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The burden that cytomegalovirus (CMV) portends for haematopoietic and solid-organ transplant recipients cannot be understated. Valganciclovir and ganciclovir have successfully been used for prevention and treatment of CMV infections, although with serious side effects such as leucopenia and some development of resistance. Until recently, available therapies for ganciclovir-resistant CMV have significant toxicities. Although advances have been made in the field, the unmet medical needs for effective and well-tolerated therapies are significant.This review aims to summarise the current and emerging CMV antiviral drugs and discusses future perspectives in the field.We searched for relevant articles with pertinent keywords: "Cytomegalovirus OR CMV", "Transplant" and "Antiviral". Articles published after 2019 were given preference. Articles were reviewed by the authors for relevance and impact to the subject of interest.We outline in this review current advances in prophylaxis of CMV infection with letermovir, breakthrough CMV infections while on or after prophylaxis, the development of resistant and refractory CMV infections, and the newly approved anti-CMV agent, maribavir, in haematopoietic and solid-organ transplant recipients.Prevention of CMV infections after transplant has improved greatly over the past few years. Despite major advancements, breakthrough CMV infections and development of refractory and resistant CMV infections remain major complications post transplantation. We highlight emerging therapeutics that tolerably and effectively prevent and treat CMV infections, especially refractory and resistant cases.

Background: Cytomegalovirus (CMV) infection is a well-recognised complication of solid organ and hematopoietic cell transplantation. However, CMV infection also occurs in patients with human immunodeficiency virus infection, previously immunocompetent intensive care unit patients, and individuals on immunosuppressive medications for various underlying diseases. Objectives: This review describes the comparative effects of CMV infection in distinct types of acquired immunosuppression. Sources: Selected peer-reviewed publications on CMV infections published until December 2021. Content: CMV infection affects various organ systems through direct cytolytic mechanisms but may also exert indirect effects by promoting pro-inflammatory and immunosuppressive responses. This has been well studied in transplant recipients, for whom antiviral prophylaxis and pre-emptive therapy have now become standard practice. These strategies not only prevent direct CMV disease manifestations but also mitigate various immunopathological processes to reduce graft-vs.-host disease, graft rejection, and the occurrence of secondary bacterial and fungal infections. The efficacy of neither prophylactic nor pre-emptive treatment of CMV infection has been demonstrated for patients with critical illness- or medication-induced immunosuppression. Many observational studies have shown an independent association between CMV reactivation and a prolonged duration of mechanical ventilation or increased mortality in the intensive care unit. Furthermore, data suggest that CMV reactivation may increase pulmonary inflammation and prolong the duration of mechanical ventilation. Implications: A large number of observational and experimental studies suggest attributable morbidity and mortality related to CMV infection, not only in transplant recipients and patients with human immunodeficiency virus infection but also in patients with critically illness- or medication-induced immunosuppression. Adequately powered randomised controlled trials investigating the efficacy of prophylaxis or pre-emptive treatment of CMV infection in these patients are lacking, with a notable exception for transplant recipients.

Respiratory viral infections (RVIs) are of major clinical importance in immunocompromised patients and represent a substantial cause of morbidity and mortality in patients with hematologic malignancies and those who have undergone hematopoietic cell transplantation. Similarly, patients receiving immunotherapy with CD19-targeted chimeric antigen receptor–modified T cells, natural killer cells, and genetically modified T-cell receptors are susceptible to RVIs and progression to lower respiratory tract infections. In adoptive cellular therapy recipients, this enhanced susceptibility to RVIs results from previous chemotherapy regimens such as lymphocyte-depleting chemotherapy conditioning regimens, underlying B-cell malignancies, immune-related toxicities, and secondary prolonged, profound hypogammaglobulinemia. The aggregated risk factors for RVIs have both immediate and long-term consequences. This review summarizes the current literature on the pathogenesis, epidemiology, and clinical aspects of RVIs that are unique to recipients of adoptive cellular therapy, the preventive and therapeutic options for common RVIs, and appropriate infection control and preventive strategies.

The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transpl. Infect. Dis. Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A new approach was employed with the goal of better serving clinical providers by publishing each standalone topic in the infectious diseases series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious diseases and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The fourth topic in the series focuses on the management and treatment of cytomegalovirus (CMV) resistant and refractory infections. The diagnosis, definitions of resistant and refractory CMV, risk factors, virological genotypes and treatment algorithms are reviewed.

