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1.  A Novel Fibrosis Index Comprising a Non-Cholesterol Sterol Accurately Predicts HCV-Related Liver Cirrhosis 
PLoS ONE  2014;9(4):e93601.
Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5–6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) = −12.17+ (age×0.11) + (BMI (kg/m2)×0.23) + (D7-lathosterol (μg/100 mg cholesterol)×(−0.013)) + (Platelet count (x109/L)×(−0.018)) + (Prothrombin-INR×3.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86–0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82–0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.
doi:10.1371/journal.pone.0093601
PMCID: PMC3974766  PMID: 24699777
2.  How Well Do Discharge Diagnoses Identify Hospitalised Patients with Community-Acquired Infections? – A Validation Study 
PLoS ONE  2014;9(3):e92891.
Background
Credible measures of disease incidence, trends and mortality can be obtained through surveillance using manual chart review, but this is both time-consuming and expensive. ICD-10 discharge diagnoses are used as surrogate markers of infection, but knowledge on the validity of infections in general is sparse. The aim of the study was to determine how well ICD-10 discharge diagnoses identify patients with community-acquired infections in a medical emergency department (ED), overall and related to sites of infection and patient characteristics.
Methods
We manually reviewed 5977 patients admitted to a medical ED in a one-year period (September 2010-August 2011), to establish if they were hospitalised with community-acquired infection. Using the manual review as gold standard, we calculated the sensitivity, specificity, predictive values, and likelihood ratios of discharge diagnoses indicating infection.
Results
Two thousand five hundred eleven patients were identified with community-acquired infection according to chart review (42.0%, 95% confidence interval [95%CI]: 40.8–43.3%) compared to 2550 patients identified by ICD-10 diagnoses (42.8%, 95%CI: 41.6–44.1%). Sensitivity of the ICD-10 diagnoses was 79.9% (95%CI: 78.1–81.3%), specificity 83.9% (95%CI: 82.6–85.1%), positive likelihood ratio 4.95 (95%CI: 4.58–5.36) and negative likelihood ratio 0.24 (95%CI: 0.22–0.26). The two most common sites of infection, the lower respiratory tract and urinary tract, had positive likelihood ratios of 8.3 (95%CI: 7.5–9.2) and 11.3 (95%CI: 10.2–12.9) respectively. We identified significant variation in diagnostic validity related to age, comorbidity and disease severity.
Conclusion
ICD-10 discharge diagnoses identify specific sites of infection with a high degree of validity, but only a moderate degree when identifying infections in general.
doi:10.1371/journal.pone.0092891
PMCID: PMC3963967  PMID: 24663388
3.  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.
Trial registration
ClinicalTrials.gov: NCT00132860.
doi:10.1186/1471-2466-13-77
PMCID: PMC3890498  PMID: 24373580
COPD; Inflammation; Mortality; Prognosis; YKL-40
5.  Statin Therapy and Mortality in HIV-Infected Individuals; A Danish Nationwide Population-Based Cohort Study 
PLoS ONE  2013;8(3):e52828.
Background
Recent studies have suggested that statins possess diverse immune modulatory and anti-inflammatory properties. As statins might attenuate inflammation, statin therapy has been hypothesized to reduce mortality in HIV-infected individuals. We therefore used a Danish nationwide cohort of HIV-infected individuals to estimate the impact of statin use on mortality before and after a diagnosis of cardiovascular disease, chronic kidney disease or diabetes.
Methods
We identified all Danish HIV-infected individuals (1,738) who initiated HAART after 1 January 1998, and achieved virological suppression within 180 days. Date of first redemption of a prescription of statin was obtained from the Danish National Prescription Registry. We used Poisson regression analysis to assess adjusted mortality rate ratios (aMRR). First, time was censored at date of virological failure (VL >500 copies/ml). Second, time was not censored at virological failure. All analyses were adjusted for potential confounders.
Results
In the analyses confined to observation time without virological failure (+ censoring) statin therapy was associated with a non-statistically significant reduced rate of death (aMRR 0.75; 95% CI: 0.33–1.68). No difference was observed in the analysis with no censoring (aMRR 1.17; 95% CI: 0.66–2.07). Use of statin seemed to reduce mortality in individuals after a diagnosis of comorbidity {(+ censoring: aMRR: 0.34; 95% CI: 0.11–1.04), (−censoring: aMRR: 0.64; 95% CI: 0.32–1.29)}. No difference in rate of death could be detected before first date of diagnosis of comorbidity {(+ censoring: aMRR: 1.12; 95% CI: 0.34–3.62), (−censoring: aMRR: 0.90; 95% CI: 0.28–2.88)}.
