Bacteriophages for the treatment of pseudomonas-infected vascular prosthesis.

We present a case report detailing therapeutic application of two lytic antipseudomonal bacteriophages to treat a chronic relapsing Pseudomonas aeruginosa infection of a prosthetic aortic graft. As there are currently no Danish laboratories offering phages for clinical therapy, and this case, to our knowledge represents the first applied phage therapy in Denmark, the practical and regulatory aspects of offering this treatment option in Denmark is briefly reviewed along with the clinical case.

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).

Feasibility, quality and validity of narrative multisource feedback in postgraduate training: a mixed-method study.

OBJECTIVES: To examine a narrative multisource feedback (MSF) instrument concerning feasibility, quality of narrative comments, perceptions of users (face validity), consequential validity, discriminating capacity and number of assessors needed. DESIGN: Qualitative text analysis supplemented by quantitative descriptive analysis. SETTING: Internal Medicine Departments in Zealand, Denmark. PARTICIPANTS: 48 postgraduate trainees in internal medicine specialties, 1 clinical supervisor for each trainee and 376 feedback givers (respondents). INTERVENTION: This study examines the use of an electronic, purely narrative MSF instrument. After the MSF process, the trainee and the supervisor answered a postquestionnaire concerning their perception of the process. The authors coded the comments in the MSF reports for valence (positive or negative), specificity, relation to behaviour and whether the comment suggested a strategy for improvement. Four of the authors independently classified the MSF reports as either 'no reasons for concern' or 'possibly some concern', thereby examining discriminating capacity. Through iterative readings, the authors furthermore tried to identify how many respondents were needed in order to get a reliable impression of a trainee. RESULTS: Out of all comments coded for valence (n=1935), 89% were positive and 11% negative. Out of all coded comments (n=4684), 3.8% were suggesting ways to improve. 92% of trainees and supervisors preferred a narrative MSF to a numerical MSF, and 82% of the trainees discovered performance in need of development, but only 53% had made a specific plan for development. Kappa coefficients for inter-rater correlations between four authors were 0.7-1. There was a significant association (p<0.001) between the number of negative comments and the qualitative judgement by the four authors. It was not possible to define a specific number of respondents needed. CONCLUSIONS: A purely narrative MSF contributes with educational value and experienced supervisors can discriminate between trainees' performances based on the MSF reports.

[Toxic shock syndrome].

Toxic shock syndrome is a potentially deadly toxin-mediated disease in which quick diagnosis is imperative for treatment and prognosis. This is a case report of a 21-year-old woman admitted with high fever, confusion, petechial rash and hypotension. During catherisation a tampon was found, and from a vaginal swab Staphylococcus aureus was grown. The patient was hospitalised for eight days, two of which were at the intensive care unit for norepinephrine infusion for hypotension. She was successfully treated with the antibiotics dicloxacillin and clindamycin.

Whole-Exome Sequencing of Patients With Recurrent HSV-2 Lymphocytic Mollaret Meningitis.

Recurrent lymphocytic meningitis, also referred to as Mollaret meningitis, is a rare neurological disease characterized mainly by reactivation of herpes simplex virus 2 (HSV-2) from sensory ganglia. However, the underlying host immune determinants and viral factors rendering some individuals unable to maintain HSV-2 latency are largely unknown. We collected a cohort of 15 patients diagnosed with Mollaret meningitis. By whole-exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in (1) ubiquitin-proteasome pathways, (2) the autophagy machinery, and (3) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived double-stranded DNA ligands revealed reduced antiviral interferon responses in most patients. These findings may contribute to a better understanding of disease pathogenesis and protective immunity to HSV in the central nervous system, and may ultimately be of importance for identification of targets for development of improved prophylaxis and treatment of this disease.

Low incidence of HCC in chronic hepatitis C patients with pretreatment liver stiffness measurements below 17.5 kilopascal who achieve SVR following DAAs.

