Bacteremia With Anaerobic Bacteria and Association With Colorectal Cancer: A Population-based Cohort Study.

BACKGROUND: There is a well-described association between bacteremia with bovis group streptococci or Clostridium septicum and an increased probability of a colorectal cancer (CRC) diagnosis. We wanted to investigate the existence of a similar association between CRC and bacteremia with other bacteria belonging to the gut microbiota.. METHODS: A population based cohort study in a population about 2 million people including 45 774 bacteremia episodes and 231 387 blood culture negative cases was performed in the Region of Southern Denmark and Region Zealand from 2007-2016. Episodes of bacteremia were combined with the Danish central register for CRC. We performed Cox's regression analysis with hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The study results confirmed previous findings of an increased risk of a CRC diagnosis after bacteremia with the bovis group streptococci (risk within a year: 4.3%; HR [95% CI]: 8.46 [3.51-20.4]) or C. septicum (20.8%; 76.2 [42.0-138]). Furthermore, Bacteroides ovatus (6.7%; 20.3 [5.04-81.8]), Bacteroides uniformis (5.4%; 16.2 [4.02-65.7]), Clostridium tertium (3.6 %; 13.9 [1.96-99.4]), Fusobacterium spp. (excluding F. necrophorum) (3.0 %; 8.51 [2.73-26.5]), and Gram-positive anaerobic cocci (3.6 %; 10.9 [4.50-26.3]) were also associated with an increased risk of a CRC diagnosis compared to patients with negative blood cultures (0.4%). CONCLUSIONS: Bacteremia with specific gut microbiota anaerobic bacteria is associated with a high risk of a diagnosis of CRC, indicating the need for colorectal workup. Importantly, this strategy also holds the possible additional benefit of detecting adenomas or other premalignant conditions, which were not included in the present study.

Tuberculosis incidence and mortality in people living with human immunodeficiency virus: a Danish nationwide cohort study.

OBJECTIVES: To explore changes over time in the epidemiology of tuberculosis (TB) in Denmark in people living with human immunodeficiency virus (HIV) (PLWH). METHODS: In this nationwide, population-based cohort study we included all adult PLWH from the Danish HIV Cohort Study (1995-2017) without previous TB. We estimated TB incidence rate (IR), all-cause mortality rate (MR), associated risk and prognostic factors using Poisson regression. RESULTS: Among 6982 PLWH (73 596 person-years (PY)), we observed 217 TB events (IR 2.9/1000 PY, 95% CI 2.6-3.4: IR 6.7, 95% CI 5.7-7.9 among migrants and IR 1.4, 95% CI 1.1-1.7 among Danish-born individuals; p < 0.001). The IR of concomitant HIV/TB remained high and unchanged over time. The IR of TB diagnosed >3 months after HIV diagnosis declined with calendar time, longer time from HIV diagnosis, and CD4 cell recovery. Independent TB risk factors were African/Asian/Greenland origin (adjusted incidence rate ratio (aIRR) 5.2, 95% CI 3.5-7.6, aIRR 6.5, 95% CI 4.2-10.0, aIRR 7.0, 95% CI 3.4-14.6, respectively), illicit drug use (aIRR 6.9, 95% CI 4.2-11.2), CD4 <200 cells/µL (aIRR 2.7, 95% CI 2.0-3.6) and not receiving antiretroviral therapy (aIRR 3.7, 95% CI 2.5-5.3). Fifty-five patients died (MR 27.9/1000 PY, 95% CI 21.4-36.3), with no improvement in mortality over time. Mortality prognostic factors were Danish-origin (adjusted mortality rate ratio (aMRR) 2.3, 95% CI 1.3-4.3), social burden (aMRR 3.9, 95% CI 2.2-7.0), CD4 <100 cells/µL at TB diagnosis (aMRR 2.6, 95% CI 1.3-4.9), TB diagnosed >3 months after HIV versus concomitant diagnosis (aMRR 4.3, 95% CI 2.2-8.7) and disseminated TB (aMRR 3.3, 95% CI 1.1-9.9). CONCLUSION: Late HIV presentation with concomitant TB remains a challenge. Declining TB rates in PLWH were observed over time and with CD4 recovery, highlighting the importance of early and successful antiretroviral therapy. However, MR remained high. Our findings highlight the importance of HIV and TB screening strategies and treatment of latent TB in high-risk groups.

