Version January 2024
INTRODUCTION — The spectrum of human illness caused by cytomegalovirus (CMV) is diverse and mostly dependent on the host. CMV infections in immunocompromised patients cause substantial morbidity and mortality, especially among transplant recipients and those infected with the human immunodeficiency virus (HIV). Infection in the immunocompetent host is generally asymptomatic or may present as a mononucleosis syndrome. However, occasionally, primary CMV infection can lead to severe organ-specific complications with significant morbidity and mortality [1,2]. Infection of pregnant women, even if asymptomatic, is occasionally associated with the syndrome of congenital CMV in newborns. (See "Cytomegalovirus infection in pregnancy".)
The manifestations and treatment of CMV infection in immunocompetent adults will be reviewed here. The diagnosis of CMV infections in immunocompetent and immunocompromised patients is discussed separately. CMV infection in neonates, children, and immunocompromised hosts is also presented separately. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection" and "Congenital cytomegalovirus infection: Clinical features and diagnosis" and "Congenital cytomegalovirus infection: Management and outcome" and "Overview of cytomegalovirus infections in children" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis" and "AIDS-related cytomegalovirus gastrointestinal disease" and "AIDS-related cytomegalovirus neurologic disease".)
INFECTION, LATENCY, AND REACTIVATION — Like other members of the Herpesvirus family, CMV establishes latent infection after the resolution of acute (or primary) infection. Productive (lytic) infection leads to the synthesis of immediate-early, early, and late viral proteins [3]. Viral deoxyribonucleic acid (DNA) has been detected in monocytes, dendritic cells, megakaryocytes, and myeloid progenitor cells in the bone marrow [4].
Secondary symptomatic disease may present later in the life of the host, reflecting one of two possibilities: reactivation of latent CMV or reinfection with a novel exogenous strain [5]. One prospective study of 205 postpartum seropositive women found that approximately one-third of the participants had CMV reinfection over a mean of 35 months of follow-up [5]. In this study, reinfection was determined by the appearance of new antibodies with strain-specific binding to unique polymorphic determinants on the envelope glycoprotein of CMV. A similar frequency of reinfection was noted in a study of healthy seropositive women over 30 months of follow-up; furthermore, CMV viremia and viruria were common, suggesting that naturally acquired immunity to CMV does not alter shedding patterns [6].
Reactivation of CMV may occur at any time during the life of the human host, although the risk is higher in the setting of systemic immunosuppression, either iatrogenic or secondary to underlying medical conditions, such as the acquired immunodeficiency syndrome (AIDS). As an example, in one study, glucocorticoid use was associated with an increased risk of CMV colitis in otherwise immunocompetent adults [7]. Titers of CMV-specific immunoglobulin (Ig)G do not appear to predict the risk of reactivation in immunocompetent hosts; therefore, the importance of CMV-specific IgG in the control of reactivation is uncertain [8].
The bulk of CMV-related disease in immunocompetent hosts is related to primary infection. The differentiation between endogenous reactivation and exogenous reinfection is difficult in clinical practice.
IMMUNOLOGY — In immunocompetent hosts, T cells play an important role in controlling viral replication and disease but do not eliminate the virus completely. High frequencies of specific cytomegalovirus CD4+ and CD8+ T cell responses have been demonstrated in immunocompetent hosts [9,10]. Using cytokine flow cytometry and overlapping peptides comprising more than 200 CMV open reading frames (ORFs), researchers have been able to demonstrate that 151 ORFs are immunogenic for CD4+ and CD8+ T cells [10]. Furthermore, CMV-specific T cell responses are typically robust. In one study, CMV-specific T cell responses involved approximately 10 percent of both CD4+ and CD8+ memory cells within the peripheral blood of CMV-seropositive individuals, whereas, in CMV-seronegative individuals, cross-reactive T cell recognition of CMV proteins was limited to CD8+ T cells and was rare [10].
EPIDEMIOLOGY — The proportion of humans with evidence of prior cytomegalovirus infection varies throughout the world, with seroprevalence rates ranging between 40 and 100 percent of the adult population [11]. Seroprevalence generally correlates inversely with a country's socioeconomic development, with highest rates observed in resource-limited countries throughout Africa and Asia [12].
The prevalence of CMV-specific antibody increases with age [13-16]. As an example, in a study from Finland, the seroprevalence rates were 47 percent in 10- to 12-year-olds, 68 percent in 15- to 35-year-olds, and 81 percent among 36- to 60-year-olds [13]. In a United States-based study, CMV seroprevalence increased from 36 percent in 6- to 11-year-olds to 91 percent in those aged >80 years [14].
