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Background: Chronic lung allograft dysfunction (CLAD) encompasses three main phenotypes: bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS) and a Mixed phenotype combining both pathologies. How the airway structure in its entirety is affected in these phenotypes is still poorly understood., Methods: A detailed analysis of airway morphometry was applied to gain insights on the effects of airway remodelling on the distribution of alveolar ventilation in end-stage CLAD. Ex vivo whole lung μCT and tissue-core μCT scanning of six control, six BOS, three RAS and three Mixed explant lung grafts (9 male, 9 female, 2014-2021, Leuven, Belgium) were used for digital airway reconstruction and calculation of airway dimensions in relation to luminal obstructions., Findings: BOS and Mixed explants demonstrated airway obstructions of proximal bronchioles (starting at generation five), while RAS explants particularly had airway obstructions in the most distal bronchioles (generation >12). In BOS and Mixed explants 76% and 84% of bronchioles were obstructed, respectively, while this was 22% in RAS. Bronchiolar obstructions were mainly caused by lymphocytic inflammation of the airway wall or fibrotic remodelling, i.e. constrictive bronchiolitis. Proximal bronchiolectasis and imbalance in distal lung ventilation were present in all CLAD phenotypes and explain poor lung function and deterioration of specific lung function parameters., Interpretation: Alterations in the structure of conducting bronchioles revealed CLAD to affect alveolar ventilatory distribution in a regional fashion. The significance of various obstructions, particularly those associated with mucus, is highlighted., Funding: This research was funded with the National research fund Flanders (G060322N), received by R.V., Competing Interests: Declaration of interests JK and VG and MV are junior research fellows of the Research Foundation Flanders (FWO; 1198920N and 1102020N and 1SE433N). MV received compensation from Sanofi for attending the ERS 2023 congress. GPLA is a supported by an European Respirology Society Clinical Fellowship Grant. SB is supported by the Paul Corris International Clinical Research Training Scholarship. LJDS (De Sadeleer) is supported by the European Union's Horizon Europe research and innovation programme as a Marie Sklodowska-Curie actions postdoctoral fellowship (grant agreement No. 101066289)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: COPD is characterized by chronic airway inflammation, small airways changes, with disappearance and obstruction, and also distal/alveolar destruction (emphysema). The chronology by which these three features evolve with altered mucosal immunity remains elusive. This study assessed the mucosal immune defense in human control and end-stage COPD lungs, by detailed microCT and RNA transcriptomic analysis of diversely affected zones., Methods: In 11 control (non-used donors) and 11 COPD (end-stage) explant frozen lungs, 4 cylinders/cores were processed per lung for microCT and tissue transcriptomics. MicroCT was used to quantify tissue percentage and alveolar surface density to classify the COPD cores in mild, moderate and severe alveolar destruction groups, as well as to quantify terminal bronchioles in each group. Transcriptomics of each core assessed fold changes in innate and adaptive cells and pathway enrichment score between control and COPD cores. Immunostainings of immune cells were performed for validation., Results: In mildly affected zones, decreased defensins and increased mucus production were observed, along CD8+ T cell accumulation and activation of the IgA pathway. In more severely affected zones, CD68+ myeloid antigen-presenting cells, CD4+ T cells and B cells, as well as MHCII and IgA pathway genes were upregulated. In contrast, terminal bronchioles were decreased in all COPD cores., Conclusion: Spatial investigation of end-stage COPD lungs show that mucosal defense dysregulation with decreased defensins and increased mucus and IgA responses, start concomitantly with CD8+ T-cell accumulation in mild emphysema zones, where terminal bronchioles are already decreased. In contrast, adaptive Th and B cell activation is observed in areas with more advanced tissue destruction. This study suggests that in COPD innate immune alterations occur early in the tissue destruction process, which