Background A systematic review and meta-analysis of real-world observational studies was conducted to summarize the impact of letermovir cytomegalovirus (CMV) primary prophylaxis (PP) among adult allogeneic hematopoietic cell transplant (allo-HCT) recipients. Methods Systematic searches in Medline/PubMed, Embase, and conferences (from database inception to October 2021) were conducted to identify studies for inclusion. Random-effects models were used to derive pooled estimates on the relative effectiveness of letermovir PP compared to controls. Results Forty-eight unique studies (N = 7104 patients) were included, most of which were comparative, single-center, and conducted in the United States. Letermovir PP was associated with statistically significant reduction in odds of CMV reactivation (pooled odds ratio [pOR], 0.13 and 0.24; P < .05), clinically significant CMV infection (pOR, 0.09 and 0.19; P < .05), and CMV disease (pOR, 0.31 and 0.35; P < .05) by day +100 and day +200 after allo-HCT, respectively. Letermovir PP was associated with significantly lower odds of all-cause (pOR, 0.73; P < .01) and nonrelapse mortality (pOR, 0.65; P = .01) beyond day 200 after allo-HCT. Conclusions Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.

Background Letermovir (LTV) has reduced non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant (allo-HCT) recipients by reducing the rate of clinically significant cytomegalovirus infections (CS-CMVi). The impact of LTV prophylaxis (PP) on other infections is unclear. We investigated the effects of LTV on human herpes virus 6 (HHV6) DNAemia in HCT recipients with or without CS-CMVi and studied the interaction of HHV6 DNAemia with CS-CMVi and its impact on NRM. Methods We performed a single center, retrospective cohort study from March 2016 to December 2018 of consecutive allo-HCT recipients who are CMV recipient seropositive (R+) with or without LTV prophylaxis. Baseline characteristics and infectious complications data were collected. Outcomes of interest was NRM at 100 days, 24 weeks and 48 weeks post allo-HCT. Univariate analysis was performed to identify risk factors for HHV6 reactivation within the first year including CS-CMVi and risk factors for NRM at 48 weeks post transplant. A logistic regression was performed to identify independent risk factors for HHV6 DNAemia and NRM at 48 weeks. Patients with relapse were excluded from NRM analysis. Results A total of 539 allo-HCT recipients were included in our analysis; 124 (23%) with and 415 (77%) without LTV PP. HHV6 DNAemia was identified in 111 (21%) allo-HCT recipients within the first year of transplant, where CS-CMVi occurred in 241 (45%) (table 1). Risk factors for HHV6 DNAemia included African American race, underlying ALL, Haploidentical or cord HCT, marrow or cord source of stem cells, use of Post-cyclophosphamide, and CS-CMVi. On multivariate analysis, CS-CMVi was the only independent predictor of HHV6 reactivation (Adjusted OR: 1.69) (table 1). Independent predictors of NRM on logistic regression included CS-CMVi (OR: 1.67, CI 95% 1.03-2.62), and age > 40 years (OR: 2.21, CI 95% 1.24-3.95), and matched related donor allo-HCT (OR: 0.36, CI 95% 0.18-0.70) as a protective factor (table 2). Conclusion HHV6 DNAemia is strongly associated with CS-CMVi, which is probably a reflection of poor T cell recovery post HCT such as Haploidentical or Cord blood HCT. Furthermore, CS-CMVi was associated with NRM whereas HHV6 DNAemia was not. Larger studies are needed to better elucidate this interaction. Disclosures Gabriella Rondon, MD, Omeros: Advisor/Consultant Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Background SARS-CoV-2 B.1.1.529 (Omicron) variant was first identified in November 2021 in South Africa and was notable for its increased transmissibility and rapid spread worldwide. In the United States, this variant led to a surge in COVID-19 cases by December 2021. As a result, we experienced a steep rise in cases among patients and employees at our institution starting December 22nd, 2021. Therefore, we compared the incidence and characteristics of hospital-onset COVID-19 (HO-COVID-19) in our cancer patients prior to and during the surge of the Omicron variant. Methods