Reactivation of Latent Cytomegalovirus Infection after Major Surgery: Risk Factors and Outcomes

Abstract

Background:

Reactivation of latent cytomegalovirus (CMV) infection occurs in previously immunocompetent critically ill individuals and may be associated with increased morbidity and mortality. Our aim was to explore risk factors for and outcomes after CMV reactivation in patients undergoing major surgery.

Patients and Methods:

We performed a retrospective case control study of patients without underlying immunocompromise who developed post-operative CMV reactivation from 2004–2016. Cases included patients testing positive for CMV by viral load, culture, or histopathology. Controls were matched by age, gender, type, and year of surgery.

Results:

Sixteen CMV cases were matched to 32 controls. Median age was 65 and median time from surgery to CMV diagnosis was 32 days. Symptoms included fever (94%), hepatitis (75%), myelosuppression (56%), and diarrhea (38%). Despite similar baseline comorbidities, cases were more likely to return to surgery (odds ratio [OR] 6.31; 95% confidence interval [CI], 1.29–30.74), require renal replacement therapy (OR 18.54; 95% CI, 2.36–145.6), total parenteral nutrition (OR 33.0; 95% CI, 6.60–262.37) and corticosteroids (OR 18.78; 95% CI, 4.5–103.9). Length of stay was increased (median 51 vs. 8 days, p = 0.005), co-infections were more common (OR 15.10; 95% CI, 1.89–120.8), and mortality was higher (38% vs. 0%, p < 0.01).

Conclusions:

Cytomegalovirus reactivation occurs in previously immunocomptent patients post-operatively and is associated with poor outcomes including other infections and mortality. Potential risk factors include prolonged length of stay, surgical complications, and corticosteroid use. It is not clear from our study whether CMV reactivation is a surrogate marker of severe illness and post-operative complications or if CMV reactivation plays a causative role in the development of these adverse outcomes.

Cytomegalovirus (CMV) is a β-herpesvirus that infects the majority of the human population and persists in a state of life-long latency with constant immune surveillance needed to prevent viral replication [1 –3]. Reactivation among critically ill patients without prior immunosuppression has been recognized over the past few decades as a potential contributor to morbidity and mortality [4], including in the surgical intensive care unit (ICU) [5,6]. Rates of reactivation vary but are approximately 30%–40% [7]. Most prior studies included patients with diverse comorbidities such as burns, sepsis, and trauma, some of whom had undergone major surgery, but few focusing on the post-operative subgroup specifically.

Some of the poor outcomes associated with CMV reactivation in this population include prolonged length of stay, development of other infections, prolonged mechanical ventilation, and higher overall mortality [5,8 –11]. In one study of 186 patients undergoing cardiac surgery, 16.5% of seropositive patients developed detectable CMV DNAemia at a median of 17 days post-operatively, which was associated independently with an increased risk of ongoing hospitalization/death at 30 days [12]. Cytomegalovirus-seropositive patients also have an increased risk of post-operative re-intubation [13], and cases of CMV colitis requiring intravenous ganciclovir have been reported after left ventricular assist device placement [14]. Risk factors identified previously for CMV reactivation include older age, longer length of stay, multiple blood transfusions, renal failure, steroid use, re-intubation, diabetes mellitus, and lymphopenia [5,6, 12,13,15]. The role of CMV-specific T-cell immunity has been explored, with higher rates of reactivation in those testing QuantiFERON^®-CMV (Qiagen, Germantown, MD) negative at ICU admission [16 –18].

It is unclear whether CMV reactivation contributes causally to poor outcomes or is simply a marker of underlying severity of illness [4,19]. Reactivation occurs in the respiratory tract as well as the blood [5,16], and it has been hypothesized that CMV may contribute to the pathogenesis of acute respiratory distress syndrome and culture-negative pneumonia [20]. Given the availability of effective, safe antiviral treatments, an improved understanding of the burden of disease and contribution of CMV to poor post-operative outcomes could support intervention with virologic surveillance and pre-emptive therapy or antiviral prophylaxis. The aim of our study was to explore CMV as a post-surgical complication, identify potential risk factors for reactivation, and determine impact on outcomes.

Patients and Methods

Study design, case identification, and data collection

This retrospective case control study was conducted at Tufts Medical Center, a 415-bed academic medical center in Boston, Massachusetts. Institutional Review Board approval was obtained; informed consent was not required given the minimal risk and retrospective nature of the study.

