Yvonne F. Heijdra

Current clinical guideline definitions of airflow obstruction and COPD overdiagnosis in primary care

The aim of the present study was to establish the agreement between two recommended definitions of airflow obstruction in symptomatic adults referred for spirometry by their general practitioner, and investigate how rates of airflow obstruction change when pre-bronchodilator instead of post-bronchodilator spirometry is performed. The diagnostic spirometric results of 14,056 adults with respiratory obstruction were analysed. Differences in interpretation between a fixed 0.70 forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) cut-off point and a sex- and age-specific lower limit of normal cut-off point for this ratio were investigated. Of the subjects, 53% were female and 69% were current or ex-smokers. The mean post-bronchodilator FEV1/FVC was 0.73 in males and 0.78 in females. The sensitivity of the fixed relative to the lower limit of normal cut-off point definition was 97.9%, with a specificity of 91.2%, positive predictive value of 72.0% and negative predictive value of 99.5%. For the subgroup of current or ex-smokers aged ≥50 yrs, these values were 100, 82.0, 69.2 and 100%, respectively. The proportion of false positive diagnoses using the fixed cut-off point increased with age. The positive predictive value of pre-bronchodilator airflow obstruction was 74.7% among current or ex-smokers aged ≥50 yrs. The current clinical guideline-recommended fixed 0.70 forced expiratory volume in one second/forced vital capacity cut-off point leads to substantial overdiagnosis of obstruction in middle-aged and elderly patients in primary care. Using pre-bronchodilator spirometry leads to a high rate of false positive interpretations of obstruction in primary care.

An autonomous mobile system for the management of COPD

INTRODUCTION Managing chronic disease through automated systems has the potential to both benefit the patient and reduce health-care costs. We have developed and evaluated a disease management system for patients with chronic obstructive pulmonary disease (COPD). Its aim is to predict and detect exacerbations and, through this, help patients self-manage their disease to prevent hospitalisation. MATERIALS The carefully crafted intelligent system consists of a mobile device that is able to collect case-specific, subjective and objective, physiological data, and to alert the patient by a patient-specific interpretation of the data by means of probabilistic reasoning. Collected data are also sent to a central server for inspection by health-care professionals. METHODS We evaluated the probabilistic model using cross-validation and ROC analyses on data from an earlier study and by an independent data set. Furthermore a pilot with actual COPD patients has been conducted to test technical feasibility and to obtain user feedback. RESULTS Model evaluation results show that we can reliably detect exacerbations. Pilot study results suggest that an intervention based on this system could be successful.

Revertant Somatic Mosaicism by Mitotic Recombination in Dyskeratosis Congenita

Revertant mosaicism is an infrequently observed phenomenon caused by spontaneous correction of a pathogenic allele. We have observed such reversions caused by mitotic recombination of mutant TERC (telomerase RNA component) alleles in six patients from four families affected by dyskeratosis congenita (DC). DC is a multisystem disorder characterized by mucocutaneous abnormalities, dystrophic nails, bone-marrow failure, lung fibrosis, liver cirrhosis, and cancer. We identified a 4 nt deletion in TERC in a family with an autosomal-dominant form of DC. In two affected brothers without bone-marrow failure, sequence analysis revealed pronounced overrepresentation of the wild-type allele in blood cells, whereas no such skewing was observed in the other tissues tested. These observations suggest that this mosaic pattern might have resulted from somatic reversion of the mutated allele to the normal allele in blood-forming cells. SNP-microarray analysis on blood DNA from the two brothers indeed showed independent events of acquired segmental isodisomy of chromosome 3q, including TERC, indicating that the reversions must have resulted from mitotic recombination events. Subsequently, after developing a highly sensitive method of detecting mosaic homozygosity, we have found four additional cases with a mosaic-reversion pattern in blood cells; these four cases are part of a cohort of 17 individuals with germline TERC mutations. This shows that revertant mosaicism is a recurrent event in DC. This finding has important implications for improving diagnostic testing and understanding the variable phenotype of DC.

Inspiratory muscle training protocol for patients with chronic obstructive pulmonary disease (IMTCO study): a multicentre randomised controlled trial

Introduction Inspiratory muscle training (IMT) has been applied during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). However, it remains unclear if the addition of IMT to a general exercise training programme leads to additional clinically relevant improvements in patients with COPD. In this study, we will investigate whether the addition of IMT to a general exercise training programme improves 6 min walking distance, health-related quality of life, daily physical activity and inspiratory muscle function in patients with COPD with inspiratory muscle weakness. Methods and analysis Patients with COPD (n=170) with inspiratory muscle weakness (Pi,max <60 cm H2O or <50%pred) will be recruited to a multicentre randomised placebo controlled trial of IMT and allocated into one of the two groups. Patients in both groups will follow a 3 month general exercise training programme, in combination with home-based IMT. IMT will be performed with a recently developed device (POWERbreathe KH1). This device applies an inspiratory load that is provided by an electronically controlled valve (variable flow resistive load). The intervention group (n=85) will undertake an IMT programme at a high intensity (≥50% of their Pi,max), whereas the placebo group (n=85) will undertake IMT at a low training intensity (≤10% of Pi,max). Total daily IMT time for both groups will be 21 min (6 cycles of 30 breaths). Improvement in the 6 min walking distance will be the primary outcome. Inspiratory muscle function, health-related quality of life and daily physical activity will be assessed as secondary outcomes. Ethics and dissemination Ethics approval has been obtained from relevant centre committees and the study has been registered in a publicly accessible clinical trial database. The results will be easily interpretable and should immediately be communicated to healthcare providers, patients and the general public. Results This can be incorporated into evidence-based treatment recommendations for clinical practice. ClinicalTrials.gov NCT01397396.