Conclusion
Statin therapy might reduce all-cause mortality in HIV-infected individuals, but the impact on individuals with no comorbidity seems small or absent. An unambiguous proof of a causal relation can only be obtained in a randomized controlled trial, but the sample size predicted may be prohibitive for its conduct.
doi:10.1371/journal.pone.0052828
PMCID: PMC3587599  PMID: 23469159
6.  PNPLA 3 I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection 
BMC Medical Genetics  2012;13:82.
Background
Hepatic steatosis in HCV patients has been postulated as a risk factor associated with a higher frequency of fibrosis and cirrhosis. A single genetic variant, PNPLA3 I148M, has been widely associated with increased hepatic steatosis. Previous studies of the PNPLA3 I148M sequence variant in HCV infected individuals have reported an association between this variant and prevalence of steatosis, fibrosis, and cirrhosis. To evaluate the impact of PNPLA3 I148M variant on metabolic traits and treatment response in HCV genotype 2 and 3 infected patients.
Methods
Three hundred and eighty-two treatment naïve HCV genotype 2 or 3 infected patients were included in a phase III, open label, randomized, multicenter, investigator-initiated trial (the NORDynamIC study), in which pretreatment liver biopsies were mandatory. PNPLA3I148M genotyping was performed in a total of 359 Caucasian patients.
Results
In HCV genotype 2 infected patients carrying the PNPLA3 148M allele, there was significantly increased insulin resistance (P = 0.023) and lower viral load (P = 0.005) at baseline as well as the first seven days of antiviral treatment. These results were not observed in HCV genotype 3 infected patients.
Conclusions
Our results suggest a possible association between the PNPLA3 148M allele and insulin resistance as well as baseline viral load in HCV genotype 2, but not in genotype 3.
doi:10.1186/1471-2350-13-82
PMCID: PMC3495049  PMID: 22978414
Hepatitis C; PNPLA 3; Insulin resistance; Viral load
7.  Risk of Diabetes Mellitus in Persons with and without HIV: A Danish Nationwide Population-Based Cohort Study 
PLoS ONE  2012;7(9):e44575.
Objective
In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals.
Methods
We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996–2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses.
Results
In the period 1996–1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57–5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03–5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42–7.39). In the period 1999–2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72–1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21–0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine.
Conclusion
Native HIV–infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM.
doi:10.1371/journal.pone.0044575
PMCID: PMC3440341  PMID: 22984529
8.  Plasma HIV Viral Rebound following Protocol-Indicated Cessation of ART Commenced in Primary and Chronic HIV Infection 
PLoS ONE  2012;7(8):e43754.
Objectives
The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onward transmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIV infection (CHI).
Design
Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450) trials.
Methods
Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences in pVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression. Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimated through a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop.
Results
Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48–51) weeks after stopping ART. Four weeks after stopping treatment, although the proportion with pVL≥400 copies/ml was similar (78% PHI versus 79% CHI), levels were 0.45 (95% CI 0.26–0.64) log10 copies/ml lower for PHI versus CHI, and remained lower up to 48 weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir >500 cells/mm3 was comparable to that experienced by PHI participants.
Conclusions
Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increased transmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.
doi:10.1371/journal.pone.0043754
PMCID: PMC3432055  PMID: 22952756
9.  Impact of Obesity on the Bioavailability of Peginterferon-α2a and Ribavirin and Treatment Outcome for Chronic Hepatitis C Genotype 2 or 3 
PLoS ONE  2012;7(5):e37521.
Background and Aims
Having a body mass index above or equal to 30 kg/m2 in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear.
Methods
This study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 µg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC).
Results
Patients with BMI ≥30 kg/m2 showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140).
Conclusions
Reduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.
doi:10.1371/journal.pone.0037521
PMCID: PMC3360051  PMID: 22655053
11.  Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection 
The Journal of Infectious Diseases  2011;203(6):780-790.
Background. Chronic human immunodeficiency virus (HIV) infection is associated with intestinal permeability and microbial translocation that contributes to systemic immune activation, which is an independent predictor of HIV disease progression. The association of microbial translocation with clinical outcome remains unknown.
Methods. This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples.
