Inflammation and subjective health : the role of sickness behaviour

Sickness behaviour refers to a set of coordinated behavioural and psychological changes in response to inflammation aimed to redirect available energy to the immune system to promote recovery. Sickness behaviour symptoms closely resemble important determinants of poor self-rated health, which in turn has been coupled to increased levels of inflammatory cytokines. However, it is not known if this association between inflammatory cytokines and self-rated health is mediated by sickness behaviour. Furthermore, it has not yet been established if other systemic and local inflammatory markers affect self-rated health, sickness behaviour and other patient reported outcome measures (PROMs). This thesis main aim was to investigate sickness behaviour as a determinant of self-rated health and as a possible mediator in an association between inflammatory markers and subjective health perception in primary care patients and in patients with asthma. In paper I, a questionnaire to measure sickness behaviour, SicknessQ, was developed and validated in two steps. First, sickness behaviour was experimentally induced by injecting endotoxin in healthy volunteers. The participants completed 37 items describing a broad range of sickness symptoms, items that responded to acute inflammatory provocation were selected and psychometric properties were tested in 172 primary care patients. The results demonstrated adequate psychometric properties for the resulting 10-item SicknessQ-scale and gave support for using SicknessQ as a brief instrument to assess human sickness behaviour. In paper II, the relationship between inflammatory markers, health anxiety, sickness behaviour and self-rated health was investigated in 311 primary care patients, 172 of which were also part of the study population in paper I. Furthermore, mediation analysis was conducted to exploratory investigate if putative relationships between inflammatory markers and self-rated health were statistically mediated by sickness behaviour. The results showed that poor self-rated health was associated with increased sickness behaviour and higher health anxiety. In addition, elevated levels of IL-6 were associated with poor self-rated health in men, although this association was not mediated by sickness behaviour. In paper III and IV, the longitudinal associations between self-rated health, sickness behaviour, asthma-related quality of life, inflammatory markers (paper III: FENO, ECP, EDN, IgE, paper IV: IL-5, IL-6) and lung function were investigated with repeated measurements in 181 patients with allergic asthma during 12-months. Poor self-rated health was associated with increased sickness behaviour, poorer asthma-related quality of life and high levels of seasonal IgE and food IgE but not total IgE or FENO, ECP or EDN. In men, a u-shaped relationship was found where both low and high levels of IL-6 were associated with increased sickness behaviour. Analysed over time, a worsening in sickness behaviour was associated with a worsening of self-rated health. Also, an improvement of asthma-related quality of life was associated with an improvement in self-rated health. In men, but not women, increased lung function measured as FEV1 was associated with an increase in IL-6, better self-rated health and increased asthma-related quality of life over the year. In this thesis, new knowledge is gathered to understand the underpinnings and interrelations between self-rated health, sickness behaviour and inflammation. More sickness behaviour emerged as a more consistent determinant of poor self-rated health compared to inflammatory markers, for which mixed results were found. The results of the thesis highlight the role of sickness behaviour in subjective health perception. LIST OF SCIENTIFIC PAPERS I. A global measure of sickness behaviour: Development of the Sickness Questionnaire Andreasson A, Wicksell R.K, Lodin K, Karshikoff B, Axelsson J, Lekander M. (2016). J Health Psychol. 2016. Epub 2016/07/28. II. Associations between inflammation, self-rated health and sickness behaviour in primary care Lodin K, Lekander M, Petrovic P, Hedman E, Andreasson A. Manuscript III. Associations between self-rated health, sickness behaviour and inflammatory markers in primary care patients with allergic asthma: a longitudinal study Lodin K, Lekander M, Syk J, Alving K, Andreasson A. NPJ Primary Care Respiratory Medicine. 2017;27(1):67. IV. Longitudinal co-variations between inflammatory cytokines, lung function and patient reported outcomes in patients with asthma Lodin K, Lekander M, Syk J, Alving K, Predrag P, Andreasson A. PLoS One, 2017. 12(9): p. e0185019