Publications by authors named "Leïla Belkhir"

44 Publications

Seroprevalence of SARS-CoV-2 infection in health care workers of a teaching hospital in Belgium: self-reported occupational and household risk factors for seropositivity.

Diagn Microbiol Infect Dis 2021 May 5;100(4):115414. Epub 2021 May 5.

Department of Internal Medicine and Infectious Diseases, Cliniques universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium. Electronic address:

This study aims to evaluate SARS-CoV-2 seroprevalence among health care workers (HCWs) and to assess self-reported risk factors for seropositivity. A total of 3255 HCWs were included and the overall seroprevalence was 7.8%. The likelihood of seropositivity was higher in participants reporting any COVID-19 symptoms within the last 4 months (OR 8.32, 95% CI 5.83-11.88, P < 0.001). Being a female HCW (OR 1.32, 95% CI 1.11-2.32, P < 0.01), having a cohabitant who was infected with SARS-CoV-2 (OR 2.55, 95% CI 1.78-3.66 P < 0.001) or a cohabitant who was a nursing home caregiver (OR 3.71, 95% CI 1.59-8.65, P = 0.002) were independently associated with an increased risk of seropositivity. Working in a COVID-19 unit (OR 1.64, 95% CI 1.21-2.23, P < 0.001) and being exposed to a SARS-CoV-2 infected co-worker (OR 1.30,95% CI 0.97-1.74, P = 0.016) resulted in higher seropositivity rate. Even if in-hospital exposure may play a significant role, increased infection risk is most likely attributable to household contact.
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http://dx.doi.org/10.1016/j.diagmicrobio.2021.115414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098032PMC
May 2021

Very low Immunization Rate in Kidney Transplant Recipients after one Dose of the BNT162b2 Vaccine: Beware not to Lower the Guard!

Transplantation 2021 May 12. Epub 2021 May 12.

Department of Nephrology, Saint Luc University Clinics, Brussels, Belgium. Institut de Recherche Expérimentale et Clinique, Saint Luc University Clinics, Brussels, Belgium. Department of Internal Medicine and Infectious Disease, Saint Luc University Clinics, Brussels, Belgium. Department of Abdominal Surgery and Kidney Transplantation, Saint Luc University Clinics, Brussels, Belgium Department of Microbiology, Saint Luc University Clinics, Brussels, Belgium.

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http://dx.doi.org/10.1097/TP.0000000000003818DOI Listing
May 2021

Follow-up of functional exercise capacity in patients with COVID-19: It is improved by telerehabilitation.

Respir Med 2021 07 30;183:106438. Epub 2021 Apr 30.

Service de Pneumologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL & Dermatologie, Université Catholique de Louvain, Brussels, Belgium; Secteur de Kinésithérapie et Ergothérapie, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address:

Background: The impact of the COVID-19 pandemic on functional exercise capacity seemed quickly clinically evident. The objective of this study was to assess the functional exercise capacity of patients with severe COVID-19 and to evaluate the effect of a telerehabilitation program in the specific context of the COVID-19 pandemic.

Method: Patients hospitalized for severe or critical COVID-19 were recruited. The functional exercise capacity (1-min sit-to-stand test (STST)) was prospectively quantified at discharge. A telerehabilitation program was then proposed. A control group was composed with the patients refusing the program.

Results: At discharge, none of the 48 recruited patients had a STST higher than the 50th percentile and 77% of them were below the 2.5th percentile. SpO2 was 92.6 ± 3.0% after STST and 15 patients had oxygen desaturation. After 3-months of follow-up, the number of repetitions during STST significantly increased either in telerehabilitation (n = 14) (p < 0.001) or in control groups (n = 13) (p = 0.002) but only one patient had a result higher than the 50th percentile (in Telerehabilitation group) and 37% of them were still under the 2.5th percentile for this result. The improvement was significantly and clinically greater after the telerehabilitation program (p = 0.005). No adverse events were reported by the patients during the program.

Conclusions: Patients hospitalized for COVID-19 have a low functional exercise capacity at discharge and the recovery after three months is poor. The feasibility and the effect of a simple telerehabilitation program were verified, this program being able to substantially improve the functional recovery after three months.
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http://dx.doi.org/10.1016/j.rmed.2021.106438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084600PMC
July 2021

Determinants of IgG antibodies kinetics after severe and critical COVID-19.

