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.

Hepatitis B transmission/reactivation associated with Hepatitis B core antibody and Hepatitis C nucleic acid testing positive organs: A report from the Organ Procurement and Transplantation Network Disease Transmission Advisory Committee.

BACKGROUND: Better access to direct-acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation. AIM: To determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy. METHODS: The number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as "proven" or "probable" transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of "proven" or "probable" cases was conducted. RESULTS: From January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV-) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV- livers as well as non-liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41-1117) days post-transplant in the setting of missing, inadequate, or truncated prophylaxis. CONCLUSION: HBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non-transplant population, possibly due to the common use of HBV prophylaxis in the at-risk transplant population.

Cytomegalovirus Immune reconstitution in cord blood transplant recipients on letermovir prophylaxis.

INTRODUCTION: Cytomegalovirus (CMV) can cause significant morbidity and mortality in cord blood transplant (CBT) recipients. Development of CMV-specific cell-mediated immunity (CMV-CMI) has been associated with protection against CMV clinically significant reactivation (CsCMV). In this study, we evaluated CMV-CMI reconstitution during letermovir prophylactic therapy, which prevents CsCMV without complete suppression of CMV reactivation. METHODS: We measured CMV-CMI in CMV-seropositive CBT recipients pre-transplant after Day+90 of letermovir prophylaxis and at Days +180, and +360- post-transplant using a dual color CMV-specific IFNγ/IL2 FLUOROSpot. CsCMV and nonCsCMV reactivations were abstracted from medical records. CsCMV was defined as CMV viral load ≥5,000 IU/ml using a whole blood assay. RESULTS: Among 70 CBT recipients, 31 developed CMV-CMI by Day+90 and an additional eight and five participants by Days +180 and +360, respectively. Thirty-eight participants developed CMV reactivation, including nine with CsCMV. Most reactivations (33 of 38) occurred before Day+180. Early CMV-CMI was present in six out of nine participants with CsCMV, indicating a lack of protection against CsCMV. Moreover, the magnitude of CMV-CMI at Day+90 did not differ between participants with CsCMV and nonCsCMV. CONCLUSION: Approximately 50% of CBT recipients reconstituted CMV-CMI during letermovir prophylactic therapy. However, CMV-CMI did not reach levels protective against CsCMV. Extension of CMV prophylaxis beyond Day+90 may be considered in CMV-seropositive CBT recipients.

Cognitive impairment burden in older and younger adults across the kidney transplant care continuum.

BACKGROUND: Younger kidney transplant (KT) candidates and recipients may have cognitive impairment due to chronic diseases and reliance on dialysis. METHODS: To quantify cognitive impairment burden by age across the KT care continuum, we leveraged a two-center cohort study of 3854 KT candidates at evaluation, 1114 recipients at admission, and 405 recipients at 1-year post-KT with measured global cognitive performance (3MS) or executive function (Trail Making Test). We also estimated burden of severe cognitive impairment that affects functional dependence (activities of daily living [ADL] < 6 or instrumental activities of daily living [IADL] < 8). RESULTS: Among KT candidates, global cognitive impairment (18-34 years: 11.1%; 35-49 years: 14.0%; 50-64 years: 19.5%; ≥65 years: 22.0%) and severe cognitive impairment burden (18-34 years: 1.1%; 35-49 years: 3.0%; 50-64 years: 6.2%; ≥65 years: 7.7%) increased linearly with age. Among KT recipients at admission, global cognitive impairment (18-34 years: 9.1%; 35-49 years: 6.1%; 50-64 years: 9.3%; ≥65 years: 15.7%) and severe cognitive impairment burden (18-34 years: 1.4%; 35-49 years: 1.4%; 50-64 years: 2.2%; ≥65 years: 4.6%) was lower. Despite lowest burden of cognitive impairment among KT recipients at 1-year post-KT across all ages (18-34 years: 1.7%; 35-49 years: 3.4%; 50-64 years: 4.3%; ≥65 years: 6.5%), many still exhibited severe cognitive impairment (18-34 years: .0%; 35-49 years: 1.9%; 50-64 years: 2.4%; ≥65 years: 3.5%). CONCLUSION: Findings were consistent for executive function impairment. While cognitive impairment increases with age, younger KT candidates have a high burden comparable to community-dwelling older adults, with some potentially suffering from severe forms. Transplant centers should consider routinely screening patients during clinical care encounters regardless of age.

