Health Psychology - Psychoneuroimmunology (*Start of Exam 2*)

Examples of *pro-inflammatory cytokines* (will treat together)

- Interleukin - 6 (IL-6) - Tumor Necrosis Factor - Alpha (TNF-α) - Interferon (IFN) *Pro-inflammatory cytokines trigger C-Reactive Protein (CRP)*

Effects of Infectious Disease on History I

5000 a day were dying in Rome in the 2nd Epidemic.

Ways to inhibit the immune system: (2)

1. Cortisol 2. Parasympathetic Nervous System Activation

Ways to activate the immune system: (2)

1. Pathogens: Exposure to bacteria or virus 2. Sympathetic Nervous System Activation

Infections & Future Risk of Depression (4)

Benros et al 2013 Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders - A Nationwide Study - JAMA Psychiatry Importance: Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking. Objective: To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders. Design: Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex. Setting: Individual data drawn from Danish longitudinal registers. Participants: A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91 637 people having hospital contacts for mood disorders. Main Outcomes and Measures: The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk. Results: A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, 1.39-1.52). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, 1.60- 1.64). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, 2.25-2.46). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease. Conclusions and Relevance: Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients.

Cytokines

Cytokine = A molecule immune cells use to communicate to each other - Act locally as well as circulate in the blood (e.g. like a hormone - Released as part of the response to a pathogen - Important marker that inflammation has occurred - Highly varied in their biological effects and targets (Also play a role in specific immunity, though in this course only focus on them as products of the natural immune system) >>Technically, CRP is not a proinflammatory cytokine. It belongs to a different class of molecules (Acute Phase Proteins), but for the purposes of this course, we will treat them together.

Acute Stress: Pro-inflammatory Cytokines TSST Study

Dickerson et al 2009 Social-Evaluative Threat and Proinflammatory Cytokine Regulation An Experimental Laboratory Investigation - Psych Science This study experimentally tested whether a stressor characterized by social-evaluative threat (SET), a context in which the self can be judged negatively by others, would elicit increases in proinflammatory cytokine activity and alter the regulation of this response. This hypothesis was derived in part from research on immunological responses to social threat in nonhuman animals. Healthy female participants were assigned to perform a speech and a math task in the presence or absence of an evaluative audience (SET or non-SET, respectively). As hypothesized, stimulated production of the proinflammatory cytokine tumor necrosis factor-a (TNF-a) increased from baseline to poststressor in the SETcondition, but was unchanged in the non-SET condition. Further, the increases in TNF-a production correlated with participants' cognitive appraisals of being evaluated. Additionally, the ability of glucocorticoids to shut down the inflammatory response was decreased in the SET condition. These findings underscore the importance of social evaluation as a *threat capable of eliciting proinflammatory cytokine activity and altering its regulation*

Acute Stress: Antibody Response - Vaccination/Stress Study (Methods) (8)

Edwards, KM., et al. "Acute stress exposure prior to influenza vaccination enhances antibody response in women." Brain, Behavior, and Immunity, v. 20 issue 2, 2006, p. 159-68. Animal studies have shown that an acute stressor in close temporal proximity to immune challenge can enhance the response to delayed-type hypersensitivity and antibody response to vaccination. The current study examined the eVects of acute exercise or mental stress prior to inXuenza vaccination on the subsequent antibody response to each of the three viral strains. Sixty young healthy adults (31 men, 29 women) were randomly allocated to one of three task conditions: dynamic exercise, mental stress, or control. After an initial baseline, participants completed their allocated 45min task and then received the inXuenza vaccine. Plasma cortisol and interleukin-6 were determined at the end of baseline, after the task, and after 60 min recovery. Antibody titres were measured prevaccination and at 4 weeks and 20 weeks post-vaccination follow-ups. For the A/Panama strain, women in both the exercise and mental stress conditions showed higher antibody titres at both 4 and 20 weeks than those in the control condition, while men responded similarly in all conditions. Interleukin-6 at +60min recovery was found to be a signiWcant predictor of subsequent A/Panama antibody response in women. In line with animal research, the current study provides preliminary evidence that acute stress can enhance the antibody response to vaccination in humans.

Acute Stress: Antibody Response (graphs) Vaccination/Stress Study (Results)

Edwards, KM., et al. "Acute stress exposure prior to influenza vaccination enhances antibody response in women." Brain, Behavior, and Immunity, v. 20 issue 2, 2006, p. 159-68. Animal studies have shown that an acute stressor in close temporal proximity to immune challenge can enhance the response to delayed-type hypersensitivity and antibody response to vaccination. The current study examined the eVects of acute exercise or mental stress prior to inXuenza vaccination on the subsequent antibody response to each of the three viral strains. Sixty young healthy adults (31 men, 29 women) were randomly allocated to one of three task conditions: dynamic exercise, mental stress, or control. After an initial baseline, participants completed their allocated 45min task and then received the inXuenza vaccine. Plasma cortisol and interleukin-6 were determined at the end of baseline, after the task, and after 60 min recovery. Antibody titres were measured prevaccination and at 4 weeks and 20 weeks post-vaccination follow-ups. For the A/Panama strain, women in both the exercise and mental stress conditions showed higher antibody titres at both 4 and 20 weeks than those in the control condition, while men responded similarly in all conditions. Interleukin-6 at +60min recovery was found to be a signiWcant predictor of subsequent A/Panama antibody response in women. In line with animal research, the current study provides preliminary evidence that acute stress can enhance the antibody response to vaccination in humans.

