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.

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.

Integrating healthcare for follow-up of adult COVID-19 patients in an outpatient clinic: A matter of cooperation.

RATIONALE AIMS AND OBJECTIVES: A large number of patients infected with SARS-CoV-2 (COVID-19) need outpatient follow-up after hospitalization. As these patients may experience a broad range of symptoms, as do patients infected with the related SARS-CoV-1 virus, we set up a multidisciplinary outpatient clinic involving pulmonologists, internists, and geriatricians. Patients were allocated to a specialist based on symptoms reported on a self-developed questionnaire of expected symptoms of COVID-19. This study aimed to evaluate the effectiveness of this outpatient clinic. METHODS: In this retrospective study, the medical records of patients who presented to the outpatient clinic for follow-up after hospitalization for COVID-19 up to 31 August 2020, were reviewed. RESULTS: In total, 266 patients were seen at the outpatient clinic at least once. Overall, 100 patients were seen by a pulmonologist, 97 by an internist, and 65 by a geriatrician. A referral between these 3 medical specialists was needed for only 14 patients (5.3%). Fifty patients were seen by a psychologist, mostly those with a HADS score >10. Only 5 (2.2%) of the 221 patients who were not directly referred to a psychologist based on triage needed psychological support. Forty-eight patients (18%) were also seen by a physiatrist. CONCLUSION: Identifying which medical specialist (pulmonologist, internist, and/or geriatrician) should see patients attending a post-COVID outpatient clinic based on patient-reported symptoms proved an effective approach to managing the flow of post-COVID patients.

The ADMIT series--Issues in Inhalation Therapy. 7. Ways to improve pharmacological management of COPD: the importance of inhaler choice and inhalation technique.

Since inhalation therapy will probably remain the preferred route of treatment for patients with chronic obstructive pulmonary disease (COPD), it is important to provide helpful information that may assist physicians and nurses in selecting the appropriate device(s) for individual patients as well as prescribing the correct medication. In line with the GOLD guidelines, the Aerosol Drug Management Improvement Team (ADMIT) propose a three-part "therapy adjustment strategy", which provides health care professionals with a way to monitor and check the delivery of inhaled medication. The strategy is a summation of the key principles behind the evidence-based management of stable COPD and exacerbations. It offers physicians a rapid and user-friendly overview of the requirements of COPD management starting with making the diagnosis and continuing with optimisation of therapy in follow-up appointments. It includes everything from check lists for disease assessment and recommendations for reducing risk factors to selecting the proper inhalers and continuous checking of compliance and correct inhaler technique. These practical COPD therapy adjustment algorithms have been used as part of an interactive online course developed by the ADMIT group (www.admit-online.info). The COPD "flash" video available at this web site offers suggestions on how to organise a complete doctor-patient consultation.

The ADMIT series--issues in inhalation therapy. 2. Improving technique and clinical effectiveness.

Aerosol inhalation is considered the optimal route for administering the majority of drugs for the treatment of obstructive airways diseases. A number of Pressurised Metered-Dose and Dry Powder Inhalers are available for this purpose. However, inhalation of therapeutic aerosols is not without difficulty; it requires precise instructions on the inhalation manoeuvre, which is different from spontaneous normal breathing. Also, the characteristics of the inhaler device have to be suitable for the user. Available data indicate a frequent lack of knowledge demonstrated by health professionals and patients on the inhalation manoeuvre and handling of inhalers, resulting in a reduction of therapeutic benefit. This paper reviews the literature concerning the fundamental aspects of inhaler devices, inhalation manoeuvre and device selection, in an attempt to increase the knowledge of, and to optimise the clinical use of, therapeutic inhalers.

Bronchial challenge, assessed with forced expiratory manoeuvres and airway impedance.

