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.

Clinical Characteristics of Patients Undergoing Right Heart Catheterizations in Community Hospitals.

Background Recognition of precapillary pulmonary hypertension (PH) has significant implications for patient management. However, the low a priori chance to find this rare condition in community hospitals may create a barrier against performing a right heart catheterization (RHC). This could result in misclassification of PH and delayed diagnosis/treatment of precapillary PH. Therefore, we investigated patient characteristics and echocardiographic parameters associated with the decision whether to perform an RHC in patients with incident PH in 12 Dutch community hospitals. Methods and Results In total, 275 patients were included from the OPTICS (Optimizing PH Diagnostic Network in Community Hospitals) registry, a prospective cohort study with patients with incident PH; 157 patients were diagnosed with RHC (34 chronic thromboembolic PH, 38 pulmonary arterial hypertension, 81 postcapillary PH, 4 miscellaneous PH), while 118 patients were labeled as probable postcapillary PH without hemodynamic confirmation. Multivariable analysis showed that older age (>60 years), left ventricular diastolic dysfunction grade 2-3, left atrial dilatation were independently associated with the decision to not perform an RHC, while presence of prior venous thromboembolic events or pulmonary arterial hypertension-associated conditions, right atrial dilatation, and tricuspid regurgitation velocity ≥3.7 m/s favor an RHC performance. Conclusions Older age and echocardiographic parameters of left heart disease were independently associated with the decision to not perform an RHC, while presence of prior venous thromboembolic events or pulmonary arterial hypertension-associated conditions, right atrial dilation, and severe PH on echocardiography favored an RHC performance. As such, especially elderly patients may be at an increased risk of diagnostic delays and missed diagnoses of treatable precapillary PH, which could lead to a worse prognosis.

Real-World Effectiveness of Reslizumab in Patients With Severe Eosinophilic Asthma - First Initiators and Switchers.

BACKGROUND: Reslizumab, a biologic targeting IL-5, has been shown to reduce asthma exacerbations and maintenance oral corticosteroid use in randomized controlled trials and pre-post studies in patients with severe eosinophilic asthma. However, real-world effectiveness data of reslizumab are scarce, and it is unknown whether reslizumab has added value after switching from another type 2 biologic. OBJECTIVE: To evaluate (1) the real-world effectiveness of reslizumab on severe asthma exacerbations, maintenance oral corticosteroid use, and overall treatment response, both in biologic-naive patients who initiated reslizumab and in those who switched from another type 2 biologic; and (2) physicians' experience with reslizumab treatment. METHODS: This observational real-world study evaluated data from 134 adults with severe eosinophilic asthma included in the Dutch severe asthma registry (RAPSODI), who initiated reslizumab treatment (4-weekly infusions, 0.3 mg/kg) before April 2020 and had follow-up data for 6 months and greater. Clinical asthma experts completed surveys on their experience with reslizumab treatment. RESULTS: Overall, reslizumab reduced the exacerbation rate (odds ratio [95% CI] = 0.10 [0.05-0.21]; P < .001), oral corticosteroid use (OR [95% CI], 0.2 [0.0-0.5]; P < .001), and maintenance dose (median [CI], 5.0 [0.0-10.0] to 0.0 [0.0-5.0]; P < .001), with comparable results in biologic-naive reslizumab initiators and switchers. The overall response to reslizumab was graded good or excellent in 59.2% of patients. The additive effectiveness of reslizumab after switching from another biologic was reflected in physicians' surveys. CONCLUSIONS: Real-world data show that reslizumab reduces severe asthma exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma, both in biologic-naive reslizumab initiators and in those who switched from another type 2 biologic. This additional value of reslizumab was recognized by clinical asthma experts.

Manual vs. automated analysis of polysomnographic recordings in patients with chronic obstructive pulmonary disease.

