Respiratory Medicine Research

Group Leader
Professor Peter van Asperen
Head of the Department of Respiratory Medicine
Phone: 02 9845 3397
Email: peterv@chw.edu.au

Current research program

Conditions affecting the lungs are common causes of hospitalisation during childhood. In addition, respiratory illnesses have a major impact on a child’s quality of life (QoL) and impose a significant burden of care on families. Asthma, cystic fibrosis (CF) and other chronic respiratory disorders begin at birth or in early childhood and are life-long with high rates of disease being obvious in the elderly. Clinical research into these diseases has been carried out since the foundation of the Department in 1977. A more formal research programme commenced in Respiratory Medicine in July 1998 with the establishment of the Children’s Chest Research Centre (which constitutes “RMR”) and the aim of conducting studies into the structure and function of the lung in children with and without respiratory disease as well as assessing interventions aimed at limiting respiratory impairment in children with lung disease. Ten years on, RMR continues operations with the same aim. We work in partnership with industry to ensure that new pharmaceuticals are safe and effective in children before placement on the market. In addition to industry partnerships, we conduct studies with other hospitals and research groups using competitive research funding from bodies such as the NH&MRC and charitable foundations such as the Australasian CF Trust. Wherever possible, we provide equal access to research projects to patients throughout NSW and this entails frequent visits to regional centres such as Wagga Wagga, Port Macquarie, Coffs Harbour, the Central Coast, The Illawarra and the Central West. Our current and most recently completed research projects are listed below according to disease.

Cystic Fibrosis

Although the most common autosomal recessive genetic disease in Caucasians, the incidence of CF is such that most studies are performed on a collaborative basis, or as part of a multicentre network. At present we are focussed on the following:

Diseas Progress and Delineation of Modifiers of the Natural Course of CF

1. The Australasian Bronchoalveolar Lavage (BAL) Study – this study is being performed in all paediatric hospitals in Australia and at Starship Hospital in Auckland. This study (funded by NH&MRC) commenced in 2000 and will be complete at the end of 2009. The focus is the long-term pulmonary outcomes of directed treatment against Pseudomonas aeruginosa (PsA) found in respiratory cultures obtained by BAL as opposed to suction of sputum. The outcome measures include CT scans, lung function, QoL and BAL inflammatory and microbiological markers at 5 years of age; as well as respiratory health and health care utilisation measured for the entire first 5 years of life. To date, 2 sub-studies have evolved from this study – the first, an examination of the safety of inhaled TOBI (an antibiotic) in children under 5 and secondly, the predictive value of modifier genes and novel inflammatory proteins for respiratory health at 5 years.
2. Respiratory pathogens and their transmission – patient-to-patient spread of bacteria is a problem for CF centres worldwide – we are participating in an Australia-wide NH&MRC-funded study of the prevalence of clonal forms of PsA and the influence of these clonal strains on respiratory health over a 4 year period. In addition, 4 years ago we re-organised our CF clinics in an attempt to reduce transmission of bacteria. We are presently evaluating the influence of this change in practice on bacteria colonising the airways of young children with CF which will be of importance for the many CF centres throughout the world who, as a result of the increasing roll out of newborn screening for CF, are now faced with caring for children from 1 day of age to 18 years of age - a situation with which we have more than 25 years experience.
3. Detecting respiratory pathogens – both viral and bacterial infections are important in CF, however, obtaining respiratory specimens in order to detect these pathogens is often difficult and unpleasant, particularly in younger children. In collaboration with the Aerosol Research Group at the Woolcock Institute we are examining the utility of a face mask composed of a novel material in collecting exhaled viral and bacterial organisms. We also continue investigations of the role of fungi and fungal allergen in CF.
4. Detecting early airway disease – we are currently assessing the relative utility of a variety of non-invasive measures of lung function to detect early airway disease and measure response to interventions in young children unable to perform conventional spirometric techniques used to assess lung function in older children.
5. Disease modifying factors – we are currently involved in research collaborations attempting to identify factors which may influence outcome in CF patients including mannose binding lectin levels, ACE gene polymorphisms, modifier gene types in siblings with CF, and micro-RNAs.

