Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context. MATERIAL AND METHODS: This is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes. RESULTS: At baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (ß = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%. CONCLUSIONS: Work productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study.

Quality over quantity; eosinophil activation status will deepen the insight into eosinophilic diseases.

Eosinophil associated diseases have gained much attention recently because of the introduction of specific eosinophil targeted therapies. These diseases range from acute parasitic infections to chronic inflammatory diseases such as eosinophilic asthma. In eosinophilic asthma an increased eosinophil cell count in peripheral blood is the gold standard for determination of the pheno-/endotype and severity of disease. Despite a broad consensus there is concern on validity of this simple measurement, because the eosinophil compartment is far from homogenous. Multiple tissues harbour non-activated cells under homeostatic conditions and other tissues, normally devoid of eosinophils, become infested with these cells under inflammatory conditions. It will, therefore, be clear that eosinophils become differentially (pre)-activated at different tissue sites in homeostatic and inflammatory conditions. This complexity should be investigated in detail as it is 1) far from clear what the long-term side effects are that are caused by application of eosinophil targeted therapies in a "one size fits all" concept and 2) real-world data of eosinophil targeted therapies in asthma shows a broad variety in the treatment response. This review will focus on complex mechanisms of eosinophil activation in vivo to create a better view on the dynamics of the eosinophil compartment in health and disease both to prevent collateral damage caused by aberrant activation of eosinophils ánd to improve effectiveness of eosinophil targeted treatments.

Diagnosing eosinophilic asthma using a multivariate prediction model based on blood granulocyte responsiveness.

BACKGROUND: The identification of inflammatory asthma phenotypes, using sputum analysis, has proven its value in diagnosis and disease monitoring. However due to technical limitations of sputum analysis, there is a strong need for fast and noninvasive diagnostics. This study included the activation state of eosinophils and neutrophils in peripheral blood to phenotype and monitor asthma. OBJECTIVES: To (i) construct a multivariable model using the activation state of blood granulocytes, (ii) compare its diagnostic value with sputum eosinophilia as gold standard and (iii) validate the model in an independent patient cohort. METHODS: Clinical parameters, activation of blood granulocytes and sputum characteristics were assessed in 115 adult patients with asthma (training cohort/Utrecht) and 34 patients (validation cohort/Oxford). RESULTS: The combination of blood eosinophil count, fractional exhaled nitric oxide, Asthma Control Questionnaire, medication use, nasal polyposis, aspirin sensitivity and neutrophil/eosinophil responsiveness upon stimulation with formyl-methionyl-leucyl phenylalanine was found to identify sputum eosinophilia with 90.5% sensitivity and 91.5% specificity in the training cohort and with 77% sensitivity and 71% specificity in the validation cohort (relatively high percentage on oral corticosteroids [OCS]). CONCLUSIONS: The proposed prediction model identifies eosinophilic asthma without the need for sputum induction. The model forms a noninvasive and externally validated test to assess eosinophilic asthma in patients not on OCS.

Similar activation state of neutrophils in sputum of asthma patients irrespective of sputum eosinophilia.

Inflammatory phenotypes of asthma are associated with differences in disease characteristics. It is unknown whether these inflammatory phenotypes are reflected by the activation status of neutrophils in blood and sputum. We obtained peripheral blood and induced sputum from 21 asthma patients and stratified our samples based on sputum eosinophilia resulting in two groups (>3% eosinophils: n = 13, <3%: n = 8). Eosinophils and neutrophils from blood and sputum were analysed for expression of activation and degranulation markers by flow cytometry. Data were analysed by both classical, non-parametric statistics and a multi-dimensional approach, using principal component analysis (PCA). Patients with sputum eosinophilia were characterized by increased asthma control questionnaire (ACQ) scores and blood eosinophil counts. Both sputum neutrophils and eosinophils displayed an activated and degranulated phenotype compared to cells obtained from blood. Specifically, degranulation of all granule types was detected in sputum cells, combined with an increased expression of the activation markers (activated) Mac-1 (CD11b), programmed death ligand 1 (PD-L1) (CD274) and a decreased expression of CD62L. CD69 expression was only increased on sputum eosinophils. Surface marker expression of neutrophils was similar in the presence or absence of eosinophilia, either by single or multi-dimensional analysis. Sputum neutrophils were highly activated and degranulated irrespective of sputum eosinophilia. Therefore, we conclude that differences in granulocyte activation in sputum and/or blood are not associated with clinical differences in the two groups of asthma patients. The finding of PD-L1 expression on sputum granulocytes suggests an immunomodulatory role of these cells in the tissue.

What goes up must come down: biomarkers and novel biologicals in severe asthma.

Asthma is a heterogeneous airway disease characterized by typical symptoms in combination with variable airway obstruction. Most patients with asthma have well controlled symptoms and a low risk of asthma attacks with inhaled corticosteroid (ICS) treatment. However, a clinically important subgroup (~ 10%) remains symptomatic and/or at risk of asthma attacks despite maximum inhaled therapy. Patients with severe asthma are responsible for a significant proportion of healthcare costs attributable to asthma and have a large unmet need for better treatments. An important advance in recent years has been the recognition that severe asthma is heterogeneous with respect to clinical problems and the pattern of lower airway inflammation. Identification of eosinophilic inflammation in the airways has become an important priority as novel biologicals that target Th2 cytokines, such as anti-IL5, anti-IL-13 and combined anti-IL-4/13 are showing considerable promise as treatments for this subgroup. It has also become clear that anti-IgE (Omalizumab), the first monoclonal antibody registered for treatment of severe asthma, is only active in patients with active eosinophilic airway inflammation. The future will be identification of potentially responsive patients on the basis of raised biomarkers and, as suggested by the title of this review, targeted treatment with specific cytokine blockade that has a direct effect on the biomarkers. In this review, we outline an approach to the clinical assessment of patients potentially suitable for biological treatment and describe in detail the likely clinical impact of established and new biological treatments.

Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy.

BACKGROUND: Postoperative pain is one of the main reasons for a prolonged hospital stay after laparoscopic cholecystectomy (LC). Reduced postoperative pain might result in faster recovery and establish LC as a day-care surgical procedure. Peroperative local anaesthesia has been suggested to reduce postoperative pain. The aim of this study was to determine the effect of combined subcutaneous infiltration and intraperitoneal instillation of levobupivacaine before the start of LC on postoperative abdominal pain up to 24 h after surgery. METHODS: Patients eligible for elective LC were randomized to receive preincisional infiltration and preoperative intraperitoneal instillation of 80 ml of either 0·125 per cent levobupivacaine (experimental group) or normal saline (placebo group). The primary outcome measure was abdominal pain estimated by means of a visual analogue scale at 0·5, 2, 4, 8 and 24 h after surgery. RESULTS: Eighty of the 101 patients assessed for eligibility were randomized. There was no significant reduction in postoperative abdominal pain with levobupivacaine compared with placebo during the 24-h follow-up; the overall difference in pain score was 2·2 (95 per cent confidence interval - 4·9 to 9·3; P = 0·540). The duration of operation, use of anaesthesia, use of rescue analgesia, shoulder pain, duration of hospital stay and time to resumption of normal daily activities did not differ between the two groups. CONCLUSION: Combined subcutaneous and intraperitoneal administration of levobupivacaine did not influence postoperative abdominal pain after LC. REGISTRATION NUMBER: NCT01199406 (http://www.clinicaltrials.gov).