HMGB1, anti-HMGB1 antibodies, and ratio of HMGB1/anti-HMGB1 antibodies as diagnosis indicator in fever of unknown origin

Abstract

To evaluate the feasibility of serum HMGB1, anti-HMGB1 antibodies, and HMGB1/anti-HMGB1 ratio as a diagnosis indicator of initial clinical classification in patients with fever of unknown origin (FUO). Ninety-four patients with classical FUO and ninety healthy controls were enrolled in this study. The subjects' clinical data and serum were collected. The serum concentration of HMGB1 was detected by a commercial HMGB1 ELISA kit, while the serum concentration of anti-HMGB1 antibodies were detected by an in-house built anti-HMGB1 antibodies ELISA kit and further confirmed by immunoblotting. According to the hospital diagnosis on discharge, ninety-four FUO patients were divided into four groups, Infectious disease subgroup, autoimmune disease subgroup, malignant tumor subgroup, and undetermined subgroup. The concentrations of HMGB1 in the infectious disease subgroup and autoimmune disease subgroup were higher than those in the malignant tumor subgroup, undetermined subgroup, and healthy control group. The concentration of anti-HMGB1 antibodies in autoimmune disease subtype group was higher than those in other subgroups as well as healthy control group. According to the distribution of HMGB1 and anti-HMGB1 in scatter plots of the patients with FUO, we found that the ratio of serum HMGB1/anti-HMGB1 is an ideal clinical indicator for differential diagnosis of different subtypes of FUO. The best cut-off was 0.75, and the sensitivity, specificity, and AUC were 66.67%, 87.32%, and 0.8, respectively. Correlation analysis showed that serum concentration of HMGB1 was moderately correlated with CRP in infectious diseases subgroup, and the serum concentration of anti-HMGB1 antibodies was strongly correlated with erythrocyte sedimentation rate in autoimmune disease subgroup. Our study had showed that serum HMGB1/anti-HMGB1 antibodies ratio can help clinicians identify FUO subtypes, thereby avoiding many unnecessary examinations and tests, and improving the effectiveness of clinical diagnosis and treatment of FUO.

Figure 1

Serum HMGB1 and anti-HMGB1 antibodies in patients with FUO. (a) Serum HMGB1 in different subtypes of patients with FUO; (b) Serum anti-HMGB1 antibodies in different subtypes of patients with FUO; (c) ROC curve of serum HMGB1 in diagnosis of infectious disease subtype in patients with FUO; (d) ROC curve of serum anti-HMGB1 antibodies in diagnosis of autoimmune disease subtype in patients with FUO. (*P < 0.05; **P < 0.01 compared with HC).

Figure 2

The ratio of serum HMGB1/anti-HMGB1 antibodies in patients with FUO. (a) The distribution of the concentrations of serum HMGB1 and anti-HMGB1 antibodies in different subtypes of patients with FUO; (b) ROC curve of the ratio of serum HMGB1/anti-HMGB1 antibodies in diagnosis infectious and autoimmune disease subtypes in patients with FUO.

Figure 3

Correlation analysis of serum HMGB1 or anti-HMGB1 antibodies with disease severity markers in patients with FUO. (a) Serum HMGB1 is correlation with CRP and ESR in patients with FUO; (b) Serum anti-HMGB1 antibodies is correlation with CRP and ESR in patients with FUO.