A practical guide to real-world implementation of pre-emptive therapy for Cytomegalovirus disease prevention in high-risk seronegative liver transplant recipients with seropositive donors.

The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for Cytomegalovirus (CMV) disease prevention in high-risk CMV seronegative liver transplant recipients (LTRs) with seropositive donors (D+R-). Despite the statistical superiority of PET over prophylaxis in research settings, PET is perceived as a logistically more complex strategy that requires careful coordination of weekly CMV PCR testing, prompt initiation of CMV antivirals upon viremia detection, and timely cessation of antivirals following viremia resolution. Transplant centers may be hesitant to use PET for CMV disease prevention in D+R- LTRs out of concern that PET coordination is not feasible in clinical practice. We recently described our experience using PET in CMV D+R- LTRs in a real-world setting, and found it to be as effective for CMV disease prevention as PET performed as part of a clinical trial. Here, we describe a systematic approach for PET implementation in real-world settings and provide practical tools to address anticipated challenges. This framework can support transplant programs in overcoming logistical barriers to PET and incorporating an evidence-based and cost-effective CMV prevention strategy into routine care for high-risk CMV D+R- LTRs.

Serial Quantitation of Plasma Microbial Cell-Free DNA Before and After Diagnosis of Pulmonary Invasive Mold Infections After Hematopoietic Cell Transplant.

BACKGROUND: Plasma microbial cell-free DNA sequencing (mcfDNA-Seq) is a noninvasive test for microbial diagnosis of invasive mold infection (IMI). The utility of mcfDNA-Seq for predicting IMI onset and the clinical implications of mcfDNA concentrations are unknown. METHODS: We retrospectively tested plasma from hematopoietic cell transplant (HCT) recipients with pulmonary IMI and ≥1 mold identified by mcfDNA-Seq in plasma collected within 14 days of clinical diagnosis. Samples collected from up to 4 weeks before and 4 weeks after IMI diagnosis were evaluated using mcfDNA-Seq. RESULTS: Thirty-five HCT recipients with 39 IMIs (16 Aspergillus and 23 non-Aspergillus infections) were included. Pathogenic molds were detected in 38%, 26%, 11%, and 0% of samples collected during the first, second, third, and fourth week before clinical diagnosis, respectively. In non-Aspergillus infections, median mcfDNA concentrations in samples collected within 3 days of clinical diagnosis were higher in infections with versus without extrapulmonary spread (4.3 vs 3.3 log10 molecules per microliter [mpm], P = .02), and all patients (8/8) with mcfDNA concentrations >4.0 log10 mpm died within 42 days after clinical diagnosis. CONCLUSIONS: Plasma mcfDNA-Seq can identify pathogenic molds up to 3 weeks before clinical diagnosis of pulmonary IMI. Plasma mcfDNA concentrations may correlate with extrapulmonary spread and mortality in non-Aspergillus IMI.

Updates in Cytomegalovirus Prevention and Treatment in Solid Organ Transplantation.

The authors summarize recent updates in the prevention and management of cytomegalovirus (CMV) in solid organ transplant (SOT) recipients with a focus on CMV seronegative recipients of organs from seropositive donors (CMV D+/R-) who are at highest risk of CMV infection and disease. They discuss advantages of preemptive therapy for CMV disease prevention in CMV D+/R- liver transplant recipients, letermovir for CMV prophylaxis, and updates in the development of monoclonal antibodies and vaccines as immune-based preventative strategies. They review the roles of maribavir and virus-specific T cells for management of resistant or refractory CMV infection in SOT recipients.

Real-world effectiveness of preemptive therapy (PET) for cytomegalovirus (CMV) disease prevention in CMV high-risk donor seropositive/recipient seronegative (D+R-) liver transplant recipients (LTxR).

