Early childhood risk exposures and inflammation in early adolescence.

There is now reliable evidence that early psychosocial stress exposures are associated with behavioral health in children; the degree to which these same kinds of stress exposures predict physical health outcomes is not yet clear. We investigated the links between economic adversity, family and caregiving stress in early childhood and several markers of immune function in early adolescence. The sample is derived from the Family Life Project, a prospective longitudinal study of at-risk families. Socio-demographic and psychosocial risks have been assessed at regular intervals since the children were first assessed at 2 months of age. When the children were early adolescents, we conducted an in-depth health assessment of a subsample of families; blood samples were collected from venipuncture for interleukin(IL)-6, Tumor Necrosis Factor (TNF)-alpha, and C-reactive protein (CRP), as well as glucocorticoid resistance. Results indicated limited but reliable evidence of an association between early risk exposure and inflammation in adolescence. Specifically, caregiver depressive symptoms in early childhood predicted elevated CRP almost a decade later, and the prediction was significant after accounting for multiple covariates such as socio-economic adversity, health behaviors and body mass index. Our findings provide strong but limited evidence that early stress exposures may be associated with inflammation, suggesting one mechanism linking early stress exposure to compromised behavioral and somatic health.

Associations of mindfulness with depressive symptoms and well-being in older adults: the moderating role of neuroticism.

OBJECTIVE: To investigate whether observed interactions of mindfulness with the personality trait neuroticism extend to older adults and to aspects of psychological functioning other than depressive symptoms, and whether effects of mindfulness training in this population depend on levels of neuroticism. METHOD: We performed a secondary analysis of data from a randomized controlled trial of Mindfulness-Based Stress Reduction (MBSR) for community-dwelling older adults. We investigated whether neuroticism moderates associations of dispositional mindfulness with various aspects of psychological and physical functioning at baseline, as well as effects of MBSR on these outcomes. RESULTS: Significant two-way interactions showed that greater mindfulness was associated with fewer depressive symptoms and less negative affect at baseline in individuals with average or higher levels of neuroticism. In contrast, mindfulness was associated with greater positive affect and vitality and fewer physical symptoms regardless of the level of neuroticism. There were no effects of MBSR on these outcomes at any level of neuroticism. CONCLUSION: Mindfulness may be more protective against psychological ill-being in older adults with higher levels of neuroticism, but conducive to positive psychological and physical well-being regardless of this personality trait. The potential moderating role of neuroticism should be further evaluated in studies of mindfulness-based interventions in older adults.

Immune and neuroendocrine correlates of temperament in infancy.

There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old. Blood from venipuncture was collected for analyses of nine select innate immune cytokines; salivary cortisol collected prior to and 15 min and 30 min following a physical exam including blood draw was used as an index of neuroendocrine functioning. Analyses indicated fairly minimal significant associations between biological markers and temperament at 6 months. However, by 17 months of age, we found reliable and nonoverlapping associations between observed fearful temperament and biological markers of the immune and neuroendocrine systems. The findings provide some of the earliest evidence of robust biological correlates of fear behavior with the immune system, and identify possible immune and neuroendocrine mechanisms for understanding the origins of behavioral development.

Observed parent-child relationship quality predicts antibody response to vaccination in children.

BACKGROUND: Quality of the parent-child relationship is a robust predictor of behavioral and emotional health for children and adolescents; the application to physical health is less clear. METHODS: We investigated the links between observed parent-child relationship quality in an interaction task and antibody response to meningococcal conjugate vaccine in a longitudinal study of 164 ambulatory 10-11 year-old children; additional analyses examine associations with cortisol reactivity, BMI, and somatic illness. RESULTS: Observed Negative/Conflict behavior in the interaction task predicted a less robust antibody response to meningococcal serotype C vaccine in the child over a 6 month-period, after controlling for socio-economic and other covariates. Observer rated interaction conflict also predicted increased cortisol reactivity following the interaction task and higher BMI, but these factors did not account for the link between relationship quality and antibody response. CONCLUSIONS: The results begin to document the degree to which a major source of child stress exposure, parent-child relationship conflict, is associated with altered immune system development in children, and may constitute an important public health consideration.

Annual research review: The neuroinflammation hypothesis for stress and psychopathology in children--developmental psychoneuroimmunology.