Perioperative anidulafungin combined with triazole prophylaxis for the prevention of early invasive candidiasis in lung transplant recipients.

BACKGROUND: Invasive candidiasis (IC) is a substantial cause of morbidity and mortality among lung transplant recipients (LTRs). Postoperative factors include prolonged hospital stay, central lines, delayed chest closure, and dehiscence increase IC risk. Correspondingly, current guidelines propose targeted IC coverage early posttransplant with fluconazole or an echinocandin. METHODS: This retrospective analysis was performed on LTRs from January 2016 to January 2020 and evaluated effectiveness of a recent protocol utilizing perioperative anidulafungin for early IC prevention in addition to long-term triazole antifungal prophylaxis. Prior to this protocol, patients were primarily established on itraconazole prophylaxis alone. The primary endpoint was proven or probable IC within 90 days after transplant. Multivariable logistic regression modeling was used to assess risk factors for invasive fungal infection (IFI). RESULTS: Among 144 LTRs, there was a numerically lower incidence of IC in the protocol group, although not statistically significant (6% vs. 13%, p = 0.16). Incidence of proven or probable IFI was 7.5% in the protocol cohort and 19.5% in the pre-protocol cohort (p = 0.038). In multivariable analysis, when controlling for lung allocation score (OR 1.04, 95% CI 1.01-1.08), donor perioperative culture with fungal growth (OR 2.92, 95% CI 1.02-8.92), and dehiscence (OR 3.54, 95% CI 1.14-10.85), protocol cohort was not significantly associated with IFI (OR 0.41, 95% CI 0.12-1.23). CONCLUSIONS: To our knowledge, this is the first study investigating combination triazole/echinocandin use in the early post-lung transplant period. These findings demonstrate that in-hospital anidulafungin offers unclear benefit for early IC prevention when used in combination with triazole prophylaxis.

Guidelines for COVID-19 Management in Hematopoietic Cell Transplantation and Cellular Therapy Recipients.

There are currently limited data on the epidemiology, clinical manifestations, and optimal management of Coronavirus Disease 2019 (COVID-19) in hematopoietic cell transplantation and cellular therapy recipients. Given the experience with other respiratory viruses, we anticipate that patients may develop severe clinical disease and thus provide the following general principles for cancer centers across the nation. These guidelines were developed by members of the American Society for Transplantation and Cellular Therapy Infectious Diseases Special Interest Group. Specific practices may vary depending on local epidemiology and testing capacity, and the guidance provided in this document may change as new information becomes available.

Severe acute Q fever pneumonia complicated by presumed persistent localized Q fever endocarditis in a renal transplant recipient: A case report and review of the literature.

Q fever in solid organ transplant (SOT) recipients is rarely described in the medical literature. We present a case of severe acute Q fever pneumonia that evolved into persistent localized Q fever endocarditis in a renal transplant recipient.

Cytomegalovirus myocarditis in solid organ transplant recipients: A case series and review of literature.

Cytomegalovirus (CMV) is a DNA virus of the Herpesviridae family and is estimated to affect 15%-30% of high-risk solid organ transplant recipients. Typical manifestations of CMV end-organ disease in this population include colitis, esophagitis, and pneumonitis, and myocarditis is a rarely reported manifestation. We describe two cases of CMV myocarditis in solid organ transplant recipients and review the literature regarding previously published cases of CMV myocarditis.

Toxoplasmosis in non-cardiac solid organ transplant recipients: A case series and review of literature.

