Pediatric Annals

Day-Care Centers and the Spread of Cytomegalovirus and Parvovirus B19

Robert F Pass, MD

Abstract

Although cytomegalovirus (CMV) and human parvovirus B19 differ markedly in size and morphology as well as in epidemiologie behavior, they share several features that make each of them a potential occupational hazard for women of childbearing age who work in day-care centers (Table 1). Both viruses are commonly spread among preschoolaged children with close daily contact, and both are frequently transmitted from children to susceptible adults. Cytomegalovirus is well-established as the leading cause of congenital viral infection in the United States; recent evidence has demonstrated that parvovirus also can be transmitted from mother to fetus across the placental barrier. This article briefly reviews the clinical and epidemiologie features of each of these infections and considers control measures that are available to minimize the risk of damaging fetal infections.

CYTOMEGALOVIRUS

Clinical Significance

In children and adults with normal immune systems, CMV infection rarely results in a recognizable illness. Although acquired CMV infection can produce a mononucleosis syndrome, prospective studies in pregnant women have reported clinical evidence of infection in about 5% of women who seroconvert.1'2 In contrast, CMV infection in the fetus and in immunocompromised hosts is frequently quite virulent with pronounced clinical abnormalities.

Approximately 1 % of live births in the United States (around 37 000 per year) have congenital CMV infection. Five percent to 10% of these will have manifestations of congenital infection at birth such as hepatosplenomegaly, petechiae, jaundice, microcephaly, thrombocytopenia, anemia, hepatitis, direct hyperbilimbinemia, chorioretinitis, and intracranial calcifications.2,3 Sequelae such as mental retardation, cerebral palsy, sensorineural hearing loss, and visual impairment have been reported in more than 90% of children with congenital CMV infection who were symptomatic at birth, although the number and severity of sequelae varies widely even in these infants.4 Follow-up studies of infants who are asymptomatic as newborns and identified through screening programs have found that approximately 15% of them will have sequelae, usually hearing loss, although a small number have more severe central nervous system abnormalities.2,3,5,8 Prenatal CMV infection is clearly a leading cause of congenital deafness and mental retardation.

Table

Estimates of the risk for fetal loss when a pregnant woman of unknown antibody status is exposed have been based on the expected rate of immunity in the population, the risk of infection after exposure, and the rate of fetal demise with proven maternal gestational infection. Using this approach, the upper limit estimate is 2.5% for fetal death after household exposure and 1.5% after occupational exposure in a school.40

The risk of infection in susceptible pregnant women with household or occupational exposure (ie, day care, school, or hospital) to erythema infectiosum or transient aplastic crisis can be expected to range from 16% to 50%35,50,54 (Table 3). Recent studies have shown that when maternal infection occurs during pregnancy, the rate of fetal loss is 4% to 10%, but it is not clear that this rate is higher than expected in a suitable control population.49'55 Serologie follow-up of offspring indicates silent prenatal infection in 10% to 30%.55,56 Neither neonatal illness nor congenital malformations have yet been linked to prenatal B19 infection, but a relatively small number of infected infants have been recognized. Most reported cases of fetal death due to hydrops have occurred in the second trimester.

Ultrasound has proven valuable in identifying hydrops fetalis in cases of maternal parvovirus B19 infection.57 In a few reported cases, fetal blood sampling has allowed detection of infection in utero and observation of the evolution of fetal anemia.58 Successful treatment of fetal anemia by intrauterine transfusion has been reported56,59; however, because spontaneous resolution of fetal hydrops could also occur, intrauterine transfusion should be considered investigational for fetal…

Although cytomegalovirus (CMV) and human parvovirus B19 differ markedly in size and morphology as well as in epidemiologie behavior, they share several features that make each of them a potential occupational hazard for women of childbearing age who work in day-care centers (Table 1). Both viruses are commonly spread among preschoolaged children with close daily contact, and both are frequently transmitted from children to susceptible adults. Cytomegalovirus is well-established as the leading cause of congenital viral infection in the United States; recent evidence has demonstrated that parvovirus also can be transmitted from mother to fetus across the placental barrier. This article briefly reviews the clinical and epidemiologie features of each of these infections and considers control measures that are available to minimize the risk of damaging fetal infections.

