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Here we describe the characteristics of the first 100 laboratory confirmed COVID-19 patients admitted to the Elisabeth-Tweesteden Hospital (Tilburg, The Netherlands). The median age was 72 years, 67% was male, approximately 80% had co-morbidity, approximately 50% of which consisted of hypertension, cardiac and or pulmonary conditions and 25% diabetes. At admission 61% of patients had fever and about 50% presented at day 6 or more after onset of symptoms. At the time of writing 38 patients were discharged, 19 admitted to the intensive care unit (ICU) and 20 patients had died. The median age of ICU patients was 67 years and 63% had co-morbidity. The median time to discharge or to death was 6 and 5.5 days, respectively.

Objective: To describe disease presentation and clinical characteristics of patients with COVID-19 presenting to the Emergency Department (ED) of Bernhoven hospital in Uden, the Netherlands., Design: Prospective, descriptive study., Method: The registry focused on atypical symptoms and co-infections. We hypothesized that patients older than 70 years more often have atypical symptoms. The number of co-infections is unknown. Therefore, we prospectively registered medical history, duration of symptoms, symptoms, temperature, lab results and co-infections of patients with confirmed COVID-19 in the period March 4-16th., Results: The clinical characteristics of 107 patients were registered. The average age was 71 years and 41% was female. The median duration of symptoms was 5 days. 19% of patients had not been referred to pulmonary or internal medicine. Symptoms were fever (78%), respiratory complaints (78%), chest pain (28%), abdominal pain (13%), and diarrhea (34%). In 54% of the COVID-19 patients at the ED, the temperature was ≥ 38,0°C, CRP ≥ 50 in 51%, leucocytosis in 12% and elevated LD in 61%. Of 31 patients 24 (77%) had an absolute lymphopenia. Co-infections were seen in 16% of patients. The mortality in the ED was 2% and ICU-admission 5%. On March 25th, 2020 the overall mortality was 22% and ICU-admission 15%., Conclusion: We have seen patients with a very serious disease resulting in a high mortality and ICU-admission. Over 35% of patient did not have the typical symptoms of fever and respiratory complaints; atypical symptoms like chest pain, abdominal pain and diarrhea are frequently seen. There is no difference between patients over and under 70 years. COVID-19 patients can present with atypical symptoms, co-infections and distributed over various medical specialties.

Background: A reduction in duration of antibiotic therapy is crucial in minimizing the development of antimicrobial resistance, drug-related side effects and health care costs. The minimal effective duration of antimicrobial therapy for febrile urinary tract infections (fUTI) remains a topic of uncertainty, especially in male patients, those of older age or with comorbidities. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy., Methods: A secondary analysis of a randomized placebo-controlled 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. Patients indicated to receive antimicrobial treatment for more than 14 days were excluded from randomization. The biomarkers procalcitonin (PCT), mid-regional proadrenomedullin (MR-proADM), and C-reactive protein (CRP) were compared in their ability to predict clinical cure or failure through the 10-18 day post-treatment visit., Results: Biomarker concentrations were measured in 249 patients, with a clinical cure rate of 94% in the 165 randomized and 88% in the 84 non-randomized patients. PCT, MR-proADM and CRP concentrations did not differ between patients with clinical cure and treatment failure, and did not predict treatment outcome, irrespective of 7 or 14 day treatment duration (ROC AUC 0.521; 0.515; 0.512, respectively). PCT concentrations at presentation were positively correlated with bacteraemia (τ = 0.33, p < 0.001) and presence of shaking chills (τ = 0.25, p < 0.001), and MR-proADM levels with length of hospital stay (τ = 0.40, p < 0.001), bacteraemia (τ = 0.33, p < 0.001), initial intravenous treatment (τ = 0.22, p < 0.001) and time to defervescence (τ = 0.21, p < 0.001). CRP did not display any correlation to relevant clinical parameters., Conclusions: Although the biomarkers PCT and MR-proADM were correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection who were treated for either 7 or 14 days. CRP had no added value in the management of patients with fUTI., Trial Registration: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