BACKGROUND AND AIMS: To evaluate the ability of pretreatment liver stiffness measurements (pLSM) to predict hepatocellular carcinoma (HCC), incident decompensation and all-cause mortality in chronic hepatitis C (CHC) patients who achieved sustained virological response (SVR) after treatment with direct-acting antivirals (DAAs). METHODS: 773 CHC patients with SVR after DAA treatment and no prior liver complications were identified retrospectively. Optimized cut-off of 17.5 kPa for incident HCC was selected by maximum Youden's index. Patients were grouped by pLSM: <10 kPa [reference], 10-17.4 kPa and ≥17.5 kPa. Primary outcomes were incident hepatocellular carcinoma and secondary outcomes were incident decompensated cirrhosis and all-cause mortality, analyzed using cox-regression. RESULTS: Median follow-up was 36 months and 43.5% (336) had cirrhosis (LSM>12.5 kPa). The median pLSM was 11.6 kPa (IQR 6.7-17.8, range 2.5-75) and pLSM of <10 kPa, 10-17.4 kPa and 17.5-75 kPa was seen in 41.5%, 32.2% and 26.3%. During a median follow-up time of 36 months, 11 (1.4%) developed HCC, 14 (1.5%) developed decompensated cirrhosis, and 38 (4.9%) patients died. A pLSM of 17.5 kPa identified patients with a high risk of HCC with a negative predictive value of 98.9% and incidence rate of HCC in the 17.5-75 kPa group of 1.40/100 person years compared to 0.14/100 person years and 0.12/100 person years in the 10-17.4 kPa and <10 kPa groups, p<0.001. CONCLUSION: Pretreatment LSM predicts risk of HCC, decompensation and all-cause mortality in patients with SVR after DAA treatment. Patients with a pLSM <17.5 kPa and no other risk factors for chronic liver disease appear not to benefit from HCC surveillance for the first 3 years after treatment. Longer follow-up is needed to clarify if they can be safely excluded from post treatment HCC screening hereafter.

Implementation of treatment recommendations for chronic hepatitis B in patients attending specialized hospital care in Denmark - a region wide study.

Objective: To evaluate implementation of national guideline recommendations on treatment initiation for chronic hepatitis B (CHB) in Denmark.Methods: Using DANHEP, a nationwide cohort of chronic hepatitis B and C patients attending specialized hospital care in Denmark, we performed a descriptive cohort study from January 2002 through December 2017. We identified patients with CHB in 3 of 5 Danish regions, with at least two hospital/outpatient clinic visits during the study period.Results: We identified 990 CHB patients who remained untreated throughout the study period, and 265 who initiated treatment. At their last visit 952/990 (96%, 95% CI 95-97) untreated patients did not meet current national criteria for treatment initiation while 198/265 (75%, 95% CI 69-80) who initiated treatment met the national criteria. Overall, 198/236 (84%, 95% CI 79-88) who met national treatment criteria, initiated treatment.Conclusion: The majority of CHB patients received care in line with national guideline recommendations for treatment initiation. We found that only few patients eligible for treatment remained untreated. However, a fourth of patients who received treatment were not eligible according to national guidelines.

[Two cases of leptospirosis with involvement of the central nervous system].

A 26-year-old woman developed fever, myalgias and headaches two weeks after having been scratched by a rat, which she kept as a pet. She had limited renal involvement and marginal pleocytosis in the cerebrospinal fluid (CSF). A 51-year-old man had just returned from a holiday with water sports activities and was admitted with fever, severe headaches, neck pain, myalgias and signs of acute renal failure and pleocytosis in the CSF. Both patients had positive Leptospira DNA polymerase chain reaction in their CSF and were treated to full remission.

[Prophylaxis of reactivation of hepatitis B and hepatitis C virus infection in immunosuppressive therapy].

The use of immunosuppressive agents can be vital. However, immunosuppression may also cause reactivation of hepatitis B virus (HBV) infection which can be fatal. To reduce the risk of reactivation prophylactic antiviral treatment is recommended in patients with chronic HBV infection. In patients with former HBV infection prophylaxis is also recommended if anti-CD20 agents are used and in cases of transplantation. Immunosuppression in patients with hepatitis C virus (HCV) infection does not seem to lead to severe hepatic manifestations, and reactivation of HCV in this context generally has a mild clinical course.

