Publications by authors named "Wim Adriaensen"

36 Publications

HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires.

Vaccines (Basel) 2021 Mar 17;9(3). Epub 2021 Mar 17.

Department of Computer Science, University of Antwerp, 2020 Antwerp, Belgium.

Susceptibility for leishmaniasis is largely dependent on host genetic and immune factors. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors for leishmaniasis, little is known regarding the mechanisms that underpin these associations. To better understand this underlying functionality, we first collected all known leishmaniasis-associated HLA variants in a thorough literature review. Next, we aligned and compared the protection- and risk-associated HLA-DRB1 allele sequences. This identified several amino acid polymorphisms that distinguish protection- from risk-associated HLA-DRB1 alleles. Subsequently, T cell epitope binding predictions were carried out across these alleles to map the impact of these polymorphisms on the epitope binding repertoires. For these predictions, we used epitopes derived from entire proteomes of multiple species. Epitopes binding to protection-associated HLA-DRB1 alleles shared common binding core motifs, mapping to the identified HLA-DRB1 amino acid polymorphisms. These results strongly suggest that HLA polymorphism, resulting in differential antigen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes. A set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, was prioritized for further epitope discovery in the search for novel subunit-based vaccines.
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http://dx.doi.org/10.3390/vaccines9030270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002611PMC
March 2021

Cellular Immune Phenotypes and Worsening Scores of Frailty-Associated Parameters Over an 18-Month Period in the Very Old.

J Gerontol A Biol Sci Med Sci 2021 Jul;76(8):1356-1361

Department of Immunology, University of Tübingen, Germany.

Frailty has been related to inflammaging and certain immune parameters. In previous analyses of participants older than 80 years of age in the longitudinal BELFRAIL cohort study, the main focus was on T-cell phenotypes and the association with cytomegalovirus (CMV) serostatus and survival, finding that a CD4:CD8 ratio greater than 5 was associated with frailty, impaired activities of daily living (ADLs), and mortality (but only in women). Here, we phenotyped peripheral blood immune cells via multicolor flow cytometry and correlated these with the dynamics of changes in ADL, geriatric depression score, Mini-Mental State Examination, and Short Physical Performance Battery from baseline values over 18 months follow-up. We found that higher frequencies of B cells and late-differentiated CD8+ T cells at 18 months from baseline were associated with ADL impairment that had worsened over the preceding 18 months. There were no significant associations with monocyte, dendritic cell, or natural killer (NK) cell phenotypes. No associations with the Geriatric Depression Scale, the Mini-Mental State Examination, or the Short Physical Performance Battery were found. Thus, while these results do not establish causality, they suggest that certain adaptive immune, but not innate immune, parameters are associated with a worsened ADL in the very old.
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http://dx.doi.org/10.1093/gerona/glab089DOI Listing
July 2021

Diagnostic accuracy of direct agglutination test, rK39 ELISA and six rapid diagnostic tests among visceral leishmaniasis patients with and without HIV coinfection in Ethiopia.

PLoS Negl Trop Dis 2020 12 31;14(12):e0008963. Epub 2020 Dec 31.

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Diagnosis of a first-time visceral leishmaniasis (VL) infection in Ethiopia is established by use of a rapid diagnostic test (RDT) detecting antibodies against rK39, direct agglutination test (DAT) and microscopy according to the national algorithm. The performance of individual tests and algorithm is variable and depends on several factors, one being HIV status. Limited data are available on the performance of tests in VL-HIV coinfected patients. Assessment of the performance of DAT (ITM-A), rK39 ELISA (Serion) and six RDT (Onsite Leishmania Ab CTK, Antigen ICT Xinjier, IT Leish Biorad, Kalazar Detect Inbios, rK39 IgG1 Coris, rk28 IgG1 Coris) for the diagnosis of VL was done on a panel of 91 stored serum and plasma samples of 'first-episode' suspected VL patients, with HIV coinfection (n = 51) and without (n = 40). A combined reference standard was used: either positive microscopy on tissue aspirates, or in case of negative microscopy, positive PCR results on the aspirate slide. Additionally, endemic healthy controls (n = 20), non-endemic controls (n = 10) and patients with confirmed malaria infection (n = 10) were tested for specificity evaluation. Sensitivities ranged from 69.2% for DAT (applied cut-off ≥ 1/3200) to 92.2% for the Onsite RDT, whereas specificities ranged from 20.0% for Kalazar Antigen ICT to 100% for IT Leish and rK39 IgG1. Sensitivities from all assays decreased upon stratification according to HIV status but was only significantly different for rK39 Serion ELISA (p-value 0.0084) and the Onsite RDT (p-value 0.0159). In conclusion, performance of commercially available assays for VL on samples from Northern-Ethiopian patients varied widely with a substantial decrease in sensitivity in the VL-HIV coinfected group. Clear guidelines on minimal performance criteria of individual tests and algorithms are needed, as well as which reference standard should be used to determine the performance.
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http://dx.doi.org/10.1371/journal.pntd.0008963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774845PMC
December 2020

Evaluation of C-reactive protein and myxovirus resistance protein A to guide the rational use of antibiotics among acute febrile adult patients in Northwest Ethiopia.

Int J Infect Dis 2020 Dec 28;101:276-282. Epub 2020 Sep 28.

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium. Electronic address:

Objectives: In low-resource settings, treatment is often given empirically without knowledge of the aetiology due to a lack of diagnostics. In the search for reliable rapid tests to guide treatment work-up, this study was performed to determine whether two biomarkers could differentiate bacterial from non-bacterial infections in acute febrile patients.

Methods: Adults with acute fever were recruited at a referral hospital in Ethiopia. The QuikRead Go test was used to quantify C-reactive protein (qCRP) and the FebriDx test was used for combined qualitative detection of the bacterial CRP marker with myxovirus resistance protein A (MxA), a viral biomarker.

Results: Of the 200 patients included in this study, most presented with 2-3 days of fever, headache, and joint pain. Antibiotics were prescribed for 83.5% and antimalarials for 36.5%, while a bacterial infection was only confirmed in 5% and malaria in 11%. The median qCRP level for confirmed bacterial infections was 128 mg/l. The FebriDx and QuikRead Go test had an overall agreement of 72.0%.