CMV seroprevalence also varies by race and ethnicity; in one United States study among individuals aged 6 to 49 years, seroprevalence was 40 percent in non-Hispanic White Americans, 71 percent in non-Hispanic Black Americans, and 77 percent in Mexican Americans [15]. Another study demonstrated that the incidence of new CMV infections occurred at an earlier age among non-Hispanic Black Americans (16.3 years) and Mexican Americans (17.5 years) compared with non-Hispanic White Americans (29.3 years) [17].
In the United States-based study mentioned above, other factors associated with CMV seropositivity included female sex, foreign birthplace, low household income, household crowding, and low household education [15].
TRANSMISSION — Cytomegalovirus has been cultured from multiple sites, including urine, blood, throat, cervix, semen, stool, tears, and breast milk [18,19]. Transmission can occur via multiple routes:
●Sexual exposure – Sexual modes of transmission are supported by evidence that seroprevalence rates are higher among patients with multiple sexual partners or a history of prior sexually transmitted diseases and that virus can be detected in the genital tract [20]. In a study of otherwise healthy women with primary CMV infection, the CMV DNA load in vaginal fluid was higher than that in other sources, including saliva, urine, and whole blood [21].
●Close contact – Seroconversion is well described among family members [22] and children in daycare centers [23]. Contacts are probably exposed to virus shed from the upper respiratory tract and urine. Protracted viral shedding is much more common among children than immunocompetent adults.
●Blood or tissue exposure – Transmission of CMV following transfusion of blood products [7,24,25] and transplantation of organs from seropositive donors is well documented. In a study of more than 600 immunocompetent CMV-seronegative blood product recipients, CMV seroconversion was demonstrated in 0.9 percent [26]. The estimated risk of transfusion per unit of blood was 0.38 percent. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients".)
●Occupational exposure – Susceptible workers in daycare centers and other facilities with many children are at risk of seroconversion [23]. Health care workers may also be exposed, but the actual risk of seroconversion among susceptible individuals appears to be low [27].
●Perinatal exposure – Neonates and infants may be infected with CMV in utero during maternal viremia, during exposure to secretions in the birth canal, or postnatally from breast milk. (See "Cytomegalovirus infection in pregnancy".)
There is evidence that CMV can survive in saliva on environmental surfaces for variable periods, depending on the surface. In one study, CMV in filtered human saliva was applied to environmental surfaces, and samples were evaluated by culture and real-time polymerase chain reaction [28]. CMV was found to be viable on metal and wood to one hour, on glass and plastic to three hours, and on rubber, cloth, and cracker to six hours. Dry surfaces were less likely to yield viable virus during environmental sampling than wet surfaces.
Behavioral measures to prevent transmission of CMV are presented separately. Such measures are particularly important in pregnant women in order to reduce perinatal infections. (See "Cytomegalovirus infection in pregnancy", section on 'Behavioral risk reduction interventions'.)
CMV MONONUCLEOSIS — A syndrome resembling infectious mononucleosis is the most common presentation of symptomatic cytomegalovirus infection in immunocompetent adults. Classic mononucleosis is an illness characterized by significant, often protracted fevers and lassitude in the setting of absolute lymphocytosis and atypical lymphocytes [18]. (See 'Laboratory abnormalities' below.)
Infectious mononucleosis is most commonly caused by Epstein-Barr virus (EBV) and is diagnosed by the presence of heterophile antibody [18]. When the patient with symptoms and signs of classic infectious mononucleosis is heterophile negative, then the most likely etiology is CMV infection, and additional diagnostic testing should be pursued. CMV-specific serology has been the mainstay of diagnostic testing for acute infections for many decades. Acute infection is strongly suggested by the detection of either CMV-specific IgM antibody or a four-fold or greater rise in CMV-specific IgG performed in paired specimens obtained at least two weeks apart. However, when serologic testing is not conclusive, molecular assays (polymerase chain reaction testing) can also play an important role in confirming the cause of heterophile-negative mononucleosis and other acute presentations of CMV. (See "Approach to the diagnosis of cytomegalovirus infection" and "Overview of diagnostic tests for cytomegalovirus infection" and "Infectious mononucleosis".)
A landmark study of 494 patients with infectious mononucleosis was significant for the following results [29]:
●79 percent of patients had infectious mononucleosis secondary to EBV as diagnosed by heterophile antibody.
