Platelet Integrin αIIbß3 Activation is Associated with 25-Hydroxyvitamin D Concentrations in Healthy Adults.

BACKGROUND: Cardiovascular events are associated with low circulating vitamin D concentrations, although the underlying mechanisms are poorly understood. This study investigated associations between 25-hydroxyvitamin D concentrations, platelet function, and single-nucleotide polymorphisms (SNPs) in genes influencing vitamin D biology in the 500 Functional Genomics (500FG) cohort. METHODS: In this observational study, platelet activation and function were measured by flow cytometry by binding of fibrinogen to the activated fibrinogen receptor integrin αIIbß3 and expression of P-selectin, markers of platelet aggregation and degranulation, respectively. These parameters were correlated to serum 25-hydroxyvitamin D and genotyping was performed to investigate SNPs in genes important for vitamin D biology. RESULTS: Circulating 25-hydroxyvitamin D concentrations correlated inversely with baseline platelet binding of fibrinogen to integrin αIIbß3 (Pearson's r= -0.172, p = 0.002) and platelet responses to platelet agonist cross-linked collagen-related peptide (CRP-XL) (Pearson's r= -0.196,p = 0.002). This effect was due to circulating vitamin D levels ≤50nmol/L, since no differences in platelet fibrinogen binding were observed between subjects with normal 25-hydroxyvitamin D concentrations (>75nmol/L) and a 25-hydroxyvitamin D insufficiency (50-75 nmol/L). No correlations between 25-hydroxyvitamin D concentrations and platelet P-selectin expression were found. Several SNPs in the GC region of the vitamin D binding proteingene were associated with platelet responses to CRP-XL. CONCLUSION: Low circulating vitamin D concentrations are associated with increased platelet fibrinogen binding to integrin αIIbß3 in unstimulated samples and after stimulation with CRP-XL. These findings may contribute to the increased incidence of cardiovascular events in vitamin D deficient adults and its seasonal variation. Further studies are needed to investigate causality.

Microbiological and immunological characteristics of a lethal pulmonary Aspergillus niger infection in a non-neutropenic patient.

Invasive pulmonary aspergillosis is increasingly described in non-neutropenic patients, such as patients with COPD receiving corticosteroids and the critically ill. Here, we present a case of a lethal pulmonary Aspergillus niger infection in a COPD patient. Immunological tests showed an impaired innate and adaptive immune response to Aspergillus. A history of COPD, unresponsiveness to antibiotics and especially a suggestive CT-scan should trigger the clinician to consider diseases caused by Aspergillus.

Evaluation of the COPDnet integrated care model in patients with COPD: the study protocol.

Background: Projections on the future suggest a further rise in the prevalence of patients with COPD, and in COPD related morbidity, mortality, and health care costs worldwide. Given the substantial impact on the individual and on society, it is important to establish a care process that maximizes outcomes in relation to the costs and efforts made. In an attempt to bridge this gap, we set out to develop an evidence-based model of integrated care for patients with COPD, named the COPDnet integrated care model. Purpose: The current study protocol sets out to 1) evaluate the feasibility of employing the COPDnet model in present real-life care within the context of the Dutch health care system, 2) explore the potential health status benefits, and 3) analyze the costs of care of this model. Patients and methods: In this prospective study, feasibility and health status changes will be evaluated with an experimental before and after study design. The costs of the diagnostic trajectory will be calculated according to a standard economic health care evaluation approach. Furthermore, the feasibility and cost of care studies will comprise both quantitative and qualitative data collection. For the studies on the feasibility and change in health status, all new patients qualifying for shared care by primary and secondary care professionals according to the Dutch Standard of Care for COPD, and patients referred by their general practitioners to one of the COPDnet hospitals will be included. To evaluate the feasibility and costs of care, semi-structured interviews will be held with patients, hospital personnel, health care professionals in the affiliated primary care region, and hospital and primary care group managers. Conclusions: The COPDnet integrated care model for COPD patients has been designed according to the current insights regarding effective care for patients with a chronic condition in general, and for patients with COPD in particular. It will be evaluated for its feasibility, potential health status benefits, and the costs of care of the diagnostic trajectory in secondary care.

The COPDnet integrated care model.

