Persistent Fatigue Induced by Interferon-Alpha

Chronic fatigue syndrome (CFS), or myalgic encephalomyelitis (ME), is a mysterious condition. The main symptom of CFS is extreme and often unrelenting fatigue; others include muscle and joint pain, sleep issues, and flu-like symptoms.

There is some evidence implicating the immune system in the pathogenesis of CFS, but the exact role of immune mechanisms in this condition, especially at its onset, have yet to be established. Genetic polymorphisms in immune genes are associated with CFS as well as other disease-related fatigue.


A large multidisciplinary team of scientists working with King’s College (London, UK) has presented a study of interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6–12 months of IFN-α treatment, and at six-month post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained.

Cytokines were measured using MSD V-PLEX sandwich immunoassays and plates read on an MSD QuickPlex SQ 120. MSD Pro-inflammatory Panel 1 (human) kits were used for the measurement of IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α, and a custom Cytokine Panel 1 (human) kit was used for the measurement of IL-7, IL-17 A and VEGF. To assess kynurenine pathway metabolites plasma aliquots were analyzed chromatographic system was composed of a Waters Acquity UPLC separations module connected to a Xevo TQ MS triple-quadrupole mass spectrometer, equipped with a Z-spray ESI ion source.

The team reported that 18 patients undergoing IFN-α treatment (33%) were subsequently defined as having ‘persistent fatigue’ (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered ‘resolved fatigue’. There was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week 4. There were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls.

Alice Russell, PhD, the lead author of the study, said, “Our findings suggest that people who have an exaggerated immune response to a trigger may be more at risk of developing CFS.” Interestingly, once the CFS-like illness developed, there were no longer any detectable differences between the immune systems of those who developed the symptoms and those who did not. The study was published on December 17, 2018, in the journal Psychoneuroendocrinology.

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