Cees van Nieuwkoop

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (38)189.39 Total impact

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    ABSTRACT: To review the recent advances in the diagnostic and therapeutic approach to adults presenting with febrile urinary tract infection (UTI) in the emergency department (ED).
    Current opinion in infectious diseases. 11/2014;
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    ABSTRACT: Bacterial infections such as febrile urinary tract infection (fUTI) may run a complicated course which is difficult to foretell on clinical evaluation only. Because the conventional biomarkers erythrocyte sedimentation rate (ESR), leukocyte count, C-reactive protein (CRP) and procalcitonin (PCT) have a limited role in the prediction of a complicated course of disease, a new biomarker - plasma midregional pro-adrenomedullin (MR-proADM) - was evaluated in patients with fUTI. We conducted a prospective multicentre cohort study including consecutive patients with fUTI at 35 primary care centres and 8 emergency departments. Clinical and microbiological data were collected and plasma biomarker levels were measured at presentation to the physician. Survival was assessed after 30 days. Of 494 fUTI patients, median age was 67 [IQR 49-78] years, 40% were male; two third of them had significant co-existing medical conditions. Median MR-proADM level was 1.42 [IQR 0.67-1.57] nmol/L; significantly elevated MR-proADM levels were measured in patients with bacteraemia, those admitted to the ICU, and in 30- and 90-day non-survivors, as compared to patients without these characteristics. The diagnostic accuracy for predicting 30-day mortality in fUTI, reflected by the area-under-the-curve of receiver operating characteristics were: MR-proADM 0.83 (95%CI: 0.71-0.94), PCT 0.71 (95%CI: 0.56-0.85); whereas CRP, ESR and leukocyte count lacked diagnostic value in this respect. This study shows that MR-proADM assessed on first contact predicts a complicated course of disease and 30-day mortality in patients with fUTI and in this respect has a higher discriminating accuracy than currently available biomarkers ESR, CRP, PCT and leukocyte count. This article is protected by copyright. All rights reserved.
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    ABSTRACT: Introduction : Inhibition of tissue factor, the primary initiator of coagulation in sepsis, attenuates morbidity in primates infused with Escherichia coli. In a human endotoxemia model, microparticles expressing procoagulant TF (MP-TF) are released in blood concurrently with markers of inflammation and coagulation. We investigated whether the release of MP-TF into blood is accompanied by procoagulant and inflammatory changes in patients with E. coli urinary tract infection. Materials and methods : In a multicenter cohort study, we determined clinical disease severity using APACHE II scores and measured plasma MP-TF activity, TAT, sE-selectin, sVCAM-1, procalcitonin and monocyte count in blood of 215 patients with community-acquired febrile E. coli urinary tract infections. Results : Plasma MP-TF activity on admission corresponded with clinical disease severity (APACHE II score; P = 0.006) and correlated significantly but weakly with plasma markers of disease severity (sE-selectin, sVCAM-1, procalcitonin). Additionally, median plasma MP-TF activity was higher in patients than in healthy controls (197 vs. 79 fM Xa/min; P< 0.0001), and highest in bacteraemic patients (325 fM Xa/min). MP-TF activity showed a weak inverse correlation with monocyte count (rs-0.22; P= 0.016) and a weak correlation with TAT (rs 0.23, P= 0.017). After 3 days of antibiotic treatment, upon resolution of the infection, plasma MP-TF activity and TAT concentrations declined. Conclusions : Microparticle-associated procoagulant tissue factor activity is related to disease severity and bacteremia in febrile E. coli UTI patients and may contribute to the prothrombotic state in gram-negative sepsis.
