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Cytomegalovirus (CMV) reactivation has been described in adults with critical illness caused by diverse etiologies, especially severe sepsis, and observational studies have linked CMV reactivation with worse clinical outcomes in this setting. In this study, we review observational clinical data linking development of CMV reactivation with worse outcomes in patients in the intensive care unit, discuss potential biologically plausible mechanisms for a causal association, and summarize results of initial interventional trials that examined the effects of CMV prevention. These data, taken together, highlight the need for a randomized, placebo-controlled efficacy trial (1) to definitively determine whether prevention of CMV reactivation improves clinical outcomes of patients with critical illness and (2) to define the underlying mechanism(s).

Background Children receiving an allogeneic hematopoietic cell transplant (HCT) are at risk for cytomegalovirus (CMV) infection in the post-transplant period, necessitating routine surveillance for CMV. Some patients will not have CMV detected while others will have intermittent or persistent CMV detection. Prior analyses assessing the association of CMV infection on hospitalization in the post-transplant period have been limited by methods that did not consider the time-varying nature of the exposure (CMV reactivation) and its confounders or aim to obtain causal effect estimates. We aimed to assess the causal effect of CMV reactivation on hospitalization using a causal modeling approach. The Effect of CMV Infection on Hospitalization Using Generalized Estimating Equations and Marginal Structural Models Methods A cohort of allogeneic HCT patients transplanted at Children’s Hospital of Philadelphia January 2004–April 2017 was assembled and followed for 100 days after transplant. Eligible patients included those under CMV surveillance, defined as having ≥2 CMV whole blood polymerase chain reaction tests in the first month after HCT. All information was abstracted from medical charts. The association of CMV reactivation on the rate of hospitalization was estimated using traditional generalized estimating equations and repeated using a marginal structural model that accounted for time-varying exposure, confounders and non-random drop-out and obtained effects with causal interpretations. Results The study cohort included 340 pediatric allogeneic HCT recipients under CMV surveillance testing. 46.5% were female and the median age was 9 (range: 0 to 26). The CMV infection rate was 33.9%, with a median time to CMV detection of 23.5 days (range: 4-100). CMV infection was common in Donor+/Recipient+ (58.9%) and Donor-/Recipient+ (34.6%) patients. A traditional model estimates an additional week of CMV infection was associated with a 22% increase in average weekly hospitalization (Incidence rate ratio: 1.22, 95%: 1.12 -1.34). A marginal structure model estimates an additional week of CMV infection is associated with 3% increase in average weekly hospitalization incidence (Incidence rate ratio: 1.03, 95%: 0.91-1.16). Conclusion Our research showed the effect of CMV on hospitalization diminished after properly considering the time-varying nature of the CMV infection status and its confounders. Disclosures Brian T. Fisher, DO, MPH, MSCE, Astellas (Advisor or Review Panel member)Merck (Grant/Research Support)Pfizer (Grant/Research Support)

Background CMV reactivation is associated with significant morbidity and mortality in allo-HCT recipients and could be a resource intensive condition to manage. Limited data are available on the economic ramification of CMV reactivation in allo-HCT. Therefore, we aimed to examine healthcare cost and length of hospital stay (LOS) among allo-HCT recipients treated for CMV infection. Methods We performed a retrospective cohort study that included 56 consecutive allo-HCT recipients who were diagnosed with CMV infection within 100 days post-transplant and admitted to two medical centers, University of Texas MD Anderson Cancer Center and University of Chicago, Department of Infectious Disease between January 2016 and December 2017. CMV-related hospitalization was determined as an inpatient admission with or for CMV reactivation within 100 days post-transplant. Data were limited to only the first CMV-related hospitalization. Descriptive statistics were reported on patient characteristics, first CMV-related hospitalization and costs. Results Most patients were 40 years or older (64%), female (55%), Caucasian (66%), CMV seropositive recipients (87%), received a matched unrelated donor HCT (49%) and had a myeloablative or reduced intensity conditioning regimen (65%) (Figure 1). The median duration of CMV episode was 40 days. Seventy-one percent of the patients were treated with foscarnet for CMV infection. Acute kidney injury was the most frequent CMV treatment-related complication (67%) followed by myelosuppression (55%) and end-stage renal disease (36%). Of 56 encounters, 16% required admission to intensive care unit with a median duration of 9 days. The median length of stay for hospitalization was 23 days and healthcare cost for CMV-related hospitalization was $71,840. The median hospitalization cost and LOS varied by reason for hospitalizations, type of anti-CMV therapy and treatment-related complications (Figure 2). Figure 1. Baseline characteristics, CMV episodes, outcomes, and cost. Figure 2. CMV Outcomes among allo-HCT recipients Conclusion Our study showed even a single episode of CMV-related hospitalization led to significant resource use and hospitalization costs. This study highlights the need for interventions to prevent of CMV-related hospitalization, thereby reducing associated cost and resource use. Disclosures Kathleen Mullane, DO, Pharm D, FIDSA, FAST, MERCK (Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau) Ella Ariza Heredia, MD, Merck Sharp & Dohme (Grant/Research Support)Oxford Immunotec (Grant/Research Support) Yuexin Tang, PhD, Merck and Co., Inc. (Employee) Amit D. Raval, PhD, Merck and Co., Inc (Employee) Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix (Consultant, Research Grant or Support)Clinigen (Consultant)Merck (Consultant, Research Grant or Support)Novartis (Research Grant or Support)Oxford Immunotec (Consultant, Research Grant or Support)Shire/Takeda (Research Grant or Support)Viracor (Research Grant or Support)

