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Mood and Cytokine Response to Influenza Virus in Older Adults

¹ University of Iowa, Iowa City.
² Iowa State University, Ames.
³ Eastern Virginia Medical School, Norfolk.

Address correspondence to Susan K. Lutgendorf, PhD, Department of Psychology, E11 Seashore Hall, University of Iowa, Iowa City, IA 52242. E-mail: susan-lutgendorf{at}uiowa.edu

	Abstract

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Background. Previous research has indicated that older adults with severe life stress show attenuated immune responses to influenza vaccination. Associations among mood, optimism, stress, and the in vitro cytokine response to influenza virus and vaccine were evaluated in 18 healthy older adults with low to moderate life stress.

Methods. Peripheral blood mononuclear cells were stimulated in cultures with 1999–2000 influenza vaccine viruses (A/Beijing/262/95, A/Sydney/5/97, and B/Yamanashi/166/98) and the 2000–2001 trivalent vaccine (containing A/New Caledonia/20/99, A/Panama/2007/99, and B/Yamanashi/166/98). The levels of T-helper type 1 (interleukin-2 and interferon-) and type 2 (interleukin-10) cytokines were measured in culture supernatants.

Results. Stress, age, and current health practices were unrelated to cytokine production. Older adults reporting greater anger, fatigue, confusion, and total mood disturbance had poorer cytokine responses to live virus and vaccine stimulation. In contrast, older adults who reported greater vigor and those who were more optimistic had greater cytokine responses to both live virus and vaccine. These relationships were largely unaffected by medications or health conditions.

Conclusions. These findings suggest that among older adults, even mild to moderate mood disturbance is associated with an attenuated cellular immune response to live influenza virus and vaccine.

The T_H1 response has been assessed by interleukin-2 (IL-2) and interferon- (IFN-) responses after in vitro stimulation of peripheral blood mononuclear cells by influenza vaccine or live virus preparations. Older adults show lower vaccine- and virus-stimulated IL-2 and IFN- production both before and after vaccination as compared with younger adults, although findings are less consistent when live virus stimulation is used (7,8,11,13). The T_H2 response is often assessed by measuring the stimulated interleukin-10 (IL-10) response. Older adults show greater IL-10 responses to live virus both before and after vaccination than do younger adults, suggesting an elevated T_H2 response in older adults (8). However, the vaccine-stimulated IL-10 response is lower in older adults after vaccination, and there are no age-related differences before vaccination (7).

Chronic and severe stress is related to poorer immune response to vaccination. Older adults with the severe life stress of caring for a spouse with dementia were less likely to mount fourfold antibody responses after vaccination compared with nonstressed older adults. Caregivers also produced less IL-1ß and IL-2 in response to stimulation by lipopolysaccharide and vaccine, respectively, both before and after vaccination (14). In another study, only 16% of caregivers, compared with 39% of controls, showed protective antibody responses to at least one strain of the influenza vaccine (15).

Little is known about whether moderate levels of life stress and mood disturbance among older adults are associated with an impaired response to influenza vaccine or virus, or whether certain psychosocial factors may protect against aging-related decreases in immune response to influenza virus. Previously, we found a decline in immune function among older adults undergoing the moderate life stress of housing relocation (16). In addition, among a community-dwelling sample of older adults who had recently received an influenza vaccination, perceived stress was associated with lower influenza-specific antibody titers and IL-2 response to in vitro stimulation by influenza virus (17). With respect to mood disturbance, more negative and fewer positive affects have been associated with poorer antibody responses to hepatitis B vaccination (18), keyhole limpet hemacyanin inoculation (19), and orally ingested rabbit albumin (20). Among older adults, affective states have been associated with immune and endocrine functioning (21). For example, older women who reported more depression, anger, fatigue, and overall mood disturbance and less vigor had higher levels of IL-6, a cytokine that is an indicator of poor health status in older adults (22). Dispositional optimism may play a protective role with respect to immune functioning: Optimistic persons have been shown to have more CD4+ cells and higher natural killer cell cytotoxicity (23). A large epidemiologic study of older men found that optimism predicted better perceived health, vitality, and mental health (24), and a recent study found that optimism was associated with a greater IL-10 response to in vitro stimulation by influenza virus among older adults (17).