BACKGROUND: Despite superiority of preemptive therapy (PET) compared to universal prophylaxis for prevention of cytomegalovirus (CMV) disease in the CAPSIL randomized trial among CMV D+R- liver transplant recipients (LTxRs), real-world effectiveness may be lower because of logistical concerns about feasibility of PET. METHODS: We retrospectively assessed PET as standard clinical care at a single transplant center among 50 consecutive adult CMV D+R- LTxRs undergoing a first liver transplant between 4/4/2019 and 5/18/2021 and compared outcomes and adherence to those randomized to PET in the CAPSIL study (N = 100). The primary outcome was CMV disease and secondary outcomes were biopsy-confirmed acute allograft rejection, retransplant, invasive fungal infections, and death, all assessed by 1-year post-transplant. Exploratory outcomes included virologic parameters and measures of adherence to protocol-specified CMV qPCR monitoring. RESULTS: Baseline characteristics were similar between groups. The cumulative incidence of CMV disease at 1-year post-transplant was 4/50 (8%) versus 9/100 (9%) in the real-world and CAPSIL cohorts, respectively, p = 1.0. The rate of breakthrough CMV disease during the 100-day PET period was low (2/50 [4%]) and similar to the PET cohort from the CAPSIL study (3/100 [3%]).  All secondary and exploratory outcomes were not significantly different between the real-world and CAPSIL PET cohorts. CONCLUSIONS: In this first reported study of real-world PET, the feasibility and effectiveness for CMV disease prevention and for other clinical outcomes in CMV D+R- LTxRs were similar to those reported with PET in a clinical trial. Additional studies to confirm feasibility and generalizability in other settings are warranted.

Combined assessment of Epstein-Barr virus viral capsid antigen and Epstein-Barr virus nuclear antigen-1 serology for post-transplant lymphoproliferative disorder risk stratification in adult solid organ transplant recipients.

BACKGROUND: Epstein-Barr virus (EBV) seronegative solid organ transplant recipients (SOTRs) are at increased risk for post-transplant lymphoproliferative disorder (PTLD). Assays for EBV serostatus assess antibody to both EBV viral capsid antigen (VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1), but PTLD risk among SOT recipients with discordant VCA and EBNA-1 results is unknown. METHODS: We performed a retrospective, single-center cohort study to determine the risk of PTLD among adult (≥ 18 years) SOTRs with discordant pre-transplant VCA and EBNA-1 IgG compared to that of SOTRs with concordantly negative or concordantly positive serology using univariable and multivariable Cox-proportional hazards models. RESULTS: Of 4106 SOTRs, the number (%) who were concordantly positive, concordantly negative, and discordant was 3787 (92.2%), 149 (3.6%), and 170 (4.2%), respectively. The adjusted hazard of PTLD was significantly higher among discordant SOTRs compared to concordantly positive SOTRs (aHR 2.6, 95% CI 1.04-6.6, p =.04) and lower compared to concordantly negative SOTRs (aHR 0.27, 95% CI 0.10-0.76, p <.001). The adjusted hazard of EBV+ PTLD among those with discordant serology was also significantly higher compared to the concordantly positive cohort (aHR 3.53, 95% CI 1.04-12.0, p =.04) and significantly lower compared to the concordantly negative cohort (aHR 0.23, 95% CI 0.06-0.82, p =.02). CONCLUSIONS: Risk of PTLD among SOTRs with discordant VCA and EBNA-1 may be intermediate between those with concordantly positive and negative serology. If confirmed in future studies, revision of national EBV serology reporting to include both VCA and EBNA results may be needed to optimize PTLD risk stratification.

Delayed mortality among solid organ transplant recipients hospitalized for COVID-19.

INTRODUCTION: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. METHODS: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. RESULTS: Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p =<0.001], lung transplant (vs. non-lung transplant) [aHR 1.5 (1.0-2.3), p=0.05], heart failure [aHR 1.9 (1.2-2.9), p=0.006], chronic lung disease [aHR 2.3 (1.5-3.6), p<0.001] and body mass index ≥ 30 kg/m 2 [aHR 1.5 (1.1-2.0), p=0.02]. These associations were similar for mortality by day 28. Compared to diagnosis during early 2020 (March 1-June 19, 2020), diagnosis during late 2020 (June 20-December 31, 2020) was associated with lower mortality by day 28 [aHR 0.7 (0.5-1.0, p=0.04] but not by day 90 [aHR 0.9 (0.7-1.3), p=0.61]. CONCLUSIONS: In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment.