C-reactive protein and albumin kinetics after antibiotic therapy in community-acquired bloodstream infection.

OBJECTIVES: We assessed C-reactive protein (CRP) and plasma albumin (PA) kinetics to evaluate community-acquired bloodstream infection (CA-BSI) patients' 1-year outcomes. METHODS: Population-based study, with CRP and PA measurements on day 1 (D1) and D4. Relative CRP variations in relation to D1 CRP value were evaluated (CRP-ratio). Patients were classified as fast response, slow response, non-response, and biphasic response. RESULTS: A total of 935 patients were included. At D4, the CRP-ratio was lower in survivors on D365 in comparison with D4-D30 non-survivors and D30-D365 non-survivors (p<0.001). In comparison with fast response patients, non-response and biphasic response patients had 2.74 and 5.29 increased risk, respectively, of death in D4-D30 and 2.77 and 3.16 increased risk, respectively, of death in D31-D365. PA levels remained roughly unchanged from D1-D4, but lower D1 PA predicted higher short and long-term mortality (p<0.001). The discriminative performance of the CRP-ratio and D1 PA to identify patients with poor short and long-term mortality after adjustments was acceptable (AUROC=0.79). CONCLUSIONS: Serial CRP measurements at D1 and D4 after CA-BSI is clinically useful to identify patients with poor outcome. Individual patterns of CRP-ratio response with PA at D1 further refine our ability of predicting short or long-term mortality.

Prescription of antimicrobials in primary health care as a marker to identify people living with undiagnosed HIV infection, Denmark, 1998 to 2016.

BackgroundDevelopment of additional diagnostic strategies for earlier HIV diagnosis are needed as approximately 50% of newly diagnosed HIV-infected individuals continue to present late for HIV care.AimWe aimed to analyse antimicrobial consumption in the 3 years preceding HIV diagnosis, assess whether there was a higher consumption in those diagnosed with HIV compared with matched controls and whether the level of consumption was associated with the risk of HIV infection.MethodsWe conducted a nested case-control study, identifying all individuals (n = 2,784 cases) diagnosed with HIV in Denmark from 1998 to 2016 and 13 age-and sex-matched population controls per case (n = 36,192 controls) from national registers. Antimicrobial drug consumption was estimated as defined daily doses per person-year. We used conditional logistic regression to compute odds ratios and 95% confidence intervals.ResultsIn the 3 years preceding an HIV diagnosis, we observed more frequent and higher consumption of antimicrobial drugs in cases compared with controls, with 72.4% vs 46.3% having had at least one prescription (p < 0.001). For all antimicrobial classes, the association between consumption and risk of subsequent HIV diagnosis was statistically significant (p < 0.01). The association was stronger with higher consumption and with shorter time to HIV diagnosis.ConclusionHIV-infected individuals have a significantly higher use of antimicrobial drugs in the 3 years preceding HIV diagnosis than controls. Prescription of antimicrobial drugs in primary healthcare could be an opportunity to consider proactive HIV testing. Further studies need to identify optimal prescription cut-offs that could endorse its inclusion in public health policies.

Improving the evidence for indicator condition guided HIV testing in Europe: Results from the HIDES II Study - 2012 - 2015.

BACKGROUND: It is cost-effective to perform an HIV test in people with specific indicator conditions (IC) with an undiagnosed HIV prevalence of at least 0.1%. Our aim was to determine the HIV prevalence for 14 different conditions across 20 European countries. METHODS: Individuals aged 18-65 years presenting for care with one of 14 ICs between January 2012 and June 2014 were included and routinely offered an HIV test. Logistic regression assessed factors associated with testing HIV positive. Patients presenting with infectious mononucleosis-like syndrome (IMS) were recruited up until September 2015. RESULTS: Of 10,877 patients presenting with an IC and included in the analysis, 303 tested positive (2.8%; 95% CI 2.5-3.1%). People presenting with an IC in Southern and Eastern Europe were more likely to test HIV positive as were people presenting with IMS, lymphadenopathy and leukocytopenia/ thrombocytopenia. One third of people diagnosed with HIV after presenting with IMS reported a negative HIV test in the preceding 12 months. Of patients newly diagnosed with HIV where data was available, 92.6% were promptly linked to care; of these 10.4% were reported lost to follow up or dead 12 months after diagnosis. CONCLUSION: The study showed that 10 conditions had HIV prevalences > 0.1%. These 10 ICs should be adopted into HIV testing and IC specialty guidelines. As IMS presentation can mimic acute HIV sero-conversion and has the highest positivity rate, this IC in particular affords opportunities for earlier diagnosis and public health benefit.

