Novel Physiology and Imaging Approaches for Enhanced Detection of Lung Disease in Common Variable Immunodeficiency

Background Common variable immunodeficiency (CVID) is an inborn error of immunity (IEI) characterized by hypogammaglobulinemia and impaired specific antibody responses. This fundamental crippling of immunity predisposes affected individuals to respiratory infections, inflammation, and malignancy, all of which contribute to CVID-associated lung disease. Early detection and treatment of lung disease in individuals with CVID is crucial for reducing both morbidity and mortality. However, existing diagnostic techniques carry limitations, ranging from the radiation exposure associated with computed tomography (CT) to the insensitivity of pulmonary function tests (PFTs). Objectives We aimed to assess the feasibility and sensitivity of novel lung monitoring tools (multiple breath washout [MBW] and hyperpolarized 129-xenon magnetic resonance imaging [XeMRI]) in individuals with CVID and known lung disease, compared with CT and PFTs. Methods MBW and XeMRI tests were performed during a single visit, and CT scan and PFT results were abstracted from clinical documentation within 3 months of the study visit. The MBW test assesses the gas clearing efficiency of the lungs by measuring the rate of clearance of a tracer gas over repeated cycles of free breathing (primary outcome is the lung clearance index [LCI], where a higher value reflects abnormal pulmonary physiology). XeMRI measures regional lung ventilation and gas exchange using hyperpolarized xenon gas as a contrast agent. Ventilation defect percent (VDP) serves as a whole-lung measure of ventilation inhomogeneity. Results We describe a cohort of five individuals with CVID and known lung disease, defined as bronchiectasis or interstitial lung disease on CT scan. Only one was classified as abnormal based on pulmonary function tests (PFTs). In contrast, 4/5 (80%) individuals were identified as abnormal through the MBW test; all five participants exhibited an abnormal VDP (Table 1). Table 1. CVID participant clinical info and lung function data compared with thresholds of normal. HC = healthy control; BE = bronchiectasis; ILD = interstitial lung disease; FVC = forced vital capacity; FEV1 = forced vital capacity in one second; TLC = total lung capacity; DLCO = diffusing capacity of the lungs for carbon monoxide; LCI = lung clearance index; VDP = ventilation defect percent. PFT and MBW z-scores are calculated using the reference equations from the Global Lung Function Initiative. Abnormal results are considered z-scores: <-1.65 (for PFTs) and >1.65 (for MBW). A VDP greater than 1% is considered abnormal, based on a threshold set in previous work. CVID Participant Data, Compared to Thresholds of Normal Participant 1 2 3 4 5 Clinical Info Age 35 22 34 38 56 Sex Male Male Male Male Male Lung Disease BE/ILD BE ILD ILD BE PFTs z-score FVC 0.04 0.62 -2.60* 0.57 1.60 FEV1 1.37 0.98 -3.27* -0.29 1.18 TLC -1.33 0.28 n/a 0.44 1.10 DLCO -0.34 -0.01 -5.26* -0.28 -0.01 MBW z-score LCI 1.88* 1.27 7.71* 1.92* 1.95* XeMRI VDP (%) 1.82* 1.93* 6.26* 1.88* 1.92* * denotes above/below the threshold of normal. Conclusions These findings illustrate that MBW and XeMRI can detect lung pathology in CVID patients overlooked by standard PFTs and without the radiation risk of CT scans. These novel modalities may, in the future, offer additional screening tools for clinicians to monitor for lung disease in this high-risk population, potentially providing an opportunity for earlier diagnosis and treatment. Figure 1. Representative images of ventilation from hyperpolarized xenon MRI. Yellow colored image is the xenon MRI signal overlaid on top of the structural MRI proton image. (A) A healthy 32-year-old participant (VDP = 0.37%) and (B) CVID participant 1 with CT-diagnosed interstitial lung disease and bronchiectasis (VDP = 1.82%). Arrows indicate regions of defective ventilation.