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Flemming Skjøth,1,2 Henrik Nielsen,3,4 Jacob Bodilsen3,4 1Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 2Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark; 3Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; 4Institute of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Jacob Bodilsen, Department of Infectious Diseases, Aalborg University Hospital, Mølleparkvej 4, Aalborg, 9000, Denmark, Tel +45 97660566, Email Jacob.bodilsen@rn.dkPurpose: Following the implementation of the 3rd version of the Danish National Patient Register (DNPR-3), information on whether hospitalizations were inpatient, outpatient, or emergency room (ER) contacts was no longer readily available. This study examined the positive predictive values (PPV) of a common algorithm to characterize hospitalizations as inpatient, outpatient, or emergency room (ER) contacts in both DNPR-2 and DNPR-3.Patients and Methods: All hospital contacts in North Denmark Region were identified in the DNPR within a 1-year window of the implementation of DNPR-3 in early 2019. An algorithm based upon proportion of overnight (± 50%) and elective (± 50%) contacts for each hospital department was developed. Next, PPVs of these categorizations were computed using manual characterization of all departments and clinics by two experienced clinicians as reference. Second, the reliability of various time intervals to join department contacts and subsequent categorization of overnight hospital stays as proxies for inpatient contacts was explored.Results: The algorithm yielded PPVs of 91% and 89% for hospital units and related contacts categorized as inpatient in DNPR-2 and 100% for both parameters in DNPR-3. In outpatient units, the PPVs were 99% in both DNPR-2 and DNPR-3, whereas the corresponding PPVs were 99.6% and 99% on the contact level. In contrast, the PPV for ERs was 33% in DNPR-2 and 56% in DNPR-3, primarily due to misclassification of outpatient clinics. Still, the proportion of correctly categorized ER contacts was 87% in DNPR-2 and 85% in DNPR-3. Using time intervals from 0 to 12 hours to join department contacts showed that overnight hospitalizations comprised inpatient contacts in 97% in DNPR-2 and 98% in DNPR-3. However, the sensitivity was moderate at 76– 78% for all inpatient hospitalizations in DNPR-2 and DNPR-3.Conclusion: This algorithm accurately categorized hospitalizations as inpatient, outpatient, or ER contacts in both DNPR-2 and DNPR-3.Keywords: epidemiological methods, medical record linkage, registries, research design, validation studies, Danish National Patient Registry, DNPR, LPR-3, Landspatientregisteret

Lærke Storgaard Duerlund,1 Shakil Shakar,2 Henrik Nielsen,1 Jacob Bodilsen1 1Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; 2The Department of Medicine, Regionshospitalet Nordjylland Hjørring, Hjørring, DenmarkCorrespondence: Jacob BodilsenDepartment of Infectious Diseases, Aalborg University Hospital, Mølleparkvej, 4, Aalborg, 9000, Denmark, Tel +45 97660566, Email Jacob.bodilsen@rn.dkPurpose: To examine the positive predictive value (PPV) of International Classification version 10 (ICD-10) diagnosis codes for long coronavirus disease 2019 (long-COVID) in a Danish Health registry.Patients and Methods: This was a medical record review of all patients with a diagnosis code of long-COVID (DB948A) at all hospitals in the North Denmark Region from February 27, 2020 through June 30, 2021. Confirmed long-COVID was categorized as fulfillment of all three criteria: (1) a positive polymerase chain reaction (PCR) test for SARS-CoV-2 on a respiratory sample or a positive serum antibody test, (2) symptoms suggestive of long-COVID with no other diagnosis considered more likely, and (3) symptom duration > 6 weeks.Results: A total of 306 patients were assigned a hospital diagnosis code for long-COVID corresponding to 1.4% of all SARS-CoV-2 positive individuals during the study period (n=21,727). Next, 40 patients were excluded due to incomplete diagnostic evaluation at time of record review leaving 266 patients for analysis. The patients had a median age of 51 years (interquartile range 43– 60) and 175/266 (66%) were females. Long-COVID was confirmed in 249/266 yielding an overall PPV of 94% (95%CI: 90– 96) and did not differ substantially according to most age groups, sex, previous hospitalization for COVID-19, or by using 12 weeks of symptom duration as cut-off. The PPV was low for children and adolescents (n=5), the very elderly (n=9), and those included by secondary long-COVID diagnoses (n=10).Conclusion: The overall PPV of diagnosis codes for long-COVID in the North Denmark Region was high and was likely suitable for future registry-based studies of long-COVID. Caution is advised at the extremes of age and secondary diagnosis codes.Keywords: post-COVID, coronavirus disease 2019, diagnosis codes, validation, epidemiology

