Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Cytomegalovirus Bonnie Bean To cite this article: Bonnie Bean (1990) Cytomegalovirus, Postgraduate Medicine, 88:6, 147-154, DOI: 10.1080/00325481.1990.11716428 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11716428
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Cornell University Library]
Date: 22 July 2017, At: 02:45
-@
CME credit article
Cytomegalovirus An update for primary care physicians
Bonnie Bean, MD
Preview Cytomegalovirus infection is spread in various ways-from mother to fetus or baby, from small children in day-care centers to caregivers and parents, by blood transfusions, by sexual contact. Although the illness is usually inconsequential, congenital infection can have severe consequences, including mental retardation and hearing loss. Or Bean describes the different aspects of this virus and discusses a promising vaccine that may prevent congenital disease.
Cytomegalovirus (CMV) is the consummate parasite. It infects most people asymptomatically. When illness does occur, it is mild and nonspecific. There are no epidemics to call attention to the virus. Yet, CMV is now considered the most common infectious cause of mental retardation and congenital deafuess in the United States. CMV is a member of the herpesvirus family, along with herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus. A latent state follows initial infection, with CMV probably located in the white blood cells and involving many organs and organ systems. At a later time it is reactivated, usually by some form of immunosuppression, such as organ or bone marrow transplantation, cancer chemotherapy, or AIDS. The virus is very labile and survives only a few hours outside a human host. 1 In infected persons it can be found in saliva, tears, blood, stool, and cervical secretions and in especially high titers in urine and semen. Transmission occurs primarily by intimate or close personal contact with
infected secretions (table 1). Airborne transmission plays a minor role.
Congenital and perinatal infection Congenital CMV infection results from transplacental passage of the virus from mother to fetus (figure 1). Presumably this occurs while the mother is viremic. The outcome of intrauterine infection depends upon the immune status of the mother. If she is seropositive at the outset of pregnancy, and thus experiences reactivation of a latent infection, the fetus has a 30% to 40% chance of being infected.2 The risk of clinically manifest disease or sequelae in the baby is, however, only Oo/o to 1o/o. 3 If the mother is seronegative, and thus experiences a primary CMV infection, the outcome may be quite different. Once again the baby has a 30% to 40% chance of being infected.2 While most (85% to 90%) of these infants are normal at birth, 10% to 20% of them will go on to have hearing loss and behavioral, psychomotor, or neurologic problems before entering schooP
VOL 88/NO 6/NOVEMBER 1, 1990/POSTGRADUATE MEDICINE • CYTOM.GALOVIRUS
It has recendy been shown that mental retardation and learning disabilities do not occur in the absence of impaired hearing,4 and thus impaired hearing is the most important consequence of congenital CMV infection. In 10% to 15% of infected newborns, abnormalities are obvious at birth and may be severe. They include jaundice, hepatosplenomegaly, microcephaly, thrombocytopenic purpura or petechiae, and cerebral calcifications. Mortality is 20% to 30% in these babies, and survivors almost always experience severe hearing loss, seizures, and mental and psychomotor retardation.3 Severe disease appears more likely if the mother is infected during the first 27 weeks of pregnancy. 2 Overall, the risk of a woman's having an affected child if she has primary CMV during pregnancy can be estimated at 10% to 15%. This risk is not high enough to routinely recommend termination of pregnancy in this situation. At present, there is no effective treatrne~t for congenital CMY, although newer, promising drugs, such as ganciclovir sodium (Cytovene) (figure 2), are being investigated in this setting. During and after birth the mother is the most important source of CMV infection for an infant. About 50% ofbabies born to mothers excreting CMV from the cervix are infected.5 In addition, 30% ofbabies nursed by seropositive mothers become infected. 5In all of these cases, infection has been asymptomatic continued 147
Children in day-care centers transmit cytomegalovirus among themselves, to caregivers, and to their families; seronegative mothers who become infected can, in turn, transmit the virus to the fetus during pregnancy.
Table 1. Modes of transmission of cytomegalovirus In neonates
Transplacental Perinatal (mother's genital tract) Breast milk Intimate contact with infected secretions of caregivers or siblings Blood transfusion In children
Contact with infected secretions of peers, siblings In adults
Sexual intercourse Blood transfusion Organ transplantation
Figure 1. Large (cytomegalic) cell containing basophilic nuclear inclusions, found in lung of baby with congenital cytomegalovirus infection. (Hematoxylin-eosin stain, X400)
Courtesy of Nevenka Gould, MD, Michael Reese Hospital and Medical Center. Chicago.
