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.

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• 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