affects both the alveoli and the terminal bronchioles, before the onset of an adaptive immune response., Competing Interests: IG reports travel support from AstraZeneca, not related to the content of this work. MV reports travel support from Sanofi, not related to the content of this manuscript. SE reports consulting fees from GSK, lecture honoraria from GSK, Boehringer Ingelheim, Chiesi and AstraZeneca, travel support from GSK and Sanofi, not related to the content of this manuscript. WJ reports grants and lecture honoraria from AstraZeneca and Chiesi, consulting fees from AstraZeneca, Griffols, GSK and Chiesi and travel support from Chiesi and AstraZeneca; has a leadership or fiduciary role in Board of VRGT and Board of ArtiQ, and is a co-founder and shareholder of ArtiQ NV. NK served as consultant for Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Astra Zeneca, RohBar, Veracyte, Augmanity, CSL Behring, Thyron, BMS, Biotech, Gilead, Galapagos, Chiesi, Arrowhead, Sofinnova and GSK, reports equity in Pliant and Thyron, and has a patent in new therapies for IPF, new therapies for ARDS and new biomarkers for IPF, licensed to Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Fays, Geudens, Gyselinck, Kerckhof, Vermaut, Goos, Vermant, Beeckmans, Kaes, Van Slambrouck, Mohamady, Willems, Aversa, Cortesi, Hooft, Aerts, Aelbrecht, Everaerts, McDonough, De Sadeleer, Gohy, Ambroise, Janssens, Ceulemans, Van Raemdonck, Vos, Hackett, Hogg, Kaminski, Gayan-Ramirez, Pilette and Vanaudenaerde.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19) which can lead to acute respiratory distress syndrome (ARDS) and evolve to pulmonary fibrosis. Computed tomography (CT) is used to study disease progression and describe radiological patterns in COVID-19 patients. This study aimed to assess disease progression regarding lung volume and density over time on follow-up in vivo chest CT and give a unique look at parenchymal and morphological airway changes in "end-stage" COVID-19 lungs using ex vivo microCT., Methods: Volumes and densities of the lung/lobes of three COVID-19 patients were assessed using follow-up in vivo CT and ex vivo whole lung microCT scans. Airways were quantified by airway segmentations on whole lung microCT and small-partition microCT. As controls, three discarded healthy donor lungs were used. Histology was performed in differently affected regions in the COVID-19 lungs., Results: In vivo , COVID-19 lung volumes decreased while density increased over time, mainly in lower lobes as previously shown. Ex vivo COVID-19 lung volumes decreased by 60% and all lobes were smaller compared to controls. Airways were more visible on ex vivo microCT in COVID-19, probably due to fibrosis and increased airway diameter. In addition, small-partition microCT showed more deformation of (small) airway morphology and fibrotic organization in severely affected regions with heterogeneous distributions within the same lung which was confirmed by histology., Conclusions: COVID-19-ARDS and subsequent pulmonary fibrosis alters lung architecture and airway morphology which is described using in vivo CT, ex vivo microCT, and histology., Competing Interests: Conflicts of Interest: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1488/coif). BMV, GGR, WAW, and WJ report funding from KU Leuven (No. C16/19/005). WAW reports funding from Roche, Boehringer Ingelheim, and Galapagos. GMV and DEVR report funding from the Broere Charitable Foundation. LJC reports funding from Medtronic. RV reports funding from UZ Leuven (No. STG15/023). RV, VG, JK, A Vanstapel, TG, MV, and IG report funding from the Research Foundation-Flanders (FWO) (No. 12G8715N to RV, No. 11L9822N to VG, No. 1198920N to JK, No. 1102020N to A Vanstapel, No. 1S73921N to TG, No. 1SE4322N to MV, and No. 11N3922N to IG). MNB reports funding from the Ghent University Special Research Fund for the UGCT Centre of Expertise BOF.EXP.2017.0007. The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: SARS-CoV-2 is a single-stranded positive-sense RNA virus. Several negative-sense SARS-CoV-2 RNA species, both full-length genomic and subgenomic, are produced transiently during viral replication. Methodologies for rigorously characterising cell tropism and visualising ongoing viral replication at single-cell resolution in histological sections are needed to assess the virological and pathological phenotypes of future SARS-CoV-2 