Alveolar membrane and capillary function in COVID-19 convalescents: insights from chest MRI

Objectives To investigate potential presence and resolution of longer-term pulmonary diffusion limitation and microvascular perfusion impairment in COVID-19 convalescents. Materials and methods This prospective, longitudinal study was carried out between May 2020 and April 2023. COVID-19 convalescents repeatedly and age/sex-matched healthy controls once underwent MRI including hyperpolarized 129Xe MRI. Blood samples were obtained in COVID-19 convalescents for immunophenotyping. Ratios of 129Xe in red blood cells (RBC), tissue/plasma (TP), and gas phase (GP) as well as lung surface-volume ratio were quantified and correlations with CD4+/CD8+ T cell frequencies were assessed using Pearson’s correlation coefficient. Signed-rank tests were used for longitudinal and U tests for group comparisons. Results Thirty-five participants were recruited. Twenty-three COVID-19 convalescents (age 52.1 ± 19.4 years, 13 men) underwent baseline MRI 12.6 ± 4.2 weeks after symptom onset. Fourteen COVID-19 convalescents underwent follow-up MRI and 12 were included for longitudinal comparison (baseline MRI at 11.5 ± 2.7 weeks and follow-up 38.0 ± 5.5 weeks). Twelve matched controls were included for comparison. In COVID-19 convalescents, RBC-TP was increased at follow-up (p = 0.04). Baseline RBC-TP was lower in patients treated on intensive care unit (p = 0.03) and in patients with severe/critical disease (p = 0.006). RBC-TP correlated with CD4+/CD8+ T cell frequencies (R = 0.61/ − 0.60) at baseline. RBC-TP was not significantly different compared to matched controls at follow-up (p = 0.25). Conclusion Impaired microvascular pulmonary perfusion and alveolar membrane function persisted 12 weeks after symptom onset and resolved within 38 weeks after COVID-19 symptom onset. Clinical relevance statement 129Xe MRI shows improvement of microvascular pulmonary perfusion and alveolar membrane function between 11.5 ± 2.7 weeks and 38.0 ± 5.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease. Key Points • The study aims to investigate long-term effects of COVID-19 on lung function, in particular gas uptake efficiency, and on the cardiovascular system. • In COVID-19 convalescents, the ratio of 129Xe in red blood cells/tissue plasma increased longitudinally (p = 0.04), but was not different from matched controls at follow-up (p = 0.25). • Microvascular pulmonary perfusion and alveolar membrane function are impaired 11.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease at 38.0 weeks. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-024-10669-9.


Imaging Methods
Regional lung perfusion was evaluated by three-dimensional dynamic contrast-enhanced (DCE) timeresolved angiography with stochastic trajectories volume-interpolated breath-hold examination (TWIST-VIBE) using the following MR imaging parameters: TR/TE 2.85/0.72 ms; flip angle 20°; 50 three-dimensional data sets with an update rate of 1.0-1.2s; acquisition matrix 224 × 182; field of view 50 cm × 40.6 cm; 0.04 mmol/kg gadoteric acid at 5cc/s i.v.; 44-52 reconstructed coronal slices (slice thickness 5 mm) covering the whole lung were acquired in a single breath-hold.
Cardiac function was evaluated by retrospectively ECG-gated cine balanced steady-state free precession sequences during short inspiratory breath holds using short-axis views covering the whole heart with following MRI parameters: TR/TE 43.35/

Data Analysis
129 Xe dissolved-phase imaging data were reconstructed using the parallel imaging/compressed sensing routine of Berkeley Advanced Reconstruction Toolbox (1).Reconstructed images of the 129 Xe dissolved phase were then separated in RBC and TP signals using hierarchical IDEAL (2).Masks were generated based on an SNR threshold and voxel values summed within the mask to obtain whole lung values for dissolved-phase ratios.
Data from dynamic spectroscopy were apodized by a von Hann window, zero-filled to two-fold resolution, Fourier-transformed and the first 15 spectra discarded.Zeroth order phase correction was performed by applying DISPA to the gas-phase resonance (3).Real parts of complex Lorentzians were fit to the real parts of the spectra for RBC, TP and gas resonance.
In diffusion-weighted imaging, a function of the form

Results
Supporting second-order approximation in the analysis of time-dependent diffusion by Mitra et al. was fit to the data in order to determine lung surface-volume ratio Sa/Vg.Here, Δ denotes the diffusion time, D0 = 0.14 cm 2 /s denotes the free diffusion coefficient of 129 Xe dilute in air, α = 0.289 denotes a constant depending on diffusion-weighting gradient lobes, and B' an additional fitting parameter depending on lung microstructure but not readily interpretable in terms of histologic quantities.CSSR data were Fourier-transformed and phase-corrected to zeroth and first order and peak amplitudes in real parts of the spectra integrated numerically.The ratio of RBC and GP amplitudes was computed and the model function F fit to the data.First-pass DCE MR images were used for calculating parenchymal microvascular pulmonary blood flow maps by using a pixel-by-pixel deconvolution analysis with a home-written plugin for Visage 7 software (Visage Imaging, Inc.).Arterial input function was derived with a region of interest in the main pulmonary artery.Regions of interest were drawn on the lung perfusion maps excluding larger pulmonary vessels.Mean parenchymal pulmonary blood flow was calculated for the total lung.Eur Radiol (2024) Kern AL, Pink I, Bonifacius A et al Short-axis cine MR images were analyzed with dedicated software (CVI42 software, Circle Cardiovascular Imaging Inc.).Cine images were analyzed by semiautomated contour detection for left-ventricular and right-ventricular endo-and epicardial contours in end-diastole and end-systole by TK.Papillary muscles as well as myocardial trabeculations were included in the blood pool (4).Manual corrections were performed if necessary.Using short-axis cine images, the following parameters were evaluated for the left ventricle and the right ventricle: stroke volume, ejection fraction, end-diastolic volume and end-systolic volume, myocardial mass.Volumes and masses were normalized to body surface area.