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.

An Ocean between the Waves: Trends in Antimicrobial Consumption in Hospitalized Patients with COVID-19.

We assessed the antibiotic use in SARS-CoV-2-infected patients during four different waves of the COVID-19 pandemic, as well as its trends over the period and associated risk factors. We performed a cross-sectional retrospective analysis nested in a prospectively collected cohort of hospitalized adult patients with COVID-19 at a university hospital in Spain. A total of 2415 patients were included in this study, among whom 1120 corresponded to the first wave. The highest percentage of patients receiving some sort of antibiotic treatment was higher during the first wave (77.6%) than during the others; nevertheless, our calculation of the average DOT (days of antibiotic treatment) per 100 patient days of stay found that the highest antibiotic prescription rate corresponded to the second pandemic wave (61.61 DOT/100 patient days), which was associated with a higher ICU admission rate and a lower SpO2/FiO2 ratio at admission. After the second wave, the prescription rates presented a steady downward trend. With regard to the use of specific antibiotic families, amoxicillin/clavulanate was the most used antibiotic in our cohort (14.20 DOT/100 patient days) due to a high prescription rate during the first wave. According to the "AWaRe" WHO classification, antibiotics corresponding to the "Watch" group were the most prescribed (27.92 DOT/100 patient days). The antibiotic use rate fell progressively, but it remained high during all four waves analyzed. In conclusion, antibiotic use was high throughout all the waves that were analyzed, despite a relatively low incidence of bacterial coinfection and superinfection. Efforts should be made to keep antimicrobial stewardship programs active, especially in complicated epidemiological situations, such as the SARS-CoV-2 pandemic.

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.

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.

Autoantibodies against type I IFNs in patients with critical influenza pneumonia.

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.

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.

Epidemiología y frecuencia de enfermedades de transmisión sexual y su repercusión en la mucosa bucal: una revisión narrativa / Epidemiology and frequency of sexually transmitted diseases and their impact on oral mucosa: a narrative review

El objetivo de la presente revisión fue analizar y compa- rar las publicaciones sobre la prevalencia de manifestaciones bucales de pacientes infectados por el Virus de la Inmuno- deficiencia Humana, Virus del Papiloma Humano y sífilis. Se seleccionaron los artículos más relevantes y se abordó la incidencia según sexo, edad, distribución geográfica y locali- zaciones anatómicas frecuentes. Se encontró que las lesiones orales más prevalentes producidas por el Virus de la Inmu- nodeficiencia Humana son la candidiasis oral, la leucoplasia vellosa y enfermedades periodontales, entre otras. La sífilis presentó una frecuencia de 7,5% de manifestaciones orales en la etapa primaria, 92,5% en la secundaria y rara vez lesio- nes en la terciaria. Las formas más prevalentes fueron parches mucosos, pápulas y úlceras. Las lesiones orales benignas rela- cionadas con el Virus del Papiloma Humano halladas fueron la verruga vulgar, el papiloma plano, el condiloma acuminado y la hiperplasia epitelial focal. La prevalencia de carcinomas orofaríngeos y orales fue del 33,6% y del 22,2% respectiva- mente. Se encontraron similitudes en el comportamiento se- xual y las vías de transmisión de las enfermedades analizadas, y se observó que son más prevalentes en adultos jóvenes de sexo masculino y en países en vías de desarrollo (AU)

The aim of this review was to analyze and compare pub- lications on the prevalence of oral manifestations in patients infected with Human Immunodeficiency Virus, Human Pap- illoma Virus and syphilis. The most reliable studies were se- lected, and incidence was evaluated according to gender, age, geographic location and frequent anatomic sites. It was found that the most prevalent Human Immunodeficiency Virus oral lesions were oral candidiasis, hairy leukoplakia and perio- dontal diseases, among others. Syphilis had a 7.5% preva- lence of oral manifestations in the primary stage, 92.5% in the secondary, and rarely lesions in the tertiary. The most prevalent forms were mucous patches, papules and ulcers. The benign oral lesions related to the Human Papilloma Vi- rus were verruca vulgaris, squamous papilloma, condyloma acuminatum and multifocal epithelial hyperplasia. The preva- lence of oropharyngeal and oral carcinomas were 33.6% and 22.2%, respectively. Similarities were found in sexual behavior and transmis- sion routes of the diseases analyzed, which were more preva- lent among young adult males, and in developing countries (AU)

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.

Gene expression of Candida albicans strains isolates from patients with denture stomatitis submitted to treatments with photodynamic therapy and nystatin.

The study evaluated the effect of antimicrobial photodynamic therapy (aPDT) and nystatin (NYS) in the expression of genes (ACT1, ALS1, CAP1, CAT1, EFG1, HWP1, LIP3, PLB1, SAP1, and SOD1) involved in the virulence of Candida albicans strains recovered from patients with denture stomatitis (DS). These strains were isolated from the patients before (initial) and after treatment (final), and 45 days after the treatments (follow-up). For gene expression analyses, RNA was isolated from the clinical strains, followed by cDNA synthesis and qPCR using specific primers for each target gene. The samples that present integrity were pooled to increase the RNA yield. In the end, four patients treated with aPDT and five patients treated with NYS had the clinical isolates of C. albicans submitted to gene expression evaluation. The data demonstrated a statistical difference in the expression of PLB1 and ACT1 for the different therapies (aPDT versus NYS). Also, there was a statistical difference in the expression of CAT1, SOD1, and LIP3 at the time intervals assessed (initial, final, and follow-up). In contrast, no statistical difference was found in the expression of ALS1, HWP1, EFG1, CAP1, CAT1, SOD1, LIP3, and SAP1 between the therapies, while no significant difference was detected at the time intervals evaluated for ALS1, HWP1, EFG1, CAP1, and SAP1. Therefore, the topical treatments for DS with aPDT or NYS did not effect the expression of most C. albicans virulence genes evaluated.

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.

A randomized clinical trial evaluating Photodithazine-mediated Antimicrobial Photodynamic Therapy as a treatment for Denture stomatitis.

OBJECTIVE: This randomized clinical trial assessed antimicrobial Photodynamic Therapy (aPDT) mediated by Photodithazine (PDZ) to treat patients with denture stomatitis (DS). METHODOLOGIES: Patients with DS were randomly assigned to the groups: aPDT (n = 30) and nystatin (NYS, n = 35). aPDT patients received 6 aPDT sessions, three times a week for 15 days, which involved PDZ (200 mg/L) topical application (20 min) on the palate and upper denture, followed by LED illumination (660 nm, 50 J/cm²). NYS patients were instructed to rinse one dropper of this medication for one minute, four times a day, for 15 days. Microbiological collections of dentures and palates were performed and cultured on blood agar and CHROMAgar Candida. Microbial viability was determined, and photographs of the palates were taken for clinical evaluation. Data were analyzed by Repeated Measure Linear Model and Bonferroni (p ≤ 0.05). RESULTS: aPDT was more effective to reduce the total microbiota than NYS. At the end of the treatments, aPDT reduced 1.98 from the palate and 1.91 log10 from the denture, while NYS reduced 0.05 and 0.17 log10, respectively. Moreover, aPDT was as effective as NYS to reduce Candida. Reductions of 0.68 and 0.77 log10 were observed in the palate and denture of aPDT group, while reductions of 0.57 and 1.43 log10 were achieved in the NYS group, respectively. Regarding to oral lesion, 53.3 and 54.2 % of the patients from aPDT and NYS groups had clinical improvement. However, the recurrence of DS was observed in both groups. CONCLUSION: PDZ-mediated aPDT is a promising treatment for DS.

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.