CYTOMEGALOVIRUS

Clinical Significance

In children and adults with normal immune systems, CMV infection rarely results in a recognizable illness. Although acquired CMV infection can produce a mononucleosis syndrome, prospective studies in pregnant women have reported clinical evidence of infection in about 5% of women who seroconvert.1'2 In contrast, CMV infection in the fetus and in immunocompromised hosts is frequently quite virulent with pronounced clinical abnormalities.

Approximately 1 % of live births in the United States (around 37 000 per year) have congenital CMV infection. Five percent to 10% of these will have manifestations of congenital infection at birth such as hepatosplenomegaly, petechiae, jaundice, microcephaly, thrombocytopenia, anemia, hepatitis, direct hyperbilimbinemia, chorioretinitis, and intracranial calcifications.2,3 Sequelae such as mental retardation, cerebral palsy, sensorineural hearing loss, and visual impairment have been reported in more than 90% of children with congenital CMV infection who were symptomatic at birth, although the number and severity of sequelae varies widely even in these infants.4 Follow-up studies of infants who are asymptomatic as newborns and identified through screening programs have found that approximately 15% of them will have sequelae, usually hearing loss, although a small number have more severe central nervous system abnormalities.2,3,5,8 Prenatal CMV infection is clearly a leading cause of congenital deafness and mental retardation.

Table

TABLE 1Comparison of Epidemiologie and Clinical Features of Cytomegalovirus and Parvovirus Bl9 Infections

TABLE 1

Comparison of Epidemiologie and Clinical Features of Cytomegalovirus and Parvovirus Bl9 Infections

In immunocompromised hosts, both primary and reactivation CMV infections have caused severe multisystem disease usually characterized by fever, malaise, arthralgias, transaminase abnormalities, and in severe cases, pneumonitis, gastrointestinal ulceration and sight-threatening retinitis.9 Greater impairment of cellular immunity, such as that encountered in acquired immunodeficiency syndrome patients and bone marrow transplant recipients, has been associated with the more virulent CMV infections. Blood products from seropositive donors can transmit CMV to seronegative recipients. Although transfusionacquired CMV is usually asymptomatic, it has been associated with a heterophile-negative mononucleosis even in the normal host and has been responsible for severe infection in inmunocompromised hosts and in small premature newboms. In newboms and other patient groups where it is desirable to prevent transfusionacquired CMV infection, serologie screening of donors is used to select those who are seronegative.

Epidemiology

The prevalence of CMV infection in a population increases with age; serologie surveys have found higher prevalence of serum antibody in developing countries and in lower socioeconomic groups in developed countries.10 Acquisition of CMV occurs frequently in infancy in populations where the majority of women are seropositive and breastfeeding is widely practiced; seroprevalence is higher in young children in cultures where sharing of child-care duties results in grouping of children.10 The proportion of women of childbearing age who are susceptible to CMV (seronegative) ranges from around 20% in low income populations to over 50% in upper and middle income groups. Some routes for spread of CMV have been well-defined, including from mother to infant (transplacentally, during birth, and from milk) and through blood products and transplanted organs. Aside from these special situations, the mechanisms for CMV spread can only be surmised. The virus is shed in a number of bodily secretions including saliva, urine, tears, semen, and cervical secretions for periods of weeks to months after initial infection.10 Young children in day-care centers with viruria of more than 2 years duration have been observed.11,12 Acquisition of CMV appears to require direct contact with infected secretions. Thus, high rates of infection (30% to 50% per year) have been observed in adults who take care of CMV shedding infants and in women with multiple sex partners.13'18 In contrast, the incidence of CMV infection in women of childbearing age in the general population is about 2% per year.