148
and no abnormalities or sequelae have been seen. Nevenheless, these children can serve as sources of infection for other children and adults.
The problem of day care The most important source of CMV infection for seronegative women is small children, especially those attending day-care centers. About 80% of children cared for at such centers acquire CMV infection during childhood (compared with 20% cared for at home). 5 The infection itself is asymptomatic and without sequelae, but children can shed virus in the throat, and especially in the urine, from months to years afterward. The primary "reservoirs" in day-care centers appear to be toddlers, who transmit the virus among themselves by passing around toys that they have had in their mouths and by touching and kissing each other. When these toddlers return home, similar behaviors there result in a high transmission rate,6 and seronegative mothers become infected. They, in turn, can transmit the virus to the fetus during pregnancy. This sequence of events has acrually been documented.? For workers in day-care centers, diapers are a potential source of infection, as is close personal contact with the children. Although most centers stress good hygienic practices after diapering, such as proper diaper disposal and careful hand washing, the risk of CMV infection among
day-care workers may be as high as 11% per year (compared with 2% to 5% among the general population).8 Half of the women in the United States are CMV-seronegative when they reach childbearing age. With large numbers of children in daycare cemers, the potential exists for many women to acquire primary CMV during pregnancy and transmit it to their infants. The magnitude of the problem has prompted some to suggest that all women be tested for CMV antibodies either before gestation or early in pregnancy. The purpose would not be to diagnose CMV infection but to identifY those women who are seronegative and to counsel them regarding avoidance of infection during preg:nancy, including possible occupational changes for those involved in the care of small children.
CMV mononucleosis CMV infection in adults is usually asymptomatic. At rimes, however, mononucleosis results. CMV is, in fact, the most common cause of heterophil-negative mononucleosis in young adults. The syndrome is indistinguishable from that caused by Epstein-Barr virus, except that patients tend to be somewhat older (median age, 28 versus 17 years). Patients almost always have fever, myalgias, and rnalaise. 9 Sore throat, headache, and splenomegaly are less common. The blood smear reveals atypical lymphocytosis, and hetero-
CYTOM.CIALOVIRUS • VOL881NO 6/NOVEMBER 1, 1990IPOSTGRADUATE MEDICINE
If newboms become infected with cytomegalovirus by receiving blood products from seropositive donors, morbidity and mortality can be as high as 50%.
0
Structure: Synthetic nucleoside analogue of guanine Mechanism: Inhibits viral DNA synthesis Spectrum: Cytomegalovirus, herpes simplex virus, varicella-zoster virus, Epstein-Barr virus (clinical studies have been done only for cytomegalovirus)
Excretion: Renal Principal use: Severe cytomegalovirus infections in immunocompromised patients Adverse effects: Neutropenia, anemia, thrombocytopenia, rash, central nervous system effects (headache, behavior change, psychosis) Ganciclovir
Figure 2. Chemical configuration of ganciclovir sodium (Cytovene).
phil antibody tests are negative. Results of liver function tests, especially transaminase levels, are moderately elevated. Most patients recover uneventfully, but complications such as meningoencephalitis, myocarditis, hemolytic anemia, thrombocytopenia, polyneuritis, and Guillain-Barre syndrome have been reponed. Antiviral therapy with ganciclovir is not indicated in these patients unless complications are severe. Among adults, CMV is almost certainly a sexually transmitted disease, although the evidence for this is only indirect. The virus can be isolated from the genital tracts of 1% to 34% of women, depending upon socioeconomic class, and from semen in high titers. CMV infection is extremely common among homosexual men.
