Peak In- and Expiratory Flow Revisited: Reliability and Reference Values in Adults.

BACKGROUND: While peak in- and expiratory flow rates offer valuable information for diagnosis and monitoring in respiratory disease, these indices are usually considered too variable to be routinely used for quantification in clinical practice. OBJECTIVES: The aim of the study was to obtain reproducible measurements of maximal inspiratory flow rates and to construct reference equations for peak in- and expiratory flows (PIF and PEF). METHOD: With coaching for maximal effort, 187 healthy Caucasian subjects (20-80 years) performed at least 3 combined forced inspiratory and expiratory manoeuvres, until at least 2 peak inspiratory flow measurements were within 10% of each other. The effect on PIF preceded by a slow expiration instead of a forced expiration and PIF repeatability over 3 different days was also investigated in subgroups. Reference values and limits of normal for PIF, mid-inspiratory flow, and PEF were obtained according to the Lambda-Mu-Sigma statistical method. RESULTS: A valid PIF could be obtained within 3.3 ± 0.6(SD) attempts, resulting in an overall within-test PIF variability of 4.6 ± 3.2(SD)%. A slow instead of a forced expiration prior to forced inspiration resulted in a significant (p < 0.001) but small PIF increase (2.5% on average). Intraclass correlation coefficient for between-day PIF was 0.981 (95% CI: 0.960-0.992). Over the entire age range, inter-subject PIF variability was smaller than in previous reports, and PIF could be predicted based on its determinants gender, age, and height (r2 = 0.53). CONCLUSIONS: When adhering to similar criteria for the measurement of effort-dependent portions of inspiratory and expiratory flow-volume curves, performed according to current ATS/ERS standards, it is possible to obtain reproducible PIF and PEF values for use in routine clinical practice.

The quantitative link of lung clearance index to bronchial segments affected by bronchiectasis.

In adult patients with cystic fibrosis (CF), the lung clearance index (LCI) derived from the multiple breath washout relates to both acinar and conductive ventilation heterogeneity. The latter component predicts an association between LCI and the number of bronchial segments affected by bronchiectasis. Here, we experimentally demonstrated this association in patients with CF, and also examined an ancillary group of patients with non-CF bronchiectasis. We conclude that lung disease severity in terms of number of bronchial segments results in an associated LCI increase, likely constituting a portion of LCI that cannot be reversed by treatment in patients with CF lung disease.

Transfer factor, lung volumes, resistance and ventilation distribution in healthy adults.

Monitoring of chronic lung disease requires reference values of lung function indices, including putative markers of small airway function, spanning a wide age range.We measured spirometry, transfer factor of the lung for carbon monoxide (TLCO), static lung volume, resistance and ventilation distribution in a healthy population, studying at least 20 subjects per sex and per decade between the ages of 20 and 80 years.With respect to the Global Lung Function Initiative reference data, our subjects had average z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC of -0.12, 0.04 and -0.32, respectively. Reference equations were obtained which could account for a potential dependence of index variability on age and height. This was done for (but not limited to) indices that are pertinent to asthma and chronic obstructive pulmonary disease studies: forced expired volume in 6 s, forced expiratory flow, TLCO, specific airway conductance, residual volume (RV)/total lung capacity (TLC), and ventilation heterogeneity in acinar and conductive lung zones.Deterioration in acinar ventilation heterogeneity and lung clearance index with age were more marked beyond 60 years, and conductive ventilation heterogeneity showed the greatest increase in variability with age. The most clinically relevant deviation from published reference values concerned RV/TLC values, which were considerably smaller than American Thoracic Society/European Respiratory Society-endorsed reference values.

Evidence of an acinar response following treatment for exacerbation in adult patients with cystic fibrosis.

