Comparison of fungal vs bacterial infections in the medical intensive liver unit: Cause or corollary for high mortality?

BACKGROUND: Due to development of an immune-dysregulated phenotype, advanced liver disease in all forms predisposes patients to sepsis acquisition, including by opportunistic pathogens such as fungi. Little data exists on fungal infection within a medical intensive liver unit (MILU), particularly in relation to acute on chronic liver failure. AIM: To investigate the impact of fungal infections among critically ill patients with advanced liver disease, and compare outcomes to those of patients with bacterial infections. METHODS: From our prospective registry of MILU patients from 2018-2022, we included 27 patients with culture-positive fungal infections and 183 with bacterial infections. We compared outcomes between patients admitted to the MILU with fungal infections to bacterial counterparts. Data was extracted through chart review. RESULTS: All fungal infections were due to Candida species, and were most frequently blood isolates. Mortality among patients with fungal infections was significantly worse relative to the bacterial cohort (93% vs 52%, P < 0.001). The majority of the fungal cohort developed grade 2 or 3 acute on chronic liver failure (ACLF) (90% vs 64%, P = 0.02). Patients in the fungal cohort had increased use of vasopressors (96% vs 70%, P = 0.04), mechanical ventilation (96% vs 65%, P < 0.001), and dialysis due to acute kidney injury (78% vs 52%, P = 0.014). On MILU admission, the fungal cohort had significantly higher Acute Physiology and Chronic Health Evaluation (108 vs 91, P = 0.003), Acute Physiology Score (86 vs 65, P = 0.003), and Model for End-Stage Liver Disease-Sodium scores (86 vs 65, P = 0.041). There was no significant difference in the rate of central line use preceding culture (52% vs 40%, P = 0.2). Patients with fungal infection had higher rate of transplant hold placement, and lower rates of transplant; however, differences did not achieve statistical significance. CONCLUSION: Mortality was worse among patients with fungal infections, likely attributable to severe ACLF development. Prospective studies examining empiric antifungals in severe ACLF and associations between fungal infections and transplant outcomes are critical.

Comparative outcomes for over 100 deceased donor kidney transplants from SARS-CoV-2 positive donors: A single-center experience.

Emerging data support the safety of transplantation of extra-pulmonary organs from donors with SARS-CoV-2-detection. Our center offered kidney transplantation (KT) from deceased donors (DD) with SARS-CoV-2 with and without COVID-19 as a cause of death (CoV + COD and CoV+) to consenting candidates. No pre-emptive antiviral therapies were given. We retrospectively compared outcomes to contemporaneous DDKTs with negative SARS-CoV-2 testing (CoVneg). From February 1, 2021 to January 31, 2022, there were 220 adult KTs, including 115 (52%) from 35 CoV+ and 33 CoV + COD donors. Compared to CoVneg and CoV+, CoV + COD were more often DCD (100% vs. 40% and 46%, p < .01) with longer cold ischemia times (25.2 h vs. 22.9 h and 22.2 h, p = .02). At median follow-up of 5.7 months, recipients of CoV+, CoV + COD and CoVneg kidneys had similar rates of delayed graft function (10.3%, 21.8% and 21.9%, p = .16), rejection (5.1%, 0% and 8.5%, p = .07), graft failure (1.7%, 0% and 0%, p = .35), mortality (0.9%, 0% and 3.7%; p = .29), and COVID-19 diagnoses (13.6%, 7.1%, and 15.2%, p = .33). Though follow-up was shorter, CoV + COD was associated with lower but acceptable eGFR on multivariable analysis. KT from DDs at various stages of SARS-CoV-2 infection appears safe and successful. Extended follow-up is required to assess the impact of CoV + COD donors on longer term graft function.

Utilization and outcomes of deceased donor SARS-CoV-2-positive organs for solid organ transplantation in the United States.