Experimental animal and adult human data suggest that stress exposure is associated with alterations in immune system function that may underlie increased susceptibility to disease and behavioral disorders. The implications of these data for child psychology and psychiatry are not yet clear. The current review seeks to distil and translate the relevant animal and adult human work to children to advance a developmental model of psychoneuroimmunology. In addition to reviewing key specific findings, we consider biological/conceptual models and technical aspects of psychoneuroimmunology work in pediatric populations, and outline the rationales and advantages of integrating hypotheses concerning neuroinflammation in developmental studies of psychopathology.

Depressive symptoms and immune response to meningococcal conjugate vaccine in early adolescence.

Research findings in psychoneuroimmunology document reliable, bidirectional linkages among psychological processes, the nervous system, and the immune system. However, available data are based almost entirely on animal and adult human studies; the application to children and adolescents is uncertain. We capitalized on the experimental leverage provided by a routine vaccination to examine the link between mood symptoms and the immune response to a vaccine challenge in early adolescence. One hundred twenty-six 11-year-olds for whom vaccine response data were available were assessed at prevaccination and 4 weeks, 3 months, and 6 months following vaccination; self-report ratings of depression and anxiety as well as measures of psychosocial and somatic risk were assessed prior to vaccine response. Analyses indicated that children's internalizing mood symptoms were associated with elevated and persistently higher antibody responses, with evidence extending to two of the four serogroups. The associations remained after controlling for multiple possible confounders (social class, body mass index, sleep, psychosocial risk, and pubertal status). The observed enhanced vaccine response associated with depressive and anxious symptoms in early adolescence may reflect an important developmental difference in immune system-brain interplay between adults and children, and it underscores the need for further developmental studies of psychoneuroimmunology.

Big 5 personality traits and interleukin-6: evidence for "healthy Neuroticism" in a US population sample.

The current study investigated if the Big 5 personality traits predicted interleukin-6 (IL-6) levels in a national sample over the course of 5years. In addition, interactions among the Big 5 were tested to provide a more accurate understanding of how personality traits may influence an inflammatory biomarker. Data included 1054 participants in the Midlife Development in the U.S. (MIDUS) biomarkers subproject. The Big 5 personality traits were assessed in 2005-2006 as part of the main MIDUS survey. Medication use, comorbid conditions, smoking behavior, alcohol use, body mass index, and serum levels of IL-6 were assessed in 2005-2009 as part of the biomarkers subproject. Linear regression analyses examined personality associations with IL-6. A significant Conscientiousness*Neuroticism interaction revealed that those high in both Conscientiousness and Neuroticism had lower circulating IL-6 levels than people with all other configurations of Conscientiousness and Neuroticism. Adjustment for health behaviors diminished the magnitude of this association but did not eliminate it, suggesting that lower comorbid conditions and obesity may partly explain the lower inflammation of those high in both Conscientiousness and Neuroticism. Our findings suggest, consistent with prior speculation, that average to higher levels of Neuroticism can in some cases be associated with health benefits - in this case when it is accompanied by high Conscientiousness. Using personality to identify those at risk may lead to greater personalization in the prevention and remediation of chronic inflammation.

Prenatal maternal anxiety predicts reduced adaptive immunity in infants.

Prenatal anxiety has been linked with altered immune function in offspring in animal studies, but the relevance for human health is unknown. We examined prenatal maternal anxiety as a predictor of adaptive immunity in infants at 2 and 6 months of age as part of a prospective longitudinal study. The humoral immune response to hepatitis B vaccine was assessed at 2 months (n=80) and 6 months (n=76) of age. Prenatal anxiety predicted lower hepatitis B antibody titers at 6 months of age independent of obstetric and socio-demographic covariates; the effects were limited to those infants who had not completed the 3-dose vaccine series (for transformed titer values, r=-.36, p<.05). Cell-mediated immune responses at 2 (n=56) and 6 (n=54) months of age were examined by ELISpot assays for interferon(IFN)-γ, interleukin(IL)-2, and IL-4 responder cell frequencies to three antigens: hepatitis B surface antigen, tetanus toxoid, and phytohaemagglutinin (PHA). Prenatal maternal anxiety was associated with reduced IFN-γ and increased IL-4 responder cell frequencies at 6 months of age, independent of obstetric and socio-demographic covariates. No effect of prenatal anxiety was found on adaptive immunity at 2 months of age. The findings provide the first demonstration in humans that prenatal anxiety alters adaptive immunity in the infant.