Cases were identified by searching medical records for patients with positive CMV cultures, histopathology, or viral loads. Patients undergoing major surgery between 2004 and 2016 who developed CMV infection from one day to three months post-operatively were identified. Human immunodeficiency virus (HIV)-positive patients, transplant recipients, patients with hematologic malignancy, younger than 16 years of age, or seronegative for CMV were ineligible. In order to capture cases in which CMV likely contributed substantially to the overall disease state (i.e., moderate to severe reactivation), patients were excluded if they had only low-level viremia, defined as a single low-positive test at or below the level of quantification that resolved spontaneously, or an isolated positive viral culture from a urine or bronchoalveolar lavage (BAL) sample who did not receive antiviral therapy. All cases were reviewed individually to ensure they met inclusion/exclusion criteria, collect clinical data, and ascertain what symptoms were present and likely attributable to CMV at the time of diagnosis.

Clinical data including demographics, clinical characteristics, underlying immunosuppression, receipt of corticosteroids during and before hospitalization, surgical details including type and number of operations, length of stay, co-infections (within one month of hospitalization), and one-year survival were collected from medical records. The Charlson Comorbidity Index was calculated [21,22]. Laboratory results were obtained pre-operatively, at the time of CMV reactivation, and at hospital discharge.

Control selection

Control patients were selected by searching electronic medical records using the International Classification of Disease Ninth Edition (ICD-9) procedure codes for patients undergoing the same or similar operations to CMV cases [23]. Each case was matched individually to two controls by year of surgery (within seven years), age (within seven years), and gender. The same exclusion criteria were applied to controls as for cases.

CMV diagnosis and treatment

Viral load, viral culture, and histopathology testing were performed using standard techniques. Over the study period, three viral load assays were used: (1) the Hybrid Capture^® CMV DNA assay (version 2.0; Digene, Silver Spring, MD), a whole-blood assay with a detection range of 2.1 to >830 pg/mL (1997–2008); (2) a whole blood assay performed by Quest Diagnostics (Chantilly, VA) with a range of detection of 200 to >200,000 copies per milliliter (2008–2011); and (3) a plasma viral load assay (Simplexa™ kit, Focus Diagnostics, Cypress, CA) with a range of detection of 1,000 (values below 1,000 can be detected but not quantified) to 500,000 copies per milliliter (2011 to the present). Invasive procedures were performed when indicated to obtain tissue that was examined for characteristic CMV inclusion bodies with hematoxylin and eosin (H&E) staining and immunohistochemical stains using CMV-specific mouse monoclonal antibodies (Cell Marque, Sigma-Aldrich, Rocklin, CA). Tissue, urine, and BAL samples were cultured by shell-vial and conventional viral culture using human fibroblast cell lines, with CMV detection by direct immunofluorescence using conjugated monoclonal antibodies against immediate early antigen 1 and 2 (Light Diagnostics™, EMD Millipore Corporation, Temecula, CA). These tests were ordered by treating clinicians when indicated, typically as part of the diagnostic evaluation of a febrile illness.

Cytomegalovirus end-organ disease required laboratory confirmation of CMV plus clinical evidence of organ dysfunction, categorized as proven (positive pathology/cultures at a non-blood site with attributable symptoms), probable (DNAemia plus attributable symptoms), or possible (DNAemia with clinical symptoms suggestive of end-organ involvement but a potential alternative diagnosis present). Patients with CMV syndrome had detection of CMV in blood plus two or more of: fever for two or more days; new/increased malaise; neutropenia (<1.5 × 10³/mcL) or thrombocytopenia (<150 × 10³/mcL); or elevated aspartate aminotransferase/alanine aminotransferase (more than two times the upper limit of normal).

Treatment of CMV infection was with intravenous ganciclovir 5 mg/kg twice daily or oral valganciclovir 900 mg twice daily with doses adjusted for renal impairment according to the package insert [24,25]. Throughout the study period, there were no recommendations or protocols in place for routine screening of this patient group with either viral load or antibody testing, no prophylaxis was used, and all patient management (for example, duration of therapy and frequency of viral load monitoring after treatment completion) was at the discretion of the treating clinicians.

Statistical analysis

Descriptive statistics were calculated, with categorical data reported as counts and percentages, and continuous data as means ± standard deviations if normally distributed and medians with ranges if non-normally distributed. Missing data for the variables of interest were negligible.

