Asthma is a chronic heterogeneous disease, usually characterized by chronic airway inflammation, affecting almost 20% of the population in different countries.1 More than 15% of asthma patients may have severe asthma,2 and these patients are responsible for most of the health costs in asthma. According to International ERS/ATS guideline, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller (GINA steps 4–5) to prevent it from becoming ‘uncontrolled’ or asthma which remains ‘uncontrolled’ despite this therapy.3,4 Asthma is associated with a strong oxidative stress, which results both from the increase of the oxidative forces and from the reduction of the antioxidant capacity.5,6 The complexity of asthma is due to the multiple phenotypes and endotypes that might lead to the persistence of symptoms, the poor response to conventional pharmacotherapy and the susceptibility of the patient to comorbidities.5,7

Asthma2 and obesity6 have a considerable impact on public health and their prevalence has increased in recent years. Obesity is a known risk factor for asthma9–14 and for the severity of respiratory symptoms by increasing airway hyperreactivity and contributing towards a more difficult-to-control asthma phenotype.1,13–17 It is also known that obesity has a significant negative effect on all lung volumes, decreasing lung function.8

Obesity can make asthma more difficult to control10,14,17 and is associated with a lower quality of life10 and a reduced beneficial effect of asthma medications.10,11,13,14,17 Some of the known mechanisms for the increased risk of severe asthma in obese patients are: anatomical changes of the airways (such as obstruction),10 production of adipokines10,12,17 (such as leptin), impaired glucose-insulin metabolism,10,12,18 altered nutrient levels,10 genetic and epigenetic changes10 and inflammation.10,17 Systemic inflammation (particularly obese patients with high levels of IL-612,13 and TNF-α13), seems to have impact in severe asthma, but obese asthmatic patients do not appear to have increased airway cellular inflammation., they seem to have separate mechanisms that are specific to the obese state, rather than the conventional Th type 2-mediated inflammatory pathway.13,19 The current evidence suggests that while oxidative stress is important in asthma, it does not fully explain the characteristics associated with the obese-asthma phenotype.17

Omalizumab is a humanized monoclonal antibody that binds to the constant region (Fc) of immunoglobulin E (IgE). Omalizumab blocks the binding of IgE to its high affinity receptor Fc_R1, situated on the surface of the mast cells (and other cells). Consequently, activation of the mast cells and liberation of its pro-inflammatory mediators is inhibited.20 It is recommended as add-on therapy, in patients of six years or older, with severe allergic IgE-mediated persistent asthma, who are inadequately controlled despite the best available treatment (according to guidelines1) and need continuous or frequent treatment with oral corticosteroids (defined as 4 or more courses in the previous year).21

The literature about severe asthma in obese patients is scarce. Several clinical controlled trials showed that omalizumab reduces asthma-related symptoms, decreases corticosteroid use, and improves quality of life of asthmatic patients,22–24 however there is little information regarding the effects of omalizumab on obese patients with severe asthma. The aim of the current prospective study was to assess the impact of the treatment with omalizumab in obese patients with inadequately controlled severe persistent allergic (IgE-mediated) asthma.

A total of 32 adults with severe asthma were prospectively followed during a 12 month period. Most of the patients were female (75%). The mean age was 53 years-old. Nineteen (59.4%) patients were obese. Table 1 lists the characteristics of the study population and of each group (obese and non-obese), at T0 and T12 “show Table 1 here”. At the beginning of the study there were no statistically significant differences between the 2 groups regarding gender, age, total IgE, omalizumab monthly dose, exacerbations in the previous 12 months, ACT, FEV1, FVC and equivalent daily dose of budesonide, with the exception of BMI which was significantly higher in obese patients group (33.5 vs. 25.8kg/m2, p<0.001).

The comparative analysis of the population at T0 and T12 showed that, after 12 months of treatment with omalizumab, there was a statistically significant improvement in all the parameters under analysis, with exception of FVC. There was a significant reduction in BMI (30.4 vs. 29.4kg/m2, p<0.001), in the number of exacerbations in the previous 12 months (6.0 vs. 0.5, p<0.001) and in the equivalent daily dose of budesonide (1213.8 vs. 736.3μg, p<0.001); and a significant improvement in ACT (10.6 vs. 23.2, p<0.001) and in FEV1 (56.9 vs. 65.0%, p<0.001) (Table 1).

The comparative analysis of the two groups showed that at the end of the study, obese patients had a significantly higher FEV1 than non-obese patients (70.2 vs.58.8%, p=0.017). There were no other significant differences between the two groups, unless BMI which was significantly higher in obese patients (32.1 vs. 25.4kg/m2, p<0.001) (Table 1).

The analysis of each group showed that: obese patients had a statistically significant improvement in ACT and FEV1, and a statistically significant reduction in BMI, exacerbations in the previous 12 months and equivalent daily dose of budesonide; non-obese patients had a statistically significant improvement in ACT and a significant reduction in the exacerbations in the previous 12 months and in the equivalent daily dose of budesonide (Table 1). In the end of the study 18 (94.7%) obese patients had a loss of 4.9±3.9% of their initial weight.