OBJECTIVE: The Methacholine concentration at which a 20% decrease of the forced expiratory volume in 1s (PC20_FEV1) or a 40% increase in airway resistance (PC40_Rrs6) occur are accepted indicators for airway hyperresponsiveness. We hypothesised that the level of detection of bronchial hyperresponsiveness will differ between the two methods. METHODS: The response to Methacholine was assessed by forced oscillation technique (FOT) and spirometry in 20 stable hyperresponsive asthmatics. The effects of repeated lung function measurements on respiratory muscle fatigue were measured from maximal inspiratory mouth pressure (MIP). After each dose, patients scored their perception of dyspnoea on a BORG scale. Differences in patient's burden were measured by comparing the BORG-score at PC40_Rrs6 (BORG-PC40_Rrs6) and at PC20_FEV1 (BORG-PC20_FEV1). Reproducibility was also evaluated. RESULTS: The PC20_FEV1-values were 2.2 (0.4) doubling dose higher as compared to the PC40_Rrs6 (P<0.001). The mean BORG-score at PC40_Rrs6 was 1.7 points lower as compared to the BORG-score at PC20_FEV1 (P<0.001). The difference (mean(sd)) between the PC20_FEV1 of measurement 1 and 2 was -0.1 (1.4) doubling dose, and -0.3 (2.7) doubling dose for PC40_Rrs6. The MIP after Methacholine provocation was 1.0(0.2) kPa lower as compared to the MIP before the challenge test (P<0.001), suggesting respiratory muscle fatigue. CONCLUSION: Measuring PC40_Rrs6 shortens the challenge test and lowers the concentrations of bronchoconstrictor agents as compared to measurements of PC20_FEV1. The FOT-method was less strenuous for patients. In spite of the fact that the reproducibility is two-fold worse than measuring PC20_FEV1, it still remains quite acceptable at a mean of 0.3 doubling dose. The respiratory muscle strength was deteriorated after the challenge test.

Salbutamol pMDI gives less protection to methacholine induced airway obstruction than salbutamol via spacer or DPI.

BACKGROUND: Inhalation device and inhalation technique influence the deposition of drug in the lung. This study evaluated the efficacy of salbutamol as a bronchoprotective agent administered via Diskus, Turbuhaler, pMDI or pMDI + Volumatic against methacholine-induced bronchoconstriction. METHODS: Twenty stable asthmatics participated in this open randomised comparison of the protective effects of 200 microg salbutamol, administered via the various inhalation devices on methacholine-induced airway obstruction, with respect to pulmonary function and dyspnoea sensation. The inhalation technique was controlled by measuring the peak inspiratory flow (and actuation time, in the case of pMDI and Volumatic) through the device, during inhalation. RESULTS: Inhalation of salbutamol increased the provocative dose of methacholine by 1.2 doubling doses (dd) for pMDI, 1.9 dd for Diskus, 2.3 dd for Turbuhaler and 2.5 dd for Volumatic. Salbutamol via pMDI provided less protection from methacholine-induced airway obstruction than did salbutamol administered via Diskus, Turbuhaler or Volumatic (P<0.05). The inadequate pMDI use of 70% of our patients might contribute to a lower deposition of drug in the central airways, resulting in the lower protective effect. However, the PC20_FEV1 of the adequate- and inadequate pMDI users showed no significant difference. CONCLUSION: Salbutamol administered via pMDI gave less protection from methacholine-induced bronchoconstriction than did salbutamol via Diskus, Turbuhaler or Volumatic. This study suggests that the pMDI may be less suitable for protecting a patient against bronchoconstriction due to airway hyperresponsiveness.

The course of inhalation profiles during an exacerbation of obstructive lung disease.

BACKGROUND: Acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are associated with increased airflow Limitation, hyperinflation and respiratory muscle fatigue. It is unclear, whether patients are able to perform adequate inhalations through various inhalation devices with different orfices during an exacerbation. The aim of this study was to examine the evolution of inhalation profiles of patients inhaling through Diskus, Turbuhaler, pressurized metered dose inhaler (pMDI) and Volumatic and consequently the appropriateness of using the various devices during an exacerbation. MEASUREMENTS: 15 hospitalized patients participated in this randomized comparison of inhalation profiles through the four placebo-devices. For each device, triplicate inhalation profiles were recorded during day 1-9 of admission and in stable phase (day 50). RESULTS: The mean percentage of patients performing optimum inhalation profiles was 100% for Diskus, 60% for Turbuhaler, 14% for pMDI and 87% for Volumatic over the interval of day 1-9 and day 50. Patients with an inspiratory muscle strength (MIP) of less than 6kPa were generally unable to generate the optimum flow through the Turbuhaler (>60 l/min). CONCLUSION: The Diskus and Volumatic can be used effectively in the acute phase of an exacerbation of asthma or COPD. The Turbuhaler could be optimally used after the fifth day of convalescence. The pMDI is rather unsuitable during an exacerbation.

Does the inhalation device affect the bronchodilatory dose response curve of salbutamol in asthma and chronic obstructive pulmonary disease patients?