Introduction: This research project sets out to design an integrated disease management model for patients with COPD who were referred to a secondary care setting and who qualified for pharmacological and nonpharmacological intervention options. Theory and methods: The integrated disease management model was designed according to the guidelines of the European Pathway Association and the content founded on the Chronic Care Model, principles of integrated disease management, and knowledge of quality management systems. Results: An integrated disease management model was created, and comprises 1) a diagnostic trajectory in a secondary care setting, 2) a nonmedical intervention program in a primary care setting, and 3) a pulmonary rehabilitation service in a tertiary care setting. The model also includes a quality management system and regional agreements about exacerbation management and palliative care. Discussion: In the next phase of the project, the COPDnet model will be implemented in at least two different regions, in order to assess the added value of the entire model and its components, in terms of feasibility, health status benefits, and costs of care. Conclusion: Based on scientific theories and models, a new integrated disease management model was developed for COPD patients, named COPDnet. Once the model is stable, it will be evaluated for its feasibility, health status benefits, and costs.

Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD.

BACKGROUND: This study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD. METHODS: 219 patients with COPD (FEV1: 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H2O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time. FINDINGS: No significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI -13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI -1.5 to -0.01, p=0.049) were observed in the intervention group. INTERPRETATION: Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results.

Increased Platelet-Monocyte Interaction in Stable COPD in the Absence of Platelet Hyper-Reactivity.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is well known for its cardiovascular co-morbidities. Increased platelet-monocyte interaction is found in COPD and may reflect altered platelet function and a potential role for anti-platelet therapy. OBJECTIVES: The objectives were to investigate platelet-monocyte interaction, platelet activation and reactivity and plasmatic coagulation in stable COPD. METHODS: Platelet-monocyte interaction and platelet activation were determined by flow cytometry in 30 stable COPD patients and 25 controls. Platelet activation was measured by binding of fibrinogen to the activated fibrinogen receptor and platelet P-selectin expression at baseline and after platelet stimulation with platelet agonists. Plasmatic coagulation was measured by D-dimer and thrombin generation. RESULTS: Platelet-monocyte interaction was increased in stable COPD (median fluorescence intensity of platelet CD61 was 19.8 [IQR 14.0-33.2] vs. 10.0 [IQR 8.7-16.7], p = 0.002). In contrast, platelet activation and reactivity, reflected by fibrinogen binding and P-selectin expression, were the same in both groups. Plasma P-selectin and interleukin-6 were increased in COPD (p = 0.01 and p = 0.02, respectively), whereas soluble fibrinogen, D-dimer and thrombin generation were similar. CONCLUSIONS: Increased platelet-monocyte interaction was found in the absence of platelet hyper-reactivity and activation of plasmatic coagulation in stable COPD. Future clinical evaluation of the effects of different anti-platelet drugs in COPD is warranted, as anti-platelet therapy may interfere with platelet-monocyte interaction.

The effects of signal transducer and activator of transcription three mutations on human platelets.

Involvement of signal transducer and activator of transcription 3 (STAT3) in inflammation is well known. Recently, a role for STAT3 in platelet activation and platelet production has been suggested. Platelets exhibit important immune functions and engagement of STAT3 in platelet physiology may link inflammation and hemostasis. This study investigated the effects of STAT3 loss-of-function mutations and single nucleotide polymorphisms (SNPs) in STAT3 on glycoprotein VI (GPVI)-mediated platelet activation and platelet numbers in humans. Two cohorts were studied. The first cohort concerned patients with STAT3 loss-of-function mutations. Platelet numbers were investigated in eight patients and GPVI-mediated platelet activation was functionally tested in four patients. Additional experiments were performed to investigate underlying mechanisms. The second cohort concerned 334 healthy volunteers and investigated the consequences of SNPs in STAT3 on GPVI-mediated platelet activation and platelet numbers. Platelet activation was lower in STAT3 loss-of-function patients at baseline and after stimulation of the GPVI receptor, reflected by decreased P-selectin expression. This was independent of gene transcription. Blockade of the adenosine di-phosphate (ADP) pathway resulted in a further decrease of P-selectin expression, particularly in STAT3 loss-of-function patients. In contrast, the SNPs in STAT3 did not influence GPVI-mediated platelet activation. Also, platelet numbers were not affected by STAT3 loss-of-function mutations, nor was there an association with the SNPs. In conclusion, STAT3 signaling does not seem to play a major role in thrombopoiesis. We confirm that STAT3 is involved in GPVI-mediated platelet activation in humans, independent of gene transcription. GPVI-mediated platelet activation is highly dependent on secondary ADP release. Our findings suggest that STAT3 modulation may affect inflammation, hemostasis, and their interaction.

