Evaluation of the clinical relevance of the Biofire© FilmArray pneumonia panel among hospitalized patients.

PURPOSE: Panel PCR tests provide rapid pathogen identification. However, their diagnostic performance is unclear. We assessed the performance of the Biofire© FilmArray pneumonia (PN)-panel against standard culture in broncho-alveolar lavage (BAL) samples. METHODS: Setting: University Hospital Basel (February 2019 to July 2020), including hospitalized patients with a BAL (± pneumonia). We determined sensitivity and specificity of the PN-panel against standard culture. Using univariate logistic regression, we calculated odds ratios (OR) for pneumonia according to PN-panel and culture status, stratifying by chronic pulmonary disease. We calculated ORs for pneumonia for different pathogens to estimate the clinical relevance. RESULTS: We included 840 adult patients, 60% were males, median age was 68 years, 35% had chronic pulmonary disease, 21% had pneumonia, and 36% had recent antibiotic use. In 1078 BAL samples, bacterial pathogens were detected in 36% and 16% with PN-panel and culture, respectively. The overall sensitivity and specificity of the PN-panel was high, whereas the positive predictive value was low. The OR of pneumonia was 1.1 (95% CI 0.7-1.6) for PN-panel-positive only; 2.6 (95% CI 1.3-5.3) for culture-positive only, and 1.6 (95% CI 1.0-2.4) for PN-panel and culture-positive. The detection rate of Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis in the PN-panel was high but not associated with pneumonia. CONCLUSION: While sensitivity and specificity of PN-panel are high compared to culture, pathogen detection did not correlate well with a pneumonia diagnosis. Patients with culture-positive BAL had the highest OR for pneumonia-thus the impact of the PN-panel on clinical management needs further evaluation in randomized controlled trials.

SARS-CoV-2 outbreak in a tri-national urban area is dominated by a B.1 lineage variant linked to a mass gathering event.

The first case of SARS-CoV-2 in Basel, Switzerland was detected on February 26th 2020. We present a phylogenetic study to explore viral introduction and evolution during the exponential early phase of the local COVID-19 outbreak from February 26th until March 23rd. We sequenced SARS-CoV-2 naso-oropharyngeal swabs from 746 positive tests that were performed at the University Hospital Basel during the study period. We successfully generated 468 high quality genomes from unique patients and called variants with our COVID-19 Pipeline (COVGAP), and analysed viral genetic diversity using PANGOLIN taxonomic lineages. To identify introduction and dissemination events we incorporated global SARS-CoV-2 genomes and inferred a time-calibrated phylogeny. Epidemiological data from patient questionnaires was used to facilitate the interpretation of phylogenetic observations. The early outbreak in Basel was dominated by lineage B.1 (83·6%), detected first on March 2nd, although the first sample identified belonged to B.1.1. Within B.1, 68·2% of our samples fall within a clade defined by the SNP C15324T ('Basel cluster'), including 157 identical sequences at the root of the 'Basel cluster', some of which we can specifically trace to regional spreading events. We infer the origin of B.1-C15324T to mid-February in our tri-national region. The other genomes map broadly over the global phylogenetic tree, showing several introduction events from and/or dissemination to other regions of the world via travellers. Family transmissions can also be traced in our data. A single lineage variant dominated the outbreak in the Basel area while other lineages, such as the first (B.1.1), did not propagate. A mass gathering event was the predominant initial source of cases, with travel returners and family transmissions to a lesser extent. We highlight the importance of adding specific questions to epidemiological questionnaires, to obtain data on attendance of large gatherings and their locations, as well as travel history, to effectively identify routes of transmissions in up-coming outbreaks. This phylogenetic analysis in concert with epidemiological and contact tracing data, allows connection and interpretation of events, and can inform public health interventions. Trial Registration: ClinicalTrials.gov NCT04351503.

Fever of Unknown Origin and Incidence of Cancer.