Transfusion CMV Historically, CMV infection has occurred in 7% to 30% of persons receiving blood transfusions. 10 The risk depends upon the volume of blood received and has been estimated at 2.4% per unit of blood. There is reason to believe, however, that this is decreasing with newer transfusion practices, and it may now be as low as 0. 14% per unit of celkomaining blood products. 11 How the virus is transmitted in blood products is not known. It may involve transfusion of actively infected donor white blood cells. More likely, donor white blood cells latently infected with CMV are tranSfused. In the process of reacting to recipient tissues, these lymphocytes are activated and become capable of supporting viral replication. They can
VOL 88/NO 6/NOVEMBER 1. 1990/PQSTGRADUATE MEDICINE • CYTOIII!QALOVIRUS
also transmit the virus to other recipient cells. Evidence for latent CMV infection in otherwise healthy persons has actually been found in peripheral blood lymphocytes with use of DNA hybridization techniques. 12 Primary CMV infection, reactivation of latent disease, and exogenous reinfection can all result from transfusion. Among those infected as older children and adults, however, fewer than 10% are symptomatic and no long-term effects have been seen. 10 This is not the case when seronegative newborns receive blood products from CMV-seropositive donors. Morbidity and mortality in infected infants can then be as high as 50%, 13 and some experts recommend that CMV-seronegative blood products be provided for infants weighing less than 1,200 g at birth. continued on page 153 149
Cytomegalovirus can be a major cause of prolonged illness, graft failure, and death in highly immunosuppressed patients, such as those receiving organ transplants.
Other patients who might benefit from CMV-seronegative blood products (if they are themselves seronegative) include pregnant women and recipients of seronegative organs and bone marrow. Blood banks may be limited, however, in the number of such units they can provide. Seropositivity rates vary from 30% to 80% in communities in the United States, and the blood bank in a community where most people are seropositive may not be able to meet the needs of all its seronegative clients.
Bonnie Bean, MD Dr Bean is associate director, clinical microbiology laboratory, department of pathology, and attending physician, department of medicine, Michael Reese Hospital and Medical Center, Chicago. Her interests include treatment of varicellazoster infections and costeffective use of laboratory tests.
AIDS More than 90% of homosexual men are infected with CMY, 14 and sexual transmission appears to be quite common. The frequency of actual disease in AIDS patients is difficult to ascertain but has been estimated at 7.4%. 14 In patients who are infected with human immunodeficiency virus, CMV commonly causes sight-threatening retinitis and gastrointestinal disease, especially colitis. Pneumonia can be seen in conjunction with other pathogens. Encephalitis and adrenal necrosis with hypoadrenalism also occur. Unlike immunocompetent hosts, patients with human immunodeficiency virus who have symptomatic CMV disease should undergo a trial of ganciclovir and their response and tolerance be assessed. Patients with retinitis must be maintained on the drug for the remainder of their lives
to prevent relapse and blindness. Maintenance therapy for other manifestations of CMV depends upon initial response, whether or not relapse occurs when therapy is discontinued, and tolerance to the drug. There is also some evidence that CMV infection may hasten progression to AIDS in persons with human immunodeficiency virus. 11 Whether or not anti-CMV therapy would alter this situation is unknown at present.
Other rnanifatarions Most primary CMV infections are
acquired before 30 years of age. Older persons, even though they may be immunocompetent, appear to have frequent reactivation of CMV infec-
VOL 88/NO 6/NOVEMBER 1, 1990IPOSTGRADUATE MEDICINE • CYTOMEGALOVIRUS
tions. 16 These are asymptomatic and are characterized by elevated CMV IgG titers in the absence of viral shedding from the throat or genitourinary tract. The situation may be very similar to that of varicella-roster virus, where reactivation becomes more common in old age as cellmediated immunity wanes. CMV antigens have been found in the arterial walls of patients with atherosclerotic disease, and another herpesvirus may cause atherosclerosis in chickens. Smooth-muscle cells in the media of normal arterial walls appear to be a site of CMV latency. Whether or not atherosclerotic disease results from reactivation at these sites remains to be seen. 17 CMV has been found in several continued
153
hwnan malignancies, including Kaposi's sarcoma, prostatic carcinoma, cervical carcinoma, and adenocarcinomas. Recently, DNA sequences have been found to cause twnor formation in immortalized rodent cells. 18 The role that CMV may play in twnorigenesis in hwnans, however, is unknown. In highly immunosuppressed patients, such as those receiving transplanted kidney, heart, liver, or bone marrow, CMV can be a major cause of prolonged illness, graft failure, and death. Methods of prevention and treatment are being actively investigated, including donor selection, ~tiviral chemotherapy, and vaccination.