BACKGROUND: Treating acute infectious exacerbations in cystic fibrosis (CF) patients with intravenous antibiotic therapy leads to variability in lung function and the ventilation distribution response. Part of the variable lung clearance index (LCI) response could be associated with the variable peripheral effects of intravenous antibiotic administration. OBJECTIVES: We explored to what extent the peripheral lung zones of CF patients could contribute to lung function improvements following treatment for infectious exacerbations. METHODS: Over a 1-year period, 15 adult CF patients admitted for acute exacerbations were recruited. Lung function and multiple breath washout (MBW) tests were performed on the day of admission and at discharge. From the MBW test, we obtained acinar and conductive indices of ventilation heterogeneity and LCI. RESULTS: The mean age (±SD) was 26 ± 5 years. Upon admission, the FEV1 was 54 ± 16% predicted and the LCI was 181 ± 26% predicted. After treatment, the average FEV1 increased to 61 ± 20% predicted (p < 0.001) and the LCI decreased to 173 ± 28% predicted (p = 0.042). The change in LCI was associated with a change in acinar (ρ = +0.54; p = 0.039) but not in conductive ventilation heterogeneity (p > 0.1). CONCLUSIONS: In CF patients in whom an improvement in LCI was obtained after treatment for an acute infectious exacerbation, this was paralleled by a decrease in acinar ventilation heterogeneity.

Lung clearance index in adult cystic fibrosis patients: the role of convection-dependent lung units.

We investigated the extent of convective ventilation heterogeneity contributing to the observed lung clearance index values in adult cystic fibrosis patients, as the result of two simulated scenarios, either 1) a fixed part of the lungs becoming increasingly less compliant, or 2) an increasingly greater part of the lung being less compliant. In 25 cystic fibrosis patients and 25 matched controls, we computed the lung clearance index and also quantified curvilinearity of the washout concentration curve, where curvilinearity is equal to 0 (linear in semilog plot) reflects homogeneous ventilation and curvilinearity equal to 1 corresponds to the presence of an infinitesimally slowly emptying lung unit. In the cystic fibrosis group (forced expiratory volume in 1 s 27-100% predicted), lung clearance index and curvilinearity average±sd values were 10.3±2.3 and 0.57±0.13, respectively, and were significantly different from control values (6.2±0.4 and 0.18±0.07; both p<0.001); lung clearance index and curvilinearity were also correlated (R = 0.67; p<0.001). The average curvilinearity value in the cystic fibrosis group was found to be compatible with a cumulative volume of underventilated lung of 40-50%, depending on the simulation scenario considered. The degree of washout curvilinearity observed here indicates that a major determinant of the abnormal lung clearance index values observed in adult cystic fibrosis patients is ventilation heterogeneity generated between convection-dependent lung units, while the remainder of lung clearance index abnormality with respect to normal controls potentially represents the small airways within these lung zones.

Ventilation heterogeneity in the acinar and conductive zones of the normal ageing lung.

RATIONALE: Small airways function studies in lung disease have used three promising multiple breath washout (MBW) derived indices: indices of ventilation heterogeneity in the acinar (S(acin)) and conductive (S(cond)) lung zones, and the lung clearance index (LCI). Since peripheral lung structure is known to change with age, ventilation heterogeneity is expected to be affected too. However, the age dependence of the MBW indices of ventilation heterogeneity in the normal lung is unknown. OBJECTIVES: The authors systematically investigated S(acin), S(cond) or LCI as a function of age, testing also the robustness of these relationships across two laboratories. METHODS: MBW tests were performed by never-smokers (50% men) in the age range 25-65 years, with data gathered across two laboratories (n=120 and n=60). For comparison with the literature, the phase III slopes from classical single breath washout tests were also acquired in one group (n=120). MEASUREMENTS AND MAIN RESULTS: All three MBW indices consistently increased with age, representing a steady worsening of ventilation heterogeneity in the age range 25-65. Age explained 7-16% of the variability in S(acin) and S(cond) and 36% of the variability in LCI. There was a small but significant gender difference only for S(acin). Classical single breath washout phase III slopes also showed age dependencies, with gender effects depending on the normalisation method used. CONCLUSIONS: With respect to the clinical response, age is a small but consistent effect that needs to be factored in when using the MBW indices for the detection of small airways abnormality in disease.

Small airways function in breast cancer patients before and after radiotherapy.