Viral Infection - What do viruses do? (6)

Figure from: http://philschatz.com/biology-book/contents/m44597.html http://medicalassessmentonline.com/terms.php?R=492&L=I A viral infection is any type of infection that is caused by a virus. Viruses are made up of the genetic material known as DNA or RNA, which the virus uses to replicate. Viruses are not living organisms and need a "living" host in order to reproduce-otherwise it cannot survive. They cannot multiply on their own, so they have to invade a 'host' cell and take over its machinery in order to be able to make more virus particles. In order for a virus to survive, it must invade and attach itself to a living cell. It will then multiply and produce more virus particles. When a virus enters your body, it invades some of your cells and takes over the cell machinery, redirecting it to produce the virus, and in so doing causes disease. Viruses can be transmitted in numerous ways, such as through contact with an infected person, swallowing, inhalation, or unsafe sex. Factors such as poor hygiene and eating habits can increase your risk of contracting a viral infection. Bacteria are living organisms made up of just one cell, and bacteria are capable of multiplying by themselves, as they have the power to divide. In contrast, a virus cannot reproduce if it does not have a host. Bacteria are classified by their shapes.

Depression & Cardiovascular Disease

Gan et al 2014 Depression and the risk of coronary heart disease- a meta-analysis of prospective cohort studies - BMC Psychiatry *Background* Several systematic reviews and meta-analyses demonstrated the association between depression and the risk of coronary heart disease (CHD), but the previous reviews had some limitations. Moreover, a number of additional studies have been published since the publication of these reviews. We conducted an updated meta-analysis of prospective studies to assess the association between depression and the risk of CHD. *Methods* Relevant prospective studies investigating the association between depression and CHD were retrieved from the PubMed, Embase, Web of Science search (up to April 2014) and from reviewing reference lists of obtained articles. Either a random-effects model or fixed-effects model was used to compute the pooled risk estimates when appropriate. *Results* Thirty prospective cohort studies with 40 independent reports met the inclusion criteria. These groups included 893,850 participants (59,062 CHD cases) during a follow-up duration ranging from 2 to 37 years. The pooled relative risks (RRs) were 1.30 (95% CI, 1.22-1.40) for CHD and 1.30 (95% CI, 1.18-1.44) for myocardial infarction (MI). In the subgroup analysis by follow-up duration, the RR of CHD was 1.36 (95% CI, 1.24-1.49) for less than 15 years follow-up, and 1.09 (95% CI, 0.96-1.23) for equal to or more than 15 years follow-up. Potential publication bias may exist, but correction for this bias using trim-and-fill method did not alter the combined risk estimate substantially. *Conclusions* The results of our meta-analysis suggest that depression is independently associated with a significantly increased risk of CHD and MI, which may have implications for CHD etiological research and psychological medicine.

General Lord Cornwallis' Surrender at Yorktown:

General Lord Cornwallis' Surrender at Yorktown: "I have the mortification to inform your Excellency that I have been forced to give up the post of York and Gloucester and surrender the troops under my command....The troops being much weakened by sickness, as well as by the fire of the besiegers...Our numbers had been diminished by the Enemy's fire, but particularly by Sickness, and the strength and spirits of those in the works were much exhausted by the fatigue... - October 19th (Height of Malaria Season

Heart Rate Variability (HRV) & Self-Reported Health

Jarczok et al Thayer 2015 Investigating the Associations of Self-Rated health- HRV is more strongly associated tha inflammatory and other frequently used biomarkers - PLoS One The present study aimed to investigate the possible mechanisms linking a single-item measure of global self-rated health (SRH) with morbidity by comparing the association strengths between SRH with markers of autonomic nervous system (ANS) function, inflammation, blood glucose and blood lipids. Cross-sectional comprehensive health-check data of 3947 working adults (age 42±11) was used to calculate logistic regressions, partial correlations and compare correlation strength using Olkins Z. Adjusted logistic regression models showed a negative association between SRH (higher values indicating worse health) and measures of heart rate variability (HRV). Glycemic markers were positively associated with poor SRH. No adjusted association was found with inflammatory markers, BP or lipids. In both unadjusted and adjusted linear models Pearson's correlation strength was significantly higher between SRH with HRV measures compared to SRH with other biomarkers. This is the first study investigating the association of ANS function and SRH. We showed that a global measure of SRH is associated with HRV, and that all measures of ANS function were significantly more strongly associated with SRH than any other biomarker. The current study supports the hypothesis that the extent of brain-body communication, as indexed by HRV, is associated with self-rated health

Chronic (Caregiving) Stress and Cytokine Levels (3)

