Infections In Transplant Patients Research Articles

Unveiling the mycobiota: The fungal frontier of human health

The microbiota and its effect on health has been extensively studied over the past decade. In many studies, the term microbiota has become synonymous with the bacterial component of the microbiota. Other microbes in the microbiota, such as viruses and fungi, have been neglected until recently. This special issue provides some background on the mycobiota and explores the role of gut fungi in human diseases such as cancer, metabolic diseases, and infection by Clostridiodes difficile, and describes the incidence of fungal infections in transplant patients. The mycobiota, once overlooked, now garners increasing attention.

Clinico-epidemiological characteristics of early- versus late-onset cytomegalovirus disease among renal transplant recipients: A two-decade experience

BackgroundReactivation of cytomegalovirus (CMV) infection in transplant patients is high because of immunosuppression. We have evaluated the clinical and epidemiological characteristics of early versus late onset of CMV infection among renal transplant recipients. MethodsA single center retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between January 2002 and December 2021. CMV disease was classified as early or late depending on its detection prior to or after 90 days post-transplantation. Herein, we reported the differences between early and late onset of CMV disease with respect to clinical symptoms, the use of immunosuppression and the impact on graft outcomes. ResultsOut of total 2164 renal transplant recipients, 156 patients (7.2%) were diagnosed with CMV disease. Among these 156 patients, 25 patients (16%) had early CMV while 131 patients (84%) had late CMV. Overall, the two groups did not differ with respect to the induction or maintenance of immunosuppressive agents. However, the proportion of CMV syndrome was greater among early (56.0%) than late (26.7%) CMV groups (p = 0.01). In contrast, tissue invasive disease was more frequent among late (73.3%) in comparison to early (44.0%) CMV groups (p = 0.01). Among clinical symptoms, diarrhea was more frequent in late (63.4%) vs. early (36%) CMV-affected patients (p = 0.01). Graft loss occurred in 4.0% of early CMV group vs. 25.2% of late CMV group (p = 0.03). Neither of the clinical groups differed with respect to occurrence of biopsy-proven allograft rejection post-infection. ConclusionsEarly CMV disease presents more frequently as CMV syndrome while late CMV disease usually manifests itself as tissue invasive disease. Graft loss is more common in patients with late onset of CMV disease.

Hepatitis E virus infection of transplanted kidneys

Immunocompromised patients are at risk of chronic hepatitis E (HEV) infection. Recurrent T cell and borderline rejections in a pediatric patient with high HEV copy numbers led us to study HEV infection within renal transplants. To investigate the frequency of renal HEV infection in transplanted patients, 15 samples from patients with contemporaneous diagnoses of HEV infection were identified at our center. Ten samples had sufficient residual paraffin tissue for immunofluorescence (IF) and RNA-fluorescence-in-situ-hybridization (RNA-FISH). The biopsy of the pediatric index patient was additionally sufficient for tissue polymerase chain reaction and electron microscopy. HEV RNA was detected in paraffin tissue of the index patient by tissue polymerase chain reaction. Subsequently, HEV infection was localized in tubular epithelial cells by IF, RNA-FISH, and electron microscopy. One additional biopsy from an adult was positive for HEV by RNA-FISH and IF. Focal IF positivity for HEV peptide was observed in 7 additional allografts. Ribavirin therapy was not successful in the pediatric index patient; after relapse, ribavirin is still administered. In the second patient, successful elimination of HEV was achieved after short-course ribavirin therapy. HEV infection is an important differential diagnosis for T cell rejection within transplanted kidneys. Immunostaining of HEV peptide does not necessarily prove acute infection. RNA-FISH seems to be a reliable method to localize HEV.

Modulatory immune responses in fungal infection associated with organ transplant - advancements, management, and challenges.

Organ transplantation stands as a pivotal achievement in modern medicine, offering hope to individuals with end-stage organ diseases. Advancements in immunology led to improved organ transplant survival through the development of immunosuppressants, but this heightened susceptibility to fungal infections with nonspecific symptoms in recipients. This review aims to establish an intricate balance between immune responses and fungal infections in organ transplant recipients. It explores the fundamental immune mechanisms, recent advances in immune response dynamics, and strategies for immune modulation, encompassing responses to fungal infections, immunomodulatory approaches, diagnostics, treatment challenges, and management. Early diagnosis of fungal infections in transplant patients is emphasized with the understanding that innate immune responses could potentially reduce immunosuppression and promise efficient and safe immuno-modulating treatments. Advances in fungal research and genetic influences on immune-fungal interactions are underscored, as well as the potential of single-cell technologies integrated with machine learning for biomarker discovery. This review provides a snapshot of the complex interplay between immune responses and fungal infections in organ transplantation and underscores key research directions.