BACKGROUND: Diagnostic tools for determining causes of fever of unknown origin (FUO) have improved over time. We examined if cancer incidence among these patients changed over a 20-year period. METHODS: Population-based cohort study using nationwide Danish registries. We identified individuals diagnosed with FUO (1998-2017) to quantify their excess risk of cancer compared with the general population. Follow-up for cancer started 1 month after FUO. We computed absolute risks and standardized incidence ratios (SIRs) of cancer, and mortality rate ratios adjusted for age, sex, and cancer stage. RESULTS: Among 6620 patients with FUO (46.9% male; median age: 39 years), 343 were diagnosed with cancer (median follow-up: 6.5 years). The 1- to <12-month risk was 1.2%, and the SIR was 2.3 (95% CI, 1.8-2.9). The increased 1- to <12-month SIR was mainly due to an excess of Hodgkin lymphoma (SIR = 41.7) non-Hodgkin lymphoma (SIR = 16.1), myelodysplastic syndrome/chronic myeloproliferative diseases (SIR = 6.0), lower gastrointestinal cancer (SIR = 3.3), and urinary tract cancer (SIR = 2.9). Beyond 1-year follow-up, malignant melanoma, hepatobiliary tract/pancreatic cancer, and brain/CNS/eye cancer were diagnosed more often than expected. The 1- to <12-month cancer SIR attenuated over time, and for the 2013-2017 period we found no excess risk. Patients diagnosed with cancer ≤1 year after FUO had similar mortality to cancer patients without this diagnosis. CONCLUSIONS: Patients with FUO have a higher 1- <12-month cancer SIR; thereafter, the incidence for most cancers equals that of the general population. Decreasing SIRs over time suggests improvements in the initial diagnostic workup for FUO.

Epidemiology and precision of SARS-CoV-2 detection following lockdown and relaxation measures.

OBJECTIVES: Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is key to the clinical and epidemiological assessment of CoVID-19. We cross-validated manual and automated high-throughput testing for SARS-CoV-2-RNA, evaluated SARS-CoV-2 loads in nasopharyngeal-oropharyngeal swabs (NOPS), lower respiratory fluids, and plasma, and analyzed detection rates after lockdown and relaxation measures. METHODS: Basel-S-gene, Roche-E-gene, and Roche-cobas®6800-Target1 and Target2 were prospectively validated in 1344 NOPS submitted during the first pandemic peak (Week 13). Follow-up cohort (FUP) 1, 2, and 3 comprised 10,999, 10,147, and 19,389 NOPS submitted during a 10-week period until Weeks 23, 33, and 43, respectively. RESULTS: Concordant results were obtained in 1308 cases (97%), including 97 (9%) SARS-CoV-2-positives showing high quantitative correlations (Spearman's r > .95; p < .001) for all assays and high precision by Bland-Altman analysis. Discordant samples (N = 36, 3%) had significantly lower SARS-CoV-2 loads (p < .001). Following lockdown, detection rates declined to <1% in FUP-1, reducing single-test positive predictive values from 99.3% to 85.1%. Following relaxation, rates flared up to 4% and 12% in FUP-2 and -3, but infected patients were younger than during lockdown (34 vs. 52 years, p < .001). In 261 patients providing 936 NOPS, SARS-CoV-2 loads declined by three orders of magnitude within 10 days postdiagnosis (p < .001). SARS-CoV-2 loads in NOPS correlated with those in time-matched lower respiratory fluids or in plasma but remained detectable in some cases with negative follow-up NOPS, respectively. CONCLUSION: Manual and automated assays significantly correlated qualitatively and quantitatively. Following a successful lockdown, declining positive predictive values require independent dual-target confirmation for reliable assessment. Confirmatory and quantitative follow-up testing should be obtained within <5 days and consider lower respiratory fluids in symptomatic patients with SARS-CoV-2-negative NOPS.

Bilateral acute renal cortical necrosis after a dog bite: case report.

BACKGROUND: Capnocytophaga canimorsus is a Gram-negative capnophilic rod and part of dogs/cats' normal oral flora. It can be transmitted by bites, scratches, or even by contact of saliva with injured skin. Asplenic patients and patients with alcohol abuse are at particular risk for fulminant C. canimorsus sepsis. However, also immunocompetent patients can have a severe or even fatal infection. This is the first case of a severe C. canimorsus infection in an immunocompromised host complicated by acute renal cortical necrosis with a "reverse rim sign" in contrast-enhanced computed tomography on hospital admission. CASE PRESENTATION: We report the case of a 44-year functionally asplenic patient after an allogeneic stem cell transplantation, who presented with septic shock after a minor dog bite injury 4 days prior. Because of abdominal complaints, epigastric pain with local peritonism, and radiological gallbladder wall thickening, an abdominal focus was suspected after the initial work-up. The patient underwent emergent open cholecystectomy, but the clinical suspicion of abdominal infection was not confirmed. Septic shock was further complicated by cardiomyopathy and disseminated intravascular coagulation. As a causative pathogen, C. canimorsus could be isolated. The clinical course was complicated by permanent hemodialysis and extensive acral necrosis requiring amputation of several fingers and both thighs. CONCLUSION: We present a severe case of a C. canimorsus infection in a functionally asplenic patient after a minor dog bite. The clinical course was complicated by septic shock, disseminated intravascular coagulation, and the need for multiple amputations. In addition, the rare form of acute renal failure - bilateral acute renal cortical necrosis - was visible as "reverse rim sign" on computed tomography scan. This case is an example of the potential disastrous consequences when omitting pre-emptive antibiotic therapy in wounds inflicted by cats and dogs, particularly in asplenic patients.