    Thrombosis Research 01/2014; · 3.13 Impact Factor
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    Diabetes care 12/2013; 36(12):e193-e194. · 7.74 Impact Factor
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    ABSTRACT: Background: In patients with multidrug-resistant (MDR) bacteria causing lower urinary tract infection (lUTI), intravesical gentamicin (iGM) installation is a potential treatment when other options are limited. Locally iGM precludes systemic toxicity and development of antimicrobial resistance is unlikely because of high urinary concentration and lack of selective pressure on commensal gut flora. Methods: In a cohort study adult patients with recurrent lUTI (>3/yr) by MDR bacteria were treated with iGM (80 mg gentamicin in 20 mL NaCl 0.9%) by intermittent self-catheterization (IC). Results: Fourteen patients (8 males; range 34-79 yr) were included. Underlying disorders were dysfunctional voiding requiring IC (n=6), chronic bacterial prostatitis (n=3), vesicoureteral reflux (n=3), urethral stricture managed by IC (n=1) and neobladder (n=1). Causative (recurrent) uropathogens were E. coli (n=9, ESBL+: 4), P. aeruginosa (n=2), K. pneumonia (n=1), E. faecalis(n=1, MIC GM 16 mg/l, chronic prostatitis); MDR (>3 antibiotic classes) was found in 12/14 patients. In all, prior oral prophylaxis had failed. After an initial phase of daily instilment for 3 hrs or overnight, interval between instilments varied between individuals from every 3th day to once weekly. Ten of 14 patients (71%) were free of symptomatic UTI during iGM (median 42, range 6-148 wks). Four patients had a total of 12 recurrences of symptomatic UTI in the treatment period. Five patients had a total of 13 positive cultures (>10^3 CFU/ml and leukocyturia >5/HPF) during treatment; 2/13 strains were resistant to gentamicin (E. coli, MIC 24 mg/l and E. faecalis, MIC 1024 mg/l). In 2 cases UTI recurred after treatment due to an abnormality in the upper urinary tract (infected ureteral stone and megaureters), with clearance of UTI after surgery. No side effects were reported and GM plasma levels at the end of instilments were below detection (<0.1 mg/l, performed in 12/14 pts). Conclusion: Intravesical administration of gentamicin suppressed symptomatic infection in 71% of patients with recurrent UTI due to MDR bacteria, where oral prophylaxis had failed. Intravesical instilment can also be of diagnostic value to identify a focus of infection in the upper urinary tract.
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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    ABSTRACT: Urinary tract infection (UTI) encompasses a variety of clinical syndromes ranging from mild to life-threatening conditions. As such, it represents an interesting model for the development of an analytically based scoring system of disease severity and/or host response. Here we test the feasibility of this concept using (1)H NMR based metabolomics as the analytical platform. Using an exhaustively clinically characterized cohort and taking advantage of the multi-level study design, which opens possibilities for case-control and longitudinal modeling, we were able to identify molecular discriminators that characterize UTI patients. Among those discriminators a number (e.g. acetate, trimethylamine and others) showed association with the degree of bacterial contamination of urine, whereas others, such as, for instance, scyllo-inositol and para-aminohippuric acid, are more likely to be the markers of morbidity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-012-0411-y) contains supplementary material, which is available to authorized users.
