Introduction
Cytomegalovirus (CMV) is a major β herpes virus and a significant human pathogen. Infection is common with seroprevalence rates increasing steadily from 65% among 40 to 49 year olds to 91% in those aged 80 years or over [
1]. After primary infection, CMV, like other β herpes viruses, establishes life-long latency. In immunocompetent individuals, asymptomatic viral shedding may be detectable in saliva or urine; however, cell-mediated host immune responses prevent the development of overt CMV disease.
In contrast, CMV infection has been shown to lead to significant disease in immunocompromised hosts such as those with HIV infection or transplant recipients. End-stage HIV-infected patients with a CD4 lymphocyte count of less than 50 cells/mm
3 are at the highest risk of developing CMV retinitis [
2]. In transplant recipients, CMV disease occurs in 11 to 72% of patients especially in the first three months after transplant while the patients are receiving maximum immunosuppression [
3]. In addition to febrile syndrome and end-organ disease directly as a result of viral replication, immunomodulatory characteristics of CMV may contribute to opportunistic infections, allograft rejection, and higher mortality in transplant recipients. Clinical trials have shown that preventive approaches utilizing antiviral agents have lead to a reduction in the rates of CMV infection and disease, and indirect sequelae associated with CMV [
3‐
5]. Currently, prophylaxis or periodic monitoring and antiviral therapy targeted towards patients with viral replication are routinely employed at many transplant centers.
It has increasingly come to be recognized that critically ill patients who are traditionally considered immunocompetent may also be at risk for CMV infection. For example, septic insult as a result of bacterial or fungal infections has the potential to promote the release of immunomodulatory cytokines and lead to reactivation of CMV [
6,
7]. Reactivation from the latency rather than primary infection is believed to be the cause of CMV infection because none of the critically ill CMV seronegative patients developed CMV infection as opposed to 13 to 56% of seropositive patients [
8,
9]. Several observational studies have shown an association between CMV infection in critically ill patients and poor clinical outcomes [
8,
10,
11]. However, available data are limited by relatively small sample sizes, diversity in patient populations studied, difference in methodological assays employed for CMV, and variability in reported outcomes that preclude generalizability of the results of the individual reports. The objectives of this review are to summarize the frequency and predictors of CMV infection, and outcomes in critically ill immunocompetent patients with CMV infection. Additionally, we discuss the pathophysiologic basis of CMV reactivation and the implications of these data for optimizing outcomes in critically ill patients.
Materials and methods
English-language reports of published studies on CMV infection in critically ill immunocompetent patients were identified through November 2008 by cross-referencing the following medical subject headings (MeSH) keywords and text words: cytomegalovirus, immunocompetence, critical illness, intensive care units, intensive care, reactivation, sepsis, and shock. Databases searched included PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. Bibliographies of original articles were manually reviewed for additional articles. Non-English-language reports were also identified in PubMed using the same keywords in order to supplement our search.
We included studies in which: critically ill immunocompetent adults were monitored either retrospectively or prospectively for the development of CMV infection in the ICU and; the rate of CMV infection was explicitly reported. CMV infection was defined as evidence of positive viral cultures, antigenemia, and/or DNAemia by PCR from blood or a clinical specimen. Patients were considered to be immunocompetent if they were not solid organ or hematopoietic stem cell transplant recipients, not infected with HIV, did not have primary immunodeficiencies, and were not recipients of immunosuppressive agents such as calcineurin-inhibitors, anti-TNF-α drugs, anti-lymphocyte antibodies, or chemotherapeutic agents for treating cancer. We excluded studies in which an increase in CMV serologic titers in the absence of viremia was the sole evidence for CMV infection.
Two of the authors independently searched articles and extracted the following data for analyses: study design, inclusion criteria, type and frequency of CMV assays, rate of CMV infection, rate of CMV IgG positivity, the time elapsed from ICU admission to CMV infection, risk factors for CMV infection, and outcomes (i.e. mortality, duration of ICU stay). Any discrepancies were resolved by review and discussion. Authors of published studies were contacted if reported data required further clarification. Additional mortality data was provided in one study [
12].