Cutibacterium modestum and "Propionibacterium humerusii" represent the same species that is commonly misidentified as Cutibacterium acnes.

Cutibacterium spp. play an increasing role in soft tissue and implant-associated infections. We isolated a novel Cutibacterium spp. from an implant and investigated this isolate using multiple identification approaches. Correct identification was hampered by inconsistent reference data. The isolate was characterised using conventional methods such as Gram stain, MALDI-TOF MS, and antimicrobial susceptibility testing against multiple antimicrobials. Partial 16S rRNA gene sequencing and whole genome sequencing were also performed. In addition, we summarised the available published sequence data and compared prior data to our strain. Conventional phenotypic identification of our isolate resulted in Cutibacterium spp. After analysis of 16S rRNA gene and genome sequences, our isolate was identified as C. modestum, a very recently described species. The 16S rRNA gene analysis was hampered by three incorrect nucleotides within the 16S rRNA gene reference sequence of C. modestum M12T (accession no. LC466959). We also clearly demonstrate that this novel species is identical to tentatively named "Propionibacterium humerusii". Retrospective data analysis indicates that C. modestum is a clinically important Cutibacterium species often misidentified as C. acnes. The isolation and identification of Cutibacterium spp. is still a challenge. The correct description of very recently named C. modestum and the availability of a correct 16S rRNA sequence of the type strain may help to clarify the taxonomical uncertainty concerning "P. humerusii". The novel C. modestum is an additional, clinically important species within the genus Cutibacterium and may represent a new member of the human skin microbiome.

Splanchnic venous thrombosis is a marker of cancer and a prognostic factor for cancer survival.

It is unknown if splanchnic venous thrombosis (SVT) is a marker of occult cancer and a prognostic factor for cancer survival. Using Danish medical registries, we conducted a nationwide cohort study including all patients with first-time SVT (n = 1191) between 1994 and 2011. We followed the patients for subsequent cancer diagnoses and calculated absolute risks and standardized incidence ratios (SIRs). We formed a matched comparison cohort of cancer patients without SVT, and assessed the prognostic impact of SVT on cancer survival by applying the Kaplan-Meier method and Cox regression. We followed the patients for a median of 1.6 years, and found that SVT was a marker of occult cancer. The 3-month cancer risk was 8.0% and the SIR was 33 (95% confidence interval, 27-40), compared with the general population. Increased risk was mainly found for liver cancer (risk = 3.5%; SIR = 1805), pancreatic cancer (risk = 1.5%; SIR = 256), and myeloproliferative neoplasms (risk = 0.7%; SIR = 764). The overall SIR remained increased twofold after 1 or more years of follow-up. SVT was also a prognostic factor for survival in patients with liver and pancreatic cancer. The clinical impact may be a more thorough diagnostic work-up in patients presenting with SVT.

Repeated doxycycline treatment among patients with neuroborreliosis: a nationwide, population-based, registry-based, matched cohort study.