Coronavirus disease-19 has had a marked impact on the transplant population and processes of care for transplant centers and organ allocation. Several single-center studies have reported successful utilization of deceased donors with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests. Our aims were to characterize testing, organ utilization, and transplant outcomes with donor SARS-CoV-2 status in the United States. We used Scientific Registry of Transplant Recipients data from March 12, 2020 to August 31, 2021 including a custom file with SARS-CoV-2 testing data. There were 35 347 donor specimen SARS-CoV-2 tests, 77.5% upper respiratory samples, 94.6% polymerase chain reaction tests, and 1.2% SARS-CoV-2-positive tests. Donor age, gender, history of hypertension, and diabetes were similar by SARS-CoV-2 status, while positive SARS-CoV-2 donors were more likely African-American, Hispanic, and donors after cardiac death (p-values <.01). Recipient demographic characteristics were similar by donor SARS CoV-2 status. Adjusted donor kidney discard (odds ratio = 2.08, 95% confidence interval [CI] 1.66-2.61) was higher for SARS-CoV-2-positive donors while donor liver (odds ratio = 0.44, 95% CI 0.33-0.60) and heart recovery (odds ratio = 0.44, 95% CI 0.31-0.63) were significantly reduced. Overall post-transplant graft survival for kidney, liver, and heart recipients was comparable by donor SARS-CoV-2 status. Cumulatively, there has been significantly lower utilization of SARS-CoV-2 donors with no evidence of reduced recipient graft survival with variations in practice over time.

Early success transplanting kidneys from donors with new SARS-CoV-2 RNA positivity: A report of 10 cases.

Transplantation of solid organs from donors with active SARS-CoV-2 infection has been advised against due to the possibility of disease transmission to the recipient. However, with the exception of lungs, conclusive data for productive infection of transplantable organs do not exist. While such data are awaited, the organ shortage continues to claim thousands of lives each year. In this setting, we put forth a strategy to transplant otherwise healthy extrapulmonary organs from SARS-CoV-2-infected donors. We transplanted 10 kidneys from five deceased donors with new detection of SARS-CoV-2 RNA during donor evaluation in early 2021. Kidney donor profile index ranged from 3% to 56%. All organs had been turned down by multiple other centers. Without clear signs or symptoms, the veracity of timing of SARS-CoV-2 infection could not be confirmed. With 8-16 weeks of follow-up, outcomes for all 10 patients and allografts have been excellent. All have been free of signs or symptoms of donor-derived SARS-CoV-2 infection. Our findings raise important questions about the nature of SARS-CoV-2 RNA detection in potential organ donors and suggest underutilization of exceptionally good extrapulmonary organs with low risk for disease transmission.

Routine testing for herpes simplex virus in bronchoalveolar lavage specimens is unwarranted.

Herpes simplex virus (HSV) infections of the lung are rare, but HSV is occasionally detected in bronchoalveolar lavage (BAL) specimens. We assessed whether routinely performing HSV PCR tests in BAL specimens is warranted. HSV was detected in 7% (52/722) of BALs. In 47% of HSV-positive patients a typical respiratory virus or pathologic microorganism was identified. Oral HSV reactivation was identified in 27%; however, anti-HSV therapy was initiated in just three patients following the positive HSV test. Patients undergoing BAL for transplant surveillance received anti-HSV prophylaxis more often than those with acute respiratory failure, but both groups did not differ significantly in terms of patient outcome or co-infections. No patient was diagnosed with HSV pneumonia. These findings suggest that positive HSV PCR results in BAL specimens most commonly represents contamination from oral HSV reactivation, and that HSV PCR should be ordered selectively, rather than routinely, as part of a test panel.

Alternative pneumocystis prophylaxis in solid organ transplant recipients at two large transplant centers.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for Pneumocystis jirovecii pneumonia (PJP) prophylaxis and has activity against other opportunistic infections (OIs) after solid organ transplant (SOT). We aimed to describe the incidence, reasons for and outcomes of use of alternative prophylactic agents (APAs) across SOT programs in our high volume centers. METHODS: Solid organ transplant recipients (SOTRs) at our centers from 1/2015-12/2016 were identified. Pharmacy records identified APA (pentamidine, atovaquone, or dapsone) use within 1 year. Records were reviewed for allergies, laboratory values at APA initiation, diagnostic tests for TMP-SMX-preventable OIs, and APA side effects. RESULTS: An APA was initiated in 105/1173 (8.9%) SOTRs. Of these, 51 (48.6%) were because of sulfonamide allergy recorded pre-SOT, mostly rash/hives (58.8%). The remaining 54 (51.4%) had TMP-SMX discontinued post-SOT, mostly for neutropenia (48%) and renal effects (34%). Differences occurred across programs, with kidney transplant never stopping TMP-SMX for renal issues. Of those changed to APAs post-transplant, 19 (35%) were later successfully re-challenged with TMP-SMX. With thresholds in mind, 67 (64%) received an APA unnecessarily, accounting for up to $100 000/y excess cost. Potential TMP-SMX-preventable OIs occurred in 7 (5 Nocardia; 2 PJP). APA side effects occurred in 14/105 (13.3%). CONCLUSIONS: Use of APAs for PJP prophylaxis after SOT is less than previously reported but often unwarranted. Such decisions require scrutiny to avoid TMP-SMX-preventable OIs, cost and important APA side effects. Use of reasonable thresholds for cessation of TMP-SMX and data-driven approaches to re-challenge would substantially reduce APA use.