PURPOSE: The sleep quality, as assessed by polysomnography (PSG), of patients with chronic obstructive pulmonary disease (COPD) can be severely disturbed. The manual analysis of PSGs is time-consuming, and computer systems have been developed to automatically analyze PSGs. Studies on the reliability of automated analyses in healthy subjects show varying results, and the purpose of this study was to assess whether automated analysis of PSG by one certain automatic system in patients with COPD provide accurate outcomes when compared to manual analysis. METHODS: In a retrospective study, the full-night polysomnographic recordings of patients with and without COPD were analyzed automatically by Matrix Sleep Analysis software and manually. The outcomes of manual and automated analyses in both groups were compared using Bland-Altman plots and Students' paired t tests. RESULTS: Fifty PSGs from patients with COPD and 57 PSGs from patients without COPD were included. In both study groups, agreement between manual and automated analysis was poor in nearly all sleep and respiratory parameters, like total sleep time, sleep efficiency, sleep latency, amount of rapid eye movement sleep and other sleep stages, number of arousals, apnea-hypopnea index, and desaturation index. CONCLUSION: Automated analysis of PSGs by the studied automated system in patients with COPD has poor agreement with manual analysis when looking at sleep and respiratory parameters and should, therefore, not replace the manual analysis of PSG recordings in patients with COPD.

Temazepam 10mg does not affect breathing and gas exchange in patients with severe normocapnic COPD.

BACKGROUND: Benzodiazepines can improve sleep quality, but are also thought to cause respiratory depression in patients with chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the effects of temazepam on indices of circadian respiratory function, dyspnea, sleep quality, and sleepiness in patients with severe COPD and insomnia. METHODS: In a double-blind, randomized, placebo-controlled, cross-over study in 14 stable patients with COPD (mean FEV(1) 0.99+/-0.3L) with insomnia, polysomnography with continuous transcutaneous capnography and oximetry, arterial gas sampling, hypercapnic ventilatory response, multiple sleep latency test, Epworth Sleepiness Scale, dyspnea and sleep visual analogue scales (VAS) were performed at baseline, after one week of temazepam 10mg at bedtime and after one week of placebo. RESULTS: Temazepam did not cause statistically significant changes in mean transcutaneous carbon dioxide tension during sleep compared to placebo (5.9+/-1.0 kPa vs. 6.3+/-1.4 kPa, p-value 0.27), nor in mean oxygen saturation (92+/-3% vs. 92+/-2%, p-value 0.31), nor in any of the other investigated variables, except for the total sleep time and sleep latency VAS, which improved with temazepam. CONCLUSIONS: One week usage of temazepam 10mg does not influence circadian respiratory function, dyspnea, and sleepiness in patients with stable, severe, normocapnic COPD and insomnia and it improves total sleep time and subjective sleep latency. However, this is a preliminary explorative study for assessing the feasibility to perform a larger study on this topic. The clinical implications of this study are very limited.

Respiratory muscle strength and muscle endurance are not affected by acute metabolic acidemia.

Respiratory muscle fatigue in asthma and chronic obstructive lung disease (COPD) contributes to respiratory failure with hypercapnia, and subsequent respiratory acidosis. Therapeutic induction of acute metabolic acidosis further increases the respiratory drive and, therefore, may diminish ventilatory failure and hypercapnia. On the other hand, it is known that acute metabolic acidosis can also negatively affect (respiratory) muscle function and, therefore, could lead to a deterioration of respiratory failure. Moreover, we reasoned that the impact of metabolic acidosis on respiratory muscle strength and respiratory muscle endurance could be more pronounced in COPD patients as compared to asthma patients and healthy subjects, due to already impaired respiratory muscle function. In this study, the effect of metabolic acidosis was studied on peripheral muscle strength, peripheral muscle endurance, airway resistance, and on arterial carbon dioxide tension (PaCO(2)). Acute metabolic acidosis was induced by administration of ammonium chloride (NH(4)Cl). The effect of metabolic acidosis was studied on inspiratory and expiratory muscle strength and on respiratory muscle endurance. Effects were studied in a randomized, placebo-controlled cross-over design in 15 healthy subjects (4 male; age 33.2 +/- 11.5 years; FEV(1) 108.3 +/- 16.2% predicted), 14 asthma patients (5 male; age 48.1 +/- 16.1 years; FEV(1) 101.6 +/- 15.3% predicted), and 15 moderate to severe COPD patients (9 male; age 62.8 +/- 6.8 years; FEV(1) 50.0 +/- 11.8% predicted). An acute metabolic acidemia of BE -3.1 mmol x L(-1) was induced. Acute metabolic acidemia did not significantly affect strength or endurance of respiratory and peripheral muscles, respectively. In all subjects airway resistance was significantly decreased after induction of metabolic acidemia (mean difference -0.1 kPa x sec x L(-1) [95%-CI: -0.1 - -0.02]. In COPD patients PaCO(2) was significantly lowered during metabolic acidemia (mean difference -1.73 mmHg [-3.0 - -0.08]. In healthy subjects and in asthma patients no such effect was found. Acute metabolic acidemia did not significantly decrease respiratory or peripheral muscle strength, respectively muscle endurance in nomal subjects, asthma, or COPD patients. Metabolic acidemia significantly decreased airway resistance in asthma and COPD patients, as well as in healthy subjects. Moreover, acute metabolic acidemia slightly improved blood gas values in COPD patients. The results suggest that stimulation of ventilation in respiratory failure, by induction of metabolic acidemia will not lead to deterioration of the respiratory failure.

