Infectious Diseases

Cytomegalovirus

OVERVIEW: What every practitioner needs to know

Are you sure your patient has cytomegalovirus? What should you expect to find?

Human cytomegalovirus (CMV) infection can present with a large variety of symptoms depending on the host which is infected. The symptoms of CMV disease are determined largely by the end organ which is infected.

  • In congenital CMV infection, the disease is largely determined by a primary infection of the mother during pregnancy. The virus infects the placenta from the mother's blood and causes fibrosis and thrombosis of placental blood vessels. This interferes with the oxygen supply to the developing fetus and the result is severe congenital malformations. The infected baby may be born with microencephalopathy, CMV retinitis compromising vision and sensorineural deafness. CMV infection in utero is the leading cause of deafness in newborns in the USA.

  • In young adults, CMV is the cause of an infectious mononucleosis syndrome, characterized by diffuse lymphadenopathy, splenomegaly, fever, malaise and loss of appetite. It is not the usual picture of Epstein-Barr virus (EBV) mono, where a sore throat, adenopathy of the neck and occipital region may predominate. CMV mono is heterophile-negative with a negative monospot test.

  • In immunocompromised patients, CMV can reactivate or cause a primary infection with distinct features. Patients with AIDS may develop sight-threatening CMV retinitis, CMV encephalitis, transverse myelitis or severe colitis. Stem cell transplant patients or AIDS patients can develop severe viral pneumonia with a diffuse interstitial pattern on chest X-ray. This may be severe and not respond to antiviral treatment. In stem cell and solid organ transplant patients, the most common manifestation of CMV disease is a "CMV syndrome" characterized by fever, leukopenia, thrombocytopenia, and elevated liver function tests. In heart transplant patients, CMV may accelerate graft rejection and graft atherosclerosis, termed rejection vasculopathy. CMV infection may also present as viral myocarditis.

  • The key symptoms, physical findings and diagnostic findings of CMV disease are determined by the target organ of the CMV infection. These include the following:

    • CMV retinitis: This is a sight threatening retinal destructive infection with specific findings on ophthalmoscopic exam. A characteristic picture of retinal hemorrhage, white patchy exudates of destroyed retinal cells, edema, and loss of vision in peripheral fields is seen. A laboratory test for CMV DNA by polymerase chain reaction (PCR) in plasma is positive in 85% of cases.

    • CMV colitis: Severe watery diarrhea presents with lower abdominal pain. A colonoscopy reveals mucosal inflammation and mucosal ulcers. Biopsy of the ulcer tissue reveals nuclear inclusions, and CMV antigens can be detected by immunofluorescence assay.

    • CMV esophagitis: Immunocompromised patients can present with difficulty swallowing and pain with eating. Endoscopic exam reveals esophageal ulcers. Biopsy of ulcer shows intranuclear inclusions and CMV antigens are present.

    • CMV hepatitis: This is characterized by 4-fold to 10-fold rise in transaminases. The patient is rarely jaundiced, but the bilirubin may be mildly elevated. The rise in serum transaminase levels never approaches the high levels seen in Hepatitis A, B or C.

    • CMV pneumonia: This occurs most commonly following stem cell transplantation. It is characterized by a diffuse interstitial viral pneumonia which is frequently bilateral and gives a ground glass appearance on chest X-ray. CMV pneumonia blocks oxygen transport and leads to hypoxia. CMV pneumonia is life-threatening with a high mortality rate.

    • CMV adrenalitis: In AIDS patients, CMV can infect the adrenal glands, leading to tissue destruction and adrenal insufficiency. A patient may present with low blood pressure and findings of hypoaldosteronism, as well as a decrease in corticosteroids.

    • CMV meningo-encephalitis: A patient may present with a stiff neck and findings of a diffuse encephalopathic picture with confusion, decrease in cognitive function, and severe headache. A newborn may have microencephalopathy, and sensineural deafness.

    • CMV radiculopathy: In AIDS patients, CMV infection of the Schwann cells encasing spinal nerves may produce a polyradiculopathy. This may produce bilateral leg weakness, incontinence of bowel and bladder, and a cauda equina syndrome.

How did the patient develop cytomegalovirus? What was the primary source from which the infection spread?