We identified HO-COVID-19, as per the CDC definition, from our infection control surveillance database, and additional contact tracing information was reviewed to determine the possible sources of HO-COVID-19. Whole-genome sequencing studies were conducted randomly on nasopharyngeal swabs of patients and employees who had COVID-19 during the study period. Results Twenty-six HO-COVID-19 infections were identified from the beginning of the pandemic (February 2020) through February 2022 (Table 1). Only 17 cases occurred over 22 months from the beginning of the pandemic through early December 2021 (Figure 1). These HO-COVID-19 occurred during the 3 COVID-19 surges that were epidemiologically attributed to the variants seen prior to Omicron. Among these 17 patients, 12 (70%) were symptomatic, 9 (53%) had a link to an infected employee, 7 (41%) died during their hospitalization (3 of the deaths were attributable to COVID-19), and 10 (59%) recovered and were discharged. Over 6 weeks (from December 22nd, 2021, through February 1st, 2022), 9 HO-COVID-19 were discovered during the Omicron variant surge (Figure 1). Six (67%) of these patients were symptomatic, 8 (89%) had a link to an infected employee, 2 (22%) died (1 death was attributed to COVID-19 ), and 7 (78%) recovered and were discharged. Table 1.Characteristics and demographics of patients with hospital-onset COVID-19.Abbreviation: PCR, polymerase chain reaction; HOCI, hospital-onset COVID-19 infections.Figure 1.Bar chart of nosocomial COVID-19 cases graphed against line graphs of COVID-19 infections diagnosed weekly among patient and employee at MD Anderson Cancer Center between March 2020 through February 2022 Conclusion The Omicron variant surge led to marked increases in HO-COVID-19 despite the continuous adoption of enhanced infection control practices, testing on admission, and daily symptoms screening of patients and employees. Disclosures Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Background Patients with COVID-19 and underlying malignancies, particularly those receiving immunosuppressive therapy, are at higher risk of severe COVID-19 disease. Our retrospective cohort study examines the outcomes of COVID-19 infection in patients with different underlying malignancies admitted to a 710- beds comprehensive cancer center during the first 2 years of the pandemic. Methods All patients with cancer admitted to MD Anderson Cancer Center with a positive PCR test for SARS-CoV-2 were included in a clinical case registry from 3/22/20 (first hospitalized COVID-19 patient) to 3/31/22. This clinical registry was approved at the beginning of the COVID-19 pandemic by the Quality Improvement Assessment Board at MDACC. Clinical information including type of malignancy, date of admission, length of stay, need for invasive mechanical ventilation (IMV), and in-hospital mortality was obtained from their electronic medical records. Statistical analysis was performed using a two-proportion z-test where p< 0.05 was considered significant. Results A total of 1748 patients with cancer and COVID-19 infection were admitted over a 2-year period (3.2% of total hospital admissions during the same period), 49% had hematological malignancies (HM) (see table). Patients with HM had significantly higher readmission rates (17.3% vs 9.1%, p< 0.0001), IMV rates (7.8% vs 4.4%, p=0.0029), and inpatient mortality rates (13.6% vs 7.1%, p< 0.0001). compared to patients with solid tumors (ST). Total mortality rate was 8.8% (154 patients), even higher in patients with different types of HM, such as lymphoma 18.1%, AML 14.2%, MM 8.4%, CML 7.1% while the mortality for ST was 7.1%. COVID-19 Hospitalized Patients at UT-MDACC (3/22/20-3/31/22) UT-MDACC: The University of Texas MD Anderson Cancer Center *p-value Conclusion HM patients hospitalized with COVID-19 infection had more severe disease and worse outcomes based on readmissions, IMV, and mortality rates. Preventive measures, prompt diagnosis and early treatments should be considered on this patient population. Disclosures Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Background Pneumonia is the most common infectious cause of morbidity and excess mortality complicating hematopoietic