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.

Associations between bone attenuation and prevalent vertebral fractures on chest CT scans differ with vertebral fracture locations.

Vertebral fracture (VF) locations are bimodally distributed in the spine. The association between VF and bone attenuation (BA) measured on chest CT scans varied according to the location of VFs, indicating that other factors than only BA play a role in the bimodal distribution of VFs. INTRODUCTION: Vertebral fractures (VFs) are associated with low bone mineral density but are not equally distributed throughout the spine and occur most commonly at T7-T8 and T11-T12 ("cVFs") and less commonly at T4-T6 and T9-T10 ("lcVF"). We aimed to determine whether associations between bone attenuation (BA) and VFs vary between subjects with cVFs only, with lcVFs only and with both cVFs and lcVFs. METHODS: Chest CT images of T4-T12 in 1237 smokers with and without COPD were analysed for prevalent VFs according to the method described by Genant (11,133 vertebrae). BA (expressed in Hounsfield units) was measured in all non-fractured vertebrae (available for 10,489 vertebrae). Linear regression was used to compare mean BA, and logistic regression was used to estimate the association of BA with prevalent VFs (adjusted for age and sex). RESULTS: On vertebral level, the proportion of cVFs was significantly higher than of lcVF (5.6% vs 2.0%). Compared to subjects without VFs, BA was 15% lower in subjects with cVFs (p < 0.0001), 25% lower in subjects with lcVFs (p < 0.0001) and lowest in subjects with cVFs and lcVFs (- 32%, p < 0.0001). The highest ORs for presence of VFs per - 1SD BA per vertebra were found in subjects with both cVFs and lcVFs (3.8 to 4.6). CONCLUSIONS: The association between VFs and BA differed according to VF location. ORs increased from subjects with cVFs to subjects with lcVFs and were highest in subjects with cVFs and lcVFs, indicating that other factors than only BA play a role in the bimodal VF distribution. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00292552.

Association between vertebral fractures and coronary artery calcification in current and former smokers in the ECLIPSE cohort.

In smokers and former smokers from the ECLIPSE cohort, there is an association between prevalent vertebral fractures (VFs) and coronary artery calcification (CAC). Chest CT scans provide the opportunity to evaluate VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions. INTRODUCTION: Prevalence of VFs among smokers and patients with chronic obstructive pulmonary disease (COPD) is high, and an association between CAC and osteoporosis has been described. We investigated the associations between VFs and CAC (expressed in Agatston score) in (former) smokers. METHODS: Current and former smokers from the ECLIPSE study (designed to determine underlying COPD progression mechanisms) were studied. Baseline Agatston score (zero (0), medium (1-400), or high (> 400)), baseline bone attenuation (BA), and prevalent and incident VFs (vertebrae T1-L1) were assessed on CT. RESULTS: A total of 586 subjects were included (mean age 59.8 ± 8.3; 62.3% men; 70.1% with COPD; 21.0% with prevalent VFs; 196 with zero, 266 with medium, and 124 with high Agatston score). Of these, 23.4% suffered incident VFs within 3 years. In multivariate models, prevalent VFs were associated with medium (1.83 [95% CI 1.01-3.30]) and with high (OR = 3.06 [1.45-6.47]) Agatston score. After adjustment for BA, prevalent VFs were still associated with high (OR = 2.47 [1.13-5.40]), but not significantly with medium Agatston score (OR = 1.57 [0.85-2.88]). Similarly, after adjustment for BA, high (OR = 2.06 [1.02-4.13]) but not medium Agatston score (OR = 1.61 [0.88-2.94]) was associated with prevalent VFs. Agatston score at baseline was not associated with short-term VF incidence. CONCLUSION: In (former) smokers, there was an association between prevalent VFs and Agatston score. Chest CT scans provide the opportunity to also evaluate for VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions.

