Short-course antibiotic therapy of 5 days in community-acquired pneumonia (CAP5): study protocol for a randomised controlled trial.

INTRODUCTION: The optimal duration of antibiotic therapy for community-acquired pneumonia (CAP) is unsettled. Short-course therapy has proved successful in clinical trials but is not yet implemented in everyday clinical practice. Validation of results from randomised controlled trials is crucial to evaluate existing evidence and provide clinicians with assurance of using new treatment strategies. In a pragmatic framework, we aim to assess the use of short-course antibiotic therapy guided by the onset of clinical stability in patients hospitalised with CAP. METHODS AND ANALYSIS: This study is a randomised controlled trial with a non-inferiority design that will examine the efficacy of short-course antibiotic therapy in patients hospitalised with CAP. From six hospitals across Denmark, we plan to enrol 564 patients between 2019 and 2024. Within 3-5 days after initiating antibiotic therapy, participants will be randomised 1:1 to parallel treatment arms: (1) short-course antibiotic therapy of 5 days or (2) antibiotic therapy of at least 7 days. The primary outcome will be 90-day readmission-free survival and will be estimated as an absolute risk difference with a predefined non-inferiority margin of -6%. Secondary outcomes will comprise other safety measures including new antibiotics, adverse events, length of hospital stay and postdischarge outpatient visits. Both intention-to-treat and per-protocol analyses will be performed. ETHICS AND DISSEMINATION: This study has been approved by the Health Research Ethics Committee of the Capital Region of Denmark (identifier number: H-19014479). Trial data will be made available in anonymous form when the trial has ended. TRIAL REGISTRATION NUMBER: NCT04089787, ClinicalTrials.Gov.

Excess length of stay and readmission following hospital-acquired bacteraemia: a population-based cohort study applying a multi-state model approach.

OBJECTIVES: Population-based estimates of excess length of stay after hospital-acquired bacteraemia (HAB) are few and prone to time-dependent bias. We investigated the excess length of stay and readmission after HAB. METHODS: This population-based cohort study included the North Denmark Region adult population hospitalized for ≥48 hours, from 2006 to 2018. Using a multi-state model with 45 days of follow-up, we estimated adjusted hazard ratios (aHRs) for end of stay and discharge alive. The excess length of stay was defined as the difference in residual length of stay between infected and uninfected patients, estimated using a non-parametric approach with HAB as time-dependent exposure. Confounder effects were estimated using pseudo-value regression. Readmission after HAB was investigated using the Cox regression. RESULTS: We identified 3457 episodes of HAB in 484 291 admissions in 205 962 unique patients. Following HAB, excess length of stay was 6.6 days (95% CI, 6.2-7.1 days) compared with patients at risk. HAB was associated with decreased probability of end of hospital stay (aHR, 0.60; 95% CI, 0.57-0.62) driven by the decreased hazard for discharge alive; the aHRs ranged from 0.30 (95% CI, 0.23-0.40) for bacteraemia stemming from 'heart and vascular' source to 0.72 (95% CI, 0.69-0.82) for the 'urinary tract'. Despite increased post-discharge mortality (aHR, 2.76; 95% CI, 2.38-3.21), HAB was associated with readmission (aHR, 1.42; 95% CI, 1.31-1.53). CONCLUSION: HAB was associated with considerably excess length of hospital stay compared with hospitalized patients without bacteraemia. Among patients discharged alive, HAB was associated with increased readmission rates.

Incidence of Hepatocellular Carcinoma and Decompensated Liver Cirrhosis and Prognostic Accuracy of the PAGE-B HCC Risk Score in a Low Endemic Hepatitis B Virus Infected Population.

Purpose: We aimed to determine incidence of hepatocellular carcinoma (HCC) and decompensated liver cirrhosis in persons with chronic hepatitis B virus (HBV) infection in Denmark stratified by disease phase, liver cirrhosis, and treatment status at baseline. Additionally, we aimed to assess the prognostic value of the PAGE-B HCC risk score in a mainly non-cirrhotic population. Patients and Methods: In this register-based cohort study, we included all individuals over the age of 18, with chronic HBV infection first registered between 2002 and 2016 in at least one of three nationwide registers. The study population was followed until HCC, decompensated liver cirrhosis, death, emigration, or December 31, 2017, which ever came first. Results: Among 6016 individuals included in the study, 10 individuals with and 23 without baseline liver cirrhosis developed HCC during a median follow up of 7.3 years (range 0.0-15.5). This corresponded to five-year cumulative incidences of 7.1% (95% confidence interval (CI) 2.0-12.3) and 0.2% (95% CI 0.1-0.4) in persons with and without baseline liver cirrhosis. The five-year cumulative incidence of decompensated liver cirrhosis was 0.7% (95% CI 0.5-1.0). Among 2038 evaluated for liver events stratified by disease phase, incidence of HCC was low in all who were non-cirrhotic and untreated for HBV at baseline. PAGE-B score was evaluated in 1529 persons. The 5-year cumulative incidence of HCC was 0, 0.8 (95% CI 0.5-1.8), and 8.7 (95% CI 1.0-16.4) in persons scoring <10, 10-17 and >17, respectively (c-statistic 0.91 (95% CI 0.84-0.98)). Conclusion: We found low incidence of HCC and decompensated liver cirrhosis in persons with chronic HBV infection in Denmark. Moreover, the PAGE-B score showed good accuracy for five-year risk of developing HCC in the population with chronic HBV infection in Denmark.