Variables were compared with odds ratios, 95% confidence intervals, and p values, calculated using conditional logistic regression treating the data as matched. Where this was not possible because of low numbers, standard logistic regression was performed, or data were compared with a Fisher exact test or Wilcoxon rank-sum test, treating the data as unmatched. Survival data were visualized in Kaplan-Meier curves and compared using the log-rank test. P values <0.05 were considered statistically significant. All analyses were performed with the R statistical software platform version 3.4.1 (RStudio version 1.0.153).

Results

Thirty-two patients with post-operative CMV reactivation were identified initially, however, 16 met exclusion criteria (9 with low-level viremia, 6 with an isolated positive BAL culture, 1 with an isolated positive urine culture). Details of the individual 16 patients in our final cohort are shown in Supplementary Table S1. Cytomegalovirus cases were matched 2:1 to 32 control patients (see Supplementary Table S2 for matching details). Median age of CMV cases was 65 (range, 34–84), 8 (50%) were male, and all were admitted to hospital post-operatively. Seven (44%) underwent abdominal surgery, 4 (25%) cardiac, 2 (12.5%) vascular, and 1 (6.2%) each of gynecologic, neurosurgical, and thoracic surgical procedures. Half of the procedures were elective and the majority of patients (88%) were admitted to the ICU (median ICU stay, 49 days; range, 4–81). Cytomegalovirus reactivation usually was not diagnosed until several weeks post-operatively (median, 32 days; range, 17–93).

Fifteen patients had CMV DNAemia, and one had histopathologic evidence of CMV colitis with no blood viral load testing performed. Clinical features are described in Table 1. Patients had an array of symptoms prior to and at the time of their CMV diagnosis, most commonly fever and hepatitis. All except one received antiviral therapy (median treatment duration, 13 days; range, 4–169).

Table 1.

Characteristics of Cytomegalovirus in Cases Developing Post-Operative Reactivation

Characteristic	Details (n = 16)
CMV viremia, no. (%)	15 (94%)
Peak viral load, median, range
Assay #1, pg/mL (n = 6)	53, 4.4–329
Assay #2, copies/mL (n = 5)	11,088, 3,860–18,308
Assay #3, copies/mL (n = 4)	3,954, 1–23,136
Positive histopathology for CMV, no. (%)	1 (6%)
Days from…, median, range
Surgery to CMV diagnosis	32, 17–93
Symptom onset to CMV diagnosis	14, 6–37
CMV to death (within 1 y) (n = 13)	38, 5–269
Co-infection to CMV	14, -36–45
First dose of corticosteroids to CMV	20, -9–72
Symptoms present at time of CMV onset, no. (%)
Fever	15 (94%)
Hepatitis	12 (75%)
Bone marrow suppression	9 (56%)
Nausea/vomiting	7 (44%)
Diarrhea	6 (38%)
Abdominal pain	6 (38%)
Pneumonia	5 (31%)
Malaise	1 (6%)
None	0
Site of disease, no. (%)
CMV syndrome only	5 (31%)
Upper GI	3 (19%)
Pulmonary	3 (19%)
Disseminated (multiple sites)	2 (13%)
Lower GI	2 (13%)
Upper & lower GI	1 (6%)
Type of disease, no. (%)
Proven	1 (6%)
Probable	9 (56%)
Possible	6 (38%)
Laboratory results at CMV onset
Hemoglobin, g/dL, mean ± SD	8.8 ± 1.4
White blood count, × 10³/mcL, mean ± SD	13.2 ± 6.9
Absolute neutrophil count, × 10³/μL, mean ± SD	10.5 ± 6.3
Absolute lymphocyte count, × 10³/mcL, mean ± SD	1.1 ± 0.8
Platelet count, × 10³/mcL, mean ± SD	210 ± 121
Creatinine, mg/dL, median, range	1.14, 0.36–6.26
Type of antiviral therapy, no. (%)
IV ganciclovir only	8 (50%)
IV ganciclovir and oral valganciclovir	5 (31%)
Oral valganciclovir only	2 (13%)
None	1 (6%)
Days of antiviral therapy (n = 15), median, range	13, 4–169

CMV = cytomegalovirus; SD = standard deviation; GI = gastrointestinal; IV = intravenous.

A comparison of cases and controls is shown in Table 2. Charlson scores and immunosuppressive therapy at time of admission were similar. Cytomegalovirus cases had a substantially longer length of stay and had a higher median number of operations during their admission, typically because of the development of complications after the initial surgery. They were also more likely to require total parenteral nutrition and renal replacement therapy. In-hospital mortality was higher among CMV cases (38% vs. 0%, p < 0.001). Overall one-year survival is shown in Figure 1. There were no differences in lymphocyte counts between the two groups at any of the measured time points.

