Characterizing Pulmonary Gas Exchange in Inborn Errors of Immunity Using Hyperpolarized Xenon MRI

Rationale Inborn errors of immunity (IEIs) predispose individuals to recurrent respiratory infections and immune dysregulation, which together can drive inflammatory lung complications, including interstitial lung disease and thickening of the interstitial (alveolar–capillary) membrane. These changes are often subtle and may not be captured by conventional lung function testing. Hyperpolarized 129Xe MRI (XeMRI) is a novel, noninvasive technique that quantifies regional gas exchange by leveraging xenon’s solubility in distinct pulmonary compartments: airspaces (Gas), interstitial membrane (Mem), and capillary red blood cells (RBC). Objectives Evaluate whether XeMRI can detect differences in pulmonary gas exchange in people with IEIs (pwIEIs) by comparing gas exchange ratios (Mem/Gas, RBC/Gas, and RBC/Mem) with healthy controls (HCs). Methods XeMRI was performed using a four-echo, 3D radial spectroscopic sequence to quantify compartment-specific signals (Gas, Mem, and RBC). All scans were acquired during a standardized breath-hold following inhalation of a hyperpolarized 129Xe/N2 mixture. Carbon monoxide transfer coefficients (Kco), reported as GLI z-scores, were obtained from routine testing within three months of imaging for qualitative comparison. Group differences between pwIEIs and HCs were assessed using two-sided Mann–Whitney U tests for Mem/Gas (xenon uptake in membrane relative to gas), RBC/Gas (xenon uptake in RBCs relative to gas), and RBC/Mem (xenon uptake in RBCs relative to membrane). Results Seventeen pwIEIs (3F/14M; median age 28 years [Q1–Q3: 16–37]) and ten HC (3F/7M; median age 22 years [Q1–Q3: 15–23]) were included; HC recruitment is ongoing. Mem/Gas was significantly higher in pwIEIs than in HCs (0.0159 vs. 0.0134, p = 0.0459), while RBC/Mem was significantly lower in pwIEIs (0.4124 vs. 0.4624, p = 0.0355). RBC/Gas did not differ between groups (0.0057 vs. 0.0057, p=0.9019). Four pwIEIs (23.5%) had reduced Kco values (z < 1.3, <10th percentile); however, Kco showed no clear relationship with any gas-exchange ratios Conclusions: pwIEIs, many of whom had normal lung function tests, showed increased xenon signal within the interstitial compartment with reduced transfer into the blood relative to the membrane signal. This pattern is consistent with mild interstitial pathology and suggests that XeMRI may provide a sensitive, noninvasive method for detecting interstitial pulmonary involvement in pwIEIs. Figure 1. XeMRI-derived gas-exchange ratios in people with inborn errors of immunity and healthy controls. Violin plots show group differences in hyperpolarized XeMRI ratios: (A) RBC/Gas, (B) RBC/Mem, and (C) Mem/Gas. People with inborn errors of immunity had a higher Mem/Gas ratio (p=0.0459) and lower RBC/Mem ratio (p = 0.0355) compared to healthy controls, with no difference in RBC/Gas ratio (p=0.9019). White-filled points denote individuals with reduced Kco (z < −1.3, <10th percentile). RBC, red blood cell; Mem, interstitial (alveolar-capillary) membrane; Gas, airspaces; HC, healthy controls; IEI, inborn error of immunity; Kco, carbon monoxide transfer coefficient.