Jacob Bodilsen,1 Lykke Larsen,2 Christian Thomas Brandt,3,4 Lothar Wiese,4 Birgitte Rønde Hansen,5 Christian Østergaard Andersen,6 Hans Rudolf Lüttichau,7 Jannik Helweg-Larsen,8 Merete Storgaard,9 Henrik Nielsen1,10 1Department of Infectious Diseases, Aalborg University Hospital, Aalborg, 9000, Denmark; 2Department of Infectious Diseases, Odense University Hospital, Odense, 5000, Denmark; 3Department of Infectious Diseases, Nordsjællands Hospital, Hillerød, 3400, Denmark; 4Department of Infectious Diseases, Sjælland University Hospital, Roskilde, 4000, Denmark; 5Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, 2650, Denmark; 6Department of Clinical Microbiology, Hvidovre University Hospital, Copenhagen, 2650, Denmark; 7Department of Infectious Diseases, Herlev Gentofte Hospital, Copenhagen, 2730, Denmark; 8Department of Infectious Diseases, Rigshospitalet, Copenhagen, 2100, Denmark; 9Department of Infectious Diseases, Aarhus University Hospital, Aarhus, 8200, Denmark; 10Department of Clinical Medicine, Aalborg University, Aalborg, 9000, DenmarkCorrespondence: Jacob BodilsenDepartment of Infectious Diseases, Aalborg University Hospital, Mølleparkvej 4, Aalborg, DK9000, DenmarkTel +45 97660566Email Jacob.bodilsen@rn.dkAbstract: 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.Keywords: CNS infections, epidemiology, database, cohort studies, bacterial meningitis, viral meningitis, encephalitis, brain abscess, cerebral abscess, neurosyphilis, syphilis, Lyme neuroborreliosis, borreliosis

Jacob Bodilsen,1 Steffen Leth,2,3 Stig Lønberg Nielsen,4,5 Jon Gitz Holler,6 Thomas Benfield,7 Lars Haukali Omland8 1Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; 2Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark; 3Department of Medicine, Regional Hospital Unit West Jutland, Herning, Denmark; 4Research Unit for Infectious Diseases, Odense University Hospital, Odense, Denmark; 5University of Southern Denmark, Odense, Denmark; 6Department of Pulmonary and Infectious Diseases, Hillerød Hospital, Hillerød, Denmark; 7Department of Infectious Diseases, Copenhagen University Hospital – Amager and Hvidovre, Hvidovre, Denmark; 8Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, DenmarkCorrespondence: Jacob BodilsenDepartment of Infectious Diseases, Aalborg University Hospital, Mølleparkvej 4, Aalborg, 9000, DenmarkEmail Jacob.bodilsen@rn.dkPurpose: To examine the positive predictive value (PPV) of International Classification version 10 (ICD-10) diagnosis codes for Coronavirus disease 2019 (COVID-19).Patients and Methods: Medical record review of all patients assigned a diagnosis code of COVID-19 (DB342A or DB972A) at six Danish departments of infectious diseases from February 27 through May 4, 2020. Confirmed COVID-19 diagnosis was defined as either: 1) definite, a positive polymerase chain reaction (PCR) for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) on a respiratory sample combined with symptoms suggestive of COVID-19: 2) probable, clinical presentation of COVID-19 without detection of SARS-CoV-2 and no alternative diagnoses considered more likely; or 3) possible, clinical presentation of COVID-19 without detection of SARS-CoV-2, and the patient was discharged or deceased before further investigations were carried out. We computed the PPV with 95% confidence intervals (CI) as the number of patients with confirmed (i.e., definite, probable, and possible) COVID-19 divided by the number of patients assigned a diagnosis code for COVID-19.Results: The study included 710 patients with a median age of 61 years (interquartile range [IQR] 47– 74) and 285/710 (40%) were female. COVID-19 was confirmed in 706/710 (99%) with 705/710 (99%) categorized as definite, 1/710 (0.1%) as probable, and 0 patients as possible COVID-19. The diagnosis was disproven in 4/710 (0.6%) patients who were hospitalized due to bacterial pneumonia (n = 2), influenza (n = 1), and urinary tract infection (n = 1). The overall PPV for COVID-19 was 99% (95% CI 99– 100) and remained consistently high among all subgroups including sex, age groups, calendar period, and stratified by diagnosis code and department of infectious diseases (range 97– 100%).Conclusion: The overall PPV of diagnosis codes for COVID-19 in Denmark was high and may be suitable for future registry-based prognosis studies of COVID-19.Keywords: Coronavirus disease 2019; COVID-19, SARS-CoV-2, diagnosis codes, ICD-10, positive predictive value; PPV, validation, epidemiology

Ann-Brit E Hansen,1– 3 Hanne T Vestergaard,4 Ram B Dessau,5 Jacob Bodilsen,6 Nanna S Andersen,7 Lars H Omland,1 Claus B Christiansen,8 Svend Ellermann-Eriksen,9 Lene Nielsen,10 Thomas Benfield,2,3 Henrik T Sørensen,11 Christian Ø Andersen,12 Anne-Mette Lebech,1,3 Niels Obel1,3 1Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 2Department of Infectious Diseases, Amager Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; 3Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 4Department of Virus & Microbiological Special Diagnostics, Statens Serum Institute, Copenhagen, Denmark; 5Department of Clinical Microbiology, Slagelse Hospital, Slagelse, Denmark; 6Departments of Infectious Diseases and Clinical Microbiology, Aalborg University Hospital, Aalborg, Denmark; 7Department of Clinical Microbiology, Odense University Hospital, Odense, Denmark; 8Department of Clinical Microbiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 9Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark; 10Department of Clinical Microbiology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark; 11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 12Department of Clinical Microbiology, Amager Hvidovre University Hospital, University of Copenhagen, Hvidovre, DenmarkCorrespondence: Ann-Brit E HansenDepartment of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen Ø DK-2100, DenmarkTel +45 30299306Email