Sepsis
Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: Incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers

https://doi.org/10.1016/j.jcrc.2014.10.002Get rights and content

Abstract

Purpose

Cytomegalovirus (CMV) reactivation, a significant cause of morbidity and mortality in immunosuppression, may affect “immunocompetent” seropositive critically ill patients. The aim of this prospective, observational study was to define the incidence, risk factors, and the association with morbidity and mortality of CMV reactivation in a general population of critically ill immunocompetent patients. We also studied the relationship between reactivation and patients' inflammatory response, as expressed by cytokine levels and stress up-regulation by salivary cortisol.

Methods

This study included mechanically ventilated CMV-seropositive patients. A quantitative real-time polymerase chain reaction (PCR) was performed for CMV plasma DNAemia determination, upon intensive care unit (ICU) admission and weekly thereafter until day 28. Cytomegalovirus reactivation was defined as CMV plasma DNAemia greater than or equal to 500 copies/mL. Upon ICU admission, interferon γ, interleukin (IL) 10, IL-17A, IL-2, IL-6, and tumor necrosis factor α were quantified in plasma, and morning saliva was obtained to measure cortisol. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II score, whereas the degree of organ dysfunction was quantified by Sequential Organ Failure Assessment score. Mortality, duration of mechanical ventilation, and ICU length of stay were recorded.

Results

During the study period, 80 (51 men) patients with a median age of 63 years fulfilled the inclusion criteria. Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio [OR], 1.50; confidence interval [CI], 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation (P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28-day observation period (P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups.

Conclusions

Cytomegalovirus reactivation occurred in 13.75% of critically ill, immunocompetent patients. The degree of inflammation and the total number of transfused red blood cells units constituted risk factors. Cytomegalovirus reactivation was associated with more severe of organ dysfunction, but not with a worse clinical outcome.

Introduction

Primary cytomegalovirus (CMV) infection occurs primarily during childhood and is usually asymptomatic [1], [2]. Approximately two thirds of healthy adults are immune [1]. Long life latency follows the primary infection because the virus remains in the nucleus of polymorphonuclear cells [1], [3], [4]. Cytomegalovirus reactivation is prevented by cell-mediated immunity. However, in cases of immunosuppression, such as HIV disease, transplantation, or iatrogenic immunosuppression, CMV reactivation may cause severe end-organ disease, including encephalitis, pneumonitis, hepatitis, retinitis, colitis, and graft rejection [5].

It has been long recognized that immunocompetent critically ill patients may be at risk for CMV reactivation. This has been studied in separate intensive care unit (ICU) populations, including in severe sepsis, septic shock, postsurgery, trauma, or burn injury. Conclusions on the incidence and associated risk factors as well as the effects of CMV reactivation on outcome are compromised by differences in the virological methods used, in the ICU population studied, and in the timing of CMV screening [6]. Although CMV is a well-accepted pathogen in immunosuppressed patients, it still remains unclear, whether CMV reactivation is causing mortality or accompanies high mortality, in ICU immunocompetent patients.

Cytomegalovirus reactivation in a representative, general, nonimmunosuppressed ICU population, such as seen in everyday clinical practice, has received less attention. In fact, only 1 prospective study is available, with surgical and medical ICU patients, having a broad range of underlying diagnoses [7]. Cytomegalovirus reactivation has been attributed to the impaired host immune function and to an augmented stress response associated with critical illness: systemic inflammatory response syndrome (SIRS) and, in particular, sepsis may induce an increase in plasma concentration of corticosteroids and catecholamines, leading to subsequent immune abnormalities [8], [9]. Moreover, CMV reactivation during critical illness has been partially attributed to the release of cytokines, such as tumor necrosis factor α (TNF-α). Tumor necrosis factor α can enhance CMV replication, by generating a pathway that leads to the activation of nuclear factor κB (NF-κB) [10], [11]. Therefore, CMV reactivation might be an index of immunosuppression related to critical illness [12]. The potential relationship between immune function, the degree of stress, and CMV reactivation in general ICU patients has not been previously investigated.

Given the above considerations, we conducted a prospective, observational, double-center study, to define the incidence and risk factors for CMV reactivation in critically ill immunocompetent patients. We also wished to define whether CMV reactivation has any effect on morbidity and mortality. We evaluated CMV plasma DNAemia by polymerase chain reaction (PCR), in consecutive days after ICU admission. We also measured on admission in the ICU serum cytokines, reflecting the degree of the immunological response and salivary cortisol, as a measure of stress up-regulation [13].

Section snippets

Study design

This prospective observational study was conducted in 2 polyvalent ICUs, between June 2010 and July 2012: in the 23-bed ICU of “Attikon” Hospital and in the 30-bed ICU of “Evangelismos” Hospital. Inclusion criteria in the study were the use of mechanical ventilation and the positive anti-CMV immunoglobulin G (IgG) titers. Exclusion criteria were negative anti-CMV IgG titers, younger than 18 years, mechanical ventilation for more than 72 hours before ICU admission, imminent death, no need for

Patients' characteristics

During the study period, 811 patients were hospitalized in the 2 ICUs. Of these, 80 patients, all mechanically ventilated, fulfilled the inclusion criteria. Most common reasons for exclusion were intubation more than 72 hours before ICU admission, no mechanical ventilation during ICU stay, or CMV seronegativity. Patients composed of medical (n = 52, 64%), surgical (n = 11, 14%), trauma (n = 14, 18%), and burn injury (n = 3, 4%) cases. Baseline characteristics are depicted in Table 1. DNA

Discussion

In this prospective study, CMV reactivation occurred in approximately 14% of critically ill, immunocompetent patients. Independent risk factors for reactivation included the total number of red blood cell transfused during ICU stay and the degree of inflammation, as expressed by CRP upon admission in the ICU. High IL-10 tended also to contribute. Cytomegalovirus reactivation was associated with more severe organ dysfunction throughout the 28-day period of critical illness, but not with

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