KEYSTONE, COLO. – Adult asthma phenotypes offer little guidance in the identification and management of severe, therapy-resistant asthma in children.

Cluster analysis was recently used to identify two subgroups with discordance between symptom expression and eosinophilic airway inflammation specific to refractory adult asthma (Am. J. Respir. Crit. Care Med. 2008;178:218-24). In addition, a treatment strategy based on minimizing eosinophilic inflammation proved superior to standard care in reducing exacerbation frequency (Lancet 2002;360:1715-21).

Recent efforts to replicate the findings in severe pediatric asthma, however, met with disappointing results, study coauthor Dr. Andrew Bush said at a meeting on allergy and respiratory diseases. The ability to identify asthma phenotypes that exhibit differences in clinical response could enable more targeted therapy and spare children unlikely to benefit from exposure to powerful anti-inflammatories like methotrexate and cyclosporine. The pediatric study did include an unvalidated post hoc analysis showing that a sputum normalization strategy in the first month after changing treatment may reduce asthma exacerbations (Thorax 2012;67:193-8).

Persistent airflow limitation is also a hallmark of severe, therapy-resistant asthma (STRA) in adults, and is typically defined using a postcorticosteroid trial, postacute bronchodilator response in forced expiratory volume in 1 second (FEV₁), and z scores. What is not known for children, however, is what dose, route of administration, and duration of steroids is best, or what dose of bronchodilator is most effective.

"There really is no good pediatric evidence," said Dr. Bush, professor of pediatric respirology at the Royal Brompton Hospital and Imperial College in London. "The point in finding this out is that if you really do have persistent airflow obstruction [in] a child, there is no point in flogging them with more and more medications, if in fact they’re not going to open their airways."

Corticosteroid response is another cornerstone for identifying and managing STRA in adults. However, when Dr. Bush and his colleagues looked at corticosteroid response in a group of 50 children who had severe asthma by American Thoracic Society and American College of Surgeons criteria, 50% of the children had such good lung function that the adult definition of response, based on an FEV₁ of at least 80% or a 15% increase, could not be applied.

"The adult definition of corticosteroid response based on lung function does not work in kids," he said.

Clinical phenotypes such as female gender and obesity, which are associated with more severe asthma after childhood, have also proved unreliable. Another unpublished study by the group involving 40 boys and 36 girls (aged 6-19 years) with STRA found no sex differences; it also found that young people with STRA had an average body mass index of 19 kg/m², which was identical to the average BMI of a cohort of age-matched children with mild asthma and was lower than the mean of 20.4 kg/m² in age-matched controls.

The children with STRA had symptoms for an average of 2-6 years, an average of six steroid bursts (range, 1-30), and three hospital admissions (range, 0-21) in the previous year; 21% had ever been intubated because of their asthma.

Asthma Control Test scores were low in the children with STRA (average, 13.5), and lung function varied widely from an FEV₁ of 33% to 121% of predicted (average, 70%).

The children with STRA had a strong positive history of atopy (82%) and family history of atopy (84% in a first-degree relative), Dr. Bush noted.

"Indeed, if I see a child with alleged severe, therapy-resistant asthma who is not atopic, I take another further good hard look at the diagnosis," he said.

Getting the Basics Right

One of the most important steps in managing children with genuine STRA is to distinguish them from those with difficult asthma, in whom biologic therapies are not justified.

"In really severe childhood asthmatics, potentially reversible factors will be found in more than half of those not responding to treatment," Dr. Bush said at the meeting, sponsored by National Jewish Health.

The most important factors to look for are adherence, cigarettes, allergens, and psychosocial issues. He suggested that nurse-led home visits are particularly beneficial in identifying these factors. When nurses from Royal Brompton visited 71 "hard-core asthmatics," potentially modifiable factors were identified in 79%, and only 32 patients were thought to need further invasive investigation. A quarter could not produce a complete set of medications, a third were picking up fewer than half of their prescriptions, 38% did not have good inhaler technique despite multiple attempts at testing, and medication issues contributed to poor control in 48%.

"These guys know the nurses are coming; it’s not like the nurses come at 3:00 in the morning and bang on the door and say show me your medications," he said.

Dr. Bush reported no relevant financial disclosures.

Adult Phenotypes No Help in Severe Pediatric Asthma