Validation of a risk score to differentiate autoimmune and viral encephalitis: a Nationwide Cohort Study in Denmark.

BACKGROUND: A score to differentiate autoimmune (AE) and viral encephalitis (VE) early upon admission has recently been developed but needed external validation. The objective of this study was to evaluate the performance of the score in a larger and more diagnostically diverse patient cohort. METHODS: We conducted a retrospective nationwide and population-based cohort study including all adults with encephalitis of definite viral (2015-2022) or autoimmune aetiology (2009-2022) in Denmark. Variables included in the score-model were extracted from patient records and individual risk scores were assessed. The performance of the score was assessed by receiver-operating characteristics (ROC) curve analyses and calculation of the area under the curve (AUC). RESULTS: A total of 496 patients with encephalitis [AE n = 90, VE n = 287 and presumed infectious encephalitis (PIE) n = 119] were included in the study. The score was highly accurate in predicting cases of AE reaching an AUC of 0.94 (95% CI 0.92-0.97). Having a score ≥ 3 predicted AE with a PPV of 87% and an NPV of 91%. The risk score was found to perform well across aetiological subgroups and applied to the PIE cohort resulted in an AUC of 0.88 (95% CI 0.84-0.93). CONCLUSION: The excellent performance of the score as reported in the development study was confirmed in this significantly larger and more diverse cohort of patients with encephalitis in Denmark. These results should prompt further prospective testing with wider inclusion criteria.

Rationale and design of NUDGE-FLU-CHRONIC and NUDGE-FLU-2: Two nationwide randomized trials of electronic nudges to increase influenza vaccination among patients with chronic diseases and older adults during the 2023/2024 influenza season.

BACKGROUND: Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively. METHODS: Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2. DISCUSSION: NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications. TRIAL REGISTRATION: NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030726.

Pulmonary arteriovenous malformations in patients with previous brain abscess: a cross-sectional population-based study.

BACKGROUND AND PURPOSE: Pulmonary arteriovenous malformations (PAVMs) may cause recurrent brain abscess. The primary aim was to determine the prevalence of PAVM amongst survivors of brain abscess. The proportion with cardiac right-to-left shunts was also assessed post hoc. METHODS: This was a cross-sectional population-based study of adult (≥18 years) survivors of cryptogenic bacterial brain abscess in Denmark from 2007 through 2016. Patients were invited for bubble-echocardiography to detect vascular right-to-left shunting and, if abnormal, subsequent computed tomography thorax for diagnosis of PAVM. Data are presented as n/N (%) or median with interquartile range (IQR). RESULTS: Study participation was accepted by 47/157 (30%) eligible patients amongst whom two did not appear for scheduled bubble-echocardiography. The median age of participants was 54 years (IQR 45-62) and 19/57 (33%) were females compared with 59 years (IQR 48-68, p = 0.05) and 41/85 females (48%, p = 0.22) in non-participants. Bubble-echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting. The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06-11.8) amongst all examined participants. Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population. CONCLUSIONS: Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients. The prevalence of cardiac right-to-left shunts amongst brain abscess patients corresponds to the prevalence in the general population.

Brain Abscess Caused by Oral Cavity Bacteria: A Nationwide, Population-based Cohort Study.

BACKGROUND: Oral cavity bacteria are the most frequent etiology of brain abscess. Yet, data on the clinical presentation and outcome are scarce. METHODS: We performed a nationwide, population-based study comprising all adults (aged ≥18 years) with brain abscess due to oral cavity bacteria in Denmark from 2007 through 2020. Prognostic factors for unfavorable outcome (Glasgow outcome scale, 1-4) were examined using modified Poisson regression to compute adjusted relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Among 287 identified patients, the median age was 58 years (interquartile range, 47-66), and 96 of 287 (33%) were female. Preexisting functional impairment was absent or mild in 253 of 280 (90%), and risk factors for brain abscess included immunocompromise in 95 of 287 (33%), dental infection in 68 of 287 (24%), and ear-nose-throat infection in 33 of 287 (12%). Overall, a neurological deficit was present in 246 of 276 (86%) and in combination with headache and fever in 64 of 287 (22%). Identified microorganisms were primarily the Streptococcus anginosus group, Fusobacterium, Actinomyces, and Aggregatibacter spp., and 117 of 287 (41%) were polymicrobial. Unfavorable outcome occurred in 92 of 246 (37%) at 6 months after discharge and was associated with antibiotics before neurosurgery (RR, 3.28; 95% CI, 1.53-7.04), rupture (RR, 1.89; 95% CI, 1.34-2.65), and immunocompromise (RR, 1.80; 95% CI, 1.29-2.51), but not with specific targeted antibiotic regimens. Identified dental infection was associated with favorable prognosis (RR, 0.58; 95% CI, .36-.93). CONCLUSIONS: Brain abscess due to oral cavity bacteria often occurred in previously healthy individuals without predisposing dental infections. Important risk factors for unfavorable outcome were rupture and immunocompromise. However, outcome was not associated with specific antibiotic regimens supporting carbapenem-sparing strategies.