Results. Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2–16.1; P<.001), with minimal change after adjustment for inflammatory markers, CD4+ T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D-dimer.
Conclusions. sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.
doi:10.1093/infdis/jiq118
PMCID: PMC3071127  PMID: 21252259
12.  Impact of IL28B-Related Single Nucleotide Polymorphisms on Liver Histopathology in Chronic Hepatitis C Genotype 2 and 3 
PLoS ONE  2012;7(1):e29370.
Background and Aims
Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naïve patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory.
Methods
Three hundred and thirty-nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology.
Results
IL28B CCrs12979860 genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CCrs12979860 genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients.
Conclusion
This study shows that the CCrs12979860 SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection.
doi:10.1371/journal.pone.0029370
PMCID: PMC3258245  PMID: 22253715
13.  Impact of Non-HIV and HIV Risk Factors on Survival in HIV-Infected Patients on HAART: A Population-Based Nationwide Cohort Study 
PLoS ONE  2011;6(7):e22698.
Background
We determined the impact of three factors on mortality in HIV-infected patients who had been on highly active antiretroviral therapy (HAART) for at least one year: (1) insufficient response to (HAART) and presence of AIDS-defining diseases, (2) comorbidity, and (3) drug and alcohol abuse and compared the mortality to that of the general population.
Methodology/Principal Findings
In a Danish nationwide, population-based cohort study, we used population based registries to identify (1) all Danish HIV-infected patients who started HAART in the period 1 January 1998–1 July 2009, and (2) a comparison cohort of individuals matched on date of birth and gender (N = 2,267 and 9,068, respectively). Study inclusion began 1 year after start of HAART. Patients were categorised hierarchically in four groups according to the three risk factors, which were identified before study inclusion. The main outcome measure was probability of survival from age 25 to 65 years. The probability of survival from age 25 to age 65 was substantially lower in HIV patients [0.48 (95% confidence interval (CI) 0.42–0.55)] compared to the comparison cohort [0.88 (0.86 to 0.90)]. However, in HIV patients with no risk factors (N = 871) the probability of survival was equivalent to that of the general population [0.86 (95% CI 0.77–0.92)]. In contrast, the probability of survival was 0.58 in patients with HIV risk factors (N = 704), 0.30 in patients with comorbidities (N = 479), and 0.03 in patients with drug or alcohol abuse (N = 313).
Conclusions
The increased risk of death in HIV-infected individuals is mainly attributable to risk factors that can be identified prior to or in the initial period of antiretroviral treatment. Mortality in patients without risk factors on a successful HAART is almost identical to that of the non–HIV-infected population.
doi:10.1371/journal.pone.0022698
PMCID: PMC3143183  PMID: 21799935
14.  Head and neck cancer in HIV patients and their parents: a Danish cohort study 
Clinical Epidemiology  2011;3:217-227.
Background:
The mechanism for the increased risk of head and neck cancer (HNC) observed in HIV patients is controversial. We hypothesized that family-related risk factors increase the risk of HNC why we estimated the risk of this type of cancer in both HIV patients and their parents.
Methods:
We estimated the cumulative incidence and incidence rate ratios (IRRs) of HNC in 1) a population of all Danish HIV patients identified from the Danish HIV Cohort Study (n = 5053) and a cohort of population controls matched on age and gender (n = 50,530) (study period; 1995–2009) and 2) the parents of HIV patients and population controls (study period 1978–2009). To assess the possible impact of human papilloma virus (HPV)–associated cancers, the sites of squamous cell HNCs were categorized as HPV related, potentially HPV related, and potentially HPV unrelated.
Results:
Seventeen (0.3%) HIV patients vs 80 (0.2%) population controls were diagnosed with HNC cancer in the observation period. HIV patients had an increased risk of HNC (IRR 3.05 [95% CI 1.81–5.15]). The IRR was considerably increased in HIV patients older than 50 years (adjusted IRR; 4.58 [95% CI 2.24–9.35]), diagnosed after 1995 (adjusted IRR 6.31 [95% CI 2.82–14.08]), previous or current smoker (adjusted IRR 4.51 [95% CI 2.47–8.23]), with baseline CD4 count 350 cells/μL (adjusted IRR; 3.89 [95% CI 1.95–7.78]), and men heterosexually infected with HIV (adjusted IRR 5.54 [95% CI 1.96–15.66]). Fifteen (83%) of the HIV patients diagnosed with HNC were current or former smokers. The IRR of squamous cell HNC in HIV patients was high at HPV-relate sites, potentially HPV-related sites, and potentially HPV-unrelated sites. Both fathers and mothers of HIV patients had an increased risk of HNC (adjusted IRR for fathers 1.78 [95% CI 1.28–2.48], adjusted IRR for mothers 2.07 [95% CI 1.05–4.09]).
