Publications by authors named "Jaap T van Dissel"

182 Publications

The predictive value of TIMP-2 and IGFBP7 for kidney failure and 30-day mortality after elective cardiac surgery.

Sci Rep 2021 01 13;11(1):1071. Epub 2021 Jan 13.

Department of Nephrology, Leiden University Medical Center (Building 1, C7-Q), Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Acute kidney injury (AKI) is an important risk factor for chronic kidney disease, renal replacement therapy (RRT), and mortality. However, predicting AKI with currently available markers remains problematic. We assessed the predictive value of urinary tissue inhibitor of metalloprotease-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) regarding the need for RRT, and 30-day mortality, in elective cardiac surgery patients. In 344 elective cardiac surgery patients, we measured urinary TIMP-2 and IGFBP7 and serum creatinine at baseline and directly after surgery. Discrimination of both urinary biomarkers was assessed by the C-statistic. Model improvement for each biomarker when added to a basic model containing serum creatinine and duration of surgery was tested by the net-reclassification index (cf-NRI) and integrated discrimination index (IDI). At baseline, mean age was 66 years and 67% were men. Of all patients, 22 required RRT following surgery. IGFBP7 pre- and post-surgery and change in TIMP-2 during surgery predicted RRT with a C-statistic of about 0.80. However, a simple model including baseline serum creatinine and duration of surgery had a C-statistic of 0.92, which was improved to 0.93 upon addition of post-surgery TIMP-2 or IGFBP7, with statistically significant cf-NRIs but non-significant IDIs. Post-surgery TIMP-2 and IGFBP predicted 30-day mortality, with C-statistics of 0.74 and 0.80. In conclusion, in elective cardiac surgery patients, pre- and peri-operative clinical variables were highly discriminating about which patients required RRT after surgery. Nonetheless, in elective cardiac surgery patients, urinary TIMP-2 and IGFBP7 improved prediction of RRT and 30-day mortality post-surgery.
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http://dx.doi.org/10.1038/s41598-020-80196-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806984PMC
January 2021

Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency.

J Clin Immunol 2021 02 18;41(2):382-392. Epub 2020 Nov 18.

Department of Pediatric Immunology and Infectious Diseases, UMC Utrecht, Lundlaan 6, 3584 EA, Utrecht, The Netherlands.

Background: Patients with an IgG subclass deficiency (IgSD) ± specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study.

Objective: To compare the efficacy of PA and IRT in a randomized crossover trial.

Methods: A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared.

Results: The overall efficacy of the two regimens did not differ (p = 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%, p < 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64, p < 0.01).

Conclusion: We found comparable efficacy of IRT and PA in patients with IgSD ± SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT.

Clinical Implication: Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA.
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http://dx.doi.org/10.1007/s10875-020-00841-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858555PMC
February 2021

Effectiveness of oseltamivir in reduction of complications and 30-day mortality in severe seasonal influenza infection.

Int J Antimicrob Agents 2020 Nov 6;56(5):106155. Epub 2020 Sep 6.

Department of Infectious Diseases and Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands.

Objectives: The benefit of oseltamivir treatment in patients admitted with influenza virus infection and the design of studies addressing this issue have been questioned extensively. As the burden of influenza disease is substantial and oseltamivir treatment is biologically plausible, this study assessed the clinical benefit of oseltamivir treatment in adult patients admitted with severe seasonal influenza virus infection in daily practice.

Patients And Methods: A multi-centre, retrospective cohort study was conducted to compare the effectiveness of treatment with and without oseltamivir <48 h after admission in patients admitted with laboratory-confirmed influenza virus infection in three large hospitals in the Netherlands. Propensity score matching was used to compare clinically relevant outcome variables.

Results: In total, 390 patients were included in this study, of whom 80% had comorbidities. Thirty-day mortality, as well as the composite endpoint of 30-day mortality or intensive care unit admission >48 h after admission, were reduced by 9% (P=0.04) and 11% (P=0.02), respectively. Length of hospital stay and in-hospital mortality rates all showed a trend towards reduction. The median duration between symptom onset and initiation of treatment was 3 days.

Conclusions: This study supports that, in daily practice, patients admitted with influenza virus infection should be treated with oseltamivir within 48 h of admission, even if they have had complaints for >48 h.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106155DOI Listing
November 2020

Incidence and costs of hospitalized adult influenza patients in The Netherlands: a retrospective observational study.

Eur J Health Econ 2020 Jul 16;21(5):775-785. Epub 2020 Mar 16.

Centre for Infectious Diseases Epidemiology and Surveillance, Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA, Bilthoven, The Netherlands.

Objective: Influenza virus infections cause a high disease and economic burden during seasonal epidemics. However, there is still a need for reliable disease burden estimates to provide a more detailed picture of the impact of influenza. Therefore, the objectives of this study is to estimate the incidence of hospitalisation for influenza virus infection and associated hospitalisation costs in adult patients in the Netherlands during two consecutive influenza seasons.

Methods: We conducted a retrospective study in adult patients with a laboratory confirmed influenza virus infection in three Dutch hospitals during respiratory seasons 2014-2015 and 2015-2016. Incidence was calculated as the weekly number of hospitalised influenza patients divided by the total population in the catchment populations of the three hospitals. Arithmetic mean hospitalisation costs per patient were estimated and included costs for emergency department consultation, diagnostics, general ward and/or intensive care unit admission, isolation, antibiotic and/or antiviral treatment. These hospitalisation costs were extrapolated to national level and expressed in 2017 euros.