Kanel et al 2006 Effect of Alzheimer Caregiving Stress and Age on Frailty Markers Interleukin-6, C-Reactive Protein, and D-Dimer - Jnl of Gerontology Med Sci *BACKGROUND:* Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the "frailty syndrome," defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. *METHODS:* Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 +/- 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. *RESULTS:* Caregivers had higher mean levels of IL-6 (1.38 +/- 1.42 vs 1.00 +/- 0.92 pg/mL, p =.032) and of D-dimer (723 +/- 530 vs 471 +/- 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (beta =.20, p =.029) and of borderline significance for IL-6 (beta =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (beta =.50, p <.001) and IL-6 (beta =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. *CONCLUSIONS:* The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Psychological Stress & Progression to AIDS in HIV Infected Men (3)

Leserman et al 2000 Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS - Am Jnl Psychiatry OBJECTIVE: This study examined prospectively the effects of stressful events, depressive symptoms, social support, coping methods, and cortisol levels on progression of HIV-1 infection. METHOD: Eighty-two homosexual men with HIV type-1 infection without AIDS or symptoms at baseline were studied every 6 months for up to 7. 5 years. Men were recruited from rural and urban areas in North Carolina, and none was using antiretroviral medications at entry. Disease progression was defined as CD4(+) lymphocyte count <200/microl or the presence of an AIDS indicator condition. RESULTS: Cox regression models with time-dependent covariates were used adjusting for race, baseline CD4(+) count and viral load, and cumulative average antiretroviral medications. Faster progression to AIDS was associated with higher cumulative average stressful life events, coping by means of denial, and higher serum cortisol as well as with lower cumulative average satisfaction with social support. Other background (e.g., age, education) and health habit variables (e.g., tobacco use, risky sexual behavior) did not significantly predict disease progression. The risk of AIDS was approximately doubled for every 1.5-unit decrease in cumulative average support satisfaction and for every cumulative average increase of one severe stressor, one unit of denial, and 5 mg/dl of cortisol. CONCLUSIONS: Further research is needed to determine if treatments based on these findings might alter the clinical course of HIV-1 infection Dependent Measures Stressful life events. To obtain a list of stressful life events and difficulties, we modified the Psychiatric Epidemiology Research Interview (27). Stressors were objectively rated by using a manual of norms and vignettes, a methodology similar to that developed by Brown and Harris (28). Norms for each stressful event were based on the degree of threat that most people would experience given the particular circumstances (e.g., financial impact, life threat, personal involvement). The objective threat rating was made independently of the subject's rating in order to reduce the possibility that worsening disease might lead to higher stressful event scores. One of two trained raters (previously shown to have high interrater reliability) (12) used the manual to rate the impact of each stressor from 0 (no threat) to 4 (severe threat). All ratings were summed at each visit, except that we removed stressors that were likely to be caused by disease progression (e.g., drop in CD4+ count, retirement due to worsening of HIV-1 infection).

Cytokines, CRP & Major Depression

Liu, Y.; Ho, RC.; Mak, A. 2011 "IL-6, TNF-α, and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder- A meta-analysis- J Affective Disorders Background: Many studies have explored the association between soluble interleukin-2 receptor (sIL-2R), cytokines and major depressive disorder (MDD). However, the results of these studies were not consistent. The aim of our study is to compare the levels of sIL-2R and cytokines in the blood between MDD patients and controls by a meta-analysis and to identify moderators accounting for potential heterogeneity in the levels of sIL-2R and cytokines in MDD patients versus controls by meta-regression analyses. Methods: A comprehensive literature search was performed to identify studies comparing the levels of sIL-2R and cytokines between MDD patients and controls. We pooled the effect sizes for standardized mean differences (SMD) of the levels of sIL-2R and cytokines. We also performed meta-regression and sensitivity analyses to investigate the roles of age, gender, sample type, ethnic origin and selected studies' quality in explaining potential heterogeneity and differences in results respectively. Results: Twenty-nine studies were selected for this analysis. The levels of sIL-2R, TNF-α and IL-6 in MDD patients were significantly higher than those of healthy controls (SMD=0.555, pb0.001, SMD=0.567, p=0.010; SMD=0.680, pb0.001). Mean age of all subjects was a significant moderator to explain the high heterogeneity of IL-6. Sensitivity analysis found that European but not non-European subjects have higher levels difference of sIL-2R, TNF-α and IL-1β between MDD patients and controls. Limitation: The severity of MDD was not considered. Conclusion: The blood levels of sIL-2R, TNF-α and IL-6 were significantly higher in MDD patients than controls. Age, samples source and ethnic origins may play a potential role in heterogeneity. Howren, Lankin, & Suls 2009 Associations of Depression With C-Reactive Protein, IL-1, and IL-6- A Meta-Analysis - Psychosomatic Medicine Objective: To assess the magnitude and direction of associations of depression with C-reactive protein (CRP), interleukin (IL)-1, and IL-6 in community and clinical samples. Methods: Systematic review of articles published between January 1967 and January 2008 in the PubMed and PsycINFO electronic databases was performed. Effect sizes were calculated as stat d and meta-analyzed, using random-effects models. Results: Each inflammatory marker was positively associated with depression; CRP, d _ 0.15 (95% CI _ 0.10, 0.21), p _ .001; IL-6, d _ 0.25 (95% CI _ 0.18, 0.31), p _ .001; IL-1, d _ 0.35 (95% CI _ 0.03, 0.67), p _ .03; IL-1ra, d _ 0.25 (95% CI _ 0.04, 0.46), p _ .02. Associations were strongest in clinically depressed patient samples—but were also significant in community-based samples—and when clinical interviews were used. Studies adjusting for body mass index (BMI) had smaller associations, albeit significant. Relationships were inconsistent with respect to age, medication, and sex. Depression was related to CRP and IL-6 among patients with cardiac disease or cancer. Conclusions: Depression and CRP, IL-1, and IL-6 are positively associated in clinical and community samples and BMI is implicated as a mediating/moderating factor. Continuity in clinic- and community-based samples suggests there is a dose-response relationship between depression and these inflammatory markers, lending strength to the contention that the cardiac (or cancer) risk conferred by depression is not exclusive to patient populations. Available evidence is consistent with three causal pathways: depression to inflammation, inflammation to depression, and bidirectional relationships. Key words: depression, inflammation, C-reactive protein, interleukin-1, interleukin-6, meta-analysis.

