Glen P. Westall

Description:Solid organ transplantation (SOT) offers a new lease on life for patients with end-stage organ disease; however, lifelong immunosuppressive therapy to prevent rejection increases the risk of serious infections.1 Several novel immune biomarker assays are now available to measure immune activity and predict the risk of infection and rejection, with accumulating evidence encouraging uptake into clinical practice.1 These include both infection-specific assays (predominantly for cytomegalovirus [CMV]) and pathogen-agnostic, global immune biomarker assays. Global assays, which are heavily focused on functional analysis of bulk T cells and less on other immune cells, have the potential to provide a measure of the net state of immunosuppression. Pathogen-specific assays could allow the identification of patients at higher risk for infection, informing personalized interventions such as reductions in immunosuppression, more intensive clinical monitoring, or targeted antimicrobial prophylaxis.1,2 Ultimately, these assays could improve our ability to predict and prevent infections in transplant recipients, with the potential to reduce hospitalizations, minimize other adverse events of immunosuppression (ie, cancers), improve quality of life, and increase survival.

Description:Background: Predicting which lung transplant recipients (LTR) will develop cytomegalovirus (CMV) infection remains challenging. The aim of this retrospective cohort study was to further explore the predictive utility of global immune biomarkers within recipient seropositive (R+) LTRs, focusing on the mitogen component of the QuantiFERON (QF)-CMV assay and the absolute lymphocyte count (ALC). Methods: R+ LTR with QF-CMV testing performed at 5 mo posttransplant were included. ALC and mitogen were evaluated as predictors of CMV infection (>150 IU/mL) in plasma and/or bronchoalveolar lavage fluid using Cox regression, controlling for antiviral prophylaxis. Optimal cutoffs were calculated with receiver-operating characteristic curves. Results: CMV infection occurred in 111 of 204 patients (54%) and was associated with donor seropositivity (80/111 [72%] versus 42/93 [45%], P < 0.001), lower ALC (median 1.1 versus 1.4 × 1000 cells/μL, P = 0.004), and lower mitogen (2.8 versus 4.6, P = 0.03) values. Adjusted for serostatus and prophylaxis, each unit decrease in ALC (hazard ratio, 1.56 per 1000 cells/μL; 95% confidence interval, 1.19-2.08; P = 0.002) and mitogen (hazard ratio, 1.09 per 1 IU/mL; 95% confidence interval, 1.03-1.14; P = 0.001) were independently associated with CMV. Combining these 2 biomarkers did not substantially improve model performance. Conclusions: In R+ LTRs, donor serostatus, ALC values, and the mitogen component of the QF-CMV assay were able to predict postprophylaxis CMV infection. Combining serostatus with either biomarker alone improved predictions, but using both tests together did not increase predictive utility further. These values could be used to risk stratify patients and inform decision-making regarding the duration of antiviral prophylaxis and frequency of virologic monitoring.

Description:Cytomegalovirus (CMV) infections continue to be associated with significant morbidity and mortality following solid organ transplantation and haemopoietic stem cell transplantation. Advances in understanding the biology of CMV in the immunosuppressed host will translate into improved management approaches and better clinical outcomes. Updated definitions of resistant and refractory CMV infections will lead to more consistent reporting of CMV outcomes, better inform appropriate antiviral strategies and influence clinical trial design. Improved knowledge of the immunological control of CMV in the immunosuppressed host has led to novel diagnostics, emerging therapeutic cellular therapies and the development of an informed rationale for prophylactic and pre-emptive strategies. As the boundaries of transplantation are extended, new patterns of CMV infection are being recognised. Finally, recent studies support the use of novel antiviral therapies in transplant recipients in the appropriate clinical setting. In this review, we provide an update on important new and emerging concepts in the management of CMV in immunosuppressed transplant recipients.

Description:Background: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung fibrotic disorder of unknown cause. It has been reported that bacterial and viral co-infections exacerbate disease pathogenesis. These pathogens use adhesion molecules such as platelet activating factor receptor (PAFR) and intercellular adhesion molecule-1 (ICAM-1) to gain cellular entry, causing infections. Methods: Immunohistochemical staining was carried out for lung resections from IPF patients (n = 11) and normal controls (n = 12). The quantification of PAFR and ICAM-1 expression is presented as a percentage in the small airway epithelium. Also, type 2 pneumocytes and alveolar macrophages were counted as cells per mm2 of the parenchymal area and presented as a percentage. All image analysis was done using Image Pro Plus 7.0 software. Results: PAFR expression significantly increased in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Similar trend was observed for ICAM-1 expression in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Furthermore, the proportion of positively expressed type 2 pneumocytes and alveolar macrophages was higher in IPF than in normal control. Conclusions: This is the first study to show PAFR and ICAM-1 expression in small airway epithelium, type 2 pneumocytes and alveolar macrophages in IPF. These findings could help intervene microbial impact and facilitate management of disease pathogenesis.

Description:Background: Cystic fibrosis (CF) is a life-shortening multisystem genetic disease. Although progressive pulmonary disease is the predominant cause of morbidity and mortality, improvements in treatment for CF-related lung disease, with associated increase in longevity, have increased the prevalence of extrapulmonary manifestations1. Methods: To discuss these issues, a multidisciplinary meeting of international leaders and experts in the field was convened in November 2021 at the Shaping Initiatives and Future Trends Symposium with the goal of highlighting shifting management paradigms in CF. The main topics covered were: (1) nutrition and obesity, (2) exocrine pancreas, (3) CF-related diabetes, (4) CF liver disease, (5) CF-related bone disease, and (6) post-lung transplant care. This document summarizes the proceedings, highlighting the key priorities and important research questions that were discussed. Results: Improved life expectancy, the advent of cystic fibrosis transmembrane conductance regulator modulators, and the increasing appreciation of the heterogeneity or spectrum of disease are leading to a shift in management for patients with cystic fibrosis. Care should be individualized to ensure that increased longevity is accompanied by improved extra-pulmonary care and reduced morbidity.