Accuracy of transcutaneous carbon dioxide tension measurements during cardiopulmonary exercise testing.

BACKGROUND: Measurements of transcutaneous carbon dioxide tension (PtcCO(2)) with current devices are proven to provide clinically acceptable agreement with measurements of partial arterial carbon dioxide tension (PaCO(2)) in several settings but not during cardiopulmonary exercise testing (CPET). OBJECTIVES: The primary objective of this study was to investigate the agreement between PaCO(2) and PtcCO(2) measurements (using a Tosca 500 with a Tosca sensor 92) during CPET. A secondary objective was to investigate the agreement between arterial and transcutaneous oxygen saturation (SaO(2), SpO(2)) as measured with this sensor during CPET. METHODS: In patients with various pulmonary diseases, PtcCO(2) and SpO(2) were continuously measured and compared with arterial blood gas samples during CPET. A maximum bias of 0.5 kPa and 95% limits of agreement (LOA) of 1 kPa between carbon dioxide pressure (PCO(2)) measurements were determined as clinically acceptable. RESULTS: In total 101 'paired' arterial and transcutaneous measurements were obtained from 21 patients. Bias between PaCO(2) and PtcCO(2) was -0.03 kPa with LOA from -0.78 to 0.71 kPa. Bias between SaO(2) and SpO(2) was -1.0% with LOA from -2.83 to 0.83%. CONCLUSIONS: Transcutaneous estimations of PCO(2) and SpO(2) are accurate and can be used in CPET, circumvening the need for arterial cannulation.

Sleep, hypnotics and chronic obstructive pulmonary disease.

The quality of sleep is significantly compromised in many patients with chronic obstructive pulmonary disease (COPD) and may be further diminished when certain comorbidities are present. A reduced sleep quality is associated with daytime consequences like fatigue, psychiatric problems and an impaired quality of life. Sleep induces physiologic alterations in respiratory function, which can become pathologic and may provoke or worsen hypoxemia and hypercapnia in COPD. Dyspnea, cough and excessive mucus production should be optimised to minimise causes for sleep disturbance. Pharmacological therapy may be helpful; sedatives like benzodiazepines and non-benzodiazepine benzodiazepine-receptor agonists (NBBRAs) are (equally) effective in improving sleep quality. Whether or not these hypnotics produce serious adverse respiratory effects during sleep, remains unclear due to opposing studies. Therefore, their use should be as short as possible.

Extent of uncontrolled disease and associated medical costs in severe asthma--a PHARMO study.

OBJECTIVE: Asthma is a major public health problem with considerable economic impact. The highest costs being observed in patients with severe asthma. Furthermore, despite the use of recommended therapies, asthma control can still be poor. Therefore, the objective of this study was to assess the extent of uncontrolled disease and associated medical costs in severe asthma. METHODS: The PHARMO Record Linkage System includes among others drug dispensing and hospitalizations for > or = 2 million subjects in The Netherlands. Severe asthma patients used long-acting beta-agonists and inhaled corticosteroids for over 200 days and short-acting beta-agonists for at least 100 days in 2004. Severe uncontrolled asthma was defined as a hospitalization for asthma or use of multiple short courses of oral corticosteroids assessed in 2004. Reimbursed costs of asthma drugs and hospitalizations were calculated during this year. A matched nested-case control study was performed to identify treatment-related risk factors for uncontrolled disease. Information on clinical diagnosis of (severity of) asthma was not available. RESULTS: About 17% of patients with severe asthma aged 12-49 years (N = 1158) showed lack of control. Excess drug costs for severe uncontrolled asthma with hospitalization mounted up to 700 Euro per patient per year and 300 Euro per patient per year for patients without hospitalization. Including hospital admission costs, excess costs mounted up to over 10,000 Euro per patient per year. Lack of control did not seem to be caused by under-treatment. CONCLUSION: Poor control of severe asthma leads to disproportionately increased direct costs compared to severe controlled asthma, especially when hospital admission is required.