Coronavirus disease 2019 in an orthotopic liver transplant recipient living with human immunodeficiency virus.

Coronavirus disease 2019 (COVID-19), mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with flu-like illness and severe pneumonia with acute respiratory distress syndrome (ARDS). Immunocompromised patients merit particular attention as altered host immunity may influence both disease severity and duration of viral shedding as is described with several other ribonucleic acid respiratory viruses. Yet immunocompromised status alone, in the absence of other comorbidities, may not necessarily predict severe illness presentations and poorer clinical outcomes as indicated by recent reports of COVID-19-infected solid organ transplant recipients and people living with human immunodeficiency virus (HIV). Such patients may even be spared the robust inflammatory response that precipitates ARDS associated with COVID-19, complicating the management of iatrogenic immunosuppression in this setting. We present a case of an orthotopic liver transplant recipient with well-controlled HIV who successfully recovered from a mild, flu-like illness attributed to SARS-CoV-2.

Heart or lung transplant outcomes in HIV-infected recipients.

BACKGROUND: Limited published data exist on outcomes related to heart and/or lung transplantation in human immunodeficiency virus (HIV)-infected individuals. METHODS: We conducted a multicenter retrospective study of heart and lung transplantation in HIV-infected patients and describe key transplant- and HIV-related outcomes. RESULTS: We identified 29 HIV-infected thoracic transplant recipients (21 heart, 7 lung, and 1 heart and/or lung) across 14 transplant centers from 2000 through 2016. Compared with an International Society for Heart and Lung Transplantation registry cohort, we demonstrated similar 1-, 3-, and 5-year patient and allograft survivals for each organ type with a median follow up of 1,064 (range, 184-3,745) days for heart and 1,540 (range, 116-3,206) days for lung recipients. At 1 year, significant rejection rates were high (62%) for heart transplant recipients (HTRs). Risk factors for rejection were inconclusive, likely because of small numbers, but may be related to cautious early immunosuppression and infrequent use of induction therapy. Pulmonary bacterial infections were high (86%) for lung transplant recipients (LTRs). Median CD4 counts changed from baseline to 1 year from 399 to 411 cells/µl for HTRs and 638 to 280 cells/µl for LTRs. Acquired immunodeficiency syndrome-related events, including infections and malignancies, were rare. Rates of severe renal dysfunction suggest a need to modify nephrotoxic anti-retrovirals and/or immunosuppressants. CONCLUSIONS: HIV-infected HTRs and LTRs have similar survival rates to their HIV-uninfected counterparts. Although optimal immunosuppression is not defined, it should be at least as aggressive as that for HIV-uninfected recipients. Such data may help pave the way for the use of hearts and lungs from HIV-infected donors in HIV-infected recipients through HIV Organ Policy Equity Act protocols.

Recommended foscarnet dose is not associated with improved outcomes in cytomegalovirus salvage therapy.

BACKGROUND: Cytomegalovirus (CMV) infection causes significant morbidity and mortality in transplant recipients. Ganciclovir and valganciclovir have proven efficacy but are limited by resistance and toxicity, whereas foscarnet typically retains activity when CMV has become resistant to other antivirals. Foscarnet dosing used in practice may be discordant with what is recommended in product labeling, as the result of an unconventional dosing nomogram or prescriber preference; however, it is unknown how discordant foscarnet dosing affects outcomes. OBJECTIVE: Our purpose was to characterize the relationship between initial foscarnet dosing intensity (relative to product labeling) and key effectiveness and safety endpoints. STUDY DESIGN: This single-center, retrospective study included immunosuppressed adults with CMV viremia who received foscarnet between January 2012-July 2017. Subjects were divided into low dose (LD) and non-low dose (NLD) groups, according to foscarnet dose intensity. The primary endpoint was time-to-CMV eradication. Secondary endpoints included time-to-CMV clearance, acute kidney injury, hematologic toxicity, and mortality. RESULTS: Of 87 subjects, 38 met inclusion. Primary immunosuppression reasons were solid organ (63%) or hematopoietic cell transplant (29%). Seventeen and 21 subjects were in the LD and NLD groups, respectively. Median time-to-CMV eradication was 17 days (LD group) versus 13 days (NLD group), p = 0.823. Median time-to-CMV clearance was also non-significant (p = 0.505). There was no association between initial foscarnet dosing intensity and acute kidney injury, hematologic toxicity, or mortality (24% in both groups). CONCLUSIONS: These findings suggest outcomes may be sensitive to other factors and underscore the need for further studies to improve understanding of foscarnet dosing in immunosuppressed patients.