ann-brit.eg.hansen.02@regionh.dkBackground: The long-term prognosis following herpes simplex virus (HSV) central nervous system (CNS) infection is still debated.Patients and Methods: We examined outcomes in all Danish residents who, during 2000– 2016, tested PCR positive for HSV-1 (n=208) or HSV-2 (n=283) in the cerebrospinal fluid, compared to comparison cohorts from the general population (n=2080 and n=2830).Results: One-year mortality was increased among HSV-1 patients (difference 19.3%; 95% CI: 13.6% to 25.0%) and HSV-2 patients (difference 5.3%; 95% CI: 2.5% to 8.1%), but thereafter mortality was not increased. After exclusion of persons diagnosed with cancer prior to study inclusion, one-year mortality difference for HSV-2 patients was 1.7% (− 0.1% to 3.5%). After five years, HSV-1 patients had lower employment (difference − 19.8%; 95% CI: − 34.7% to − 4.8%) and higher disability pension rates (difference 22.2%; 95% CI: 8.4% to 36.0%) than the comparison cohort, but similar number of inpatient days, outpatient visits, and sick leave. HSV-2 patients had employment and disability pension rates comparable to the comparison cohort, but more inpatient days (difference 1.5/year; 95% CI: − 0.2 to 3.2), outpatient visits (difference 1.3/year; 95% CI: 0.3 to 3.2), and sick leave days (difference 9.1/year; 95% CI: 7.9 to 10.4).Conclusion: HSV-1 and HSV-2 CNS infections differ substantially with respect to prognosis. HSV-1 CNS infection is followed by increased short-term mortality and long-term risk of disability. HSV-2 CNS infection has no substantial impact on mortality or working capability but is associated with increased morbidity.Keywords: herpes simplex virus encephalitis, herpes simplex virus meningitis, prognosis, outcome, cohort study

Jacob Bodilsen,1 Michael Dalager-Pedersen,1 Nicolai Kjærgaard,1 Diederik van de Beek,2 Matthijs C Brouwer,2 Henrik Nielsen,1 and the DASGIB study group 1Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; 2Department of Neurology, Amsterdam Neuroscience, Academic Medical Centre, Amsterdam, The Netherlands Purpose: To evaluate the positive predictive value (PPV) of ICD-10 diagnosis codes for brain abscess in the Danish National Patient Registry (DNPR). Patients and methods: We examined medical records of all patients with a first-time diagnosis code of brain abscess in the DNPR from 2007 to 2016. Patients were categorized with either confirmed or disproved brain abscess using a priori defined criteria. We computed the PPV as the proportion of confirmed diagnoses. Results: We identified 709 patients, of whom the medical records could not be retrieved for 15 patients, leaving 694 for further analyses. Of these, 444 had a confirmed brain abscess and 250 had another proven diagnosis, including 47 cases of intracranial empyema. The overall PPV was 64% (95% CI: 60–68) ranging from 24% to 96% among the different codes evaluated. By including only patients with either 1) both a diagnosis and surgical procedure code for brain abscess or 2) patients admitted to hospital with certain primary diagnosis codes (DG060[C,E,F] or DG079B) without newly diagnosed central nervous system (CNS) cancer, spondylodiscitis/intraspinal abscess, or procedure codes for evacuation of intracranial empyema, the PPV increased to 84% (95% CI 80–87) and 89% (395/444) of all confirmed cases were identified. Conclusion: The overall PPV of diagnosis codes for brain abscess in the DNPR was moderate. However, by exclusion of newly diagnosed CNS tumors, spondylodiscitis/intraspinal abscess, and intracranial empyemas, the PPV was high and therefore suitable for future registry-based studies of brain abscess. Keywords: cerebral abscess, register, PPV, intracranial abscess, epidemiology

Background: Sensorineural hearing loss (SNHL) has been suggested to occur in patients with Lyme neuroborreliosis (LNB); however, a clear association has never been documented. The present study prospectively investigated the development of SNHL in patients admitted for treatment of LNB using distortion-product-oto-acoustic emissions (DPOAE) as a measure of cochlear function., Methods: DOAE were measured in patients with LNB on the day of diagnosis, during treatment, and 30-60 days after discharge. Frequencies were categorized as Low (1, 1.5, 2 kHz), Mid (3, 4, 5 kHz), Mid-high (6, 7, 8 kHz), and High (9, 10 kHz). Pure Tone Audiometry (PTA3) was performed at discharge and 60 days after. Patients were treated with i.v. ceftriaxone or oral doxycycline for 14 days according to guidelines., Results: DPOAE measurements were obtained in 25 patients with LNB at admission and in 18 patients at follow-up. Median age was 56 years (IQR, 48-64 years), and 16 (67%) were men. Fourteen (78%) of 18 patients showed improvement in Emission Threshold Levels (ETL) from admission to follow-up in low, mid-, and mid-high frequency categories, where ETLs increased by median levels of 3.2 (-4.1 to 8.3), 7.5 (-2.8 to 9.8), and 4.7 dB (-4.3 to 10.1). A decline was observed in the high frequency category, median -3.3 dB (-9.1 to 6.7). SNHL defined by pure tone average (PTA3) >20 dB was present in 11 out of 23 (48%) at discharge and in 9 out of 16 patients (56%) 60 days after discharge, which differed significantly from matched controls (Mann-Whitney test, p  = 0.036)., Conclusion: LNB can lead to cochlear outer-hair cell dysfunction, resulting in temporary and long-term SNHL.