Radiotherapy treatments for early stage breast cancer patients potentially affect the lung in its most distal air spaces, and previous studies have indicated consistently low baseline values for diffusing capacity in breast cancer patients. We aimed to quantitatively assess baseline small airway function and the acute effects of radiotherapy in breast cancer patients with no confounding effects from respiratory disease or considerable smoking history. In 60 breast cancer patients selected from an ongoing randomized controlled trial, the small airways function was assessed at baseline and 3 months later, after having received either conventional radiotherapy (CR; n = 26) or hypofractionated tomotherapy (TT; n = 34). All indices of small airway function in breast cancer patients were found to be indistinguishable from healthy controls. The total lung capacity was significantly decreased and ventilation heterogeneity was significantly increased 3 months after baseline in the CR arm, but not in the TT arm. When corrected for hemoglobin and lung volume, pulmonary diffusing capacity was not affected by radiotherapy in either treatment arm. Alternatively, discarding patients receiving chemotherapy or loco-regional treatment did not affect these results. We conclude that middle-aged women with breast cancer, but no history of respiratory disease, have normal baseline small airways function. Conventional radiotherapy induces a restrictive pattern and increases heterogeneity of ventilation, the latter most likely resulting from differential expansion between locally irradiated peripheral lung zones and the remainder of the lung. The TT modality did not lead to any such changes.

Evidence of improved small airways function after azithromycin treatment in diffuse panbronchiolitis.

A 67-year-old never-smoker was diagnosed with diffuse panbronchiolitis (DPB) and was started on 250 mg azithromycin twice weekly. Over a 16-month observation period, lung function was assessed monthly, including a dedicated small airways test, the multiple breath nitrogen washout (MBW) with indices S(cond) and S(acin) of ventilation heterogeneity at the level of the conductive and acinar air spaces, respectively. Baseline measurements indicated moderate airway obstruction, air trapping and considerable dysfunction of the small airways around the acinar entrance. Treatment resulted in excellent symptomatic improvement paralleled by marked improvements in FEV(1), FVC, RV/TLC, S(cond) and S(acin); by contrast, there were no consistent changes in FEF(75) or TL(CO). While improvements were such that S(cond) fell within normal limits after 5 months, S(acin) remained abnormal even after 16 months of treatment. This suggests a distinct acinar structural abnormality in DPB that cannot be reversed by azithromycin.

Inflammation and airway function in the lung periphery of patients with stable asthma.

BACKGROUND: An important role for exhaled nitric oxide (NO) measurement could be in the distinction between proximal and peripheral lung contributions to inflammation, with a particular interest for the alveolar lung zone and its implication on airway function. OBJECTIVE: We aimed to isolate the acinar lung zone contribution to both inflammation and airway function to seek a relationship between them. METHODS: In 30 patients with asthma with an asthma control test score exceeding 20, indices of conductive and acinar ventilation heterogeneity (Scond, Sacin) were obtained from a multiple breath washout. NO production in the conductive airways (J'aw(NO)), alveolar NO concentration (CA(NO)), and the standard exhaled NO at 50 mL/s (FENO(50)) were obtained from exhaled NO. RESULTS: Scond was consistently abnormal in all patients with stable asthma, but without any correlation to inflammation abnormality in that compartment (J'aw(NO)). Sacin was particularly abnormal in the asthma subgroup receiving >500 microg budesonide equivalent, and a correlation was found between Sacin and CA(NO) (r = 0.61; P = .015); in this subgroup, a weak association was found between Scond and J'aw(NO) or FENO(50) (r = 0.50; P = .059 for both). CONCLUSION: The persistent functional abnormality of small conductive airways in patients with stable asthma is largely independent of inflammation as measured by exhaled NO. In the alveolar compartment, a functional correlate of alveolar NO was found in a subgroup of patients with stable asthma on moderate-to-high maintenance doses of inhaled steroids. These patients in particular could benefit from novel therapies specifically aimed at improving airway functionality at the level of the acinar entrance and beyond.

The ADMIT series--Issues in Inhalation Therapy. 7. Ways to improve pharmacological management of COPD: the importance of inhaler choice and inhalation technique.

