AFTER TRAVELING to Puerto Rico, JD, a 57-year-old commercial salesman, presented to his primary care provider with dysuria, fatigue, malaise, and a low-grade fever. He had a history of hypertension, dyslipidemia, and type 2 diabetes that were all well controlled with medications. His provider diagnosed a urinary tract infection (UTI) and prescribed an antibiotic.
Although his urinary signs and symptoms improved, the fatigue continued and JD developed a cough a few weeks later. He was diagnosed with serum sickness from his UTI treatment and prescribed steroids. His cough improved, but, despite multiple rounds of antibiotics, the underlying fatigue and low-grade fever did not resolve. He later required hospitalization and parenteral antibiotics after being diagnosed with bacterial pneumonia.
A year after his initial presentation, JD was admitted to the hospital with sepsis and a 103° F (39.4° C) fever. The infectious disease team was consulted, and a thorough workup was completed. JD tested negative for syphilis, influenza, Epstein-Barr virus, herpes simplex virus, and Lyme disease.
JD's health history revealed that, following vague symptoms, his wife had been diagnosed with cytomegalovirus (CMV) 11 years earlier. His lab work was positive for CMV immunoglobulin M (IgM) and negative for immunoglobulin G (IgG), indicating a recent infection, and his CMV viral load was significant (see CMV lab analysis and interpretation). JD had an active CMV infection.
CMV is a common infection that affects patients across their lifespan. The virus is part of the herpes family, with multiple strains. Recent information indicates that the virus may be more clinically significant than previously thought in immunocompetent individuals who experience acute or critical illnesses.1-3
According to the CDC, more than 50% of all adults have been infected with CMV.4 Approximately 1 in 200 neonates is born with CMV antibodies, with about 1 in 5 children experiencing ongoing health problems as a result.4 Once an individual is infected, the virus remains dormant but may reactivate at any time. The rates of global seroprevalence range from 45% to 100% in the general population, with the lowest rates found in Western Europe and the US.5
Developing countries and regions characterized by lower socioeconomic status have increased rates of CMV, and estimates of seroprevalence increase with age. The primary virus may not be solely responsible for the high rates of infection, as dormant viruses may reactivate in older adults and allow for transmission.6
CMV is transmitted through contact with infected blood and body fluids, spreading through sexual transmission or close contact with an infected individual.4 Less commonly, it may also be transmitted through casual or non-intimate contact with secretions, such as saliva and urine, and can live on some environmental surfaces for up to 6 hours.7 The risk of transmission is higher during the primary infection compared with the reactivated virus. However, individuals with a positive IgG may still transmit CMV to susceptible individuals through blood and tissue products.8
Based on his history and lab results, JD presumably contracted primary CMV while traveling, or from his wife while he was immuno-suppressed from active infection or prescribed steroids. Similarly, solid-organ transplant recipients are at increased risk for CMV reactivation because they are immunosuppressed.9
For neonates and infants, transmission may occur in utero, during the birth process, or while breastfeeding. The risk of transmission varies depending on the trimester. Primary infection is associated with a 30% to 40% risk of transmission in the first and second trimesters and a 40% to 70% risk in the third.5 Transmission in the first trimester is associated with poorer fetal outcomes.5 Severe and permanent complications of fetal transmission include hearing loss and neurologic impairments.
Due to exposure to blood and body fluids, there is also a theoretical occupational risk for healthcare and day-care workers. The risk of seroconversion, which describes the time for infection antibodies to develop and be detected via serologic testing, is low in these circumstances.10
Presentation and diagnosis
In healthy adults, the primary CMV infection will often be asymptomatic.11 Individuals may develop a viral-type syndrome, similar to mononucleosis, which can include fever, fatigue, myalgia, anorexia, lymphadenopathy, and a rash.11 Symptoms are typically more pronounced in very young patients and older adults. Those with severe CMV infection or reactivation may present with various complications (see Organ-specific complications). In JD's case, a protracted fever and lymphocytosis were key signs of CMV.
The incubation period for CMV is 40 days on average. It may manifest as a viral infection with vague symptoms, such as pharyngitis and lymphadenopathy.4 Antibody testing, the most common method to confirm a primary infection, can distinguish current from past infections. IgM antibodies are detectable 2 weeks after the onset of symptoms and persist for 4 to 6 months. IgG antibodies are detectable 2 to 3 weeks after the onset of symptoms and persist for life.11
Other testing options are available as well. Non-antibody tests may assess for active infection, but these do not differentiate primary infection from reactivation.11 Antigen detection provides a measurement of the CMV antigen in white blood cells.11 Polymerase chain reaction testing may also quantify a patient's viral load with high sensitivity and specificity.12
The level of patient viremia, or the viral load in a patient's blood, correlates with the likelihood of developing signs and symptoms and the infection severity.13 Besides blood, viral cultures can be utilized to test a patient's urine, stool, and tissue specimens. The low diagnostic yield and a longer testing period of up to 4 weeks, however, makes this test less ideal and may result in a delayed diagnosis or unfavorable outcomes.11 Biopsy and surgical pathology may also be utilized to determine if the issue is being caused by CMV or another infection, including hepatitis or pneumonia. These options may lead to a clearer diagnosis and an earlier intervention, preventing further complications such as organ failure.