J Med Virol 2021 May 4. Epub 2021 May 4.

Division of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

The kinetics of IgG antibodies after coronavirus disease 2019 (COVID-19) remain poorly understood. We investigated factors influencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibody levels and time to seronegativation during the follow-up of severe and critically ill patients. We retrospectively reviewed serological evaluations drawn during the follow-up of severe or critical laboratory-proven COVID-19 patients hospitalized at a large academic hospital. Specific IgG titers were measured using a chemiluminescent assay targeting anti-spike and anti-nucleocapsid protein IgG. The influence of time, demographic factors, clinical and paraclinical characteristics, and COVID-19 therapeutics on IgG levels were assessed through linear regression using a mixed-effect model, and delay until IgG negativation through a Weibull regression model. The cohort included 116 patients with a total of 154 IgG measurements drawn at a median of 79 days after diagnosis. IgG antibodies were increased with age (p = 0.005) and decreased significantly over time (p = 0.0002). Using elapsed time and age as covariates, we demonstrated higher IgG levels in patients with a higher body mass index (BMI) (p = 0.0026) and lower IgG levels in immunocompromised patients (p = 0.032). A high BMI was further found to delay and immunodeficiency to hasten significantly seronegativation, whereas no significant effect was observed with corticosteroids. These data highlight the waning over time of IgG antibodies after severe or critical COVID-19. Age, BMI, and immunosuppression also appear to influence the IgG kinetics, while short-term corticotherapy does not. Those data improve the understanding of SARS-CoV-2 serology while further research should determine the determinants of long-term seroprotection.
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http://dx.doi.org/10.1002/jmv.27059DOI Listing
May 2021

Delayed Large Local Reactions to mRNA Vaccines.

N Engl J Med 2021 Apr 21. Epub 2021 Apr 21.

Cliniques Universitaires Saint-Luc Université Catholique de Louvain, Brussels, Belgium

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http://dx.doi.org/10.1056/NEJMc2104751DOI Listing
April 2021

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Nat Commun 2021 04 15;12(1):2349. Epub 2021 Apr 15.

Infectious and Tropical Diseases Department, Angers University Hospital, Angers, France.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
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http://dx.doi.org/10.1038/s41467-021-22446-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050319PMC
April 2021

Integrative respiratory follow-up of severe COVID-19 reveals common functional and lung imaging sequelae.

Respir Med 2021 05 4;181:106383. Epub 2021 Apr 4.

Radiology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium; Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Belgium.

Background: COVID-19 pandemic resulted in an unprecedented number of hospitalizations in general wards and intensive care units (ICU). Severe and critical COVID-19 patients suffer from extensive pneumonia; therefore, long-term respiratory sequelae may be expected.

Research Question: We conducted a cohort study to determine respiratory sequelae in patients with severe and critical COVID-19. We aimed at evaluating the proportion of patients with persisting respiratory symptoms and/or abnormalities in pulmonary function tests (PFT) or in lung imaging.

Study Design: and methods: This is a single center cohort study including COVID-19 survivors who underwent a three-month follow-up with clinical evaluation, PFT and lung high-resolution computed tomography (HRCT). All clinical, functional, and radiological data were centrally reviewed. Multiple linear regression analysis was performed to identify factors associated with residual lesions on HRCT.

Results: Full clinical evaluation, PFT and lung HRCT were available for central review in 126, 122 and 107 patients, respectively. At follow-up, 25% of patients complained from dyspnea and 35% from fatigue, lung diffusion capacity (DLCO) was decreased in 45%, 17% had HRCT abnormalities affecting more than 5% of their lung parenchyma while signs of fibrosis were found in 21%. In multiple linear regression model, number of days in ICU were related to the extent of persisting lesions on HRCT, while intubation was associated with signs of fibrosis at follow-up (P = 0.0005, Fisher's exact test). In contrast, the severity of lung imaging or PFT changes were not predictive of fatigue and dyspnea.