FIG. 1.

Kaplan-Meier survival plot demonstrating one-year post-operative survival in cytomegalovirus (CMV) cases compared with controls. P value refers to results of log-rank test.

Table 2.

Baseline Characteristics, Comorbidity, and Outcome Data for Cases Who Experienced Cytomegalovirus MV Reactivation Compared with Controls Who Did Not

Characteristic	Cases (n = 16)	Controls (n = 32)	OR (95% CI)	p
Demographics
Age at surgery, median, range	65, 34–84	67, 33–88	1.03 (0.82–1.29)	0.82
Year of surgery, median, range	2009, 2004–2014	2010, 2006–2015	0.34 (0.10–1.04)	0.06
Male gender, no. (%)	8 (50%)	16 (50%)	—	—
White race (vs. non-white), no. (%)	13 (81%)	22 (69%)	2.30 (0.43–12.24)	0.33
CMV antibody positive (vs. unknown), no. (%)	7 (44%)	4 (13%)	6.00 (1.21–29.73)	0.03
Baseline comorbidities and immunosuppression
Charlson score on admission, mean ± SD	4.9 ± 2.1	3.9 ± 2.4	1.30 (0.93–1.81)	0.12
Pre-existing dialysis, no. (%)	1 (6%)	2 (6%)	1	1
Pre-existing diabetes mellitus, no (%)	5 (31%)	15 (47%)	0.72 (0.26–1.98)	0.52
Pre-operative long-term corticosteroid use, no. (%)	2 (13%)	3 (9%)	1.44 (0.19–11.12)	0.73
Any steroid-sparing immunosuppressive medications prior to admission, no. (%)	3 (19%)	2 (6%)	3.00 (0.50–17.95)	0.23
Any previous corticosteroids or other immunosuppression combined, no. (%)	4 (25%)	5 (15.6%)	1.71 (0.41–7.05)	0.46
Proven to be HIV negative, no. (%)	5 (31%)	5 (16%)	3.35 (0.59–18.88)	0.17
Surgical admission details
Type of surgery, no. (%)
Abdominal	7 (44%)	14 (44%)	—	—
Cardiac	4 (25%)	8 (25%)
Other	5 (31%)	10 (31%)
Surgery emergent (vs. elective), no. (%)	8 (50%)	14 (44%)	1.47 (0.32–6.66)	0.62
Return to surgery within 3 mo, no. (%)	7 (44%)	3 (9%)	6.31 (1.29–30.74)	0.02
Number of operations during admission, median, range	2, 1–6	1, 1–2	13.36 (1.77–100.9)	0.01
Admitted, no. (%)	16 (100%)	31 (97%)	—	1^a
Length of stay, median, range	51, 11–87	8, 2–25	1.27 (1.12–1.61)^b	0.005
Admitted to ICU, no. (%)	14 (88%)	20 (63%)	4.20 (0.95–29.77)^b	0.09
ICU length of stay	49, 4–81	4, 2–17	1.14 (0.99–1.31)	0.07
Renal replacement therapy >24 h during admission, no. (%)	10 (63%)	2 (6%)	18.54 (2.36–145.6)	0.006
Total parenteral nutrition >24 h during admission, no. (%)	11 (69%)	2 (6%)	33.00 (6.60–262.37)^b	<0.001
New corticosteroids during admission, no. (%)	13 (81%)	6 (19%)	18.78 (4.5–103.9)^b	<0.001
Number of days receiving corticosteroids, median, range	26, 1–87	11, 4–18	1.14 (1.02–1.36)^b	0.06
Average daily dose of corticosteroids, in hydrocortisone equivalents, mean ± SD	217 ± 103	149 ± 146	1.006 (0.997–1.017)	0.25
Co-infections (within 1 mo of admission/discharge)
Any significant co-infection, no. (%)	11 (69%)	3 (9%)	19.08 (2.44–149.1)	0.005
C. difficile infection, no. (%)	3 (19%)	2 (6%)	4.65 (0.46–46.88)	0.19
Bacteremia, no. (%)	6 (38%)	1 (3%)	12.00 (1.45–99.67)	0.02
Fungal infection, no. (%)	4 (25%)	0	—	0.009^aa
Viral infection, no. (%)	3 (19%)	0	—	0.03^a
Total number of co-infections, median, range	1, 0–3	0, 0–1	11.67 (1.51–90.19)	0.02
Days to first post-operative non-CMV infection, median, range^c	11 (6–74)	11 (9–13)	1.06 (0.96–1.63)^b	0.54
Laboratory data
Pre-operative/admission
Hemoglobin, g/dL, mean ± SD	11.7 ± 2.2	11.9 ± 2.1	0.95 (0.70–1.28)	0.73
White blood count, × 10³/mcL, mean ± SD	9.0 ± 3.9	10.5 ± 3.5	0.87 (0.72–1.06)	0.17
Absolute neutrophil count, × 10³/mcL, mean ± SD	6.3 ± 3.5	8.1 ± 3.4	0.82 (0.65–1.03)	0.09
Absolute lymphocyte count, × 10³/mcL, mean ± SD	1.2 ± 0.7	1.3 ± 0.9	0.74 (0.31–1.78)	0.50
Platelet count, × 10³/mcL, mean ± SD	196 ± 94	216 ± 58	0.995 (0.99–1.01)	0.32
Creatinine, mg/dL, median, range	1.12, 0.5–8.4	1.02, 0.51–10.89	1.13 (0.84–1.55)	0.42
Discharge/post-operative
Hemoglobin, × 10³/mcL, mean ± SD	9.1 ± 1.5	10.1 ± 1.8	0.63 (0.38–1.02)	0.06
White blood count, × 10³/mcL, mean ± SD	12.1 ± 6.3	10.9 ± 6.1	1.03 (0.93–1.41)	0.57
Absolute neutrophil count, × 10³/mcL, mean ± SD	10.4 ± 5.2	8.6 ± 5.6	1.06 (0.93–1.20)	0.38
Absolute lymphocyte count, × 10³/mcL, mean ± SD	1.0 ± 0.8	1.3 ± 0.7	0.46 (0.12–1.82)	0.27
Platelet count, × 10³/mcL, mean ± SD	185 ± 85	269 ± 92	0.99 (0.98–0.99)	0.03
Creatinine, mg/dL, median, range	0.94, 0.4–4.2	0.91, 0.34–10.42	1.04 (0.71–1.50)	0.85
Outcome
90-d mortality, no. (%)	7 (44%)	2 (8%)	7.09 (0.83–60.36)	0.07
In-hospital mortality, no. (%)	6 (38%)	0	—	<0.001^a