Gestational and Fetal Infection

Cohort studies with serologie follow-up of mothers and testing of offspring for congenital infection at birth indicate that approximately 40% of mothers who seroconvert during pregnancy transmit the virus to the fetus.1,2,19'22 As noted above, most of these infected infants will be normal at birth and will remain free of sequelae. Although the effect of gestational age at the time of maternal infection has not been as clearly established as with congenital rubella, there is good evidence that congenital CMV infection following maternal infection during the first half of pregnancy is more likely to result in fetal damage than is late gestational infection.2 Prenatal diagnosis of congenital CMV infection has been accomplished in a small number of cases through sampling of amniotic fluid or fetal blood for virologie or serologie studies.23"25 However, there is currently no means of prenatal diagnosis of established reliability; therefore, procedures performed with this aim should be considered research and their results interpreted with great caution.

CMV in Day-Care Centers

Since around 10% of infants acquire CMV early in life from a maternal source and excrete virus for years, grouping young children for care will inevitably bring infected children in contact with susceptible children. Studies in day-care centers have shown that preschool-aged children frequently transmit virus to their classmates who share the same room.26"28 The precise mechanisms for transmission have not been defined; however, several observations suggest that direct contact is important. In day-care centers in Alabama, low rates (~ 10%) of excretion were found in infants under 1 year of age who were, for the most part, nonambulatory and had limited opportunity for direct contact with each other.26'29 Excretion rates increased dramatically during the second year of life when children were ambulatory and had many opportunities for contact and exchange of secretions. In addition, cultures from toys, hands of day-care workers, and classroom surfaces have yielded CMV occasionally.30 As a result of child-to-child transmission, some day-care center classrooms have attained strikingly high rates of infection, around 80% to 100% among 2- to 3-year-olds. The workers in these classrooms experience a level of exposure to CMV unlikely to be encountered in any other occupation.

Table

TABLE 2Incidence of CMV Infection in Day-Care Workers and Controls

TABLE 2

Incidence of CMV Infection in Day-Care Workers and Controls

Cohort studies of day-care workers and molecular tracking of CMV strains from them have shown that their incidence of CMV infection is markedly increased and that they are acquiring the virus from children in their care.15'17 Three recent studies of day-care workers have reported annual seroconversion rates of 11%,15 20%,17 and 7.9%16 compared with a rate of around 2% in hospital workers15,31 (Table 2). The risk of CMV infection appears to be increased for workers who take care of children under the age of 3.17

Parents of children in day-care centers are also at increased risk for CMV infection. As with day-care workers, follow-up studies of parents demonstrated increased seroconversion rates, and molecular analysis of DNA from CMV strains linked virus recovered from parents to that excreted by children attending the day-care center.14,32 We found parental seroconversion co be associated with excretion of virus by the child; parents of children in the day-care center who did not shed virus did not become infected. Among parents of children who shed virus, the incidence of infection was highest (45% per year) for those whose infected child was under the age of 18 months.14

Spread of CMV in day-care centers will clearly result in exposure of susceptible women of childbearing age. In our studies, more than 90% of the day-care workers have been women between the ages of 15 and 40. Department of Labor data in 1984 estimated that there were more than 1 million day-care workers in the United States.33 The vast majority of these workers are women of childbearing age, as are the mothers of children in day care. Although the potential for exposure and infection of pregnant women with CMV from a day-care source is great, the proportion of congenital CMV cases that result from this exposure cannot be estimated reliably at this time. Whether the tremendous growth in the use of day-care centers will result in an increase in the number of cases of congenital CMV infection will be difficult if not impossible to determine because congenital CMV infection is not a reportable disease and population-based estimates of rates for the United States are not kept.

