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ObjectiveTo explore how parents judge disease severity of their febrile child and to identify symptoms they associate with serious illness, minor illness or health.DesignSemistructured interviews were conducted. Interviews were audio taped, transcribed verbatim and analysed thematically.ParticipantsParents of children aged 0–5 years with a febrile illness.SettingParticipants were recruited at the paediatric ward and the emergency department.ResultsTwenty-six interviews were conducted, in which 37 parents participated. Parents described disease severity of their child mainly in terms of changes in their child’s normal characteristics (behaviour and physical features). They found it harder to describe specific disease symptoms such as dyspnoea or dehydration. Their child being active, eating and drinking well, and smiling were perceived as reassuring, whereas high fever, moving very little and uncertainty about the type of infections were mentioned as alarming symptoms. Previous experience with febrile illnesses in their children was of great influence on the number and accuracy of symptoms they reported.ConclusionParents used the normal behaviour and physical features of their child as a reference frame for judging disease severity. With a larger deviation from the child’s normal characteristics, parents considered the illness more serious. They were less able to describe specific symptoms of disease such as dyspnoea or dehydration. This knowledge is important for clinicians in their communication with parents of children with febrile illness.

The aim of this study is to evaluate the influence of chest X-ray (CXR) results on antibiotic prescription in children suspected of lower respiratory tract infections (RTI) in the emergency department (ED). We performed a secondary analysis of a stepped-wedge, cluster randomized trial of children aged 1 month to 5 years with fever and cough/dyspnoea in 8 EDs in the Netherlands (2016–2018), including a 1-week follow-up. We analysed the observational data of the pre-intervention period, using multivariable logistic regression to evaluate the influence of CXR result on antibiotic prescription. We included 597 children (median age 17 months [IQR 9–30, 61% male). CXR was performed in 109/597 (18%) of children (range across hospitals 9 to 50%); 52/109 (48%) showed focal infiltrates. Children who underwent CXR were more likely to receive antibiotics, also when adjusted for clinical signs and symptoms, hospital and CXR result (OR 7.25 [95% CI 2.48–21.2]). Abnormalities on CXR were not significantly associated with antibiotic prescription.Conclusion: Performance of CXR was independently associated with more antibiotic prescription, regardless of its results. The limited influence of CXR results on antibiotic prescription highlights the inferior role of CXR on treatment decisions for suspected lower RTI in the ED.What is Known:• Chest X-ray (CXR) has a high inter-observer variability and cannot distinguish between bacterial or viral pneumonia.• Current guidelines recommend against routine use of CXR in children with uncomplicated respiratory tract infections (RTIs) in the outpatient setting.What is New:• CXR is still frequently performed in non-complex children suspected of lower RTIs in the emergency department• CXR performance was independently associated with more antibiotic prescriptions, regardless of its results, highlighting the inferior role of chest X-rays in treatment decisions.

The study aimed to explore the use of diagnostics for febrile children presenting to European emergency departments (EDs), the determinants of inter-hospital variation, and the association between test use and hospitalization. We performed a secondary analysis of a cross-sectional observational study involving 28 paediatric EDs from 11 countries. A total of 4560 children Conclusion: the use of diagnostics for febrile children was highly variable across European EDs, yet patient and hospital characteristics could only partly explain inter-hospital variability. Focus groups of participating sites should help define reasons for unexpected variation. What is Known:• Although previous research has shown variation in the emergency department (ED) management of febrile children, there is limited information on the use of diagnostics in European EDs.• A deeper knowledge of variability and its determinants can steer optimization of care. What is New:• The use of diagnostics for febrile children was highly variable across European EDs, yet patient and hospital characteristics could only partly explain inter-hospital variability.• Data on between-centre comparison offer opportunities to further explore factors influencing unwarranted variation.

Introduction: Several international studies have reported sex differences in COVID-19 mortality. The Dutch healthcare system is characterized by as strong focus on primary care and active patient participation in medical choices, such as invasive therapies. This study aims at identifying potential sex-specific predictors of in-hospital mortality and non-ICU policy in patients with COVID-19. Methods: In this observational cohort study, we included participants hospitalized with COVID-19 during the first wave (March-May 2020) of the pandemic in six regional hospitals in the Netherlands. We computed descriptive statistics and logistic regression models using sex-disaggregated data to identify predictors of in-hospital mortality. Followingly, we analyzed the clinical features of female and male COVID-19 patients who had a non-ICU policy.Results: We included 1262 patients (63.7% men) in this study. Higher age, higher LDH level, lower diastolic blood pressure, and lower peripheral oxygen saturation were associated with in-hospital mortality in female and male patients. Shorter symptom duration before admission and more comorbidities associated with in-hospital mortality only in female patients. 33.8% of the female and 30.6% of the male patients had a non-ICU policy. We identified a significant rise in this policy in female patients over the course of the first wave compared to males, which could not be explained solely by age and clinical differences. Discussion: Potential sex differences in symptom development and the sex-specific impact of immune dysfunction on COVID-19 prognosis need further evaluation. Sex differences in ICU care preferences of these patients should be examined to identify underlying gender-related patterns.

