REVIEWS OF INFECTIOUS DISEASES • VOL. 12, SUPPLEMENT 7 • SEPTEMBER-OCTOBER 1990
© 1990 by The University of Chicago. All rights reserved. 0162-0886/90/1205-0046$02.00
Congenital and Perinatal Cytomegalovirus Infections Charles A. Alford, Sergio Stagno, Robert F. Pass, and William J. Britt
From the Department of Pediatrics, School of Medicine, University of Alabama at Birmingham, and The Children's Hospital of Alabama, Birmingham, Alabama
Cytomegaloviruses (CMV) are ubiquitous agents that commonly infect many animals, including humans [1]. These viruses are highly species-specific. Human CMV, like herpes simplex virus, is an ancient virus closely linked to its natural host, human beings; evidence of infection has been detected in the absence of evidence of measles and influenza infections in Tiriyo Indians from a remote part of Brazil [2]. Over the generations, many (probably thousands of) genetically different strains of CMV have emerged that continually circulate in the general population throughout the world [3]. As with other herpesvirus infections, primary CMV infection often is followed by persistent and/or recurrent infections. The latter are most often due to reactivation of latent virus, but reinfection also occurs, probably because of the antigenic diversity of CMV. These characteristics must be taken into consideration when attempting to understand the complex natural history of human CMV infections. Interpretations are further complicated by the peculiar symbiotic relationship between CMV and human beings. In the vast majority of cases, CMV infections are subclinical, including those acquired in utero and at or shortly after birth. Even grossly compromised
hosts tolerate CMV infections well. When the congenital and perinatal infections are considered, the picture becomes even more complex, since it involves the infected pregnant woman, her fetus, or her infant in a situation in which the mother is most often subclinically infected. Congenital Infection CMV is the most frequent known cause of congenital viral infections in humans [1, 3]. It is endemic throughout the world, occurring in rv 10,70 of all newborn infants. However, the prevalence of congenital CMV infection ranges widely among different populations (0.20,70->30,70) [4, 5]. Contrary to what might be expected, there is a direct rather than an inverse relationship between prevalence of congenital CMV infection and the rate of preexisting maternal immunity. This phenomenon results from the inability of maternal immunity to prevent the reactivation of CMV during pregnancy and, more important, to reliably prevent its transmission to the fetus [6-8]. Therefore, the prevalence of congenital infections is higher among those in lower socioeconomic sectors of developed countries and in developing nations of the world, where primary infection in children and latent infection in adults are more common.
This work was supported in part by grants no. POI HDI0699 from the National Institute of Child Health and Human Development, no. 5 MOl RR32 from the General Clinical Research Center, and no. 6-490 from the March of Dimes Birth Defects Foundation. Reprints will not be available. Please address correspondence to Dr. Charles A. Alford, Department of Pediatrics, School of Medicine, Children's Hospital Tower, Suite 72, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Symptomatic Infection
Only rv5% of the infants with congenital CMV infection have typical cytomegalic inclusion disease (CID), another 50,70 have atypical involvement, and 90% have no clinical manifestations at birth [9]. Early studies focused on symptomatic infections,
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Cytomegalovirus is the most common cause of congenital and perinatal viral infections throughout the world. Congenital infection occurs in 1% of all live births in developed countries and in an even higher percentage in developing nations. As a result of transmission during birth, by breast milk, and by blood transfusions, perinatal infections are much more prevalent than congenital infections. The vast majority of these infections are chronic, subclinical forms, but symptomatic infections are sufficiently prevalent and dangerous to represent a major unsolved public health problem throughout the world. In this review the epidemiologic, clinical, immunologic, and therapeutic facets of cytomegaloviral infections in pregnant women and their offspring will be discussed.
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infection indicate frequent involvement of the hepato biliary, immunologic, hematologic, and central nervous systems [9]. The following are found in decreasing order of frequency: increased levels of cord IgM (>20 mg/dL), atypical lymphocytosis (~5070), elevated levels of serum aspartate transaminase (>80 IJ.U/mL), thrombocytopenia «100,000 platelets/rum"), conjugated hyperbilirubinemia (direct serum bilirubin >2 mg/dl.), and increased levels of protein in CSF (>120 mg/dL). Among the most severely affected infants, mortality may be as high as 30070, and death may occur in the neonatal period or months later [9]. More important, the likelihood that infants who survive symptomatic congenital CMV infection will have normal intellectual development and hearing is small. Of the original group of 17 patients described by Weller and Hanshaw, only two were normal at 14 and 20 months of age [10]. One infant had subnormal vision as a result of chorioretinitis and optic atrophy. The remaining 14 infants had various degrees of mental retardation with or without other sequelae, such as seizures, blindness, paraparesis, or diplegia. Subsequent reports also demonstrated a high. rate of CNS damage in infants with CID [12, 13]. In addition, Weller and Hanshaw described disorders of hearing, language, and learning in these children. With these reports plus our prospective study of 52 patients with CID, almost 100 cases have been followed [9]. Microcephaly, usually in combination with mental retardation or a significant delay in psychomotor development, has occurred in almost 70070 of the children. Seizures, paralysis, and motor abnormalities were also common. In addition, sensorineural hearing loss (bilateral or unilateral, severe to profound) and ocular abnormalities have occurred in 53070 and 14% of children, respectively. Ninety percent of the children had severe debilitating complications. As the children have grown older, it is evident that hearing loss can be progressive. In a longitudinal study Williamson et al. reported on 17 patients with symptomatic congenital CMV infection [16]. In addition to the abnormalities described by previous investigators, they found that 14 children had delays in the development of expressive language. For 11 of these children, the delays could be related to hearing loss or cognitive deficits, but three other children had delayed expressive language skills with normal or disproportionately high language comprehension that could not be directly attributed to auditory or mental impairment. Also,