Results: The study population consisted of 380 hospitalised adult influenza patients. The seasonal cumulative incidence was 3.5 cases per 10,000 persons in respiratory season 2014-2015, compared to 1.8 cases per 10,000 persons in 2015-2016. The arithmetic mean hospitalisation cost per influenza patient was €6128 (95% CI €4934-€7737) per patient in 2014-2015 and €8280 (95% CI €6254-€10,665) in 2015-2016, potentially reaching total hospitalisation costs of €28 million in 2014-2015 and €20 million in 2015-2016.

Conclusions: Influenza virus infections lead to 1.8-3.5 hospitalised patients per 10,000 persons, with mean hospitalisation costs of €6100-€8300 per adult patient, resulting in 20-28 million euros annually in The Netherlands. The highest arithmetic mean hospitalisation costs per patient were found in the 45-64 year age group. These influenza burden estimates could be used for future influenza cost-effectiveness and impact studies.
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http://dx.doi.org/10.1007/s10198-020-01172-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095032PMC
July 2020

Mortality prediction by SOFA score in ICU-patients after cardiac surgery; comparison with traditional prognostic-models.

BMC Anesthesiol 2020 03 13;20(1):65. Epub 2020 Mar 13.

Department of Intensive Care, Leiden University Medical Center, University of Leiden, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, the Netherlands.

Background: There are many prognostic models and scoring systems in use to predict mortality in ICU patients. The only general ICU scoring system developed and validated for patients after cardiac surgery is the APACHE-IV model. This is, however, a labor-intensive scoring system requiring a lot of data and could therefore be prone to error. The SOFA score on the other hand is a simpler system, has been widely used in ICUs and could be a good alternative. The goal of the study was to compare the SOFA score with the APACHE-IV and other ICU prediction models.

Methods: We investigated, in a large cohort of cardiac surgery patients admitted to Dutch ICUs, how well the SOFA score from the first 24 h after admission, predict hospital and ICU mortality in comparison with other recalibrated general ICU scoring systems. Measures of discrimination, accuracy, and calibration (area under the receiver operating characteristic curve (AUC), Brier score, R, and Ĉ-statistic) were calculated using bootstrapping. The cohort consisted of 36,632 Patients from the Dutch National Intensive Care Evaluation (NICE) registry having had a cardiac surgery procedure for which ICU admission was necessary between January 1st, 2006 and June 31st, 2018.

Results: Discrimination of the SOFA-, APACHE-IV-, APACHE-II-, SAPS-II-, MPM-II - models to predict hospital mortality was good with an AUC of respectively: 0.809, 0.851, 0.830, 0.850, 0.801. Discrimination of the SOFA-, APACHE-IV-, APACHE-II-, SAPS-II-, MPM-II - models to predict ICU mortality was slightly better with AUCs of respectively: 0.809, 0.906, 0.892, 0.919, 0.862. Calibration of the models was generally poor.

Conclusion: Although the SOFA score had a good discriminatory power for hospital- and ICU mortality the discriminatory power of the APACHE-IV and SAPS-II was better. The SOFA score should not be preferred as mortality prediction model above traditional prognostic ICU-models.
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http://dx.doi.org/10.1186/s12871-020-00975-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068937PMC
March 2020

Lack of evidence for the presence of leprosy bacilli in red squirrels from North-West Europe.

Transbound Emerg Dis 2020 Mar 2;67(2):1032-1034. Epub 2019 Dec 2.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Leprosy is a human infectious disease caused by Mycobacterium leprae or Mycobacterium lepromatosis that can also occur in animals and even manifest as zoonosis. Recently, both mycobacteria were detected in red squirrels (Sciurus vulgaris) from the British Isles. To further explore the presence of leprosy bacilli in North-West Europe, we screened Belgian and Dutch squirrels. Tissue samples from 115 animals tested by qPCR were negative for both pathogens. No molecular or pathological evidence was found of the presence of these zoonotic pathogens in North-West Europe.
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http://dx.doi.org/10.1111/tbed.13423DOI Listing
March 2020

Perioperative proADM-change is associated with the development of acute respiratory distress syndrome in critically ill cardiac surgery patients: a prospective cohort study.

Biomark Med 2019 09 23;13(13):1081-1091. Epub 2019 Sep 23.

Department of Intensive Care, Leiden University Medical Center, Leiden, The Netherlands.

Biomarkers of acute respiratory distress syndrome (ARDS) after cardiac-surgery may help risk-stratification and management. Preoperative single-value proADM increases predictive capacity of scoring-system EuroSCORE. To include the impact of surgery, we aim to assess the predictive value of the perioperative proADM-change on development of ARDS in 40 cardiac-surgery patients. ProADM was measured in nine sequential blood samples. The Berlin definition of ARDS was used. For data-analyses, a multivariate model of EuroSCORE and perioperative proADM-change, linear mixed models and logistic regression were used. Perioperative proADM-change was associated with ARDS after cardiac-surgery, and it was superior to EuroSCORE. A perioperative proADM-change >1.5 nmol/l could predict ARDS. Predicting post-surgery ARDS with perioperative proADM-change enables clinicians to intensify lung-protective interventions and individualized fluid therapy to minimize secondary injury.
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http://dx.doi.org/10.2217/bmm-2019-0028DOI Listing
September 2019

Clinical factors, C-reactive protein point of care test and chest X-ray in patients with pneumonia: A survey in primary care.