PARVOVIRUS B19

Clinical Significance

In the normal host, the most frequent clinical manifestations associated with human parvovirus B19 infection are rash and arthropathy. Studies of outbreaks of erythema infectiosum or fifth disease established parvovirus as the cause of this common childhood exanthem through measurement of specific IgM antibody, DNA hybridization, and immune electron microscopy.34'35 Erythema infectiosum is characterized by an erythematous rash on the face, giving a "slapped cheek" appearance; patients usually do not have fever or constitutional symptoms.

Three stages in the progress of the exanthem have been distinguished.36 The first stage involves the characteristic facial rash with circumoral pallor. In the second stage, which follows approximately 1 day after the first, the rash spreads as a maculopapular eruption beginning on the proximal extremities and spreading to the distal parts and trunk. During a few days to a week, these lesions develop a lace-like reticular pattern and then fade. The third stage refers to a period after the rash has faded during which skin trauma may stimulate localized reappearance of the rash. The course of erythema infectiosum is sufficiently characteristic to serve as a herald of epidemic activity and exposure to parvovirus B19 in schools and day-care centers. However, clinical evaluation of persons infected through household contact or in school outbreaks has shown that many will not have a classic erythema infectiosum illness.34,35 Approximately two thirds of black subjects and approximately one fifth of white subjects with serologically diagnosed parvovirus infection are asymptomatic.35

In adults, erythema infectiosum is frequently accompanied by joint symptoms. As many as 60% of adults have had arthralgias.37 Joint symptoms are seen more commonly in women than men. In some cases, these have persisted for months following a course suggestive of rheumatoid arthritis.38

The significance of parvovirus B19 as a pathogen is its ability to infect erythroid precursor cells. The course of human B19 infection was defined through the study of adult volunteers infected experimentally by intranasal inoculation.39 The susceptible adults had a high-titered viremia that began 5 to 7 days after inoculation and persisted to 10 to 15 days postinoculation. Reticulocytes were undetectable in the penpheral blood by 7 to 10 days after infection and returned a week to 10 days later with the appearance of serum antibody. Some volunteers showed a biphasic illness, with fever, myalgias, and nonspecific symptoms during the viremia when virus was also present in respiratory secretions. A more typical B19 illness with rash and arthralgias occurred 17 to 18 days after inoculation; this observation suggests that patients are likely to be infectious prior to the onset of the characteristic clinical disease. In the normal host, erythroid aplasia during B19 infection is not clinically apparent because the duration of aplasia is short (7 to 10 days) compared with the life span of a red blood cell. However, in individuals who have rapid turnover of red blood cells and a need for increased red cell production, such as sickle cell disease, hemoglobin SC disease, β-thalassemia, and hereditary spherocytosis, parvovirus B19 appears to be the principal etiology of transient aplastic crisis.35-40

Parvovirus B19 is also a significant pathogen in immunocompromised patients in whom it can produce a severe chronic anemia. Red cell aplasia with chronic viremia has been observed in children with acute leukemia on chemotherapy,41 patients with human immunodeficiency virus infection,42 and patients with congenital immunodeficiencies,43 including brothers in whom chronic anemia and persistent B19 infection were the principal manifestations of immune deficit.44 In some immunodeficient patients, intravenous treatment with pooled human immune globulin has resulted in prompt reticulocytosis and clearance of viremia.42'44

The fetus appears to have difficulty with parvovirus B19 for both hematologie and immunologie reasons. The rapid increase in growth, blood volume, and red cell number as well as the shortened survival of red cells during intrauterine life make the fetus particularly vulnerable to parvovirus- induced red cell aplasia. Immunologie factors may play a role as well; maternal antibody does not cross the placenta in significant quantities until late in the second trimester. Fetal antibody appears to be insufficient in either quantity or quality to terminate viremia.40 Anemia, congestive heart failure, and nonimmune hydrops have been the clinical hallmarks of fetal infection.45 Although B19 has been found in the myocardium and histopathologic changes have been noted in the liver and other tissues, the hydrops and fetal death appear to be caused by the severe anemia.45'47 Congenital malformations have not been attributed to human B19 infection, although it should be noted that certain animal parvoviruses have specific teratogenic effects.48