Objective: To assess the diagnostic value of existing clinical prediction models (CPM; ie, statistically derived) in febrile young infants at risk for serious bacterial infections., Methods: A systematic literature review identified eight CPMs for predicting serious bacterial infections in febrile children. We validated these CPMs on four validation cohorts of febrile children in Spain (age <3 months), France (age <3 months) and two cohorts in the Netherlands (age 1-3 months and >3-12 months). We evaluated the performance of the CPMs by sensitivity/specificity, area under the receiver operating characteristic curve (AUC) and calibration studies., Results: The original cohorts in which the prediction rules were developed (derivation cohorts) ranged from 381 to 15 781 children, with a prevalence of serious bacterial infections varying from 0.8% to 27% and spanned an age range of 0-16 years. All CPMs originally performed moderately to very well (AUC 0.60-0.93). The four validation cohorts included 159-2204 febrile children, with a median age range of 1.8 (1.2-2.4) months for the three cohorts <3 months and 8.4 (6.0-9.6) months for the cohort >3-12 months of age. The prevalence of serious bacterial infections varied between 15.1% and 17.2% in the three cohorts <3 months and was 9.8% for the cohort >3-12 months of age. Although discriminative values varied greatly, best performance was observed for four CPMs including clinical signs and symptoms, urine dipstick analyses and laboratory markers with AUC ranging from 0.68 to 0.94 in the three cohorts <3 months (ranges sensitivity: 0.48-0.94 and specificity: 0.71-0.97). For the >3-12 months' cohort AUC ranges from 0.80 to 0.89 (ranges sensitivity: 0.70-0.82 and specificity: 0.78-0.90). In general, the specificities exceeded sensitivities in our cohorts, in contrast to derivation cohorts with high sensitivities, although this effect was stronger in infants <3 months than in infants >3-12 months., Conclusion: We identified four CPMs, including clinical signs and symptoms, urine dipstick analysis and laboratory markers, which can aid clinicians in identifying serious bacterial infections. We suggest clinicians should use CPMs as an adjunctive clinical tool when assessing the risk of serious bacterial infections in febrile young infants., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Febrile urinary tract infections (fUTI) can often be treated safely with oral antimicrobials in an outpatient setting. However, a minority of patients develop complications that may progress into septic shock. An accurate assessment of disease severity upon emergency department (ED) presentation is therefore crucial in order to guide the most appropriate triage and treatment decisions., Methods: Consecutive patients were enrolled with presumptive fUTI across 7 EDs in the Netherlands. The biomarkers mid-regional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and a clinical score (PRACTICE), were compared in their ability to predict a clinically severe course of fUTI, initial hospital admission and subsequent readmission using area under the receiver operating characteristic (AUROC) curves., Results: Biomarker concentrations were measured in 313 patients, with 259 (83%) hospitalized upon ED presentation, and 54 (17%) treated as outpatients. Of these outpatients, 12 (22%) were later hospitalized. MR-proADM had the highest diagnostic accuracy for predicting a complicated fUTI (AUROC [95% CI]: 0.86 [0.79-0.92]), followed by PCT (AUROC [95% CI]: 0.69 [0.58-0.80]). MR-proADM concentrations were unique in being significantly elevated in patients directly admitted and in outpatients requiring subsequent hospitalization, compared to those completing treatment at home. A virtual triage algorithm with an MR-proADM cut-off of 0.80  nmol/L resulted in a hospitalization rate of 66%, with only 2% secondary admissions., Conclusion: MR-proADM could accurately predict a severe course in patients with fUTI, and identify greater patient numbers who could be safely managed as outpatients. An initial assessment on ED presentation may focus resources to patients with highest disease severities., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fever in children in primary care is commonly caused by benign infections, but often worries parents. Information about the duration of fever and its predictors may help in reassuring parents, leading to diminished consultation of health care., Aim: To determine which signs and symptoms predict a prolonged duration of fever in febrile children in primary care and evaluate whether C-reactive protein (CRP) measurement has an additive predictive value for these symptoms., Design and Setting: A prospective cohort study at a GPs' cooperative (GPC) out-of-hours service., Method: Children (aged 3 months to 6 years) presenting with fever as stated by the parents were included. Exclusion criteria were no communication in Dutch possible, previous enrolment in the study within 2 weeks, referral to the hospital directly after visiting the GPC, or no informed consent. The main outcome measure was prolonged duration of fever (>3 days) after initial contact., Results: Four-hundred and eighty children were analysed, and the overall risk of prolonged duration was 13% (63/480). Multivariate analysis combined model of patient history and physical examination showed that 'sore throat' (OR 2.8; 95% CI = 1.30 to 6.01) and 'lymph nodes palpable' (OR 1.87; 95% CI = 1.01 to 3.49) are predictive for prolonged duration of fever. The discriminative value of the model was low (AUC 0.64). CRP had no additive value in the prediction of prolonged duration of fever (OR 1.00; 95% CI = 0.99 to 1.01)., Conclusion: The derived prediction model indicates that only a few signs and symptoms are related to prolonged duration of fever. CRP has no additional value in this model. Overall, because the discriminative value of the model was low, the duration of fever cannot be accurately predicted., (© British Journal of General Practice 2015.)

