Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19. We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression. In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001). In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV₁) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS.A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005–2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV₁, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV₁with open-label azithromycin.BOS occurred less in patients receiving azithromycin: 12.5versus44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092–0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV₁(p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV₁in 52.2% patients. No serious adverse events were noted.Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV₁and reduces BOS 2 yrs after LTx.

To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.

Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re‐LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re‐LTx for CLAD. Patients who underwent re‐LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre‐ and post‐re‐LTx were collected and analyzed. A total of 143 patients underwent re‐LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re‐LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59–4.24; p < 0.0001 and HR = 2.61, 1.51–4.51; p = 0.0006, respectively). Patients waiting at home prior to re‐LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23–0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re‐LTx for rCLAD is worse compared to BOS. Consequently, re‐LTx for rCLAD should be critically discussed, particularly when additional peri‐operative risk factors are present.