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Home , Cytomegalovirus, Herpesviridae

Cytomegalovirus GREGORY H. TAYLOR, M.D., University of Maryland School of Medicine, Baltimore, Maryland

Cytomegalovirus (CMV) is a prevalent viral . The majority of persons with acute CMV will experience an inapparent . Primary CMV infection will O A patient informa- cause up to 7 percent of cases of mononucleosis syndrome and will manifest symp- tion handout on cyto- megalovirus, written toms almost indistinguishable from those of Epstein-Barr -induced mononucle- by the author of this osis. CMV, or heterophil-negative mononucleosis, is best diagnosed using a positive article, is provided on IgM serology. Complications of acute CMV infection in immunocompetent persons page 526. are rare, except in newborns. The virus usually is spread through close personal con- tact; risk can be reduced by following simple hygienic and handwash- ing techniques. Severe illness can occur after reactivation of the latent virus in immunosuppressed persons. The retina is the most common site of CMV-induced pathology in persons with human immunodeficiency virus infection. Advances in the treatment of human immunodeficiency virus infection with highly active antiretrovi- ral therapy (HAART) have decreased the incidence of CMV but have resulted in a new set of ophthalmologic complications induced by restoration of immune competency and the pro-inflammatory response of the patient to CMV. If HAART restores the patient’s CD4 cell count to above 100 to 150 per mm3 (100 to 150 106 per L), it may preclude lifelong treatment for CMV retinitis. (Am Fam Physician 2003;67:519-24,526. Copyright© 2003 American Academy of Family Physicians.)

ytomegalovirus (CMV) is a CMV is not highly contagious. It is con- prevalent pathogen, with 40 to tracted from close personal contact with peo- 100 percent of the general ple who excrete the virus in their body fluids population showing prior (e.g., saliva, urine, blood, breast milk, semen, exposure by serology.1 Up to and even transplanted organ tissue). It also 20C percent of children in the United States can be shed from the throat and uterine will have contracted CMV before puberty. cervix. Children may in turn be reinfected with dif- Initial infection in newborns and reactiva- ferent strains of the virus.2 Infection also is tion of the virus in immunocompromised common during adolescence, which directly persons can result in severe pathology. CMV corresponds to the start of sexual activity. also is a serious pathogen in patients who have CMV is a member of the received an organ transplant. family, which includes the Epstein-Barr virus Day care workers are at increased risk of (EBV), virus, varicella-zoster acute CMV infection, especially those who virus, and herpesvirus 6, 7, and 8. work with children under two years of age.2,3 Primary infection is usually inapparent. In this setting, CMV is most likely spread As with other herpes , CMV remains through close contact with infected children latent within the host, reactivating and and subsequent, inadequate handwashing.4 shedding when the host’s immune system is The higher rates of acute CMV infection compromised. among adolescents and day care workers are of concern because of the resultant congenital infection in women who contract primary Cytomegalovirus is not highly contagious and is contracted CMV while pregnant. Health care workers from close personal contact with persons who excrete the who treat patients with known, active CMV infection seem to be at no greater risk of con- virus in their bodily fluids. tracting CMV than the general population.5 Family physicians are most likely to encounter