The risk of toxoplasmosis in high-risk cardiac transplant recipients is well recognized prompting universal donor and candidate screening with administration of targeted post-transplant chemoprophylaxis in high-risk (D+/R-) cardiac transplant patients. In contrast, until recently, there have been neither well-defined recommendations nor consensus regarding toxoplasmosis preventive strategies among non-cardiac solid organ transplant recipients. We report 3 cases of post-transplant toxoplasmosis in non-cardiac transplant recipients (one lung and two liver); all 3 infections presumed to be donor-derived. Not surprisingly, pre-transplant Toxoplasma serology was negative in all the patients. None of the patients were on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis of toxoplasmosis. The median time from transplant to onset of infection was 90 days (range: 30-120 days). Clinical presentations included cerebral (n = 1) and disseminated infections (n = 2). Two of the 3 patients, both with disseminated infection died (mortality ~ 67%).

Oral Vancomycin Prophylaxis as Secondary Prevention Against Clostridioides difficile Infection in the Hematopoietic Stem Cell Transplantation and Hematologic Malignancy Population.

Clostridioides difficile infection (CDI) is a common complication in the hematopoietic stem cell transplantation (HSCT) and hematologic malignancy (HM) population. CDI is associated with increased hospital length of stay, health care and societal costs, morbidity, and mortality. Identifying strategies for secondary prevention of CDI is of extreme importance in the HSCT/HM population. In this study, our primary objective was to evaluate the effectiveness and safety of an oral vancomycin prophylaxis (OVP) protocol for secondary prevention of CDI in a retrospective cohort of adult autologous/allogeneic HSCT recipients and patients with HM who did not undergo HSCT with a first CDI episode treated with concomitant broad-spectrum antibiotics (BSA). Patients were diagnosed and treated for CDI as inpatients and/or outpatients and were divided into 2 groups based on a preprotocol versus postprotocol analysis: the OVP group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently received OVP posttreatment and a no OVP (NOVP) group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently did not receive OVP posttreatment. OVP was defined as vancomycin 125 mg every 12 hours for up to 7 days after BSA discontinuation. The primary endpoint was recurrent CDI (rCDI), defined as symptoms of loose stools/diarrhea with high clinical suspicion for CDI prompting empiric therapy within 60 days of completion of treatment/prophylaxis for the first CDI episode. The incidence of vancomycin-resistant enterococcal (VRE) infection and 60-day mortality were also compared between the 2 groups. Multivariate logistic regression was created from associated variables to identify independent associations with rCDI. A total of 50 patients were included, 21 in the OVP group (42%) and 29 in the NOVP group (58%). The mean patient age was 58 years, and the cohort was 60% male and 86% Caucasian. HSCT was performed in 60% of the patients, and 76% of CDI cases were diagnosed during hospitalization. The rate of rCDI was significantly lower in the OVP group compared with the NOVP group (5% [1 of 21] versus 35% [10 of 29]; P= .016), with no subsequent increase in VRE infection rate (14% [3 of 21] versus 10% [3 of 29]; P = .686). By multivariable logistic regression, rCDI was inversely associated with OVP (odds ratio [OR], .14; 95% confidence interval [CI], .007 to .994; P = .049) and directly associated with outpatient CDI diagnosis (OR, 8.72; 95% CI, 1.816 to 49.158; P = .007). No between-group differences were found in 60-day mortality (10% [2 of 21] for OVP versus 7% [2 of 29] for NOVP; P > 0.999). OVP appears to be safe and effective for secondary prevention of CDI in the HSCT/HM population. Prospective trials are needed to validate the effectiveness of OVP in this vulnerable population to prevent rCDI.

Gastrointestinal mucormycosis in immunocompromised hosts.