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and congenital CMV infection was considered a rare and often fatal disease [10-13]. In many of the patients included in the early reports, CMV infection was not diagnosed until late in infancy, and it is conceivable that some of these infections were acquired postnatally. More troublesome from the clinical point of view was that many patients were referred to the investigators because of developmental problems, a process that may have automatically selected a group of patients at a higher risk of persistent abnormalities and neurologic damage. More sensitive and specific methods of diagnosis, particularly of isolation of virus, have allowed prospective longitudinal study of both symptomatic and initially asymptomatic patients. Such studies have resulted in an increased awareness of the infection and its clinical spectrum. Clinically apparent infections are characterized by involvement of multiple organs, in particular the reticuloendothelial and central nervous systems. Weller and Hanshaw defined the abnormalities found most frequently in infants with CID as hepatomegaly, splenomegaly, microcephaly, jaundice, and petechiae [10]. A combination of petechiae, hepatosplenomegaly, and jaundice are the most frequently noted presenting signs. In addition, the magnitude of the prenatal insult is emphasized by the occurrence of microcephaly with or without cerebral calcifications, intrauterine growth retardation, and prematurity. Inguinal hernia in boys and chorioretinitis with or without optic atrophy are less common. Pneumonitis, a common clinical manifestation of CMV infection following bone marrow and renal transplantation in adults, is not usually a part of the clinical presentation of congenital CMV infection in newborn infants. In our experience, diffuse interstitial pneumonitis occurs in 1 month [23, 25] and in 25070-50070 of infants exposed to CMV in the birth canal [22]. Given the current rates of seropositivity of the mothers, the prevalence of CMV excretion in the genital tract at delivery, and the prevalence of breast feeding, in the United States rvlOJo-150J0 of infants become perinatally infected by 6 months of age. The incubation period of perinatal CMV infection ranges from 4 to 12 weeks. Although the quantity of virus excreted by infants with perinatal infection is less than that seen with intrauterine acquisition, the infection is also chronic, with shedding of virus persisting for years [4]. The vast majority of infants with perinatal CMV infections remain asymptomatic. However, recent reports indicate that this infection may be temporally associated with protracted interstitial pneumonitis. With this condition CMV may be the only pathogen or it may coexist with Chlamydia trachomatis,
Pneumocystis carinii, Ureaplasma urealyticum, and/or common respiratory viruses. Follow-up
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As indicated in the previous section, most infants with congenital CMV infections have no early clinical manifestations, and the long-term outcome for these children is much better than that for children with symptomatic infection. Nevertheless, there is now solid evidence from controlled prospective studies that at least 5070 and perhaps as many as 15070 of them are at risk of having developmental abnormalities such as sensorineural hearing loss, microcephaly, motor defects (spastic diplegia or quadriplegia), mental retardation, chorioretinitis, and dental defects. These abnormalities usually become apparent within the first 2 years of life, but progressive hearing loss can occur even later. More than 250 patients with asymptomatic congenital infection have been followed longitudinally by us and others using serial clinical, psychometric, audiometric, and visual assessments [4, 17-20]. The single most important late-appearing abnormality in children born with subclinical congenital CMV infection is sensorineural hearing loss. The impairment is bilateral in nearly one-half of the cases and is of sufficient magnitude (50-100 dB) to' produce serious difficulties with verbal communication and learning [21]. Another alarming observation is that in at least 25070 of these patients, as with the symptomatic group, hearing impairments have either developed or become more severe after the first year of life. The possibility is raised by this progressive deterioration that the overall incidence as well as the magnitude of the auditory defects in those already less severely involved will increase with time. Consequently, infants with proven congenital CMV infection, whether symptomatic or not, should have careful, serial audiometric examinations. These prospective studies of children born with subclinical congenital CMV infection also have revealed a wide but significant spectrum of neurologic complications. It has been estimated that within the first 2 years of life, an additional 2070-7070 of the infants born with subclinical infections develop microcephaly with various degrees of mental retardation and neuromuscular defects. How often milder forms of brain damage, such as learning or behavioral difficulties, will occur as these children grow older
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Immunologic Responses
Although maternal immunity is influential, immaturity of the immune response of the fetus and of young infants is believed to be the major determinant of virulence of the congenitally and early postnatally acquired infections. Intrauterine, perinatal, or early postnatal acquisition of CMV characteristically causes a more chronic infection with regard to virus excretion than does infection acquired in later life. Virus is consistently shed into the urine for ~5 years and frequently into the nasopharynx for 2-4 years [29-31]. The quantity of virus excreted in these sites is much greater than that found in infected older children and adults. Although the vast majority of congenitally and perinatally infected infants are asymptomatic, the levels of virus shed more closely approximate or even exceed those detectable in seriously ill immunocompromised older persons. The highest levels of virus are detected in the first 6 months after infection. During this period, infants with clinically apparent congenital infection excrete