OBJECTIVES: To investigate receipt of antibiotics among patients with neuroborreliosis after initial antibiotic treatment, likely attributable to posttreatment symptoms. METHODS: We performed a nationwide, matched, population-based cohort study in Denmark (2009-2021). We included all Danish patients with neuroborreliosis, i.e. a positive Borrelia burgdorferi intrathecal antibody index test and a cerebrospinal fluid leukocyte count ≥10 × 106/l, and initially treated with doxycycline. To form a comparison cohort, we randomly extracted individuals from the general population matched 1:10 to patients with neuroborreliosis on date of birth and sex. The main outcome was receipt of doxycycline, and the secondary outcome was receipt of phenoxymethylpenicillin. We calculated short-term (<1 year) and long-term (≥1 year) hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: We included 463 patients with neuroborreliosis and 2,315 comparison cohort members. Compared with the comparison cohort members, patients with neuroborreliosis initially treated with doxycycline had increased receipt of additional doxycycline within 1 year (HR: 38.6, 95%CI: 17.5-85.0) and ≥1 years (HR: 3.5, 95%CI: 1.9-6.3). Compared with comparison cohort members, patients with neuroborreliosis had no increased receipt of phenoxymethylpenicillin (<1 year HR 1.0, 95%CI: 0.7-1.3; ≥1 years HR 1.2, 95%CI: 0.9-1.5). CONCLUSIONS: After initial antibiotic treatment, patients with neuroborreliosis have increased receipt of doxycycline particularly within one year after initial antibiotic therapy but also subsequently. The lack of increased receipt of phenoxymethylpenicillin suggests that the receipt of doxycycline was not merely due to differences in healthcare-seeking behaviour, increased risk of early Lyme borreliosis due to exposure, or differences in antibacterial usage in general.

Obtainment of prescribed analgesics among patients with Lyme neuroborreliosis; a nationwide, population-based matched cohort study.

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.

Healthcare-seeking behavior preceding diagnosis of Lyme neuroborreliosis: population-based nationwide matched nested case-control study.

OBJECTIVES: To identify diagnostic opportunities, we investigated healthcare-seeking behavior among patients with Lyme neuroborreliosis (LNB) within 28 weeks before diagnosis. METHODS: We conducted a population-based, nationwide matched nested case-control study (Denmark, 2009-2021). As cases, we included all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis). We randomly selected controls from the general population, matched 10:1 on date of birth and sex. Exposures were assignment of diagnostic codes for symptoms, contact to medical specialties, medical wandering, and undergoing diagnostic procedures. We calculated the weekly and 3-months proportion of individuals with exposures and calculated absolute risk differences with corresponding 95% confidence intervals (95%CI). RESULTS: We included 1,056 cases with LNB and 10,560 controls. Within 3 months before diagnosis, the most frequent assigned symptoms were pain (difference: 13.0%, 95%CI: 10.9-15.1). Cases with LNB exhibited increased contact to most specialties, particularly general practitioners (difference: 48.7%, 95%CI: 46.0-51.4), neurology (difference: 14.3%, 95%CI: 11.7-16.8), and internal medicine (difference: 11.1%, 95%CI: 8.7-13.5), and medical wandering (difference: 17.1%, 95%CI: 14.3-20.0). Common diagnostic procedures included imaging of the brain (difference: 10.2, 95%CI: 8.3-12.1), the spine (difference: 8.8%, 85%CI: 7.0-10.6), and the abdomen (difference: 7.2%, 95%CI: 5.4-9.1). The increase in healthcare-seeking behavior was observed up to 12 weeks preceding diagnosis. CONCLUSIONS: Pain appears to be an ambiguous symptom of LNB, potentially contributing to delays in establishing the correct diagnosis. It would be difficult to identify patients with LNB more effectively as the increased healthcare-seeking behavior preceding diagnosis is distributed across many medical specialties.

Risk of haematologic cancers among individuals tested for Borrelia burgdorferi antibodies, and Borrelia burgdorferi seropositive individuals: a nationwide population-based matched cohort study.

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.

Risk of cardiac conduction disorders, and pacemaker implantations among individuals tested for serum Borrelia burgdorferi antibodies, a nationwide, matched, population-based cohort study.

OBJECTIVES: To investigate the short- and long-term risks of atrioventricular block and other cardiac conduction disorders associated with being tested for Borrelia burgdorferi (Bb) antibodies or Bb seropositivity as measures of confounding by indication and Bb infection, respectively. METHODS: We performed a nationwide population-based matched cohort study (Denmark, 1993-2021). We included 52 200 Bb-seropositive individuals (stratified as only Bb-IgM-seropositive [n = 26 103], only Bb-IgG-seropositive [n = 18 698], and Bb-IgM-and-IgG-seropositive [n = 7399]) and two age- and sex-matched comparison cohorts: 104 400 Bb-seronegative individuals and 261 000 population controls. We investigated the risk associated with being tested for serum Bb antibodies and being Bb seropositive. Outcomes were atrioventricular block and other conduction disorders. We calculated short-term odds ratios (aOR) (within 1 month), and long-term hazard ratios (aHR) (after 1 month) adjusted for age, sex, diabetes, chronic heart failure, and kidney disease with 95% CI. RESULTS: Compared with population controls, individuals tested for Bb antibodies had increased short- and long-term risks of atrioventricular block (aOR 47.9, 95% CI: 30.0-76.7, aHR 1.3, 95% CI:1.2-1.3), and other conduction disorders (aOR 18.2, 95% CI: 10.1-32.8, aHR 1.2, 95% CI: 1.1-1.4). Compared with Bb-seronegative individuals, only Bb-IgM-and-IgG-seropositive individuals had increased short-term risk of atrioventricular block (aOR: 2.1, 95% CI: 1.5-3.1). DISCUSSION: The results suggest that Bb antibody testing is included in the diagnostic work-up of conduction disorders. Finally, that Bb seropositivity is not associated with other conduction disorders than atrioventricular block or with increased long-term risk of conduction disorders.