Ventricular assist device-related infections and solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

The Infectious Diseases Community of Practice of the American Society of Transplantation has published evidenced-based guidelines on the prevention and management of infectious complications in SOT recipients since 2004. This updated guideline reviews the epidemiology of ventricular assist device (VAD) infections and provides recommendations for the management and prevention of these infections. Almost one half of those awaiting heart transplantation are supported with VADs. Despite advances in device technologies, VAD infections commonly complicate mechanical circulatory support and remain typified by common components and anatomic locations. These infections have important implications for transplant candidates, most notably increased wait-list mortality. Strategic management of these infections is crucial for successful transplantation. Coincidentally, explantation of all VAD components at the time of transplantation is often the definitive cure for the device-associated infection. Highlighted in this updated guideline is the reported success of transplantation in patients with a variety of pre-existing VAD infections and guidance on post-transplant management strategies.

Epidemiology of infection in mechanical circulatory support: A global analysis from the ISHLT Mechanically Assisted Circulatory Support Registry.

BACKGROUND: Despite advances in device technology and treatment strategies, infection remains a major cause of adverse events (AEs) in mechanical circulatory support (MCS) patients. To characterize the epidemiology of MCS infection, we examined the type, location, and timing of infection in the International Society for Heart and Lung Transplantation Registry (ISHLT) for Mechanically Assisted Circulatory Support (IMACS) over 3 years, 2013 to 2015. METHODS: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definitions were used to categorize AE infections occurring in MCS patients within IMACS. The IMACS infection variables were mapped to ISHLT definitions for infection where feasible. Three categories of MCS infection were defined as ventricular assist device (VAD) specific, VAD related, and non-VAD. RESULTS: There were 10,171 patients enrolled from January 2013 through December 2015. Infection was the most common AE, with 3,788 patients (37%) experiencing ≥ 1 infection, and 6,758 AE infections reported overall. Non-VAD infection was the largest category, 4,501: 34.0% pneumonias, 30.6% non-VAD-related bloodstream infections (BSIs), 24.15% urinary tract infections (UTIs), and 10.2% gastrointestinal infections. VAD-specific infection was the second largest category, 1,756: 82.9% driveline, 12.8% pocket, and 4.3% pump/or cannula infections. VAD-related infection was the smallest category, 501: 47.5% BSIs, 47.5% mediastinitis, and 5.0% mediastinitis/pocket infections. All 3 categories were more frequently reported ≤ 3 months after implant. CONCLUSIONS: Non-VAD infection, including pneumonia, BSI, UTI, and gastrointestinal infection, was the leading category of infection in MCS patients and the most frequently reported ≤ 3 months after implant. These results provide evidence to support resourcing and strengthening infection prevention strategy early after implantation in MCS.

Prevention and Treatment of Cytomegalovirus Infections in Solid Organ Transplant Recipients.

Despite advances in prevention and treatment, cytomegalovirus (CMV) infection and disease remain an expected problem in solid organ transplant recipients. Because of the effect of immunosuppressing medications, CMV primary, secondary, and reactivated infection requires antiviral medications to prevent serious direct and indirect effects of the virus. Side effects and drug resistance, however, often limit the capacity of traditional antiviral therapies. This article updates the clinician on current and promising approaches to the management and control of CMV in the solid organ transplant recipient.

Outcomes of Heart Transplant After Left Ventricular Assist Device Specific and Related Infection.

