Comparative epidemiology of bacteraemia in two ageing populations: Singapore and Denmark.

Burden of bacteraemia is rising due to increased average life expectancy in developed countries. This study aimed to compare the epidemiology and outcomes of bacteraemia in two similarly ageing populations with different ethnicities in Singapore and Denmark. Historical cohorts from the second largest acute-care hospital in Singapore and in the hospitals of two Danish regions included patients aged 15 and above who were admitted from 1 January 2006 to 31 December 2016 with at least 1 day of hospital stay and a pathogenic organism identified. Among 13 144 and 39 073 bacteraemia patients from Singapore and Denmark, similar 30-day mortality rates (16.5%; 20.3%), length of hospital stay (median 14 (IQR: 9-28) days; 11 (6-21)), and admission rate to ICU (15.5%; 15.6%) were observed, respectively. Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus ranked among the top four in both countries. However, Singaporeans had a higher proportion of patients with diabetes (46.8%) and renal disease (29.5%) than the Danes (28.0% and 13.7%, respectively), whilst the Danes had a higher proportion of patients with chronic pulmonary disease (18.0%) and malignancy (35.3%) than Singaporeans (9.7% and 16.2%, respectively). Our study showed that top four causative organisms and clinical outcomes were similar between the two cohorts despite pre-existing comorbidities differed.

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.

Detection of infections by computerized capture of peaks in longitudinally measured C-reactive protein levels.

We developed four algorithms for the automatic capture of C-reactive protein (CRP) peaks in 296 adult patients with acute myeloid leukemia who had bloodstream infection (BSI) episodes, negative blood cultures (BCs) or possible infections where no BCs were performed. The algorithms detected CRP peaks for 418-446 of the 586 documented BSI episodes (71.3-76.1%) and 2714-3118 of the 4382 negative BCs (61.9-71.2%). The four algorithms captured 382-789 CRP peaks in which there were neither BSI episodes nor negative BCs. We conclude that automatic capture of CRP peaks is a tool for the monitoring of BSI episodes and possibly other infections in patients with acute myeloid leukemia.

Discriminating between Lyme neuroborreliosis and other central nervous system infections by use of biomarkers CXCL13 and IL-6.

CXCL13 in cerebrospinal fluid has gradually become an established biomarker for Lyme neuroborreliosis (LNB), however the diagnostic performance of CXCL13 may be improved by the addition of IL-6, a non-specific infection biomarker. The aim of this study was to measure the concentrations of CXCL13 and IL-6 in cerebrospinal fluid, in the attempt to evaluate the diagnostic performance of these two biomarkers, in the differentiation between definite and possible LNB, as well as between LNB and other neuroinfections. This study used a cross-sectional design to quantify the levels of CXCL13 and IL-6 in cerebrospinal fluid (CSF) specimens from consecutive patients examined for central nervous system (CNS) infections at Lillebaelt Hospital in the Region of Southern Denmark. CXCL13 and IL-6 were measured simultaneously using the Bio-Plex 200 multiplex Cytokine Immunoassay System (Bio-Rad). Based on clinical and paraclinical findings, we grouped patients into six separate groups: definite LNB, possible LNB, Viral CNS infection, non-Borrelia Bacterial CNS infection, Other CNS disease (with pleocytosis) and Negative (without pleocytosis). A combined interpretation of four variables (leukocyte cell counts, protein concentration, CXCL13 and IL-6 concentrations in CSF) is presented using principal component cluster analysis. We included by chart review 390 patients discharged with definite LNB (n = 31), possible LNB (n = 10), confirmed Viral or non-Borrelia Bacterial CNS infection (n = 34), Other CNS disease (n = 58), and Negative (n = 257) for CXCL13 and IL-6 analysis. Principal component analysis (PCA) revealed three distinct clusters based on leukocyte cell counts, protein concentration, CXCL13 and IL-6 concentrations in CSF from 380 included patients (10 possible LNB patients excluded). The clusters clearly differentiate the groups: definite LNB, non-Borrelia Bacterial CNS infection and Negative (without pleocytosis). A receiver operating characteristic (ROC) curve comparing LNB patients (n = 31) and all non-LNB conditions with CSF pleocytosis (n = 99) indicated an optimal CXCL13 cut-off value of 50.7 pg/mL, resulting in a sensitivity and a specificity of 93.6 and 91.1%, respectively. The ROC analysis comparing patients with confirmed non-LNB CNS infection (n = 34) and all others with CSF pleocytosis (n = 97) resulted in an optimal IL-6 cut-off value of 111.5 pg/mL, yielding a sensitivity and a specificity of 78.8% and 82.5% respectively. Of the ten possible LNB patients, three cases (with CXCL13 levels above cut-off) fall within the LNB cluster, and one case is just outside, providing some laboratory support for the diagnosis of LNB. The remaining six possible LNB patients (with CXCL13 levels below the 50.7 cut-off) had little support for the diagnosis of LNB in the PCA-plot. The results of this study confirm that CXCL13 is a valuable supplement for diagnosis of LNB, and that the combination of CXCL13 and IL-6 may be used to differentiate cases of LNB from other CNS infections. Furthermore, IL-6 can be of differential diagnostic value when evaluating patients with possible LNB.