cell transplantation (HCT) and treatment of hematologic malignancy. Standard bronchoscopic and noninvasive microbiologic testing identify causative pathogens in less than half of cases. The Karius Test, a plasma next-generation sequencing assay of microbial cell-free DNA, may improve diagnostic yield in these patients. Methods Patients with active hematologic malignancy or recent HCT undergoing bronchoscopy for suspected pneumonia were prospectively enrolled in this observational study conducted at 10 United States medical centers. A panel of expert clinicians blinded to Karius Test results reviewed a standardized panel of microbiologic and molecular testing from bronchoalveolar lavage and blood samples for bacterial and fungal testing, nasopharyngeal swab for respiratory viral testing, imaging results, clinical documentation, and any additional microbiologic or molecular testing collected per usual standard of care to adjudicate a probable cause of pneumonia. The panel then adjudicated whether a probable cause of pneumonia or other clinically relevant infection was identified by the Karius Test. Results Between January 3, 2020 and February 4, 2022, 257 patients were enrolled. A planned interim analysis of the first 69 sequentially enrolled patients in the per protocol population was conducted. An adjudicated probable cause of pneumonia was identified by standard care in 18/69 (26%) patients. The Karius Test identified an adjudicated probable cause of pneumonia in 10/51 (20%) patients when no cause of pneumonia was identified by standard care testing. The combination of standard care and the Karius Test together identified a probable cause of pneumonia in 28/69 (41%) patients. At least one additional pathogen adjudicated as a probable cause of pneumonia was identified by the Karius Test in 6/18 (33%) of patients with positive standard care testing. Conclusion The Karius Test notably increased the probability of identifying a pathogenic cause of pneumonia among immunocompromised patients undergoing bronchoscopy. The additive diagnostic value of the Karius Test may significantly enhance management of this common condition. Disclosures Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support Radha Duttagupta, PhD, Karius Inc: Stocks/Bonds Sanjeet S. Dadwal, MD, FACP, FIDSA, AlloVir: Advisor/Consultant|AlloVir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope: Advisor/Consultant|Aseptiscope: Stocks/Bonds|Astellas: Speaker's Bureau|Cidara: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Speaker's Bureau|Takeda: Speaker's Bureau Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Ghady Haidar, MD, Karius, Allovir, and AstraZeneca: Grant/Research Support Alfred Luk, MD, Karius: Grant/Research Support Jamie Todd, MD, Altavant Sciences: Advisor/Consultant|AstraZeneca: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|CareDx: Grant/Research Support|Cellarity: Advisor/Consultant|Natera: Advisor/Consultant Genovefa Papanicolaou, MD, AlloVir: Board Member|AlloVir: Serve as member of DSMC|Amplyx: Board Member|Amplyx: Serve as member of DSMC|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|CSL Behring: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Investigator for Merck|MSD: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Board Member|Octapharma: Serve as EAC member|Partners RX: Advisor/Consultant|SymBio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Takeda: Investigator for Takeda|Vera: Board Member|Vera: Serve as member of DSMC Elena Nemirovich-Danchenko, MD PhD, Karius: Stocks/Bonds Mona Mughar, BS, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Yuen Cho, MS, CLS(CA-DPH), Karius: Stocks/Bonds Asim A. Ahmed, MD, Karius: Employee|Karius: Stocks/Bonds Desiree Hollemon, MSN, MPH, Karius: Stocks/Bonds David K. Hong, MD, Janssen Pharmaceutical Companies of Johnson & Johnson: Employee|Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Marla Lay Vaughn, BS, MT(ASCP), Karius: Employee|Karius: Stocks/Bonds Tim Blauwkamp, PhD, Karius: Board Member|Karius: Ownership Interest Zivjena Vucetic, MD, Karius: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds Thomas L. Holland, MD, Aridis: Advisor/Consultant|Lysovant: Advisor/Consultant.