Epidemiology

Serologie evidence of previous infection has been reported in 30% to 60% of adults in seroprevalence surveys.40,49 The prevalence of antibody has been lower in children with 15% to 60% of school-aged children and 2% to 15% of preschoolers testing positive.49 The changes in age-related prevalence of antibody to B19 suggest that the infection is most often acquired during early childhood, and indeed, most reported outbreaks have involved preschool and school-aged children and adults in close contact with them. Spread of the virus is thought to occur through the respiratory route or through contact with oropharyngeal secretions.40'49 Erythema infectiosum and transient aplastic crisis usually appear around 4 to H days after household exposure, but incubation periods of up to 20 days have been observed.34,35,49 Virus is frequently detectable in respiratory secretions during the prodromal period of erythema infectiosum but is not found during the characteristic illness, suggesting that transmission is most likely to occur during the prodromal period.34,39 With household exposure, the rate of secondary infection as indicated by IgM antibody to B19 is approximately 50%.35 Attack rates of 36% and 38% have been reported among susceptible health-care workers exposed to patients with transient aplastic crisis.50

Table

TABLE 3Secondary Attack Rates for Serologically Defined Parvovirus B19 Infection in Various Settings After Exposure to Erythema lnfectlosum or Transient Aplastic Crisis Patient

TABLE 3

Secondary Attack Rates for Serologically Defined Parvovirus B19 Infection in Various Settings After Exposure to Erythema lnfectlosum or Transient Aplastic Crisis Patient

Gestational and Fetal Infection

Studies of pregnant women not selected for exposure or residence in a community experiencing an epidemic have shown seroconversion rates of 1% to 1.5% per year.51,52 A study of women who experi' enced spontaneous abortion or stillbirth showed a B19 infection rate of 1%, identical to the rate observed in matched controls.51 In fetuses with nonimmune hydrops fetalis, only 8% had evidence of B19 infection by in situ DNA hybridization.53 Parvovirus appears to be an uncommon cause of fetal death and to account for only a small proportion of hydrops fetalis, the disorder most characteristic of B19 fetal infection.

Table

TABLE 4Estimated Frequency and Consequences of CMV and Parvovirus Bl 9 Infections During Pregnancy

TABLE 4

Estimated Frequency and Consequences of CMV and Parvovirus Bl 9 Infections During Pregnancy

Estimates of the risk for fetal loss when a pregnant woman of unknown antibody status is exposed have been based on the expected rate of immunity in the population, the risk of infection after exposure, and the rate of fetal demise with proven maternal gestational infection. Using this approach, the upper limit estimate is 2.5% for fetal death after household exposure and 1.5% after occupational exposure in a school.40

The risk of infection in susceptible pregnant women with household or occupational exposure (ie, day care, school, or hospital) to erythema infectiosum or transient aplastic crisis can be expected to range from 16% to 50%35,50,54 (Table 3). Recent studies have shown that when maternal infection occurs during pregnancy, the rate of fetal loss is 4% to 10%, but it is not clear that this rate is higher than expected in a suitable control population.49'55 Serologie follow-up of offspring indicates silent prenatal infection in 10% to 30%.55,56 Neither neonatal illness nor congenital malformations have yet been linked to prenatal B19 infection, but a relatively small number of infected infants have been recognized. Most reported cases of fetal death due to hydrops have occurred in the second trimester.

Ultrasound has proven valuable in identifying hydrops fetalis in cases of maternal parvovirus B19 infection.57 In a few reported cases, fetal blood sampling has allowed detection of infection in utero and observation of the evolution of fetal anemia.58 Successful treatment of fetal anemia by intrauterine transfusion has been reported56,59; however, because spontaneous resolution of fetal hydrops could also occur, intrauterine transfusion should be considered investigational for fetal anemia due to parvovirus at this time.