Background: Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi (Bb) sensu lato complex. Previous studies have suggested an association between Lyme borreliosis and heart failure, which have been suggested to be a possible manifestation of Lyme carditis. We aimed to investigate the risk of heart failure among individuals tested for serum Bb antibodies, and serum Bb seropositive individuals., Methods: We performed a matched nationwide cohort study (Denmark, 1993-2020) and included 52,200 Bb seropositive individuals, and two age- and sex-matched comparison cohorts: 1) 104,400 Bb seronegative comparison cohort members, and 2) 261,000 population controls. We investigated the risk associated with 1) being tested for serum Bb antibodies, and 2) being Bb seropositive. Outcomes were: 1) a composite of heart failure, cardiomyopathy, and/or myocarditis diagnosis, and 2) redemption of cardiovascular medicine used for treatment of heart failure. We calculated short-term odds ratios (aOR) (within 1 month) and long-term hazard rates (aHR) (after 1 month) adjusted for age, sex, diabetes, pre-existing heart failure, and kidney disease., Results: Compared with the population controls, individuals tested for Bb antibodies, regardless of the test result, had increased short-term risk of heart failure, cardiomyopathy, and myocarditis (aOR 8.3, 95 %CI: 6.7-10.2), and both increased short- and long-term risk of redemption of cardiovascular medicine (aOR 4.3, 95 %CI: 3.8-4.8, aHR 1.13, 95 % CI: 1.11-1.15). The Bb seropositive individuals had no increased short- or long-term risk of any outcome compared with Bb seronegative comparison cohort members., Conclusions: In conclusion, Bb antibody tests seemed to be performed in the diagnostic work-up of heart failure, but Bb seropositivity was not associated with heart failure., Competing Interests: Conflict of interest MMT has received travel grants outside this work from GlaxoSmithKline Pharma A/S. RBD has advisory board activity with Pfizer. JHS reports institutional research grant from Medtronic (outside this study), speakers’ honorarium from Medtronic and membership of an advisory board in Medtronic. AML reports speakers’ honorarium/travel grants/advisory board activity and unrestricted grant from Gilead, speakers honorarium /travel grants from GSK, speaker's honorarium/advisory board activity from Pfizer outside this work. None of the authors report any conflict of interests in connection with this article., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Radicular pain is the most predominant symptom among adults with Lyme neuroborreliosis (LNB) but the duration preceding and following diagnosis remains unknown. We aimed to investigate whether patients with LNB have increased obtainment of analgesics before and after diagnosis and for how long., Methods: We performed a nationwide, population-based, matched cohort study (2009-2021). all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis) were included. To form a comparison cohort, individuals from the general population were randomly extracted and matched 10:1 to patients with LNB on age and sex. Outcomes were obtainment of simple analgesics, antiepileptics, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, tramadol, and other opioids. We calculated monthly and six-monthly proportions of individuals with obtainment of analgesics and absolute risk differences., Results: 1,056 patients with LNB and 10,560 comparison cohort members were included. An increased proportion of patients with LNB obtained analgesics from 3 months before study inclusion, especially simple analgesics, tramadol, and other opioids. Within the 0-1-month period after study inclusion, patients with LNB most frequently obtained simple analgesics (15 %), antiepileptics (11 %), and tramadol (10 %). Thereafter, obtainment of analgesics declined within a few months. A slightly larger proportion of patients with LNB obtained antiepileptics up to 2.5 years after diagnosis., Conclusions: Up to 3 months preceding diagnosis, LNB was preceded by increased obtainment of analgesics, which suggests diagnostic delay. Importantly, most patients with LNB did not obtain analgesics after the immediate disease course, although obtainment remained more frequent up to 2.5 years after., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: In a nationwide, matched cohort study, we aimed to investigate risks of haematologic cancers among individuals tested for Borrelia burgdorferi (Bb) antibodies, and among serum Bb seropositive individuals., Methods: We identified all Bb seropositive individuals in Denmark (1993-2020) (n = 52 200) and constructed two age- and sex-matched comparison cohorts: (a) Bb seronegative controls (n = 104 400) and (b) background population controls (n = 261 000). We calculated short-term OR (aOR) (<1 month of study inclusion), and long-term hazard ratios (aHR) (>1 month after study inclusion) adjusted for age and sex. We stratified seropositive individuals on only Bb-IgM seropositive (n = 26 103), only Bb-IgG seropositive (n = 18 698), and Bb-IgM-and-IgG seropositive (n = 7399)., Results: Compared with the background population, individuals tested for Bb antibodies had increased short-term (aOR: 12.6, 95% CI: 10.1-15.6) and long-term (aHR: 1.3, 95% CI: 1.2-1.4) risk of haematologic cancers. The Bb seropositive individuals had no increased risk of haematologic cancers compared with those who tested negative for Bb, except that Bb-IgM-and-IgG seropositive individuals had increased long-term risk of chronic lymphatic leukaemia (aHR: 2.0, 95% CI: 1.2-3.4)., Discussion: Our results suggest that Bb antibody testing is included in the work-up of unspecific symptoms preceding diagnosis of haematologic cancers. Bb-IgM-and-IgG seropositivity was associated with a two-fold increased long-term risk of chronic lymphatic leukaemia, which warrants further investigation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Scope: These European Society of Clinical Microbiology and Infectious Diseases guidelines are intended for clinicians involved in diagnosis and treatment of brain abscess in children and adults., Methods: Key questions were developed, and a systematic review was carried out of all studies published since 1 January 1996, using the search terms 'brain abscess' OR 'cerebral abscess' as Mesh terms or text in electronic databases of PubMed, Embase, and the Cochrane registry. The search was updated on 29 September 2022. Exclusion criteria were a sample size <10 patients or publication in non-English language. Extracted data was summarized as narrative reviews and tables. Meta-analysis was carried out using a random effects model and heterogeneity was examined by I 2 tests as well as funnel and Galbraith plots. Risk of bias was assessed using Risk Of Bias in Non-randomised Studies - of Interventions (ROBINS-I) (observational studies) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (diagnostic