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.

The 2021 Dutch Working Party on Antibiotic Policy (SWAB) guidelines for empirical antibacterial therapy of sepsis in adults.

BACKGROUND: The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults. METHODS: Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements). RESULTS: Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment. CONCLUSIONS: Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.

Dysregulated Innate and Adaptive Immune Responses Discriminate Disease Severity in COVID-19.

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.

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.

Myeloid-related protein-8/14 facilitates bacterial growth during pneumococcal pneumonia.

BACKGROUND: Streptococcus pneumoniae is the most commonly identified pathogen in community-acquired pneumonia (CAP). Myeloid-related protein (MRP) 8/14 is a major component of neutrophils that is released upon infection or injury. MRP8/14 is essential for protective immunity during infection by a variety of micro-organisms through its capacity to chelate manganese and zinc. Here, we aimed to determine the role of MRP8/14 in pneumococcal pneumonia. METHODS: MRP8/14 was determined in bronchoalveolar lavage fluid (BALF) and serum of CAP patients, in lung tissue of patients who had succumbed to pneumococcal pneumonia, and in BALF of healthy subjects challenged with lipoteichoic acid (a component of the gram-positive bacterial cell wall) via the airways. Pneumonia was induced in MRP14 deficient and normal wildtype mice. The effect of MRP8/14 on S. pneumoniae growth was studied in vitro. RESULTS: CAP patients displayed high MRP8/14 levels in BALF, lung tissue and serum. Healthy subjects challenged with lipoteichoic acid demonstrated elevated MRP8/14 in BALF. Likewise, mice with pneumococcal pneumonia had high MRP8/14 levels in lungs and the circulation. MRP14 deficiency, however, was associated with reduced bacterial growth and lethality, in the absence of notable effects on the inflammatory response. High zinc levels strongly inhibited growth of S. pneumoniae in vitro, which was partially reversed by MRP8/14. CONCLUSIONS: In sharp contrast to its previously reported host-protective role in several infections, the present results reveal that in a model of CAP, MRP8/14 is misused by S. pneumoniae, facilitating bacterial growth by attenuating zinc toxicity toward the pathogen.

Interleukin 1 receptor-associated kinase m impairs host defense during pneumococcal pneumonia.

BACKGROUND: Streptococcus pneumoniae is the most common causative organism in community-acquired pneumonia. Pneumococci that try to invade the lower airways are recognized by innate immune cells through pattern recognition receptors, including Toll-like receptors 2, 4, and 9. Interleukin 1 (IL-1) receptor-associated kinase (IRAK)-M is a proximal inhibitor of Toll-like receptor signaling. METHODS: To determine the role of IRAK-M in host defense during pneumococcal pneumonia, IRAK-M- deficient and wild-type mice were intranasally infected with S. pneumoniae. RESULTS: IRAK-M-deficient mice demonstrated a reduced lethality after infection with S. pneumoniae via the airways. Whereas bacterial burdens were similar in IRAK-M-deficient and wild-type mice early (3 hours) after infection, from 24 hours onward the number of pneumococci recovered from lungs and distant body sites were 10-100-fold lower in the former mouse strain. The diminished bacterial growth and dissemination in IRAK-M-deficient mice were preceded by an increased early influx of neutrophils into lung tissue and elevated pulmonary levels of IL-1ß and CXCL1. IRAK-M deficiency did not influence bacterial growth after intravenous administration of S. pneumoniae. CONCLUSIONS: These data suggest that IRAK-M impairs host defense during pneumococcal pneumonia at the primary site of infection at least in part by inhibiting the early immune response.

Routine vaccination for influenza and pneumococcal disease and its effect on COVID-19 in a population of Dutch older adults.

