Long-term wastewater monitoring of SARS-CoV-2 viral loads and variants at the major international passenger hub Amsterdam Schiphol Airport: A valuable addition to COVID-19 surveillance.

Wastewater-based epidemiological surveillance at municipal wastewater treatment plants has proven to play an important role in COVID-19 surveillance. Considering international passenger hubs contribute extensively to global transmission of viruses, wastewater surveillance at this type of location may be of added value as well. The aim of this study is to explore the potential of long-term wastewater surveillance at a large passenger hub as an additional tool for public health surveillance during different stages of a pandemic. Here, we present an analysis of SARS-CoV-2 viral loads in airport wastewater by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) from the beginning of the COVID-19 pandemic in Feb 2020, and an analysis of SARS-CoV-2 variants by whole-genome next-generation sequencing from Sep 2020, both until Sep 2022, in the Netherlands. Results are contextualized using (inter)national measures and data sources such as passenger numbers, clinical surveillance data and national wastewater surveillance data. Our findings show that wastewater surveillance was possible throughout the study period, irrespective of measures, as viral loads were detected and quantified in 98.6 % (273/277) of samples. Emergence of SARS-CoV-2 variants, identified in 91.0 % (161/177) of sequenced samples, coincided with increases in viral loads. Furthermore, trends in viral load and variant detection in airport wastewater closely followed, and in some cases preceded, trends in national daily average viral load in wastewater and variants detected in clinical surveillance. Wastewater-based epidemiology at a large international airport is a valuable addition to classical COVID-19 surveillance and the developed expertise can be applied in pandemic preparedness plans for other (emerging) pathogens in the future.

Regional reemergence of a SARS-CoV-2 Delta lineage amid an Omicron wave detected by wastewater sequencing.

The implementation and integration of wastewater-based epidemiology constitutes a valuable addition to existing pathogen surveillance systems, such as clinical surveillance for SARS-CoV-2. In the Netherlands, SARS-CoV-2 variant circulation is monitored by performing whole-genome sequencing on wastewater samples. In this manuscript, we describe the detection of an AY.43 lineage (Delta variant) amid a period of BA.5 (Omicron variant) dominance in wastewater samples from two wastewater treatment plants (WWTPs) during the months of August and September of 2022. Our results describe a temporary emergence, which was absent in samples from other WWTPs, and which coincided with peaks in viral load. We show how these lineage estimates can be traced back to lineage-specific substitution patterns. The absence of this variant from reported clinical data, but high associated viral loads suggest cryptic transmission. Our findings highlight the additional value of wastewater surveillance for generating insights into circulating pathogens.

Identification of circulating monocytes as producers of tuberculosis disease biomarker C1q.

Tuberculosis (TB) is a prevalent disease causing an estimated 1.6 million deaths and 10.6 million new cases annually. Discriminating TB disease from differential diagnoses can be complex, particularly in the field. Increased levels of complement component C1q in serum have been identified as a specific and accessible biomarker for TB disease but the source of C1q in circulation has not been identified. Here, data and samples previously collected from human cohorts, a clinical trial and a non-human primate study were used to identify cells producing C1q in circulation. Cell subset frequencies were correlated with serum C1q levels and combined with single cell RNA sequencing and flow cytometry analyses. This identified monocytes as C1q producers in circulation, with a pronounced expression of C1q in classical and intermediate monocytes and variable expression in non-classical monocytes.

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

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.

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

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.

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

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.

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

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.

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

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, R2, and C-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-, MPM24-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-, MPM24-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.

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

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.

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

Aim: 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. Materials & methods: 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. Results: 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. Conclusion: Predicting post-surgery ARDS with perioperative proADM-change enables clinicians to intensify lung-protective interventions and individualized fluid therapy to minimize secondary injury.

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

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.

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

Background: 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.Objectives: 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.Methods: 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.Results: 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 (p = 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.Conclusion: 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.

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

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

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 ß-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.

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

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

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 ß-lactam antibiotics. OBJECTIVES: We hypothesized that non-lytic rifampicin compared with lytic ß-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 ß-lactam compared with treatment with ß-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 ß-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.

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

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.

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

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.

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

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.