Value of lung diffusing capacity for nitric oxide in systemic sclerosis.

A decreased lung diffusing capacity for carbon monoxide (DLCO ) in systemic sclerosis (SSc) is considered to reflect losses of alveolar membrane diffusive conductance for CO (DMCO ), due to interstitial lung disease, and/or pulmonary capillary blood volume (VC ), due to vasculopathy. However, standard DLCO does not allow separate DMCO from VC . Lung diffusing capacity for nitric oxide (DLNO ) is considered to be more sensitive to decrement of alveolar membrane diffusive conductance than DLCO . Standard DLCO and DLNO were compared in 96 SSc subjects with or without lung restriction. Data showed that DLNO was reduced in 22% of subjects with normal lung volumes and DLCO , whereas DLCO was normal in 30% of those with decreased DLNO . In 30 subjects with available computed tomography of the chest, both DLCO and DLNO were negatively correlated with the extent of pulmonary fibrosis. However, DLNO but not DLCO was always reduced in subjects with ≥ 5% fibrosis, and also decreased in some subjects with < 5% fibrosis. DMCO and VC partitioning and Doppler ultrasound-determined systolic pulmonary artery pressure could not explain individual differences in DLCO and DLNO . DLNO may be of clinical value in SSc because it is more sensitive to DMCO loss than standard DLCO , even in nonrestricted subjects without fibrosis, whereas DLCO partitioning into its subcomponents does not provide information on whether diffusion limitation is primarily due to vascular or interstitial lung disease in individual subjects. Moreover, decreased DLCO in the absence of lung restriction does not allow to suspect pulmonary arterial hypertension without fibrosis.

Standardisation and application of the single-breath determination of nitric oxide uptake in the lung.

Diffusing capacity of the lung for nitric oxide (DLNO), otherwise known as the transfer factor, was first measured in 1983. This document standardises the technique and application of single-breath DLNO This panel agrees that 1) pulmonary function systems should allow for mixing and measurement of both nitric oxide (NO) and carbon monoxide (CO) gases directly from an inspiratory reservoir just before use, with expired concentrations measured from an alveolar "collection" or continuously sampled via rapid gas analysers; 2) breath-hold time should be 10 s with chemiluminescence NO analysers, or 4-6 s to accommodate the smaller detection range of the NO electrochemical cell; 3) inspired NO and oxygen concentrations should be 40-60 ppm and close to 21%, respectively; 4) the alveolar oxygen tension (PAO2 ) should be measured by sampling the expired gas; 5) a finite specific conductance in the blood for NO (θNO) should be assumed as 4.5 mL·min-1·mmHg-1·mL-1 of blood; 6) the equation for 1/θCO should be (0.0062·PAO2 +1.16)·(ideal haemoglobin/measured haemoglobin) based on breath-holding PAO2 and adjusted to an average haemoglobin concentration (male 14.6 g·dL-1, female 13.4 g·dL-1); 7) a membrane diffusing capacity ratio (DMNO/DMCO) should be 1.97, based on tissue diffusivity.

2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung.

This document provides an update to the European Respiratory Society (ERS)/American Thoracic Society (ATS) technical standards for single-breath carbon monoxide uptake in the lung that was last updated in 2005. Although both DLCO (diffusing capacity) and TLCO (transfer factor) are valid terms to describe the uptake of carbon monoxide in the lung, the term DLCO is used in this document. A joint taskforce appointed by the ERS and ATS reviewed the recent literature on the measurement of DLCO and surveyed the current technical capabilities of instrumentation being manufactured around the world. The recommendations in this document represent the consensus of the taskforce members in regard to the evidence available for various aspects of DLCO measurement. Furthermore, it reflects the expert opinion of the taskforce members on areas in which peer-reviewed evidence was either not available or was incomplete. The major changes in these technical standards relate to DLCO measurement with systems using rapidly responding gas analysers for carbon monoxide and the tracer gas, which are now the most common type of DLCO instrumentation being manufactured. Technical improvements and the increased capability afforded by these new systems permit enhanced measurement of DLCO and the opportunity to include other optional measures of lung function.

[Pulmonary CO/NO transfer: physiological basis, technical aspects and clinical impact]. / Le double transfert pulmonaire CO/NO : bases physiologiques, aspects techniques et intérêt pratique.

Diseases affecting the alveolar-capillary membrane or the capillary blood vessels can impair pulmonary gas exchanges and lung diffusion. The single-breath transfer factor of the lung for carbon monoxide (TL,CO) is the classical technique for measuring gas transfer from the alveolus to the pulmonary capillary blood. Pulmonary gas exchanges can also be explored by the transfer factor of the lung for nitric oxide (TL,NO). TL,NO represents a better index for the diffusing capacity of the alveolar-capillary membrane whereas TL,CO is more influenced by red blood cell resistance. Membrane diffusing capacity (DM) and pulmonary capillary blood volume (Vc) derivated from TL,CO and TL,NO by the Roughton-Forster equation can give additional insights into pulmonary pathologies. The clinical impact of the CO/NO transfer has still to be precised even if this measurement seems to provide an alternative way of investigating the alveolar membrane and the blood reacting with the gas.

