SARS-CoV-2 infection induces robust mucosal antibody responses in the upper respiratory tract.

Despite multiple research efforts to characterize coronavirus disease 2019 (COVID-19) in humans, there is no clear data on the specific role of mucosal immunity on COVID-19 disease. Here, we longitudinally profile the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal HCoV-OC43 S proteins in serum and nasopharyngeal swabs from COVID-19 patients. Results showed that specific antibody responses against SARS-CoV-2 and HCoV-OC43 S proteins can be detected in the upper respiratory tract. We found that COVID-19 patients mounted a robust mucosal antibody response against SARS-CoV-2 S with specific secretory immunoglobulin A (sIgA), IgA, IgG, and IgM antibody subtypes detected in the nasal swabs. Additionally, COVID-19 patients showed IgG, IgA, and sIgA responses against HCoV-OC43 S in the local mucosa, whereas no specific IgM was detected. Interestingly, mucosal antibody titers against SARS-CoV-2 peaked at day 7, whereas HCoV-OC43 titers peaked earlier at day 3 post-recruitment, suggesting an immune memory recall to conserved epitopes of beta-HCoVs in the upper respiratory tract.

mRNA COVID-19 Vaccination Does Not Exacerbate Symptoms or Trigger Neural Antibody Responses in Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens. METHODS: This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens. RESULTS: Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred. DISCUSSION: In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable.

Dynamics of Gene Expression Profiling and Identification of High-Risk Patients for Severe COVID-19.

The clinical manifestations of SARS-CoV-2 infection vary widely, from asymptomatic infection to the development of acute respiratory distress syndrome (ARDS) and death. The host response elicited by SARS-CoV-2 plays a key role in determining the clinical outcome. We hypothesized that determining the dynamic whole blood transcriptomic profile of hospitalized adult COVID-19 patients and characterizing the subgroup that develops severe disease and ARDS would broaden our understanding of the heterogeneity in clinical outcomes. We recruited 60 hospitalized patients with RT-PCR-confirmed SARS-CoV-2 infection, among whom 19 developed ARDS. Peripheral blood was collected using PAXGene RNA tubes within 24 h of admission and on day 7. There were 2572 differently expressed genes in patients with ARDS at baseline and 1149 at day 7. We found a dysregulated inflammatory response in COVID-19 ARDS patients, with an increased expression of genes related to pro-inflammatory molecules and neutrophil and macrophage activation at admission, in addition to an immune regulation loss. This led, in turn, to a higher expression of genes related to reactive oxygen species, protein polyubiquitination, and metalloproteinases in the latter stages. Some of the most significant differences in gene expression found between patients with and without ARDS corresponded to long non-coding RNA involved in epigenetic control.

Antifungal prophylaxis with nebulized amphotericin-B in solid-organ transplant recipients with severe COVID-19: a retrospective observational study.

COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a frequent complication in the intensive care unit (ICU). However, little is known about this life-threatening fungal superinfection in solid organ transplant recipients (SOTRs), including whether targeted anti-mold prophylaxis might be justified in this immunosuppressed population. We performed a multicentric observational retrospective study of all consecutive ICU-admitted COVID-19 SOTRs between August 1, 2020 and December 31, 2021. SOTRs receiving antifungal prophylaxis with nebulized amphotericin-B were compared with those without prophylaxis. CAPA was defined according the ECMM/ISHAM criteria. Sixty-four SOTRs were admitted to ICU for COVID-19 during the study period. One patient received antifungal prophylaxis with isavuconazole and was excluded from the analysis. Of the remaining 63 SOTRs, nineteen (30.2%) received anti-mold prophylaxis with nebulized amphotericin-B. Ten SOTRs who did not receive prophylaxis developed pulmonary mold infections (nine CAPA and one mucormycosis) compared with one who received nebulized amphotericin-B (22.7% vs 5.3%; risk ratio 0.23; 95%CI 0.032-1.68), but with no differences in survival. No severe adverse events related to nebulized amphotericin-B were recorded. SOTRs admitted to ICU with COVID-19 are at high risk for CAPA. However, nebulized amphotericin-B is safe and might reduce the incidence of CAPA in this high-risk population. A randomized clinical trial to confirm these findings is warranted.

Whole-Blood Gene Expression Profiles Associated with Mortality in Community-Acquired Pneumonia.