Integral Health Status-Based Cluster Analysis in Moderate-Severe COPD Patients Identifies Three Clinical Phenotypes: Relevant for Treatment As Usual and Pulmonary Rehabilitation.

PURPOSE: The purposes of the study are to identify clinical phenotypes that reflect the level of adaptation to the disease and to examine whether these clinical phenotypes respond differently to treatment as usual (TAU) and pulmonary rehabilitation (PR), the latter with its strong emphasis on improving adaptation. METHODS: Clusters were identified by a cluster analysis using data on many subdomains of the four domains of health status (HS) (physiological functioning, functional impairment, symptoms and quality of life) in 160 outpatients with chronic obstructive pulmonary disease (COPD) receiving TAU. By discriminant analysis in the TAU sample, all 459 PR patients could be assigned to one of the identified clusters. The effect of TAU and PR on HS was examined with paired t tests. RESULTS: Three distinct phenotypes were identified in the TAU sample. Two types were labelled adapted: phenotype 1 (moderate COPD-low impact on HS, n = 53) and phenotype 3 (severe COPD-moderate impact on HS, n = 73). One type was labelled non-adapted: phenotype 2 (moderate COPD-high impact on HS, n = 34). After 1-year TAU, the integral health status of all patients did not improve in any subdomain. In contrast, at the end of PR, significant improvements in HS were found in all three phenotypes especially the non-adapted. CONCLUSIONS: Different phenotypes exist in COPD that are based on behavioural aspects (i.e. the level of adaptation to the disease). Non-adapted patient responds better to treatments with a strong emphasis on improving adaptation by learning the patient better self-management skills. Knowing to which clinical phenotype a patient belongs helps to optimize patient-tailored treatment.

Prevalence and Localization of Pulmonary Embolism in Unexplained Acute Exacerbations of COPD: A Systematic Review and Meta-analysis.

BACKGROUND: Patients with COPD experience episodes of increased inflammation, so-called acute exacerbations of COPD (AE-COPD). In 30% of AE-COPD cases, no clear cause is found. Since there is well-known cross talk between inflammation and thrombosis, the objectives of this study were to determine the prevalence, embolus localization, clinical relevance, and clinical markers of pulmonary embolism (PE) in unexplained AE-COPD. METHODS: A systematic search was performed using MEDLINE and EMBASE platforms from 1974 to October 2015. Prospective and cross-sectional studies that included patients with AE-COPD and used pulmonary CT-angiography for diagnosis of PE were included. RESULTS: The systematic search resulted in 1,650 records. The main reports of 22 articles were reviewed, and 7 studies were included. The pooled prevalence of PE in unexplained AE-COPD was 16.1% (95% CI, 8.3%-25.8%) in a total of 880 patients. Sixty-eight percent of the emboli found were located in the main pulmonary arteries, lobar arteries, or interlobar arteries. Mortality and length of hospital admission seemed to be increased in patients with unexplained AE-COPD and PE. Pleuritic chest pain and cardiac failure were more frequently reported in patients with unexplained AE-COPD and PE. In contrast, signs of respiratory tract infection was less frequently related to PE. CONCLUSIONS: PE is frequently seen in unexplained AE-COPD. Two-thirds of emboli are found at locations that have a clear indication for anticoagulant treatment. These findings merit clinical attention. PE should receive increased awareness in patients with unexplained AE-COPD, especially when pleuritic chest pain and signs of cardiac failure are present, and no clear infectious origin can be identified.

Differences in systemic adaptive immunity contribute to the 'frequent exacerbator' COPD phenotype.

