Touching Lives - July 2008

Cell study sheds new light on lung disease

Bronchiolitis is most commonly responsible for acute respiratory distress in young children. It is usually caused by a virus known as respiratory syncytial virus (RSV), which infects most children at some stage. But while many shake it off after only a cough or cold, others experience much more serious, sometimes life-threatening symptoms.

The reasons why the same virus should have such a profound effect on some youngsters and cause only mild illness in others has been a mystery. The two-year Action Medical Research study was funded by a generous distribution of £120,000 from the Jean Coubrough Charitable Trust.

The results could help in the development of new treatments to save tiny lives and end the agony of parents who have to watch their infants suffer. Professor Rosalind Smyth, Head of the Division of Child Health in the School of Reproductive and Developmental Medicine at the University of Liverpool, has led the research team.

Struggling for breath

She says, “There are few more distressing sights for a parent than their tiny baby struggling for breath. Bronchiolitis is the most common single cause of infant hospitalisation in the UK and represents a huge problem for young babies and a very big burden for the health services.

“^There is no effective vaccine or specific treatment for RSV bronchiolitis. Some babies without any other apparent health problems can become severely ill^, but just why the severity of the illness should vary so much from one child to another is unknown.” Bronchiolitis is transmitted in tiny airborne droplets from sneezes and coughs and is most common in the winter. It occurs when the smallest airways in the lungs, called the bronchioles, become inflamed, which in turn leads to a build up of mucus. This makes it harder for the child to breathe as the amount of air entering the lungs is dramatically reduced, and babies suffering from lung congestion will often be too breathless to eat or drink, causing their condition to deteriorate rapidly.

Looking at young bronchiolitis patients in intensive care at Alder Hey Children’s Hospital in Liverpool, Professor Smyth’s team has focused on the importance of white blood cells known as neutrophils, which infiltrate the airways in response to the RSV infection.

Immune response behaviour

Previous studies into RSV suggest that an over-exuberant immune response to infection might cause the severity of these babies’ symptoms, but there have been very few studies which have investigated this in small babies with bronchiolitis. Babies in intensive care have regular suction to clear their airways of thick secretions. The team has developed techniques to study these secretions and investigate the cells and proteins which are brought into the airways as part of the immune response in bronchiolitis.

Large numbers of neutrophils are found in the lungs of infants with bronchiolitis and the team has highlighted the importance of a receptor on neutrophils, known as Tolllike receptor 4 (TLR4), that attaches to the RSV virus in the lungs of infants with bronchiolitis. This in turn affects the way neutrophils secrete substances that may damage the lungs.

Professor Smyth says, “Action Medical Research funded previous studies which focused on the proteins produced during the course of infection, but our most recent work has looked at the cells which leave the infants’ bloodstream and are found in the lower airways. The team has looked at how the behaviour of these neutrophils from the lung fluid is altered and how that might contribute to the severity of their illness.

“Our studies should help lead to effective treatments in the future and could identify those babies at highest risk. Though most do eventually recover they can become very ill indeed and when I see these tiny babies in hospital it brings home to me what a problem this disease actually is.

“If we can understand exactly what is going on in these badly affected babies then it may be possible to reduce the inflammation in the airways, so that babies do not become so ill and recover more quickly.”

Valuable funding

Laboratory work of this sort is hugely demanding, calling for specialist skills and adequate time to collect samples and process results.

Professor Smyth says, “^Without the support of Action Medical Research it would be impossible to make this kind of progress^. It is very hard to attract funding for this sort of research and setting up a study using young patients like this is difficult, but it is particularly valuable because it gives us real life clinical situations and enables us to build up a whole spectrum of evidence.

“Bronchiolitis is a disease that has been studied for the best part of 40 years and though we have come a long way we still don’t have a completely clear picture. We have secured new funding and our work will go on in the hope that we can identify the exact function of the neutrophils and the substances they secrete.”

Action Medical Research’s support in this area of research continues with the funding of a team at Imperial College London. Led by Dr Dan Agranoff, these researchers are looking for differences in the blood of infants infected with RSV, healthy infants and those with other diseases. They hope this information will make accurate diagnosis of RSV easier and help to predict which babies will require treatment in intensive care.