Impact of C-reactive protein and albumin levels on short, medium, and long term mortality in patients with diffuse large B-cell lymphoma.

Objectives and study design: In this population-based study of 602 patients, we amended C-reactive protein (CRP) and plasma albumin (PA) levels around the diagnosis of diffuse large B-cell lymphoma (DLBCL) to the International Prognostic Index (IPI) and assessed 0-90, 91-365, and +365-day survival.Results: The CRP did not contribute to the IPI's prognostic or discriminatory ability, regardless of time period, particularly not in models with PA. In contrast, the PA was an important contributor, especially in the 0-90 day period, but also up to one year after the diagnosis. For day 0-90, the model with the IPI only had an Area Under the Receiver Operating Characteristics (AUROC) of 0.742, whereas the IPI with PA as a continuous variable rendered an AUROC of 0.841. Especially the lower PA quartile (18-32 g/L) contributed to the worse prognosis.Conclusions: The amendment of PA to the IPI may significantly improve the short-term prognostic and discriminative ability.Key messagesThe amendment of the plasma albumin (PA) level to the International Prognostic Index significantly improved the prediction of mortality up to one year after the diagnosis of diffuse large B-cell lymphoma.It was especially the lower quartile of the PA level (18-32 g/L) that contributed to the worse prognosis.

Longitudinal trajectory patterns of plasma albumin and C-reactive protein levels around diagnosis, relapse, bacteraemia, and death of acute myeloid leukaemia patients.

BACKGROUND: No study has evaluated C-reactive protein (CRP) and plasma albumin (PA) levels longitudinally in patients with acute myeloid leukaemia (AML). METHODS: We studied defined events in 818 adult patients with AML in relation to 60,209 CRP and PA measures. We investigated correlations between CRP and PA levels and daily CRP and PA levels in relation to AML diagnosis, AML relapse, or bacteraemia (all ±30 days), and death (─30-0 days). RESULTS: On the AML diagnosis date (D0), CRP levels increased with higher WHO performance score (PS), e.g. patients with PS 3/4 had 68.1 mg/L higher CRP compared to patients with PS 0, adjusted for relevant covariates. On D0, the PA level declined with increasing PS, e.g. PS 3/4 had 7.54 g/L lower adjusted PA compared to PS 0. CRP and PA levels were inversely correlated for the PA interval 25-55 g/L (R = - 0.51, p < 10-5), but not for ≤24 g/L (R = 0.01, p = 0.57). CRP increases and PA decreases were seen prior to bacteraemia and death, whereas no changes occurred up to AML diagnosis or relapse. CRP increases and PA decreases were also found frequently in individuals, unrelated to a pre-specified event. CONCLUSIONS: PA decrease is an important biomarker for imminent bacteraemia in adult patients with AML.

Association between risk factors and testicular microlithiasis.

