The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses.

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 via induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. Here, we investigated the adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants and its effects on the responsiveness of immune cells upon stimulation with heterologous stimuli. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by inflammatory cytokine production after stimulation - higher IL-1/IL-6 release and decreased IFN-α production. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need for additional studies to elucidate their effects on both innate and adaptive immune responses.

Acute Neuropsychiatric Symptoms During COVID-19: Results From Two Independent Cohort Studies.

ABSTRACT: Converging evidence suggests that COVID-19 infects not only the respiratory system, but also has a large impact on the central nervous system (CNS), leading to acute neuropsychiatric symptoms (NPSs) such as anxiety and delirium. It is thus far unclear which acute NPSs are most common in COVID-19 and if NPSs are associated with an altered COVID-19 disease course. We used data from two independent retrospective cohort studies performed in an academic hospital. A total of 93 patients with NPS and 125 patients without NPS were included. Main outcome measures consisted of type of acute NPS, COVID-19 severity (based on CT severity score), admission to the intensive care unit (ICU), and mortality. Most common acute NPSs were delirium, anxiety, and mood symptoms. NPS patients were more often admitted to the ICU than patients without NPS. However, there was no difference in duration of ICU admission, CT severity score, and mortality. Somatic comorbidity was similar between the two groups. These data suggest that delirium, anxiety, and mood symptoms were the most common NPS. Independent of other clinical characteristics, ICU admission in COVID-19 patients was associated with NPS. We recommend that all COVID-19 patients should be actively screened for acute NPS such as delirium, anxiety, and mood symptoms, especially when admitted to an ICU.

Diagnostic variation for febrile children in European emergency departments.

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 < 16 years were included, with fever as reason for consultation. We excluded neonates and children with relevant comorbidities. Our primary outcome was the proportion of children receiving testing after primary evaluation, by country and by focus of infection. Variability between hospitals and effects of blood testing on patient disposition were explored by multilevel regression analyses, adjusting for patient characteristics (age group, triage level, appearance, fever duration, focus of infection) and hospital type (academic, teaching, other). The use of routine diagnostics varied widely, mostly in the use of blood tests, ranging from 3 to 75% overall across hospitals. Age < 3 months, high-acuity triage level, ill appearance, and suspicion of urinary tract infection displayed the strongest association with blood testing (odds ratios (OR) of 8.71 (95% CI 5.23-14.53), 19.46 (3.66-103.60), 3.13 (2.29-4.26), 10.84 (6.35-18.50), respectively). Blood testing remained highly variable across hospitals (median OR of the final model 2.36, 1.98-3.54). A positive association was observed between blood testing and hospitalization (OR 13.62, 9.00-20.61). 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.

Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study.

The hypercoagulable state observed in COVID-19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID-19 patients. This study included 1154 COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80-1.30]) or length of hospital stay (7.0 [4-12] vs. 7.0 [4-12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05-0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID-19 patients.

The influence of chest X-ray results on antibiotic prescription for childhood pneumonia in the emergency department.

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.

Evaluation of a clinical decision rule to guide antibiotic prescription in children with suspected lower respiratory tract infection in The Netherlands: A stepped-wedge cluster randomised trial.

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.

Measuring vital signs in children with fever at the emergency department: an observational study on adherence to the NICE recommendations in Europe.

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 <50%.• Children under 1 year of age, those with an urgent triage level and with respiratory infections had a higher likelihood of undergoing complete measurements.

The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

Background and objective: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs). Methods: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h). Results: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods. Conclusion: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.

Corrigendum: The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

[This corrects the article DOI: 10.3389/fimmu.2023.980711.].

Timing and sequence of vaccination against COVID-19 and influenza (TACTIC): a single-blind, placebo-controlled randomized clinical trial.

