Cytomegalovirus infection

Are You Confident of the Diagnosis?

Symptomatic infection with human cytomegalovirus (CMV) may occur in the newborn or in immunocompromised individuals, including those infected with HIV/AIDS, hematopoietic stem cell transplant (HSCT) recipients, and organ transplant recipients. Symptoms of infection with CMV in such populations are extremely variable. Immunocompetent individuals rarely exhibit any symptoms of disease other than a mild mononucleosis-like syndrome. In this chapter, CMV is classified in the following manner: cytomegalic inclusion disease of the newborn, CMV mononucleosis in the immunocompetent population, CMV in transplant recipients, and CMV in the AIDS population.

  • Characteristic findings on physical examination

Congenital CMV disease is the most common cause of intrauterine infection in humans, and congenital infection is the leading infectious cause of deafness and mental retardation in the US. Cytomegalic inclusion disease of the newborn occurs after primary or recurrent infection of a pregnant woman followed by vertical transmission of the disease to the fetus. Since CMV is usually asymptomatic in immunocompetent adults, diagnosis of CMV infection in a pregnant woman using clinical manifestations alone is quite difficult. Of pregnant women with primary CMV infection, less than 5% exhibit symptoms of infection. Suspicion of CMV infection in the fetus may occur when certain ultrasound findings are seen, but only 5-25% of fetuses infected with CMV exhibit such findings. The findings include echogenic bowel, ascites, fetal hydrops, intracranial or liver calcifications, microcephaly, pleural effusion, and early onset intrauterine growth restriction.

If primary maternal infection occurs during pregnancy, especially during the first trimester, the rate of transmission is about 40%, compared with only 1% following secondary infection. Ten to fifteen percent of congenitally-infected infants will have symptoms at birth including intrauterine growth retardation, microcephaly, cerebral atrophy, jaundice, thrombocytopenia, seizures, hepatosplenomegaly, intracranial calcifications, petechiae, and a “blueberry muffin” appearance secondary to extramedullary erythropoiesis (Figure 1). About 5% of these infants will die, primarily of disseminated intravascular coagulation, hepatic dysfunction, or bacterial superinfection. Of the ones who survive, studies estimate that 60-90% will develop long-term neurological sequelae including sensorineural hearing loss (unilateral and bilateral), mental retardation, cerebral palsy, paraparesis, and impaired vision or blindness from chorioretinitis.

Figure 1.

“Blueberry muffin” infant.

Most congenitally-infected infants (85-90%) have no signs or symptoms at birth. However, 7-15% of clinically asymptomatic patients may develop late sequelae, including sensorineural hearing loss, which is by far the most common sequela. In the fetus, the presence of ultrasound findings suspicious for CMV infection should prompt immediate testing of the fetus.

CMV infection in immunocompetent patients results from acute primary infection with CMV, most commonly in the form of CMV-induced mononucleosis. CMV infection should be suspected in a patient with fever, fatigue, and malaise without any physical examination findings or historical features pointing to a specific diagnosis. The syndrome is clinically indistinguishable from Epstein-Barr Virus (EBV) infectious mononucleosis. There are no characteristic findings on physical examination that definitively establish or suggest the diagnosis of CMV infection. Similar to EBV infection, 80-100% of patients develop a maculopapular, morbilliform eruption when given ampicillin (or other penicillins) during the illness.

Other possible skin eruptions independent of antibiotic administration include erythema nodosum, erythema multiforme, cutaneous vasculitis, vasculopathy, and scleroderma without inclusion bodies. Also similar to EBV infection, patients infected with CMV may have atypical lymphocytes and mild transaminitis, but the heterophile spot test in patients with CMV is negative. The course of the disease is usually benign and self-limited. Rarely, complications may develop which include hemolytic anemia, splenic infarction, interstitial pneumonia, thrombocytopenia, Guillain-Barre syndrome, meningoencephalitis, myocarditis, arthritis, pleuritis, and syndromes involving the gastrointestinal or genitourinary systems.