Background Robust infection control (IC) measures were deployed across healthcare institutions at the start of the COVID-19 pandemic, resulting in increased use of personal protective equipment (PPE), enhanced contact precautions, and emphasis on hand hygiene. The impact of these IC measures on the rates of hospital-acquired infections (HAIs), such as multidrug-resistant organisms (MDROs), device-related infections (DRIs), Clostridium difficile infection (CDI), and respiratory viral infections (RVIs) is not known. Here, we aim to evaluate the effect of the enhanced IC practices on the occurrence of various HAIs in a comprehensive cancer center. Methods We analyzed the monthly HAIs rates from September 2017 through March 2022, including data 42 months pre-pandemic (September 2016-February 2020) and 24 months during the pandemic (March 2020-August 2021). Reported HAIs were calculated using denominators of patient days for CDI and MDROs, per 1,000 admissions for RVIs, and catheter days for DRIs. The incidence rate ratios (IRR) were calculated for all HAIs. Results When comparing pre-pandemic to the pandemic period, a significant increase in the overall incidence rate (IR) of MDROs from 0.56 to 0.67 per 1,000 patient days with an IRR of 1.19 (95% CI 1.02-1.39), a decrease in the IR of CLABSIs and a stable IR of CAUTIs and VAEs were observed (Table 1). A significant decrease was observed in the IR of CDI (IRR 0.65 (95% CI 0.55-0.78)). The total IR of hospital-acquired RVIs per 1,000 admissions (5.24 to 1.82; IRR 0.36; 95% CI 0.30-0.44) decreased, as did each respiratory virus (Respiratory Syncytial Virus (0.51 to 0.15; IRR 0.30), Influenza (0.50 to 0.24; IRR 0.50), Parainfluenza (1.21- to 0.34; IRR 0.28), Rhinovirus (1.91 to 0.5; IRR 0.26), and Human Metapneumovirus (0.19 to 0.05; IRR 0.24) during their respective respiratory viral seasons (Figure 1). Table 1.Comparison of hospital-acquired infection incidence rates during pre-pandemic and pandemic periods.Abbreviations. IR, incidence rate; IRR, incidence rate ratio; MDRO, multidrug-resistant organisms; ESBL, extended-spectrum beta-lactamase; PsA, Pseudomonas aeruginosa; CRE, carbapenem-resistant Enterobacterales; LabID, laboratory identified; MRSA, methicillin-resistant Staphylococcus aureus; CDI, Clostridium difficile infection; CAUTI, catheter-associated urinary tract infection; VAE, ventilator-associated events; CLABSI, catheter-associated bloodstream infection; RVI, respiratory viral infections; RSV, respiratory syncytial virus.Figure 1.Nosocomial respiratory viral infections diagnosed at MD Anderson Cancer Center prior to and during the COVID-19 pandemic Conclusion Implementing strict IC measures during the COVID-19 pandemic in a cancer hospital led to a significant decrease in many HAIs and a reduction in nosocomial RVIs. However, whether these enhanced measures, such as masking at all times as part of patient care, are needed during the upcoming respiratory viral seasons is not known. Disclosures Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Background The Coronavirus Disease 2019 (COVID-19) has significantly impacted cancer patients with some reported mortality as high as 25%. The Immunodeficiency Scoring Index (ISI) was developed as a prognostic tool in allogeneic hematopoietic cell transplant (allo-HCT) recipients with respiratory syncytial virus but also for other respiratory viruses to predict severe infections and mortality. The purpose of our study was to correlate the ISI in HCT recipients with COVID-19 and associated complications such as hospitalization, supplemental oxygen use, and mortality. Methods We performed a cohort study of HCT recipients of all ages with COVID-19 between March 2020 and October 2021. We included only patients who were diagnosed by a PCR-based assay. We excluded patients for whom an ISI score, as previously described, could not be calculated. Outcomes of interest included 60-day mortality, hospital and ICU admission due to COVID-19, and supplemental oxygen requirements. A univariate analysis using Fischer exact testing for nominal variables was performed. Results Out of the 219 HCT with COVID-19, 101 were excluded due to alternative methods of diagnosis (13), lack of laboratory values needed to calculate an ISI at time of COVID-19 diagnosis (79), or COVID-19 diagnosed prior to transplant (9). Out of the remaining 118 patients, the median age was 60 years (range 6-85), most were male (56%), Caucasian (57%), and had no smoking history (64%). Most patients had an alloHCT (66%) with matched related donor [MRD] (25%), or matched unrelated donor [MUD] (21%) (Table 1). Median time from transplant to COVID-19 was 615 days (range 2-5692), median ISI was 3 (range 0-11), and 92% of patients were unvaccinated prior to COVID-19 (Table 1). On univariate analysis, an ISI of moderate to high (score ≥3) was associated with COVID-19 related hospitalization [p=0.0147] and an ISI ≥ 4 was associated with 60-day all-cause (p=0.045) and COVID-19-related (p-0.019) mortality (Table 2). Table 1: Patient Characteristics Abbreviations: Hematopoietic Cell Transplant (HCT); Chronic Obstructive Pulmonary Disease (COPD); Chronic Kidney Disease (CKD); End-Stage Renal Disease (ESRD); Acute Lymphocytic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Lymphocytic Leukemia (CLL); Chronic Myelogenous Leukemia (CML) Myeloproliferative Disorder (MDS); Matched Related Donor (MRD); Matched Unrelated Donor (MUD); Mismatched Unrelated Donor (MMUD); Graft versus Host Disease (GvHD); Lower Respiratory Tract Infection (LRI); White Blood Cell (WBC); Absolute Neutrophil Count (ANC); Absolute Lymphocyte Count (ALC). Table 2: Univariate Analysis of Outcomes due to COVID-19 in HCT Recipients Abbreviations: Immunodeficiency Scoring Index (ISI); Hematopoietic Cell Transplant (HCT); Allogenic (Allo); Autologous (Auto); Lower Respiratory Infection (LRI); High-Flow Nasal Cannula (HFNC) Figure 1: Survival Curve (Kaplan-Meier Curve) Comparing Time to Death in Patients with an ISI Score of 4 or Greater. (Log-rank 0.0295) Conclusion An ISI of 4 or greater was a prognostic marker for worse outcomes such as COVID-related and all-cause mortality in HCT recipients. Whether an aggressive and prompt management of high-risk patients with COVID-19 may impact these outcomes needs to be determined in future studies. Disclosures Gabriella Rondon, MD, Omeros: Advisor/Consultant Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious diseases guidelines for the care of hematopoietic cell transplant (HCT) recipients. A new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The third topic in the series focuses on the prevention of cytomegalovirus infection and disease in HCT recipients by reviewing prophylaxis and preemptive therapy approaches; key definitions, relevant risk factors, and diagnostic monitoring considerations are also reviewed.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N=1605) or PTCy (SibCy, N=403), and related haploidentical transplants receiving PTCy (HaploCy, N=757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P=0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P=0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

