LEICESTER, UK—While most studies have focused on similarities in the disease pathology of asthma patients, new evidence supports the other side of that debate—that asthma is a heterogeneous disease. In a recent study of 259 adults receiving treatment for symptomatic asthma, there was considerable variability in induced sputum cell counts, particularly among nonatopic patients.[1]

“The striking new finding,” said lead investigator Ruth H. Green, MD, “is that we found a distinct subgroup of 60 patients with mild to moderate asthma who had neutrophilic airway inflammation with no eosinophils.” This subgroup did not respond as well to inhaled corticosteroids as did the overall population, which had predominantly eosinophilic inflammation, stressed Dr. Green, a research fellow at the Institute for Lung Health at Glenfield Hospital in Leicester, United Kingdom.

CONSISTENT SYMPTOMS AND TREATMENTS

These asthma patients had consistent symptoms and at least one of the following: significant airway responsiveness to inhaled methacholine (less than 8 mg/mL was required to cause the forced expiratory volume in one second [FEV1] to drop 20%); FEV1 levels rose more than 15% within 10 minutes of inhaling 200 µg of albuterol; or they displayed more than 20% daily variability in peak expiratory flow (PEF) when the PEF was measured twice a day for two weeks.

The patients had no clinical or radiologic evidence of bronchiectasis and no symptoms of acute lower respiratory tract infection within a month of study entry. FEV1 exceeded 65% predicted, and all patients had a smoking history of less than 10 pack-years.

Patients received the stepwise asthma therapy described in the asthma guidelines of the British Thoracic Society (BTS). Step 1 consists of ß2-agonists for intermittent asthma; steps 2 and 3 call for inhaled corticosteroids for more persistent asthma.[2]

Lower airway inflammation was assessed through sputum induction and analysis. The asthma patients’ findings were compared to those of 34 asthma-free controls. The controls were nonsmokers or ex-smokers who had not smoked within 12 months of study entry. Smoking histories also consisted of less than 10 pack-years, and all controls had normal spirometric results and airway responsiveness to methacholine.

SPUTUM COUNTS POINTS TO DIFFERENCES

Patients with atopic asthma had a higher mean daily inhaled corticosteroid dose than did those with nonatopic asthma (424 vs 416 µg). Nonatopic asthma was associated with less airway responsiveness to methacholine and a higher mean sputum neutrophil count (54.1% vs 45.0% for atopic asthma).

One hundred thirty-five (53%) of the asthma patients had sputum eosinophil counts outside the normal range, making sputum evidence of eosinophilic airway inflammation the most common abnormality overall. Among patients being treated with inhaled corticosteroids, the median sputum eosinophil count was significantly lower in those with atopic asthma than in those with nonatopic asthma (1.1% vs 3.3%). The heterogeneity found in the induced sputum cell counts was apparent even among patients who took only ß2-agonists for their asthma.

In the subgroup of patients with mild to moderate asthma who had primarily neutrophilic airway inflammation, sputum neutrophil levels were elevated while sputum eosinophil counts remained in the normal range. Compared to the overall study population, these 60 patients tended to be older (mid-40s to mid-50s), female, and nonatopic.

RESPONSE TO INHALED STEROIDS

From a group of 92 asthma patients who were taking only ß2-agonists and met BTS criteria for a step up in treatment, 49 were randomly chosen to receive 400 µg of inhaled budesonide twice daily. Of these subjects, 11 displayed neutrophilic airway inflammation with normal sputum eosinophil levels.

After two months, these 11 patients had experienced significantly less improvement in their asthma symptoms (measured with a visual analog scale) than did the rest of the inhaled budesonide users. They also displayed smaller FEV1 increases and greater airway responsiveness to methacholine.

“We do not have a clear explanation for the development of neutrophilic airway inflammation in these patients,” Dr. Green and colleagues acknowledged. Neither current smoking nor early chronic obstructive pulmonary disease appears to explain the unusual inflammatory cell profile, but the possibility of subtle subclinical bronchiectasis or lower respiratory tract infection cannot be excluded, they said.

Treatment for these patients is problematic, added Dr. Green, because they appear to respond poorly to inhaled corticosteroids and nothing is available to treat their neutrophilic inflammation. “Such a treatment will have to be developed, but we are a long way off from that,” she said.

—Timothy Begany