Risk of heart failure among individuals tested for Borrelia burgdorferi sensu lato antibodies, and serum Borrelia burgdorferi sensu lato seropositive individuals; a nationwide population-based, registry-based matched cohort study.

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.

A rare Danish case of Yersinia pseudotuberculosis pyogenic liver abscess.

Yersinia pseudotuberculosis is a rare Gram-negative bacillus that cause enterocolitis and terminal ileitis. We report the first Danish case with Y. pseudotuberculosis multiple pyogenic liver abscess presenting with 6 weeks intermittently fever, fatigue, and weight loss. The patient was successfully treated with percutaneous drainage and intravenous piperacillin/tazobactam and oral ciprofloxacin.

Fever of Unknown Origin: A Validation Study of Danish ICD-10 Diagnosis Codes.

Background: Real-world data in form of routinely collected clinical data are a valuable resource for epidemiological research in infectious disease. We examined the validity of a discharge diagnosis of fever of unknown origin from hospital discharge registries. Methods: We identified patients with a first in- or outpatient diagnosis (primary or secondary) of fever of unknown origin (ICD-10 code R50.0; R50.8, R50.9) recorded in the Danish National Patient Registry (DNPR) between 2010 and 2017 in the North Denmark Region. We based the validation cohort on a mix of patients diagnosed at a highly specialized university department of infectious diseases (n=100), other internal medicine departments (n=50), and patients diagnosed at a regional non-university hospital (n=50). We estimate positive predictive value (PPV) of diagnosis for fever of unknown origin using medical records as reference. Results: The PPV of a diagnosis of fever of unknown origin for patients diagnosed at the infectious disease department was 61% (95% CI: 51-71%). For other internal medicine departments, it was 14% (95% CI: 6-27%), and for the non-university hospital it was 16% (95% CI: 7-29%). To achieve higher PPVs, we excluded immunocompromised patients, patients who were diagnosed with infection, cancer or rheumatic disease within 7 days after admission, and/or patients with a short hospital stay (maximum 3 days) and no subsequent hospital contact within 1 month. The PPV for diagnoses from the Department of Infectious Diseases improved to 82% (95% CI: 68-91%) for other internal medicine departments it improved to 31% (95% CI: 11-59%), and for the non-university hospital it improved to 36% (95% CI: 13-65%). Conclusion: We found that only diagnoses made in the Department of Infectious Diseases accurately identified fever of unknown origin, whereas diagnoses made in other units mainly covered infection-related fever, cancer-related fever, or short unspecific fever without further diagnostic work-up.

Direct antimicrobial resistance prediction from clinical MALDI-TOF mass spectra using machine learning.

Early use of effective antimicrobial treatments is critical for the outcome of infections and the prevention of treatment resistance. Antimicrobial resistance testing enables the selection of optimal antibiotic treatments, but current culture-based techniques can take up to 72 hours to generate results. We have developed a novel machine learning approach to predict antimicrobial resistance directly from matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectra profiles of clinical isolates. We trained calibrated classifiers on a newly created publicly available database of mass spectra profiles from the clinically most relevant isolates with linked antimicrobial susceptibility phenotypes. This dataset combines more than 300,000 mass spectra with more than 750,000 antimicrobial resistance phenotypes from four medical institutions. Validation on a panel of clinically important pathogens, including Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, resulting in areas under the receiver operating characteristic curve of 0.80, 0.74 and 0.74, respectively, demonstrated the potential of using machine learning to substantially accelerate antimicrobial resistance determination and change of clinical management. Furthermore, a retrospective clinical case study of 63 patients found that implementing this approach would have changed the clinical treatment in nine cases, which would have been beneficial in eight cases (89%). MALDI-TOF mass spectra-based machine learning may thus be an important new tool for treatment optimization and antibiotic stewardship.