Cytokines, Inflammation, Sickness Behavior & Depression (about Hep C & Cancer)

Lotrich et al 2011 The Role of Inflammation in the Pathophysiology of depression - different treatments and their effects - J Rheumatology Compelling evidence suggests that inflammation contributes to the development of depression. Many depressed individuals have higher levels of proinflammatory mediators, which appear to interact with many of the pathophysiological domains of depression, including neuroendocrine function, neurotransmitter metabolism, and synaptic plasticity. This is further supported by observation that therapeutic administration of interferon-α (IFN-α) leads to depression in a significant proportion of patients. These findings suggest that targeting proinflammatory cytokines and their signaling pathways may represent a unique therapeutic opportunity to treat depression and related conditions, such as labile anger, irritability, and fatigue

Malaria, Mosquitoes, and the American Revolution (5)

Mosquitos need tempeartures between 50 and 104 F with the ideal being around 95 and humid, which is the midsummer weather in virginia and the carolinas. They like to bread near the edges of fresh water such as swamps, ponds, and irrigated fields. Lowlands of the carolina's became big for rice farming with the flooding of the fields and ideal for mosquitoes. To reproduce the mosquitoes need a meal. Slave ships brought malaria to the coast. People born and raised locally developed immunity if they survived. If came from malaria resistent zones you were at great risk. People would go away to the west or the north during fever season. Thomas jefferson rice cultivation "requires the whole country to be laid under water during a season of the year, [and] sweeps off numbers of the inhabitants annually with pestilential fevers." In charleston in the 1750's, 3:1 ratio of people buried for baptized. That is a huge death ratio. 77% of all deaths were between august and november Among infants 90% of those dying died between august and november One observer in 1783: "Carolina is in the spring a paradise, in summer a hell, and in the autumn a hospital." Cornwallis in charge of the southern strategy after fall of charleston, but his troops were not immune to malaria Cornwallis' surrender at yorktown" October 19th, height of malaria season he surrendered. "I have the mortification to inform your Exellency that I have been forced to give up the post of York and Gloucester and surrender the troops under my command....The trooops being much weakened by sickness, as wel as by the fire of the besiegers...Our numbers had been diminished by the Enemy's fire, but particularly by Sickness, and the strength and spirits of those in the works were much exhausted by the fatigue... Differnetial immunity the local militias were resistant.

Rate your health study (4)

Pick one of the following: Excellent Good Fair Poor Very Poor Don't Know Bopp et al 2012 Health Risk or Resource? Gradual and Independent Association between Self-Rated Health and Mortality Persists Over 30 Years - PLoS One Background: Poor self-rated health (SRH) is associated with increased mortality. However, most studies only adjust for few health risk factors and/or do not analyse whether this association is consistent also for intermediate categories of SRH and for follow-up periods exceeding 5-10 years. This study examined whether the SRH-mortality association remained significant 30 years after assessment when adjusting for a wide range of known clinical, behavioural and socio-demographic risk factors. Methods: We followed-up 8,251 men and women aged $16 years who participated 1977-79 in a community based health study and were anonymously linked with the Swiss National Cohort (SNC) until the end of 2008. Covariates were measured at baseline and included education, marital status, smoking, medical history, medication, blood glucose and pressure. Results: 92.8% of the original study participants could be linked to a census, mortality or emigration record of the SNC. Loss to follow-up 1980-2000 was 5.8%. Even after 30 years of follow-up and after adjustment for all covariates, the association between SRH and all-cause mortality remained strong and estimates almost linearly increased from ''excellent'' (reference: hazard ratio, HR 1) to ''good'' (men: HR 1.07 95% confidence interval 0.92-1.24, women: 1.22, 1.01-1.46) to ''fair'' (1.41, 1.18- 1.68; 1.39, 1.14-1.70) to ''poor''(1.61, 1.15-2.25; 1.49, 1.07-2.06) to ''very poor'' (2.85, 1.25-6.51; 1.30, 0.18-9.35). Persons answering the SRH question with ''don't know'' (1.87, 1.21-2.88; 1.26, 0.87-1.83) had also an increased mortality risk; this was pronounced in men and in the first years of follow-up. *Conclusions: SRH is a strong and ''dose-dependent'' predictor of mortality*. The association was largely independent from covariates and remained significant after decades. *This suggests that SRH provides relevant and sustained health information beyond classical risk factors or medical history* and reflects salutogenetic rather than pathogenetic pathways.