Conclusions: An over-prescription of antibiotics for febrile patients was observed, even for those with low CRP levels and without a confirmed bacterial infection. The added value of the FebriDx was limited, while the combined use of rapid tests for qCRP and malaria should be considered for the management of acute febrile illness and antibiotic stewardship.
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http://dx.doi.org/10.1016/j.ijid.2020.09.1444DOI Listing
December 2020

Sexual Transmission of Visceral Leishmaniasis: A Neglected Story.

Trends Parasitol 2020 12 15;36(12):950-952. Epub 2020 Sep 15.

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

For visceral leishmaniasis (VL), a major vector-borne parasitic disease, an alternative sexual transmission route is well documented in dogs but evidence is lacking in humans. Here, we discuss the current knowledge and key questions to be answered as it may be an additional obstacle in ongoing VL elimination programs.
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http://dx.doi.org/10.1016/j.pt.2020.08.002DOI Listing
December 2020

Minimally Invasive Microbiopsies as an Improved Sampling Method for the Diagnosis of Cutaneous Leishmaniasis.

Open Forum Infect Dis 2020 Sep 17;7(9):ofaa364. Epub 2020 Aug 17.

Unit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Current sampling methods to diagnose cutaneous leishmaniasis are invasive and painful. An alternative and minimally invasive microbiopsy device was evaluated in a diverse range of cutaneous leishmaniasis lesions in Ethiopia. Using polymerase chain reaction-based diagnosis, the microbiopsy outperformed the routine skin slit sample by detecting more patients while pain scores were significantly lower.
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http://dx.doi.org/10.1093/ofid/ofaa364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486950PMC
September 2020

Towards the trachoma elimination target in the Southern region of Ethiopia: How well is the SAFE strategy being implemented?

J Infect Dev Ctries 2020 06 29;14(6.1):3S-9S. Epub 2020 Jun 29.

Institute of Tropical Medicine, Clinical Sciences Department, Antwerp, Belgium.

Introduction: Trachoma is one of the 20 neglected tropical diseases and a serious public health problem in Ethiopia. To reach the WHO elimination target by 2020, SAFE (Surgery, Antibiotics, Facial cleanliness, Environmental improvement) strategy has been implemented in the Southern Nations, Nationalities, and Peoples' Region (SNNPRs), Ethiopia. Scarce evidence exists regarding recent progress in achieving elimination of active trachoma (< 5%) and how well the SAFE strategy implemented.

Methodology: A retrospective analysis of programmatic data in the period 2013-2018 was used. All trachoma endemic districts in SNNPR were included. Data collected from the Federal Ministry of Health on trachoma prevalence and SAFE strategy were analyzed.

Results: Out of 134 endemic districts, only 35 had their planned impact survey, of which only 11 districts achieved the elimination target. Six districts reverted backwards from eliminated status to low (1) or moderate (5) level. The median prevalence of active trachoma in these 35 districts was 10% in 2017/18. In 2017, the mean antibiotic treatment coverage was 90%, but only 56% and 68% of districts implemented and reported on "F" and "E" components, respectively. In the high prevalence districts, only 10% delivered their planned five rounds of Zithromax® mass distribution.

Conclusions: These data showed a lack in planned impact surveys with only a limited number of districts reached the WHO elimination threshold by 2018. Lack of attention on high prevalent districts, and recent reversal of trachoma eliminated districts to moderate or low prevalence levels argue for urgent and prioritized implementation of the SAFE strategy.
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http://dx.doi.org/10.3855/jidc.11703DOI Listing
June 2020

Whole Blood Stimulation Assay as a Treatment Outcome Monitoring Tool for VL Patients in Ethiopia: A Pilot Evaluation.

J Immunol Res 2020 23;2020:8385672. Epub 2020 Jan 23.

Unit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Visceral leishmaniasis (VL) is a lethal disease if left untreated. Current treatments produce variable rates of treatment failure and toxicity without sterile cure, rendering treatment efficacy monitoring essential. To avoid repeated invasive tissue aspirates as well as empirical treatment, there is a need for new tools that allow a less-invasive and early assessment of treatment efficacy in the field. Cross-sectional studies have suggested levels of cytokines/chemokines after whole blood stimulation as good markers of cure, but longitudinal studies are lacking. In this study, we followed 13 active VL cases in an endemic area in Ethiopia by measuring the production of IFN-, TNF-, IP-10, IL-2, IL-10, MCP-1, and MIG before, during, and at the end of treatment. After 24 hours of stimulation of whole blood with soluble antigen, we observed an early, robust, and incremental increase of IFN-, TNF-, and IP-10 levels in all patients during treatment. Moreover, based on the IFN- levels that showed an average 13-fold increase from the time of diagnosis until the end of treatment, we could almost perfectly discriminate active from cured status. Similar concentrations and patterns were found in stimulation assays with the two main species. The levels of IFN-, IP-10, or TNF- also seemed to be inversely associated with the parasite load at baseline. Despite a 1/10 drop in concentrations, similar patterns were observed in IFN- and IP-10 levels when dried plasma spots were stored at 4°C for an average of 225 days. All the above evidence suggests a detectable restoration of cell-mediated immunity in VL and its association with parasite clearance. With a potential application in rural settings by means of dried plasma spots, we recommend to further explore the early diagnostic value of such assays for treatment efficacy monitoring in large cohort studies including treatment failure cases.
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http://dx.doi.org/10.1155/2020/8385672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193677PMC
February 2021

Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV.

EBioMedicine 2020 May 28;55:102748. Epub 2020 Apr 28.

Unit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, Belgium.

Background: Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment.

Methods: Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine learning approach to establish a clinically-useful 4-gene set.

Findings: Distinct signatures of differentially expressed genes between D0 and D29 were identified for patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average area-under-the-ROC-curve of 0.95 (CI: 0.75-1.00).

