Long-Term Weight Changes After Starting Anti-IL-5/5Ra Biologics in Severe Asthma: The Role of Oral Corticosteroids.

BACKGROUND: Many patients with severe asthma are overweight or obese, often attributed to unintentional weight gain as a side effect of oral corticosteroids (OCSs). Anti-IL-5/5Ra biologics significantly reduce OCS use, but their long-term effects on weight are unknown. OBJECTIVES: To examine (1) weight change up to 2 years after anti-IL-5/5Ra initiation in subgroups on the basis of maintenance OCS use at start of treatment and (2) whether cumulative OCS exposure before or changes in OCS exposure during treatment are related to weight change. METHODS: Real-world data on weight and cumulative OCS dose from adults included in the Dutch Registry of Adult Patients with Severe asthma for Optimal DIsease management before and at least 2 years after starting anti-IL-5/5Ra were analyzed using linear mixed models and linear regression analyses. RESULTS: For the included 389 patients (55% female; mean body mass index, 28 ± 5 kg/m2; 58% maintenance OCS), mean weight decreased -0.27 kg/y (95% CI, -0.51 to -0.03; P = .03), with more weight loss in patients with maintenance OCS use than in those without maintenance OCS use (-0.87 kg/y [95% CI, -1.21 to -0.52; P < .001] vs +0.54 kg/y [0.26 to 0.82; P < .001]). Greater weight loss at 2 years was associated with higher cumulative OCS dose in the 2 years before anti-IL-5/5Ra initiation (ß = -0.24 kg/g; 95% CI, -0.38 to -0.10; P < .001) and, independently, greater reduction in cumulative OCS dose during follow-up (ß = 0.27 kg/g; 95% CI, 0.11 to 0.43; P < .001). CONCLUSIONS: Anti-IL-5/5Ra therapy is associated with long-term weight reduction, especially in patients with higher OCS exposure before treatment and those able to reduce OCS use during treatment. However, the effect is small and does not apply to all patients, and so additional interventions seem necessary if weight change is desired.

Real-World Effectiveness of IL-5/5Ra Targeted Biologics in Severe Eosinophilic Asthma With Comorbid Bronchiectasis.

BACKGROUND: Bronchiectasis is a common comorbidity in patients with asthma and is associated with increased disease severity. In patients with severe eosinophilic asthma, biologics targeting IL-5/5Ra have beneficial effects on oral corticosteroid (OCS) use and exacerbation frequency. However, how coexisting bronchiectasis affects the response to such treatments is unknown. OBJECTIVE: To evaluate the real-world effectiveness of anti-IL-5/5Ra therapy in patients with severe eosinophilic asthma and comorbid bronchiectasis on exacerbation frequency and daily maintenance and cumulative OCS dose. METHODS: This real-world study evaluated data from 97 adults with severe eosinophilic asthma and computed tomography-confirmed bronchiectasis from the Dutch Severe Asthma Registry, who initiated anti-IL5/5Ra biologics (mepolizumab, reslizumab, and benralizumab) and had follow-up data for 12 months or greater. The analysis was performed for the total population and subgroups with or without maintenance OCS use. RESULTS: Anti-IL-5/5Ra therapy significantly reduced exacerbation frequency in patients with maintenance OCS use as well as in those without it. In the year before biologic initiation, 74.5% of all patients had two or more exacerbations, which decreased to 22.1% in the follow-up year (P < .001). The proportion of patients on maintenance OCS decreased from 47% to 30% (P < .001), and in the OCS-dependent patients (n = 45) maintenance OCS dose decreased from median (interquartile range) of 10.0 mg/d (5-15 mg/d) to 2.5 mg/d (0-5 mg/d) after 1 year (P < .001). CONCLUSIONS: This real-world study shows that anti-IL-5/5Ra therapy reduces exacerbation frequency and daily maintenance as well as the cumulative OCS dose in patients with severe eosinophilic asthma and comorbid bronchiectasis. Although it is an exclusion criterion in phase 3 trials, comorbid bronchiectasis should not preclude anti-IL-5/5Ra therapy in patients with severe eosinophilic asthma.