Vaccine A live attenuated vaccine has been under investigation for prevention of CMV for the past 10 years. Recently it was shown to prevent severe disease but not infection in volunteers challenged with wild-type virus. 19 Earlier, this vaccine was thought incapable of inducing a latent state in hwnans. Advances in technology used to detect viruses and new information about viral strain variation may mean, however, that this question needs to be reexamined. A recent cost-benefit analysis of vaccination strategies has shown that more than half the cases of severe congenital CMV disease and its sequelae could be prevented by vaccination of susceptible women. 20
154
opment and use should be vigor-
Conclusion
ously pursued. Rl't'l Cytomegalovirus (CMV) infection in otherwise healthy children and adults is common but inconsequential. It is the importance of CMV as a cause of congenital deafness and mental retardation that demands a continuing search fur a means of prevention. At present, CMV vaccine is the most promising in this regard. Its devd-
Rdi:rences 1. Faix RG. Swvival of cytomegalovirus on environmenral surfaces. J Pediatr 1985;106(4):649-52 2. Stagna S, Pass RF, Ooud G, et al. Primary cytomegalovirus infection in pregnancy: incidence, transmission to ferus, and clinical outcome. JAMA 1986;256(14): 1904-8 3. Stagna S, Whidey RJ. Herpesvirus infections of pregnancy. I. Cytomegalovirus and Epstein-Barr virus infections. N EnglJ Med 1985;313(20): 1270-4 4. Conboy 1J, Pass RF, Stagno S, et al. lntellecrual development in school-aged children with asymptomatic congeniral cytomey,alovirus infection. Pediatrics 1986;77(6):801-6 5. Pass RF, Hutto C. Group day care and cytomegaloviral infections of mothers and children. Rev Infect Dis 1986;8(4):599-605 6. Pass RF, Hutto C, Rides R, et al. Increased rate of cytomey,alovirus infection among parents of children atrending day-care centers. N Engl J Med 1986;314(22): 1414-8 7. Pass RF, Little EA, Stagno S, et al. Young children as a probable source of maternal and congeniral cytomey,alovirus infection. N Engl J Med 1987;316(22):1366-70 8. Adler SP. Cytomegalovirus and child day care: evidence for an increased infection rate among daycare workers. N Engl J Med 1989;321 (19): 1290-6 9. Cohen JI, Corey GR. Cytomegalovirus infection in the normal host. Medicine {Baltimore) 1985;64(2):100-14 10. Adler SP. Transfusion-associated cytomegalovirus infections. Rev Infect Dis 1983;5(6):977-93 11. Preiksairis JK, Brown L, McKenzie M. The risk of cytomegalovirus infection in seronegative transfusion recipients not receiving exogenous immunosuppression. J Infect Dis 1988; 157(3):523-9
Earn credit on this article. See CME Quiz.
-@
Address for correspondence: Bonnie Bean, MD, Department of Pathology, Michael Reese Hospital and Medical Cemer, Lake Shore Or at 31st St, Chicago, IL 60616.
12. Schrier RD, Nelson JA, Oldstone MB. Detection of human cytomegalovirus in peripheral blood lymphocytes in a natural infection. Science 1985;230(4729): 1048-51 13. Yeap AS, Gnunet FC, Halleigh EB, et al. Prevention of transfusion-acquired cytomegalovirus infections in newborn infants. J Pediatr 1981; 98(2):281-7 14. Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS): clinical findings, diagnosis, and treatment. Ann Intern Med 1988;108(4):585-94 15. Webster A, Lee CA, Cook DG, et al. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet 1989;2(8654):63-6 16. McVoy MA, Adler SP. Immunologic evidence for frequent age-related cytomegalovirus reactivation in seropositive immunocompetent individuals. J Infect Dis 1989;160(1):1-10 17. Hendrix MG, Salimans MM, van Bovm CP, et al. High prevalence of latently present cytomegalovirus in arterial walls of patienlli suffering from grade III atherosclerosis. Am J Patho1 1990; 136(1):23-8 18. d-Beik T, Razzaque A, Jariwalla R, et al. Multiple transforming regions of human cytomegalovirus DNA J V~tol1986;60(2):645-52 19. Plotkin SA, Starr SE, Friedman HM, et al. Protective effects ofTowne cytomegalovirus vaccine against low-passage cytomegalovirus administered as a challenge. J Infect Dis 1989;159(5):860-5 20. Porath A, McNutt RA, Smiley IM, et al. Effectiveness and cost benefit of a proposed live cytomegalovirus vaccine in the prevention of congeniral disease. Rev Infect Dis 1990;12(1):31-40
CYTOMBGALOVIRUS • VOL 88/NO 6/NOVEMBER 1, 1990/POSTGRAOUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Cytomegalovirus Bonnie Bean To cite this article: Bonnie Bean (1990) Cytomegalovirus, Postgraduate Medicine, 88:6, 147-154, DOI: 10.1080/00325481.1990.11716428 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11716428
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Cornell University Library]
Date: 22 July 2017, At: 02:45
-@
CME credit article
Cytomegalovirus An update for primary care physicians
Bonnie Bean, MD
Preview Cytomegalovirus infection is spread in various ways-from mother to fetus or baby, from small children in day-care centers to caregivers and parents, by blood transfusions, by sexual contact. Although the illness is usually inconsequential, congenital infection can have severe consequences, including mental retardation and hearing loss. Or Bean describes the different aspects of this virus and discusses a promising vaccine that may prevent congenital disease.