Eur J Gen Pract 2019 Oct 28;25(4):229-235. Epub 2019 Aug 28.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

In patients with an acute lower respiratory tract infection (LRTI), general practitioners (GPs) often find it challenging to decide to prescribe antibiotics or not. C-reactive protein (CRP) point of care test (POCT), and chest X-ray are diagnostic tests that can optimize the treatment decision. However, their usefulness in clinical practice is unknown. To determine the proportion of Dutch GPs using CRP and chest X-ray in patients with an acute LRTI. To determine whether clinical factors and C-reactive protein point of care test affect the behaviour in requesting chest X-rays. In 2014, a questionnaire was sent to a random sample of 900 Dutch GPs. Outcome parameters are the use of CRP and chest X-ray, the percentage of GPs who guide their decision in requesting chest X-rays by CRP testing and the GP's expectation regarding presence or absence of pneumonia. In addition, considerations for requesting chest X-rays were assessed. Two hundred and fifty-five completed questionnaires (29%) were returned. In 2014, 54% of the responding GPs used the CRP test. These GPs tend to use fewer chest X-rays ( = 0.07). GPs overestimate the chance that pneumonia will be present on the radiograph. Seventy percent consider the possibility of abnormalities other than pneumonia as the main reason for requesting a chest X-ray. In patients with an acute lower respiratory tract infection, GPs report that CRP results affect their behaviour regarding the request of a chest X-ray in patients with lower respiratory tract infection and therefore research is needed to substantiate the use of these diagnostic tools for this purpose.
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http://dx.doi.org/10.1080/13814788.2019.1649651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853238PMC
October 2019

The Oral Pheneticillin Absorption Test: An Accurate Method to Identify Patients with Inadequate Oral Pheneticillin Absorption.

Antibiotics (Basel) 2019 Aug 15;8(3). Epub 2019 Aug 15.

Centre for Human Drug Research (CHDR), 2333 CL Leiden, The Netherlands.

Severe streptococcal infections are commonly treated with intravenous followed by oral penicillin (pheneticillin) therapy. However, switching from iv to oral therapy is complicated by the variability in oral pheneticillin absorption. We employed an Oral Absorption Test (OAT) for pheneticillin to identify patients in whom oral pheneticillin absorption is poor. Out of 84 patients 30 patients (36%) were identified as insufficient absorbers. Treatment failure due to pheneticillin malabsorption can be avoided by performing an OAT, and these patients should be treated by another antibiotic, which is known to be absorbed well.
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http://dx.doi.org/10.3390/antibiotics8030119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784104PMC
August 2019

Archival, paleopathological and aDNA-based techniques in leprosy research and the case of Father Petrus Donders at the Leprosarium 'Batavia', Suriname.

Int J Paleopathol 2019 12 17;27:1-8. Epub 2019 Aug 17.

Dept Biochemistry, Faculty of Medical Sciences, Anton de Kom Universiteit van Suriname, Paramaribo, Suriname.

Objective: We assessed whether Petrus Donders (died 1887), a Dutch priest who for 27 years cared for people with leprosy in the leprosarium Batavia, Suriname, had evidence of Mycobacterium (M.) leprae infection. A positive finding of M. leprae ancient (a)DNA would contribute to the origin of leprosy in Suriname.

Materials: Skeletal remains of Father Petrus Donders; two additional skeletons excavated from the Batavia cemetery were used as controls.

Methods: Archival research, paleopathological evaluation and aDNA-based testing of skeletal remains.

Results: Neither archives nor inspection of Donders skeletal remains revealed evidence of leprosy, and aDNA-based testing for M. leprae was negative. We detected M. leprae aDNA by RLEP PCR in one control skeleton, which also displayed pathological lesions compatible with leprosy. The M. leprae aDNA was genotyped by Sanger sequencing as SNP type 4; the skeleton displayed mitochondrial haplogroup L3.

Conclusion: We found no evidence that Donders contracted leprosy despite years of intense leprosy contact, but we successfully isolated an archaeological M. leprae aDNA sample from a control skeleton from South America.

Significance: We successfully genotyped recovered aDNA to a M. leprae strain that likely originated in West Africa. The detected human mitochondrial haplogroup L3 is also associated with this geographical region. This suggests that slave trade contributed to leprosy in Suriname.

Limitations: A limited number of skeletons was examined.

Suggestions For Further Research: Broader review of skeletal collections is advised to expand on diversity of the M. leprae aDNA database.
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http://dx.doi.org/10.1016/j.ijpp.2019.08.001DOI Listing
December 2019

Repetitive urinary tract infections and two prostatic masses: Prostatic soft tissue infection with Actinomyces neuii.

Int J Infect Dis 2019 Sep 6;86:55-56. Epub 2019 Jul 6.