Conclusion:
HIV appears to be a marker of behavioral or family-related risk factors that affect the incidence of HNC in HIV patients.
doi:10.2147/CLEP.S19875
PMCID: PMC3157492  PMID: 21857789
HIV; head and neck cancer incidence; matched cohort; population controls; parents
15.  Lung cancer in HIV patients and their parents: A Danish cohort study 
BMC Cancer  2011;11:272.
Background
HIV patients are known to be at increased risk of lung cancer but the risk factors behind this are unclear.
Methods
We estimated the cumulative incidence and relative risk of lung cancer in 1) a population of all Danish HIV patients identified from the Danish HIV Cohort Study (n = 5,053) and a cohort of population controls matched on age and gender (n = 50,530) (study period; 1995 - 2009) and 2) their parents (study period; 1969 - 2009). Mortality and relative risk of death after a diagnosis of lung cancer was estimated in both populations.
Results
29 (0.6%) HIV patients vs. 183 (0.4%) population controls were diagnosed with lung cancer in the observation period. HIV patients had an increased risk of lung cancer (adjusted incidence rate ratio (IRR); 2.38 (95% CI; 1.61 - 3.53)). The IRR was considerably increased in HIV patients who were smokers or former smokers (adjusted IRR; 4.06 (95% CI; 2.66 - 6.21)), male HIV patients with heterosexual route of infection (adjusted IRR; 4.19 (2.20 - 7.96)) and HIV patients with immunosuppression (adjusted IRR; 3.25 (2.01 - 5.24)). Both fathers and mothers of HIV patients had an increased risk of lung cancer (adjusted IRR for fathers; 1.31 (95% CI: 1.09 - 1.58), adjusted IRR for mothers 1.35 (95% CI: 1.07 - 1.70)). Mortality after lung cancer diagnose was increased in HIV patients (adjusted mortality rate ratio 2.33 (95%CI; 1.51 - 3.61), but not in the parents. All HIV patients diagnosed with lung cancer were smokers or former smokers.
Conclusion
The risk was especially increased in HIV patients who were smokers or former smokers, heterosexually infected men or immunosuppressed. HIV appears to be a marker of behavioural or family related risk factors that affect the incidence of lung cancer in HIV patients.
doi:10.1186/1471-2407-11-272
PMCID: PMC3135571  PMID: 21702995
HIV; lung cancer incidence; matched cohort; population controls; parents; immunosuppression
16.  Development of Diagnostic Criteria for Serious Non-AIDS Events in HIV Clinical Trials 
HIV clinical trials  2010;11(4):205-219.
Purpose
Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial.
Methods
SNA definitions were developed based upon the following: (1) criteria from a previous trial (SMART), (2) review of published literature, (3) an iterative consultation and review process with the ERC and other content experts, and (4) evaluation of draft SNA criteria using retrospectively collected reports in another trial (ESPRIT).
Results
Final criteria are presented for acute myocardial infarction, congestive heart failure, coronary artery disease requiring drug treatment, coronary revascularization, decompensated liver disease, deep vein thrombosis, diabetes mellitus, end-stage renal disease, non-AIDS cancer, peripheral arterial disease, pulmonary embolism, and stroke. Of 563 potential SNA events reported in ESPRIT and reviewed by an ERC, 72% met “confirmed” and 13% “probable” criteria. Twenty-eight percent of cases initially reviewed by the ERC required follow-up discussion (adjudication) before a final decision was reached.
Conclusion
HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication.
doi:10.1310/hct1104-205
PMCID: PMC3109979  PMID: 20974576
clinical trials; cardiovascular disease; endpoint review committees; HIV; serious non-AIDS events
17.  Risk of Myocardial Infarction in Parents of HIV-infected Individuals: a population-based Cohort Study 
BMC Infectious Diseases  2010;10:169.