Novel Therapies for CF

1. Studies of Aztreonam Lysinate (AL) – we are about to embark on our third multi-centre study of this new inhaled anti-PsA antibiotic developed by Corus Pharma. In Australia (and most other parts of the world), by necessity, antibiotics used for inhalation are in fact intravenous preparations which are not formulated for contact with the airway surface – thus the precise dosage reaching the airway mucous is unknown and adverse events to this route of administration are not uncommon. We have completed a short–term study of AL in children with moderately-severe lung disease, and are currently performing a two-year long follow-up study as well as commencing a study in children with milder lung disease. An additional element of these studies is the evaluation of a new nebuliser which decreases nebulisation time for each dose of antibiotic from 25 to 2 minutes.
2. Dry Powder Mannitol (DPM) – after participation in a successful study of the short-term effectiveness of DPM in CF in 2005, we are, at present, at the midpoint of year-long study of this mucolytic. Pharmaxis Ltd, the developer of this medication has also provided us with an unrestricted grant to study the effectiveness of DPM in respiratory exacerbations. The added benefit of this therapy is that the product involved is derived from natural sources and can be administered in any setting using a simple hand-held inhaler.
3. Vibration Plate Therapy – in conjunction with the endocrinology department we are assessing the effect of this non-invasive non-pharmaceutical therapy on lung function and the function of tendons, bones and muscle.
4. The effectiveness of airway clearance techniques – clearance of mucus from the airways is one of the mainstays of therapy in CF. The effectiveness of various forms of physiotherapy as airway clearance therapies have been notoriously difficult to assess. We have now recruited a full-time research physiotherapist to help in the group’s investigations of the relative efficacy of manual physiotherapy techniques, airway clearance appliances as well as pharmaceuticals.

Asthma

While advances in the treatment and recognition of asthma have meant that the death rate for asthma has decreased, the number of children requiring hospital admission for treatment of their asthma has doubled over the last 20 years. We have carried out, and continue to conduct, research projects into the development, diagnosis, pathophysiology, management and potential prevention of this disease.

Disease Progress and Delineation of Modifiers of Asthma

1. The pathophysiology of asthma - we maintain a large collection of lung tissue from children with and without a history of lung disease which has been donated for research by the children’s parents and this tissue is currently being used in collaboration with groups in Perth and London to investigate the development and progression of asthma in early childhood as well as the normal growth and development of the airways from birth to maturity using computer-assisted morphometric techniques.
2. The detection and role of viruses in asthma – invasive techniques are usually required to obtain samples to detect viruses in respiratory secretions. We are examining a simple non-invasive means of delineating the role of viral infections in children and their caregivers in determining the severity and duration of exacerbations of asthma.
3. New modes of measuring lung function in young children – conventional methods of measuring lung function require the co-operation of a child as well as the mastery of often difficult techniques. In recent years, methods for measuring lung function in younger children have been developed which no longer require either co-operation or technical mastery but do require administration of sedative medications. In conjunction with other groups throughout the world and the Woolcock Institute locally, we are currently evaluating a new effort independent technique which can be performed on conscious preschool children.

Novel Therapies and Management Approaches

1. We have, and continue to, perform a number of studies examining the efficacy and safety of new medications and other interventions for the treatment and prevention of asthma. These studies include those evaluating existing therapies used in new ways, such as the use of an oral anti-leukotriene agent as a rescue medication to be used for asthma exacerbations compared with using it daily as a preventative therapy. We have also been involved in evaluating educational interventions designed to enhance health professionals’ knowledge about paediatric asthma and its management as well as enabling them to deliver education about asthma to parents of children with asthma.

Other Lung Disease and other fields of investigation

Although the group mainly focuses on the investigation of CF and asthma, we also perform investigations both alone and in collaboration, relating to other forms of lung disease in children.

Chronic Cough

1. Cough is the most common symptom presenting to general practitioners in Australia and internationally. The burden of cough is great – both in terms of the QoL experienced by the child concerned, and in substantial medication costs as these children are often treated inappropriately with repeated doses of antibiotics, with high dose anti-asthma medication or cough preparations. The cause of chronic cough is poorly understood and this multi-centre NH&MRC-funded study is designed to evaluate the utility of a protocol for the diagnosis and management of cough in a tertiary setting, and the feasibility of then deploying the protocol in a general practice setting as a clinical guideline for chronic cough.