(1) Background: Information regarding gene expression profiles and the prognosis of community-acquired pneumonia (CAP) is scarce. We aimed to examine the differences in the gene expression profiles in peripheral blood at hospital admission between patients with CAP who died during hospitalization and those who survived. (2) Methods: This is a multicenter study of nonimmunosuppressed adult patients who required hospitalization for CAP. Whole blood samples were obtained within 24 h of admission for genome-expression-profile analysis. Gene expression profiling identified both differentially expressed genes and enriched gene sets. (3) Results: A total of 198 samples from adult patients who required hospitalization for CAP were processed, of which 13 were from patients who died. Comparison of gene expression between patients who died and those who survived yielded 49 differentially expressed genes, 36 of which were upregulated and 13 downregulated. Gene set enrichment analysis (GSEA) identified four positively enriched gene sets in survivors, mainly associated with the interferon-alpha response, apoptosis, and sex hormone pathways. Similarly, GSEA identified seven positively enriched gene sets, associated with the oxidative stress, endoplasmic reticulum stress, oxidative phosphorylation, and angiogenesis pathways, in the patients who died. Protein-protein-interaction-network analysis identified FOS, CDC42, SLC26A10, EIF4G2, CCND3, ASXL1, UBE2S, and AURKA as the main gene hubs. (4) Conclusions: We found differences in gene expression profiles at hospital admission between CAP patients who died and those who survived. Our findings may help to identify novel candidate pathways and targets for potential intervention and biomarkers for risk stratification.

Characteristics and Outcomes by Ceiling of Care of Subjects Hospitalized with COVID-19 During Four Waves of the Pandemic in a Metropolitan Area: A Multicenter Cohort Study.

INTRODUCTION: The profiles of patients with COVID-19 have been widely studied, but little is known about differences in baseline characteristics and in outcomes between subjects with a ceiling of care assigned at hospital admission and subjects without a ceiling of care. The aim of this study is to compare, by ceiling of care, clinical features and outcomes of hospitalized subjects during four waves of COVID-19 in a metropolitan area in Catalonia. METHODS: Observational study conducted during the first (March-April 2020), second (October-November 2020), third (January-February 2021), and fourth wave (July-August 2021) of COVID-19 in five centers of Catalonia. All subjects were adults (> 18 years old) hospitalized with a proven SARS-CoV-2 infection and with therapeutic ceiling of care assessed by the attending physician at hospital admission. RESULTS: A total of 5813 subjects were analyzed. Subjects with a ceiling of care were mainly older (difference in median age of 20 years), with more comorbidities (Charlson index 3 points higher) and with fewer clinical signs at baseline than patients without a ceiling of care. Some features of their clinical profiles changed among waves. There were differences in treatments received during hospital admission across waves, but not between subjects with and without a ceiling of care. Subjects with a ceiling of care had a death incidence more than four times the death incidence of subjects a without a ceiling of care (risk ratio (RR) ranging from 3.5 in the first wave to almost 6 in the third and fourth). Incidence of severe pneumonia and complications for subjects with a ceiling of care was around 1.5 times the incidence in subjects without a ceiling of care. DISCUSSION: Analysis of hospitalized subjects with SARS-CoV-2 infection should be stratified according to therapeutic ceiling of care to avoid bias and outcome misestimation.

SARS-Cov-2 incubation period according to vaccination status during the fifth COVID-19 wave in a tertiary-care center in Spain: a cohort study.

BACKGROUND: The incubation period of an infectious disease is defined as the elapsed time between the exposure to the pathogen and the onset of symptoms. Although both the mRNA-based and the adenoviral vector-based vaccines have shown to be effective, there have been raising concerns regarding possible decreases in vaccine effectiveness for new variants and variations in the incubation period. METHODS: We conducted a unicentric observational study at the Hospital Universitari de Bellvitge, Barcelona, using a structured telephone survey performed by trained interviewers to estimate the incubation period of the SARS-CoV-2 Delta variant in a cohort of Spanish hospitalized patients. The distribution of the incubation period was estimated using the generalized odds-rate class of regression models. RESULTS: From 406 surveyed patients, 242 provided adequate information to be included in the analysis. The median incubation period was 2.8 days (95%CI: 2.5-3.1) and no differences between vaccinated and unvaccinated patients were found. Sex and age are neither shown not to be significantly related to the COVID-19 incubation time. CONCLUSIONS: Knowing the incubation period is crucial for controlling the spread of an infectious disease: decisions on the duration of the quarantine or on the periods of active monitoring of people who have been at high risk of exposure depend on the length of the incubation period. Furthermore, its probability distribution is a key element for predicting the prevalence and the incidence of the disease.

