Benign recurrent lymphocytic meningitis (Mollaret's meningitis) in Denmark: a nationwide cohort study.

BACKGROUND AND PURPOSE: Data on clinical features and outcomes of benign recurrent lymphocytic meningitis (BRLM) are limited. METHODS: This was a nationwide population-based cohort study of all adults hospitalized for BRLM associated with herpes simplex virus type 2 (HSV-2) at the departments of infectious diseases in Denmark from 2015 to 2020. Patients with single-episode HSV-2 meningitis were included for comparison. RESULTS: Forty-seven patients with BRLM (mean annual incidence 1.2/1,000,000 adults) and 118 with single-episode HSV-2 meningitis were included. The progression risk from HSV-2 meningitis to BRLM was 22% (95% confidence interval [CI] 15%-30%). The proportion of patients with the triad of headache, neck stiffness and photophobia/hyperacusis was similar between BRLM and single-episode HSV-2 meningitis (16/43 [37%] vs. 46/103 [45%]; p = 0.41), whilst the median cerebrospinal fluid leukocyte count was lower in BRLM (221 cells vs. 398 cells; p = 0.02). Unfavourable functional outcomes (Glasgow Outcome Scale score of 1-4) were less frequent in BRLM at all post-discharge follow-up visits. During the study period, 10 (21%) patients with BRLM were hospitalized for an additional recurrence (annual rate 6%, 95% CI 3%-12%). The hazard ratio for an additional recurrence was 3.93 (95% CI 1.02-15.3) for patients with three or more previous episodes of meningitis. CONCLUSIONS: Clinical features of BRLM were similar to those of single-episode HSV-2 meningitis, whilst post-discharge outcomes were more favourable. Patients with three or more previous episodes of meningitis had higher risk of an additional recurrence.

Viral lumbosacral radiculitis (Elsberg syndrome) in Denmark.

PURPOSE: To describe clinical features and outcomes of viral lumbosacral radiculitis (Elsberg syndrome). METHODS: Nationwide population-based cohort study of all adults hospitalised for viral lumbosacral radiculitis at departments of infectious diseases in Denmark from 2015 to 2020. RESULTS: Twenty-eight patients with viral lumbosacral radiculitis were included (mean annual incidence: 1.2/1,000,000 adults). The median age was 35 years (IQR 27-43), and 22/28 (79%) were female. All patients had urinary retention, with 17/28 (61%) needing a catheter. On admission, at least one sign or symptom of meningitis (headache, neck stiffness, photophobia/hyperacusis) was present in 18/22 (82%). Concurrent genital herpetic lesions were present in 11/24 (46%). The median cerebrospinal fluid leukocyte count was 153 cells/µL (IQR 31-514). Magnetic resonance imaging showed radiculitis/myelitis in 5/19 (26%). The microbiological diagnosis was herpes simplex virus type 2 in 19/28 (68%), varicella-zoster virus in 2/28 (7%), and unidentified in 7/28 (25%). Aciclovir/valaciclovir was administered in 27/28 (96%). At 30 days after discharge, 3/27 (11%) had persistent urinary retention with need of catheter. At 180 days after discharge, moderate disabilities (Glasgow Outcome Scale score of 4) were observed in 5/25 (20%). CONCLUSIONS: Urinary retention resolved within weeks in most patients with viral lumbosacral radiculitis, but moderate disabilities according to the Glasgow Outcome Scale were common at the end of follow-up.

Neurosyphilis among people with and without HIV infection: A Danish nationwide prospective, population-based cohort study 2015-2021.

