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To evaluate Red blood cell distribution width (RDW) as a sepsis prognostic biomarker. 203 septic patients admitted to the ICU. Analysis of RDW dynamics, hospital mortality discrimination ability and the added value when incorporated to the SOFA, LODS, SAPS-II and APACHE-II scores using the AUC-ROC. Non-survivors presented higher RDW values during the first week after ICU admission (p = 0.048). Only SOFA and RDW were independently associated with mortality when adjusted by Charlson, immunosuppression, nosocomial infection, NEWS2, SAPS-II, septic shock and haemoglobin (p < 0.05). After adjustment, AUC-ROC was 0.827, 0.822, 0.824, 0.834 and 0.812 for each model including admission, 24, 48 and 72-h and 7-days RDW, respectively. When added to the scores, 24-h RDW and admission RDW improved their discrimination ability (SOFA AUC-ROC = 0.772 vs 0.812 SOFA + admission RDW, p = 0.041; LODS AUC-ROC = 0.687 vs 0.710, p = 0.002; SAPS-II AUC-ROC = 0.734 vs 0.785, p = 0.021; APACHE-II AUC-ROC = 0.672 vs 0.755, p = 0.003). Admission RDW with SOFA presented the better discrimination ability for mortality. RDW is an independent prognostic marker of death in septic patients admitted in the ICU that improves SOFA, LODS, APACHE-II and SAPS-II discrimination ability. This parameter could be incorporated to the prognostic scores as a marker of systemic dysfunction and dysregulated inflammatory response. •During the first week after ICU admission, non-survivors septic patients presented higher RDW.•Along with SOFA, RDW was the only independently factor associated with mortality after adjustment.•When added to the prognostic scores, 24-hoursh RDW and mostly admission RDW improved their discrimination ability.•RDW is an available parameter that reflects the dysregulated inflammatory response and systemic dysfunction.

Enterococcus faecalis infective endocarditis (EFIE) is a severe disease of increasing incidence. The objective was to analyze whether the outcome of patients with native valve EFIE (NVEFIE) treated with a short course of ampicillin plus ceftriaxone (4wAC) was similar to patients treated according to international guidelines (6wAC). Between January 2008 and June 2018, 1,978 consecutive patients with definite native valve IE were prospectively included in a national registry. Outcomes of patients with NVEFIE treated with 4wAC were compared to those of patients who received 6wAC. Three hundred and twenty-two patients (16.3%) had NVEFIE. One hundred and eighty-three (56.8%) received AC. Thirty-nine patients (21.3%) were treated with 4wAC for four weeks and 70 patients (38.3%) with 6wAC. There were no differences in age or comorbidity. Patients treated 6wAC presented a longer duration of symptoms before diagnosis (21 days, IQR 7-60 days vs. 7 days, IQR 1-22 days; p = 0.002). Six patients presented perivalvular abscess and all of these received 6wAC. Surgery was performed on 14 patients (35.9%) 4wAC and 34 patients (48.6%) 6wAC (p = 0.201). In-hospital mortality, one-year mortality and relapses among 4wAC and 6wAC patients were 10.3% vs. 11.4% (p = 0.851); 17.9% vs. 21.4% (p = 0.682) and 5.1% vs. 4.3% (p = 0.833), respectively. In conclusion, a four-week course of AC may be considered as an alternative regimen in NVEFIE, notably in patients with shorter duration of symptoms and those without perivalvular abscess. These results support the performance of a randomized clinical trial to evaluate the efficacy of this short regimen.

Severely ill COVID-19 patients are at high risk of nosocomial infections. The aim of the study was to describe the characteristics of candidemia during the pre-pandemic period (January 2019–February 2020) compared to the pandemic period (March 2020–September 2021). Antifungal susceptibilities were assessed using the EUCAST E.Def 7.3.2 broth dilution method. Fluconazole-resistant C. parapsilosis isolates (FRCP) were studied for sequencing of the ERG11 gene. The incidence of candidemia and C. parapsilosis bloodstream infection increased significantly in the pandemic period (p = 0.021). ICU admission, mechanical ventilation, parenteral nutrition and corticosteroids administration were more frequent in patients with candidemia who had been admitted due to COVID-19. Fifteen cases of FRCP fungemia were detected. The first case was recorded 10 months before the pandemic in a patient transferred from another hospital. The incidence of FRCP in patients admitted for COVID-19 was 1.34 and 0.16 in all other patients (p < 0.001). ICU admission, previous Candida spp. colonization, arterial catheter use, parenteral nutrition and renal function replacement therapy were more frequent in patients with candidemia due to FRCP. All FRCP isolates showed the Y132F mutation. In conclusion, the incidence of candidemia experienced an increase during the COVID-19 pandemic and FRCP fungemia was more frequent in patients admitted due to COVID-19.

