Michael J. Cannon

Seroprevalence of Cytomegalovirus Infection in the United States, 1988–1994

BACKGROUND Cytomegalovirus (CMV) is a leading cause of congenital illness and disability, including hearing loss and mental retardation. However, there are no nationwide estimates of CMV seroprevalence among pregnant women or the overall population of the United States. METHODS To determine CMV prevalence in a representative sample of the US population, we tested serum samples for CMV-specific immunoglobulin G from participants aged > or =6 years (n=21,639) in the third National Health and Nutrition Examination Survey (1988-1994). RESULTS The prevalence of CMV infection was 58.9% in individuals > or =6 years old. CMV seroprevalence increased gradually with age, from 36.3% in 6-11-year-olds to 90.8% in those aged > or =80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans. Racial and/or ethnic differences in CMV seroprevalence persisted when controlling for household income level, education, marital status, area of residence, census region, family size, country of birth, and type of medical insurance. Among women, racial and/or ethnic differences were especially significant; between ages 10-14 years and 20-24 years, seroprevalence increased 38% for non-Hispanic black persons, 7% for non-Hispanic white persons, and <1% for Mexican Americans. CONCLUSIONS On the basis of these results, we estimate that each year in the United States approximately 340,000 non-Hispanic white persons, 130,000 non-Hispanic black persons, and 50,000 Mexican American women of childbearing age experience a primary CMV infection. Given the number of women at risk and the significance of congenital disease, development of programs for the prevention of CMV infection, such as vaccination or education, is of considerable public health importance.

Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection.

Cytomegalovirus establishes a lifelong latent infection following primary infection that can periodically reactivate with shedding of infectious virus. Primary infection, reactivation and reinfection during pregnancy can all lead to in utero transmission to the developing fetus. Congenital CMV infections are a major cause of permanent hearing loss and neurological impairment. In this literature review, we found that CMV infection was relatively common among women of reproductive age, with seroprevalence ranging from 45 to 100%. CMV seroprevalence tended to be highest in South America, Africa and Asia and lowest in Western Europe and United States. Within the United States, CMV seroprevalence showed substantial geographic variation as well, differing by as much as 30 percentage points between states, though differences might be explained by variation in the types of populations sampled. Worldwide, seroprevalence among non‐whites tended to be 20–30 percentage points higher than that of whites (summary prevalence ratio (PR) = 1.59, 95% confidence interval (CI) = 1.57–1.61). Females generally had higher seroprevalences than males, although in most studies the differences were small (summary PR = 1.13, 95% CI=1.11–1.14). Persons of lower socioeconomic status were more likely to be CMV seropositive (summary PR = 1.33, 95% CI = 1.32–1.35). Despite high seroprevalences in some populations, a substantial percentage of women of reproductive age are CMV seronegative and thus at risk of primary CMV infection during pregnancy. Future vaccine or educational campaigns to prevent primary infection in pregnant women may need to be tailored to suit the needs of different populations. Published in 2010 by John Wiley & Sons, Ltd.

Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004.

BACKGROUND. Congenital cytomegalovirus (CMV) infection causes permanent disabilities in more than 5500 children each year in the United States. The likelihood of congenital infection and disability is highest for infants whose mothers were CMV seronegative before conception and who acquire infection during pregnancy. METHODS. To provide a current, nationally representative estimate of the seroprevalence of CMV in the United States and to investigate trends in CMV infection, serum samples from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 were tested for CMV-specific immunoglobulin G antibody, and results were compared with those from NHANES III (1988-1994). Individuals aged 6-49 years (21,639 for NHANES III and 15,310 for NHANES 1999-2004) were included. RESULTS. For NHANES 1999-2004, the overall age-adjusted CMV seroprevalence was 50.4%. CMV seroprevalence was higher among non-Hispanic black and Mexican American children compared with non-Hispanic white children and increased more quickly in subsequent age groups. CMV seropositivity was independently associated with older age, female sex, foreign birthplace, low household income, high household crowding, and low household education. Compared with NHANES 1988-1994, the overall age-adjusted CMV seroprevalence for NHANES 1999-2004 was not significantly different. CONCLUSIONS. Many women of reproductive age in the United States are still at risk of primary CMV infection during pregnancy. There is an urgent need for vaccine development and other interventions to prevent and treat congenital CMV. The substantial disparities in CMV risk among seronegative women suggest that prevention strategies should include an emphasis on reaching racial or ethnic minorities and women of low socioeconomic status.