BACKGROUND: Some COPD patients are more susceptible to exacerbations than others. Mechanisms underlying these differences in susceptibility are not well understood. We hypothesized that altered cell mediated immune responses may underlie a propensity to suffer from frequent exacerbations in COPD. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from 24 stable COPD patients, eight frequent exacerbators (≥3 diary-card exacerbations/year) and 16 infrequent exacerbators (< 3 diary-card exacerbations/year). Detailed multi-parameter flow cytometry was used to study differences in innate and adaptive systemic immune function between frequent and infrequently exacerbating COPD patients. RESULTS: The 24 COPD patients had a mean (SD) age of 76.3 (9.4) years and FEV1 1.43 (0.60)L, 53.3 (18.3)% predicted. PBMCs of frequent exacerbators (FE) contained lower frequencies of CD4+ T central memory cells (CD4+ Tcm) compared to infrequent exacerbators (IE) (FE = 18.7 %; IE = 23.9 %; p = 0.035). This observation was also apparent in absolute numbers of CD4+ Tcm cells (FE = 0.17 × 10^6/mL; IE = 0.25 × 10^6/mL; p = 0.035). PBMCs of FE contained a lower frequency of CD8+ T effector memory cells expressing HLA-DR (Human Leukocyte Antigen - D Related) compared to IE COPD patients (FE = 22.7 %; IE = 31.5 %; p = 0.007). CONCLUSION: Differences in the adaptive systemic immune system might associate with exacerbation susceptibility in the 'frequent exacerbator' COPD phenotype. These differences include fewer CD4+ T central memory cells and CD8+ T effector memory cells. TRIAL REGISTRATION: Not applicable.

Respiratory constraints during activities in daily life and the impact on health status in patients with early-stage COPD: a cross-sectional study.

In patients with chronic obstructive pulmonary disease (COPD), exercise capacity is reduced, resulting over time in physical inactivity and worsened health status. It is unknown whether ventilatory constraints occur during activities of daily life (ADL) in early stages of COPD. The aim of this study was to assess respiratory mechanics during ADL and to study its consequences on dyspnoea, physical activity and health status in early-stage COPD compared with healthy controls. In this cross-sectional study, 39 early-stage COPD patients (mean FEV1 88±s.d. 12% predicted) and 20 controls performed 3 ADL: climbing stairs, vacuum cleaning and displacing groceries in a cupboard. Respiratory mechanics were measured during ADL. Physical activity was measured with accelerometry. Health status was assessed by the Nijmegen Clinical Screening Instrument. Compared with controls, COPD patients had greater ventilatory inefficiency and higher ventilatory requirements during ADL (P<0.05). Dyspnoea scores were increased in COPD compared with controls (P<0.001). During ADL, >50% of the patients developed dynamic hyperinflation in contrast to 10-35% of the controls. Higher dyspnoea was scored by patients with dynamic hyperinflation. Physical activity was low but comparable between both groups. From the patients, 55-84% experienced mild-to-severe problems in health status compared with 5-25% of the controls. Significant ventilatory constraints already occur in early-stage COPD patients during common ADL and result in increased dyspnoea. Physical activity level is not yet reduced, but many patients already experience limitations in health status. These findings reinforce the importance of early diagnosis of COPD and assessment of more than just spirometry.

Extensive pulmonary sarcoid reaction in a patient with BMPR-2 associated idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension is a progressive life-threatening disease characterized by vascular remodeling. There is evidence that varied immune mechanism play an important role in progression of pulmonary hypertension.  We describe a case of a 35-year-old woman with idiopathic pulmonary arterial hypertension (IPAH) and a novel BMPR2 mutation, who underwent a successful lung transplantation.  Extensive granulomatous inflammation was seen in the resected lungs. The granulomatous inflammation found in the histology supports  a sarcoid-like reaction due to pulmonary hypertension in the context of the BMPR2 mutation.

Overweight Is an Independent Risk Factor for Reduced Lung Volumes in Myotonic Dystrophy Type 1.

BACKGROUND: In this large observational study population of 105 myotonic dystrophy type 1 (DM1) patients, we investigate whether bodyweight is a contributor of total lung capacity (TLC) independent of the impaired inspiratory muscle strength. METHODS: Body composition was assessed using the combination of body mass index (BMI) and fat-free mass index. Pulmonary function tests and respiratory muscle strength measurements were performed on the same day. Patients were stratified into normal (BMI < 25 kg/m(2)) and overweight (BMI ≥ 25 kg/m(2)) groups. Multiple linear regression was used to find significant contributors for TLC. RESULTS: Overweight was present in 59% of patients, and body composition was abnormal in almost all patients. In overweight patients, TLC was significantly (p = 2.40×10(-3)) decreased, compared with normal-weight patients, while inspiratory muscle strength was similar in both groups. The decrease in TLC in overweight patients was mainly due to a decrease in expiratory reserve volume (ERV) further illustrated by a highly significant (p = 1.33×10(-10)) correlation between BMI and ERV. Multiple linear regression showed that TLC can be predicted using only BMI and the forced inspiratory volume in 1 second, as these were the only significant contributors. CONCLUSIONS: This study shows that, in DM1 patients, overweight further reduces lung volumes, as does impaired inspiratory muscle strength. Additionally, body composition is abnormal in almost all DM1 patients.