Department of Internal Medicine and Infectious Diseases, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; Center for Infectious Disease Control, National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. Electronic address:

Actinomyces infection is a tissue destructive, low-grade infection that often resembles malignancy. We report the case of a 70-year-old male with repeated, culture-negative urinary tract infections while intermittently catheterized. At presentation, the patient reported a new episode of urinary tract infection with white discharge in his urine. Transrectal ultrasonography showed two lesions in the prostate, suspect for prostate cancer. However, biopsy did not show cancer, and anaerobic culture grew Actinomyces neuii. A 3-month antibiotic course of amoxicillin eventually cured the infection. This is a case of prostatic soft tissue infection with A. neuii. It is important to consider Actinomyces infection in patients with a non-malignant prostatic mass. Although β-lactam antibiotics do not penetrate the prostate well, the Actinomyces infection was cured by prolonged amoxicillin treatment in this case. It is possible that the tissue damage enhanced the amoxicillin concentration in the infected prostate.
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http://dx.doi.org/10.1016/j.ijid.2019.06.029DOI Listing
September 2019

Using flexible methods to determine risk factors for ventilator-associated pneumonia in the Netherlands.

PLoS One 2019 20;14(6):e0218372. Epub 2019 Jun 20.

Department of Infectious Disease Modelling, Epidemiology and Surveillance, Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Seven hospitals participated in the Dutch national surveillance for ventilator-associated pneumonia (VAP) and its risk factors. We analysed time-independent and time-dependent risk factors for VAP using the standard Cox regression and the flexible Weighted Cumulative Effects method (WCE) that evaluates both current and past exposures. The prospective surveillance of intensive care patients aged ≥16 years and ventilated ≥48 hours resulted in the inclusion of 940 primary ventilation periods, comprising 7872 ventilation days. The average VAP incidence density was 10.3/1000 ventilation days. Independent risk factors were age (16-40 years at increased risk: HR 2.42 95% confidence interval 1.07-5.50), COPD (HR 0.19 [0.04-0.78]), current sedation score (higher scores at increased risk), current selective oropharyngeal decontamination (HR 0.19 [0.04-0.91]), jet nebulizer (WCE, decreased risk), intravenous antibiotics for selective decontamination of the digestive tract (ivSDD, WCE, decreased risk), and intravenous antibiotics not for SDD (WCE, decreased risk). The protective effect of ivSDD was afforded for 24 days with a delay of 3 days. For some time-dependent variables, the WCE model was preferable over standard Cox proportional hazard regression. The WCE method can furthermore increase insight into the active time frame and possible delay herein of a time-dependent risk factor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586305PMC
February 2020

Non-lytic antibiotic treatment in community-acquired pneumococcal pneumonia does not attenuate inflammation: the PRISTINE trial.

J Antimicrob Chemother 2019 08;74(8):2385-2393

Department of Infectious Diseases, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.

Background: The inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)]. An acute release of these components occurs when pneumococcal infection is treated with β-lactam antibiotics.

Objectives: We hypothesized that non-lytic rifampicin compared with lytic β-lactam antibiotic treatment would attenuate the inflammatory response in patients with pneumococcal pneumonia.

Methods: In the PRISTINE (Pneumonia treated with RIfampicin aTtenuates INflammation) trial, a randomized, therapeutic controlled, exploratory study in patients with community-acquired pneumococcal pneumonia, we looked at LTA release and inflammatory and clinical response during treatment with both rifampicin and β-lactam compared with treatment with β-lactam antibiotics only. The trial is registered in the Dutch trial registry, number NTR3751 (European Clinical Trials Database number 2012-003067-22).

Results: Forty-one patients with community-acquired pneumonia were included; 17 of them had pneumococcal pneumonia. LTA release, LTA-mediated inflammatory responses, clinical outcomes, inflammatory biomarkers and transcription profiles were not different between treatment groups.

Conclusions: The PRISTINE study demonstrated the feasibility of adding rifampicin to β-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia, but, despite solid in vitro and experimental animal research evidence, failed to demonstrate a difference in plasma LTA concentrations and subsequent inflammatory and clinical responses. Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, LTA plasma concentration could be too low to mount a response via Toll-like receptor 2 in vitro, but may nonetheless have an effect in vivo.
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http://dx.doi.org/10.1093/jac/dkz207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640306PMC
August 2019

Intravesical Gentamicin Treatment for Recurrent Urinary Tract Infections Caused by Multidrug Resistant Bacteria.

J Urol 2019 03;201(3):549-555

Departments of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: Antimicrobial resistance leads to complications in the management of recurrent urinary tract infections. In some patients with recurrent urinary tract infections who have limited treatment options intravenous therapy with reserve antibiotics is often required. In this study we assessed the effectiveness, safety and feasibility of prophylactic treatment with intravesical gentamicin in patients with refractory recurrent urinary tract infections caused by multidrug resistant microorganisms.

Materials And Methods: This was a prospective trial of 63 adults with recurrent urinary tract infections caused by multidrug resistant pathogens who were enrolled at 1 academic and 1 general hospital in The Netherlands between 2014 and 2017. The intervention was overnight intravesical instillations of gentamicin for 6 months. The primary outcome was the recurrence rate of urinary tract infections compared to that in the preceding 6 months. Secondary objectives included assessment of the safety of intravesical gentamicin instillation and its influence on the development of antibiotic resistance in uropathogens.