Background: C-Reactive protein (CRP) is an important diagnostic marker for serious bacterial infections in febrile children. C-Reactive protein bedside testing could potentially accelerate the diagnostic evaluation and shorten length of stay (LOS)., Objective: The aim of the study was to study the effect of introducing CRP bedside testing on the LOS of febrile children at the emergency department (ED)., Design and Intervention: A prospective observational study with a preimplementation cohort (2008) with traditional CRP testing and a postimplementation cohort (2009-2011) in which CRP bedside testing was introduced., Patients and Setting: All previously healthy children with fever, aged 1 month to 16 years, attending the ED of a university hospital were included; non-ill-appearing children with an upper airway infection were not eligible for CRP bedside testing., Analysis and Main Outcome Measure: Multivariable linear regression and propensity score analyses were used to determine the effect of CRP bedside testing on the logarithmic transformation length of stay [(log)LOS]., Results: The preimplementation cohort included 609 children of whom 286 (47%) had traditional CRP. The postimplementation cohort included the following 1330 children: 728 (55%) children had bedside CRP and 156 (12%) children had traditional CRP. Bedside CRP significantly lowered the median LOS of children in whom an additional diagnostic CRP test was performed, from 178 minutes (interquartile range, 135-232 minutes) to 148 minutes (interquartile range, 108-200 minutes) (30 minutes, 19% of total LOS). A significant reduction of 15% of the (log)LOS remained after adjusting for other determinants of (log)LOS; propensity score analysis showed a 16% reduction., Conclusions: C-Reactive protein bedside testing substantially lowered the LOS of children with fever at the ED in whom an additional diagnostic CRP test was performed.

