Interleukin-12 (IL-12)/IL-10 Ratio as a Marker of Disease Severity in Crimean-Congo Hemorrhagic Fever

LETTER

Saksida et al. present an insightful analysis of correlations between cytokine levels, viral load, antibody titers, and clinical severity in a group of 46 patients with acute Crimean-Congo hemorrhagic fever (CCHF) (5). As noted by the study's authors, similar results have been found in other studies of CCHF and other viral hemorrhagic fevers (7, 8).

It is known that interleukin-12 (IL-12) plays a significant role in the activation of the Th1 immune response and, at the same time, that IL-10 action results in a negative regulation of this process (4). The apparent opposing relationship that exists between the two interleukins has led to several studies successfully employing the ratio of these cytokines (usually IL-10/IL-12) in the assessment of immune status, e.g., as a measure of the balance between an anti-inflammatory and a proinflammatory state (2, 3, 6), or Th1 versus Th2 dominance (1).

Given that (i) the IL-10/IL-12 ratio has been effectively used to link immune states to clinical parameters in previous studies, (ii) in the CCHF study under discussion, the relationship of this ratio to disease course/outcome and viral load was not assessed, (iii) the correlation between IL-12 and viral load was not statistically significant, and (iv) the difference in IL-12 levels between “severe” and “fatal” subgroups was not statistically significant, we decided to perform a supplemental statistical analysis, using the ratio between IL-12 and IL-10 in place of either cytokine alone (possibly reflecting the Th1/Th2 ratio), in an effort to better approach the combined effects of these cytokines. It should be emphasized that the goal of this supplemental analysis was to assess whether investigation of this ratio should be pursued in further studies of CCHF; the relatively large amount of data available in this study provides a valuable opportunity for this assessment. Nonetheless, the retrospective nature of our analysis makes drawing any deeper conclusions questionable.

In our analysis, we performed the same statistical tests as Saksida et al., namely, Mann-Whitney U tests for differences between patient subgroups and a Pearson test for the correlation between cytokine ratio and viral load (5). Since several patients had undetectable IL-12 levels (value = 0), we used the ratio of IL-12/IL-10 to avoid division by zero. GraphPad Prism version 5 for Windows (La Jolla, CA) was used for all analyses.

Our analysis showed that the IL-12/IL-10 ratio was higher in the moderate subgroup (mean, 3.2; 95% confidence interval [CI], 1.44 to 4.95) than in either the severe (mean, 0.6; 95% CI, 0.26 to 0.94) or the fatal (mean, 0.21; 95% CI, 0.071 to 0.35) subgroup; the difference between the severe and fatal subgroups was less pronounced. Furthermore, a significant correlation was found between the IL-12/IL-10 ratio and viral load (r = −0.485; 95% CI, −0.688 to −0.213). The results and corresponding P values are summarized in Fig. 1 and 2.

Fig 1.

Comparison of IL-12/IL-10 concentration ratio and clinical course/outcome in patients with acute CCHF. The horizontal lines in the boxes show medians, while the top and bottom horizontal lines of the boxes (hinges) depict the 75th and 25th percentiles of the data sets, respectively. The whiskers denote the 5th and 95th percentiles of data sets, and the dots denote outliers.

Fig 2.

Correlation between IL-12/IL-10 concentration ratio and viral load in patients with acute CCHF.

In conclusion, our supplemental analysis shows that the IL-12/IL-10 ratio may be a useful way to approach immune status and its clinical significance in CCHF and, perhaps, other viral hemorrhagic fevers. We propose its use in further studies, as it may prove to be an important predictive marker of disease severity, supplementary to viral load and antibody titers.