To describe the impact of different doses of corticosteroids on the evolution of patients with COVID-19 pneumonia, based on the potential benefit of the non-genomic mechanism of these drugs at higher doses. Observational study using data collected from the SEMI-COVID-19 Registry. We evaluated the epidemiological, radiological and analytical scenario between patients treated with megadoses therapy of corticosteroids vs low-dose of corticosteroids and the development of complications. The primary endpoint was all-cause in-hospital mortality according to use of corticosteroids megadoses. Of a total of 14,921 patients, corticosteroids were used in 5,262 (35.3%). Of them, 2,216 (46%) specifically received megadoses. Age was a factor that differed between those who received megadoses therapy versus those who did not in a significant manner (69 years [IQR 59-79] vs 73 years [IQR 61-83]; p < .001). Radiological and analytical findings showed a higher use of megadoses therapy among patients with an interstitial infiltrate and elevated inflammatory markers associated with COVID-19. In the univariate study it appears that steroid use is associated with increased mortality (OR 2.07 95% CI 1.91-2.24 p < .001) and megadose use with increased survival (OR 0.84 95% CI 0.75-0.96, p 0.011), but when adjusting for possible confounding factors, it is observed that the use of megadoses is also associated with higher mortality (OR 1.54, 95% CI 1.32-1.80; p < .001). There is no difference between megadoses and low-dose (p .298). Although, there are differences in the use of megadoses versus low-dose in terms of complications, mainly infectious, with fewer pneumonias and sepsis in the megadoses group (OR 0.82 95% CI 0.71-0.95; p < .001 and OR 0.80 95% CI 0.65-0.97; p < .001) respectively. There is no difference in mortality with megadoses versus low-dose, but there is a lower incidence of infectious complications with glucocorticoid megadoses.

In this international multicenter study, we aimed to determine the independent risk factors associated with increased 30 day mortality and the impact of cancer and novel treatment modalities in a large group of patients with and without cancer with COVID-19 from multiple countries. We retrospectively collected de-identified data on a cohort of patients with and without cancer diagnosed with COVID-19 between January and November 2020 from 16 international centers. We analyzed 3966 COVID-19 confirmed patients, 1115 with cancer and 2851 without cancer patients. Patients with cancer were more likely to be pancytopenic and have a smoking history, pulmonary disorders, hypertension, diabetes mellitus, and corticosteroid use in the preceding 2 wk (p≤0.01). In addition, they were more likely to present with higher inflammatory biomarkers (D-dimer, ferritin, and procalcitonin) but were less likely to present with clinical symptoms (p≤0.01). By country-adjusted multivariable logistic regression analyses, cancer was not found to be an independent risk factor for 30 day mortality (p=0.18), whereas lymphopenia was independently associated with increased mortality in all patients and in patients with cancer. Older age (≥65y) was the strongest predictor of 30 day mortality in all patients (OR = 4.47, p<0.0001). Remdesivir was the only therapeutic agent independently associated with decreased 30 day mortality (OR = 0.64, p=0.036). Among patients on low-flow oxygen at admission, patients who received remdesivir had a lower 30 day mortality rate than those who did not (5.9 vs 17.6%; p=0.03). Increased 30 day all-cause mortality from COVID-19 was not independently associated with cancer but was independently associated with lymphopenia often observed in hematolgic malignancy. Remdesivir, particularly in patients with cancer receiving low-flow oxygen, can reduce 30 day all-cause mortality. National Cancer Institute and National Institutes of Health.

We aimed to evaluate the clinical outcome of Systemic Autoimmune Diseases (SADs) patients hospitalized with COVID-19 in Spain, before the introduction of SARS-CoV-2 vaccines. A nationwide, retrospective and observational analysis of the patients admitted during 2020, based on the ICD10 codes in the National Registry of Hospital Discharges, was performed. Among 117,694 patients, only 892 (0.8%) presented any type of SAD before COVID-19-related admission: Sjogren’s Syndrome constituted 25%, Systemic Vasculitides 21%, Systemic Lupus Erythematosus 19%, Sarcoidosis 17%, Systemic Sclerosis 11%, Mixed and Undifferentiated Connective Tissue Disease 4%, Behçet’s Disease 4% and Inflammatory Myopathies 2%. The in-hospital mortality rate was higher in SAD individuals (20% vs. 16%, p < 0.001). After adjustment by baseline conditions, SADs were not associated with a higher mortality risk (OR = 0.93, 95% CI 0.78–1.11). Mortality in the SADs patients was determined by age (OR = 1.05, 95% CI 1.04–1.07), heart failure (OR = 1.67, 95% CI 1.10–2.49), chronic kidney disease (OR = 1.29, 95% CI 1.05–1.59) and liver disease (OR = 1.97, 95% CI 1.13–3.44). In conclusion, the higher COVID-19 mortality rate seen in SADs patients hospitalized in Spain in 2020 was related to the higher burden of comorbidities, secondary to direct organ damage and sequelae of their condition. Whilst further studies should evaluate the impact of baseline immunosuppression on COVID-19 outcomes in this population, efforts should be focused on the optimal management of SAD to minimize the impact of the organ damage that has been shown to determine COVID-19 prognosis.