  • The patient develops CMV disease following CMV primary infection or reactivation of latent infection. Following a primary infection, a patient carries CMV in a latent form all during their life. The CMV is latent in primitive hematopoietic cells of the monocytic series and possibly in vascular endothelial cells. The cellular immune system controls CMV and prevents CMV replication, but when cellular immunity is compromised by HIV, organ transplant, stem cell transplant, steroid medication, or chemotherapy, the virus can reactivate and cause end-organ disease. CMV is most frequently acquired as a young child by sharing saliva, or later by sexual transmission. CMV infected urine from a newborn infant, who can shed CMV in the urine for many months can also infect other family members. Evidence of CMV infection increases with increasing age, and by age 70, approximately 80% of healthy adults in the USA will test positive for CMV antibodies.

In the USA between 40-60% of adults are infected, and in developing counties as high as 80% of young adults with have evidence of CMV infection. Most will have no symptoms of CMV infection.

The basic epidemiology:

  • A neonate acquiring CMV infection is infected when the mother has a primary CMV infection during pregnancy. Reactivation of CMV during pregnancy may account for a small number of congenital CMV infections. The sero-negative mother may acquire primary CMV infection from another child, who is in day care and gets infected in day care, bringing the infection home to the household.

  • In solid organ transplant patients the biggest risk for infection is associated with a sero-negative recipient (R-) who acquires an organ from a sero-positive donor (D+). In stem cell transplant, the biggest risk is associated with the sero-negative donor (D-) who donates to the sero-positive recipient (R+). In AIDS patients, reactivation of latent CMV due to a decline in CMV-specific T cells as a result of HIV infection, leads to end-organ disease. A recent blood transfusion from a CMV positive donor, where the blood has not been filtered to remove infected white blood cells (WBCs) may also lead to infection with CMV.

  • In a healthy young adult, a recent history of a new sex partner or a new "kissing partner" may lead to the exchange of CMV infected cells and development of CMV-mononucleosis.

Which individuals are of greater risk of developing cytomegalovirus?

  • Specific conditions which predispose newborns to disease include a primary CMV infection in a mother during pregnancy, this needs to be explored via:

    • A careful history

    • Laboratory testing for recent CMV infection

      • Serum IgM antibodies for CMV and assays for CMV DNA

      • PCR assay for CMV DNA of amniotic fluid and blood

  • In solid organ transplant recipients:

    • A careful history for the CMV sero-positive status of the donor

    • The regimen of immune suppression employed should be explored

    • The CMV viral load determined by DNA PCR assay of blood should be measured

  • In stem cell transplant patients the greatest risk is the CMV negative donor(D-) giving stem cells to the CMV positive recipient(R+):

    • A careful history of the CMV ser0-positive status of donor and recipient

    • The regimen employed for ablation in the stem cell recipient should be explored as some regimens may be more efficient in reactivating CMV in the sero-positive recipient.

    • CMV viral load determined by DNA PCR assay of blood should be measure.

  • In AIDS patients, end-organ disease such as CMV retinitis or CMV colitis:

    • Occurs when the CD4+ cell count is less than 100/ml

    • DNA PCR assay of the blood should be measured

Beware: there are other diseases that can mimic cytomegalovirus:

  • In a newborn, CMV is the most common infectious cause of congenital malformations. Other diseases that can mimic some of the symptoms include:

    • Down's syndrome

    • Neonatal herpes simplex infection

    • Newborn HIV infection

  • In an AIDS patient:

    • HSV esophagitis may mimic CMV esophagitis

    • Mycobacterium intracellulare infection of the large bowel may mimic CMV colitis

    • Cotton wool spots on the retina may mimic CMV retinitis

    • In the central nervous system (CNS), HIV infection, diffuse HSV encephalitis, or multifocal leukoencephalopathy may mimic CMV meningoencephalitis.

    • Pneumocystis jiroveci pneumonia may mimic CMV pneumonia

  • In a transplant patient:

    • Graft versus host disease or early graft rejection

    • Sepsis may mimic the CMV syndrome

    • In a stem cell transplant, Pneumocystis jiroveci pneumonia may mimic CMV pneumonia

  • EBV mononucleosis with a positive monospot test may mimic CMV mononucleosis

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • The peripheral white blood count (WBC) will usually show a low WBC of 4000-6000; lymphocyte predominance of greater than 50% will be present on the differential. Atypical lymphocytes of 10% may be present in CMV mononucleosis.

