Jennifer K. Chow

Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit.

BACKGROUND Candida albicans has been the most common cause of fungal bloodstream infections (BSIs) in intensive care units (ICUs); however, infections due to non-albicans Candida species have been increasing in prevalence. We examined factors associated with BSIs due to non-albicans Candida species, compared with C. albicans BSIs, in an ICU patient population. METHODS For our case-comparator study, we identified consecutive adult ICU patients with BSIs due to non-albicans Candida species or C. albicans at 2 tertiary care hospitals during the period 1995-2005. Data collected included demographic characteristics, comorbidities, exposure to antibiotics and antifungals, and ICU-related factors, such as total parenteral nutrition, blood product transfusions, invasive procedures, central venous catheter use, hemodialysis, and mechanical ventilation. We built a multivariable logistic regression model that identified variables that differentiate BSIs due to non-albicans Candida species from BSIs due to C. albicans. RESULTS There were 67 patients with BSIs due to non-albicans Candida species and 79 patients with C. albicans BSIs. Variables were adjusted for time at risk. In multivariable models, factors associated with an increased risk of BSIs due to non-albicans Candida species, compared with C. albicans BSIs, included fluconazole exposure (odds ratio, 11.6; 95% confidence interval, 2.28-58.8), central venous catheter exposure (odds ratio, 1.95; 95% confidence interval, 1.10-3.47), and mean number of antibiotics per day (odds ratio, 2.31; 95% confidence interval, 0.71-7.54). Total parenteral nutrition exposure was associated with a decreased risk (odds ratio, 0.16; 95% confidence interval, 0.05-0.47) of BSIs due to non-albicans Candida species, compared with C. albicans BSIs. Duration of stay in the ICU was not significantly different between the 2 groups. Specific antibiotics, such as vancomycin and piperacillin-tazobactam, were not independently associated with BSI due to non-albicans Candida species. CONCLUSIONS Receipt of fluconazole and central venous catheter exposure were associated with an increased risk of BSI due to non-albicans Candida species, and total parenteral nutrition was associated with a decreased risk of BSI due to non-albicans Candida species, compared with BSI due to C. albicans. Patients without characteristics of infection due to non-albicans Candida species might benefit from empirical antifungal therapy with fluconazole.

Risk factors for albicans and non-albicans candidemia in the intensive care unit.

Objective:To determine risk factors for bloodstream infections (BSI) with Candida non-albicans (C-NA) species and Candida albicans (CA) among critically ill patients. Design:Case-control study. Setting:Adult medical and surgical intensive care units (ICUs) at two university hospitals. Patients:Consecutive patients with C-NA and CA BSIs from 1995–2005 formed the two case groups. Controls were patients without candidemia who were randomly selected in a ratio of 5:1 and matched by study hospital, ICU type (medical vs. surgical) and by ICU admission date within a 3-month period. Interventions:Data collected included demographics, comorbidities, exposure to antibiotics and antifungals, and ICU factors such as total parenteral nutrition (TPN), blood product transfusions, invasive procedures, central venous catheters, hemodialysis, and mechanical ventilation. We built multivariable logistic regression models, which identified risk factors for C-NA or CA BSIs compared with controls. Variables were adjusted for time-at-risk. Measurements and Main Results:There were 67 patients with C-NA BSIs, 79 patients with CA BSIs, and 780 controls. In multivariable models, factors associated with an increased risk of C-NA compared with controls included major pre-ICU operations [odds ratio; (95% confidence interval)] [2.12; (1.14–3.97)], gastrointestinal procedures [2.24; (1.49–3.38)], enteric bacteremia [3.43; (1.39–8.48)], number of hemodialysis days [6.20; (2.67–14.4)], TPN duration [2.87; (1.40–5.90)], and mean number of red blood cell transfusions [2.72; (1.33–5.58)]. Factors associated with an increased risk of CA BSIs compared to controls were very similar and included major ICU operations [1.26; (1.14–3.97)], enteric bacteremia [3.45; (1.38–8.63)], number of hemodialysis days [3.84; (1.75–8.40)], TPN duration [11.0; (5.52–21.7)] and mean number of red blood cell transfusions [1.97; (0.98–3.99)]. Conclusions:We found multiple common risk factors for both non-C. albicans and C. albicans BSIs, however we could not differentiate between these two groups based on clinical characteristics alone.