Since inhalation therapy will probably remain the preferred route of treatment for patients with chronic obstructive pulmonary disease (COPD), it is important to provide helpful information that may assist physicians and nurses in selecting the appropriate device(s) for individual patients as well as prescribing the correct medication. In line with the GOLD guidelines, the Aerosol Drug Management Improvement Team (ADMIT) propose a three-part "therapy adjustment strategy", which provides health care professionals with a way to monitor and check the delivery of inhaled medication. The strategy is a summation of the key principles behind the evidence-based management of stable COPD and exacerbations. It offers physicians a rapid and user-friendly overview of the requirements of COPD management starting with making the diagnosis and continuing with optimisation of therapy in follow-up appointments. It includes everything from check lists for disease assessment and recommendations for reducing risk factors to selecting the proper inhalers and continuous checking of compliance and correct inhaler technique. These practical COPD therapy adjustment algorithms have been used as part of an interactive online course developed by the ADMIT group (www.admit-online.info). The COPD "flash" video available at this web site offers suggestions on how to organise a complete doctor-patient consultation.

The ADMIT series - Issues in inhalation therapy. 4) How to choose inhaler devices for the treatment of COPD.

For patients with COPD, inhalation is the preferred route of administration of respiratory drugs for both maintenance and acute treatment. Numerous inhaler types and devices have been developed, each with their own particularities, advantages and disadvantages. Nevertheless, published COPD management guidelines pay little attention to the optimal choice of inhaler devices for COPD patients. Although efficacy and safety are the primary factors determining the choice of an inhaler device, randomised controlled trials (RCTs) directly comparing the efficacy and safety of different inhalers in COPD patients are scarce. Systematic reviews on this subject failed to find significant differences between devices for any of the clinical outcomes studied. When selecting a device for the delivery of inhaled drugs in 'real life' patients with COPD, other factors should be considered. These include availability and affordability of the inhaled drugs and inhaler devices, the uniformity of inhaler devices when several drugs are to be inhaled, the ability of patients to handle correctly the selected device - in particular taking into account the advanced age of the average COPD patient, and finally the patient's preference. The prescribing clinician's task is to provide comprehensive instructions for correct handling of the device and to review regularly the patient's inhalation technique.

The effect of posture-induced changes in peripheral nitric oxide uptake on exhaled nitric oxide.

Airway and alveolar NO contributions to exhaled NO are being extracted from exhaled NO measurements performed at different flow rates. To test the robustness of this method and the validity of the underlying model, we deliberately induced a change in NO uptake in the peripheral lung compartment by changing body posture between supine and prone. In 10 normal subjects, we measured exhaled NO at target flows ranging from 50 to 350 ml/s in supine and prone postures. Using two common methods, bronchial NO production [Jaw(NO)] and alveolar NO concentration (FANO) were extracted from exhaled NO concentration vs. flow or flow(-1) curves. There was no significant Jaw(NO) difference between prone and supine but a significant FANO decrease from prone to supine ranging from 23 to 33% depending on the method used. Total lung capacity was 7% smaller supine than prone (P = 0.03). Besides this purely volumetric effect, which would tend to increase FANO from prone to supine, the observed degree of FANO decrease from prone to supine suggests a greater opposing effect that could be explained by the increased lung capillary blood volume (V(c)) supine vs. prone (P = 0.002) observed in another set of 11 normal subjects. Taken together with the relative changes of NO and CO transfer factors, this V(c) change can be attributed mainly to pulmonary capillary recruitment from prone to supine. Realistic models for exhaled NO simulation should include the possibility that a portion of the pulmonary capillary bed is unavailable for NO uptake, with a maximum capacity of the pulmonary capillary bed in the supine posture.

Pulmonary function patterns and their association with genotype and phenotype in adult cystic fibrosis patients.

