William J. Doyle

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

Types of Stressors That Increase Susceptibility to the Common Cold in Healthy Adults

Two-hundred seventy-six volunteers completed a life stressor interview and psychological questionnaires and provided blood and urine samples. They were then inoculated with common cold viruses and monitored for the onset of disease. Although severe acute stressful life events (less than 1 month long) were not associated with developing colds, severe chronic stressors (1 month or longer) were associated with a substantial increase in risk of disease. This relation was attributable primarily to under- or unemployment and to enduring interpersonal difficulties with family or friends. The association between chronic stressors and susceptibility to colds could not be fully explained by differences among stressed and nonstressed persons in social network characteristics, personality, health practices, or prechallenge endocrine or immune measures.

Emotional Style and Susceptibility to the Common Cold

Objective: It has been hypothesized that people who typically report experiencing negative emotions are at greater risk for disease and those who typically report positive emotions are at less risk. We tested these hypotheses for host resistance to the common cold. Methods: Three hundred thirty‐four healthy volunteers aged 18 to 54 years were assessed for their tendency to experience positive emotions such as happy, pleased, and relaxed; and for negative emotions such as anxious, hostile, and depressed. Subsequently, they were given nasal drops containing one of two rhinoviruses and monitored in quarantine for the development of a common cold (illness in the presence of verified infection). Results: For both viruses, increased positive emotional style (PES) was associated (in a dose‐response manner) with lower risk of developing a cold. This relationship was maintained after controlling for prechallenge virus‐specific antibody, virus‐type, age, sex, education, race, body mass, and season (adjusted relative risk comparing lowest‐to‐highest tertile = 2.9). Negative emotional style (NES) was not associated with colds and the association of positive style and colds was independent of negative style. Although PES was associated with lower levels of endocrine hormones and better health practices, these differences could not account for different risks for illness. In separate analyses, NES was associated with reporting more unfounded (independent of objective markers of disease) symptoms, and PES with reporting fewer. Conclusions: The tendency to experience positive emotions was associated with greater resistance to objectively verifiable colds. PES was also associated with reporting fewer unfounded symptoms and NES with reporting more.

Psychological stress, cytokine production, and severity of upper respiratory illness.

OBJECTIVE The purpose of this study is to assess the role of psychological stress in the expression of illness among infected subjects and to test the plausibility of local proinflammatory cytokine production as a pathway linking stress to illness. METHODS After completing a measure of psychological stress, 55 subjects were experimentally infected with an influenza A virus. Subjects were monitored in quarantine daily for upper respiratory symptoms, mucus production, and nasal lavage levels of interleukin (IL)-6. RESULTS Higher psychological stress assessed before the viral challenge was associated with greater symptom scores, greater mucus weights, and higher IL-6 lavage concentrations in response to infection. The IL-6 response was temporally related to the two markers of illness severity, and mediation analyses indicated that these data were consistent with IL-6 acting as a major pathway through which stress was associated with increased symptoms of illness. However, this pattern of data is also consistent with increases in IL-6 occurring in response to tissue damage associated with illness symptoms. CONCLUSIONS Psychological stress predicts a greater expression of illness and an increased production of IL-6 in response to an upper respiratory infection.

Socioeconomic status is associated with stress hormones.

Objective: We assess whether socioeconomic status (SES) is associated with basal levels of cortisol and catecholamines and determine if any association between SES and these hormones can be explained (is mediated) by behavioral, social, and emotional differences across the SES gradient. Methods: One hundred ninety-three adult subjects, including men and women and whites and African-Americans, provided 24-hour urine catecholamine samples on each of 2 days and seven saliva cortisol samples on each of 3 days beginning 1 hour after wakeup and ending 14 to 16 hours later. Values for both hormones were averaged across days to obtain basal levels. Results: Lower SES (income and education) was associated with higher levels of cortisol and epinephrine and marginally higher levels of norepinephrine. These associations were independent of race, age, gender, and body mass. Low SES was also associated with a greater likelihood of smoking, of not eating breakfast, and with less diverse social networks. Further analyses provided evidence consistent with the hypothesis that these behavioral and social variables mediate the link between SES and the three stress hormones. Conclusions: Lower SES was associated in a graded fashion with higher basal levels of cortisol and catecholamines. These associations occurred independent of race, and the data were consistent with mediation by health practices and social factors. AUC = area under the curve; BMI = body mass index; CARDIA = Coronary Artery Risk Development in Young Adults Study; ELISA = enzyme-linked immunosorbent assay; HPA = hypothalamic-pituitary adrenocortical axis; ISEL = Interpersonal Support Evaluation List; LET = Life Engagement Test; SES = socioeconomic status; SNS = sympathetic nervous system.