Interpretation: A simple blood-based signature thus holds significant promise to facilitate treatment efficacy monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients.

Funding: Project funding was provided by the AfricoLeish project, supported by the European Union Seventh Framework Programme (EU FP7).
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http://dx.doi.org/10.1016/j.ebiom.2020.102748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195535PMC
May 2020

Longitudinal evaluation of asymptomatic Leishmania infection in HIV-infected individuals in North-West Ethiopia: A pilot study.

PLoS Negl Trop Dis 2019 10 8;13(10):e0007765. Epub 2019 Oct 8.

Medical College, University of Gondar, Gondar, Ethiopia.

Background: In endemic regions, asymptomatic Leishmania infection is common. In HIV patients, detection of asymptomatic Leishmania infection could potentially identify those at risk of visceral leishmaniasis (VL). However, data on the prevalence, incidence, and determinants of asymptomatic infection, and the risk of VL are lacking.

Methods: We conducted a cross-sectional survey at a single ART centre, followed by a prospective cohort study amongst HIV-infected adults in HIV care in a district hospital in a VL-endemic area in North-West Ethiopia (9/2015-8/2016). Asymptomatic Leishmania infection was detected using the direct agglutination test (DAT), rK39-rapid diagnostic test (RDT)), PCR on peripheral blood and the KAtex urine antigen test, and defined as positivity on any Leishmania marker. All individuals were followed longitudinally (irrespective of the Leishmania test results). Risk factors for asymptomatic Leishmania infection were determined using logistic regression.

Results: A total of 534 HIV-infected individuals enrolled in HIV care were included in the study. After excluding 13 patients with a history of VL and an 10 patients with incomplete baseline Leishmania tests, 511 were included in analysis. The median age was 38 years (interquartile range (IQR) 30-45), 62.6% were male. The median follow-up time was 12 months (IQR 9-12). No deaths were reported during the study period. Most (95.5%) were on antiretroviral treatment at enrolment, for a median of 52 months (IQR 27-79). The median CD4 count at enrolment was 377 cells/mm3 (IQR 250-518). The baseline prevalence of Leishmania infection was 12.8% in males and 4.2% in females. Overall, 7.4% tested positive for rK39, 4.3% for DAT, 0.2% for PCR and 0.2% for KAtex. Independent risk factors for a prevalent infection were male sex (odds ratio (OR) 3.2; 95% confidence intervals (CI) 14-7.0) and concurrent malaria infection (OR 6.1; 95% CI 1.9-18.9). Amongst the 49 prevalent (baseline) infections with further follow-up, the cumulative incidence of losing the Leishmania markers by one year was 40.1%. There were 36 incident infections during the course of the study, with a cumulative one-year risk of 9.5%. Only one case of VL was detected during follow-up.

Conclusions: We found a high prevalence of asymptomatic Leishmania infection, persisting in most cases. The incidence was more modest and overt VL was rare. Larger and longer studies with more complete follow-up may help to decide whether a test and treat strategy would be justified in this context.

Trial Registration: ClinicalTrials.gov NCT02839603.
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http://dx.doi.org/10.1371/journal.pntd.0007765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799935PMC
October 2019

Cutaneous Leishmaniasis Due to .

EClinicalMedicine 2018 Dec 8;6:69-81. Epub 2019 Jan 8.

Unit of HIV and Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

is the main causative species for cutaneous leishmaniasis (CL) in Ethiopia. Despite its considerable burden, has been one of the most neglected species. In this review, published evidence on history, geography, vector, reservoir, epidemiology, parasitology, and immunology is discussed and knowledge gaps are outlined. endemic regions are limited to the highland areas, although nationwide studies on CL prevalence are lacking. and are the sandfly vectors and hyraxes are considered to be the main reservoir, but the role of other sandfly species and other potential reservoirs requires further investigation. Where and how transmission occurs exactly are also still unknown. Most CL patients in Ethiopia are children and young adults. Lesions are most commonly on the face, in contrast to CL caused by other species which may more frequently affect other body parts. CL lesions caused by seem atypical and more severe in their presentation as compared to other species. Mucocutaneous leishmaniasis and diffuse cutaneous leishmaniasis are relatively common, and healing of lesions caused by seems to take longer than that of other species. A thorough documentation of the natural evolution of as well as in depth studies into the immunological and parasitological characteristics that underpin the atypical and severe clinical presentation are needed. Better understanding of CL caused by this parasite species will contribute to interventions related to transmission, prevention, and treatment.
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http://dx.doi.org/10.1016/j.eclinm.2018.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537575PMC
December 2018

Serum Levels of Soluble CD40 Ligand and Neopterin in HIV Coinfected Asymptomatic and Symptomatic Visceral Leishmaniasis Patients.

Front Cell Infect Microbiol 2018 11;8:428. Epub 2018 Dec 11.

Unit of NTDs, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Human Immunodeficiency Virus (HIV) co-infection drastically increases the risk of developing overt visceral leishmaniasis (VL). The asymptomatic infection window constitutes an opportunity to identify those HIV patients at highest risk by defining early markers associated with disease susceptibility or resistance. As intracellular parasite killing is essential, we investigated whether serum markers of macrophage activation were notably affected in HIV patients with an asymptomatic infection or overt visceral leishmaniasis disease. Serum levels of soluble CD40 ligand and neopterin were assessed in 24 active VL-HIV patients, 35 HIV patients with asymptomatic infection and 35 HIV endemic controls. All patients were recruited in endemic regions of North-West Ethiopia. The serum levels of sCD40L and neopterin significantly decreased and increased in HIV patients with active VL compared to HIV patients with asymptomatic infection, respectively. No statistically significant differences could be detected in neopterin and sCD40L levels between asymptomatically infected HIV patients and endemic HIV control patients. However, an inverse trend, between antibody positivity or VL development and neopterin levels could be seen. The CD4+ T-cell count was inversely correlated with serum neopterin levels, but not with sCD40L levels. Our results in HIV coinfected patients, correspond with the postulated protective role of sCD40L in VL and underline the importance of the CD40-CD40L pathway in resistance against the parasite. Neopterin levels suggest an increased macrophage activation upon infection and could have a value in clinical algorithms to, although non-specifically, improve prediction of VL development in HIV patients with asymptomatic infection.
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http://dx.doi.org/10.3389/fcimb.2018.00428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297181PMC
September 2019

Antigen Detection in Urine for Noninvasive Diagnosis and Treatment Monitoring of Visceral Leishmaniasis in Human Immunodeficiency Virus Coinfected Patients: An Exploratory Analysis from Ethiopia.

