Ex Vivo Perfusion Treatment of Infection in Human Donor Lungs

Abstract

Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (n = 8), lungs underwent EVLP for 12 h with high‐dose antibiotics (ciprofloxacin 400 mg or azithromycin 500 mg, vancomycin 15 mg/kg, and meropenem 2 g). In the control group (n = 7), lungs underwent EVLP for 12 h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic‐treated cases but in only two control cases. Perfusate endotoxin levels at 12 h were significantly lower in the antibiotic group compared with the control group. EVLP with broad‐spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12 h were strongly correlated with levels of perfusates tumor necrosis factor α, IL‐1β and macrophage inflammatory proteins 1α and 1β at 12 h. In conclusion, EVLP treatment of infected donor lungs with broad‐spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.

Ex vivo lung perfusion as a human platform for preclinical small molecule testing

“…Our group recently used a leukocyte filter in a rat model to decrease cytokine levels and improve lung function (23), while another group claims such filters offer little benefit in a pig EVLP model (24). Another study delivered high-dose antibiotics to perfused lungs prior to their transplant, with resultant decreases in allograft bacterial burden observed (25). This intervention may prove clinically significant in the practice of clinical EVLP in the coming years.…”

Machine Perfusion of Extended Criteria Donor Organs: Immunological Aspects

“…In a clinical study, NMP showed the capacity to remove donor dendritic cells generating non-classical monocytes, which are directly involved in immune surveillance, from the graft (36). NMP of donor after brain death (DBD) lungs with clinically diagnosed infection significantly reduced bacterial counts in the fluid of the bronchoalveolar lavage and inflammatory injury by decreasing endotoxin levels and key inflammatory mediators [TNF-α, IL-1β, macrophage inflammatory protein (MIP)-1α, MIP-1β] when combined with broad-spectrum antibiotic treatment (35). The administration of mesenchymal stromal cells (MSCs) ameliorated ischemic injury in donor lungs during ex vivo NMP and attenuated the subsequent IRI after Tx (84).…”

“…MP reduced IRI in experimental and clinical models of ECD organ Tx resulting in protection from inadequate activation of innate immunity (1,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Figure 2 summarizes frequently described MP settings including the underlying mechanisms.…”

Recent advances in lung transplantation

“…EVLP allows fluid to be drawn from extravascular compartments in edematous lungs such that gas exchange can be improved and marginal lungs rendered usable, and anti-inflammatory cytokines or mesenchymal stem cells (MSCs) can be employed to accelerate repair after injury, encourage recovery in intercellular alveolar epithelial tight junctions, improve oxygenation, and decrease vascular resistance 43 – 46 . In addition, antibiotics can be administered to reduce or eradicate donor lung infection 47 , gastric acid-injured donor lungs can be potentially salvaged 48 , and perfusate can be analyzed to detect biomarkers that predict high risk for early allograft dysfunction 49 , 50 . Finally, Yeung et al .…”