Ischemic Heart Disease in Chronic Hepatitis B: A Danish Nationwide Cohort Study.

Objective: Data on the risk of ischemic heart disease (IHD) in patients with chronic hepatitis B virus (CHB) are conflicting. Our objective was to address the rate of IHD in patients with CHB compared with individuals without CHB (control-persons) from the general population. Study Design and Setting: We conducted a cohort study of prospectively obtained data from Danish nationwide registries. We produced cumulative incidence curves and calculated the unadjusted incidence rate ratio (IRR) of IHD in persons with and without CHB. The adjusted association between having CHB and developing IHD was examined using a cause-specific Cox regression model. Results: In total, 6472 persons with CHB and 62,251 age- and sex-matched individuals from the general population were followed for 48,840 and 567,456 person-years, respectively, during which 103 (1,59%) with CHB and 1058 (1,70%) control-persons developed IHD. The crude IRR was 1.13 (95% CI: 0.91-1.39). CHB did not have a statistically significant effect on the rate of IHD after adjusting for several confounding factors (adjusted hazard ratio: 0.96, 95% CI: 0.76-1.21). Conclusion: In this nationwide cohort study, we did not find any difference between rate of IHD in persons with CHB in comparison with the general population.

Mortality and cause of death in persons with chronic hepatitis B virus infection versus healthy persons from the general population in Denmark.

The study aimed to determine adjusted all-cause mortality and cause of death in persons with chronic hepatitis B virus (HBV) infection compared with age- and sex-matched persons from the general population. We used nationwide registers to identify persons aged ≥18 years with chronic HBV infection in 2002-2017 in Denmark and included 10 age- and sex-matched controls for each. Follow-up was from 6 months after diagnosis until death, emigration, or 31 December 2017. Mortality rate ratios (MRRs) adjusted for age, sex, employment, origin and comorbidity were calculated using Poisson regression. Unadjusted cause-specific mortality rate ratios with 95% confidence intervals were calculated assuming a Poisson distribution. A total of 6988 persons with chronic HBV infection and 69,847 controls were included. During a median follow-up of 7.7 years (range 0.0-15.5), 315 (5%) persons with-and 1525 (2%) without-chronic HBV infection died. The adjusted all-cause MRR was 1.5 (95% CI 1.2-2.0). Persons with chronic HBV infection had increased mortality due to liver disease including hepatocellular carcinoma (MRR 12.3 [8.6-17.7]), external causes (MRR 3.3 [2.5-4.7]), endocrine disease (MRR 3.2 [1.8-5.4]), genitourinary disease (MRR 3.2 [1.2-7.6]) and neoplasms (except hepatocellular carcinoma; MRR 1.6 [1.2-2.0]). In conclusion, this study showed an increased all-cause mortality in persons with chronic HBV infection in comparison with age- and sex-matched persons without chronic HBV infection which remained after adjustment for several confounding factors. Excess mortality was mainly associated with liver disease, but also external factors, endocrine disease, genitourinary disease and neoplasms (excluding hepatocellular carcinoma).

Risk factors for hospital-acquired bacteraemia - an explorative case-control study of hospital interventions.

