and selected sociodemographic features were extracted from the national Australian Household and Population Census 2021. A spatial cluster analysis was used to detect hotspots (i.e., areas and their neighbours with higher asthma prevalence than the entire study area average) of asthma prevalence. We also used a spatial Bayesian Poisson model to examine the relationship between sociodemographic features and asthma prevalence. All analyses were performed at the SA2 level. RESULTS: Data were analysed from 4,621,716 children aged 0-14 years from 2,321 SA2s across the whole country. Overall, children's asthma prevalence was 6.27%, ranging from 0 to 16.5%, with significant hotspots of asthma prevalence in areas of greater socioeconomic disadvantage. Socioeconomically disadvantaged areas had significantly higher asthma prevalence than advantaged areas (prevalence ratio [PR] = 1.10, 95% credible interval [CrI] 1.06-1.14). Higher asthma prevalence was observed in areas with a higher proportion of Indigenous individuals (PR = 1.13, 95% CrI 1.10-1.17). CONCLUSIONS: We identified significant geographic variation in asthma prevalence and sociodemographic predictors associated with the variation, which may help in designing targeted asthma management strategies and considerations for service enhancement for children in socially deprived areas.

Comparing Cytology Brushes for Optimal Human Nasal Epithelial Cell Collection: Implications for Airway Disease Diagnosis and Research.

Primary nasal epithelial cells and culture models are used as important diagnostic, research and drug development tools for several airway diseases. Various instruments have been used for the collection of human nasal epithelial (HNE) cells but no global consensus yet exists regarding the optimal tool. This study compares the efficiency of two cytology brushes (Olympus (2 mm diameter) and Endoscan (8 mm diameter)) in collecting HNE cells. The study involved two phases, with phase one comparing the yield, morphology and cilia beat frequency (CBF) of cells collected from paediatric participants using each of the two brushes. Phase two compared nasal brushing under general anaesthetic and in the awake state, across a wide age range, via the retrospective audit of the use of the Endoscan brush in 145 participants. Results indicated no significant difference in CBF measurements between the two brushes, suggesting that the choice of brush does not compromise diagnostic accuracy. However, the Endoscan brush collected significantly more total and live cells than the Olympus brush, making it a more efficient option. Importantly, the Endoscan brush is more cost-effective, with a notable price difference between the two brushes.

Management of asthma in children with long QT syndrome.

The Long QT syndrome (LQTS) is a rare disorder in which patients are prone to life threatening ventricular arrhythmia and is a leading cause of sudden death in childhood. Asthma is common and its management in those with LQTS presents a number of potential difficulties. The mainstay of therapy in LQTS is beta-blockade, which may worsen symptoms of asthma. Conversely, beta-agonist therapy is the mainstay of asthma management; which, in those with LQTS, may provoke ventricular arrhythmias. We review available data regarding the management of coexistent LQTS and asthma, and provide a summary of the necessary considerations in managing these patients.

Daytime predictors of nocturnal hypercapnic hypoventilation in children with neuromuscular disorders.

OBJECTIVES: To examine objective daytime predictors of nocturnal hypercapnic hypoventilation (NHH) and identify a forced vital capacity (FVC) z-score cut off that predicts NHH using the 2012 Global Lung Function Initiative (GLI) reference equations in pediatric neuromuscular patients. DESIGN: Single-centre retrospective medical record review. SETTING: Tertiary pediatric hospital in Australia. PATIENTS: Children (<18 years old) with a neuromuscular disorder (NMD) who had a diagnostic sleep study over a 5-year period. RESULTS: Fifty children were included, median age 11.9 years (interquartile range [IQR]: 4.5-14.3). The majority of children had a diagnosis of Duchenne Muscular Dystrophy (32%). NHH was diagnosed in 18 children (36%). Multivariate logistic regression analysis performed for the entire cohort confirmed a statistically significant association between NHH and scoliosis (odds ratio [OR]: 3.3, p = 0.03), but not age (OR: 1.01, p = 0.26), body mass index z-score (OR: 0.86, p = 0.26) or use of a wheelchair for mobility (OR: 1.25, p = 0.72). For the subset of 29 children who had spirometry testing (median age 12.9 years [IQR: 10.2-14.3]), FVC z-score was the only statistically significant predictor of NHH (OR: 0.45, p = 0.02). NHH was predicted by an FVC z-score <-3.24 (sensitivity 78%, specificity 73%), or FVC <60% predicted (sensitivity 78%, specificity 73%). There was a strong positive correlation between FVC and forced expiratory volume in 1 s z-scores (rp = 0.98, p = 0.00) and FVC and peak expiratory flow  z-scores (rp = 0.72, p = 0.00). CONCLUSION: Children with a NMD and scoliosis or a lower FVC z-score have increased odds of having NHH.

Sleep quality and obstructive sleep apnoea in Indigenous and non-Indigenous Australian children.