Discussion
Our review demonstrates that depending on the methodological assay used and the patient populations studied, CMV infection occurs in 0 to 36% of the critically ill otherwise immunocompetent hosts in the ICU. Among the most frequently studied inciting event for CMV infection in these patients is sepsis [
6,
7,
13,
16,
17]. The risk of CMV infection was five-fold higher in patients with sepsis even when controlled for age and the initial severity of illness [
10]. In a murine model of CMV infection, cecal ligation and puncture resembling post-surgical intraabdominal sepsis led to reactivation of latent CMV in the lungs and ultimately pulmonary fibrosis [
41,
42]. The propensity of sepsis to promote CMV infection may result from its pleiotropic effects on the host immune system. Pro-inflammatory cytokine production such as TNF-α and IL-1β in the early phase of sepsis has the potential to activate NF-κB and other transcription factors that are key in the reactivation of CMV from latency [
43,
44]. The later phase of sepsis, characterized by the generation of immunosuppressive cytokines such as IL-10 and IL-4 is often referred to as compensatory anti-inflammatory response syndrome [
45,
46]. Once latent virus is reactivated, these cytokines may further enhance CMV replication. Indeed, in lung transplant recipients, elevated levels of IL-10 in the BAL and/or plasma were associated with delayed CMV clearance [
47]. A sustained high level of IL-10 in patients with sepsis has been associated with poor outcomes, presumably due to excessive anti-inflammatory effects [
48].
Transfusion within 24 hours of admission was identified as a risk factor for high-grade CMV viremia in critically ill patients [
11]. This association may be explained by potential transmission of CMV by blood products, but more likely by the immunomodulatory effect of transfusion
per se. Previous studies have shown that allogeneic blood transfusion resulted in a reduction in T-helper cells, induction of suppressor T cells, and suppression of natural killer cell activity [
49]. The transfusion-related immunosuppression has been associated with clinically important sequelae such as improvement of renal allograft survival, increased risk of tumor recurrence, and postoperative infections [
50‐
52]. The risk of CMV transmission by leukocyte depleted blood products is at least as low as by CMV seronegative blood products [
53,
54], supporting the hypothesis that transfusion-related immunomodulatory effect plays a major role in CMV infection in critically ill patients if transfusion were truly a risk factor. However, these data were not available for most studies. For example, only one in three studies that evaluated transfusion as potential risk factors for CMV infection reported use of leukocyte depleted blood products explicitly [
18].
A body of literature based largely on serologic assays for the diagnosis of CMV suggests that severe burn injuries are a major risk factor for CMV infection [
55,
56]. At least a four-fold rise in serologic titers suggestive of CMV reactivation has been documented in 45 to 56% of the burn patients [
19,
21,
22]. Recently, in a study where patients with severe burn injuries comprised a subset of critically ill patients, CMV viremia using PCR was observed in 55% (11/20) of the burn patients [
11]. Burn injuries are associated with profound changes in cell-mediated immunity and a predominant T-helper 1 cell response that may facilitate CMV infection [
57‐
59]. Susceptibility to sepsis due to the loss of skin integrity in these patients may also contribute to the risk of CMV infection.
Attempts to utilize the severity of 'critical illness' to predict CMV infection have not shown a correlation between scoring systems such as APACHE II or SAPS II and the risk of CMV [
7,
8,
10,
11,
13,
16,
18]. Severity of illness scores have typically been assessed in the first 24 hours after ICU admission whereas CMV infection does not usually occur until late in the ICU stay. Additionally, these scores are based on age, physiologic parameters, basic laboratory values, and chronic medical conditions and may not be necessarily representative of host immunologic deficits that lead to CMV infection.
CMV infection rate was 0.8 to 2.1% in two studies where the PCR assay was performed only once at a mean of 1.8 and 4 days following the onset of illness requiring ICU admission [
12,
15]. The median time to first detectable CMV viremia was 12 days (range 3 to 57 days) in a study where the PCR assay was performed thrice weekly [
11]. Thus, it appears that CMV infection is a rare event very early in the course of critically ill patients and that most infections develop between 4 and 12 days after the onset of illness requiring ICU stay, which could lead to a hypothesis that CMV infection may coincide with the development of compensatory anti-inflammatory response syndrome, and not with the initial surge of pro-inflammatory cytokines.