Background
Previous studies have indicated an increased risk of myocardial infarction (MI) in HIV infected individuals especially after start of highly active antiretroviral therapy (HAART). It is however controversial whether the increased risk of atherosclerotic disease is exclusively associated with the HIV disease and HAART or whether life-style related or genetic factors also increase the risk in this population. To establish whether the increased risk of myocardial infarction in HIV patients partly reflects an increased risk of MI in their families, we estimated the relative risk of MI in parents of HIV-infected individuals.
Methods
From the Danish HIV Cohort Study and the Danish Civil Registration System we identified the parents of all HIV-infected patients born in Denmark after 1952 in whom a Danish born mother was identifiable. For each HIV patient, 4 matched population controls and their parents were identified. Cumulative incidence functions were constructed to illustrate time to first MI of the parents as registered in the Danish National Hospital Registry. Incidence rate ratios (IRR) were estimated by Cox's regression analyses. Due to the confidential type of the analysed data the study was approved by the Danish Data Protection Agency.
Results
2,269 mothers and 2,022 fathers of HIV patients as well as 9,076 mothers and 8,460 fathers of control subjects were identified. We observed an increased risk of MI in mothers of HIV patients (adjusted IRR, 1.31; 95% CI: 1.08-1.60). The strongest association was seen in case the offspring was infected heterosexually (adjusted IRR, 1.59; 95% CI: 1.07-2.35) or by IV drug abuse (IVD) (adjusted IRR, 1.63; 95% CI: 1.02-2.60). In fathers of HIV patients the risk of MI was only increased if the offspring was infected by IVD (adjusted IRR, 1.42; 95% CI: 1.01-2.00).
Conclusion
Mothers of HIV-infected patients have an increased risk of MI. We presume that this stems from family related life style risk factors, some of which may also influence the risk of MI in HIV-infected patients.
doi:10.1186/1471-2334-10-169
PMCID: PMC2909236  PMID: 20546604
18.  Mortality after Hospitalization for Pneumonia among Individuals with HIV, 1995–2008: A Danish Cohort Study 
PLoS ONE  2009;4(9):e7022.
Background
HIV–infected persons are at increased risk of pneumonia, even with highly active antiretroviral treatment (HAART). We examined the impact of pneumonia on mortality and identified prognostic factors for death among HIV–infected.
Methodology/Principal Findings
In a nationwide, population-based cohort of individuals with HIV, we included persons hospitalized with pneumonia from the Danish National Hospital Registry and obtained mortality data from the Danish Civil Registration System. Comparing individuals with and without pneumonia, we used Poisson regression to estimate relative mortality and logistic regression to examine prognostic factors for death following pneumonia. From January 1, 1995, to July 1, 2008, we observed 699 episodes of first hospitalization for pneumonia among 4,352 HIV patients. Ninety-day mortality after pneumonia decreased from 22.4% (95% confidence interval [CI]: 16.5%–28.9%) in 1995–1996 to 8.4% (95% CI: 6.1%–11.6%) in 2000–2008. Mortality remained elevated for more than a year after hospitalization for pneumonia: adjusted mortality rate ratio 5.38 (95% CI: 4.27–6.78), 1.80 (95% CI: 1.36–2.37), and 1.62 (95% CI: 1.32–2.00) for days 0–90, 91–365, and 366+, respectively. The following variables predicted mortality within 90 days following hospitalization for pneumonia (adjusted Odds Ratios): male sex (3.77, 95% CI: 1.37–10.4), Charlson Comorbidity Index score ≥2 (3.86, 95% CI: 2.19–6.78); no current HAART (3.58, 95% CI: 1.83–6.99); history of AIDS (2.46, 95% CI: 1.40–4.32); age per 10 year increase (1.43, 95% CI: 1.11–1.85); and CD4+ cell count ≤200 (2.52, 95% CI: 1.37–4.65).
Conclusions/Significance
The first hospitalization for pneumonia among HIV–infected individuals was associated with elevated risk of death up to more than a year later. Use of HAART decreased the risk, independent of current CD4+ cell count. Prognosis following pneumonia improved over calendar time.
doi:10.1371/journal.pone.0007022
PMCID: PMC2737147  PMID: 19750011
19.  Procalcitonin versus C-reactive protein for predicting pneumonia in adults with lower respiratory tract infection in primary care 
Background
The role of procalcitonin in diagnosing bacterial infection has mainly been studied in patients with severe infections. There is no study on the value of procalcitonin measurements in adults with lower respiratory tract infection (LRTI) treated in primary care.