Effect of bariatric surgery on lung function and asthma control after 8 years of follow-up.

Background: Bariatric surgery has a proven beneficial effect on asthma symptoms and lung function in patients with class III obesity and asthma. The effects of bariatric surgery on asthma control and small airway function persist for at least 12 months after bariatric surgery. However, long-term follow-up data are lacking. Objectives: To evaluate the very-long term effects of bariatric surgery on asthma symptoms and lung function. Methods: In a prospective, longitudinal follow-up study, we planned an 8-year follow-up visit for patients previously included in the OBAS 1.0 trial, which evaluated the effects of bariatric surgery on asthma control and lung function in patients with asthma and class III obesity in The Netherlands. Results: Fifteen of 78 patients from the OBAS trial completed the 8-year follow-up visit. Nine patients underwent bariatric surgery, and six patients did not. After 8 years of follow-up, asthma control (Asthma Control Questionnaire [ACQ] score at 12 months of 0,4 versus an ACQ score of 0.7 at 8 years of follow-up; p = 0.075) and small airway function (R5-R20 (frequency-dependent resistance at 5Hz-20Hz); score at 12 months of 0,25 versus an ACQ score of 0.07 at 8 years of follow-up; p = 0.345) remained clinically stable compared with 12 months of follow-up. Patients who underwent bariatric surgery had a statistically significant weight regain between 12 months of follow-up and 8 years of follow-up (median [interquartile range] body mass index 30.2 kg/m² [23.9-43.4 kg/m²] versus 32.3 kg/m² [24.0-36.4 kg/m²]; p = 0.025). However, the impact of weight regain on asthma control, and asthma quality of life was clinically insignificant (ACQ, ß (regression coefficient) = 0.04; 95% Confidence Interval [0.02; 0.06]; p < 0.001; and AQLQ; ß = -0.04 CI [-0.07; -0.009]; p = 0.013). Conclusion: These results emphasize the importance of bariatric surgery in treating obesity-related asthma.

Procalcitonin-Guided Antibiotic Prescription in Patients With COVID-19: A Multicenter Observational Cohort Study.

BACKGROUND: Despite the low rate of bacterial coinfection, antibiotics are very commonly prescribed in hospitalized patients with COVID-19. RESEARCH QUESTION: Does the use of a procalcitonin (PCT)-guided antibiotic protocol safely reduce the use of antibiotics in patients with a COVID-19 infection? STUDY DESIGN AND METHODS: In this multicenter cohort, three groups of patients with COVID-19 were compared in terms of antibiotic consumption, namely one group treated based on a PCT-algorithm in one hospital (n = 216) and two control groups, consisting of patients from the same hospital (n = 57) and of patients from three similar hospitals (n = 486) without PCT measurements during the same period. The primary end point was antibiotic prescription in the first week of admission. RESULTS: Antibiotic prescription during the first 7 days was 26.8% in the PCT group, 43.9% in the non-PCT group in the same hospital, and 44.7% in the non-PCT group in other hospitals. Patients in the PCT group had lower odds of receiving antibiotics in the first 7 days of admission (OR, 0.33; 95% CI, 0.16-0.66 compared with the same hospital; OR, 0.42; 95% CI, 0.28-0.62 compared with the other hospitals). The proportion of patients receiving antibiotic prescription during the total admission was 35.2%, 43.9%, and 54.5%, respectively. The PCT group had lower odds of receiving antibiotics during the total admission only when compared with the other hospitals (OR, 0.23; 95% CI, 0.08-0.63). There were no significant differences in other secondary end points, except for readmission in the PCT group vs the other hospitals group. INTERPRETATION: PCT-guided antibiotic prescription reduces antibiotic prescription rates in hospitalized patients with COVID-19, without major safety concerns.

Association between elevated serum triglycerides and asthma in patients with obesity: An explorative study.