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.

Ramsay Hunt syndrome and concurrent varicella-zoster virus meningitis in Denmark: A nationwide cohort study.

Ramsay Hunt syndrome (RHS) is a manifestation of reactivated varicella-zoster virus (VZV) from the geniculate ganglion. Data on clinical features and outcomes of patients with RHS and concurrent VZV meningitis (henceforth RHS meningitis) are limited. Thus, we conducted a nationwide population-based cohort study of all adults hospitalized for RHS meningitis at the departments of infectious diseases in Denmark from 2015 to 2020. Patients with VZV meningitis without cranial nerve palsies were included for comparison. In total, 37 patients with RHS meningitis (mean annual incidence: 1.6/1 000 000 adults) and 162 with VZV meningitis without cranial nerve palsies were included. In RHS meningitis, the median age was 52 years (interquartile range: 35-64), and in addition to peripheral facial nerve palsy (100%), dizziness (46%), and hearing loss (35%) were common symptoms. The triad of headache, neck stiffness, and photophobia/hyperacusis was less common in RHS meningitis than in VZV meningitis without cranial nerve palsies (0/27 [0%] vs. 24/143 [17%]; p = 0.02). At 30 days after discharge, 18/36 (50%) patients with RHS meningitis had persistent peripheral facial nerve palsy, with no statistically significant difference between those treated with and without adjuvant glucocorticoids (6/16 [38%] vs. 12/20 [60%]; p = 0.18). Additional sequelae of RHS meningitis included dizziness (29%), neuralgia (14%), tinnitus/hyperacusis (11%), hearing loss (9%), headache (9%), fatigue (6%), and concentration difficulties (3%). In conclusion, clinical features and outcomes of RHS meningitis were primarily related to cranial neuropathies.

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.

Group A Streptococcus Meningitis in Adults, Denmark.

We report a 21-fold increase in group A Streptococcus meningitis in adults in Denmark during October 13, 2022-April 12, 2023, concurrent with an outbreak of invasive streptococcal disease. We describe clinical characteristics of the outbreak cases and prognosis for patients in comparison to those for previous sporadic cases.

Association of Self-reported Systemic Reactions Following SARS-CoV-2 Vaccination With Immunological Response in the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE).

Background: Side effects to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are a key concern contributing to vaccine hesitancy, but more individuals may be encouraged if SARS-CoV-2 vaccines were known to lead to a stronger immune response. Methods: Included were adult participants from the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE) who completed a questionnaire to assess systemic reactions following SARS-CoV-2 vaccination (BTN162b2, mRNA-1273, ChAdOx1) and had SARS-CoV-2 spike immunoglobulin G (IgG) levels measured at baseline and post-vaccine. A symptom score was developed to measure severity of systemic adverse reactions (+1 for each moderate, +2 for each severe). Post-vaccination SARS-CoV-2 spike IgG levels were compared between participants with different scores using multivariable linear regression. Results: A total of 6528 participants were included (56.3% females; median age [interquartile range], 64 [54-75] years). After the first vaccination, no association was found between symptom score and post-vaccine dose spike IgG level (P = .575). Following the second vaccination, significantly higher spike IgG levels were observed according to higher symptom scores (P < .001); adjusted geometric mean ratios were 1.16 (95% CI, 1.04-1.30), 1.24 (95% CI, 1.09-1.41), 1.25 (95% CI, 1.06-1.46), and 1.21 (95% CI, 1.08-1.35), for scores of 2, 3, 4, and ≥5, respectively, compared with a score of 0. After adjustment for pre-vaccine dose spike IgG, this association was attenuated. Conclusions: An association was found between more severe adverse reactions and stronger antibody response after the second vaccination but not the first, likely attributed to higher levels of preexisting immunity gained from response to first vaccination. Regardless of side effects, most people experienced an effective immune response following vaccination.

