more_vert
Recent developments in the treatment of adult asthma could be adapted to treat suppurative lung disease and wheezing in children, according to new research from the Murdoch Children’s Research Institute.
Lung diseases are a major source of morbidity and health care use for children in Australia and worldwide. Not only do these conditions cause significant short term effects for children, they also have lifelong impacts on lung function.
Preschool asthma or wheezing is a leading cause of hospital admission for young children in Australia. Recent work has shown that nearly one-third of hospitalised children will be readmitted within 12 months, despite specialist care. Current management strategies, including oral corticosteroids, are often ineffective and do not prevent or adequately manage acute episodes.
Suppurative lung disease in children spans a spectrum of conditions characterised by persistent wet cough. A recent survey in a high risk Indigenous Australian population reported a community prevalence of 12% for the spectrum of suppurative lung conditions in children. Chronic wet cough affects up to 40% of children who attend paediatric respiratory clinics. Current management primarily includes prolonged broad-spectrum antibiotic use, despite evidence that antibiotics frequently fail to solve the problem and that disease recurrence is common.
Similar challenges facing children with these conditions were encountered in severe adult asthma but were recently overcome via a treatable traits approach. This approach led to the development of highly effective monoclonal antibodies that are now considered the standard of care for adults.
We aimed to develop this approach for children with suppurative lung disease and wheezing, two of the most common conditions of childhood.
Studying the treatable traits
This study involved 93 children who were having lung fluid and blood samples taken at the Royal Children’s Hospital in Melbourne as part of their clinical care. We performed a comprehensive immunological analysis of both sample types, with a focus on the bronchoalveolar lavage (BAL), which captures the cells and soluble factors involved in the immune response of the lower airway.
Although the clinical presentations of these two diseases are different, we found that similar inflammatory endotypes are present in the lungs and therefore the same anti-inflammatory treatments could be effective against both.
Specifically, about 50% of children in each disease group showed a hyperinflammatory response that could potentially be treated with therapies already approved for use in children. This hyperinflammatory endotype was characterised by elevated lung neutrophil count as well as strong enrichment for type-2 immunity, including heightened levels of the proteins IL-4 and pentraxin-3.
The other 50% of children in each disease group showed an immune response in the lungs that was similar to healthy controls, which we termed the non-inflammatory endotype. This highlighted that many children with these lung diseases do not show any evidence of lung inflammation, which is important for clinical management.
When exploring the clinical usefulness of our findings, we found that participants could be accurately assigned to either the hyper- or non- inflammatory endotypes based on measurement of only three factors in BAL: neutrophil count, IL-4 levels and pentraxin-3 levels.
As this is the first report to provide a detailed assessment of lung immunity in children with wheezing and suppurative lung disease, we acknowledge that our findings should be validated in larger, multicentre studies.
Targeted intervention may offer new hope
This work highlights the potential for a treatable traits approach for children with these conditions, where children showing a common, hyperinflammatory pathobiology (independent of clinical definition) could be considered for targeted intervention with existing anti-inflammatory therapies.
This may include repurposing medications already approved for use in Australia for the management of asthma in older children, such as dupilumab, which is a dual inhibitor of IL-4 and IL-13. This repurposing approach for asthma medication has been used successfully in chronic obstructive pulmonary disease and a small series of adults with suppurative lung disease.
The non-inflammatory endotype is also of significant interest given the similarity in inflammatory profile to controls. Not all children who present with suppurative lung disease will progress to irreversible lung disease. Similarly, many children who present with wheeze in early life will grow out of this condition without intervention.
We are now exploring whether these endotypes are associated with clinical outcomes to inform a personalised medicine approach. The ability to identify children with a lower risk presentation could provide reassurance to families and prevent unnecessary treatment. In the case of suppurative lung disease, it would also allow antibiotic used to be rationalised.
Future work will assess whether these endotypes can be identified using less invasive specimens that could be readily measured in the general practice setting, given that this is where most children with these conditions are managed.
In conclusion, our study provides a significant gain in our understanding of pulmonary inflammation in children with wheeze and suppurative lung disease. We identified both hyperinflammatory and non-inflammatory endotypes present in both disease groups. If validated in larger studies, our findings have the potential to change clinical management by identifying a personalised approach for treating these conditions.
Dr Melanie R. Neeland is a research immunologist and team leader at the Murdoch Children’s Research Institute. Her research aims to understand the early life immune origins of childhood lung disease to improve the care delivered to children in Australia.
Professor Sarath C. Ranganathan is an expert in respiratory medicine and an internationally recognised clinician scientist. He is a consultant in paediatric respiratory medicine at the Royal Children’s Hospital, head of the respiratory research group at the Murdoch Children’s Research Institute, and head of the University of Melbourne Medical School.
Dr Shivanthan Shanthikumar is paediatric respiratory specialist at the Royal Children’s Hospital and a clinician–scientist fellow at the Melbourne Children’s Campus. His clinical areas of expertise include childhood asthma, and his research activity spans laboratory-based profiling of childhood respiratory disease to health services research.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
Subscribe to the free InSight+ weekly newsletter here. It is available to all readers, not just registered medical practitioners.
If you would like to submit an article for consideration, send a Word version to mjainsight-editor@ampco.com.au.