CMV is one of the most common infections occurring in organ transplant and hematopoietic stem cell transplantation (HSCT) recipients. Without appropriate prophylaxis, as many as 30-80% (depending on donor and recipient serological status) of these patients may experience CMV infection. Patients that have received liver, kidney, or heart transplants may exhibit either CMV syndrome or progress to tissue-invasive CMV disease, the latter resulting in end organ damage. CMV syndrome presents with transient fever and malaise frequently associated with leukopenia or thrombocytopenia. It should be noted, however, that fever may be absent in patients receiving high-dose immunosuppression. Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, nephritis, hepatitis, encephalitis, myocarditis, and retinitis, etc.). Presentation with hepatitis, leukopenia, and pneumonitis is referred to as the “deadly triad,” and these patients often succumb to bacterial or opportunistic superinfections that most commonly infect the lung.

In patients who have received allogenic bone marrow transplants, CMV onset occurs between 50-70 days after transplantation. Of the patients that become infected with CMV, pneumonia is the most serious complication with a mortality of more than 50%. Newer prophylactic regimens, however, have reduced the incidence to fewer than 5% of allogeneic HSCT recipients. Additionally, due to ganciclovir prophylaxis and pre-emptive treatment, CMV disease has become a more significant problem after day 100 of transplantation. In both hematopoietic and solid organ transplant recipients, infection with CMV is a major risk factor for invasive bacterial and fungal infections. Overall, CMV increases the risk of graft rejection and decreases the ability of the host’s immune system to defend against infection.

Since the advent of highly active anti-retroviral therapy (HAART), the incidence of CMV disease in the AIDS population has decreased. Many HIV patients are infected with CMV, however, CMV disease usually only occurs in those with severe immunodeficiency. The mean CD4 count at diagnosis is less than 25/mm3.

CMV retinitis is the most frequent form of CMV disease in AIDS patients, accounting for 80-90% of CMV disease in that patient population, followed by infection of the gastrointestinal tract. Clinical symptoms of CMV retinitis include floaters, blurry vision, and the loss of visual field proportions. It is a painless condition but may progress rapidly to blindness if not evaluated and treated promptly. On fundoscopic examination, one may visualize a yellow-white exudate with hemorrhage or a white granular lesion.

Infection of the gastrointestinal tract can result in CMV colitis with symptoms of diarrhea, hematochezia, and abdominal pain that may progress to perforation of bowel. CMV esophagitis presents with odynophagia. CMV inclusions are found in endothelial cells when biopsy is performed. CMV can affect the nervous system as a polyradiculopathy that causes bowel and bladder dysfunction accompanied by lower extremity weakness or MRI findings that show periventricular enhancement. CMV encephalitis is generally indistinguishable from HIV encephalitis.

In the immunocompromised patient, the most common skin lesions are ulcers (Figure 2), usually on the perianal area and buttock. These cutaneous ulcerations are the result of CMV infection of the vascular endothelium and subsequent destruction of blood vessels. Other cutaneous manifestations that have been reported include purpura, petechiae, morbilliform eruption, maculopapular rash, vesicles, and indurated plaques and nodules (Figure 3, Figure 4, Figure 5).

Figure 2.

An ulcer in an AIDS patient with CMV infection. Reproduced from Boldogh I, Patel JA, Tyring SK, Chonmaitree T. Cytomegalovirus. In: Tyring SK, Moore AY, Lupi O, editors. Mucocutaneous manifestations of viral diseases (2nd edition). United Kingdom: Informa; 2010. pp 145-164, with permission.

Figure 3.

Cutaneous manifestations of CMV in immunocompromised patient. Reproduced from Boldogh I, Patel JA, Tyring SK, Chonmaitree T. Cytomegalovirus. In: Tyring SK, Moore AY, Lupi O, editors. Mucocutaneous manifestations of viral diseases (2nd edition). United Kingdom: Informa; 2010. pp 145-164, with permission.

Figure 4.

Cutaneous manifestations of CMV in immunocompromised patient. Reproduced from Boldogh I, Patel JA, Tyring SK, Chonmaitree T. Cytomegalovirus. In: Tyring SK, Moore AY, Lupi O, editors. Mucocutaneous manifestations of viral diseases (2nd edition). United Kingdom: Informa; 2010. pp 145-164, with permission.