Cytomegalovirus (CMV) is the consummate parasite. It infects most people asymptomatically. When illness does occur, it is mild and nonspecific. There are no epidemics to call attention to the virus. Yet, CMV is now considered the most common infectious cause of mental retardation and congenital deafuess in the United States. CMV is a member of the herpesvirus family, along with herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus. A latent state follows initial infection, with CMV probably located in the white blood cells and involving many organs and organ systems. At a later time it is reactivated, usually by some form of immunosuppression, such as organ or bone marrow transplantation, cancer chemotherapy, or AIDS. The virus is very labile and survives only a few hours outside a human host. 1 In infected persons it can be found in saliva, tears, blood, stool, and cervical secretions and in especially high titers in urine and semen. Transmission occurs primarily by intimate or close personal contact with
infected secretions (table 1). Airborne transmission plays a minor role.
Congenital and perinatal infection Congenital CMV infection results from transplacental passage of the virus from mother to fetus (figure 1). Presumably this occurs while the mother is viremic. The outcome of intrauterine infection depends upon the immune status of the mother. If she is seropositive at the outset of pregnancy, and thus experiences reactivation of a latent infection, the fetus has a 30% to 40% chance of being infected.2 The risk of clinically manifest disease or sequelae in the baby is, however, only Oo/o to 1o/o. 3 If the mother is seronegative, and thus experiences a primary CMV infection, the outcome may be quite different. Once again the baby has a 30% to 40% chance of being infected.2 While most (85% to 90%) of these infants are normal at birth, 10% to 20% of them will go on to have hearing loss and behavioral, psychomotor, or neurologic problems before entering schooP
VOL 88/NO 6/NOVEMBER 1, 1990/POSTGRADUATE MEDICINE • CYTOM.GALOVIRUS
It has recendy been shown that mental retardation and learning disabilities do not occur in the absence of impaired hearing,4 and thus impaired hearing is the most important consequence of congenital CMV infection. In 10% to 15% of infected newborns, abnormalities are obvious at birth and may be severe. They include jaundice, hepatosplenomegaly, microcephaly, thrombocytopenic purpura or petechiae, and cerebral calcifications. Mortality is 20% to 30% in these babies, and survivors almost always experience severe hearing loss, seizures, and mental and psychomotor retardation.3 Severe disease appears more likely if the mother is infected during the first 27 weeks of pregnancy. 2 Overall, the risk of a woman's having an affected child if she has primary CMV during pregnancy can be estimated at 10% to 15%. This risk is not high enough to routinely recommend termination of pregnancy in this situation. At present, there is no effective treatrne~t for congenital CMY, although newer, promising drugs, such as ganciclovir sodium (Cytovene) (figure 2), are being investigated in this setting. During and after birth the mother is the most important source of CMV infection for an infant. About 50% ofbabies born to mothers excreting CMV from the cervix are infected.5 In addition, 30% ofbabies nursed by seropositive mothers become infected. 5In all of these cases, infection has been asymptomatic continued 147
Children in day-care centers transmit cytomegalovirus among themselves, to caregivers, and to their families; seronegative mothers who become infected can, in turn, transmit the virus to the fetus during pregnancy.
Table 1. Modes of transmission of cytomegalovirus In neonates
Transplacental Perinatal (mother's genital tract) Breast milk Intimate contact with infected secretions of caregivers or siblings Blood transfusion In children
Contact with infected secretions of peers, siblings In adults
Sexual intercourse Blood transfusion Organ transplantation
Figure 1. Large (cytomegalic) cell containing basophilic nuclear inclusions, found in lung of baby with congenital cytomegalovirus infection. (Hematoxylin-eosin stain, X400)
Courtesy of Nevenka Gould, MD, Michael Reese Hospital and Medical Center. Chicago.