Am J Trop Med Hyg 2018 10;99(4):957-966

Leishmaniasis Research and Treatment Center, University of Gondar, Gondar, Ethiopia.

Diagnosis of visceral leishmaniasis (VL) and assessment of treatment response in human immunodeficiency virus (HIV)-coinfected patients still relies on invasive tissue aspiration. This hampers scale-up and decentralization of care in resource-limited settings. Noninvasive diagnostics are urgently needed. KATEX is a frequently used latex agglutination test for antigen in urine that has never been evaluated in HIV-coinfected individuals from -endemic areas. This was an exploratory sub-study embedded within the screening phase of a trial in highly endemic northwestern Ethiopia. All patients were HIV-positive and aspirate-confirmed VL cases. We assessed diagnostic accuracy of KATEX for VL diagnosis and as test of cure at end of treatment, using tissue aspirate parasite load as reference methods. We also described the evolution of weekly antigen levels during treatment. Most of the 87 included patients were male (84, 97%), young (median age 31 years), and had poor immune status (median cluster of differentiation type 4 count 56 cells/μL). KATEX had moderate sensitivity (84%) for VL diagnosis. KATEX had moderate sensitivity (82%) and a moderate negative predictive value (87%) but only low specificity (49%) and a low positive predictive value (40%) for the assessment of treatment outcomes. Weekly antigen levels showed characteristic patterns during treatment of patients with different initial parasite loads and treatment outcomes. Antigen detection in urine using KATEX can contribute to improved VL diagnosis in HIV-coinfected patients but has limited use for monitoring of treatment response. Better noninvasive diagnostics are needed to reduce reliance on invasive methods and thus to expand and improve clinical care for VL in resource-limited settings.
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http://dx.doi.org/10.4269/ajtmh.18-0042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159592PMC
October 2018

Antigenuria to Predict Initial Treatment Failure and Relapse in Visceral Leishmaniasis/HIV Coinfected Patients: An Exploratory Study Nested Within a Clinical Trial in Ethiopia.

Front Cell Infect Microbiol 2018 29;8:94. Epub 2018 Mar 29.

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Biomarkers predicting the risk of VL treatment failure and relapse in VL/HIV coinfected patients are needed. Nested within a two-site clinical trial in Ethiopia (2011-2015), we conducted an exploratory study to assess whether (1) levels of antigenuria measured at VL diagnosis were associated with initial treatment failure and (2) levels of antigenuria at the end of treatment (parasitologically-confirmed cure) were associated with subsequent relapse. antigenuria at VL diagnosis and cure was determined using KAtex urine antigen test and graded as negative (0), weak/moderate (grade 1+/2+) or strongly-positive (3+). Logistic regression and Kaplan-Meier methods were used to assess the association between antigenuria and (1) initial treatment failure, and (2) relapse over the 12 months after cure, respectively. The analysis to predict initial treatment failure included sixty-three coinfected adults [median age: 30 years interquartile range (IQR) 27-35], median CD4 count: 56 cells/μL (IQR 38-113). KAtex results at VL diagnosis were negative in 11 (17%), weak/moderate in 17 (27%) and strongly-positive in 35 (36%). Twenty (32%) patients had parasitologically-confirmed treatment failure, with a risk of failure of 9% (1/11) with KAtex-negative results, 0% (0/17) for KAtex 1+/2+ and 54% (19/35) for KAtex 3+ results. Compared to KAtex-negative patients, KAtex 3+ patients were at increased risk of treatment failure [odds ratio 11.9 (95% CI 1.4-103.0); : 0.025]. Forty-four patients were included in the analysis to predict relapse [median age: 31 years (IQR 28-35), median CD4 count: 116 cells/μL (IQR 95-181)]. When achieving VL cure, KAtex results were negative in 19 (43%), weak/moderate (1+/2+) in 10 (23%), and strongly positive (3+) in 15 patients (34%). Over the subsequent 12 months, eight out of 44 patients (18%) relapsed. The predicted 1-year relapse risk was 6% for KAtex-negative results, 14% for KAtex 1+/2+ and 42% for KAtex 3+ results [hazard ratio of 2.2 (95% CI 0.1-34.9) for KAtex 1+/2+ and 9.8 (95% CI 1.8-82.1) for KAtex 3+, compared to KAtex negative patients; : 0.03]. A simple field-deployable urine antigen test can be used for risk stratification of initial treatment failure and VL relapse in HIV-patients. A dipstick-format would facilitate field implementation.
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http://dx.doi.org/10.3389/fcimb.2018.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884955PMC
April 2019

Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients.

Front Immunol 2017 12;8:1943. Epub 2018 Jan 12.

Unit of HIV and Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Patients with visceral leishmaniasis (VL)-human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL-HIV-coinfected patients.
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http://dx.doi.org/10.3389/fimmu.2017.01943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770372PMC
January 2018

Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial.

Clin Infect Dis 2018 01;66(3):444-451

Institute of Tropical Medicine, Antwerp, Belgium.

Background: We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation.

Methods: The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/μL at month 12; and (3) 12-month follow-up after stopping PSP. The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis.

Results: For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up. The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count. Forty-five patients were relapse-free and in follow-up at month 12 of PSP. This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation. Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period. During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up. No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period.

Conclusions: It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL. The management of those failing to reach this level remains to be defined.

Clinical Trials Registration: NCT01360762.
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http://dx.doi.org/10.1093/cid/cix807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848371PMC
January 2018

CD4:8 Ratio Above 5 Is Associated With All-Cause Mortality in CMV-Seronegative Very Old Women: Results From the BELFRAIL Study.

