A phospholipid-based formulation for the treatment of airway inflammation in chronic respiratory diseases.

Inflammation, the major hallmark of all chronic respiratory diseases is generally managed by inhaled corticosteroids. However, long term high dose treatment can result in significant side effects. Hence, there is a medical need for non-steroidal anti-inflammatory therapies to address airway inflammation. Phospholipids have been shown to reduce inflammation in several inflammatory conditions; however, their clinical translation has been limited to liposomal formulations traditionally used as drug carriers and their biological activity has not been investigated. Here we report the first application of empty liposomes as an anti-inflammatory treatment in airway inflammation. In the current study, liposomes (UTS-001) were prepared from cholesterol and a synthetic phospholipid (DOPC). The formulation was characterised in terms of size, charge, polydispersity index, morphology and stability as colloidal suspension and freeze-dried nanoparticles. Time-dependant uptake of UTS-001 in airway epithelial cells was observed which was inhibited by nystatin demonstrating that the uptake is via the caveolae pathway. In-vitro, in primary nasal epithelial cells, UTS-001 treatment successfully attenuated IL-6 levels following TNF-α stimulation. Consistent with the in-vitro findings, in-vivo, in the ovalbumin model of allergic airway inflammation, UTS-001 significantly reduced total immune cell counts in bronchoalveolar lavage fluid and reduced airway hyperresponsiveness in response to increasing doses of methacholine challenge. Therefore, our results establish UTS-001 as a potential anti-inflammatory treatment that may be useful as a therapeutic for lung inflammatory diseases.

Evaluating the Alimentary and Respiratory Tracts in Health and disease (EARTH) research programme: a protocol for prospective, longitudinal, controlled, observational studies in children with chronic disease at an Australian tertiary paediatric hospital.

INTRODUCTION: Chronic gastrointestinal and respiratory conditions of childhood can have long-lasting physical, psychosocial and economic effects on children and their families. Alterations in diet and intestinal and respiratory microbiomes may have important implications for physical and psychosocial health. Diet influences the intestinal microbiome and should be considered when exploring disease-specific alterations. The concepts of gut-brain and gut-lung axes provide novel perspectives for examining chronic childhood disease(s). We established the 'Evaluating the Alimentary and Respiratory Tracts in Health and disease' (EARTH) research programme to provide a structured, holistic evaluation of children with chronic gastrointestinal and/or respiratory conditions. METHODS AND ANALYSIS: The EARTH programme provides a framework for a series of prospective, longitudinal, controlled, observational studies (comprised of individual substudies), conducted at an Australian tertiary paediatric hospital (the methodology is applicable to other settings). Children with a chronic gastrointestinal and/or respiratory condition will be compared with age and gender matched healthy controls (HC) across a 12-month period. The following will be collected at baseline, 6 and 12 months: (i) stool, (ii) oropharyngeal swab/sputum, (iii) semi-quantitative food frequency questionnaire, (iv) details of disease symptomatology, (v) health-related quality of life and (vi) psychosocial factors. Data on the intestinal and respiratory microbiomes and diet will be compared between children with a condition and HC. Correlations between dietary intake (energy, macro-nutrients and micro-nutrients), intestinal and respiratory microbiomes within each group will be explored. Data on disease symptomatology, quality of life and psychosocial factors will be compared between condition and HC cohorts.Results will be hypothesis-generating and direct future focussed studies. There is future potential for direct translation into clinical care, as diet is a highly modifiable factor. ETHICS AND DISSEMINATION: Ethics approval: Sydney Children's Hospitals Network Human Research Ethics Committee (HREC/18/SCHN/26). Results will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04071314.

Research priorities for childhood chronic conditions: a workshop report.

BACKGROUND: Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy. OBJECTIVE: To identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices. SETTING: An Australian paediatric hospital and health consumer organisations. METHODS: Recruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed. RESULTS: Seventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services). CONCLUSION: Research priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda.

Fat-soluble vitamin deficiency in children and adolescents with cystic fibrosis.

AIMS: Determine the prevalence of fat-soluble vitamin deficiency in children with cystic fibrosis (CF) aged ≤18 years in New South Wales (NSW), Australia, from 2007 to 2010. METHODS: A retrospective analysis of fat-soluble vitamin levels in children aged ≤18 years who lived in NSW and attended any of the three paediatric CF centres from 2007 to 2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed. RESULTS: Deficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin level test in the study period. The prevalence of vitamins D and E deficiency fell from 22.11% in 2007 to 15.54% in 2010, and 20.22% to 13.89%, respectively. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Low vitamin K was present in 29% in 2007, and prevalence of prolonged prothrombin time increased from 19.21% to 22.62%. Fat-soluble vitamin deficiency is present in 10%-35% of children with pancreatic insufficiency, but only a very small proportion of children who are pancreatic-sufficient. CONCLUSIONS: This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Fat-soluble vitamin testing is essential to identify deficiency in pancreatic-insufficient children who may be non-compliant to supplementation or require a higher supplement dose, and pancreatic-sufficient children who may be progressing to insufficiency. Testing of vitamin K-dependent factors needs consideration. Further studies are needed to monitor rates of vitamin deficiency in the CF community.

Single high-dose oral vitamin D3 (stoss) therapy--a solution to vitamin D deficiency in children with cystic fibrosis?

OBJECTIVES: To determine the safety and efficacy of stoss therapy on vitamin D levels over a 12 month period in children with cystic fibrosis and vitamin D deficiency (<75 nmol/L). STUDY DESIGN: Retrospective chart review of 142 paediatric CF patients from 2007 till 2011. RESULTS: Thirty eight children received stoss therapy and 37 children with vitamin D deficiency were not treated and served as a control group. The stoss treated group had a significant and sustained increase in 25-hydroxyvitamin D levels measured at 1, 3, 6 and 12 months post treatment compared to controls (94.82 ± 41.0 nmol/L, p=0.001; 81.54 ± 24.6 nmol/L, p=0.001; 92.18 ± 36.5 nmol/L, p=0.008 and 64.6 ± 20.0 nmol/L, p=0.006 respectively). At 12 months post intervention, the mean difference in vitamin D levels from baseline between the stoss treated group and controls was significant at 15 nmol/L compared to 5 nmol/L (p=0.038). CONCLUSION: Stoss therapy effectively achieves and maintains levels of 25-hydroxyvitamin D greater than 75 nmol/L over 12 months.