Excretion and viability of SARS-CoV-2 in feces and its association with the clinical outcome of COVID-19.

The main objective was to evaluate the viability of the SARS-CoV-2 viral particles excreted in stools. In addition, we aimed to identify clinical factors associated with the detection of SARS-CoV-2 RNA in feces, and to determine if its presence is associated with an unfavorable clinical outcome, defined as intensive care unit (ICU) admission and/or death. A prospective multicenter cohort study of COVID-19 adult patients, with confirmed SARS-CoV-2 infection by RT-PCR assay in nasopharyngeal (NP) swabs admitted to four hospitals in Spain, from March 2020 to February 2021. Sixty-two adult COVID-19 patients had stool samples collected at admission and/or during the follow up, with a total of 79 stool samples. SARS-CoV-2 RNA was detected in stool samples from 27 (43.5%) out of the 62 patients. Replicative virus, measured by the generation of cytopathic effect in cell culture and subsequent RT-PCR confirmation of a decrease in the Ct values, was not found in any of these stool samples. Fecal virus excretion was not associated with the presence of gastrointestinal symptoms, or with differences in the evolution of COVID-19 patients. Our results suggest that SARS-CoV-2 replicative capacity is null or very limited in stool samples, and thus, the fecal-oral transmission of SARS-CoV-2 as an alternative infection route is highly unlikely. In our study, the detection of SARS-CoV-2 RNA in feces at the beginning of the disease is not associated with any clinical factor nor with an unfavorable clinical outcome.

Impact of early interferon-ß treatment on the prognosis of patients with COVID-19 in the first wave: A post hoc analysis from a multicenter cohort.

BACKGROUND: Interferon-ß is an attractive drug for repurposing and use in the treatment of COVID-19, based on its in vitro antiviral activity and the encouraging results from clinical trials. The aim of this study was to analyze the impact of early interferon-ß treatment in patients admitted with COVID-19 during the first wave of the pandemic. METHODS: This post hoc analysis of a COVID-19@Spain multicenter cohort included 3808 consecutive adult patients hospitalized with COVID-19 from 1 January to 17 March 2020. The primary endpoint was 30-day all-cause mortality, and the main exposure of interest was subcutaneous administration of interferon-ß, defined as early if started ≤ 3 days from admission. Multivariate logistic and Cox regression analyses were conducted to identify the associations of different variables with receiving early interferon-ß therapy and to assess its impact on 30-day mortality. A propensity score was calculated and used to both control for confounders and perform a matched cohort analysis. RESULTS: Overall, 683 patients (17.9%) received early interferon-ß therapy. These patients were more severely ill. Adjusted HR for mortality with early interferon-ß was 1.03 (95% CI, 0.82-1.30) in the overall cohort, 0.96 (0.82-1.13) in the PS-matched subcohort, and 0.89 (0.60-1.32) when interferon-ß treatment was analyzed as a time-dependent variable. CONCLUSIONS: In this multicenter cohort of admitted COVID-19 patients, receiving early interferon-ß therapy after hospital admission did not show an association with lower mortality. Whether interferon-ß might be useful in the earlier stages of the disease or specific subgroups of patients requires further research.

Impact of the COVID-19 Pandemic on Survival in the Patients With the Intra-Abdominal Infections.

Objective: To analyze the availability and access to the hospital for the patients with intra-abdominal infections (IAIs) by Escherichia coli (E. coli) as a result of the coronavirus disease 2019 (COVID-19) pandemic and the impact of these changes in the diagnosis and their effects on the death of these patients. Methods: Two prospective observational cohorts of the patients with IAI by E. coli were conducted in 2016 (the pre-COVID-19, n = 108) and in 2020 (during the COVID-19, n = 96) at the University Hospital of Seville, Spain. The demographic and clinical variables of the patients were collected and analyzed. The patients were followed-up for 120 days, until the hospital discharge or death. The bivariate and multivariate analyses were performed. Results: Both the cohorts were homogeneous according to age, sex, emergency surgery cause, immunosuppression, neutropenia, acquisition type, and previous intervention. The patients attended during the COVID-19 had significantly higher Charlson comorbidity index and the more McCabe score, required more emergency surgery, had more severe infections with the higher rates of septic shock and sepsis, and the presence of additional care support such as a nasogastric tube. They were diagnosed later; the time intervals between the symptoms onset (SO) to the first medical contact or surgical intervention (SI) and between the first medical contact to the admission or SI were significantly higher. The death rates during the COVID-19 and the pre-COVID-19 were 16.7 and 6.5%, respectively (p = 0.02). Finally, the multivariate analysis in both the cohorts together identified the patients diagnosed during the COVID-19, the longer period from SO to SI, septic shock, and the Charlson comorbidity index as the independent factors associated with death. Conclusion: This study showed the impact of the COVID-19 pandemic on the clinical outcome and death due to IAI with an extension of the time between SO and SI.