The Italian data on SARS-CoV-2 infection in transplanted patients support an organ specific immune response in liver recipients.

The study of immune response to SARSCoV-2 infection in different solid organ transplant settings represents an opportunity for clarifying the interplay between SARS-CoV-2 and the immune system. In our nationwide registry study from Italy, we specifically evaluated, during the first wave pandemic, i.e., in non-vaccinated patients, COVID-19 prevalence of infection, mortality, and lethality in liver transplant recipients (LTRs), using non-liver solid transplant recipients (NL-SOTRs) and the Italian general population (GP) as comparators. Case collection started from February 21 to June 22, 2020, using the data from the National Institute of Health and National Transplant Center, whereas the data analysis was performed on September 30, 2020.To compare the sex- and age-adjusted distribution of infection, mortality, and lethality in LTRs, NL-SOTRs, and Italian GP we applied an indirect standardization method to determine the standardized rate. Among the 43,983 Italian SOTRs with a functioning graft, LTRs accounted for 14,168 patients, of whom 89 were SARS-CoV-2 infected. In the 29,815 NL-SOTRs, 361 cases of SARS-CoV-2 infection were observed. The geographical distribution of the disease was highly variable across the different Italian regions. The standardized rate of infection, mortality, and lethality rates in LTRs resulted lower compared to NL-SOTRs [1.02 (95%CI 0.81-1.23) vs. 2.01 (95%CI 1.8-2.2); 1.0 (95%CI 0.5-1.5) vs. 4.5 (95%CI 3.6-5.3); 1.6 (95%CI 0.7-2.4) vs. 2.8 (95%CI 2.2-3.3), respectively] and comparable to the Italian GP. According to the most recent studies on SOTRs and SARS-CoV-2 infection, our data strongly suggest that, in contrast to what was observed in NL-SOTRs receiving a similar immunosuppressive therapy, LTRs have the same risk of SARS-CoV-2 infection, mortality, and lethality observed in the general population. These results suggest an immune response to SARS-CoV-2 infection in LTRS that is different from NL-SOTRs, probably related to the ability of the grafted liver to induce immunotolerance.

Management of COVID-19 Infection in a Small Bowel Transplant Recipient: A Case Report

The COVID-19 pandemic has caused millions of people to become infected worldwide. Some patients may have disease progression and may need treatment with an anti-COVID-19 agent, hospitalization, and even intensive care. The risk factors for disease progression include old age, diabetes mellitus, pulmonary disease, cardiac disease, immunodeficiency, and immunosuppressant treatment. Therefore, managing COVID-19 infection in transplant patients under immunosuppressant treatments needs specific consideration, especially the side effects of anti-COVID-19 agents and the interaction between immunosuppressants and anti-COVID-19 agents. In this report, we present the case of a small bowel transplant patient who had a COVID-19 infection. The patient was initially treated for paxlovid, and she developed bloody stools and dizziness. The treatment was then changed to molnupiravir without discontinuation of tacrolimus. The patient recovered smoothly after a 5-day treatment with molnupiravir. Here, we discuss the management experience of such patients and review the relevant literature.

Risk of Staphylococcus aureus Bacteremia Before and After Solid Organ Transplantation.

Solid organ transplant recipients are at high risk for Staphylococcus aureus bacteremia, but the risks before and after transplantation require further research. We performed a population-based retrospective self-controlled study using the State Inpatient Database from 10 states in the United States. Adult and pediatric patients who had solid organ transplantation from 2004 to 2018 were tracked longitudinally for 1 y before and after transplantation outside of the immediate peritransplant periods. The exposure of interest was solid organ transplantation, and the outcome of interest was hospitalization with S. aureus bacteremia. Of 75 549 patients, 581 (0.77%) and 239 (0.32%) were hospitalized with S. aureus bacteremia in the pretransplant and posttransplant periods, respectively ( P < 0.001). Overall, the odds of hospitalization with S. aureus bacteremia increased from 7 to 12 mo to 1 to 6 mo before transplantation (odds ratio, 1.24; 95% confidence interval, 1.05-1.46) and then decreased following transplantation (odds ratio, 0.35; 95% confidence interval, 0.28-0.45; 7-12 mo after transplantation). The decreased rate after transplantation was driven by the cases associated with central line-associated bloodstream infections and endocarditis among kidney and heart transplant recipients. Odds of hospitalization with S. aureus bacteremia did not change after liver transplantation, whereas they increased after lung transplantation. In addition to immunosuppression, the reversal of organ failure and associated requirements for organ support following transplantation may play an important role in the risk of S. aureus bacteremia in solid organ transplant recipients. These results can guide infection prevention approaches and future research on S. aureus infections in transplant patients.

