Altered interferon-γ response in patients with Q-fever fatigue syndrome
Introduction
At present, the Netherlands is faced with the aftermath of the largest Q-fever outbreak worldwide lasting from 2007 to 2011.1 During this period, over 4000 patients with symptomatic acute Q-fever were reported, and it was estimated that over 40,000 individuals experienced a latent infection.2, 3 Although most patients with symptomatic acute Q-fever recover completely with only a serological scar left, infection with Coxiella burnetii is notorious for causing long-term sequelae, i.e., chronic Q-fever and Q-fever fatigue syndrome (QFS). Chronic Q-fever, characterized by the persistence of viable C. burnetii, may develop in 1–5% of both symptomatic and asymptomatic cases of acute Q-fever. Chronic Q-fever presents mainly as vascular infection,4 including mycotic aneurysms and infections of vascular prosthesis, and endocarditis.5 QFS, a debilitating fatigue syndrome following acute Q-fever, may become manifest in approximately 20% of patients.6, 7, 8, 9, 10 Lasting up to 10 years after the acute illness,11 QFS is considered to be the major cause of the Q-fever-related economical burden following the Dutch outbreak.12 The pathophysiological mechanisms underlying QFS remain to be elucidated. Interpretations range from compensation-driven and psychogenic perpetuation of the original symptoms,7 to attribution of the syndrome to cytokine dysregulation due to chronic immune stimulation.7 The latter might be caused by persisting C. burnetii, or by persisting non-infectious C. burnetii antigens.13, 14, 15, 16, 17, 18 White blood cells from QFS patients exposed to Q-fever antigens were found to exhibit a marked interleukin-6 (IL-6) production,13 and the IL-6 production was similar in both chronic Q-fever patients and seropositive controls, which was significantly higher than in seronegative controls.19 In addition, the group of QFS patients contained significantly more interferon-γ (IFNγ) responders than a group of controls, whilst the proportion of IL-2 responders was lower among QFS patients.13 IFNγ is a cytokine that plays an important role in the host defence against intracellular bacteria such as C. burnetii.20, 21, 22, 23 To date, no diagnostic test is available to diagnose QFS directly and diagnosis partly relies on measurement of C. burnetii-specific antibodies, e.g. serology, reflecting humoral immunity. Recently our group developed a C. burnetii-specific whole blood IFNγ production assay, which is a promising diagnostic tool for C. burnetii infection,24 with similar performance and practical advantages over serology.25 In addition, a high IFNγ/IL-2 ratio appeared to be indicative of chronic Q-fever, and may be a useful diagnostic marker for chronic Q-fever and treatment monitoring.19, 26 In addition, as suggested in animal experiments, antigen-specific IFNγ production could also be a useful tool for diagnosis of acute Q-fever.27
In the present study, we addressed the question whether there is an aberrant antigen-specific IFNγ production and IFNγ/IL-2 ratio in QFS patients. If so, this might provide additional insight in the potential pathophysiological mechanisms underlying this debilitating long-term complication and might contribute, as immunological markers, to the diagnostic workup of QFS.
Section snippets
Study population
The study population consisted of QFS patients (n = 20), Q-fever seropositive controls (n = 135), and patients with proven chronic Q-fever (n = 28). All QFS patients were diagnosed with QFS at the Radboud Expertise Centre for Q-fever, Nijmegen, the Netherlands, after a uniform work-up according to the Dutch guideline on QFS.28 All QFS patients met the following diagnostic criteria: i. fatigue lasted ≥6 months; ii. sudden onset of severe fatigue (defined as a score ≥35 on the subscale fatigue
Patients and controls
At the time of blood collection, QFS was already diagnosed but treatment had yet to be started (Table 1). The symptom duration of QFS patients, defined as the time of symptom onset until blood sampling, varied between 12 and 51 months (Table 1). All seropositive controls had IgG phase I or phase II titres ≥1:32, but IgG phase I ≤1:512, and none of them showed serological signs of an acute or recent Q-fever infection, reflected by IgM antibodies in absence of IgG antibodies. The mean age of QFS
Discussion
In this study we assessed the antigen-specific IFNγ production and IFNγ/IL-2 ratio in C. burnetii-stimulated whole blood of QFS patients. We found that the IFNγ production of QFS and chronic Q-fever patients was not significantly different, but for both significantly increased compared to seropositive controls. In addition, the IFNγ/IL-2 ratio in QFS patients was similar to that in seropositive controls, but lower than in chronic Q-fever patients. Of note, no differences in IL-2 production
Conclusion
In conclusion, the IFNγ production in QFS patients is significantly higher than in seropositive controls, and the IFNγ/IL-2 ratio is significantly lower than in chronic Q-fever patients.
Further investigation in larger cohorts of QFS patients is warranted, as these results point to an altered cell-mediated immunity in QFS, and hence opens up avenues for better understanding the pathogenesis of this enigmatic complication of Q-fever and of other fatigue syndromes.
Acknowledgment
The authors wish to thank all participating hospitals in facilitating collection of blood samples of chronic Q-fever patients.
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2022, VaccineCitation Excerpt :The Interferon γ-(IFN-γ) recall-assay (IFN-γ-RA) detects IFN-γ after stimulation of peripheral mononuclear blood cells (PMBC) with antigen. The IFN–γ-RA is increasingly used in humans and animals to analyse the cellular immune response after C. burnetii infection or vaccination [22,25–27]. Since 2010, an inactivated C. burnetii PhI-vaccine (Coxevac®, Ceva Sante Animal, Libourne, France) is licenced in Germany for immunization of cattle and goats.
Cytokine profiles in patients with Q fever fatigue syndrome
2019, Journal of InfectionCitation Excerpt :It is possible that this is part of the recovery process of acute Q fever. The fact that we did not find differences in Coxiella-specific whole blood IFNγ production between QFS patients and asymptomatic Q fever seropositive controls in the present study, as compared with previous studies,11 could be explained by the observation that patients with more severe and longer-lasting acute Q fever produce more IFNγ.19 In the current study, 13 out of 19 asymptomatic Q fever seropositive controls suffered from a symptomatic initial infection, i.e., acute Q fever, whereas the Q fever seropositive controls of the previous study all had had an asymptomatic initial infection.
Post-bacterial infection chronic fatigue syndrome is not a latent infection
2019, Medecine et Maladies InfectieusesCitation Excerpt :The long-term persistence of non-viable in situ or circulating C. burnetii cell components including antigens or DNA is the sole biological finding currently correlating with these subjective symptoms. The circulation of these bacterial cell components could result in an altered cell immunity and in an altered cytokine production [12,14–16]. The subsequent ongoing production of pro-inflammatory cytokines could then be responsible for fatigue.
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2018, Environment InternationalCitation Excerpt :A few years before this study, between 2007 and 2009, the area had experienced the largest described Q-fever epidemic to date (Van Der Hoek et al., 2012). It has been suggested that previous infection with Coxiella burnetii (the causative agent of Q-fever) may add an increased sensitivity to other infectious agents (Hussain-Yusuf et al., 2012; Marmion et al., 2009; Raoult et al., 2005; Waag, 2007; Keijmel et al., 2016; Hatchette et al., 2003; Morroy et al., 2011). It is relevant to note that at the time of our study, Q-fever incidence had dropped again to pre-epidemic levels (Freidl et al., 2017).