Survival of chronic hypercapnic COPD patients is predicted by smoking habits, comorbidity, and hypoxemia.

STUDY OBJECTIVES: Chronic hypercapnia in patients with COPD has been associated with a poor prognosis. We hypothesized that, within this group of chronic hypercapnic COPD patients, factors that could mediate this hypercapnia, such as decreased maximum inspiratory mouth pressure (P(I(max))), decreased maximum expiratory mouth pressure (P(E(max))), and low hypercapnic ventilatory response (HCVR), could be related to survival. Other parameters, such as arterial blood gas values, airway obstruction (FEV1), body mass index (BMI), current smoking status, and the presence of comorbidity were studied as well. METHODS: A cohort of 47 chronic hypercapnic COPD patients recruited for short-term trials (1 to 3 weeks) in our institute was followed up for 3.8 years on average. Survival was analyzed using a Cox proportional hazards model. The risk factors considered were analyzed, optimally adjusted for age and gender. RESULTS: At the time of analysis 18 patients (10 male) were deceased. After adjusting for age and gender, P(I(max)), P(E(max)), and HCVR were not correlated with survival within this hypercapnic group. Current smoking (hazard ratio [HR], 7.0; 95% confidence interval [CI], 1.4 to 35.3) and the presence of comorbidity (HR, 5.5; 95% CI, 1.7 to 18.7) were associated with increased mortality. A higher Pa(O2) affected survival positively (HR, 0.6 per 5 mm Hg; 95% CI, 0.4 to 1.0). Pa(CO2) tended to be lower in survivors, but this did not reach statistical significance (HR, 2.0 per 5 mm Hg; 95% CI, 0.9 to 4.3). FEV1 and BMI were not significantly related with survival in hypercapnic COPD patients. CONCLUSION: In patients with chronic hypercapnia, only smoking status, the presence of comorbidity, and Pa(O2) level are significantly associated with survival. Airway obstruction, age, and BMI are known to be predictors of survival in COPD patients in general. However, these parameters do not seem to significantly affect survival once chronic hypercapnia has developed.

Effects of acetazolamide and furosemide on ventilation and cerebral blood volume in normocapnic and hypercapnic patients with COPD.

STUDY OBJECTIVES: Effects of chronic metabolic alkalosis and acidosis and their relation to central chemoregulation may differ between normocapnic and chronic hypercapnic patients with COPD. The relationship between responses of inspired ventilation (VI), mouth occlusion pressure (P(0.1)), and cerebral blood volume (CBV), to short-term changes in arterial PCO(2) was measured. PATIENTS AND METHODS: Seventeen patients with chronic hypercapnia and COPD (PaCO(2) > 6.0 kPa) and 16 normocapnic patients with COPD (PaCO(2) < or = 6.0 kPa) [FEV(1) 27% predicted] were studied under baseline metabolic conditions and after 1 week of treatment with oral furosemide, 40 mg/d, or acetazolamide, 500 mg/d. Hypercapnia (change in end-tidal carbon dioxide > 1 kPa) was induced by administering adequate amounts of carbon dioxide in the inspired air. CBV was measured using near-infrared spectroscopy. RESULTS: Compared with baseline metabolic condition, chronic metabolic acidosis and alkalosis did not change ventilatory (Delta VI/Delta PaCO(2)) and cerebrovascular (Delta CBV/Delta PaCO(2)) reactivity. Base excess (BE) decreased by 6.8 +/- 1.1 mEq/L and 6.9 +/- 1.6 mEq/L, respectively, in the normocapnic and chronic hypercapnic COPD groups during metabolic acidosis, resulting in a not-quite-significant leftward shift of both the ventilatory and cerebrovascular carbon dioxide response curve. BE increased by 2.3 +/- 1.2 mEq/L and 1.2 +/- 1.3 mEq/L, respectively, during chronic metabolic alkalosis in both COPD groups, without concomitant shift. Poor correlations between ventilatory and cerebrovascular carbon dioxide responsiveness (Delta CBV/Delta PaCO(2) and Delta VI/Delta PaCO(2), Delta CBV/Delta PaCO(2) and Delta P(0.1)/Delta PaCO(2), respectively) were found irrespective of baseline, respiratory condition, and induced metabolic state. CONCLUSIONS: Normocapnic and chronic hypercapnic COPD patients have the same ventilatory and cerebrovascular carbon dioxide responsiveness irrespective of induced metabolic state.