Invasive Aspergillosis in Liver Transplant Recipients in The Current Era.

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multi-center 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in eight cases (13%). 12-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotics usage (adjusted odds ratio [aOR], 4.74; p=0.03) and history of pneumonia (aOR, 48.7; p=0.01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; p=0.01), systemic antibiotics usage (aOR, 5.03; p=0.04), and anti-mold prophylaxis (aOR, 11.9; p=0.02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ration [aHR], 86.9; p<0.001), ICU stay (aHR, 3.67; p=0.02), disseminated IA (aHR, 8.98; p<0.001), and dialysis (aHR, 2.93; p=0.001) were identified as independent risk factors associated with 12-week all-cause mortality; while recent receipt of tacrolimus (aHR, 0.11; p=0.001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted anti-mold prophylactic and appropriate treatment strategies against IA.

Influence of induction therapy and antiretroviral regimen on outcomes in kidney transplant recipients living with human immunodeficiency.

PURPOSE: Kidney transplantation has a survival benefit for people with human immunodeficiency virus (HIV) and end-stage kidney disease, however increased rates of rejection remain an issue. Questions remain regarding the impact of induction immunosuppression therapy and antiretroviral (ARV) choice on long-term outcomes. METHODS: We performed a multicenter retrospective analysis of outcomes in recipients with HIV who received kidneys from donors without HIV transplanted between 2004 and 2019. The association between induction and ARV regimens and long-term outcomes including rejection, graft, and recipient survival over 5 years was investigated using Cox regression modeling. RESULTS: Seventy-eight kidney transplants (KT) performed in 77 recipients at five US transplant centers were included, with median follow up of 7.1 (4.3-10.7) years. Overall recipient and graft survival were 83% and 67%, respectively. Rejection occurred in 37% (29/78). Recipients with rejection were more likely to be younger, recipients of deceased donor organs, and Black. Receipt of rabbit anti-thymocyte globulin (rATG) induction without protease-inhibitor (PI)-based ARVs was associated with 83% lower risk of rejection (adjusted hazard ratio (aHR) 0.17 (95% CI 0.05-0.63), p =.007) and a non-statistically significantly lower risk of graft failure (aHR 0.18 (0.03-1.16), p =.07) when compared to those who received other induction and ARV combinations. CONCLUSIONS: In this multicenter retrospective study, we found a trend toward lower rejection and improved graft survival among those who received both rATG for induction and PI-sparing ARVs.

HIV-Positive Liver Transplant Does not Alter the Latent Viral Reservoir in Recipients With Antiretroviral Therapy-Suppressed HIV.

The latent viral reservoir (LVR) remains a major barrier to HIV-1 curative strategies. It is unknown whether receiving a liver transplant from a donor with HIV might lead to an increase in the LVR because the liver is a large lymphoid organ. We found no differences in intact provirus, defective provirus, or the ratio of intact to defective provirus between recipients with ART-suppressed HIV who received a liver from a donor with (n = 19) or without HIV (n = 10). All measures remained stable from baseline by 1 year posttransplant. These data demonstrate that the LVR is stable after liver transplantation in people with HIV. Clinical Trials Registration. NCT02602262 and NCT03734393.

Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

BACKGROUND: Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. METHODS: Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. RESULTS: Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection. CONCLUSIONS: Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

Clinical features, treatment, and outcomes of mpox in solid organ transplant recipients: A multicenter case series and literature review.

In 2022, the largest global outbreak of mpox to date emerged. In the immunocompetent host, mpox generally presents as a self-limiting illness. However, immunosuppression, such as that seen with advanced HIV, has been associated with significant morbidity and mortality related to mpox infection. To evaluate the impact of immunosuppression related to solid organ transplantation on clinical features and outcomes of mpox we established a multicenter case registry. Eleven cases from 7 participating centers in the USA were submitted. All cases occurred in males. The majority were kidney transplant recipients (91%, n = 10). Median duration of symptoms at presentation was 6 days (range, 3-14 days). Rates of hospitalization were high (73%, n = 8) with a median length of stay of 4.5 days (range, 1-10 days). Mpox in solid organ transplant recipients was associated with a high burden of skin lesions and systemic symptoms. Fever, fatigue, pharyngitis, and proctitis were commonly reported. Other clinical features included headache, myalgia, epididymo-orchitis, urinary retention, hematemesis, pneumonitis, and circulatory shock. All patients received treatment with tecovirimat. There was 1 mpox-related death in the cohort. Infection was reported to have resolved at 30-day follow-up in all other cases.

Donor call simulation: A novel medical education tool to evaluate trainees' clinical decision-making in transplant infectious disease.