Assessing and restoring adaptive immunity to HSV, VZV, and HHV-6 in solid organ and hematopoietic cell transplant recipients.

BACKGROUND: Herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV), and human herpesvirus 6 (HHV-6) cause severe infections in immunocompromised hosts. Interventions to optimize virus-specific adaptive immunity may have advantages over antivirals in the prophylaxis and treatment of these infections. OBJECTIVES: We sought to review adaptive immune responses and methods for assessing and replenishing cellular and humoral immunity to HSV, VZV, and HHV-6 in solid organ transplant and hematopoietic cell transplant recipients. SOURCES: We searched PubMed for relevant studies on immune responses to HSV, VZV, and HHV-6 as well as studies describing methods for evaluating and restoring cell-mediated immunity to other double-stranded DNA viruses in transplant recipients. Recent studies, randomized controlled trials, and investigations highlighting key concepts in clinical virology were prioritized for inclusion. CONTENT: We describe the mechanisms of adaptive immunity to HSV, VZV, and HHV-6 and limitations of antivirals as prophylaxis and treatment for these infections in solid organ transplant and hematopoietic cell transplant recipients. We review methods for measuring and restoring cellular immunity to double-stranded DNA viruses; their potential applications to management of HSV, VZV, and HHV-6 in immunocompromised hosts; and barriers to clinical use. Vaccination and virus-specific T cell therapies are discussed in detail. IMPLICATIONS: The growing repertoire of diagnostic and therapeutic techniques focused on virus-specific adaptive immunity provides a novel approach to management of viral infections in transplant recipients. Investigations to optimize such interventions specifically in HSV, VZV, and HHV-6 are needed.

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.

Epstein-Barr virus posttransplant lymphoproliferative disorder: update on management and outcomes.

PURPOSE OF REVIEW: Management of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV PTLD) is complex, involving risk stratification, prevention and/or preemptive measures involving monitoring EBV DNAemia and balancing treatment options, using a combination of reduction of immune suppression, anti-B cell therapy, and cytotoxic T lymphocytes (CTLs). RECENT FINDINGS: The highest risk factor for the development of EBV PTLD in hematopoietic cell transplant (HCT) remains T cell depletion, with increasing use of antithymocyte globulin (ATG) or alemtuzumab in conditioning. In solid organ transplantation (SOT), the incidence of PTLD is highest among EBV seronegative recipients who are at risk for primary EBV infection following transplant in the first 12 months. Prevention is a critical component of the management of EBV PTLD. Although preemptive therapy remains standard of care, there continues to be heterogenicity and debate over the optimal choice of EBV DNA quantification and the threshold to use. Novel therapies such as donor-derived multipathogen and EBV specific CTLs for the prevention and third party CTLs for the treatment of EBV PTLD are promising, with rapidly expanding evidence, including large scale Phase III trials currently underway. SUMMARY: With an increasing number of risk groups for developing EBV PTLD in HCT and SOT, management strategies using prophylaxis or preemptive therapy remain standard of care, however the use of prophylactic or preemptive EBV specific or multipathogen CTLs show promising results and safety profiles.

CMV and HSV Pneumonia After Immunosuppressive Agents for Treatment of Cytokine Release Syndrome Due to Chimeric Antigen Receptor-modified T (CAR-T)-Cell Immunotherapy.

Pneumonia due to cytomegalovirus and herpes simplex virus-1 caused substantial morbidity after hematopoietic cell transplantation before the institution of preventative approaches. End-organ disease from herpesviruses is poorly described after chimeric antigen receptor-modified T-cell immunotherapy. We report 2 cases of cytomegalovirus pneumonia and 1 case of herpes simplex virus-1 gingivostomatitis, esophagitis, and pneumonia after chimeric antigen receptor-modified T-cell immunotherapy for the treatment of hematologic malignancies.

COVID-19 in Solid Organ Transplant Recipients: a Review of the Current Literature.

