Madeleine R. Heldman

Cytomegalovirus (CMV) remains one of the most common and consequential pathogens in solid organ transplant (SOT) and allogeneic hematopoietic cell transplant (HCT) despite current prevention strategies. Even a partially effective CMV vaccine could reduce morbidity and mortality associated with CMV in SOT recipients (SOTr) and HCT recipients (HCTr), as well as decrease costs, toxicities, and the risk of antiviral resistance. Despite progress since the first CMV vaccine (Towne) was developed in the 1970s, no CMV vaccine has achieved regulatory approval. Differences in CMV epidemiology, host risk factors, and immune reconstitution between SOTr and HCTr, and heterogeneity in CMV vaccination goals across transplant populations, complicate the development of CMV vaccine candidates in transplantation. Incompletely defined immune correlates of protection and logistical barriers inherent to CMV vaccine clinical trial execution, such as unpredictable timing of transplantation and variable access to central laboratory monitoring, create additional challenges. This review describes the potential benefits of a CMV vaccine in HCTr and SOTr, summarizes prior trials of CMV vaccines in transplantation and the lessons learned, and provides a framework for overcoming historical barriers with innovative trial designs and validated biologic endpoints in the modern era of CMV prophylaxis to advance CMV vaccine candidates through clinical stages of development.

Toxoplasma gondii infection poses a significant risk for donor seropositive recipient seronegative heart transplant patients without prophylaxis. Guidelines remain unclear on the optimal duration of prophylaxis in this population. We present a case of disseminated toxoplasmosis presenting as a subacute diarrheal illness leading to fulminant infection with pulmonary involvement in a 38-year-old woman 6 months after stopping primary chemoprophylaxis.

CMV cell–mediated immunity (CMV–CMI) testing has emerged as a promising tool to refine CMV risk stratification and inform prevention strategies in transplant recipients, while recent data assess its role in novel cellular therapies. By identifying patients with robust CMV‐specific immune responses, these assays can reduce unnecessary antiviral exposure and support individualized decisions on prophylaxis and preemptive therapy. The strongest evidence comes from the solid organ transplant (SOT) setting, where immune‐guided strategies can safely shorten prophylaxis duration, particularly in kidney and lung transplantation. In allogeneic hematopoietic cell transplant (HCT) recipients, CMV–CMI could also guide prophylaxis discontinuation and post‐prophylaxis surveillance, although data remain more limited and its added value beyond established clinical markers unclear. In chimeric antigen receptor (CAR)‐T‐cell therapy recipients, CMV–CMI reaches a nadir at Week 2 post‐infusion and recovers by Week 4, defining a window of increased vulnerability during which most CMV reactivation occurs. Assessment at this timepoint may help identify high‐risk patients; however, the clinical impact of CMV reactivation, and as a result the need for preventive strategies, remain unclear in this setting. Importantly, the major strength of CMV–CMI lies in its consistently high negative predictive value of robust T‐cell responses, while its ability to pinpoint highest‐risk patients remains limited. Its widespread use is hindered by assay discordance, limited geographic access, and unproven cost‐effectiveness. Despite these limitations, CMV–CMI remains the best‐studied strategy for individualized CMV management; further standardization and prospective validation are needed to define its role in increasingly complex immunocompromised populations. image

Background: Lomentospora prolificans is a rare and often fatal cause of invasive mold disease (IMD), particularly in immunocompromised individuals. Treatment remains difficult due to intrinsic resistance to most antifungals and the challenges of achieving therapeutic drug levels in the central nervous system. Fosmanogepix and olorofim are novel antifungal agents with promising activity against difficult-to-treat molds, including L. prolificans , and show potential for excellent central nervous system penetration. Case Summary: We report a case of disseminated L. prolificans infection with pulmonary, ocular, and central nervous system involvement in a 73-year-old man following haploidentical hematopoietic cell transplantation for peripheral T-cell lymphoma. Despite early neutrophil engraftment, the absence of graft-versus-host disease, and treatment with fosmanogepix, his infection progressed to fatal fungal meningitis. Conclusion: This case underscores the limitations of relying on in vitro susceptibility results to predict clinical response in the absence of clinical breakpoints, particularly in deep-seated infections where drug penetration may be limited. While prior case reports have described successful outcomes with novel agents, publication bias may overrepresent favorable results. This case supports the urgent need for rigorous evaluation of emerging antifungal therapies in real-world settings.

Antivirals form a foundation for protecting immunocompromised individuals (ICIs) from influenza complications. Neuraminidase inhibitors have demonstrated benefit for both prophylaxis and treatment in ICIs, including when given >48 hours after symptom onset. Baloxavir is a newer antiviral that has potent effects on viral kinetics in immunocompetent people, but data on baloxavir in ICIs are currently limited. Optimization of antiviral therapy to minimize viral replication within ICIs and reduce the risk of treatment-emergent antiviral resistance (eg, through combination regimens) may prevent viral evolution within ICIs and mitigate transmission of virulent or resistant variants to the general public. Unfortunately, ICIs have been excluded from most clinical trials evaluating novel influenza preventive and therapeutic strategies. Inclusion of ICIs in such clinical trials is essential to facilitate acquisition of clinical and virologic data in patients with specific immunocompromising conditions and ensure that ICIs have equitable access to valuable interventions.

Background: New and minimally invasive tools to aid the diagnosis of invasive fungal diseases (IFD) are urgently needed as the immunocompromised population at highest risk increases. Advancements in molecular technology have rendered new diagnostics more readily available for clinical use. Methods: This case-control study used prospectively collected archived plasma specimens and data from the Aspergillus Technology Consortium Repository to investigate the diagnostic performance of microbial cell-free DNA (mcfDNA) sequencing as a minimally invasive diagnostic for IFDs in a population of high-risk immunocompromised hosts including hematologic malignancy, stem cell, and solid organ transplants patients. The 2008 Mycoses Study Group/European Organization for the Research and Treatment of Cancer diagnostic criteria served as the gold standard for test performance. Results: Sixty-five adult subjects with proven or probable IFD and 65 controls without IFD were included. Among IFD episodes Aspergillus was the most common pathogen (70.8%, 46/65), followed by Mucorales (10.8%, 7/65). Overall, sensitivity was 47.7% and specificity was 100%. Sensitivity varied based on disease certainty and pathogen; sensitivity was higher in proven versus probable IFD (60.0% vs 37.1%, respectively) and higher for subjects with invasive mucormycosis (100%) compared with aspergillosis (45.7%). Conclusions: A positive result by mcfDNA sequencing may reduce the need for invasive sampling in patients with suspected IFD. In this exploratory analysis, its high sensitivity and specificity for invasive mucormycosis suggests it could be useful for early treatment and intervention of this IFD. Future studies should focus on understanding how specific factors impact the sensitivity of mcfDNA sequencing for invasive aspergillosis.