    Metabolomics 12/2012; 8(6):1227-1235. · 4.43 Impact Factor
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    ABSTRACT: Background: Vitamin D affects both the innate and adaptive immune system, for instance by affecting the secretion of the antimicrobial peptide cathelicidin (LL-37), thought to be involved in the host defense in UTI. Vitamin D deficiency has been shown to play a role in many infectious diseases, but an association with acquisition and a complicated course of febrile urinary tract infections (UTIs) is uncertain. Methods: A prospective, multicenter case-control study included consecutive adults with febrile UTI presenting at 7 emergency departments and 35 primary healthcare centers in The Netherlands. Cases were subdivided in E. coli UTI patients with and without bacteremia. Healthy controls were enrolled at the same primary healthcare centers. Vitamin D status was determined by measuring plasma 25-hydroxyvitamin D (25[OH]D) level. Deficiency was defined as a plasma 25[OH]D level ≤20 ng/mL (≤50 nmol/L). LL-37 was measured in the urine by ELISA. Results: In total, 133 participants were included: 87 patients with febrile UTI (43 patients without and 44 with bacteremia), and 46 healthy controls. The median age was 66 years [IQR 53-79], and 52 (39%) were men. Cases and controls were comparable with respect to risk factors for vitamin D deficiency. The overall median plasma 25[OH]D level was 18.7 ng/mL [IQR 11.5–26.0]; plasma 25[OH]D level of healthy controls (median 17.6 ng/mL [IQR 13.8-26.5]) did not differ from patients with bacteremia (median 17.9 ng/mL [IQR 9.2-25.0]) and without bacteremia (median 19.5 ng/mL [IQR 13.7-26.6]). Vitamin D deficiency (≤ 20 ng/mL) was common in this population (59%); only 20 participants (15%) had a sufficient vitamin D level (≥ 30 ng/mL). LL-37 level was significantly higher in patients with bacteremia (median 22.7 ng/mL [IQR 2.0-48.9]) and patients without bacteremia (median 15.5 ng/mL [2.0-40.4]) compared to healthy controls (median 2.0 ng/mL [IQR 2.0-2.0]), also after correction for urine dilution. The concentration of LL-37 was independent of vitamin D level. Conclusion: In this case-control study, we found no association between vitamin D deficiency and the risk of acquisition of febrile UTI or a complicated course with bacteremia. Though urine concentration of the antimicrobial peptide LL-37 was increased in febrile UTI, there was no relation with vitamin D plasma level.
    IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012
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    ABSTRACT: Urinary tract infection (UTI) is the most common bacterial infection leading to substantial morbidity and considerable health care expenditures across all ages. Here we present an exploratory UPLC-MS study of human urine in the context of febrile, complicated urinary tract infection aimed to reveal and identify possible markers of a host response on infection. A UPLC-MS based workflow, taking advantage of Ultra High Resolution (UHR) Qq-ToF-MS, and multivariate data handling were applied to a carefully selected group of 39 subjects with culture-confirmed febrile Escherichia coli UTI. Using a combination of unsupervised and supervised multivariate modeling we have pinpointed a number of peptides specific for UTI. An unequivocal structural identification of these peptides, as O-glycosylated fragments of the human fibrinogen alpha 1 chain, required MS2 and MS3 experiments on two different MS platforms: ESI-UHR-Qq-ToF and ESI-ion trap, a blast search and, finally, confirmation was achieved by matching experimental tandem mass spectra with those of custom synthesized candidate-peptides. In conclusion, exploiting non-targeted UPLC-MS based approach for the investigation of UTI related changes in urine, we have identified and structurally characterized unique O-glycopeptides, which are, to our knowledge, the first demonstration of O-glycosylation of human fibrinogen alpha 1-chain.
    Journal of proteomics 10/2011; 75(3):1067-73. · 5.07 Impact Factor
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    ABSTRACT: Background: Diabetes mellitus (DM) is considered a risk factor for febrile urinary tract infection (UTI), but the association of DM with the subsequent course of disease and outcome is unclear. Methods: A prospective observational multicenter cohort study included consecutive adult patients with febrile UTI presenting at emergency departments of 7 hospitals and 35 primary care units. The effect of pre-existing DM on microbiological etiology, bacteremia and ICU admission, duration of fever and hospital admission, clinical and microbiological failure within 1 month, and 30-day mortality was assessed by multivariable logistic regression to establish whether DM is an independent risk factor for adverse outcomes. Factors included in the model were age, sex, DM, comorbidities, and presence of SIRS-criteria at presentation. Results: Of 858 consecutive patients, 140 had DM (94% type II DM). Patients with DM were older (median 73 [IQR 60-80] vs 64 [IQR 61-81] yr), predominantly male (48% vs 35%, p 0.006), had more comorbidity (74% vs 52%, p <0.001), and were more frequently admitted to hospital (81% vs 64%, p<0.001) compared to 718 patients without DM. Escherichia coli (52-58%) was the most common causal uropathogen in both groups, whereas Klebsiella spp (9.0% vs 4.9%, p 0.03) and Enterococcus spp (10.5% vs 4.1%, p<0.001) were more frequently found in DM. DM was not associated with longer fever duration (all median 2. 0 [IQR 1.0-3.0] d), prolonged hospital admission (overall median 6.0 [IQR 4.0-11.5] d) or clinical failure (OR 1.10, 95%-CI: 0.72-1.69), compared to those without DM. Patients with DM more often had bacteremia (OR 1.55, 95% CI 1.03-2.34), ICU admission (2.08, 95% CI 0.94-4.59), microbiological failure (OR 3.03, 95% CI 1.69-5.47) and mortality within 30 days (3.29, 95% CI 1.34-8.09). However, when adjusted for possible confounders and comorbidity, DM was not an independent risk factor for any of these adverse outcomes. Conclusion: Although it is widely held that patients with DM have a more complicated course of infections, our data show that DM is not associated with adverse outcomes in an unselected population of patients with febrile UTI.