In the present study, the majority of the population was obese. The risk factor obesity for the development of asthma is widely described in the literature. A meta-analysis based on prospective studies of Bather and Sutherland showed that the odds of developing asthma for individuals with obesity compared to those with normal weight were twice as high (OR 1.92, 95% CI 1.43–2.59).30,31 In addition to being a risk factor for asthma, obesity seemed to promote a more persistent and severe asthma phenotype, independently of socio-demographic and lifestyle determinants, such as physical activity and dietary patterns.13,14,16,17,30

In patients with severe allergic IgE-mediated persistent asthma it had already been demonstrated that treatment with add-on omalizumab significantly reduced symptoms,32,33 rescue medication32,33 and asthma exacerbations.20,32,33 In our study, the comparative analysis of the population at T0 and T12 showed that, after 12 months of treatment with omalizumab, there was a statistically significant improvement in almost all the analyzed parameters. As described, there was a significant reduction in the number of exacerbations in the previous 12 months, in the equivalent daily dose of budesonide, and a significant improvement in ACT. In the analysis performed for each group separately (obese and non-obese), similarly to what happened with the population, there was a significant improvement in the three parameters already described.

The data about the effect of omalizumab on lung function are inconsistent.33 The study of Özgür et al. showed that long-term therapy with omalizumab had a significant improvement in lung function (FEV1).34 In the present study, after 12 months of treatment with omalizumab, not only there was a significant improvement in FEV1 in the study population, but there was also a statistically significant difference between the two study groups regarding lung function. At the beginning of the study, the two groups were homogeneous, with no statistically significant differences in any of the parameters under analysis (gender, age, total IgE, omalizumab dose, number of exacerbations in the previous 12 months, ACT, FEV1, FVC and equivalent dose of busonide), with the exception of BMI. At the end of the study, the stability between groups was maintained, with the exception of FEV1 which was different for the two groups, as obese patients had a significantly higher FEV1 compared to non-obese patients, without significant changes in FVC. The analysis of each study group in T0 vs. T12, showed that FEV1 of obese patients was significantly higher in T12, and that there was no statistically significant difference in FEV1 of non-obese patients. Based on these results we believe that the significant improvement of lung function in the study population was mainly due to the improvement observed in obese patients group, because in non-obese patients there was no significant difference. In addition, we found that the improvement in lung function was most probably not due to weight loss (which in obese patients was not satisfactory; it was below 5%35), because unlike FEV1, there was no significant change in FVC (which is the spirometric parameter most influenced by obesity8).

The mechanisms underlying the clinical and anti-inflammatory efficacy of omalizumab are not fully understood. The published data about the impact of omalizumab in lung function of asthmatic patients are inconsistent and this may be due to the fact that there are no studies specifically with obese patients, which as we have now seen, was the subpopulation on which there was greater impact. Omalizumab can neutralize free IgE, interrupting a key step in the allergic inflammatory cascade, preventing IgE from binding to mast cells, basophils, and dendritic cells, and down-regulating IgE receptor expression in these inflammatory cells, thereby inhibiting degranulation and the release of inflammatory mediators.36 Anti-IgE therapy is a treatment modality that mediates its effects through decreasing inflammation following improved anti-oxidant capability,35 this loss of inflammation may have been the mechanism responsible for the lung function improvement seen in our obese asthmatic patients.

The mechanisms underlying the epidemiology of obesity and asthma phenotypes are still not clear. It is known that the increased abdominal and chest wall mass causes a decrease in the functional residual capacity and a reduction in lung and tidal volumes16 and, that obesity is a pro-inflammatory state leading to an increase in inflammation.16 Weight loss is associated with improvement in lung function, symptoms, morbidity and overall health status,13,16 and it should be part of asthma management in obese patients.10 In this study, there was a reduction in BMI after 12 months of treatment with omalizumab, which was significantly reduced in the whole population and in the obese patients group. According to our data the reduction in BMI may have been due to decreased use of corticosteroids and to less limitation in the activities of daily living as a consequence of the best asthma control and FEV1 improvement, since no measures were taken towards weight loss during the 12-month follow-up.

This study was limited by the small sample size and also because the particular measures adopted by each patient for weight loss were not studied, however it was a prospective study where, for the first time, the subpopulation of obese patients with severe asthma was studied. Despite the limitations, with this study we found that the impact of treatment with omalizumab is greater in obese patients. Although weight loss is important in obese patients with asthma and, in the present study the weight loss was significant in the group of patients with improvement in almost all the parameters analyzed (obese patients group), we could not explain this relationship. It might have been the better disease control which consequently led to less physical inactivity and hence weight loss or there may have been another mechanism behind this relationship. Recent studies suggest that obesity may have a causal relationship with asthma,37 but more prospective studies are still needed in the subpopulation of obese patients with severe asthma.

In summary, our study showed that omalizumab, used as an add-on to optimized standard therapy, in patients with severe allergic IgE-mediated persistent asthma, significantly improved asthma control, reduced rescue medication and asthma exacerbations. We have demonstrated for the first time that, in the subpopulation of obese patients with severe asthma, treatment with omalizumab significantly improved lung function (FEV1). Therefore, our results reinforced the importance of omalizumab used as add-on therapy especially in obese severe asthmatic patients where it has a greater impact.

Our study also provides a rational for future studies exploring the obese-asthmatic patients treated with omalizumab and the immunological pathways that might lead to asthma that is associated with obesity.

The authors have no conflicts of interest to declare.