A key question is whether CMV infection adversely affects outcomes in critically ill patients. Virtually all studies have documented that CMV infection was related to prolonged mechanical ventilation and duration of ICU stay in patients with CMV infection. CMV infection has also been associated with organ system failure and at least two studies have documented significantly higher mortality rates in patients with CMV infection compared with those without it [
9,
18]. Thus, although these data do not prove a causal association as CMV infection may have been more likely to develop or diagnosed in sicker patients, existing evidence suggests that CMV infection is associated with poor outcomes even in immunocompetent critically ill patients. We believe that a causal association between these can only be assessed by carefully conducted clinical trials designed to show whether suppression of CMV has a mitigating effect on the severity of illness.
Another major unresolved issue is whether CMV infection is associated with overt disease or clinical manifestations directly attributable to this virus in critically ill patients. CMV infection in immunocompetent patients generally presents with mononucleosis-like symptoms including fever and malaise with liver enzyme abnormalities [
60,
61], which are typically benign. However, 31 to 42% of the hospitalized patients with CMV infection may have organ involvement [
60,
62] and rarely life-threatening CMV infection has also been reported [
63,
64]. In critically ill patients, 10% (2/20) of those with CMV infection eventually developed severe CMV disease (pneumonitis, neurologic disease) in one study [
10]. CMV pneumonia has also been diagnosed in 29 to 50% of patients with ARDS or VAP [
29‐
31]; however, this does not necessarily mean that CMV is the cause of ARDS or VAP. Critical illness due to serious pulmonary disease may predispose these patients to CMV infection in the lungs. In a cohort study in the ICU, 17% of critically ill patients who experienced fever for three or more days had CMV infection [
18]. Current guidelines for the evaluation of new fever in critically ill adult patients list transfusion-associated CMV mononucleosis as a cause of fever [
65]. However, it remains to be determined whether and how often CMV produces febrile syndrome and whether coexistent infection with HHV-6 is a contributor to this entity as shown in the transplant setting [
34,
36‐
40].
Experimental studies have shown that ganciclovir prevented murine CMV reactivation and the development of pulmonary fibrosis in immunocompetent mice with sepsis [
42]. Two retrospective studies where small subsets of ICU patients received antiviral agents for CMV infection have yielded inconclusive results and data on the utility and efficacy of antiviral therapy for CMV in critically ill immunocompetent patients are largely lacking [
17,
18]. Employment of potent antiviral therapy in all critically ill patients may be impractical, logistically infeasible, and potentially harmful given a large number of ICU patients and potential adverse effects of ganciclovir such as bone marrow suppression or teratogenicity. A more prudent approach may be to identify subgroups of patients at high risk for developing CMV infection and targeting antiviral prophylaxis towards these patients. These subgroups may include patients with sepsis, persistent fever, or those receiving transfusion. An alternative approach is to employ antiviral therapy only in those with CMV viremia. Regardless, carefully conducted clinical trials are warranted to discern the impact of antiviral agents on clinically meaningful outcomes before employing antiviral therapy or even considering routine monitoring of CMV in critically ill patients.
Several limitations of our study deserve to be acknowledged. We found considerable heterogeneity in the methodology used to assess CMV infection and in patient characteristics. As noted in the Results, the frequency and type of CMV monitoring influenced the rate of CMV infection. Although all the studies in this review were conducted in the ICU, the overall mortality of the studied patients ranged from 5 to 71% [
7,
15], suggesting that study populations were significantly diverse. Furthermore, these studies were published over a period spanning nearly two decades in different regions with diverse clinical practices. Considering the heterogeneity of available data, quantitative analyses such as meta-analysis can be misleading [
66,
67] and our results are therefore presented in a descriptive fashion only. Second, while we excluded the recipients of iatrogenic immunosuppressive agents that enhance the risk of CMV reactivation, critically ill patients in whom corticosteroids were employed were included. Controversy abounds whether corticosteroids alone without other immunosuppressive agents lead to reactivation of CMV from latency or merely promote the replication of activated virus [
68‐
70]. Corticosteroids were employed in a subset of patients in 5 of 12 studies in this review. Given that corticosteroid use is a common practice in the ICU [
71], these studies reflect clinical scenarios encountered by care providers and therefore their inclusion in this review was deemed appropriate.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
RO participated in the study design, literature search, data acquisition, interpretation of the data, and the drafting of the manuscript. NS participated in the study design, literature search, data acquisition, interpretation of the data, and the revision and editing of the manuscript. Both authors read and approved the final manuscript.