BACKGROUND: Left ventricular assist device (LVAD) infections including drivelines, pump pockets, and bacteremia are difficult to manage and conservative treatments may not be effective as the infected foreign material remains. METHODS: We performed a retrospective analysis of all 170 HeartMate II (Thoratec, Pleasanton, CA) implantations as bridge to transplant (BTT) between 2004 and 2012 at our institution. Sixty-one patients (36%) developed a culture positive driveline infection, pump pocket infection, bacteremia, or a combination of these. Twenty-six out of 61 patients with an infection and 49 out of 109 patients without an infection went on to receive a heart transplant. RESULTS: The 1- and 3-year freedom from LVAD infection was 60% and 32%, respectively. While early infection tends to first present as driveline infections, late infections tend to present initially as bacteremia. The 1-year likelihood of receiving a transplant in the patients with an LVAD infection group was 37%, compared with 43% in patients without an infection (p = 0.36). One-year survival to transplantation was 76% in patients with LVAD infection compared with 81% without (p = 0.33). The 1- and 3-year posttransplant survival in patients with a LVAD infection was 96% and 91%, respectively, compared with 92% and 88% in patients without an infection (p = 0.48) . CONCLUSIONS: In this nonmatched cohort of LVAD patients with and without infection, selected patients with controlled LVAD infection have an equal chance of getting transplanted with excellent early and late post-transplant survival.

Selecting suitable solid organ transplant donors: Reducing the risk of donor-transmitted infections.

Selection of the appropriate donor is essential to a successful allograft recipient outcome for solid organ transplantation. Multiple infectious diseases have been transmitted from the donor to the recipient via transplantation. Donor-transmitted infections cause increased morbidity and mortality to the recipient. In recent years, a series of high-profile transmissions of infections have occurred in organ recipients prompting increased attention on the process of improving the selection of an appropriate donor that balances the shortage of needed allografts with an approach that mitigates the risk of donor-transmitted infection to the recipient. Important advances focused on improving donor screening diagnostics, using previously excluded high-risk donors, and individualizing the selection of allografts to recipients based on their prior infection history are serving to increase the donor pool and improve outcomes after transplant. This article serves to review the relevant literature surrounding this topic and to provide a suggested approach to the selection of an appropriate solid organ transplant donor.

Evolution and impact of drive-line infection in a large cohort of continuous-flow ventricular assist device recipients.

BACKGROUND: Drive-line infections (DLIs) frequently complicate ventricular assist device (VAD) support. We sought to describe the detailed effects of DLIs over time in patients with continuous-flow VADs, including the onset, risk factors, organisms involved, association with invasive infections, and outcomes. METHODS: We reviewed data for patients with HeartMate II VADs (HMII) who were implanted at the Cleveland Clinic from October 2004 to September 2011 and followed through December 2011. DLIs were defined according to published criteria. RESULTS: DLIs developed in 45 of 194 HMII VADs over a median period of 232 days (range 22 to 883 days). Hazard for DLI was 2.0%/month, but transiently peaked at 11%/month at 7.5 months after implant. Pseudomonas aeruginosa accounted for 31%, 42% and 55% of initial, final and deep DLIs, respectively. Of the 40 superficial DLIs, 13 (32.5%) became deep. DLI-associated bacteremia and hospitalization occurred in 14 of 45 (31%) and 30 of 45 (67%), respectively. All patients received antibiotics (median 171 days), but only 3 of 44 (6.8%) developed an antibiotic complication. DLIs increased the risk for death while on VAD support (HR 2.20, 95% CI 1.20 to 4.05; p = 0.01). Six and 12 months after DLI, mortality was 9.8% and 31%, but the competing event of transplantation occurred successfully in 20% and 28%, respectively. CONCLUSIONS: Most DLIs begin superficially with peak hazard at 7.5 months after implant. Depth of infection and infecting organism may evolve over months on support, with Pseudomonas becoming more prominent. Although effectively managed for prolonged periods, DLIs are associated with reduced survival on VAD support. Earlier transplantation is the most successful approach to treatment.

Impact of pretransplant rifaximin therapy on early post-liver transplant infections.

Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period.

Home testing for HIV: hopefully, a step forward.

An over-the-counter at-home test for human immunodeficiency virus (HIV) infection has been approved and will likely be available soon. It is intended to decrease the percentage of HIV-infected people unaware of their infection (estimated at 18% of the 1.2 million people infected in the United States). Since early and continued treatment prevents disease progression and reduces HIV transmission, testing is the first step toward effective care.