Increasing treatment intensity should be considered in patients with milder asthma and the persistent airflow limitation (PAL) phenotype, a new analysis of the landmark ATLANTIS study suggests.

The PAL phenotype is present in people living with asthma across the spectrum of disease, according to findings from the Assessment of Small Airways Involvement in Asthma (ATLANTIS) study conducted across counties and led by researchers from the Netherlands.

Published in The Lancet Respiratory Medicine, the results showed that PAL was not only present in patients with severe asthma, but also in 16% of patients with Global Initiative for Asthma (GINA) step 1 asthma and 29% of patients with GINA step 2.

Patients with the PAL phenotype had asthma for a longer period of time, were more often male and current smokers and had more severe small airways
dysfunction than those without PAL. Patients with PAL also had a distinct type of inflammation, characterised by a higher proportion of eosinophils in sputum and blood, a higher blood monocyte count, and lower proportion of sputum macrophages.

The presence of PAL in patients with mild asthma severity was clinically relevant because it was independently associated with an increased risk of future asthma
exacerbations, (hazard ratio of 5·55), the researchers said.

They called for a step-up in treatment for people with PAL, given its association with eosinophilic inflammation and higher risks of exacerbations.

“The PAL phenotype occurs across the full spectrum of asthma severity,” they said.

“Not only is it present in people with less severe asthma, it is also an important predictor of exacerbations. In severe asthma, it has been shown that patients with PAL respond well to add-on treatment with long-acting muscarinic antagonists. People with mild asthma (GINA step 1 and 2) could increase treatment intensity with the aim of reducing the risk of exacerbations,” they wrote

Black hole in asthma knowledge

Researcher and clinician Professor Greg King, from The Woolcock Institute of Medical Research and a Conjoint Professor of Respiratory Medicine at The University of Sydney School of Medicine, said the airflow limitation and impaired lung function was one of the “big black holes in our knowledge and treatment of asthma”.

“It is an extremely important problem but there is almost no research about it,” he said. “It affects up to one in three people and not enough is known about it.”

He said clinicians should take steps to measure patient lung function as part of standard management within a comprehensive assessment of the disease. “You don’t know of the abnormality unless you measure it,” he said. Likewise, he said respiratory specialists should measure inflammation in patients.

“Management has evolved enough that every respiratory physician should be thinking: is inflammation active, and what sort of inflammation are we dealing with?”.

“Physicians should categorise the patients really well, thinking about inflammation, what is driving the asthma, how active is the asthma, what is the lung function. Those are very basic characterisations of the patient underlying physiology.”

Professor King said more research was urgently needed to determine the underlying mechanism behind the disease.

“We don’t have disease-modifying treatments,” he said. “The treatments we have are great but they’re not doing anything to treat the underlying processes. That’s really brought out in persistent airflow limitation. We don’t actually know the underlying mechanisms or causes of it. If we don’t understand the causes of it, we have no chance of finding disease modifications or prevention.”

The new analysis of the ATLANTIC study drew on 773 patients, with 760 (98%) who had post-bronchodilator FEV1 /FVC data available. At an average age of 44 years and 76% non-smokers, 33% had PAL overall. Patients with PAL were older (46.15) and had been diagnosed with asthma a decade earlier than the patient group without PAL. More than half (51%) were men, compared to 38% of women.

Those with PAL were also more common in the GINA step 4 and 5 categories of more severe and difficult-to-treat disease.