Background: Novel mRNA-based vaccines have been used to protect against SARS-CoV-2, especially in vulnerable populations who also receive an annual influenza vaccination. The TACTIC study investigated potential immune interference between the mRNA COVID-19 booster vaccine and the quadrivalent influenza vaccine, and determined if concurrent administration would have effects on safety or immunogenicity. Methods: TACTIC was a single-blind, placebo-controlled randomized clinical trial conducted at the Radboud University Medical Centre, the Netherlands. Individuals ≥60 years, fully vaccinated against COVID-19 were eligible for participation and randomized into one of four study groups: 1) 0.5 ml influenza vaccination Vaxigrip Tetra followed by 0.3 ml BNT162b2 COVID-19 booster vaccination 21 days later, (2) COVID-19 booster vaccination followed by influenza vaccination, (3) influenza vaccination concurrent with the COVID-19 booster vaccination, and (4) COVID-19 booster vaccination only (reference group). Primary outcome was the geometric mean concentration (GMC) of IgG against the spike (S)-protein of the SARS-CoV-2 virus, 21 days after booster vaccination. We performed a non-inferiority analysis of concurrent administration compared to booster vaccines alone with a predefined non-inferiority margin of -0.3 on the log10-scale. Findings: 154 individuals participated from October, 4, 2021, until November, 5, 2021. Anti-S IgG GMCs for the co-administration and reference group were 1684 BAU/ml and 2435 BAU/ml, respectively. Concurrent vaccination did not meet the criteria for non-inferiority (estimate -0.1791, 95% CI -0.3680 to -0.009831) and antibodies showed significantly lower neutralization capacity compared to the reference group. Reported side-effects were mild and did not differ between study groups. Interpretation: Concurrent administration of both vaccines is safe, but the quantitative and functional antibody responses were marginally lower compared to booster vaccination alone. Lower protection against COVID-19 with concurrent administration of COVID-19 and influenza vaccination cannot be excluded, although additional larger studies would be required to confirm this. Trial registration number: EudraCT: 2021-002186-17. Funding: The study was supported by the ZonMw COVID-19 Programme.

Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial.

OBJECTIVES: To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. METHODS: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. RESULTS: A total of 6112 participants with a median age of 69 years (interquartile range, 65-74) and median of 2 (interquartile range, 1-3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87-1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46-1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35-1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66-1.28). DISCUSSION: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs.

ePOCT+ and the medAL-suite: Development of an electronic clinical decision support algorithm and digital platform for pediatric outpatients in low- and middle-income countries.

Electronic clinical decision support algorithms (CDSAs) have been developed to address high childhood mortality and inappropriate antibiotic prescription by helping clinicians adhere to guidelines. Previously identified challenges of CDSAs include their limited scope, usability, and outdated clinical content. To address these challenges we developed ePOCT+, a CDSA for the care of pediatric outpatients in low- and middle-income settings, and the medical algorithm suite (medAL-suite), a software for the creation and execution of CDSAs. Following the principles of digital development, we aim to describe the process and lessons learnt from the development of ePOCT+ and the medAL-suite. In particular, this work outlines the systematic integrative development process in the design and implementation of these tools required to meet the needs of clinicians to improve uptake and quality of care. We considered the feasibility, acceptability and reliability of clinical signs and symptoms, as well as the diagnostic and prognostic performance of predictors. To assure clinical validity, and appropriateness for the country of implementation the algorithm underwent numerous reviews by clinical experts and health authorities from the implementing countries. The digitalization process involved the creation of medAL-creator, a digital platform which allows clinicians without IT programming skills to easily create the algorithms, and medAL-reader the mobile health (mHealth) application used by clinicians during the consultation. Extensive feasibility tests were done with feedback from end-users of multiple countries to improve the clinical algorithm and medAL-reader software. We hope that the development framework used for developing ePOCT+ will help support the development of other CDSAs, and that the open-source medAL-suite will enable others to easily and independently implement them. Further clinical validation studies are underway in Tanzania, Rwanda, Kenya, Senegal, and India.

[Chest x-rays do not aid in antibiotic treatment decisions for children with lower respiratory infections in the Emergency Department]. / Thoraxfoto draagt niet bij aan besluit over antibiotica bij kinderen met een luchtweginfectie op de SEH.

The chest x-ray (CXR) was the gold standard in the diagnosis of pneumonia in children. However, CXR has limitations and cannot discriminate in etiology. Current guidelines recommend against routine use of CXR in children with uncomplicated lower respiratory tract infections (LRTI). We used routine care data from a multicentre RCT including 597 children with LRTI symptoms, to evaluate the influence of CXR on antibiotic prescription in the emergency department (ED). CXR remains frequently performed in non-complex children suspected of LRTI in the ED (18%). Children who underwent CXR were more likely to receive antibiotics, even when adjusted for symptoms, hospital and CXR results. Our study highlights the inferior role of CXR in treatment decisions for children with LRTI as CXR, regardless of its results, is independently associated with more antibiotic prescriptions.

Rifapentine and isoniazid for prevention of tuberculosis in people with diabetes (PROTID): protocol for a randomised controlled trial.