Sleep Habits and Susceptibility to the Common Cold

BACKGROUND Sleep quality is thought to be an important predictor of immunity and, in turn, susceptibility to the common cold. This article examines whether sleep duration and efficiency in the weeks preceding viral exposure are associated with cold susceptibility. METHODS A total of 153 healthy men and women (age range, 21-55 years) volunteered to participate in the study. For 14 consecutive days, they reported their sleep duration and sleep efficiency (percentage of time in bed actually asleep) for the previous night and whether they felt rested. Average scores for each sleep variable were calculated over the 14-day baseline. Subsequently, participants were quarantined, administered nasal drops containing a rhinovirus, and monitored for the development of a clinical cold (infection in the presence of objective signs of illness) on the day before and for 5 days after exposure. RESULTS There was a graded association with average sleep duration: participants with less than 7 hours of sleep were 2.94 times (95% confidence interval [CI], 1.18-7.30) more likely to develop a cold than those with 8 hours or more of sleep. The association with sleep efficiency was also graded: participants with less than 92% efficiency were 5.50 times (95% CI, 2.08-14.48) more likely to develop a cold than those with 98% or more efficiency. These relationships could not be explained by differences in prechallenge virus-specific antibody titers, demographics, season of the year, body mass, socioeconomic status, psychological variables, or health practices. The percentage of days feeling rested was not associated with colds. CONCLUSION Poorer sleep efficiency and shorter sleep duration in the weeks preceding exposure to a rhinovirus were associated with lower resistance to illness.

State and trait affect as predictors of salivary cortisol in healthy adults.

We measured affect in 334 healthy adults on each of 7 days over a 3-week period. On the last day, salivary cortisol was assessed 14 times yielding scores for total concentration, morning rise amplitude, and slope of the time function. Trait negative affect (NA) was associated with higher total cortisol concentrations and greater morning rise in men. Cortisol levels for men low in trait positive affect (PA) did not decrease in the afternoon, resulting in a relatively high, flat rhythm. In contrast, women high in trait PA had low morning cortisol resulting in a low flat rhythm. State (person-centered) NA was not associated with same-day cortisol measures. State PA was associated with decreased total cortisol concentration in women. These are the first results showing associations between cortisol and trait PA. Differences in rhythmicity found here are noteworthy given the possible role of cortisol dysregulation in disease incidence, morbidity, mortality, and severity.

Otitis media with effusion in preschool children.

The incidence, prevalence, and natural history of otitis media with effusion (OME) and middle ear high negative pressure (HNP) were investigated in a group of 2 to 6 year old preschool children. The children were examined monthly over a two year period from September 1981 to August 1983. The middle ear status was assessed using a decision‐tree algorithm which combined the findings of pneumatic otoscopy, tympanometry, and acoustic reflex measurements. Fifty‐three percent of the children in the first year and 61% in the second year developed OME; also during the two years, HNP was documented in 66% of the children. Eighty percent of OME episodes lasted only two months. The prevalence of OME and HNP showed a seasonal variation and a strong association with the presence of upper respiratory infections (URIs). The incidence of OME was independent of age. These data indicate that OME and HNP are prevalent conditions with a high spontaneous recovery in the preschool population.

State and trait negative affect as predictors of objective and subjective symptoms of respiratory viral infections

State and trait negative affect (NA) were measured in healthy people immediately before an illness was induced through exposure to a respiratory virus. State NA, disease-specific health complaints (e.g., runny nose, congestion, and sneezing), and an associated objective marker of disease severity (mucus secretion weights) were assessed daily during the illness. Baseline trait and state NA were both associated with increased numbers of subsequent complaints. Although greater numbers of complaints among people high in state NA were explicable in terms of greater disease severity, the association of trait NA and symptoms was independent of objective disease. The trait NA complaint association was also independent of state NA and hence not attributable to trait-elicited state affect. Greater trait NA was associated with biases in complaining during but not before illness. This suggested failure to discriminate between symptoms rather than increased sensitivity or hypochondriacal response.

Objective and Subjective Socioeconomic Status and Susceptibility to the Common Cold

OBJECTIVE We ask whether subjective socioeconomic status (SES) predicts who develops a common cold when exposed to a cold virus. DESIGN 193 healthy men and women ages 21-55 years were assessed for subjective (perceived rank) and objective SES, cognitive, affective and social dispositions, and health practices. Subsequently, they were exposed by nasal drops to a rhinovirus or influenza virus and monitored in quarantine for objective signs of illness and self-reported symptoms. MAIN OUTCOME MEASURES Infection, signs and symptoms of the common cold, and clinical illness (infection and significant objective signs of illness). RESULTS Increased subjective SES was associated with decreased risk for developing a cold for both viruses. This association was independent of objective SES and of cognitive, affective and social disposition that might provide alternative spurious (third factor) explanations for the association. Poorer sleep among those with lesser subjective SES may partly mediate the association between subjective SES and colds. CONCLUSIONS Increased Subjective SES is associated with less susceptibility to upper respiratory infection, and this association is independent of objective SES, suggesting the importance of perceived relative rank to health.