Pulmonary function test quality in the elderly: a comparison with younger adults.

BACKGROUND: Elderly patients may be at greater risk for misdiagnosis and inappropriate treatment as a consequence of pulmonary function test underutilization and tests being conducted with low quality expectations. This study sought to determine if elderly patients are able to achieve both spirometry and diffusion capacity (DLCO) quality scores comparable to a younger adult population. METHODS: This was a retrospective review of pulmonary function data over a 22 month period. A list of every subject age ≥ 80 years (elderly group) and ages 40-50 years (control group) tested during the time period was compiled. The quality of spirometry and DLCO testing were examined. RESULTS: Overall, 92.6% (139/150) of the elderly group and 91.5% (163/178) of the control group spirometry tests satisfied all American Thoracic Society/European Respiratory Society acceptability and reproducibility criteria (P = .84), and 84.9% (96/113) of the elderly group and 88.5% (108/122) of the control group DLCO tests satisfied all the acceptability and reproducibility criteria (P = .45). CONCLUSIONS: Elderly patients referred to a hospital-based pulmonary function test lab can be expected to achieve spirometry and DLCO quality scores comparable to younger adult patients.

Long-term intersession variability for single-breath diffusing capacity.

BACKGROUND: Characterizing long-term diffusing capacity (DL(CO)) variability is important in assessing quality control for DL(CO) equipment and patient management. Long-term DL(CO) variability has not been reported. OBJECTIVES: It was the aim of this study to characterize long-term variability of DL(CO) in a cohort of biocontrols and to compare different methods of selecting a target value. METHODS: Longitudinal DL(CO) monitoring of biocontrols was performed as part of the inhaled insulin development program; 288 biocontrols were tested twice monthly for up to 5 years using a standardized technique. Variability, expressed either as percent change or DL(CO) units, was assessed using three different target values. RESULTS: The 90th percentile for mean intersession change in DL(CO) was between 10.9 and 15.8% (2.6-4.1 units) depending on the target value. Variability was lowest when the mean of all DL(CO) tests was used as the target value and highest when the baseline DL(CO) was used. The average of the first six DL(CO) tests provided an accurate estimate of the mean DL(CO) value. Using this target, the 90th percentile for mean intersession change was 12.3% and 3.0 units. Variability was stable over time and there were no meaningful associations between variability and demographic factors. CONCLUSIONS: DL(CO) biocontrol deviations >12% or >3.0 units, from the average of the first six tests, indicate that the instrument is not within quality control limits and should be carefully evaluated before further patient testing.

Facing the noise: addressing the endemic variability in D(LCO) testing.

Single-breath diffusing capacity of the lung for carbon monoxide (D(LCO)) is a common pulmonary function test that measures the ability of the lung to exchange gas across the alveolar-capillary interface. D(LCO) testing is used to narrow the differential diagnosis of obstructive and restrictive lung disease, to aid in disability and transplant assessment, and to monitor medication toxicity. The variability in the measurement limits the utility of the test. Variability is attributable to differences in equipment, testing conditions, patient factors, and reference equations. Laboratories can minimize variability by ensuring that equipment meets recommended standards, implementing effective quality control programs, standardizing testing conditions and testing procedures, and accounting for pertinent patient characteristics.

How should the lower limit of the normal range be defined?

Lung function parameters vary considerably with age and body size, so that, unlike many laboratory tests, the normal range of expected values must be individualized. For spirometry, only low values are considered to be abnormal, so the lower limit of normal (LLN) is taken to be equal to the 5th percentile of a healthy, non-smoking population. Simple and commonly used "rules of thumb," such as an FEV(1)/FVC < 0.70 to indicate air-flow obstruction, or assuming values < 80% of predicted to be abnormal, are inaccurate and will cause misclassification, specifically under-diagnosis of abnormalities in younger, taller individuals and over-diagnosis in those older or shorter. A much more accurate LLN for the FEV(1)/FVC ratio, which recognizes the change with age of this measurement, can be easily determined by subtracting 10 (10% or 0.10) from the age specific FEV(1)/FVC predicted for any individual. The analysis and mathematical descriptions of reference data have become increasingly sophisticated in recent years, but the interpretation of values near the LLN continues to carry uncertainty, due to an overlap in values between low normal values and those reflecting early disease. Among patients referred to a pulmonary function laboratory, the pre-test probability of disease may be relatively high, so that even individuals with values above the LLN may be more likely than not to have respiratory disease. A future goal for the pulmonary community would be the development of risk stratified outcome data that would allow an estimation of the probability of disease with progressive decrements in lung function. While interpreting spirometry results near the LLN will continue to be problematic, a more important task for the pulmonary community is to focus on finding the pool of individuals with clear-cut, but undiagnosed, COPD. And for this, good quality spirometry remains the best tool and must be widely available.