  • CMV-induced hepatitis produces an increase in:

    • Serum transaminases to 4-10 fold above normal

    • A 2-3 fold elevation in alkaline phosphatase

    • Bilirubin may be mildly elevated, but frank jaundice is rare

    • CMV hepatitis may accompany primary CMV, CMV mononucleosis, or CMV reactivation in a transplant patient.

    • An elevation of hepatic enzymes is part of the CMV syndrome in transplant patients.

Results that confirm the diagnosis

  • Serum studies include:

    • A positive IgG antibody indicates CMV infection

    • The CMV IGgM antibody indicates a primary infection, but this may also be elevated in CMV reactivation

    • The presence of an immunofluorescent assay for CMV pp65 antigen in peripheral blood mononuclear cells indicates CMV viremia as does a CMV DNA PCR assay in plasma or blood.

      • The copy number for a positive CMV DNA PCR has a lower cut-off of 200 copies/ml depending on the laboratory test used. In July 2012, the first quantitative CMV DNA test was approved by the FDA(COBAS AmpliPrep/COBAS Taqman CMV Test{CAP/CTM CMV} and was calibrated to the WHO CMV International Standard. This test has a linear quantitation range from 150 to 10,000.000 copies/ml or 137 to 9100,000 IU/ml (1 copy=0.91IU)

      • In active CMV replication, the plasma viral load may be 5000-100,000 copies/ml

  • On biopsy specimens of the esophagus or the inflamed colon or bronchoalveolar lavage specimens:

    • The presence of macrophages or white cells with intranuclear inclusions depicting an "Owl's eye" appearance is diagnostic for active CMV replication.

  • In CMV pneumonia, broncholavage with a CMV DNA copy number of greater than 20,000/ml correlates well with positive histologic findings.

  • The measurement of CMV DNA viral load is becoming the gold standard for active CMV replication:

    • The CMV DNA by PCR in plasma is present in 85% of patients with CMV retinitis.

    • In CMV meningoencephalitis the detection of CMV DNA by PCR in CSF or pp65 antigen in mononuclear cells of the CSF are equivalent assays for CMV disease.

    • In biopsy specimens CMV DNA by PCR assay or the presence of CMV pp65 antigen in cells confirm a diagnosis of active CMV replication

    • The first FDA approved quantitative CMV DNA test (CAP/CTM CMV) and its calibration to the WHO CMV International standard will allow comparison between laboratory developed tests and enable clinicians to use the results in patient management decisions.

What imaging studies will be helpful in making or excluding the diagnosis of cytomegalovirus?

  • CMV Pneumonia: Chest X-ray may show a characteristic picture of diffuse interstitial pneumonitis.

  • Congenital CMV infection:

    • Abdominal computed tomography (CT) may show the profound hepato-splenomegaly seen in congenial CMV

    • Head CT may also reveal the microencephalopathy and the cerebral calcifications seen in babies with congenital CMV infection ($$)

  • CMV meningoencephalitis:

    • A head magnetic resonance imaging (MRI) can exclude HSV encephalitis since this usually presents with temporal lobe edema and hemorrhagic necrosis of the temporal lobe. CMV meningoencephalitis may show a diffuse encephalitis on brain MRI or show signs localizing to the thalamus ($$$$)

*($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has cytomegalovirus, what therapies should you initiate immediately?

Key principles of therapy:

  • Begin early treatment with IV ganciclovir or oral valganciclovir as soon as a diagnosis is established.

    • CMV DNA by PCR in the plasma as a measure of viral load can be followed to measure the effects of treatment.

    • If oral Valganciclovir is to be used, start at a dose of 900 mg po twice a day for 21 days as initial treatment

    • This is a loading dose and it can be reduced to 450mg po twice a day after 3 weeks.

    • For CMV retinitis, either IV ganciclovir or oral valganciclovir can be used.

      • An intraocular device impregnated with ganciclovir can be implanted by an ophthalmologist and is effective treatment.

    • For treatment of active CMV infection, ganciclovir is much superior to acyclovir.

    • If infection is associated with a ganciclovir-resistant strain of CMV, foscarnet is the treatment of choice. Treatment with ganciclovir or valganciclovir is usually continued for 3 weeks.

    • For very high viral loads of CMV, treatment is continued until CMV DNA by PCR is no longer detectable in the plasma.

  • In solid organ transplant patients, most centers would:

    • Start transplant recipients on CMV prophylaxis with valganciclovir for 3 to 6 months following kidney, heart, lung, or liver transplant.