Short-term and long-term risk of mortality and neurodevelopmental impairments after bacterial meningitis during infancy in children in Denmark and the Netherlands: a nationwide matched cohort study.

BACKGROUND: Few studies have reported the long-term consequences of bacterial meningitis during infancy, and studies that have been done usually do not include a comparison cohort. We aimed to assess short-term and long-term risk of mortality, neurodevelopmental impairment (NDI), and health-care use and household income in cohorts of children with and without a history of bacterial meningitis during infancy in Denmark and the Netherlands. METHODS: In this nationwide cohort study, infants with a history of bacterial meningitis before age 1 year were identified through the Danish Medical Birth Registry and Danish National Patient Registry using International Classification of Diseases (ICD)-10 codes and through the Netherlands Reference Laboratory for Bacterial Meningitis. Infants were matched (1:10) by sex and birth month and year to a comparison cohort of the general population without a history of bacterial meningitis. We analysed mortality using Cox proportional hazards regression. In Denmark, diagnoses of NDIs were based on ICD-10 codes; in the Netherlands, special educational needs were used as a functional NDI outcome. Risk ratios (RRs) of NDIs were estimated using modified Poisson regression. We also analysed long-term health-care use in Denmark and household income in both countries. All regression analyses were adjusted for sex and year of birth, and stratified by pathogen whenever sample size allowed. FINDINGS: We included 2216 children with a history of bacterial meningitis (570 [25·7%] in Denmark between Jan 1, 1997, and Dec 31, 2018, and 1646 [74·3%] in the Netherlands between Jan 1, 1995, and Dec 31, 2018), matched to 22 127 comparison cohort members. Median age at diagnosis was 2·8 months (IQR 0·4-7·1) in Denmark and 4·3 months (0·7-7·4) in the Netherlands. Mortality risks within 3 months after disease onset were 3·9% (95% CI 2·6-5·8%) in Denmark and 5·9% (4·7-7·0) in the Netherlands, compared with 0·0% (p<0·0001) and 0·1% (p<0·0001) in the comparison cohorts. Survivors had an increased risk of moderate or severe NDIs at age 10 years (RR 5·0 [95% CI 3·5-7·1] in Denmark and 4·9 [4·0-6·2] in the Netherlands) compared to children in the comparison cohort, particularly after pneumococcal and group B streptococcal meningitis. In Denmark, a history of bacterial meningitis was associated with increased health-care use in the 10 years following diagnosis (rate ratio 4·5 [95% CI 3·9-5·2] for outpatient visits and 4·1 [3·6-4·7] for hospital admissions). INTERPRETATION: Our study shows increased risk of mortality in the short and long term, a five times increase in risk of NDIs, and increased health-care use after bacterial meningitis during infancy. Together with context-specific incidence data, our results can advance pathogen-specific estimation of the meningitis burden and inform service provision at the individual and population level. FUNDING: Bill & Melinda Gates Foundation, the Stichting Remmert Adriaan Laan Fonds, and the Netherlands Organisation for Health Research and Development.

Temporal Changes, Patient Characteristics, and Mortality, According to Microbiological Cause of Infective Endocarditis: A Nationwide Study.

