Hendrika Boezen

Severe exacerbations predict excess lung function decline in asthma

Severe asthma exacerbations are periods of intense airway inflammation that have been hypothesised to contribute to structural changes in the airways. If so, accelerated lung function decline over time should be more prevalent in adult patients with asthma who have frequent exacerbations than those without, but to date this has not been demonstrated. A cohort study was performed in order to investigate the effect of severe exacerbations on the progression of airway obstruction in 93 nonsmoking asthmatics with moderate-to-severe disease prior to treatment with inhaled corticosteroids. Subjects were followed for ≥5 yrs (median follow-up 11 yrs). In total, 56 (60.2%) subjects experienced at least one severe exacerbation (median rate 0.10·yr−1). Oral corticosteroid use and more severe airway obstruction at baseline were associated with a higher exacerbation rate. Independent of these variables, asthma patients with frequent exacerbations had a significantly larger annual decline in forced expiratory volume in one second (FEV1; median difference (95% confidence interval) 16.9 (1.5–32.2) mL·yr−1). Exacerbation rate significantly predicted an excess decline in FEV1, such that one severe exacerbation per year was associated with a 30.2 mL greater annual decline in FEV1. These data support the hypothesis that exacerbations, indicating intermittent periods of worsening airway inflammation, are associated with excess lung function decline in asthma.

Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma

Background Asthma is a genetically complex disease characterized by respiratory symptoms, intermittent airway obstruction and airway hyper‐responsiveness due to airway inflammation and remodelling. The ADAM33 gene is associated with asthma and airway hyper‐responsiveness and is postulated as a gene for airway remodelling.

Childhood factors associated with asthma remission after 30 year follow up

Background: Factors contributing to either “complete” or “clinical” remission of asthma are important to know since there is no cure for the disease. Methods: A cohort of 119 allergic asthmatic children was examined three times with a mean follow up of 30 years. They were aged 5–14 years at visit 1 (1966–9), 21–33 years at visit 2 (1983–6), and 32–42 years at visit 3 (1995–6). Complete remission of asthma at visit 3 was defined as no asthma symptoms, no use of inhaled corticosteroids, normal lung function (FEV1 >90% predicted), and no bronchial hyperresponsiveness (PC10 >16 mg/ml). Clinical remission was defined as no asthma symptoms and no use of inhaled corticosteroids. Results: 22% of the group was in complete remission of asthma at visit 3 and a further 30% was in clinical remission (total 52%); 57% of subjects in clinical remission had bronchial hyperresponsiveness and/or a low lung function. Logistic regression analyses showed that a higher FEV1 in childhood and more improvement in FEV1 from age 5–14 to 21–33 were associated with both complete and clinical asthma remission at age 32–42. Conclusions: Complete remission of asthma was present in a small subset of asthmatics while half the subjects showed clinical remission. Both complete and clinical remission were associated with a higher lung function level in childhood and a higher subsequent increase in FEV1. These results support the view that defining remission only on the basis of symptoms and medication use will overlook subjects with subclinical active disease and possibly associated airway remodelling.

Distribution of peak expiratory flow variability by age, gender and smoking habits in a random population sample aged 20-70 yrs

Peak expiratory flow (PEF) variability can be considered as an index of bronchial lability. Population studies on PEF variability are few. The purpose of the current paper is to describe the distribution of PEF variability in a random population sample of adults with a wide age range (20-70 yrs), and to assess relationships to age, gender and smoking habits. PEF data were collected in 511 participants of the Dutch part of the European Community Respiratory Health Survey. A training effect was found, absolute PEF values on the first measurement day being significantly lower. Females had greater PEF variability (adjusted for age, height and pack-years) and lower absolute PEFs than males. The mean within-day variation (amplitude % mean) was 3.66% (SD 2.03%), whereas the mean day-to-day variation was relatively small: 0.08% (SD 1.53%). Absolute PEFs were lower and amplitude % mean were significantly higher in older age groups. Smoking was significantly associated with lower mean PEFs and greater amplitude % mean. We observed lower mean values of the amplitude % mean than other investigators, possibly related to lower frequency of PEF recording (twice daily). We conclude that PEF and PEF variability have a normal or log-normal distribution. When studying PEF variability, age, gender and smoking habits should be taken into account.

Early development of the metabolic syndrome after chemotherapy for testicular cancer

BACKGROUND The metabolic syndrome (MS) might increase the risk of cardiovascular disease in testicular cancer (TC) survivors. We investigated its prevalence, development, vascular implications, and the role of gonadal function. METHODS TC survivors treated with chemotherapy and follow-up ≥3 years (N = 370, study I) were retrospectively evaluated for the development of cardiovascular risk factors. A subgroup followed 3-20 years (N = 173, study II) was compared with controls (N = 1085) for MS prevalence and evaluated for vascular function. RESULTS In TC survivors (study I), 24% developed overweight, 24% hypercholesterolemia, and 30% hypertension, after median follow-up of 1.7, 0.9, and 5.1 years, respectively. At the median follow-up of 5 years (study II), 25% of survivors have the MS {odds ratio (OR) 2.2, [95% confidence interval (CI) 1.5-3.3] compared with controls}. Survivors with MS have features of inflammation and prothrombotic state, increased carotid artery intima-media thickness. Survivors with testosterone levels <15 nmol/l (22%) have an increased risk of the MS (OR 4.1, 95% CI 1.8-9.3). CONCLUSIONS The current data suggest that the MS occurs at earlier age in TC survivors treated with chemotherapy compared with controls and is accompanied by early signs of atherosclerosis. As low testosterone may have a causal role, it is a target for interventions.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma

Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co‐morbidity between these conditions.