Differences in mortality in Fusobacterium necrophorum and Fusobacterium nucleatum infections detected by culture and 16S rRNA gene sequencing.

Fusobacterium species are components of the normal microbiota of the oral cavity, gastrointestinal tract, and female genital tract. They are increasingly recognized as causative agents of oral, laryngeal, and tonsillar infections. Several fusobacterial species are involved in infections, with F. necrophorum and F. nucleatum being the most commonly cultured subtypes. In this study, we aimed to investigate clinical and prognostic differences in terms of mortality and association with malignancy between F. necrophorum and F. nucleatum detected by culture and 16S rRNA gene sequencing. This is a systematic, comparative, retrospective, non-interventional study. Data were extracted from the Department of Clinical Microbiology, Region Zealand, Denmark: all patients with F. necrophorum or F. nucleatum detected by culture or 16S rRNA gene sequencing from 1st of January 2010 to 30th of June 2015 were included. In total, F. necrophorum was detected in samples from 75 patients, and F. nucleatum in samples from 68 patients (total: n = 143). Thirteen patients had a current cancer diagnosis at the time of fusobacterial sampling. Multivariate analyses revealed a significant association of "current cancer" with 30-day mortality. Fusobacterial subtype was not associated with mortality neither in overall nor in subgroups with or without current cancer. Despite differences in clinical disease pattern between F. necrophorum and F. nucleatum, mortality was unaffected by fusobacterial subtype. Mortality was significantly related to comorbidity, especially a current diagnosis of cancer. Our data highlights the current debate whether fusobacterial involvement in cancer may have disease-altering properties, rather than being opportunistic pathogens secondary to cancer disease.

[Atypical mycocutaneous manifestation of Leishmania tropica in a refugee].

In this case report a male 19-year-old Syrian refugee presented with a sore throat. A biopsy from larynx detected Leishmania tropica compatible with leishmaniasis, although L. tropica does not normally cause mucosal leishmaniasis (CL). An immunodeficiency was detected, and the patient was treated for hypogammaglobulinaemia and CL three times, before the symptoms disappeared. Leishmaniasis is a disease, which should be taken into consideration, when refugees present with atypical clinical manifestations, especially in immunosuppressed patients.

High mortality from pyogenic vertebral osteomyelitis: a retrospective cohort study.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: In this pilot study, we aimed to assess the incidence, diagnostic strategies, treatment regimens, and outcomes of pyogenic vertebral osteomyelitis (PVO), in a non-urban, Northern European population during 1 year. SETTING: Region Zealand, Denmark. METHODS: All patients admitted to a hospital in Region Zealand during 2013 and subsequently discharged with a diagnosis of PVO or discitis were eligible for screening. Discharge diagnosis codes were obtained from a central register and patients were identified with unique identification numbers from the Danish Civil Registration System. RESULTS: Forty-one consecutive patients were included. Patients presented with back pain (78%), fever (76%), elevated C-reactive protein levels (95%), and bacteremia (76%). Nine patients (22%) were treated empirically, as no bacterial etiology was isolated from blood culture or biopsy. The median duration of antibiotic treatment was 92 days, and we report an in-hospital mortality of 15%. CONCLUSIONS: This study supports previous findings of increasing incidence of PVO. In addition, we found a high rate of bacteremia and a high mortality in this single year cohort. Treatment regimens were heterogeneous and prolonged, due to delayed diagnosis and various or unknown microbial etiology. The study suggests that back pain, fever, and increased C-reactive protein levels are frequent in patients with PVO, and efforts should be made on securing early diagnosis and microbial etiology. Further studies of predictors of different clinical outcomes are warranted. Treatment of culture-negative cases and clinical value of bone biopsies are of special interest.

Liver-related morbidity and mortality in patients with chronic hepatitis C and cirrhosis with and without sustained virologic response.

