High relevance of invasive fungal disease in chronic liver transplant failure: a comprehensive cross-sectional study

Abstract

Invasive fungal infection (IFI) is a severe complication in organ transplant patients and a major diagnostic and therapeutic challenge. The aim of this comprehensive retrospective study was the characterization of IFI in context of chronic liver transplant failure regarding prevalence, morphological changes, and inducing fungal species. All explanted liver transplants due to chronic transplant failure from Heidelberg University Hospital were extensively reexamined for the presence of mycotic infection. Special stains were performed to uncover severity and associated conditions of IFI and fungal species were identified on the molecular level. Light-microscopic examination revealed fungal infection in 41 (27.5%) of 149 explanted livers with chronic transplant failure, with 68% representing newly specified cases compared to primary reports. We could show an increase of the proportion of mycotic infections during the investigated time period (1991-2021) as well as a shorter transplant survival when compared to the non-affected organs. Typically, large bile ducts were affected, accompanied by acute inflammation with frequent abscess and bile concrement formation. In 35 of 41 cases, the identification of the fungal species was achieved, revealing Candida albicans as prominent species (74.3%). In three autopsy livers of patients that died after liver transplantation of septic multiorgan failure, Candida spp. could be identified. Our data show the underestimated prevalence and high diagnostic and clinical relevance of mycotic infection in chronic liver transplant failure. Adapting diagnostic procedures, molecular pathological analyses, and therapeutic strategies is relevant to identify and prevent chronic transplant organ failure caused by IFIs.

Keywords: Chronic transplant failure; Invasive fungal infection; Liver transplantation; Mycosis.

Fig. 1

Classification of the severity of IFI. A The 41 identified IFI cases were classified in low (dark green), moderate (medium green), and high (bright green) loads of fungal structures and amount of infected tissue. B Exemplary microscopic pictures of biliary necrosis including a small inclusion with low fungal load (HE stain), with C showing a detail of B with PAS stain. D A large bile duct with biliary concrement and a moderate fungal load (HE stain), with E showing a detail of D with GMS stain. F A large bile duct with biliary abscess and high fungal load (HE stain), with G showing a detail of F in GMS stain. The used parts for the details are marked with a black square. Scale bar: A, C = 1000 µm; B, D, F = 100 µm; E = 200 µm

Fig. 2

Histopathological investigations led to a discovery of unknown cases of IFI. The collective of 149 explanted transplant livers were investigated for IFIs. A Cases were classified in unaffected cases without mycoses (blue), previously diagnosed mycoses (dark orange), and mycoses that were newly identified by histopathological investigations (bright orange). B Transplant survival of livers with identified mycoses (orange) and without mycoses (blue) in days. C Percentage of liver explants with histopathologically identified mycosis between 1991 and 2021. Dotted line: linear regression

Fig. 3

Morphological characterization of IFIs. The 41 identified cases of IFIs were investigated for histopathologic characterizations. A Localization of fungal infection within the liver was classified in biliary tree (dark green), intravascular mycosis (medium green), and a mixed infection of both structures (bright green). B Morphological changes were classified in abscess formation, formation of bile concrements, and necrosis. C Infection was classified as acute (dark green) and acute on chronic infection (bright green)

Fig. 4

Pathogen pattern of IFIs on species level. From 35 samples, an identification of fungal pathogens on species level was performed