Impact of age and comorbidities on SARS-CoV-2 vaccine-induced T cell immunity.

BACKGROUND: Older age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood. METHODS: In a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51-72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections. RESULTS: We show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified. CONCLUSIONS: SARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization.

Vaccination has proven very effective in protecting against severe disease and hospitalization of people with COVID-19, the disease caused by SARS-CoV-2. It is still unclear, however, how the different components of the immune system respond to SARS-CoV-2 vaccination and protect from infection and severe disease. Two of the most predominant components of the immune system are specialized proteins and cells. The proteins circulate in the blood and help clear the virus by binding to it, while the cells either kill the virus or help other cells to produce more antibodies. Here, we examined the response of these two components to the SARS-CoV-2 vaccine in 655 Danish citizens. The response of both components was lower in people over 75 years old and with other diseases. These findings help in understanding the immune responses following SARS-CoV-2 vaccination in people at increased risk of severe symptoms of COVID-19.

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.

Risk Factors and Prognosis of Epilepsy Following Brain Abscess: A Nationwide Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: Epilepsy in patients with brain abscess is frequent, but risk factors and prognosis remain undetermined. This study examined risk factors of epilepsy among survivors of brain abscess and associated prognosis. METHODS: Nationwide, population-based healthcare registries were used to compute cumulative incidences and cause-specific adjusted hazard rate ratios (adj. HRRs) with 95% CIs for epilepsy among 30-day survivors of brain abscess from 1982 through 2016. Data were enriched with clinical details by medical record review of patients hospitalized from 2007 through 2016. Adjusted mortality rate ratios (adj. MRRs) were examined using epilepsy as a time-dependent variable. RESULTS: The study included 1,179 30-day survivors of brain abscess among whom 323 (27%) developed new-onset epilepsy after a median of 0.76 years (interquartile range [IQR] 0.24-2.41). At admission for brain abscess, the median age was 46 years (IQR 32-59) in patients with epilepsy compared with 52 years (IQR 33-64) in those without epilepsy. The proportion of female individuals was similar in patients with and without epilepsy (37%). Adj. HRRs for epilepsy were 2.44 (95% CI 1.89-3.15) for aspiration or excision of brain abscess, 2.37 (1.56-3.60) for alcohol abuse, 1.75 (1.27-2.40) for previous neurosurgery or head trauma, 1.62 (1.17-2.25) for stroke, and 1.55 (1.04-2.32) for age group 20-39 years. Cumulative incidences were increased in patients with alcohol abuse (52% vs 31%), aspiration or excision of brain abscess (41% vs 20%), previous neurosurgery or head trauma (41% vs 31%), and stroke (46% vs 31%). Analysis using clinical details from medical record review of patients from 2007 through 2016 demonstrated adj. HRRs of 3.70 (2.24-6.13) for seizures at admission for brain abscess and 1.80 (1.04-3.11) for frontal lobe abscess. By contrast, adj. HRR was 0.42 (0.21-0.86) for occipital lobe abscess. Using the entire registry-based cohort, patients with epilepsy had an adj. MRR of 1.26 (1.01-1.57). DISCUSSION: Important risk factors of epilepsy were seizures during admission for brain abscess, neurosurgery, alcoholism, frontal lobe abscess, and stroke. Epilepsy was associated with an increased mortality. Antiepileptic treatment may be guided by individual risk profiles, and a specialized follow-up is highlighted by an increased mortality in survivors with epilepsy.

Clinical features and prognostic factors in adults with brain abscess.

