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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.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.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.Psychological stress predicts a greater expression of illness and an increased production of IL-6 in response to an upper respiratory infection.