Vertebral bone attenuation in Hounsfield Units and prevalent vertebral fractures are associated with the short-term risk of vertebral fractures in current and ex-smokers with and without COPD: a 3-year chest CT follow-up study.

CT scans performed to evaluate chronic obstructive pulmonary disease (COPD) also enable evaluation of bone attenuation (BA; a measure of bone density) and vertebral fractures (VFs). In 1239 current/former smokers with (n = 999) and without (n = 240) COPD, the combination of BA and prevalent VFs was associated with the incident VF risk. INTRODUCTION: Chest CT scans are increasingly used to evaluate pulmonary diseases, including COPD. COPD patients have increased risk of osteoporosis and VFs. BA on CT scans is correlated with bone mineral density and prevalent VFs. The aim of this study was to evaluate the association between BA and prevalent VFs on chest CT scans, and the risk of incident VFs in current and former smokers with and without COPD. METHODS: In participants of the ECLIPSE study with baseline and 1-year and 3-year follow-up CT scans, we evaluated BA in vertebrae T4-T12 and prevalent and incident VFs. RESULTS: A total of 1239 subjects were included (mean age 61.3 ± 8.0, 61.1% men, 999 (80.6%) COPD patients). The mean BA was 155.6 ± 47.5 Hounsfield Units (HU); 253 (20.5%) had a prevalent VF and 296 (23.9%) sustained an incident VF within 3 years. BA and prevalent VFs were associated with incident VFs within 1 (per - 1SD HR = 1.38 [1.08-1.76] and HR = 3.97 [2.65-5.93] resp.) and 3 years (per - 1SD HR = 1.25 [1.08-1.45] and HR = 3.10 [2.41-3.99] resp.), while age, sex, body mass index (BMI), smoking status and history, or presence of COPD was not. In subjects without prevalent VFs and BA, and for 1-year incidence, BMI values were associated with incident fractures (1 year, BA per - 1SD HR = 1.52 [1.05-2.19], BMI per SD HR = 1.54 [1.13-2.11]; 3 years, per - 1SD HR = 1.37 [1.12-1.68]). CONCLUSIONS: On CT scans performed for pulmonary evaluation in (former) smokers with and without COPD, the combination of BA and prevalent VFs was strongly associated with the short-term risk of incident VFs.

Diagnosis of vertebral deformities on chest CT and DXA compared to routine lateral thoracic spine X-ray.

X-ray, CT and DXA enable diagnosis of vertebral deformities. For this study, level of agreement of vertebral deformity diagnosis was analysed. We showed that especially on subject level, these imaging techniques could be used for opportunistic screening of vertebral deformities in COPD patients. INTRODUCTION: X-ray and CT are frequently used for pulmonary evaluation in patients with chronic obstructive pulmonary disease (COPD) and also enable to diagnose vertebral deformities together with dual-energy X-ray absorptiometry (DXA) imaging. The aim of this research was to study the level of agreement of these imaging modalities for diagnosis of vertebral deformities from T4 to L1. METHODS: Eighty-seven subjects (mean age of 65; 50 males; 57 COPD patients) who had X-ray, chest CT (CCT) and DXA were included. Evaluable vertebrae were scored twice using SpineAnalyzer™ software. ICCs and kappas were calculated to examine intra-observer variability. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUROC) were calculated to compare vertebral deformities diagnosed on the different imaging modalities. RESULTS: ICCs for height measurements were excellent (> 0.94). Kappas were good to excellent (0.64-0.77). At vertebral level, the AUROC was 0.85 for CCT vs. X-ray, 0.74 for DXA vs. X-ray and 0.77 for DXA vs. CCT. Sensitivity (51%-73%) and PPV (57%-70%) were fair to good; specificity and NPV were excellent (≥ 96%). At subject level, the AUROC values were comparable. CONCLUSIONS: Reproducibility of height measurements of vertebrae is excellent with all three imaging modalities. On subject level, diagnostic performance of CT (PPV 79-82%; NPV 90-93%), and to a slightly lesser extend of DXA (PPV 73-77%; NPV 80-89%), indicates that these imaging techniques could be used for opportunistic screening of vertebral deformities in COPD patients.