Background: Adults with a high body mass index (BMI) have an increased risk of developing asthma. To explore the impact of increased lipids on the presence of asthma, this study investigated the relationship between lipid levels and inflammatory markers in patients with asthma and controls with obesity. Objective: We hypothesized that higher lipid levels are more prevalent in patients with obesity and asthma. Methods: In this explorative cohort study, 96 patients with asthma and 45 controls were included. All the patients participated in one of three asthma studies; two of these studies included only patients with obesity. An asthma diagnosis was defined by the presence of typical clinical symptoms, reversible airway obstruction (+12% improvement in forced expiratory volume in the first second of expiration after bronchodilator), or bronchial hyperreactivity (Histamine PC20 < 8 mg/mL), or a fractional exhaled nitric oxide of > 50 ppb. We compared lipid levels and neutrophils and eosinophils in patients with asthma and the controls with a wide BMI range (17.8-63.8 kg/m²). Multivariable logistic regression was used to analyze the data. Results: Serum triglycerides were statistically significantly higher in patients with obesity and asthma adjusted for BMI, blood eosinophils, and statin use (odds ratio [OR] 2.56 [95% confidence interval, 1.34-4.88]; p = 0.004). Inclusion or exclusion of those who used long-acting ß2-agonists and inhaled corticosteroids led to comparable adjusted ORs for blood triglyceride and blood eosinophils levels. Conclusion: Elevated serum triglycerides were associated with the presence of asthma in patients with obesity. This indicated that elevated triglycerides might be a yet unrecognized trait that contributed to the development of asthma. The precise cause and effect of these high triglyceride levels in the patients with asthma and with obesity were not determined in this study.Clinical trial Trial registration NCT03278561, www.clinicaltrials.gov; NL4262, NL3056, trialregister.nl.

Short-term and long-term effect of a high-intensity pulmonary rehabilitation programme in obese patients with asthma: a randomised controlled trial.

OBJECTIVE: To determine the short-term and long-term effects of a high intensity pulmonary rehabilitation programme on asthma control, body composition, lung function and exercise capacity in obese asthma patients. METHODS: Patients with obesity (body mass index (BMI)≥30 kg·m-2) and suboptimal controlled asthma (Asthma Control Questionnaire (ACQ)≥0.75) were randomly assigned to a 3-month pulmonary rehabilitation programme (PR only), pulmonary rehabilitation programme with the use of an internet based self-management support programme (PR+SMS) or usual care. The pulmonary rehabilitation programme included high-intensity interval training, nutritional intervention and psychological group sessions. Patients in the usual care group were advised to lose weight and to exercise. The primary outcome was the difference of change of ACQ between PR only and PR+SMS after 3 months. Total follow-up was 12 months. RESULTS: 34 patients were included in the study (14 PR only, nine PR+SMS, 11 control). Compared with patients in usual care, patients in the PR only group had a significant reduction in BMI and significant improvements in asthma control, exercise capacity and aerobic capacity after 3 months. These improvements persisted during 12 months of follow-up. No difference in ACQ between PR+SMS and PR only groups was observed. However, users of the SMS programme had a significantly lower BMI after 12 months compared with subjects in the PR only group. CONCLUSION: A high-intensity pulmonary rehabilitation programme provides sustained improvements in asthma control, body composition and exercise capacity in obese asthmatics that are not optimally controlled and, therefore, should be considered in the treatment of these patients.

Prediction of Airflow Obstruction and the Risk of Complications in Morbidly Obese Patients Undergoing Bariatric Surgery.

Morbidly obese subjects with airflow obstruction who underwent laparoscopic bariatric surgery appear to have the greatest risk to develop complications. In a retrospective cohort study, we identified a waist circumference ≥ 120 cm, smoking history ≥5PY and history of obstructive lung disease as statistically significant predictors of airflow obstruction. The resulting algorithm, aimed to identify subjects with airflow obstruction before bariatric surgery, was validated in a prospective study. The algorithm was found to be effective in identifying patients with low risk of airflow obstruction (negative predictive value 94.7%). Airflow obstruction, however, was not associated with post-operative complications as we expected. In contrast, inspiratory capacity and the Epworth Sleepiness scale were more promising predictors for post-operative complications in subjects undergoing bariatric surgery.

Discrepancies Between BMI and Classic Cardiovascular Risk Factors.