BACKGROUND: Comparative data on clinical presentation, laboratory characteristics, treatment, and outcome of neurosyphilis (NS) in people living with HIV (PLWH) and NS patients without HIV are scarce. METHODS: Nationwide, population-based, prospective cohort study on all adults with NS diagnosed between 2015 and 2021 at departments of infectious diseases in Denmark. RESULTS: We identified 108 patients with NS, which equals a yearly incidence of 0.3/100,000 adults. The median age was 49 years, 85 (79%) were male, 43 (40%) were men having sex with men and 20 (22%) were PLWH. Ninety-five (88%) had early NS, 37 (34%) had ocular or ocular and otogenic NS, and 27 (25%) had symptomatic meningitis. Most common symptoms were visual disturbance (44%), skin rash (40%), fatigue (26%) and chancre (17%). Median CSF leukocyte count was 27 × 106 cells/L. PLWH less often had neurological deficits (p = 0.02). Unfavorable outcome was observed in 23 (21%) at discharge of whom 0 were PLWH (p = 0.01). Among the 88 NS patients without HIV a CSF leukocyte count of ≥ 30 × 106 cells/L was associated with unfavorable outcome (OR = 3.3 (95% confidence interval: 1.1-10.4)). CONCLUSIONS: PLWH with NS have better outcomes than NS patients without HIV infection.

Clinical features and prognostic factors in adults with viral meningitis.

Clinical features applicable to the entire spectrum of viral meningitis are limited, and prognostic factors for adverse outcomes are undetermined. This nationwide population-based prospective cohort study included all adults with presumed and microbiologically confirmed viral meningitis in Denmark from 2015 until 2020. Prognostic factors for an unfavourable outcome (Glasgow Outcome Scale score of 1-4) 30 days after discharge were examined by modified Poisson regression. In total, 1066 episodes of viral meningitis were included, yielding a mean annual incidence of 4.7 episodes per 100 000 persons. Pathogens were enteroviruses in 419/1066 (39%), herpes simplex virus type 2 in 171/1066 (16%), varicella-zoster virus in 162/1066 (15%), miscellaneous viruses in 31/1066 (3%) and remained unidentified in 283/1066 (27%). The median age was 33 years (IQR 27-44), and 576/1066 (54%) were females. In herpes simplex virus type 2 meningitis, 131/171 (77%) were females. Immunosuppression [32/162 (20%)] and shingles [90/149 (60%)] were frequent in varicella-zoster virus meningitis. The triad of headache, neck stiffness and hyperacusis or photophobia was present in 264/960 (28%). The median time until lumbar puncture was 3.0 h (IQR 1.3-7.1), and the median CSF leucocyte count was 160 cells/µl (IQR 60-358). The outcome was unfavourable in 216/1055 (20%) 30 days after discharge. Using unidentified pathogen as the reference, the adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 0.95-1.88) for enteroviruses, 1.55 (95% CI 1.00-2.41) for herpes simplex virus type 2, 1.51 (95% CI 0.98-2.33) for varicella-zoster virus and 1.37 (95% CI 0.61-3.05) for miscellaneous viruses. The adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 1.03-1.75) for females. Timing of acyclovir or valacyclovir was not associated with the outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus. In summary, the outcome of viral meningitis was similar among patients with different aetiologies, including those with presumed viral meningitis but without an identified pathogen. Females had an increased risk of an unfavourable outcome. Early antiviral treatment was not associated with an improved outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus.

[First Danish case of tick-borne encephalitis virus vaccine failure].

Tick-borne encephalitis virus (TBEV) is spreading geographically, and new risk areas are expected throughout Denmark. In this case report, we describe the first Danish case of vaccine breakthrough tick-borne encephalitis (TBE) in a 76-year old female suffering from severe symptoms with need of intensive-care therapy. We want to draw attention to TBE as a differential diagnosis in all undiagnosed patients with symptoms of viral encephalitis, regardless of travel history and vaccine status. TBEV can cause severe disease, especially in the elderly. Patients with vaccine breakthrough infection may develop a more severe disease than non-vaccinated.

[Danish malaria research from the frail beginning to internationally acknowledged research].

Malaria - and particularly the disease caused by Plasmodium falciparum - remains a direct as well as indirect cause of poverty and immense human suffering. Research is imperative to alleviate this situation and to control and eventually eradicate the disease. Since the mid-1970s, Danish scientists have contributed increasingly to this effort by publishing more than 700 scientific papers and by training about 60 highly skilled malaria researchers. The efforts which continue to be thoroughly dependent on extensive external funding and public goodwill are briefly reviewed in this article.

