Research report: Immunological signatures of sepsis in abdominal solid organ transplant recipients: A multilayer and multicentric prospective cohort study

Patients who have undergone abdominal solid organ transplantation appear to fare better once sepsis strikes than similarly ill patients without a transplant history, and a new study offers the most detailed picture yet of the immune state that accompanies that advantage. In a post hoc analysis of the prospective, multicenter SepsisDataNet.NRW cohort, researchers found that 30-day survival was 84 percent among 50 septic transplant recipients compared with 66 percent among 488 non-transplant patients. After adjusting for age and disease severity, transplantation remained independently associated with reduced mortality, with a hazard ratio of 0.49 and a 95 percent confidence interval of 0.26 to 0.95.

The study, published in Intensive Care Medicine, went beyond clinical outcomes to profile the immune response across multiple biological layers: serum cytokines, flow cytometric immunophenotyping, plasma proteomics, and intracellular signaling measured with proximity ligation assays in peripheral blood mononuclear cells. The cohort enrolled adults meeting Sepsis-3 criteria between March 2018 and May 2022 at five university and tertiary care centers in North Rhine-Westphalia, Germany. Most transplant recipients had received kidney or simultaneous pancreas-kidney grafts, with a median interval of 6.9 years between transplantation and sepsis onset.

The survival paradox itself is not new. Prior observational studies have suggested that transplant recipients, despite being more susceptible to infection under chronic immunosuppression, show reduced sepsis-attributable mortality of up to 18.5 percent compared with non-transplant populations. What has been missing is a mechanistic account. The new analysis confirms the survival difference and links it to a coherent immune phenotype: attenuated systemic inflammation, reduced adaptive immune cell counts, relative preservation of selected innate immune readouts, and alterations in immunometabolic markers.

Cytokine measurements told the first part of the story. Septic transplant patients had significantly lower interleukin-6 concentrations than non-transplant patients at both day 1 and day 4 after sepsis diagnosis, with median day 1 values of 87.4 versus 234.55 picograms per milliliter. Tumor necrosis factor alpha levels, initially comparable, tended to be lower in transplant recipients on day 4, a difference that narrowly missed statistical significance. In contrast, interleukin-18 concentrations were significantly higher in the transplant group at day 4, a pattern the authors interpret cautiously as possibly compatible with persistent innate immune activation, while emphasizing that inflammasome activity and cellular cytokine sources were not directly assessed.

Flow cytometry, available in 131 patients, revealed a pronounced shift in leukocyte composition. Transplant recipients showed markedly reduced adaptive immune compartments, including lower total lymphocyte, CD4-positive T cell, total T cell, and B cell counts, consistent with pharmacological immunosuppression and lymphopenia. Yet the granulocyte proportion was significantly increased, and when lymphocyte subsets were expressed as proportions, natural killer cells were significantly enriched. Crucially, monocytic HLA-DR expression, a marker that typically falls in sepsis-induced immunoparalysis, was relatively higher in transplant patients, at a median of 5,922 antibodies per cell versus 4,097 in non-transplant patients. Both groups showed low overall expression, but innate immune dysfunction appeared less pronounced in the transplant group.

Plasma proteomics, performed in 105 propensity score-matched patients, reinforced this picture. The most differentially abundant proteins were associated with neutrophil degranulation, including LYZ, GSN, CST3, SERPINA1, CFD, and B2M, alongside enrichment of innate immune, complement, and lipid metabolic response networks, with marked alterations in cholesterol homeostasis proteins and an association with glucocorticoid response. The authors caution, however, that several of these proteins accumulate in chronic kidney disease, which was closely linked to transplantation status in this predominantly kidney-transplant cohort, so the proteomic signature may partly reflect impaired renal clearance rather than altered host-response biology alone.

At the single-cell level, proximity ligation assays uncovered a distinct immunometabolic marker profile. Septic transplant patients showed significantly higher GLUT1 expression in their peripheral blood mononuclear cells, indicating greater glucose uptake potential, and increased interaction between the mitochondrial proteins TFAM and TFB2M, a marker of mitochondrial biogenesis. Both associations remained independent after adjustment for age and SOFA score, whereas phospho-ERK activity showed only a non-significant trend. These findings point to concurrent alterations in glucose handling and mitochondrial regulation within immune cells during sepsis in transplant recipients.

To explore whether transplantation itself reshapes metabolism independent of sepsis, the team analyzed an exploratory ex vivo cohort of non-septic kidney transplant recipients from the e:KID study. Paired serum metabolomics in 34 patients showed that glucose concentrations rose significantly 12 months after transplantation while lactate fell, accompanied by increased LDL, VLDL, and triglyceride levels, reduced HDL-associated metabolites, and decreased branched-chain amino acids. Yet when paired peripheral blood mononuclear cells from these patients were stimulated with lipopolysaccharide in the laboratory, the elevated GLUT1 expression and TFAM/TFB2M interaction seen in septic transplant patients were not reproduced. The authors stress that this ex vivo cohort should be viewed as complementary and hypothesis-generating rather than mechanistically confirmatory, and that the findings do not demonstrate the sepsis phenotype exists before sepsis develops.

The study carries important limitations. All analyses were performed post hoc, so they identify associations rather than causal relationships, and the survival advantage cannot be attributed to any specific mechanism. Residual confounding is a real concern: transplant patients were younger but had a heavier comorbidity burden, higher creatinine levels, and more frequent urinary tract infections, and SOFA scores do not fully distinguish chronic from acute renal dysfunction. Sample sizes varied across analytical layers, with as few as 18 to 41 transplant patients in molecular subsets, and the near-exclusive focus on abdominal, mostly kidney, transplants limits generalizability to other transplant populations. Maintenance immunosuppression was also frequently reduced or discontinued at sepsis onset, meaning the observed phenotype reflects real-world intensive care management rather than the isolated effect of chronic immunosuppressive therapy.

Even with those caveats, the convergence of clinical and molecular data supports a striking reframing. Rather than global immunosuppression, septic transplant recipients appear to occupy a rebalanced immune state, with dampened systemic inflammation, fewer adaptive cells, and comparatively preserved innate function and immunometabolic activity. Whether these features actually contribute to the survival difference remains an open question that the authors say requires validation in larger, independent cohorts across broader transplant types. If confirmed, the immune and metabolic networks identified here could inform future strategies for managing sepsis, a syndrome that kills through dysregulated host response and for which immunosuppression has long been assumed to be uniformly harmful.

Subject of Research: Immune signatures and survival outcomes in septic abdominal solid organ transplant recipients

Article Title: Immunological signatures of sepsis in abdominal solid organ transplant recipients: A multilayer and multicentric prospective cohort study

Article References: Witowski, A., Bracht, T., Kröger, L., Rump, K., Nowak, H., Bergmann, L., Unterberg, M., Rahmel, T., Westhus, B., Wolf, A., Thon, P., Ziehe, D., Putensen, C., Ehrentraut, S., Zarbock, A., Wappler, F., Defosse, J., Henzler, D., Sitek, B., … Koos, B. (2026). Immunological signatures of sepsis in abdominal solid organ transplant recipients: A multilayer and multicentric prospective cohort study. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08612-1

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08612-1

Keywords: sepsis, solid organ transplantation, immunosuppression, cytokines, flow cytometry, proteomics, immunometabolism, monocytic HLA-DR, GLUT1, kidney transplantation, mortality, intensive care