BACKGROUND: Evaluating organ suitability for transplantation based on infection risk is a core competency in transplant infectious disease (TID). It is unclear if trainees have opportunities to practice during training. We created a simulation curriculum to develop and evaluate this skill among infectious disease (ID) trainees. METHODS: We created six simulation questions about organ suitability for transplant based on infection risk. During trainees' TID rotations, faculty texted or paged the simulation cases posing as the transplant coordinator. Trainees had 15 min to ask questions before deciding the suitability of the organ and explained their clinical reasoning in a survey. Trainees completed a post-simulation survey to evaluate its effectiveness. RESULTS: ID trainees, including residents and fellows on rotation, from seven centers participated. Eighty-seven percent (13/15) of trainees felt the simulation was effective in teaching them this concept, and 80% (12/15) felt prepared for clinical practice. The proportion of correct responses was generally high among the six different cases (43%-100%); correct responses increased for some cases in the post-activity survey. Of the 100 clinical reasoning decisions made during the activity, 19% were discordant, where the trainee correctly identified suitable organs for incorrect reasons. CONCLUSION: Our simulation was effective in teaching when to accept or reject an organ for transplant and was a valuable educational tool. By evaluating clinical reasoning for decisions our simulation provides educators with nuanced insight and allows for targeted coaching. This study demonstrates a critical need for further educational tools in TID.

National Landscape of Human Immunodeficiency Virus-Positive Deceased Organ Donors in the United States.

BACKGROUND: Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. METHODS: We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. RESULTS: Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL <400 copies/mL. The median CD4 T-cell count (interquartile range) was 194/µL (77-331/µL), and the median CD4 T-cell percentage was 27.0% (16.8%-36.1%). Major HIV DRMs were detected in 42%, including nonnucleoside reverse-transcriptase inhibitors (33%), integrase strand transfer inhibitors (4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. CONCLUSION: The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor-based regimens is rare, which is reassuring regarding safety.

White paper on antimicrobial stewardship in solid organ transplant recipients.

Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a "one-size-fits-all" style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.

Adverse Effects of Immunosuppression: Infections.

Immunosuppressive therapies are currently indicated for a wide range of diseases. As new agents emerge and indications evolve the landscape grows increasingly complex. Therapies can target pathologic immune system over-activation in rheumatologic or autoimmune disease, or conditioning and graft versus host disease (GVHD) prophylactic regimens may eliminate or inhibit host immune function to improve graft survival and risk of complication in solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). With immunosuppressive therapy, infections occur. Complex disease states, host factors, and concomitant therapies contribute to a "net state" of immunosuppression that must be considered and may confound perceived increased infection risks in patients receiving treatment.

Liver Transplantation Using Hepatitis C Virus-Viremic Donors Into Hepatitis C Virus-Aviremic Recipients as Standard of Care.

Liver transplantation (LT) using allografts from hepatitis C virus (HCV)-viremic/nucleic acid testing-positive donors' (DNAT+) organs into HCV-aviremic recipients (rHCV-) has been limited owing to nearly universal HCV transmission and concerns regarding availability, safety, and efficacy post-LT with direct-acting antiviral (DAA) therapy. We report our experience of LT using DNAT+ organs into rHCV- as a routine standard of care. Following verification of DAA access, absence of critical drug-drug interactions (DDIs) with DAAs, and informed consent, allocated DNAT+ organs were offered to patients on the waiting list for LT irrespective of recipient HCV status. Between June 2018 and December 2019, 292/339 rHCV- received an LT. Forty-seven patients were excluded from analysis because of recipient HCV viremia, refusal to receive DNAT+ organs, or inability to receive DAA therapy post-LT. Of these 292 patients, 61 rHCV- received DNAT+ livers (study group), and 231 rHCV- received DNAT- (aviremic donors [nuclear acid test-negative donors]) livers (control group). Recipient and donor characteristics as well as 1-year post-LT patient and graft survival were similar between groups. In the study group, 4 patients died, and 1 patient required retransplantation within the first year post-LT (all unrelated to HCV); 56 patients received DAA therapy, with a median time from LT to the start of DAA treatment of 66.9 days (interquartile range [IQR], 36-68.5), and 51 patients completed DAA treatment, all achieving sustained virologic response for 12 or more weeks (SVR-12) (1 patient required retreatment owing to relapse following initial DAA therapy). No patients had evidence of fibrosing cholestatic hepatitis or extrahepatic manifestations of HCV. This report indicates that transplantation of DNAT+ livers into rHCV- and subsequent DAA therapy is associated with clinical outcomes comparable to those achieved with DNAT- allografts.

The time is now: antimicrobial stewardship in solid organ transplantation.