Figure 5.

Cutaneous manifestations of CMV in immunocompromised patient. Reproduced from Boldogh I, Patel JA, Tyring SK, Chonmaitree T. Cytomegalovirus. In: Tyring SK, Moore AY, Lupi O, editors. Mucocutaneous manifestations of viral diseases (2nd edition). United Kingdom: Informa; 2010. pp 145-164, with permission.

  • Expected results of diagnostic studies

Tissue diagnosis of CMV infection is very specific, but not sensitive. On histology, CMV is characterized by the “owl’s eye” appearance representing inclusion bodies within infected endothelial cells (Figure 6). As the name cytomegalovirus suggests, the cells are enlarged 2 to 3 times their normal size, contain large intranuclear inclusions, and are surrounded by a clear halo. Confusion may occur because the inclusions appear similar to those seen in herpes simplex virus and varicella zoster virus infection.

Figure 6.

“Owl’s eye” appearance of nuclear inclusion bodies within infected endothelial cells. Reproduced from Boldogh I, Patel JA, Tyring SK, Chonmaitree T. Cytomegalovirus. In: Tyring SK, Moore AY, Lupi O, editors. Mucocutaneous manifestations of viral diseases (2nd edition). United Kingdom: Informa; 2010. pp 145-164, with permission.

The most accurate method to test for fetal infection with CMV is amniocentesis after 21 weeks’ gestation with CMV polymerase chain reaction (PCR) amplification, which is 90% sensitive and specific. Detection cannot predict severity of disease. In the newborn, the most accurate test is the isolation of CMV in urine. CMV may be shed in the urine of children infected as newborns for up to 8 years.

Other diagnostic modalities include tissue culture, histologic-cytologic detection, immunologic methods, nucleic acid testing, and antigen detection. Conventional culture has largely been replaced by shell vial culture using fluorescein-labeled antibodies due to its advantage of yielding results in several days as compared to weeks with comparable sensitivity. CMV can be isolated for tissue culture in urine, saliva, breast milk, stool, semen, cervical secretions, and peripheral blood, but urine and saliva are the most commonly used.

Other diagnostic methods include immunofluorescence with monoclonal antibodies specific to the pp65 antigen in leukocytes and radiolabeled or biotin-labeled DNA or RNA probes. Such methods use peripheral blood cells, autopsy tissue, biopsies, and amniotic cells. Serologic modalities include complement fixation, enzyme-linked immunosorbent assay (ELISA), hemagglutination inhibition, and latex agglutination assay.

Who is at Risk for Developing this Disease?

All persons are at risk of developing CMV infection, but those at risk of developing disease include newborns, fetuses, immunocompromised individuals, and HIV/AIDS patients. CMV virus is ubiquitous worldwide, with seroprevalence varying geographically. In developing countries, seroprevalence rates can reach close to 100%, while in developed countries only about 50% of adults have evidence of infection. In the US, higher rates are associated with older age, female gender, and lower household income. Sixty to eighty percent of infected humans exhibit no clinical symptoms. Approximately, 0.2-2.5% of newborns in the US each year have congenital CMV infection, but 90% are asymptomatic.

In the US, CMV seroprevalence is 25-30% higher in Hispanic blacks and Mexican Americans than non-Hispanic whites. CMV seroprevalence is 15-20% higher in lower- and middle-income households when compared with higher income households. Newborns with congenital CMV also exhibit similar seroprevalence as mentioned above for the general population. Poor, non-white mothers are more likely to have children with congenital CMV infection.

Sexual transmission also appears to play a role in CMV infection, as individuals with sexual risk factors, including multiple partners, male homosexuals, and a history of sexually transmitted diseases, are more likely to be infected with CMV. Females have been shown to have a higher seroprevalence compared with males.