Studies on brain abscess are hampered by single-centre design with limited sample size and incomplete follow-up. Thus, robust analyses on clinical prognostic factors remain scarce. This Danish nationwide, population-based cohort study included clinical details of all adults (≥18 years) diagnosed with brain abscess in the Danish National Patient Registry from 2007 through 2014 and the prospective clinical database of the Danish Study Group of Infections of the Brain covering all Danish departments of infectious diseases from 2015 through 2020. All patients were followed for 6 months after discharge. Prognostic factors for mortality at 6 months after discharge were examined by adjusted modified Poisson regression to compute relative risks with 95% confidence intervals (CI). Among 485 identified cases, the median age was 59 years [interquartile range (IQR 48-67)] and 167 (34%) were female. The incidence of brain abscess increased from 0.4 in 2007 to 0.8 per 100 000 adults in 2020. Immuno-compromise was prevalent in 192/485 (40%) and the clinical presentation was predominated by neurological deficits 396/485 (82%), headache 270/411 (66%), and fever 208/382 (54%). The median time from admission until first brain imaging was 4.8 h (IQR 1.4-27). Underlying conditions included dental infections 91/485 (19%) and ear, nose and throat infections 67/485 (14%), and the most frequent pathogens were oral cavity bacteria (59%), Staphylococcus aureus (6%), and Enterobacteriaceae (3%). Neurosurgical interventions comprised aspiration 356/485 (73%) or excision 7/485 (1%) and was preceded by antibiotics in 377/459 (82%). Fatal outcome increased from 29/485 (6%) at discharge to 56/485 (12%) 6 months thereafter. Adjusted relative risks for mortality at 6 months after discharge was 3.48 (95% CI 1.92-6.34) for intraventricular rupture, 2.84 (95% CI 1.45-5.56) for immunocompromise, 2.18 (95% CI 1.21-3.91) for age >65 years, 1.81 (95% CI 1.00-3.28) for abscess diameter >3 cm, and 0.31 (95% CI 0.16-0.61) for oral cavity bacteria as causative pathogen. Sex, neurosurgical treatment, antibiotics before neurosurgery, and corticosteroids were not associated with mortality. This study suggests that prevention of rupture of brain abscess is crucial. Yet, antibiotics may be withheld until neurosurgery, if planned within a reasonable time period (e.g. 24 h), in some clinically stable patients. Adjunctive corticosteroids for symptomatic perifocal brain oedema was not associated with increased mortality.

Cohort Profile:The Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 vaccines (ENFORCE).

PURPOSE: The ENFORCE cohort is a national Danish prospective cohort of adults who received a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as part of the Danish National SARS-CoV-2 vaccination programme. It was designed to investigate the long-term effectiveness, safety and durability of SARS-CoV-2 vaccines used in Denmark. PARTICIPANTS: A total of 6943 adults scheduled to receive a SARS-CoV-2 vaccine in the Danish COVID-19 vaccination programme were enrolled in the study prior to their first vaccination. Participants will be followed for a total of 2 years with five predetermined follow-up visits and additional visits in relation to any booster vaccination. Serology measurements are performed after each study visit. T-cell immunity is evaluated at each study visit for a subgroup of 699 participants. Safety information is collected from participants at visits following each vaccination. Data on hospital admissions, diagnoses, deaths and SARS-CoV-2 PCR results are collected from national registries throughout the study period. The median age of participants was 64 years (IQR 53-75), 56.6% were women and 23% were individuals with an increased risk of a serious course of COVID-19. A total of 340 (4.9%) participants tested positive for SARS-CoV-2 spike IgG at baseline. FINDINGS TO DATE: Results have been published on risk factors for humoral hyporesponsiveness and non-durable response to SARS-CoV-2 vaccination, the risk of breakthrough infections at different levels of SARS-CoV-2 spike IgG by viral variant and on the antibody neutralising capacity against different SARS-CoV-2 variants following primary and booster vaccinations. FUTURE PLANS: The ENFORCE cohort will continuously generate studies investigating immunological response, effectiveness, safety and durability of the SARS-CoV-2 vaccines. TRIAL REGISTRATION NUMBER: NCT04760132.

Durability of Antibody Response after Primary Pneumococcal Double-Dose Prime-Boost Vaccination in Adult Kidney Transplant Recipients and Candidates: 18-Month Follow-Up in a Non-Blinded, Randomised Clinical Trial.