    Infectious Diseases Society of America 2011 Annual Meeting; 10/2011
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    ABSTRACT: Although febrile urinary tract infections (UTIs) are relatively common in adults, data on optimal treatment duration are limited. Randomized controlled trials specifically addressing the elderly and patients with comorbidities have not been performed. This review highlights current available evidence. Premenopausal, non-pregnant women without comorbidities can be treated with a 5-7 day regimen of fluoroquinolones in countries with low levels of fluoroquinolone resistance, or, if proven susceptible, with 14 days of trimethoprim-sulfamethoxazole. Oral β-lactams are less effective compared with fluoroquinolones and trimethoprim-sulfamethoxazole. In men with mild to moderate febrile UTI, a 2-week regimen of an oral fluoroquinolone is likely sufficient. Although data are limited, this possibly holds even in the elderly patients with comorbidities or bacteremia.
    Current Infectious Disease Reports 09/2011; 13(6):571-8.
  • European Journal of Internal Medicine 08/2011; 22(4):e28-30. · 2.30 Impact Factor
  • Cees van Nieuwkoop
    The Journal of pediatrics 01/2011; 158(1):171. · 4.02 Impact Factor
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    ABSTRACT: A 20-year-old woman presented with a 2-week history of fever and malaise. Physical examination was unremarkable. Viral infection was suspected and Epstein-Barr virus serology confirmed acute infectious mononucleosis. During admission, she gradually developed pancytopenia and liver enzyme abnormalities. The patient clinically deteriorated with persisting fever, orthostatic hypotension and hepatosplenomegaly. Bone marrow examination showed haemophagocytic lymphohistiocytosis (HLH). Treatment with high-dose corticosteroids was started and patient recovered quickly. Ferritin decreased immediately, fever resolved within 3 days, viral clearance was reached within 3 weeks. Steroid therapy was gradually tapered off in three months. The Histiocyte Society recommends immunochemotherapy with steroids, etoposide and cyclosporine. Potential side effects of etoposide are severe bone marrow depression and leukaemia. Our patient survived on corticosteroids alone. Early recognition of HLH and prompt treatment are of utmost importance for survival. Treatment with steroids alone can be life-saving.
    Case Reports 01/2011; 2011.
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    ABSTRACT: Clean intermittent catheterisation (CIC) of the bladder is used to imitate normal bladder emptying in patients with bladder dysfunction. CIC is associated with urinary tract infection (UTI) that may be difficult to treat in the case of antimicrobial resistance. The aim of this study was to establish the effect and safety of intravesical gentamicin treatment in such settings. In 2009, intravesical gentamicin treatment was started in selected patients. Here we describe our experience with two patients treated until March 2010. Two patients using CIC suffering recurrent UTI with multiresistant Escherichia coli were treated with daily administration of 80 mg intravesical gentamicin. On treatment they appeared asymptomatic. During 8- and 9-month follow-up they were free of UTI, urine cultures were negative and there were no side effects. A systematic review was conducted through searches of PubMed and other databases. Clinical trials that met the eligibility criteria and displayed the efficacy or safety of intravesical aminoglycoside treatment in patients using CIC were studied. Study selection was performed by two independent reviewers. Eight studies were included for review. Owing to study heterogeneity, a meta-analysis could not be performed. Of four controlled studies using neomycin or kanamycin, two demonstrated a significant reduction in bacteriuria, whilst two other trials did not. One case series on neomycin/polymyxin showed that the majority of patients still developed bacteriuria. Three case series using gentamicin all pointed towards a significant reduction in bacteriuria and UTIs. There were no clinically relevant side effects reported but follow-up in all studies was limited. Although data are limited, intravesical treatment with gentamicin might be a reasonable treatment option in selected patients practicing CIC who suffer recurrent UTIs with highly resistant microorganisms.