Interpretation: Although most hospitalized COVID-19 patients recover, a substantial proportion complains from persisting dyspnea and fatigue. Impairment of DLCO and signs suggestive of fibrosis are common but are not strictly related to long-lasting symptoms.
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http://dx.doi.org/10.1016/j.rmed.2021.106383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019490PMC
May 2021

Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: A retrospective study from an academic center in Belgium.

Diabetes Metab Syndr 2021 Jan-Feb;15(1):149-157. Epub 2020 Dec 14.

Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Avenue Hippocrate, 10, 1200, Brussels, Belgium.

Background And Aims: We describe the characteristics and short-term prognosis of in-patients with diabetes and COVID-19 admitted to a Belgian academic care center.

Methods: We retrospectively reviewed the data on admission from patients with known or newly-diagnosed diabetes and confirmed COVID-19. First, survivors were compared to non-survivors to study the predictive factors of in-hospital death in patients with diabetes. Secondly, diabetic patients with SARS-CoV-2 pneumonia were matched for age and sex with non-diabetic patients with SARS-CoV-2 pneumonia, to study the prognosis and predictive factors of in-hospital death related to diabetes.

Results: Seventy-three diabetic patients were included. Mean age was 69 (±14) years. Women accounted for 52%. Most patients had type 2 diabetes (89.0%), long-term complications of hyperglycemia (59.1%), and hypertension (80.8%). The case-fatality rate (CFR) was 15%. Non-survivors had more severe pneumonia based on imaging (p 0.029) and were less often treated with metformin (p 0.036). In patients with SARS-CoV-2 pneumonia, CFR was 15.6% in diabetic (n = 64) and 25.0% in non-diabetic patients (n = 128), the difference being non-significant (p 0.194). Predictive factors of in-hospital death were elevated white blood cells count (HR 9.4, CI 1.50-58.8, p 0.016) and severe pneumonia on imaging (HR 25.0, CI 1.34-466, p 0.031) in diabetic patients, and cognitive impairment (HR 5.80, CI 1.61-20.9, p 0.007) and cardiovascular disease (HR 5.63, CI 1.54-20.6, p 0.009) in non-diabetic patients.

Conclusion: In this monocentric cohort from Belgium, diabetic in-patients with COVID-19 had mostly type 2 diabetes, prevalent hyperglycemia-related vascular complications and comorbidities including hypertension. In this cohort, the CFR was not statistically different between patients with and without diabetes.
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http://dx.doi.org/10.1016/j.dsx.2020.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833262PMC
March 2021

Optimal sampling strategies for darunavir and external validation of the underlying population pharmacokinetic model.

Eur J Clin Pharmacol 2021 Apr 11;77(4):607-616. Epub 2020 Nov 11.

Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier 72, B01.72.0, Brussels, Belgium.

Purpose: A variety of diagnostic methods are available to validate the performance of population pharmacokinetic models. Internal validation, which applies these methods to the model building dataset and to additional data generated through Monte Carlo simulations, is often sufficient, but external validation, which requires a new dataset, is considered a more rigorous approach, especially if the model is to be used for predictive purposes. Our first objective was to validate a previously published population pharmacokinetic model of darunavir, an HIV protease inhibitor boosted with ritonavir or cobicistat. Our second objective was to use this model to derive optimal sampling strategies that maximize the amount of information collected with as few pharmacokinetic samples as possible.

Methods: A validation dataset comprising 164 sparsely sampled individuals using ritonavir-boosted darunavir was used for validation. Standard plots of predictions and residuals, NPDE, visual predictive check, and bootstrapping were applied to both the validation set and the combined learning/validation set in NONMEM to assess model performance. D-optimal designs for darunavir were then calculated in PopED and further evaluated in NONMEM through simulations.

Results: External validation confirmed model robustness and accuracy in most scenarios but also highlighted several limitations. The best one-, two-, and three-point sampling strategies were determined to be pre-dose (0 h); 0 and 4 h; and 1, 4, and 19 h, respectively. A combination of samples at 0, 1, and 4 h was comparable to the optimal three-point strategy. These could be used to reliably estimate individual pharmacokinetic parameters, although with fewer samples, precision decreased and the number of outliers increased significantly.