Transcriptomic analysis of human cytomegalovirus to survey the indirect effects on renal transplant recipients

Post-transplant human cytomegalovirus (HCMV) viremia has been linked to adverse “indirect effects” among transplant patients. HCMV-created immunomodulatory mechanisms could be associated with the indirect effects. ObjectiveIn the present study, the RNA-Seq whole transcriptome of renal transplant (RT) patients was analyzed to seek the underlying pathobiologic pathways associated with the long-term indirect effects of HCMV. MethodsTo investigate the activated biological pathways in HCMV infection, total RNA was extracted from PBMCs of 2 RT patients with active HCMV and 2 RT patients without infection and then were sequenced using RNA-Seq. The resulted raw data were analyzed by conventional RNA-Seq software to determine the Differentially Expressed Genes (DEGs). Afterward, Gene Ontology (GO) and pathway enrichment analyses were conducted to determine the enriched pathways and biological processes by DEGs. Eventually, the relative expressions of some significant genes were validated in the twenty external RT patients. ResultThe analysis of RNA-Seq data related to RT patients with HCMV active viremia led to the identification of 140 up-regulated and 100 down-regulated DEGs. KEGG pathway analysis revealed the enrichment of DEGs in IL18 signaling, AGE-RAGE signaling pathway in diabetic complications, signaling by GPCR, Platelet activation, signaling and aggregation, Estrogen signaling pathway and signaling by Wnt due to HCMV infection. The expression levels of six genes involved in enriched pathways including F3, PTX3, ADRA2B, GNG11, GP9, HBEGF were then verified using RT-qPCR. The results were in consistent with RNA-Seq resultsoutcomes. ConclusionThis study specifies some pathobiological pathways which are activated in HCMV active infection and could be linked to the adverse indirect effects caused by HCMV infection in transplant patients.

Prophylaxis of Fungal Infections in Transplant Patients:What has Changed in Recent Years?

Objective: The present work aimed to review the invasive fungal infections (IFIs) and antifungal prophylaxis used in the last 20 years in transplant patients to identify the changes that occurred in this period and discuss the most current conducts. Methods: This is a systematic review in which the PubMed database was used, in which scientific articles from the last 20 years were selected, covering clinical trials, randomized controlled trials, systematic reviews of the literature and meta-analyses. Results: According to the present study, posaconazole and voriconazole are the antifungal drugs of choice for IFI prophylaxis in hematopoietic stem cell transplantation (HSCT). However, as posaconazole is not available in the public health system in Brazil, the most viable option remains voriconazole. Regarding IFI prophylaxis in solid organ transplantation (SOT), it was observed that there are variations depending on the transplanted target organ, and there is no evidence of its need in kidney transplantation. Although azoles are also the most used and bring clear benefits in liver and lung transplantation, some current studies have placed echinocandins on the same level, encouraging their use to prevent IFI in these patients. Conclusion: In the last five years, there has been a great shortage of clinical trials comparing different antifungal prophylaxis. New studies are needed to establish the most appropriate protocols for each condition and profile of the transplanted patient.

Absolute Lymphocyte Count as a Marker for Cytomegalovirus Infection After Heart Transplantation.