BACKGROUND: Diabetes mellitus (DM) increases the risk of tuberculosis (TB) and will hamper global TB control due to the dramatic rise in type 2 DM in TB-endemic settings. In this trial, we will examine the efficacy and safety of TB preventive therapy against the development of TB disease in people with DM who have latent TB infection (LTBI), with a 12-week course of rifapentine and isoniazid (3HP). METHODS: The 'Prevention of tuberculosis in diabetes mellitus' (PROTID) consortium will randomise 3000 HIV-negative eligible adults with DM and LTBI, as evidenced by a positive tuberculin skin test or interferon gamma release assay, to 12 weeks of 3HP or placebo. Participants will be recruited through screening adult patients attending DM clinics at referral hospitals in Tanzania and Uganda. Patients with previous TB disease or treatment with a rifamycin medication or isoniazid (INH) in the previous 2 years will be excluded. The primary outcome is the occurrence of definite or probable TB disease; secondary outcome measures include adverse events, all-cause mortality and treatment completion. The primary efficacy analysis will be intention-to-treat; per-protocol analyses will also be carried out. We will estimate the ratio of TB incidence rates in intervention and control groups, adjusting for the study site using Poisson regression. Results will be reported as efficacy estimates (1-rate ratio). Cumulative incidence rates allowing for death as a competing risk will also be reported. Approximately 1000 LTBI-negative, HIV-negative participants will be enrolled consecutively into a parallel cohort study to compare the incidence of TB in people with DM who are LTBI negative vs positive. A number of sub-studies will be conducted among others to examine the prevalence of LTBI and active TB, estimate the population impact and cost-effectiveness of LTBI treatment in people living with DM in these African countries and address gaps in the prevention and therapeutic management of combined TB-DM. DISCUSSION: PROTID is anticipated to generate key evidence to guide decisions over the use of TB preventive treatment among people with DM as an important target group for better global TB control. TRIAL REGISTRATION: ClinicalTrials.gov NCT04600167 . Registered on 23 October 2020.

Primary Care Case Management of Febrile Children: Insights From the ePOCT Routine Care Cohort in Dar es Salaam, Tanzania.

Aim: To provide insight in the primary health care (PHC) case management of febrile children under-five in Dar es Salaam, and to identify areas for improving quality of care. Methods: We used data from the routine care arm of the ePOCT trial, including children aged 2-59 months who presented with an acute febrile illness to two health centers in Dar es Salaam (2014-2016). The presenting complaint, anthropometrics, vital signs, test results, final diagnosis, and treatment were prospectively collected in all children. We used descriptive statistics to analyze the frequencies of diagnoses, adherence to diagnostics, and prescribed treatments. Results: We included 547 children (47% male, median age 14 months). Most diagnoses were viral: upper respiratory tract infection (60%) and/or gastro-enteritis (18%). Vital signs and anthropometric measurements taken by research staff and urinary testing failed to influence treatment decisions. In total, 518/547 (95%) children received antibiotics, while 119/547 (22%) had an indication for antibiotics based on local guidelines. Antibiotic dosing was frequently out of range. Non-recommended treatments were common (29%), most often cough syrup and vitamins. Conclusion: Our study points to challenges in using diagnostic test results, concerns regarding quality of antibiotic prescriptions, and frequent use of non-evidence-based complementary medicines in PHC in Tanzania. Larger studies on diagnostic and treatments processes in PHC in Tanzania are needed to inform effective solutions to support PHC workers in case management of children.

Parental assessment of disease severity in febrile children under 5 years of age: a qualitative study.

OBJECTIVE: To explore how parents judge disease severity of their febrile child and to identify symptoms they associate with serious illness, minor illness or health. DESIGN: Semistructured interviews were conducted. Interviews were audio taped, transcribed verbatim and analysed thematically. PARTICIPANTS: Parents of children aged 0-5 years with a febrile illness. SETTING: Participants were recruited at the paediatric ward and the emergency department. RESULTS: Twenty-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. CONCLUSION: Parents 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.

Few bacterial co-infections but frequent empiric antibiotic use in the early phase of hospitalized patients with COVID-19: results from a multicentre retrospective cohort study in The Netherlands.

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.

Risk factors for in-hospital mortality in laboratory-confirmed COVID-19 patients in the Netherlands: A competing risk survival analysis.

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.

Clinical characteristics and outcomes of 952 hospitalized COVID-19 patients in The Netherlands: A retrospective cohort study.

OBJECTIVE: To describe clinical characteristics, disease course and outcomes in a large and well-documented cohort of hospitalized COVID-19 patients in the Netherlands. METHODS: We 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. RESULTS: The 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. CONCLUSION: Hospitalized 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.

The Role of the Respiratory Microbiome and Viral Presence in Lower Respiratory Tract Infection Severity in the First Five Years of Life.

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.