J Gerontol A Biol Sci Med Sci 2017 Sep;72(9):1155-1162

Department of Public Health and Primary Care, KU Leuven,Belgium.

The occurrence and general applicability of the CD4:8 ratio as a surrogate predictor of mortality among the oldest old have only been tested in a few longitudinal studies. Here, the predictive value of CD4:8 ratio for mortality with respect to the role of cytomegalovirus (CMV) infection was investigated. Using polychromatic flow cytometry, the CD4:8 ratio and T-cell subsets of 235 individuals aged 81.5 years or older were analyzed, and mortality data were collected after a mean period of 3.3 years. The hazard for all-cause mortality adjusted for age, comorbidity, and CMV serostatus increased 1.53-fold (95% CI: 0.94-2.51) with every increment in the CD4:8 ratio from R < 1, to 1 < R < 5 and R > 5 among women. A negative hazard ratio of 0.50 for CMV seropositivity in women indicated an apparently protective effect of this virus. In men, no associations with survival were observed. No mediation effect could be found for the CD4:8 ratio with respect to the relationship between CMV serostatus and mortality. Very elderly CMV-negative women with a R > 5 experienced the highest mortality rates, independent of age and comorbidity. The associations of CMV serostatus and CD4:8 ratio with mortality seem to reflect distinct pathways mediating life span in very old humans.
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http://dx.doi.org/10.1093/gerona/glw215DOI Listing
September 2017

The clinical impact of valvular heart disease in a population-based cohort of subjects aged 80 and older.

BMC Cardiovasc Disord 2016 Jan 12;16. Epub 2016 Jan 12.

Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

Background: In our ageing society, valvular heart diseases (VHD) have become an increasing public health problem. However, the lack of studies describing the impact of these diseases on the outcome of very old subjects makes it difficult to appreciate their real clinical burden.

Methods: Prospective, observational, population-based cohort study in Belgium. Five hundred fifty six subjects aged 80 years and older were followed up for 5.1 ± 0.25 years for mortality and 3.0 ± 0.25 years for hospitalization. Echocardiograms were performed at baseline. The Cumulative Illness Rating Scale (CIRS) was calculated for each subject.

Results: The prevalence of moderate-to-severe VHD was 17% (n = 97). Mitral stenosis was more prevalent in women and an age-dependent increase of the prevalence of severe aortic stenosis was seen. The overall disease burden was higher in participants with VHD (median CIRS 3 [IQR 3-5] vs 4 [IQR 3-6] (P = 0.008)). Moderate-to-severe VHD, and more specifically mitral stenosis and aortic stenosis, was found to be an independent predictor of both all-cause (HR 1.42 (95% CI 1.04-1.95)) and cardiovascular mortality (HR 2.13 (95% CI 1.38-3.29)). Moderate-to-severe VHD was also found to be an independent predictor of the need for a first unplanned hospitalization (HR 1.43 (95% CI 1.06-1.94)).

Conclusions: A high prevalence of moderate-to-severe VHD was found in the very old. Moderate-to-severe VHD was identified as an independent risk factor for all-cause and cardiovascular mortality and as well for unplanned hospitalizations, independent of other structural cardiac abnormalities, ventricular function and major co-morbidities.
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http://dx.doi.org/10.1186/s12872-016-0184-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709950PMC
January 2016

Prevalence and Prognostic Impact of Valve Area-Gradient Patterns in Patients ≥80 Years With Moderate-to-Severe Aortic Stenosis (from the Prospective BELFRAIL Study).

Am J Cardiol 2015 Sep 26;116(6):925-32. Epub 2015 Jun 26.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium; Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address:

Although degenerative aortic valve stenosis (AS) is common with increasing age, limited data exist regarding the prevalence and prognostic impact of its various valve area-gradient patterns in patients ≥80 years. To test this, echocardiograms were obtained in 542 randomly selected subjects aged ≥80 years recruited in the Belgium Cohort Study of the Very Elderly study (BFC80+). Subjects were divided into 3 groups: no or mild AS, moderate AS, and severe AS. Patients with severe AS were further stratified into those with high mean gradients (HG-AS) and those with paradoxically low mean gradients (LG-AS). Prevalence of moderate-to-severe AS was 14.7% and that of severe AS was 5.9%. In patients with severe AS, most (72%) exhibited paradoxical LG-AS. All patients with severe HG-AS were asymptomatic at the time of inclusion, whereas 48% of those with severe paradoxical LG-AS had significant symptoms. During follow-up, there were 2 aortic valve replacements and 230 deaths, of which 100 (43%) were of cardiovascular origin. Five-year overall survival rate was significantly worse in severe HG-AS than in any of the other groups (22 ± 14% vs 62 ± 2% in no or mild AS, 48 ± 7% in moderate AS, and 43 ± 10% in severe paradoxical LG-AS, p <0.01). Survival rate was similar among severe paradoxical LG-AS with and without low flow. In conclusion, in this large population-based sample of subjects ≥80 years, the prevalence of severe AS was 5.9%. Most of these subjects presented with the severe paradoxical LG-AS and a third of them were symptomatic. In this elderly community, severe HG-AS is a major determinant of prognosis, even in the absence of symptoms, whereas severe paradoxical LG-AS seems to behave similarly to moderate AS.
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http://dx.doi.org/10.1016/j.amjcard.2015.05.062DOI Listing
September 2015

Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study.

Exp Gerontol 2015 Sep 4;69:53-61. Epub 2015 Jun 4.

Centre of General Practice, Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Kapucijnenvoer 33, Blok J, 3000 Leuven, Belgium; Institute of Health and Society, Université Catholique de Louvain, Clos Chapelle-Aux-Champs 30, Bte 3005, 1200 Brussels, Belgium.

Background: Certain inflammatory biomarkers increase with age, provide information about general burden of illness and could cause or reflect any collateral damage to healthy cells and organs. However, comparative studies to predict adverse outcomes are missing. Therefore, our study validated and identified the principal prognostic marker to predict important adverse outcomes in the oldest old from an extensive battery of serum inflammatory markers.

Methods: A large battery of potential 'inflammaging' markers (IL-1α, IL1-β, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, EGF, VEGF, MCP-1, usCRP, prealbumin) was assessed in a representative sample of 415 heterogenic individuals 80years of age or older in the BELFRAIL study. Kaplan-Meier, Cox proportional hazards and CART analyses determined the overall prognostic value of these markers for predicting all-cause, cardiovascular and non-cardiovascular mortality as well as hospitalization.

Results: Serum IL-6 and usCRP levels were strongly associated with time of survival, independent of cause of death. Serum IL-6 levels had the most robust dose-response relationship with mortality. To a lesser extent, IL-10 and IL-1β were associated with all-cause mortality but were restricted to non-cardiovascular or cardiovascular mortality, respectively. Having a low IL-6 at baseline (<1.77pg/ml) could predict 90% of those who were not at risk for all-cause mortality after 3years, even after adjusting for confounders. Similarly, we observed an 83.6% chance of identifying those cases with 0 or 1 hospitalization using low IL-6 serum levels.

Conclusion: The results suggest that a single measurement of low IL-6 serum levels is the first choice to guide clinical practice in the oldest old and could summarize the short-term risk of death and hospitalization.
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http://dx.doi.org/10.1016/j.exger.2015.06.005DOI Listing
September 2015

General practitioners' judgement of chronic heart failure in the oldest old: Insights from the BELFRAIL study.

Int J Cardiol 2015 Jul 5;191:120-7. Epub 2015 May 5.

Department of Public Health and Primary Care, KU Leuven (KUL), Leuven, Belgium; Institute of Health and Society, Université Catholique de Louvain (UCL), Brussels, Belgium.

Background And Objectives: Conflicting evidence exists about the value of general practitioners' (GPs') diagnoses of chronic heart failure (CHF), especially in older persons. Therefore, the relationship between GPs' judgement of CHF and objective cardiac abnormalities and their respective prognostic value for 5-year mortality in patients aged 80 and older was studied.

Methods And Results: These analyses were embedded within the prospective, population-based BELFRAIL study. At baseline, 525 patients (mean age 85 ± 3.7 years, 37% men) were clinically assessed by their GPs, had NT-proBNP levels determined and received a detailed echocardiography at home. GPs were asked to judge the presence of CHF and to list their arguments in favour or against CHF. Cause-specific mortality was collected until 5.2 ± 0.25 years after baseline. GPs suspected CHF in 154 patients (29%). The prevalence of objective cardiac abnormalities was 35% (n=183). GPs' judgement predicted objective cardiac abnormalities inaccurately (sensitivity 45% (95% CI 38-53), specificity 79% (95% CI 75-83)). However, both objective cardiac abnormalities and GPs' diagnoses of CHF were good predictors of 5-year mortality (HR 2.1 (95% CI 1.6-2.7) vs 1.7 (95% CI 1.3-2.3), respectively). Furthermore, the presence of objective cardiac abnormalities was not significantly better than GPs' judgement in identifying patients at risk for mortality, although a trend for better cardiovascular mortality risk classification was noted (NRI 10% (95% CI -2 to 21%), P=0.13).

Conclusions: Although GPs' judgement of CHF and objective cardiac abnormalities correlated poorly, the validity of GPs' clinical judgement for mortality risk stratification was demonstrated.
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http://dx.doi.org/10.1016/j.ijcard.2015.05.002DOI Listing
July 2015

Short-term prognostic value of forced expiratory volume in 1 second divided by height cubed in a prospective cohort of people 80 years and older.

BMC Geriatr 2015 Feb 25;15:15. Epub 2015 Feb 25.

Institute of Health and Society, Université Catholique de Louvain (UCL), Clos Chapelle-aux-Champs 30, bte B1.30.15, 1200, Brussels, Belgium.

Background: Spirometry-based parameters of pulmonary function such as forced expiratory volume in 1 second (FEV1) have prognostic value beyond respiratory morbidity and mortality. FEV1 divided by height cubed (FEV1/Ht(3)) has been found to be better at predicting all-cause mortality than the usual standardization as percentage of predicted "normal values" (FEV1%) and its use is independent of reference equations. Yet, limited data are available on the very old adults (80 years and older) and in association to other adverse health outcomes relevant for this age group. This study aims to investigate the short-term prognostic value of FEV1/Ht(3) for all-cause mortality, hospitalization, physical and mental decline in a cohort of very old adults.

Methods: In a population-based prospective cohort study of 501 very old adults in Belgium, comprehensive geriatric assessment and spirometry were performed at baseline and after 1.7 ± 0.21 years. Kaplan-Meier curves for 3-year all-cause mortality and hospitalization rates and multivariable analysis adjusted for age, sex, smoking status, co-morbidities, anemia, high C reactive protein and creatinine levels examined the association of FEV1/Ht(3) with all-cause mortality, unplanned hospitalization and decline in mental and physical functioning. Physical functioning was assessed by activities of daily living, a battery of physical performance tests and grip strength. Mental functioning was assessed with mini mental state examination and 15 items geriatric depression scale.

Results: Individuals in the lowest quartile of FEV1/Ht(3) had a statistically significant increased adjusted risk for all-cause mortality (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.10-2.60) and unplanned hospitalization (HR 1.65, 95% CI 1.21-2.25), as well as decline in physical (odds ratio [OR] 1.89, 95% CI 1.05-3.39) and mental functioning (OR 2.39, 95% CI 1.30-4.40) compared to the rest of the study population.

Conclusions: In a cohort of very old adults, low FEV1 expressed as FEV1/Ht(3) was found to be a short-term predictor of all-cause mortality, hospitalization and decline in physical and mental functioning independently of age, smoking status, chronic lung disease and other co-morbidities. Further research is needed on FEV1/Ht(3) as a potential risk marker for frailty and adverse health outcomes in this age group.
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http://dx.doi.org/10.1186/s12877-015-0013-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345023PMC
February 2015

Airflow limitation by the Global Lungs Initiative equations in a cohort of very old adults.