Candidaemia associated with decreased in vitro fluconazole susceptibility: is Candida speciation predictive of the susceptibility pattern?

BACKGROUND Candidaemia is often treated with fluconazole in the absence of susceptibility testing. We examined factors associated with candidaemia caused by Candida isolates with reduced susceptibility to fluconazole. METHODS We identified consecutive episodes of candidaemia at two hospitals from 2001 to 2007. Species identification followed CLSI methodology and fluconazole susceptibility was determined by Etest or broth microdilution. Susceptibility to fluconazole was defined as: full susceptibility (MIC < or = 8 mg/L); and reduced susceptibility (MIC > or = 32 mg/L). Complete resistance was defined as an MIC > 32 mg/L. RESULTS Of 243 episodes of candidaemia, 190 (78%) were fully susceptible to fluconazole and 45 (19%) had reduced susceptibility (of which 27 were fully resistant). Of Candida krusei and Candida glabrata isolates, 100% and 51%, respectively, had reduced susceptibility. Despite the small proportion of Candida albicans (8%), Candida tropicalis (4%) and Candida parapsilosis (4%) with reduced fluconazole susceptibility, these species composed 36% of the reduced-susceptibility group and 48% of the fully resistant group. In multivariate analysis, independent factors associated with reduced fluconazole susceptibility included male sex [odds ratio (OR) 3.2, P < 0.01], chronic lung disease (OR 2.7, P = 0.01), the presence of a central vascular catheter (OR 4.0, P < 0.01) and prior exposure to antifungal agents (OR 2.2, P = 0.04). CONCLUSIONS A significant proportion of candidaemia with reduced fluconazole susceptibility may be caused by C. albicans, C. tropicalis and C. parapsilosis, species usually considered fully susceptible to fluconazole. Thus, identification of these species may not be predictive of fluconazole susceptibility. Other factors that are associated with reduced fluconazole susceptibility may help clinicians choose adequate empirical anti-Candida therapy.

Vaccination of Solid-Organ Transplantation Candidates

Verifying immunization status and updating vaccinations are important steps in the evaluation of patients who are solid-organ transplant candidates because the potential benefits of vaccination outweigh the risk of adverse events. Because patients with end-organ disease, such as end-stage renal disease and cirrhosis, have reduced immune responses to many vaccines, vaccination should be performed as early as possible during the course of these diseases. Furthermore, it is particularly important for live vaccines to be updated during the pretransplant assessment because such vaccines are contraindicated once a patient is maintained on immunosuppression. Current information on vaccination for adult solid-organ transplant candidates is reviewed.

Increased Serum Iron Levels and Infectious Complications after Liver Transplantation

BACKGROUND Elevated serum iron levels have been associated with infectious outcomes in various patient populations but, to our knowledge, have never been studied after liver transplantation. METHODS The relationship between serum iron levels and infectious outcomes after liver transplantation was evaluated in a nested case-control study using prospectively collected data and serum samples. Unadjusted and adjusted hazard ratios were calculated for each iron marker predictor variable (iron level, unsaturated iron-binding capacity, total iron-binding capacity, transferrin saturation, and ferritin level) and time to development of each of 6 outcomes (cytomegalovirus [CMV] disease, invasive fungal infection, bacteremia, invasive fungal infection or bacteremia, any infection, and 1-year mortality rate). RESULTS Serum measurements (n = 109) corresponding to increased levels of serum iron were independently associated with an increased risk of any infection and death. After adjusting for the number of red blood cell transfusions, donor CMV-seropositive status, and fungal colonization, ferritin level was independently associated with the development of any infection (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14). After adjusting for the number of red blood cell transfusions, development of CMV disease, and administration of intravenous steroids for treatment of rejection, ferritin level was also was independently associated with death (hazard ratio, 1.11; 95% confidence interval, 1.04-1.18). Similar results were found for unsaturated iron binding capacity for the same 2 outcomes. CONCLUSIONS A better understanding of iron metabolism and its relationship to infection could help guide future infection prognosis, prevention, and management efforts in this high-risk population.