Phages are naturally occurring viruses that selectively kill bacterial species without disturbing the individual's normal flora, averting the collateral damage of antimicrobial usage. The safety and the effectiveness of phages have been mainly confirmed in the food industry as well as in animal models. In this study, we report on the successful isolation of phages specific to Vancomycin-resistant Enterococci, including

Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R− patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

Background There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. Methods Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. Results A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012). Conclusions The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877., Immunocompromised adults with severe parainfluenza received nebulized DAS181 or placebo for up to 10 days. The primary endpoint was not met, but a subgroup of severely immunocompromised patients experienced a faster return to room air by day 28 (P = .012).

Background Vancomycin-resistant enterococci (VRE) are a major cause of morbidity and mortality in immunocompromised patients. Tracking the dissemination of VRE strains is crucial to understand the dynamics of emergence and spread of VRE in the hospital setting. Methods Whole genome sequencing (WGS) and phylogenetic analyses were performed to identify dominant VRE strains and potential transmission networks between 35 patients with VRE-positive rectal swabs and their rooms (main rooms and bathrooms) on the leukemia (LKM) and the hematopoietic cell transplant (HCT) floors. Sequence types (STs), drug resistance genes, and patients’ outcomes were also determined. Results A total of 89 VRE strains grouped into 10 different STs, of which newly described STs were isolated from both floors (ST736, ST494, ST772, and ST1516). We observed highly genetically related strains transmitted between rooms, floors, and time periods in an average period of 39 days (ranging from 3 to 90 days). Of 5 VRE bacteremia events, 3 strains were lacking the pili operon fms14–17–13 (ST203) and the remaining 2 were resistant to daptomycin (DAP; ST736, ST664). Of 10 patients harboring DAP-resistant strains, only 2 were exposed to DAP within 4 months before strain recovery. Conclusions Our comparisons of VRE strains derived from the environment and immunocompromised patients confirmed horizontal transfer of highly related genetic lineages of multidrug-resistant (particularly to DAP) VRE strains between HCT and LKM patients and their room environment. Implementing WGS can be useful in distinguishing VRE reservoirs where interventions can be targeted to prevent and control the spread of highly resistant organisms.

Patients with hematologic malignancies and recipients of hematopoietic cell transplantation (HCT) are more likely to experience severe coronavirus disease 2019 (COVID-19) and have a higher risk of morbidity and mortality after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with the general population, these patients have suboptimal humoral responses to COVID-19 vaccines and subsequently increased risk for breakthrough infections, underscoring the need for additional therapies, including pre- and postexposure prophylaxis, to attenuate clinical progression to severe COVID-19. Therapies for COVID-19 are mostly available for adults and in the inpatient and outpatient settings. Selection and administration of the best treatment options are based on host factors; virus factors, including circulating SARS-CoV-2 variants; and therapeutic considerations, including the clinical efficacy, availability, and practicality of treatment and its associated side effects, including drug-drug interactions. In this paper, we discuss how we approach managing COVID-19 in patients with hematologic malignancies and recipients of HCT and cell therapy.

To evaluate the cost-effectiveness of letermovir versus no prophylaxis for the prevention of cytomegalovirus infection and disease in adult cytomegalovirus-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients. A decision model for 100 patients was developed to estimate the probabilities of cytomegalovirus infection, cytomegalovirus disease, various other complications, and death in patients receiving letermovir versus no prophylaxis. The probabilities of clinical outcomes were based on the pivotal phase 3 trial of letermovir use for cytomegalovirus prophylaxis versus placebo in adult cytomegalovirus-seropositive recipients of an allo-HCT. Costs of prophylaxis with letermovir and of each clinical outcome were derived from published sources or the trial clinical study reports. Incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life year (QALY) gained were used in the model. One-way and probabilistic sensitivity analyses were conducted to explore uncertainty around the base-case analysis. In this model, the use of letermovir prophylaxis would lead to an increase of QALYs (619) and direct medical cost ($1 733 794) compared with no prophylaxis (578 QALYs; $710 300) in cytomegalovirus-seropositive recipients of an allo-HCT. Letermovir use for cytomegalovirus prophylaxis was a cost-effective option versus no prophylaxis with base-case analysis ICER $25 046/QALY gained. One-way sensitivity analysis showed the most influential parameter was mortality rate. The probabilistic sensitivity analysis showed a 92% probability of letermovir producing an ICER below the commonly accepted willingness-to-pay threshold of $100 000/QALY gained. Based on this model, letermovir use for cytomegalovirus prophylaxis was a cost-effective option in adult cytomegalovirus-seropositive recipients of an allo-HCT.