Aim
To evaluate the accuracy of plasma procalcitonin in predicting radiographic pneumonia, bacterial infection, and adverse outcome in a population of adults with LRTI treated in primary care.
Design of study
Prospective, observational study.
Setting
Forty-two general practices and an outpatient clinic at the Department of Infectious Diseases, Odense University Hospital, Denmark.
Method
A total of 364 patients with LRTI were prospectively enrolled from 42 general practices. Patients were examined with chest radiography, microbiological analyses, and measurements of C-reactive protein (CRP) and procalcitonin. The outcome measure was hospitalisation within 4 weeks of enrolment.
Results
Median procalcitonin was 0.05 ng/ml, which was below the functional sensitivity of the assay (0.06 ng/ml). In predicting radiographic pneumonia, bacterial infection, and hospitalisation, the sensitivities of procalcitonin >0.06 ng/ml were 0.70, 0.51, and 0.67, and of CRP ≥20 mg/l were 0.73, 0.56, and 0.74 respectively. Corresponding positive predictive values were between 0.09 and 0.28.
Conclusion
Both procalcitonin >0.06 ng/ml and CRP ≥20 mg/l were associated with radiographic pneumonia, bacterial infection, and subsequent hospitalisation, but positive predictive values were too low for any of the two inflammatory markers to be of use in clinical practice. To measure procalcitonin values accurately in the primary care setting, a more sensitive method is needed, but there was no indication that procalcitonin is superior to CRP in identifying patients with pneumonia, bacterial aetiology, or adverse outcome.
PMCID: PMC2099638  PMID: 17727748
C-reactive protein; diagnostic tests; pneumonia; primary health care; procalcitonin; respiratory tract infections; routine
20.  Aetiology and prediction of pneumonia in lower respiratory tract infection in primary care 
Background
Knowledge of predominant pathogens and their association with outcome are of importance for the management of lower respiratory tract infection (LRTI). As antibiotic therapy is indicated in pneumonia and not in acute bronchitis, a predictor of pneumonia is needed.
Aim
To describe the aetiology and outcome of LRTI in adults with pneumonic and adults with non-pneumonic LRTI treated in general practice and to identify predictors of radiographic pneumonia.
Design of study
Prospective, observational study.
Setting
Forty-two general practices and an outpatient clinic at Odense University Hospital, Denmark.
Method
A total of 364 adults diagnosed with community-acquired LRTI by their GP were studied with chest radiography, vital signs, biochemical markers of inflammation (C-reactive protein [CRP] and leukocyte count), and microbiological examinations. Primary outcome measure was hospitalisation within 4 weeks.
Results
Pneumonia was radiographically verified in 48 of 364 patients (13%). Bacterial infection was seen more often in patients with pneumonia (33% versus 17%, P<0.001), and viral infection more often in non-pneumonic patients (26% versus 13%, P<0.05). Hospitalisation was more common in patients with pneumonia compared to non-pneumonic patients (19 versus 3%, P<0.001); and in patients with pneumococcal infection compared with patients without pneumococcal infection (26 versus 4%, P = 0.001). The positive predictive value of GPs' diagnosis of pneumonia was low (0.23), but the vital signs, CRP, and leukocyte count had comparably low positive predictive values (0.23–0.30).
Conclusion
Streptococcus pneumoniae was the most common bacterial pathogen. The risk of hospitalisation was highest among patients with pneumonia or pneumococcal infection; this emphasises the importance of coverage of S. pneumoniae when treatment is indicated. CRP should not be introduced for diagnosis of radiographic pneumonia in general practice before its use has been investigated in prospective, controlled intervention trials using CRP-guided treatment algorithms.
PMCID: PMC2099637  PMID: 17727747
pneumonia; primary health care; respiratory tract infections
21.  Determination of the Underlying Cause of Death in Three Multicenter International HIV Clinical Trials 
HIV clinical trials  2008;9(3):177-185.
Purpose
Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials.
Method
Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999–2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated.
Results
Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51%) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached.
Conclusion
ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths.
doi:10.1310/hct0903-177
PMCID: PMC2441601  PMID: 18547904
cause of death; endpoint review committees; clinical trials; HIV; mortality
22.  The prognostic value of the suPARnostic® ELISA in HIV-1 infected individuals is not affected by uPAR promoter polymorphisms 
Background
High blood levels of soluble urokinase Plasminogen Activator Receptor (suPAR) are associated with poor outcomes in human immunodeficiency-1 (HIV-1) infected individuals. Research on the clinical value of suPAR in HIV-1 infection led to the development of the suPARnostic® assay for commercial use in 2006. The aim of this study was to: 1) Evaluate the prognostic value of the new suPARnostic® assay and 2) Determine whether polymorphisms in the active promoter of uPAR influences survival and/or suPAR values in HIV-1 patients who are antiretroviral therapy (ART) naive.