Purpose of review: The approach to ongoing organ transplantation and management of COVID-19 in solid organ transplant recipients (SOTR) has evolved tremendously since the pandemic's beginning. We summarize the current literature surrounding the virology of SARS-CoV-2, epidemiology of COVID-19 in transplant recipients, review the clinical features and complications of COVID-19 in SOTR, and discuss the safety and efficacy of current therapies and candidate vaccines in this population. Recent findings: Despite initial suspensions in organ transplantation during early 2020, routine donor testing and de-crowding of hospitals have allowed transplant activity to resume at pre-pandemic rates. COVID-19-associated mortality in SOTR is similar to that of the general population, and lower than that of patients with end-organ disease awaiting transplant. The optimal approach to immunosuppression in SOTR with COVID-19 is unknown and disease severity may influence management decisions. Many vaccines in development are likely to be safe for immunocompromised hosts, though post-marketing investigations will be required to determine the efficacy in the SOTR. Summary: Though there are multiple unique considerations in the care of SOTR with COVID-19, immunosuppression does not appear to have a detrimental impact on overall outcome. Organ transplantation remains a lifesaving intervention and can be safely performed despite a global pandemic.

Immunosuppression in solid organ transplant recipients with Covid-19: More data, but still complicated.

"Outcomes of COVID-19 in solid organ transplant (SOT) recipients: a matched cohort study" by Pereira et al found similar 28 day mortality among hospitalized SOT recipients and comorbidity matched controls, shedding light on the relationship between immunosuppression and Covid-19 outcomes.

Association of Inherited Chromosomally Integrated Human Herpesvirus 6 with Neurologic Symptoms and Management after Allogeneic Hematopoietic Cell Transplantation.

Reactivation of human herpesvirus 6 (HHV-6) after allogeneic hematopoietic cell transplantation (HCT) is associated with neurologic complications, but the impact of donor and/or recipient inherited chromosomally integrated HHV-6 (iciHHV-6) on post-HCT central nervous system (CNS) symptoms and diagnostic and therapeutic interventions is not well understood. The aims of the present study were (1) to compare the cumulative incidence of CNS symptoms in the first 100 days following allogeneic HCT among patients with donor and/or recipient iciHHV-6 (iciHHV-6pos)with that of patients with neither donor nor recipient iciHHV-6 (iciHHV-6neg) and (2) to assess the role of HHV-6 detection in driving potentially unnecessary interventions in iciHHV-6pos patients. We performed a retrospective matched cohort study of 87 iciHHV-6pos and 174 iciHHV-6neg allogeneic HCT recipients. HHV-6 testing was performed at the discretion of healthcare providers, who were unaware of iciHHV-6 status. The cumulative incidence of CNS symptoms was similar in iciHHV-6pos (n = 37; 43%) and iciHHV-6neg HCT recipients (n = 81; 47%; P = .63). HHV-6 plasma testing was performed in similar proportions of iciHHV-6pos (n = 6; 7%) and iciHHV-6neg (9%) patients and was detected in all tested iciHHV-6pos HCTs and 2 (13%) iciHHV-6neg HCTs. This resulted in more frequent HHV-6-targeted antiviral therapy after iciHHV-6pos HCT (odds ratio, 12.8; 95% confidence interval, 1.5 to 108.2) with associated side effects. HHV-6 plasma detection in 2 iciHHV-6pos patients without active CNS symptoms prompted unnecessary lumbar punctures. The cumulative incidence of CNS symptoms was similar after allogeneic HCT involving recipients or donors with and without iciHHV-6. Misattribution of HHV-6 detection as infection after iciHHV-6pos HCT may lead to unnecessary interventions. Testing for iciHHV-6 may improve patient management.

COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: A comparative analysis from a multicenter study.

Lung transplant recipients (LTR) with coronavirus disease 2019 (COVID-19) may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with COVID-19 to compare mortality by 28 days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with COVID-19, 1,081 (66%) were hospitalized including 120/159 (75%) LTR and 961/1457 (66%) non-lung SOTR (p = .02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p = .032), and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0-2.6, p = .04). Among LTR, chronic lung allograft dysfunction (aOR 3.3, 95% CI 1.0-11.3, p = .05) was the only independent risk factor for mortality and age >65 years, heart failure and obesity were not independently associated with death. Among SOTR hospitalized for COVID-19, LTR had higher mortality than non-lung SOTR. In LTR, chronic allograft dysfunction was independently associated with mortality.