Background: Fever in children is common and mostly caused by self-limiting infections. However, parents of febrile children often consult in general practice, in particular during out-of-hours care. To improve management, it is important to understand experiences of GPs managing these consultations., Objective: To describe GPs' experiences regarding management of childhood fever during out-of-hours care., Methods: A descriptive qualitative study using purposeful sampling, five focus group discussions were held among 37 GPs. Analysis was based on constant comparative technique using open and axial coding., Results: Main categories were: (i) Workload and general experience; (ii) GPs' perceptions of determinants of consulting behaviour; (iii) Parents' expectations from the GP's point of view; (iv) Antibiotic prescribing decisions; (v) Uncertainty of GPs versus uncertainty of parents and (vi) Information exchange during the consultation. GPs felt management of childhood fever imposes a considerable workload. They perceived a mismatch between parental concerns and their own impression of illness severity, which combined with time-pressure can lead to frustration. Diagnostic uncertainty is driven by low incidences of serious infections and dealing with parental demand for antibiotics is still challenging., Conclusion: Children with a fever account for a high workload during out-of-hours GP care which provides a diagnostic challenge due to the low incidence of serious illnesses and lacking long-term relationship. This can lead to frustration and drives antibiotics prescription rates. Improving information exchange during consultations and in the general public to young parents, could help provide a safety net thereby enhancing self-management, reducing consultations and workload, and subsequent antibiotic prescriptions., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Even though childhood fever is mostly self-limiting, children with fever constitute a considerable workload in primary care. Little is known about the number of contacts and management during general practitioners' (GPs) out-of-hours care. We investigated all fever related telephone contacts, consultations, antibiotic prescriptions and paediatric referrals of children during GP out-of-hours care within 1 year., Design: Observational cohort study., Setting and Patients: We performed an observational cohort study at a large Dutch GP out-of-hours service. Children (<12 years) whose parents contacted the GP out-of-hours service for a fever related illness in 2012 were included., Main Outcome Measures: Number of contacts and consultations, antibiotic prescription rates and paediatric referral rates., Results: We observed an average of 14.6 fever related contacts for children per day at GP out-of-hours services, with peaks during winter months. Of 17,170 contacts in 2012, 5343 (31.1%) were fever related and 70.0% resulted in a GP consultation. One in four consultations resulted in an antibiotic prescription. Prescriptions increased by age and referrals to secondary care decreased by age (p<0.001). The majority of parents (89.5%) contacted the out-of-hours service only once during a fever episode (89.5%) and 7.6% of children were referred to secondary care., Conclusions: This study shows that childhood fever does account for a large workload at GP out-of-hours services. One in three contacts is fever related and 70% of those febrile children are called in to be assessed by a GP. One in four consultations for childhood fever results in antibiotic prescribing and most consultations are managed in primary care without referral., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Clinical prediction rules (CPRs) to identify children with serious infections lack validation in low-prevalence populations, which hampers their implementation in primary care practice., Aim: To evaluate the diagnostic value of published CPRs for febrile children in primary care., Design and Setting: Observational cohort study among febrile children (<16 years) who consulted five GP cooperatives (GPCs) in the Netherlands., Method: Alarm signs of serious infection and clinical management were extracted from routine clinical practice data and manually recoded with a structured electronic data-entry program. Eight CPRs were selected from literature. CPR-variables were matched with alarm signs and CPRs were applied to the GPC-population. 'Referral to emergency department (ED)' was used as a proxy outcome measure for 'serious infection'. CPR performance was assessed by calibration analyses, sensitivity, specificity, and area under the ROC-curve (ROC-area)., Results: A total of 9794 GPC-contacts were eligible, 54% male, median age 2.3 years (interquartile range 1.0-4.6 years) and 8.1% referred to ED. Frequencies of CPR-variables varied from 0.5% (cyanosis, drowsy) to 25% (temperature ≥40°C). Alarm signs frequently included in CPRs were 'ill appearance', 'inconsolable', and 'abnormal circulatory or respiratory signs'. The height of the CPR's predicted risks generally corresponded with being (or not being) referred to the ED in practice. However, calibration-slopes indicated that three CPRs underestimated the risk of serious infection in the GPC-population. Sensitivities ranged from 42% to 54%, specificities from 68% to 89%. ROC-areas ranged from 0.52 to 0.81, with best performance of CPRs for children aged <3 months., Conclusion: Published CPRs performed moderately well in the primary out-of-hours care population. Advice is given on how to improve translation of CPRs to primary care practice., (© British Journal of General Practice 2015.)