Results: The mean number of urinary tract infections was reduced from 4.8 to 1.0 during intravesical treatment. The resistance rate of the uropathogens decreased from 78% to 23%. No systemic absorption or clinically relevant side effects were observed.

Conclusions: Intravesical gentamicin instillation reduced the number of urinary tract infection episodes and the degree of antimicrobial resistance.
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http://dx.doi.org/10.1016/j.juro.2018.10.004DOI Listing
March 2019

[The severe flu season of 2017-2018: making a case for the vaccination of healthcare professionals].

Ned Tijdschr Geneeskd 2018 09 6;162. Epub 2018 Sep 6.

Rijksinstituut voor Volksgezondheid en Milieu, Centrum voor Infectieziektebestrijding, Bilthoven.

The 2017/2018 influenza season was severe and lasted twice as long as usual. Hospitals struggled to meet the demand for care. In addition to a high number of patients with flu and its complications, other factors played a role. These included absenteeism of informal caretakers and professional home care staff due to having flu themselves, and added strain on hospital capacity due to flu-related sick leave of hospital staff. A minority of the latter group is vaccinated annually against influenza. The authors of this article argue that all healthcare providers should take the yearly influenza vaccination. This will prove beneficial to the employer and employees, since non-attendance among employees will be reduced during peak demand and thus ensure continuity of care capacity. It will also have a positive impact in terms of patient safety and professionalism through improved protection of vulnerable patients against nosocomial influenza infection.
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September 2018

Another perspective on the treatment of postoperative endophthalmitis: Unclear evidence for the role of vitrectomy.

Acta Ophthalmol 2018 Dec 4;96(8):e1042-e1043. Epub 2018 Jun 4.

Infectious diseases, RIVM, Bilthoven, Utrecht, The Netherlands.

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http://dx.doi.org/10.1111/aos.13810DOI Listing
December 2018

Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

Euro Surveill 2018 04;23(15)

Department Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases.
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http://dx.doi.org/10.2807/1560-7917.ES.2018.23.15.18-00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836195PMC
April 2018

Influenza Season and ARDS after Cardiac Surgery.

N Engl J Med 2018 02;378(8):772-773

Leiden University Medical Center, Leiden, the Netherlands

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http://dx.doi.org/10.1056/NEJMc1712727DOI Listing
February 2018

A prospective multicentre randomized placebo-controlled superiority trial in patients with suspected bacterial endophthalmitis after cataract surgery on the adjuvant use of intravitreal dexamethasone to intravitreal antibiotics.

Acta Ophthalmol 2018 Jun 7;96(4):348-355. Epub 2017 Dec 7.

The Rotterdam Eye Hospital, Rotterdam, the Netherlands.

Purpose: We aimed to determine whether intravitreal dexamethasone as an adjuvant to intravitreal antibiotics is beneficial in the treatment of suspected bacterial endophthalmitis after cataract surgery.

Methods: Randomized, placebo-controlled superiority trial in three tertiary referral centres in the Netherlands. Patients with suspected bacterial endophthalmitis within 6 weeks after cataract surgery were eligible. A diagnostic vitreous biopsy was taken for culture, and patients received intravitreal injections of 400 μg dexamethasone (without preservatives) or placebo, in addition to 0.2 mg vancomycin and 0.05 mg gentamicin. The vancomycin and dexamethasone or placebo injections were repeated once at day 3 or 4. Primary outcome measure was best-corrected visual acuity (BCVA) at 1 year.

Results: Between 1 November 2004 and 1 March 2014 (excluding two interruptions totalling 20 months), 324 eligible patients presented. A total of 167 patients (81 dexamethasone, 86 placebo) were available for the intention-to-treat analysis. Biopsies of 114 patients (68%) were culture-positive. Final BCVA did not differ between the dexamethasone and the placebo group (logMAR 0.31 ± 0.58 versus 0.27 ± 0.50; p = 0.90), nor did the number of patients with final vision of no light perception (LP, 7 versus 13). Pain, corneal oedema, the absence of a red fundus reflex on presentation, LP on presentation and culture of virulent pathogens from biopsy were statistically significantly associated with an unfavourable visual outcome.

Conclusion: Intravitreal dexamethasone without preservatives as an adjuvant to intravitreal antibiotics does not improve visual acuity (VA) in patients treated for suspected bacterial endophthalmitis after cataract surgery.
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http://dx.doi.org/10.1111/aos.13610DOI Listing
June 2018

Long-term Carriage of Extended-Spectrum β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in the General Population in The Netherlands.

Clin Infect Dis 2018 04;66(9):1368-1376

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Background: This longitudinal study aimed to investigate (risk factors for) persistence of carriage and molecular characteristics of extended-spectrum and plasmid-encoded AmpC β-lactamase-producing (ESBL/pAmpC) Escherichia coli and Klebsiella pneumoniae (ESBL-E/K) in adults in the Dutch community.

Methods: Following a cross-sectional study (ESBL-E/K prevalence, 4.5%), a subset of ESBL-E/K-positive (n = 76) and -negative (n = 249) individuals volunteered to provide 5 monthly fecal samples and questionnaires. ESBL-E/K was cultured using selective enrichment/culture, and multilocus sequence types (MLSTs) were determined. ESBL/pAmpC-genes were analyzed using polymerase chain reaction (PCR) and sequencing. Plasmids were characterized and subtyped by plasmid MLST. Risk factors for persistent carriage were analyzed using logistic regression.

