Health disparities by socioeconomic status (SES) in the US are well established for a wide range of health outcomes.1 The US Department of Health and Human Services declared as 1 of the 2 major goals of the Healthy People 2010 initiative “to eliminate health disparities among different segments of the population.” The pathophysiologic mechanisms linking lower SES to the earlier onset of disease are not well understood. In particular, very little is known about the role of the immune system in creating and sustaining health disparities.
Recent studies have shown that cytomegalovirus (CMV) may be a factor in immunosenescence.2–4 Indeed, CMV has been considered a more important predictor of mortality than many of the well-known traditional immune function markers such as CD4:CD8 ratio, T-cell proliferation, and B cell counts in older age populations.5 CMV has also been implicated in cardiovascular disease and more recently linked to cognitive and physical decline.6–10 Primary infection with CMV can occur at a very young age, and is often asymptomatic. The virus remains persistent in the infected host's cells for life. Containment of the virus becomes an immune system priority.11,12 Studies have identified positive age-related gradients in antibody response to CMV that are accompanied by higher shedding of CMV DNA.12 Because impaired cellular immune response can result in increased CMV viral replication, these studies suggest that an increase in CMV antibody titer is a good marker of compromised cell mediated immunity observed in aging.12,13
Previously, data from the Third National Health and Nutrition Examination Survey (NHANES) III have described large disparities in CMV prevalence in the US by education, income, and race and ethnicity over a range of ages.14,15 These SES disparities in seroprevalence emerge as early as age 6 years, converging over age 65 years when more than 90% of the population is exposed. Socioeconomic disparities in CMV seroprevalence provide important information about the link between socioeconomic determinants and exposure to CMV, but do not provide any indication of the variability in immune response to CMV among those who are seropositive. The social patterning of immune response among seropositive individuals has not been fully explored. Recent work identified an association between lower education and increased immune response to CMV and Herpes Simplex Virus Type 1 (HSV-1) in a community-based sample of Latinos ages 65 years and over.16 It is unclear whether similar gradients are found across a broader range of categories of age, race, and ethnicity. If socioeconomic gradients in CMV antibody levels are sustained across the life course, it may well represent an important immunologic pathway linking socioeconomic status to adult immune function and overall health. Therefore, we analyzed NHANES III data for subjects aged 25 years and older to assess social patterning in immune response to CMV.
Participants were part of the National Health and Nutrition Examination Survey (NHANES) III conducted by the National Center for Health Statistics from 1988 to 1994. The sample was a complex, stratified, multistage probability cluster of the US population including interview, clinical examination, and laboratory tests. Persons less than 5 or over 60 years of age, non-Hispanic black persons, and Mexican Americans were sampled at a higher frequency than other groups to obtain adequate sample sizes for subgroup analysis. The complete methodology and response rates of NHANES III have been published previously.17 To focus on adult socioeconomic status and antibody response to existing infection, our analysis includes individuals 25 years and older who are seropositive to CMV (n = 10,882). Those classified as CMV-seropositive represent 81% of respondents aged 25 years and older. As reported elsewhere, correlates of CMV seropositivity in the US include lower education and income, older age, and non-Hispanic black and Mexican American ethnicity.14,15 Of the 10,882 subjects, 1161 CMV seropositive individuals (12%) were lacking data on one or more covariates, primarily income, leaving a final sample of 9721 subjects. Individuals with missing income were slightly more likely to be women with less education, but did not differ in CMV antibody levels.
Cytomegalovirus antibody levels were tested using frozen stored sera specimens from NHANES III to estimate the seroprevalence of CMV infection (CMV IgG) in participants aged 6 years and above and released in 2006. CMV-specific IgG was measured by an Enzyme Linked Immunoassay (ELISA) (Quest International, Inc., Miami, FL). IgG optical density and ELISA index values were subsequently released in 2007 to the investigators by special request to the National Center for Health Statistics. As the original aim of the CMV testing was to identify seropositivity rather than continuous antibody levels, 32% of the IgG values for the full sample (and 48% of the values for the sample 25 years and over) were given a top-coded value of the maximum detectable threshold, which was set for each test batch. ELISA Index values between 0.90 and 1.05 (1% of the sample) were considered indeterminate with regard to seropositivity by the laboratory (Quest International, Inc.). We conservatively classified these individuals as seronegative to ensure that our analysis focused on antibody response among seropositive individuals and did not reflect underlying differences in seropositivity.