Eur Respir J 2015 Jul 16;46(1):123-32. Epub 2015 Apr 16.

Institute of Health and Society, Université Catholique de Louvain (UCL), Brussels, Belgium Dept of Public Health and Primary Care, Katholieke Universiteit Leuven (KUL), Leuven, Belgium.

The cut-off for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) defining airflow limitation for chronic obstructive pulmonary disease (COPD) is still contested. We assessed airflow limitation prevalence by the lower limit of normal (LLN) of Global Lungs Initiative (GLI) 2012 reference values and its predictive ability for all-cause mortality and hospitalisation in very old adults (aged ≥80 years) compared with the fixed cut-off. In a Belgian population-based prospective cohort of 411 very old adults, airflow limitation prevalence by the 5th percentile of GLI 2012 z-scores (GLI-LLN) and fixed cut-off (0.70) were compared with COPD reported by general practitioners (GPs). Survival and Cox regression multivariable analysis assessed the association of airflow limitation by both cut-offs with 5-year all-cause mortality and first hospitalisation at 3 years. 9.2% had airflow limitation by GLI-LLN and 27% by fixed cut-off, without good agreement (kappa coefficient ≤0.40) with GP-reported COPD (9%). Only airflow limitation by GLI-LLN was independently associated with mortality (adjusted hazard ratio 2.10, 95% CI 1.30-3.38). FEV1/FVC <0.70 but ≥GLI-LLN (17.8%) had no significantly higher risk for mortality or hospitalisation. In a cohort of very old adults, airflow limitation by GLI-LLN has lower prevalence than by fixed cut-off, independently predicts all-cause mortality and does not miss individuals with significantly higher all-cause mortality and hospitalisation.
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http://dx.doi.org/10.1183/09031936.00217214DOI Listing
July 2015

Multimorbidity measures were poor predictors of adverse events in patients aged ≥80 years: a prospective cohort study.

J Clin Epidemiol 2015 Feb 19;68(2):220-7. Epub 2014 Dec 19.

Institut de Recherche Santé et Societé, Université Catholique de Louvain (UCL), à Clos Chapelle-aux-champs, 30 bte 30.15 - 1200 Woluwe-Saint-Lambert, Brussels, Belgium; Department of Public and Primary HealthCare, Katholieke Universiteit Leuven (KUL), Kapucijnenvoer 35 blok d, box 7001, B-3000, Leuven, Belgium.

Objectives: To assess and compare the ability of two measures of multimorbidity and a simple disease count (DC) to predict health outcomes in a population of patients aged ≥80 years.

Study Design And Setting: A prospective, observational, and population-based cohort study including 567 individuals [3.0 years (standard deviation ± 0.25) follow-up].

Results: Of the patients, 37.6% were reported with five or more diseases. Multimorbidity was measured by means of a modified Charlson comorbidity index [mCCI; median score, 5 (range, 4-15)], Cumulative Illness Rating Scale [CIRS; median score, 4 (range, 1-11)], and a simple DC of 22 selected chronic conditions [median score, 4 (range, 0-13)]. All measures were independently related to mortality [adjusted hazard ratio (HR) mCCI, 2.5 (confidence interval {CI}: 1.5, 4.1); CIRS, 2.1 (CI: 1.4, 3.2); DC, 2.1 (CI: 1.4, 3.2)] and hospitalization [adjusted HR DC, 2.3 (CI: 1.7, 3.1); mCCI, 2.1 (CI: 1.5, 3.0), CIRS, 1.9 (CI: 1.5, 2.6)] but not to functional decline. Areas under the curve for mortality and hospitalization were all below 0.70. Net reclassification improvements did not indicate that any one measure provided a significant benefit over the others.

Conclusion: In this population, the mCCI, CIRS, and unweighted DC predicted mortality and hospitalization but not functional decline. There is no clear advantage of using one measure over another.
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http://dx.doi.org/10.1016/j.jclinepi.2014.08.010DOI Listing
February 2015

Interleukin-6 predicts short-term global functional decline in the oldest old: results from the BELFRAIL study.

Age (Dordr) 2014 21;36(6):9723. Epub 2014 Nov 21.

Centre of General Practice, Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Kapucijnenvoer 33, Blok J, 3000, Leuven, Belgium,

The chronic inflammatory state at old age may contribute to the pathophysiology of or reflect chronic conditions resulting in loss of physical and mental functioning. Therefore, our objective was to examine the predictive value of a large battery of serum inflammatory markers as risk indicators for global functional decline and its specific physical and mental determinants in the oldest old. Global functional decline and specific aspects of physical and mental functional decline were assessed during an average of 1.66 years (±0.21) in a sample of 303 persons aged 80 years or older of the BELFRAIL study. Serum levels of 14 inflammatory proteins, including cytokines, growth factors, and acute phase proteins, were measured at baseline. Almost 20 % of the participants had a significant global functional decline over time. Interleukin (IL)-6 serum levels were uniquely positively associated with global functional decline, even after correcting for multiple confounders (odds ratio 1.51). Odds ratios for the individual aspects (physical dependency, physical performance, cognition, and depression) of functioning were lower, and composite scores of physical or mental decline were not significant. The proportion of global functional decline exhibited a dose-response curve with increasing levels of IL-6. Thus, IL-6 is an independent risk indicator for accelerated global functional decline in the oldest old. Our results suggest that simple serum levels of IL-6 may be very useful in short-term identification or evaluation of global functional status in the oldest old.
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http://dx.doi.org/10.1007/s11357-014-9723-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237718PMC
June 2015

No relation between CMV infection and mortality in the oldest old: results from the Belfrail study.

Age Ageing 2015 Jan 15;44(1):130-5. Epub 2014 Jul 15.

Department of Public Health and Primary Care, KULeuven, Kapucijnenvoer 33 blok J, 3000 Leuven, Belgium Institute of Health and Society, Université Catholique de Louvain, Brussels, Belgium.

Objective: previous studies have demonstrated an association between cytomegalovirus (CMV) infection and mortality in adults. In this prospective study, it was investigated whether these findings could be confirmed in the oldest old.