Results: Of the initially ESBL-E/K-positive participants, 25 of 76 (32.9%) remained positive in all subsequent samples; 51 of 76 persons (67.1%) tested ESBL-E/K negative at some time point during follow-up, of which 31 (40.8%) stayed negative throughout the longitudinal study. Carriers often carried the same ESBL gene and plasmid, but sometimes in different ESBL-E/K strains, indicative for horizontal transfer of plasmids. Of the 249 initially ESBL-E/K-negative participants, the majority (n = 218 [87.6%]) tested negative during 8 months of follow-up, whereas 31 of 249 (12.4%) participants acquired an ESBL-E/K. Escherichia coli phylogenetic group B2 and D and travel to ESBL high-prevalence countries were associated with prolonged carriage.

Conclusions: ESBL-E/K carriage persisted for >8 months in 32.9% of the initially ESBL-positive individuals, while 12.4% of initially negative individuals acquired ESBL-E/K during the study. A single positive test result provides no accurate prediction for prolonged carriage. Acquisition/loss of ESBL-E/K does not seem to be a random process, but differs between bacterial genotypes.
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http://dx.doi.org/10.1093/cid/cix1015DOI Listing
April 2018

A 38-year-old woman with necrotising cervical lymphadenitis due to Histoplasma capsulatum.

Infection 2017 Dec 18;45(6):917-920. Epub 2017 Aug 18.

Department of Infectious Diseases, Leiden University Medical Center, Room C5-42, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Case Presentation: We analysed a 38-year-old woman with disseminated histoplasmosis for primary immunodeficiency. Her blood showed no IFN-γ response while her peripheral blood mononuclear cells (PBMCs) did. We identified IFN-γ autoantibodies of the IgG class in her serum.

Conclusion: IFN-γ autoantibodies leading to infections were so far mainly detected in people from Asian descent, where it was found to be associated with certain HLA types. This may be the first patient of African descent, and without the typical HLA types that predispose to this problem, that produces IFN-γ autoantibodies.
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http://dx.doi.org/10.1007/s15010-017-1060-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696445PMC
December 2017

IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database.

Hum Mutat 2017 10 3;38(10):1286-1296. Epub 2017 Aug 3.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

IFN-γ signaling is essential for the innate immune defense against mycobacterial infections. IFN-γ signals through the IFN-γ receptor, which consists of a tetramer of two IFN-γR1 chains in complex with two IFN-γR2 chains, where IFN-γR1 is the ligand-binding chain of the interferon-γ receptor and IFN-γR2 is the signal-transducing chain of the IFN-γ receptor. Germline mutations in the gene IFNGR1 encoding the IFN-γR1 cause a primary immunodeficiency that mainly leads to mycobacterial infections. Here, we review the molecular basis of this immunodeficiency in the 130 individuals described to date, and report mutations in five new individuals, bringing the total number to 135 individuals from 98 kindreds. Forty unique IFNGR1 mutations have been reported and they exert either an autosomal dominant or an autosomal recessive effect. Mutations resulting in premature stopcodons represent the majority of IFNGR1 mutations (60%; 24 out of 40), followed by amino acid substitutions (28%, 11 out of 40). All known mutations, as well as 287 other variations, have been deposited in the online IFNGR1 variation database (www.LOVD.nl/IFNGR1). In this article, we review the function of IFN-γR1 and molecular genetics of human IFNGR1.
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http://dx.doi.org/10.1002/humu.23302DOI Listing
October 2017

Hospitalization for community-acquired febrile urinary tract infection: validation and impact assessment of a clinical prediction rule.

BMC Infect Dis 2017 06 6;17(1):400. Epub 2017 Jun 6.

Dept of Internal Medicine, Haga Hospital, The Hague, The Netherlands.

Background: There is a lack of severity assessment tools to identify adults presenting with febrile urinary tract infection (FUTI) at risk for complicated outcome and guide admission policy. We aimed to validate the Prediction Rule for Admission policy in Complicated urinary Tract InfeCtion LEiden (PRACTICE), a modified form of the pneumonia severity index, and to subsequentially assess its use in clinical practice.

Methods: A prospective observational multicenter study for model validation (2004-2009), followed by a multicenter controlled clinical trial with stepped wedge cluster-randomization for impact assessment (2010-2014), with a follow up of 3 months. Paricipants were 1157 consecutive patients with a presumptive diagnosis of acute febrile UTI (787 in validation cohort and 370 in the randomized trial), enrolled at emergency departments of 7 hospitals and 35 primary care centers in the Netherlands. The clinical prediction rule contained 12 predictors of complicated course. In the randomized trial the PRACTICE included guidance on hospitalization for high risk (>100 points) and home discharge for low risk patients (<75 points), in the control period the standard policy regarding hospital admission was applied. Main outcomes were effectiveness of the clinical prediction rule, as measured by primary hospital admission rate, and its safety, as measured by the rate of low-risk patients who needed to be hospitalized for FUTI after initial home-based treatment, and 30-day mortality.

Results: A total of 370 patients were included in the randomized trial, 237 in the control period and 133 in the intervention period. Use of PRACTICE significantly reduced the primary hospitalization rate (from 219/237, 92%, in the control group to 96/133, 72%, in the intervention group, p < 0.01). The secondary hospital admission rate after initial outpatient treatment was 6% in control patients and 27% in intervention patients (1/17 and 10/37; p < 0.001).