Letermovir, a cytomegalovirus (CMV) terminase-complex inhibitor, is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). In a phase III, double-blind, randomized trial, letermovir significantly reduced the risk of clinically significant CMV infection (CS-CMVi) vs placebo through Week 24 post-HCT. This analysis investigated outcomes in participants with detectable CMV DNA at randomization, who were excluded from the primary efficacy analysis. In total, 70 of 565 randomized participants had detectable CMV DNA at randomization (letermovir 48; placebo 22). Study treatment completion rates were greater in letermovir-treated participants compared with placebo (52.1% vs 9.1%). The incidence of CS-CMVi or imputed primary endpoint events through Week 24 were 64.6% and 90.9% in the letermovir and placebo groups, respectively (treatment difference -26.1%; P = .010). Kaplan-Meier event rates for CS-CMVi onset through Week 14 (end-of-treatment period) were 33.1% for letermovir and 86.6% for placebo (P < .001). Median viral loads at the CS-CMVi events was similar in both treatment arms. All-cause mortality through Week 24 posttransplant was 15.0% for letermovir and 18.2% for placebo; through Week 48, mortality rates were 26.5% and 40.9%, respectively (P = .268). Overall, clinical outcomes were similar to those reported for participants with undetectable CMV DNA at randomization.

The outbreak of coronavirus disease 2019 (COVID‐19) has rapidly spread globally since being identified as a public health emergency of major international concern and has now been declared a pandemic by the World Health Organization (WHO). In December 2019, an outbreak of atypical pneumonia, known as COVID‐19, was identified in Wuhan, China. The newly identified zoonotic coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), is characterized by rapid human‐to‐human transmission. Many cancer patients frequently visit the hospital for treatment and disease surveillance. They may be immunocompromised due to the underlying malignancy or anticancer therapy and are at higher risk of developing infections. Several factors increase the risk of infection, and cancer patients commonly have multiple risk factors. Cancer patients appear to have an estimated twofold increased risk of contracting SARS‐CoV‐2 than the general population. With the WHO declaring the novel coronavirus outbreak a pandemic, there is an urgent need to address the impact of such a pandemic on cancer patients. This include changes to resource allocation, clinical care, and the consent process during a pandemic. Currently and due to limited data, there are no international guidelines to address the management of cancer patients in any infectious pandemic. In this review, the potential challenges associated with managing cancer patients during the COVID‐19 infection pandemic will be addressed, with suggestions of some practical approaches. Implications for Practice The main management strategies for treating cancer patients during the COVID‐19 epidemic include clear communication and education about hand hygiene, infection control measures, high‐risk exposure, and the signs and symptoms of COVID‐19. Consideration of risk and benefit for active intervention in the cancer population must be individualized. Postponing elective surgery or adjuvant chemotherapy for cancer patients with low risk of progression should be considered on a case‐by‐case basis. Minimizing outpatient visits can help to mitigate exposure and possible further transmission. Telemedicine may be used to support patients to minimize number of visits and risk of exposure. More research is needed to better understand SARS‐CoV‐2 virology and epidemiology., Cancer patients have an increased risk of contracting COVID‐19. This article addresses the challenges associated with managing cancer patients during the COVID‐19 infection pandemic and suggests some practical approaches.

Brincidofovir (BCV) is a lipid conjugate of cidofovir with good oral bioavailability, enabling optimal intracellular levels of the active drug. Lower rates of nephrotoxicity and myelotoxicity make it a favorable alternative. Despite a greater safety profile among pediatric hematopoietic cell transplant recipients, the oral formulation has been associated with increased gastrointestinal toxicity in adult hematopoietic cell transplant recipients. Oral BCV continues to be developed as a countermeasure against smallpox, while a potentially safer intravenous preparation has been out licensed to another company. BCV has demonstrated great in vitro potency against double-stranded DNA viruses, especially adenovirus. Because of its importance for immunocompromised patients, this review aims to evaluate BCV’s clinical and safety profile to support its continued development.

Refractory or resistant cytomegalovirus (CMV) infections are challenging complications after hematopoietic cell transplantation (HCT). Most refractory or resistant CMV infections are associated with poor outcomes and increased mortality. Prompt recognition of resistant or refractory CMV infections, understanding the resistance pathways, and the treatment options in HCT recipients are imperative.New definitions for refractory and resistant CMV infections in HCT recipients have been introduced for future clinical trials. Interestingly, refractory CMV infections are more commonly encountered in HCT recipients when compared with resistant CMV infections. CMV terminase complex mutations in UL56, UL89, and UL51 could be associated with letermovir resistance; specific mutations in UL56 are the most commonly encountered in clinical practice. Finally, brincidofovir, maribavir, letermovir, and CMV-specific cytotoxic T-cell therapy expanded our treatment options for refractory or resistant CMV infections.Many advances have been made to optimize future clinical trials for management of refractory or resistant CMV infections, and to better understand new resistance mechanisms to novel drugs. New drugs or strategies with limited toxicities are needed to improve outcomes of difficult to treat CMV infections in HCT recipients.

Baloxavir, a cap-dependent endonuclease inhibitor, was recently approved for treatment of severe influenza infections. Combining baloxavir with oseltamivir has been proposed to increase the response rate. We report 2 hematopoietic cell transplant recipients with severe influenza infections who were treated with this combination and discuss possible reasons for their different responses.