Physician Empathy & Cold Symptoms

Rakel et al 2009 Practitioner Empathy and the Duration of the Common Cold - Family Medicine *Objective:* This study's objective was to assess the relationship of empathy in medical office visits to subsequent outcomes of the common cold. *Methods:* A total of 350 subjects ≥ 12 years of age received either a standard or enhanced physician visit as part of a randomized controlled trial. Enhanced visits emphasized empathy on the part of the physician. The patient-scored Consultation and Relational Empathy (CARE) questionnaire assessed practitioner-patient interaction, especially empathy. Cold severity and duration were assessed from twice-daily symptom reports. Nasal wash was performed to measure the immune cytokine interleukin-8 (IL-8). *Results*: Eighty-four individuals reported perfect (score of 50) CARE scores. They tended to be older with less education but reported similar health status, quality of life, and levels of optimism. In those with perfect CARE scores, cold duration was shorter (mean 7.10 days versus 8.01 days), and there was a trend toward reduced severity (mean area under receiver-operator characteristics curve 240.40 versus 284.49). After accounting for possible confounding variables, cold severity and duration were significantly lower in those reporting perfect CARE scores. In these models, a perfect score also correlated with a larger increase in IL-8 levels. *Conclusions*: Clinician empathy, as perceived by patients with the common cold, significantly predicts subsequent duration and severity of illness and is associated with immune system changes. Patients were eligible to be enrolled in the study if they were at least 12 years of age and answered "yes" to the question, "Do you think that you have a cold?" They also needed to report one of the following four symptoms: (1) nasal discharge (runny nose), (2) nasal obstruction (nasal congestion, stopped up nose, stuffiness), (3) sneezing, and (4) sore throat (raw throat, scratchy throat). They were not eligible if any of these symptoms arose more than 36 hours prior to the intake evaluation. *Instruments and Measures* Consultation and Relational Empathy. The Consultation and Relational Empathy (CARE) measure is a questionnaire designed to measure several aspects of the clinical encounter related to empathy.13,14 CARE assesses empathy from the patient's perspective and has been validated in primary care settings. Patients completed the CARE measure once, directly following their clinician visits at the time of enrollment. CARE assesses 10 areas of consultations to see if clinicians made patients feel at ease, (2) allowed them to "tell their story," (3) really listened, (4) were interested in them as a whole person, (5) fully understood their concerns, (6) showed care and compassion, (7) were positive, (8) explained things clearly, (9) helped them take control, and (10) helped create a plan of action. For each item, clinicians are rated on a scale from 1-5, from poor to excellent. Ratings are summed to produce a possible CARE score range from 0-50, 50 being a perfect score

C-Reactive Protein (CRP) and Self-Reported Health

Shanahan et al 2014 Self-rated health and C-reactive protein in young adults - BBI Background: Poor self-rated health (SRH) and elevated inflammation and morbidity and mortality are robustly associated in middle- and older-aged adults. Less is known about SRH-elevated inflammation associations during young adulthood and whether these linkages differ by sex. Methods: Data came from the National Longitudinal Study of Adolescent Health. At Wave IV, young adults aged 24-34 reported their SRH, acute and chronic illnesses, and sociodemographic and psychological characteristics relevant to health. Trained fieldworkers assessed medication use, BMI, waist circumference, and also collected bloodspots from which high-sensitivity CRP (hs-CRP) was assayed. The sample size for the present analyses was N = 13,236. Results: Descriptive and bivariate analyses revealed a graded association between SRH and hs-CRP: Lower ratings of SRH were associated with a higher proportion of participants with hs-CRP >3 mg/L and higher mean levels of hs-CRP. Associations between SRH and hs-CRP remained significant when acute and chronic illnesses, medication use, and health behaviors were taken into account. When BMI was taken into account, the association between SRH and hs-CRP association fully attenuated in females; a small, but significant association between SRH and hs-CRP remained in males. *Conclusion: Poor SRH and elevated hs-CRP are associated in young adults, adjusting for other health status measures, medication use, and health behavior.* In males, SRH provided information about elevated hs-CRP that was independent of BMI. In females, BMI may be a better surrogate indicator of global health and pro-inflammatory influences compared to SRH.