Conclusions: Although the proposed PRACTICE prediction rule is associated with a lower number of hospital admissions of patients presenting to the ED with presumptive febrile urinary tract infection, futher improvement is necessary to reduce the occurrence of secondary hospital admissions.

Trial Registration: NTR4480 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4480 , registered retrospectively 25 mrt 2014 (during enrollment of subjects).
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http://dx.doi.org/10.1186/s12879-017-2509-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461732PMC
June 2017

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Clin Immunol 2017 07 6;180:111-119. Epub 2017 May 6.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.
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http://dx.doi.org/10.1016/j.clim.2017.05.008DOI Listing
July 2017

Treatment duration of febrile urinary tract infection: a pragmatic randomized, double-blind, placebo-controlled non-inferiority trial in men and women.

BMC Med 2017 Apr 3;15(1):70. Epub 2017 Apr 3.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Background: In adults with febrile urinary tract infection (fUTI), data on optimal treatment duration in patients other than non-pregnant women without comorbidities are lacking.

Methods: A randomized placebo-controlled, double-blind, non-inferiority trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥ 18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days (the second week being ciprofloxacin 500 mg or placebo orally twice daily). Patients indicated to receive antimicrobial treatment for at least 14 days were excluded from randomization. The primary endpoint was the clinical cure rate through the 10- to 18-day post-treatment visit with preset subgroup analysis including sex. Secondary endpoints were bacteriologic cure rate at 10-18 days post-treatment and clinical cure at 70-84 days post-treatment.

Results: Of 357 patients included, 200 were eligible for randomization; 97 patients were randomly assigned to 7 days and 103 patients to 14 days of treatment. Overall, short-term clinical cure occurred in 85 (90%) patients treated for 7 days and in 94 (95%) of those treated for 14 days (difference -4.5%; 90% CI, -10.7 to 1.7; P  = 0.072, non-inferiority not confirmed). In women, clinical cure was 94% and 93% in those treated for 7 and 14 days, respectively (difference 0.9; 90% CI, -6.9 to 8.7, P  = 0.011, non-inferiority confirmed) and, in men, this was 86% versus 98% (difference -11.2; 90% CI -20.6 to -1.8, P  = 0.025, inferiority confirmed). The bacteriologic cure rate was 93% versus 97% (difference -4.3%; 90% CI, -9.7 to 1.2, P  = 0.041) and the long-term clinical cure rate was 92% versus 91% (difference 1.6%; 90% CI, -5.3 to 8.4; P  = 0.005) for 7 days versus 14 days of treatment, respectively. In the subgroups of men and women, long-term clinical cure rates met the criteria for non-inferiority, indicating there was no difference in the need for antibiotic retreatment for UTI during 70-84 days follow-up post-treatment.

Conclusions: Women with fUTI can be treated successfully with antibiotics for 7 days. In men, 7 days of antibiotic treatment for fUTI is inferior to 14 days during short-term follow-up but it is non-inferior when looking at longer follow-up.

Trial Registration: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].
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http://dx.doi.org/10.1186/s12916-017-0835-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376681PMC
April 2017

ICARES: a real-time automated detection tool for clusters of infectious diseases in the Netherlands.

BMC Infect Dis 2017 03 9;17(1):201. Epub 2017 Mar 9.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM), Bilthoven, The Netherlands.

Background: Clusters of infectious diseases are frequently detected late. Real-time, detailed information about an evolving cluster and possible associated conditions is essential for local policy makers, travelers planning to visit the area, and the local population. This is currently illustrated in the Zika virus outbreak.

Methods: In the Netherlands, ICARES (Integrated Crisis Alert and Response System) has been developed and tested on three syndromes as an automated, real-time tool for early detection of clusters of infectious diseases. From local general practices, General Practice Out-of-Hours services and a hospital, the numbers of routinely used syndrome codes for three piloted tracts i.e., respiratory tract infection, hepatitis and encephalitis/meningitis, are sent on a daily basis to a central unit of infectious disease control. Historic data combined with information about patients' syndromes, age cohort, gender and postal code area have been used to detect clusters of cases.

Results: During the first 2 years, two out of eight alerts appeared to be a real cluster. The first was part of the seasonal increase in Enterovirus encephalitis and the second was a remarkably long lasting influenza season with high peak incidence.

Conclusions: This tool is believed to be the first flexible automated, real-time cluster detection system for infectious diseases, based on physician information from both general practitioners and hospitals. ICARES is able to detect and follow small regional clusters in real time and can handle any diseases entity that is regularly registered by first line physicians. Its value will be improved when more health care institutions agree to link up with ICARES thus improving further the signal-to-noise ratio.
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http://dx.doi.org/10.1186/s12879-017-2300-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345172PMC
March 2017

Pulmonary immune responses against Aspergillus fumigatus are characterized by high frequencies of IL-17 producing T-cells.

J Infect 2017 01 9;74(1):81-88. Epub 2016 Nov 9.

Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

In healthy individuals and in patients with invasive aspergillosis, Aspergillus-specific T-cells in peripheral blood display mainly a Thelper1 phenotype. Although in other fungal infections Thelper17 immunity is important, it was suggested that in aspergillus infection Thelper17 cells do not play a role or may even be detrimental.

