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On the frontline in the battle against severe asthma

For years there was concern among the medical community that asthma was being under-diagnosed. A paper published last year in the journal Archives of Disease in Childhood turned this concern on its head, arguing rather that the condition was being over-diagnosed, with inhalers being used almost as a “fashion accessory”. The article, as well as other research claiming that asthma is being over-diagnosed, has been covered prominently in the media.

Prof Peter Howarth, Professor of Allergy and Respiratory Medicine and Honorary Consultant Physician within Medicine at the University of Southampton, has contributed to national, European and international (World Health Organisation) guidelines on the management of rhinitis and asthma. He says the main learning point from these papers is the importance of diagnosing asthma accurately before potentially unnecessary treatment is dispensed.

“There has been publicity recently, particularly from NICE, stating that asthma is over-diagnosed, and then there are previous studies that suggest that asthma is under-diagnosed,” Prof Howarth told the Medical Independent (MI).

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Prof Peter Howarth

“I think the message that is coming out is there needs to be a definite diagnosis before patients are started on treatment because asthma is a chronic incurable disease that is suppressed by treatment.

“And if you stop that treatment then the asthma is there underneath, so when you make a diagnosis you are really starting someone on lifelong treatment. And what NICE have been arguing, and I think is correct, is the diagnosis should not be based on a doctor saying ‘you have got asthma, here is the inhaler’; there needs to be objective measures and they have advocated not only the measurement of lung function, but also the measurement of something called exhaled nitric oxide, which is an indirect marker of inflammation within the airways.”

Diagnosis

The emphasis on objective measures has implications in respect of who actually conducts the diagnosis.

“These diagnoses are normally made in the community, yet general practitioners are not experienced in measuring exhaled nitric oxide and don’t necessarily have the equipment and it would probably cost a couple of thousand pounds to purchase,” said Prof Howarth.

“If that advice is followed through it would need careful consideration.”

Prof Howarth also said it is “improbable” that patients with severe asthma, which is one of his research interests, could ever be solely managed in the community.

“I think these patients with severe asthma are normally under specialist care and that any administration of treatment will probably have to come through specialist advice rather than general practice,” he said.

It is estimated that 10 per cent of asthma sufferers have the severe form of the disease.

“These are people that have poorly controlled disease, frequent exacerbations, they carry a much greater burden, not only a personal impact, but also healthcare economic impacts,” said Prof Howarth. “If you take the indirect and direct costs, those 10 per cent are estimated to account for somewhere between 40 and 50 per cent of the total asthma healthcare costs.”

Prof Howarth coordinates the Wessex Severe Asthma Cohort, a well-characterised group of over 300 patients with treatment resistant asthma, established to facilitate basic science and interventional studies in severe asthma. The research centres take tissues directly from the airways (through techniques known as lavage, brushing and biopsy) to obtain samples for analysis, using these approaches to understand the biology of respiratory diseases and investigating the impact of established and new therapies.

‘I think with severe asthma we are at the stage of really still trying to understand the disease and what we appreciate is that it isn’t one condition, it is a heterogeneous disorder…’

He is joint lead for the Difficult Airways Service in Southampton, providing a secondary and tertiary referral service for treatment-resistant asthma and established the Clinical Allergy Service providing a clinical allergy and immunology service for the Wessex region. This close patient involvement provides the basis for the translational research programme and the appreciation of unmet clinical needs. He is also involved in EU consortia involving severe asthma.

Unmet need

“The treatment is the same for severe asthma, but you estimate the dosage to higher levels. These patients often remain inadequately controlled,” outlined Prof Howarth. “There is a big unmet need. Many have to go onto oral steroid tablets to try and control their disease. Asthma is an airways disease, we normally try to treat it locally with inhalers, but when you give steroid tablets, they benefit the asthma, but they also take steroids to the rest of the body and have a lot of unnecessary consequences.”

Prof Howarth has recently taken on a role as a global medical expert with GSK. One of the reasons for accepting the role is because of the development of the new severe asthma drug, mepolizumab. Prof Howarth was involved in trials that were pivotal for the registration of this new treatment for severe eosinophilic asthma. Eosinophils represent 1 to 6 per cent of the circulating white blood cells. They are important for protection against parasitic infestations and as mediators of allergic inflammatory responses. Different chronic disorders of the airways arise as a result of an inflammatory pathogenesis, in which eosinophils play a significant role and influence on the degree of severity. In bronchial asthma tissue, eosinophilia is present in 40-60 per cent of cases; in the eosinophilic phenotype, blood and sputum eosinophils correlate with the severity of disease. The new therapy is a humanised monoclonal antibody (mAb) antagonising IL-5.

The drug is licensed and currently is awaiting further approval in the UK and Ireland.

The development of new treatments should go hand-in-hand with better treatment pathways, according to Prof Howarth.

“As we move into having these more expensive biologics available, we have to use them responsibly, so there has to be a common management pathway to ensure patients aren’t given them unnecessarily,” he said.

‘These diagnoses are normally made in the community, yet general practitioners are not experienced in measuring exhaled nitric oxide and don’t necessarily have the equipment’

“There are issues that you have to identify, not only does the patient have severe asthma, but that they haven’t got severe asthma because they are not taking the treatment they are meant to take because clearly if they are not doing that then being on standard inhaler therapy will be far less expensive than going onto a biologic. So you have to check their compliance with their medication. You have to check that there aren’t other reasons for the fact that they have persistent symptoms. There needs to be recognition that you can have asthma but you may have other conditions as well that may give rise to symptoms, so that when you treat them for their asthma, those symptoms don’t improve and they could be perceived as having severe asthma when in fact it is something else.”

Advances

Prof Howarth said there have been significant advances made in the treatment of asthma since he first began working in the field in the early 1980s.

“There have been tremendous advances since I first started because historically asthma was thought of as being a bronchoconstrictor disease, a disease of smooth muscle, so it was treated just with bronchodilators. Then people became aware that there was underlying inflammation within the airways and inhaled steroids had suppressed that inflammation. It became the cornerstone of therapy and the guidelines adopted that. And I have seen a tremendous improvement over the years in the community management of asthma, as those guidelines have been followed such that we now see far fewer patients in hospital being admitted with acute exacerbations, so the management of asthma has improved.”

The development of dry powder inhalers are another area of progress, according to Prof Howarth, as they ensure more of the medication is delivered to the airway rather than being deposited in the throat, which is a problem with traditional metred-dose inhalers.

“I think most of the asthma therapy is moving towards these dry powder inhalers and moving away from the older pressurised inhalers, which have been good treatments, but they are not sufficient, and so the new inhalers would be more effective at delivering the drugs to the airways.”

While much progress has been made, Prof Howarth said there are still many challenges remaining, particularly for the severe non-eosinophilic asthma cohort.

“I think with severe asthma we are at the stage of really still trying to understand the disease and what we appreciate is that it isn’t one condition, it is a heterogeneous disorder and that is why finding a treatment for the eosinophilic phenotype, [which accounts for 40 per cent of severe asthma patients] is excellent,” he concluded.

“But there still is 60 per cent that we don’t have good treatments for and we are still trying to understand what is happening in those individuals.”

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