    • In stem cell transplant centers:

      • ganciclovir prophyasis is not started because of the bone marrow suppressive side effects of ganciclovir.

      • preemptive therapy with ganciclovir in the absence of end organ disease is started when a CMV DNA by PCR assay is positive in blood or plasma, or the pp65 immunofluorescent assay for CMV antigens in peripheral blood mononuclear cells is positive.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

  • If CMV disease is suggested, empiric treatment with ganciclovir can be started as soon as diagnostic samples are obtained. This may be empiric treatment for CMV esophagitis, CMV retinitis,CMV colitis, or CMV meningo-encephalitis. For these disease manifestations, treatment should be begun if these infections are highly suspected.

  • For compromised renal function, the dose of ganciclovir should be adjusted.

  • If a co-infection of CMV and HSV is suspected, ganciclovir therapy should be employed as it will be effective against both CMV and HSV as well as against varicella-zoster virus (VZV).

Table I. Drugs for CMV

Table I.

Drugs for CMV
Drug Adult dosage
Valganciclovir-Valcyte 900mg PO bid for 21 daysfollowed by 900mg once per day
Ganciclovir-generic CytoveneVitasert implant 5mg/kg IV q12h for 14-21 daysfollowed by 5mg/kg IV once per day or 6mg/kg IV 5 times per week or 1 gram PO tid4.5mg intraocularly every 5-8 months
Foscarnet-generic Foscavir 60mg/kg IV q8h or 90mg/kg IV q12h for 14-21 days followed by 90-120 mg/kg IV once per day
Cidofovir-generic Vistide 5mg/kg IV once per week for 2 weeks then 5mg/kg IV q 2 wks

2. Next list other key therapeutic modalities.

  • What other therapies are helpful for reducing complications?

  • Other therapies which are approved for therapy of CMV disease are

  • Cidofovir and Foscarnet:

    • Foscarnet therapy is the treatment of choice for ganciclovir-resistant CMV infection.

    • Cidofovir is used to treat CMV retinitis in AIDS patients.To decrease risk of nephrotoxicity, pretreatment with IV fluids and oral probenecid must be given with each cidofovir dose

  • CMV immune globulin can be used in conjunction with ganciclovir to treat:

    • CMV pneumonia in stem cell transplant patients

    • primary CMV infection in pregnant mothers

    • prophylaxis in transplant patients

  • Controversial or evolving therapies:

  • Maribavir, a specific inhibitor of the CMV UL97 protein kinase enzyme and inhibitor of CMV egress has been effective in treating refractory or ganciclovir-resistant CMV disease. Maribavir is currently undergoing Phase Il trials in solid organ and stem cell transplant patients.

  • Letromovir, an inhibitor of CMV terminase, is under clinical development by Merck

  • There are experimental CMV vaccines undergoing trial, but none have been approved for clinical use.

What complications could arise as a consequence of cytomegalovirus?

What should you tell the family about the patient's prognosis?

  • Risk factors for a poor outcome are:

    • A patient with a very high CMV viral load detected by CMV DNA PCR assay

    • CMV pneumonia in stem cell transplant recipients has a very high mortality rate, in spite of treatment with ganciclovir and intravenous high titered CMV immunoglobulin.

    • Children with congenital CMV infection have a high morbidity from CMV congenital defects, such a microencephalopathy and CMV retinitis. Children with congenital CMV infection are also at risk to have sensineural hearing loss.

  • Patients with CMV retinitis may have loss of vision, in spite of therapy with ganciclovir.

  • Patients with neutropenia or thrombocytopenia may be unable to tolerate treatment with ganciclovir because of its bone marrow suppressive effects. If neutropenia develops while receiving ganciclovir, treatment with granulocyte colony stimulating factor (G-CSF) may be useful to correct this.

How do you contract cytomegalovirus and how frequent is this disease?

More detailed epidemiology:

  • CMV infection is contracted by being exposed to CMV infected urine or saliva as a child

  • CMV is also a sexually transmitted disease

  • CMV can be acquired by blood transfusion. Most CMV infections are asymptomatic.

  • In low socio-economic groups, CMV infection is more common and may reach 50% by age 20.

  • In the USA, about 65% of adults have evidence of CMV infection by seropositivity for CMV IgG antibody by age 45-50.