Washing our hands of the congenital cytomegalovirus disease epidemic

BackgroundEach year in the United States, an estimated 40,000 children are born with congenital cytomegalovirus (CMV) infection, causing an estimated 400 deaths and leaving approximately 8000 children with permanent disabilities such as hearing or vision loss, or mental retardation. More children are affected by serious CMV-related disabilities than by several better-known childhood maladies, including Down syndrome, fetal alcohol syndrome, and spina bifida.DiscussionCongenital CMV is a prime target for prevention not only because of its substantial disease burden but also because the biology and epidemiology of CMV suggest that there are ways to reduce viral transmission. Because exposure to the saliva or urine of young children is a major cause of CMV infection among pregnant women, it is likely that good personal hygiene, especially hand-washing, can reduce the risk of CMV acquisition. Experts agree that such measures are likely to be efficacious (i.e., they will work if consistently followed) and the American College of Obstetricians and Gynecologists recommends that physicians counsel pregnant women about preventing CMV acquisition through careful attention to hygiene. However, because of concerns about effectiveness (i.e., Will women consistently follow hygienic practices as the result of interventions?), the medical and public health communities appear reluctant to embrace primary CMV prevention via improved hygienic practices, and educational interventions are rare. Current data on the effectiveness of such measures in preventing CMV infection are promising, but limited. There is strong evidence, however, that educational interventions can prevent other infectious diseases with similar transmission modes, suggesting that effective interventions can also be found for CMV. Until a CMV vaccine becomes available, effective educational interventions are needed to inform women about congenital CMV prevention.SummaryPerhaps no single cause of birth defects and developmental disabilities in the United States currently provides greater opportunity for improved outcomes in more children than congenital CMV. Given the present state of knowledge, women deserve to be informed about how they can reduce their risk of CMV infection during pregnancy, and trials are needed to identify effective educational interventions.

Incidence of cytomegalovirus infection among the general population and pregnant women in the United States

BackgroundCytomegalovirus (CMV) is a common opportunistic infection among HIV-infected individuals, a major source of serious complications among organ-transplant recipients, and a leading cause of hearing loss, vision loss, and mental retardation among congenitally infected children. Women infected for the first time during pregnancy are especially likely to transmit CMV to their fetuses. More children suffer serious disabilities caused by congenital CMV than by several better-known childhood maladies such as Down syndrome or fetal alcohol syndromeMethodsUsing CMV seroprevalence data from the nationally representative Third National Health and Nutrition Examination Survey, we estimated CMV incidence among the general United States population and among pregnant women. We employed catalytic models that used age-specific CMV seroprevalences as cumulative markers of past infections in order to derive estimates of three basic parameters: the force of infection, the basic reproductive rate, and the average age of infection. Our main focus was the force of infection, an instantaneous per capita rate of acquisition of infection that approximates the incidence of infection in the seronegative population.ResultsAmong the United States population ages 12–49 the force of infection was 1.6 infections per 100 susceptible persons per year (95% confidence interval: 1.2, 2.4). The associated basic reproductive rate of 1.7 indicates that, on average, an infected person transmits CMV to nearly two susceptible people. The average age of CMV infection was 28.6 years. Force of infection was significantly higher among non-Hispanic Blacks (5.7) and Mexican Americans (5.1) than among non-Hispanic Whites (1.4). Force of infection was significantly higher in the low household income group (3.5) than in the middle (2.1) and upper (1.5) household income groups. Based on these CMV incidence estimates, approximately 27,000 new CMV infections occur among seronegative pregnant women in the United States each year.ConclusionThese thousands of CMV infections in pregnant women, along with the sharp racial/ethnic disparities in CMV incidence, are compelling reasons for accelerating research on vaccines and other interventions for preventing congenital CMV disease. Nevertheless, the relatively low force of infection provides encouraging evidence that modestly effective vaccines and rates of vaccination could significantly reduce CMV transmission.

Blood-borne and sexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiency virus infection

BACKGROUND Human herpesvirus 8 (HHV-8), the causal agent of Kaposis sarcoma, is transmitted sexually among homosexual men, but little is known of its transmission among women. Although HHV-8 has been detected in blood, there has been no clear evidence of blood-borne transmission. METHODS We identified risk factors for HHV-8 infection in 1295 women in Baltimore, Detroit, New York, and Providence, Rhode Island, who reported high-risk sexual behavior or drug use. HHV-8 serologic studies were performed with two enzyme-linked immunosorbent assays. RESULTS In univariate analyses, HHV-8 was associated with black race, Hispanic ethnic background, a lower level of education, and infection with syphilis, the human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). The risk of seropositivity for HHV-8 increased with the frequency of injection-drug use (P<0.001); HHV-8 seroprevalence among the women who used drugs daily was three times that among women who never injected drugs. Among the women with a low risk of sexual transmission, HHV-8 seroprevalence was 0 percent in those who had never injected drugs and 36 percent in those who had injected drugs (P<0.001). However, injection-drug use was linked less strongly to HHV-8 infection than to infection with HBV or HCV. In a multivariate analysis, independent predictors of HHV-8 seropositivity included HIV infection (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.2), syphilis infection (odds ratio, 1.8; 95 percent confidence interval, 1.1 to 2.8), and daily injection-drug use (odds ratio, 3.2; 95 percent confidence interval, 1.4 to 7.6). CONCLUSIONS Both injection-drug use and correlates of sexual activity were risk factors for HHV-8 infection in the women studied. The independent association of HHV-8 infection with injection-drug use suggests that HHV-8 is transmitted through needle sharing, albeit less efficiently than HBV, HCV, or HIV.