First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial

The purpose of our study was to compare progression-free survival and quality of life (QOL) after cisplatin–gemcitabine (CG) or epirubicin–gemcitabine (EG) in chemotherapy-naive patients with unresectable non-small-cell lung cancer. Patients (n=240) were randomised to receive gemcitabine 1125 mg m−2 (days 1 and 8) plus either cisplatin 80 mg m−2 (day 2) or epirubicin 100 mg m−2 (day 1) every 3 weeks for a maximum of five cycles. Eligible patients had normal organ functions and Eastern Cooperative Oncology Group performance status ⩽2. QOL was measured with European Organisation for Research and Treatment of Cancer QLQ-C30 and LC13 questionnaires. There were no significant differences in median progression-free survival (CG 26 weeks, EG 23 weeks), median overall survival (CG 43 weeks, EG 36 weeks), or tumour response rates (CG 46%, EG 36%). Toxicity was mainly haematologic. In the EG arm granulocytopenia occurred more frequently, leading to more febrile neutropenia. Also, elevation of serum transaminases, mucositis, fever, and decline in LVEF were more common in the EG arm. In the CG arm, more patients experienced elevated serum creatinine levels, sensory neuropathy, nausea, and vomiting. Global QOL was not different in both arms. Progression-free survival, overall survival, response rate, and QOL were not different between both arms; however, overall toxicity was more severe in the EG arm.

Relation between respiratory symptoms, pulmonary function and peak flow variability in adults.

BACKGROUND--A study was carried out to determine whether subjects with respiratory symptoms are more likely to have impaired lung function or increased airway lability, and to quantify these relationships in a population of adults. METHODS--Data were collected from 511 participants (aged 20-70 years) from the Dutch part of the European Community Respiratory Health Survey (ECRHS). The symptoms analysed were: wheeze, dyspnoea > or = grade 3, nocturnal dyspnoea, cough and phlegm, and history of allergy. Lung function was measured by peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1). PEF variability was used as an index for bronchial lability. RESULTS--Both FEV1 and PEF were decreased with increasing numbers of symptoms. Subjects with one symptom had an increased risk of having an FEV1 value of < 70% (OR = 4.2) and this risk increased with an increasing number of symptoms. Subjects with three or more symptoms had an increased risk of having a PEF value of < 70%, a diurnal variation in PEF of > 10% (both OR = 4.4), and an increased risk of high between day variation (OR = 6.6). CONCLUSIONS--Subject-reported symptoms are related to impaired lung function and to increased variability of peak flow.

Susceptibility to air pollution in elderly males and females

It is important to know which individuals in the general population have increased susceptibility to air pollution. The aim of this study was to identify susceptible subgroups by studying airways hyperresponsiveness (AHR), high total immunoglobulin (Ig)E and sex. Diary data on lower and upper respiratory symptoms (LRS and URS, respectively), cough, and morning and evening peak expiratory flow (PEF) were collected in 327 elderly patients (50–70 yrs) for a period of 3 months. Acute effects of particulate matter with a diameter <10 µm, black smoke, sulphur dioxide and nitrogen dioxide on symptoms and PEF were estimated using logistic regression. In total, 48 (14.7%) subjects had AHR+/IgE+, 112 (34.3%) had AHR−/IgE+, 42 (12.8%) had AHR+/IgE− and 125 (38.2%) had AHR−/IgE−. In the AHR+/IgE+ group, each 10 µg·m−3 increase in air pollution was associated with a significant increase in prevalence of URS (odds ratio ranging 1.03–1.19), cough (1.03–1.08) and fall in morning PEF (1.04–1.26). In the AHR+/IgE+ group, males responded predominantly with symptoms and females with a fall in morning PEF. In conclusion, elderly individuals with both airway hyperresponsiveness and high total immunoglobulin E are especially susceptible to air pollution. Identifying susceptible subgroups might enlarge insight into the actual mechanisms by which air pollution evokes specific modes of response.

Genetic Analysis in A Dutch Study Sample Identifies More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk (vol 105, pg 395, 2010)

OBJECTIVES:Genetic susceptibility is known to make a major contribution to the pathogenesis of ulcerative colitis (UC). Recently, three studies, including a genome-wide association study (GWAS), reported novel UC risk loci.METHODS:The top-20 single-nucleotide polymorphisms (SNPs) from the first UC-GWAS were genotyped, as part of the studys replication phase, in 561 UC cases and 728 controls from our Dutch UC study sample. We genotyped eight SNPs identified in two more studies, in these individuals, and replicated all significantly associated SNPs in an additional 894 UC cases and 1,174 controls from our Dutch UC study sample. A combined analysis for all patients (n=1,455) and controls (n=1,902) was performed. Dose–response models were constructed with the associated risk alleles.RESULTS:We found 12 SNPs tagging ten loci, including HLA-DRA, IL10, IL23R, JAK2, S100Z, ARPC2, and ECM1, to be associated with UC. We identified 10q26, flagged by the UC-GWAS but not confirmed in its replication phase, as a UC locus and found a trend toward association for GAS7. No association with disease localization or severity was found. The dose–response models show that individuals carrying 11 or more risk alleles have an odds ratio of 8.2 (confidence interval 3.0–22.8) for UC susceptibility.CONCLUSIONS:We confirmed the association of multiple loci with UC in the Dutch population and found evidence for association of 10q26 and a trend suggesting association for GAS7. Genetic models show that multiple risk loci in an individual increase the risk for developing UC.