Conclusions: Optimal sampling strategies derived from this model could be used in clinical practice to enhance therapeutic drug monitoring or to conduct additional pharmacokinetic studies.
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http://dx.doi.org/10.1007/s00228-020-03036-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935830PMC
April 2021

A biological profile for diagnosis and outcome of COVID-19 patients.

Clin Chem Lab Med 2020 10 15;58(12):2141-2150. Epub 2020 Oct 15.

Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.

Objectives As severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pandemic is increasing its victims on a global scale with recurring outbreaks, it remains of outmost importance to rapidly identify people requiring an intensive care unit (ICU) hospitalization. The aim of this study was to identify Coronavirus Disease 2019 (COVID-19) biomarkers, to investigate their correlation with disease severity and to evaluate their usefulness for follow-up. Methods Fifty patients diagnosed with SARS-Cov-2 were included in March 2020. Clinical and biological data were collected at admission, during hospitalization and one month after discharge. Patients were divided into two severity groups: non-ICU (28) and ICU and/or death (22) to stratify the risk. Results Blood parameters in COVID-19 patients at admission showed increased C-reactive protein (CRP) (100%), ferritin (92%), lactate dehydrogenase (LDH) (80%), white blood cell (WBC) count (26%) with lymphopenia (52%) and eosinopenia (98%). There were significant differences in levels of CRP, ferritin, D-dimers, fibrinogen, lymphocyte count, neutrophil count and neutrophil-to-lymphocyte ratio (NLR) among the two severity groups. Mapping of biomarker's kinetics distinguished early and late parameters. CRP, ferritin, LDH, lymphopenia and eosinopenia were present upon admission with a peak at the first week. Late biomarkers such as anemia, neutrophilia and elevated liver biomarkers appeared after one week with a peak at three weeks of hospitalization. Conclusions We confirmed that high-values of CRP, NLR, D-dimers, ferritin as well as lymphopenia and eosinopenia were consistently found and are good markers for risk stratification. Kinetics of these biomarkers correlate well with COVID-19 severity. Close monitoring of early and late biomarkers is crucial in the management of critical patients to avoid preventable deaths.
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http://dx.doi.org/10.1515/cclm-2020-0626DOI Listing
October 2020

Testing of patients and coronavirus disease 2019 (COVID-19) infection before scheduled deliveries.

J Perinat Med 2020 Nov;48(9):995-996

Department of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

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http://dx.doi.org/10.1515/jpm-2020-0444DOI Listing
November 2020

Impact of solid cancer on in-hospital mortality overall and among different subgroups of patients with COVID-19: a nationwide, population-based analysis.

ESMO Open 2020 09;5(5):e000947

Department of General Medical Oncology and Multidisciplinary Breast Centre, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.

Background: Cancer seems to have an independent adverse prognostic effect on COVID-19-related mortality, but uncertainty exists regarding its effect across different patient subgroups. We report a population-based analysis of patients hospitalised with COVID-19 with prior or current solid cancer versus those without cancer.

Methods: We analysed data of adult patients registered until 24 May 2020 in the Belgian nationwide database of Sciensano. The primary objective was in-hospital mortality within 30 days of COVID-19 diagnosis among patients with solid cancer versus patients without cancer. Severe event occurrence, a composite of intensive care unit admission, invasive ventilation and/or death, was a secondary objective. These endpoints were analysed across different patient subgroups. Multivariable logistic regression models were used to analyse the association between cancer and clinical characteristics (baseline analysis) and the effect of cancer on in-hospital mortality and on severe event occurrence, adjusting for clinical characteristics (in-hospital analysis).

Results: A total of 13 594 patients (of whom 1187 with solid cancer (8.7%)) were evaluable for the baseline analysis and 10 486 (892 with solid cancer (8.5%)) for the in-hospital analysis. Patients with cancer were older and presented with less symptoms/signs and lung imaging alterations. The 30-day in-hospital mortality was higher in patients with solid cancer compared with patients without cancer (31.7% vs 20.0%, respectively; adjusted OR (aOR) 1.34; 95% CI 1.13 to 1.58). The aOR was 3.84 (95% CI 1.94 to 7.59) among younger patients (<60 years) and 2.27 (95% CI 1.41 to 3.64) among patients without other comorbidities. Severe event occurrence was similar in both groups (36.7% vs 28.8%; aOR 1.10; 95% CI 0.95 to 1.29).