In the current study, we evaluated the in vitro T_H1 (IL-2 and IFN-) and T_H2 (IL-10) cytokine responses to both killed influenza vaccine and live viral preparations in healthy older adults with moderate or low levels of life stress. We assessed cytokine responses, stress, mood, and optimism 1 month before the 2000–2001 trivalent influenza vaccination. We assessed cytokine responses to in vitro stimulation with live viral strains contained in the 1999–2000 vaccine to evaluate the T-cell memory response to the previous year's influenza vaccination, and we measured cytokine response to in vitro stimulation with the 2000–2001 trivalent influenza vaccine to simulate response to the upcoming influenza vaccination. We hypothesized that older adults with higher levels of stress and disturbed mood would show lower T_H1 and T_H2 responses to live virus and vaccine stimulation. We also hypothesized that optimism would have a protective effect. We predicted that more optimistic adults would show better cytokine responses to stimulation. Finally, because T_H1 responses show greater decreases with age, we predicted that the T_H1 response would be more vulnerable to the effects of life stress and disturbed mood than would the T_H2 response.

	METHODS

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Participants
The participants were 14 women and 4 men between the ages of 75 and 91 years (mean age, 83.9 years; standard deviation, 54.8) recruited from 2 independent-living retirement homes and the local senior citizens' center. All had received the previous year's influenza vaccine. We excluded potential participants if they had experienced serious medical illness or major surgery within the previous 3 months or infectious illness within the previous 2 weeks, had a condition associated with immune dysfunction (e.g., cancer within the previous 5 years, autoimmune diseases), were currently taking systemic corticosteroids or immunosuppressant medication, or were engaging in extensive daily exercise. Health problems reported by participants included hypertension (56%), history of stroke or coronary heart disease (22%), and osteoarthritis (17%). Participants reported taking a variety of medications including beta-blockers (33%), estrogen replacement therapy (17%), and selective serotonin reuptake inhibitors (SSRIs) (6%).

Participants completed questionnaires and had 20 ml of peripheral venous blood drawn between 7:00 AM and 10:00 AM 1 month before receiving the 2000–2001 trivalent influenza vaccination (Fluzone; Aventis Pasteur, Swiftwater, PA).

Biobehavioral Measures
Participants completed questionnaires that captured demographic and health information and a health practices questionnaire that documented potential immune confounds including exercise, sleep, and consumption of alcohol, cigarettes, and caffeine, and medications taken during the 7 days before the blood was drawn. The 14-item Perceived Stress Scale (25) assessed how often participants felt nervous, angry, in control of stress, and effective in coping with stress during the past month. The short form of the Profile of Mood States (26) consists of 37 mood adjectives that participants rated on a Likert-type scale based on how they had felt during the past week. Factors underlying the scale include anxiety, depression, anger, vigor, fatigue, and confusion. A composite score of total mood disturbance, representing total distress, can be calculated by summing all subscale scores except vigor and subtracting the vigor score. The 8-item Life Orientation Test (27) assessed dispositional optimism, which is the general expectancy of positive versus negative outcomes.

Cytokine Measures
Our study methods are described in another publication (17). We purified peripheral blood mononuclear cells from venous whole blood using Ficoll-Paque (Amersham Biosciences, Piscataway, NJ) and resuspended them at 3 x 10⁶ cells/ml in serum-free AIM V medium (Gibco^R, Invitrogen, Carlsbad, CA). We plated the resulting cell cultures (850 µl) in 5 wells of a 24-well culture plate. We stimulated 3 wells with one of the following live virus preparations harvested from amniotic fluid: 50 µl of the 1999–2000 strain A/Beijing/262/95, 56 µl of the 1999–2000 strain A/Sydney/5/97, and 50 µl of the 1999–2000 strain B/Yamanashi/166/98 (the final concentration for each virus was 10 HAU/ml). We stimulated a fourth well with killed 2000–2001 trivalent vaccine (A/New Caledonia/20/99, A/Panama/2007/99, and B/Yamanashi/166/98) so that the final concentration of vaccine was 0.18 µg/ml. To a fifth control well, we added 50 µl medium. We chose antigen concentrations that yielded maximal responses on initial dose-response curves. B/Yamanashi/166/98 was common to both the 1999–2000 and 2000–2001 vaccines, whereas A/New Caledonia/20/99 and A/Panama/2007/99 were new virus strains.

We incubated plates for 96 hours at 37°C in 5% carbon dioxide. We harvested supernatant at 48 and 96 hours, and we took cytokine values used in analyses from the time of maximum production (48 hours for IL-2 and 96 hours for IL-10 and IFN-). We measured concentrations of IL-2, IFN-, and IL-10 in each supernatant in duplicate by an enzyme-linked immunoassay using a standardized kit (BD Biosciences Pharmingen, San Diego, CA). We determined reported cytokine levels by subtracting the cytokine concentration in the unstimulated control wells from the concentrations in corresponding stimulated wells. Cytokine concentrations detected in cultures stimulated with A/Sydney/5/97 were lower than in the control culture, indicating a problem with the A/Sydney/5/97 virus used in the current experiment. Therefore, A/Sydney/5/97 data were not included in subsequent analyses.