Abstract Vital signs can help clinicians identify children at risk of serious illness. The NICE guideline for fever in under-fives recommends a routine measurement of temperature, heart rate, capillary refill and respiratory rate in all febrile children visiting the emergency department (ED). This study aims to evaluate the measurement of paediatric vital signs in European EDs, with specific attention to adherence to this NICE guideline recommendation. In a prospective observational study, we included 4560 febrile children under 16 years from the ED of 28 hospitals in 11 European countries (2014–2016). Hospitals were academic (n = 17), teaching (n = 10) and non-teaching (n = 1) and ranged in annual paediatric ED visits from 2700 to 88,000. Fifty-four percent were male, their median age was 2.4 years (IQR 1.1–4.7). Temperature was measured most frequently (97%), followed by capillary refill (86%), heart rate (73%), saturation (56%) and respiratory rate (51%). In children under five (n = 3505), a complete measurement of the four NICE-recommended vital signs was performed in 48% of patients. Children under 1 year of age, those with an urgent triage level and with respiratory infections had a higher likelihood of undergoing complete measurements. After adjustment for these factors, variability between countries remained. Conclusion: Measuring vital signs in children with fever in the ED occurs with a high degree of practice variation between different European hospitals, and adherence to the NICE recommendation is moderate. Our study is essential as a benchmark for current clinical practice, in order to tailor implementation strategies to different European settings.What is Known:• Vital signs can quickly provide information on disease severity in children in the emergency department (ED), and the NICE guideline for fever in under-fives recommends to routinely measure temperature, heart rate, capillary refill and respiratory rate.• Data regarding measurement of vital signs in routine practice across European EDs is currently unavailable.What is New:• Measurement of vital signs in febrile children is highly variable across European EDs and across patient subgroups, and compliance to the NICE recommendation is • Children under 1 year of age, those with an urgent triage level and with respiratory infections had a higher likelihood of undergoing complete measurements.

Background: Children with fever and respiratory symptoms represent a large patient group at the emergency department (ED). A decision rulebased treatment strategy improved targeting of antibiotics in these children in a recent clinical trial. This study aims to evaluate the impact of the decision rule on healthcare and societal costs, and to describe costs of children with suspected lower respiratory tract infections (RTIs) in the ED in general. Methods: In a stepped-wedge, cluster randomized trial, we collected cost data of children 1 month to 5 years of age with fever and cough/dyspnea in 8 EDs in The Netherlands (2016–2018). We calculated medical costs and societal costs per patient, during usual care (n = 597), and when antibiotic prescription was guided by the decision rule (n = 402). We calculated costof-illness of this patient group and estimated their annual costs at national level. Results: The cost-of-illness of children under 5 years with suspected lower RTIs in the ED was on average €2130 per patient. At population level this is €15 million per year in The Netherlands (€1.7 million/100,000 children under 5). Mean costs per patient in usual care (€2300) were reduced to €1870 in the intervention phase (P = 0.01). Main cost drivers were hospitalization and lost parental workdays. Conclusions: Implementation of a decision rule-based treatment strategy in children with suspected lower RTI was cost-saving, due to a reduction in hospitalization and parental absenteeism. Given the high frequency of this disease in children, the decision rule has the potential to result in a considerable cost reduction at population level.