Education was measured as the respondent's years of completed education. A linear specification of years of education provided the best model fit. Family income was self-reported pretax family income for the 12-months prior to the survey including wages, salaries, income from self-employment, veteran's benefits, interest dividends, rental income, and public assistance. Income data were recorded in 28 income categories (none; less than $1000; $1000–$20,000 in $1000 increments; $20,000–$50,000 in $5000 increments; and greater than $50,000). We coded family income as the midpoint of each of the reported categories (using $65,000 for the incomes above $50,000) and adjusted for inflation between the 2 NHANES III phases, using the Consumer Price Index. Income was log-transformed due to the skewness of the distribution. Race/ethnicity was grouped in 4 categories (non-Hispanic white, non-Hispanic black, Mexican-American, and other).
A modified Charlson index was used to control for the potential impact of current chronic health conditions on immune response. The Charlson index employs a weighting system for each condition category based on the adjusted risk of 1-year mortality.18 A higher score reflects a more severe burden of comorbidity. Weights were assigned for having myocardial infarction, cerebrovascular/peripheral vascular disease, chronic pulmonary disease, connective tissue/autoimmune disease, ulcer, liver disease, diabetes, moderate to severe renal disease, and any tumor. Points for each condition were summed to create the final score, as previously described.18
To assess the potential effects of any immune-related conditions or current infections not captured in our Charlson index, we created 2 medication variables to represent whether an individual was taking, near the time of the blood sample, any of the major classes of drugs that are: (i) treatments for concurrent infection (ie, antibiotics, cold medicines, antivirals, antiretrovirals, etc.) or (ii) treatments for autoimmune disorders (ie, corticosteroids, immunologic agents, immunomodulators, antiarthritics). Other control variables included: sex; age in years; marital status (1 = married or cohabitating; 2 = widowed, separated, or divorced; 3 = never married); census region of residence; urban or rural residence; household size (persons in the dwelling); an indicator for current, former, or never smoking status; and body mass index (BMI).
The association of education and income, with CMV antibodies was tested using censored normal regressions to account for the right-censoring of CMV values. This model is a generalization of the Tobit model that allows censored values to vary from observation to observation, rather than a constant upper or lower censoring point.19 In our case, because different CMV testing batches were arbitrarily top-coded at different values, this model was the most appropriate. All observations were assigned the CMV value reported, and an additional indicator variable was created: 0, if the observation was not right-censored and 1, if the observation was right-censored. All analyses were conducted using STATA 10.0 (STATA, College Station, TX) survey commands to account for the complex survey design, and the sample completing the laboratory components was weighted to reflect the noninstitutionalized population of the United States. The command “cnreg” was used in STATA for the right-censored models.
Statistically significant interactions between income and sex and between education and sex were identified, leading to subsequent stratification by sex. Other covariates included in preliminary models included age, race-ethnicity, Charlson index, census region of residence, urban or rural residence, marital status, prescription medication use, smoking status, or obesity. Of these, only age, race/ethnicity, and the Charlson index were associated with CMV antibody levels in fully adjusted models. The final model thus regresses CMV antibody levels on education, income, age, race/ethnicity, and the Charlson index, stratified by sex.
Sample descriptives for the 9797 participants are shown in Table 1. There was a higher mean CMV antibody level among women compared with men, and lower levels of former and current smoking among women than among men. There were only slight differences in other variables by sex.
CMV Antibody Levels, Education, and Income: Full Sample
Figures 1 and 2 illustrate the adjusted relationship of categorical education and income with CMV values across age, based on predicted values. CMV antibody levels increased substantially with age. Within a given age group, levels were higher for those with less education and less income. Increasing age was associated with higher CMV antibody levels at the rate of 0.03 ELISA units per year after age 25, consistent with a decreased ability of the immune system to maintain control over the virus with age (Table 2).
Both education and family income were inversely associated with CMV antibody levels. Each additional year of education was associated with a 0.05 reduction in the CMV ELISA index value. Thus, holding all else constant, an additional 5 years of education was associated with roughly the same reduction in CMV values as would be seen in a respondent 8 years younger. Non-Hispanic blacks, on average, had higher CMV levels compared with non-Hispanic whites, and women had higher levels on average than men, holding all else constant. In fully adjusted models, having more chronic conditions as measured by the Charlson Index was also associated with higher CMV levels.
CMV Antibody Levels, Education, and Income: by Sex
The associations of education and income with CMV varied by sex (Table 2). For women, years of education were more strongly associated with CMV levels than for men, for whom the association with income was stronger. For women, each additional year of education was associated with a 0.08 reduction in the CMV index, so that an additional 5 years of education was associated with a reduction in CMV values similar to that seen in women approximately 13 years younger, holding all else constant. For men, the association with income appeared to dominate that of education, such that a doubling of family income was associated with a 0.44 lower index value of CMV, all else held constant. For men, this 0.44 reduction in the index value is equivalent to the reduction associated with being 11 years younger.