Data Analysis
We assessed all variables for normality of distribution and outliers. No outliers were present. Because of the non-normal distribution of cytokine levels, we calculated nonparametric Spearman correlations to evaluate relationships between psychosocial measures and cytokine responses. We assessed potential covariates, including demographic variables (age, marital status, and education) and health practices (sleep, smoking, caffeine and alcohol consumption, and exercise) for relationships with cytokine levels and found them to be unrelated to cytokine response (all p values >.10). Therefore, we did not control for demographic and health practice variables in the analyses.

In addition, we used nonparametric Mann–Whitney analyses to determine whether subsets of participants who reported a history of cardiovascular disease (coronary heart disease or stroke) or were taking estrogen or beta-blockers differed from other participants in cytokine responses. We found no significant differences in cytokine responses between participants who did and did not report cardiovascular disease (all p values >.10) or between participants taking estrogen replacement and those who did not (all p values >.10). Participants taking beta-blockers had a lower IL-10 response to B/Yamanashi/166/98 than did participants who were not taking beta-blockers (U(17) = 10.00, p =.045). Therefore, we evaluated Spearman correlations for those taking versus not taking beta-blockers separately for this outcome. We found no other significant differences between participants taking versus not taking beta-blockers (all p values >.10). However, as an additional precaution, we recalculated all significant correlations between psychosocial measures and cytokine responses after removing participants with cardiovascular disease and participants taking SSRIs, estrogen, and beta-blockers.

	RESULTS

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Table 1 shows the means, standard deviations, and ranges of the Perceived Stress Scale, Profile of Mood States, and Life Orientation Test scores, and Table 2 reports cytokine means and standard deviations. Scores on all Profile of Mood States subscales were comparable to those from a sample of healthy older women from a previous study in our laboratory (22). Furthermore, scores were substantially lower than those found in a sample of older caregivers of patients with Alzheimer's disease, suggesting that the current participants had less stress and mood disturbance than did the previously studied caregivers.

View this table: [in this window] [in a new window]   Table 3. Spearman Correlations Between Psychosocial Measures and Cytokine Responses to Influenza Virus and Vaccine.

View larger version (13K): [in this window] [in a new window]   Figure 1. Interleukin-10 (IL-10) production (in nanograms/milliliter) in response to trivalent vaccine is expressed as a function of anger (r =.48, p =.05). POMS = Profile of Mood States

View larger version (16K): [in this window] [in a new window]   Figure 3. Interleukin-2 (IL-2) production (in nanograms/milliliter) in response to trivalent vaccine is expressed as a function of confusion (r = –.63, p =.005). POMS = Profile of Mood States

Secondary Analyses
We recalculated all significant Spearman correlations between psychosocial measures and cytokine responses after removing participants with a history of cardiovascular disease and participants taking SSRIs, estrogen, and beta-blockers. Effect sizes generally increased after we removed 4 participants with cardiovascular disease, and all results remained significant despite the decrease in power. Effect sizes did not change after we removed 1 person who was taking SSRIs or after we removed 3 participants who were taking estrogen, although significance levels (p values) decreased slightly as a result of the diminished sample size. Changes in effect sizes were more noticeable after we removed 6 participants who were taking beta-blockers, but changes were not in a systematic direction, with some effect sizes increasing slightly and some decreasing slightly. Overall, these results suggest participants' health conditions and medication use did not systematically affect results, with the exception that including persons with a history of cardiovascular disease may have dampened effect sizes.

	DISCUSSION

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This study evaluated cross-sectional associations between mood and influenza virus-stimulated and vaccine-stimulated cytokines in older adults. In general, greater mood disturbance was associated with lower cytokine levels in response to both virus and vaccine stimulation, whereas optimism and vigor were associated with greater cytokine responses. Higher levels of anger, fatigue, and overall mood disturbance were related to lower T_H1 cytokine responses to live virus, whereas vigor and optimism were related to greater T_H1 cytokine responses to live virus. Similarly, greater fatigue, confusion, and overall mood disturbance were associated with poorer T_H1 cytokine responses to killed vaccine, whereas greater vigor and optimism were associated with a more robust T_H1 cytokine response to vaccine. Findings concerning the T_H2 cytokine response were not as consistent. T_H2 cytokine responses to live virus were not associated with mood, but greater anger and fatigue were associated with a poorer T_H2 cytokine response to vaccine. These relationships appeared to be largely unaffected by medications or health conditions, and we observed no significant relationships between health practices and cytokine responses. Our findings are consistent with previous work indicating that chronically stressed older adults show poorer antibody and cytokine responses to vaccination (14,15). These results are particularly noteworthy, however, because participants in the current study reported low levels of stress and mood disturbance, but even mild to moderate mood disturbance was associated with poorer cytokine responses to influenza virus and vaccine.