148
and no abnormalities or sequelae have been seen. Nevenheless, these children can serve as sources of infection for other children and adults.
The problem of day care The most important source of CMV infection for seronegative women is small children, especially those attending day-care centers. About 80% of children cared for at such centers acquire CMV infection during childhood (compared with 20% cared for at home). 5 The infection itself is asymptomatic and without sequelae, but children can shed virus in the throat, and especially in the urine, from months to years afterward. The primary "reservoirs" in day-care centers appear to be toddlers, who transmit the virus among themselves by passing around toys that they have had in their mouths and by touching and kissing each other. When these toddlers return home, similar behaviors there result in a high transmission rate,6 and seronegative mothers become infected. They, in turn, can transmit the virus to the fetus during pregnancy. This sequence of events has acrually been documented.? For workers in day-care centers, diapers are a potential source of infection, as is close personal contact with the children. Although most centers stress good hygienic practices after diapering, such as proper diaper disposal and careful hand washing, the risk of CMV infection among
day-care workers may be as high as 11% per year (compared with 2% to 5% among the general population).8 Half of the women in the United States are CMV-seronegative when they reach childbearing age. With large numbers of children in daycare cemers, the potential exists for many women to acquire primary CMV during pregnancy and transmit it to their infants. The magnitude of the problem has prompted some to suggest that all women be tested for CMV antibodies either before gestation or early in pregnancy. The purpose would not be to diagnose CMV infection but to identifY those women who are seronegative and to counsel them regarding avoidance of infection during preg:nancy, including possible occupational changes for those involved in the care of small children.
CMV mononucleosis CMV infection in adults is usually asymptomatic. At rimes, however, mononucleosis results. CMV is, in fact, the most common cause of heterophil-negative mononucleosis in young adults. The syndrome is indistinguishable from that caused by Epstein-Barr virus, except that patients tend to be somewhat older (median age, 28 versus 17 years). Patients almost always have fever, myalgias, and rnalaise. 9 Sore throat, headache, and splenomegaly are less common. The blood smear reveals atypical lymphocytosis, and hetero-
CYTOM.CIALOVIRUS • VOL881NO 6/NOVEMBER 1, 1990IPOSTGRADUATE MEDICINE
If newboms become infected with cytomegalovirus by receiving blood products from seropositive donors, morbidity and mortality can be as high as 50%.
0
Structure: Synthetic nucleoside analogue of guanine Mechanism: Inhibits viral DNA synthesis Spectrum: Cytomegalovirus, herpes simplex virus, varicella-zoster virus, Epstein-Barr virus (clinical studies have been done only for cytomegalovirus)
Excretion: Renal Principal use: Severe cytomegalovirus infections in immunocompromised patients Adverse effects: Neutropenia, anemia, thrombocytopenia, rash, central nervous system effects (headache, behavior change, psychosis) Ganciclovir
Figure 2. Chemical configuration of ganciclovir sodium (Cytovene).
phil antibody tests are negative. Results of liver function tests, especially transaminase levels, are moderately elevated. Most patients recover uneventfully, but complications such as meningoencephalitis, myocarditis, hemolytic anemia, thrombocytopenia, polyneuritis, and Guillain-Barre syndrome have been reponed. Antiviral therapy with ganciclovir is not indicated in these patients unless complications are severe. Among adults, CMV is almost certainly a sexually transmitted disease, although the evidence for this is only indirect. The virus can be isolated from the genital tracts of 1% to 34% of women, depending upon socioeconomic class, and from semen in high titers. CMV infection is extremely common among homosexual men.