Previous studies indicate an association between reduced absolute lymphocyte count (ALC) and cytomegalovirus (CMV) infection after solid organ transplantation and have therefore highlighted the potential of ALC as a simple tool to predict CMV infection in transplant patients. This study aimed to examine the utility of ALC as a valuable marker for CMV infection in heart transplant patients. Clinical information and ALC data of all adult patients who received orthotopic heart transplantation at the Medical University of Vienna between January 2004 and May 2019 were collected. We performed a multivariable Cox regression model that incorporates repeated measurements of ALC as a time-varying continuous factor in 2 ways, first as continuous logarithmic factor considering a 50% decrease of ALC levels and second as binary factor using a threshold of 610 cells/μL. One hundred fifty-eight (39%) patients developed CMV infection over the course of 2 y. Patients with lymphopenia were shown to be at higher risk of developing CMV infection both in the continuous approach (HR [per 50% reduction] 1.29; confidence interval [CI], 1.09-1.53; P = 0.003) and the binary approach with a cutoff of 610 cells/μL (HR 1.74; CI, 1.20-2.51; P = 0.003). This study demonstrated a strong association between reduced ALC and the development of CMV infection after heart transplantation. ALC value monitoring could provide an additional tool to assess individualized CMV risk after solid organ transplantation.

S10.2d Fungal beta-glucans and mannan performances in HIV-associated histoplasmosis

S10.2 Fungal Infections in Transplant Patients, September 24, 2022, 10:30 AM - 12:00 PMObjectivesDiagnosis of histoplasmosis in people living with HIV (PLWHIV) remains challenging despite developments in Histoplasma antigen and molecular detection tools. Fungal markers such as Beta-(1,3)-D-glucan (BDG) and galactomannan Aspergillus antigen (GM) are widely available, but the experience is limited during PLWHIV workup for suspicion of histoplasmosis. Our objective was to evaluate and compare BDG and GM performances for the diagnosis of HIV-associated histoplasmosis.MethodsWe performed a diagnostic accuracy study using primary serum samples stored frozen in a certified biorepository (CRB Amazonie-DC-2021-4649). Samples consisted of consecutive hospitalized PLWHIV unexposed to oral antifungals during the previous month (EDIRAPHIS study-NCT01884779). All patients gave consent for biobanking and ancillary studies on fungal markers.Histoplasmosis cases, proven (EORTC/MSG criteria) and probable (polyclonal or monoclonal Histoplasma antigen detections in urines or serum), as well as negative controls, were randomly selected. Patients with a proven or suspected Pneumocystis jirovecii infection were excluded. Following manufacturers’ instructions, samples were blindly tested for BDG and GM using Fungitell® and PlateliaTM Aspergillus Ag assays, respectively.Gold standard definition used three scenarios: EORTC scenario (cases and controls defined according to the EORTC/MSG 2020 criteria for endemic mycoses); strict scenario with proven cases restricted to those positives to all three previous Histoplasma antigen detections, and controls conversely negatives for all methods; and a large scenario with proven or probable cases and controls negatives for all methods.ResultsWe included 121 samples, 92 HIV-associated histoplasmosis cases (34 proven and 58 probable), and 29 negative controls. Compared with controls, histoplasmosis cases were significantly younger and advanced in the course of HIV disease [median CD4 count level 33/mm3 (15-87) vs 116 (62-245)].BDG and GM median detection levels were significantly higher among histoplasmosis cases compared with controls across all scenarios [368 (176-441) pg/ml vs 142 (89-211) for BDG and 2.5 (1.3-4.8) vs 0.19 (0.14-0.36) for GM, in cases vs controls of the strict scenario, respectively].In the strict scenario, at 150 pg/ml and 0.5 for BDG and GM respectively, sensitivity, specificity, positive and negative likelihood ratios were respectively: 95% [95%confidence interval (CI), 85-100] vs 90% [77-100], 52% [34-70] vs 83% [69-97], 2 [1.4-3.0] vs 5.3 [2.4-12.0], and 0.1 [0.01-0.7] vs 0.12 [0.03-0.45]. ROC curves found AUCs of 0.82 [0.68-0.91] vs 0.92 [0.80-0.98], and optimal thresholds at 288 pg/ml and 1.29, for BDG and GM, respectively (Fig. 1). Post-test probabilities showed best performances at the lowest thresholds for negative testing of both BDG and GM, and at the 0.7 thresholds for a positive GM test (Fig. 2).ConclusionBDG and GM may not be used for the same objective when searching for HIV-associated histoplasmosis. Although a negative BDG test at the lowest thresholds should rule out histoplasmosis in a screening context, limitations of a positive BDG test, even at the highest thresholds, call for a consecutive positive GM test before starting patients on antifungal therapy targeting histoplasmosis. Still, when considering the highest costs of BDG testing, higher balanced diagnostic performances, and lower costs of GM testing alone, one may favor the use of GM, notably in resources-limited settings.