Using the Lower Limit of Normal Instead of the Conventional Cutoff Values to Define Predictors of Pulmonary Function Impairment in Subjects With Chronic Heart Failure.

BACKGROUND: Using the newer lower limit of normal criterion instead of the conventional cutoff values to define pulmonary function abnormalities may result in different predictors of pulmonary function impairment in patients with heart failure. Therefore, we assessed predictors of pulmonary function impairment in subjects with chronic heart failure according to the lower limit of normal in comparison with conventional cutoff values. METHODS: In this prospective cross-sectional study, 164 chronic heart failure subjects (age 68 ± 10 y, 78% men, 88% New York Heart Association class I-II) with left ventricular ejection fraction <40% underwent pulmonary function tests. Predictors of pulmonary function impairment were assessed using the lower limit of normal and conventional cutoff values (ie, 80% predicted value and the fixed ratio of FEV1/FVC <0.7). RESULTS: The lower limit of normal criterion identified an extra independent predictor of diffusion impairment compared with the 80% predicted value; in addition to body mass index, pack-years, and alveolar volume, female sex also turned out to be an independent predictor. A smoking history of ≥10 pack-years was a significant predictor of diffusion impairment and airway obstruction using the lower limit of normal criterion but not using the conventional cutoff values. However, lowering the cutoff points of conventional criteria to match the more stringent lower limit of normal and thus avoid overdiagnosis of diffusion impairment and airway obstruction in the elderly produced similar results as the lower limit of normal. CONCLUSIONS: The lower limit of normal identifies more predictors of diffusion impairment and airway obstruction compared with conventional cutoff values in subjects with chronic heart failure with left ventricular systolic dysfunction. However, lowering the conventional cutoff points yielded similar results as the lower limit of normal. (ClinicalTrials.gov registration NCT01429376.).

Prevention of exacerbations in patients with COPD and vitamin D deficiency through vitamin D supplementation (PRECOVID): a study protocol.

BACKGROUND: Vitamin D is well known for its function in calcium homeostasis and bone mineralisation, but is increasingly studied for its potential immunomodulatory properties. Vitamin D deficiency is a common problem in patients with COPD. Previous studies have not demonstrated a beneficial effect of vitamin D on exacerbation rate in COPD patients. However, subgroup analyses suggested protective effects in vitamin D deficient patients. Our objective is to assess the effect of vitamin D supplementation on exacerbation rate specifically in vitamin D deficient COPD patients. METHODS/DESIGN: We will perform a randomised, multi-center, double-blind, placebo-controlled intervention study. The study population consists of 240 COPD patients aged 40 years and older with vitamin D deficiency (25-hydroxyvitamin D concentration < 50 nmol/L). Participants will be recruited after an exacerbation and will be randomly allocated in a 1:1 ratio to receive vitamin D3 16800 IU or placebo orally once a week during 1 year. Participants will receive a diary card to register the incidence of exacerbations and changes in medication during the study period. Visits will be performed at baseline, at 6 months and at 12 months after randomisation. Participants will undergo spirometry, measurement of total lung capacity and assessment of maximal respiratory mouth pressure. Several physical performance and hand grip strength tests will be performed, questionnaires on quality of life and physical activity will be filled in, a nasal secretion sample and swab will be obtained and blood samples will be taken. The primary outcome will be exacerbation rate. DISCUSSION: This study will be the first RCT aimed at the effects of vitamin D supplementation on exacerbation rate in vitamin D deficient COPD patients. Also, in contrast to earlier studies that used infrequent dosing regimens, our trial will study effects of a weekly dose of vitamin D supplementation. Secondly, the immunomodulatory effects of vitamin D on host immune response of COPD patients and underlying mechanisms will be studied. Finally, the effects on physical functioning will be examined. TRIAL REGISTRATION: This trial is registered in ClinicalTrials.gov, ID number NCT02122627 . Date of Registration April 2014.

Serial pulmonary function tests to diagnose COPD in chronic heart failure.