FEBRUARY 1, 2003 / VOLUME 67, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 519 festations typical of EBV-induced mono- Cytomegalovirus-induced mononucleosis can be symptomati- nucleosis (e.g., lymphadenopathy, spleno- cally indistinguishable from Epstein-Barr virus-induced megaly, pharyngeal ) also can occur with CMV (Table 1), although less frequently. 8 mononucleosis. Patients with mononucleosis may present with nonspecific skin (e.g., generalized maculopapular, urticarial, and scarlatiniform CMV during the work-up of patients present- rashes).9 These rashes are not a direct cause of ing with an syn- CMV proliferation within the skin but are the drome, acute , or as an opportunistic result of an immunologic response to the infection in persons with human immunode- virus.10 The classic hypersensitivity drug ficiency virus (HIV) infection. associated with ampicillin therapy given to patients with EBV-induced mononucleosis also CMV Infection can occur in CMV-induced mononucleosis. A typical mononucleosis syndrome consists Elevation of transaminase levels is a of an acute febrile illness with an increase of common feature of acute CMV infection, oc- 50 percent or more in the number of lympho- curring in up to 92 percent of patients, and cytes or , with at least 10 percent of often it can be mistaken for acute hepatitis. In the lymphocytes being atypical. Five to 7 per- contrast to other viral causes of hepatitis, cent of immunocompetent patients with this patients with CMV are anicteric, and their syndrome who present to a physician’s office aspartate transaminase and alanine transami- will have acute CMV infection.6 nase levels rarely go above five times their nor- CMV-induced mononucleosis can be symp- mal ranges.11 Other laboratory abnormalities tomatically indistinguishable from EBV- found in association with acute CMV infec- induced mononucleosis.7 , fever up to tion include anemia, , and 39.4°C (103.0°F), chills, sore throat, headache, positive cold agglutinins.12 and fatigue can be the predominant features of Guillain-Barré syndrome related to CMV both viruses. Many of the same clinical mani- has been documented, as have the much less frequent complications of , myo- carditis, or fulminant hepatitis.13 These severe TABLE 1 complications rarely appear in immunocom- Presentations of Acute Cytomegalovirus Infection petent persons. As of 1996, only 34 cases of in a Normal Person severe organ involvement of the brain, , liver, or lungs have been documented.14 Common Less common Rare * Exudative Icteric hepatitis Diagnosis Mononucleosis syndrome Splenomegaly Guillain-Barré syndrome Any febrile illness in which more than Fever Cervical adenopathy Encephalitis 10 percent of the patient’s lymphocytes are Malaise Nonspecific rash atypical should raise the suspicion of Sore throat Anemia Pneumonitis mononucleosis. Though EBV will be the Headache Increased levels on liver causative agent in the majority of cases, the function tests differential diagnosis includes CMV, toxoplas- mosis, acute , human her- Antibiotic rash pesvirus 6, and drug reaction.15 Acute HIV infection also may present as a mononucleo- *—Most common presentation. sis-like syndrome, but HIV-infected patients lack the atypical lymphocytosis.

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The possibility of acute CMV infection culture is not useful in the diagnosis of pri- should be explored if a negative heterophil mary CMV infection, because a positive test antibody test rules out EBV mononucleosis. may just reflect via a transient CMV infection, serum sickness, or another reactivation from the latent state. High quan- viral illness rarely causes a false-positive het- tities of circulating CMV by PCR in the im- erophil antibody test. The best diagnostic test for establishing CMV mononucleosis is serol- ogy for CMV IgM antibodies, which should be positive in the majority of patients during Acute Mononucleosis Syndrome the symptomatic phase of the illness. How- ever, antibodies may not peak until four to Mononucleosis-like illness seven weeks into the infectious process. In contrast to many other viral illnesses, the IgM Monospot Positive for EBV antibodies produced in response to acute CMV infection may remain elevated for up to one year or longer following acute infection in Negative up to 20 percent of patients. This may make it confusing to rule out CMV infection as the cause of a fever. In infected patients, the level Lymphocytosis or No lymphocytosis of IgG antibodies to CMV should continue to >10% atypical or <10% atypical increase at least fourfold during acute infec- tion. Therefore, monitoring the IgG antibody EBV IgM Risk factors for HIV p24 antigen, level is the best method to determine that HIV viral RNA, or HIV DNA* CMV is the cause of fever in these cases. CMV IgM tests typically cost between $66 and $98. Thus, it may not be prudent to order Positive Negative an entire panel of serologies at once in patients presenting with mononucleosis symptoms. A EBV mononucleosis CMV IgM cost-effective testing algorithm was developed for managing these patients who are het- erophil-negative (Figure 1).15 Patients who were Monospot-negative were categorized into Positive Negative those with or without an absolute lymphocy- tosis or greater than 10 percent atypical lym- CMV mononucleosis , , B, C, phocytes. EBV IgM testing was ordered on or † those with positive parameters; testing for CMV IgM was ordered if the EBV IgM was *—Use branched-chain DNA to detect non-B subtype HIV. negative. Knowing that a patient’s symptoms †—Human herpesvirus 6 diagnosis by fourfold rise in titer or plasma DNA. are secondary to acute CMV infection can therefore preclude further costly work-up. Laboratory tests that may be rendered FIGURE 1. Laboratory evaluation of acute mononucleosis syndrome. falsely positive from acute CMV infection (EBV = Epstein Barr virus; HIV = human immunodeficiency virus; CMV = cytomegalovirus.) include rheumatoid factor, positive direct Coombs’, polyclonal hypergammaglobulin- Adapted from Tsaparas YF, Brigden ML, Mathias R, Thomas E, Raboud J, Doyle P. Proportion positive for Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, emia, , and a transient posi- Toxoplasma, and human immunodeficiency virus types 1 and 2 in heterophil- tive antinuclear antibody (speckled pattern). negative patients with an absolute lymphocytosis or an instrument-generated CMV polymerase chain reaction (PCR) or atypical lymphocyte flag. Arch Pathol Lab Med 2000;124:1324-30.