BACKGROUND: Literature pertaining to the prevalence of obstructive sleep apnoea (OSA) and sleep quality among Indigenous Australian children is sparse. This study assessed various sleep related parameters and outcomes between Indigenous and non-Indigenous Australian children. METHODS: Children referred to the sleep health service in the Northern Territory of Australia for a clinically suspected sleep disorder between 2015 and 2021 were included in this study. Self-reported sleep measures alongside polysomnography data were assessed and compared between these two diverse ethnic population. RESULTS: Of the 671 sleep studies assessed, 121 (18%) were from Indigenous children. The majority of patients were male (61%), with a median age of 5.7 (3.5, 8.9) years, and body mass index (BMI) in the normal range (57%). Indigenous children were significantly older (median 7.2 years (4.5, 11.9), with a higher BMI (p = 0.005) and a greater proportion living in very remote locality (14% vs. 6% non-Indigenous, p = 0.001). Indigenous children had higher Paediatric Daytime Sleepiness Scale scores (p = 0.001), higher screen use before bed (p = 0.005), later bedtimes (p = 0.001) and reduced total sleep time (p = 0.034) compared to non-Indigenous children. Prevalence of OSA was higher in Indigenous children (55% vs. 48%) and with greater severity compared to non-Indigenous children. CONCLUSIONS: In this study, OSA was more prevalent and more severe in Indigenous children than their non-Indigenous peers. However, this may not necessarily be extrapolated to the general Indigenous paediatric population. Sleep hygiene and sleep quantity was also decreased further impacting adequate sleep. This highlights the importance of identifying and managing these addressable parameters and for targeted interventions.

Cystic fibrosis-related diabetes and lung disease: an update.

The development of cystic fibrosis-related diabetes (CFRD) often leads to poorer outcomes in patients with cystic fibrosis including increases in pulmonary exacerbations, poorer lung function and early mortality. This review highlights the many factors contributing to the clinical decline seen in patients diagnosed with CFRD, highlighting the important role of nutrition, the direct effect of hyperglycaemia on the lungs, the immunomodulatory effects of high glucose levels and the potential role of genetic modifiers in CFRD.

Avatar acceptability: views from the Australian Cystic Fibrosis community on the use of personalised organoid technology to guide treatment decisions.

BACKGROUND: Patient-oriented research approaches that reflect the needs and priorities of those most affected by health research outcomes improves translation of research findings into practice. Targeted therapies for cystic fibrosis (CF) are now a viable treatment option for some eligible individuals despite the heterogeneous patient-specific therapeutic response. This has necessitated development of a clinical tool that predicts treatment response for individual patients. Patient-derived mini-organs (organoids) have been at the forefront of this development. However, little is known about their acceptability in CF patients and members of the public. METHODS: We used a cross-sectional observational design to conduct an online survey in people with CF, their carers and community comparisons. Acceptability was examined in five domains: 1) willingness to use organoids, 2) perceived advantages and disadvantages of organoids, 3) acceptable out-of-pocket costs, 4) turnaround time and 5) source of tissue. RESULTS: In total, 188 participants completed the questionnaire, including adults with CF and parents of children with CF (90 (48%)), and adults without CF and parents of children without CF (98 (52%)). Use of organoids to guide treatment decisions in CF was acceptable to 86 (95%) CF participants and 98 (100%) community participants. The most important advantage was that organoids may improve treatment selection, improving the patient's quality of life and life expectancy. The most important disadvantage was that the organoid recommended treatment might be unavailable or too expensive. CONCLUSIONS: These findings indicate acceptance of patient-derived organoids as a tool to predict treatment response by the majority of people surveyed. This may indicate successful future implementation into healthcare systems.

Diet and visually significant cataracts in galactosaemia: is regular follow up necessary?

INTRODUCTION: Classic galactosaemia is caused by a recessively inherited deficiency of the enzyme galactose 1 phosphate uridyl transferase (GALT). Patients with classical galactosaemia are at increased risk of developing cataracts. We sought to retrospectively review the incidence and severity of cataracts in the cohort of galactosaemia patients attending our national treatment centre and to assess a possible effect of dietary compliance on cataract formation and the benefits of regular ophthalmic follow-up. METHODS: We retrospectively reviewed the clinical notes of all patients currently attending our centre with classic galactosaemia and identified all those in whom cataracts had been diagnosed by an ophthalmologist. Compliance to diet was also reviewed and compared with a matched control group. RESULTS: Of 100 active patient charts, 14 had cataracts diagnosed at some stage. Six of these persisted whereas eight regressed. Three occurred soon after birth. Age at cataract formation varied from soon after birth to 19 years of age. There was no significant difference in the cataract group between those who were compliant and those who were noncompliant with diet (p = 0.09). There was no difference in compliance between the cataract group and the control group (p = 0.16). None of the cataracts found were affecting vision. CONCLUSION: Cataracts affecting vision were not found in our cohort. A direct relationship between dietary compliance and cataract formation was not demonstrated. On the basis of our data, regular life-long ophthalmic exam of patients with classic galactosemia seems to be unnecessary. TAKE-HOME MESSAGE: Cataracts which develop in patients with classical Galactosaemia do not usually affect vision and may be unrelated to compliance to diet.

Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis.

It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test. Young children with CF have glucose abnormalities detected by CGM that fluctuate over time.

Peak OGTT glucose is associated with lower lung function in young children with cystic fibrosis.