studies). The Grading of Recommendations Assessment, Development and Evaluation approach was applied to classify strength of recommendations (strong or conditional) and quality of evidence (high, moderate, low, or very low)., Questions Addressed by the Guidelines and Recommendations: Magnetic resonance imaging is recommended for diagnosis of brain abscess (strong and high). Antimicrobials may be withheld until aspiration or excision of brain abscess in patients without severe disease if neurosurgery can be carried out within reasonable time, preferably within 24 hours (conditional and low). Molecular-based diagnostics are recommended, if available, in patients with negative cultures (conditional and moderate). Aspiration or excision of brain abscess is recommended whenever feasible, except for cases with toxoplasmosis (strong and low). Recommended empirical antimicrobial treatment for community-acquired brain abscess in immuno-competent individuals is a 3rd-generation cephalosporin and metronidazole (strong and moderate) with the addition of trimethoprim-sulfamethoxazole and voriconazole in patients with severe immuno-compromise (conditional and low). Recommended empirical treatment of post-neurosurgical brain abscess is a carbapenem combined with vancomycin or linezolid (conditional and low). The recommended duration of antimicrobial treatment is 6-8 weeks (conditional and low). No recommendation is offered for early transition to oral antimicrobials because of a lack of data, and oral consolidation treatment after ≥6 weeks of intravenous antimicrobials is not routinely recommended (conditional and very low). Adjunctive glucocorticoid treatment is recommended for treatment of severe symptoms because of perifocal oedema or impending herniation (strong and low). Primary prophylaxis with antiepileptics is not recommended (conditional and very low). Research needs are addressed., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Early switch to oral antimicrobials has been suggested as a treatment strategy in patients with brain abscess, but the practice is controversial., Objectives: This review aimed to summarize the background, current evidence, and future perspectives for early transition to oral antimicrobials in patients with brain abscess., Sources: The review was based upon a previous systematic review carried out during the development of the ESCMID guidelines on diagnosis and treatment of brain abscess. The search used 'brain abscess' or 'cerebral abscess' as text or MESH terms in PubMed, EMBASE, and the Cochrane Library. Studies included in the review were required to be published in the English language within the last 25 years and to have a study population of ≥10 patients. Other studies known by the authors were also included., Content: In this review, the background for some experts to suggest early transition to oral antimicrobials in patients with mild and uncomplicated brain abscess was clarified. Next, results from observational studies were summarized and limitations discussed. Indirect support for early oral treatment of brain abscess was described with reference to other serious central nervous system infections and general pharmacological considerations. Finally, variations within and between countries in the use of early transition to oral antimicrobials in patients with brain abscess were highlighted., Implications: Early transition to oral antimicrobials in patients with uncomplicated brain abscess may be of benefit for patients due to convenience of treatment and potential decreased risks associated with prolonged hospitalization and intravenous lines. The strategy may also confer a more rational allocation of healthcare resources and decrease expenses. However, the benefit/risk ratio for this strategy remains unresolved at present., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© 2023. The Author(s).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hearing loss and deafness are well-known sequelae from bacterial meningitis (ABM) and may result in social dysfunction and learning difficulties. Yet, the timely development of hearing loss and restitution is poorly studied, especially among adults. Hearing loss was revisited using otoacoustic emissions (OAEs) to determine the occurrence, magnitude, and development of hearing loss among adults with ABM., Methods: Distortion product OAEs were measured in patients with ABM the day of admission and days 2, 3, 5-7, and 10-14 and at follow-up 30-60 days after discharge. Frequencies were categorized as low (1, 1.5, 2 kHz), mid (3, 4, 5 kHz), mid-high (6, 7, 8 kHz), and high (9, 10 kHz). Audiometry was performed on discharge and 60 days after. Results were compared with 158 healthy controls., Results: OAE was obtained in 32 patients. ABM was due to S. pneumoniae in 12 patients (38%). All patients were treated with dexamethasone. OAE emission threshold levels (ETLs) were significantly decreased upon admission and at follow-up in all frequencies compared with healthy controls. A substantial and significant decrease in ETLs was found in S. pneumoniae meningitis. Sensorineural hearing loss (SNHL) >20 dB was present in 13 of 23 (57%) at discharge and in 11 of 18 patients (61%) 60 days after discharge. Hearing recovery decreased from day 3., Conclusions: Hearing loss in ABM still affects >60% of patients despite treatment with dexamethasone. In S. pneumoniae meningitis, SNHL is profound and permanent. A window of opportunity for systemic or local treatments aiming to preserve cochlear function is proposed., Competing Interests: Potential conflicts of interest. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: Obesity may alter the severity of infection with Coronavirus disease 2019 (COVID-19). Age may impact the association between body weight and severity of COVID-19 in patients with obesity. The aim of the study was to examine the association between obesity and severity of infection in a Danish cohort hospitalized with COVID-19 in the initial wave of the pandemic., Patients and Methods: Based on data from the nationwide, clinical database: COVID-DK, risks of intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and mortality were compared among patients with and without obesity. Interaction with age was examined and we used Inverse Probability of Treatment Weighting regression for confounder adjustment., Results: Among 524 patients, 142 (27%) were admitted to the ICU, 112 (21%) required IMV, and 109 (21%) died. Compared to COVID-19 patients without obesity, patients with obesity displayed a non-significant increased risk of ICU admission (Relative Risk [RR] 1.19, 95% Confidence Interval [CI] 0.88; 1.60), IMV (RR 1.23, CI 0.86; 1.75) and mortality (RR 1.21, CI 0.84; 1.75). COVID-19 patients with obesity, <60 years had highly increased risk of ICU admission (RR 1.92, CI 1.14; 3.24) and IMV (RR 1.95, CI 1.09; 3.49)., Conclusions: In hospitalized COVID-19 