Low Serum Complement Level is Associated with Higher Mortality in Tuberculous Meningitis: a Retrospective Cohort Study

Overview

Journal Encephalitis

Date 2023 Jul 20

PMID 37469713

Authors

Hansol Im

Taewon Kim

Seunghee Na

In-Uk Song

Seong-Hoon Kim

Yoon-Sang Oh

Juhee Oh

Woojun Kim

Affiliations

Soon will be listed here.

Abstract

Purpose: We evaluated the associations between serum complement levels and tuberculous meningitis (TBM), bacterial meningitis (BM), and viral meningitis (VM), as well as the association between serum complement levels and mortality in TBM.

Methods: Background information and blood/cerebrospinal fluid analysis results were collected from 2009 to 2019. Patients who had serum complement level data collected at admission and who were diagnosed with TBM (n = 97), BM (n = 31), or VM (n = 557) were enrolled.

Results: Initial serum complement levels were significantly lower in the TBM group than the VM group in both the total population and the propensity score-matched population. In the TBM and VM groups, compared to patients with initial highest-quartile C4 level, patients in the lowest quartile (C4 < 24.3 mg/dL) had significantly greater odds of TBM diagnosis (odds ratio, 2.2; 95% confidence interval, 1.0-4.5; p = 0.038). In the TBM group, patients with the lowest-quartile C3 level (<96.9 mg/dL) experienced a significantly higher 90-day mortality rate compared to other TBM patients (hazard ratio, 19.0; 95% confidence interval, 2.1-167.4.5; p = 0.008).

Conclusion: Both serum C3 and C4 levels were significantly lower in the TBM group than in the VM group. TBM patients with lower serum C3 level had a significantly higher mortality rate than those with higher C3 level.

References

Morgan B . The role of complement in neurological and neuropsychiatric diseases. Expert Rev Clin Immunol. 2015; 11(10):1109-19. DOI: 10.1586/1744666X.2015.1074039. View

Thwaites G, van Toorn R, Schoeman J . Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013; 12(10):999-1010. DOI: 10.1016/S1474-4422(13)70168-6. View

Avirutnan P, Mehlhop E, Diamond M . Complement and its role in protection and pathogenesis of flavivirus infections. Vaccine. 2009; 26 Suppl 8:I100-7. PMC: 2768071. DOI: 10.1016/j.vaccine.2008.11.061. View

Jagatia H, Tsolaki A . The Role of Complement System and the Immune Response to Tuberculosis Infection. Medicina (Kaunas). 2021; 57(2). PMC: 7909539. DOI: 10.3390/medicina57020084. View

Lucas M, Brouwer M, van de Beek D . Delayed cerebral thrombosis in bacterial meningitis: a prospective cohort study. Intensive Care Med. 2012; 39(5):866-71. DOI: 10.1007/s00134-012-2792-9. View

Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J . British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect. 2009; 59(3):167-87. DOI: 10.1016/j.jinf.2009.06.011. View

Mook-Kanamori B, Brouwer M, Geldhoff M, van der Ende A, van de Beek D . Cerebrospinal fluid complement activation in patients with pneumococcal and meningococcal meningitis. J Infect. 2014; 68(6):542-7. DOI: 10.1016/j.jinf.2013.12.016. View

Esmail H, Lai R, Lesosky M, Wilkinson K, Graham C, Horswell S . Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis. Proc Natl Acad Sci U S A. 2018; 115(5):E964-E973. PMC: 5798330. DOI: 10.1073/pnas.1711853115. View

Ferguson J, Weis J, Martin J, Schlesinger L . Complement protein C3 binding to Mycobacterium tuberculosis is initiated by the classical pathway in human bronchoalveolar lavage fluid. Infect Immun. 2004; 72(5):2564-73. PMC: 387845. DOI: 10.1128/IAI.72.5.2564-2573.2004. View

10.

Wilkinson R, Rohlwink U, Misra U, van Crevel R, Mai N, Dooley K . Tuberculous meningitis. Nat Rev Neurol. 2017; 13(10):581-598. DOI: 10.1038/nrneurol.2017.120. View

11.

Zwahlen A, Nydegger U, Vaudaux P, Lambert P, Waldvogel F . Complement-mediated opsonic activity in normal and infected human cerebrospinal fluid: early response during bacterial meningitis. J Infect Dis. 1982; 145(5):635-46. DOI: 10.1093/infdis/145.2.635. View

12.

Kim S, Cho O, Park S, Lee E, Kim M, Lee S . Rapid diagnosis of tuberculous meningitis by T cell-based assays on peripheral blood and cerebrospinal fluid mononuclear cells. Clin Infect Dis. 2010; 50(10):1349-58. DOI: 10.1086/652142. View

13.

Greenwood B, Onyewotu I, Whittle H . Complement and meningococcal infection. Br Med J. 1976; 1(6013):797-9. PMC: 1639447. DOI: 10.1136/bmj.1.6013.797. View

14.

Manyelo C, Solomons R, Snyders C, Mutavhatsindi H, Manngo P, Stanley K . Potential of Host Serum Protein Biomarkers in the Diagnosis of Tuberculous Meningitis in Children. Front Pediatr. 2019; 7:376. PMC: 6773834. DOI: 10.3389/fped.2019.00376. View

15.

Harris C . Expanding horizons in complement drug discovery: challenges and emerging strategies. Semin Immunopathol. 2017; 40(1):125-140. PMC: 5794834. DOI: 10.1007/s00281-017-0655-8. View

16.

Lubbers R, Sutherland J, Goletti D, de Paus R, van Moorsel C, Veltkamp M . Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis. Front Immunol. 2018; 9:2427. PMC: 6206241. DOI: 10.3389/fimmu.2018.02427. View

17.

Yoon J, Min G, Park S, Park S, Lee S, Cho B . Incidence and risk factors of hepatic veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation in adults with prophylactic ursodiol and intravenous heparin or prostaglandin E1. Bone Marrow Transplant. 2021; 56(7):1603-1613. DOI: 10.1038/s41409-021-01215-y. View

18.

Sinha M, Garg R, Hk A, Agarwal A, Singh M, Verma R . Vision impairment in tuberculous meningitis: predictors and prognosis. J Neurol Sci. 2010; 290(1-2):27-32. DOI: 10.1016/j.jns.2009.12.012. View

19.

Goonetilleke U, Scarborough M, Ward S, Hussain S, Kadioglu A, Gordon S . Death is associated with complement C3 depletion in cerebrospinal fluid of patients with pneumococcal meningitis. mBio. 2012; 3(2). PMC: 3312214. DOI: 10.1128/mBio.00272-11. View

20.

Peterson P, Gekker G, Hu S, Sheng W, Anderson W, Ulevitch R . CD14 receptor-mediated uptake of nonopsonized Mycobacterium tuberculosis by human microglia. Infect Immun. 1995; 63(4):1598-602. PMC: 173196. DOI: 10.1128/iai.63.4.1598-1602.1995. View