Jesper Eugen-olsen

The aim of the present study was to evaluate the potential of diagnostic tests based on interferon-gamma inducible protein (IP)-10 and monocyte chemotactic protein (MCP)-2, and compare the performance with the QuantiFERON TB Gold In-Tube (QFT-IT; Cellestis, Carnagie, Australia) test. IP-10 and MCP-2 were determined in supernatants from whole blood stimulated with Mycobacterium tuberculosis-specific antigens. Samples were obtained from 80 patients with culture- and/or PCR-proven tuberculosis (TB), and 124 unexposed healthy controls: 86 high school students and 38 high school staff. IP-10 and MCP-2 test cut-offs were established based on receiver operating characteristic curve analysis. TB patients produced significantly higher levels (median) of IP-10 (2158 pg x mL(-1)) and MCP-2 (379 pg x mL(-1)) compared with interferon (IFN)-gamma (215 pg x mL(-1)). The QFT-IT, IP-10 and MCP-2 tests detected 81, 83 and 71% of the TB patients; 0, 3 and 0% of the high school students and 0, 16 and 3...

HIV-infected patients could exhibit accelerated ageing, since age-associated complications like sarcopenia; increased inflammation; lipodystrophy with loss of subcutaneous adipose tissue and/or gain of visceral adipose tissue (VAT); and cardiovascular disease occur at an earlier age. Inflammation is involved in age-associated complications. However, it is not understood whether it is the same inflammatory changes that are involved in the various ageing-associated complications. Our objective was to study whether leptin, interleukin 6 (IL-6), and soluble urokinase plasminogen activator receptor (suPAR) were associated distinctively with adiposity, lipodystrophy and sarcopenia, in HIV-infected patients and healthy Controls. Systemic leptin levels were significantly higher in patients with lipodystrophy than without, whereas there was no difference in IL-6 or suPAR levels. Leptin was significantly positively associated with fat mass index (FMI) and abdominal VAT, but not with lean mass...

BACKGROUND AND AIMSLuminal nitric oxide (NO) is greatly increased in the colon of patients with collagenous and ulcerative colitis. To define the source and consequence of enhanced NO production we have studied expression of NO synthase (NOS) isoforms and nitrotyrosine in mucosal biopsies from these patients. In addition, effects on colonic fluid transfer caused by manipulating the substrate of NOS

Better outcomes in patients suspected of community-acquired infections requires the optimal and timely assessment of disease severity at the point of first contact with the health care system, which is typically in the emergency department. This study was conducted using a previously described, prospectively collected cohort of patients with systemic inflammatory response syndrome (SIRS) that were admitted to an emergency department and a department of infectious diseases at a university hospital. Plasma samples were collected and disease severity scores calculated upon admission. A multiplex immunoassay and a newly developed enzyme-linked immunosorbent assay (ELISA)-based assay were used to measure the soluble urokinase-type plasminogen activator receptor, soluble triggering receptor expressed on myeloid cells-1, and macrophage migration inhibitory factor. The area under the receiver operating characteristic (ROC) curve for the prediction of 30- and 180-day mortality was used to co...

Eugen-Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Møller LN, Jeppesen J, Lyngbæk S, Fenger M, Olsen MH, Hildebrandt PR, Borch-Johnsen K, Jørgensen T, Haugaard SB (Copenhagen University, Hvidovre Hospital, Hvidovre; Copenhagen University Hospital, Glostrup; Copenhagen University Hospital, Copenhagen; Copenhagen University Hospital, Glostrup; Copenhagen University, Hvidovre Hospital, Hvidovre; Steno Diabetes Center, Gentofte; University of Aarhus, Aarhus; University of Copenhagen, Copenhagen; Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark). Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296–308.Background. Low-grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type-2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in ris...

Background: Little is known about post-consultation mortality among individuals consulting hospitals with symptoms of TB, but with normal X-Ray and a negative TB sputum smear result. This study aimed first to assess post-consultation mortality among these presumed TB negative (pTBneg) individuals and second to investigate whether the level of plasma soluble urokinase plasminogen activator receptor (suPAR) can be used to identify pTBneg individuals with a high mortality risk. Methods: 1682 individuals with symptoms of TB were examined and enrolled in a prospective study in Guinea-Bissau from April 2004 to December 2006. Of these 1216 received a negative TB diagnose; 1007 of these pTBneg individuals could be followed in the community for subsequent survival. To compare with mortality in the general population, 4983 age-matched controls were followed. Plasma suPAR levels were measured using the suPARnostic ELISA (ViroGates, Denmark) in samples drawn at time of consultation. Results: Th...