Background. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) infection elicits inflammatory manifestations that relate with a “cytokine storm.” Objective. The aim of this research was to assess the role of circulating interleukin 6 (IL-6) levels and other inflammatory markers in patients with coronavirus disease 2019 (COVID-19) on metabolic functions and accompanying clinical complications. Patients and Methods. A total of 165 patients diagnosed with COVID-19 pneumonia were examined for medical features and inflammatory markers such as blood IL-6, CRP, ferritin, LDH, neutrophil/lymphocyte index (NLI), D-Dimer, and Red Cell Distribution Width (RDW). Regression analyses concerning electronically collected medical data were adjusted by appropriate factors and confounding variables. Results. Plasma IL-6 determinations evidenced a consistent association with hospital stay days, Intensive Care Unit (ICU) admission, and mortality rates. Similar trends were found for other proinflammatory variables, where ferritin and NLI showed a remarkable value as surrogates. Hyperglycaemia and the Charlson Comorbidity Index Score were positively associated with the inflammatory response induced by the SARS-COV-2 infection. An unhealthy lifestyle such as smoking and alcoholic drinks consumption as well as excessive body adiposity influenced inflammatory-related outcomes in the screened patients. Conclusion. IL-6 together with other inflammatory biomarkers accompanied poor clinical and metabolic outcomes in COVID-19-infected patients. IL-6 may result in a suitable proxy to individually categorise patients in order to manage this infectious pandemic.

Objectives In some patients, acute, life-threatening respiratory injury produced by viruses such as SARS-CoV and other viral pneumonia are associated with an over-exuberant cytokine release. Elevated levels of blood IL-6 had been identified as a one of the risk factors associated with severe COVID-19 disease. Anti-IL6 inhibitors are among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. At present, their use is prioritized to patients with severe interstitial pneumonia (Brescia-COVID Scale-COVID 2-3) with hyperinflammation as determined by the presence of elevated IL6 and/or d-dimer, or progressive d-dimer increase, in patients who otherwise are subsidiary to ICU admission. However, many uncertainties remain on the actual role of anti-IL6 inhibitors in this setting, and whether current use and timing is the right one. There is the hypothesis that the use of anti-IL6 inhibitors at an earlier state during the hyperinflammatory syndrome would be beneficial and may avoid progressing to ARDS. On the other hand, the standard of care has changed and nowadays the use of corticosteroids has become part of the SOC in the treatment of COVID-19 pneumonia. Our limited experience suggests that better treatment outcomes can be achieved when combining IL6-inhibitors (e.g. sarilumab) with corticosteroids. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. This study will also provide supportive evidence to that provided by currently ongoing studies on the efficacy and safety of sarilumab in this clinical context. Trial design A phase two multi-center randomised controlled trial (RCT) with two parallel arms (1:1 ratio). Participants They will be hospitalized patients, of at least 18 years of age, with severe COVID-19 who have positive RT-PCR test and have radiographic evidence of pulmonary infiltrates by imaging or rales/crackles on exam and SpO2 ≤ 94% on room air that requires supplemental oxygen. Patients must present elevation of inflammatory parameters (IL-6 > 40 pg/mL or d-dimer >1.0 mcg/ml) or, alternatively, progressive worsening in at least two of these inflammatory parameters in the prior 24-48h: CRP, LDH, serum ferritin, lymphopenia, or d-dimer. Exclusion criteria: high oxygen requirements (including face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula, or mechanical ventilation), admission to ICU, pregnancy or lactation, allergy or hypersensitivity to sarilumab or corticoesteroids, immunosuppressive antibody therapy within the past 5 months, AST/ALT values > 10 x ULN, neutropenia (< 0.5 x 109/L), severe thrombocytopenia (< 50 x 109/L), sepsis caused by an alternative pathogen, diverticulitis with risk of perforation or ongoing infectious dermatitis. The study will be conducted in several hospitals in Spain. Intervention and comparator Patients randomised to the experimental arm will receive sarilumab + methylprednisolone plus SOC for COVID-19. Patients included in the control arm will receive methylprednisolone plus SOC for COVID-19. Corticosteroids will be given to all patients at a 1mg/kg/d of methylprednisolone for at least 3 days. Clinical follow-up visits will be performed at 3, 5, and 15 days after treatment randomization. Patients in the control group (SOC group without sarilumab) progressing to Brescia- COVID 2-3 plus inflammatory markers, will be given the option to be rescued with sarilumab at the same doses and, in that case, be included in an open-label phase and be followed up for additional weeks (with visits at 3, 7 and 15 days after sarilumab rescue administration). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia-COVID 2-3 will be rescued according to local clinical practice protocols. A final follow-up visit will be conducted for all patients at day 29 from randomization, regardless of initial treatment assignment. Main outcomes Primary end point is the proportion of patients progressing to either severe respiratory failure (Brescia-COVID ≥2), ICU admission, or death. Randomization Randomization codes were produced by means of the PROC PLAN of the SAS system, with a 1:1 assignment ratio, stratifying by centre and using blocks multiple of 2 elements. The randomization schedule will be managed through the eCRF in a concealed manner. Blinding (masking) All study drugs will be administered as open label. No blinding methods will be used in this trial. Numbers to be randomised (simple size) The target sample size will be 200 COVID-19 patients, who will be allocated randomly to control arm (100) and treatment arm (100). Trial status Protocol Code: SARTRE Protocol Date: May 05th 2020. Version: 2.0 The study has been approved by the Spanish Competent Authority (AEMPS) as a low intervention clinical trial. Start of recruitment: August, 2020 End of recruitment: May, 2021 Trial registration Identifier: EudraCT Number: 2020-002037-15 ; Registration date: 26 May 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2 ).