significantly more virus than do those with subclinical involvement or with perinatal and early postnatal infections [29-31]. Nevertheless, all of the subclinically infected infants and children shed considerably more virus than do adults, even years after infection. The humoral immune response to congenital CMV infection is similar to that associated with other congenital infections. Both transplacental transfer of maternal IgG antibodies and fetal production of IgM occur during pregnancy, so that at delivery the amounts of antibody in the cord and maternal sera are equivalent when measured by standard serologic methods [30, 32-34]. As the level of maternal antibody - usually the major component in cord serum - declines, the infant begins to produce IgG antibody and continues to produce IgM antibody for weeks to months after delivery; production of IgG antibody continues for years if not for life, except for antibodies to so-called early CMV antigens and, in some cases, complement-fixation antibodies [30]. The humoral immune responses provoked by the perinatally and early postnatally acquired infections are similar to responses observed with congenital infection, except, of course, that antibody production begins after delivery but still in the presence of various amounts of maternal antibody [30, 32]. With these infections, production of antibody by the infant usually begins between 4 and 18 weeks postnatally, depending on whether the infection was acquired natally by exposure to infected genital secretions, through blood transfusion, or through consumption of infected breast milk. Studies using radioimmunoprecipitation techniques indicate that some infants born with symptomatic congenital CMV infection, when compared with infants who are subclinically infected, have a defect in their IgG antibody response to CMVspecified proteins. The antibody response to virusencoded proteins in the former group is deficient both qualitatively and quantitatively during the first 6 months of life but recovers later [35]. In infants and children with chronic congenital and perinatal infection, abnormalities in cell-mediated immunity differ from those observed in adults with CMV mononucleosis. Only one defect has consistently been observed in the chronically infected infants and children, namely, an inability of their lymphocytes to elicit a blastogenic response and induce production of interferon in vitro when challenged with CMV antigens [29, 36-39]. This defect is more profound than that seen in adults with
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studies indicate that this form of pneumonitis may result in chronic lung disease [28]. In premature infants who require prolonged and intensive medical care, blood transfusions are an important iatrogenic cause of CMV infection. In one study, among 74 infants exposed to blood from one or more seropositive donors and who had CMVseronegative mothers, 13.5070 acquired CMV infection [26]. The risk of infection increased to 24% among those patients who received >50 mL of packed red blood cells and who were exposed to at least one seropositive donor. Among infants whose mothers were seropositive and whose blood donors were seropositive, the rate of infection was 15%. In contrast, none of the infants whose mothers were seronegative and whose blood donors were seronegative became infected. Fatal or serious illness occurred in 50070 of the seronegative infants who became infected and in none of the infected infants of seropositive mothers. This observation indicates that passive antibody cannot always prevent infection but can ameliorate its clinical expression. In infected infants CMV excretion usually begins between 30 and 150 days after exposure to CMV, with a mean of rv50 days. Characteristically, this iatrogenic infection is associated with rapid deterioration, septic appearance, hepatosplenomegaly, pneumonitis, or exacerbation of pulmonary problems [26, 27].
Alford et al.
Perinatal CMV Injection
Infection in Pregnant Women Spread of CMV by the oral and respiratory routes appears to be the dominant means of transmission during childhood and probably during adulthood as well. However, now there is clear evidence that CMV can be transmitted venereally. In many populations a burst of infection occurs with the advent of puberty. Infection rates as assessed by antibody
status are much higher in promiscuous populations; genital shedding of virus, including the frequency and amount of virus shed, is also markedly increased in these populations [5, 42, 44]. A number of large-scale, prospective studies of CMV infection in pregnant women have been performed in this country and abroad [45-49]. In different populations the prevalence of primary infection has ranged from 0.7070 to 4070 (average, 2070) per gestation among susceptible seronegative women. The rates of both primary and recurrent CMV infection in pregnant women are higher in low-income populations [49]. Young infants and children with subclinical infection appear to be the major source of primary infection in pregnant women [50, 51]. Day care centers and similar settings where pregnant women are in daily contact with children, especially toddlers, are high-risk settings for primary infection, with increased risk of intrauterine transmission [52]. Recurrent infection is defined as intermittent excretion of virus from single or multiple sites for a number of years as opposed to chronic or prolonged excretion of virus, which characterizes certain forms of CMV infection. Recurrent infection can result from one mechanism or a combination of three mechanisms. First, following primary infection, a low-grade chronic infection may be established in which excretion of virus only periodically reaches detectable levels. Second, reinfection may occur in immune persons because of antigenic and genetic disparity among CMV strains [53].Third, CMV may become latent in various organs during the primary infection, as with herpes simplex virus, and be repeatedly reactivated in later life in response to different stimuli. Molecular epidemiologic studies in which viral DNA is analyzed by restriction enzyme techniques suggest that in pregnant women re; -;dvation or persistence of virus is more common than reinfection [54]. However, reinfection of the genital tract and probably of other sites is relatively common in promiscuous populations, and coinfection with multiple strains of CMV has been detected in the semen of homosexual men. Recurrent infection is relatively common in women. The prevalence of cervical shedding has ranged from 3070 to 18070 (average, 9070); of urinary excretion, from 3070 to 9070 (average, 3.5070); and of pharyngeal shedding, from 1070 to 2070 (average, 1.8070) [43]. In postpartal women the breast is the most common site of reactivation of virus, with rates ranging from 14070 to 27070 of the total popula-