Conclusions: This population-based analysis demonstrates that solid cancer is an independent adverse prognostic factor for in-hospital mortality among patients with COVID-19. This adverse effect was more pronounced among younger patients and those without other comorbidities. Patients with solid cancer should be prioritised in vaccination campaigns and in tailored containment measurements.
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http://dx.doi.org/10.1136/esmoopen-2020-000947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520811PMC
September 2020

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization.

Eur J Drug Metab Pharmacokinet 2020 Dec;45(6):703-713

Belgian Federal Agency for Medicines and Health Products, 1060, Brussels, Belgium.

Background And Objective: In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization.

Methods: We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals.

Results: The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens.

Conclusion: The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.
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http://dx.doi.org/10.1007/s13318-020-00648-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511144PMC
December 2020

Impact of an Improvised System on Preserving Oxygen Supplies in Patients With COVID-19.

Arch Bronconeumol 2021 Jan 27;57 Suppl 1:77-79. Epub 2020 Aug 27.

Service de Médecine Interne et Maladies Infectieuses, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Louvain Centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique (IREC), Université Catholique de Louvain, Avenue Hippocrate 55, 1200 Brussels, Belgium.

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http://dx.doi.org/10.1016/j.arbres.2020.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450946PMC
January 2021

Absence of SARS-CoV-2 in the effluent of peritoneal dialysis patients.

Perit Dial Int 2020 09 1;40(5):499-503. Epub 2020 Sep 1.

Department of Nephrology, 36673Cliniques Universitaires Saint-Luc, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.

The pandemic of respiratory disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is life-threatening in peritoneal dialysis (PD) patients. In PD patients with systemic viral infections, peritoneal effluent may be theoretically contaminated. We searched for the presence of SARS-CoV-2 genetic material by real-time reverse transcriptase-polymerase chain reaction assays in serial PD effluents of three PD infected patients. Nasopharyngeal swabs obtained at admission showed high viral load in all three patients, whereas none of the PD effluent specimen tested positive, even after dialysate concentration. Those results support at most a very low SARS-CoV-2 dissemination risk by the peritoneal effluent of PD patients. Imposing special disposal procedures, such as the instillation of hypochlorite in the drainage bags to prevent viral spread to health-care workers, are probably not required.
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http://dx.doi.org/10.1177/0896860820953061DOI Listing
September 2020

Clinical usefulness of fully automated chemiluminescent immunoassay for quantitative antibody measurements in COVID-19 patients.

J Med Virol 2021 03 24;93(3):1465-1477. Epub 2020 Aug 24.

Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

Since December 2019, we have been in the battlefield with a new threat to the humanity, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), characterized by viral pneumonia. It may be asymptomatic or cause various symptoms, ranging from flu-like symptoms to acute respiratory distress syndrome and eventually death. At present, the only reliable test for COVID-19 diagnosis is quantitative reverse transcriptase-polymerase chain reaction. Assessing the immune response against SARS-CoV-2 could increase the detection sensitivity of infected population. Hereby, we report the performances of a fully automated chemiluminescent immunoassay (CLIA) on 276 serum samples. One hundred samples obtained from COVID-19 negative subjects (COVID-19 free) were analyzed to evaluate the diagnostic specificity of antibody (Ab) detection. Thereafter, 176 samples obtained from 125 patients with confirmed COVID-19 (COVID-19 patients) were selected to assess the diagnostic sensitivity of the CLIA. All samples were analyzed on MAGLUMI 800 platform. All COVID-19 free samples had Ab levels below the cutoff values. Hence, the diagnostic specificity was estimated at 100% (95% confidence interval [CI] = 96.3-100.0; positive predictive value = 100%). By the 18th day from the onset of symptoms, we reached an optimal diagnostic sensitivity (more than 95.0%) In fact, the diagnostic sensitivity increased over time and between 15 and 25 days after symptoms onset, reached 95.5% (95% CI = 84.9-99.2). The new automated CLIA analyzer appeared to be a robust and reliable method to measure specific Ab against COVID-19 at high throughput. Our data suggest that combining Ab and nucleic acid detection could increase diagnostic sensitivity.
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http://dx.doi.org/10.1002/jmv.26430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436871PMC
March 2021

SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.