BACKGROUND: Testicular microlithiasis and its clinical significance are not fully understood. Testicular microlithiasis and risk factors have been associated with testicular cancer. The role of testicular microlithiasis is investigated. PURPOSE: To investigate the association between testicular microlithiasis and socioeconomic and other pre-diagnostic factors. MATERIAL AND METHODS: All men who had a scrotal ultrasound examination at the Department of Radiology, Vejle Hospital, during 2001-2013 were included. They were categorized as patients with and without testicular microlithiasis and compared with pre-diagnostic data from a nationwide registry. A total of 2404 men (283 [11.8%] with testicular microlithiasis and 2121 [88.2%] without testicular microlithiasis) were included. The association between testicular microlithiasis and pre-diagnostic conditions was investigated with logistic regression. RESULTS: Overall, we found no statistically significant differences in demographics, socioeconomic characteristics, or testicular diseases in men with and without testicular microlithiasis. Men with testicular microlithiasis had more often been treated for infertility (odds ratio [OR] 2.09, 95% confidence interval [CI] 0.84-5.24) and testicular torsion (OR 1.58, 95% CI 0.34-7.36) compared to men without testicular microlithiasis. We found no association between sexually transmitted diseases and testicular microlithiasis. CONCLUSION: Treatment for infertility and torsion was non-significantly associated with testicular microlithiasis and no other association was found. These data do not suggest early exposure is related to testicular microlithiasis.

Danish Childhood Cancer Registry.

AIM OF DATABASE: The overall aim is to monitor the quality of childhood cancer care in Denmark; to register late effects of treatment; to analyze complications of permanent central venous catheters (CVCs); to study blood stream infections in children with cancer; and to study acute toxicity of high-dose methotrexate infusions in children with leukemia. STUDY POPULATION: All children below 15 years of age at diagnosis living in Denmark diagnosed after January 1, 1985 according to the International Classification of Diseases 10, including diagnoses DC00-DD48. MAIN VARIABLES: Cancer type, extent of disease, treatment, participation in international studies, recurrence of malignant disease, survival, yearly follow-up status, causes of death, and development of secondary malignancies. Type of CVC, causes for removal of the CVC, type of blood stream infection, pathogens isolated, antimicrobial sensitivity, and outcome of antimicrobial chemotherapy. DESCRIPTIVE DATA: Since 1985, 4,944 children below 15 years of age have been registered in the database. There has been no significant change in the incidence of childhood cancer in Denmark since 1985. The 5-year survival has increased significantly since 1985 and is now 86%. The median number of days from diagnosis to initiation of therapy is 7 days and in 80% of the children less than 14 days. Clinical data of 95% of the patients are reported to open international studies. CONCLUSION: The survival of Danish children with cancer since 2003 compares favorably with other international population-based studies. The annual reports support the collaboration within pediatric oncology in Denmark.

The "true" incidence of surgically treated deep prosthetic joint infection after 32,896 primary total hip arthroplasties: a prospective cohort study.

BACKGROUND AND PURPOSE: It has been suggested that the risk of prosthetic joint infection (PJI) in patients with total hip arthroplasty (THA) may be underestimated if based only on arthroplasty registry data. We therefore wanted to estimate the "true" incidence of PJI in THA using several data sources. PATIENTS AND METHODS: We searched the Danish Hip Arthroplasty Register (DHR) for primary THAs performed between 2005 and 2011. Using the DHR and the Danish National Register of Patients (NRP), we identified first revisions for any reason and those that were due to PJI. PJIs were also identified using an algorithm incorporating data from microbiological, prescription, and clinical biochemistry databases and clinical findings from the medical records. We calculated cumulative incidence with 95% confidence interval. RESULTS: 32,896 primary THAs were identified. Of these, 1,546 had first-time revisions reported to the DHR and/or the NRP. For the DHR only, the 1- and 5-year cumulative incidences of PJI were 0.51% (0.44-0.59) and 0.64% (0.51-0.79). For the NRP only, the 1- and 5-year cumulative incidences of PJI were 0.48% (0.41-0.56) and 0.57% (0.45-0.71). The corresponding 1- and 5-year cumulative incidences estimated with the algorithm were 0.86% (0.77-0.97) and 1.03% (0.87-1.22). The incidences of PJI based on the DHR and the NRP were consistently 40% lower than those estimated using the algorithm covering several data sources. INTERPRETATION: Using several available data sources, the "true" incidence of PJI following primary THA was estimated to be approximately 40% higher than previously reported by national registries alone.

Importance of blood cultures from peripheral veins in pediatric patients with cancer and a central venous line.