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mononucleosis and in contrast persists for many years whether the infections are symptomatic or asymptomatic in infancy [29, 39]. This deficit in antigen recognition appears to be CMV-specific and occurs in the presence of normal blastogenic responses to mitogens [29, 39]. In one study the blastogenic defect could not be ascribed to the antigen-presenting cells (monocyte/macrophage) from congenitally infected infants, as has been implied from infection in vitro of monocyte cells obtained from seropositive adults. Because the numbers of T4 (helper/inducer) and T8 (cytotoxic/suppressor) cells are normal-despite the high levels of virus and severe generalized disease in congenitally infected infants - there is the implication of a relative reduction in the circulating levels of cytotoxic T8 cells, since in adults with CMV mononucleosis these levels become elevated. Other studies have suggested either a reduction in the number of T cells or a deficiency in cytotoxic T cell function in infants with CID. Still, the extent and exact nature of the immune defect in congenitally infected infants have yet to be resolved. In keeping with the greater levels of virus excretion in the infected infant, a greater antigenic load is implied because of excessivestimulation of the humoral immune system [20, 41]. There is an acceleration in the development of serum immunoglobulin, especially IgM, in production of rheumatoid factor, and in levels of circulating immune complexes with both subclinical and symptomatic congenital infection as well as with natally acquired infection. Overstimulation of the humoral immune system is more striking with CID as is the amount of virus excreted [41]. In addition, larger circulating immune complexes are associated with the symptomatic infection, whereas smaller complexes predominate in the subclinical infection [41]. With fatal CID, immune complexes may be deposited in the renal glomeruli. All of these findings suggest that there may be an immunopathologic component with the more severe CMV infections in fetuses and young infants.
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tuses have a greater and more persistent antibody response to CMV-encoded proteins than do those women who do not transmit virus in utero [57]. This finding suggests that women who transmit virus in utero have a greater viral or antigenic load, although the reasons are unclear. In a few cases, maternal cellmediated immunity, as measured by specific lymphocyte blastogenesis, has been depressed in women who delivered congenitally infected infants, but this defect is not consistent and does not necessarily correlate with intrauterine transmission or virulence of the fetal infection [29, 36-38]. The role of the placenta in containing CMV infections during pregnancy is another ill-defined area that is potentially important for understanding the pathogenesis of intrauterine infection. Placental infection has been detected both with and without fetal involvement, as with other intrauterine infections. CMV can be transmitted in utero with equal facility throughout gestation, but preliminary evidence suggests that the fetal infection is more virulent when acquired in the first half of gestation [49]. Treatment and Prophylaxis Various antiviral agents have been used in attempts to treat symptomatic congenital infection [58]. The preparations have included leukocyte interferon, interferon stimulators (measlesvirus and pyran copolymer), transfer factor, and nucleoside drugs (idoxuridine, floxuridine, cytosine arabinoside, adenine arabinoside, and acyclovir). Each of these regimens had little or no clinical benefit and unacceptable degrees of toxicity. Therefore, none of these regimens was clinically useful. Recently, a congener of acyclovir, ganciclovir or 9-[(l,3-dihydroxy-2-propoxy)methyl]guanine, was shown to have potent activity against CMV in vitro. Apparently, ganciclovir interferes with the production of viral DNA and the packaging of viral particles. Both controlled and uncontrolled studies limited to various immunosuppressed adult populations, including those with AIDS, suggest that the drug is clinically effective for treatment of certain forms of CMV disease, most particularly chorioretinitis and gastrointestinal infection. Although treatment with ganciclovir is said to prolong survival in patients with disseminated disease, its value for treatment of pneumonitis and other organ-system disease is still under study. Ganciclovir reduces or eliminates virus excretion and viremia during administration, but both return at variable intervals
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tion. Among seropositive women, ~30OJo can intermittently excrete CMV into breast milk during the first year after delivery, most commonly between the second and fourth months postpartum (25). Among adults, younger age favors both primary and recurrent CMV infection. With recurrent infection of the genitourinary tracts of young women, shedding of virus declines steadily from puberty to age 30 years, when excretion either ceases or is markedly reduced [55]. During pregnancy, gestational age also influences excretion from the genital and urinary tracts in young women. Genital shedding increases, on the average,from 1.5% in the first trimester to 13.5%near term. A similar but lessstriking effect Occurs with viruria [56). With intrauterine infection, maternal factors that are as yet undefined influence the transmission of virus in utero and the virulence of the fetal infection. As previously noted, CMV can be transmitted in utero with both primary and reactivated maternal infections, a feature that accounts for the inordinately high prevalence of congenital CMV infection as compared with that of other intrauterine viral infections [6, 8]. Since in most populations throughout the world CMV infection is initially acquired before the childbearing years, transmission of reactivated virus in utero in immune women is likely the most common cause of congenital infection [6, 8]. The source of the virus for intrauterine transmission under these circumstances has never been defined. Latently infected maternal white blood cells, endometrial or cervical cells, or even maternal or paternal germinal cells are all possible sources. Maternal immunity does modify the virulence of the fetal infection [8, 49]. Most generalized CID of the newborn is the result of primary maternal infection. Damage following recurrent infection is relatively rare. Nevertheless, even with primary infection an innate barrier exists against transmission of virus in utero. Intrauterine transmission occurs in