Clinical value of FDG-PET/CT in bacteremia of unknown origin with catalase-negative gram-positive cocci or Staphylococcus aureus.

INTRODUCTION: Bacteremia is associated with high mortality, especially when the site of infection is unknown. While conventional imaging usually focus on specific body parts, FDG-PET/CT visualizes hypermetabolic foci throughout the body. PURPOSE: To investigate the ability of FDG/PET-CT to detect the site of infection and its clinical impact in bacteremia of unknown origin with catalase-negative Gram-positive cocci (excluding pneumococci and enterococci) or Staphylococcus aureus (BUOCSA). METHODS: We retrospectively identified 157 patients with 165 episodes of BUOCSA, who subsequently underwent FDG-PET/CT. Data were collected from medical records. Decision regarding important sites of infection in patients with bacteremia was based on the entire patient course and served as reference diagnosis for comparison with FDG-PET/CT findings. FDG-PET/CT was considered to have high clinical impact if it correctly revealed site(s) of infection in areas not assessed by other imaging modalities or if other imaging modalities were negative/equivocal in these areas, or if it established a new clinically relevant diagnosis, and/or led to change in antimicrobial treatment. RESULTS: FDG-PET/CT detected sites of infection in 56.4% of cases and had high clinical impact in 47.3%. It was the first imaging modality to identify sites of infection in 41.1% bacteremia cases, led to change of antimicrobial therapy in 14.7%, and established a new diagnosis unrelated to bacteremia in 9.8%. Detection rate and clinical impact were not significantly influenced by duration of antimicrobial treatment preceding FDG-PET/CT, days from suspicion of bacteremia to FDG-PET/CT-scan, type of bacteremia, or cancer. CONCLUSION: FDG-PET/CT appears clinically useful in BUOCSA. Prospective studies are warranted for confirmation.

Risk factors for contagious gastroenteritis in adult patients with diarrhoea in the emergency department - a prospective observational multicentre study.

BACKGROUND: Infectious gastroenteritis is common in the emergency department (ED). Patients infected with either Norovirus or toxigenic Clostridium difficile require special isolation procedures. The aims were to describe the aetiology of infectious gastroenteritis in the ED, evaluate whether current isolation procedures, based on clinical judgement are sufficient, and to identify information that might be used to identify patients requiring isolation. METHODS: Prospective, observational, multicentre study. We collected information on symptoms, vital signs, travel history, the recent use of antibiotics, and infectious contacts and tested faecal samples for Norovirus, C. difficile, and enteropathogenic bacteria. RESULTS: The study enrolled 227 patients, of whom 163 (71%) delivered a faecal sample for Norovirus analysis (13% positive), 171 (74%) for C. difficile (13% positive), and 173 (76%) for enteropathogenic bacteria (16% positive). In total 71% of the patients were isolated using strict precautions, 29% of the isolated patient and 14% of the patients who were not isolated had had a highly contagious GE. Risk factors for Norovirus included frequent vomiting (OR 5.5), recent admission of another patient with Norovirus (OR 2.6), and a short duration of diarrhoea. Risk factors for C. difficile infections included older age (OR 6.0), longer duration of diarrhoea (OR 5.2), mucus in stool (OR 3.5), and previous antibiotic use (OR 23.4). CONCLUSION: Highly contagious GE occurs in » of the GE patients in the EDs, isolation based on clinical judgement is not very efficient. Several risk factors can predict the presence of Norovirus or toxigenic Clostridium difficile. It is uncertain whether this knowledge can improve isolation practices in ED settings. TRIAL REGISTRATION: This study was retrospectively registered in the Clinical Trials Data Base ( NCT02685527 ) and prospectively approved by the Regional Committees on Health Research Ethics for Southern Denmark (project ID S20140200) and Ethics Committee at the Medical Association of Schleswig-Holstein ["Ethikkommission bei der Ärztekammer Schleswig-Holstein", project ID 120/15(I)] and registered with the Danish Data Protection Agency (project ID nr. 2008-58-0035/ 1608).