The effects of race/ethnicity appeared stronger for women than for men. In fully adjusted models, non-Hispanic black women had a CMV index value that was 0.78 points higher than non-Hispanic white women, and Mexican-American women had an index 0.91 points higher than non-Hispanic white women, though the standard error was much larger for Mexican-Americans. The magnitude of these differences is large compared with the 0.03 unit increase with 1 year of age. For men, non-Hispanic blacks had CMV values 0.31 units higher than to non-Hispanic whites, holding all else constant. In fully adjusted models, the Charlson Index was associated with higher levels of CMV for the full sample, slightly less so for women than for men. Adjusting for current conditions and comorbidities did not account for the relationship of SES and race/ethnicity, with CMV antibody response.
CMV Antibody Levels, Education, and Income: by Age
It is possible that SES differences in antibody response would emerge only in older age groups at greater risk of immune decline. To test this hypothesis we interacted both education and income with continuous age, and also with dichotomous age (above and below age 65 years). None of these interactions was statistically significant, providing no support for the possibility that the associations of education and income with CMV antibody response depend on age.
We find a substantial association between socioeconomic status and an indirect marker of cell-mediated immunity in a nationally representative sample of the US population. Our study confirms recent findings of an association between level of education and CMV antibody response in a community-based study of elderly Latinos.16 The findings suggest that impaired cell-mediated immunity may be one way that SES is related to health outcomes in the US population.
CMV has been called the “driving force” behind age-associated alterations to the T-cell immune system. The cost of constant CMV immunologic vigilance throughout life may be high.11 This theory is based on evidence that aging populations experience increased CMV-specific CD8+ T-cell proliferation, reducing the availability of CD8+ T-cell carrying receptors that are specific for other pathogens or foreign antigens that the immune system may encounter. This large clonal expansion of CMV-specific CD8 T cells found in aging populations limits the capacity of the immune system to mount an efficient immune response.20 The reduction in the number of naive cells able to combat new antigens21 resulting from CMV-specific clonal expansion can directly hinder immune response in medically important ways, as observed in poorer immune responses to influenza vaccination among those with higher CMV IgG antibody levels.22 These effects may be particularly relevant for older adults, for whom poor vaccine response is related to higher rates of clinical illness such as influenza infection and pneumonia.23
Recent work has shown that persistent CMV infection in the elderly is an important component of a set of immunologic parameters designated the “immunologic risk phenotype.”21 This set of immunologic markers, including persistent CMV, high CD8 cells, low CD4 cell percentages, and poor T-cell proliferation, are predictive of mortality among healthy elderly individuals.2,11 In addition to these associations, high levels of CMV IgG antibody are strongly correlated in older people with increases in serum cytokines such as tumor necrosis factor (TNF–α) and interleukin (IL)-6.22 This inflammatory pathway may explain the observed links between CMV and cardiovascular disease, frailty, cognitive outcomes, and Alzheimer disease.6–10 Unfortunately, cytokines were not assayed in NHANES III, and so we are unable to test their potential relationship to CMV antibody levels in our sample. Testing of C-reactive protein (CRP) data in NHANES III preceded high-sensitivity assay techniques, resulting in 60% of the CRP values in our sample falling below the detectable threshold, limiting its usefulness in our analyses. It is possible that immune response to latent infection may explain some of the socioeconomic gradients in cardiovascular disease and other inflammatory-associated conditions that have thus far remained unexplained.
Given the evidence for the role of CMV in diseases of aging, the strong patterning of CMV antibody levels by income, education, and race/ethnicity in NHANES III may be a substantively important pathophysiologic mechanism linking SES to health outcomes. Differences in CMV antibody levels were not accounted for by existing chronic conditions, or by health behaviors such as smoking and obesity that might influence immune function. The observed differences were also not explained by factors associated with CMV seropositivity, such as the number of persons in the household or region of residence.14
Although it is clear that CMV antibody levels are higher in lower SES respondents, firm conclusions about the causes of these differences cannot be drawn from the current data. Several studies have used herpesviruses, including CMV, as a marker of subclinical immune response to psychosocial stressors.24 Increases in herpesvirus antibody titers have been linked to a wide array of stressors, including caregiving for a family member with Alzheimer disease,25 involvement in a difficult marriage,26 anticipation of space flight by astronauts,27 traumatic life events,13 academic stress in medical students and military cadets,28 as well as psychological traits of loneliness and anxiety.29 Thus, it is possible that our results reflect the impact of SES-related psychological stress on down-regulation of the cellular immune response. Further studies should examine whether stress is an important factor in the relationship between SES and immune response to CMV in the US population.
