Bacterial And Fungal Bloodstream Infections in Solid Organ Transplant Recipients: Results From A Danish Cohort With Nationwide Follow-up

Abstract Objectives: Bloodstream infections (BSI) are prevalent after solid organ transplantation (SOT). In this study, we aimed to investigate the incidence and risk factors for BSI in the first 5 years post-transplantation. Methods: The study included 1322 SOT (kidney, liver, lung and heart) recipients transplanted from 2010 to 2017 with a total of 5616 years of follow-up. Clinical characteristics and microbiology were obtained from the Centre of Excellence for Personalized Medicine of Infectious Complications in Immune Deficiency (PERSIMUNE) data repository with nationwide follow-up. Incidence was investigated in the different SOT groups. Risk factors associated with BSI were assessed in the combined group in time-updated multivariable Cox regressions. 

Results: The cumulative incidence of first BSI in the first 5 years post-transplantation differed in the SOT groups with a lower incidence in heart transplant recipients than in the other SOT groups (heart: 4.4%, CI 0.0e9.7%, vs. kidney: 24.6%, CI 20.9e28.2%, liver: 24.7%, CI 19.4e29.9%, and lung: 19.6%, CI 14.5e24.8%, p <0.001). Age above 55 years (HR 1.71, CI 1.2e2.4, p¼0.002) and higher Charlson comorbidity index score (HR per unit increase: 1.25, CI 1.1e1.4, p<0.001) at transplantation, current cytomegalovirus (CMV) infection (HR 4.5, CI 2.6e7.9, p<0.001) and current leucopenia (HR 13.3, CI 3.7e47.9, p<0.001) were all associated with an increased risk of BSI. 

Conclusion: In SOT recipients, the incidence of BSI differed with the type of transplanted organ. The risk of BSI was higher in older recipients and in recipients with comorbidity, current CMV infection or leucopenia. Thus, increased attention towards BSI in recipients with these characteristics is warranted. Dina Leth Møller, Clin Microbiol Infect 2022;28:391

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Introduction Solid organ transplantation (SOT) is a well-established treatment for patients with end-stage organ failure [1]. However, the use of immunosuppressive medication for the prevention and treatment of rejection increases the risk of infections in SOT recipients [1]. Bloodstream infections (BSI) are prevalent and severe complications that contribute to mortality after transplantation [2e6]. Previous studies have found that up to 40% of SOT recipients develop a BSI in the first year post-transplantation [7e10], and risk factors for BSI include re-transplantation, treatment at intensive care units (ICUs) and previous exposure to antibiotics (reviewed in [11]).

Knowledge of pathogen composition and resistance patterns is crucial for empiric treatment and thereby the outcome of BSI [11]. It has been suggested that the pathogen composition varies with type of the transplanted organ [2]. However, few studies have investigated the variance in pathogen composition over time post-transplantation and consensus has not been reached [3,6,12]. Furthermore, BSI composition in SOT recipients, in general, has changed over the last two decades with a shift toward Gram-negative bacteria possibly due to fewer central line-associated BSI [2,4,13]. These changes, and the rapid increase in multidrug resistant organisms (MDRO) [4,9,11], underline the need for new studies of the pathogen composition in SOT recipients.

In this prospective study with nationwide follow-up, we aimed to investigate the incidence, pathogen composition, and risk factors of BSI in the first year and first 5 years post-transplantation in a large cohort of SOT recipients.

Materials and methods

In this prospective study, we included adult single-organ SOT recipients  18 years of age with heart, lung, liver or kidney transplantation at Rigshospitalet, University Hospital of Copenhagen, Denmark, in the period 1 January 2010 to 31 December 2017. Rigshospitalet is a tertiary hospital and a highly specialized transplantation center. Liver and lung transplantations in Denmark are exclusively performed at Rigshospitalet and the study included 52% of all SOT recipients transplanted nationwide during the study period [14]. The study participants were included from the  Management of Posttransplant Infections in Collaborating Hospitals (MATCH) cohort [15].

Clinical characteristics including transplantation-specific data, Charlson comorbidity index (CCI) score, biochemistry and microbiology were retrieved from the Centre of Excellence for Personalized Medicine of Infectious Complications in Immune Deficiency (PERSIMUNE) data repository [16]. Data were prospectively generated as part of the clinical work and merged in the PERSIMUNE data repository. The PERSIMUNE data repository contains data from clinical databases and national registries including the Danish Microbiology Database (MiBa), which contains data on all blood cultures, including antibiotic resistance profiles, from all Departments of Clinical Microbiology in Denmark with complete coverage since 2010 [17]. The standard immunosuppressive regimen and antimicrobial prophylaxis used can be seen in the supplementary materials (Supplementary material text S1).

The retrieval of the data was approved by the National Committee on Health Research Ethics (H-170024315) and the Data Protection Agency (04433, RH-2016-47).

Bloodstream infections

All blood cultures were collected on clinical indication. The blood cultures were analyzed using either BACT/ALERT® (Biomerieux, Marcy l'Etoile, France) or BACTEC FX® (Becton, Dickinson and Company, Franklin Lakes, USA) microbial detection systems. BSI were defined according to the Centers for Disease Control and Prevention (CDC) criteria as the isolation of a bacterial or fungal pathogen from a blood culture unless the pathogen could be regarded as contamination [18]. Contaminants were excluded unless they were isolated on two or more separate occasions within two days. Multiple blood cultures with the same pathogen were regarded as part of the same BSI if they occurred within 14 days after the previous culture [19].