Lower respiratory tract infections (LRTIs) in children are common and, although often mild, a major cause of mortality and hospitalization. Recently, the respiratory microbiome has been associated with both susceptibility and severity of LRTI. In this current study, we combined respiratory microbiome, viral, and clinical data to find associations with the severity of LRTI. Nasopharyngeal aspirates of children aged one month to five years included in the STRAP study (Study to Reduce Antibiotic prescription in childhood Pneumonia), who presented at the emergency department (ED) with fever and cough or dyspnea, were sequenced with nanopore 16S-rRNA gene sequencing and subsequently analyzed with hierarchical clustering to identify respiratory microbiome profiles. Samples were also tested using a panel of 15 respiratory viruses and Mycoplasma pneumoniae, which were analyzed in two groups, according to their reported virulence. The primary outcome was hospitalization, as measure of disease severity. Nasopharyngeal samples were isolated from a total of 167 children. After quality filtering, microbiome results were available for 54 children and virology panels for 158 children. Six distinct genus-dominant microbiome profiles were identified, with Haemophilus-, Moraxella-, and Streptococcus-dominant profiles being the most prevalent. However, these profiles were not found to be significantly associated with hospitalization. At least one virus was detected in 139 (88%) children, of whom 32.4% had co-infections with multiple viruses. Viral co-infections were common for adenovirus, bocavirus, and enterovirus, and uncommon for human metapneumovirus (hMPV) and influenza A virus. The detection of enteroviruses was negatively associated with hospitalization. Virulence groups were not significantly associated with hospitalization. Our data underlines high detection rates and co-infection of viruses in children with respiratory symptoms and confirms the predominant presence of Haemophilus-, Streptococcus-, and Moraxella-dominant profiles in a symptomatic pediatric population at the ED. However, we could not assess significant associations between microbiome profiles and disease severity measures.

SummaryThe mRNA-based BNT162b2 vaccine from Pfizer/BioNTech was the first registered COVID-19 vaccine and has been shown to be up to 95% effective in preventing SARS-CoV-2 infections. Little is known about the broad effects of the new class of mRNA vaccines, especially whether they have combined effects on innate and adaptive immune responses. Here we confirmed that BNT162b2 vaccination of healthy individuals induced effective humoral and cellular immunity against several SARS-CoV-2 variants. Interestingly, however, the BNT162b2 vaccine also modulated the production of inflammatory cytokines by innate immune cells upon stimulation with both specific (SARS-CoV-2) and non-specific (viral, fungal and bacterial) stimuli. The response of innate immune cells to TLR4 and TLR7/8 ligands was lower after BNT162b2 vaccination, while fungi-induced cytokine responses were stronger. In conclusion, the mRNA BNT162b2 vaccine induces complex functional reprogramming of innate immune responses, which should be considered in the development and use of this new class of vaccines.

ObjectiveTo describe clinical characteristics, disease course and outcomes in a large and well-documented cohort of hospitalized COVID-19 patients in the Netherlands.MethodsWe conducted a multicentre retrospective cohort study in The Netherlands including 952 of 1183 consecutively hospitalized patients that were admitted to participating hospitals between March 2nd, 2020, and May 22nd, 2020. Clinical characteristics and laboratory parameters upon admission and during hospitalization were collected until July 1st.ResultsThe median age was 69 years (IQR 58–77 years) and 605 (63.6%) were male. Cardiovascular disease was present in 558 (58.6%) patients. The median time of onset of symptoms prior to hospitalization was 7 days (IQR 5–10). A non ICU admission policy was applicable in 312 (32.8%) patients and in 165 (56.3%) of the severely ill patients admitted to the ward. At admission and during hospitalization, severely ill patients had higher values of CRP, LDH, ferritin and D-dimer with higher neutrophil counts and lower lymphocyte counts. Overall in-hospital mortality was 25.1% and 183 (19.1%) patients were admitted to ICU, of whom 56 (30.6%) died. Patients aged ≥70 years had high mortality, both at the ward (52.4%) and ICU (47.4%). The median length of ICU stay was 8 days longer in patients aged ≥70 years compared to patients aged ≤60 years.ConclusionHospitalized COVID-19 patients aged ≥70 years had high mortality and longer ICU stay compared to patients aged ≤60 years. These findings in combination with the patient burden of an ICU admission and possible long term complications after discharge should encourage us to further investigate the benefit of ICU admission in elderly and fragile COVID-19-patients.

Background To date, survival data on risk factors for COVID-19 mortality in western Europe is limited, and none of the published survival studies have used a competing risk approach. This study aims to identify risk factors for in-hospital mortality in COVID-19 patients in the Netherlands, considering recovery as a competing risk. Methods In this observational multicenter cohort study we included adults with PCR-confirmed SARS-CoV-2 infection that were admitted to one of five hospitals in the Netherlands (March to May 2020). We performed a competing risk survival analysis, presenting cause-specific hazard ratios (HRCS) for the effect of preselected factors on the absolute risk of death and recovery. Results 1,006 patients were included (63.9% male; median age 69 years, IQR: 58–77). Patients were hospitalized for a median duration of 6 days (IQR: 3–13); 243 (24.6%) of them died, 689 (69.9%) recovered, and 74 (7.4%) were censored. Patients with higher age (HRCS 1.10, 95% CI 1.08–1.12), immunocompromised state (HRCS 1.46, 95% CI 1.08–1.98), who used anticoagulants or antiplatelet medication (HRCS 1.38, 95% CI 1.01–1.88), with higher modified early warning score (MEWS) (HRCS 1.09, 95% CI 1.01–1.18), and higher blood LDH at time of admission (HRCS 6.68, 95% CI 1.95–22.8) had increased risk of death, whereas fever (HRCS 0.70, 95% CI 0.52–0.95) decreased risk of death. We found no increased mortality risk in male patients, high BMI or diabetes. Conclusion Our competing risk survival analysis confirms specific risk factors for COVID-19 mortality in a the Netherlands, which can be used for prediction research, more intense in-hospital monitoring or prioritizing particular patients for new treatments or vaccination.