    • CMV seropositivity increases with age, and by age 80 in the USA, 75-80% of adults are positive.

  • In the transplant setting, the biggest risk for a CMV negative recipient (R-) is to acquire an organ from a CMV positive donor (D+), described as a D+ R- recipient.

  • In stem cell transplant patients, the greatest risk is a CMV negative donor (D-) and a CMV positive recipient (R+)

  • There is no seasonal variation for CMV infection.

  • Transmission occurs from exposure to a CMV-infected adult or child, which causes primary infection.

  • Reactivation of latent CMV infection occurs in immunocompromised individuals, especially those who have AIDS and those who are treated with immunosuppressive therapy.

  • There is no zoonotic transmission for human CMV; humans cannot be infected by animal strains of CMV.

What other clinical manifestations may help me to diagnose and manage cytomegalovirus?

The most helpful information for the clinician is to know the settings which make CMV disease a possibility. Primary CMV infection in a pregnant woman is a risk for congenital CMV. Advanced HIV infection with low CD4 counts is a risk factor for infection. Among recipients of solid organ transplants, the highest risk is receiving an organ from a CMV positive donor (D+) when the recipient is CMV negative (R-). In recipients of stem cell transplants, the greatest risk is when the donor is CMV negative (D-) and the recipient CMV positive (R+). A CMV DNA by PCR assay of blood or plasma is the best measure of active CMV replication or viremia.

How can cytomegalovirus be prevented?

CMV disease can be best prevented by the use of Ganciclovir as prophylaxis in the setting of AIDS to prevent recurrences of CMV retinitis or in organ transplantation to prevent disease. Preemptive therapy with ganciclovir is also effective for solid organ transplant recipients or stem cell transplant recipients. Preemptive therapy is started before CMV end organ disease has occurred by detection of CMV DNA in blood or detection of CMV pp65antigen in PBMCs. Preemptive therapy can be used following engraftment in stem cell transplant patients and avoids long term use of ganciclovir prophylaxis and the bone marrow toxicities of ganciclovir

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

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Merigan, TC. "A controlled trial of Ganciclovir to prevent CMV disease after heart transplantation". N.E.J.M. 1992. pp. 1182-1186.

Emanuel, D. "Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination for Ganciclovir and high dose intravenous immune globulin". Ann. Int. Med. 1988. pp. 783-788.

Caliendo, AM. "Distinguishing cytomegalovirus (CMV) infection and disease with CMV nucleic acid assays". J.Clin. Microbiol.. vol. 40. 2002. pp. 1581-1586.

Hirsch, HH. "An international multicenter performance analysis of cytomegalovirus load tests". Clin Infectious Diseases. vol. 56. 2013. pp. 367-373.

Boeckh, M, Ljungman, P. "How I treat cytomegalovirus in hematopoietic cell transplant recipients". Blood. vol. 113. 2009. pp. 5711-5719.

Kotton, CN. "Transplantation Society International CMV Consensus Group: International consensus guidelines on the management of cytomegalovirus in solid organ transplantation". Transplantation. vol. 7. 2010. pp. 779-795.

Martin, DF. "Treatment of cytomegalovirus retinitis with an intraocular sustained release ganciclovir implant. A randomized controlled clinical trial". Arch. Ophthalmol.. vol. 112. 1994. pp. 1531-1539.

Mills, J. "Treatment of cytomegalovirus retinitis in patients with AIDS Rev". Infect. Dis. vol. 3. 1988. pp. 5522-5531.

Spector, SA. "Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS". N.E.J.M.. vol. 334. 1996. pp. 1491-1497.

Winston, DJ. "Randomized comparison of ganciclovir and high dose acyclovir for long-term cytomegalovirus prophylaxis in liver-transplant recipients". Lancet. vol. 346. 1995. pp. 69-74.

Schmidt, GM. "A randomized controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants". N.E.J.M.. vol. 324. 1991. pp. 1005-1011.

Boeckh, M. "Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation. A randomized double-blind study". Blood. vol. 88. 1996. pp. 4063-4071.

Stagno, S. "Congenital cytomegalovirus infection. The relative importance of primary and recurrent infection". N.E.J.M.. vol. 306. 1982. pp. 945-949.

Ljungman, P. "Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous gamma globulin.Experience of European bone marrow transplantation Clin". Infect Dis. vol. 14. 1992. pp. 831-835.

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