patients, obesity conferred an approximately 20% increased risk for ICU admission, IMV, and death, although these relationships did not reach statistical significance. COVID-19 patients with obesity and <60 years had an almost doubled risk of ICU admission and IMV., Competing Interests: Jens Meldgaard Bruun, Sigrid Bjerge Gribsholt and Bjørn Richelsen received honoraria for lectures at Novo Nordisk Denmark A/S. Thomas Lars Benfield received grants or contracts from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen's Charitable Fund, GSK, Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Pentabase, Roche, Novartis, Kancera AB, Janssen, and Astra Zeneca. Thomas Lars Benfield received honoraria for lectures at GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, Abbvie, and Astra Zeneca. TLB received donation of trial medication from Eli Lilly. Other authors declare no conflict of interest., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: We aimed to describe attitudes toward treatment of herpes simplex virus type 2 (HSV-2) meningitis and prioritize future trials., Methods: This was a self-administered online survey of HSV-2 meningitis treatment among infectious diseases (ID) specialists in France, Sweden, Australia, and Denmark., Results: A total of 223 ID specialists (45% female) from France (36%), Denmark (24%), Sweden (21%), and Australia (19%) participated in the survey, primarily from university hospitals (64%). The estimated overall response rate was 11% and ranged from 6% (Australia) to 64% (Denmark). Intravenous (IV) acyclovir followed by oral valacyclovir was the favored treatment in 110 of 179 (61%), whereas monotherapy with either IV acyclovir or oral valacyclovir was used by 35 of 179 (20%) and 34 of 179 (19%), respectively. The median total duration was reported to be 7 days (interquartile range, 7-10 days) regardless of antiviral regimen. Immunocompromise influenced decisions on antiviral treatment in 110 of 189 (58%) of respondents, mainly by prolonged total duration of treatment (36/110 [33%]), prolonged IV administration (31/110 [28%]), and mandatory antiviral treatment (25/110 [23%]). Treatment with acyclovir/valacyclovir versus placebo and comparison of acyclovir versus valacyclovir were assigned the highest prioritization scores for future randomized controlled trials on HSV-2 meningitis., Conclusions: Perceptions of indications for as well as type and duration of antiviral treatment varied substantially among ID specialists., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Clinical guidelines disagree on the diagnostic usefulness of Borrelia burgdorferi (Bb) serum antibodies (serum-Bb) in investigation of Lyme neuroborreliosis (LNB). We investigated the association between serum-Bb and Bb intrathecal antibody index (Bb-AI) and rates of seroconversion and seroreversion after LNB., Methods: Danish residents who had a Bb-AI and corresponding serum-Bb measured between 1994 and 2020 were identified at all Danish departments of clinical microbiology. We used descriptive statistics to examine the proportions of positive Bb-AI combined with positive or negative serum-Bb antibody tests. Next, the rate of seroconversion and seroreversion among those with positive Bb-AI and either an initial negative or positive serum-Bb was estimated., Results: We included 34 609 individuals with a Bb-AI and corresponding serum-Bb. The proportion of individuals with positive Bb-AI who had negative serum-Bb was 16.8% (95% CI, 15.1-18.6). The proportion of individuals with positive serum-Bb IgM, serum-Bb IgG, or serum-Bb IgM and IgG antibodies who had positive Bb-AI was 10.6% (95% CI, 9.5-11.8), 24.7% (95% CI, 23.0-26.4), and 45.0% (95% CI, 42.4-48.0), respectively. The proportion of children (<18 years) with positive serum-Bb IgM and IgG antibodies who had a positive Bb-AI was 59.7% (95% CI, 53.4-65.8). The proportion of individuals with positive Bb-AI with initial negative or positive serum-Bb antibodies who seroconverted or seroreverted within 2 years was 17.3% (95% CI, 6.9-27.8) and 23.2% (95% CI, 19.1-27.7), respectively., Conclusions: Serum-Bb antibodies could not predict results of Bb-AI. A fifth of both seronegative and seropositive individuals with positive Bb-AI seroconverted or seroreverted within 2 years., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19., Methods: Using healthcare records from the Capital Region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis., Results: We included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N = 432) and the pooled risk ratio was 0.91 (CI 0.60-1.38) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (0.76-1.66), while we observed no increased risk of bleeding 0.63 (0.13-2.94). The relative risk of venous thromboembolism was 0.80 (0.43-1.47)., Conclusion: We found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To identify individual characteristics associated with serological COVID-19 vaccine responsiveness and the durability of vaccine-induced antibodies., Methods: Adults without history of SARS-CoV-2 infection from the Danish population scheduled for SARS-CoV-2 vaccination were enrolled in this parallel group, phase 4 study. SARS-CoV-2 Spike IgG and Spike-ACE2-receptor-blocking antibodies were measured at days 0, 21, 90, and 180. Vaccine responsiveness was categorized according to Spike IgG and Spike-ACE2-receptor-blocking levels at day 90 after first vaccination. Nondurable vaccine response was defined as day-90 responders who no longer had significant responses by day 180., Results: Of 6544 participants completing two vaccine doses (median age 64 years; interquartile range: 54-75), 3654 (55.8%) received BTN162b2, 2472 (37.8%) mRNA-1273, and 418 (6.4%) ChAdOx1 followed by an mRNA vaccine. Levels of both types of antibodies increased from baseline to day 90 and then decreased to day 180. The decrease was more pronounced for levels of Spike-ACE2-receptor-blocking antibodies than for Spike IgG. Proportions with vaccine hyporesponsiveness and lack of durable response were 5.0% and 12.1% for Spike IgG and 12.7% and 39.6% for Spike-ACE2-receptor-blocking antibody levels, respectively. Male sex, vaccine type, and number of comorbidities were associated with all four outcomes. Additionally, age ≥75 years was associated with hyporesponsiveness for Spike-ACE2-receptor-blocking antibodies (adjusted odds ratio: 1.59; 95% confidence interval: 1.25-2.01) but not for Spike IgG., Discussion: Comorbidity, male sex, and vaccine type were risk factors for hyporesponsiveness and nondurable response to COVID-19 vaccination. The functional activity of vaccine-induced antibodies declined with increasing age and had waned to pre-second-vaccination levels for most individuals after 6 months., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21-28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15-0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron., (© 2022. The Author(s).)

