A large subgroup of mild-to-moderate asthma is persistently noneosinophilic

Abstract

Rationale: Airway eosinophilia is typical of asthma, and many controller treatments target eosinophilic disease. Asthma is clinically heterogeneous, however, and a subgroup of people with asthma do not have airway eosinophilia. The size of this subgroup is uncertain because prior studies have not examined repeated measures of sputum cytology to determine when people with asthma have intermittent versus persistent sputum eosinophila and when they are persistently noneosinophilic.

Objectives: To determine the prevalence and clinical characteristics of the noneosinophilic asthma phenotype.

Methods: We analyzed sputum cytology data from 995 subjects with asthma enrolled in clinical trials in the Asthma Clinical Research Network where they had undergone sputum induction and measures of sputum cytology, often repeatedly, and assessment of responses to standardized asthma treatments.

Measurements and main results: In cross-sectional analyses, sputum eosinophilia (≥2% eosinophils) was found in only 36% of subjects with asthma not taking an inhaled corticosteroid (ICS) and 17% of ICS-treated subjects with asthma; an absence of eosinophilia was noted frequently, even in subjects with asthma whose disease was suboptimally controlled. In repeated measures analyses of people with asthma not taking an ICS, 22% of subjects had sputum eosinophilia on every occasion (persistent eosinophilia); 31% had eosinophilia on at least one occasion (intermittent eosinophilia); and 47% had no eosinophilia on every occasion (persistently noneosinophilic). Two weeks of combined antiinflammatory therapy caused significant improvements in airflow obstruction in eosinophilic asthma, but not in persistently noneosinophilic asthma. In contrast, bronchodilator responses to albuterol were similar in eosinophilic and noneosinophilic asthma.

Conclusions: Approximately half of patients with mild-to-moderate asthma have persistently noneosinophilic disease, a disease phenotype that responds poorly to currently available antiinflammatory therapy.

Figure 1.

Cross-sectional analysis of sputum eosinophils in mild-to-moderate asthma. (A) Frequency distribution of sputum eosinophils in subjects not treated with inhaled corticosteroids (ICS) at baseline assessment (n = 350). (B) Frequency distribution of sputum eosinophils in subjects treated with ICS at baseline (n = 645). (C) Sputum eosinophils in mild-to-moderate subjects with asthma given standardized low-dose ICS for 4–6 weeks. Asthma control was assessed at the end of the standardized treatment phase. Subjects were considered not well controlled if FEV₁ was less than 70% of predicted, or if daytime symptoms or short-acting β-agonist use were present on greater than or equal to 6 days per week, or if nocturnal awakening was present on greater than or equal to 2 nights per week during the final 2 weeks of low-dose ICS treatment (either beclomethasone, 160 μg, or triamcinolone acetonide, 800 μg daily). Subjects were considered well-controlled if FEV₁ was greater than 70% of predicted and either diurnal variation in peak flow was less than 20% or if daytime symptoms or short-acting β-agonist use were present less than or equal to 5 days per week or nocturnal awakening was present less than or equal to 1 night per week during the final 2 weeks of low-dose ICS treatment. The frequency of sputum eosinophilia was significantly lower in the subgroup with suboptimal asthma control (P = 0.004).

Figure 2.

Receiver operating characteristics (ROC) analysis of peripheral blood eosinophils and fractional exhaled nitric oxide (FE_NO) as biomarkers of sputum eosinophilia. The red line shows the ROC curve for peripheral blood eosinophils, where the highest combination of sensitivity and specificity was reached at a threshold of 220/μl, which yielded 72% sensitivity and 69% specificity (area under the curve, 0.77). The black line shows the ROC curve for FE_NO, where the highest combination of sensitivity and specificity was achieved at a threshold of 20 ppb, which yielded 64% sensitivity and 73% specificity (area under the curve, 0.72).

Figure 3.

Cross-sectional analysis of sputum neutrophils in mild-to-moderate asthma. (A) Frequency distribution of sputum neutrophils in subjects not treated with inhaled corticosteroids (ICS) at baseline assessment (n = 350). (B) Frequency distribution of sputum neutrophils in subjects treated with ICS at baseline (n = 645).

Figure 4.

Sputum eosinophil percentage in the inhaled corticosteroid (ICS)− and ICS-positive subjects with asthma assessed by single and repeated measures. (A) Subjects with asthma not treated with steroids (ICS−). Frequency of sputum eosinophilia in all subjects at baseline (n = 350) compared with the baseline frequency in the subgroup who had repeated measures (n = 157), and with the frequency of eosinophilia during any one of two to four sputum inductions. (B) Subjects with asthma treated with steroids (ICS-positive). Frequency of sputum eosinophilia in all subjects at baseline (n = 645) compared with the baseline frequency in the subgroup who had repeated measures (n = 167), and with the frequency of eosinophilia during any one of two to four sputum inductions. (C and D) Median sputum eosinophil percentage at different time points in the ICS− (C) and ICS-positive (D) asthma subgroups. The graphs reveal three subgroups of subjects with asthma: (1) those with persistently eosinophilic asthma whose sputum eosinophil percentage is greater than or equal to 2% on every occasion it was measured, (2) those with intermittently eosinophilic asthma whose sputum eosinophil percentage is greater than 2% on at least one occasion but can be less than 2% on some occasions, and (3) a third subgroup whose sputum eosinophil percentage is persistently less than 2% on all occasions measured. Note that the number of subjects varies at each time point; as indicated in the main manuscript, the number of repeated measures ranged from two to four.

Figure 5.

Clinical characteristics of eosinophil phenotypes in 157 inhaled corticosteroids (ICS)− subjects with repeated sputum measures. The histograms show the percentage of subjects in each eosinophil subgroup categorized by abnormalities in body mass index, FEV₁, PC₂₀ for methacholine, serum IgE level, aeroallergen skin test reactivity, and sputum neutrophils. The comparative statistics are the P values for trend using ordinal logistic regression to assess for trends among the eosinophil subgroups. (A) Body mass index categorized as normal (<25 kg/m²); overweight (25–30 kg/m²); or obese (>30 kg/m²). (B) FEV₁ categorized as normal (FEV₁ ≥80%) or abnormal (FEV₁ 61–79%). (C) PC₂₀ for methacholine was categorized as moderately to severely abnormal (PC₂₀ <1 mg/ml); mildly abnormal (PC₂₀ 1–4 mg/ml); or borderline abnormal (PC₂₀ 4–16 mg/ml). (D) IgE was categorized as normal (<80 IU) or high (≥80 IU). (E) Allergen skin test reactivity categorized based on the number of positive skin tests to a panel of 10–12 aeroallergens; the two categories were designated as a positive reaction to more than or less than half of the allergens tested. (F) Sputum neutrophils categorized as normal (<61% neutrophils) or abnormal (>61% neutrophils). BHR = bronchial hyperresponsiveness; IEA = intermittently eosinophilic asthma; NEA = noneosinophilic asthma; PEA = persistently eosinophilic asthma.

Figure 6.

Change in FEV₁ in a subgroup of the inhaled corticosteroid–negative group (n = 77) who received a period of intense combined therapy (PICT) for 10–14 days. The PICT consisted of 0.5 mg of prednisone/kg/day, 800 μg of budesonide twice per day, and 20 mg of zarfirlukast twice per day. Prebronchodilator FEV₁ was measured before and after the PICT. In addition, maximal bronchodilator reversibility was measured after the PICT and involved measures of spirometry after up to 720 μg of inhaled albuterol, as previously described (17). The data represent means and standard error.