●73 patients were heterophile antibody negative; almost half of these patients had CMV infection as defined by rising complement-fixing antibodies. It was concluded that CMV mononucleosis represented primary infection in previously seronegative patients.
CMV mononucleosis can be accompanied by dermatologic manifestations in approximately one-third of patients including macular, papular, maculopapular, rubelliform, morbilliform, and scarlatiniform eruptions [1]. Exposure to ampicillin or related beta-lactam antibiotics has also been associated with the development of a characteristic generalized maculopapular rash in patients with CMV mononucleosis, analogous to that seen with EBV [30,31].
Differences between EBV and CMV mononucleosis — While the syndromes caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are similar, several important distinctions warrant emphasis:
●The mononucleosis syndrome associated with CMV infection has been described as "typhoidal" in presentation, since systemic symptoms and fever predominate and signs of enlarged cervical lymph nodes and tonsillitis are not as commonly seen as they are in EBV [29]. As an example, in studies in Israel and the United States, cervical lymphadenopathy occurred in 13 to 17 percent of patients [2,32]. These observations contrast sharply with the finding of diffuse lymphadenopathy in more than 80 percent of patients with classic EBV-related mononucleosis [18].
●However, children with CMV are more likely than adults to present with cervical lymphadenopathy. In one age-based comparative study of CMV in patients without underlying immunosuppression, cervical lymphadenopathy was documented in 86 percent of children less than 12 years compared with only 6 percent in adults [33].
●Unlike EBV, CMV uncommonly causes exudative tonsillopharyngitis [29,34].
●Based upon data from case series, splenomegaly appears to be more common in patients with mononucleosis associated with EBV than CMV [1,2,20,29,35].
●Adults with CMV-related mononucleosis tend to be somewhat older than those with EBV infection at the time of clinical presentation [18,29].
Mononucleosis caused by EBV is discussed in greater detail separately. (See "Infectious mononucleosis".)
Laboratory abnormalities — Two cardinal hematologic abnormalities help to define the syndrome of mononucleosis: an absolute lymphocytosis with greater than 50 percent mononuclear cells and the presence of more than 10 percent atypical lymphocytes on peripheral blood smear [1,2,18]. These laboratory abnormalities do not differ significantly among patients with different etiologies of mononucleosis. Extreme elevations of the peripheral white blood cell (WBC) count are rare [2].
While the presence of atypical lymphocytes is required for the diagnosis, not all patients with active CMV infection have atypical cells at the time of presentation. In a review of 82 patients with CMV mononucleosis, 11 patients did not initially meet blood smear criteria for mononucleosis but did so later in the course of their illness [2].
An absolute lymphocytosis may persist in patients for several months after the resolution of symptoms. In the first published series of patients with CMV mononucleosis, persistent lymphocytosis was documented in 8 of 18 patients (44 percent) and lasted between 2 and 11 months from the time of the original diagnosis [36]. The persistence of atypical lymphocytes did not correlate with the duration of clinical symptoms.
In addition to the cardinal hematologic manifestations of mononucleosis, other abnormalities may also be seen, including [1,2,37-41]:
●Mild-to-moderate anemia
●Reduced haptoglobin levels
●Cold agglutinins
●Elevated levels of rheumatoid factor
●Positive antinuclear antibodies
●Thrombocytopenia
●Disseminated intravascular coagulation [42]
ORGAN-SPECIFIC COMPLICATIONS — Disease localized to a single organ has been described in immunocompetent hosts, even presenting as a fulminant, multisystem disorder. However, these cases are rare and limited to small series and case reports [43].
Gastrointestinal manifestations — Gastrointestinal involvement with CMV is uncommon in immunocompetent hosts but can cause significant morbidity and mortality [44-49]. While CMV colitis is almost always secondary to the reactivation of latent infection in immunosuppressed patients, CMV colitis in the immunocompetent host can occur in the setting of primary infection. (See "AIDS-related cytomegalovirus gastrointestinal disease".)
In one review of 15 cases of CMV colitis among patients without underlying immunosuppression, the following findings were noted [50]:
●Seven patients had probable primary CMV infection based upon seroconversion at time of diagnosis, detection of CMV-specific IgM antibody, or positive viral cultures in the absence of detectable antibodies.
●Diarrhea, fever, and abdominal pain were common presenting symptoms.
●Among patients reporting diarrhea, stool was described as grossly bloody in 53 percent and positive for occult blood in 20 percent.
●Profuse gastrointestinal hemorrhage was the presenting symptom in the two patients without prodromal diarrhea.