BACKGROUND: Knowledge on hospital-related interventions as risk factors for hospital-acquired bacteraemia (HAB) is sparse. AIM: We aimed to investigate hospital interventions as risk factors for HAB. METHODS: Prospectively through one year, we identified episodes of HAB in a single tertiary hospital. We used a matched incidence density sampled case-control design. Matching on sex and age group, we sampled controls (1:2) from the adult hospital population with ongoing hospitalization for ≥48 h. Using conditional logistic regression, we estimated odds ratios (OR) with 95% confidence intervals (CI). For adjusted ORs (aOR), adjustments were made for length of hospital stay, type and urgency of admission, and Charlson Comorbidity Index score level. FINDINGS: From 15th October 2019 through 14th October 2020, we identified 115 incident episodes of HAB and matched them with 230 controls. HAB patients were more often admitted as 'medicine or emergency surgery'-patients (94% vs 87%) and had a longer hospital stay before inclusion (median days 20 vs 12). They were more frequently categorized as having a 'low level comorbidity' (58% vs 39%) but had higher prevalence of haematologic (15% vs 6%) or metastatic cancer (13% vs 10%). Our estimates for central venous catheters were aOR of 3.46 (95% CI 1.92-6.23), haemodialysis; aOR 5.05 (95% CI 1.41-18.06), immunosuppressive treatment including chemotherapy; aOR of 1.72 (95% CI 1.00-2.96). CONCLUSION: Central venous catheters and haemodialysis were the most prominent risk factors. Immunosuppressive treatment including therapy may play an important role in the development of HAB.

Incidence and mortality of hospital-acquired bacteraemia: a population-based cohort study applying a multi-state model approach.

OBJECTIVE: The effect of hospital-acquired bacteraemia on mortality is sparsely investigated. We investigated the incidence and hospital-acquired bacteraemia impact on mortality. METHODS: We conducted a 13-year population-based cohort study using the North Denmark Bacteraemia Research Database and Danish health registries. The population comprised all adult patients with a hospital admission lasting ≥48 hr. We used Poisson regression to estimate trends in incidence. The 30-day mortality of hospital-acquired bacteraemia was estimated using an illness-death multistate model with recovery using the population at risk of hospital-acquired bacteraemia as reference. RESULTS: We identified 3588 episodes of hospital-acquired bacteraemia in 484 264 admissions. The incidence increased proportionally by 1.02 episodes yearly (95% CI 1.01-1.03) between 2006 and 2018. Hospital-acquired bacteraemia was associated with increased mortality (adjusted hazard ratio (aHR) 4.32, 95% CI 3.95-4.72), especially hospital-acquired bacteraemia with unknown source (aHR 6.42 (95% CI 5.67-7.26), "thoracic incl. pneumonia" (aHR 5.89, 95% CI 3.45-10.12) and abdominal source (aHR 4.33, 95% CI 3.27-5.74). The relative impact on mortality diminished with age (aHR 5.66, 95% CI 2.00-16.01 in 18-40 years old vs. 3.69, 95% CI 3.14-4.32 in 81-105 years old) and comorbidity (aHR 5.75, 95% CI 4.45-7.42 in low vs. 3.55, 95% CI 3.16-3.98 in high comorbidity), and was higher in elective admissions (aHR 9.09, 95% CI 7.14-11.57 vs. aHR of 4.03, 95% CI 3.67-4.42). DISCUSSION: Hospital-acquired bacteraemia is associated with high mortality, especially when the source is unknown or originating from the thoracic cavity.

[Ramsay Hunt syndrome can present with vesicular elements on the tongue, facial nerve palsy and meningitis].

Ramsay Hunt syndrome (RHS) is caused by a reactivation of the varicella zoster virus (VZV). It normally involves the triad of earache, peripheral facial nerve palsy and ipsilateral rash but can present without/with minimal visible rashes. In this case report, a 53-year-old male was admitted to hospital after a week-long headache, right-sided earache and peripheral facial nerve palsy. Vesicular elements were observed on the right side of the tongue. Cerebrospinal fluid (CSF) analysis showed 195 monocytes/mm3, and PCR verified VZV in the CSF. To avoid misdiagnosis, early recognition of the symptoms of RHS and diagnostic workup is advised.

Neutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease: correlations and 5-year mortality - a cohort study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and progressive decline in pulmonary function. Neutrophil-to-lymphocyte ratio (NLR), YKL-40 and calprotectin are biomarkers of inflammation and predict mortality in patients with different inflammatory diseases. We aimed to investigate the correlation between levels of these three biomarkers and neutrophil granulocyte and lymphocyte count in patients with moderate to very severe COPD stratified by use of systemic glucocorticoids. Furthermore, we studied the ability of these biomarkers to predict all-cause mortality. METHODS: 386 patients with moderate to very severe COPD were followed prospectively for 10 years. Patients were divided into two groups according to systemic glucocorticoid use at baseline. Correlations between biomarkers were assessed by Spearman's Rho, and mortality was evaluated in uni- and multivariate Cox regression analyses with hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Plasma calprotectin was positively correlated with neutrophil granulocyte count and NLR. No significant association was found between plasma YKL-40 and the cellular biomarkers, irrespective of glucocorticoid treatment. In the group not treated with systemic glucocorticoids, plasma calprotectin [HR 1.002 (95% CI 1.000 - 1.004)], NLR [HR 1.090 (1.036 - 1.148)] and lymphocyte count [HR 0.667 (0.522 - 0.851)] were significantly associated with higher mortality. In the group treated with systemic glucocorticoids, higher plasma YKL-40 was significantly associated with mortality in univariate Cox regression analysis [HR 1.006 (1.003 - 1.008)]. CONCLUSIONS: Calprotectin was related to neutrophil granulocyte count and NLR in patients with moderate to very severe COPD in stable phase and not in treatment with systemic glucocorticoids. Lymphopenia, higher plasma calprotectin and higher NLR were independent predictors of increased all-cause mortality in this group. Our data also suggests that treatment with systemic glucocorticoids has a significant impact on the ability of inflammatory biomarkers to predict all-cause mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT00132860.

Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is hallmarked by inflammatory processes and a progressive decline of lung function. YKL-40 is a potential biomarker of inflammation and mortality in patients suffering from inflammatory lung disease, but its prognostic value in patients with COPD remains unknown. We investigated whether high plasma YKL-40 was associated with increased mortality in patients with moderate to very severe COPD. METHODS: Four hundred and ninety-three patients with moderate to very severe COPD were followed prospectively for up to 10 years. Patients were divided into two groups according to plasma YKL-40: concentration higher than the 75th percentile for age-matched healthy subjects (i.e. high levels) and normal levels. Outcome was overall survival (OS) and was evaluated in uni- and multivariate proportional hazards Cox regression analyses and adjusted for factors affecting mortality. RESULTS: Median plasma YKL-40 was increased in patients with COPD (81 ng/ml, p < 0.001) compared to healthy subjects (40 ng/ml). Patients with high plasma YKL-40 had a hazard ratio (HR) of 1.42 (95% CI: 1.15-1.75, p = 0.001) for all-cause mortality. Multivariate analysis showed that YKL-40 (HR 1.38; 95% CI: 1.11-1.72, p = 0.004), age (HR 1.05; 95% CI: 1.03-1.06, p < 0.0001), Severe COPD (HR 1.35; 95 CI: 1.03-1.76, p = 0.03) very severe COPD (HR 2.19; 95% CI: 1.60 - 2.99 < 0.0001), neutrophil granulocyte count (HR 1.05; 95% CI: 1.01-1.08, p = 0.01), and a smoking history of > 40 years (HR 1.38; 95% CI: 1.11-1.71, p = 0.003) were independent prognostic markers of OS. CONCLUSION: High plasmaYKL-40 is associated with increased mortality in patients with moderate to very severe COPD, suggesting a role for YKL-40 as a potential biomarker of mortality in this patient group.

Calprotectin--a marker of mortality in COPD? Results from a prospective cohort study.

Calprotectin comprises more than 45% of the cytosolic content of neutrophil granulocytes. Because pathogenesis, disease activity and disease progression in COPD are believed to be partly dependent of neutrophil driven inflammation we decided to investigate whether plasma level of calprotectin (p-calprotectin) was associated with all-cause mortality in patients with COPD. We measured p-calprotectin in blood samples from 460 patients with moderate to very severe COPD in stable phase. Patients were stratified into three groups according to p-calprotectin level. Outcome measure was all-cause mortality. Analyses were adjusted for factors known to influence mortality using a Cox regression analysis. We found a time dependent correlation between p-calprotectin levels and mortality during the first 5 years of follow-up. Increasing levels of p-calprotectin were associated with concomitant increases in mortality from HR 1.56 (CI 95%: 1.03 -2.38) at calprotectin between 100 -200 ng/ml to HR 2.02 (CI 95%: 1.27-3.19) at calprotectin >200 ng/ml. P-calprotectin could be a useful marker of all-cause mortality in patients suffering from moderate to very severe COPD.

[Sparse effect of long-term treatment with macrolides in patients with chronic obstructive pulmonary disease]. / Sparsom effekt af langtidsbehandling med makrolider ved kronisk obstruktiv lungesygdom.

Macrolides have been proposed to have a positive effect in patients with inflammatory lung diseases, including patients with chronic obstructive pulmonary disease (COPD), who suffer from acute exacerbations. Increased use of macrolides for long-term treatment of patients with COPD has been observed. The evidence of a treatment effect of macrolides in this area is sparse, but some studies suggest that it might be beneficial on the number of exacerbations and the length between them. At present there is not sufficient evidence to issue a general recommendation for prescribing macrolides for the long-term treatment of COPD.