Methods
DNA samples were collected retrospectively from 145 Danes infected with HIV-1 with known seroconversion times. In addition, plasma was collected retrospectively from 81 of these participants for use in the suPAR analysis. Survival was analysed using Kaplan Meier analysis.
Results
Survival was strongly correlated to suPAR levels (p < 0.001). Levels at or above 6 ng/ml were associated with death in 13 of 27 patients within a two-years period; whereas only one of 54 patients with suPAR levels below 6 ng/ml died during this period. We identified two common uPAR promoter polymorphisms: a G to A transition at -118 and an A to G transition at -465 comparative to the transcription start site. These promoter transitions influenced neither suPAR levels nor patient survival.
Conclusion
Plasma suPAR levels, as measured by the suPARnostic® assay, were strongly predictive of survival in ART-naïve HIV-1 infected patients. Furthermore, plasma suPAR levels were not influenced by uPAR promoter polymorphisms.
doi:10.1186/1471-2334-7-134
PMCID: PMC2216028  PMID: 18021410
23.  Cause-Specific Excess Mortality in Siblings of Patients Co-Infected with HIV and Hepatitis C Virus 
PLoS ONE  2007;2(8):e738.
Background
Co-infection with hepatitis C in HIV-infected individuals is associated with 3- to 4-fold higher mortality among these patients' siblings, compared with siblings of mono-infected HIV-patients or population controls. This indicates that risk factors shared by family members partially account for the excess mortality of HIV/HCV-co-infected patients. We aimed to explore the causes of death contributing to the excess sibling mortality.
Methodology and Principal Findings
We retrieved causes of death from the Danish National Registry of Deaths and estimated cause-specific excess mortality rates (EMR) for siblings of HIV/HCV-co-infected individuals (n = 436) and siblings of HIV mono-infected individuals (n = 1837) compared with siblings of population controls (n = 281,221). Siblings of HIV/HCV-co-infected individuals had an all-cause EMR of 3.03 (95% CI, 1.56–4.50) per 1,000 person-years, compared with siblings of matched population controls. Substance abuse-related deaths contributed most to the elevated mortality among siblings [EMR = 2.25 (1.09–3.40)] followed by unnatural deaths [EMR = 0.67 (−0.05–1.39)]. No siblings of HIV/HCV co-infected patients had a liver-related diagnosis as underlying cause of death. Siblings of HIV-mono-infected individuals had an all-cause EMR of 0.60 (0.16–1.05) compared with siblings of controls. This modest excess mortality was due to deaths from an unknown cause [EMR = 0.28 (0.07–0.48)], deaths from substance abuse [EMR = 0.19 (−0.04–0.43)], and unnatural deaths [EMR = 0.18 (−0.06–0.42)].
Conclusions
HCV co-infection among HIV-infected patients was a strong marker for family-related mortality due to substance abuse and other unnatural causes. To reduce morbidity and mortality in HIV/HCV-co-infected patients, the advances in antiviral treatment of HCV should be accompanied by continued focus on interventions targeted at substance abuse-related risk factors.
doi:10.1371/journal.pone.0000738
PMCID: PMC1939735  PMID: 17710138
24.  A comparison of high-mobility group-box 1 protein, lipopolysaccharide-binding protein and procalcitonin in severe community-acquired infections and bacteraemia: a prospective study 
Critical Care  2007;11(4):R76.
Introduction
High-mobility group box-1 protein (HMGB1) has been known as a chromosomal protein for many years. HMGB1 has recently been shown to be a proinflammatory cytokine with a role in the immunopathogenesis of sepsis. Lipopolysaccharide-binding protein (LBP) has a central role in the innate immune response when the host is challenged by bacterial pathogens. Procalcitonin (PCT) has been suggested as a marker of severe bacterial infections and sepsis. The aim of the present study was to investigate levels of HMGB1, LBP and PCT in a well-characterised sepsis cohort. The study plan included analysis of the levels of the inflammatory markers in relation to the severity of infection, to the prognosis and to the ability to identify patients with bacteraemia.