Brain Mechanisms: Pro-Inflammatory Cytokines & Social Rejection - Social Rejection Study

Slavich, Way, Eisenberger, & Taylor 2010 Neural sensitivity to social rejection is associated with inflammatory responses to social stress - PNAS Although stress-induced increases in inflammation have been implicated in several major disorders, including cardiovascular disease and depression, the neurocognitive pathways that underlie inflammatory responses to stress remain largely unknown. To examine these processes, we recruited 124 healthy young adult participants to complete a laboratory-based social stressor while markers of inflammatory activity were obtained from oral fluids. A subset of participants (n = 31) later completed an fMRI session in which their neural responses to social rejection were assessed. As predicted, exposure to the laboratory-based social stressor was associated with significant increases in two markers of inflammatory activity, namely a soluble receptor for tumor necrosis factor-α (sTNFαRII) and interleukin- 6 (IL-6). In the neuroimaging subsample, greater increases in sTNFαRII (but not IL-6) were associated with greater activity in the dorsal anterior cingulate cortex and anterior insula, brain regions that have previously been associated with processing rejection related distress and negative affect. These data thus elucidate a neurocognitive pathway that may be involved in potentiated inflammatory responses to acute social stress. As such, they have implications for understanding how social stressors may promote susceptibility to diseases with an inflammatory component

Viral Infections (5)

Some further background... http://www.medicinenet.com/viral_infections_pictures_slideshow/article.htm *Respiratory Viral Infections* Respiratory viral infections affect the lungs, nose, and throat. These viruses are most commonly spread by inhaling droplets containing virus particles. Examples include: Rhinovirus is the virus that most often causes the common cold, but there are more than 200 different viruses that can cause colds. Cold symptoms like coughing, sneezing, mild headache, and sore throat typically last for up to 2 weeks. Seasonal influenza is an illness that affects about 5% to 20% of the population in the US every year. More than 200,000 people per year are hospitalized annually in the US due to complications of the flu. Flu symptoms are more severe than cold symptoms and often include body aches and severe fatigue. The flu also tends to come on more suddenly than a cold. Respiratory Syncytial Virus (RSV) is an infection that can cause both upper respiratory infections (like colds) and lower respiratory infections (like pneumonia and bronchiolitis). It can be very severe in infants, small children, and elderly adults. Frequent hand-washing, covering the nose and mouth when coughing or sneezing, and avoiding contact with infected individuals can all reduce the spread of respiratory infections. Disinfecting hard surfaces and not touching the eyes, nose, and mouth can help reduce transmission as well. *Viral Skin Infections* Viral skin infections can range from mild to severe and often produce a rash. Examples of viral skin infections include: Molluscum contagiosum causes small, flesh-colored bumps most often in children ages 1 to 10 years old; however, people of any age can acquire the virus. The bumps usually disappear without treatment, usually in 6 to 12 months. Herpes simplex virus-1 (HSV-1) is the common virus that causes cold sores. It's transmitted through saliva by kissing or sharing food or drink with an infected individual. Sometimes, HSV-1 causes genital herpes. An estimated 85% of people in the US have HSV-1 by the time they are in their 60s. Varicella-zoster virus (VZV) causes itchy, oozing blisters, fatigue, and high fever characteristic of chickenpox. The chickenpox vaccine is 98% effective at preventing infection. People who have had chickenpox or the chickenpox vaccine are at risk for developing shingles, an illness caused by the same virus. Shingles can occur at any age, but it occurs most often in people age 60 or older. The best way to avoid viral skin infections is to avoid skin-to-skin contact (especially areas that have a rash or sores) with an infected individual. Some viral skin infections, such as varicella-zoster virus, are also transmitted by an airborne route. Communal showers, swimming pools, and contaminated towels can also potentially harbor certain viruses. *Foodborne Viral Infections* Viruses are one of the most common causes of food poisoning. The symptoms of these infections vary depending on the virus involved. Hepatitis A is a virus that affects the liver for a few weeks up to several months. Symptoms may include yellow skin, nausea, diarrhea, and vomiting. Up to 15% of infected individuals experience recurrent illness within 6 months of infection. Norovirus has been reported to be responsible for outbreaks of severe gastrointestinal illness that happen on cruise ships, but it causes disease in many situations and locations. About 20 million people in the U.S. become sick from these highly contagious viruses every year. Rotavirus causes severe, watery diarrhea that can lead to dehydration. Anyone can get rotavirus, but the illness occurs most often in babies and young children. Rotaviruses and noroviruses are responsible for many (but not all) cases of viral gastroenteritis, which causes inflammation of the stomach and intestines. People may use the terms "stomach virus" or "stomach flu" to refer to viral gastroenteritis, which causes nausea, vomiting, diarrhea, and abdominal pain. It's not pleasant to think about it, but foodborne viral illnesses are transmitted via the fecal-oral route. This means that a person gets the virus by ingesting virus particles that were shed through the feces of an infected person. Someone with this type of virus who doesn't wash their hands after using the restroom can transfer the virus to others by shaking hands, preparing food, or touching hard surfaces. Contaminated water is another potential source of infection. *Sexually Transmitted Viral Infections* Sexually transmitted viral infections spread through contact with bodily fluids. Some sexually transmitted infections can also be transmitted via the blood (blood-borne transmission). Human papillomavirus (HPV) is the most common sexually-transmitted infection in the US. There are many different types of HPV. Some cause genital warts while others increase the risk of cervical cancer. Vaccination can protect against cancer-causing strains of HPV. Hepatitis B is a virus that causes inflammation in the liver. It's transmitted through contaminated blood and bodily fluids. Some people with the virus don't have any symptoms while others feel like they have the flu. The hepatitis B vaccine is more than 90% effective at preventing infection. Genital herpes is a common sexually-transmitted infection caused by herpes simplex virus-2 (HSV-2). Herpes simplex virus-1 (HSV-1), the virus responsible for cold sores, can also sometimes cause genital herpes. There's no cure for genital herpes. Painful sores often recur during outbreaks. Antiviral medications can decrease both the number and length of outbreaks. Human immunodeficiency virus (HIV) is a virus that affects certain types of T cells of the immune system. Progression of the infection decreases the body's ability to fight disease and infection, leading to acquired immune deficiency syndrome (AIDS). HIV is transmitted by coming into contact with blood or bodily fluids of an infected person. *Other Viral Infections* Viruses are abundant in the world and cause many other infections ranging from mild to life-threatening. Epstein-Barr virus (EBV) is a type of herpes virus that's associated with fever, fatigue, swollen lymph nodes, and an enlarged spleen. EBV is a very common virus that causes mononucleosis ("mono"). More than 90% of adults have been infected with this "kissing disease" that is spread primarily through saliva. West Nile virus (WNV) is a virus that's most commonly transmitted by infected mosquitos. Most people (70% to 80%) with WNV don't have any symptoms while others develop a fever, headache, and other symptoms. Less than 1% of people with WNV develop inflammation of the brain (encephalitis) or inflammation of the tissue surrounding the brain and spinal cord (meningitis). Viral meningitis is an inflammation of the lining of the brain and spinal cord that causes headache, fever, stiff neck, and other symptoms. Many viruses can cause viral meningitis, but a group of viruses called enteroviruses are most often to blame.