Survivors of Preterm Birth

1. Over the last 5 years, our group has been conducting a long-tern follow up of 10 year old children who were born extremely prematurely. This study identified and studied 126 children who by virtue of their extremely preterm births (all these children weighed less than 1kg at birth) required care in a neonatal intensive care unit including mechanical ventilation. While it is known that many of these children survive infancy, their long-term prognosis as far as lung function and disease are concerned, has been unclear. Our studies have indicated that while these children do have subtle reductions in their lung function at 10 years of age, they have substantially reduced exercise capability. Our future work in this field will attempt to find the cause for this impairment as we have found that they have normal cardiac functioning. Moreover, the effect of an early fitness training program in such children is an area we would like to explore.

Cardiopulmonary Fitness

1. One of our group members is an expert in exercise physiology and is also involved in collaborative studies of cardiopulmonary fitness in children with other chronic illnesses such as haemophilia and insulin-dependent diabetes, which, while not being diseases of the lung, affect functioning of the cardio-pulmonary system during exercise. His interests extend beyond children with chronic illness to those who are junior elite athletes, and his work includes studies examining the relationships between fitness and muscle functioning and the presence of certain genes relating to muscle function.

Other Conditions

1. Many of our other studies also have direct and immediate clinical applicability. For instance, we are part of an Australia-wide network which is performing a surveillance study looking at the enhanced detection of pneumococcal infections in children presenting to tertiary hospitals with pleural effusions. In this study we are using a simple colorimetric kit-based assay to detect strep pneumoniae in pleural fluid and in urine. Should this prove to be as sensitive as culture-based detection which takes a number of days, then referring hospitals may be able to use this simple kit and commence appropriate antibiotic therapy avoiding the need for a child to be transferred to a major city hospital. Other studies are examining the value of serum markers in predicting disease progression in children with bronchiolitis obliterans after bone marrow transplants, and in children with connective tissue disorders affecting the lung. All of this work is aimed at rapid detection of the presence of disease, predicting adverse outcomes or more rapid disease progression, so that more appropriate clinical care can be instituted or so that more intensive surveillance of at-risk children takes place so that early intervention is possible. These types of studies also provide us with notions of novel interventions which we are able to investigate in future research.

Major achievements in last 10 years

Without doubt, the members of RMR consider our greatest achievement over the last 10 years (RMR formally commenced operation in July 1998) to be the assembly of a well-functioning clinical research team with a breadth of training and expertise, able to perform a variety of research projects. The type of research performed by the RMR group has proved to have significant clinical applicability over the last decade, and this is true of projects we have performed alone, and in conjunction with other investigators including industry partners. Moreover, as a result of our efforts, our patients have seen changes in the way their disease is investigated and managed, and the hospital has seen an increase in the number of techniques available for patient testing.

In addition to making a significant contribution to the foundation of the Exercise Testing Laboratory located within CHISM, our group has also been involved in the acquisition of equipment in the KARC. We have established exercise testing as an important tool in the assessment of children with chronic lung diseases and also other chronic diseases which may impact on cardiopulmonary functioning. In conjunction with the Department of Physiotherapy we were also able to verify the accuracy of a simple running test for assessing the effect of intensive antibiotic therapy in children with CF. This test is now being used in rural and regional hospitals where sophisticated equipment for assessment used in large tertiary hospitals is not available. The hospital’s microbiology department is now able to offer quantitative assessment of bacteria in specimens as a result of our involvement in the Australasian BAL study. As a result of our participation in the evaluation of dry power mannitol as a diagnostic test for asthma, staff members in the RFU were able to gain experience in administration, and interpretation of the results of the test in patients 2 years prior to the test being approved by the TGA and launched in Australian hospitals.

Much of the impact of our research has been patient- focused. Our local research showed that intravenous antibiotics delivered in the home were just as effective as those administered in hospital and that the weight gain of those at home was greater than for those receiving in-hospital care. This has meant that some children can now stay in their own homes during this therapy. They can therefore sleep in their own beds, eat meals with their families and go to their own schools during the day - a better option for the family and also for the hospital as it means that the bed this child would have occupied can be used for some other child needing treatment. In the next few months, the hospital will be rolling out a home iv service for children with other conditions largely based on the success of our program.

