Transcriptomic clustering of critically ill COVID-19 patients.

BACKGROUND: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit. METHODS: In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings. RESULTS: We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results. CONCLUSIONS: These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies.

Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

BACKGROUND: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. METHODS: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. RESULTS: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic. CONCLUSION: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

Deploying unsupervised clustering analysis to derive clinical phenotypes and risk factors associated with mortality risk in 2022 critically ill patients with COVID-19 in Spain.

BACKGROUND: The identification of factors associated with Intensive Care Unit (ICU) mortality and derived clinical phenotypes in COVID-19 patients could help for a more tailored approach to clinical decision-making that improves prognostic outcomes. METHODS: Prospective, multicenter, observational study of critically ill patients with confirmed COVID-19 disease and acute respiratory failure admitted from 63 ICUs in Spain. The objective was to utilize an unsupervised clustering analysis to derive clinical COVID-19 phenotypes and to analyze patient's factors associated with mortality risk. Patient features including demographics and clinical data at ICU admission were analyzed. Generalized linear models were used to determine ICU morality risk factors. The prognostic models were validated and their performance was measured using accuracy test, sensitivity, specificity and ROC curves. RESULTS: The database included a total of 2022 patients (mean age 64 [IQR 5-71] years, 1423 (70.4%) male, median APACHE II score (13 [IQR 10-17]) and SOFA score (5 [IQR 3-7]) points. The ICU mortality rate was 32.6%. Of the 3 derived phenotypes, the A (mild) phenotype (537; 26.7%) included older age (< 65 years), fewer abnormal laboratory values and less development of complications, B (moderate) phenotype (623, 30.8%) had similar characteristics of A phenotype but were more likely to present shock. The C (severe) phenotype was the most common (857; 42.5%) and was characterized by the interplay of older age (> 65 years), high severity of illness and a higher likelihood of development shock. Crude ICU mortality was 20.3%, 25% and 45.4% for A, B and C phenotype respectively. The ICU mortality risk factors and model performance differed between whole population and phenotype classifications. CONCLUSION: The presented machine learning model identified three clinical phenotypes that significantly correlated with host-response patterns and ICU mortality. Different risk factors across the whole population and clinical phenotypes were observed which may limit the application of a "one-size-fits-all" model in practice.

Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

BACKGROUND: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. METHODS: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. RESULTS: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). CONCLUSION: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Pneumatosis cystoides intestinalis: a rare cause of acute abdomen.

We present the case of an 87-year-old male with Parkinson's disease, admitted to the Emergency Room due to acute abdomen, without leukocytosis or neutrophilia, with PCR of 0.74 and lactate of 2.5. The emergency abdominal computed tomography (CT) scan showed a pneumoperitoneum and significant intestinal pneumatosis on the small bowel loops in the right abdomen. There was a 3.2 cm slight dilation, without portal venous gas and an adequate opacification of the superior mesenteric artery and its main branches. An emergency laparotomy was performed that showed subserosal cysts in the jejunum and ileum, with no signs of transmural perforation. The patient was discharged after a good postoperative evolution.

Antimicrobial management of Tropheryma whipplei endocarditis: the Spanish Collaboration on Endocarditis (GAMES) experience.

OBJECTIVES: Tropheryma whipplei has been detected in 3.5% of the blood culture-negative cases of endocarditis in Spain. Experience in the management of T. whipplei endocarditis is limited. Here we report the long-term outcome of the treatment of previously reported patients who were diagnosed with infective endocarditis (IE) caused by T. whipplei from the Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España (GAMES) and discuss potential options for antimicrobial therapy for IE caused by T. whipplei. PATIENTS AND METHODS: Seventeen patients with T. whipplei endocarditis were recruited between 2008 and 2014 in 25 Spanish hospitals. Patients were classified according to the therapeutic regimen: ceftriaxone and trimethoprim/sulfamethoxazole, doxycycline + hydroxychloroquine and other treatment options. RESULTS: Follow-up data were obtained from 14 patients. The median follow-up was 46.5 months. All patients completed the antibiotic treatment prescribed, with a median duration of 13 months. Six patients were treated with ceftriaxone and trimethoprim/sulfamethoxazole (median duration 13 months), four with doxycycline + hydroxychloroquine (median duration 13.8 months) and four with other treatment options (median duration 22.3 months). The follow-up after the end of the treatments was between 5 and 84 months (median 24 months). CONCLUSIONS: All treatment lines were effective and well tolerated. Therapeutic failures were not detected during the treatment. None of the patients died or experienced a relapse during the follow-up. Only six patients received antibiotic treatment in accordance with guidelines. These data suggest that shorter antimicrobial treatments could be effective.