P16.36: Effectiveness of SARS-Cov 2 Vaccination in Kidney Transplant Patients in Chile

Introduction: The humoral response to COVID-19 vaccines in transplant recipients has been reported to be lower than the obtained in the general population. For the Pfizer vaccine, an antibody response in 5-59% of those vaccinated is described, depending on the immunosuppressive maintenance therapy implemented, with a 56% of cellular response after the 2nd dose of the vaccine. The clinical significance of this poorer immune reaction is unclear. On the other hand, the degree of response to the Sinovac vaccine, the most used early in Chile, is unknown. Taking into account that the lethality of SARS-CoV-2 infection in transplanted patients was 6 times higher than the general population during the first wave of the pandemic (renal FUTAC data), we carried out this study with the aim of knowing the clinical effectiveness of the first two vaccines implemented in Chile in kidney transplant patients. Methods: Prospective, observational, multicenter study. The FUTAC database was available with a periodic report from all transplant centers in the country with 98% coverage and information available from 3/27/2020 to 7/7/2021. The data of transplanted patients who were infected with SARS-COV-2 were recorded comparing between those who had been fully vaccinated or not, with the Sinovac or Pfizer vaccine, evaluating the incidence of hospitalization and lethality. The group with complete vaccination was defined if the infection occurred 15 days after the second dose and the unvaccinated group corresponded to those without vaccination, with incomplete vaccination or in a period < 15 days after the second dose. Results: Of a total of 424 cases, 16 were discarded due to incomplete data, analysing 408 patients, of which 336 (82%) suffered the infection without being effectively vaccinated and 72 (18%) who were fully vaccinated. Of the total patients fully vaccinated, 57% (40/70) received Sinovac vaccine and 43% (30/70) Pfizer. No differences were found between COVID-19 infection rates between 2020 and 2021. Of the fully vaccinated patients, 42/72 (58%) were hospitalized, and 14/72. (19%) died; in this group, there are 7 patients who are alive but seriously ill at the time of closing the registry. In the unvaccinated group, 53% (179/336) were hospitalized and 15% (50/336) died, without significant differences in hospitalization or fatality rates. No differences were found in hospitalization or fatality rates between those vaccinated with Pfizer or Sinovac. Conclusions: The transplanted population, although fully vaccinated, maintains a high fatality rate, which is still 6 times higher than the general population. Although these data could be biased by the patients who did not consult, they were an input to decide a third dose of vaccination just applied to this highly vulnerable population, whose results are waiting to be evaluated. In Chile, the third booster dose was started in September 2021 and a 4th booster dose is currently being delivered starting in January 2022. Marion Alarcon; Loreto Oliva; Silvana Morales.

High Predictive Value of the Soluble ZEBRA Antigen (Epstein-Barr Virus Trans-Activator Zta) in Transplant Patients with PTLD.

The ZEBRA (Z EBV replication activator) protein is the major transcription factor of EBV, expressed upon EBV lytic cycle activation. An increasing body of studies have highlighted the critical role of EBV lytic infection as a risk factor for lymphoproliferative disorders, such as post-transplant lymphoproliferative disease (PTLD). We studied 108 transplanted patients (17 PTLD and 91 controls), retrospectively selected from different hospitals in France and in the Netherlands. The majority of PTLD were EBV-positive diffuse large B-cell lymphomas, five patients experienced atypical PTLD forms (EBV-negative lymphomas, Hodgkin’s lymphomas, and T-cell lymphomas). Fourteen patients among the seventeen who developed a pathologically confirmed PTLD were sZEBRA positive (soluble ZEBRA, plasma level above 20 ng/mL, measured by an ELISA test). The specificity and positive predictive value (PPV) of the sZEBRA detection in plasma were 98% and 85%, respectively. Considering a positivity threshold of 20 ng/mL, the sensitivity of the sZEBRA was 82.35% and the specificity was 94.51%. The mean of the sZEBRA values in the PTLD cases were significantly higher than in the controls (p < 0.0001). The relevance of the lytic cycle and, particularly, the role of ZEBRA in lymphomagenesis is a new paradigm pertaining to the prevention and treatment strategies for PTLD. Given the high-specificity and the predictive values of this test, it now appears relevant to investigate the lytic EBV infection in transplanted patients as a prognostic biomarker.

Polygenic Innate Immunity Score to Predict the Risk of Cytomegalovirus Infection in CMV D+/R- Transplant Recipients. A Prospective Multicenter Cohort Study.

Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/recipient mismatch (D+/R-) transplant recipients.

Mortality Due to COVID-19 in Renal Transplant Recipients, Related to Variants of SARS-CoV-2 and Vaccination in Mexico

BackgroundSARS-CoV-2 infection in transplant patients has shown greater lethality and vaccination in this group of patients has shown less information. The objective of this study is to show the statistics in Mexico of lethality in kidney recipients infected with COVID-19 in relation to vaccination and variants of the coronavirus.MethodsThis is a bibliographic search of kidney transplant recipient patients since the start of the pandemic in Mexico to determine lethality after SARS-CoV-2 compared to the general population and in relation to patients, the 4 most important infectious peaks in the country due to identified variants, and also before and after vaccination.ResultsThe global lethality is 26.91% from the beginning of the pandemic to April 9, 2022 in kidney recipients in Mexico (130 deaths of 483 infected kidney transplant recipients) compared to the national lethality of 5.60%. Variant B. 1.1.220 represented the highest lethality with 30.43% and the lowest lethality was Omicron with 16.41%. The lethality prior to vaccination was 30.94% and 23.46% after it.ConclusionBoth some variants and vaccination have influenced a lower lethality due to COVID-19 in Mexico in kidney transplant patients; It is important to consider global recommendations, such as a third or fourth dose, a combination of mRNA vaccines and vectors in order to reduce lethality in this group of patients.

Absolute Lymphocyte Count as a Prognostic Factor for Cytomegalovirus Infection After Heart Transplantation

<h3>Purpose</h3> Previous studies have suggested a correlation between reduced absolute lymphocyte count (ALC) & cytomegalovirus (CMV) infection and have therefore highlighted the potential of ALC as a simple tool to predict CMV infection in transplant patients. This study aims to examine the prognostic value of ALC on CMV infection in heart transplant patients. <h3>Methods</h3> Clinical information and ALC data of all adult patients who received orthotopic heart transplantation between January 2004 and May 2019 were collected. We performed a multivariable Cox regression model that incorporates repeated measurements of ALC as a time-varying continuous prognostic factor in two ways, first as binary variable with a threshold of 610 cells/μL and secondly as a continuous variable. Furthermore, landmark analyses to evaluate the mean ALC level of the preceding month, at 1, 3 & 6 months were performed. <h3>Results</h3> 549 patients received heart transplantation during this study period. 407 patients met the inclusion criteria for the primary endpoint investigation. An ALC ≥610 cells/μL was associated with a significantly lower risk of CMV infection (HR 0.57; CI 0.40-0.83; p=0.003). The continuous approach showed similar results with a significantly reduced risk of infection in patients with higher ALC (HR[2-fold increase] 0.78; CI 0.66-0.91; p=0.002). Landmark analyses of mean ALC levels at month 1 & 3, respectively, after transplantation showed a significantly decreased risk of infection in patients with a higher mean ALC (HR[2-fold increase] 0.81; CI 0.65-0.99; p=0.043 & HR 0.46; CI 0.29-0.74; p=0.001). <h3>Conclusion</h3> Absolute lymphocyte count is strongly associated with CMV infection after heart transplantation. ALC value monitoring could serve as an additional tool to predict and minimize the risk of CMV infection.

Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies.

HEV infection can lead to chronicity and rapid progression to liver fibrosis and cirrhosis in immunocompromised organ transplant recipients. Robust animal models are urgently needed to study the pathogenesis and test the efficacy of vaccines and antiviral drugs in immunosuppressed settings. Cyclosporin A was used to induce immunosuppression. Rabbits were challenged with genotype 3 or 4 HEV (i.e., the rabbit-derived HEV3 and human-derived HEV3 or HEV4). We assessed HEV markers within 13weeks post inoculation (wpi) and pathological changes by hematoxylin and eosin and Masson staining at 4, 8, or 13 wpi. Chronic HEV infection was successfully established in immunocompromised rabbits. HEV RNA and/or antigens were detected in the liver, kidney, intestine, urine, and cerebrospinal fluid samples. Chronically infected animals exhibited typical characteristics of liver fibrosis development. Intrahepatic transcriptomic analysis indicated activation of both innate and adaptive immunity. Establishment of HEV chronicity likely contributed to the inhibited T-cell immune response. Ribavirin is effective in clearing HEV infection in immunocompromised rabbits. Most interestingly, vaccination completed before immunosuppression conferred full protection against both HEV3 and HEV4 infections, but vaccination during immunosuppression was only partially protective, and the efficacy did not improve with increased or additional vaccine doses. The immunocompromised rabbit model of both chronic HEV3 and HEV4 infection that was established captured the key features of chronic HEV infection in transplant patients, including liver fibrogenesis, and revealed the distinct effectiveness of vaccination administered before or under immunosuppression. This rabbit model is valuable for understanding the pathogenesis of chronic hepatitis E, as well as for evaluating antiviral agents and vaccines.