Mindfulness-based stress reduction for older adults: effects on executive function, frontal alpha asymmetry and immune function.

BACKGROUND/AIMS: Mindfulness-based stress reduction (MBSR) has enhanced cognition, positive emotion, and immunity in younger and middle-aged samples; its benefits are less well known for older persons. Here we report on a randomized controlled trial of MBSR for older adults and its effects on executive function, left frontal asymmetry of the EEG alpha band, and antibody response. METHODS: Older adults (n = 201) were randomized to MBSR or waiting list control. The outcome measures were: the Trail Making Test part B/A (Trails B/A) ratio, a measure of executive function; changes in left frontal alpha asymmetry, an indicator of positive emotions or approach motivation; depression, mindfulness, and perceived stress scores, and the immunoglobulin G response to a protein antigen, a measure of adaptive immunity. RESULTS: MBSR participants had a lower Trails B/A ratio immediately after intervention (p < 0.05); reduced shift to rightward frontal alpha activation after intervention (p = 0.03); higher baseline antibody levels after intervention (p < 0.01), but lower antibody responses 24 weeks after antigen challenge (p < 0.04), and improved mindfulness after intervention (p = 0.023) and at 21 weeks of follow-up (p = 0.006). CONCLUSIONS: MBSR produced small but significant changes in executive function, mindfulness, and sustained left frontal alpha asymmetry. The antibody findings at follow-up were unexpected. Further study of the effects of MBSR on immune function should assess changes in antibody responses in comparison to T-cell-mediated effector functions, which decline as a function of age.

Multisystem physiological dysfunction is associated with depressive symptoms in a population-based sample of older adults.

OBJECTIVE: To evaluate the association between multisystem physiological dysfunction and depressive symptom severity in the US older adults. METHODS: We examined 2405 adults of age 60 years and older by using the data from the 2005-2008 National Health and Nutrition Examination Survey. We constructed a summary score of "physiological dysfunction," encompassing cardiovascular function, glucose regulation, liver function, and renal function. Overall depressive symptoms were obtained from the 9-item Patient Health Questionnaire depression scale, and factor analysis was used to derive affective and somatic symptom scores. We employed multiple linear regression models to estimate associations between physiological dysfunction scores and affective, somatic, and overall depressive symptoms, while adjusting for demographic, socioeconomic factors, and other potentially confounding factors. RESULTS: Greater multisystem physiological dysfunction scores were associated with an increased severity of overall, affective, and somatic depressive symptoms. These associations persisted after adjusting for all covariates: beta = 0.23 (95% confidence interval (CI) = 0.13, 0.32); beta = 0.08 (95% CI = 0.04, 0.11); beta = 0.12 (95% CI = 0.06, 0.18), respectively. CONCLUSIONS: Our results suggest that the multisystem physiological dysfunction is associated with late-life depressive symptoms. Additional longitudinal studies of links between allostatic load, psychosocial stress events throughout the life course, and late-life depressive symptoms may shed further light on this association.

Depressive symptoms, pain, chronic medical morbidity, and interleukin-6 among primary care patients.

OBJECTIVE: Pain, chronic medical morbidity, and depression are highly prevalent problems that frequently co-occur in primary care. Elevated levels of inflammatory markers are linked with all three of these conditions and may play an important role in patients' comorbidities. The current study aimed to examine if the associations among pain, chronic medical morbidity, and the inflammatory marker interleukin (IL)-6 are dependent on depression status in primary care patients. SETTING, SUBJECTS, AND OUTCOME MEASURES: Primary care patients (N = 106) aged 40 and older were assessed for pain (36-item Medical Outcomes Study Survey Form), chronic medical morbidity (checklist of chronic health conditions), and depressive symptoms (Center for Epidemiologic Studies Depression Scale), and provided a blood sample for the measurement of serum IL-6. RESULTS: Among patients with elevated depressive symptoms, higher IL-6 levels were associated with both greater pain and greater chronic medical comorbidity. IL-6 was unrelated to pain or chronic medical comorbidity among patients without clinically significant depressive symptoms. In mediation analyses, chronic medical morbidity did not mediate the association between IL-6 and pain, and depression severity and pain remained independently associated after adjustment for chronic medical comorbidity. CONCLUSIONS: Depression may increase primary care patients' vulnerability to pain and elevated levels of inflammatory markers such as IL-6.