Pretransplant lymphopenia is a novel prognostic factor in cytomegalovirus and noncytomegalovirus invasive infections after liver transplantation.

Infection after liver transplantation (LT) remains a leading cause of morbidity and mortality. The risk of infection after LT is highest in those who are most immunosuppressed, but to date, no standard blood marker of ones degree of immunosuppression or risk index has been established. The purpose of this study was to determine whether pretransplant lymphopenia (absolute lymphocyte count < 500 cells/mm3 within 24 hours before LT) is a candidate marker of immunosuppression and could be useful in predicting the risk of cytomegalovirus (CMV) disease and non‐CMV invasive infections after LT. Data were extracted from medical records for all primary, solitary LT procedures performed at Tufts Medical Center from 1999 to 2009. Two hundred seventy‐six patients had sufficient data to be included in the analysis. Among these patients, 52% developed CMV or non‐CMV invasive infections within 5 years of LT. Within 2 years, 23 (8%) had CMV disease, and 103 (37%) at least 1 non‐CMV invasive infection. More lymphopenic patients than nonlymphopenic patients developed CMV (21% versus 4%, P < 0.001) and non‐CMV invasive infections (50% versus 33%, P = 0.02). In a multivariate survival analysis, pretransplant lymphopenia was the strongest independent predictor of CMV disease [hazard ratio (HR) = 5.52, 95% confidence interval (CI) = 2.31‐13.1, P = 0.001] after adjustments for known risk factors, including CMV serostatus (HR = 4.72, 95% CI = 2.01‐11.1, P < 0.001). Both pretransplant lymphopenia (HR = 1.64, 95% CI = 1.14‐2.53, P = 0.03) and CMV (HR = 2.93, 95% CI = 1.23‐6.92, P = 0.02) independently predicted non‐CMV infections. Our results suggest that pretransplant lymphopenia is a novel independent predictor of both CMV disease and non‐CMV invasive infections after LT and is a candidate marker of immunosuppression in LT recipients. Liver Transpl 20:1497‐1507, 2014.

Role of Secondary Prophylaxis With Valganciclovir in the Prevention of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients

Background Cytomegalovirus (CMV) is a major contributor to morbidity and mortality in solid organ transplant recipients (SOTRs). Ganciclovir and valganciclovir are highly effective antiviral drugs with a well-established role in primary prophylaxis and treatment of CMV disease. Our objective in this study was to examine the effect of secondary prophylaxis (SP) on the risk of relapse in SOTRs following an episode of CMV disease. Methods We performed a retrospective cohort study of SOTRs from 1995 to 2015 and used propensity score-based inverse probability of treatment weighting methodology to control for confounding by indication. A weighted Cox model was created to determine the effect of SP on time to relapse within 1 year of treatment completion. Results Fifty-two heart, 34 liver, 79 kidney, and 5 liver-kidney transplant recipients who completed treatment for an episode of CMV infection/disease were included. A total of 120 (70.6%) received SP (median duration, 61 days; range, 5-365) and 39 (23%) relapsed. SP was protective against relapse from 0 to 6 weeks following treatment completion (hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.05-0.69). However, after 6 weeks, risk of relapse did not significantly differ between the 2 groups (HR, 1.18; 95% CI, 0.46-2.99). Conclusions Our findings demonstrate that use of SP following treatment of CMV disease did not confer long-term protection against relapse, although it did delay relapse while patients were receiving antivirals. This suggests that SP has limited clinical utility in the overall prevention of recurrent CMV disease.

Characteristics and Outcomes of Neutropenia after Orthotopic Liver Transplantation