BACKGROUND: Chronic hepatitis C (CHC) causes liver cirrhosis in 5%-20% of patients, leading to increased morbidity and mortality. This study aimed to estimate liver-related morbidity and mortality among patients with CHC and cirrhosis in Denmark with and without antiviral treatment and sustained virologic response (SVR). Furthermore we aimed to estimate the rate of hepatocellular carcinoma (HCC) and decompensation associated with certain prognostic factors. MATERIALS AND METHODS: Patients with CHC and cirrhosis registered in the Danish Database for Hepatitis B and C were eligible. Cirrhosis was based on liver biopsy, transient elastography, and clinical cirrhosis. Data were extracted from nationwide registries. The study period was from 2002 until 2013. RESULTS: Of 1,038 patients included, 716 (69%) were male and the median age was 52 years. Median follow-up was 3.8 years, 360 patients died, and 233 of 519 treated patients achieved SVR. Alcohol overuse and hepatitis C virus genotype 3 were associated with an increased incidence rate (IR) of HCC, whereas diabetes and alcohol overuse were associated with increased IRs of decompensation. Achieving SVR reduced all-cause mortality (adjusted mortality rate ratio 0.68 [95% CI 0.43-1.09]) and liver-related mortality (mortality rate ratio 0.6 [95% CI 0.36-1]), as well as liver-related morbidity with adjusted IR ratios of 0.37 (95% CI 0.22-0.62) for HCC and 0.31 (95% CI 0.17-0.57) for decompensation. The IRs of HCC and decompensation remained elevated in patients with alcohol overuse after SVR. CONCLUSION: Alcohol overuse, hepatitis C genotype 3, and diabetes were associated with liver-related morbidity in patients with CHC and cirrhosis. SVR markedly reduced liver-related morbidity and mortality; however, special attention to patients with alcohol overuse should continue after SVR.

Vertical transmission of hepatitis B virus during pregnancy and delivery in Denmark.

OBJECTIVE: In Denmark, pregnant women have been screened for hepatitis B virus (HBV) since 2005, and children born to HBV-infected mothers offered hepatitis B immunoglobulin at birth, vaccination against HBV at birth and after 1, 2 and 12 months. The purpose of this study was to determine the risk of vertical HBV transmission in children born to mothers with chronic HBV infection, to investigate the antibody response in the children and to investigate possible maternal predictive risk factors for HBV transmission. MATERIALS AND METHODS: Through the Danish Database for Hepatitis B and C, we identified 589 HBV-infected women who had given birth to 686 children, of whom 370 children were born to 322 women referred to hospital. 132 (36%) children, born to 109 mothers, were included in the study; 128 children had blood samples tested for HBsAg, anti-HBc (total), anti-HBs and HBV-DNA and four children had saliva samples tested for anti-HBc. RESULTS: We found vertical HBV transmission in Denmark to be 2.3% [95% CI: 0.5, 6.5], a high proportion of HBsAg-negative children with low levels of anti-HBs (18.4%) and a high proportion (15.2%) with resolved HBV infection. No maternal risk factor was statistically significantly associated with HBV vertical transmission. CONCLUSION: In a HBV low prevalence setting as Denmark, despite a national vaccination program, vertical HBV transmission occurred in 2.3% of children born to HBV-infected mothers. In addition, a high proportion of the children had insufficient anti-HBs levels and a high proportion had serological signs of resolved HBV infection.

[Diagnostics and treatment of spondylodiscitis].

Spondylodiscitis, infection of the spine and intervertebral discs, is a rare condition with increasing incidence. Early diagnosis can be challenging due to the non-specific symptoms such as back pain and fever. Diagnosis is verified by MRI. Microbial aetiology is pursued by blood cultures or surgical biopsy, however, some cases remain culture-negative. Long-term antibiotic treatment is standard of care. Some patients receive surgical treatment. One-year mortality is up to 20%. Recently, published data suggest that six weeks of antibiotics equals 12 weeks in culture-positive cases.

Changes in antimicrobial susceptibility patterns of Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus over the past decade.