Computed tomography score and pulmonary function in infants with chronic lung disease of infancy.

Chronic lung disease of infancy (CLDI) remains a common outcome among infants born extremely prematurely. In older children and adults with lung disease, pulmonary function and computed tomography (CT) scores are used to follow up respiratory disease and assess disease severity. For infants and toddlers, however, these outcomes have been used very infrequently and most often, a dichotomous respiratory outcome (presence or absence of CLDI) is employed. We evaluated the performance of CT score and pulmonary function to differentiate infants and toddlers with CLDI from a control group. CT scans, forced expiratory flows and pulmonary diffusing capacity were obtained in 39 CLDI patients and 41 controls (aged 4-33 months). CT scans were quantified using a scoring system, while pulmonary function was expressed as Z-scores. CT score outperformed pulmonary function in identifying those with CLDI. There were no significant correlations between CT score and pulmonary function. CT score had a better performance than pulmonary function in differentiating individuals with CLDI; however, these outcomes may reflect differing components of the pulmonary pathophysiology of CLDI. This new information on pulmonary outcomes can assist in designing studies with these parameters. Future studies will be required to evaluate which of the outcomes can better detect improvement with therapeutic intervention and/or lung growth.

Clinical validation of the lower limit of normal in lung diffusing capacity: is the lower 5th percentile really the best cut-off value?

The lower limit of normal (LLN) in pulmonary diffusing capacity has been determined by using the lower 5th percentile or 95% confidence interval (CI) obtained from a normal reference population. We aimed to test clinical cut-off values (1-99% CI) and to determine the LLN in a population with interstitial lung disease and in healthy subjects, using receiver operating characteristic (ROC) curve analysis. The best cut-off value of the LLN for differentiating subjects with pathologic proven interstitial lung disease (ILD) from healthy subjects was not the 95% CI, but the 90% CI, which gave 95% sensitivity and 100% specificity. Thus, the 90% CI or the lower 10th percentile for the cut-off value of the LLN might be better than the 95% CI or the lower 5th percentile in differentiating subjects with pathologic proven ILD from healthy subjects.

Diffusing capacity.

The diffusing capacity for carbon monoxide (DL(CO)) is a commonly performed and clinically useful pulmonary function test that provides a quantitative measure of gas transfer in the lungs. It is valuable for evaluating and managing patients with a wide variety of pulmonary disorders, especially patients with interstitial lung disease, pulmonary vascular disease, and obstructive lung disease. Important aspects of the DL(CO) test are discussed including the physiologic principles governing diffusion, testing technique and equipment, technical and physiologic factors influencing DL(CO) variability, DL(CO) test interpretation, and the clinical utility of DL(CO) measurement.

American Thoracic Society/European Respiratory Society 2005 standardization of DL measurement: impact on performance.

BACKGROUND AND OBJECTIVE: An updated standardization statement on measurement of DL(CO) was issued by the American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force in 2005. The aim of this study was to evaluate the effects of new recommendations on the success rate, test efficiency, measurement variability and reported results of DL(CO) testing. METHODS: We prospectively evaluated 55 Chinese patients without previous experience of the DL(CO) test in 2006. Performance and results of the test according to the ATS 1995 and ATS/ERS 2005 acceptability criteria were compared. RESULTS: Using the 2005 criteria, the success rate (maximum four trials) improved from 65% to 85% (change: 20%, 95% CI: 9-31%; P = 0.001). The test efficiency as measured by two-trial and three-trial success rates increased from 25% and 51% to 60% and 78%, respectively (both P < 0.0005). The measurement variability was defined as the mean of absolute differences between two acceptable trial results of DL(CO) for each patient. The means (SD) were 0.60 (0.53) and 0.53 (0.57) mL/min/mm Hg for the old and new criteria, respectively (P = 0.623). The mean DL(CO) decreased slightly by 0.5%, from 14.93 +/- 5.74 (SD) (old criteria) to 14.86 +/- 5.75 mL/min/mm Hg (new criteria) overall, with a mean difference (SD) of -0.07 (0.20) mL/min/mm Hg for the 36 subjects meeting both criteria (paired t-test, P = 0.048). CONCLUSIONS: Success rate and test efficiency for DL(CO) measurement were improved when the new recommendations were adopted. The effects on measurement variability and reported results were minimal.

Standardization of the single-breath diffusing capacity in a multicenter clinical trial.