CMV infection that occurs in childhood is asymptomatic and frequently occurs in the day care setting, where transmission of saliva and other secretions is more common. In immunocompetent adults, the virus is transmitted through secretions, which are more likely to occur during sexual activity or intimate physical interactions. Blood transfusion carries a 3-4% risk of CMV transmission; however, since CMV is carried in polymorphonuclear lymphocytes, the use of leukocyte-depleted or cryopreserved blood decreases the risk and is particularly useful when transplant recipients require transfusion.

HIV patients with low CD4 counts are more susceptible to CMV disease. As mentioned previously, the mean CD4 count of HIV patients diagnosed with CMV disease is less than 25/mm3. This should be distinguished from CMV positivity, in which patients are not symptomatic, and may occur in HIV patients with any CD4 count.

Transplant recipients are at risk for development of CMV disease and there are three patterns of transmission. Ninety-five percent of organ transplant recipients are infected with CMV when seropositive, latently infected, donor cells are transferred to a seronegative recipient. The incidence of CMV disease in these patients is 50-65%. The second pattern of infection is when a seropositive recipient undergoes reactivation of latent CMV infection. The incidence of symptomatic disease is 10-20%. The third pattern of CMV infection in transplant recipients is referred to as superinfection. It occurs when a seropositive donor allograft is transplanted into a seropositive recipient. The incidence of disease in these patients is 15-25%.

What is the Cause of the Disease?

  • Etiology

CMV, or human herpes virus 5, is a DNA virus that belongs to the family Herpesviridae and the subfamily Betaherpesvirinae. The virus enters the human host through mucosal surfaces of the upper respiratory tract, gastrointestinal tract, and urogenital tract. Thus, possible sources of infection include oral secretions, urine, breast milk, semen, and cervical and vaginal secretions. Indirect transmission can occur via contaminated fomites.

The virus uses polymorphonuclear cells to disseminate through the body and may spread to infect various organs. In the fetus and neonate, CMV infection most commonly involves salivary glands and neurons. In immunocompetent individuals, the virus typically infects lymphoid tissues. In immunocompromised patients infected with CMV, the virus targets the lungs or other organs.

  • Pathophysiology

Upon infection of cells, CMV causes cytomegaly and condensation of the nuclear mass, while infection of organs results in inflammation and resultant organ dysfunction. Lung infection results in cytomegaly and nuclear inclusion bodies accompanied by inflammation. in cutaneous ulcerations, nuclear inclusions are found in capillary endothelial cells. In the gastrointestinal tract, ulcerations occur that can result in hemorrhage and bowel perforation with resultant pneumatosis intestinalis. In the liver, CMV infection causes mild to moderate hepatitis in 30-50% of transplant patients and abnormal liver function tests are common. Cytomegalic cells are also found in the bile duct epithelium of newborns infected with CMV.

It is possible that CMV causes immunosuppression by decreasing the ratio of helper T lymphocytes to suppressor lymphocytes. Furthermore, CMV has been found in various human tumors, implicating it as a possible contributor to tumorigenesis. In immunocompetent adults, CMV clears within a few months of the primary infection, evades the host immune system to remain latent, and can reactivate at any time.

Systemic Implications and Complications

In the immunocompetent patient infected with CMV, there are generally no systemic complications. In the AIDS patient, systemic complications include CMV retinitis, CMV colitis, and CMV esophagitis. Therapy involves early diagnosis and aggressive treatment. CMV retinitis is diagnosed by fundoscopic examination and should be performed if clinical symptoms are suggestive of disease. A low threshold should be maintained for ophthalmologic evaluation because CMV retinitis rapidly causes blindness.

CMV colitis and esophagitis are diagnosed by endoscopy with biopsy showing cytomegalic inclusions. In the transplant patient, systemic complications occur as a result of CMV infection and include severe, life-threatening bacterial, fungal, or opportunistic infection. Therapy involves early diagnosis of such infections and aggressive treatment.

Treatment Options

No antiviral therapy is recommended for the treatment of congenital CMV infection. There are no surgical procedures or physical modalities in the treatment of CMV. The medical treatment options in Table I are for CMV-infected AIDS patients and transplant recipients.