BACKGROUND: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients and candidates. The long-term durability of the antibody (AB) response is unknown. The same applies to a dose-dependent immune response. METHODS: We studied the durability of the vaccine response after 18 months in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs). Both groups received either a normal dose (ND) or a double dose (DD) of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine. The average pneumococcal AB geometric mean concentration (GMC) was evaluated. A level ≥ 1 mg/L was considered protective against invasive pneumococcal disease (IPD). RESULTS: Sixty WLPs and 70 KTRs were included. The proportion of participants protected declined from 52% to 33% in WLPs and from 29% to 16% in KTRs, with the previously significant dose-effect in WLPs no longer present (40% DD vs. 27% ND; p = 0.273). Average pneumococcal AB GMCs remained significantly above baseline levels (all groups p ≤ 0.001). Drug-induced immunosuppression diminished the vaccine dose-effect. CONCLUSIONS: At follow-up, the pneumococcal prime-boost vaccination still provided significantly elevated average pneumococcal AB GMCs in both populations. Though the proportion of participants protected against IPD in WLP-DD and WLP-ND were statistically comparable, a DD may still be recommended for WLPs (EudraCT: 2016-004123-23).

Immunogenicity and safety of double dosage of pneumococcal vaccines in adult kidney transplant recipients and waiting list patients: A non-blinded, randomized clinical trial.

BACKGROUND: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients, but is not thoroughly tested in this population. Furthermore, a pneumococcal vaccine dose effect has never been investigated, though observed in healthy adults. To assess whether a double dose of 13-valent pneumococcal conjugate vaccine (PCV13) and of 23-valent pneumococcal polysaccharide vaccine (PPV23) increases the immunogenicity of prime-boost vaccination in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs), a phase 3, randomized, non-blinded trial was conducted. METHODS: KTRs and WLPs were in parallel groups assigned either normal or double dosage of both vaccines 12 weeks apart. A 'protective response' was an average geometric mean concentration ≥ 1 mg/L based on 12 vaccine shared serotype-specific IgG antibodies. Furthermore, number of antibodies with ≥ 2-fold rises and individual serotype-specific antibody concentrations were evaluated. Follow-up was 48 weeks. RESULTS: Seventy-four KTRs and 65 WLPs were enrolled. In WLPs, double dosage resulted in a significantly higher proportion of participants with a 'protective response' (66.7%), 5 weeks after PPV23, compared to normal dosage (35.5%), p = 0.015. KTRs exhibited no dose effect. After PPV23, all four groups had increased their number of serotypes with ≥ 2-fold rises (p ≤ 0.05 for both WLPs groups; p ≤ 0.01 for both KTRs groups). Vaccines were safe, well tolerated and still immunogenic at week 48. CONCLUSIONS: Data suggests that double dosage of pneumococcal vaccines used according to the prime-boost strategy might be recommendable for WLPs. Furthermore, our data supports PPV23́s additive effect to PCV13 in KTRs and WLPs. (EudraCT: 2016-004123-23).

Herpes Simplex Virus 2 Meningitis in Adults: A Prospective, Nationwide, Population-Based Cohort Study.

BACKGROUND: Data on the clinical presentation are scarce and prognostic factors of herpes simplex virus type 2 (HSV-2) meningitis remain unknown. METHODS: Prospective, nationwide, population-based database identifying all adults treated for HSV-2 meningitis at departments of infectious diseases in Denmark from 2015 to 2020. Unfavorable outcome was defined as Glasgow Outcome Scale (GOS) scores of 1-4 and Extended GOS scores of 1-6. Modified Poisson regression was used to compute relative risks with 95% confidence intervals for unfavorable outcome. RESULTS: HSV-2 meningitis was diagnosed in 205 patients (76% female; median age [interquartile range (IQR)], 35 [27-49] years) yielding an incidence of 0.7/100 000 population/y. Common symptoms were headache (195 of 204 patients [95%]), photophobia or phonophobia (143 of 188 [76%]), and neck stiffness (106 of 196 [54%]). The median (IQR) time to lumbar puncture was 2.0 (1-4.8) hours, and the median cerebrospinal fluid (CSF) leukocyte count was 360 (166-670) × 10 × 6/L, with a mononuclear predominance of 97% (91%-99%). Lumbar puncture was preceded by brain imaging in 61 of 205 patients (30%). Acyclovir or valacyclovir was administered in 197 of 205 patients (96%) for a median (IQR) of 10 (7-14) days. Unfavorable outcome was observed in 64 of 205 patients (31%) at discharge and 19 of 181 (11%) after 6 months and was not associated with female sex (relative risk [95% confidence interval], 1.08 [.65-1.79]), age ≥35 years (1.28 [.83-1.97]), immunocompromise (1.07 [.57-2.03]), or CSF leukocyte count >1000 × 10 × 6/L (0.78 [.33-1.84]). CONCLUSIONS: HSV-2 meningitis often presented as meningeal symptoms in younger women. Unfavorable outcome at discharge was common and was not associated with sex, age, immunocompromise, or CSF leukocyte count. Sequelae persisted beyond 6 months in one-tenth of patients.

