Lung Diffusing Capacities Normality Thresholds in Pulmonary Fibrosis and Emphysema (DLNO-DLCO_emph)

Lung Diffusing Capacity Thresholds for the Assessment of Pulmonary Fibrosis and Emphysema: a Structure-to-function Study

The investigators tested the usefulness of lung diffusing capacities for carbon monoxide (DLco) and nitric oxide (DLNO) normality thresholds of 5th and 2.5th percentiles for the assessment of intersitial pulmonary fibrosis (IPF) and pulmonary emphysema (PE). Computed tomography (CT) of the chest was taken as a gold standard for the presence of lung parenchymal abnormalities typical of these conditions. The investigators retrospectively utilized the DLco and DLNO data obtained by a single device in sixty-six subjects with IPF included in two previous studies and in fifty-four new subjects with PE, both documented by quantitative CT of the chest.

Study Overview

• Status: Completed
• Conditions: Interstitial Pulmonary Fibrosis, Emphysema

Detailed Description

The measurement of pulmonary diffusion is the key diagnostic and monitoring tool to examine the integrity of air-blood barrier. Traditionally, the lung diffusing capacity for carbon monoxide (DLco) has been widely used in both interstitial pulmonary fibrosis (IPF) and pulmonary emphysema (PE) and is currently recommended as a standard lung function measure. More recently, the measurement of lung diffusing capacity for nitric oxide (DLNO) was introduced and subsequently standardized on the premise that it is a more specific marker of alveolar membrane diffusive conductance (DM) than DLco. For DLco, several predicting equations were made available over the years, but the changes in equipment and measurement techniques made them outdated, and a new set of standardized reference equations was provided by the Global Lung Function Initiative (GLI). For the DLNO, reference equations were provided by four small studies and the data of three of them were eventually pooled by a European Respiratory Society (ERS) Task Force to derive predicting equations with suitable sample size. Major limitations of this initiative were that no sex-specific separate equations were derived, and the pooled data had been obtained by different devices without robust technical standardization. Sex- and device-specific predicting equations for DLNO have been subsequently made available by two studies, using a single device or including sex and device as covariates.

The choice of reference equations is a crucial issue in the assessment of respiratory function, as it may impact on both definition of normality and assessment of severity. Although for long time the sex-, age- and size-biased percentages of predicted were used for these purposes, the use of z-score is currently recommended as an unbiased estimator of the probability for an individual to deviate from normality. The 5th percentile (-1.645 z-score) of the reference population is currently recommended as the lower limit of normal (LLN5) for all standard lung function measurements including DLco, but for DLNO either LLN5 or the 2.5th percentile (LLN2.5, -1.960 z-score) have been also recommended.

In any case, lung function measures are a continuum and a z-score below a probabilistic threshold such as the LLN5 or LLN2.5 does not necessarily indicate a clinically meaningful abnormality to diagnose a disease but gives the probability of a false positive diagnosis in a healthy subject. By converse, z-scores above these thresholds do not allow to rule out disease with certainty due to the known overlap between healthy and diseased distributions, which may vary depending on various factors including nature and severity of disease, type and method of measures, and reference equations. These proposed limits of normality were based on the distribution in healthy population but not validated for the accuracy to separate diseased from healthy subjects.

The investigators designed the present study with the primary aim to test whether the z-score thresholds of DLco and DLNO separating IPF and PE from healthy subjects may differ from LLN5 or LLN2.5. A secondary aim of the study was to estimate the impact of the choice of test and predicting equations on severity stratification in relation to the extent of lung parenchymal abnormalities typical of IPF and PE. For these purposes, the investigators retrospectively utilized the DLco and DLNO data obtained by a single device in sixty-six subjects with IPF included in two previous studies and in fifty-four new subjects with PE, both documented by quantitative CT of the chest.

• Study Type: Observational
• Enrollment (Actual): 120

Contacts and Locations

Study Locations

• Italy
  • Genova, Italy, 16132
    • IRCCS Ospedale Policlinico San Martino

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Asymptomatic healthy controls with lung function parameters above the LLN5, i.e., -1.645 z-score. Moreover, subjects of white European ancestry with CT-determined IPF and/or PE

Description

Inclusion Criteria:

• Asymptomatic healthy controls with lung function parameters above the LLN5, i.e., -1.645 z-score
• Subjects of white European ancestry with CT-determined IPF and/or PE

Exclusion Criteria:

• All subjects with history of any comorbidities potentially affecting lung diffusing capacity, i.e., congestive heart failure, liver or kidney diseases, and morbid obesity

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Healthy control; Asymptomatic healthy subjects, selected among health professionals and their relatives
Interstitial Pulmonary Fibrosis (IPF); Subjects from investigators' previous studies with interstitial pulmonary fibrosis (IPF), 43 due to usual or nonspecific interstitial pneumonia and 23 to systemic sclerosis
Subjects with a smoking history ≥10 pack-years and computed tomography-determined emphysema

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lung diffusing capacities for carbon monoxide (DLco) and nitric oxide (DLNO) normality thresholds in IPF and emphysema		"Baseline" or "Day 1"
The receiver operating characteristics (ROC)-derived DLco and DLNO normality thresholds for the assessment of interstitial pulmonary fibrosis (IPF) and pulmonary emphysema (PE)	DLco and DLNO thresholds may change depending on chosen reference equations, device, sex, and disease condition	"Baseline" or "Day 1"

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

Publications and helpful links

General Publications

• Zavorsky GS, Hsia CC, Hughes JM, Borland CD, Guenard H, van der Lee I, Steenbruggen I, Naeije R, Cao J, Dinh-Xuan AT. Standardisation and application of the single-breath determination of nitric oxide uptake in the lung. Eur Respir J. 2017 Feb 8;49(2):1600962. doi: 10.1183/13993003.00962-2016. Print 2017 Feb.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2025
• Primary Completion (Actual): June 30, 2025
• Study Completion (Actual): July 7, 2025

Study Registration Dates

• First Submitted: July 16, 2025
• First Submitted That Met QC Criteria: July 24, 2025
• First Posted (Actual): July 29, 2025

Study Record Updates

• Last Update Posted (Actual): July 29, 2025
• Last Update Submitted That Met QC Criteria: July 24, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Lung diffusing capacity; pulmonary emphysema; Lower limit of normal; interstitial pulmonary fibrosis
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Lung Diseases, Interstitial; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Fibrosis; Pulmonary Emphysema; Emphysema
• Other Study ID Numbers: Liguria: 59/2025 - id 14300

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: Beginning 1 year after publication with no end date
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Study Data/Documents

1. Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No