BACKGROUND: It is unknown whether serial pulmonary function tests are necessary for the correct diagnosis of chronic obstructive pulmonary disease (COPD) in patients with stable non-congested chronic heart failure (CHF). The aim of this study was to determine the prevalence of COPD in outpatients with stable CHF without pulmonary congestion using initial as well as confirmatory spirometry three months after treatment for COPD. METHODS: Spirometry was performed in 187 outpatients with stable CHF without pulmonary congestion on chest radiograph who had a left ventricular ejection fraction < 40% (mean age 69 ± 10 years, 78% men). COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease guidelines. The diagnosis of COPD was confirmed three months after treatment with tiotropium in newly diagnosed COPD patients. RESULTS: Using a three month follow-up spirometry to confirm initial diagnosis of de novo COPD did not change COPD prevalence significantly: 32.6% initially versus 32.1% after three months of follow-up. Only 1 of 25 (4%) patients with newly diagnosed COPD was not reproducibly obstructed at follow-up. COPD was greatly under- (19%) and overdiagnosed (32%). CONCLUSIONS: Spirometry should be used under stable and euvolemic conditions to decrease the burden of undiagnosed or overdiagnosed COPD in patients with CHF. Under these conditions, a confirmatory spirometry is unnecessary, as it does not change a newly established diagnosis of COPD in the vast majority of patients with CHF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01429376.

Pulmonary function impairment in patients with chronic heart failure: lower limit of normal versus conventional cutoff values.

OBJECTIVE: To determine the prevalence of pulmonary function abnormalities in patients with chronic heart failure (HF) according to recent American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines using the lower limit of normal (LLN) compared to conventional cutoff values. BACKGROUND: Recent ATS/ERS guidelines recommend the use of the LLN instead of the conventional cutoff values to define pulmonary function impairment to avoid misclassification of patients. However, studies addressing the prevalence of pulmonary function abnormalities according to both definitions in patients with chronic HF are lacking. METHODS: In this prospective cross-sectional study, 164 chronic HF outpatients (age 68 ± 10 years, 78% men, 88% New York Heart Association class I-II) with left ventricular ejection fraction < 40% underwent spirometry and measurement of diffusing capacity. Body plethysmography was performed in patients with abnormal spirometry results. RESULTS: Diffusion impairment and airway obstruction were found in 44-58% and 26-37% of the patients, respectively, depending on the definition used (LLN versus conventional cutoff values, p < 0.05). However, restriction was infrequent, irrespective of the definition used (7% versus 5%, respectively, p > 0.05). The LLN identified fewer patients with abnormal lung function, whereas the conventional cutoff values classified more patients with diffusion impairment, airway obstruction, or a mixed category. Twenty-seven percent of patients were misclassified by the conventional cutoff values. CONCLUSION: Pulmonary function abnormalities, especially diffusion impairment and airway obstruction, were highly prevalent in patients with chronic HF. Conventional cutoff values classified more patients with diffusion impairment, airway obstruction, or a mixed category compared to the LLN.

Impact of switching to new spirometric reference equations on severity staging of airflow obstruction in COPD: a crosssectional observational study in primary care.

BACKGROUND: Severity of airflow obstruction in chronic obstructive pulmonary disease (COPD) is based on forced expiratory volume in one second expressed as percentage predicted (FEV1%predicted) derived from reference equations for spirometry results. AIMS: To establish how switching to new spirometric reference equations would affect severity staging of airflow obstruction in the Dutch primary care COPD patient population. METHODS: Spirometry tests of 3,370 adults aged >40 years with obstruction (postbronchodilator FEV1/forced vital capacity (FVC) <0.70) were analysed. The presence and severity of obstruction were defined using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Postbronchodilator FEV1%predicted was calculated using three reference equations: corrected European Community of Steel and Coal (ECSC) (currently recommended in Dutch primary care), Swanney et al., and Global Lung Initiative (GLI). Discordances between severity classifications based on these equations were analysed. RESULTS: We studied 1,297 (38.5%) females and 2,073 males. Application of contemporary reference equations (i.e. Swanney and GLI) changed the GOLD severity stages obtained with the ECSC equations, mostly into milder stages. Severity of airflow obstruction was staged differently in 14.0% and 6.3%, respectively, when the Swanney et al. and GLI reference equations were applied. CONCLUSIONS: Compared with the (corrected) ECSC equations, switching to more contemporary reference equations would result in lower FEV1 predicted values and affect interpretation of spirometry by reclassifying 6-14% of primary care COPD patients into different (mostly milder) severity stages. If and how this will affect GPs' treatment choices in individual patients with COPD requires further investigation.