© 1990 by The University of Chicago. All rights reserved. 0162-0886/90/1205-0046$02.00
Congenital and Perinatal Cytomegalovirus Infections Charles A. Alford, Sergio Stagno, Robert F. Pass, and William J. Britt
From the Department of Pediatrics, School of Medicine, University of Alabama at Birmingham, and The Children's Hospital of Alabama, Birmingham, Alabama
Cytomegaloviruses (CMV) are ubiquitous agents that commonly infect many animals, including humans [1]. These viruses are highly species-specific. Human CMV, like herpes simplex virus, is an ancient virus closely linked to its natural host, human beings; evidence of infection has been detected in the absence of evidence of measles and influenza infections in Tiriyo Indians from a remote part of Brazil [2]. Over the generations, many (probably thousands of) genetically different strains of CMV have emerged that continually circulate in the general population throughout the world [3]. As with other herpesvirus infections, primary CMV infection often is followed by persistent and/or recurrent infections. The latter are most often due to reactivation of latent virus, but reinfection also occurs, probably because of the antigenic diversity of CMV. These characteristics must be taken into consideration when attempting to understand the complex natural history of human CMV infections. Interpretations are further complicated by the peculiar symbiotic relationship between CMV and human beings. In the vast majority of cases, CMV infections are subclinical, including those acquired in utero and at or shortly after birth. Even grossly compromised
hosts tolerate CMV infections well. When the congenital and perinatal infections are considered, the picture becomes even more complex, since it involves the infected pregnant woman, her fetus, or her infant in a situation in which the mother is most often subclinically infected. Congenital Infection CMV is the most frequent known cause of congenital viral infections in humans [1, 3]. It is endemic throughout the world, occurring in rv 10,70 of all newborn infants. However, the prevalence of congenital CMV infection ranges widely among different populations (0.20,70->30,70) [4, 5]. Contrary to what might be expected, there is a direct rather than an inverse relationship between prevalence of congenital CMV infection and the rate of preexisting maternal immunity. This phenomenon results from the inability of maternal immunity to prevent the reactivation of CMV during pregnancy and, more important, to reliably prevent its transmission to the fetus [6-8]. Therefore, the prevalence of congenital infections is higher among those in lower socioeconomic sectors of developed countries and in developing nations of the world, where primary infection in children and latent infection in adults are more common.
This work was supported in part by grants no. POI HDI0699 from the National Institute of Child Health and Human Development, no. 5 MOl RR32 from the General Clinical Research Center, and no. 6-490 from the March of Dimes Birth Defects Foundation. Reprints will not be available. Please address correspondence to Dr. Charles A. Alford, Department of Pediatrics, School of Medicine, Children's Hospital Tower, Suite 72, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Symptomatic Infection
Only rv5% of the infants with congenital CMV infection have typical cytomegalic inclusion disease (CID), another 50,70 have atypical involvement, and 90% have no clinical manifestations at birth [9]. Early studies focused on symptomatic infections,
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Cytomegalovirus is the most common cause of congenital and perinatal viral infections throughout the world. Congenital infection occurs in 1% of all live births in developed countries and in an even higher percentage in developing nations. As a result of transmission during birth, by breast milk, and by blood transfusions, perinatal infections are much more prevalent than congenital infections. The vast majority of these infections are chronic, subclinical forms, but symptomatic infections are sufficiently prevalent and dangerous to represent a major unsolved public health problem throughout the world. In this review the epidemiologic, clinical, immunologic, and therapeutic facets of cytomegaloviral infections in pregnant women and their offspring will be discussed.
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infection indicate frequent involvement of the hepato biliary, immunologic, hematologic, and central nervous systems [9]. The following are found in decreasing order of frequency: increased levels of cord IgM (>20 mg/dL), atypical lymphocytosis (~5070), elevated levels of serum aspartate transaminase (>80 IJ.U/mL), thrombocytopenia «100,000 platelets/rum"), conjugated hyperbilirubinemia (direct serum bilirubin >2 mg/dl.), and increased levels of protein in CSF (>120 mg/dL). Among the most severely affected infants, mortality may be as high as 30070, and death may occur in the neonatal period or months later [9]. More important, the likelihood that infants who survive symptomatic congenital CMV infection will have normal intellectual development and hearing is small. Of the original group of 17 patients described by Weller and Hanshaw, only two were normal at 14 and 20 months of age [10]. One infant had subnormal vision as a result of chorioretinitis and optic atrophy. The remaining 14 infants had various degrees of mental retardation with or without other sequelae, such as seizures, blindness, paraparesis, or diplegia. Subsequent reports also demonstrated a high. rate of CNS damage in infants with CID [12, 13]. In addition, Weller and Hanshaw described disorders of hearing, language, and learning in these children. With these reports plus our prospective study of 52 patients with CID, almost 100 cases have been followed [9]. Microcephaly, usually in combination with mental retardation or a significant delay in psychomotor development, has occurred in almost 70070 of the children. Seizures, paralysis, and motor abnormalities were also common. In addition, sensorineural hearing loss (bilateral or unilateral, severe to profound) and ocular abnormalities have occurred in 53070 and 14% of children, respectively. Ninety percent of the children had severe debilitating complications. As the children have grown older, it is evident that hearing loss can be progressive. In a longitudinal study Williamson et al. reported on 17 patients with symptomatic congenital CMV infection [16]. In addition to the abnormalities described by previous investigators, they found that 14 children had delays in the development of expressive language. For 11 of these children, the delays could be related to hearing loss or cognitive deficits, but three other children had delayed expressive language skills with normal or disproportionately high language comprehension that could not be directly attributed to auditory or mental impairment. Also,
