Sputum testing offers key to improving asthma therapy

Medical Tribune May 2009 P15

David Brill

Individualizing therapy on the basis of sputum cell counts could help to improve the treatment of severe asthma, new research suggests.

A recent small-scale randomized study found that patients treated in this way had significantly fewer exacerbations and were able to safely reduce their prednisone doses.

The trial involved a rare subset of patients with high levels of eosinophils in the sputum, but the same principles could be extended to other types of asthma, the researchers say.

“Our philosophy ... has been to measure bronchitis by a simple processing of sputum. Identify the type of bronchitis and treat it accordingly based on the type of cell. It’s a very simple message,” said lead author Dr. Parameswaran Nair, an associate professor of medicine at McMaster University, Ontario, Canada.

“Most patients with eosinophilia are easy to treat and can be controlled with small or moderate doses of inhaled corticosteroids. But in the severe patients people [should] take a step back if the patient is not getting better with prednisone and think ‘what is the type of bronchitis? Should we not understand what’s going on here before we increase or add new treatments?’”

The study, which lasted 26 weeks in total, included only patients whose sputum eosinophilia had persisted despite prior prednisone treatment. Nine received five monthly infusions of mepolizumab (750 mg) – a monoclonal antibody which disrupts the activation of eosinophils by targeting interleukin-5 – and 11 received placebo. [N Engl J Med 2009 Mar 5;360(10):985-93]

There was only one asthma exacerbation in the mepolizumab group and this was associated with sputum neutrophilia rather than eosinophilia. Placebo patients, in contrast, experienced a total of 12 exacerbations – nine associated with eosinophilia and three with neutrophilia (P=0.002).

Patients taking mepolizumab reduced their prednisone dosage by a mean of 83.4 percent of the maximum possible reduction, compared to 47.7 percent for patients on placebo (P=0.04).

The accumulation of eosinophils in the airway is thought to be an important event in the pathogenesis of asthma but the exact role of the cells remains unclear. Previous studies have failed to show any benefit of anti-interleukin-5 antibodies as a therapy for asthma, but these trials did not tailor the therapy to specific patients.

“We argued that if we give it to every patient with asthma it’s not going to work – it’s only going to work if you’ve got eosinophilia to begin with,” said Nair.

The McMaster respiratory group, led by Professor Freddy Hargreave, has already demonstrated the benefits of individualizing therapy in an earlier randomized trial of 117 asthma patients. The number and severity of eosinophilic exacerbations were both reduced using the sputum-based approach, as compared to standard treatment according to Canadian guidelines. [Eur Respir J 2006 Mar;27(3):483-94]

Nair hopes that latest new study will raise awareness of the benefits of sputum testing for asthma, admitting that he is “very frustrated” that such a simple procedure has not caught on more widely.

“A rheumatologist would aspirate fluid from a joint to look at inflammation before giving anti-inflammatories, and a gastrointestinal surgeon would take a rectal biopsy for colitis before giving corticosteroids.

“But we in respiratory medicine are giving bucketloads of corticosteroids and anti-inflammatory drugs without measuring inflammation. Most physicians all over the world only measure forced expiratory volume in 1 second (FEV1), which is just a measure of airway caliber and not of bronchitis,” he said.

The results of another study, published in the same edition of the journal, lend further support to the theories of Nair et al. In a randomized double-blind trial of 61 patients, UK researchers showed that mepolizumab, compared to placebo, reduced severe exacerbations and improved quality of life in patients with refractory eosinophilic asthma. [N Engl J Med 2009 Mar 5;360(10):973-84]

A separate study, meanwhile, is already underway at McMaster to assess the effects of blocking neutrophils, which are typically found in asthma patients who have bronchitis caused by an infection.

Paracetamol in infancy raises childhood asthma risk

Medical Tribune November 2008 SFXX
David Brill

Exposure to paracetamol during infancy could increase the subsequent risk of developing asthma, new research suggests.

Children aged 6 to 7 had a 46 percent increased risk of having asthma symptoms if they had received paracetamol for fever during their first year of life, data from the International Study of Asthma and Allergies in Childhood showed.

Use of the drug in infancy was also associated with an increased risk of rhinoconjunctivitis and eczema (odds ratios 1.48 and 1.35, respectively).

The authors of the Lancet study reviewed questionnaires completed by the parents or guardians of 205,487 children in 31 countries. [372(9643):1039-48]

“Because it was an epidemiological study we were unable to determine whether the relationship was causal … but when you put it together with all the other evidence we have it does suggest that paracetamol might be an important risk factor for the development of asthma,” said lead researcher Professor Richard Beasley, Medical Research Institute of New Zealand, Wellington.

Paracetamol should remain the preferred drug for relief of fever and pain in infancy but should be used sparingly, he said, noting that WHO guidelines recommend that the drug only be used for those with high fever (38.5°C or higher).

Beasley stressed that infants should not be switched to aspirin, which can cause the rare but potentially fatal Reye’s syndrome.

Current usage of paracetamol also increased the risk of asthma in a dose-dependent fashion. Children taking the drug on a regular basis were over three times as likely to have symptoms compared to those who were not taking it at all (odds ratio 3.23).

Dr. Chiang Wen Chin, an associate consultant in the department of pediatric allergy, immunology and rheumatology at KK Women’s and Children’s Hospital (KKH), Singapore, said that paracetamol use over the past 50 years has been safe and that the drug would remain first line for the majority of children (10mg/kg 4 to 6 hourly).

She added that ibuprofen can be given as a second line antipyretic, with tepid sponging also an option if the fever does not resolve.

Chiang noted, however, that there is a group of children who display angioedema and uticaria from high doses of paracetamol. [Pediatrics 2005 Nov;116(5):e675-80]

“We have demonstrated this in our own local patients that have presented to our clinic in KKH. Most of these children have allergic rhinitis, although not all of these have asthma,” she said.

“Our understanding of this pathophysiology is that paracetamol is a nonspecific COX-1 and COX-2 inhibitor, especially at high doses, and that this may result in a shunting of arachidonic acid production to predominantly leukotriene production, resulting in the release of various mediators such as mast cells and histamine release,” she said.

Beasley added that further studies – including randomized controlled trials of paracetamol in infancy – are needed to better understand the association with asthma.