Purpose: It is important to advise parents when to consult a doctor when their child has fever. To provide evidence-based, safety-net advice for young febrile children, we studied the risk of complications, the occurrence of alarm symptoms, the duration of fever., Methods: In a 7-day prospective follow-up study, we included 463 consecutive children aged 3 months to 6 years who presented with fever at a general practitioner out-of-hours service. We excluded 43 children with complicated illnesses at presentation. In a structured assessment, the duration of fever before presentation was noted and a physical examination was performed. Parents reported alarming symptoms and rectal temperature in a diary for 1 week. The total duration of fever included its duration before presentation. Median duration of fever was estimated using the Kaplan-Meier test., Results: During follow-up, 3.2% of the children with uncomplicated illness at presentation developed a complicated illness. The presence of alarming symptoms dropped from 79.3% at day 2 of the fever episode to 36.7% at day 9. The estimated median duration of the total fever episode was 4.0 days (95% confidence interval, 3.6-4.4)., Conclusions: In children with uncomplicated illnesses, the daily occurrence of alarming symptoms reported by parents was high. The median duration of fever was 4 days. The predictive value of alarming symptoms reported by parents for complicated illness should be reconsidered.

Brucellosis, a zoonotic infection characterised by undulant fever, has a low incidence in the Netherlands and is therefore rarely considered. We describe 3 patients aged 26, 47 and 56 years old; each presented with long-standing fever as predominant symptom after having travelled to an endemic area, Iraq or Turkey, 1 week to 4 months prior to manifestation of illness. They had similar symptoms: fever, weight loss, chills, night sweats and dry cough. Blood cultures of all patients became positive for gram-negative rods after 3-4 days of incubation. One patient had imported and consumed sheep-milk cheese from which a genetically indistinguishable Brucella strain was cultured. In another patient, identification of the bacterium proved difficult, resulting in delayed prescription of adequate antibiotic treatment. Serologic testing confirmed the diagnosis in this case. In the laboratory, there is a considerable risk of airborne transmission of the disease necessitating clear notification of the suspicion of brucellosis when material for culturing is submitted.

Background: KABISA TRAVEL is a clinical decision support system developed by the Institute of Tropical Medicine of Antwerp, Belgium, for the diagnosis of febrile illnesses after a stay in the tropics. This study aimed to compare the diagnostic accuracy of KABISA TRAVEL with that of expert travel physicians., Methods: From December 2007 to April 2009, travelers with fever after a stay in the tropics were included in a multicenter trial conducted in travel referral centers in the Netherlands, Italy, Spain, and Belgium. Physicians were asked (1) to rank their first assessment diagnoses, (2) to enter in KABISA TRAVEL clinical and laboratory data available within 36 hours, and (3) to interact with the tutor until its final diagnostic ranking. Both physicians and KABISA TRAVEL rankings were then compared with the final diagnosis confirmed by reference methods. The clinical utility was also surveyed., Results: A total of 205 cases with confirmed diagnosis were evaluated (male/female ratio: 1.85; mean age: 35 y). Most patients were western travelers or expatriates (60%) and were returning from sub-Saharan Africa (58%). Travel physicians and KABISA TRAVEL ranked the correct diagnosis in the first place for 70 and 72% of the cases, respectively, and within the top five both for 88% of them. Travel physicians reported having been suggested useful further investigations in 16% of the cases, and having been helped for obtaining the diagnosis in 24%. This was reported more frequently when they had initially missed the diagnosis (suggestion: 48% in missed vs 12% in found diagnoses, p < 0.001; helpful: 48% in missed vs 21% in found diagnoses, p = 0.005)., Conclusions: KABISA TRAVEL performed as well as expert travel physicians in diagnosing febrile illnesses occurring after a tropical stay. Clinicians perceived the system as more helpful when they had not immediately considered the correct diagnosis., (© 2011 International Society of Travel Medicine.)