PURPOSE OF REVIEW: To provide a summary of complications of antimicrobials and opportunities for antimicrobial stewardship (AS) in solid organ transplant (SOT) patient care. RECENT FINDINGS: Personalized, precision antimicrobial prescribing in SOT aiming to avoid negative consequences of antimicrobials is essential to improving patient outcomes. The positive impact AS efforts in transplant care has been recognized and bespoke activities tailored to special interests of transplant patients and providers are evolving. Strategies to optimize stewardship interventions targeting antibacterial, antiviral, and antifungal drug selection and dosing in the transplant population have been recently published though clinical integration using a 'handshake' stewardship model is an optimal starting point in transplant care. Other recent studies involving transplant recipients have identified opportunities to shorten duration or avoid antimicrobials for certain commonly encountered clinical syndromes. This literature, informing recent consensus clinical practice guidelines, may help support institutional practice guidelines and protocols. Proposals to track and report stewardship process and outcome measures as a routine facet of programmatic transplant quality reporting have been published. However, developing novel metrics accounting for nuances of transplant patients and programs is critical. Important studies are needed to evaluate organizational transplant prescribing cultures and optimal behavioral science-based interventions relevant to antimicrobial use in this population. SUMMARY: Consequences of antimicrobial use, such as drug toxicities, and Clostridiodes difficile (CDI) and multidrug-resistant organisms colonization and infection disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Stewardship programs encompassing transplant patients aim to personalize antimicrobial prescribing and optimize outcomes. Further studies are needed to better understand optimal intervention strategies in SOT.

Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HHV-6A, HHV-6B, HHV-7, and HHV-8 in the pre- and post-transplant period. The majority of HHV-6 (A and B) and HHV-7 infections in transplant recipients are asymptomatic; symptomatic disease is reported infrequently across organs. Routine screening for HHV-6 and 7 DNAemia is not recommended in asymptomatic patients, nor is prophylaxis or preemptive therapy. Detection of viral nucleic acid by quantitative PCR in blood or CSF is the preferred method for diagnosis of HHV-6 and HHV-7 infection. The possibility of chromosomally integrated HHV-6 DNA should be considered in individuals with persistently high viral loads. Antiviral therapy should be initiated for HHV-6 encephalitis and should be considered for other manifestations of disease. HHV-8 causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease and is also associated with hemophagocytic syndrome and bone marrow failure. HHV-8 screening and monitoring may be indicated to prevent disease. Treatment of HHV-8 related disease centers on reduction of immunosuppression and conversion to sirolimus, while chemotherapy may be needed for unresponsive disease. The role of antiviral therapy for HHV-8 infection has not yet been defined.

Antimicrobial stewardship in transplant patients.

PURPOSE OF REVIEW: To provide an update on the current landscape of antimicrobial stewardship in solid organ transplant (SOT) recipients. RECENT FINDINGS: Constructing personalized antimicrobial prescribing approaches to avoid untoward consequences of antimicrobials while improving outcomes is an emerging and critical aspect of transplant medicine. Stewardship activities encompassing the specialized interests of transplant patients and programs are evolving. New literature evaluating strategies to optimize antimicrobial agent selection, dosing, and duration have been published. Additionally, consensus guidance for certain infectious clinical syndromes is available and should inform institutional clinical practice guidelines. Novel metrics for stewardship-related outcomes in transplantation are desperately needed. Though exciting new molecular diagnostic technologies will likely be pivotal in the care of immunocompromised patients, optimal clinical adaptation and appropriate integration remains unclear. Important studies understanding the behaviors influencing antimicrobial prescribing in organizational transplant cultures are needed to optimize interventions. SUMMARY: Consequences of antimicrobial use, such as Clostridiodes difficile and infections with multidrug-resistant organisms disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Application of ASP interventions tailored to SOT recipients is recommended though further studies are needed to provide guidance for best practice.

Tuberculosis after liver transplantation in a large center in New York City: QuantiFERON® -TB Gold-based pre-transplant screening performance and active tuberculosis post-transplant.