BACKGROUND: Screening for Cystic Fibrosis-related diabetes is recommended in patients with CF <10 years old when there are concerns about growth and lung function. The Oral Glucose Tolerance Test (OGTT) is recommended but has not been validated in this cohort. We sought to determine whether the 2-h OGTT, the gold standard diagnostic test for CFRD, detects clinical decline in children with CF <10 years old. METHODS: We analysed blood glucose(BG) levels collected every 30 min during OGTT in 27 children with CF < 10 years old, comparing the 2-hour BG (BG120min), peak BG (BGmax) and Area Under the Curve(AUC) for glucose and the association with lung function and nutritional status. We also compared the OGTT results with results from Continuous Glucose Monitoring (CGM) performed in 11 participants. RESULTS: The BGmax was higher than the BG120min in 25/27 (93%) participants. There was a significant inverse correlation between BGmax and weight z-score (rs = -0.56, p = .002) and between BGmax and FEV1 (rs = -0.54, p = .014) that was not present for BG120min. A significant inverse correlation was also identified between fasting insulin level and elevated glucose on CGM, defined as AUC >7.8 mmol/L (rs = - 0.69, p = .027) or as % time > 7.8 (rs = - 0.76, p = .011). CONCLUSIONS: Children with CF < 10 years of age with higher BGmax on OGTT have lower lung function and weight z- scores that may not be identified using the 2 h OGTT BG120min. CGM also identifies glucose excursions in young children with CF.

Children with bronchiectasis have poorer lung function than those with cystic fibrosis and do not receive the same standard of care.

BACKGROUND: Children with cystic fibrosis (CF) are routinely managed in a multidisciplinary clinic at tertiary pediatric centers. However, children with bronchiectasis may not be managed in the same way. We sought to compare the management model and clinical outcomes of children with bronchiectasis with children diagnosed with CF, in a single pediatric center. METHODS: We identified patients with bronchiectasis from hospital medical records at an urban tertiary pediatric hospital and identified a sex- and age-matched CF patient at the same center to compare lung function, nutritional status, frequency of physiotherapy and respiratory physician visits, and number of microbiological samples taken for bacterial culture. RESULTS: Twenty-two children with bronchiectasis were identified, mean (standard deviation [SD]) age was 11 (3) years. The most common known etiology for bronchiectasis was postinfective (6 of 22) but was unknown in 8 of 22. The cohort with bronchiectasis had poorer lung function (FEV1 mean [SD] percent predicted 78.6 [20.5] vs 94.5 [14.7], P = .005) and had less outpatient reviews by the respiratory physician (P < .001) and respiratory physiotherapist (P < .001) when compared to those with CF. Nutritional parameters did not differ between the groups. Many children (10 of 22, 45%) with bronchiectasis did not have any microbiological respiratory tract samples taken for evaluation. CONCLUSION: Children with bronchiectasis at this institution have poorer lung function than children with CF, and are deserving of improved multidisciplinary care.

Long-term morbidity of respiratory viral infections during chemotherapy in children with leukaemia.

BACKGROUND: Respiratory viruses are a common cause of infection in immunosuppressed children undergoing cancer therapy. Pulmonary sequelae have been documented following respiratory viral infections (RVIs) in hematopoietic stem cell transplant (HSCT) recipients; however potential late effects in children undergoing nonmyeloablative chemotherapy have not been investigated. AIM: To evaluate the long-term pulmonary morbidity of respiratory viral infections during chemotherapy in children with acute lymphoblastic leukemia (ALL). METHODS: Childhood ALL survivors, aged 7 to 18 years, greater than 6 months posttreatment were recruited. Exclusion criteria included HSCT or proven bacterial/fungal respiratory infection during treatment. Subjects were classified into "viral" or "control" groups according to retrospective medical records that documented the presence of laboratory-proven RVIs during chemotherapy. Symptom questionnaires (Liverpool, ISAAC) and lung function testing (spirometry, plethysmography, diffusing capacity, forced oscillation technique to ATS/ERS standards) were then performed cross-sectionally at the time of recruitment. RESULTS: Fifty-four patients (31 viral, 23 control) were recruited: median (range) age 11.2 (7.2-18.1) years, and at 4.9 (0.5-13) years posttherapy. Abnormalities were detected in 17 (31%) individuals (8 viral, 9 control), with the most common being DLCO impairment (3 viral, 4 control) and reduced respiratory reactance at 5 Hz (5 viral, 6 control). Children with RVIs during chemotherapy reported more current respiratory symptoms, particularly wheeze (odds ratio [OR], 3.0; 95% confidence interval [CI]: 0.9-10.0; P = .09) and cough (OR, 2.7; 95% CI: 0.8-9.5; P = .11). No differences in lung function tests were observed between the two groups. CONCLUSIONS: Our study found children with RVIs during chemotherapy developed more long-term respiratory symptoms than controls; however, differences did not reach statistical significance. No differences in static lung function were found between the two groups. Overall, pulmonary abnormalities and/or significant ongoing respiratory symptoms were detected in nearly a third of ALL survivors treated without HSCT. Larger, prospective studies are warranted to evaluate the etiology and clinical significance of these findings.