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Head of Division
Professor Peter D Sly MBBS MD DSc FRACP
Professor Sly established the Division of Clinical Sciences at the Institute in 1991. He is currently Director, Clinical Research and Education, Princess Margaret Hospital for Children; Professorial Fellow and Coordinator of Postgraduate Education, School of Paediatrics and Child Health, University of Western Australia; Senior Principal Research Fellow, NHMRC; Respiratory Physician, Princess Margaret Hospital for Children.
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Divisional Summary
The Divisional activities centre broadly around three main themes:
1. Asthma
Studies on the mechanisms underlying the development of asthma, involve longitudinal birth cohorts and mechanistic studies in laboratory animals. These studies are largely conducted as part of the Asthma Program grant and NHMRC project grants and involve collaboration between the teams headed by the Program grant PIs: Peter Sly (Clinical Sciences), Pat Holt (Cell Biology); Wayne Thomas (Molecular Biotechnology), Peter Le Souef (UWA School of Paediatrics and Child Health), Steve Stick (Clinical Sciences and PMH Department of Respiratory Medicine), and John Upham (University of Queensland), together with Deb Strickland (Cell Biology) and Phil Stumbles (Cell Biology and Murdoch University).
Significant achievements from the program grant during 2008 include:
a. Defining the antibody response in children with asthma exacerbations and the changes occurring during convalescence. IgE to house dust mite allergens decreased while IgE to P6 antigen of the nasopharyngeal colonising bacterium H. influenzae increased to high titre. The already low IgG antibody levels of children admitted for asthma exacerbations did not recover and even fell during convalescence. The importance of the low IgG in the development was further elaborated by showing that children with frequent episodic or persistent asthma had lower titres than children with infrequent episodes.
b. Defining a novel pathway responsible for amplifying innate immune responses to respiratory viral infections in atopics presenting with acute severe asthma. Our data show, for the first time the role of pre-existing IgE antibodies in recruiting and amplifying the innate immune responses involving the pro-inflammatory alternatively activated macrophages during acute exacerbations of asthma in children.
c. Identifying mechanisms by which airway epithelial cells regulate DC function. Our data show that cytokines secreted by epithelial cells regulate maturation of airway mucosal dendritic cell maturation and function, in particular balancing the response to pathogenic and non-pathogenic stimuli.
• The Global Prevention of Asthma in Children (GPAC) study is funded by the Immune Tolerance Network and the National Institute of Allergy and Infectious Diseases, USA and uses oral mucosal immunoprophylaxis (hence forth known as OMIP) to prevent the development of allergic sensitisation in asthma. This project represents a major collaborative venture between Peter Sly and Pat Holt (Cell Biology), together with A/Professor Philip Robinson (Royal Children’s Hospital, Melbourne) and Professor Hugh Sampson (Mt. Sinai Hospital, New York, USA). Over 15,000 doses of allergen or placebo have been given to 50 children without and treatment-related serious adverse events, demonstrating that immunoprophylaxis in high risk children is safe. This cohort has finished treatment and is now in the follow-up phase.
2. Early Detection of Lung Disease in Cystic Fibrosis
During 2008 we formalized the collaboration between Clinical Sciences; the Department of Respiratory Medicine, PMH; the Department of Respiratory Medicine, Royal Children’s Hospital, Melbourne; and the Murdoch Children’s Research Institute into the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). We officially launched AREST CF and unveiled our website (www.arestcf.org) at a public function held at the Institute in December 2008. The community support bodies, Cystic Fibrosis Western Australia and Cystic Fibrosis Victoria partner with us in this venture. The program is extremely well accepted in both clinics with >95% of eligible families participating.
The AREST CF program has grown from an early surveillance program initiated in Perth in 1999 that involved bronchoalveolar lavage (BAL) to evaluate pulmonary infection and inflammation and infant lung function testing. The program was extended to include measurement of preschool lung function in 2003 and chest computed tomography (CT) scanning in 2005. The Melbourne clinic joined the program in 2005 and we have been successfully operating as a single entity since. The current program consists of a comprehensive assessment soon after diagnosis (av. age 3 months) and an annual assessment until age 6 years or when the child can expectorate sputum. Each assessment includes chest CT and BAL under general anaesthesia; lung function testing (infant techniques until age 2y, and pre-school techniques thereafter); assessment of pulmonary inflammation and infection from BAL; and research into novel markers of inflammation, oxidative stress and lung destruction in BAL and urine.