BACKGROUND: Obesity is related to increased cardiovascular risk. It is unknown whether increasing levels of obesity also increase levels of cardiovascular risk factors and systemic inflammation. This study describes the relationship between classic cardiovascular risk factors and inflammatory markers with BMI in a group of obese and non-obese subjects. MATERIALS AND METHODS: Obese subjects (BMI ≥ 30 kg/m2; n = 576; mean ± SD BMI 43.8 ± 7.58 kg/m2) scheduled for bariatric surgery were included. The reference population consisted of non-obese volunteers (BMI < 30 kg/m2; n = 377, BMI 25.0 ± 2.81 kg/m2). The relationship between BMI quintiles and the levels of cardiovascular risk factors was analyzed. Adipose tissue volumetry was performed in 42 obese subjects using abdominal CT scans. RESULTS: The obese group included more women and subjects with type 2 diabetes mellitus, hypertension, and current smoking behavior. In obese subjects, HDL-C and triglycerides decreased with increasing BMI. Systolic and diastolic blood pressure, total cholesterol, LDL-C, and apoB were not related to BMI in the obese group, in contrast to the non-obese group. Inflammatory markers CRP, leukocyte count, and serum complement C3 increased with increasing BMI in the obese group, while these relations were less clear in the non-obese group. The subcutaneous adipose tissue surface was positively correlated to BMI, while no correlation was observed between BMI and visceral adipose tissue. CONCLUSIONS: Markers of inflammation are strongest related to BMI in obese subjects, most likely due to increased adipose tissue mass, while cardiovascular risk factors do not seem to deteriorate above a certain BMI level. Limited expansion capacity of visceral adipose tissue may explain these findings.

Pre-surgical Pulmonary Rehabilitation in Asthma Patients Undergoing Bariatric Surgery.

This pilot study was performed to investigate the feasibility of pre-surgical pulmonary rehabilitation (PR) in morbidly obese patients with uncontrolled asthma, undergoing bariatric surgery. Four morbidly obese female patients with asthma participated in a 12-week PR program (exercise, diet, and psychological intervention) before undergoing bariatric surgery, and the outcomes were compared to a matched group of seven female controls (bariatric surgery only). In patients who participated in PR, asthma control and asthma quality of life improved dramatically after 3 months of PR. Besides, asthma control was better at the moment of surgery. The results of this pilot study show that PR is feasible in morbidly obese asthmatics and should be considered for a selected group of patients with uncontrolled asthma before undergoing bariatric surgery.

Effect of an Outpatient Pulmonary Rehabilitation Program on Exercise Tolerance and Asthma Control in Obese Asthma Patients.

PURPOSE: To compare the effects of an outpatient pulmonary rehabilitation (PR) program on exercise tolerance and asthma control in obese and nonobese patients with asthma. METHODS: Nonobese (body mass index [BMI] <30 kg/m) and obese (BMI ≥ 30 kg/m) patients with asthma who participated in a local multidisciplinary 12-week PR program were analyzed retrospectively. Effects of PR were assessed by changes in 6-minute walking distance (6MWD) and Asthma Control Questionnaire (ACQ). RESULTS: A total of 138 asthma patients were included: 53 (38.4%) obese and 85 (61.6%) nonobese. At baseline, obese patients with asthma had a lower level of exercise tolerance reflected by a lower 6MWD (525 m vs 621 m; P < .001). After PR, the 6MWD improved significantly in both groups (≥50 m in nonobese vs ≥45 m in obese; P < .001 in both groups). The improvement in 6MWD was clinically relevant in 71% of the nonobese and 60% of the obese patients. These patients had lower 6MWD (P = .024), higher usage of long-acting ß-agonist (P = .034) and oral corticosteroids (P = .033). Asthma control also improved in both groups (ΔACQ -0.3 in nonobese vs ΔACQ -0.4 in obese; P = .021 and P = .019, respectively). Clinically relevant improvement was achieved by 46.5% of nonobese and 51.9% of obese patients with asthma. The improvements between the groups were not statistically different. CONCLUSIONS: A standardized PR program is feasible in obese patients with asthma and they benefit as much as nonobese patients with asthma. However, there are still a large number of patients who show no clinically significant improvement. Patients with more severe asthma seem to benefit the most from PR.

Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma.

BACKGROUND: The pathogenesis of asthma in obese subjects is poorly understood and has been described as a specific phenotype in these patients. Weight loss improves asthma control and lung function. Whether this improvement is the result of better mechanical properties of the airways or decreased systemic and bronchial inflammation remains unclear. METHODS: A longitudinal study in obese patients with asthma (bariatric surgery and asthma group (BS+A), n=27) and obese control (bariatric surgery without asthma group (BS-A), n=39) subjects undergoing bariatric surgery, and obese patients with asthma without intervention (no bariatric surgery and asthma group (NBS+A), n=12). Lung function, asthma control, cellular infiltrates in bronchial biopsies and circulating markers of systemic inflammation were measured during follow up at 3, 6 and 12 months. RESULTS: Bariatric surgery resulted in a profound weight loss at 12 months. In the BS+A group as well as the BS-A group FEV1, functional residual capacity, total lung capacity improved, whereas FEV1/FVC only improved in the BS-A group. In addition, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire, inhaled corticosteroid use and PD20 improved in BS+A, whereas in the NBS+A group only ACQ improved. Small airway function R5-R20 improved in both surgery groups, however the change in the BS+A group was greater, resulting in a comparable R5-R20 between BS+A and BS-A at 12-month follow-up. Besides improvement of systemic inflammation (high sensitivity C-reactive protein, adiponectin and leptin) after BS, only a decrease in mast cell numbers was detectable in the BS+A group. CONCLUSIONS: Bariatric surgery improved small airway function, decreased systemic inflammation and number of mast cells in the airways. These effects could explain the improvement of asthma control, quality of life and lung function. Therefore bariatric surgery, in addition to all other positive effects, also improves asthma in subjects with morbid obesity. TRIAL REGISTRATION NUMBER: 3204.

Underdiagnosis and overdiagnosis of asthma in the morbidly obese.

BACKGROUND: The prevalence of obesity and asthma has increased concurrently over the last decades, suggesting a link between obesity and asthma. However, asthma might not be adequately diagnosed in this population. AIM: To investigate whether not only overdiagnosis but also underdiagnosis of asthma is present in an obese population. METHODS: Morbidly obese subjects with or without physician-diagnosed asthma were recruited from a pre-operative screening programme for bariatric surgery, and were characterized using an extensive diagnostic algorithm. RESULTS: 473 subjects were screened; 220 met inclusion criteria, and 86 agreed to participate. Among the 32 participating subjects who had a physician diagnosis of asthma, reversible airway obstruction and/or bronchial hyperresponsiveness could only be detected in 19 patients (59%, 95% CI [0.41-0.76]), whereas in 13 patients (41%, 95% CI [0.24-0.50]) the diagnosis of asthma could not be confirmed (overdiagnosis). In contrast, in the remaining 54 patients, 17 (31%, 95% CI [0.20-0.46]) were newly diagnosed with asthma (underdiagnosis). CONCLUSION: Besides overdiagnosis, there is also substantial underdiagnosis of asthma in the morbidly obese. Symptoms could be incorrectly ascribed to either obesity or asthma, and therefore also in the morbidly obese the diagnosis of asthma should also be based on pulmonary function testing.

Systemic inflammation and lung function impairment in morbidly obese subjects with the metabolic syndrome.