To optimally define the association between time to effective antibiotic therapy and clinical outcomes in adult community-acquired bacterial meningitis. A systematic review of the literature describing the association between time to antibiotics and death or neurological impairment due to adult community-acquired bacterial meningitis was performed. A retrospective cohort, multivariable and propensity-score based analyses were performed using individual patient clinical data from Australian, Danish and United Kingdom studies. Heterogeneity of published observational study designs precluded meta-analysis of aggregate data (I 2  = 90.1%, 95% CI 71.9-98.3%). Individual patient data on 659 subjects were made available for analysis. Multivariable analysis was performed on 180-362 propensity-score matched data. The risk of death (adjusted odds ratio, aOR) associated with treatment after two hours was 2.29 (95% CI 1.28-4.09) and increased substantially thereafter. Similarly, time to antibiotics of greater than three hours was associated with an increase in the occurrence of neurological impairment (aOR 1.79, 95% CI 1.03-3.14). Among patients with community-acquired bacterial meningitis, odds of mortality increase markedly when antibiotics are given later than two hours after presentation to the hospital., (© 2022. The Author(s).)

Background: The advised standard treatment for bacterial brain abscess following surgery is 6 to 8 weeks of intravenous (IV) antibiotic treatment, but an early switch to oral antibiotic treatment has been suggested to be equally effective., Methods: This investigator-initiated, international, multi-center, parallel group, open-label, randomized (1:1 allocation) controlled trial will examine if oral treatment after 2 weeks of IV antibiotic therapy is non-inferior to standard 6-8 weeks of IV antibiotics for bacterial brain abscess in adults (≥ 18 years of age). The study will be conducted at hospitals across Denmark, the Netherlands, France, Australia, and Sweden. Exclusion criteria are severe immunocompromise or impaired gastro-intestinal absorption, pregnancy, device-related brain abscesses, and brain abscess caused by nocardia, tuberculosis, or Pseudomonas spp. The primary objective is a composite endpoint at 6 months after randomization consisting of all-cause mortality, intraventricular rupture of brain abscess, unplanned re-aspiration or excision of brain abscess, relapse, or recurrence. The primary endpoint will be adjudicated by an independent blinded endpoint committee. Secondary outcomes include extended Glasgow Outcome Scale scores and all-cause mortality at end of treatment as well as 3, 6, and 12 months since randomization, completion of assigned treatment, IV catheter associated complications, durations of admission and antibiotic treatment, severe adverse events, quality of life scores, and cognitive evaluations. The planned sample size is 450 patients for a one-sided alpha of 0.025 and a power of 90% to exclude a difference in favor of standard treatment of more than 10%. Date of initiation of first study center was November 3, 2020, with active recruitment for 3 years and follow-up for 1 year of all patients., Discussion: The results of this study may guide future recommendations for treatment of bacterial brain abscess. If early transition to oral antibiotics proves non-inferior to standard IV treatment, this will provide considerable health and costs benefits., Trial Registration: ClinicalTrials.gov NCT04140903, first registered 28.10.2019. EudraCT number: 2019-002845-39, first registered 03.07.2019., (© 2021. The Author(s).)

Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials., Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load., Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group ( P  = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P  = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log 10 copies/mL ( p  <0·05) and -0·82 log 10 in the placebo group ( P  <0·05)., Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42., Competing Interests: Dr. Mortensen reports a Gilead Travel Grant, outside the submitted work. Dr Østergaard reports personal fees from GlaxoSmithKlinePharma A/S, Gilead Science Denmark A/S, Pfizer A/S, MSD Denmark A/S, and Sanofi Pasteur Europe, outside the submitted work. Dr. Kjolby reports grants from The Lundbeck Foundation, during the conduct of the study; and has or has had stocks in Genmab, Novo Nordisk, Novartis, Amgen, and Regeneron. All other authors have nothing to disclose., (© 2021 The Authors.)

Background Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) may worsen the prognosis of coronavirus disease 2019, but any association could be confounded by the cardiometabolic conditions indicating ACE-I/ARB use. We therefore examined the impact of ACE-Is/ARBs on respiratory tract infection outcomes. Methods and Results This cohort study included all adult patients hospitalized with influenza or pneumonia from 2005 to 2018 in Denmark using population-based medical databases. Thirty-day mortality and risk of admission to the intensive care unit in ACE-Is/ARBs users was compared with nonusers and with users of calcium channel blockers. We used propensity scores to handle confounding and computed propensity score-weighted risks, risk differences (RDs), and risk ratios (RRs). Of 568 019 patients hospitalized with influenza or pneumonia, 100 278 were ACE-I/ARB users and 37 961 were users of calcium channel blockers. In propensity score-weighted analyses, ACE-I/ARB users had marginally lower 30-day mortality than users of calcium channel blockers (13.9% versus 14.5%; RD, -0.6%; 95% CI, -1.0 to -0.1; RR, 0.96; 95% CI, 0.93-0.99), and a lower risk of admission to the intensive care unit (8.0% versus 9.6%; RD, -1.6%; 95% CI, -2.0 to -1.2; RR, 0.83; 95% CI, 0.80-0.87). Compared with nonusers, current ACE-I/ARB users had lower mortality (RD, -2.4%; 95% CI, -2.8 to -2.0; RR, 0.85; 95% CI, 0.83-0.87), but similar risk of admission to the intensive care unit (RD, 0.4%; 95% CI, 0.0-0.7; RR, 1.04; 95% CI, 1.00-1.09). Conclusions Among patients with influenza or pneumonia, ACE-I/ARB users had no increased risk of admission to the intensive care unit and slightly reduced mortality after controlling for confounding.