Persistent COVID-19 symptoms 1 year after hospital discharge: A prospective multicenter study.

OBJECTIVE: To determine the health status and exercise capacity of COVID-19 survivors one year after hospital discharge. METHODS: This multicenter prospective study included COVID-19 survivors 12 months after hospital discharge. Participants were randomly selected from a large cohort of COVID-19 patients who had been hospitalized until 15th April 2020. They were interviewed about persistent symptoms, underwent a physical examination, chest X-ray, and a 6-minute walk test (6MWT). A multivariate analysis was performed to determine the risk factors for persistent dyspnea. RESULTS: Of the 150 patients included, 58% were male and the median age was 63 (IQR 54-72) years. About 82% reported ≥1 symptoms and 45% had not recovered their physical health. The multivariate regression analysis revealed that the female sex, chronic obstructive pulmonary disease, and smoking were independent risk factors for persistent dyspnea. Approximately 50% completed less than 80% of the theoretical distance on the 6MWT. Only 14% had an abnormal X-ray, showing mainly interstitial infiltrates. A third of them had been followed up in outpatient clinics and 6% had undergone physical rehabilitation. CONCLUSION: Despite the high rate of survivors of the first wave of the COVID-19 pandemic with persistent symptomatology at 12 months, the follow-up and rehabilitation of these patients has been really poor. Studies focusing on the role of smoking in the persistence of COVID-19 symptoms are lacking.

Effect of positive microbiological testing on antibiotic de-escalation and outcomes in community-acquired pneumonia: a propensity score analysis.

OBJECTIVES: The usefulness of routine microbiological testing for rationalising antibiotic use in hospitalised patients with community-acquired pneumonia (CAP) continues to be a subject of debate. We aim to determine the effect of positive microbiological testing on antimicrobial de-escalation and clinical outcomes in CAP. METHODS: A retrospective analysis of a prospectively collected cohort of non-immunosuppressed adults hospitalised with CAP was performed. The primary study outcome was antimicrobial de-escalation. Secondary outcomes included 30-day case-fatality rate, adverse events, and CAP recurrence. Adjustment for confounders was performed by inverse probability weighting propensity score, logistic regression, and cause-specific Cox model. RESULTS: Of 3677 patients with CAP, 1924 (52.3%) had any positive microbiological test. Antimicrobial de-escalation was performed in 648/1924 (33.7%) of patients with positive microbiological testing and in 179/1753 (10.2%) of those with non-positive results. When propensity score was entered into the multivariate analysis, positive microbiological testing (adjusted OR (AOR)], 2.59; 1.96-3.41) and clinical stability at day 3 (AOR 1.87; 1.45-2.10) were two of the main factors independently associated with antimicrobial de-escalation. After applying an adjusted cause-specific Cox model, antimicrobial de-escalation was not associated with a higher 30-day case-fatality rate (adjusted hazard ratio (AHR), 0.44 (95% CI, 0.14-1.43)), higher frequency of adverse events (AHR, 0.77 (95% CI, 0.53-1.12)), or CAP recurrence (AHR, 0.65 (95% CI, 0.35-1.14)). DISCUSSION: Antimicrobial de-escalation was more often performed in hospitalised patients with CAP who had positive microbiological tests than in those with non-positive results, and it did not adversely affect relevant clinical outcomes.

A comprehensive assessment of long-term SARS-CoV-2-specific adaptive immune memory in convalescent COVID-19 Solid Organ Transplant recipients.

Long-term adaptive immune memory has been reported among immunocompetent individuals up to eight months following SARS-CoV-2 infection. However, limited data is available in convalescent patients with a solid organ transplant. To investigate this, we performed a thorough evaluation of adaptive immune memory at different compartments (serological, memory B cells and cytokine [IFN-γ, IL-2, IFN-γ/IL12 and IL-21] producing T cells) specific to SARS-CoV-2 by ELISA and FluoroSpot-based assays in 102 convalescent patients (53 with a solid organ transplants (38 kidney, 5 liver, 5 lung and 5 heart transplant) and 49 immunocompetent controls) with different clinical COVID-19 severity (severe, mild and asymptomatic) beyond six months after infection. While similar detectable memory responses at different immune compartments were detected between those with a solid organ transplant and immunocompetent individuals, these responses were predominantly driven by distinct COVID-19 clinical severities (97.6%, 80.5% and 42.1%, all significantly different, were seropositive; 84% vs 75% vs 35.7%, all significantly different, showed IgG-producing memory B cells and 82.5%, 86.9% and 31.6%, displayed IFN-γ producing T cells; in severe, mild and asymptomatic convalescent patients, respectively). Notably, patients with a solid organ transplant with longer time after transplantation did more likely show detectable long-lasting immune memory, regardless of COVID-19 severity. Thus, our study shows that patients with a solid organ transplant are capable of maintaining long-lasting peripheral immune memory after COVID-19 infection; mainly determined by the degree of infection severity.