Elevated inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are well-known risk factors for cardiovascular mortality. The less familiar marker, soluble urokinase plasminogen activator receptor (suPAR), is known to predict cancer, infections and all-cause mortality. We determined whether suPAR, CRP and IL-6 are predictive of both all-cause and cardiovascular mortality in a black population, highly burdened by cardiovascular disease and HIV infection. We included 1425 black South Africans, of which 208 died within five years after baseline data collection. EDTA plasma biomarker levels were determined, while all-cause and cardiovascular mortality were used as endpoints. At baseline suPAR, CRP and IL-6 were higher in non-survivors than in survivors (P<0.001). SuPAR (HR 1.27, 95% CI 1.09-1.48), IL-6 (HR 1.49, 95% CI 1.24-1.78) and CRP (HR 1.39, 95% CI 1.17-1.65) predicted all-cause mortality, while only suPAR (HR 1.40, 95% CI 1.04-1.87) and IL-6 (HR 1.61, 9...

As respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause serious respiratory tract infections, the routes of transmission of these viruses are important to elucidate. We examined the modes of virus shedding and shedding duration of RSV and hMPV in young children. From each child in a group of 44 children (37 RSV-positive, 6 hMPV-positive, and 1 co-infected child), aged between 0.5-38 months, hospitalised at Hvidovre Hospital, Copenhagen, Denmark, one nasopharyngeal aspirate (NPA), saliva, urine, and faeces sample were collected at inclusion and weekly in a three-week period. Sweat and blood samples were obtained at inclusion. The presence of RSV and hMPV RNA was detected using real-time RT-PCR. We detected RSV RNA in 28 saliva specimens, 5 stool samples, and 3 sweat samples. hMPV RNA was detected in one saliva specimen and two sweat samples. Four of the five children shedding RNA in faeces had diarrhoea and children shedding RNA in sweat were either less than five...

The main objective of this study was to investigate the association between two markers of low-grade inflammation; soluble urokinase plasminogen activator receptor (suPAR) and high-sensitive C-reactive protein (hs-CRP); and coronary artery calcification (CAC) score detected by cardiac computed tomography (CT) scan. A cross sectional study of 1126 randomly sampled middle-aged men and women. CAC score was measured by a non-contrast cardiac CT scan and total 10-year cardiovascular mortality risk was estimated using the Systematic Coronary Risk Evaluation (SCORE). Plasma samples were analysed for suPAR and hs-CRP. The association of suPAR and hs-CRP to CAC was evaluated by logistic regression analyses adjusting for categorised SCORE. The additive effect of suPAR to SCORE was evaluated by comparing area under curve (AUC) and net reclassification improvement (NRI). The odds of being in a higher CAC category, i.e. having more severe CAC, increased 16% (odds ratio (OR) 1.16, p = 0.02) when ...

The soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of mortality risk in various patient populations. However, little is known about the implications of lifestyle for suPAR levels in the general population. Lifestyle, demographic, and cardiovascular disease (CVD) risk factor data were collected from 5,538 participants in the Danish population-based Inter99 study. Their suPAR levels were measured using a sandwich enzyme-linked immunosorbent assay. In the final adjusted model, smoking and morbid obesity were strongly associated with higher suPAR levels (P < 0.001). An unhealthy diet and alcohol abstinence in men were also associated with higher suPAR levels. Physical activity in leisure time had a modest impact on suPAR levels in univariate analysis, but not in the final adjusted model. In conclusion, smoking and morbid obesity were strongly associated with higher serum suPAR levels in this general population. Diet and alcohol consumption also seemed to impa...

We have investigated the role of the recently described mutation in CCR2b named 64I in relation to HIV resistance, CD4 T-cell counts, and disease progression in Danish individuals by polymerase chain reaction (PCR)-based methods as well as sequenced full-length CXCR4 and CCR5 genes from HIV-infected long-term nonprogressors for possible mutations. In total, 215 Danish individuals were analyzed for 64I allele frequency; disease progression was followed in 105 HIV-1-positive homosexual Danish men from their first known positive HIV-1 test result and up to 11 years. In 87 individuals, the CD4 T-cell count was monitored closely. We found no significant difference in 64I allele frequency between HIV-1-seropositive persons (0.08), high-risk HIV-1-seronegative persons (0.11), and blood donors (0.06). No significant difference was observed in annual CD4 T-cell decline, CD4 T-cell counts at the time of AIDS, in AIDS-free survival as well as survival with AIDS, between 64I allele carriers and wild-type individuals. Among 9 long-term nonprogressors, 2 carried the 64I allele, while none of 9 fast progressors carried the 64I allele. However, this was not significantly different (p=.47). Long-term nonprogression could not be explained by CXCR4 polymorphism or other polymorphisms in the CCR5 gene than the CCR5delta32 allele. Furthermore, we were not able to detect any significant independent effect of the 64I allele on development to AIDS, overall survival, and annual CD4 T-cell decline in this cohort.