●Pathology findings supported the diagnosis of inflammatory colitis with Cowdry inclusions, typical of CMV disease.
In a retrospective review, investigators identified 86 immunocompetent patients with CMV-associated gastroenterocolitis [48]. Patients with defined congenital or acquired immunodeficiency, use of anticancer chemotherapeutic or immunosuppressive medications, or documented inflammatory bowel disease were excluded from the study This case series was remarkable for the following findings:
●The average age of immunocompetent patients with gastroenterocolitis was 65.5 years and the majority (61.6 percent) were male.
●Almost 80 percent had underlying medical comorbidities including diabetes mellitus (40 percent), hypertension (36 percent), cardiovascular disease (24 percent), or end-stage renal disease requiring dialysis (17 percent). Twenty-one percent of patients had no other chronic or acute medical conditions.
●The colon was the most commonly involved organ, with colon-predominant disease noted in 70 percent of patients and colon-only disease seen in 62 percent. Upper gastrointestinal track disease predominated in 22 percent of cases while small bowel-dominant disease was seen in only 8 percent. The most common symptoms reported by patients with colon-predominant disease (n = 60) were hematochezia (55 percent), abdominal pain (22 percent), and diarrhea (20 percent). Patients with upper tract-predominant disease (n = 19) reported nausea and vomiting (37 percent), melena (21 percent), odynophagia (16 percent), hematemesis (11 percent), and abdominal pain (11 percent).
●The most common endoscopic appearance of colon-predominant and upper gastrointestinal-predominant disease was discrete ulceration without exudate.
In another large study of 173 gastrointestinal CMV infections, gastrointestinal hemorrhage was a more common presenting symptom among immunocompetent patients while abdominal pain and diarrhea were more common in immunocompromised patients [51].
In another retrospective study of 12 immunocompetent adults with CMV colitis, the most commonly identified endoscopic abnormalities were well-demarcated ulcerations (50 percent), ulceroinfiltrative changes (25 percent), and pseudomembrane formation (25 percent) [52]. The presence of abnormal mucosal surfaces prior to CMV infection may increase the risk of this infection. As an example, evidence of gastrointestinal CMV in patients with pre-existing inflammatory bowel disease has been described [53-55].
CMV colitis can be confused with ischemic colitis when an older adult patient presents with bloody diarrhea and abdominal pain [44]. CMV has also been implicated as a cause of esophagitis [56,57], gastritis [58-60], Ménétrier's disease (protein-losing hypertrophic gastropathy) [61], ileitis [62], appendicitis [63], colonic obstruction [64], and proctocolitis with perforation [65] in patients without underlying immunosuppression. (See "Approach to the patient with large gastric folds", section on 'Ménétrier's disease'.)
Hepatic manifestations — Liver function test (LFT) abnormalities are frequently encountered in patients with symptomatic CMV infection [1]. Subclinical transaminitis is the most common finding in immunocompetent patients; elevations of alkaline phosphatase and total bilirubin are less typical. Occasionally, patients will present with more significant LFT abnormalities or clinical signs of hepatic dysfunction. Portal vein thrombosis has also been described as a rare complication of acute CMV-associated hepatitis [66,67].
Though infrequent, CMV should also be included in the differential diagnosis of granulomatous hepatitis [1,68,69]. Prolonged, unexplained fever is the most common presentation. This condition is associated with the characteristic biopsy findings of multiple noncaseating epithelioid granulomas, portal triaditis, and focal necrosis [68]. (See "Evaluation of the adult patient with hepatic granuloma".)
Neurologic manifestations — CMV infection has been associated with numerous neurologic sequelae in the immunocompetent host.
Encephalitis — Although rare, encephalitis is a serious potential complication of CMV infection, and this entity should be considered in the differential diagnosis of unexplained encephalitis. In one study of 10 cases of isolated CMV encephalitis, there were no fatalities and only one patient had persistent neurologic deficits six months after diagnosis [43].
Guillain-Barré syndrome — Guillain-Barré syndrome (GBS) has been associated with a variety of infectious agents, including CMV and Campylobacter infections. This incidence of CMV-related GBS has been estimated to occur in approximately 0.6 to 2.2 cases per 1000 cases of primary CMV infection (versus 0.25 to 0.65 cases per 1000 cases of C. jejuni infection) [70]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Infection'.)