Fisher exact test, performed because of cell counts of 0% or 100%.

Unpaired analysis using standard logistic regression performed because of low cell counts or minimal overlap between groups (and therefore failure of conditional logistic regression).

One co-infection was on same day as surgery, excluded.

OR = odds ratio; CI = confidence interval; CMV = cytomegalovirus; ICU = intensive care unit; SD = standard deviation; HIV = human immunodeficiency virus.

Cytomegalovirus cases were more likely to receive corticosteroids during their admission (OR 18.8; 95% CI 4.5–103.9) and received them for a longer duration (median 26 vs. 11 days, p = 0.06). In all but one patient, steroids were started before the onset of CMV, typically several weeks before. Average daily doses amongst those receiving steroids were similar. Patients with CMV reactivation were also more likely than controls to develop a confirmed co-infection (OR 15.1; 95% CI 1.9–120.8). In nine of 11 patients the co-infection preceded CMV diagnosis by a median of approximately two weeks.

Discussion

Reactivation of latent CMV infection has been well described in immunosuppressed individuals including transplant recipients and people with HIV/acquired immune deficiency syndrome (AIDS). However, CMV is not typically considered as a potential post-operative complication in patients without prior immunosuppression, and its incidence and significance in this setting are not well understood. In this study, we have described a group of patients with moderate to severe CMV reactivation after major surgery, who experienced greater morbidity and mortality compared with age-matched controls, despite having similar indications for surgery and comorbidity scores at baseline.

Identification of patients at risk for CMV reactivation after surgery can be challenging. The results of our analysis suggest that the group at highest risk could include those admitted for extended periods of time, especially in the ICU, who have experienced surgical complications requiring several operations, and received other interventions such as corticosteroids, renal replacement therapy, and total parenteral nutrition. Clinical presentations were non-specific and although fever was a common symptom, this may have been biased by the fact that patients without fever were tested less frequently.

Similar to previous studies, clinical outcomes were worse among our cases who experienced CMV reactivation [5,8,9]. Mortality was higher and patients with CMV were more likely to have other serious infections, which mostly occurred before the diagnosis of CMV was made. There are several potential explanations for the observed association between CMV and the development of other serious infections. There could be confounded by the underlying complicated surgery itself, which could predispose patients to bacterial infections. There is a growing body of evidence to suggest that surgery itself induces immunologic dysfunction, with cytokine derangements similar to those seen in sepsis resulting in a degree of immunosuppression [26]. External factors such as steroid use could also lead to relative immune compromise and increased risk of infections including CMV. Finally, CMV itself is known to express immunomodulatory proteins that can result in secondary immunosuppression [27].