Kidney Int 2020 11 10;98(5):1296-1307. Epub 2020 Aug 10.

Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium. Electronic address:

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome.
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http://dx.doi.org/10.1016/j.kint.2020.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416689PMC
November 2020

COVID-19 Infection in Kidney Transplant Recipients: A Single-Center Case Series of 22 Cases From Belgium.

Kidney Med 2020 Jul-Aug;2(4):459-466. Epub 2020 Jun 15.

Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

Rationale & Objective: The world is facing a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although kidney transplant recipients are at increased risk for viral infections, the impact of their chronic immunosuppressed status on the risk for acquiring coronavirus disease 2019 (COVID-19) and disease severity is unknown.

Study Design: All cases of COVID-19 infection in our cohort of kidney transplant recipients were prospectively monitored. Clinical features, management, and outcomes were recorded. A standard strategy of immunosuppression minimization was applied: discontinue the antimetabolite drug and reduce trough levels of calcineurin or mammalian target of rapamycin inhibitors. Unless contraindicated, hydroxychloroquine was administered only to hospitalized patients.

Setting & Participants: 22 COVID-19 infections were diagnosed in our cohort of 1,200 kidney transplant recipients.

Results: Most common initial symptoms included fever, cough, or dyspnea. 18 (82%) patients required hospitalization. Of those patients, 3 had everolimus-based immunosuppression. Computed tomography of the chest at admission (performed in 15 patients) showed mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1) involvement. Immunosuppression reduction was initiated in all patients. Hydroxychloroquine was administered to 15 patients. 11 patients required supplemental oxygen; 2 of them were admitted to an intensive care unit (ICU) with mechanical ventilation. After a median of 10 days, 13 kidney transplant recipients were discharged, 2 were hospitalized in non-ICU units, 1 was in the ICU, and 2 patients had died.

Limitations: Small sample size and short follow-up.

Conclusions: The clinical presentation of COVID-19 infection was similar to that reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with 11% mortality among kidney transplant recipients hospitalized with COVID-19 infection.
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http://dx.doi.org/10.1016/j.xkme.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295531PMC
June 2020

Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.

J Neurol 2021 Mar 30;268(3):751-757. Epub 2020 Jul 30.

Department of Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Hippocrate 10, 1200, Brussels, Belgium.

Background: Evidence of immune-mediated neurological syndromes associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is limited. We therefore investigated clinical, serological and CSF features of coronavirus disease 2019 (COVID-19) patients with neurological manifestations.

Methods: Consecutive COVID-19 patients with neurological manifestations other than isolated anosmia and/or non-severe headache, and with no previous neurological or psychiatric disorders were prospectively included. Neurological examination was performed in all patients and lumbar puncture with CSF examination was performed when not contraindicated. Serum anti-gangliosides antibodies were tested when clinically indicated.

Results: Of the 349 COVID-19 admitted to our center between March 23rd and April 24th 2020, 15 patients (4.3%) had neurological manifestations and fulfilled the study inclusion/exclusion criteria. CSF examination was available in 13 patients and showed lymphocytic pleocytosis in 2 patients: 1 with anti-contactin-associated protein 2 (anti-Caspr2) antibody encephalitis and 1 with meningo-polyradiculitis. Increased serum titer of anti-GD1b antibodies was found in three patients and was associated with variable clinical presentations, including cranial neuropathy with meningo-polyradiculitis, brainstem encephalitis and delirium. CSF PCR for SARS-CoV-2 was negative in all patients.

Conclusions: In SARS-Cov-2 infected patients with neurological manifestations, CSF pleocytosis is associated with para- or post-infectious encephalitis and polyradiculitis. Anti-GD1b and anti-Caspr2 autoantibodies can be identified in certain cases, raising the question of SARS-CoV-2-induced secondary autoimmunity.
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http://dx.doi.org/10.1007/s00415-020-10108-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391231PMC
March 2021

Exploration of Reduced Doses and Short-Cycle Therapy for Darunavir/Cobicistat in Patients with HIV Using Population Pharmacokinetic Modeling and Simulations.