Interprofessional Pulmocheck care pathway: An innovative approach to managing pediatric asthma care in the Netherlands.

OBJECTIVES: Under-diagnosis and suboptimal asthma control in children persists. An innovative care pathway was developed by a hospital department of pediatrics with the aim to detect pulmonary problems in children and provide appropriate treatment possibilities through systematic feedback towards the referring primary care physician. Primary care physicians can use this pathway to refer children with asthma-like symptoms for a one-day assessment. Goals are to measure the usage of the pathway by primary care general practitioners (GPs), the outcomes in terms of new diagnoses of asthma, the reduction in regular referrals, generated recommendations/therapy and the adequacy of asthma follow-up. METHODS: We collected all feedback letters sent to the GP concerning children who underwent the Pulmocheck in 2010, 2011 and 2012. Furthermore, all GPs, who had referred a child to the Pulmocheck in this period and that subsequently was diagnosed with asthma and was further managed in primary care, were sent a follow-up questionnaire in 2014. RESULTS: There were 121 referrals from 51 GPs in 3 years to this pathway. In 59.5% of these referrals a new diagnosis of asthma was established. In 90.9% one or more changes in clinical management were advised. The response rate to the follow-up questionnaires was 65.7% of which 4.8% of the children with new established asthma were reviewed four times or more in the follow-up period, 17.4% two times, 65.2% once, and in 8.7% were not followed. CONCLUSIONS: The specialty pediatric asthma care pathway revealed a high number of children with newly diagnosed asthma, but was also helpful to exclude this diagnosis. However, the referral rate of GPs to this pathway was low, but in the children, that were referred several changes in the clinical management were advised and the frequency of monitoring of the children with diagnosed asthma was not in accordance with the asthma guidelines.

Current status of research on osteoporosis in COPD: a systematic review.

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of osteoporosis. However, the prevalence, correlates and effectiveness of treatment of osteoporosis in COPD patients remain unclear. We performed a systematic review of the literature to answer three questions. 1) What is the prevalence of osteoporosis in COPD? 2) What are identified correlates of osteoporosis in COPD? 3) What are the effects of treatment of osteoporosis in COPD? A computerised literature search in MEDLINE/PubMed and the Cochrane database was carried out. In addition, reference lists were searched by hand and authors were contacted if necessary. The prevalence of osteoporosis and osteopenia varied 9-69% and 27-67%, respectively. Prevalence of osteoporosis was generally higher than in healthy subjects and some other chronic lung diseases. Correlates of osteoporosis in COPD are mainly measures of body composition, disease severity and the use of corticosteroids, although causality has not been proven. Effects of treatment of osteoporosis have not been investigated in samples consisting of COPD patients only. Longitudinal follow-up to assess determinants of osteoporosis in COPD and randomised placebo-controlled trials on the effects of treatment of osteoporosis in patients with COPD only are warranted.

Overtreatment with inhaled corticosteroids and diagnostic problems in primary care patients, an exploratory study.

BACKGROUND: Underdiagnosis and undertreatment of patients with asthma or chronic obstructive pulmonary disease are widely discussed in the literature. Not much is known about the possible overdiagnosis and consequently the overtreatment with inhaled corticosteroids (ICS). Aim. This study investigates how often ICS are prescribed without a proper indication and how big the diagnostic problem is caused by inappropriate prescription and use of ICS. METHODS: All patients referred to a primary care diagnostic centre during 6 months who used ICS without a clear indication were included. Their GPs were questioned about the reasons for prescribing ICS. If still no diagnosis could be assessed, GPs were advised to stop ICS and renew spirometry after a steroid-free period of at least 3 months. After 1 year, the use of ICS was evaluated and the diagnoses were reassessed. RESULTS: Of all referred patients (2271), 1171 used ICS, 505 (30%) without a clear indication. After 1 year, final results showed that 11% of all patients originally using ICS had no indication to use ICS and had successfully ceased using this mediation. For 15%, the reasons for using ICS remained unclear. CONCLUSIONS: Overtreatment with ICS in primary care seems to be considerable, which falsely labels patients as asthmatic and which generates unnecessary costs and possible side effects. The awareness of GPs of the need for proper diagnostic testing before prescribing ICS needs to be improved. Overtreatment with ICS in primary care patients can be diminished by systematically supporting the GP in the diagnostic procedures and decision making.