Invasive mucormycosis is a rare fungal infection in immunocompromised hosts, but it carries a high mortality rate. Primary gastrointestinal disease is the least frequent form of presentation. Early diagnosis and treatment are critical in the management; however, symptoms are typically non-specific in gastrointestinal disease, leading to delayed therapy. To describe the clinical presentation, diagnosis, treatment and outcomes of gastrointestinal mucormycosis in immunocompromised hosts, we reviewed all cases of primary gastrointestinal mucormycosis in immunocompromised hosts reported in English literature as well as in our Institution from January 1st 1991 to December 31st 2013 for a total of 31 patients. About 52% of patients underwent solid organ transplant (SOT), while the rest had an underlying haematologic malignancy. Abdominal pain was the most common presenting symptom, followed by gastrointestinal bleeding and fever. Gastric disease was more common in SOT, whereas those with haematologic malignancy presented with intestinal disease (P = 0.002). Although gastrointestinal mucormycosis remains an uncommon condition in immunocompromised hosts, it carries significant morbidity and mortality, particularly in cases with intestinal involvement. A high index of suspicion is of utmost importance to institute early and appropriate therapy and improve outcomes.

Stability in the cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995 to 2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies.

As invasive mucormycosis (IM) numbers rise, clinicians suspect prior voriconazole worsens IM incidence and severity, and believe combination anti-fungal therapy improves IM survival. To compare the cumulative incidence (CI), severity and mortality of IM in eras immediately before and after the commercial availability of voriconazole all IM cases from 1995 to 2011 were analysed across four risk-groups (hematologic/oncologic malignancy (H/O), stem cell transplantation (SCT), solid organ transplantation (SOT) and other), and two eras, E1 (1995-2003) and E2, (2004-2011). Of 101 IM cases, (79 proven, 22 probable): 30 were in E1 (3.3/year) and 71 in E2 (8.9/year). Between eras, the proportion with H/O or SCT rose from 47% to 73%, while 'other' dropped from 33% to 11% (P = 0.036). Between eras, the CI of IM did not significantly increase in SCT (P = 0.27) or SOT (P = 0.30), and patterns of anatomic location (P = 0.122) and surgical debridement (P = 0.200) were similar. Significantly more patients received amphotericin-echinocandin combination therapy in E2 (31% vs. 5%, P = 0.01); however, 90-day survival did not improve (54% vs. 59%, P = 0.67). Since 2003, the rise of IM reflects increasing numbers at risk, not prior use of voriconazole. Frequent combination of anti-fungal therapy has not improved survival.

Cytomegalovirus IgG is Associated With Physical Function But Not Muscle Density in People With HIV.

BACKGROUND: Cytomegalovirus (CMV) seropositivity is associated with poor outcomes, including physical function impairment, in people without HIV. We examined associations between CMV IgG titer and physical function in virologically suppressed people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating pitavastatin for primary prevention of atherosclerotic cardiovascular disease in PWH. This analysis focused on participants enrolled in a substudy with additional biomarker testing, imaging [coronary CT angiography], and physical function measures at entry. CMV IgG was measured using quantitative enzyme immunoassay, physical function by Short Physical Performance Battery, and muscle density and area by CT. Associations between CMV IgG (risk factor) and outcomes were evaluated using the partial Spearman correlation and linear and log-binomial regression. RESULTS: Among 717 participants, 82% male, the median CMV IgG was 2716 (Q1, Q3: 807, 6672) IU/mL, all above the limit of quantification. Among 631 participants with imaging, there was no association between CMV IgG and CT-based muscle density or area, controlling for age (r = -0.03 and r = -0.01, respectively; P ≥ 0.38). Among 161 participants with physical function data, higher CMV IgG was associated with poorer overall modified Short Physical Performance Battery score ( P = 0.02), adjusted for age, nadir CD4, and high-sensitivity C-reactive protein. CONCLUSIONS: Higher CMV IgG titer was associated with poorer physical function, not explained by previous immune compromise, inflammation, or muscle density or area. Further mechanistic studies are needed to understand this association and whether CMV-specific therapy can affect physical function in PWH.

Helicobacter canis bacteremia in a patient with fever of unknown origin.