Fibulin-1 and soluble urokinase-type plasminogen activator receptor (suPAR) emerged as mediators in the development of sclerotic disease. SuPAR along with C-reactive protein (CRP) and albumin delineate inflammatory processes associated with extracellular matrix turnover in atherosclerosis. We explored the independent relationship of fibulin-1 with these inflammatory markers in a bi-ethnic South African population. This study included 290 Africans (men: n=130 and women: n=160) and 343 sex- and age-matched Caucasians (men: n=160 and women: n=183). Serum fibulin-1, suPAR, CRP and albumin levels were measured along with conventional cardiovascular and metabolic variables. In both single and age-adjusted regression analyses, fibulin-1 correlated with both suPAR and albumin in African men and with suPAR in Caucasian men. These findings were absent in women. In multivariate regression analysis, these associations were confirmed in African men (R(2)=0.22; β=0.329; p<0.001) and Caucasian men (R(2)=0.14; β=0.234; p=0.008). Fibulin-1 independently associated positively with suPAR in all men, but inversely with albumin in African men only. These results are indicating the presence of potential subclinical inflammation (suPAR) within the extracellular matrix of endothelial tissue, contributing to the potential onset of cardiac fibrosis or vascular sclerosis among these South African men with lower albumin levels.

Soluble urokinase plasminogen activator receptor (suPAR) is associated with inflammation and may predict lipodystrophy and dysmetabolism in human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy. We aimed to assess firstly, whether suPAR levels are elevated in treated and untreated HIV-1-infected Africans compared to uninfected controls at baseline and at a 3-year follow-up, and secondly whether suPAR levels are correlated with

Fibulin-1, a circulating extracellular matrix glycoprotein, has been associated with arterial disease and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) in diabetes. Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, has been associated with subclinical atherosclerosis. Therefore, we aimed to explore the interplay between these biomarkers and mild to moderate aortic valve stenosis (AS). In 374 patients with mild to moderate AS, we investigated the relationship of fibulin-1 with NT-proBNP, levels of suPAR and the degree of AS at baseline and after one and four years of treatment with Simvastatin 40 mg and Ezetimibe 10 mg or placebo. During treatment, fibulin-1 became more closely associated with NT-proBNP (βyear0 = 0.10, p = 0.08, βyear1 = 0.16, p = 0.005, βyear4 = 0.22, p<0.001) and suPAR (βyear0 = 0.05, p = 0.34, βyear1 = 0.16, p = 0.006, βyear4 = 0.13, p = 0.03) at the expense of the association to aortic valve area index (AVAI) (βyear0 = -0.14, p = 0.005, βyear1 = -0.08, p = 0.11, βyear4 = -0.06, p = 0.22) independently of age, gender, creatinine, and serum aspartate aminotransferase (Adj.Ryear02 = 0.19, Adj.Ryear12 = 0.22, Adj.Ryear42 = 0.27). Fibulin-1 was unrelated to aortic regurgitation, left ventricular mass, and ejection fraction. In patients with baseline AVAI<0.58 cm2/m2 (median value), fibulin-1 was more closely associated to NT-proBNP (βyear0 = 0.25, βyear1 = 0.21, βyear4 = 0.22, all p<0.01), and suPAR (βyear0 = 0.09, p = 0.26, βyear1 = 0.23, βyear4 = 0.21, both p<0.01) independently of age, gender, AST and treatment allocation. Increased levels of fibulin-1 were independently associated with higher levels of suPAR and NT-proBNP especially in patients with lower AVAI, suggesting that fibulin-1 may be an early marker of AS as well as cardiac fibrosis secondarily to elevated left ventricular hemodynamic load.