SARS-CoV-2 viral load in nasopharyngeal swabs is not an independent predictor of unfavorable outcome.

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient's hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO2, neutrophils > 7.5 × 103/µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome.

Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study.

The aim was to analyze the characteristics and predictors of unfavorable outcomes in solid organ transplant recipients (SOTRs) with COVID-19. We conducted a prospective observational cohort study of 210 consecutive SOTRs hospitalized with COVID-19 in 12 Spanish centers from 21 February to 6 May 2020. Data pertaining to demographics, chronic underlying diseases, transplantation features, clinical, therapeutics, and complications were collected. The primary endpoint was a composite of intensive care unit (ICU) admission and/or death. Logistic regression analyses were performed to identify the factors associated with these unfavorable outcomes. Males accounted for 148 (70.5%) patients, the median age was 63 years, and 189 (90.0%) patients had pneumonia. Common symptoms were fever, cough, gastrointestinal disturbances, and dyspnea. The most used antiviral or host-targeted therapies included hydroxychloroquine 193/200 (96.5%), lopinavir/ritonavir 91/200 (45.5%), and tocilizumab 49/200 (24.5%). Thirty-seven (17.6%) patients required ICU admission, 12 (5.7%) suffered graft dysfunction, and 45 (21.4%) died. A shorter interval between transplantation and COVID-19 diagnosis had a negative impact on clinical prognosis. Four baseline features were identified as independent predictors of intensive care need or death: advanced age, high respiratory rate, lymphopenia, and elevated level of lactate dehydrogenase. In summary, this study presents comprehensive information on characteristics and complications of COVID-19 in hospitalized SOTRs and provides indicators available upon hospital admission for the identification of SOTRs at risk of critical disease or death, underlining the need for stringent preventative measures in the early post-transplant period.

Identification and validation of clinical phenotypes with prognostic implications in patients admitted to hospital with COVID-19: a multicentre cohort study.

BACKGROUND: The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality. METHODS: In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model. FINDINGS: Three distinct phenotypes were derived in the derivation cohort (n=2667)-phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])-and reproduced in the internal validation cohort (n=1368)-phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4-4·3) for patients with phenotype A, 30·5% (28·5-32·6) for patients with phenotype B, and 60·7% (53·7-67·2) for patients with phenotype C (log-rank test p<0·0001). The predicted phenotypes in the internal validation cohort and external validation cohort showed similar mortality rates to the assigned phenotypes (internal validation cohort: 5·3% [95% CI 3·4-8·1] for phenotype A, 31·3% [28·5-34·2] for phenotype B, and 59·5% [48·8-69·3] for phenotype C; external validation cohort: 3·7% [2·0-6·4] for phenotype A, 23·7% [21·8-25·7] for phenotype B, and 51·4% [41·9-60·7] for phenotype C). INTERPRETATION: Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated. FUNDING: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.

Development and validation of a prediction model for 30-day mortality in hospitalised patients with COVID-19: the COVID-19 SEIMC score.