    International journal of antimicrobial agents 12/2010; 36(6):485-90. · 3.03 Impact Factor
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    ABSTRACT: To assess risk factors for fluoroquinolone resistance in community-onset febrile Escherichia coli urinary tract infection (UTI). A nested case-control study within a cohort of consecutive adults with febrile UTI presenting at primary healthcare centres or emergency departments during January 2004 through December 2009. Resistance was defined using EUCAST criteria (ciprofloxacin MIC >1.0 mg/L). Cases were subjects with fluoroquinolone-resistant E. coli, and controls those with fluoroquinolone-susceptible isolates. Multivariable logistic regression analysis was used to identify potential risk factors for fluoroquinolone resistance. Of 787 consecutive patients, 420 had E. coli-positive urine cultures. Of these, 51 (12%) were fluoroquinolone resistant. Independent risk factors for fluoroquinolone resistance were urinary catheter [odds ratio (OR) 3.1; 95% confidence interval (CI) 0.9-11.6], recent hospitalization (OR 2.0; 95% CI 1.0-4.3) and fluoroquinolone use in the past 6 months (OR 17.5; 95% CI 6.0-50.7). Environmental factors (e.g. contact with animals or hospitalized household members) were not associated with fluoroquinolone resistance. Of fluoroquinolone-resistant strains, 33% were resistant to amoxicillin/clavulanate and 65% to trimethoprim/sulfamethoxazole; 14% were extended-spectrum β-lactamase (ESBL) positive compared with <1% of fluoroquinolone-susceptible isolates. Recent hospitalization, urinary catheter and fluoroquinolone use in the past 6 months were independent risk factors for fluoroquinolone resistance in community-onset febrile E. coli UTI. Contact with animals or hospitalized household members was not associated with fluoroquinolone resistance. Fluoroquinolone resistance may be a marker of broader resistance, including ESBL positivity.
    Journal of Antimicrobial Chemotherapy 12/2010; 66(3):650-6. · 5.34 Impact Factor
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    ABSTRACT: Guidelines recommend that two blood cultures be performed in patients with febrile urinary tract infection (UTI), to detect bacteremia and help diagnose urosepsis. The usefulness and cost-effectiveness of this practice have been criticized. This study aimed to evaluate clinical characteristics and the biomarker procalcitonin (PCT) as an aid in predicting bacteremia. A prospective observational multicenter cohort study included consecutive adults with febrile UTI in 35 primary care units and 8 emergency departments of 7 regional hospitals. Clinical and microbiological data were collected and PCT and time to positivity (TTP) of blood culture were measured. Of 581 evaluable patients, 136 (23%) had bacteremia. The median age was 66 years (interquartile range 46 to 78 years) and 219 (38%) were male. We evaluated three different models: a clinical model including seven bed-side characteristics, the clinical model plus PCT, and a PCT only model. The diagnostic abilities of these models as reflected by area under the curve of the receiver operating characteristic were 0.71 (95% confidence interval (CI): 0.66 to 0.76), 0.79 (95% CI: 0.75 to 0.83) and 0.73 (95% CI: 0.68 to 0.77) respectively. Calculating corresponding sensitivity and specificity for the presence of bacteremia after each step of adding a significant predictor in the model yielded that the PCT > 0.25 μg/l only model had the best diagnostic performance (sensitivity 0.95; 95% CI: 0.89 to 0.98, specificity 0.50; 95% CI: 0.46 to 0.55). Using PCT as a single decision tool, this would result in 40% fewer blood cultures being taken, while still identifying 94 to 99% of patients with bacteremia.The TTP of E. coli positive blood cultures was linearly correlated with the PCT log value; the higher the PCT the shorter the TTP (R(2) = 0.278, P = 0.007). PCT accurately predicts the presence of bacteremia and bacterial load in patients with febrile UTI. This may be a helpful biomarker to limit use of blood culture resources.