Table I.
Intravenous ganciclovir 5mg/kg once daily (oral dose: 100mg 3 times daily with food–not as effective)
Oral valganciclovir Treatment of CMV retinitis:Induction: 900mg by mouth twice daily with food.Maintenance: 900mg by mouth once a dayPrevention of CMV disease: 900mg by mouth once daily within 10 days of transplantation until 100 days post-transplantation
Intravenous foscarnet Induction: 180mg/kg/day (adjust dose based on creatinine clearance)Maintenance: 120mg/kg/day (adjust dose based on creatinine clearance)
Intravenous cidofovir Induction: 330µg (one injection every other week x three doses)Maintenance: 330µg (one injection every 4 weeks after induction therapy)
Fomivirsen Induction: 5mg/kg weekly x 2 consecutive weeks (adjust dose based on creatinine clearance)Maintenance: 5mg/kg once every 2 weeks (adjust dose based on creatinine clearance)
Interferon (not FDA approved)
Intravenous immunoglobulins (not FDA approved)

Optimal Therapeutic Approach for this Disease

The therapeutic approach for CMV infection should include prevention and treatment.

Prevention of CMV infection in immunocompromised patients who have not yet been infected begins with selection of appropriate blood products. CMV antibody-negative donor blood should be used in this population. Prophylactic treatment of immunocompromised individuals and transplant patients with cytomegalovirus immune globulin (CMVIG) has been shown to decrease the rate and severity of CMV disease and complications of infection. It does not prevent primary infection with CMV. There are two CMV vaccines in clinical trials: CMV gB/MF59 subunit vaccine and a live, attenuated, high- passage Towne strain vaccine. Both vaccines have been shown to induce neutralizing antibodies. Other vaccines in development include a DNA vaccine carrying phosphoprotein 65 and glycoprotein B as well as the CMV-MVA vaccine which places three small pieces of CMV DNA in a weakened virus called MVA. These vaccines are currently in phase III and II trials respectively.

First-line treatment for CMV infection that is life-threatening or threatening to vision is ganciclovir, which is an acyclic nucleoside analogue of guanine. It suppresses active infection through inhibition of DNA synthesis, but does not cure CMV infection. It is more bioavailable in the intravenous formulation, which is best for the initiation of treatment of CMV disease. Oral ganciclovir is less effective, but is most commonly used for long-term maintenance. Treatment with ganciclovir is recommended in immunocompromised patients infected with CMV and prophylaxis of CMV in transplant recipients.

Valganciclovir, a prodrug of ganciclovir, is available orally and has significantly increased bioavailability compared to ganciclovir, with similar safety and efficacy profiles. Valganciclovir has been approved for the treatment of CMV retinitis in adult patients with AIDS, as well as for prophylaxis of CMV disease in organ transplant recipients. It is the drug of choice in mild to moderate CMV disease. Side effects of ganciclovir include thrombocytopenia, neutropenia that is reversible, azoospermia, renal insufficiency, and central nervous system (CNS) symptoms.

Although still uncommon, ganciclovir resistance in CMV has been increasing in frequency. The second-line agent for treatment of CMV infections, specifically CMV retinitis in AIDS patients, is foscarnet. It is also virustatic and inhibits DNA replication but has a different mechanism of action from ganciclovir. It is effective against ganciclovir-resistant CMV strains and is non-toxic to bone marrow. It is administered intravenously. Side effects include renal dysfunction (dose-limiting), electrolyte abnormalities, genital ulceration from excretion in urine (Figure 7), nausea, vomiting, CNS disturbances, and deposition in bone, teeth, and cartilage.

Figure 7.

Genital ulceration from excretion of foscamet in urine. Reproduced from Boldogh I, Patel JA, Tyring SK, Chonmaitree T. Cytomegalovirus. In: Tyring SK, Moore AY, Lupi O, editors. Mucocutaneous manifestations of viral diseases (2nd edition). United Kingdom: Informa; 2010. pp 145-164, with permission.

Cidofovir is an acyclic nucleoside phosphonate approved for treatment of CMV retinitis in patients who cannot take ganciclovir or foscarnet. It is administered intravenously with probenecid to protect the kidneys from failure. Side effects include nephrotoxicity, neutropenia, metabolic acidosis, and ocular hypotonia.

