The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT patients with recurrent and/or drug-resistant CMV infection or disease.

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Background: /objective: There are no large, multi-centre studies of Australians with bronchiectasis. The Australian Bronchiectasis Registry (ABR) was established in 2015 to create a longitudinal research platform. We aimed to describe the baseline characteristics of adult ABR participants and assess the impact of disease severity and exacerbation phenotype on quality of life (QoL). Methods: The ABR is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis. We analysed the baseline data of adult patients (≥18 years). Results: From March 2016-August 2018, 799 adults were enrolled from 14 Australian sites. Baseline data were available for 589 adults predominantly from six tertiary centres (420 female, median age 71 years (interquartile range 64-77), 14% with chronic Pseudomonas aeruginosa infection). Most patients had moderate or severe disease based on the Bronchiectasis Severity Index (BSI) (84%) and FACED (59%) composite scores. Using Global Lung function Initiative-2012 reference equations, the majority of patients (48%) had normal spirometry; only 34% had airflow obstruction (FEV 1 /FVC < LLN). Disease severity scores (BSI and FACED) were negatively correlated with QoL-Bronchiectasis domain scores (r s between −0.09 and −0.58). The frequent exacerbator phenotype (≥3 in the preceding year) was identified in 23%; this group had lower scores in all QoL-B domains (p ≤ 0.001) and more hospitalisations (p < 0.001) than those with < 3 exacerbations. Conclusions: The largest cohort of Australian adults with bronchiectasis has been described. Using contemporary criteria, most patients with bronchiectasis did not have airflow obstruction. The frequent exacerbation trait connotes poorer QoL and greater health-care utilisation.

Infections with cytomegalovirus (CMV) can induce severe complications after solid organ transplantation (SOT). The prognosis for ganciclovir-resistant CMV infection and disease is particularly poor. Whereas adoptive transfer of CMV-specific T cells has emerged as a powerful tool in hematopoietic stem cell transplant patients, its translation into the SOT setting remains a significant challenge as underlying immunosuppression inhibits the virus-specific T-cell response in vivo. Here, we demonstrate successful expansion and adoptive transfer of autologous CMV-specific T cells from a seronegative recipient of a seropositive lung allograft with ganciclovir-resistant CMV disease, resulting in the long-term reconstitution of protective anti-viral immunity, CMV infection, disease-free survival and no allograft rejection.

This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy-confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269.

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SummaryBronchiolitis obliterans syndrome (BOS) is associated with lack of immunosuppression of T cell proinflammatory cytokines and increased T cell granzyme B. Repeated antigen-driven proliferation down-regulates T cell CD28. We hypothesized that down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules (CD134, CD137, CD152 and CD154) on T cells may be associated with BOS. Co-stimulatory molecules, granzyme B, perforin and intracellular cytokines were measured by flow cytometry on T cells from stable lung transplant patients (n = 38), patients with BOS (n = 20) and healthy controls (n = 10). There was a significant increase in the percentage of CD4/28 null and CD8/28 null T cells producing granzyme B, interferon (IFN)-g and tumour necrosis factor (TNF)-a in BOS compared with stable patients. Down-regulation of CD28 was associated with steroid resistance and up-regulation of CD134, CD137, CD152 and CD154 on CD4 + T cells and CD137 and CD152 on CD8 + T cells. There was a significant correlation between increased CD28 null /CD137 T cells producing IFN-g, TNF-a with BOS grade (r = 0·861, P < 0·001 for CD28 null /CD137 IFN-g/CD8) and time post-transplant (r = 0·698, P < 0·001 for CD28 null /CD137 IFN-g/CD8). BOS is associated with down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules on steroid-resistant peripheral blood proinflammatory CD4+ and CD8 + T cells. Therapeutic targeting of alternate co-stimulatory molecules on peripheral blood CD28 null T cells and monitoring response using these assays may help in the management of patients with BOS.

BOS is associated with increased cytotoxic/proinflammatory CD8+ T, NKT-like, and NK cells in the small airways. Treatments that increase GCR in these lymphocyte subsets may improve graft survival.