variants. We aimed to provide a robust methodology for examining the human lung, the major target organ of this RNA virus., Methods: A prospective cohort study took place at the University Hospitals Leuven in Leuven, Belgium. Lung samples were procured postmortem from 22 patients who died from or with COVID-19. Tissue sections were fluorescently stained with the ultrasensitive single-molecule RNA in situ hybridisation platform of RNAscope combined with immunohistochemistry followed by confocal imaging., Findings: We visualised perinuclear RNAscope signal for negative-sense SARS-CoV-2 RNA species in ciliated cells of the bronchiolar epithelium of a patient who died with COVID-19 in the hyperacute phase of the infection, and in ciliated cells of a primary culture of human airway epithelium that had been infected experimentally with SARS-CoV-2. In patients who died between 5 and 13 days after diagnosis of the infection, we detected RNAscope signal for positive-sense but not for negative-sense SARS-CoV-2 RNA species in pneumocytes, macrophages, and among debris in the alveoli. SARS-CoV-2 RNA levels decreased after a disease course of 2-3 weeks, concomitant with a histopathological change from exudative to fibroproliferative diffuse alveolar damage. Taken together, our confocal images illustrate the complexities stemming from traditional approaches in the literature to characterise cell tropism and visualise ongoing viral replication solely by the surrogate parameters of nucleocapsid-immunoreactive signal or in situ hybridisation for positive-sense SARS-CoV-2 RNA species., Interpretation: Confocal imaging of human lung sections stained fluorescently with commercially available RNAscope probes for negative-sense SARS-CoV-2 RNA species enables the visualisation of viral replication at single-cell resolution during the acute phase of the infection in COVID-19. This methodology will be valuable for research on future SARS-CoV-2 variants and other respiratory viruses., Funding: Max Planck Society, Coronafonds UZ/KU Leuven, European Society for Organ Transplantation., Competing Interests: Declaration of interests SF received support for travel from Pfizer and Gilead. RV received consulting fees from AstraZeneca. JW received consulting and speaker's fees and support for travel from Pfizer, Gilead and MSD., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF) are distinct respiratory diseases that share features such as the obstruction of small airways and disease flare-ups that are called exacerbations and are often caused by infections. Along the airway epithelium, immunoglobulin (Ig) A contributes to first line mucosal protection against inhaled particles and pathogens. Dimeric IgA produced by mucosal plasma cells is transported towards the apical pole of airway epithelial cells by the polymeric Ig receptor (pIgR), where it is released as secretory IgA. Secretory IgA mediates immune exclusion and promotes the clearance of pathogens from the airway surface by inhibiting their adherence to the epithelium. In this review, we summarize the current knowledge regarding alterations of the IgA/pIgR system observed in those major obstructive airway diseases and discuss their implication for disease pathogenesis.

Mucosal surfaces are lined by epithelial cells, which provide a complex and adaptive module that ensures first-line defense against external toxics, irritants, antigens, and pathogens. The underlying mechanisms of host protection encompass multiple physical, chemical, and immune pathways. In the lung, inhaled agents continually challenge the airway epithelial barrier, which is altered in chronic diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis. In this review, we describe the epithelial barrier abnormalities that are observed in such disorders and summarize current knowledge on the mechanisms driving impaired barrier function, which could represent targets of future therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carlier, de Fays and Pilette.)

We report the story of a 81 year old man referred for confusion and unexplained hyperthermia. He had no meningeal sign. Routine emergency examinations (CT scanner and lumbar punction) were not contributory, but, later, PCR for herpes virus was highly positive and cerebral CT scan showed the temporal lobe necrosis typical of an herpes virus meningoencephalitis. This severe neurologic emergency is then shortly discussed.