Downloaded from http://cid.oxfordjournals.org/ at Deakin University Library on August 11, 2015
and congenital CMV infection was considered a rare and often fatal disease [10-13]. In many of the patients included in the early reports, CMV infection was not diagnosed until late in infancy, and it is conceivable that some of these infections were acquired postnatally. More troublesome from the clinical point of view was that many patients were referred to the investigators because of developmental problems, a process that may have automatically selected a group of patients at a higher risk of persistent abnormalities and neurologic damage. More sensitive and specific methods of diagnosis, particularly of isolation of virus, have allowed prospective longitudinal study of both symptomatic and initially asymptomatic patients. Such studies have resulted in an increased awareness of the infection and its clinical spectrum. Clinically apparent infections are characterized by involvement of multiple organs, in particular the reticuloendothelial and central nervous systems. Weller and Hanshaw defined the abnormalities found most frequently in infants with CID as hepatomegaly, splenomegaly, microcephaly, jaundice, and petechiae [10]. A combination of petechiae, hepatosplenomegaly, and jaundice are the most frequently noted presenting signs. In addition, the magnitude of the prenatal insult is emphasized by the occurrence of microcephaly with or without cerebral calcifications, intrauterine growth retardation, and prematurity. Inguinal hernia in boys and chorioretinitis with or without optic atrophy are less common. Pneumonitis, a common clinical manifestation of CMV infection following bone marrow and renal transplantation in adults, is not usually a part of the clinical presentation of congenital CMV infection in newborn infants. In our experience, diffuse interstitial pneumonitis occurs in 1 month [23, 25] and in 25070-50070 of infants exposed to CMV in the birth canal [22]. Given the current rates of seropositivity of the mothers, the prevalence of CMV excretion in the genital tract at delivery, and the prevalence of breast feeding, in the United States rvlOJo-150J0 of infants become perinatally infected by 6 months of age. The incubation period of perinatal CMV infection ranges from 4 to 12 weeks. Although the quantity of virus excreted by infants with perinatal infection is less than that seen with intrauterine acquisition, the infection is also chronic, with shedding of virus persisting for years [4]. The vast majority of infants with perinatal CMV infections remain asymptomatic. However, recent reports indicate that this infection may be temporally associated with protracted interstitial pneumonitis. With this condition CMV may be the only pathogen or it may coexist with Chlamydia trachomatis,
Pneumocystis carinii, Ureaplasma urealyticum, and/or common respiratory viruses. Follow-up
Downloaded from http://cid.oxfordjournals.org/ at Deakin University Library on August 11, 2015
As indicated in the previous section, most infants with congenital CMV infections have no early clinical manifestations, and the long-term outcome for these children is much better than that for children with symptomatic infection. Nevertheless, there is now solid evidence from controlled prospective studies that at least 5070 and perhaps as many as 15070 of them are at risk of having developmental abnormalities such as sensorineural hearing loss, microcephaly, motor defects (spastic diplegia or quadriplegia), mental retardation, chorioretinitis, and dental defects. These abnormalities usually become apparent within the first 2 years of life, but progressive hearing loss can occur even later. More than 250 patients with asymptomatic congenital infection have been followed longitudinally by us and others using serial clinical, psychometric, audiometric, and visual assessments [4, 17-20]. The single most important late-appearing abnormality in children born with subclinical congenital CMV infection is sensorineural hearing loss. The impairment is bilateral in nearly one-half of the cases and is of sufficient magnitude (50-100 dB) to' produce serious difficulties with verbal communication and learning [21]. Another alarming observation is that in at least 25070 of these patients, as with the symptomatic group, hearing impairments have either developed or become more severe after the first year of life. The possibility is raised by this progressive deterioration that the overall incidence as well as the magnitude of the auditory defects in those already less severely involved will increase with time. Consequently, infants with proven congenital CMV infection, whether symptomatic or not, should have careful, serial audiometric examinations. These prospective studies of children born with subclinical congenital CMV infection also have revealed a wide but significant spectrum of neurologic complications. It has been estimated that within the first 2 years of life, an additional 2070-7070 of the infants born with subclinical infections develop microcephaly with various degrees of mental retardation and neuromuscular defects. How often milder forms of brain damage, such as learning or behavioral difficulties, will occur as these children grow older
5747
8748
Immunologic Responses
Although maternal immunity is influential, immaturity of the immune response of the fetus and of young infants is believed to be the major determinant of virulence of the congenitally and early postnatally acquired infections. Intrauterine, perinatal, or early postnatal acquisition of CMV characteristically causes a more chronic infection with regard to virus excretion than does infection acquired in later life. Virus is consistently shed into the urine for ~5 years and frequently into the nasopharynx for 2-4 years [29-31]. The quantity of virus excreted in these sites is much greater than that found in infected older children and adults. Although the vast majority of congenitally and perinatally infected infants are asymptomatic, the levels of virus shed more closely approximate or even exceed those detectable in seriously ill immunocompromised older persons. The highest levels of virus are detected in the first 6 months after infection. During this period, infants with clinically apparent congenital infection excrete