In a serologic study of patients with GBS, recent CMV infection was detected in 13 percent of patients by serology [71]. In a subsequent prospective study of 506 patients with GBS, 63 (12.4 percent) were found to have primary CMV infection, as detected by IgM detection with IgG avidity in combination with plasma CMV polymerase chain reaction (PCR) [70]. In a series of 42 patients with GBS and serologic evidence of recent or past CMV infection, PCR testing of the cerebrospinal fluid demonstrated CMV DNA in approximately one-third of cases [72].
Patients with CMV-related GBS are generally younger than those with Campylobacter-related and idiopathic forms of the syndrome [70,73]. The median age of patients with CMV-related GBS is 32 years, and 85 percent of patients are women [70].
In one study, patients with CMV-related GBS experienced more prominent sensory deficits, respiratory insufficiency, and cranial nerve impairments than those with Campylobacter-related and idiopathic forms of the syndrome [73]. However, in another study, facial palsy was the only clinical finding that was significantly more common in patients with CMV-related GBS compared with non-CMV-related GBS [70]. Studies on the long-term outcomes of CMV-related GBS have provided conflicting results. In one study, recovery from GBS appeared to be slower in patients in whom either CMV or Campylobacter infections were identified [74]. However, in another study, patients with CMV-related GBS were less likely to have severe long-term neurologic sequelae than patients with GBS that was not related to CMV [70].
CMV-related GBS is typically associated with the development of antibodies to ganglioside GM2, although the exact role of these antibodies remains unresolved [71,75]. Importantly, anti-GM2 IgM antibodies are often detected not only in patients with CMV-related GBS but also in patients with CMV infection who do not have GBS [70]. One group demonstrated that CMV-infected fibroblasts express surface epitopes capable of binding anti-GM2 antibodies [76]. This observation suggests that molecular mimicry between CMV-infected cells and GM2 may be important in disease pathogenesis.
GBS is discussed in greater detail separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)
Other — Other focal neurologic deficits have been described in patients with CMV, including brachial plexus neuropathy [77], diffuse axonal peripheral neuropathy [78], transverse myelitis [79-81], Horner's syndrome [2], and cranial nerve palsies [79].
Some investigators have hypothesized that proinflammatory cytokines secreted in the setting of CMV infection might lead to amyloid deposition, resulting in Alzheimer disease [82]. In a longitudinal clinicopathological study of aging and dementia, CMV antibody levels were associated with the neurofibrillary tangles of Alzheimer disease [82]. Immunocytochemical analysis showed induction of amyloid-beta in human foreskin fibroblasts (HFFs) infected with each of three CMV strains. There was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid formation. Further study is necessary to determine whether CMV infection plays a role in the pathogenesis of Alzheimer disease.
Pulmonary manifestations — CMV pneumonia is rarely described in immunocompetent hosts [83,84]. Although pulmonary complaints and radiologic abnormalities were cited in earlier reports of immunocompetent patients, proof that CMV is the actual cause of these abnormalities is generally lacking [1]. A few cases have suggested the direct role of CMV through detection of CMV by PCR in the blood and bronchoalveolar specimens and the resolution of clinical symptoms, hypoxemia, and pulmonary infiltrates following the institution of CMV-specific therapy [84].
Ocular manifestations — CMV retinitis is a well-known occurrence in patients with advanced immunosuppression from HIV infection. However, CMV infection of the eye is uncommon among immunocompetent individuals and, until the more widespread availability of molecular diagnostics, had been limited to rare case reports [78,85-90]. With the development of the PCR, CMV infection has been identified with increasing frequency among immunocompetent patients presenting with anterior uveitis [91-95]. This was illustrated in a study in which immunocompetent patients presenting with anterior uveitis associated with elevated intraocular pressure (hypertensive anterior uveitis) underwent PCR analysis of anterior chamber aqueous fluid [91]. Among 105 samples, 24 (23 percent) had evidence of CMV DNA. In patients presenting with evidence of CMV-related anterior uveitis, CMV viral load within the aqueous fluid appears to correlate with the degree of corneal endothelial cell loss [93]. PCR analysis of vitreous fluid has also been used to confirm the diagnosis of CMV retinitis in immunocompetent patients [90]. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)
Cardiovascular manifestations
Pericarditis and myocarditis — Pericarditis and myocarditis have been described in immunocompetent patients with acute CMV infection [1,96-101]. While CMV DNA has been detected by PCR and in situ hybridization in endomyocardial tissue from patients with isolated myocarditis and dilated cardiomyopathy, direct causality has not been clearly demonstrated [100]. Furthermore, in a study of 245 patients with dilated cardiomyopathy, viral genomes were isolated in 165 (67 percent); CMV DNA was isolated in only two patients [102]. However, in an autopsy study of 40 patients with fatal myocarditis, CMV DNA was isolated in 15 patients [103]. (See "Acute pericarditis: Clinical presentation and diagnosis" and "Clinical manifestations and diagnosis of myocarditis in adults".)
