title: The effects of obesity on asthma and a randomised controlled trial assessing a total diet replacement programme in people with difficult-to-treat asthma and obesity
Creators: name: Sharma, Varun
Publisher: name: University of Glasgow
Year: 2024

description: In this thesis, three studies are reported in patients with difficult-to-treat asthma. The primary focus is a randomised controlled study assessing a weight management programme in participants with difficult-to-treat asthma and obesity compared to usual care. The other two are retrospective analyses: one, a study to assess if any correlation or relationship exists between obesity and markers of type 2 inflammation in asthma, the other assessing if there is any difference in sleep parameters using wearable technology between participants with mild and difficult-to-treat asthma. 

Obesity-associated asthma is a complex phenotype on the rise often characterised by more difficult-to-treat disease, increased morbidity and mortality and great economic burden. Previous studies assessing weight loss in asthma suggest a benefit in asthma control and quality of life but have issues with heterogeneity in populations and interventions studied, lack controls or robustness. In excess, adipose organ dysfunction results in an imbalance in adipokine-mediated pro-inflammatory and anti-inflammatory markers favouring airway inflammation and hyperresponsiveness. Additionally, a few studies have suggested an inverse effect of increasing obesity on markers of type 2 inflammatory markers potentially limiting their use in this cohort. Complicating matters, sleep breathing disorders, common in obesity, such as obstructive sleep apnoea syndrome are known to increase asthma exacerbation severity. Robust and well-constructed trials assessing conservative options for weight management in people with obesity and asthma are needed. The CounterweightPlus weight management programme is one such option, with an evidence base in type 2 diabetes mellitus. We hypothesised that use of this dietitian-supported total diet replacement weight management programme would result in improved asthma control and quality of life in people with difficult-to-treat asthma and obesity. 

We performed a single-centre, open-label randomised controlled trial assessing the Counterweight-Plus programme (CWP) against usual care (UC) in people with difficult-to-treat asthma and obesity. This programme entails a 12-week c850 calorie/day total diet replacement phase followed by a food re-introduction and then weight maintenance phase up to one-year with dietitian input. Follow-up visits occurred at 16-weeks (the primary outcome) and 52-weeks. Primary outcome assessed the change in Asthma Control Questionnaire (ACQ6) scores at 16-weeks between groups and key secondary outcomes included change in Asthma Quality of Life (AQLQ) scores at 16-weeks, comparing proportions of people experiencing minimal clinically important difference (MCID) in ACQ6 and AQLQ, and assessing these outcomes again at one-year. 

Thirty-three participants attended at 16-weeks for primary outcome assessment. Weight-loss was greater with CWP compared to UC (mean difference –12kg [95%CI –17, -7kg]; p &lt; 0.001). ACQ6 and AQLQ scores improved with CWP compared to UC (mean difference –0.7 [95%CI –1.4, 0.0], p = 0.048; mean difference 0.8 [95%CI 0.2, 1.3], p = 0.013 respectively) and a greater proportion of participants achieved MCID in ACQ6 with CWP and UC (53 vs 19%, p = 0.041) at 16-weeks.

Twenty-nine participants attended at 52-weeks with weight-loss sustained with CWP (median weight change –14kg [IQR –15, -9kg]) compared to UC (median 2kg [IQR –7, 8]; p = 0.015). The 53% achieving MCID in ACQ6 at 16-weeks sustained this at 52-weeks (compared to UC 25%, p = 0.101). A higher proportion of participants achieved MCID in AQLQ with CWP compared to UC (71 vs 6%, p &lt; 0.001), including AQLQ symptom domain (71 vs 31%; p = 0.024), activity domain (53 vs 19%; p = 0.041) and environmental domain (65 vs 19%; p = 0.008). Furthermore, CWP resulted in a reduction in number of prednisolone courses from 4 (IQR 2, 5) at baseline to 0 (0, 2) at 52-weeks (p&lt;0.001). 

Interpretations from this data are limited by considerable missing data, primarily because of the COVID-19 pandemic restrictions. No significant conclusions can therefore be drawn regarding effects of weight loss on lung function, markers of inflammation or activity levels. The study was underpowered at the one-year time-point limiting conclusions about effects of weight loss on asthma control and quality of life.

Additionally, we performed a retrospective analysis assessing the effects of obesity on type 2 biomarkers in mild (n = 51) and difficult-to-treat (n = 102) asthma from two datasets of recent in-house trials. We assessed body mass index (BMI) against fractional exhaled nitric oxide (FeNO) and peripheral eosinophil count. When stratified by BMI tertile, we observed reduced FeNO levels in the highest BMI tertile compared to the lowest (18 vs 25ppb respectively, p = 0.014) and, within the difficult-to-treat group only, reduced eosinophils in the highest BMI tertile compared to the lowest (0.2x109/L vs 0.3x109/L respectively; p = 0.020). Adjusted linear regression (corrected for age, sex, smoking status, atopic status, rhinitis and both inhaled and oral corticosteroid use) showed BMI was a predictor of FeNO (β= −2.848, p = 0.019). Interpretation of these results must be with caution as numerous limitations must be acknowledged including unequal weighting of groups, possible effects of both confounder and collider bias, and the retrospective nature of this study. A dedicated prospective trial is warranted based on these findings. 

Accelerometers have been validated against polysomnography to assess sleep metrics in general and asthma populations. We hypothesised that accelerometer-derived sleep parameters would differ between healthy BMI mild and obesity-associated difficult-to-treat asthma groups and conducted a retrospective analysis on overnight accelerometer data derived from two recent in-house trials. Participants in these trials wore accelerometer devices twentyfour hours a day for seven days. Data from 124 participants (80 difficult-to-treat, 24 mild asthma) showed broadly comparable results in sleep window time, sleep time, sleep efficiency and wake onset time with a clinically unclear difference of roughly forty minutes in median sleep onset time. Results were also similar to general population results from previous studies. This retrospective study also had unequal weighting of groups, lacked corroboration from sleep diaries or objective assessments of sleep quality or sleep-disordered breathing, limiting its clinical effectiveness.

In summary, effects of obesity on asthma are not fully understood, in particular with relevance to airway inflammation and type 2 biomarkers. Use of a total diet replacement weight management programme results in improved asthma control and quality of life in the short term with encouraging longer-term signals in asthma quality of life and frequency of exacerbation. Further research is needed to elucidate mechanisms underlying obesity-mediated asthma and to assess effects of this weight management programme on lung function and inflammation. A larger sample size is needed to definitively assess effects of the Counterweight Plus programme on asthma outcomes at one-year.