significantly more virus than do those with subclinical involvement or with perinatal and early postnatal infections [29-31]. Nevertheless, all of the subclinically infected infants and children shed considerably more virus than do adults, even years after infection. The humoral immune response to congenital CMV infection is similar to that associated with other congenital infections. Both transplacental transfer of maternal IgG antibodies and fetal production of IgM occur during pregnancy, so that at delivery the amounts of antibody in the cord and maternal sera are equivalent when measured by standard serologic methods [30, 32-34]. As the level of maternal antibody - usually the major component in cord serum - declines, the infant begins to produce IgG antibody and continues to produce IgM antibody for weeks to months after delivery; production of IgG antibody continues for years if not for life, except for antibodies to so-called early CMV antigens and, in some cases, complement-fixation antibodies [30]. The humoral immune responses provoked by the perinatally and early postnatally acquired infections are similar to responses observed with congenital infection, except, of course, that antibody production begins after delivery but still in the presence of various amounts of maternal antibody [30, 32]. With these infections, production of antibody by the infant usually begins between 4 and 18 weeks postnatally, depending on whether the infection was acquired natally by exposure to infected genital secretions, through blood transfusion, or through consumption of infected breast milk. Studies using radioimmunoprecipitation techniques indicate that some infants born with symptomatic congenital CMV infection, when compared with infants who are subclinically infected, have a defect in their IgG antibody response to CMVspecified proteins. The antibody response to virusencoded proteins in the former group is deficient both qualitatively and quantitatively during the first 6 months of life but recovers later [35]. In infants and children with chronic congenital and perinatal infection, abnormalities in cell-mediated immunity differ from those observed in adults with CMV mononucleosis. Only one defect has consistently been observed in the chronically infected infants and children, namely, an inability of their lymphocytes to elicit a blastogenic response and induce production of interferon in vitro when challenged with CMV antigens [29, 36-39]. This defect is more profound than that seen in adults with
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studies indicate that this form of pneumonitis may result in chronic lung disease [28]. In premature infants who require prolonged and intensive medical care, blood transfusions are an important iatrogenic cause of CMV infection. In one study, among 74 infants exposed to blood from one or more seropositive donors and who had CMVseronegative mothers, 13.5070 acquired CMV infection [26]. The risk of infection increased to 24% among those patients who received >50 mL of packed red blood cells and who were exposed to at least one seropositive donor. Among infants whose mothers were seropositive and whose blood donors were seropositive, the rate of infection was 15%. In contrast, none of the infants whose mothers were seronegative and whose blood donors were seronegative became infected. Fatal or serious illness occurred in 50070 of the seronegative infants who became infected and in none of the infected infants of seropositive mothers. This observation indicates that passive antibody cannot always prevent infection but can ameliorate its clinical expression. In infected infants CMV excretion usually begins between 30 and 150 days after exposure to CMV, with a mean of rv50 days. Characteristically, this iatrogenic infection is associated with rapid deterioration, septic appearance, hepatosplenomegaly, pneumonitis, or exacerbation of pulmonary problems [26, 27].
Alford et al.
Perinatal CMV Injection
Infection in Pregnant Women Spread of CMV by the oral and respiratory routes appears to be the dominant means of transmission during childhood and probably during adulthood as well. However, now there is clear evidence that CMV can be transmitted venereally. In many populations a burst of infection occurs with the advent of puberty. Infection rates as assessed by antibody
status are much higher in promiscuous populations; genital shedding of virus, including the frequency and amount of virus shed, is also markedly increased in these populations [5, 42, 44]. A number of large-scale, prospective studies of CMV infection in pregnant women have been performed in this country and abroad [45-49]. In different populations the prevalence of primary infection has ranged from 0.7070 to 4070 (average, 2070) per gestation among susceptible seronegative women. The rates of both primary and recurrent CMV infection in pregnant women are higher in low-income populations [49]. Young infants and children with subclinical infection appear to be the major source of primary infection in pregnant women [50, 51]. Day care centers and similar settings where pregnant women are in daily contact with children, especially toddlers, are high-risk settings for primary infection, with increased risk of intrauterine transmission [52]. Recurrent infection is defined as intermittent excretion of virus from single or multiple sites for a number of years as opposed to chronic or prolonged excretion of virus, which characterizes certain forms of CMV infection. Recurrent infection can result from one mechanism or a combination of three mechanisms. First, following primary infection, a low-grade chronic infection may be established in which excretion of virus only periodically reaches detectable levels. Second, reinfection may occur in immune persons because of antigenic and genetic disparity among CMV strains [53].Third, CMV may become latent in various organs during the primary infection, as with herpes simplex virus, and be repeatedly reactivated in later life in response to different stimuli. Molecular epidemiologic studies in which viral DNA is analyzed by restriction enzyme techniques suggest that in pregnant women re; -;dvation or persistence of virus is more common than reinfection [54]. However, reinfection of the genital tract and probably of other sites is relatively common in promiscuous populations, and coinfection with multiple strains of CMV has been detected in the semen of homosexual men. Recurrent infection is relatively common in women. The prevalence of cervical shedding has ranged from 3070 to 18070 (average, 9070); of urinary excretion, from 3070 to 9070 (average, 3.5070); and of pharyngeal shedding, from 1070 to 2070 (average, 1.8070) [43]. In postpartal women the breast is the most common site of reactivation of virus, with rates ranging from 14070 to 27070 of the total popula-