A 57-year-old woman with common variable immune deficiency and liver failure of unknown etiology presented with recurrent fevers over a 5-month period. She was found to have Helicobacter canis bacteremia. Immunocompromised hosts with exposure to cats or dogs may be at risk for infection with this organism, which may be challenging to diagnose.

Patient years lost due to cytomegalovirus serostatus mismatching in the scientific registry of transplant recipients.

Background: The cytomegalovirus (CMV) mismatch rate in deceased donor kidney transplant (DDKT) recipients in the US remains above 40%. Since CMV mismatching is common in DDKT recipients, the cumulative effects may be significant in the context of overall patient and graft survival. Our primary objective was to describe the short- and long-term risks associated with high-risk CMV donor positive/recipient negative (D+/R-) mismatching among DDKT recipients with the explicit goal of deriving a mathematical mismatching penalty. Methods: We conducted a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients (SRTR) database using donor-matched DDKT recipient pairs (N=105,608) transplanted between 2011-2022. All-cause mortality and graft failure hazard ratios were calculated from one year to ten years post-DDKT. All-cause graft failure included death events. Survival curves were calculated using the Kaplan-Meier estimation at 10 years post-DDKT and extrapolated to 20 years to provide the average graft days lost (aGDL) and average patient days lost (aPDL) due to CMV D+/R- serostatus mismatching. We also performed an age-based stratification analysis to compare the relative risk of CMV D+ mismatching by age. Results: Among 31,518 CMV D+/R- recipients, at 1 year post-DDKT, the relative risk of death increased by 29% (p<0.001), and graft failure increased by 17% (p<0.001) as compared to matched CMV D+/R+ group (N=31,518). Age stratification demonstrated a significant increase in the risk associated with CMV mismatching in patients 40 years of age and greater. The aGDL per patient due to mismatching was 125 days and the aPDL per patient was 100 days. Conclusion: The risks of CMV D+/R- mismatching are seen both at 1 year post-DDKT period and accumulated throughout the lifespan of the patient, with the average CMV D+/R- recipient losing more than three months of post-DDKT survival time. CMV D+/R- mismatching poses a more significant risk and a greater health burden than previously reported, thus obviating the need for better preventive strategies including CMV serodirected organ allocation to prolong lifespans and graft survival in high-risk patients.

Frequently Asked Questions on Coronavirus Disease 2019 Vaccination for Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Recipients From the American Society for Transplantation and Cellular Therapy and the American Society of Hematology.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), disproportionately affects immunocompromised and elderly patients. Not only are hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell recipients at greater risk for severe COVID-19 and COVID-19-related complications, but they also may experience suboptimal immune responses to currently available COVID-19 vaccines. Optimizing the use, timing, and number of doses of the COVID-19 vaccines in these patients may provide better protection against SARS-CoV-2 infection and better outcomes after infection. To this end, current guidelines for COVID-19 vaccination in HCT and CAR T-cell recipients from the American Society of Transplantation and Cellular Therapy Transplant Infectious Disease Special Interest Group and the American Society of Hematology are provided in a frequently asked questions format.

Revised Guidelines for Coronavirus Disease 19 Management in Hematopoietic Cell Transplantation and Cellular Therapy Recipients (August 2022).

This document is intended as a guide for diagnosis and management of Coronavirus Disease 2019 (COVID-19), caused by the virus SARS-CoV-2, in adult and pediatric HCT and cellular therapy patients. This document was prepared using available data and with expert opinion provided by members of the (ASTCT) Infectious Diseases Special Interest Group (ID-SIG) and is an update of pervious publication. Since our original publication in 2020, the NIH and IDSA have published extensive guidelines for management of COVID-19 which are readily accessible ( NIH Guidelines , IDSA Guidelines ). This update focuses primarily on issues pertaining specifically to HCT/cellular therapy recipients. Information provided in this manuscript may change as new information becomes available.

Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study.

BACKGROUND: The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection. METHODS: We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality. RESULTS: Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age >50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33-1.95) and fungal (OR, 2.20; 95% CI, 1.28-3.76) coinfections. CONCLUSIONS: Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes.