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).

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.

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.

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.

Incidence and characteristics of sexually transmitted acute hepatitis C virus infection among HIV-positive men who have sex with men in Copenhagen, Denmark during four years (2006-2009): a retrospective cohort study.

We determined the incidence of hepatitis C virus among Danish human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) and described their characteristics. We included 871 HIV-positive MSM seen from 1 January 2006 to 31 December 2009 at Rigshospitalet in Copenhagen; drug users were excluded. We found 13 incident infections, i.e. a yearly incidence of 0.4%.

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.

Physicians' communication with patients about adherence to HIV medication in San Francisco and Copenhagen: a qualitative study using Grounded Theory.

BACKGROUND: Poor adherence is the main barrier to the effectiveness of HIV medication. The objective of this study was to explore and conceptualize patterns and difficulties in physicians' work with patients' adherence to HIV medication. No previous studies on this subject have directly observed physicians' behavior. METHODS: This is a qualitative, cross-sectional study. We used a Grounded Theory approach to let the main issues in physicians' work with patients' adherence emerge without preconceiving the focus of the study. We included physicians from HIV clinics in San Francisco, U.S.A. as well as from Copenhagen, Denmark. Physicians were observed during their clinical work and subsequently interviewed with a semi-structured interview guide. Notes on observations and transcribed interviews were analyzed with NVivo software. RESULTS: We enrolled 16 physicians from San Francisco and 18 from Copenhagen. When we discovered that physicians and patients seldom discussed adherence issues in depth, we made adherence communication and its barriers the focus of the study. The main patterns in physicians' communication with patients about adherence were similar in both settings. An important barrier to in-depth adherence communication was that some physicians felt it was awkward to explore the possibility of non-adherence if there were no objective signs of treatment failure, because patients could feel "accused." To overcome this awkwardness, some physicians consciously tried to "de-shame" patients regarding non-adherence. However, a recurring theme was that physicians often suspected non-adherence even when patients did not admit to have missed any doses, and physicians had difficulties handling this low believability of patient statements. We here develop a simple four-step, three-factor model of physicians' adherence communication. The four steps are: deciding whether to ask about adherence or not, pre-questioning preparations, phrasing the question, and responding to the patient's answer. The three factors/determinants are: physicians' perceptions of adherence, awkwardness, and believability. CONCLUSION: Communication difficulties were a main barrier in physicians' work with patients' adherence to HIV medication. The proposed model of physicians' communication with patients about adherence--and the identification of awkwardness and believability as key issues--may aid thinking on the subject for use in clinical practice and future research.

[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.

Patients' answers to simple questions about treatment satisfaction and adherence and depression are associated with failure of HAART: a cross-sectional survey.

Psychosocial and behavioral factors have been shown to be associated with adherence to highly active antiretroviral therapy (HAART) and treatment effectiveness. These factors have often been identified in selected populations through complex or time-consuming questionnaires. In this study we aimed at asking all the patients of a large population-based cohort receiving HAART a few short, explicit, and direct questions about these factors, and to examine the associations between their answers and prevalent treatment failure. All patients receiving HAART in western Denmark and central Copenhagen were offered participation. Participants answered a short, self-administered, anonymous questionnaire assessing psychosocial and behavioral factors and treatment adherence. Findings were linked with data on demographics, disease history, and treatment effect. Treatment failure was defined as two consecutive measurements of HIV-RNA above 400 copies per milliliter taken at least 14 days apart. Prevalence odds ratios were estimated by logistic regression. We found that a total of 887 of 1126 patients returned a completed questionnaire (response rate 79%). The overall rate of treatment failure in participants was 20%. Adjusted odds ratio estimates for treatment failure were 2.3 (confidence interval [CI] 1.3-4.3) for patients who stated poor treatment satisfaction, 2.1 (CI 1.2-3.7) for patients not fully disagreeing that they were depressed, and 2.8 (CI 1.5-5.4) for patients who stated to have been nonadherent within the preceding 4 days. Because of the cross-sectional nature of the study, causality could not be determined. These questions, however, may be relevant screening tools in clinical practice and in follow-up studies.