    Critical care (London, England) 11/2010; 14(6):R206. · 4.72 Impact Factor
  • Urology 11/2010; 76(5):1270-1. · 2.42 Impact Factor
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    ABSTRACT: Radiologic evaluation of adults with febrile urinary tract infection (UTI) is frequently performed to exclude urological disorders. This study aims to develop a clinical rule predicting need for radiologic imaging. We conducted a prospective, observational study including consecutive adults with febrile UTI at 8 emergency departments (EDs) in the Netherlands. Outcomes of ultrasounds and computed tomographs of the urinary tract were classified as "urgent urological disorder" (pyonephrosis or abscess), "nonurgent urologic disorder," "normal," and "incidental nonurological findings." Urgent and nonurgent urologic disorders were classified as "clinically relevant radiologic findings." The data of 5 EDs were used as the derivation cohort, and 3 EDs served as the validation cohort. Three hundred forty-six patients were included in the derivation cohort. Radiologic imaging was performed for 245 patients (71%). A prediction rule was derived, being the presence of a history of urolithiasis, a urine pH ≥7.0, and/or renal insufficiency (estimated glomerular filtration rate, ≤40 mL/min/1.73 m(3)). This rule predicts clinically relevant radiologic findings with a negative predictive value (NPV) of 93% and positive predictive value (PPV) of 24% and urgent urological disorders with an NPV of 99% and a PPV of 10%. In the validation cohort (n = 131), the NPV and PPV for clinically relevant radiologic findings were 89% and 20%, respectively; for urgent urological disorders, the values were 100% and 11%, respectively. Potential reduction of radiologic imaging by implementing the prediction rule was 40%. Radiologic imaging can selectively be applied in adults with febrile UTI without loss of clinically relevant information by using a simple clinical prediction rule.
    Clinical Infectious Diseases 10/2010; 51(11):1266-72. · 9.37 Impact Factor
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    Hetty Jolink, Jan den Hartigh, Leo G Visser, Cees van Nieuwkoop
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    ABSTRACT: A patient known to have renal insufficiency was admitted to the hospital with fever and pancytopenia after returning from a trip to Mali. Pancytopenia was not caused by a tropical infection but was a side effect of atovaquone/proguanil used as malaria chemoprophylaxis. High and prolonged detectable proguanil serum levels can result in bone marrow suppression in patients with renal insufficiency. This should be taken into account in a returning traveller with fever and pancytopenia.
    European Journal of Clinical Pharmacology 08/2010; 66(8):811-2. · 2.74 Impact Factor
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    ABSTRACT: In a prospective study involving 642 patients with febrile urinary tract infection (UTI), we found antimicrobial pretreatment (odds ratio [OR], 3.3), an indwelling urinary catheter (OR, 2.8), and malignancy (OR, 2.7) to be independent risk factors for bacteremia with a uropathogen that was not cultured or recognized in the urine. Although the diagnostic value of blood cultures has been questioned in UTI, we advocate performing blood cultures for patients with these risk factors.
    Clinical Infectious Diseases 06/2010; 50(11):e69-72. · 9.37 Impact Factor

Publication Stats

191 Citations
189.39 Total Impact Points


  • 2006–2014
    • Leiden University Medical Centre
      • Department of Infectious Diseases
      Leyden, South Holland, Netherlands
  • 2011
    • Rijnland Hospital, Leiderdorp
      Лейдердорпе, South Holland, Netherlands
  • 2010
    • Bronovo Hospital
      's-Gravenhage, South Holland, Netherlands