BACKGROUND: When an infection is suspected in a child with cancer and a central venous line (CVL), cultures are often only obtained from the CVL and not from a peripheral vein (PV). This study was undertaken to evaluate the importance of concomitant blood cultures from the CVL and a PV. PROCEDURE: Clinical data and the results of all cultures taken concomitantly from the CVL and a PV were registered prospectively in children admitted with fever from April 2008 to December 2012 at the Department of Pediatrics at Aarhus University Hospital Skejby. RESULTS: During the study period 654 paired cultures obtained from the CVL and from a PV within two hour of each other were included. A true bloodstream infection (BSI) was registered in 112 episodes. In 20 (17%) out of 112, true BSI growth of a microorganism was detected only in the culture from a PV including seven cases of Escherichia coli and three cases of Staphylococcus aureus. In 52 episodes the same microorganism was cultured from both the CVL and a PV. Twenty-four of these episodes were classified as catheter-related bloodstream infections (CRBSI) using differential time to positivity. In total, 64 (57%) of all true BSI were defined as CRBSI. CONCLUSIONS: Blood cultures should be obtained from a PV in addition to cultures from CVL at the onset of fever in pediatric patients with cancer in order to maximize the findings of true BSIs. The frequency of CRBSI may be over-estimated if blood cultures are drawn from CVL only.

Central venous catheters and catheter locks in children with cancer: a prospective randomized trial of taurolidine versus heparin.

BACKGROUND: To determine if the catheter lock taurolidine can reduce the number of catheter-related bloodstream infections (CRBSI) in pediatric cancer patients with tunneled central venous catheters (CVC). PROCEDURE: During a study period of 34 months, 129 newly placed tunneled CVCs in 112 patients were randomly assigned to standard lock with heparin solution or experimental lock with a taurolidine solution (ClinicalTrials.gov Identifier NCT00735813). RESULTS: Sixty-five CVCs were included in the standard group and 64 CVCs in the experimental group. The groups were comparable regarding patients' characteristics. A total number of 72 bloodstream infections of which 33 were CRBSIs were observed during 39,127 CVC-days. A lower rate of CRBSI (0.4 per 1,000 CVC-days) was observed in the experimental arm compared with the standard arm (1.4 per 1,000 CVC-days, incidence rate ratio (IRR) = 0.26; 95% confidence interval (CI) 0.09-0.61; P = 0.001). A lower rate of total bloodstream infections (1.2 per 1,000 CVC-days) was also observed in the experimental arm compared with the standard arm (2.5 per 1,000 CVC-days, IRR = 0.49; 95% CI 0.29-0.82; P = 0.004). Median interval from catheter insertion until first CRBSI was significantly lower in the standard group (156 days, range 12-602) compared with the experimental group (300 days, range 12-1,176; P = 0.02). Premature removal of the CVC due to infection and overall CVC survival were similar in the two study groups. CONCLUSION: Locking of long-term tunneled CVC with taurolidine significantly reduces catheter-related bloodstream infections in children with cancer.

Biofilm formation in long-term central venous catheters in children with cancer: a randomized controlled open-labelled trial of taurolidine versus heparin.

Taurolidine has demonstrated inhibition of biofilm formation in vitro. The aim of this study was to compare the effect of catheter locking with taurolidine vs heparin in biofilm formation in central venous catheters. Forty-eight children with cancer were randomized to catheter locking by heparin (n = 22) or taurolidine (n = 26), respectively. After removal, catheters were examined by standardized scanning electron microscopy to assess quantitative biofilm formation. Biofilm was present if morphologically typical structures and bacterial cells were identified. Quantitative and semi-quantitative cultures were also performed. Biofilm was identified in 23 of 26 catheters from the taurolidine group and 21 of 22 catheters from the heparin group. A positive culture was made of six of the catheters locked with taurolidine and heparin, respectively (p = 0.78). The rate of catheter-related bloodstream infections (CRBSI) was 0.1 per 1000 catheter-days using taurolidine and 0.9 per 1000 catheter-days using heparin (p = 0.03). This randomized trial confirmed that the use of taurolidine as catheter-lock compared with heparin reduced the rate of CRBSIs; this reduction was not related to a reduction in the intraluminal biofilm formation and the rate of bacterial colonization detected by scanning electron microscopy in the two groups.