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.

[Whipple's disease]. / Whipples sygdom.

Whipple's disease (WD) is a rare, chronic, systemic infection caused by the bacterium Tropheryma whipplei. New molecular techniques and epidemiological data over the latest decade have contributed to better understanding of this infection. The classical form of WD is characterized by arthritis followed years after by diarrhoea, weight loss and malabsorption but other clinical forms without intestinal involvement have been described. Prompt recognition and treatment of the infection is important, as the disease can be fatal if untreated. New studies are required to establish the optimal therapy regimen.

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.

[Intracerebral abscess after infection with non-toxigenic Vibrio cholerae]. / Cerebral absces med Vibrio cholerae non-01 efter badning i dansk havvand.

We present the first case of intracerebral abscess after blood-borne infection with non-toxigenic Vibrio cholerae (non-01). The patient was a 66 year-old woman who was infected after swimming in Danish seawater during an unusually hot summer. She had predisposing haemochromatosis and a skin lesion on the ankle. We treated the patient with meropenem and ciprofloxacin for six weeks followed by ciprofloxacin for four weeks, and she recovered with hemiparesis and speech impairment. Marine Vibrio species may produce intracranial infection in predisposed individuals, even in temperate climate zones.

Subconjunctival Dirofilaria repens Infestation: A Light and Scanning Electron Microscopy Study.

BACKGROUND: To present a case of subconjunctival infestation with Dirofilaria repens which is very rare in Northern Europe. METHODS: A 61-year-old male presented with a swelling and redness of the left supraorbital region migrating to the eyelid and the left eyeball resulting in conjunctival injection, proptosis and diplopia. The patient underwent incisional extraction of a nine cm long worm, which was analysed histologically. RESULTS: The worm was structureless, greyish-white in colour and measuring nine cm in length and 0.5 mm in diameter. Histopathological examination of the worm showed an outer thick, multi-layered cuticle with longitudinal ridges. Beneath the cuticle, a thick muscle layer was observed and internally the intestine and a single reproductive tube containing spermatozoa were noted. Scanning electron microscopy of the worm showed tapered ends, transverse striations and longitudinal ridges at the anterior end. The tail was relatively short with spirally coiled ridges indicating a male Dirofilaria repens. CONCLUSIONS: Humans are an uncommon and accidental host of Dirofilaria repens which is rarely seen in Northern Europe but should be considered as a differential diagnosis to other nematode ocular infections. A travel history is helpful in diagnosing the potential involved organisms. No further treatment is necessary beyond surgical removal since this organism fails to mature and thereby does not cause microfilariaemia in humans.

[Actinomyces diagnosed after prolonged clinical investigation focused on cancer]. / Aktinomykose diagnosticeret efter langvarig cancerudredning.

We describe a prolonged diagnostic process of 7 months before an infection with Actinomyces species could be diagnosed. Initially, a malignant tumour of the pelvic area was suspected. The patient underwent 3 CT-scans, 4 ultrasound scans and 5 biopsies before the diagnosis was suspected. Only the fourth microbiological investigation could confirm the diagnosis. This case emphasizes the necessity of microbiological examination of biopsies, when a tumour is found and malignancy cannot be confirmed, and is a reminder of Actinomyces species as an important pathogen in such cases.

[Chikungunya fever, "that which bends". Epidemic in Africa and Asia--several cases imported to Denmark]. / Chikungunya-feber: den sammenbøjede. Epidemi i Afrika og Asien--enkelte tilfaelde importeret til Danmark.

Within the last year there has been a re-emergence of chikungunya fever in Africa, Asia and several of the islands in the Indian Ocean. Chikungunya fever is caused by the alfa virus chikungunya, which is transmitted by the Aedes mosquito. Travellers as well as the local population are at risk, and several cases have been imported to Denmark. We review the epidemiology, aetiology, symptoms, diagnosis and treatment. The main symptoms are fever, arthralgia and rash. No vaccination or specific treatment exist and therefore travellers must try to avoid mosquito bites.