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mononucleosis and in contrast persists for many years whether the infections are symptomatic or asymptomatic in infancy [29, 39]. This deficit in antigen recognition appears to be CMV-specific and occurs in the presence of normal blastogenic responses to mitogens [29, 39]. In one study the blastogenic defect could not be ascribed to the antigen-presenting cells (monocyte/macrophage) from congenitally infected infants, as has been implied from infection in vitro of monocyte cells obtained from seropositive adults. Because the numbers of T4 (helper/inducer) and T8 (cytotoxic/suppressor) cells are normal-despite the high levels of virus and severe generalized disease in congenitally infected infants - there is the implication of a relative reduction in the circulating levels of cytotoxic T8 cells, since in adults with CMV mononucleosis these levels become elevated. Other studies have suggested either a reduction in the number of T cells or a deficiency in cytotoxic T cell function in infants with CID. Still, the extent and exact nature of the immune defect in congenitally infected infants have yet to be resolved. In keeping with the greater levels of virus excretion in the infected infant, a greater antigenic load is implied because of excessivestimulation of the humoral immune system [20, 41]. There is an acceleration in the development of serum immunoglobulin, especially IgM, in production of rheumatoid factor, and in levels of circulating immune complexes with both subclinical and symptomatic congenital infection as well as with natally acquired infection. Overstimulation of the humoral immune system is more striking with CID as is the amount of virus excreted [41]. In addition, larger circulating immune complexes are associated with the symptomatic infection, whereas smaller complexes predominate in the subclinical infection [41]. With fatal CID, immune complexes may be deposited in the renal glomeruli. All of these findings suggest that there may be an immunopathologic component with the more severe CMV infections in fetuses and young infants.
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tuses have a greater and more persistent antibody response to CMV-encoded proteins than do those women who do not transmit virus in utero [57]. This finding suggests that women who transmit virus in utero have a greater viral or antigenic load, although the reasons are unclear. In a few cases, maternal cellmediated immunity, as measured by specific lymphocyte blastogenesis, has been depressed in women who delivered congenitally infected infants, but this defect is not consistent and does not necessarily correlate with intrauterine transmission or virulence of the fetal infection [29, 36-38]. The role of the placenta in containing CMV infections during pregnancy is another ill-defined area that is potentially important for understanding the pathogenesis of intrauterine infection. Placental infection has been detected both with and without fetal involvement, as with other intrauterine infections. CMV can be transmitted in utero with equal facility throughout gestation, but preliminary evidence suggests that the fetal infection is more virulent when acquired in the first half of gestation [49]. Treatment and Prophylaxis Various antiviral agents have been used in attempts to treat symptomatic congenital infection [58]. The preparations have included leukocyte interferon, interferon stimulators (measlesvirus and pyran copolymer), transfer factor, and nucleoside drugs (idoxuridine, floxuridine, cytosine arabinoside, adenine arabinoside, and acyclovir). Each of these regimens had little or no clinical benefit and unacceptable degrees of toxicity. Therefore, none of these regimens was clinically useful. Recently, a congener of acyclovir, ganciclovir or 9-[(l,3-dihydroxy-2-propoxy)methyl]guanine, was shown to have potent activity against CMV in vitro. Apparently, ganciclovir interferes with the production of viral DNA and the packaging of viral particles. Both controlled and uncontrolled studies limited to various immunosuppressed adult populations, including those with AIDS, suggest that the drug is clinically effective for treatment of certain forms of CMV disease, most particularly chorioretinitis and gastrointestinal infection. Although treatment with ganciclovir is said to prolong survival in patients with disseminated disease, its value for treatment of pneumonitis and other organ-system disease is still under study. Ganciclovir reduces or eliminates virus excretion and viremia during administration, but both return at variable intervals
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tion. Among seropositive women, ~30OJo can intermittently excrete CMV into breast milk during the first year after delivery, most commonly between the second and fourth months postpartum (25). Among adults, younger age favors both primary and recurrent CMV infection. With recurrent infection of the genitourinary tracts of young women, shedding of virus declines steadily from puberty to age 30 years, when excretion either ceases or is markedly reduced [55]. During pregnancy, gestational age also influences excretion from the genital and urinary tracts in young women. Genital shedding increases, on the average,from 1.5% in the first trimester to 13.5%near term. A similar but lessstriking effect Occurs with viruria [56). With intrauterine infection, maternal factors that are as yet undefined influence the transmission of virus in utero and the virulence of the fetal infection. As previously noted, CMV can be transmitted in utero with both primary and reactivated maternal infections, a feature that accounts for the inordinately high prevalence of congenital CMV infection as compared with that of other intrauterine viral infections [6, 8]. Since in most populations throughout the world CMV infection is initially acquired before the childbearing years, transmission of reactivated virus in utero in immune women is likely the most common cause of congenital infection [6, 8]. The source of the virus for intrauterine transmission under these circumstances has never been defined. Latently infected maternal white blood cells, endometrial or cervical cells, or even maternal or paternal germinal cells are all possible sources. Maternal immunity does modify the virulence of the fetal infection [8, 49]. Most generalized CID of the newborn is the result of primary maternal infection. Damage following recurrent infection is relatively rare. Nevertheless, even with primary infection an innate barrier exists against transmission of virus in utero. Intrauterine transmission occurs in