Focus of infection and microbiological etiology in community-acquired infections in hospitalized adult patients in the Faroe Islands.

BACKGROUND: The aim of the present study was to gain national data on the clinical and microbiological characteristics of community-acquired infections in the Faroe Islands and to compare these data with data from other geographical areas. METHODS: A prospective, observational study involving all patients > = 16 years admitted at the Department of Medicine at the National Hospital, Torshavn, Faroe Islands from October 2013 until April 2015. RESULTS: Of 5279 admissions, 1054 cases were with community-acquired infection and were included in the study. Out of these 1054 cases, 471 did not meet the criteria for SIRS (Systemic Inflammatory Response Syndrome), while the remaining 583 cases had sepsis. Mean age was 68 years. At least one comorbidity was found in 80% of all cases. Documented infections were present in 75%, and a plausible pathogen was identified in 29% of all cases. The most common gram-positive pathogen was Staphylococcus aureus, and the most frequent gram-negative pathogen was Escherichia coli. The most common focus of infection was lower respiratory tract, followed by urinary tract, and skin-soft tissue/bone-joint. Bacteremia was found in 10% of the cases. CONCLUSION: In community-acquired infections in hospitalized patients in the Faroe Islands the lower respiratory tract and the urinary tract were the most frequent foci of infection. Gram-negative pathogens and Escherichia coli were the most frequent pathogens in infection without Systemic Inflammatory Response Syndrome, in sepsis and in bacteremia. Our data on clinical characteristics and microbiological etiology provide new information which may be used to develop local guidelines for the managing of patients admitted with community-acquired infections.

Epidemiology of community-acquired sepsis in the Faroe Islands - a prospective observational study.

INTRODUCTION: The aim of the study was to gather nation-wide epidemiological and clinical data in order to characterize community-acquired sepsis in the Faroe Islands, and to compare these data with epidemiological studies performed in other geographical areas. METHODS: A prospective, observational study conducted from October 2013 until April 2015 to characterize sepsis, and to calculate incidence rates for community-acquired sepsis of any severity, community-acquired severe sepsis, community-acquired septic shock and community-acquired sepsis without community-acquired severe sepsis or community-acquired septic shock. RESULTS: Of 5279 admissions, 583 cases fulfilled the criteria for community-acquired sepsis of any severity. The mean age of all cases was 67.6 ± 18.3 years. Men accounted for 298 (51.5%) admissions. Charlson comorbidity index was greater than 2 in 247 (42.4%) cases. The incidence of community-acquired sepsis of any severity was 1414/100,000 person-years at risk (95% CI, 1374-1440). The incidence rate for community-acquired sepsis without community-acquired severe sepsis and community-acquired septic shock was 719/100,000 person-years at risk (95% CI, 695-742), for community-acquired severe sepsis 644/100,000 person-years at risk (95% CI, 623-668), for community-acquired septic shock 51/100,000 person-years at risk (95% CI, 45-58). The highest incidence was seen in elderly patients. CONCLUSION: The incidence rates were slightly higher in men and increased with age, especially in those older than 85 years. Incidence rates of sepsis of any severity were higher than previously published from other countries.

Etiology of Shock in the Emergency Department: A 12-Year Population-Based Cohort Study.

