Introduction
There is significant debate over including variables like altitude and race in lung function prediction. Some experts argue that race lacks biological justification and may perpetuate health disparities.1 Currently, no comprehensive reference equations exist for individuals from diverse geographic areas and ethnic backgrounds. Using race-specific equations can disadvantage under-represented groups. The American Thoracic Society (ATS) recommends pulmonary function testing (PFT) laboratories adopt a race-neutral approach using the Global Lung Function Initiative (GLI) global reference equations, which pool data across all races and ethnicities.2 While race-neutral equations are available for spirometry,3 similar approaches for lung volumes and pulmonary diffusing capacity are expected soon.
Several studies show that lung function measurements are influenced by race/ethnicity.4 For instance, race/ethnicity accounts for 15% of the variance in vital capacity (VC), with black people having ~15% lower VC than age, height and sex-matched white people.5 Pulmonary diffusing capacity for carbon monoxide (DLCO) is also approximately 2 to 4 mL/min/mm Hg lower in black people compared with white people, even when adjusted for age, height, sex, vital capacity, and haemoglobin (Hb) concentration.6 7 Using DLCO prediction equations for white people in the black population incorrectly overestimates the lower limit of normal (LLN) by ~12%,8 mislabelling many healthy black individuals as having abnormal DLCO values.
The simultaneous measurement of lung diffusing capacity for nitric oxide (DLNO) and lung diffusing capacity for carbon monoxide (DLCO) using the NO–CO double diffusion technique9 has recently gained popularity. The European Respiratory Society’s (ERS) 2017 standards provide universal guidelines for this technique, likely increasing its use among pulmonologists. DLNO is recommended for routine PFT due to its technical advantages over CO10 and its patient-friendliness compared with the multistep Roughton and Forster technique.11 Given the racial disparities observed in DLNO, particularly among African Americans, it is crucial to assess if race-neutral reference equations for DLNO might be more effective than race-specific reference equations.
One of the most promising aspects of DLNO measurement is its relative insensitivity to inspired oxygen concentration. Unlike DLCO, where an ~1% decrease in inspired oxygen concentration correlates with an ~1.3% increase in DLCO,12–14 the change in DLNO remains negligible.15 However, it remains unclear whether DLNO is influenced in individuals who were born and raised at moderate altitudes since birth (2240 m, herewith called midlanders), where arterial oxygen pressure typically averages around 70 mm Hg.16 Is there an adaptation to the alveolar-capillary membrane that enhances DLNO among individuals accustomed to such altitudes throughout their lives?
This study has two primary aims: first, to investigate differences in DLNO, DLCO, alveolar volume (VA) and the rate of change of NO or CO from alveolar gas (KNO, KCO) between Mexican Hispanics from Mexico City and those from sea level (lowlanders) and second to examine racial disparities in diffusing capacity between white people of Eastern European origin and Mexican Hispanics. By merging datasets of Eastern European descent10 with Mexican Hispanics, we assessed racial/ethnic differences in pulmonary diffusing capacity, allowing for a comparison between race-specific and race-neutral approaches in developing reference equations. We hypothesised that race/ethnicity would independently predict DLCO, DLNO, VA, KCO and KNO, potentially interacting with factors like height, height², age or age². Additionally, we proposed that being born and raised at 2240 m altitude would induce adaptations to the alveolar-capillary membrane, enhancing DLNO, VA and KNO compared with individuals raised at sea level, after controlling for other covariates.