Objective: To examine predefined risk factors and outcome of seizures in community-acquired bacterial meningitis (CABM)., Design: Observational cohort studies SETTING: Denmark PARTICIPANTS: In the derivation cohort, we retrospectively included all adults (>15 years of age) with CABM in North Denmark Region from 1998 to 2014 and at Hvidovre and Hillerød hospitals from 2003 to 2014. In the validation cohort, we prospectively included all adults (>18 years of age) with CABM treated at all departments of infectious diseases in Denmark from 2015 to 2017., Primary and Secondary Outcome Measures: In the derivation cohort, we used modified Poisson regression to compute adjusted relative risks (RRs) with 95% confidence intervals for predefined risk factors for seizures during CABM as well as for risks of death and unfavourable outcome assessed by the Glasgow Outcome Scale score (1-4). Next, results were validated in the validation cohort., Results: In the derivation cohort (n=358), risk factors for seizures at any time were pneumococcal aetiology (RR 1.69, 1.01-2.83) and abnormal cranial imaging (RR 2.27, 1.46-3.53), while the impact of age >65 years and immunocompromise was more uncertain. Examining seizures occurring after admission, risk factors were abnormal cranial imaging (RR 2.23, 1.40-3.54) and immunocompromise (RR 1.59, 1.01-2.50). Seizures at any time were associated with increased risks of in-hospital mortality (RR 1.45, 1.01-2.09) and unfavourable outcome at discharge (RR 1.27, 1.02-1.60). In the validation cohort (n=379), pneumococcal aetiology (RR 1.69, 1.10-2.59) and abnormal cranial imaging (RR 1.68, 1.09-2.59) were confirmed as risk factors for seizures at any time. For seizures occurring after admission, only pneumococcal meningitis (RR 1.92, 1.12-3.29) remained significant. Seizures at any time were also associated with in-hospital mortality (RR 3.26, 1.83-5.80) and unfavourable outcome (RR 1.23, 1.00-1.52) in this cohort., Conclusions: Pneumococcal aetiology, immunocompromise and abnormal cranial imaging were risk factors for seizures in CABM. Seizures were strongly associated with mortality and unfavourable outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Campylobacter concisus has been associated with prolonged mild diarrhoea, but investigations regarding the efficacy of antimicrobial treatment have not been reported previously. We initiated a phase 3, single-centre, randomized, double-blinded, placebo-controlled study comparing the efficacy of 500 mg once-daily dose of azithromycin with a 500 mg once-daily dose of placebo for three days, for the treatment of C. concisus diarrhoea in adult patients with a follow-up period of ten days. If symptoms persisted at day ten, the patient was offered cross-over study treatment of three days and another ten-day follow-up period. The primary efficacy endpoint was the clinical response, defined as time to cessation of diarrhoea (<3 stools/day or reversal of accompanying symptoms). Our estimated sample size was 100 patients. We investigated a total of 10,036 diarrheic stool samples from 7,089 adult patients. Five-hundred and eighty-eight C. concisus positive patients were assessed for eligibility, of which 559 were excluded prior to randomization. The three main reasons for exclusion were duration of diarrhoea longer than 21 days (n = 124), previous antibiotic treatment (n = 113), and co-pathogens in stools (n = 87). Therefore, 24 patients completed the trial with either azithromycin (n = 12) or placebo (n = 12). Both groups presented symptoms of mild, prolonged diarrhoea with a mean duration of 18 days (95% CI: 16-19). One person in the azithromycin group and four from the placebo group chose to continue with crossover medication after the initial ten-day period. In the azithromycin group, there was a mean of seven days (95% CI: 5-9) to clinical cure and for the placebo group it was ten days (95% CI: 6-14) (OR-3 (95% CI: -7-1). We observed no differences in all examined outcomes between azithromycin treatment and placebo. However, due to unforeseen recruitment difficulties we did not reach our estimated sample size of 100 patients and statistical power to conclude on an effect of azithromycin treatment was not obtained., Trial Registration: Clinicaltrials.gov identifier: NCT01531218., Competing Interests: The authors have declared that no competing interests exist.

Background: Community-acquired bacterial meningitis (CABM) is a life-threatening disease and timing of antibiotic therapy remains crucial. We aimed to analyse the impact of antibiotic timing on the outcome of CABM in a contemporary cohort., Methods: We conducted a population-based cohort study based on chart reviews of all adult cases (>16 years of age) of CABM in North Denmark from 1998 to 2014 excluding patients given pre-hospital parenteral antibiotics. We used modified Poisson regression analyses to compute the adjusted risk ratio (adj. RR) with 95 % confidence intervals (CIs) for in-hospital mortality and unfavourable outcome at discharge by time after arrival to hospital to adequate antibiotic therapy., Results: We identified 195 adults with CABM of whom 173 patients were eligible for further analyses. The median door-to-antibiotic time was 2.0 h (interquartile range (IQR) 1.0-5.5). We observed increased adjusted risk ratios for in-hospital mortality of 1.6 (95 % CI 0.8-3.2) and an unfavourable outcome at discharge of 1.5 (95 % CI 1.0-2.2, p = 0.03) when treatment delays exceeded 6 h versus treatment within 2 h of admission. These findings corresponded to adjusted risk ratios of in-hospital mortality of 1.1 per hour of delay (95 % CI 0.8-1.5) and an unfavourable outcome at discharge of 1.1 per hour of delay (95 % CI 1.0-1.3) within the first 6 h of admission. Some patients (31 %) were diagnosed after admission and had more delays in antibiotic therapy and correspondingly increased in-hospital mortality (30 vs 14 %, p = 0.01) and unfavourable outcome (62 vs 37 %, p = 0.002)., Conclusions: Delay in antibiotic therapy was associated with unfavourable outcome at discharge.

A healthy Danish man presented with infected prepatellar bursitis 8 months after being involved in a car accident in Malaysia resulting in exposure of a laceration of his knee to stagnant water. Tissue samples grew Burkholderia pseudomallei and diagnostic work up revealed no secondary foci. The patient was successfully treated with surgical debridement and 3 months of oral trimethoprim-sulfamethoxazole. At 6 months follow-up the patient was without relapse., (2015 BMJ Publishing Group Ltd.)