INTRODUCTION: The knowledge of the etiology and associated mortality of undifferentiated shock in the emergency department (ED) is limited. We aimed to describe the etiology-based proportions and incidence rates (IR) of shock, as well as the associated mortality in the ED. METHODS: Population-based cohort study at a University Hospital ED in Denmark from January 1, 2000, to December 31, 2011. Patients aged ≥18 years living in the ED-catchment area (N = 225,000) with a first-time ED presentation with shock (n = 1,553) defined as hypotension (systolic blood pressure ≤100 mm Hg) and ≥1 organ failures were included. Discharge diagnoses defined the etiology and were grouped as follows: distributive septic shock (SS), distributive non-septic shock (NS), cardiogenic shock (CS), hypovolemic shock (HS), obstructive shock (OS), and other conditions (OC). Outcomes were etiology-based characteristics, annual IR per 100,000 person-years at risk (95% confidence intervals [CIs]), mortality at 0 to 7-, and 0 to 90 days (95% CIs) and hazard rates (HR) at 0 to 7, 8 to 90 days (95% CIs). Poisson and Cox regression models were used for analyses. RESULTS: Among 1,553 shock patients: 423 (27.2%) had SS, 363 (23.4%) NS, 217 (14.0%) CS, 479 (30.8%) HS, 14 (0.9%) OS, and 57 (3.7%) OC. The corresponding IRs were 16.2/100,000 (95% CI: 14.8-17.9), 13.9/100,000 (95% CI: 12.6-15.4), 8.3/100,000 (95% CI: 7.3-9.5), 18.4/100,000 (95% CI: 16.8-20.1), 0.5/100,000 (95% CI: 0.3-0.9), and 2.2/100,000 (95% CI: 1.7-2.8). SS IR increased from 8.4 to 28.5/100,000 during the period 2000 to 2011. Accordingly, the 7-, and 90-day mortalities of SS, NS, CS, and HS were 30.3% (95% CI: 25.9-34.7) and 56.2% (95% CI: 50.7-61.5), 12.7% (95% CI: 9.2-16.1) and 22.6% (95% CI: 18.1-27.7), 34.6% (95% CI: 28.2-40.9) and 52.3% (95% CI: 44.6-59.8), 19.2% (95% CI: 15.7-22.7), and 36.8% (95% CI: 33.3-43.3). SS (HR = 1.46 [95% CI: 1.03-2.07]), and CS (HR = 2.15 [95% CI: 1.47-3.13]) were independent predictors of death within 0 to 7 days, whereas SS was a predictor within 8 to 90 days (HR = 1.66 [95% CI: 1.14-2.42]). CONCLUSION: HS and SS are frequent etiological characteristics followed by NS and CS, whereas OS is a rare condition. We confirm the increasing trend of SS, as previously reported. Seven-day mortality ranged from 12.7% to 34.6%, while 90-day mortality ranged from 22.6% to 56.2%. The underlying etiology was an independent predictor of mortality.

Prediction of 28-days mortality with sequential organ failure assessment (SOFA), quick SOFA (qSOFA) and systemic inflammatory response syndrome (SIRS) - A retrospective study of medical patients with acute infectious disease.

AIMS: Evaluating the use of sequential organ failure assessment (SOFA) ≥ 2 compared to quick SOFA (qSOFA) and to systemic inflammatory response syndrome (SIRS) in assessing 28-days mortality in medical patients with acute infection. METHODS: In total, 323 patients with verified infection were stratified in accordance to Sepsis-3. SOFA, qSOFA and SIRS were calculated using registered variables. Adverse outcome was death within 28-days of admission. RESULTS: In total, 190 (59%) patients had a SOFA score≥2 and the overall in-hospital mortality was 21 (6%). Scores of SOFA and qSOFA were both significantly elevated in non-survivors. SOFA showed good accuracy (Area under the receiver operating characteristic (AUROC)=0.83, 95% CI, 0.76 - 0.90) for 28-days mortality compared with qSOFA (AUROC=0.67, 95% CI, 0.54 - 0.80) and SIRS (AUROC=0.62, 95% Cl 0.49 - 0.74). SOFA was≥2 in all patients who died, while qSOFA and SIRS was≥2 in 8 (38%) and 17 (81%) of the patients who died, respectively. CONCLUSION: SOFA score≥2 was better than SIRS and qSOFA to predict mortality within 28-days of admission among patients with acute infectious disease.

Real-life data patterns of C-reactive protein and albumin level trajectories around bacteremia.