BACKGROUND: Obesity and asthma are associated. There is a relationship between lung function impairment and the metabolic syndrome. Whether this relationship also exists in the morbidly obese patients is still unknown. Hypothesis. Low-grade systemic inflammation associated with the metabolic syndrome causes inflammation in the lungs and, hence, lung function impairment. METHODS: This is cross-sectional study of morbidly obese patients undergoing preoperative screening for bariatric surgery. Metabolic syndrome was assessed according to the revised NCEP-ATP III criteria. RESULTS: A total of 452 patients were included. Patients with the metabolic syndrome (n = 293) had significantly higher blood monocyte (mean 5.3 versus 4.9, P = 0.044) and eosinophil percentages (median 1.0 versus 0.8, P = 0.002), while the total leukocyte count did not differ between the groups. The FEV1/FVC ratio was significantly lower in patients with the metabolic syndrome (76.7% versus 78.2%, P = 0.032). Blood eosinophils were associated with FEV1/FVC ratio (adj. B -0.113, P = 0.018). CONCLUSION: Although the difference in FEV1/FVC ratio between the groups is relatively small, in this cross-sectional study, and its clinical relevance may be limited, these data indicate that the presence of the metabolic syndrome may influence lung function impairment, through the induction of relative eosinophilia.

Pulmonary function testing and complications of laparoscopic bariatric surgery.

BACKGROUND: Obesity is associated with respiratory symptoms and impaired pulmonary function, which could increase the risk of complications after bariatric surgery. The purpose of this study is to assess the relationship between pulmonary function parameters before, and the risk of complications after, laparoscopic bariatric surgery. METHODS: This prospective study included patients (age 18-60, BMI >35 kg/m2), who were eligible for bariatric surgery. Spirometry was performed in all patients. Complications up to 30 days after bariatric surgery were recorded. RESULTS: Four hundred eighty-five patients were included (304 laparoscopic sleeve gastrectomy, 181 laparoscopic gastric bypass). There were 53 complications (8 pulmonary, 27 surgical, 14 infectious, 4 other) in 50 patients (10%). There were 35 re-admissions (7.2%), and 17 re-laparoscopies (3.5%). Subjects with and without complications did not differ significantly with respect to demographics, weight, BMI, abdominal circumference or fat percentage. Subjects with complications had a significantly lower mean FEV1 (mean 86.9% predicted) and FVC (95.6% predicted) compared to patients without complications (95.9% predicted, p = 0.005, and 100.1% predicted, p = 0.045, respectively). After adjustment for age, gender, BMI, and smoking, abnormal spirometry value remained the single predictive covariable of postoperative complications: FEV1/FVC <70% adjusted OR 3.1 (95% CI 1.4-6.8, p = 0.006) and ΔFEV1 ≥12 % adjusted OR 2.9 (95% CI 1.3-6.6, p = 0.010). CONCLUSIONS: The risk of pulmonary complications after laparoscopic bariatric surgery is low. However, subjects with abnormal spirometry test results have a threefold risk of complications after laparoscopic bariatric surgery. Preoperative pulmonary function testing might be useful to predict the risk of complications of laparoscopic bariatric surgery.

Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype.

Obesity is associated with local T-cell abnormalities in adipose tissue. Systemic obesity-related abnormalities in the peripheral blood T-cell compartment are not well defined. In this study, we investigated the peripheral blood T-cell compartment of morbidly obese and lean subjects. We determined all major T-cell subpopulations via six-color flow cytometry, including CD8+ and CD4+ T cells, CD4+ T-helper (Th) subpopulations, and natural CD4+CD25+FoxP3+ T-regulatory (Treg) cells. Moreover, molecular analyses to assess thymic output, T-cell proliferation (T-cell receptor excision circle analysis), and T-cell receptor-ß (TCRB) repertoire (GeneScan analysis) were performed. In addition, we determined plasma levels of proinflammatory cytokines and cytokines associated with Th subpopulations and T-cell proliferation. Morbidly obese subjects had a selective increase in peripheral blood CD4+ naive, memory, natural CD4+CD25+FoxP3+ Treg, and Th2 T cells, whereas CD8+ T cells were normal. CD4+ and CD8+ T-cell proliferation was increased, whereas the TCRB repertoire was not significantly altered. Plasma levels of cytokines CCL5 and IL-7 were elevated. CD4+ T-cell numbers correlated positively with fasting insulin levels. The peripheral blood T-cell compartment of morbidly obese subjects is characterized by increased homeostatic T-cell proliferation to which cytokines IL-7 and CCL5, among others, might contribute. This is associated with increased CD4+ T cells, with skewing toward a Treg- and Th2-dominated phenotype, suggesting a more anti-inflammatory set point.