Background Respiratory syncytial virus (RSV) infection causes significant morbidity in hematopoietic cell transplant (HCT) recipients. However, antibody responses that correlate with recovery from RSV disease are not fully understood. Methods In this study, antibody repertoire in paired serum and nasal wash samples from acutely RSV-A–infected HCT recipients who recovered early ( Results Anti-F serum responses were similar between these 2 groups for antibody repertoires, neutralization titers, anti-F binding antibodies (prefusion and postfusion proteins), antibody avidity, and binding to specific antigenic sites. In contrast, nasal washes from early-recovered individuals demonstrated higher binding to F peptide containing p27. While the serum RSV G antibody repertoires in the 2 groups were similar, the strongest difference between early-recovered and late-recovered patients was observed in the titers of nasal wash antibodies, especially binding to the central conserved domain. Most importantly, a significantly higher antibody affinity to RSV G was observed in nasal washes from early-recovered individuals compared with late-recovered HCT recipients. Conclusions These findings highlight the importance of mucosal antibodies in resolution of RSV-A infection in the upper respiratory tract.

Cytomegalovirus (CMV) infection remains a major complication after allogeneic hematopoietic cell transplantation (allo-HCT). We conducted a retrospective study to determine the clinical and economic burden of pre-emptive therapy (PET) for CMV infection in 100 consecutive hospitalized adult CMV positive serostatus allo-HCT recipients and compared their hospitalization cost with allo-HCT recipients hospitalized with graft vs host disease without CMV infection (control group) and across 19 US cancer centers for hospitalized patients with CMV infection between 2012 and 2015 (Vizient database). A total of 192 CMV episodes of PET for CMV infection occurred within 1 year post-HCT. PET consisted of ganciclovir (41% of episodes), foscarnet (40%), and valganciclovir (38%) with the longest average length of stay in foscarnet-treated patients (41 days). The average direct cost per patient admitted for PET was $116 976 (range: $7866-$641 841) compared with $12 496 (range: $2004-$43 069) in the control group (P < .0001). The total direct cost per encounter was significantly higher in patients treated with foscarnet and had nephrotoxicity ($284 006) compared with those who did not ($112 195). The average cost amongst the 19 US cancer centers, including our institution, was $42 327 with major disparities in cost and clinical outcomes. PET for CMV infection is associated with high economic burden in allo-HCT recipients.

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection in infants, the elderly, and immunocompromised patients. RSV antibodies play a role in preventing reinfection and in clearance of RSV, but data regarding the levels of viral protein-specific antibodies elicited and their contribution to patient recovery from RSV-induced disease are limited. We prospectively enrolled a cohort of RSV-infected adult hematopoietic cell transplant (HCT) recipients (n = 40). Serum and nasal-wash samples were obtained at enrollment (acute samples) and convalescence (convalescent samples). We measured (1) humoral IgG and mucosal IgA binding antibody levels to multiple RSV proteins (F, G, N, P, and M2-1) by Western blot (WB), (2) neutralizing antibody (Nt Ab) titers by microneutralization assay, and (3) palivizumab-like antibody (PLA) concentrations by an ELISA-based competitive binding assay developed in the lab. Finally, we tested for correlations between protein-specific antibody levels and duration of viral shedding (normal: cleared in &lt, 14 days and delayed: cleared ≥14 days), as well as RSV/A and RSV/B subtypes. Convalescent sera from HCT recipients had significantly higher levels of anti-RSV antibodies to all 5 RSV structural proteins assayed (G, F, N, P, M2-1), higher Nt Abs to both RSV subtypes, and higher serum PLAs than at enrollment. Significantly higher levels of mucosal antibodies to 3 RSV structural proteins (G, N, and M2-1) were observed in the convalescent nasal wash versus acute nasal wash. Normal viral clearance group had significantly higher levels of serum IgG antibodies to F, N, and P viral proteins, higher Nt Ab to both RSV subtypes, and higher PLA, as well as higher levels of mucosal IgA antibodies to G and M2-1 viral proteins, and higher Nt Ab to both RSV subtypes compared to delayed viral clearance group. Normal RSV clearance was associated with higher IgG serum antibody levels to F and P viral proteins, and PLAs in convalescent serum (p &lt, 0.05). Finally, overall antibody levels in RSV/A- and/B-infected HCT recipients were not significantly different. In summary, specific humoral and mucosal RSV antibodies are associated with viral clearance in HCT recipients naturally infected with RSV. In contrast to the humoral response, the F surface glycoprotein was not a major target of mucosal immunity. Our findings have implications for antigen selection in the development of RSV vaccines.

PURPOSE BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698 ) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.