Phenotypic clusters, long-term asthma control and response to specific

To assess whether the derived cluster designations have clinical relevance regarding subse- quent risk of exacerbations, we performed survival analysis of time to asthma exacerbation over approximately 4.5 years follow-up. Consistent with the effective randomization of treat- ment assignment, treatment group did not differ between clusters (p = 0.91, Table 3.6, Table 3.7), enabling unbiased assessment of the relationship between cluster grouping and long- term asthma control (Figure 3.3). Kaplan-Meier analysis confirmed that cluster grouping was strongly predictive of time to first course of oral prednisone (Figure 3.10a, Kaplan- Meier log-rank p < 0.0001) and time to initiation of additional asthma controller therapies (Figure 3.10b, p = 0.001). The most striking differences were observed within the first 12 months post-randomization, by which time the majority of subjects in Clusters 4 and 5

Cluster 1: Relatively mild asthmatics with a low atopic burden (LLL) • The largest subgroup of patients (28.8%)

• No history of atopic dermatitis, lowest prevalence of hay fever or skin prick test reactivity, lowest IgE levels

• Preserved lung function(highest FEV1/FVC ratio)

• Lowest bronchodilator response, intermediate airway hyperresponsiveness. • No prior hospitalization for asthma and the lowest reported prevalence of ED visits • Lowest risk of poor long-term asthma control**

Cluster 2: Highly atopic asthmatics with preserved lung function (HLM)

• Universally report atopic dermatitis, high prevalence of allergic rhinitis and skin test reactivity • Preserved lung function (highest FEV1)

• Intermediate bronchodilator response and airways hyper responsiveness • No prior hospitalization, but intermediate rates of prior ED visits • Low-intermediate risk of poor long-term asthma control**

Cluster 3: Highly atopic asthmatics with reduced lung function and severe airways hyperresponsiveness (HHM)

• Rarely report atopic dermatitis (in contrast to HLM cluster),but highest prevalence of allergic rhinitis and skin test reactivity

• Most reduced lung function (low FEV1/FVC ratio)

• High bronchodilator response and most severe airways hyper responsiveness

• Few prior hospitalizations, but intermediate rates of prior ED visits (similar to HLM cluster) • Intermediate risk of poor long-term asthma control**

Cluster 4: Asthmatics with reduced lung function and high exacerbation rates, but lower atopic burden (MHH)

• No history of atopic dermatitis, intermediate prevalence of hay fever (52.9%), lower IgE levels • Most reduced lung function (low FEV1/FVC ratio, similar to HHH cluster)

• High bronchodilator response and most severe airways hyper responsiveness • Most reports of prior hospitalization

• Intermediate risk of poor long-term asthma control**

Cluster 5: Asthmatics with most severe disease at baseline, high atopic burden, highest exacerbation rates (HHH)

• Smallest subgroup of patients (9.3%)

• Nearly universal atopic dermatitis, highest prevalence of skin test reactivity, highest IgE levels, highest eosinophilia, intermediate prevalence of allergic rhinitis

• Reduced lung function (low FEV1/FVC ratio) (similar to MHH cluster)

• Highest bronchodilator response and severe airways hyperresponsiveness • Most reports of prior hospitalization and highest rate of ER visits • Highest risk of poor long-term asthma control**

* Atopy-Obstruction-Exacerbation classification denoted in parenthesis.

** Poor long-term asthma control risk is defined from prospective survival analysis of time to first course of oral prednisone. This variable was derived using the defined cluster groupings and was therefore not considered in the spectral cluster analyses used to define the clusters.

(66% and 64%, respectively) had required at least one course of oral steroids, as compared to only 56% and 54% of subjects in Clusters 3 and 2, and only 46% of patients in Cluster 1. These established trends persisted for the remainder of the trial, with greater separation of cluster groupings over time. At the end of the 4-year trial observation period, about a 3-fold difference in the percentage of subjects not requiring oral prednisone was observed between the two most extreme groups (32% in Cluster 1 vs. 11% in cluster 5, p < 0.0001). Simi- lar relationships were noted for time to initiation of additional asthma controller therapies (Figure 3.10b).

We next assessed whether treatment response to specific inhaled anti-inflammatory con- troller medications differed by cluster group. As originally reported in the primary outcomes assessment of the CAMP trial [82], use of inhaled budesonide, compared to placebo, sig- nificantly reduced the number of asthma exacerbations Further, it was found that for the entire cohort nedocromil did not significantly reduce exacerbation rates or additional con- troller therapies compared to placebo. However, in a post hoc evaluation stratified by cluster grouping, significant heterogeneity in treatment response rates to both medications is found (Figure 3.4, Table 3.6, Table 3.7, 3.8, 3.9, 3.10): whereas subjects stratified to the three more mild clusters demonstrated treatment response patterns similar to those reported in the cohort as a whole, the therapeutic efficacy of nedocromil was similar to that of budes- onide (as significantly greater than placebo) among subjects in the two most severe clusters (Clusters 4 and 5) - those with the highest risk of exacerbation. Subjects in Cluster 4 those with the lowest atopic burden, worst lung function, and high baseline exacerbation rates demonstrated significant reductions in exacerbation rates when randomized to nedocromil (1.7 fold reduction compared to placebo at 12 months, 1.6 fold reduction at 4 years) that was similar to the reduction in exacerbation observed among those randomized to budesonide (1.6 fold reduction compared to placebo at 12 months, 1.4 fold reduction at 4 years). In this group, there was no difference in exacerbation reduction between those randomized to nedocromil or budesonide (p = 0.96). Similar effects were noted in Cluster 5 (p = 0.22 for difference between nedocromil and budesonide groups), though the magnitude of treatment effect (compared to placebo) was substantially lower than for subjects in Cluster 4. For subjects in Cluster 5- those with a high atopic burden, low lung function and the highest

0 10 20 30 40 0 20 40 60 80 100

Time to First Prednisone Burst

Months of follow−up

P

ercent occurrence of outcome

Number at risk 300 177 146 117 104 cluster 1 202 103 83 69 60 cluster 2 218 113 86 63 59 cluster 3 225 99 70 54 45 cluster 4 96 42 29 18 14 cluster 5 cluster 1 (LLL) cluster 2 (HLM) cluster 3 (HHM) cluster 4 (MHH) cluster 5 (HHH) Log−rank p < 0.001

(a) Prednisone use

0 10 20 30 40 0 20 40 60 80 100

Time to Use of Additional Asthma Therapy

Months of follow−up

P

ercent occurrence of outcome

Number at risk 300 283 265 249 237 cluster 1 202 184 176 160 155 cluster 2 218 200 188 170 160 cluster 3 225 201 180 161 154 cluster 4 96 81 72 63 59 cluster 5 Log−rank p < 0.001

(b) Need for additional therapy

Kaplan-Meier plots by cluster of the cumulative probability of a first course of prednisone A: or initiation of additional asthma controller therapies (beclomethasone or other) B: during the four-year follow-up period of the CAMP trial.

baseline exacerbations there was no decrease in exacerbation rate for subjects randomized to either nedocromil (p = 0.56) or budesonide (p = 0.12).

3.3.5 Demographic, environmental, and familial determinants of phenotypic