This study shows that bariatric surgery produces clinically and statistically significant improvements in asthma control. Previous studies have suggested that bariatric surgery might improve asthma symptoms23–26
, although these studies have been criticized for not objectively diagnosing asthma in their study populations. Airway hyperresponsiveness improves with bariatric surgery in individuals with normal IgE, and the change in AHR is significantly related to change in BMI in this group. These improvements were not related to decreased inflammation and CD4+
lymphocyte function; indeed CD4+
T cell responses increased after bariatric surgery. Our study suggests that bariatric surgery should be considered for treatment of poorly controlled asthma in patients with extreme obesity, and this should be studied in larger clinical trial. Our study also provides important insights into the pathogenesis of asthma in obesity.
One singularly important insight is the relationship of atopy with asthma in obesity. Recent publications suggest that obesity is particularly a risk factor for non-atopic asthma2, 27
, and so in this study we performed a post-hoc analysis to determine if atopic status (measured by IgE level in our study cohort) affected results of this study. Non-atopic asthmatics reported significantly later onset of asthma than atopic asthmatics. They tended to have more co-morbidities and more exacerbations that atopic obese asthmatics before surgery. This suggests that the pathogenesis of asthma in the non-atopic obese group may differ from that in the atopic group, particularly as it leads to airway disease later in life.
The atopic status of participants also affected the change in AHR following bariatric surgery. There was a statistically significant interaction between IgE status and change in AHR, and change in AHR was significantly related to change in BMI in individuals with normal IgE. These observations suggest that atopic status does indeed significantly affect the AHR response to surgery.
No previous study has determined the effects of bariatric surgery on AHR. We are aware of only one previous study that quantified change in AHR in response to weight loss, and in that case diet-induced weight loss did not affect AHR28
. We do not know the reason for the difference between the results from the bariatric surgery and dietary interventions, but speculate that it could be related to differences in the amount of weight lost or the atopic status of participants (which was not reported in the dietary intervention study)28
. The finding that a marker of atopy was related to change in AHR with weight loss may also explain conflicting reports on the relationship between AHR and BMI, since these studies often do not differentiate on atopic status 29, 30
. Studies in mice are also pertinent in this regard - obese mice have increased airway reactivity compared with lean mice, even in the absence of allergen challenge31
. Obesity may lead to AHR even in the absence of allergic inflammation, suggesting that a non-allergic mechanism leads to AHR in obesity. These data have important clinical and scientific implications: weight loss may be a critical intervention to improve AHR in non-atopic individuals, and obese individuals with minimal allergic inflammation likely represent a distinct phenotype of asthma more common in older female asthmatics32, 33
With respect to markers of allergic inflammation, airway eosinophilia did not change with weight loss, nor were there differences between obese asthmatics and controls. Since the initiation of our study, cross-sectional studies have been published suggesting that airway eosinophilia does not increase, but may actually decrease, with increasing BMI34–36
. Animal models of allergic asthma suggest decreased airway eosinophilia in obese compared with lean mice.37
Our current findings provide strong support for these previous cross-sectional and animal studies. Bariatric surgery does not reduce airway eosinophilia even though symptoms and AHR improve.