Background Monitoring of microbiological cause of infective endocarditis (IE) remains key in the understanding of IE; however, data from large, unselected cohorts are sparse. We aimed to examine temporal changes, patient characteristics, and in-hospital and long-term mortality, according to microbiological cause in patients with IE from 2010 to 2017. Methods and Results Linking Danish nationwide registries, we identified all patients with first-time IE. In-hospital and long-term mortality rates were assessed according to microbiological cause and compared using multivariable adjusted logistic regression analysis and Cox proportional hazard analysis, respectively. A total of 4123 patients were included. Staphylococcus aureus was the most frequent cause (28.1%), followed by Streptococcus species (26.0%), Enterococcus species (15.5%), coagulase-negative staphylococci (6.2%), and "other microbiological causes" (5.3%). Blood culture-negative IE was registered in 18.9%. The proportion of blood culture-negative IE declined during the study period, whereas no significant changes were seen for any microbiological cause. Patients with Enterococcus species were older and more often had a prosthetic heart valve compared with other causes. For Streptococcus species IE, in-hospital and long-term mortality (median follow-up, 2.3 years) were 11.1% and 58.5%, respectively. Compared with Streptococcus species IE, the following causes were associated with a higher in-hospital mortality: S aureus IE (odds ratio [OR], 3.48 [95% CI, 2.74-4.42]), Enterococcus species IE (OR, 1.48 [95% CI, 1.11-1.97]), coagulase-negative staphylococci IE (OR, 1.79 [95% CI, 1.21-2.65]), "other microbiological cause" (OR, 1.47 [95% CI, 0.95-2.27]), and blood culture-negative IE (OR, 1.99 [95% CI, 1.52-2.61]); and the following causes were associated with higher mortality following discharge (median follow-up, 2.9 years): S aureus IE (hazard ratio [HR], 1.39 [95% CI, 1.19-1.62]), Enterococcus species IE (HR, 1.31 [95% CI, 1.11-1.54]), coagulase-negative staphylococci IE (HR, 1.07 [95% CI, 0.85-1.36]), "other microbiological cause" (HR, 1.45 [95% CI, 1.13-1.85]), and blood culture-negative IE (HR, 1.05 [95% CI, 0.89-1.25]). Conclusions This nationwide study showed that S aureus was the most frequent microbiological cause of IE, followed by Streptococcus species and Enterococcus species. Patients with S aureus IE had the highest in-hospital mortality.

Diagnostic challenges within the Bacillus cereus-group: finding the beast without teeth.

The Bacillus cereus-group (B. cereus sensu lato) includes common, usually avirulent species, often considered contaminants of patient samples in routine microbiological diagnostics, as well as the highly virulent B. anthracis. Here we describe 16 isolates from 15 patients, identified as B. cereus-group using a MALDI-TOF MS standard database. Whole genome sequencing (WGS) analysis identified five of the isolates as B. anthracis species not carrying the typical virulence plasmids pXO1 and pXO2, four isolates as B. paranthracis, three as B. cereus sensu stricto, two as B. thuringiensis, one as B. mobilis, and one isolate represents a previously undefined species of Bacillus (B. basilensis sp. nov.). More detailed analysis using alternative MALDI-TOF MS databases, biochemical phenotyping, and diagnostic PCRs, gave further conflicting species results. These cases highlight the difficulties in identifying avirulent B. anthracis within the B. cereus-group using standard methods. WGS and alternative MALDI-TOF MS databases offer more accurate species identification, but so far are not routinely applied. We discuss the diagnostic resolution and discrepancies of various identification methods.

Prevalence and Mortality of Infective Endocarditis in Community-Acquired and Healthcare-Associated Staphylococcus aureus Bacteremia: A Danish Nationwide Registry-Based Cohort Study.

Background: Staphylococcus aureus bacteremia (SAB) can be community-acquired or healthcare-associated, and prior small studies have suggested that this mode of acquisition impacts the subsequent prevalence of infective endocarditis (IE) and patient outcomes. Methods: First-time SAB was identified from 2010 to 2018 using Danish nationwide registries and categorized into community-acquired (no healthcare contact within 30 days) or healthcare-associated (SAB >48 hours of hospital admission, hospitalization within 30 days, or outpatient hemodialysis). Prevalence of IE (defined from hospital codes) was compared between groups using multivariable adjusted logistic regression analysis. One-year mortality of S aureus IE (SAIE) was compared between groups using multivariable adjusted Cox proportional hazard analysis. Results: We identified 5549 patients with community-acquired SAB and 7491 with healthcare-associated SAB. The prevalence of IE was 12.1% for community-acquired and 6.6% for healthcare-associated SAB. Community-acquired SAB was associated with a higher odds of IE as compared with healthcare-associated SAB (odds ratio, 2.12 [95% confidence interval {CI}, 1.86-2.41]). No difference in mortality was observed with 0-40 days of follow-up for community-acquired SAIE as compared with healthcare-associated SAIE (HR, 1.07 [95% CI, .83-1.37]), while with 41-365 days of follow-up, community-acquired SAIE was associated with a lower mortality (HR, 0.71 [95% CI, .53-.95]). Conclusions: Community-acquired SAB was associated with twice the odds for IE, as compared with healthcare-associated SAB. We identified no significant difference in short-term mortality between community-acquired and healthcare-associated SAIE. Beyond 40 days of survival, community-acquired SAIE was associated with a lower mortality.