Background: While cystic fibrosis (CF) lung disease is generally considered to be an obstructive disorder, other pulmonary function patterns (PFP) may occur. Furthermore, little is known about possible associations between PFP and genotype or phenotypical characteristics. Methods: Cross-sectional study including CF patients aged 16 years or more, identifying different PFP and exploring associations between PFP and genotype or phenotypical characteristics. Results: Obstructive PFP was most prevalent in our population (n = 80), comprising obstructive lung disease (62.5%), small airway (obstructive) disease (11.2%), and mixed obstructive-restrictive disorder (1.3%). However, one in four adult CF patients did not show any obstruction at all: normal (13.7%) or restrictive (8.8%) lung disease and isolated diffusion disorder (2.5%). Obstructive PFP was associated with a greater proportion of CF-related diabetes mellitus (CFRD) (P = 0.04), Pseudomonas aeruginosa colonization (P = 0.02) and frequent exacerbators (P = 0.04). We observed no association between PFP and genotype. Conclusions: Obstructive PFP remains the most common pulmonary function pattern in adult CF and is associated with CFRD, Pseudomonas aeruginosa colonization and frequent exacerbators.

Effect of airways constriction on exhaled nitric oxide.

While airway constriction has been shown to affect exhaled nitric oxide (NO), the mechanisms and location of constricted airways most likely to affect exhaled NO remain obscure. We studied the effects of histamine-induced airway constriction and ventilation heterogeneity on exhaled NO at 50 ml/s (Fe(NO,50)) and combined this with model simulations of Fe(NO,50) changes due to constriction of airways at various depths of the lung model. In 20 normal subjects, histamine induced a 26 +/- 15(SD)% Fe(NO,50) decrease, a 9 +/- 6% forced expiratory volume in 1 s (FEV(1)) decrease, a 19 +/- 9% mean forced midexpiratory flow between 25% and 75% forced vital capacity (FEF(25-75)) decrease, and a 94 +/- 119% increase in conductive ventilation heterogeneity. There was a significant correlation of Fe(NO,50) decrease with FEF(25-75) decrease (P = 0.006) but not with FEV(1) decrease or with increased ventilation heterogeneity. Simulations confirmed the negligible effect of ventilation heterogeneity on Fe(NO,50) and showed that the histamine-induced Fe(NO,50) decrease was due to constriction, with associated reduction in NO flux, of airways located proximal to generation 15. The model also indicated that the most marked effect of airways constriction on Fe(NO,50) is situated in generations 10-15 and that airway constriction beyond generation 15 markedly increases Fe(NO,50) due to interference with the NO backdiffusion effect. These mechanical factors should be considered when interpreting exhaled NO in lung disease.

The effect of conductive ventilation heterogeneity on diffusing capacity measurement.

It has long been assumed that the ventilation heterogeneity associated with lung disease could, in itself, affect the measurement of carbon monoxide transfer factor. The aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (Dl(CO)) measurement that are specifically due to conductive ventilation heterogeneity, i.e., due to a combination of ventilation heterogeneity and flow asynchrony between lung units larger than acini. We induced conductive airway ventilation heterogeneity in 35 never-smoker normal subjects by histamine provocation and related the resulting changes in conductive ventilation heterogeneity (derived from the multiple-breath washout test) to corresponding changes in diffusing capacity, alveolar volume, and inspired vital capacity (derived from the single-breath Dl(CO) method). Average conductive ventilation heterogeneity doubled (P < 0.001), whereas Dl(CO) decreased by 6% (P < 0.001), with no correlation between individual data (P > 0.1). Average inspired vital capacity and alveolar volume both decreased significantly by, respectively, 6 and 3%, and the individual changes in alveolar volume and in conductive ventilation heterogeneity were correlated (r = -0.46; P = 0.006). These findings can be brought in agreement with recent modeling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect Dl(CO) estimation errors in opposite ways. Even in the presence of flow asynchrony, these errors appear to largely cancel out in our experimental situation of histamine-induced conductive ventilation heterogeneity. Finally, we also predicted which alternative combination of specific ventilation heterogeneity and flow asynchrony could affect Dl(CO) estimate in a more substantial fashion in diseased lungs, irrespective of any diffusion-dependent effects.

Overuse of inhaled corticosteroids in COPD: five questions for withdrawal in daily practice.