Emotional benefits of mindfulness-based stress reduction in older adults: the moderating roles of age and depressive symptom severity.

OBJECTIVES: To examine the effects of age and depressive symptom severity on changes in positive affect among older adults randomly assigned to a Mindfulness-Based Stress Reduction (MBSR) program or a Waitlist Control group. Drawing from the Motivational Theory of Life-Span Development, we hypothesized that lower levels of depressive symptom severity and older age would be associated with greater positive affect in response to the MBSR intervention. METHODS: Data were collected from a sample of community-dwelling English-speaking adults (n = 200) aged ≥ 65, randomly assigned to an eight-week MBSR program or a Waitlist Control group. Our main outcome variable was a five-item measure of positive affect, which was measured at study entry as well as eight weeks and six months later. RESULTS: At the six-month follow-up, we observed group by baseline depressive symptom severity (ß = -.17, p = .02) and group by baseline depressive symptom severity by age (ß = -.14, p = .05) interactions. Among MBSR participants, greater baseline depressive symptom severity was also associated with less improvement in positive affect at the six-month follow-up (ß = -.30, p = .003). Findings were qualified by a significant depressive symptom severity by age interaction (ß = -.25, p = .01), such that MBSR participants who were 70 and over with lower baseline depressive symptom severity having the greatest improvement in positive affect at the six-month follow-up. CONCLUSION: MBSR improves positive affect for older adults with lower depressive symptom severity, perhaps because it capitalizes on naturalistic changes in control strategies.

Sleep disturbance and older adults' inflammatory responses to acute stress.

OBJECTIVES: Poor sleep diminishes mental and physical health. The objective of this study was to examine associations between sleep disturbance and interleukin-6 (IL-6) responses to acute mental stress in older adults. DESIGN: Observational study of community-dwelling, healthy older adults. SETTING: Participants completed the study in a clinical research laboratory of a mid-sized university. PARTICIPANTS: Generally healthy, community-dwelling men and women age 50 and older. MEASUREMENTS: IL-6 and negative affect at rest and following a series of challenging cognitive tests; sleep quality; depressive symptoms; perceived stress; loneliness. RESULTS: Participants categorized as poor sleepers on the basis of Pittsburgh Sleep Quality Index scores had significantly larger IL-6 responses to the cognitive stressors than good sleepers. The association between poor sleep and heightened IL-6 response to acute stress was not explained by other psychosocial factors previously linked to immune dysregulation, including depressive symptoms, perceived stress, and loneliness. CONCLUSIONS: Findings add to the growing evidence for poor sleep as an independent risk factor for poor mental and physical health. Older adults may be particularly vulnerable to effects of sleep disturbance due to significant age-related changes in both sleep and inflammatory regulation.

Moderating effects of moderate-intensity physical activity in the relationship between depressive symptoms and interleukin-6 in primary care patients.

OBJECTIVE: To determine whether the relationship between interleukin (IL)-6 and depressive symptoms is moderated by participation in moderate-intensity physical activity in a sample of primary care patients. Elevated inflammation has been associated with a number of poor health outcomes. Depressive symptoms may be related to higher levels of the inflammatory marker IL-6; however, previous findings are inconsistent, possibly due to unidentified moderating factors. METHODS: A total of 107 participants, aged ≥ 40 years, were recruited in Rochester, New York, in 2006 to 2007. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale-Revised, participation in moderate-intensity physical activity was measured using a modified version of the Community Health Activities Model Program for Seniors Activity Questionnaire for Older Adults, and serum IL-6 concentrations were determined using standard enzyme-linked immunosorbent assay protocols and high-sensitivity, anti-cytokine antibody pairs. A hierarchical multiple regression analysis was conducted. RESULTS: The correlation between IL-6 and depressive symptoms was nonsignificant (r = .086, p = .40). The association between IL-6 and depressive symptoms was moderated by participation in moderate-intensity physical activity (p = .02). Among those who did not engage in moderate-intensity physical activity, higher levels of depressive symptoms were significantly associated with higher levels of IL-6 (r = .28, p = .05), whereas this association was not significant among those who did participate in moderate-intensity physical activity (r = -.13, p = .38). CONCLUSION: Participation in moderate-intensity physical activity may buffer the risk of higher inflammation often associated with higher levels of depressive symptoms.