Interpretation of acute abdomen in the immunocompromised patients: WSES/SIS-E/WSIS/AAST/GAIS guideline

World Society of Emergency Surgery (WSES), in conjunction with Surgical Infection Society Europe (SIS-E), World Surgical Infection Society (WSIS), American Association for the Surgery of Trauma (AAST), and Global Alliance for Infection in Surgery (GAIS) developed guideline about the management of acute abdomen in immunocompromised patients, which was published in the World Journal of Emergency Surgery (WJES) on August 9, 2021. The guidelines elaborate on the definition, classification, diagnosis and treatment of immunocompromised patients. In addition, based on evidence-based medicine, it provides guidance and suggestion on the management of specific acute abdominal infections in immunocompromised patients, common acute abdominal infections in transplanted patients, patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), as well as perioperative steroid management. An interpretation of the guideline was performed to accomplish a better understanding the current status and recommendations for the management of acute abdominal conditions in immunocompromised patients, and to make forward suggestions on its limitations.

KIDNEY TRANSPLANTATION – EARLY POSTOPERATIVE COMPLICATIONS

Introduction: Kidney transplantation is an established surgical method for the treatment of end-stage chronic renal failure with good long-term results. Despite the continuous progress and development of transplantology, a number of postoperative surgical and urological complications still occur today, which could compromise the success of this operative method. Purpose: All possible surgical and urological complications in the first 60 days after kidney transplantation were followed up. Materials and Methods: This study is based on a retrospective analysis of the disease history of 35 patients who underwent kidney transplantation at the Clinic of Urology at the UMHAT "Alexandrovska" for the period from 02.2018 to 12.2019. Results: Early postoperative complications were found in 46% of the observed transplant patients. Urological complications were found in 26% of them. Discussion: The incidence of urinary tract infections in transplanted patients was 26%. During the follow-up period, there were no cases of urinary retention, stricture of the ureter and urinoma in the group of patients. The incidence of surgical complications in the transplanted patients was 29%. The incidence of postoperative hematomas was 23%. Postoperative lymphocele was diagnosed in one patient, which shows a complication rate of 3% for this diagnosis. The incidence of surgical wound infection in transplanted patients during the follow-up period was 3%. Conclusions: Our results show that the frequency of the different early postoperative urological and surgical complications correspond to the literature data from other transplant centers. They show that the transplantation activities in the Clinic of Urology in UMHAT "Alexandrovska" correspond to the world standards.

An intermittent outbreak of Burkholderia cepacia contaminating hematopoietic stem cells resulting in infusate-related blood stream infections.

Microbial contamination of hematopoietic stem cells (HSC), used for autologous and allogenic transplantations, is rare but could cause serious blood stream infection in transplanted patients. These infections occur immediately, or later following the formation of biofilm on the catheter lumen. The present study describes an intermittent B. cepacia HSC contamination associated with nosocomial bacteremia: from October 2011 to April 2015, 17B. cepacia strains were isolated in HSC bags (n = 14) and blood cultures (n = 3) in patients hospitalized in the National Bone Marrow Transplant Center. Two epidemiologic investigations in the National Blood Transfusion Center, allowing the isolation of three strains in hygiene samples, and four interventions in this institution were done. To identify the source of this contamination, a molecular investigation was done on 23B. cepacia strains isolated in our center from 2007 to 2015. PFGE analysis revealed five clusters. The major cluster included 18 strains isolated from HSC bags (n = 14), blood culture (n = 1), and water cans and bath (n = 3). The second cluster (B) including only two and the remaining clusters (C, D, and E) contained single strains isolated before the epidemic period. These findings confirmed that the origin of the outbreak was the contaminated water used in the water bath during the thawing step of HSC bags. Based on this result, new sterile water was used for every defrosting, but HSC bags contamination persisted. In May 2015, the water bath was replaced with a dry bath and no B. cepacia strain was isolated from that date to April 2020.