AIM: To assess trajectory patterns of C-reactive protein (CRP) and plasma albumin (PA) levels around bacteremia. PATIENTS & METHODS: Population-based study, 2418 community-acquired bacteremia patients, CRP and PA specimens from 30 days before through 30 days after bacteremia (day 0). A pattern was based on specimen occurring or not in days -30/-1, 0, 1/7 or 8/30. Mean daily CRP and PA levels on day -30/30 were computed for pattern subgroups. RESULTS & CONCLUSION: Mean CRP rose on day -5 and reached its peak on day 1. Mean steady PA on day -30/0 declined abruptly on day 1, increasing slowly thereafter. Trajectories did not differ between subgroups. We conclude that longitudinal analysis results can be extrapolated to all community-acquired bacteremia patients.

Risk of skin cancer in patients with HIV: A Danish nationwide cohort study.

BACKGROUND: The risk of skin cancer in patients with HIV has not been extensively studied. OBJECTIVE: We sought to determine the risk of skin cancer in patients with HIV and compare it with the risk in the background population. METHODS: In a matched, nationwide, population-based cohort study, we compared the risk of skin cancer in 4280 patients with HIV from the Danish HIV cohort study with a background population cohort, according to the level of immunosuppression and route of transmission. Primary outcomes were time to first basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or malignant melanoma. RESULTS: Patients with HIV had an increased risk of BCC and SCC with incident rate ratios of 1.79 (95% confidence interval 1.43-2.22) and 5.40 (95% confidence interval 3.07-9.52), respectively, compared with the background population. We observed no increased risk of malignant melanoma. Low nadir CD4 cell count was associated with an increased risk of SCC. The increased risk of BCC among patients with HIV was restricted to men who had sex with men. LIMITATIONS: This study was observational and included a small number of patients with melanoma. CONCLUSION: Patients with HIV have an increased risk of BCC and SCC. Low nadir, but not current, CD4 cell count as a marker of immunosuppression was associated with an increased risk of SCC.

The macrophage activation marker sMR as a diagnostic and prognostic marker in patients with acute infectious disease with or without sepsis.

Sepsis is a leading cause of mortality. This study aims to assess the utility of the soluble mannose receptor (sMR) as a biomarker of sepsis and mortality in patients hospitalized with suspected infection. Using an in-house ELISA assay the concentration of sMR was analyzed in the serum of patients from three prospective studies. Using Sepsis-3 guidelines, patients were stratified as no infection (NI, n = 68), verified infection without sepsis (NSEP, n = 133) and verified infection with sepsis (SEP, n = 190). Adverse outcome was assessed as death before 28 days. We show that the sensitivity of sMR to predict mortality [area under curve (AUC) = 0.77] exceeded the sensitivity of procalcitonin (PCT, AUC = 0.63), C-reactive protein (CRP, AUC = 0.61) and the macrophage soluble receptor, CD163 (sCD163, AUC = 0.74), while it was less accurate to predict diagnosis of sepsis [AUC(sMR) = 0.69 vs. AUC(PCT) = 0.79, AUC(CRP) = 0.71 and AUC(sCD163) = 0.66]. Median sMR was significantly higher in the group with SEP (0.55 mg/L), compared with the groups without sepsis (NI and NSEP) (0.39 mg/L, p < .0001), and among those who died compared to those who survived (0.89 mg/L vs. 0.44 mg/L, p < .0001). Our results, and the current literature, support further evaluation of sMR as a biomarker of sepsis and mortality among patients hospitalized with suspected infection.

Late Presentation for Care Among Patients With Chronic Hepatitis C: Prevalence and Risk Factors.

Patients with chronic hepatitis C may have advanced fibrosis at first evaluation. Using the European Association for the Study of the Liver (EASL) definition (FibroScan® >9.5 kPa) for "late presenter for care" (LP), we found that 32% (169 of 527) of patients were LP. Being a LP was associated with increasing age and a history of alcohol overuse.

Follicular bronchiolitis in an HIV-infected individual on combination antiretroviral therapy with low CD4+ cell count but sustained viral suppression.

