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. 2025 Jun 5:16:1601690.
doi: 10.3389/fimmu.2025.1601690. eCollection 2025.

Reduced hemolytic complement activity in the classical pathway (CH50) is a risk factor for poor clinical outcomes of patients with infections: a retrospective analysis of health insurance claims in Japan

Hiroyuki Koami  1   2 , Yutaro Furukawa  1 , Yuri Hirota  1 , Akira Sasaki  1 , Hirotaka Ogawa  1 , Ayaka Matsuoka  1 , Kota Shinada  1 , Kento Nakayama  1 , Ryota Sakurai  1 , Sachiko Iwanaga  1 , Takayuki Onohara  1 , Shogo Narumi  1 , Mayuko Koba  1 , Hirotaka Mori  2   3 , Yutaka Umemura  2   4 , Kazuma Yamakawa  2   5 , Kohji Okamoto  2   6 , Yuichiro Sakamoto  1   2
Affiliations

Reduced hemolytic complement activity in the classical pathway (CH50) is a risk factor for poor clinical outcomes of patients with infections: a retrospective analysis of health insurance claims in Japan

Hiroyuki Koami et al. Front Immunol. .

Abstract

Purpose: To evaluate whether low CH50 (a comprehensive measure of hemolytic activity of the classical complement pathway) is associated with infection-related coagulopathy, organ dysfunction, and poor clinical outcomes.

Methods: This was a retrospective study using Japanese health insurance claim data (2014-2023). Adult patients whose CH50 values were measured within one week of admission were included. We divided the patients into three groups based on the normal CH50 range: Low CH50 (< 25 U/mL; n=168), Normal CH50 (25 ≤, < 48 U/mL; n=1273), and High CH50 (48 ≤ U/mL; n=1285).

Results: Of 2,726 patients who met the inclusion criteria, logistic regression models demonstrated that decreased CH50 is a significant predictor of 180-day mortality (OR: 0.98-0.99). Cumulative survival rates in the Low CH50 group at 28 days and 180 days were both unfavorable (both p < 0.0001, Log-rank test). CH50 was significantly inversely correlated with SOFA, SIC, ISTH-overt DIC, and JAAM-2 DIC scores, and was also correlated with C3 and C4 levels. Diminished CH50 may be particularly useful in diagnosing SIC (specificity; 79.2%) and excluding ISTH-overt DIC (sensitivity; 90.5%). Moreover, patients with low levels of both CH50 and C3 had an extremely high mortality rate (25.0%).

Conclusion: Low CH50 after infection is not only significantly associated with multiple organ failure and coagulopathy but is also an independent risk factor for poor prognosis. Complement activation after infection may help to avert organ damage and to improve clinical outcomes.

Keywords: CH50; coagulopathy; health insurance claims database; infection; outcome.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. HK investigated and established the research methodology. HK, KY and YU managed the project. YS supervised the entire study. YF, KY and YU conducted the validation of the study. Data curation, formal analysis, visualization of the study and writing of the original draft were performed by HK. Review and editing the manuscript were performed by YF, YH, AS, HO, AM, KS, KN, RS, SI, TO, SN, MK, HM, YU, KY, KO, and YS. All authors revised the manuscript for important intellectual content. All authors read and approved the final version of the manuscript.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Effect of CH50 value during infection on survival. Survival analysis for 28-day (A) and 180-day (B) survival based on the degree of the CH50 value. Kaplan-Meier curves for 28-day (A) and 180-day (B) survival were created based on the CH50 level. The CH50 cut-off value was derived from the normal range. The Low-CH50 group showed a significantly lower survival rate.
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