A modified version of the CDC criteria [19] was used to define secondary BSI, where BSI was categorized as secondary if they occurred within the secondary BSI attribution period (3 days before the culture to 14 days after) of a culture with the same pathogen (only urine cultures with  105 CFU/mL were included).

The grouping of bacteria and the classification of the MDRO can be found in the supplementary materials (Supplementary material text S2 and Table S1 ).

Remaining variables and definitions

The CCI score [20] was assessed on the day of transplantation. Absolute leucopenia was defined as white blood cell (WBC) count below 1  109 /L [21]. Relative leucopenia was defined as a WBC count below 3.5  109 /L equal to the lower reference level at our Department of Clinical Biochemistry. To assess leucopenia the last blood sample with a leucocyte count prior to the BSI was used. Cytomegalovirus (CMV) was measured in plasma [15]. Current CMV infection was defined as a PCR value above 1000 copies/mL in the last blood sample tested for CMV prior to the BSI.

Follow-up 

All recipients were followed from the date of transplantation to re-transplantation, death, or the end of follow-up on 31 December 2018, whichever came first. To ensure the possibility of at least one year of follow-up for all participants, inclusion stopped on 31 December 2017. BSI incidence rates and pathogen composition were analyzed across four time periods post-transplantation: <1 month, 2e6 months, 7e12 months and 2e5 years. BSI occurring more than 5 years post-transplantation were not reported.

Statistical analysis 

Proportions were presented as percentages and continuous data as medians with interquartile range (IQR). BSI incidence rates (IR) were calculated as the number of first BSI per recipient per person-time at risk in months censoring the observation period on the day of death, re-transplantation, or at end of the investigated time period for the four different time periods investigated post-transplantation. We calculated 95% CI using Byar's approximation to the Poisson distribution. The 5-year cumulative incidence of the first BSI was calculated using the AaleneJohansen estimator with death and re-transplantation as competing risks. We tested the difference in the cumulative incidence between the different SOT groups by Gray's test. The marginal mean of recurrent BSI was calculated and further used to calculate the probability of having two or more BSI post-transplantation. Differences in the pathogen composition of the BSI stratified by the transplanted organ and the four-time periods post-transplantation were tested using a chi-squared test with subsequent post hoc analysis with BenjaminieHochberg corrections. Risk factors for BSI were investigated in a time-updated multivariable Cox proportional hazards model with re-transplantation, current CMV infections, and current leucopenia (absolute or relative) as time-dependent covariates. The model was adjusted for age, sex, and CCI score and stratified on the type of transplantation. All analyses were conducted in the statistical software R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Characteristics of recipients and blood samples Characteristics of the 1322 SOT recipients are presented in Table 1. A total of 13,366 blood cultures were collected from 1096 SOT recipients (83% of the cohort) during the study period (Table 2). Among these, 1158 (9%) were positive, 11 939 (89%) were negative and 269 (2%) were regarded as contamination. After applying CDC criteria, a total of 523 BSI in 261 (20%) recipients were found (Table 2).

Incidence of BSI The IR of the first BSI for all SOT recipients was highest in the first month post-transplantation (IR of 6.13, CI 4.88e7.62, per 100 recipients per month) and decreased gradually throughout the first year post-transplantation (IR of 1.54, CI 1.25e1.88, and 0.66, CI 0.49e0.86, per 100 recipients per month at 2e6 months and 7e12 months, respectively) (Table 2). The IRs for all time periods are shown in Table 2. The cumulative incidence of first BSI in the first year and first 5 years post-transplantation differed with type of transplanted organ (Fig. 1 and Table 2) and was significantly lower in the heart transplant group than in the other SOT groups (cumulated incidence in first 5 years post-transplantation: heart: 4.4%, CI 0.0e9.7%, vs. kidney: 24.6%, CI 20.9e28.2%, liver: 24.7%, CI 19.4e29.9%, and lung: 19.6%, CI 14.5e24.8%, Grays test for differences in cumulative incidences: p<0.001). The pathogen composition in the different SOT groups is shown in Fig. 2 and described including MDRO in the supplementary material (Supplementary material text S3 and Table S2).

Fungal BSI 

A total of 19 fungal BSI were observed in 17 (1%) recipients (5 (0.8%) kidney, 9 (3%) liver and 3 (1%) lung transplant recipients) after a median of 23 days (IQR 13e106 days) post-transplantation with Candida albicans being the most common species (42%). Eleven fungal BSI (58%) were secondary BSI. Only one resistant fungal BSI was observed with an echinocandin-resistant Candida glabrata. Risk factors for BSI To assess risk factors for the development of BSI after transplantation, we fitted a time-updated Cox proportional hazards model (Fig. 3).

 Age above 55 years (HR 1.71, CI 1.2e2.4, p¼0.002) and higher CCI score (HR 1.25 per 1 score increase, CI 1.1e1.4, p<0.001) at transplantation had higher hazards of developing a BSI compared to younger age and less comorbidity, respectively. Furthermore, current CMV infection with a PCR titre above 1000 copies/mL (HR 4.5, CI 2.6e7.9, p<0.001) and current absolute leucopenia with WBC count below 1  109 /L (HR 13.3, CI 3.7e47.9, p<0.001) after transplantation both increased the hazard for BSI significantly. To further assess current relative leucopenia as a risk factor for BSI, we altered absolute leucopenia to relative leucopenia in the previous model (Supplementary material Fig. S1) and found that relative leucopenia with WBC count below 3.5  109 /L (HR 1.81, CI 1.2e2.98, p¼0.009) likewise increased the hazard for BSI significantly

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