A 36-year-old Danish man, living in Asia, was diagnosed with Pneumocystis pneumonia (PCP) and HIV in 2013 (CD4+ count: 6 cells/µL; viral load: 518 000 copies/mL). He initiated combination antiretroviral therapy. Later that year, he was also diagnosed with granulomatosis with polyangiitis and was treated with prednisolone. Despite complete viral suppression and increasing CD4+ count (162 cells/µL), he was readmitted with PCP in April 2015. Subsequently, he returned to Denmark (CD4+ count: 80 cells/µL, viral suppression). Over the following months, he developed progressive dyspnoea. Lung function tests demonstrated severely reduced lung capacity with an obstructive pattern and a moderately reduced diffusion capacity. High resolution computer tomography revealed minor areas with tree-in-bud pattern and no signs of air trapping on expiratory views. Lung biopsy showed lymphocytic infiltration surrounding the bronchioles with sparing of the alveolar septa. He was diagnosed with follicular bronchiolitis. The patient spontaneously recovered along with an improvement of the immune system.

Complete manuscript Title: Changes in RANKL during the first two years after cART initiation in HIV-infected cART naïve adults.

BACKGROUND: By assessing the changes in concentration of soluble receptor activator of nuclear factor κ B ligand (RANKL) and osteoprotegrin (OPG) after initiation of combination antiretroviral therapy (cART) in treatment-naïve HIV-infected patients we aimed to evaluate whether the initial accelerated bone loss could be mediated by increased soluble RANKL (sRANKL) levels associated with CD4+ T cell recovery. METHODS: We used multiplex immunoassays to determine sRANKL and OPG concentrations in plasma from 48 HIV patients at baseline and 12, 24, 48 and 96 weeks after cART initiation. RESULTS: Soluble RANKL changed significantly over time (overall p = 0.02) with 25% decrease (95% CI: -42 to -5) at week 24 compared to baseline and stabilized at a lower level thereafter. We found no correlation between CD4+ T cell count increment and changes in sRANKL or between percentage change in BMD and changes in sRANKL. CONCLUSION: In this study there was no indication that the accelerated bone loss after cART initiation was mediated by early changes in sRANKL due to CD4+ T cell recovery. Future studies should focus on the initial weeks after initiation of cART. TRIAL REGISTRATION: Clinical-Trial.gov . id NCT00135460 , August 25, 2005. The study was approved by the Danish Data Protection Agency, Danish Medicines Agency and Regional Ethics Committee.

Antiretrovirals, Fractures, and Osteonecrosis in a Large International HIV Cohort.

BACKGROUND: Antiretrovirals (ARVs) affect bone density and turnover, but their effect on risk of fractures and osteonecrosis of the femoral head is less understood. We investigated if exposure to ARVs increases the risk of both bone outcomes. METHODS: EuroSIDA participants were followed to assess fractures and osteonecrosis. Poisson regression identified clinical, laboratory and demographic predictors of either bone outcome. Ever, current, and cumulative exposures to ARVs were assessed. RESULTS: During 86118 PYFU among 11820 included persons (median age 41y, 75% male, median baseline CD4 440/mm3, 70.4% virologically suppressed), there were 619 fractures (incidence/1000 PYFU 7.2; 95% CI 6.6-7.7) and 89 osteonecrosis (1.0; 0.8-1.3). Older age, white race, lower BMI, IV drug use, lower baseline CD4, HCV coinfection, prior osteonecrosis, prior fracture, cardiovascular disease, and recent non-AIDS cancer (last 12 months) were associated with fractures. After adjustment, persons who had ever used tenofovir disoproxil fumarate (TDF) (1.40; 1.15-1.70) or who were currently on TDF (1.25; 1.05-1.49) had higher incidence of fractures. There was no association between cumulative exposure to TDF and fractures (1.08/5 y exposure; 0.94-1.25). No other ARV was associated with fractures (all P > .1). Risk of osteonecrosis was associated with white race, lower nadir CD4, prior osteonecrosis, prior fracture, and prior AIDS. After mutual adjustment, no ARV was associated with osteonecrosis. CONCLUSIONS: In human immunodeficiency virus (HIV) infection, host factors, HIV-specific variables, and comorbidities contribute to risk of fractures and osteonecrosis. Exposure to TDF, but not other ARVs, was an independent risk factor for fractures.