The new version of the practice guideline 'Children with fever' has recently been published by the Dutch College of General Practitioners. There is no evidence to support antipyretic therapy in children with fever. Paracetamol (acetaminophen) is not advised for preventing seizures, but may be given to relieve other symptoms. Parents have a different attitude towards fever than do GPs. Parents are concerned about serious causes or complications of the fever. However, GPs are more interested in parameters other than fever. The practice guideline recommends that parents be advised and reassured, but also stresses that parents' concerns be considered as potential predictors of serious illness. Missed urinary tract infections can be a serious cause of fever. Therefore, urine should be examined in children younger than 2 years who are feverish with no apparent cause. Unfortunately, the guideline does not identify tropical diseases as a differential diagnosis. Finally, doctors must be alert to the possibility of dehydration. The complexity of identifying dehydrated children is discussed.

The new version of the practice guideline 'Children with fever' was recently published by the Dutch College of General Practitioners and is commented on from the perspective of paediatricians. Whether or not general practitioners should refer feverish children to the paediatrician depends on the age of the patient and the severity of the illness. All children younger than 1 month and children with warning symptoms should be referred to a paediatrician at once. One of the warning symptoms is that the child gives the impression of being seriously ill at the physical examination. As it can be difficult to ascertain the severity of the illness and to distinguish which children will develop a serious bacterial infection, observation scales can be of use, as can the general practitioner's intuitive feeling that 'something is wrong'. Emphasis is put on the fact that infections are dynamic processes and therefore good follow-up is important. Children under the age of 2 years with a fever with no apparent cause should be re-examined after 24-48 h. Parents should be properly instructed to come back for re-examination of their child if the clinical picture changes or worsens.

We describe four cases of HIV-positive patients, two from Surinam, one from the Dutch Antilles and one from Nigeria, who presented with a febrile illness and a high lactate dehydrogenase plasma level. In all four, the diagnosis of disseminated histoplasmosis was made, in three of them by liver biopsy. Two patients had retinal abnormalities compatible with a systemic fungal infection. Three patients were treated successfully with antifungal agents. One patient died. Between 2000 and 2006, only 14 patients with HIV have been found to have histoplasmosis in the Netherlands. Although histoplasmosis is not endemic in the Netherlands, physicians are more likely to see cases because of a growing number of HIV -positive immigrants from endemic regions.

Objective: Shock in the course of fever is likely caused by septic shock. Because septic shock carries a high mortality rate, early recognition could benefit the patient. We tried to predict the development of shock in medical patients with fever and a clinical infection, on the basis of clinical and microbiological information, and to evaluate the role therein of systemic inflammatory response syndrome (SIRS) criteria: abnormal body temperature, tachycardia, tachypnea, and abnormal white blood cell counts., Design: Prospective observational study., Setting: Department of Internal Medicine at a university hospital., Patients: Patients were 212 consecutive medical patients with newly onset fever (temperature, >38.0 degrees C axillary or >38.3 degrees C rectally) and a clinical source of infection., Measurements and Main Results: Of the 212 patients enrolled, 14 developed shock (i.e., a decrease in systolic arterial blood pressure of >40 mm Hg) during a maximum follow-up period of 7 days after inclusion. In univariate analyses, advanced age, prior urogenital disease, an abdominal source, nosocomial infections, and bacteremia predisposed patients to shock (p < .05). For clinical variables, obtained daily for 2 days after inclusion, a low performance (p < .001), the peak respiratory rate (p < .05), the peak heart rate (p < .05), the nadir score on the Glasgow Coma Scale (p < .005), the peak and nadir white blood cell counts (p < .005), and the nadir albumin (p < .01) and peak creatinine concentrations in blood (p < .001) predicted shock development. In multivariate analysis, the presence of bacteremia, the peak respiratory rate, the nadir Glasgow Coma Scale score, and the peak white blood cell count positively and the peak erythrocyte sedimentation rate negatively contributed to prediction of shock development. In contrast, SIRS had less predictive value, mainly because of lack of predictive value of peak heart rate and temperature in multivariate models., Conclusion: In febrile medical patients with a clinical infection, the development of shock involves an interaction between circulating microbial products and the host response, which can be recognized clinically by variables easily obtained at the bedside and partly different from the set used to define SIRS.