Inflammation is involved in the pathogenesis of depression. A few cross-sectional population-based studies have found that depression is associated with increased levels of inflammatory markers. Soluble urokinase plasminogen activation receptor (suPAR) is known to be a stable marker for inflammation. We investigated the bidirectional association between suPAR levels and use of antidepressants. suPAR level was measured in 9305 blood donors and analysed in relation to 5-years follow-up data on purchase of antidepressants and hospital diagnoses of depression from a nationwide Danish register. For men and women without prior use of antidepressants we found a significantly higher risk for incident use of antidepressants with higher suPAR values. For men, the risk of first use of antidepressants increased by 72% from the 1st to the 4th quartile (HR = 1.72, 95% CI: 1.11-2.69). For women, it increased by 108% from the 1st to the 4th quartile (HR = 2.08, 95% CI: 1.45-2.98). Previous use of antidepressants was also significantly associated with higher suPAR levels (p = 0.002). High suPAR levels are associated with an increased risk for both previous and future use of antidepressants in healthy men and women. High suPAR are also associated with increased risk for a hospital diagnosis of depression.

Using data from the Danish AIDS Cohort of HIV-infected homosexual men established in the 1980s, the prognostic value of early HIV DNA loads was evaluated. In addition to DNA measurements, concomitant serum HIV RNA levels, CD4 cell counts and CCR5 genotypes were determined. The patients were divided into 3 groups, according to whether their cell-associated HIV DNA load was < or = 100, 500 or > or = 2,500 DNA copies/10(6) peripheral blood mononuclear cells. Clinical progression rates differed significantly between the groups (p < 0.005). Cell-associated HIV DNA load had prognostic value independent of serum HIV RNA (p < 0.02). However, when HIV DNA, HIV RNA and CD4 cell counts were all included in a Cox model, only serum HIV RNA had independent prognostic value. Patients heterozygous for the CCR5 delta 32 allele had significantly lower HIV DNA loads than those homozygous for the normal allele (p < 0.05). The interplay between HIV RNA and DNA levels is discussed, together with the possibility that cell-associated HIV DNA load is a marker of the HIV RNA peak seen shortly after primary HIV infection.

Sulpha agents, which act by inhibiting the enzyme dihydropteroate synthase (DHPS), are used widely for the treatment and prophylaxis of Pneumocystis carinii pneumonia (PCP). Recently, we have shown that mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis carinii f.sp hominis are associated with failure of sulpha prophylaxis and increased mortality in HIV-1 positive patients with PCP, suggesting that DHPS mutations may cause sulpha resistance. To facilitate detection of DHPS mutations we developed a restriction fragment length polymorphism (RFLP) assay, detecting mutations at codon 55 and 57 of the P. carinii DHPS gene. The RFLP-assay was compared with direct DNA sequencing on 27 PCP isolates from HIV-1 positive patients with a mixture of wildtype and mutant DHPS types. In all samples the RFLP-assay correctly identified wildtype or DHPS mutation at codon 55 or 57. Combined with DNA extraction by a Chelex-based method, this method can be performed within 1 d and allows a fast, cost-efficient and reliable method of detection of DHPS mutations in P. carinii.

Sulpha drugs are widely used for the treatment and long-term prophylaxis of Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals. Sulpha resistance in many microorganisms is caused by point mutations in dihydropteroate synthase (DHPS), an enzyme that is essential for folate biosynthesis. We assessed whether mutations in the DHPS gene of P. carinii were associated with exposure to sulpha drugs and influenced outcome from PCP. We studied bronchoalveolar samples collected in 1989-99 from a prospective cohort of HIV-1-infected patients who had PCP. In 144 patients with 152 episodes of PCP, we analysed portions of DHPS using PCR and direct sequencing. The relation between survival, P. carinii DHPS mutations, and other predictors of treatment failure was assessed by Kaplan-Meier and multivariate Cox regression analysis. P. carinii DHPS mutations were found in 31 (20.4%) of 152 PCP episodes. 3-month survival was significantly lower in patients infected with mutant P. carinii DHPS strains than in those with wild-type strains (p=0.002). After adjustment for other prognostic variables, presence of DHPS mutations remained the most important predictor of mortality (hazard ratio 3.1 [95% CI 1.2-8.1]). DHPS mutations were significantly more common in patients who had previous exposure to sulpha drugs (18 of 29 [62%]) than in those who had no exposure (13 of 123 [10.5%]; p<0.0001). A significant increase with time in the rate of DHPS mutations (p=0.01 for trend) was closely correlated with the rate of previous or current use of sulpha drugs as chemoprophylaxis. Mutations in DHPS are associated with impaired prognosis in PCP, and may develop as a result of exposure to sulpha drugs.