Psychological side effects of immune therapies: symptoms and pathomechanism

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Introduction
Immunotherapy is a special biological therapy targeted at activating the innate immune system to fight infections or cancer, or downregulate immune response in case of autoimmune disorders or allergies. Immunotherapies that boost immune response against tumour cells or viruses are frequently associated with early neurovegetative symptoms characterised by fatigue, psychomotor slowing, anorexia and pain [1]. These symptoms show a significant overlap with the manifestations of the so-called sickness behaviour, caused by the activation of proinflammatory cytokines during infections and including symptoms of fatigue, anhedonia, low mood, social isolation and irritability [2]. Sickness behaviour is considered an adaptive response to promote healing by reducing energy expenditure towards not necessary activities and decreasing exploratory behaviour, thus it resembles a behavioural pattern very similar to anxiety and depressive symptoms. Depressive components including anhedonia, heightened pain sensitivity, and social avoidance are meant to conserve energy to fight the infection, while the anxious components were developed to avoid further conflicts which might have negative outcome on the healing process [3,4••]. Thus, an evolutionary advantageous behavioural effect of immune response, which enhances survival, is also a disturbing side effect of life saving immunotherapies leading to significant suffering, burden and loss of quality of life, and thus limiting the completion of the treatment course. Because of the sharp increase in the number of different immunotherapies and their indications in the present review we focus on the psychological side effects of the most frequently investigated interferon-alpha (IFN-alpha) treatment and shortly summarise the side effects of the newly developed immune checkpoint blocking agents.

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