In the present study, we combined data that evaluated the efficacy of mepolizumab, a monoclonal antibody to IL-5, in patients with asthma. Based on 1131 asthma patients in 7 studies, we found mepolizumab significantly lowered blood and sputum eosinophil counts, effectively reduced asthma exacerbation frequency, and improved scores on the AQLQ versus placebo. In contrast, mepolizumab had no clinically significant effects on functional airway outcomes including FEV1, PEF, PC20, and a non-significant trend for a reduction in symptom scores assessed with JACQ was observed. Moreover, mepolizumab was well tolerated with minimal adverse events associated with drug administration.
Asthma is characterized by a prominent eosinophilic inflammatory infiltration in the bronchial mucosa 
. Clinical studies have shown levels of eosinophils in peripheral-blood and BALF correlated with the clinical severity of asthma 
, suggesting that eosinophils may play a role in tissue remodeling events in patients with asthma. As IL-5 is a key cytokine in eosinophil differentiation and maturation in the bone marrow as well as in recruitment and activation at sites of allergic inflammation 
, IL-5 inhibition may have a beneficial therapeutic effect in asthma by preventing eosinophilic inflammation in pulmonary tissue. Our meta-analysis indicated that mepolizumab was significantly more effective in reducing blood and sputum eosinophils than placebo, which was in accordance with the results of previous studies involving patients with the hypereosinophilic syndrome 
However, our analysis did not demonstrate significant improvement in any of the functional airway outcomes (FEV1, PEF, and PC20
). There are several possible explanations for the lack of observed benefit in lung function from mepolizumab treatment. Firstly, noneosinophilic or neutrophilic airway inflammation might contribute to persistent asthma symptoms in patients treated with inhaled corticosteroids, and such patients would be unlikely to respond to anti–IL-5 treatment 
. Furthermore, although mepolizumab has marked effects in reducing blood eosinophils, the inability to completely abolish airway eosinophils also contributes to the lack of improvement in lung function outcomes 
. Moreover, anti–IL-5 treatment had no effect on bronchial mucosal staining of eosinophil major basic protein, suggesting that reduction in eosinophil numbers does not reflect tissue deposition of granule proteins 
. Therefore, tissue eosinophils may be less responsive to IL-5, making the elimination of IL-5 redundant. However, with the relatively small sample sizes and short follow-up duration of the included studies, the ability to draw conclusions is limited. Existing findings suggest measures of airway outcomes do not indicate improvements elicited by reduced eosinophilic airway inflammation, which have important implications for the choice of the outcomes in further clinical trials defining the potential utility of anti–IL-5 for asthma.
In contrast to the non-significant results in lung function outcomes, our meta-analysis showed a significant reduction in exacerbation rates for mepolizumab treatment compared with placebo. As exacerbations may differ from day-to-day symptoms in that they respond poorly to usual inhaled therapy and are more closely linked to increased airway inflammation 
, the link to eosinophilic inflammation may be particularly important. Several previous studies revealed that markers of eosinophilic airway inflammation increased well before the onset of exacerbations 
. In particular, Green and coworkers adjusted inhaled steroid dose according to sputum eosinophils and showed that this resulted in a dramatic reduction in exacerbation frequency 
. These findings have been confirmed in a similar study in which monitoring sputum eosinophil counts was found to benefit patients with moderate-to-severe asthma by reducing the frequency and severity of exacerbations 
. Our study also showed a significant improvement in asthma-related quality of life with mepolizumab therapy, perhaps reflecting the value to patients of the prevention of asthma exacerbations.
The different effects of mepolizumab in asthma exacerbations and lung function outcomes suggest a number of issues that need to be considered before this treatment approach administered. First of all, selection of the patient population might respond to anti–IL-5 is especially important. In the DREAM trial, Pavord et al investigated which baseline variable was associated with treatment response and identified only baseline blood eosinophils and exacerbation frequency in the previous year were associated with the efficacy of mepolizumab treatment 
. This suggests that patients who could benefit from mepolizumab would be a population with high numbers of airway eosinophils, and repeated exacerbations, who are already taking and failing conventional treatments. Another issue with defining the potential utility of mepolizumab for asthma is the choice of the clinical outcomes might be associated with eosinophilic inflammation. The separation between airway outcomes and exacerbation risk implies that separate aspects of the disorder require different management strategies. Traditional markers of asthma such as FEV1
and the acute bronchodilator response may not be related to the efficacy of anti–IL-5, while existing data suggested the pathogenesis of asthma exacerbation appear to be correlated with eosinophilic inflammation 
Limitations of the Review
Despite the intriguing results of the present meta-analysis, some potential limitations should be addressed. Firstly, this systematic review is limited to 7 studies with 1131 subjects. The sample size was not large enough to reach a convincing conclusion and could not be considered clinically directive. Secondly, the drug administration frequency and treatment duration differed in the trials involved in our meta-analysis, which made it difficult to determine the optimal dose of mepolizumab that would be mostly appropriate for patients with asthma. Thirdly, although these studies shared many common issues, there were also substantial heterogeneities across studies, notably the type of patients included, study design, follow-up duration, and definitions of asthma exacerbation. Given this limitation, the results should be interpreted cautiously. Moreover, inherent assumptions made for any meta-analysis, because the analysis pooled published data, and individual data or original data were unavailable, which restricted us doing more detailed relevant analysis and obtaining more comprehensive results.
In conclusion, the current meta-analysis indicates that mepolizumab treatment appears to be useful for control of exacerbations and improve asthma-related quality of life in individuals with persistent airway eosinophilia, but may not associate with significant improvement in functional airways outcomes. The results highlight the importance of selection the subgroup of patients with asthma might derive clinical benefit from mepolizumab treatment. Additional larger studies will be required to establish the possible role of anti–IL-5 as a therapy for asthma.