Congenital cytomegalovirus (CMV) epidemiology and awareness

This commentary highlights and discusses the implications of a number of recent studies that refine epidemiologic knowledge of CMV infection and assess awareness of congenital CMV among clinicians and the public. These studies highlight that: (1) congenital CMV results in a disease burden that is substantial and severe; (2) a high proportion of United States women of reproductive age are susceptible to CMV infection; (3) the majority of congenital CMV infections in the United States result from recurrent infections among pregnant women; (4) CMV seroprevalence and seroincidence are much higher among racial/ethnic minorities and persons of lower socioeconomic status (SES); (5) household transmission of CMV appears to be an important transmission route in the United States; (6) sexual transmission of CMV appears to be an important transmission route in some population sub-groups in the United States; (7) women have limited awareness and knowledge about congenital CMV; (8) most obstetrician/gynecologists do not counsel women about prevention of congenital CMV; (9) most women view CMV prevention messages positively.

Attribution of Congenital Cytomegalovirus Infection to Primary Versus Non-Primary Maternal Infection

Congenital cytomegalovirus (CMV) infection is a leading cause of developmental disabilities. In the United States during the period 1988-1994, approximately one-quarter of congenital CMV infections were attributable to primary maternal infection (n = 8772), and three-quarters were attributable to non-primary maternal infection (n = 29,918). Effective prevention strategies need to be developed for both primary and non-primary maternal infections.

Review of cytomegalovirus shedding in bodily fluids and relevance to congenital cytomegalovirus infection.

Congenital cytomegalovirus (CMV) infections are a leading cause of sensorineural hearing loss (SNHL) and neurological impairment. Congenital transmission of CMV can occur with maternal primary infection, reactivation, or reinfection during pregnancy. We reviewed studies of CMV shedding in bodily fluids (defined as CMV detected by culture or CMV DNA detected by polymerase chain reaction). Following diagnosis at birth, children with congenital CMV infection exhibited the highest prevalences of CMV shedding (median = 80%, number of sample population prevalences [N] = 6) and duration of shedding, with a steep decline by age five. Healthy children attending day care shed more frequently (median = 23%, N = 24) than healthy children not attending day care (median = 12%, N = 11). Peak shedding prevalences in children occurred at 1–2 years of age, confirming that young children are the key transmission risk for pregnant women. CMV shedding among children was more prevalent in urine specimens than in oral secretions (median prevalence difference = 11.5%, N = 12). Adults with risk factors such as STD clinic attendance had higher shedding prevalences (median = 22%, N = 20) than adults without risk factors (median = 7%, N = 44). In adults with risk factors, CMV was shed more frequently in urine; in adults without risk factors genital shedding was most common. The prevalence of CMV shedding in nine sample populations of pregnant women increased with advancing gestation. In seven sample populations of children with congenital CMV infection, higher viral load at birth was consistently associated with an elevated risk of SNHL. Higher CMV viral load at birth also consistently correlated with the presence of symptoms of congenital CMV at birth. Published 2011. This article is a US Government work and is in the public domain in the USA.

Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV

Congenital CMV infection is caused by in utero mother‐to‐fetus transmission and is a leading cause of birth defects and developmental disabilities. The highest risk of disability is to children born to women who have a primary infection during pregnancy, which can be detected by measuring seroconversion. We reviewed studies that reported rates of CMV seroconversion in different populations. Among pregnant women, annual seroconversion rates typically ranged from 1 to 7% (summary annual rate = 2.3%, 95% CI = 2.1–2.4%). Healthcare workers, including those caring for infants and children, had seroconversion rates similar to pregnant women (summary annual rate = 2.3%, 95% CI = 1.9–2.9%). Among day‐care providers, seroconversion rates ranged from 0 to 12.5% (summary annual rate = 8.5%, 95% CI = 6.1–11.6%). Parents whose child was not shedding CMV were much less likely to seroconvert (summary annual rate = 2.1%, 95% CI = 0.3–6.8%) than were parents who had a child shedding CMV (summary annual rate = 24%, 95% CI = 18–30%). Nevertheless, over the course of a year, most parents exposed to a CMV‐shedding child do not become infected. Other groups with elevated risk included families with a CMV‐shedding member, female minority adolescents and women attending sexually transmitted disease clinics. The relatively low rate of CMV seroconversion in most populations is encouraging for behavioural interventions and for vaccine strategies attempting to prevent infection during pregnancy. Published in 2010 by John Wiley & Sons, Ltd.