Alternative factors associated with CMV reactivation include major clinical conditions or treatments such as organ transplant and immunodeficiency.30,31 These factors are not likely to explain the differences found in this study because these conditions are usually correlated with a high level of reactivation to the point of clinical disease, such as CMV retinitis and other disorders.32 In addition, we controlled for the use of medications that indicate altered immune function such as antivirals, antiretrovirals, and corticosteroids. Antibody levels to CMV were assessed by ELISA and therefore may not necessarily reflect all aspects of cellular immune response to this virus. Further studies are needed to examine other markers of subclinical reactivation, such as CMV DNA shedding, that were not available in this study.
It is possible that increased levels of IgG-specific antibodies may indicate recent primary infection. This is unlikely to be common in our study population because initial infection with CMV (as well as reinfection) generally occurs at young ages.32 There is also no association between household size and CMV antibody levels in our sample (“household” being an important surrogate marker of exposure to infection and increased likelihood of transmission).14,33 CMV IgM antibody, which would indicate recent infection or reinfection, was in NHANES III measured only in women aged 12–49 years. For those women 25 years and older, only 1.74% tested positive for CMV IgM, suggesting that primary infection and reinfection are not important factors in our results.
Higher antibody response may indicate that the duration of the infection has been longer or that an individual has been repeatedly exposed throughout life. If this is the case, then high antibody levels may be a marker for early life or cumulative socioeconomic variation in level of exposure to these infections. This hypothesis is consistent with cross-sectional evidence that at current age-specific rates of seroprevalence, persons with less education, lower income, and nonwhite race are likely to spend a larger number of years infected with CMV by the time they reach older ages.15
Past history of exposure to pathogens, such as CMV, may be an important determinant of later life chronic conditions through encouragement of a pro- or anti-inflammatory status or through gene-environment interactions.2 Socioeconomic status is related to total pathogen burden, including CMV, HSV-1, and Helicobacterpylori, in the US and UK.34,35 The causes of increased pathogen burden and earlier acquisition of persistent pathogens in lower SES individuals are not well understood. Further studies examining the extent to which these factors modify immune response and impact chronic conditions such as cardiovascular disease are warranted.
Given that our measure of comorbidities could be considered a consequence of both our exposure and outcome of interest, we examined the possibility that inclusion of the Charlson index was producing a spurious correlation between SES and CMV antibody levels. In models excluding the Charlson index, coefficient estimates for both income and education were larger rather than smaller, suggesting that comorbidities are likely a mediating factor between SES and antibody levels but unlikely to have introduced an upward bias in our estimates.
There were some differences in our findings by sex. In models including both education and income, education was more strongly linked to CMV levels for women, whereas income was associated more strongly for men. This could reflect substantive differences in the pathways linking SES and health, whereby job-related characteristics reflected in income are more important for immune response in men. It has also been suggested that all household members may not have equal access to household income, and that household income may be a less accurate measure of the resources available to women.36
Limitations to these data included the right-censoring of a substantial fraction of our CMV observations, which did not allow a complete picture of the distribution of this outcome variable. Fortunately, censored regression techniques were able to incorporate the information provided in these top-coded values. As in many large population surveys, there was nontrivial item nonresponse, especially for income. Although those missing income data were slightly more likely to be women with less education, this group did not differ by CMV antibody levels.
A limitation to the use of CMV IgG antibody in general is the use of qualitative ELISA assays for CMV detection, making comparisons across studies difficult. Nonetheless, within studies, elevated CMV antibodies have been linked to important health risks. In a community-sample of elderly Latinos in the US, CMV antibody levels in the highest quartile were associated with greater all-cause mortality risk, decreased physical functioning, and increased cognitive decline.9,37,38 There are few data to indicate standard and recognized risk categories for antibody levels among generally healthy individuals, making it difficult to specify categories of risk. For now, qualitative sample based differences, such as being in the top quartile category of antibody levels, may be the most salient indicator for health risk. This is akin to how cytokines, such as IL-6, are considered as risk factors for cardiovascular health in large-scale studies such as the Framingham Heart Study39 and the Women's Health Study.40 While beyond the scope of this study, further research is needed to assess whether high antibody levels to CMV in the NHANES population are a risk factor for chronic health conditions such as cardiovascular disease.
Whether through subclinical reactivation due to stress, or through a longer period of immune system engagement due to earlier infection, SES differences in immune control over CMV may have fundamental implications for health. Future work should test the extent to which cell-mediated immunity, as measured by CMV antibody levels, can explain socioeconomic gradients in specific health outcomes such as cardiovascular disease and mortality. The role of CMV in immune system and inflammatory changes suggests the possibility of large public health benefits associated with a CMV vaccine. In the absence of a vaccine, future work should identify the causes of socioeconomic disparities in both CMV seroprevalence and immunity in the US population, to lessen the disproportionate health burden associated with this persistent viral infection.
We thank Geraldine McQuillan, Centers for Disease Control and Prevention, for facilitating release of the CMV antibody data used in our study.
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