Objectives: Protective heterologous beneficial effects of vaccines have been reported, and in this study we aimed to assess the impact of routine pneumococcal and influenza vaccination on the incidence and symptom duration of COVID-19 in a population of Dutch older adults. Methods: This cohort study is a secondary analysis of the BCG-CORONA-ELDERLY study, a randomised controlled trial on the effect of BCG vaccination on the cumulative incidence of respiratory tract infections requiring medical intervention in adults ≥60 years. The primary outcome was the cumulative incidence of a self-reported positive SARS-CoV-2 PCR test, and was assessed using a Fine-Gray competing risks model adjusted for baseline characteristics at enrolment. We analysed data from November 1st 2020 until the end of the main study in May 2021. Results: Routine vaccination data 2020/2021 were available for 1963/2014 (97.5 %) participants; 44/1963 (2.2 %) were excluded due to COVID-19 before vaccination. 1076/1919 (56.1 %) had received the influenza vaccine and 289/1919 (15.1 %) the pneumococcal vaccine. The cumulative incidence of COVID-19 was 0.030 (95 %CI 0.021-0.041) in those vaccinated against influenza compared to 0.029 (95 %CI 0.019-0.041) in the unvaccinated group (subdistribution hazard ratio (SDHR) 1.018; 95 %CI 0.602-1.721). For pneumococcal vaccination the cumulative incidence was 0.031 (95 %CI 0.015-0.056) for the vaccinated and 0.029 (95 %CI 0.022-0.038) for non-vaccinated individuals (SDHR 0.961; 95 %CI 0.443-2.085). BCG vaccination in the previous year and sex were not significant effect modifiers in the primary analysis. Duration of fever, cough and dyspnoea was also not significantly different between treatment arms. Conclusion: Neither influenza nor pneumococcal vaccination was associated with a lower incidence or shorter duration of COVID-19 symptoms in older adults.

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.].

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.

Gene expression profiles in alveolar macrophages induced by lipopolysaccharide in humans.

Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo, we conducted a study in eight healthy humans, in which we instilled sterile saline into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung. Six hours later, a bilateral bronchoalveolar lavage was performed and whole-genome transcriptional profiling was done on purified alveolar macrophages, comparing cells exposed to saline or LPS from the same individuals. LPS induced differential expression of 2,932 genes in alveolar macrophages; 1,520 genes were upregulated, whereas 1,440 genes were downregulated. A total of 26 biological functions were overrepresented in LPS-exposed macrophages; 44 canonical pathways affected by LPS were identified, among which the genes associated with the role of pattern recognition receptors in recognition of bacteria and viruses represented the top pathway. Other pathways included cellular immune response, signaling by tumor necrosis factor (receptor) family members, cytokine signaling and glucocorticoid receptor signaling. These results reveal for the first time a large number of functional pathways influenced by the biologically relevant challenge provided by LPS administered into the airways. These data can assist in identifying novel targets for therapeutic intervention in pulmonary diseases associated with LPS exposure, including pneumonia, asthma and chronic obstructive pulmonary disease.

Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative pneumonia.

Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M(-/-)) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M(-/-) alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M(-/-) mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M(-/-) mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen.

Loss of suppression of tumorigenicity 2 (ST2) gene reverses sepsis-induced inhibition of lung host defense in mice.

RATIONALE: After surviving the initial hyperinflammatory phase, patients with sepsis display features consistent with immunosuppression, which renders the host susceptible to nosocomial infections, in particular bacterial pneumonia. Suppression of tumorigenicity 2 (ST2) is a negative regulator of Toll-like receptor signaling implicated in endotoxin tolerance. OBJECTIVES: The present study sought to determine the role of ST2 in modulating host defense in the lung during sepsis, using a murine model of cecal ligation and puncture (CLP)-induced sepsis followed by a secondary infection with Pseudomonas aeruginosa via the airways. METHODS: CLP or sham surgery was performed on BALB/c wild-type (WT) and ST2 knockout (KO) mice, and 24 hours later animals were challenged with 10(8) live P. aeruginosa. MEASUREMENTS AND MAIN RESULTS: CLP mice demonstrated impaired clearance of Pseudomonas from their lungs and reduced pulmonary levels of tumor necrosis factor-α and IL-6 compared with sham mice. After CLP, ST2KO mice with secondary pneumonia displayed a strongly improved survival and a better bacterial clearance compared with WT mice, which was accompanied by enhanced lung inflammation. CLP did not influence the responsiveness of alveolar macrophages toward P. aeruginosa ex vivo irrespective of the st2 genotype. In contrast, CLP resulted in a reduced capacity of WT CD4(+) and CD8(+) T cells to produce IFN-γ and tumor necrosis factor-α, an immune suppressive effect that was not seen in ST2KO mice. CONCLUSIONS: These findings indicate that gene products of ST2 contribute to the immune-compromised state during sepsis and the ensuing disturbed homeostasis of lung host defense.

New clinical prediction model for early recognition of sepsis in adult primary care patients: a prospective diagnostic cohort study of development and external validation.