Depending on the involved organ systems, supporting labs may be appropriate for additional assessments. For example, a complete blood cell count with differential may show lymphocytosis, anemia, or thrombocytopenia. Additionally, mild elevation of serum aminotransferases and bilirubin levels may be seen with hepatic involvement.11
Management and complications
In many healthy individuals, CMV is eradicated quickly and clinical manifestations are mild.4 Given the prevalence of the virus and its mild and self-limiting nature, standardized screening is not recommended in healthy adults, except women who are pregnant or seeking pregnancy, due to the risk of related complications.11
Treatment for adult patients with CMV is focused on supportive care, including rest, hydration, adequate nutrition, and antipyretics. Similarly, patient and family education on the signs and symptoms of infection, transmission prevention strategies such as frequent hand hygiene, and knowing when to seek care are also important. Current clinical guidelines do not recommend antiviral medication to treat CMV in these individuals. However, immuno-compromised patients and those with comorbidities, including ocular disease or severe systemic disease, are candidates for antiviral agents such as ganciclovir or valganciclovir.11
Considerations for antiviral therapy may include interactions with other medications, risk for drug toxicity, and the possibility of emerging resistance.14 I.V. administration of CMV-specific immunoglobulin has been found to reduce mortality for those who are immuno-compromised or critically ill.11
Individuals with CMV and comorbidities are at increased risk for myocardial infarction, stroke, and cardiovascular death.11 Additionally, CMV may be a contributing factor in the pathogenesis of vascular disease, including atherosclerotic coronary artery disease.15 Higher CMV IgG levels are associated with ischemic heart disease.15 Even asymptomatic CMV infections may predispose individuals to atherosclerosis, cancer, and immuno-senescence over the course of their lifetime.15
CMV seropositivity is associated with a decreased response to influenza vaccinations. This suggests that protection against CMV could improve vaccine response in older adults as a secondary benefit, with an inferred (but unproven) reduction in influenza risk.16,17
CMV reactivation is present in approximately 16% of patients with inflammatory bowel disease, such as ulcerative colitis or Crohn disease.18 Its prevalence is as high as 25% in patients with severe disease that require a colectomy.18
Chronic CMV is also associated with Alzheimer disease. A cohort study of patients with Alzheimer disease demonstrated that 89% of Black patients and approximately 68% of White patients were seropositive for CMV.19 These findings suggest that CMV may increase the risk of Alzheimer disease, but they should be interpreted with caution as more than half of the US population has CMV.4,20
Until recently, the literature has focused on CMV in children or immunosuppressed populations, but more information on the acute and long-term impact of CMV in relatively healthy adults is becoming available.9 Educating patients and families on transmission and signs and symptoms is vital, as evidence continues to support the prevalence of the infection.
In the meantime, nurses can assess patients for common signs and symptoms of the viral infection and obtain a comprehensive health history, including:
- personal or family history of CMV
- exposure to CMV-infected blood or body fluids
- immunocompromised status, as from HIV infection or recent organ transplant
- increased risk for exposure to blood or body fluids, as in nurses and childcare workers.
Searching for a vaccine
In 2000, the development of a CMV vaccine was a high priority according to the National Academy of Medicine (formerly the Institute of Medicine).21 Since then, several have gone through different stages of development, but none have been approved for clinical use.22 For example, multiple attempts have been made to develop CMV vaccines geared toward immunocompromised populations.21 Besides the prospect of improved outcomes for immunocompromised patients, some experts also support universal immunization.23 CMV is a risk factor for all-cause mortality in large population-based cohorts in both the US and Europe.23
A recent clinical trial of a potential CMV vaccine did not meet its primary or secondary endpoints to reduce overall mortality and end-organ disease through the first year following transplant.24 Nevertheless, efforts to develop an effective vaccine continue. Given the risks to children and immunocompromised adults and the long-term health effects of infection in otherwise healthy individuals, a CMV vaccine would be cost-effective and have a significant impact on overall public health.
Once his active CMV infection was diagnosed, JD received supportive care and felt better after 4 months. His viral load resolved, and he was positive for CMV IgG, indicating a seroconversion from the primary CMV infection.
JD returned to work shortly after his acute hospitalization. He tired easily over the next several months and required weekend recuperation, but he slowly built his stamina back up. Since his hospitalization, he has been monitored closely whenever he is ill. He has had several UTIs and another episode of pneumonia, but no new CMV infections have been identified.
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