Accuracy of using the lytA gene to distinguish Streptococcus pneumoniae from related species.

The need for a microbial identification of Streptococcus pneumoniae independent of culture methods has resulted in the introduction of other laboratory principles. The verification of a proper and exclusive gene for the detection of the pneumococcus by nucleic acid-based tests is, however, still unresolved. A previously published lytA-gene-specific real-time PCR method was applied to a panel of bacterial strains to clarify the analytical sensitivity and specificity of a PCR assay targeting this gene. Furthermore, a phylogenetic analysis of published lytA gene sequences was performed to look at gene sequence differences and the theoretical match with the primers and probes. The lytA-gene-specific PCR detected 46/46 S. pneumoniae isolates. All 49 of the non-pneumococcal isolates tested negative, including 22 isolates from the mitis group streptococci. Phylogenetic analysis of 94 sequences of the lytA gene from different strains of S. pneumoniae, Streptococcus mitis and Streptococcus pseudopneumoniae showed that 70/87 S. pneumoniae sequences constituted one cluster and a further six sequences were outside but adjacent to this cluster, all with a complete match with primers and probes. The remaining 11 S. pneumoniae strains could be placed in a different cluster, which also contained the five S. mitis and two S. pseudopneumoniae strains. All strains had no match with primers and probes. The S. pneumoniae strains in the second cluster were all characterized by being bile-insoluble, an infrequent pneumococcal phenotype. Routine laboratories can utilize the additional observation that pneumococci that were negative by the specific PCR also carried the phenotype of bile insolubility, thereby observing the incidence of false-negative results produced by the PCR assay. The real-time PCR targeting the lytA gene thus constitutes a sensitive and specific assay that distinguishes S. pneumoniae from its close relatives in the mitis group.

[Infections related to central venous catheters in children affected from malignant diseases]. / Infektioner relateret til centralt venekateter hos børn med maligne lidelser.

Central venous catheters (CVC) are an essential part of the treatment of children with haematological and oncological diseases. Unfortunately, CVC also represent a major risk factor of bloodstream infections. Catheter-related bloodstream infections (CRBSI) in children are often diagnosed based on blood cultures from the CVC only. Most CRBSI can be treated without catheter removal. On suspicion of CRBSI empirical antibiotic treatment with piperacillin-tazobactam, meropenem or ampicillin in combination with gentamicin is recommended. The systemic treatment can be combined with catheter-lock therapy.

Placing of tunneled central venous catheters prior to induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Tunneled central venous catheters (CVCs) are inevitable in children with acute lymphoid leukemia (ALL). The aim of this study was to evaluate the risk of CVC-related complications in children with ALL in relation to timing of catheter placement and type of catheter. PROCEDURE: All children hospitalized from January 2000 to March 2008 with newly diagnosed ALL and with double-lumen total implantable devices (TIDs) or tunneled external catheters (TEs) were included retrospectively. We only used data related to the patient's first catheter. RESULTS: We included 98 children; 35 received a TID and the remaining 63 received a TE. A total number of 29,566 catheter days and 93 catheter-associated blood stream infections (CABSI) was identified. We found a CABSI rate of 3.1/1,000 catheter days (5.4/1,000 catheter days for TEs and 1.4/1,000 catheter days for TIDs, incidence rate ratio (IRR) 3.82 (95% CI 2.37-6.35) P = 0.0001). No difference was found in CABSI between neither early versus later placed TIDs (IRR = 0.99 (95% CI 0.41-2.45) P = 0.98) nor early versus later placed TEs (IRR = 0.81 (95% CI 0.40-1.86) P = 0.54). We found no difference between early and later placed catheters regarding non-elective removal (RR = 0.86 (95% CI 0.72-1.03) P = 0.09). TEs had a higher risk of non-elective removal compared with TIDs (RR = 3.95 (95% CI 1.88-8.29) P < 0.001). CONCLUSIONS: The study did not find that children with ALL and with early placed CVCs experienced significantly more complications compared with children with late placed catheters. This study found that children with ALL and TEs experienced more complications than children with TIDs.