Atherosclerosis — Several infectious agents have been implicated in the pathogenesis of atherosclerosis. Chlamydia pneumoniae and CMV have received the most attention. (See "Pathogenesis of atherosclerosis", section on 'Infection'.)
To date, a definitive causal relationship between infection with CMV and atheroma formation has not been clearly established. Several investigators have postulated that latent CMV infection of vascular endothelial cells promotes subsequent arterial smooth muscle cell proliferation, enhanced expression of scavenger receptors, and increased uptake of oxidized low-density lipoproteins, resulting in atherosclerosis [104].
Epidemiologic evidence has supported the association of CMV with accelerated atherosclerosis following cardiac transplantation [105]. Clinical studies have linked an increased risk of atherosclerotic coronary artery disease (CAD), restenosis of lesions following atherectomy, and postangioplasty restenosis with serologic evidence of past CMV infection [106-108].
However, not all studies have upheld the close seroepidemiologic association between viral infection and vascular plaque formation in carotid or coronary arteries [109-112]. Many pathologic studies have also failed to observe evidence of CMV in coronary plaques [113,114]. Thus, further prospective investigation into this proposed association will be necessary before firm conclusions can be reached.
Venous thrombosis — Venous thrombosis with or without associated pulmonary embolism has been reported in case reports and small case series of immunocompetent patients with acute CMV infection, often in the absence of known risk factors for hypercoagulability [115,116]. While the development of lower extremity deep vein thrombosis may be related to prolonged stasis in hospitalized patients with severe CMV disease, the development of venous thrombosis at other sites such as the portal vein, internal jugular vein, ovarian vein, splanchnic vein, and mesenteric veins suggests that CMV may have a procoagulant effect [66,67,117-121].
ASSOCIATION BETWEEN SEROPOSITIVITY AND OUTCOMES — Several studies suggest an association between CMV seropositivity and mortality [122-125]. As an example, in a population-based study of 1468 Latino adults 60 years and older, all-cause mortality was 1.43 times higher among individuals with CMV IgG antibody titers in the highest quartile compared with lower quartiles (95% CI 1.14-1.79) [122]. The hazard of cardiovascular mortality was also elevated in those with antibodies in the highest quartile (hazard ratio [HR] 1.35, 95% CI 1.01-1.80). Tumor necrosis factor and interleukin-6 levels mediated a substantial proportion of the association between high CMV antibody levels and both all-cause and cardiovascular mortality. This study suggests a link between CMV infection and mortality, potentially the result of the activation of inflammatory pathways.
In a population-based cohort study that included 13,090 patients, CMV seropositivity was associated with all-cause mortality (HR 1.16, 95% CI 1.07-1.26), and mortality rates increased as CMV IgG antibody levels rose [125]. The association persisted after adjusting for measures of socioeconomic status and potential confounders. Further studies are necessary to establish this possible association and, if validated, elucidate the biologic mechanisms underlying it.
In contrast with the studies described above, in a retrospective study that evaluated the impact of CMV serostatus on outcomes in immunocompetent intensive care unit (ICU) patients, on multivariable analysis, there was no association between CMV seropositivity and ICU mortality, which was the primary endpoint of the study [126]. There was also no association between CMV seropositivity and any of the secondary endpoints, which included in-hospital mortality, time to discharge from the ICU or hospital, time to wean from mechanical ventilation, and the need for renal replacement therapy. Similarly, in a large, prospective study evaluating the association of CMV serostatus and mortality in over 10,000 White adults aged 59 to 93, CMV seropositivity was not associated with increased all-cause or cardiovascular mortality [127].