FEBRUARY 1, 2003 / VOLUME 67, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 521 munocompromised patient may forebode the onset of end-organ involvement by CMV, and a positive PCR test in cerebral spinal fluid is of use in the diagnosis of CMV encephalitis or polyradiculopathy. Histologically, the detec- FIGURE 2. Cells from a lung biopsy demon- tion of the distinct “owl’s eye” inclusion bod- strating the classic “owl’s eye” inclusion bod- ies on tissue sample can be a highly specific ies (see arrow). method for determining organ involvement of CMV (Figure 2).16

Infection Control The Centers for Control and Pre- vention (CDC) does not recommend with- drawing children with known CMV infection from day care, because CMV is nearly univer- sally present. Health care workers with known CMV infection need not be restricted from work,because strict handwashing and educa- tion about standard precautions can control transmission of CMV.17 Serologic or virologic screening programs FIGURE 3. Retinal pathology caused by to detect CMV in women of childbearing cytomegalovirus in a patient with acquired potential are not practical or cost-effective, immunodeficiency syndrome showing retinal because seropositive status does not predict necrosis with hemorrhage. reactivation of latent infection or reinfection with a new strain of CMV.17 Restrictions on less than 50 per mm3 (50 106 per L). In the also are not made, because the era before highly active antiretroviral therapy benefits of breast milk appear to outweigh the (HAART), CMV was the most common viral small risk of the child acquiring CMV from in HIV patients. the mother. CMV-induced end-organ damage, mostly in the form of retinitis, manifested in 21 to Patients with HIV 45 percent of such patients.18 The second most common context in which A patient with HIV may present with a a family physician will encounter the clinical diverse variety of visual complaints secondary sequelae of CMV infection is in patients with to CMV retinitis, including painless blurred HIV who have a CD4 T-lymphocyte count of vision, unilateral floaters, light flashes, scotoma, or the loss of central vision, depending on the location and extent of the retinal lesion.19-21 The retinitis caused by CMV is a focal necrotiz- The Author ing type, with or without hemorrhages (Figure GREGORY H. TAYLOR, M.D., is an assistant professor in the Department of Family 3).The destruction of the retina, which causes Medicine at the University of Maryland School of Medicine, Baltimore, and clinical fac- irreversible blindness, can be arrested and sup- ulty at the Institute of Human Virology, Baltimore. Dr. Taylor earned his medical degree pressed by anti-CMV agents. These medica- from the University of Maryland School of Medicine where he also completed a resi- dency in family medicine. tions halt CMV replication but do not elimi- nate the virus. The natural course of untreated Address correspondence to Gregory H. Taylor, M.D., University of Maryland, 29 S. Greene St., Suite 300, Baltimore, MD 21201 (e-mail: [email protected]). CMV retinitis results in disease progression Reprints are not available from the author. within approximately two weeks. Before