Neutropenia after orthotopic liver transplantation (LT) is relatively common, but the factors associated with its development remain elusive. We assessed possible predictors of neutropenia (absolute neutrophil count [ANC] ≤ 1000/mm3) within the first year of LT in a cohort of 304 patients at a tertiary medical center between 1999 and 2009 using time‐dependent survival analysis to identify risk factors for neutropenia. In addition, we analyzed neutropenia as a predictor of the clinical outcomes of death, bloodstream infection (BSI), invasive fungal infection, cytomegalovirus (CMV) disease, and graft rejection within the first year of LT. Of the 304 LT recipients, 73 (24%) developed neutropenia, 5 (7%) of whom had grade 4 neutropenia (ANC < 500/mm3). The following were independent predictors for neutropenia: Child‐Turcotte‐Pugh score (hazard ratio [HR] 1.15; 95% confidence interval [CI], 1.03‐1.30; P = 0.02), BSI (HR, 2.89; 95% CI, 1.63‐5.11; P < 0.001), CMV disease (HR, 4.28; 95% CI, 1.55‐11.81; P = 0.005), baseline tacrolimus trough level (HR, 1.02; 95% CI, 1.01‐1.03; P = 0.007), and later era LT (2004‐2009 versus 1999‐2003; HR, 2.28; 95% CI, 1.43‐3.65; P < 0.001). Moreover, neutropenia was found to be an independent predictor for mortality within the first year of LT (HR, 3.76; 95% CI, 1.84‐7.68; P < 0.001). In conclusion, our data suggest that neutropenia within a year after LT is not unusual and is an important predictor of mortality. Liver Transpl 22:217‐225, 2016.

Absolute lymphocyte count: a predictor of recurrent cytomegalovirus disease in solid organ transplant recipients.

Background Recurrent cytomegalovirus (CMV) disease in solid organ transplant recipients frequently occurs despite effective antiviral therapy. We previously demonstrated that patients with lymphopenia before liver transplantation are more likely to develop posttransplant infectious complications including CMV. The aim of this study was to explore absolute lymphocyte count (ALC) as a predictor of relapse following treatment for CMV disease. Methods We performed a retrospective cohort study of heart, liver, and kidney transplant recipients treated for an episode of CMV disease. Our primary outcome was time to relapse of CMV within 6 months. Data on potential predictors of relapse including ALC were collected at the time of CMV treatment completion. Univariate and multivariate hazard ratios (HRs) were calculated with a Cox model. Multiple imputation was used to complete the data. Results Relapse occurred in 33 of 170 participants (19.4%). Mean ALC in relapse-free patients was 1.08 ± 0.69 vs 0.73 ± 0.42 × 103 cells/μL in those who relapsed, corresponding to an unadjusted hazard ratio of 1.11 (95% confidence interval, 1.03-1.21; P = .009, n = 133) for every decrease of 100 cells/μL. After adjusting for potential confounders, the association between ALC and relapse remained significant (HR, 1.11 [1.03-1.20]; P = .009). Conclusions Low ALC at the time of CMV treatment completion was a strong independent predictor for recurrent CMV disease. This finding is biologically plausible given the known importance of T-cell immunity in maintaining CMV latency. Future studies should consider this inexpensive, readily available marker of host immunity.

Iron-Related Markers are Associated with Infection after Liver Transplantation

Though serum iron has been known to be associated with an increased risk of infection, hepcidin, the major regulator of iron metabolism, has never been systematically explored in this setting. Finding early biomarkers of infection, such as hepcidin, could help identify patients in whom early empiric antimicrobial therapy would be beneficial. We prospectively enrolled consecutive patients (n = 128) undergoing first‐time, single‐organ orthotopic liver transplantation (OLT) without known iron overload disorders at 2 academic hospitals in Boston from August 2009 to November 2012. Cox regression compared the associations between different iron markers and the development of first infection at least 1 week after OLT; 47 (37%) patients developed a primary outcome of infection at least 1 week after OLT and 1 patient died. After adjusting for perioperative bleeding complications, number of hospital days, and hepatic artery thrombosis, changes in iron markers were associated with the development of infection post‐OLT including increasing ferritin (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.12‐2.05), rising ferritin slope (HR, 1.10; 95% CI, 1.03‐1.17), and increasing hepcidin (HR, 1.43; 95% CI, 1.05‐1.93). A decreasing iron (HR, 1.76; 95% CI, 1.20‐2.57) and a decreasing iron slope (HR, 4.21; 95% CI, 2.51‐7.06) were also associated with subsequent infections. In conclusion, hepcidin and other serum iron markers and their slope patterns or their combination are associated with infection in vulnerable patient populations. Liver Transplantation 23 1541–1552 2017 AASLD.