Increasing age has been clearly associated with a decline in immune function and an increased susceptibility to infection. This phenomenon is commonly referred to as immunosenescence. The role of chronic infection and inflammation in the aging process and development of immunosenescence has garnered increasing attention during years (see "Immune function in older adults"). Specifically, chronic infection with viral pathogens such as HIV and members of the herpesvirus family (specifically CMV and Epstein-Barr virus) have been linked to several markers of aging, frailty, and immunologic decline [128-132]. In one study of 87 healthy patients 60 years and older, CMV seropositivity was statistically associated with the following findings: higher lymphocyte counts, higher percent and absolute numbers of CD8 cells, and reduced CD4:CD8 ratios [132]. Epigenic age of participants was determined using DNA methylation assays targeted to specific sites in the human genome known to correlate with age. While the average biologic age of participants was lower among CMV-positive participants (70.3 versus 72.7 years in CMV-seronegative participants), the epigenic age was significantly higher in patients with CMV seropositivity (65.34 versus 59.53 years, p = 0.0116). Comparison of experimental epigenic age and predicted epigenic age suggested a 5.1-year age acceleration in the CMV-positive group.
REACTIVATION IN CRITICALLY ILL PATIENTS — CMV reactivation occurs commonly in critically ill patients [133-143]. Small observational studies and a systematic review have suggested that CMV reactivation in such patients is linked to increased length of hospital and/or intensive care unit (ICU) stay [135,137-139], duration of mechanical ventilation [135,137], severe sepsis [139], high disease severity [139], and mortality [133,135,139,144].
In a meta-analysis of 18 observational studies including nearly 2400 immunocompetent patients admitted to ICUs, CMV infection was detected in 27 percent [144]. Overall mortality during the ICU stay was increased in patients with CMV infection (at any site) when compared with those without evidence of CMV infection (odds ratio [OR] 2.16, 95% CI 1.70-2.74). The increase in mortality risk was also observed among those with CMV viremia compared with those without (OR 2.15, 95% CI 1.48-3.15) and when patients who received antiviral therapy for CMV were excluded from the analysis (OR 1.69, 95% CI 1.01-2.83).
The effect of CMV reactivation on clinical outcomes has varied among individual observational studies [138,140-143]. As an example, in a prospective blinded study of 120 critically ill immunocompetent patients who were CMV seropositive, CMV reactivation was detected by real-time polymerase chain reaction (PCR) in 39 patients (33 percent) and was independently associated with continued hospitalization or death by 30 days after admission to the ICU [138]. Viremia was detected at a median of 12 days following ICU admission and persisted for 3 to 57 days (median 17 days). Similarly, in another observational study assessing the impact of CMV reactivation on outcomes of CMV-seropositive immunocompetent patients with acute respiratory distress syndrome (ARDS), CMV viremia was observed by PCR in 74 of 271 patients (27 percent) when tested weekly during the first 30 days of admission and was associated with increased overall mortality and reduced successful ventilator weaning rate [142].
By contrast, in a prospective study of immunocompetent patients admitted to an ICU, evidence of CMV reactivation was detected in blood by real-time PCR in 11 of 80 patients (14 percent) [141]. The most significant risk factors for reactivation were the number of transfused units of packed red blood cells and higher levels of C-reactive protein at the time of admission. Patients with CMV reactivation had higher quantified Sequential Organ Failure Assessment (SOFA) scores during the entire 28-day observation period. However, the patients with reactivation had no differences in ICU length of stay, duration of mechanical ventilation, or overall mortality when compared with patients without evidence of CMV viremia during their ICU stay. In another prospective study that included 306 immunocompetent, critically ill CMV-seropositive patients with ARDS, CMV reactivation was observed in 53 of 209 patients (26 percent), but it was not associated with prolonged mechanical ventilation or increased mortality [140].
PROPHYLAXIS AGAINST REACTIVATION — To date, there is no evidence that prophylaxis or suppression of CMV viremia in critically ill patients leads to improved outcomes. As an example, in a phase II trial, the ganciclovir/valganciclovir for prevention of cytomegalovirus reactivation in acute injury of the lung (GRAIL) study, 160 CMV-seropositive immunocompetent patients with critical illness due to sepsis or trauma, patients were randomly assigned to receive prophylaxis with intravenous (IV) ganciclovir for five days followed by IV ganciclovir or oral valganciclovir or to receive placebo [145]. Antiviral prophylaxis was associated with a reduced incidence of CMV reactivation (12 versus 39 percent). However, there was no difference between the groups in interleukin (IL)-6 levels (the primary outcome) nor were there differences between the groups in incidence of secondary bacteremia or fungemia, intensive care unit (ICU) length of stay, or mortality. IL-6, a pro-inflammatory cytokine, was chosen as the primary endpoint because it has been associated with mortality in ICU patients; in addition, preliminary studies have linked CMV reactivation with increased IL-6 levels, and it was expected that the trial might detect a difference for this endpoint.
