Characteristics and long-term prognosis of Danish residents with a positive intrathecal antibody index test for herpes simplex virus or varicella-zoster virus compared with individuals with a positive cerebrospinal fluid PCR: a nationwide cohort study

OBJECTIVES: We compared characteristics and outcomes of individuals who in the cerebrospinal fluid (CSF) were positive for herpes simplex virus (HSV) or varicella-zoster virus (VZV) -intrathecal antibody index test (AI-positive) vs. individuals who were PCR-positive for HSV type 1 (HSV1), type 2 (HSV2), and for VZV. METHODS: Nationwide cohort study of all Danish residents with positive CSF-AI or -PCR for HSV or VZV (1995-2021). We calculated short- and long-term risks as age-, sex-, and comorbidity-adjusted odds ratios (aOR), adjusted hazard ratios (aHR), and absolute risk differences with 95% CIs. RESULTS: Compared with individuals with positive PCR for HSV1 (n = 321), HSV2 (n = 497), and VZV (n = 1054), individuals with a positive AI for HSV (n = 177) and VZV (n = 219) had CSF pleocytosis less frequently (leucocyte count >10/μL: HSV-AI: 39%, VZV-AI: 52%, HSV1-PCR: 81%, HSV2-PCR: 92%, VZV-PCR: 83%), and were less frequently diagnosed with central nervous system infection (aOR 95%CI: HSV-AI vs. HSV1-PCR: 0. 1 0. 1, 0. 2, HSV-AI vs. HSV2-PCR: 0. 1 0. 0, 0. 1, VZV-AI vs. VZV-PCR: 0. 2 0. 2, 0. 3). Individuals with a positive HSV-AI or VZV-AI had increased risk of demyelinating disease (aOR 95%CI; aHR 95%CI: HSV-AI vs. HSV1-PCR: 4. 6 0. 9, 24. 5; aHR not applicable, HSV-AI vs. HSV2-PCR: 10. 4 2. 3, 45. 9; 12. 4 2. 3, 66. 0, VZV-AI vs. VZV-PCR: aOR not applicable; 10. 3 1. 8, 58. 8). Disability pension was less frequent among HSV-AI than HSV1-PCR cohort members (5-year risk difference: -23. 6%, 95%CI: -35. 2, -11. 8), and more frequent among VZV-AI than VZV-PCR cohort members (5-year risk difference: 16. 8%, 95%CI: 5. 0, 28. 7). DISCUSSION: AI-positive individuals differ from PCR-positive individuals in several aspects. AI appears unspecific for current central nervous system infections.