Transfusion CMV Historically, CMV infection has occurred in 7% to 30% of persons receiving blood transfusions. 10 The risk depends upon the volume of blood received and has been estimated at 2.4% per unit of blood. There is reason to believe, however, that this is decreasing with newer transfusion practices, and it may now be as low as 0. 14% per unit of celkomaining blood products. 11 How the virus is transmitted in blood products is not known. It may involve transfusion of actively infected donor white blood cells. More likely, donor white blood cells latently infected with CMV are tranSfused. In the process of reacting to recipient tissues, these lymphocytes are activated and become capable of supporting viral replication. They can
VOL 88/NO 6/NOVEMBER 1. 1990/PQSTGRADUATE MEDICINE • CYTOIII!QALOVIRUS
also transmit the virus to other recipient cells. Evidence for latent CMV infection in otherwise healthy persons has actually been found in peripheral blood lymphocytes with use of DNA hybridization techniques. 12 Primary CMV infection, reactivation of latent disease, and exogenous reinfection can all result from transfusion. Among those infected as older children and adults, however, fewer than 10% are symptomatic and no long-term effects have been seen. 10 This is not the case when seronegative newborns receive blood products from CMV-seropositive donors. Morbidity and mortality in infected infants can then be as high as 50%, 13 and some experts recommend that CMV-seronegative blood products be provided for infants weighing less than 1,200 g at birth. continued on page 153 149
Cytomegalovirus can be a major cause of prolonged illness, graft failure, and death in highly immunosuppressed patients, such as those receiving organ transplants.
Other patients who might benefit from CMV-seronegative blood products (if they are themselves seronegative) include pregnant women and recipients of seronegative organs and bone marrow. Blood banks may be limited, however, in the number of such units they can provide. Seropositivity rates vary from 30% to 80% in communities in the United States, and the blood bank in a community where most people are seropositive may not be able to meet the needs of all its seronegative clients.
Bonnie Bean, MD Dr Bean is associate director, clinical microbiology laboratory, department of pathology, and attending physician, department of medicine, Michael Reese Hospital and Medical Center, Chicago. Her interests include treatment of varicellazoster infections and costeffective use of laboratory tests.
AIDS More than 90% of homosexual men are infected with CMY, 14 and sexual transmission appears to be quite common. The frequency of actual disease in AIDS patients is difficult to ascertain but has been estimated at 7.4%. 14 In patients who are infected with human immunodeficiency virus, CMV commonly causes sight-threatening retinitis and gastrointestinal disease, especially colitis. Pneumonia can be seen in conjunction with other pathogens. Encephalitis and adrenal necrosis with hypoadrenalism also occur. Unlike immunocompetent hosts, patients with human immunodeficiency virus who have symptomatic CMV disease should undergo a trial of ganciclovir and their response and tolerance be assessed. Patients with retinitis must be maintained on the drug for the remainder of their lives
to prevent relapse and blindness. Maintenance therapy for other manifestations of CMV depends upon initial response, whether or not relapse occurs when therapy is discontinued, and tolerance to the drug. There is also some evidence that CMV infection may hasten progression to AIDS in persons with human immunodeficiency virus. 11 Whether or not anti-CMV therapy would alter this situation is unknown at present.
Other rnanifatarions Most primary CMV infections are
acquired before 30 years of age. Older persons, even though they may be immunocompetent, appear to have frequent reactivation of CMV infec-
VOL 88/NO 6/NOVEMBER 1, 1990IPOSTGRADUATE MEDICINE • CYTOMEGALOVIRUS
tions. 16 These are asymptomatic and are characterized by elevated CMV IgG titers in the absence of viral shedding from the throat or genitourinary tract. The situation may be very similar to that of varicella-roster virus, where reactivation becomes more common in old age as cellmediated immunity wanes. CMV antigens have been found in the arterial walls of patients with atherosclerotic disease, and another herpesvirus may cause atherosclerosis in chickens. Smooth-muscle cells in the media of normal arterial walls appear to be a site of CMV latency. Whether or not atherosclerotic disease results from reactivation at these sites remains to be seen. 17 CMV has been found in several continued
153
hwnan malignancies, including Kaposi's sarcoma, prostatic carcinoma, cervical carcinoma, and adenocarcinomas. Recently, DNA sequences have been found to cause twnor formation in immortalized rodent cells. 18 The role that CMV may play in twnorigenesis in hwnans, however, is unknown. In highly immunosuppressed patients, such as those receiving transplanted kidney, heart, liver, or bone marrow, CMV can be a major cause of prolonged illness, graft failure, and death. Methods of prevention and treatment are being actively investigated, including donor selection, ~tiviral chemotherapy, and vaccination.
