Fungal sensitization and its relationship to mepolizumab response in patients with severe eosinophilic asthma

In asthma, sensitization to fungal, perennial or seasonal allergens increases the risk of uncontrolled symptoms, exacerbations, and poor disease outcomes.In severe asthma, typically 20%-29% of patients show sensitization to ≥1 fungal allergen, with Aspergillus being one of the most common.These patients have worse lung function, increased risk of oral corticosteroid use, hospitalization, and a greater degree of airflow obstruction than patients non-sensitized to fungal allergens.


Fungal sensitization and its relationship to mepolizumab response in patients with severe eosinophilic asthma
To the Editor, In asthma, sensitization to fungal, perennial or seasonal allergens increases the risk of uncontrolled symptoms, exacerbations and poor disease outcomes. 1 In severe asthma, typically 20%-29% of patients show sensitization to ≥1 fungal allergen, with Aspergillus being one of the most common. [2][3][4] These patients have worse lung function, increased risk of oral corticosteroid use, hospitalization and a greater degree of airflow obstruction than patients non-sensitized to fungal allergens. [3][4][5] Severe eosinophilic asthma is characterized by frequent exacerbations and elevated eosinophil counts. Currently, there is limited information on the prevalence of fungal allergen sensitization in patients with severe eosinophilic asthma, and its impact on clinical responses to treatments such as the anti-interleukin (IL)-5 monoclonal antibody mepolizumab. In clinical trials, mepolizumab reduced exacerbation frequency and oral corticosteroid use, improved lung function, and health-related quality of life (HRQoL) and symptoms vs placebo in patients with severe eosinophilic asthma. 6,7 This post hoc analysis of the MENSA study describes the prevalence of fungal sensitization in enrolled patients and their clinical response to mepolizumab.
MENSA was a randomized, double-blind, Phase III trial (GSK ID: 115588; NCT01691521) in patients with severe eosinophilic asthma. 7 Patients were randomized (1:1:1) to receive mepolizumab 75 mg intravenously or 100 mg subcutaneously (SC), or placebo, every 4 weeks for 32 weeks plus standard of care (further details in Appendix S1). In this analysis, all treatment groups were pooled and patients were stratified into subgroups based on their sensitization to fungal and/or perennial/seasonal allergens for the analysis of baseline characteristics and all end-points. Patients were also stratified for selected end-points based on their fungal allergen combined specific immunoglobulin (Ig)-E level percentile (0-≤50th, >50th-≤75th, 75-≤90th or >90th percentile) and IgE-sensitivity to Aspergillus fumigatus and/or Penicillium chrysogenum (selected because these thermotolerant filamentous fungi are known to colonize the airways and are associated with lung damage in severe asthma), 5 other fungal or no fungal sensitization. Further information on fungal allergens tested is included in Table S1. Allergen sensitization was  (Table 1). As expected, total serum IgE levels were higher in patients sensitized to either fungal or non-fungal allergens vs those without sensitization and were highest in patients sensitized to both (Table 1).
After 32 weeks of mepolizumab treatment, annual rates of clinically significant exacerbations were reduced by 48%-62% vs placebo across the fungal and/or perennial/seasonal allergen sensitization groups ( Figure 1A; Table S4). There was no clear trend in exacerbation reduction with increasing baseline combined IgE level to fungal allergens (Table S5). A trend for reductions in the annual rate of clinically significant exacerbations with mepolizumab vs placebo was observed in patients sensitized to Aspergillus and/or Penicillium (70%) and those not sensitized to fungal allergens (52%) ( Figure 1B; Table S4). Although a numerical reduction in exacerbation rate was also observed with mepolizumab vs placebo in patients sensitized to other fungal allergens (44%), this was not as pronounced ( Figure 1B).
Mepolizumab vs placebo was associated with a numerical trend for improved pre-bronchodilator FEV 1 from baseline in all patients except those with fungal sensitization only, although this may be due to the small sample size (n = 51) for this group ( Figure 1C; Table  S4). There was also a trend for improvement in FEV 1 from baseline with mepolizumab vs placebo in patients sensitized to Aspergillus and/or Penicillium, but no treatment difference in patients sensitized to other fungal allergens ( Figure 1D; Table S4). SGRQ and ACQ-5 scores also showed a trend for improvement with mepolizumab vs placebo in all groups ( Figure S1; Table S4); the improvement from baseline with mepolizumab exceeded the minimum clinically important difference (MCID) of 4-points for SGRQ total score and 0.5-points for ACQ-5 score in all groups (Table S4). 8,9 In addition, mepolizumab vs placebo reduced blood eosinophil counts from baseline by 80%-87% and reduced eosinophil cationic protein and eosinophil-derived neurotoxin levels in all groups (Table S6).
Overall, these results suggest that approximately two-thirds of patients with severe eosinophilic asthma are sensitized to allergens and one-third to fungal allergens. In patients with fungal and perennial/seasonal allergen or only perennial/seasonal allergen sensitization, mepolizumab reduced exacerbation frequency, with a trend for improved HRQoL and disease control, as measured by SGRQ and ACQ-5 score, respectively, vs placebo. The results were inconclusive in the fungal only subgroup, likely due to the small sample size for this group. In patients sensitized to Aspergillus and/or Penicillium but not to other fungal allergens, a trend for greater improvements in lung function and the rate of clinically significant exacerbations with mepolizumab vs placebo were seen, supporting the concept of allergic fungal airways disease as a distinct phenotype of asthma. 10 However, it is worth noting the relatively small sample size (n = 65) of this subgroup, the limited number of aeroallergens tested and that the analyses have to be interpreted with caution owing to the nature of this post hoc analysis.
In conclusion, patients with severe eosinophilic asthma are likely to benefit from mepolizumab treatment. Based on the results from our analysis of those with IgE-sensitization, individuals sensitized to Aspergillus and/or Penicillium may demonstrate the greatest response, although further investigation of this effect is required.

ACK N OWLED G EM ENTS
Editorial support (in the form of writing assistance, including development of the initial draft based on author direction, assembling tables and figures, collating authors' comments, grammatical editing and referencing) was provided by Sarah Farrar PhD, at Fishawack Indicia Ltd, UK, and was funded by GSK.