Psychiatric symptoms and proinflammatory cytokines in pregnancy.

OBJECTIVE: Clinical studies suggest that psychiatric symptoms, particularly depression, anxiety, and trauma, may be associated with inflammation, as indexed by proinflammatory cytokines. Such a link may be especially significant in pregnancy and may shed additional light on the etiology of perinatal mood disorders. METHODS: We prospectively observed 145 women selected from a community obstetric clinic serving a primarily low-income, high-psychosocial risk population. Women without evidence of medical high-risk pregnancies were screened (including psychiatric and trauma histories) and then assessed in detail (e.g., mood symptoms) at approximately 18 and 32 weeks' gestation. Blood was drawn to measure key proinflammatory markers, interleukin 6 and tumor necrosis factor α (TNF-α). Data on pregnancy and obstetric outcome were derived from medical records. RESULTS: There was considerable stability of cytokine levels within individuals and a significant mean increase across pregnancy observed for interleukin 6 (p < .001) and TNF-α (p < .001). History of trauma was associated with significantly elevated TNF-α levels (F(1,135) = 4.43, p < .05), controlling for psychosocial and obstetric covariates. In contrast, elevated measures of depression and anxiety were unrelated to proinflammatory cytokines (p > .1). Exploratory analyses indicated that neither psychiatric symptoms nor proinflammatory cytokines predicted birth weight, gestational age, or obstetric complications. CONCLUSIONS: These findings suggest that antecedent trauma may be associated with persistently elevated TNF-α levels during pregnancy. The evidence that a generalized proinflammatory state was associated with symptoms of depression or anxiety in pregnant women was not found.

Openness and conscientiousness predict 34-week patterns of Interleukin-6 in older persons.

Studies have indicated that personality may be associated with inflammatory markers such as Interleukin (IL)-6. One pathway between personality and IL-6 may be health behaviors and conditions resulting in inflammation, while an alternate pathway involves activation of stress-response systems. In a clinical trial sample of 200 older adults, we examined associations between personality traits at baseline and three measures of IL-6 spanning 34 weeks of follow-up. Results indicate that IL-6 remained very stable over time, and that higher Conscientiousness and Openness were associated with lower IL-6 across the entire 34 week period. Goal striving was the active subcomponent of Conscientiousness, while aesthetic interests was the active subcomponent of Openness in IL-6 associations. Common health behaviors and chronic illness accounted for only a portion of these effects, suggesting that other behavioral and/or physiological processes may also predispose some persons to inflammation. Personality phenotype may provide useful prognostic information for inflammation. Older adults lower in Conscientiousness and Openness constitute a target population for anti-inflammatory interventions. Openness and Conscientiousness predicts 32-week patterns of Interleukin-6 in older persons.

Associations among depression, perceived self-efficacy, and immune function and health in preadolescent children.

Experimental animal studies and adult research consistently show that stress exposure and/or psychological symptoms are associated with poorer health and immune functioning. The application to children is not yet clear, however, and we lack developmental models for studies in this area. The objective of this paper was to test the hypothesis that self-reported self-efficacy and depression, two markers of psychological well-being in children, would predict immunity and rate of illnesses. The data are based on a prospective study of 141 healthy, normally developing children aged 7-13 years who were recruited from an ambulatory pediatric setting. Children completed self-efficacy and depression measures and had blood obtained for IL-6 plasma levels and natural killer cell functional assays on three occasions, 6 months apart. Parents maintained weekly child illness diaries over 1 year using a thermometer to record fever. Parent psychiatric symptoms and income were used as covariates. Results indicated that, across the three occasions of measurement collected over the 1-year period, higher perceived self-efficacy was significantly associated with lower plasma interleukin 6 concentrations. There was no overall main effect of depressive symptoms on immune measures; however, for older girls, higher depression was associated with elevated natural killer cell cytotoxicity and an increased rate of total illnesses and febrile illnesses. The findings provide some of the first evidence that psychological processes are associated with immunity and health in a normally developing sample of preadolescents. Furthermore, the pattern of results suggests a modified model of a link between psychological well-being and immunological processes in children. These results build on and expand research on the notion of allostatic load and develop a groundwork for developmental studies in this area.

History of sudden unexpected loss is associated with elevated interleukin-6 and decreased insulin-like growth factor-1 in women in an urban primary care setting.

