Daniel C. Chambers

The lung is unique among commonly transplanted organs in that it is exposed to both the gastrointestinal tract and the external environment, locations which are characterized by heavy colonization with bacterial organisms. How effectively the lung handles this potential threat, in the setting of attempts by well-meaning clinicians to eliminate the immune response which would normally be invoked in defense, is likely to impact on the success or otherwise of the transplant procedure. Indeed, many previous investigators have confirmed strong associations between the isolation of microbes, using microscopy and culture, and lung transplant outcomes.

Alveolar macrophages (AM) must perform three seemingly opposing roles including homeostasis, driving inflammation, and facilitating tissue repair. Whilst there is now consensus (supported by a large body of human single cell RNA sequencing (scRNA-seq) data) that the cell subsets that perform these tasks can readily be found based on their transcriptome, their ontogeny has remained unclear. Moreover, there is agreement that in all types of pulmonary fibrosis (PF) there is an expanded population of profibrotic AM that may aberrantly drive PF. From a therapeutic viewpoint, there is great appeal in the notion that the transcriptional program in different AM subsets is not fixed but remains plastic and amenable to pharmacological reprogramming. Accordingly, this study addresses this question by performing scRNA-seq on human AM following treatment with drugs or perturbagens including pioglitazone, trametinib, nintedanib, lipopolysaccharide and the natural compound endiandrin A. Each treatment induced a unique global transcriptional change, driving the cells towards distinct subsets, further supported by trajectory analysis, confirming a high level of plasticity. Confirmatory experiments using qPCR demonstrated that single exposure to a compound induced a relatively stable transcriptome, whereas serial exposure to a different compound allowed the cells to be reprogrammed yet again to a different phenotype. These findings add new insight into the biology of AM and support the development of novel therapies to treat PF.

Background: Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disorder (PTLD) affects up to 10% of lung transplant patients and is associated with high morbidity and mortality. Early identification of patients at risk of PTLD and reduction in immunosuppression may be an effective way to prevent future diseases. Methods: A systematic review was conducted of all bone marrow (BMT/HSCT) and lung transplant studies published in English that assessed quantitative peripheral blood EBV PCR monitoring as a predictive measure of future PTLD occurrence. Studies on pre-emptive therapy before the diagnosis of PTLD were excluded. Results: A thousand of hundred sixty-three studies were screened, and 12 were eligible for the final analysis. The two lung transplant studies reported 60% to 80% sensitivity (SN) and 60% to 86% negative predictive value (NPV), but poor specificity (SP) (30%-75%) and positive predictive value (PPV) (30%-67%). HSCT studies also showed good SN (71.4%-100%) and NPV (94%-100%). However, the SP (range, 50%-96%) and PPV (range, 14%-75%) were poor. The included studies used nonstandardized EBV PCR testing methods, which affected the validity of the results and the applicability of the findings to other transplant programs. Most studies were retrospective and included a small number of cases. Conclusions: In conclusion, this systematic review demonstrated the lack of good-quality evidence and poor SP and PPV of EBV PCR monitoring to predict PTLD development in lung transplantation. The use of PCR-guided preemptive therapy for future PTLD prevention is questionable. Further studies with standardized EBV PCR measurements are required.

Background: Defining a transplant candidate's suitable functional status and potential for rehabilitation is complex. Six-minute walk distance (6MWD) criteria are used in candidacy assessment and pre-transplant quadriceps strength may be a predictor of rehabilitation potential. The study aims were to determine if candidates pre-transplant 6MWD and quadriceps strength are independent factors associated with post-transplant 6MWD and, compare the trajectory in 6MWD and quadriceps strength in candidates from initial assessment to waitlisting and from waitlisting to transplanted (or delisted/died). Methods: An observational repeated measures design was used. 6MWD and QS% were recorded at initial assessment, waitlisting, bi-monthly reassessments until transplanted/delisted/died and 2-, 6- 13- 26- and 52-weeks following transplantation. Results: 342 (192 males; mean (±SD) age 51±14 years; 119 COPD, 93 IIP, 72 cystic fibrosis and 58 other) were studied. Recipients had a mean increase in 6MWD of 170±127 m (p<0.001) at 52-weeks post. Weekly 6MWD recovery was greater during the 2- and 6-week period (β 21.73, p<0.001) compared to the 6- to 52-week period (β 1.28, p<0.001). In the 2- to 6-weeks after transplantation, greater pre-transplant 6MWD (p<0.001), stronger pre-transplant QS% (p=0.001), shorter post-operative hospital admission (p<0.001) and cystic fibrosis (vs other) were factors associated with a greater 6MWD. In the 6- to 52-weeks after transplantation, stronger QS% value at corresponding time (p<0.001), younger recipients (p<0.001) and greater 2-week post-transplant 6MWD (p<0.001) were factors associated with a greater 6MWD. Pre-transplant 6MWD decreased by -0.059m (p<0.001) and QS% increased by 0.014% (p<0.001) per day between initial assessment to waitlisting (n=287). Conclusions: Pre-transplant 6MWD and quadriceps strength are independent factors associated with recovery in exercise capacity after lung transplantation. However, candidates had a marked deterioration in 6MWD, but quadriceps strength had improved while being worked up for waitlisting. Quadriceps strength along with 6MWD should be considered when determining a candidate's lung transplant suitability.

Background: Keratinocyte carcinomas such as basal cell carcinomas and squamous cell carcinomas are a major burden affecting morbidity and mortality in solid organ transplant recipients (SOTRs). Best treatment includes frequent skin checks for early detection and surgery for high incidence of skin cancers. Sirolimus is an immunosuppressive drug which may reduce the burden of skin cancer but may be poorly tolerated when given orally. Topical sirolimus has been proven effective at reducing the burden of skin cancers in animal models, and its safety has long been established in children with tuberous sclerosis. A recent 12-week phase II trial of topical sirolimus suggested it was safe and effective at reducing the early signs of skin cancer in the absence of major side effects. The aim of the SiroSkin trial is to determine whether topical sirolimus can fill a major gap in current therapies by reducing the onset and number of new skin cancers thus reducing burden of disease and cost-effectiveness. Methods: Protocol for a multi-centred phase III, participant- and clinician assessor-blinded, placebo-controlled randomised trial in SOTRs. A minimum 146 participants randomised 1:1 will be treated with 1% topical sirolimus versus placebo applied to the face on a regular basis for 24 weeks. Participation is 24 months in total-24 weeks of treatment and 18 months of follow-up. Outcomes include the number of keratinocyte carcinomas at 24 weeks of treatment compared to placebo and then at 12 and 24 months after initiation of treatment. Analysis will be as per protocol and intention to treat. Conclusions: The results of this trial will inform management strategies for skin cancers in SOTRs and provide evidence for cost-effectiveness. Background: Clinicaltrials.gov NCT05860881. Registered on June 15, 2023, and on anzctr.org.au (registration number NCT05860881).

A Randomized, Double-Blind, Placebo Controlled Study to Assess the Efficacy and Safety of Two Dose Regimens (60 mg/kg and 120 mg/kg) of Weekly Intravenous Alpha1 Proteinase Inhibitor (Human) in Subjects With Pulmonary Emphysema Due to Alpha1 Antitrypsin Deficiency