INTRODUCTION: Pre-transplant screening for latent tuberculosis infection (LTBI) is a complex consideration that varies by institution. Inconsistent performance of interferon-gamma release assay (IGRA) further complicates screening. Data regarding LTBI screening outcomes and test characteristics in a large, foreign-born pre-transplant population within the United States are limited. METHODS: In this retrospective study, patients who received QuantiFERON® -TB Gold (QFT) prior to liver transplantation (LT) were included. Characteristics of patients were compared by QFT result, and predictors of indeterminate results were evaluated. Similar comparisons were performed between patients who developed active TB and those who did not. RESULTS: Of 148 patients screened, the rate of positive, indeterminate, and negative testing was 13.5% (20/148), 27% (40/148), and 59% (88/148), respectively. An indeterminate QFT result was more than 16 times more likely in patients with a Model for End-stage Liver Disease score >25 (odds ratio [OR] 16.7; 95% confidence interval [CI], 2.1-132.0; P = .008) and more than 4 times when performed in our institution's lab compared with commercial lab (OR 4.1; 95% CI, 1.34-12.44; P = .013). The overall TB incidence was 1102/100 000 transplant cases. No patient who developed active TB had a positive QFT. All were born outside of the United States (P = .06) and had pre-transplantation chest imaging demonstrating granulomatous disease (P = .006). CONCLUSION: Our experience further highlights the challenges of LTBI screening prior to LT and suggests that QFT may be a poor predictor of active TB in higher risk pre-transplant populations. Candidates should be screened as early as possible to optimize QFT performance, and local epidemiological data should be used to create institution-specific screening protocols in areas with large populations from TB-endemic regions. Management should consider TB risk factors, QFT, and imaging instead of reliance on QFT testing alone.

Comparison of outcomes with vancomycin or metronidazole for mild-to-moderate Clostridium difficile associated diarrhea among solid organ transplant recipients: A retrospective cohort study.

BACKGROUND: Current guidelines recommend oral vancomycin or fidaxomicin for the treatment of mild-to-moderate Clostridium difficile associated diarrhea (CDAD), while metronidazole is recommended as an alternative when oral vancomycin and fidaxomicin are unavailable. However, data are lacking among the solid organ transplant (SOT) population. METHODS: This single center, retrospective cohort study evaluated adult SOT recipients with mild-to-moderate CDAD. Analysis 1 evaluated patients receiving initial therapy with metronidazole vs oral vancomycin for at least 72 hours. Analysis 2 evaluated patients receiving metronidazole vs oral vancomycin for at least 70% of the treatment duration. The primary outcome was treatment failure. Secondary outcomes included CDAD recurrence and all-cause mortality. RESULTS: Analysis 1 included 71 patients (metronidazole n = 50, oral vancomycin n = 21) and analysis 2 included 75 patients (metronidazole n = 42, oral vancomycin n = 33). No significant differences in C. difficile risk factors were observed between groups in either analysis. However, in both analyses, more patients in the oral vancomycin arm received antibiotics during the CDAD episode (analysis 1, 52% vs 26%, P = .03; analysis 2, 55% vs 32%, P < .01). Neither analysis demonstrated differences in treatment failure (analysis 1, metronidazole 16%, oral vancomycin 10%, P = .71; analysis 2, metronidazole 2%, oral vancomycin 6%, P = .58). CDAD recurrence and all-cause mortality were similar across groups in both analyses. CONCLUSIONS: Results suggest that both metronidazole and oral vancomycin are reasonable options for the treatment of mild-to-moderate CDAD in patients with SOT. No difference in treatment failure was observed; however, oral vancomycin may be preferred for higher risk patients, such as those receiving concurrent antibiotics.

Multidrug-resistant organisms in liver transplant: Mitigating risk and managing infections.

Liver transplant (LT) recipients are vulnerable to infections with multidrug-resistant (MDR) pathogens. Risk factors for colonization and infection with resistant bacteria are ubiquitous and unavoidable in transplantation. During the past decade, progress in transplantation and infection prevention has contributed to the decreased incidence of infections with methicillin-resistant Staphylococcus aureus. However, even in the face of potentially effective antibiotics, vancomycin-resistant enterococci continue to plague LT. Gram-negative bacilli prove to be more problematic and are responsible for high rates of both morbidity and mortality. Despite the licensure of novel antibiotics, there is no universal agent available to safely and effectively treat infections with MDR gram-negative organisms. Currently, efforts dedicated toward prevention and treatment require involvement of multiple disciplines including transplant providers, specialists in infectious diseases and infection prevention, and researchers dedicated to the development of rapid diagnostics and safe and effective antibiotics with novel mechanisms of action. Liver Transplantation 22 1143-1153 2016 AASLD.

Whole-genome sequencing identifies emergence of a quinolone resistance mutation in a case of Stenotrophomonas maltophilia bacteremia.

Whole-genome sequences for Stenotrophomonas maltophilia serial isolates from a bacteremic patient before and after development of levofloxacin resistance were assembled de novo and differed by one single-nucleotide variant in smeT, a repressor for multidrug efflux operon smeDEF. Along with sequenced isolates from five contemporaneous cases, they displayed considerable diversity compared against all published complete genomes. Whole-genome sequencing and complete assembly can conclusively identify resistance mechanisms emerging in S. maltophilia strains during clinical therapy.