Parvovirus B19 in Day-Care Centers

Studies of outbreaks in schools and day-care centers have shown that parvovirus is readily transmitted from child to child and from child to adult. In outbreaks of erythema infectiosum in schools, between 10% and 60% of students may develop a rash illness. Gillespie et al studied a large outbreak in Connecticut, testing 571 school and day-care personnel for serologie evidence of parvovirus infection.54 The overall attack rate among susceptibles during the outbreak was 19% (46/236). Secondary cases occurred in nonteaching personnel as well as in teachers. The highest rates were seen in day-care personnel (31%) and in nonteaching middle school personnel (39%) while no secondary cases were seen among susceptible high school teachers. The risk of infection was higher for personnel with contact with larger numbers of younger children. Only one pregnant worker was found to be infected during this outbreak, and no adverse fetal outcomes were observed- However, in a study of risk factors for B19 infection in pregnant women in a community with a recent outbreak of erythema infectiosum, the highest rates of infection were found in school teachers (16%), day-care workers (9%), and homemakers (9%).60 Thus, it is clear that exposure to young children during outbreaks of erythema infectiosum is an important risk for infection in pregnant women. Fortunately, fetal infection is relatively uncommon even during community outbreaks.

CONTROL OF CMV AND PARVOVIRUS IN DAY-CARE CENTERS

The need for considering measures to prevent the spread of CMV and parvovirus in day-care centers arises principally from their importance as causes of fetal and congenital infection. Theoretically, one would also like to prevent both infections in hosts with impaired immune systems, but day-care center acquisition by immunocompromised patients has not been reported for either agent. Unfortunately, no vaccine is available for either CMV or B 19, and no means of preventing infection in women caring for infected children has been proven effective.

Although the rate of CMV excretion by children in day-care centers has varied, it is accurate to state that exposure to children shedding this virus is inevitable for day-care center workers. Because spread of the virus appears to require direct contact with infected material, procedures that prevent this contact such as careful handwashing and hygiene and perhaps the use of gloves might decrease the risk to day-care workers. Screening children for CMV excretion or excluding those known to have congenital CMV infection cannot be justified because excretion status can change and shedding of CMV is common in preschool children.613 Testing workers for antibody to CMV can be very valuable for those who could become pregnant. Those who are seropositive can be strongly reassured that day-care center exposure to CMV constitutes no known risk to their unborn child if they do become pregnant.

The Centers for Disease Control has recommended that parents of children and employees should be advised about the risk and possible consequences of parvovirus B19 infection when an outbreak of erythema infectiosum occurs.49 Exclusion of children with erythema infectiosum was not recommended because the greatest risk of transmitting virus occurs prior to the onset of erythema infectiosum symptoms. No means of preventing transmission of parvovirus is known, but handwashing was recommended as a "probably effective measure."

With both parvovirus and CMV, it is important that employees be informed of the possibility of exposure and the potential consequences of gestational infection (Table 4). It is likely that some employees will choose not to work in a day-care center because of CMV risk or will want to stay home during an erythema infectiosum outbreak. If employees have children of their own at home, they not change their risk by avoiding the workplace. With both infections, transmission of virus from child to parent probably constitutes a larger problem than day-care worker infections.

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TABLE 1

Comparison of Epidemiologie and Clinical Features of Cytomegalovirus and Parvovirus Bl9 Infections

TABLE 2

Incidence of CMV Infection in Day-Care Workers and Controls

TABLE 3

Secondary Attack Rates for Serologically Defined Parvovirus B19 Infection in Various Settings After Exposure to Erythema lnfectlosum or Transient Aplastic Crisis Patient

TABLE 4

Estimated Frequency and Consequences of CMV and Parvovirus Bl 9 Infections During Pregnancy

10.3928/0090-4481-19910801-07

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