Vaccine A live attenuated vaccine has been under investigation for prevention of CMV for the past 10 years. Recently it was shown to prevent severe disease but not infection in volunteers challenged with wild-type virus. 19 Earlier, this vaccine was thought incapable of inducing a latent state in hwnans. Advances in technology used to detect viruses and new information about viral strain variation may mean, however, that this question needs to be reexamined. A recent cost-benefit analysis of vaccination strategies has shown that more than half the cases of severe congenital CMV disease and its sequelae could be prevented by vaccination of susceptible women. 20
154
opment and use should be vigor-
Conclusion
ously pursued. Rl't'l Cytomegalovirus (CMV) infection in otherwise healthy children and adults is common but inconsequential. It is the importance of CMV as a cause of congenital deafness and mental retardation that demands a continuing search fur a means of prevention. At present, CMV vaccine is the most promising in this regard. Its devd-
Rdi:rences 1. Faix RG. Swvival of cytomegalovirus on environmenral surfaces. J Pediatr 1985;106(4):649-52 2. Stagna S, Pass RF, Ooud G, et al. Primary cytomegalovirus infection in pregnancy: incidence, transmission to ferus, and clinical outcome. JAMA 1986;256(14): 1904-8 3. Stagna S, Whidey RJ. Herpesvirus infections of pregnancy. I. Cytomegalovirus and Epstein-Barr virus infections. N EnglJ Med 1985;313(20): 1270-4 4. Conboy 1J, Pass RF, Stagno S, et al. lntellecrual development in school-aged children with asymptomatic congeniral cytomey,alovirus infection. Pediatrics 1986;77(6):801-6 5. Pass RF, Hutto C. Group day care and cytomegaloviral infections of mothers and children. Rev Infect Dis 1986;8(4):599-605 6. Pass RF, Hutto C, Rides R, et al. Increased rate of cytomey,alovirus infection among parents of children atrending day-care centers. N Engl J Med 1986;314(22): 1414-8 7. Pass RF, Little EA, Stagno S, et al. Young children as a probable source of maternal and congeniral cytomey,alovirus infection. N Engl J Med 1987;316(22):1366-70 8. Adler SP. Cytomegalovirus and child day care: evidence for an increased infection rate among daycare workers. N Engl J Med 1989;321 (19): 1290-6 9. Cohen JI, Corey GR. Cytomegalovirus infection in the normal host. Medicine {Baltimore) 1985;64(2):100-14 10. Adler SP. Transfusion-associated cytomegalovirus infections. Rev Infect Dis 1983;5(6):977-93 11. Preiksairis JK, Brown L, McKenzie M. The risk of cytomegalovirus infection in seronegative transfusion recipients not receiving exogenous immunosuppression. J Infect Dis 1988; 157(3):523-9
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Address for correspondence: Bonnie Bean, MD, Department of Pathology, Michael Reese Hospital and Medical Cemer, Lake Shore Or at 31st St, Chicago, IL 60616.
12. Schrier RD, Nelson JA, Oldstone MB. Detection of human cytomegalovirus in peripheral blood lymphocytes in a natural infection. Science 1985;230(4729): 1048-51 13. Yeap AS, Gnunet FC, Halleigh EB, et al. Prevention of transfusion-acquired cytomegalovirus infections in newborn infants. J Pediatr 1981; 98(2):281-7 14. Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS): clinical findings, diagnosis, and treatment. Ann Intern Med 1988;108(4):585-94 15. Webster A, Lee CA, Cook DG, et al. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet 1989;2(8654):63-6 16. McVoy MA, Adler SP. Immunologic evidence for frequent age-related cytomegalovirus reactivation in seropositive immunocompetent individuals. J Infect Dis 1989;160(1):1-10 17. Hendrix MG, Salimans MM, van Bovm CP, et al. High prevalence of latently present cytomegalovirus in arterial walls of patienlli suffering from grade III atherosclerosis. Am J Patho1 1990; 136(1):23-8 18. d-Beik T, Razzaque A, Jariwalla R, et al. Multiple transforming regions of human cytomegalovirus DNA J V~tol1986;60(2):645-52 19. Plotkin SA, Starr SE, Friedman HM, et al. Protective effects ofTowne cytomegalovirus vaccine against low-passage cytomegalovirus administered as a challenge. J Infect Dis 1989;159(5):860-5 20. Porath A, McNutt RA, Smiley IM, et al. Effectiveness and cost benefit of a proposed live cytomegalovirus vaccine in the prevention of congeniral disease. Rev Infect Dis 1990;12(1):31-40
CYTOMBGALOVIRUS • VOL 88/NO 6/NOVEMBER 1, 1990/POSTGRAOUATE MEDICINE
