Specific in vitro interferon-gamma and IL-2 production as biomarkers during treatment of chronic Q fever

Abstract

Background: Antibiotic treatment of chronic Q fever is cumbersome and of long duration. To monitor treatment, there is a need for alternative biomarkers. Coxiella burnetii-specific interferon (IFN)-γ and interleukin (IL)-2 production reflect the type of effector and memory T-cell response. In chronic Q fever, C. burnetii-specific IFN-γ production is higher and IL-2 production is lower than in individuals with past Q fever. Here we explore whether C. burnetii-specific IFN-γ and IL-2 production correlate to treatment response.

Methods: We studied the longitudinal C. burnetii-specific IFN-γ/IL-2 ratio in fifteen proven chronic Q fever patients. All patients were followed for at least 18 months during antibiotic treatment. Treatment was considered successful when clinical recovery was observed, a positive PCR for C. burnetii DNA in blood became persistently negative, anti-phase I IgG showed a fourfold decrease or more, and imaging techniques showed disappearance of infectious foci.

Results: Overall, the IFN-γ/IL-2 ratio declined when patients experienced a successful treatment outcome. When treatment failed, IFN-γ/IL-2 ratios did not significantly decrease. The median (±IQR) slope of the longitudinal IFN-γ/IL-2 ratio with successful treatment was -2.10 (-7.02 to -0.06), and -0.15 (-1.13 to 0.25) with unsuccessful treatment (P = 0.19). Q fever endocarditis patients had higher IFN-γ/IL-2 ratios than patients with endovascular infections.

Conclusion: We propose that the IFN-γ/IL-2 ratio can be used as an additional biomarker for monitoring chronic Q fever treatment, with declining ratios being indicative of successful treatment.

Keywords: Coxiella burnetii; Q fever; biomarker; cell-mediated immunity; interferon-gamma; interleukin-2; serology; treatment.

FIGURE 1

Detailed overview of immunological parameters in (A) patient 1 (B) patient 2, and (C) patient 3 from start of antibiotic treatment to end of study follow-up. The IFN-γ and IL-2 concentrations (dotted lines) and the IFN-γ/IL-2 ratio (black diamant) are shown on the left y-axis, the anti-phase I IgG antibody-titer (black triangle) is shown on the right y-axis. The course of antibiotic treatment is depicted above each graph.

FIGURE 2

Interferon-γ/IL-2 ratio in C. burnetii-stimulated whole blood of chronic Q fever patients during the study follow-up period, separately shown for (A) patients with successful and (B) patients with unsuccessful treatment. t = 0 is start of antibiotic treatment. Treatment was considered successful when 18 months of antibiotic treatment (or 24 months when a prosthesis remained in situ) was completed, and clinically recovery was observed, and a positive PCR for C. burnetii DNA on blood became persistently negative, and anti-phase I IgG showed a fourfold decrease or more (related to the maximum titer), and imaging techniques showed disappearance of any (vascular or valvular) infection focus. Circles indicate a positive PCR on blood/serum, squares indicate positive PCR on tissue. Vertical lines indicate stop of antimicrobial treatment.

FIGURE 3

Non-linear regression to straight curves of the longitudinal IFN-γ/IL-2 ratios of chronic Q fever patients. Patients with successful treatment are shown in green, patients with unsuccessful treatment are shown in red. The median (±IQR) slope of the patients with successful treatment was -2.10 (-7.02 to -0.06), compared to -0.15 (-1.13 to 0.25) in patients with unsuccessful treatment (P = 0.19).

FIGURE 4

Follow-up IFN-γ/IL-2 ratio from chronic Q fever patients during the study follow-up period, separately shown for (A) patients with endocarditis and (B) patients with vascular (prosthesis) infection. t = 0 is start of antibiotic treatment.