Evidence and guidelines are becoming increasingly clear about imbalance between the risks and benefits of inhaled corticosteroids (ICSs) in patients with COPD. While selected patients may benefit from ICS-containing regimens, ICSs are often inappropriately prescribed with - according to Belgian market research data - up to 70% of patients in current practice receiving ICSs, usually as a fixed combination with a long-acting ß2-adrenoreceptor agonist. Studies and recommendations support withdrawal of ICSs in a large group of patients with COPD. However, historical habits appear difficult to change even in the light of recent scientific evidence. We have built a collaborative educational platform with chest physicians and primary care physicians to increase awareness and provide guidance and support in this matter.

Spacer devices for inhaled therapy: why use them, and how?

We present an extensive review of the literature to date pertaining to the rationale for using a spacer/valved holding chamber (VHC) to deliver inhaled therapy from a pressurised, metered-dose inhaler, a discussion of how the properties of individual devices may vary according to their physical characteristics and materials of manufacture, the potential risks and benefits of ancillaries such as valves, and the evidence that they contribute tangibly to the delivery of therapy. We also reiterate practical recommendations for the correct usage and maintenance of spacers/VHCs, which we trust offer practical help and advice to patients and healthcare professionals alike.

Tracheal stenosis: a flow dynamics study.

Patients referred for treatment of tracheal stenosis typically are asymptomatic until critical narrowing of the airway occurs, which then requires immediate intervention. To understand how tracheal stenosis affects local pressure drops and explore how a dramatic increase in pressure drop could possibly be detected at an early stage, a computational fluid dynamics (CFD) study was undertaken. We assessed flow patterns and pressure drops over tracheal stenoses artificially inserted into a realistic three-dimensional upper airway model derived from multislice computed tomography images obtained in healthy men. Solving the Navier-Stokes equations (with a Yang-shih k-epsilon turbulence model) for different degrees of tracheal constriction located approximately one tracheal diameter below the glottis, the simulated pressure drop over the stenosis (DeltaP) was seen to dramatically increase only when well over 70% of the tracheal lumen was obliterated. At 30 l/min, DeltaP increased from 7 Pa for a 50% stenosis to, respectively, 46 and 235 Pa for 80% and 90% stenosis. The pressure-flow relationship in the entire upper airway model (between mouth and end of trachea) in the flow range 0-60 l/min showed a power law relationship with best-fit flow exponent of 1.77 in the absence of stenosis. The exponent became 1.92 and 2.00 in the case of 60% and 85% constriction, respectively. The present simulations confirm that the overall pressure drop at rest is only affected in case of severe constriction, and the simulated flow dependence of pressure drop suggests a means of detecting stenosis at a precritical stage.

Early detection of COPD: a case finding study in general practice.

OBJECTIVES: To estimate the prevalence of undiagnosed chronic obstructive pulmonary disease (COPD) in a population of general practice patients at risk for developing COPD. A further aim was to evaluate the presence of respiratory symptoms as a predictor for the diagnosis of COPD. METHODS: This study was conducted by eight general practitioners (GP) in six semi-rural general practices. During two consecutive months all patients attending their GP were included if they met the following criteria: current smokers between 40 and 70 yr of age, and a smoking history of at least 15 pack-years. A questionnaire regarding smoking history, respiratory symptoms, exposure to dust or chemical fumes, and history of respiratory diseases was completed for all patients. Subjects without known COPD were invited for spirometric testing. RESULTS: Off the 146 general practice patients included, 17.1% already had an established COPD diagnosis. Screening by spirometry revealed a 46.6% prevalence of COPD. Underdiagnosis of COPD was more frequent in the younger age categories (40-49 Yr; 50-59 Yr). Objective wheezing was the only sign that was significantly more frequent in COPD patients than in non-COPD patients (P<0.001). Patients with previously known COPD were significantly older, and complained more of chronic cough and fatigue than newly detected patients. CONCLUSION: Almost half of a general practice population of current smokers between 40 and 70 years of age, with a smoking history of at least 15 pack-years, was diagnosed with COPD, and roughly two thirds of these were newly detected as a result of the case finding programme.