Role of the inflammatory response in community-acquired pneumonia: clinical implications.

INTRODUCTION: Despite adequate antibiotic coverage, community-acquired pneumonia (CAP) remains a leading cause of hospitalization and mortality worldwide. It induces both a local pulmonary and a systemic inflammatory response, particularly significant in severe cases. The intensity of the dysregulated host response varies from patient to patient and has a negative impact on survival and other outcomes. AREAS COVERED: This comprehensive review summarizes the pathophysiological aspects of the inflammatory response in CAP, briefly discusses the usefulness of biomarkers, and assesses the clinical evidence for modulating the inflammatory pathways. We searched PubMed for the most relevant studies, reviews, and meta-analysis until August 2020. EXPERT OPINION: Notable efforts have been made to identify biomarkers that can accurately differentiate between viral and bacterial etiology, and indeed, to enhance risk stratification in CAP. However, none has proven ideal and no recommended biomarker-guided algorithms exist. Biomarker signatures from proteomic and metabolomic studies could be more useful for such assessments. To date, most studies have produced contradictory results concerning the role of immunomodulatory agents (e.g. corticosteroids, macrolides, and statins) in CAP. Adequately identifying the population who may benefit most from effective modulation of the inflammatory response remains a challenge.

Immunomodulatory therapy, risk factors and outcomes of hospital-acquired bloodstream infection in patients with severe COVID-19 pneumonia: a Spanish case-control matched multicentre study (BACTCOVID).

OBJECTIVES: The effect of the use of immunomodulatory drugs on the risk of developing hospital-acquired bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We aim to identify risk factors for, and outcomes of, BSI among hospitalized patients with severe COVID-19 pneumonia. METHODS: We performed a severity matched case-control study (1:1 ratio) nested in a large multicentre prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from the cohort database. Controls were matched for age, sex and acute respiratory distress syndrome. A Cox proportional hazard ratio model was performed. RESULTS: Of 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-negative staphylococci, Enterococcus faecalis and Pseudomonas aeruginosa. Polymicrobial infection accounted for 23 episodes. The median time from admission to the first episode of BSI was 15 days (IQR 9-20), and the most frequent source was catheter-related infection. The characteristics of patients with and without BSI were similar, including the use of tocilizumab, corticosteroids, and combinations. In the multivariate analysis, the use of these immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional hazard ratio (HR) model showed that after adjusting for the time factor, BSI was associated with a higher in-hospital mortality risk (HR 2.59; 1.65-4.07; p < 0.001). DISCUSSION: Hospital-acquired BSI in patients with severe COVID-19 pneumonia was uncommon and the use of immunomodulatory drugs was not associated with its development. When adjusting for the time factor, BSI was associated with a higher mortality risk.

Immunological imprinting of the antibody response in COVID-19 patients.

In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection.

Host- and Pathogen-Related Factors for Acute Cardiac Events in Pneumococcal Pneumonia.

BACKGROUND: Acute cardiac events (ACEs) are increasingly being recognized as a major complication in pneumococcal community-acquired pneumonia (CAP). Information regarding host- and pathogen-related factors for ACEs, including pneumococcal serotypes and clonal complexes, is scarce. METHODS: A retrospective study was conducted of a prospective cohort of patients hospitalized for CAP between 1996 and 2019. Logistic regression and funnel plot analyses were performed to determine host- and pathogen-related factors for ACEs. RESULTS: Of 1739 episodes of pneumococcal CAP, 1 or more ACEs occurred in 304 (17.5%) patients, the most frequent being arrhythmia (n = 207), heart failure (n = 135), and myocardial infarction (n = 23). The majority of ACEs (73.4%) occurred within 48 hours of admission. Factors independently associated with ACEs were older age, preexisting heart conditions, pneumococcal bacteremia, septic shock at admission, and high-risk pneumonia. Among 983 pneumococcal isolates, 872 (88.7%) were serotyped and 742 (75.5%) genotyped. The funnel plot analyses did not find any statistically significant association between serotypes or clonal complexes with ACEs. Nevertheless, there was a trend toward an association between CC230 and these complications. ACEs were independently associated with 30-day mortality (adjusted odds ratio, 1.88; 95% CI, 1.11-3.13). CONCLUSIONS: ACEs are frequent in pneumococcal pneumonia and are associated with increased mortality. The risk factors defined in this study may help identify patients who must undergo close follow-up, including heart rhythm monitoring, and special care to avoid fluid overload, particularly during the first 48 hours of admission. These high-risk patients should be the target for preventive intervention strategies.