Inhibiting Cytokines and Depression

Tyring et al 2006 Etanercept and clinical outcomes, fatigue, and depression in psoriasis- double-blind placebo-controlled randomised phase III trial - Lancet Background Psoriasis has substantial psychological and emotional effects. We assessed the effect of etanercept, an effective treatment for the clinical symptoms of psoriasis, on fatigue and symptoms of depression associated with the condition. Methods 618 patients with moderate to severe psoriasis received double-blind treatment with placebo or 50 mg twiceweekly etanercept. The primary efficacy endpoint was a 75% or greater improvement from baseline in psoriasis area and severity index score (PASI 75) at week 12. Secondary and other endpoints included the functional assessment of chronic illness therapy fatigue (FACIT-F) scale, the Hamilton rating scale for depression (Ham-D), the Beck depression inventory (BDI), and adverse events. Efficacy analyses were based on the allocated treatment. Analyses and summaries of safety data were based on the actual treatment received. This study is registered with ClinicalTrials.gov with the identifier NCT00111449. Findings 47% (147 of 311) of patients achieved PASI 75 at week 12, compared with 5% (15 of 306) of those receiving placebo (p0·0001; difference 42%, 95% CI 36-48). Greater proportions of patients receiving etanercept had at least a 50% improvement in Ham-D or BDI at week 12 compared with the placebo group; patients treated with etanercept also had significant and clinically meaningful improvements in fatigue (mean FACIT-F improvement 5·0 vs 1·9; p0·0001, difference 3·0, 95% CI 1·6-4·5). Improvements in fatigue were correlated with decreasing joint pain, whereas improvements in symptoms of depression were less correlated with objective measures of skin clearance or joint pain. Interpretation Etanercept treatment might relieve fatigue and symptoms of depression associated with this chronic disease.

Caregiving Stress and Antibody Responses (6)

Vedhara et al 1999 Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination - Lancet BACKGROUND: There are many reports of psychological morbidity in spousal carers of patients with dementia. The consequences of this increased stress on the immune system are unclear. We investigated whether antibody responses to influenza vaccination differed between carers and a control group, and the relation of the antibody response to the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: 50 spousal carers of dementia patients, median age 73 years (IQR 66-77), and 67 controls (68 years [66-71]) of similar socioeconomic status were enrolled. Anxiety and depression were measured by the Savage Aged Personality Screening Scale and stress by the Global Measure of Perceived Stress scale. Principal-component analysis was used to yield a summary score of emotional distress from these two scales. Salivary cortisol concentrations were measured over a single day at three times (0800-1000, 1100-1300, and 2000-2200). Participants received a trivalent influenza vaccine and IgG antibody titres to each strain were measured on days 0, 7, 14, and 28. FINDINGS: Mean scores of emotional distress were significantly higher in carers at each time point than in controls (all p<0.0003). Mean (SD) salivary cortisol concentrations, calculated as area under the curve (AUC), were higher in carers than controls at all three assessments (6 months 16.0 [8.0] vs 11.2 [4.4], p=0.0001; respectively). Eight (16%) of 50 carers and 26 (39%) of 67 controls had a four-fold increase in at least one of the IgG titres (p=0.007). There was an inverse relation between AUC cortisol and IgG antibody titre to the Nanchang strain that was significant on day 14 (r=-0.216, p=0.039). INTERPRETATION: Elderly carers of spouses with dementia have increased activation of the hypothalamic-pituitary-adrenal axis and a poor antibody response to influenza vaccine. Carers may be more vulnerable to infectious disease than the population of a similar age.