Fc gamma receptor 3B (FCGR3B-c.233C>A-rs5030738) polymorphism modifies the protective effect of malaria specific antibodies in Ghanaian children.

Immunoglobulin G (IgG) cross-linking with Fc gamma receptor IIIB (FcγRIIIB) triggers neutrophil degranulation, releasing reactive oxygen species with high levels associated with protection against malaria. The FCGR3B-c.233C>A polymorphism thought to influence the interaction between IgG and FcγRIIIB was recently associated with malaria. We studied the statistical interaction between glutamate rich protein antibodies and FCGR3B-c.233C>A genotypes on risk of malaria in a cohort of Ghanaian children. The absolute risk of malaria decreased more rapidly with increasing antibody levels for 233AA/AC individuals compared with 233CC children. This genotype related effect modification may significantly influence malaria sero-epidemiological and vaccine trial studies.

The malaria vaccine candidate GMZ2 elicits functional antibodies in individuals from malaria endemic and non-endemic areas.

BACKGROUND: GMZ2 is a hybrid protein consisting of the N-terminal region of the glutamate-rich protein fused in frame to the C-terminal region of merozoite surface protein 3 (MSP3). GMZ2 formulated in Al(OH)3 has been tested in 3 published phase 1 clinical trials. The GMZ2/alum formulation showed good safety, tolerability, and immunogenicity, but whether antibodies elicited by vaccination are functional is not known. METHODS: Serum samples prior to vaccination and 4 weeks after the last vaccination from the 3 clinical trials were used to perform a comparative assessment of biological activity against Plasmodium falciparum. RESULTS: We showed that the maximum level of immunoglobulin G (IgG) antibodies obtained by GMZ2 vaccination is independent of ethnicity, time under malaria-exposure, and vaccine dose and that GMZ2 elicits high levels of functionally active IgG antibodies. Both, malaria-naive adults and malaria-exposed preschool children elicit vaccine-specific antibodies with broad inhibitory activity against geographically diverse P. falciparum isolates. Peptide-mapping studies of IgG subclass responses identified IgG3 against a peptide derived from MSP3 as the strongest predictor of antibody-dependent cellular inhibition. CONCLUSIONS: These findings suggest that GMZ2 adjuvanted in Al(OH)3 elicits high levels of specific and functional antibodies with the capacity to control parasite multiplication.

Development and evaluation of a multiplex screening assay for Plasmodium falciparum exposure.

Transfusion transmitted malaria (TTM) in non-endemic countries is reduced by questioning blood donors and screening of donated blood. Conventional screening is performed by Indirect Fluorescence Antibody Test (IFAT). This method is manual and difficult to standardize. Here we study the diagnostic performance of a multiplex assay for detection of antibodies against Plasmodium falciparum in donor blood using IFAT as a comparator. A multiplex assay (MPA) containing the antigens GLURP-R0, GLURP-R2, MSP3, MSP1 hybrid and AMA1 was constructed using xMAP® technology. A discrimination index for exposure to P. falciparum malaria was calculated by comparing travelers with clinical malaria (n=52) and non-exposed blood donors (n=119). The index was evaluated on blood donors with suspected malaria exposure (n=249) and compared to the diagnostic performance of IFAT. At a specificity of 95.8 %, the MPA discrimination index exhibited a diagnostic sensitivity of 90.4 % in travelers hospitalized with malaria. Percent agreement with IFAT was 92.3 %. Screening plasma from blood donors with suspected malaria exposure, we found 4.8 % to be positive by IFAT and 5.2 % by MPA with an agreement of 93.2 %. The calculated index from the MPA exhibits similar diagnostic performance as IFAT for detection of P. falciparum malaria. Combining the antibody response against multiple antigens in a discrimination index increased the sensitivity of the MPA and reduced the readout to a single value.