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Multicentric evaluation of a specific intrathecal anti-Treponema pallidum IgG index as a diagnostic biomarker of neurosyphilis: results from a retro-prospective case–control study
  1. Chloé Alberto1,
  2. Nathalie Lambeng2,
  3. Christine Deffert2,
  4. Gautier Breville3,
  5. Angèle Gayet-Ageron4,
  6. Patrice Lalive3,
  7. Alexandra Calmy5,
  8. Alix Coste6,
  9. Matthaios Papadimitriou-Olivgeris7,
  10. Dominique Braun8,
  11. Reto Lienhard9,
  12. Philipp Peter Bosshard10,
  13. Lionel Fontao1,2,
  14. Laurence Toutous Trellu1
  1. 1 Division of Dermatology and Venereology, Geneva University Hospitals, Geneva, Switzerland
  2. 2 Division of Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
  3. 3 Division of Neurology, Geneva University Hospitals, Geneva, Switzerland
  4. 4 CRC & Division of Clinical Epidemiology, Department of Community Health and Medicine, Geneva University Hospitals, Geneva, Switzerland
  5. 5 HIV/AIDS Unit, Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
  6. 6 Microbiology Institute, Lausanne University Hospital, Lausanne, Switzerland
  7. 7 Infectious Diseases Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  8. 8 Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
  9. 9 Microbiology, ADMED, La Chaux-de-Fonds, Switzerland
  10. 10 Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Chloé Alberto, Division of Dermatology and Venereology, Geneva University Hospitals, Geneve 1205, Switzerland; chloe.alberto{at}unige.ch

Abstract

Background and objectives The diagnosis of neurosyphilis (NS) lacks a true ‘gold standard’, making the diagnosis challenging while consequences of a misdiagnosis are potentially severe. The aim of this study was to evaluate the diagnostic performance of measuring an antibody index (AI) for the intrathecal synthesis of specific anti-Treponema pallidum (T. pallidum) IgG for the diagnosis of NS.

Methods Specific anti-T. pallidum IgG were measured simultaneously in paired cerebrospinal fluid (CSF)–serum samples collected retrospectively and prospectively between 2007 and 2022, from patients suspected of NS, in Switzerland. An AI was calculated to account for blood–brain barrier integrity. Area under the receiver operating characteristic curve, sensitivity/specificity and positive/negative predictive values of AI test were estimated. Two NS definitions were used: NS1 included patients with NS suspicion presenting with neurological symptoms and/or acute neurosensory signs, and positive T. Pallidum Hemagglutinations Assay (TPHA)/T. pallidum particle agglutination assay (TPPA) serology and CSF-TPHA/TPPA ≥320, and either CSF-leucocytes >5 cells/mm3 and/or CSF-protein >0.45 g/L and/or a reactive CSF-venereal disease research laboratory (VDRL)/rapid plasma reagin (RPR) test. NS2 included patients with suspected NS presenting with acute ocular and/or otologic symptoms, and positive TPHA/TPPA serology, and a favourable response to NS treatment. Controls were patients diagnosed with any other central nervous system (CNS) pathologies and with positive TPHA/TPPA serology.

Results The study included 71 NS (43 NS1 and 28 NS2) and 110 controls. With a threshold of ≥1.7, sensitivity and specificity of the specific AI test were 90.7% (CI 77.7 to 97.4) and 100% (CI 96.7 to 100.0), respectively, for NS1 and 14.3% (CI 4 to 32.7) and 100% (CI 96.7 to 100.0) for NS2. In patients suspected of NS with a CNS involvement (NS1 group), NS could be confirmed by the positivity of this specific AI.

Conclusions Measurement of an intrathecal synthesis index of specific anti-T. pallidum IgG in patients with CSF inflammatory signs appears to be a valuable diagnostic test. However, in otic or ocular syphilis, presenting few CSF abnormalities, AI is not sufficient alone to confirm NS diagnosis.

Trial registration Swiss Association of Research Ethics Committees number 2019-00232.

  • SYPHILIS
  • NEUROLOGY
  • Bacterial Infections

Data availability statement

Data are available upon reasonable request. Data are available upon request.

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Data availability statement

Data are available upon reasonable request. Data are available upon request.

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Footnotes

  • CA and NL are joint first authors.

  • Handling editor Stefano Rusconi

  • Presented at This work was presented as a poster at the 16th International Society of Neuroimmunology congress in August 2023 in Québec City (Canada) and at the 32nd European Academy of Dermatology and Venereology in October 2023 in Berlin (Germany) and as an oral presentation at the Annual Meeting of the Swiss Society of Dermatology and Venereology in September 2023 in Lausanne (Switzerland).

  • Contributors CA and NL contributed to study concept and design, acquisition, analysis and interpretation of data, review of the literature, drafting/revision of the manuscript for content. CD contributed to study concept, interpretation of data and revision of the manuscript. GB contributed to interpretation of data and revision of the manuscript. AG-A contributed to study concept and design, analysis and interpretation of data and drafting/revision of the manuscript. PL and ACalmy revised the manuscript for intellectual content. ACoste, MP-O, DB, RL and PPB contributed to acquisition of data and revision of the manuscript. LF contributed to acquisition, analysis and interpretation of data, drafting/revision of the manuscript for content, review of the literature. LTT, guarantor for this study, contributed to study concept and design, revision of the manuscript for intellectual content and approved the final version for publication.

  • Funding This study was funded by Swiss National Fund (Grant CRSII5-186394), Swiss HIV Cohort Study (873).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.