Valganciclovir (VGCV) and ganciclovir (GCV) doses must be adjusted according to indication, renal function and weight. No specific therapeutic exposure values have been established. We aimed to evaluate the adequacy of VGCV/GCV doses, to assess the interpatient variability in GCV serum levels, to identify predictive factors for this variability and to assess the clinical impact. This is a prospective study at a tertiary institution including hospitalized patients receiving VGCV/GCV prophylaxis or treatment. Adequacy of the antiviral dose was defined according to cytomegalovirus guidelines. Serum levels were determined using High-Performance Liquid Chromatography. Blood samples were drawn at least 3 days after antiviral initiation. Outcome was considered favorable if there was no evidence of cytomegalovirus infection during prophylaxis or when a clinical and microbiological resolution was attained within 21 days of treatment and no need for drug discontinuation due to toxicity. Seventy consecutive patients [74.3% male/median age: 59.2 years] were included. VGCV was used in 25 patients (35.7%) and GCV in 45 (64.3%). VGCV/GCV initial dosage was deemed adequate in 47/70 cases (67.1%), lower than recommended in 7/70 (10%) and higher in 16/70 (22.9%). Large inter-individual variability of serum levels was observed, with median trough levels of 2.3 mg/L and median peak levels of 7.8 mg/L. Inadequate dosing of VGCV/GCV and peak levels lower than 8.37 or greater than 11.86 mg/L were related to poor outcome. Further studies must be performed to confirm these results and to conclusively establish if VGCV/GCV therapeutic drug monitoring could be useful to improve outcomes in specific clinical situations.

Background COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions. It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia. Methods/design The ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The study has been planned to include 278 adult patients hospitalized with severe COVID-19 infection not requiring mechanical ventilation (invasive or non-invasive). Subjects are randomly assigned in a 1:1 ratio (139 per treatment arm), stratified by center, to receive intravenously administered CP (single infusion) plus SOC or SOC alone, and are to be followed for 30 days. The primary endpoint of the study is the proportion of patients that progress to category 5, 6, or 7 (on the 7-point ordinal scale proposed by the WHO) at day 15. Interim analyses for efficacy and/or futility will be conducted once 20%, 40%, and 60% of the planned sample size are enrolled and complete D15 assessment. Discussion This clinical trial is designed to evaluate the efficacy and safety of passive immunotherapy with convalescent plasma for the treatment of adult patients hospitalized with COVID-19. The results of this study are expected to contribute to establishing the potential place of CP in the therapeutics for a new viral disease. Trial registration ClinicalTrials.gov NCT04345523 . Registered on 30 March, 2020. First posted date: April 14, 2020.