Methods
Patients suspected of having severe infections and admitted to a department of internal medicine were included in a prospective manner. Demographic data, comorbidity, routine biochemistry, microbiological data, infection focus, severity score and mortality on day 28 were recorded. Plasma and serum were sampled within 24 hours after admission. Levels of all studied markers (HMGB1, LBP, PCT, IL-6, C-reactive protein, white blood cell count and neutrophils) were measured with commercially available laboratory techniques.
Results
A total of 185 adult patients were included in the study; 154 patients fulfilled our definition of infection. Levels of HMGB1, LBP and PCT were higher in infected patients compared with a healthy control group (P < 0.0001). Levels of HMGB1, LBP and PCT were higher in the severe sepsis group compared with the sepsis group (P < 0.01). No differences were observed in levels of the inflammatory markers in fatal cases compared with survivors. Levels of all studied markers were higher in bacteraemic patients compared with nonbacteraemic patients (P < 0.05). PCT performed best in a receiver–operator curve analysis discriminating between bacteraemic and nonbacteraemic patients (P < 0.05). HMGB1 correlated to LBP, IL-6, C-reactive protein, white blood cell count and neutrophils (P < 0.001). LBP correlated to PCT, IL-6 and C-reactive protein (P < 0.001).
Conclusion
Levels of HMGB1, PCT and LBP were higher in infected patients compared with those in healthy controls, and levels were higher in severe sepsis patients compared with those in sepsis patients. Levels of all studied inflammatory markers (HMGB1, LBP, PCT, IL-6) and infection markers (C-reactive protein, white blood cell count, neutrophils) were elevated among bacteraemic patients. PCT performed best as a diagnostic test marker for bacteraemia.
doi:10.1186/cc5967
PMCID: PMC2206511  PMID: 17625012
25.  High mobility group box-1 protein in patients with suspected community-acquired infections and sepsis: a prospective study 
Critical Care  2007;11(2):R32.
Introduction
Sepsis is a serious condition with a significant morbidity and mortality. New insight into the immunopathogenesis of sepsis could promote the development of new strategies for diagnosis and therapy. High mobility group box-1 protein (HMGB1) has been known for many years as a nuclear chromosomal protein. Its role as a pro-inflammatory cytokine in sepsis and rheumatoid arthritis has been described recently. The aim of our study was to evaluate HMGB1 as a molecular marker in patients with community-acquired infections.
Methods
Patients suspected of having infections/sepsis and admitted to a department of internal medicine were included in the study in a prospective manner. Demographic data, comorbidity, routine biochemistry, microbiological data, infection focus, severity score, and mortality on day 28 were recorded. Plasma and serum were sampled at the time of admission. HMGB1 levels were measured with a commercially available enzyme-linked immunosorbent assay (ELISA). Procalcitonin levels were measured with a TRACE (time-resolved amplified cryptate emission) assay. Lipopolysaccharide-binding protein and interleukin-6 were measured with a chemiluminiscent immunometric assay. Soluble haemoglobin scavenger receptor (sCD163) levels were measured with an in-house ELISA.
Results
One hundred and ninety-four patients were included in the study. Levels of HMGB1 are presented as medians and interquartile ranges: healthy controls (0.77 ng/ml, 0.6 to 1.46), non-infected patients (1.54 ng/ml, 0.79 to 2.88), infected patients without systemic inflammatory response syndrome (2.41 ng/ml, 0.63 to 3.44), patients with sepsis (2.24 ng/ml, 1.30 to 3.75), and patients with severe sepsis (2.18 ng/ml, 0.91 to 3.85). In a receiver operator characteristic curve analysis discriminating between non-infected patients and all infected patients, the area under the curve for HMGB1 was 0.59 (P < 0.0001). HMGB1 correlated only weakly to levels of white blood cell count, neutrophils, C-reactive protein, interleukin-6, procalcitonin, and lipopolysaccharide-binding protein (P < 0.001). HMGB1 did not correlate to sCD163.
Conclusion
In a cohort of patients with suspected community-acquired infections and sepsis, HMGB1 levels were statistically significantly higher in patients compared to the healthy controls. There was no statistically significant difference between the infected and the non-infected patients. Levels of HMGB1 correlated only very weakly to other pro-inflammatory markers and did not correlate to the anti-inflammatory marker sCD163.
doi:10.1186/cc5715
PMCID: PMC2206448  PMID: 17346334

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