Experimental antiviral drugs being developed or considered for use in CMV resistant to ganciclovir are foscarnet, cidofovir letermovir, CMX-001 (orally available lipid prodrug of cidofovir), cyclopropavir, artesunate, and leflunomide.

Fomivirsen is an oligonucleotide recommended for treatment of CMV retinitis in HIV/AIDS patients via intravitreal injection in patients who can no longer receive other therapies for any reason. Side effects include inflammation of eye and increased intraocular pressure.

Patient Management

In the immunocompetent patient, it may not be necessary to go beyond explanation of the natural history of CMV.

In parents of newborns infected with CMV, explanation of the natural history and reassurance that they are not at fault for development of CMV in their newborn is necessary. Explanation of CMV seroprevalence may also be helpful. Parents should be counseled in preparation for a child who may have developmental delays and hearing loss.

In the HIV population, the importance of HAART therapy should be stressed because preservation of a normal CD4 count will prevent CMV disease. Once a patient reaches lower CD4 counts, it is important to explain the possibility of CMV disease, including signs and symptoms of disease.

For transplant recipients, in addition to explanation of CMV natural history, discussions about vaccine development, selection of appropriate donor products, and prophylactic therapy options should occur.

Unusual Clinical Scenarios to Consider in Patient Management

An unusual scenario that may be encountered is in the AIDS population. Such patients may present with anogenital lesions that are mistaken for herpes simplex infection. The lesions are treated as herpes simplex virus, but do not improve. Biopsy reveals CMV or herpes simplex virus resistant to acyclovir. Treatment with cidofovir is usually successful.

What is the Evidence?

Cannon, MJ.. “Congenital cytomegalovirus (CMV) epidemiology and awareness”. J Clin Virol. vol. 46. 2009; Dec. pp. S6-S10. (A thorough review of recent literature detailing epidemiology of CMV infection, including seroprevalence and transmission rates, in the US.)

Cannon, MJ, Schmid, DS, Hyde, TB.. “Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection”. Rev Med Virol. vol. 20. 2010. pp. 202-13. (A thorough literature review discussing seroprevalence and demographics of pregnant and non-pregnant women and relating this to congenital CMV infection.)

Feldman, DM, Timms, D, Borgida, AF.. “Toxoplasmosis, parvovirus, and cytomegalovirus in pregnancy”. Clin Lab Med. vol. 30. 2010. pp. 709-20. (The third section of this manuscript focuses on maternal and fetal infection with CMV, including a discussion of diagnosis and treatment.)

James, WD, Berger, TG, Elston, DM. Andrews' disease of the skin clinical dermatology. 2006. (The section on cytomegalovirus in this text focuses on dermatologic manifestations.)

Boldogh, I, Patel, JA, Tyring, SK, Chonmaitree, T., Tyring, SK, Moore, AY, Lupi, O. “Cytomegalovirus”. Mucocutaneous manifestations of viral Diseases. 2010. pp. 145-64. (A thorough and concise discussion of cytomegalovirus with exceptional photographs of disease manifestations.)

Gorbach, SL, Bartlett, JG, Blacklow, NR. Infectious diseases.

(A useful search engine to determine FDA-approved dosages of medications.)

Ramanan, P, Razonable, RR.. “Cytomegalovirus Infections in Solid Organ Transplantation: A Review”. Infect Chemother.. vol. 45. 2013 Sep. pp. 260-271. (Review article on the epidemiology, prevention, diagnosis, and treatment of CMV infection in transplant patients.)

Boeckh, M, Gilbert, PB.. “Search Continues for a CMV Vaccine for transplant recipients”. Lancet. vol. 3. 2016 Feb. pp. 58-59. (Discussion of previous and current vaccines under development for CMV in transplant setting.)

Wang, D, Fu, TM.. “Progress on human cytomegalovirus vaccines for prevention of congenital infection and disease”. Curr Opin Virol.. vol. 6. 2014 Jun. pp. 13-23. (Article discussing vaccines for congenital CMV infection as well as information on epidemiology and presentation of congenital CMV infection.)