Contains fulltext : 229592.pdf (Publisher’s version ) (Open Access) BACKGROUND: Knowledge on bacterial co-infections in COVID-19 is crucial to use antibiotics appropriately. Therefore, we aimed to determine the incidence of bacterial co-infections, antibiotic use and application of antimicrobial stewardship principles in hospitalized patients with COVID-19. METHODS: We performed a retrospective observational study in four hospitals (1 university, 2 non-university teaching, 1 non-teaching hospital) in the Netherlands from March to May 2020 including consecutive patients with PCR-confirmed COVID-19. Data on first microbiological investigations obtained at the discretion of the physician and antibiotic use in the first week of hospital admission were collected. RESULTS: Twelve (1.2%) of the 925 patients included had a documented bacterial co-infection (75.0% pneumonia) within the first week. Microbiological testing was performed in 749 (81%) patients: sputum cultures in 105 (11.4%), blood cultures in 711 (76.9%), pneumococcal urinary antigen testing in 202 (21.8%), and Legionella urinary antigen testing in 199 (21.5%) patients, with clear variation between hospitals. On presentation 556 (60.1%; range 33.3-73.4%) patients received antibiotics for a median duration of 2 days (IQR 1-4). Intravenous to oral switch was performed in 41 of 413 (9.9%) patients who received intravenous treatment >48 h. Mean adherence to the local guideline on empiric antibiotic therapy on day 1 was on average 60.3% (range 45.3%-74.7%). CONCLUSIONS: On presentation to the hospital bacterial co-infections are rare, while empiric antibiotic use is abundant. This implies that in patients with COVID-19 empiric antibiotic should be withheld. This has the potential to dramatically reduce the current overuse of antibiotics in the COVID-19 pandemic.

Background Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule. Methods and findings In a stepped-wedge cluster randomised trial, we included children aged 1–60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power of our study. Conclusions In this multicentre ED study, we observed that a clinical decision rule for childhood pneumonia did not reduce overall antibiotic prescription, but that it was non-inferior to usual care. Exploratory analyses showed fewer strategy failures and that fewer antibiotics were prescribed in low/intermediate-risk children, suggesting improved targeting of antibiotics by the decision rule. Trial registration Netherlands Trial Register NTR5326., In a stepped-wedge cluster randomized trial, Josephine van de Maat and colleagues evaluate a clinical decision rule to guide antibiotic prescription in children suspected of lower respiratory tract infections in The Netherlands., Author summary Why was this study done? Symptoms of lower respiratory tract infections (RTIs) are very common in children, and the most common reason for children to receive antibiotics in the emergency department (ED). A large number of these antibiotic prescriptions may be unnecessary, because most respiratory infections in children are caused by viruses, which are not susceptible to antibiotic treatment. Currently, there is no good test to determine whether an infection is caused by a virus or by bacteria, resulting in over-prescription of antibiotics, which in turn can lead to side effects and antibiotic resistance. What did the researchers do and find? We introduced a clinical decision rule for children with suspected lower RTI in the ED, advising doctors about the child’s risk of having a bacterial infection (based on their symptoms), so that they would not prescribe antibiotics to children who had a low or intermediate risk. We found that this decision rule did not reduce antibiotic prescriptions when we looked at all children, but that it was safe to use the rule. It seemed that, with this decision rule, a higher number of children responded well to their initial treatment (for example, fewer children needed antibiotics in the week after the ED visit, and more children recovered quickly) and that the antibiotic prescriptions shifted from children at low/intermediate risk towards children at high risk of bacterial infection. What do these findings mean? We observed that it was safe to use the decision rule for guiding antibiotic treatment in children with a suspected lower RTI in the ED. It also seemed that, with the decision rule, antibiotics were more often prescribed to children who actually needed them, leading to better recovery from the disease. Limitations of our study were that it took more time than expected to organise the logistics of the trial before introduction of the decision rule, and that not all children received a C-reactive protein blood test in the usual care (control) period of the trial, which may have influenced the power of the study.