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HAART, therapy would only delay the progres- anti-CMV therapy may need to be re-initiated sion of retinitis by two months in most patients if the patient’s CD4 count drops again. Fortu- treated with intravenous anti-CMV medica- nately, the incidence of CMV retinitis has tions. For those treated with intravitreous gan- decreased significantly in response to ciclovir implants, the progress of the disease HAART.24 could be delayed by seven months. Intraocular Patients who have HIV infection should be implants should be accompanied asked by their physician at each visit about by oral ganciclovir (Cytovene), 1 g orally three their visual symptoms. An ophthalmologist times per day, to prevent CMV retinitis in the should do a dilated indirect funduscopic contralateral eye. For intravenous administra- examination on patients with symptoms or a tion, intravitreous ganciclovir, 5 mg per kg CD4 count of less than 50 per mm3 every three every 12 hours, should be given for 14 to 21 to four months. Because only 10 percent of the days. Other options include intravenous cido- retinal area can be observed with the use of a fovir (Vistide), 5 mg per kg once weekly for two direct ophthalmoscope, it is not recommended weeks, then 5 mg per kg every other week, or as a diagnostic or evaluating tool.20 intravenous (Foscavir).22 A recent study23 comparing use of ganci- Extraocular Complications clovir implants plus oral ganciclovir versus The dermatologic manifestations of CMV parenteral after HAART revealed no infection may differ in patients with HIV differences between the regimens in terms of infection. Patients with CMV infection of the general health or vision measures. The rate of skin may present with nonspecific rashes, vitreous hemorrhage and was perifollicular papulopustules, vesiculobullous higher in the ganciclovir group, with higher eruptions, and nodular or ulcerative lesions.9 levels of and nephrotoxicity seen in Patients with HIV who have low CD4 counts patients in the cidofovir arm of the study. Val- may experience complications from CMV ganciclovir (Valcyte) is the oral pro-drug of involvement of the , colon, mucous ganciclovir, and has efficacy comparable to membranes (ulcerative lesions and colitis), intravenous ganciclovir. Its side effect profile is brain (meningoencephalitis), peripheral similar to that of intravenous ganciclovir, but nerves (radiculopathy and myelopathy), and it cannot be substituted for oral ganciclovir lungs (interstitial ). Primary pro- capsules on a one-to-one basis. phylaxis against CMV in those patients with HAART is the cornerstone of therapy for low CD4 counts and positive CMV PCR by preventing recurrent retinitis.21 HAART can oral ganciclovir is of questionable value.25 increase a patient’s CD4 count and decrease HAART appears to be the best method to pre- the replicative abilities of CMV. The immuno- vent CMV in patients with CD4 counts of less restoration and protective benefits provided by than 50 per mm3.24 HAART may cause pro-inflammatory compli- cations, such as vitreitis and cystoid macular Transplant Patients edema, which develop from an enhanced CMV is a problematic infection in many T-lymphocyte response to CMV.19,21 If a pa- transplant patients. Seronegative patients can tient’s retinitis remains stable with anti-CMV acquire the infection from organ donors. therapy and HAART restores the CD4 count to CMV-related disease processes manifest dif- above 100 per mm3 (100 106 per L) for a ferently depending on which organ is trans- three- to six-month period, then it may be planted. In bone marrow recipients, CMV possible to stop anti-CMV therapy.21 This infection occurs as an interstitial pneumonia should only be done with close monitoring by with high mortality. In liver recipients, hepati- an ophthalmologist and the realization that tis can be problematic and may be difficult to

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discern from organ rejection. The presenta- normal adults. Successful treatment with vidara- bine. JAMA 1977;238:2299-300. tion of “CMV syndrome” (consisting of fever, 14. Eddleston M, Peacock S, Juniper M, Warrell DA. leukopenia, atypical lymphocytes, hepato- Severe cytomegalovirus infection in immunocom- megaly, myalgia, and arthralgia) is the most petent patients. Clin Infect Dis 1997;24:52-6. 15. Tsaparas YF, Brigden ML, Mathias R, Thomas E, common manifestation of primary CMV in Raboud J, Doyle P. Proportion positive for Epstein- 26 kidney transplant patients. Barr virus, cytomegalovirus, human herpesvirus 6, Toxoplasma, and human immunodeficiency virus The author thanks Juanita Hines for her assistance types 1 and 2 in heterophile-negative patients with with the preparation of the manuscript. an absolute lymphocytosis or an instrument-gener- ated atypical lymphocyte flag. Arch Pathol Lab The author indicates that he does not have any con- Med 2000;124:1324-30. flicts of interest. Sources of funding: none reported. 16. Mattes FM, McLaughlin JE, Emery VC, Clark DA, Griffiths PD. Histopathological detection of owl’s REFERENCES eye inclusions is still specific for cytomegalovirus in the era of human herpesviruses 6 and 7. J Clin 1. de Jong MD, Galasso GJ, Gazzard B, Griffiths PD, Pathol 2000;53:612-4. Jabs DA, Kern ER, Spector SA. Summary of the II 17. Bolyard EA, Tablan OC, Williams WW, Pearson ML, International Symposium on Cytomegalovirus. Shapiro CN, Deitchmann SD. Guideline for infec- Antiviral Res 1998;39:141-62. tion control in healthcare personnel, 1998. Infect 2. Bale JF Jr., Petheram SJ, Souza IE, Murph JR. Cyto- Control Hosp Epidemiol 1998;19:407-63. megalovirus reinfection in young children. J Pediatr 18. Hoover DR, Saah AJ, Bacellar H, Phair J, Detels R, 1996;128:347-52. Anderson R, et al. Clinical manifestations of AIDS 3. Adler SP. 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