Symptoms Associated with Pro-inflammatory Cytokines

Vollmer-Conna et al 2004 *Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behaviour in humans* - Psychological Medicine Background. Elaboration of the concept of cytokine-induced sickness behaviour in recent years has opened new avenues for understanding brain involvement in sickness and recovery processes. Additionally, this has led to much speculation about the role of the immune system in neuropsychiatric syndromes, including depression and chronic fatigue. However, few studies have examined this phenomenon as it naturally occurs in sick humans, and none has attempted to document the quantitative relationships between cytokine levels and non-specific symptoms. The aim of this research was to examine human sickness behaviour and its immunological correlates in documented Epstein-Barr virus (EBV), Q fever or Ross River virus (RRV) infections. Method. We studied two separate samples. The first consisted of 21 patients with acute Q fever. The second included 48 patients with acute RRV or EBV infection. Psychological and somatic symptom profiles were derived from self-report measures completed at enrolment. Quantification of proinflammatory cytokines [interleukin (IL)-1b and IL-6] in sera and supernatants of peripheral blood mononuclear cell (PBMC) cultures was undertaken by specific ELISAs. Results. Levels of IL-1b and IL-6 spontaneously released from PBMC cultures were consistently correlated with reported manifestations of acute sickness behaviour including fever, malaise, pain, fatigue, mood and poor concentration. Conclusions. IL-1b and IL-6 produced as part of the host response represent sensitive markers of sickness behaviour in humans with acute infection. Further work is needed to systematically characterize the spectrum and natural history of sickness behaviour in humans and to elucidate its biological basis. Arthralgia is joint pain. Myalgia = muscle pain

Psychoneuroimmunology (PNI)

• Background • Basics of Immune System - Pathogens: bacteria and viruses - Protections against pathogens - barriers - natural (i.e. innate or nonspecific) immune system - specific (i.e. adaptive) immune system - Inflammation • Stress and the Immune System -Acute Stress -Chronic Stress • Glucocorticoid Resistance/Feedback Insensitivity • Cytokine Theory of Disease

HPA Axis and Depression (5)

• Chronic stress can cause Major Depression • Depressed patients have high levels of cortisol • Hippocampal atrophy and impaired declarative memory --> Due to cortisol insensitivity/feedback resistance (see PNI lecture) • Excess cortisol generally normalizes with successful antidepressant treatment

Stress & Susceptibility to the Common Cold - Intro (3) - Two measures - Background - Methods - Result - Conclusions

• Quarantine at "cold" unit for a week - At outset, assess stress (checklist and subjective) - One day after quarantine, inject cold virus (or placebo) into nose • Two separate measures: 1. Infection: verified by taking lavage of nose and detecting virus or by measuring antibody to the virus in the blood 2. Illness symptoms - Measure mucus weight (literally weigh used kleenex) - Report on symptoms each day (sniffles, coughs, aches, etc). ******** Cohen, Tyrrell, & Smith 1991 Psychological stress and susceptibility to the common cold - NEJM *BACKGROUND:* It is not known whether psychological stress suppresses host resistance to infection. To investigate this issue, we prospectively studied the relation between psychological stress and the frequency of documented clinical colds among subjects intentionally exposed to respiratory viruses. *METHODS:* After completing questionnaires assessing degrees of psychological stress, 394 healthy subjects were given nasal drops containing one of five respiratory viruses (rhinovirus type 2, 9, or 14, respiratory syncytial virus, or coronavirus type 229E), and an additional 26 were given saline nasal drops. The subjects were then quarantined and monitored for the development of evidence of infection and symptoms. Clinical colds were defined as clinical symptoms in the presence of an infection verified by the isolation of virus or by an increase in the virus-specific antibody titer. *RESULTS:* *The rates of both respiratory infection (P less than 0.005) and clinical colds (P less than 0.02) increased in a dose-response manner with increases in the degree of psychological stress.* Infection rates ranged from approximately 74 percent to approximately 90 percent, according to levels of psychological stress, and the incidence of clinical colds ranged from approximately 27 percent to 47 percent. These effects were not altered when we controlled for age, sex, education, allergic status, weight, the season, the number of subjects housed together, the infectious status of subjects sharing the same housing, and virus-specific antibody status at base line (before challenge). Moreover, the associations observed were similar for all five challenge viruses. Several potential stress-illness mediators, including smoking, alcohol consumption, exercise, diet, quality of sleep, white-cell counts, and total immunoglobulin levels, did not explain the association between stress and illness. Similarly, controls for personality variables (self-esteem, personal control, and introversion-extraversion) failed to alter our findings. *CONCLUSIONS:* Psychological stress was associated in a dose-response manner with an increased risk of acute infectious respiratory illness, and this risk was attributable to increased rates of infection rather than to an increased frequency of symptoms after infection.