Clin Pharmacokinet 2021 Feb;60(2):177-189

Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.

Background And Objectives: Protease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using cobicistat- or ritonavir-boosted darunavir 800 mg every 24 h (q24h) in protease inhibitor-naïve patients, or ritonavir-boosted darunavir 600 mg q12h in experienced patients. However, darunavir displays a large, poorly characterized, inter-individual pharmacokinetic variability. The objectives of this study were to investigate the pharmacokinetics of darunavir and to elucidate the sources of its inter-individual variability using population pharmacokinetic modeling. Then, to determine the appropriateness of current treatment guidelines and the feasibility of alternative dosing regimens in a representative cohort of adult patients using simulations.

Methods: Sparse pharmacokinetic samples were collected in 127 patients with human immunodeficiency virus type 1 infection, then supplemented with rich sampling data from a subset of 12 individuals. Data were analyzed using the nonlinear mixed-effects modeling software NONMEM. The effect of reduced doses (600 mg q24h and 400 mg q24h) or reduced frequency of administration (800 mg q24h for 5 days followed by 2 days of treatment interruption) was simulated.

Results: Our model adequately described the pharmacokinetics of darunavir. Predictors of individual exposure were CYP3A5*3 and SLCO3A1 rs8027174 genotypes, sex, and alpha-1 acid glycoprotein level. No relationship was apparent between darunavir area under the curve and treatment efficacy or safety. For reduced dose regimens, darunavir concentrations remained above the protein binding-corrected EC in the majority of subjects. More stringent pharmacokinetic targets were not reached in a significant proportion of patients.

Conclusions: These results add to the growing body of evidence that darunavir-based therapy could be simplified to reduce costs and toxicity, as well as to improve patient compliance. However, the heterogeneity in pharmacokinetic response should be considered when assessing whether individual patients could benefit from a particular regimen, for instance through the use of population pharmacokinetic models.

Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03101644, date of registration: 5 April, 2017.
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http://dx.doi.org/10.1007/s40262-020-00920-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862523PMC
February 2021

Safe use of hydroxychloroquine and its combination with azithromycin in the context of Sars-CoV-2 outbreak: Clinical experience in a Belgian tertiary center.

Travel Med Infect Dis 2020 Jul - Aug;36:101788. Epub 2020 Jun 12.

Department of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

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http://dx.doi.org/10.1016/j.tmaid.2020.101788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290202PMC
September 2020

HIV-Infected Mothers Who Decide to Breastfeed Their Infants Under Close Supervision in Belgium: About Two Cases.

Front Pediatr 2020 27;8:248. Epub 2020 May 27.

Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.

In most industrialized countries, human immunodeficiency virus (HIV) infection remains a formal contraindication to breastfeeding. However, for the past 9 years, the World Health Organization (WHO) has recommended, for developing countries, that mothers infected with HIV and treated by combined antiretroviral therapy (cART) should breastfeed their infants. HIV-infected women coming from developing countries and living in industrialized settings are increasingly expressing their natural desire to breastfeed. To avoid uncontrolled breastfeeding practices and reduce the risk of mother-to-child transmission of the virus, there is an urgent need to consider the wishes of these women. We report two cases in which specific guidelines were implemented in order to support the mothers' choice to breastfeed in Belgium. As a result of different prophylactic measures including antiretrovirals in mothers and infants and close follow-up, none of the infants were infected. National or international recommendations for HIV-infected mothers who choose to breastfeed in industrialized countries remain unclear and discordant. There is an unmet need for experts to address this emerging issue and to develop an international consensus for the monitoring and prophylactic management of exposed-infants.
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http://dx.doi.org/10.3389/fped.2020.00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266974PMC
May 2020

Symptom-based screening for COVID-19 in health care workers: The importance of fever.

J Hosp Infect 2020 May 22. Epub 2020 May 22.

Department of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint Luc, Avenue Hippocrate, 1200, Brussels.

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http://dx.doi.org/10.1016/j.jhin.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242924PMC
May 2020

In-hospital management of persons with haemophilia and COVID-19: Practical guidance.

Haemophilia 2020 Sep 29;26(5):768-772. Epub 2020 Jul 29.