Bariatric surgery did affect lymphocyte percentage in BAL and peripheral blood lymphocyte function. Obese mouse models of allergic asthma also report decreased BAL lymphocyte counts in obese compared with lean mice37
, consistent with the current findings. We also found that stimulated CD4+
T cells isolated from the peripheral blood of asthmatics had significantly increased cytokine production 12 months after surgery. Participants were using less inhaled anti-inflammatory medication at 12 months, but even high dose inhaled corticosteroids do not affect response of T cells to stimulation38
. Changes in other medications may be affecting T cell responses, this will require further investigation. However, this finding of altered lymphocyte function in obesity is consistent with previous publications. Tanaka et al
found that mitogenic and cytokine responses in T cell subsets are reduced in obese individuals compared with lean individuals 39, 40
, and Farooqi et al
found that leptin deficiency (obesity is characterized by leptin resistance) was associated with reduced circulating CD4 T cells, and impaired T cell proliferation and cytokine production 41
. The changes in CD4+
T cell cytokine release and airway lymphocytes suggest that asthma in obesity is likely not related to enhanced lymphocyte driven inflammation. Future studies which phenotype lymphocytes in BAL and blood during weight loss may provide important insights into how obesity and asthma interact to affect lymphocyte function in obese asthmatics. The important clinical implication of this observation is that anti-inflammatory therapies that target lymphocyte-driven inflammation are likely to have limited efficacy in obese asthmatics, which may help explain the reduced steroid responsiveness that has been reported in these patients6, 7
Contrary to our original hypothesis, AHR in obesity is dissociated from lymphocytic and eosinophilic inflammation. However, there are other factors associated with obesity that change with weight loss and may lead to AHR. These include the mechanical effects of breathing at low lung volumes, altered metabolic factors and co-morbidities such as sleep apnea.
Breathing at low lung volumes (which occurs in obesity) is known to lead to AHR in normal volunteers, possibly through biophysical effects on airway smooth muscle42, 43
. Breathing at low lung volumes unloads airway smooth muscle, allowing it to shorten excessively when activated. In addition, deep breaths are potent bronchodilators, this bronchodilatory effect may be compromised by breathing at low lung volumes.42
Altered metabolic factors may contribute to airway hyperresponsiveness. Studies in mice suggest that factors produced by adipose tissue may also affect AHR. For example, adiponectin decreases AHR in a mouse model of asthma19
. The results of our study show that BAL and serum adiponectin increase significantly with weight loss, and there may be a modest correlation between BAL adiponectin levels and AHR, although our study was not powered to determine this. There are multiple other mediators such as TNFα, plasminogen activator inhibitor-1 and interleukin 6 that are also altered in obesity and could contribute to airway disease44
. Future studies of the role of these mechanical and metabolic factors, and co-morbidities such as sleep apnea may provide important information on the pathogenesis of asthma in obesity.
Other interesting insights into the relationship between asthma and obesity are suggested by certain baseline characteristics of our study population. Asthmatic participants were significantly heavier than controls. We do not know the reasons for this, although a recent report from a bariatric surgery consortium found that asthma prevalence increased with increasing BMI; in fact over 30% of individuals with a BMI over 60 reported a diagnosis of asthma45
. The fact that our asthmatic participants had higher BMIs may reflect the fact that heavier patients are more likely to have asthma. Another interesting observation was the high prevalence of asymptomatic AHR in controls. The prevalence of asymptomatic AHR has been reported as 8 – 12 % in normal weight populations46, 47
. It has been suggested that obesity may be risk factor for symptomatic
AHR. Our findings suggest that asymptomatic AHR may in fact be very common in severely obese patients. It seems likely that the same factors causing asthma in obesity could be contributing to asymptomatic AHR in these severely obese patients. These observations likely warrant further investigation.
In summary, we found that bariatric surgery led to significant improvements in AHR, particularly in individuals with normal IgE levels. These improvements were not associated with detectable changes in airway inflammation but somewhat paradoxically were associated with significant increases in CD4+ T cell cytokine responses and airway lymphocytes. These data suggest that AHR and asthma symptoms in obese asthmatics are not associated with the typical lymphocyte-dependent pathways that drive asthma in lean allergic individuals. There are likely to be at least two distinct phenotypes of obese asthmatics: (i) one group with non-atopic late onset asthma with AHR that will improve with weight loss, and (ii) a group with early onset atopic disease. The former category likely have asthma developing due to obesity, the latter likely have early onset atopic asthma which is complicated by the co-existence of obesity. Future studies and interventions for obese asthmatics need to treat the subgroup of obese asthmatics with little evidence of allergic inflammation as having a distinct phenotype of asthma; therapies that target lymphocytic inflammatory pathways are likely to have limited efficacy in this population.