ObjectiveTo determine whether updating a diagnostic prediction model by adding a combination assay (tumour necrosis factor-related apoptosis-inducing ligand, interferon γ induced protein-10 and C reactive protein (CRP)) can accurately identify children with pneumonia or other serious bacterial infections (SBIs).DesignObservational double-blind diagnostic study.SettingTwo hospitals in Israel and four hospitals in the Netherlands.Patients591 children, aged 1–60 months, presenting with lower respiratory tract infections or fever without source. 96 of them had SBIs. The original Feverkidstool, a polytomous logistic regression model including clinical variables and CRP, was recalibrated and thereafter updated by using the assay.Main outcome measuresPneumonia, other SBIs or no SBI.ResultsThe recalibrated original Feverkidstool discriminated well between SBIs and viral infections, with a c-statistic for pneumonia of 0.84 (95% CI 0.77 to 0.92) and 0.82 (95% CI 0.77 to 0.86) for other SBIs. The discriminatory ability increased when CRP was replaced by the combination assay; c-statistic for pneumonia increased to 0.89 (95% CI 0.82 to 0.96) and for other SBIs to 0.91 (95% CI 0.87 to 0.94). This updated Feverkidstool improved diagnosis of SBIs mainly in children with low–moderate risk estimates of SBIs.ConclusionWe improved the diagnostic accuracy of the Feverkidstool by replacing CRP with a combination assay to predict pneumonia or other SBIs in febrile children. The updated Feverkidstool has the largest potential to rule out bacterial infections and thus to decrease unnecessary antibiotic prescription in children with low-to-moderate predicted risk of SBIs.

ObjectivesFirst, to explore parents’ views on and experiences of managing their febrile child and to assess their behaviour and needs when in search of information about fever; second, to develop and evaluate a hospital discharge information package about fever in children.DesignMixed methods: (A) qualitative study with semistructured interviews and a focus group discussion (FGD) and (B) quantitative survey.SettingEmergency department, non-acute hospital setting and day nursery in Rotterdam, The Netherlands.ParticipantsParents of children InterventionInformation package about fever in children (leaflet and website including videos).Outcome measures quantitative surveyKnowledge of fever and confidence in caring for a febrile child (Likert scale 0–5).ResultsParents found fever mostly alarming, especially high fever. Help-seeking behaviour was based on either specific symptoms or on an undefined intuition. When parents did not feel recognised in their concern or felt criticised, anxiety increased as well as the threshold to seek healthcare for future illnesses. Information was needed, especially for situations when the general practitioner or social network were less easily available. This information should be reliable, consistent, available in multiple formats and include advice on management of fever at home and precise referral to medical services. Parents reported improved knowledge about fever (pConclusionParents of children with a fever visiting the hospital are concerned about specific symptoms or based on an undefined intuition. Rather than telling parents that they should manage their child’s illness at home, healthcare professionals should recognise parental intuition and provide clear information on alarming signs and potential diagnoses to empower parents in the management of their febrile child.

A 61-year-old woman was seen at the Emergency Department with a progressive infection of the little finger. A solid hemorrhagic bulla was seen with 2 central ulcers and the diagnosis 'ecthyma contagiosum' was made. This is a self-limiting infection caused by a parapoxvirus in sheep and can be transmitted to humans through direct contact with infected animals.

Introduction Many women with a bipolar disorder are of reproductive age and will need to continue lithium treatment during pregnancy. The teratogenic and perinatal effects of lithium are known, but not the long-term effects of lithium on neurodevelopment of the children. This study investigates growth, neurological, cognitive and behavioral development of children exposed to lithium in utero. Method In an observational retrospective cohort study 15 children who were exposed to lithium in utero were investigated at 3–15 years of age. Neurological development was tested using the Hempel or Touwen examination. Cognitive development was assessed with the Bayley Scales of Infant Development III, Wechsler Preschool and Primary Scale of Intelligence or the Wechsler Intelligence Scale for Children. Parents completed the Child Behavior Checklist to assess behavioral development and a standard questionnaire about general development of the child since birth. Results One child had signs of a minor neurological dysfunction, but without further clinical implications. The results of the cognitive tests were within normal limits, although most children had lower scores on the performance IQ subtest. Growth, behavior and general development were within the normal range. Conclusions Continuing lithium therapy during pregnancy did not cause adverse effects on growth, neurological, cognitive and behavioral development of exposed children.