PMC9344132_01
Chest CT Scan 1 year pre-lung transplant. Chest CT Scan 1 year pre-lung transplant (2016), with representative coronal and axial section, demonstrating interstitial lung disease, with parenchymal fibrosis and ground glass opacities, due to alveolar lipoproteinosis caused by hereditary pulmonary alveolar proteinosis. Radiologic signs of irreversible fibrosis included thickening of intra- and interlobar septae (reticulation), traction bronchiectasis and honeycombing. Architectural distortion was more prominent in the anterior en apical lung fields compared to the postero-basal lung fields. A secondary spontaneous partial pneumothorax was present, situated bilateral apico-lateral (dehiscence: left side 8 mm and right side 5 mm). An estimate of the ratio (%) fibrosis vs. ground glass opacification or normal appearing lung parenchyma per lobe is given in blue (visual scoring by a skilled chest radiologist with expertise in pulmonary fibrosis). The respective perfusion (%) of each lung and individual lobe is given in red, illustrating regional differences due to hypoxic vasoconstriction. Perfusion was measured using technetium-99m radioisotope (122.0 MBq, 3.30 mCI) and Pulmonics software. RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe.
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Eventual findings were compatible with progressive interstitial lung disease with extensive lung fibrosis ( Figures 1  and  2 , and  Supplementary Figure 2 ).
Explanted left lung ex vivo CT, micro-CT and histology. (A)
Ex vivo CT. (B) Upper lobe lung tissue core micro-CT (C) Lower lobe lung tissue core micro-CT. (D) Upper lobe lung tissue core histology. (E) Lower lobe lung tissue core histology. Explanted left lung ex vivo CT (A), micro-CT images (B, C) and histology (D, E) of 2 lung tissue cores demonstrating severe interstitial lung disease, with heterogenous distribution, resulting in architectural deformation of the lung ultrastructure, as a result of end-stage hereditary pulmonary alveolar proteinosis. The lung was recovered at lung transplantation, and processed for imaging and histology as previously described. Multidetector CT was obtained using a Siemens Somatom (120 kV, Br59d reconstruction kernel, pixel spacing: 0.7 mm, 1 mm slice thickness) to determine the localization of cores in the lung. Afterwards, the lung was sawed in sections of 2 cm using a bandsaw, and cores of 1.4 cm diameter were taken in the apex and basal part using a hole saw. These lung tissue cores were chemically dried using hexamethyldisilazane (Sigma-Aldrich, USA) and scanned with a Skyscan 1272 microCT scanner (50 kV, 200 microA, voxel size: 8.1 microm, Bruker, Kontich, Belgium). Animated videos of the in vivo CT prior to lung transplantation and the ex vivo CT and micro-CT of the explanted left lung are presented in 
Supplemental Figure 2
. For histology, tissue cores were routinely formalin-fixed and paraffin embedded. Sections of 5 microm were subsequently stained with Hematoxylin and Eosin (H&E) using an automated H&E platform (CoverStainer, Dako Agilent) and with Periodic Acid Schiff (PAS) using an automated special staining system (Artisan Link Pro Special Staining System, Dako Agilent). Corresponding histological images are shown from upper/lower lobe tissue core: hematoxylin eosin (H&E) staining (left), and Periodic Acid Schiff (PAS) staining after diastase digestion (right) (200x total magnification). The lung parenchyma shows an overt fibrotic remodeled alveolar parenchyma, with thickening of intra- and interlobar septae (reticulation), traction bronchiectasis/bronchiolectasis, honeycombing and prominent filling of the alveolar spaces with a granular eosinophilic proteinaceous material, which stains strongly PAS positive. Architectural distortion due to these histologic changes was observed both in the apical and basal lung fields/cores.
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Eventual findings were compatible with progressive interstitial lung disease with extensive lung fibrosis ( Figures 1  and  2 , and  Supplementary Figure 2 ).
PMC9344132_02
PMC9344132_03
Evolution of pulmonary function and chest CT over time. (A) Pulmonary function. (B) Chest CT. Evolution of pulmonary function over time in relation to lung transplantation (LTx) and allogeneic hematopoietic stem cell (Allo-HCT) for hereditary pulmonary alveolar proteinosis (A), which are indicated by dotted lines. Dots represent individual measurements of lung volumes (Liters), with connecting lines between measurements showing the trend of individual lung function parameters over time. Evolution of chest computed tomography (CT) function over time (B), with representative inspiratory phase images at 3 months, 6 months 1 year and 4 years post-lung transplantation (LTx). Allogeneic hematopoietic stem cell (Allo-HCT) was performed 11 months after prior lung transplantation. At 4.5 years after lung transplantation there is currently no evidence for chronic lung allograft dysfunction, graft-versus-host disease, or recurrence of hereditary pulmonary alveolar proteinosis. FVC, forced vital capacity; FEV1, forced expiratory volume in one second; FEF25-75, forced expiratory flow at 25-75% of forced vital capacity; TLC, total lung capacity; TLCO, transfer capacity of the lung, for the uptake of carbon monoxide (CO) (also called diffusing capacity for carbon monoxide).
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There was an uneventful clinical course during the following years, except for intermittent Epstein-Barr-virus (EBV) reactivation without evolution to post-transplantation lymphoproliferative disease, but otherwise no respiratory tract infections, acute pulmonary rejection episodes, development of chronic lung allograft dysfunction, pulmonary or extra-pulmonary GvHD, or PAP-recurrence at present, 4.5 years after lung transplantation. ( Figure 3 ) Meanwhile, the patient has an excellent quality of life, is actively performing sports (fitness, paddle, cycling), has successfully finished his University Master's studies, obtained a Postgraduate Degree, and is at present full-time working as Data Analyst.