Objectives: To compare the cytokine profiles of Aspergillus-specific CD4+ T-cells in peripheral blood and in the lung. To investigate the Thelper phenotype at the primary location of A. fumigatus exposure.

Methods: Lung-derived T-cells and peripheral blood T-cells from COPD-patients were stimulated with overlapping peptides of 6 A. fumigatus proteins. Aspergillus-specific T-cells were identified on the basis of the activation marker CD154 and production of TNFα. In addition, production of the cytokines IFNγ, IL-17, IL-4 and IL-5 by the Aspergillus-specific T-cells was measured.

Results: The majority of lung-derived Aspergillus-specific T-cells displayed a Thelper17 phenotype, and only low percentages of cells produced IFNγ. In contrast, in the peripheral blood of COPD patients Aspergillus-specific T-cells displayed a Thelper1 phenotype, similar as peripheral blood-derived Aspergillus-specific T-cells from healthy individuals.

Conclusions: These data demonstrate that in A. fumigatus infection, similar as in other fungal infections, Thelper17 cells may play a more important role in the immune response than was appreciated until now.
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http://dx.doi.org/10.1016/j.jinf.2016.10.010DOI Listing
January 2017

Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults.

Clin Vaccine Immunol 2015 Jul 6;22(7):778-88. Epub 2015 May 6.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Mycobacterium bovis bacillus Calmette-Guérin (BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T cell subsets in protected versus unprotected cohorts have yielded inconsistent results. We studied the primary T cell response, both proinflammatory and regulatory T cell responses, induced by BCG vaccination in adults. Twelve healthy adult volunteers who were tuberculin skin test (TST) negative, QuantiFERON test (QFT) negative, and BCG naive were vaccinated with BCG and followed up prospectively. BCG vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive, young-adult cohort: BCG vaccination induced either gamma interferon-positive (IFN-γ(+)) interleukin 2-positive (IL-2(+)) tumor necrosis factor α-positive (TNF-α(+)) polyfunctional CD4(+) T cells concurrent with CD4(+) IL-17A(+) and CD8(+) IFN-γ(+) T cells or, in contrast, virtually absent cytokine responses with induction of CD8(+) regulatory T cells. Significant induction of polyfunctional CD4(+) IFN-γ(+) IL-2(+) TNF-α(+) T cells and IFN-γ production by peripheral blood mononuclear cells (PBMCs) was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8(+) T cells were uniquely induced. Thus, BCG vaccination either induced a broad proinflammatory T cell response with local inflammatory reactogenicity or, in contrast, a predominant CD8(+) regulatory T cell response with mild local inflammation, poor cytokine induction, and absent polyfunctional CD4(+) T cells. Further detailed fine mapping of the heterogeneous host response to BCG vaccination using classical and nonclassical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses and how these impact the ability of BCG to induce protective immunity to TB.
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http://dx.doi.org/10.1128/CVI.00162-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478523PMC
July 2015

Expression and function of S100A8/A9 (calprotectin) in human typhoid fever and the murine Salmonella model.

PLoS Negl Trop Dis 2015 Apr 10;9(4):e0003663. Epub 2015 Apr 10.

Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Background: Typhoid fever, caused by the Gram-negative bacterium Salmonella enterica serovar Typhi, is a major cause of community-acquired bacteremia and death worldwide. S100A8 (MRP8) and S100A9 (MRP14) form bioactive antimicrobial heterodimers (calprotectin) that can activate Toll-like receptor 4, promoting lethal, endotoxin-induced shock and multi-organ failure. We aimed to characterize the expression and function of S100A8/A9 in patients with typhoid fever and in a murine invasive Salmonella model.

Methods And Principal Findings: S100A8/A9 protein levels were determined in acute phase plasma or feces from 28 Bangladeshi patients, and convalescent phase plasma from 60 Indonesian patients with blood culture or PCR-confirmed typhoid fever, and compared to 98 healthy control subjects. To functionally characterize the role of S100A8/A9, we challenged wildtype (WT) and S100A9-/- mice with S. Typhimurium and determined bacterial loads and inflammation 2- and 5- days post infection. We further assessed the antimicrobial function of recombinant S100A8/A9 on S. Typhimurium and S. Typhi replication in vitro. Typhoid fever patients demonstrated a marked increase of S100A8/A9 in acute phase plasma and feces and this increases correlated with duration of fever prior to admission. S100A8/A9 directly inhibited the growth of S. Typhimurium and S. Typhi in vitro in a dose and time dependent fashion. WT mice inoculated with S. Typhimurium showed increased levels of S100A8/A9 in both the liver and the systemic compartment but S100A9-/- mice were indistinguishable from WT mice with respect to bacterial growth, survival, and inflammatory responses, as determined by cytokine release, histopathology and organ injury.

Conclusion: S100A8/A9 is markedly elevated in human typhoid, correlates with duration of fever prior to admission and directly inhibits the growth of S. Typhimurium and S. Typhi in vitro. Despite elevated levels in the murine invasive Salmonella model, S100A8/A9 does not contribute to an effective host response against S. Typhimurium in mice.
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http://dx.doi.org/10.1371/journal.pntd.0003663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393299PMC
April 2015
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