INTRODUCTION: Development of antimicrobial resistance is an ongoing and increasing problem. To provide the best possible treatment for patients it is crucial that clinicians are aware of the local antimicrobial susceptibility patterns. The aim of this study was to present an overview of the percentage of bacterial isolates that are covered by the most commonly used antibiotics in the area of Copenhagen and to provide clinicians with a practical tool to help chose the right antimicrobial treatment for their patients. METHODS: We conducted a study of all bacteria isolates tested for antimicrobial susceptibility at Hvidovre Hospital, Denmark, from 2004 to 2008. Due to a suspected rise in resistance in Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae after this period, updated data for these bacteria are shown for selected antibiotics until 2014. The department receives samples from hospitals as well as from primary healthcare. Only one isolate per species per patient per year was included. RESULTS: A total of 224,033 bacteria isolates were included in this study. The antimicrobial susceptibility of the various bacteria is presented in a table. No clinically relevant changes in resistance patterns were noted up to 2014. CONCLUSIONS: A comprehensive and manageable inventory of the resistance patterns of the major bacteria covering the 2004-2008 period is presented. Clinicians are encouraged to use the pocket-size table as guidance when choosing antibiotic treatment. FUNDING: none. TRIAL REGISTRATION: not relevant.

Antiretroviral therapy adherence strategies used by patients of a large HIV clinic in Lesotho.

A high degree of adherence to antiretroviral therapy (ART) in patients infected with human immunodeficiency virus (HIV) is necessary for long term treatment effects. This study explores the role of timing of ART intake, the information patients received from health workers, local adherence patterns, barriers to and facilitators of ART among 28 HIV-positive adults at the Senkatana HIV Clinic in Maseru, Lesotho. This qualitative, semi-structured interview study was carried out during February and March of 2011 and responses were analyzed inspired by the Grounded Theory method. Results were then compared and discussed between the authors and the main themes that emerged were categorized. The majority of the respondents reported having missed one or more doses of medicine in the past and it was a widespread belief among patients that they were required to skip the dose of ART if they were "late". The main barriers to adherence were interruptions of daily routines or leaving the house without sufficient medicine. The use of mobile phone alarms, phone clocks and support from family and friends were major facilitators of adherence. None of the patients reported to have been counseled on family support or the use of mobile phones as helpful methods in maintaining or improving adherence to ART. Being on-time with ART was emphasized during counseling by health workers. In conclusion, patients should be advised to take the dose as soon as they remember instead of skipping the dose completely when they are late. Mobile phones and family support could be subjects to focus on during future counseling particularly with the growing numbers of mobile phones in Africa and the current focus on telemedicine.

Nationwide experience of treatment with protease inhibitors in chronic hepatitis C patients in Denmark: identification of viral resistance mutations.

BACKGROUND AND AIMS: The first standard of care in treatment of chronic HCV genotype 1 infection involving directly acting antivirals was protease inhibitors telaprevir or boceprevir combined with pegylated-interferon and ribavirin (triple therapy). Phase III studies include highly selected patients. Thus, treatment response and development of viral resistance during triple therapy in a routine clinical setting needs to be determined. The aims of this study were to investigate treatment outcome and identify sequence variations after triple therapy in patients with chronic HCV genotype 1 infection in a routine clinical setting. METHODS: 80 patients, who initiated and completed triple therapy in Denmark between May 2011 and November 2012, were included. Demographic data and treatment response were obtained from the Danish Database for Hepatitis B and C. Direct sequencing and clonal analysis of the RT-PCR amplified NS3 protease were performed in patients without cure following triple therapy. RESULTS: 38 (47%) of the patients achieved cure, 15 (19%) discontinued treatment due to adverse events and remained infected, and 27 (34%) experienced relapse or treatment failure of whom 15 of 21 analyzed patients had well-described protease inhibitor resistance variants detected. Most frequently detected protease variants were V36M and/or R155K, and V36M, in patients with genotype 1a and 1b infection, respectively. CONCLUSIONS: The cure rate after triple therapy in a routine clinical setting was 47%, which is substantially lower than in clinical trials. Resistance variants towards protease inhibitors were seen in 71% of patients failing therapy indicating that resistance could have an important role in treatment response.