BACKGROUND: Standardization of the measurement of single-breath diffusing capacity of the lung for carbon monoxide (DLCO) is difficult to implement in multicenter trials as differences in equipment, training, and performance guidelines have led to high variability between and within centers. The safety assessment of inhalable insulin required the standardization of measurement of single-breath DLCO in multicenter clinical trials to optimize test precision. METHODS: This was an open-label, 24-week, parallel-group, outpatient study of inhaled human insulin in participants with type 1 diabetes who were randomly assigned to receive treatment with daily premeal inhaled or subcutaneous (SC) insulin for 12 weeks, followed by SC insulin for 12 weeks. Monitoring of single-breath DLCO using standardized methodology was performed. Standardization included uniform instrumentation, centrally trained study coordinators, and centralized data monitoring and review of quality control. Sites received feedback within 24 h for any tests of unacceptable quality with recommendations for improvement. RESULTS: A total of 226 study participants at 33 sites completed 11,335 DLCO efforts during 4,797 test sessions; 3,607 (75.2%) and 4,581 (95.5%) of all testing sessions yielded two American Thoracic Society-acceptable efforts that varied by < 1 and 2 mL/min/mm Hg, respectively. Only 65 sessions produced one or fewer acceptable efforts. The root mean square intrasubject coefficient of variation in DLCO at the end of the comparative dosing phase was 6.01%. CONCLUSIONS: The standardized methodology employed in this study demonstrates the feasibility of collecting high-quality single-breath DLCO data in the setting of a multicenter clinical trial with reliability that is comparable to spirometry.

Instrument accuracy and reproducibility in measurements of pulmonary function.

BACKGROUND: The objective of the study was to quantify the accuracy and reproducibility of five commercially available pulmonary function test (PFT) instruments (Collins CPL [Ferraris Respiratory; Louisville, CO]; Morgan Transflow Test PFT System [Morgan Scientific; Haverhill, MA]; SensorMedics Vmax 22D [VIASYS Healthcare; Yorba Linda, CA]; Jaeger USA Masterscreen Diffusion TP [VIASYS Healthcare]; and Medical Graphics Profiler DX System [Medical Graphics Corp; St. Paul, MN]) that are associated with spirometry and the measurement of pulmonary diffusing capacity. METHODS: In a multifactor, single-center, repeated-measures, full factorial 90-day study, a pulmonary waveform generator and a single-breath simulator of diffusing capacity of the lung for carbon monoxide (Dlco) were used to perform simulations of FVC and Dlco maneuvers. Accuracy was assessed as the difference between the observed and simulated values. Reproducibility was determined as the coefficient of variation of all measurements made during the study. RESULTS: All instruments demonstrated a high degree of accuracy in the measurement of FVC and FEV(1). Overall, the accuracies associated with the measurement of peak flow, forced expiratory flow, mid-expiratory phase, and diffusing capacity were generally lower and more variable among the instruments tested. The coefficients of variation of Dlco measurements over 90 days were higher than those observed for spirometry. CONCLUSIONS: This study demonstrates the feasibility of assessing the accuracy and reproducibility of modern PFT instruments using simulation testing. Our results provide an assessment of the component of PFT accuracy and reproducibility that is due to instrumentation alone.

Differences between Finnish and European reference values for pulmonary diffusing capacity.

OBJECTIVES: To compare European (ECSC) and Finnish reference values for single-breath diffusing capacity for carbon monoxide (DL(CO)). STUDY DESIGN: Finnish reference values for DL(CO), specific diffusing capacity (DL(CO)/VA) and total lung capacity (TLC) were compared with ECSC reference values calculated for different age, height and weight groups. In addition, 10 healthy subjects performed the test with both the Finnish method (inhaled volume 90% of vital capacity, VC) and the ECSC method (inhaled volume 100% of VC). METHODS: Percentual differences between the ECSC and Finnish reference values for DL(CO), TLC and DL(CO)/VA were calculated. The results of measurements of DL(CO) and TLC by using inhaled volume of 100% of VC and 90% of VC in 10 healthy subjects were compared. RESULTS: The Finnish DL(CO) reference value for men was 3-12% and for women 8-20% smaller than the ECSC reference value. TLC calculated according to Finnish equations was 2-14% greater than that based on ECSC equations. The ECSC reference value for DL(CO)/VA was about 20% greater than the Finnish reference value in men and 30% greater than that in women. The 10 healthy subjects had significantly higher DL(CO) when measured according to the ECSC method as compared with the Finnish one (p < 0.004). CONCLUSIONS: The Finnish reference values for DL(CO) were about 10% smaller, but TLC 10% and DL(CO)/VA 20-30% greater than ECSC reference values in subjects of the same age, height, weight and gender. The difference in DL(CO) is explained by the different inhaled lung volumes used in the two methods, the difference in lung volumes probably arising from ethnic differences in thoracic cavity.