Serum vitamin D in patients with chronic obstructive lung disease does not correlate with mortality--results from a 10-year prospective cohort study.

BACKGROUND: Recent studies have found vitamin D (25-OHD) deficiency and insufficiency to be common among patients with COPD. Serum level of 25-OHD seems to correlate to pulmonary function, COPD disease staging, and increased susceptibility to respiratory infections. We wanted to investigate whether vitamin D deficiency or insufficiency was associated with mortality rate in patients suffering from advanced COPD. METHODS: 25-OHD serum levels were measured in 462 patients suffering from moderate to very severe COPD. Patients were stratified into three groups according to serum levels of 25-OHD. Outcome measure was mortality in a 10 year follow-up period. Kaplan-Meier curves (KM) were plotted and mortality hazard ratios (HR) were calculated using Cox Proportional Hazard regression (Cox PH). RESULTS: Serum 25-OHD deficiency and insufficiency were prevalent. We were unable to demonstrate any association between baseline serum levels of 25-OHD and mortality rate. We found an association between mortality and age [HR 1.05 (CI 95%: 1.03-1.06)], Charlson score [HR 1.49 (CI 95%: 1.06-2.09)], increasing neutrophil count [HR 1.05 (CI 95%: 1.02-1.09)], severe [HR 1.41 (CI 95%: 1.06-1.86)]/very severe COPD [HR 2.19 (CI 95%: 1.58-3.02)] and a smoking history of more than 40 pack years [HR 1.27 (CI 95%: 1.02-1.70)]. CONCLUSIONS: Serum level of 25-OHD does not seem to be associated with mortality rate, suggesting no or only a minor role of 25-OHD in disease progression in patients with moderate to very severe COPD.

Blood borne viral infections among Danish health care workers--frequent blood exposure but low prevalence of infection.

Denmark is a country with low prevalence and incidence of blood borne viral infections. Among health care workers (HCWs) vaccination for hepatitis B is only offered to high-risk groups. The aims of this cross sectional survey were to determine the prevalence of hepatitis B, -C, and human immunodeficiency virus (HIV) among the staff at a Danish University hospital and to correlate this with risk factors for transmission. Additionally, we wanted to examine the current frequency of blood exposure, reporting habits and hepatitis B vaccination status in the staff. Of 1439 eligible hospital staffs included, 960 (67%) were HCWs. The overall human immunodeficiency virus (HIV)-, hepatitis C Virus (HCV)- and hepatitis B Virus (HBV)-prevalence was 0% (0/1439), 0.14% (2/1439) and 1.6% (23/1439), respectively. Twenty-three percent of HCWs were vaccinated against HBV. Age, blood transfusion and stay in endemic areas were associated independently to HBV infection as opposed to job-category, duration of employment, HBV vaccination status and blood exposure. Based on a 4-week recall period, the incidence of percutaneous blood exposure was 1.5/person-year. In conclusion the HIV and hepatitis prevalence was low despite frequent blood exposure and the principal risk factors were unrelated to work. Danish HCWs do not seem to be at increased risk of hepatitis B even though universal HBV vaccination has not been implemented.

GB virus C epidemiology in Denmark: different routes of transmission in children and low- and high-risk adults.

With the demonstration of an effect of GBV-C infection on the outcome of HIV infection, it has become important to understand the epidemiology of GBV-C. The purpose of this study was to determine the prevalence in high- and low-risk populations. The following populations were tested: school children, 9 and 15 years of age (n = 901), blood donors (n = 5,203), hospital employees (n = 1,432), and prisoners and injecting drug users (n = 447). In-house RT-PCR for GBV-CRNA was used together with a commercial ELISA for anti-E2 (Boehringer, Germany). In addition, questionnaires for risk factors for transmission and serological tests for HIV and hepatitis were applied. The overall prevalence of GBV-CRNA was 1.4% among children, 2.2% among blood donors, 2.2% among hospital employees, 12.5% among non-injecting prisoners, and 34.9% among drug injectors. Correspondingly anti-E2 was found in 0.3%, 12.3%, 25.0%, and 42.7%. Among hospital employees, independent risk factors for GBV-C were professions with blood exposure and sexual risk partners. Among prisoners and drug users, injecting and a sexual risk index were associated independently with GBV-C. Based on these results, the following hypothesis is suggested: GBV-C is transmitted frequently at birth or early childhood and this leads to chronic infection in most cases. Sexual transmission is the most important route of transmission in the adult population but this infection is usually transient. Blood borne transmission plays a role among health care workers and injecting drug users and GBV-C should be further evaluated as a surrogate marker for professional blood exposure.