OBJECTIVE: This open randomized study examined differences between the effects of an equal dose of salbutamol administered via the Diskus, Turbuhaler, and pMDI plus Volumatic. Measurements included dose response curves, dynamic and static lung volumes, respiratory muscle strength, and systemic effects. METHODS: The cumulative dose-response study compared the biological effects (pulmonary function, respiratory muscle function, systemic effects) of an equal dose of salbutamol delivered via four different devices in 23 patients with asthma and 21 patients with moderate or severe chronic obstructive pulmonary disease (COPD). RESULTS: Salbutamol via Volumatic showed significantly better bronchodilation than via pMDI or Turbuhaler in both patient groups. No significant difference was found between salbutamol via Volumatic and Diskus. However, the advantage of Volumatic is of marginal clinical relevance since the additional bronchodilation was a maximum of 140 ml FEV(1) and did not exceed the minimal patient-perceivable improvement. In the asthma group a more evident plasma K(+) decrease was found after salbutamol delivered via pMDI and pMDI plus Volumatic. Furthermore, especially in the COPD patients a significant decrease was observed in hyperinflation and consequently an improvement in maximal inspiratory pressure as a result of salbutamol via all devices. CONCLUSIONS: Bronchodilation by salbutamol was slightly more effective via Volumatic than via pMDI or Turbuhaler. No significant difference in bronchodilation was found between salbutamol via Volumatic and Diskus. The advantage of Volumatic is not of clinical relevance.

Inhalation profiles in asthmatics and COPD patients: reproducibility and effect of instruction.

Turbuhaler and Salbutamol-Diskus produce therapeutic doses at peak inspiratory flow (PIF) of >30 L/min. However, the optimum flow for Fluticasone-Diskus and Turbuhaler, in terms of total emitted dose and fine particle mass, is >60 L/min. The Turbuhaler achieved a higher output at this flow, as compared to Diskus. For pMDI 25 < PIF < 90 L/min, an actuation time of 0.0-0.2 sec is optimal. The aim of this study was to examine the incidence of optimum inhalation profiles, the effect of instruction, reproducibility, and the relationship between inhalation profiles and patient characteristics in stable asthmatics and mild/moderate/severe COPD patients. For each device, triplicate inhalation profiles were recorded during 6 sessions in a 10-week period. All patients achieved PIF > 30 L/min using Diskus. After instruction, all Diskus inhalations were performed with >60 L/min, except 7% of the inhalations of the severe COPD patients. At least 95% of the Turbuhaler inhalations was also performed with the minimum flow; however, 19% of the inhalations of the severe COPD patients were not optimally performed. The hand-lung coordination was inadequate in 40% of pMDI inhalation profiles, and 80% was performed with a too high flow. The reproducibility of PIF of both dry powder inhalers (DPIs) was very high (coefficient of variation = 4-10%). The reproducibility of the pMDI variables was lower (coefficient of variation = 9-18%). The major lung function variables predictive for PIF(diskus) and PIF(turbuhaler) were maximal inspiratory mouth pressure (MIP), PIF, and inspiratory capacity. No significant predictive lung function variables for PIF(pMDI) were found. Most patients performed reproducible optimum inhalation profiles through Diskus and Turbuhaler. However, in the severe COPD group, 7-19% of the patients were not able to generate the optimum flows through the DPIs. For these patients, a flow-independent aerosol delivery system might be more suitable. The majority of patients were using the pMDI incorrectly. Instruction had no effect. So, we concluded that the pMDI should not be used in these patient groups because of the coordination problems.

In Check Dial: accuracy for Diskus and Turbuhaler.

OBJECTIVE: The In Check Dial was developed to evaluate whether a patient is able to generate an adequate peak inspiratory flow (PIF) through a certain inhalation device. The inhalation profile recorder (IPR) is a calibrated instrument that measures flows through Diskus and Turbuhaler in our research setting. The aim of this study was to compare the PIFs of patients when inhaling through a Diskus or Turbuhaler connected with the IPR (PIF_diskus and PIF_TH) to the flows through the corresponding orifices of the In Check Dial (Diskus_In Check and TH_In Check). METHODS: Twenty-four stable asthma and twenty-one chronic obstructive pulmonary disease (COPD) patients inhaled, on two separate occasions, in randomised order, via the Diskus or Turbuhaler connected with the IPR. Subsequently, patients inhaled through the In Check Dial using the orifices of Diskus or Turbuhaler. RESULTS: The difference between Diskus_In Check and PIF_diskus was 3.9 (11.9)l/min (P=0.038). The difference between TH_In Check and PIF_TH was 3.5 (10.6) l/min (NS). All Diskus- and Turbuhaler-inhalations were performed with the minimum required flow of 30 l/min. However, four COPD patients inhaled with the non-optimal flow (<60 l/min) through the Turbuhaler. The In Check Dial did not indicate two of them. CONCLUSION: Measuring PIF through Diskus and Turbuhaler using the IPR and the In Check Dial, respectively shows a disagreement of 3.9l/min. A disagreement of 3.5l/min was found for the Turbuhaler. The In Check Dial did not identify two of four patients as 'non-optimal' users.