Dynamics of the systemic inflammatory response surrounding life events and the association with neuropsychiatric and somatic outcomes

Abstract Background Adverse life events and psychosocial stressors contribute to a range of neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, a large international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to subsequent risk of mental illness and somatic symptoms. Methods We compared 36,772 individuals with records of adverse life events and leukocytosis in the surrounding period with matched individuals with normal leukocyte counts, and performed an analogous comparison for socioeconomic and psychosocial stressors in cohorts of 87,936 individuals with leukocytosis and matched controls. To contrast dynamic with static inflammatory responses, we compared cohorts exhibiting leukocyte count changes with those maintaining persistently normal or persistently elevated leukocyte counts around stressor exposure. Outcomes, including new mental health and somatic symptom presentations, were evaluated within two years of the stressor. Results Following acute stressors, leukocytosis (compared with normal leukocyte counts) was associated with lower rates of subsequent anxiety disorders, cognitive symptoms and several somatic symptom diagnoses, with similar reductions in anxiety observed after chronic stressors. A dynamic inflammatory response was associated with the most favourable outcomes, with lower rates of anxiety, depression, functional neurological disorder, cognitive and sleep difficulties, fatigue, and multiple pain-related and other somatic symptoms than persistently low or high inflammation. Conclusion Our findings suggest that a well-regulated inflammatory response to stressors is associated with a reduced risk of diverse mental health and somatic outcomes, and that a transient immune activation may support recovery rather than confer risk.