Division of Infectious Diseases, Department of Internal Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

A new disease (COVID-19) caused by a coronavirus (SARS-CoV-2) that appeared in China at the end of 2019 is currently spreading globally. This emerging virus is mainly responsible for respiratory tract infections and potentially fatal pneumonia, mainly in more frail patients. Persons with haemophilia of variable severity and from all parts of the world will likely be infected and develop COVID-19. We here propose practical guidance for the in-hospital specific management of haemophilia persons with COVID-19 including their possible transfer to the intensive care unit. Rapid identification of the haemophilia status, undelayed and regular liaison with the haemophilia team, proper therapy with factor concentrates or alternative treatments appear instrumental to prevent haemophilia-related complications in this setting. Information of patients and their families about COVID-19, psychological support and good appreciation of the impact of haemophilia on therapeutic decisions including end-of-life directives are also addressed.
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http://dx.doi.org/10.1111/hae.14045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272941PMC
September 2020

Fatal e-cigarette or vaping associated lung injury (EVALI): a first case report in Europe.

Eur Respir J 2020 07 30;56(1). Epub 2020 Jul 30.

Dept of Internal Medicine and Infectious Diseases, Cliniques universitaires Saint Luc, Brussels, Belgium.

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http://dx.doi.org/10.1183/13993003.00077-2020DOI Listing
July 2020

How Probiotics Affect the Microbiota.

Front Cell Infect Microbiol 2019 15;9:454. Epub 2020 Jan 15.

Walloon Excellence in Life Sciences and BIOtechnology, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium.

Probiotics have been used to treat a variety of diseases for decades; however, what is the rationale for their application? Such a treatment was first proposed in the early nineteenth century based on observations of decreased bifidobacterial populations in children suffering from diarrhea, suggesting that oral intake of bifidobacteria could replete this subpopulation of the microbiota and improve health. Since then, studies have shown modifications in the gut or skin microbiota in the course of a variety of diseases and suggested positive effects of certain probiotics. Most studies failed to report any impact on the microbiota. The impact of probiotics as well as of bacteria colonizing food does not reside in their ability to graft in the microbiota but rather in sharing genes and metabolites, supporting challenged microbiota, and directly influencing epithelial and immune cells. Such observations argue that probiotics could be associated with conventional drugs for insulin resistance, infectious diseases, inflammatory diseases, and psychiatric disorders and could also interfere with drug metabolism. Nevertheless, in the context of a plethora of probiotic strains and associations produced in conditions that do not allow direct comparisons, it remains difficult to know whether a patient would benefit from taking a particular probiotic. In other words, although several mechanisms are observed when studying a single probiotic strain, not all individual strains are expected to share the same effects. To clarify the role of probiotics in the clinic, we explored the relation between probiotics and the gut and skin microbiota.
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http://dx.doi.org/10.3389/fcimb.2019.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974441PMC
September 2020

Coinfection of Mycobacterium malmoense and Mycobacterium chimaera in a kidney transplant recipient: A case report and review of the literature.

Transpl Infect Dis 2020 Apr 10;22(2):e13241. Epub 2020 Jan 10.

Division of Infectious Disease, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

Nontuberculous mycobacteria (NTM) are ubiquitous organisms found in soil and water. Solid organ recipients are at increased risk of NTM infections due to impaired immunity. Although the NTM infections rate is low, it increases morbidity and the risk of mortality. Diagnosis is often delayed because of the lack of specific clinical symptoms and requires a high index of suspicion. Management may be challenging: long-term treatment with risks of side effects and interactions with immunosuppressive regimen; reduction of immunosuppression; and risk of allograft rejection. Prognosis is widely variable. We report the first case of Mycobacterium malmoense chest infection with concomitant Mycobacterium chimaera urinary tract infection in a kidney transplant recipient. The evolution was marked by poor tolerance of the treatment with severe adverse events and disabled functional status.
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http://dx.doi.org/10.1111/tid.13241DOI Listing
April 2020

Should We Treat Bacteremic Prostatitis for 7 Days?

Clin Infect Dis 2020 01;70(2):351

Division of Internal Medicine and Infectious Disease, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

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http://dx.doi.org/10.1093/cid/ciz392DOI Listing
January 2020