Major findings and achievements of the current program:
• Pulmonary inflammation is common in early life and increased in the presence of infection.
• Decreased CFTR function, as indicated by sweat chloride levels, is associated with increased pulmonary inflammation.
• Early pulmonary inflammation in CF is characterised by large numbers of neutrophils, increased levels of IL-8 and free myeloperoxidase and neutrophil elastase activity; 77% have detectable IL-8 and 30% have free neutrophil elastase in 3 month BAL. Free neutrophil elastase activity in BAL is a major risk factor for subsequent bronchiectasis.
• 80% of children have at least 1 pulmonary infection by 6 years of age; 50% are asymptomatic at the time and 36% are infected with Pseudomonas aeruginosa (early acquisition is a major risk factor for bronchiectasis).
• The median age of acquisition of Pseudomonas aeruginosa is 26 months in children diagnosed following newborn screening.
• Pseudomonas aeruginosa can be eradicated with aggressive treatment, with 77% of infections eradicated after a single treatment cycle of intravenous followed by oral and inhaled antibiotics.
• Lung function in preschoolers is worse in those with respiratory symptoms and pulmonary infection and can be used clinically in the same way as lung function in older children.
• CT abnormalities are common in early life; with 18% having bronchial dilatation (bronchiectasis), 45% having bronchial wall thickening and 67% having gas-trapping at three months of age. These changes persist and are progressive in >70% of children on scans assessed 12 months apart. Forty percent of children have bronchiectasis by age 4 years.
On a sad note, Dr. Siobhain Brennan, who played a major role in establishing the program left us during 2008 to follow her dream and enrolled in the Postgraduate Medical course at UWA. We wish her all the best in her new career.
3. Children’s Environmental Health
The Division of Clinical Sciences was designated as the WHO Collaborating Centre for Children’s Environmental Health in July 2006. The terms of reference for the Centre are:
• To conduct high quality research aimed at understanding the mechanisms underlying the development of diseases of environmental origin in children, with special emphasis on respiratory disease (e.g. respiratory infections, asthma & allergies).
• To build research capacity by fostering collaborations between developed and developing nations.
• To enhance the research capacity of researchers and health care professionals by providing access to high quality education and training.
• To develop programs and curriculum to increase awareness about environmental threats, with special emphasis on respiratory diseases in children.
• To develop methods for translating research findings into public policy and intervention strategies.
Further details about the Centre can be found on our website (www.ichr.uwa.edu.au/who )
The Centre is affiliated with the School of Public Health, Division of Health Sciences at Curtin University. The Centre Staff consist of coordinators for Environmental Science (Dr. Peter Franklin), Longitudinal studies (Dr. Merci Kusel), Education and Training (Dr. Leith Sly) and Public Policy (Professor Steven Zubrick) as well as administrative support and research staff. In 2008 Ms Tania Gavidia joined the staff. She undertook an internship at WHO headquarters in Geneva with Dr. Jenny Pronzcuk in Public Health and Environment.
Key activities of the Centre include research on the mechanisms underlying the development of environmentally-related diseases in children, mechanistic studies in laboratory animals; collaboration with researchers in developing countries including Argentina, Brasil, China, India, Mexico, Nepal and Thailand, and offering an online Graduate Certificate in Children’s Environmental Health through Curtin University and Open Universities Australia. This course is also being translated into Spanish to be offered as part of the Masters program of the Instituto Nacional de Salud Publica, Cuernavaca, Mexico. The Graduate Certificate in Children’s Environmental Health is also offered through Open Universities Australia
During 2008 we accepted a commission from the Western Australian Department of Health to conduct an independent study of respiratory health and the association with air quality in Kwinana. This study, known as the Kwinana Children’s Respiratory Health Study proposes to take a detailed quantitative approach to investigating the lung function of children in this area. Children from the local primary schools have been invited to participate in the study. Participation involves taking measurements of lung function in children whilst simultaneously monitoring the air quality in this area. By measuring the lung health of children, the air quality and other factors related to respiratory health in the area, and comparing the results to similar studies around Australia, variations in lung function, air quality and other risk factors related to respiratory health can be identified. More information can be found on the study website: www.ichr.uwa.edu.au/kwinana . The study is guided by a steering a steering group with representatives from the community, industry and local and state government.
Clinical Sciences has an active collaboration with the Department of Respiratory Medicine at Princess Margaret Hospital (PMH) and the School of Paediatrics and Child Health (SPACH), UWA in a number of studies in which respiratory physiology is a major study outcome.
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