BACKGROUND: Recognising patients who need immediate hospital treatment for sepsis while simultaneously limiting unnecessary referrals is challenging for GPs. AIM: To develop and validate a sepsis prediction model for adult patients in primary care. DESIGN AND SETTING: This was a prospective cohort study in four out-of-hours primary care services in the Netherlands, conducted between June 2018 and March 2020. METHOD: Adult patients who were acutely ill and received home visits were included. A total of nine clinical variables were selected as candidate predictors, next to the biomarkers C-reactive protein, procalcitonin, and lactate. The primary endpoint was sepsis within 72 hours of inclusion, as established by an expert panel. Multivariable logistic regression with backwards selection was used to design an optimal model with continuous clinical variables. The added value of the biomarkers was evaluated. Subsequently, a simple model using single cut-off points of continuous variables was developed and externally validated in two emergency department populations. RESULTS: A total of 357 patients were included with a median age of 80 years (interquartile range 71-86), of which 151 (42%) were diagnosed with sepsis. A model based on a simple count of one point for each of six variables (aged >65 years; temperature >38°C; systolic blood pressure ≤110 mmHg; heart rate >110/min; saturation ≤95%; and altered mental status) had good discrimination and calibration (C-statistic of 0.80 [95% confidence interval = 0.75 to 0.84]; Brier score 0.175). Biomarkers did not improve the performance of the model and were therefore not included. The model was robust during external validation. CONCLUSION: Based on this study's GP out-of-hours population, a simple model can accurately predict sepsis in acutely ill adult patients using readily available clinical parameters.

Antimicrobial stewardship in the emergency department: characteristics and evidence for effectiveness of interventions.

BACKGROUND: Emergency departments (EDs) are the entrance gates for patients presenting with infectious diseases into the hospital, yet most antimicrobial stewardship programmes are primarily focused on inpatient management. With equally high rates of inappropriate antibiotic use, the ED is a frequently overlooked yet important unit for targeted antimicrobial stewardship (AMS) interventions. OBJECTIVES: We aimed to (a) describe the specific aspects of antimicrobial stewardship in the ED and (b) summarize the findings from improvement studies that have investigated the effectiveness of antimicrobial stewardship interventions in the ED setting. SOURCES: (a) a PubMed search for 'antimicrobial stewardship' and 'emergency department', and (b) published reviews on effectiveness combined with publications from the first source. CONTENT: (a) An in depth analysis of selected publications provided four key antimicrobial use processes typically performed by front-line healthcare professionals in the ED: making a (tentative) clinical diagnosis, starting empirical therapy based on that diagnosis, performing microbiological tests before starting that therapy and following up patients who are discharged from the ED. (b) Further, we discuss the literature on improvement strategies in the ED focusing on guidelines and clinical pathways and multifaceted improvement strategies. We also summarize the evidence of microbiologic culture review. IMPLICATIONS: Based on our review of the literature, we describe four essential elements of antimicrobial use in the ED. Studying the various interventions targeting these care processes, we have found them to be of a variable degree of success. Nonetheless, while there is a paucity of AS studies specifically targeting the ED, there is a growing body of evidence that AS programmes in the ED are effective with modifications to the ED setting. We present key questions for future research.

Quality indicators for appropriate antimicrobial therapy in the emergency department: a pragmatic Delphi procedure.

OBJECTIVES: Antimicrobial stewardship (AMS) has established its importance for inpatient care. AMS is, however, also urgently needed in emergency departments (ED), where many antimicrobial prescriptions are initiated. It is currently unclear what metrics stewardship teams can use to measure and improve the appropriateness of antimicrobial prescription in the ED. In this study we develop quality indicators (QIs) for antimicrobial use in the ED. METHODS: A RAND-modified Delphi procedure was used to develop a set of QIs applicable to adult patients who present at the ED with a potential infection. First, pragmatically using two recent papers of the international expert-group DRIVE-AB, potential ED-specific QIs for appropriate antimicrobial use were retrieved. Thereafter, an international multidisciplinary expert panel appraised these QIs during two questionnaire rounds with a meeting in between. RESULTS: Thirty-three potential QIs were extracted from the DRIVE-AB papers. After appraisal by 13 experts, 22 QIs describing appropriate antimicrobial use in the ED were selected. These indicators provide recommendations within five domains: stewardship prerequisites (six QIs); diagnostics (one QI); empirical treatment (ten QIs); documentation of information (four QIs); and patient discharge (one QI). CONCLUSIONS: We pragmatically developed a set of 22 QIs that can be used by stewardship teams to measure the appropriateness of antimicrobial prescription in the ED. There is probably room for additional QI development to cover all key aspects of AMS in the ED. Measuring QIs can be a first step for stewardship teams to, in collaboration with ED professionals, choose targets for improvement and optimize antimicrobial use.

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.