Our collaborative pharmaceutical studies have meant that some new therapies have become available, but equally importantly, have shown that some medications were without benefit in certain patient groups. For instance, a 2 year long study of antihistamine drops in over 500 very allergic infants at high risk of developing asthma showed that the results of the pilot study indicating this therapy as being of benefit in preventing asthma, did not apply when studied more formally. We also contributed to a study of over 1000 infants showing that the asthma medication Montelukast, is of no benefit in treating bronchiolitis despite the inflammation in the airways in these diseases having similar mechanisms. As mentioned above, in 2004, the RMR group provided data for paediatric patients as to the accuracy and tolerability of dry powder mannitol as a test for asthma. This test, which was developed in Australia, is now the test of choice in Respiratory Function Units nationwide and also in Europe. We have also been involved with the evaluation of a once daily inhaled preventer for asthma which is now approved by the TGA and are gaining experience with formulations of antibiotics developed specifically for nebulisation, at least one of which is the subject of a marketing application in Australia. These studies have also given us the opportunity to make more rapid nebulisers available to patients taking part in the study – this is of particular significance when both the cost ($1600) and the reduction in nebulisation time (by 90%) are taken into account. Nebulised hypertonic saline (a solution of 6% sodium chloride) is now a treatment option for those with CF, as a study funded jointly by the NIH and Australasian CF Research Trust performed in CF clinics in metropolitan Sydney, including ours, proved the efficacy and safety of this extremely inexpensive solution.

We have just completed data analysis and will soon publish results of our NH&MRC funded study of different forms of bedding for children with moderately severe asthma and allergy to the house dust mite. Children spend approximately one third of their lives in bed and so advice as to the effect of different types of bedding on symptoms in children with asthma is needed - the results of this study provide us with evidence to make such recommendations. As a result of our long-term follow up of children born extremely prematurely, we are now able to provide some evidence that at 10 years of age, only a mild impairment of lung function can be expected in at least a proportion of these children. This evidence can now be added to the body information provided to the parents of extremely premature neonates when they are making crucial decisions about their infant’s care. Since the commencement of 2008, the research resources as well as the clinical care of CF patients have also been enhanced as we have an up to date data registry. This contains all diagnosis information as well as clinical information pertaining to every visit since 2004 of each patient cared for at this hospital. This enables us to monitor the health of children with changes made to the care we provide, such as that effected recently by a dietician specifically engaged to manage the nutrition of children with extremely low BMI. In addition, it allows us to produce an up-to-date clinical report pertaining to each patient prior to their clinic visit – such reports have been shown in US studies, to engage families more in setting goals for children with CF.

Thus, the members of RMR consider that the work the group has performed since its inception 10 years ago, has enhanced the knowledge and management of respiratory disease in children. In addition, services provided by the hospital have been enhanced as a result of our research activities which have also had a direct impact on the patients to whom we provide care.