OBJECTIVE: To investigate the hypothesis that a history of sudden unexpected loss including number of losses and type of loss (death due to unnatural versus natural causes) would be associated with the magnitude of dysregulation. The sudden unexpected death of a loved one confers risk of morbidity and mortality, perhaps due to dysregulation in the immune/inflammatory and endocrine systems. METHODS: Female primary care patients aged >or=40 years (n = 75) completed questionnaires, a clinical interview, and a blood draw. Interleukin (IL)-6 and insulin-like growth factor (IGF)-1 were assayed, using standard enzyme-linked immunosorbent assay protocols and anticytokine antibody pairs. RESULTS: History of sudden loss was positively associated with IL-6 (mean = 4.07 pg/mL; log(10) values, B = 0.314, p = .009) and negatively associated with IGF-1 (mean = 97.05 ng/mL; B = -0.277, p = .023). A linear relationship parsimoniously captured the association between ordered categories of lifetime loss (0, 1, 2-5, 5+) and increases in log(10) IL-6 (B = 0.107, p = .005) and decreases in IGF-1 (B = -0.116, p = .005). Adjusting for illness burden, depressive symptom severity, and obesity did not change the observed associations. The hypothesized effect of type of loss was not supported. CONCLUSIONS: These preliminary findings encourage further investigations to elucidate pathways from sudden unexpected loss to biomarker changes that increase risk for morbidity and mortality.

Gender, race/ethnicity, personality, and interleukin-6 in urban primary care patients.

Gender, race/ethnicity, and personality are markers of significant psychosocial and biological variability. Each may have implications for allostatic load and resulting inflammatory processes, yet findings have been largely mixed. We investigated whether women, minorities, and those higher in Neuroticism and lower in Extraversion were at risk for elevated circulating levels of the pro-inflammatory cytokine interleukin (IL)-6 in a sample of 103 middle aged and older urban primary care patients. Regression analyses controlling for age, education, current depression levels, and chronic medical conditions revealed that women, minorities, and individuals lower in Extraversion had higher circulating levels of IL-6. Analyses of more specific personality traits revealed that the sociability and positive emotions components of Extraversion were unassociated with IL-6, but the activity facet-reflecting dispositional vigor and energy-was robustly associated with IL-6. The difference between high (+1 Standard Deviation (SD)) and low (-1 SD) trait activity was sufficient to shift IL-6 levels beyond a previously established high risk cut-point in both white and minority women. These findings suggest that while broad group differences between genders and races/ethnicities exist, personality represents an important source of individual differences in inflammation within groups. Future work should examine to what extent IL-6 levels are linked to temperament or genetic activity levels vs. physical activity itself, and whether IL-6 levels may be reduced by boosting regular activity levels in demographic segments such as women and minorities who appear susceptible to greater inflammation.

The associations between psychosocial stress and the frequency of illness, and innate and adaptive immune function in children.

OBJECTIVE: Family processes have a substantial impact on children's social and emotional well-being, but little is known about the effects of family stress on children's physical health. To begin to identify potential links between family stress and health in children, we examined associations between specific aspects of family psychosocial stress and the frequency of illnesses in children, measures of innate and adaptive immune function, and human herpesvirus 6 (HHV-6) reactivation. STUDY DESIGN: Prospective study of 169 ambulatory school-age children and parents. Parents completed multiple assessments of stress at 7 sequential six-month visits and maintained weekly illness diaries for their children over three years using a thermometer to record fever. Children had blood obtained for HHV-6 and immune function studies at each visit including natural killer (NK) cell function and the percentage of CD4 and CD8 cells associated with immune control of cytomegalovirus (CMV). RESULTS: Parental psychiatric symptoms were associated with a higher frequency of illnesses: for each 1 U increase in symptom score children had an increased 1-year rate of total illnesses of 40% (rate ratio, 1.40; 95% CI, 1.06-1.85) and febrile illnesses of 77% (rate ratio, 1.77, 95% CI, 1.00-3.13). Parental psychiatric symptom scores were also associated with enhanced NK cell function (estimate, 0.15; 95% CI, 0.05-0.26) and increased percentages of CD8+CD28-CD57+ cells in the blood of CMV seropositive children (estimate, 2.57; 95% CI, 0.36-4.79). HHV-6 reactivation was not detected. CONCLUSIONS: There is an association between specific psychosocial stress exposure and rates of illness and immune function in normally developing children.