If CMV reactivation plays a causative role in poor outcomes among post-surgical patients, which could not be established by our study, this could represent a potential opportunity for intervention with antiviral agents. Two prospective trials of antiviral therapy addressing this have recently been completed [28,29]. The largest randomly assigned critically ill patients to intravenous ganciclovir or placebo, and although they did not find a substantial difference in their primary end point (interleukin-6 levels, an inflammatory cytokine linked to both CMV reactivation and mortality), there was an increase in ventilator-free days, suggesting ganciclovir may reduce the risk of CMV-mediated lung injury [29]. Importantly there was no increase in adverse events in those receiving ganciclovir. In our study, many patients experienced adverse outcomes despite the use of antiviral agents, and it remains unclear whether earlier diagnosis and treatment would have mitigated some of these.

The use of supplemental corticosteroids in patients with septic shock has become widespread in recent years. Whereas this has been demonstrated to have short-term physiologic benefits in patients with vasopressor-refractory hypotension, overall impact on long-term survival and risk of secondary infections is less clear [30 –35]. Our findings suggest that corticosteroid use may be a risk factor for CMV reactivation, which could contribute to poor outcomes. The diagnosis of CMV should be considered during the evaluation of a febrile illness in these patients. There may be a role for antiviral prophylaxis or pre-emptive monitoring in CMV-seropositive individuals receiving prolonged steroids post-operatively.

Our results have certain limitations. This was a small retrospective study with statistical power limited by sample size, precluding multivariable analysis to control for confounding factors associated with CMV reactivation and death. Corticosteroids, for example, are typically used in patients with septic shock, which may itself also be an independent risk factor for CMV reactivation may also be associated with other adverse outcomes such as bacterial infection. Selection bias may influence interpretation of our results and generalizability. When matching controls, we could not choose them reliably based on CMV serostatus because of low rates of antibody testing, so we could not be certain that all our control patients were at risk of CMV reactivation. As there was no routine monitoring for CMV viremia, some of our controls could have re-activated without detection, leading to misclassification of potential cases as controls. Additional controls may have increased our statistical power somewhat but unfortunately these were not available. It is possible, although unlikely, that some cases could represent de novo acquisition of CMV in the ICU. Additionally, we could not determine any effect of antiviral therapy on outcomes as almost all patients were treated. Finally, similar to all retrospective observational studies, although we have demonstrated an association between CMV reactivation and poor post-operative outcomes, we were unable to attribute any causal effect to CMV. It remains unclear if CMV re-activates because these patients are complex and critically ill with prolonged ICU stays or whether CMV reactivation is indeed an independent risk factor for poor post-operative outcomes. Given the nature and limitations of our study, these findings can only be considered hypothesis-generating and require confirmation in larger prospective trials.

In conclusion, CMV reactivation occurs in previously immunocompetent patients after major surgery and is associated with poor outcomes including other serious infections and increased mortality. Possible risk factors including prolonged length of stay, development of surgical complications, and prolonged use of corticosteroids. Clinicians should consider CMV reactivation in the evaluation of patients with post-operative fevers, particularly in those patients with a complicated course and extended ICU stay. Additional studies are needed to define the role of virologic surveillance, therapeutic and prophylactic antivirals, and to improve understanding of the risk factors and pathogenesis of CMV reactivation in this complex patient population.

Footnotes

Acknowledgments

This work was previously presented in abstract for at IDWeek 2018.

The authors would like to acknowledge Shelley Bame-Aldred and Jacob Garrell for their assistance with data collection; Robin Ruthazer for statistical advice; and Jessica Paulus for help with study design.

This work was supported by the Tufts Medical Center Division of Geographic Medicine and Infectious Disease Francis P. Tally MD Fellowship, the Tufts University Harold Williams MD Medical Student Research Fellowship, and the National Institutes of Health Clinical and Translational Science Award (grant number UL1TR001064).

Author Disclosure Statement

D.R.S. reports being on advisory boards for Merck, Shire, Chimerix, Takeda, and Moderna and being a grant recipient from Merck, Summit, Actelion, Tetraphase, and Seres Therapeutics. All other authors report no potential conflicts of interest.

Supplementary Material

Supplementary Tables S1 and

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