COPD in cancer patients: higher prevalence in the elderly, a different treatment strategy in case of primary tumours above the diaphragm, and a worse overall survival in the elderly patient.

The purpose of this study was to document the influence of chronic obstructive pulmonary diseases (COPD) on stage at diagnosis, treatment strategy, and survival for unselected cancer patients (35 years and older) diagnosed between 1995 and 2004 in the Eindhoven Cancer Registry. Follow-up of all patients was complete up to January 1st, 2006. Twelve percent of all cancer patients had COPD at the time of cancer diagnosis, being about 15% in elderly patients (65+) and up to 30% among lung cancer patients, middle-aged males and all females with oesophageal and laryngeal cancer, and middle-aged women with renal cancer. Stage at diagnoses was not significantly different between cancer patients with or without COPD, except for lung cancer patients who were diagnosed at an earlier stage. Nevertheless, non-small cell lung cancer (NSCLC) patients with COPD less frequently underwent surgery, and chemotherapy, and more often radiotherapy. In the presence of COPD, women with oesophageal cancer underwent surgery less often, and patients with laryngeal cancer received radiotherapy more often. The effect of COPD on the type of oncological treatment was not different for middle-aged (35-64 years) and elderly cancer patients. In a multivariate Cox-regression model, COPD was associated with a significantly worse survival, especially for elderly patients with colon, rectum, larynx, prostate or urinary bladder cancer. In conclusion, not surprisingly, COPD is related with age and smoking-associated tumours. Therapy of cancer patients with COPD was different for head and neck tumours and primary tumours in the chest organs (above the diaphragm), for whom radiotherapy, as an alternative treatment option, was available. As COPD, especially at older age, is frequently associated with a worse prognosis, further prospective investigation of interactions seems warranted. Further, closer involvement of pulmonologists and COPD nurses in elderly cancer patients might be warranted.

Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer.

BACKGROUND: With the rising mean age, more patients will be diagnosed with one or more other serious diseases at the time of lung cancer diagnosis. Little is known about the best way to treat elderly patients with comorbidity or the outcome of treatment. This study was undertaken to evaluate the independent effects of age and comorbidity on treatment and prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: All patients with NSCLC diagnosed between 1995 and 1999 in the southern part of the Netherlands (n = 4072) were included. RESULTS: The proportion of patients with localised NSCLC who underwent surgery was 92% in patients younger than 60 years and 9% in those aged 80 years or older. In patients aged 60-79 years this proportion also decreased with comorbidity. In patients with non-localised NSCLC the proportion receiving chemotherapy was considerably higher for those aged less than 60 years (24%) than in those aged 80 or older (2%). The number of comorbid conditions had no significant influence on the treatment chosen for patients with non-localised disease. Multivariable survival analyses showed that age, tumour size, and treatment were independent prognostic factors for patients with localised disease, and stage of disease and treatment for those with non-localised disease. Comorbidity had no independent prognostic effect. CONCLUSIONS: It is questionable whether the less aggressive treatment of elderly patients with NSCLC is justified.

Effects of inhaled corticosteroids with different lung deposition on exhaled hydrogen peroxide in stable COPD patients.