Previous research found that housing stress affects secondary but not primary antibody responses to keyhole limpet hemacyanin in mice (28), but there is little evidence for a differential effect of stress on primary versus secondary immune responses in humans (29). Our results indicated that mood affected cytokine responses to both a novel vaccine and influenza strains against which participants had previously been vaccinated. The robust relationships between mood and the IFN- and IL-2 responses to live virus suggest that mood may modulate the anamnestic T_H1 response to influenza virus encountered 1 year after vaccination. In addition, the significant relationships between mood and both the IL-2 and IL-10 responses to the 2000–2001 trivalent vaccine suggest that mood may influence the ability of older adults to mount both T_H1 and T_H2 cytokine responses to an upcoming vaccine with several novel components.

Relationships between mood and the T_H1 response appeared to be more consistent than those between mood and the T_H2 response. We found that IL-2 or IFN- responses were related to many facets of distress, whereas IL-10 response was related only to fatigue and anger. Previous research has indicated that age-related changes in immunity affect the T_H1 response more than the T_H2 response. The current findings suggest that mood is more robustly related to the component of the immune response thought to be more vulnerable in older adults. Furthermore, a T_H1 type response is important in clearing the virus and therefore preventing infection and speeding recovery from influenza in older adults (8,10,11).

The hypothalamic-pituitary-adrenocortical or sympathoadrenomedullary responses to stress may be pathways by which distressed mood could influence the ability of T lymphocytes to secrete cytokines in response to the antigenic challenge of influenza virus or vaccine (30,31). Positive mood and optimism may buffer decreases in T-lymphocyte functioning associated with distress or aging by moderating hypothalamic-pituitary-adrenocortical and sympathoadrenomedullary activation; optimism has been associated with greater numbers of helper T lymphocytes in younger adults (23).

Contrary to expectations, we did not find relationships between life stress, anxiety, or depression and any cytokine response to virus or vaccine, perhaps because participants in the current study reported very low levels of perceived stress, depression, and anxiety. Lack of variability in responses and type II error with too few participants to detect the impact of low levels of distress may be responsible for the lack of significant relationships between these factors and cytokine levels. In contrast, participants were more likely to report feelings of fatigue, confusion, and lack of vigor. It is important to note that fatigue, confusion, and vigor may represent affective states rather than trait-like qualities, and perhaps short-term rather than chronic mood states may be related to cytokine responses in the current study. However, the Life Orientation Test is thought to measure dispositional optimism, and this more stable, trait-like measure was associated with cytokine responses to both virus and vaccine.

Limitations of our study include its cross-sectional design, which precludes any causal inferences. Although we have suggested that mood and optimism may influence cytokine responses, cytokine activity has been shown to cause sickness behavior, including depressed mood, fatigue, and cognitive deficits (32). This explanation is unlikely, however, because fatigue and confusion were related to lower rather than to higher IL-2 and IFN- responses in the current study. Nonetheless, longitudinal or experimental studies are needed to determine the direction of causality. Other limitations include the possibility that some relationships were not detected because of the small sample size. Therefore, we reported trends along with significant results in an attempt to avoid type II errors (i.e., not finding effects that are, in fact, present). Finally, we used the stimulated in vitro cytokine response before influenza vaccination to measure the immune response. Assessing serum antibody titers or the in vitro cytokine response to vaccine or live virus after vaccination may have yielded different results.

Conclusion
The current study extends previous research findings that older adults with severe life stress have poorer responses to influenza vaccination. Healthy older adults with mild to moderate mood disturbance had a less vigorous in vitro cytokine response to live virus and influenza vaccine, suggesting that such persons may be more vulnerable to influenza infection after vaccination. Optimism may protect against age-related decreases in immune response to infection. Future studies should further evaluate these findings in larger samples using both prevaccination and postvaccination cytokine and antibody responses.

View larger version (15K): [in this window] [in a new window]   Figure 2. Interleukin-2 (IL-2) production (in nanograms/milliliter) in response to trivalent vaccine is expressed as a function of fatigue (r = –.57, p =.01). POMS = Profile of Mood States

	Acknowledgments

The authors thank Michelle Riley and Sheila Robinson for drawing participants' blood and Colleen Clarke and Anna Hoffman for assistance with data collection.

Received May 27, 2003

Accepted August 12, 2003

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