Key publications with comments on their significance

1. Selvadurai HC, Allen J, Sachinwalla T, McCauley J, Blimkie CJ and van Asperen PP. Muscle function and resting energy expenditure in female athletes with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine (2003) 168: 1476-1480.
   This was the first publication to challenge the concept that exercise limitation in CF was purely due to a combination of malnutrition and lung disease by proposing a fundamental defect in muscle metabolism linked to the CF gene which limited exercise by imparing oxidative capacity, even in CF patients with mild disease and no nutritional problems. This publication was highlighted in an editorial in the same journal as being a significant contribution to the body of knowledge on CF and the effects of the CF gene. This finding has also had a major impact on research thinking in this area and led to further research aimed at exploring the nature of this defect in more detail.
2. McMorran BJ, Patat SA, Carlin JB, Grimwood K, Jones A, Armstrong DS, Galati JC, Cooper PJ, Byrnes CA, Francis PW, Robertson CF, Hume DA, Borchers CH, Wainwright CE and Wainwright BJ. Novel neutrophil-derived proteins in bronchoalveolar lavage fluid indicate an exaggerated inflammatory response in pediatric cystic fibrosis patients. Clinical Chemistry (2007) 53: 1782-1791.
   This is the first publication resulting from the Australasian BAL in CF study. The paper demonstrates the ability of the paediatric CF community in Australia to collaborate successfully and also that ‘spin-off’ studies using specimens stored during this 10 year long study are possible. As we have BAL fluid and serum from the first 5 years of life stored for each child in the study as well as a comprehensive record of their clinical course during this time, these specimens will form an invaluable resource for future studies of the natural history of CF.
3. Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, Lee AJ, Turner J, and Sant M. Short-course montelukast for intermittent asthma in children: a randomised controlled trial. American Review of Respiratory and Critical Care Medicine (2007) 175: 323-329.
   Traditional therapeutic approaches in childhood asthma have been to treat a child with a daily preventer medication for those with frequent episodes, and with bronchodilator and oral corticosteroid therapy as a reliever when exacerbations occur. This Australian study demonstrated that a medication previously used as a daily preventer therapy could in fact be used as non-corticosteroid reliever therapy in young children. In addition to efficacy for the child, the study also demonstrated that caregiver work absences were significantly decreased with this therapeutic approach. We are presently involved in a world wide study involving thousands of children using such a therapeutic regimen prior to the medication being licensed for use in this manner.
4. Smith LJ, van Asperen PP, McKay KO, Selvadurai H and Fitzgerald DA. Reduced exercise capacity in children born very preterm. Pediatrics (2008): in press
   While a cohort of 10 year old children who had been born extremely prematurely had only modest impairments in their lung function, they had substantially reduced exercise performance. This study presents these results and is one of a number that will be published from our investigations of this cohort of children. As these children have normal cardiac function, perhaps their families need to be encouraged to adopt a fitness program early on in life so that such reductions in capacity are no longer evident. Examination of the type and duration of such interventions will be the subject of further studies in these children.
5. James A, Green F, Abrahamson M, Bai T, Dolhnikoff M, Maud T, McKay K and Elliot J. Airway basement membrane perimeter distensibility and airway smooth muscle area in asthma. Journal of Applied Physiology (2008): in press
   Since 1999, we have been obtaining permission from families who have children dying suddenly (and coming to coronially-directed autopsy at the Westmead Institute of Forensic Medicine), to use lung tissue for research. The approach required in such situations is a special one and it is testament to our approach that approximately 50% of families decide to donate their child’s lungs for research after such an unexpected death. To have a collection of lung tissue that was obtained using a legal and ethical consent process has proven extremely valuable and while we no longer have the staff or resources to analyse this lung tissue here, we are collaborating with groups in the UK as well as Perth. This manuscript is the first from our Perth collaboration and presents results pertaining to the pathology of asthma in both adults and children with tissue obtained in Sydney, Sao Paulo, Vancouver, Calgary, Melbourne and Perth. Our second collaborative manuscript is currently under revision, and one from our collaboration with Imperial College London, is in preparation.

Research Staff

• Peter Cooper – Staff Specialist
• Dominic Fitzgerald – Staff Specialist
• Samantha Forbes – Research Nurse
• Meredith Larkin – Research Nurse
• Merilyn McArthur – Research Nurse
• Karen McKay – Research Fellow and Co-ordinator
• Tracey Marshall – CNC Asthma Education
• Anna Middleton – Research Physiotherapist
• Margherita Pitman – Research Support Worker
• Paul Robinson – Respiratory Fellow and PhD Student
• Hiran Selvadurai – Staff Specialist (50% dedicated research time)
• Peter van Asperen – Head of Department and MacIntosh Professor of Respiratory Medicine
• Phillipa Yabsley – Honours Student

Research support (2005-2008)

• NHMRC/ARC
  4 project grants with total funding share at CHW of $154, 200
• Funds from industry
  8 studies with total per patient funding at CHW of $441, 058 to March 08
• Other competitive funding
  Total funding to March 08 of $33, 000
• Other non-competitive fund
  Total funding to March 08 of $999, 922

Opportunities for Students

Postgraduate Research available at the University of Sydney.