Diagnosis in aseptic meningitis and immune response in herpes simplex virus infections

Herpes simplex virus type 1 and 2 are ubiquitous and appear often asymptomatic but some individuals suffer from recurrent infections and the causes are largely unknown. In this thesis I present results from evaluations of diagnostic and etiologic studies of methods used for the detection of acute aseptic meningitis (AAM) and in HSV-2 meningitis in particular. The second part we investigated the innate and/or adaptive immune response in patients affected by HSV-1 and 2 in primary genital infection as well as recurrent HSV-2 meningitis compared to recurrent genital infection or seropositive blood donors.

The first paper addresses the need for efficient and sensitive diagnostic methods in the management of virus infections in the central nervous system. The objective was to evaluate a real-time PCR for the detection of HSV-2 and VZV DNA from cerebrospinal fluid samples in clinically well characterized patients with HSV-2 meningitis and AAM of unknown origin. The sensitivity of real-time PCR was found to be 87% (33/38) in primary and 70% (19/27) in recurrent HSV-2 meningitis. VZV was detected in 2 of 45 samples (4.4%). The quantitative real-time PCR was also compared with the nested qualitative PCR and found to identify more cases in the recurrent meningitis group.

The second paper addresses the etiology of AAM and the diagnostic efficiency in an adult population in Stockholm, using a limited first-line combination of microbiological assays. PCR assays for HSV- DNA and enterovirus (EV) RNA in the CSF as well as ELISA for IgM to tick-borne encephalitis virus (TBEV) in serum were performed. A viral diagnosis was obtained in 255 of the 419 cases (62%) with these routinely performed assays. Thus, consistent use of CSF-PCR for EV and HSV and TBEV serology established a diagnosis in the majority of AAM patients.

The third paper addresses the immune response in patients experiencing a first episode genital HSV infection. In a prospective clinical study the cell-mediated immune response (CMI) was measured and the cytokine profile identified and followed during one year. In patients with primary HSV infection CMI responses declined over time, whereas patients with non-primary HSV infection displayed stable CMI during the follow up year. For patients with primary HSV-2 infection, levels of HSV-specific IL-10 and IL-4 responses at first visit were significantly inversely correlated with number of recurrences during the subsequent year.

The fourth paper addresses HSV-specific immune response in patients affected by recurrent meningitis caused by HSV-2. During asymptomatic periods, these patients expressed elevated T-cell blasting and cytokine responses against HSV-antigens an also an increased expression of TLR 3 and 9 on dendritic cells as well as increased TLR induced interferon responses in comparison with patients with recurrent genital HSV-2 infection and asymptomatic seropositive HSV-2 individuals. Thus, we did not find that recurrent HSV-2 meningitis was due to deficiencies in adaptive or innate immune functions.

List of scientific papers

I. Franzen-Röhl E, Tiveljung-Lindell A, Grillner L, Aurelius E (2007). Increased detection rate in diagnosis of herpes simplex virus type 2 meningitis by real-time PCR using cerebrospinal fluid samples. J Clin Microbiol. 45(8): 2516-20. Epub 2007 Jun 13
https://pubmed.ncbi.nlm.nih.gov/17567785

II. Franzen-Rohl E, Larsson K, Skoog E, Tiveljung-Lindell A, Grillner L, Aurelius E, Glimåker M (2008). High diagnostic yield by CSF-PCR for entero- and herpes simplex viruses and TBEV serology in adults with acute aseptic meningitis in Stockholm. Scand J Infect Dis. 40(11-12): 914-21
https://pubmed.ncbi.nlm.nih.gov/18615360

III. Franzen-Röhl E, Schepis D, Atterfeldt F, Franck K, Vikström A, Liljeqvist JÅ, Bergström T, Aurelius E, Kärre K, Berg L, Gaines H (2009). Herpes simplex specific T cell responses in primary infection correlate inversely with frequency of subsequent recurrences. [Manuscript]

IV. Franzen-Röhl E, Schepis D, Lagrelius M, Franck K, Jones P, Liljeqvist JÅ, Bergström T, Aurelius E, Kärre K, Berg L, Gaines H (2009). Increased cell mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis. [Manuscript]