THERAPY — Most cases of primary CMV infection in immunocompetent hosts are associated with minimal or no symptoms. Among patients with symptomatic CMV infection, especially the mononucleosis syndrome, the illness is generally self-limited, with complete recovery over a period of days to weeks. Antiviral therapy is not usually indicated.
There are several agents available for the systemic therapy of CMV infection, including ganciclovir, valganciclovir, foscarnet, and cidofovir. The efficacy and toxicities of these agents have been evaluated extensively only in immunocompromised patients. The clinical utility of these agents in the immunocompetent host remains unproven. (See "Ganciclovir and valganciclovir: An overview" and "Foscarnet: An overview" and "Cidofovir: An overview".)
Several case reports have documented successful therapy of previously healthy patients with severe manifestations of CMV infection. Patients with protracted CMV mononucleosis and many of the organ-specific complications of CMV have had successful clinical outcomes associated with the use of ganciclovir [43,48,96,146,147], valganciclovir [92,94,147-149], and foscarnet [43,48,80,85,150]. However, recurrence of CMV anterior uveitis following the discontinuation of antiviral therapy has also been reported [91]. (See 'Ocular manifestations' above.)
Since the majority of immunocompetent patients with CMV disease recover without intervention, it is difficult to prove whether or not antiviral therapy has a significant impact on the clinical outcome. Doses of the drugs and the duration of therapy also have not been clarified for this group of patients. Since severe CMV infections in this population are rare, it is unlikely that a prospective randomized trial will ever be performed comparing antiviral therapy with placebo. Thus, the severity and potential morbidity of CMV disease must be balanced against the risk of medication toxicity (eg, bone marrow toxicity) in deciding whether or not to use antivirals in an individual immunocompetent patient.
In one randomized, placebo-controlled trial of pre-emptive therapy in ventilated intensive care unit patients with evidence of CMV reactivation, there was no evidence of improved outcomes in patients treated with ganciclovir 5 mg/kg for 14 days. Specifically, 76 patients who were ventilated for at least 96 hours and demonstrated evidence of reactivation of CMV were randomized to therapy versus placebo. The trial was stopped early because of no significant difference in the primary endpoint, ventilator-free days within 60 days after randomization. In addition, there was no difference in 60-day mortality [151].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (See "Patient education: Cytomegalovirus (The Basics)".)
SUMMARY
●Clinical spectrum − Although acute (primary) cytomegalovirus (CMV) infection is generally asymptomatic or produces only nonspecific symptoms in the immunocompetent host, a broad variety of presentations have been described, ranging from a common form of infectious mononucleosis to marked systemic disease with significant morbidity. The illness is generally more innocuous in newly infected children than in adults. (See 'CMV mononucleosis' above and 'Organ-specific complications' above.)
●Transmission − Transmission can occur via multiple routes including sexual transmission, close contact, as in daycare centers, or blood and tissue exposure. (See 'Epidemiology' above.)
●CMV mononucleosis − The most common syndrome related to primary CMV infection is CMV mononucleosis. Fever and systemic symptoms predominate in CMV-related mononucleosis, while enlarged cervical lymph nodes and tonsillitis are much more commonly seen with Epstein-Barr virus (EBV) infection. Splenomegaly appears to be more common with EBV infection than with CMV infection. Hematologic findings with both infections include an absolute lymphocytosis and atypical lymphocytes. (See 'CMV mononucleosis' above.)
●Diagnosis of CMV mononucleosis − Patients with CMV-related mononucleosis are heterophile antibody negative and require further diagnostic testing specifically for CMV. Diagnosis of CMV-related mononucleosis typically relies on the use of serology or molecular diagnostic testing. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection".)
●Tissue invasive disease − CMV infection in immunocompetent patients has been associated rarely with colitis, encephalitis, myocarditis, and other organ-specific entities. (See 'Organ-specific complications' above.)
●Reactivation in critically ill patients − CMV reactivation is common in critically ill immunocompetent patients and is associated with increased length of hospital and/or intensive care unit stay, duration of mechanical ventilation, severe sepsis, high disease severity, and mortality. However, there is no evidence to date that antiviral prophylaxis or suppression of CMV viremia improves outcomes in critically ill patients. (See 'Reactivation in critically ill patients' above and 'Prophylaxis against reactivation' above.)
●Treatment − Among immunocompetent patients with mild symptomatic CMV infection, especially the mononucleosis syndrome, the illness is generally self-limited, with complete recovery over a period of days to weeks. Antiviral therapy is not usually indicated. Tissue invasive disease typically requires antiviral therapy. (See 'Therapy' above.)
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