Background CMV reactivation in seropositive, non-immunosuppressed adults with sepsis has been associated with worse clinical outcomes. To inform rational design of interventional trials determining whether CMV prevention improves outcomes, it is critical to identify the independence and strength of the association of CMV reactivation measures with clinically-relevant endpoints. Identification of patient factors associated with CMV reactivation would allow for optimization of the study population. Methods We performed a secondary pooled analysis of two prospective cohorts with sepsis: an observational cohort of ICU patients (n = 40) and the placebo cohort from a randomized, double-blind trial of ganciclovir to prevent CMV reactivation in acute critical illness (n = 66). Personnel blinded to the PCR results assessed clinical variables; CMV DNAemia was measured by quantitative plasma PCR twice weekly. Multivariable modeling using logistic and linear methods was used to examine the associations of CMV with clinical outcomes and between baseline patient factors and measures of CMV reactivation (adjusted for age, race, gender, transfusion status, study cohort, and APACHE score). Results CMV reactivation occurred at any level in 38/106 (36%), at >100 IU/mL in 25/106 (24%), and at >1,000 IU/mL in 14/106 (13%). In a multivariate model, CMV reactivation at any level, >100 IU/mL, or >1,000 IU/mL was associated with fewer days alive and not requiring ventilation: mean difference of −3.5 days ([95% CI −7.0, 0], P = 0.057), −5.1 days ([−8.9, −1.2], P = 0.012), and −6.1 days ([−10.9, −1.2], P = 0.016), respectively. Multiple measures of CMV reactivation were associated with other clinically-relevant outcomes, even after adjustment for baseline factors (Table 1). The association of APACHE score with CMV reactivation measures was inconsistent and with small effect size. We did not identify other patient variables associated with subsequent CMV reactivation. Conclusion CMV reactivation in seropositive adults with sepsis is independently and quantitatively associated with clinically-important outcomes, including death or continued hospitalization by day 28, ventilator-, ICU-, and hospital-free days. These effect sizes provide key data to inform design parameters of future interventional trials. Disclosures All authors: No reported disclosures.

Background Letermovir is a novel antiviral that was approved for cytomegalovirus (CMV) prophylaxis after allogeneic hematopoietic stem cell transplant (allo-HSCT). The objective was to assess the real-world outcomes of CMV prophylaxis with letermovir compared with preemptive therapy (PT) alone. Methods This retrospective pre- and post-study evaluated the clinical impact of using letermovir prophylaxis in CMV-seropositive allo-HSCT recipients at our institution. The electronic medical record was used to identify patients that received PT alone from July 2016 to November 2017 and letermovir prophylaxis from November 2017 to March 2019. The primary endpoint was the proportion of patients with CMV infection requiring PT through week 24 after transplant. Secondary endpoints included the proportion of patients with CMV infection requiring PT through week 14 after transplant, time to CMV infection requiring PT, incidence of CMV disease, CMV-related hospitalization and all-cause mortality through week 14 and 24 after transplant. Safety data included incidence and time to engraftment and adverse effects due to letermovir. Chi-squared and t-test were utilized for categorical and continuous data respectively. Results The baseline characteristics were similar (Table 1) and 78.7% of patients were high risk for CMV. Fewer patients in the letermovir group (n = 50) than in the historic control group (n = 100) had CMV infection requiring PT through week 24 after transplant (9 [18%] vs. 63 [63%], P < 0.001). The mean time to CMV infection requiring PT through week 24 after transplant was 93.4 days (28–161) in the letermovir group vs. 37.4 days (11–126) in the historic control group (P < 0.001). The all-cause mortality and incidence of CMV-related hospitalization were not statistically different between the two groups through week 24 after transplant (Table 2). The incidence and time to engraftment were not statistically different between the two groups (Table 3). Conclusion Letermovir prophylaxis in the real-world setting resulted in less CMV infection requiring PT when compared with a historic control of patients receiving PT alone. The majority of patients in the letermovir group experienced delayed-onset CMV reactivation. Letermovir was well-tolerated with no apparent myelosuppressive toxicities. Disclosures All authors: No reported disclosures.

We studied the seroepidemiology of cytomegalovirus (CMV) infection in 59 patients with thermal injuries. Among the 31 patients who were initially CMV seronegative, seven (22.5%) seroconverted. Patients who seroconverted had longer hospital stays (mean, 27 +/- 23.9 days v 14.9 +/- 8.8 days in seronegative patients [P = 0.03]) and they received more blood products (mean, 10.7 +/- 17.9 units v 1.8 +/- 2.8 units [P = 0.02]) than patients who remained seronegative. Among 18 patients who were initially seropositive for CMV, 10 (56%) had a fourfold or greater rise in CMV antibodies, evidence of CMV reactivation. Patients who had reactivated CMV infection tended to be younger, to have a larger burn area, and to have a longer hospital stay. No patient who experienced CMV infection, whether primary or reactivated, had serious complications attributable to CMV.