Physiologic limitations during daily life activities in COPD patients

INTRODUCTION Patients with COPD are known to be limited in their performance of activities of daily life (ADL). This observational study aims to investigate the ventilatory and metabolic demand of ADL in home settings of patients and evaluate possible mechanisms involved in physiological limitation during ADL in COPD. METHODS In their home settings, 21 stable patients with COPD (GOLD II-IV, mean FEV(1) 43% predicted) were asked to perform their most dyspnea causing activities at their usual pace until symptoms discouraged further performance. Ten healthy control subjects, matched for age and gender, performed comparable activities. Ventilatory and metabolic demands of the ADL were studied using a portable breath-by-breath system. RESULTS Compared with healthy controls, ADL time was shorter in patients (530 +/- 38 s vs. 318 +/- 37 s respectively) and activities resulted in important complaints of dyspnea. Oxygen consumption (V O(2)) during the activities was higher in patients compared to healthy subjects (957 +/- 51 vs. 768 +/- 63 mL/min resp.). Ventilatory demand (V E) for comparable activity (at isoV O(2)) was higher in patients and went together with complaints of dyspnea in patients, but not in healthy subjects. Ventilatory constraints like low ventilatory reserve and inspiratory reserve volume and dynamic hyperinflation occurred in more than 80% of the patients, especially in (very) severe patients. CONCLUSION Patients with COPD experience limitations in the performance of ADL, which lead to reductions in ADL time and dyspnea complaints. There appears to be an important role for ventilatory limitations, which become more prominent as disease progresses.

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.

Are asymptomatic airway hyperresponsiveness and allergy risk factors for asthma? A longitudinal study

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, but it is unclear whether asymptomatic AHR is associated with a higher risk of asthma. The present study assessed whether there is an association between asymptomatic AHR in adolescence and asthma in adulthood. The association between allergy and development of asthma was also investigated. A follow-up study of a general population cohort of adolescents was performed 14 yrs after baseline. Respiratory status was assessed at baseline in 1989 and at follow-up in 2003–2004 by a respiratory symptoms questionnaire, spirometry and histamine challenge. Allergy status was also assessed. The respiratory status of 199 subjects was assessed twice. In total, 91 (46%) subjects had the same AHR status in combination with respiratory symptoms at follow-up as at baseline. Adjusted for age, sex, allergy, family history of asthma and smoking history, having asymptomatic AHR was not significantly related to having asthma 14 yrs later (odds ratio (OR) 2.15, 95% confidence interval (CI) 0.67–6.83). For subjects with allergy at baseline, the OR for developing asthma was 4.45 (95% CI 1.46–13.54). Screening for asymptomatic airway hyperresponsiveness in adolescence does not identify subjects at risk of developing asthma. Conversely, the presence of allergy in adolescence does seem to be a risk factor for asthma development.

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.

Heart failure and COPD: partners in crime?

Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are both common diseases with major impact and seem to coexist more frequently than expected from their separate population prevalences. However, estimates of combined prevalence must be interpreted carefully because of imperfections and difficulties in assessment of both diseases. This review aims to highlight HF prevalence in patients with COPD and vice versa, with a critical analysis of studies performed. First, definition, diagnosis, and prevalence of COPD and of HF will be discussed. Subsequently, an overview of important studies concerning combined prevalence with their limitations will be presented. Finally, pathogenic mechanisms and diagnostic considerations in clinical practice will be discussed.

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

Background: Measurements of transcutaneous carbon dioxide tension (PtcCO₂) with current devices are proven to provide clinically acceptable agreement with measurements of partial arterial carbon dioxide tension (PaCO₂) in several settings but not during cardiopulmonary exercise testing (CPET). Objectives: The primary objective of this study was to investigate the agreement between PaCO₂ and PtcCO₂ 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 (SaO₂, SpO₂) as measured with this sensor during CPET. Methods: In patients with various pulmonary diseases, PtcCO₂ and SpO₂ 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 (PCO₂) measurements were determined as clinically acceptable. Results: In total 101 ‘paired’ arterial and transcutaneous measurements were obtained from 21 patients. Bias between PaCO₂ and PtcCO₂ was –0.03 kPa with LOA from –0.78 to 0.71 kPa. Bias between SaO₂ and SpO₂ was –1.0% with LOA from –2.83 to 0.83%. Conclusions: Transcutaneous estimations of PCO₂ and SpO₂ are accurate and can be used in CPET, circumvening the need for arterial cannulation.