BACKGROUND: The effects of inhaled corticosteroids (ICS) on markers of oxidative stress in patients with stable COPD are unclear. OBJECTIVES: The aim was to investigate the effect of ICS on exhaled H(2)O(2) in stable COPD patients and to compare ICS with different lung deposition. METHODS: Forty-one stable patients with moderate COPD (FEV(1) approximately 60% predicted) were randomized to sequence 1; first HFA-134a beclomethasone dipropionate (HFA-BDP, an ICS with more peripheral deposition) 400 microg b.i.d., then fluticasone propionate (FP, an ICS with more central deposition) 375 microg b.i.d. (n = 20) or sequence 2; first FP, then HFA-BDP (n = 21). Both 4-week treatment periods were preceded by a 4-week washout period. After each period, the concentration of H(2)O(2) in exhaled breath condensate was measured. RESULTS: The H(2)O(2) concentration decreased significantly after the first treatment period in both sequence 1 and 2 (p < 0.05, p = 0.01, respectively). In neither sequence was there a return to baseline values after the second washout, indicating a carry-over effect. The concentrations remained low in both sequences during the second treatment period. CONCLUSIONS: Both ICS appeared to reduce exhaled H(2)O(2) in stable COPD patients. However, this study showed no difference between ICS with different deposition patterns, which in part may be due to the carry-over effect.

Variability of exhaled hydrogen peroxide in stable COPD patients and matched healthy controls.

BACKGROUND: Because inflammation induces oxidative stress, exhaled hydrogen peroxide (H(2)O(2)), which is a marker of oxidative stress, may be used as a non-invasive marker of airway inflammation in chronic obstructive pulmonary disease (COPD). There are no data on the circadian variability of exhaled H(2)O(2) in COPD patients. OBJECTIVE: The aim of this study was to investigate the variability of the H(2)O(2) concentration in breath condensate of stable COPD patients and of matched healthy control subjects. METHODS: We included 20 patients with stable mild COPD (forced expiratory volume in 1 s approximately 70% of predicted) and 20 healthy subjects, matched for age, sex and pack-years, all smokers or ex-smokers. Breath condensate was collected and its H(2)O(2) concentration determined fluorometrically three times on day 0 (9 and 12 a.m., and 3 p.m.) and once on days 1, 2, 3, 8 and 21. RESULTS: The mean H(2)O(2) concentration increased significantly during the day in both the patient and control groups (p = 0.02 and p < 0.01, respectively). Over a longer period up to 21 days, the mean concentration did not change in both groups. There was no significant difference between patients and controls. The mean coefficient of variation over 21 days was 45% in the patient group and 43% in the control group (p = 0.8). CONCLUSIONS: The exhaled H(2)O(2) concentration increased significantly during the day in both stable COPD patients and controls. Over a period of 3 weeks, the mean H(2)O(2) concentration did not change and the variability within the subjects was similar in both groups.

An efficient and reproducible method for measuring hydrogen peroxide in exhaled breath condensate.

We investigated the sensitivity and reproducibility of a test procedure for measuring hydrogen peroxide (H202) in exhaled breath condensate and the effect of storage of the condensate on the H2O2 concentration, and compared the results to previous studies. Twenty stable COPD patients breathed into our collecting device twice for a period of 10 min. The total exhaled air volume (EAV) and condensate volume were measured both times and the H2O2 concentration of the condensate was determined fluorimetrically. The concentration was measured again after freezing the reaction product at -70 degrees C for a period of 10, 20 and 40 days. We collected 2-5 ml condensate in 10 min. The EAV and condensate volumes were strongly correlated. There was no significant difference between the mean H2O2 concentration of the first and second test. We obtained a detect on limit for the H2O2 concentration of 0.02 micromoll(-1). The H2O2 concentration appeared to remain stable for a period up to 40 days of freezing. Compared to previous studies we developed a more efficient breath condensate collecting device and obtained a lower H2O2 detection limit. The measurement of exhaled H2O2 was reproducible. In addition, storage of the samples up to 40 days showed no changes in H2O2 concentration.