Existing Data Sources for Clinical Epidemiology: The Danish Study Group of Infections of the Brain Database (DASGIB).

Central nervous system (CNS) infections are rare diseases that are associated with considerable morbidity and mortality. Increased knowledge based on contemporary data is a prerequisite for improved management and prevention of these serious conditions. Yet, population-based databases of patients hospitalized with CNS infections remain scarce. The Danish Study Group of Infections of the Brain (DASGIB) has prospectively registered information on all adults ≥18 years of age admitted with CNS infections at departments of infectious diseases in Denmark since 2015. The main variables collected are baseline demographics, blood and cerebrospinal fluid tests, imaging results, and outcome using the Glasgow Outcome Scale score. To investigate important aspects for each type of CNS infections, additional variables are included specifically for bacterial meningitis, viral meningitis, encephalitis, brain abscess, neurosyphilis, and Lyme neuroborreliosis. From 2015 to 2020, a total of 3579 cases of CNS infections have been recorded in the DASGIB database. Using the unique civil registration number assigned to all Danish residents, the database can be unambiguously linked with nationwide healthcare registries at the individual level. This enables researchers to conduct detailed population-based and longitudinal observational studies of risk and prognosis of CNS infections and to compare them with matched population cohorts. The database is well-suited for epidemiological research and the DASGIB network forms a solid infrastructure for future national and international collaborations.

Enterovirus Meningitis in Adults: A Prospective Nationwide Population-Based Cohort Study.

OBJECTIVE: To test the hypothesis that enterovirus meningitis (EM) is a frequent and self-limiting condition, the epidemiology of EM in adults was examined. METHODS: Using a prospective, nationwide, population-based database, all adults with EM confirmed by PCR of the CSF from 2015 to 2019 were included. Unfavorable outcome was defined as Glasgow Outcome Scale scores of 1-4 at discharge. Modified Poisson regression was used to compute adjusted relative risks (RRs). RESULTS: A total of 419 cases of EM in 418 adults (46% female, median age 31 years [interquartile range (IQR) 27-35]) yielded an incidence of 1.80/100,000/year. Admission diagnoses included CNS infection 247/397 (62%), other neurologic conditions 89/397 (22%), and cerebrovascular diseases 33/397 (8%). Genotype was available for 271 cases, of which echovirus 30 accounted for 155 (57%). Patients presented with headache 412/415 (99%), history of fever 303/372 (81%), photophobia 292/379 (77%), and neck stiffness 159/407 (39%). Fever (≥38.0°C) was observed in 192/399 (48%) at admission. The median CSF leukocyte count was 130 106/L (range 0-2,100) with polymorphonuclear predominance (>50%) in 110/396 (28%). Cranial imaging preceded lumbar puncture in 127/417 (30%) and was associated with non-CNS infection admission diagnoses and delayed lumbar puncture (median 4.8 hours [IQR 3.4-7.9] vs 1.5 [IQR 0.8-2.8], p < 0.001). Unfavorable outcome occurred in 99/419 (24%) at discharge; more often in female patients (RR 2.30 [1.58-3.33]) and less frequent in echovirus 30 (RR 0.67 [0.46-1.00]) in adjusted analyses. Outcome remained unfavorable in 22/379 (6%) after 6 months. CONCLUSIONS: EM is common among young, healthy adults. Although the long-term prognosis remains reassuring, a substantial proportion have moderate disability at discharge, especially female patients.