Effect of albumin administration on outcomes in hypoalbuminemic patients hospitalized with community-acquired pneumonia (ALBUCAP): a prospective, randomized, phase III clinical controlled trial-a trial protocol.

BACKGROUND: Community-acquired pneumonia (CAP) remains a leading cause of death worldwide, and hypoalbuminemia is associated with worse outcomes. However, it remains uncertain whether albumin administration could have any beneficial effects. We aim to assess whether the administration of albumin in hypoalbuminemic patients with CAP increases the proportion of clinically stable patients at day 5 compared with the standard of care alone. METHODS: This is a trial protocol for a superiority, non-blinded, multicenter, randomized, phase 3, interventional controlled clinical trial. The primary endpoint will be the proportion of clinical stable patients at day 5 (intention to treat), defined as those with stable vital signs for at least 24 h. The secondary endpoints will be time to clinical stability, duration of intravenous and total antibiotic treatment, length of hospital stay, intensive care unit admission, duration of mechanical ventilation and vasopressor treatment, adverse events, readmission within 30 days, and all-cause mortality. The trial has been approved by the Spanish Medicines and Healthcare Products Regulatory Agency. The investigators commit to publish the data in peer-reviewed journals within a year of the study completion date. Subjects will be recruited from three Spanish hospitals over a planned enrolment period of 2 years. A follow-up visit will be performed 1 month after discharge. We have estimated the need for a sample size of 360 patients at a two-sided 5% alpha-level with a power of 80% based on intention to treat. Eligible participants must be hospitalized, hypoalbuminemic (≤ 30 g/L), non-immunosuppressed, adults, and diagnosed with CAP. They will be randomly assigned (1:1) to receive standard care plus albumin (20 g in 100 mL) every 12 h for 4 days or standard care alone. DISCUSSION: If this randomized trial confirms the hypothesis, it should lead to a change in current clinical practice for the management of hypoalbuminemic patients with CAP. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT) 2018-003117-18 . Registered on 12 April 2019. ClinicalTrials.gov NCT04071041 . Registered on 27 August 2019.

Impact of comprehensive molecular testing to reduce antibiotic use in community-acquired pneumonia (RADICAP): a randomised, controlled, phase IV clinical trial protocol.

INTRODUCTION: Community-acquired pneumonia (CAP) continues to be a major health problem worldwide and is one of the main reasons for prescribing antibiotics. However, the causative agent is often not identified, resulting in antibiotic overtreatment, which is a key driver of antimicrobial resistance and adverse events. We aim to test the hypothesis that comprehensive molecular testing, compared with routine microbiological testing, would be effective in reducing antibiotic use in patients with CAP. METHODS AND ANALYSIS: We will perform a randomised, controlled, open-label clinical trial with two parallel groups (1:1) at two tertiary hospitals between 2020 and 2022. Non-severely immunosuppressed adults hospitalised for CAP will be considered eligible. Patients will be randomly assigned to receive either the experimental diagnosis (comprehensive molecular testing plus routine microbiological testing) or standard diagnosis (only microbiological routine testing). The primary endpoint will be antibiotic consumption measured as days of antibiotic therapy per 1000 patient-days. Secondary endpoints will be de-escalation to narrower antibiotic treatment, time to switch from intravenous to oral antibiotics, days to reaching an aetiological diagnosis, antibiotic-related side effects, length of stay, days to clinical stability, intensive care unit admission, days of mechanical ventilation, hospital readmission up to 30 days after randomisation and death from any cause by 48 hours and 30 days after randomisation. We will need to include 440 subjects to be able to reject the null hypothesis that both groups have equal days of antibiotic therapy per 1000 patient-days with a probability >0.8. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Bellvitge Hospital (AC028/19) and from the Spanish Medicines and Medical Devices Agency, and it is valid for all participating centres under existing Spanish legislation. Results will be presented at international meetings and will be made available to patients, their caregivers and funders. TRIAL REGISTRATION NUMBER: ClinicalTrials: NCT04158492. EudraCT: 2018-004880-29.