Methodology: data obtained from a prospective observational cohort study (2008-2012) of 549 community-dwelling persons in Belgium aged 80 and older.

Results: seventy-six percent were anti-CMV seropositive of whom 37.5% had an anti-CMV IgG titre in the highest tertile (>250 IU/ml). After a median time of follow-up of 1,049 days, 127 deaths occurred. Cox proportional hazard models failed to show an association between CMV serostatus and all-cause mortality. Among persons seropositive for CMV, after adjusting for multiple confounders an anti-CMV in the highest tertile was statistically significantly associated with all-cause mortality (hazard ratio: 1.64, 95% confidence interval: 1.08, 2.48).

Conclusion: in contrast to previous findings, a positive CMV serostatus was not associated with an increased risk for all-cause mortality in this cohort of very old people. This is probably the result of a survival effect. CMV seropositive subjects with high anti-CMV titres were at higher risk for all-cause mortality compared with other individuals. This may reflect CMV infection reactivation to be more common in the end stages of life.
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http://dx.doi.org/10.1093/ageing/afu094DOI Listing
January 2015

Muscle strength and physical performance as predictors of mortality, hospitalization, and disability in the oldest old.

J Am Geriatr Soc 2014 Jun 6;62(6):1030-8. Epub 2014 May 6.

Institut de Recherche Santé et Societé, Université Catholique de Louvain, Brussels, Belgium.

Objectives: To evaluate the predictive value of muscle strength and physical performance in the oldest old for all-cause mortality; hospitalization; and the onset of disability, defined as a decline in activities of daily living (ADLs), independent of muscle mass, inflammatory markers, and comorbidities.

Design: A prospective, observational, population-based follow-up study.

Setting: Three well-circumscribed areas of Belgium.

Participants: Five hundred sixty participants aged 80 and older were followed for 33.5 months (interquartile range 31.1-35.6 months).

Measurements: Grip strength, Short Physical Performance Battery (SPPB) score, and muscle mass were measured at baseline; ADLs at baseline and after 20 months; and all-cause mortality and time to first hospitalization from inclusion onward. Kaplan-Meier curves and Cox proportional hazards models were calculated for all-cause mortality and hospitalization. Logistic regression analysis was used to determine predictors of decline in ADLs.

Results: Kaplan-Meier curves showed significantly higher all-cause mortality and hospitalization in subjects in the lowest tertile of grip strength and SPPB score. The adjusted Cox proportional hazards model showed that participants with high grip strength or a high SPPB score had a lower risk of mortality and hospitalization, independent of muscle mass, inflammatory markers, and comorbidity. A relationship was found between SPPB score and decline in ADLs, independent of muscle mass, inflammation, and comorbidity.

Conclusion: In people aged 80 and older, physical performance is a strong predictor of mortality, hospitalization, and disability, and muscle strength is a strong predictor of mortality and hospitalization. All of these relationships were independent of muscle mass, inflammatory markers, and comorbidity.
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http://dx.doi.org/10.1111/jgs.12840DOI Listing
June 2014

CD4:8 ratio >5 is associated with a dominant naive T-cell phenotype and impaired physical functioning in CMV-seropositive very elderly people: results from the BELFRAIL study.

J Gerontol A Biol Sci Med Sci 2015 Feb 25;70(2):143-54. Epub 2014 Feb 25.

Department of General Practice, Katholieke Universiteit Leuven (KUL), Belgium. Institute of Health and Society, Université Catholique de Louvain (UCL), Brussels, Belgium.

A subset of older people is at increased risk of hospitalization and dependency. Emerging evidence suggests that immunosenescence reflected by an inverted CD4:8 ratio and cytomegalovirus (CMV) seropositivity plays an important role in the pathophysiology of functional decline. Nevertheless, the relation between CD4:8 ratio and functional outcome has rarely been investigated. Here, CD4:8 ratio and T-cell phenotypes of 235 community-dwelling persons aged ≥81.5 years in the BELFRAIL study and 25 younger persons (mean age 28.5 years) were analyzed using polychromatic flow cytometry. In the elderly persons, 7.2% had an inverted CD4:8 ratio, which was associated with CMV seropositivity, less naive, and more late-differentiated CD4+ and CD8+ T cells. However, 32.8% had a CD4:8 ratio >5, a phenotype associated with a higher proportion of naive T cells and absent in young donors. In CMV seropositives, this subgroup had lower proportions of late-differentiated CD4+ and CD8+ T cells and weaker anti-CMV immunoglobulin G reactivity. This novel naive T-cell-dominated phenotype was counterintuitively associated with a higher proportion of those with impaired physical functioning in the very elderly people infected with CMV. This underscores the notion that in very elderly people, not merely CMV infection but also the state of its accompanying immune dysregulation is of crucial importance with regard to physical impairment.
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http://dx.doi.org/10.1093/gerona/glu018DOI Listing
February 2015

Prognostic value of circulating cytokines on overall survival and disease-free survival in cancer patients.

Biomark Med 2014 ;8(2):297-306

Faculty of Medicine & Life Sciences, Hasselt University, Campus Diepenbeek, Martelarenlaan 42, 3500 Hasselt, Belgium.

Through their tumor-promoting and/or tumor-suppressive properties, cytokines can influence progression of cancer. We systematically reviewed the current literature on the prognostic value of the circulating cytokines IL-1α/β, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-β and IFN-γ to predict overall and disease-free survival in any type of cancer patients. PubMed was systematically searched and based on eligibility assessment using our five criteria of the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) checklist, six unique studies were reviewed. Elevated IL-6 and IL-10 levels seem independently associated with worse prognosis in terms of overall and disease-free survival. The prognostic value of IL-1α/β, IL-8, IL-12, TNF-α, TGF-β and IFN-γ could not be demonstrated. The small number of selected studies underlines the need for large well-designed prospective studies, using the REMARK checklist as a guideline, to determine which cytokines have prognostic value on survival in cancer patients.
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http://dx.doi.org/10.2217/bmm.13.122DOI Listing
October 2014
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