OBJECTIVE: To develop and validate a prediction model of mortality in patients with COVID-19 attending hospital emergency rooms. DESIGN: Multivariable prognostic prediction model. SETTING: 127 Spanish hospitals. PARTICIPANTS: Derivation (DC) and external validation (VC) cohorts were obtained from multicentre and single-centre databases, including 4035 and 2126 patients with confirmed COVID-19, respectively. INTERVENTIONS: Prognostic variables were identified using multivariable logistic regression. MAIN OUTCOME MEASURES: 30-day mortality. RESULTS: Patients' characteristics in the DC and VC were median age 70 and 61 years, male sex 61.0% and 47.9%, median time from onset of symptoms to admission 5 and 8 days, and 30-day mortality 26.6% and 15.5%, respectively. Age, low age-adjusted saturation of oxygen, neutrophil-to-lymphocyte ratio, estimated glomerular filtration rate by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, dyspnoea and sex were the strongest predictors of mortality. Calibration and discrimination were satisfactory with an area under the receiver operating characteristic curve with a 95% CI for prediction of 30-day mortality of 0.822 (0.806-0.837) in the DC and 0.845 (0.819-0.870) in the VC. A simplified score system ranging from 0 to 30 to predict 30-day mortality was also developed. The risk was considered to be low with 0-2 points (0%-2.1%), moderate with 3-5 (4.7%-6.3%), high with 6-8 (10.6%-19.5%) and very high with 9-30 (27.7%-100%). CONCLUSIONS: A simple prediction score, based on readily available clinical and laboratory data, provides a useful tool to predict 30-day mortality probability with a high degree of accuracy among hospitalised patients with COVID-19.

Impact of the COVID-19 Pandemic on Antimicrobial Consumption and Hospital-Acquired Candidemia and Multidrug-Resistant Bloodstream Infections.

During the COVID-19 pandemic, the implementation of antimicrobial stewardship strategies has been recommended. This study aimed to assess the impact of the COVID-19 pandemic in a tertiary care Spanish hospital with an active ongoing antimicrobial stewardship programme (ASP). For a 20-week period, we weekly assessed antimicrobial consumption, incidence density, and crude death rate per 1000 occupied bed days of candidemia and multidrug-resistant (MDR) bacterial bloodstream infections (BSI). We conducted a segmented regression analysis of time series. Antimicrobial consumption increased +3.5% per week (p = 0.016) for six weeks after the national lockdown, followed by a sustained weekly reduction of -6.4% (p = 0.001). The global trend for the whole period was stable. The frequency of empirical treatment of patients with COVID-19 was 33.7%. No change in the global trend of incidence of hospital-acquired candidemia and MDR bacterial BSI was observed (+0.5% weekly; p = 0.816), nor differences in 14 and 30-day crude death rates (p = 0.653 and p = 0.732, respectively). Our work provides quantitative data about the pandemic effect on antimicrobial consumption and clinical outcomes in a centre with an active ongoing institutional and education-based ASP. However, assessing the long-term impact of the COVID-19 pandemic on antimicrobial resistance is required.

Characteristics and predictors of death among 4035 consecutively hospitalized patients with COVID-19 in Spain.

OBJECTIVES: To analyse the characteristics and predictors of death in hospitalized patients with coronavirus disease 2019 (COVID-19) in Spain. METHODS: A retrospective observational study was performed of the first consecutive patients hospitalized with COVID-19 confirmed by real-time PCR assay in 127 Spanish centres until 17 March 2020. The follow-up censoring date was 17 April 2020. We collected demographic, clinical, laboratory, treatment and complications data. The primary endpoint was all-cause mortality. Univariable and multivariable Cox regression analyses were performed to identify factors associated with death. RESULTS: Of the 4035 patients, male subjects accounted for 2433 (61.0%) of 3987, the median age was 70 years and 2539 (73.8%) of 3439 had one or more comorbidity. The most common symptoms were a history of fever, cough, malaise and dyspnoea. During hospitalization, 1255 (31.5%) of 3979 patients developed acute respiratory distress syndrome, 736 (18.5%) of 3988 were admitted to intensive care units and 619 (15.5%) of 3992 underwent mechanical ventilation. Virus- or host-targeted medications included lopinavir/ritonavir (2820/4005, 70.4%), hydroxychloroquine (2618/3995, 65.5%), interferon beta (1153/3950, 29.2%), corticosteroids (1109/3965, 28.0%) and tocilizumab (373/3951, 9.4%). Overall, 1131 (28%) of 4035 patients died. Mortality increased with age (85.6% occurring in older than 65 years). Seventeen factors were independently associated with an increased hazard of death, the strongest among them including advanced age, liver cirrhosis, low age-adjusted oxygen saturation, higher concentrations of C-reactive protein and lower estimated glomerular filtration rate. CONCLUSIONS: Our findings provide comprehensive information about characteristics and complications of severe COVID-19, and may help clinicians identify patients at a higher risk of death.

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19).

OBJECTIVES: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. METHODS: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). RESULTS: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). CONCLUSIONS: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situation.