Effect of Pressure Support vs T-Piece Ventilation Strategies During Spontaneous Breathing Trials on Successful Extubation Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Daily spontaneous breathing trials (SBTs) are the best approach to determine whether patients are ready for disconnection from mechanical ventilation, but mode and duration of SBT remain controversial. Objective: To evaluate the effect of an SBT consisting of 30 minutes of pressure support ventilation (an approach that is less demanding for patients) vs an SBT consisting of 2 hours of T-piece ventilation (an approach that is more demanding for patients) on rates of successful extubation. Design, Setting, and Participants: Randomized clinical trial conducted from January 2016 to April 2017 among 1153 adults deemed ready for weaning after at least 24 hours of mechanical ventilation at 18 intensive care units in Spain. Follow-up ended in July 2017. Interventions: Patients were randomized to undergo a 2-hour T-piece SBT (n = 578) or a 30-minute SBT with 8-cm H2O pressure support ventilation (n = 557). Main Outcome and Measures: The primary outcome was successful extubation (remaining free of mechanical ventilation 72 hours after first SBT). Secondary outcomes were reintubation among patients extubated after SBT; intensive care unit and hospital lengths of stay; and hospital and 90-day mortality. Results: Among 1153 patients who were randomized (mean age, 62.2 [SD, 15.7] years; 428 [37.1%] women), 1018 (88.3%) completed the trial. Successful extubation occurred in 473 patients (82.3%) in the pressure support ventilation group and 428 patients (74.0%) in the T-piece group (difference, 8.2%; 95% CI, 3.4%-13.0%; P = .001). Among secondary outcomes, for the pressure support ventilation group vs the T-piece group, respectively, reintubation was 11.1% vs 11.9% (difference, -0.8%; 95% CI, -4.8% to 3.1%; P = .63), median intensive care unit length of stay was 9 days vs 10 days (mean difference, -0.3 days; 95% CI, -1.7 to 1.1 days; P = .69), median hospital length of stay was 24 days vs 24 days (mean difference, 1.3 days; 95% CI, -2.2 to 4.9 days; P = .45), hospital mortality was 10.4% vs 14.9% (difference, -4.4%; 95% CI, -8.3% to -0.6%; P = .02), and 90-day mortality was 13.2% vs 17.3% (difference, -4.1% [95% CI, -8.2% to 0.01%; P = .04]; hazard ratio, 0.74 [95% CI, 0.55-0.99]). Conclusions and Relevance: Among patients receiving mechanical ventilation, a spontaneous breathing trial consisting of 30 minutes of pressure support ventilation, compared with 2 hours of T-piece ventilation, led to significantly higher rates of successful extubation. These findings support the use of a shorter, less demanding ventilation strategy for spontaneous breathing trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02620358.

The medical treatment of cardiogenic shock.

Cardiogenic shock is characterized by tissue hypoperfusion due to the inadequate cardiac output to maintain the tissue oxygen demand. Despite some advances in cardiogenic shock management, extremely high mortality is still associated with this clinical syndrome. Its management is based on the immediate stabilization of hemodynamic parameters through medical care and the use of mechanical circulatory supports in specialized centers. This review aims to understand the cardiogenic shock current medical treatment, consisting mainly of inotropic drugs, vasopressors and coronary revascularization. In addition, we highlight the relevance of applying measures to other organ levels based on the optimization of mechanical ventilation and the appropriate initiation of renal replacement therapy.

Clinical features and disease progression of elderly patients at the ICU setting.

OBJECTIVE: To describe and characterize a cohort of octogenarian patients admitted to the ICU of the University Central Hospital of Asturias (HUCA). DESIGN: Retrospective, observational and descriptive study of 14 months' duration. SETTING: Cardiac and Medical intensive care units (ICU) of the HUCA (Oviedo). PARTICIPANTS: Patients over 80 years old who were admitted to the ICU for more than 24 h. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Age, sex, comorbidity, functional dependence, treatment, complications, evolution, mortality. RESULTS: The most frequent reasons for admission were cardiac surgery and pneumonia. The average admission stay was significantly longer in patients under 85 years of age (p = 0,037). 84,3% of the latter benefited from invasive mechanical ventilation compared to 46,2% of older patients (p = <0,001). Patients over 85 years of age presented greater fragility. Admission for cardiac surgery was associated with a lower risk of mortality (HR = 0,18; 95% CI (0,062-0,527; p = 0,002). CONCLUSIONS: The results have shown an association between the reason for admission to the ICU and the risk of mortality in octogenarian patients. Cardiac surgery was associated with a better prognosis compared to medical pathology, where pneumonia was associated with a higher risk of mortality. Furthermore, a significant positive association was observed between age and frailty.

Prevalence and prognostic impact of stroke in a national cohort of infective endocarditis.

BACKGROUND: Stroke is a common complication of infective endocarditis (IE). Our aim was to describe the prevalence and prognostic impact of stroke in a national cohort of IE. METHODS: Consecutive inclusion at 46 Spanish hospitals between 2008 and 2021. RESULTS: Out of 5667 IE cases, 1125 had acute stroke (19.8%): 818 ischemic strokes (811 cardioembolic strokes (193 with hemorrhagic transformation), 4 transient ischemic attacks, 3 lacunar infarctions), 127 intracranial hemorrhages, and 27 other neurological complications (cerebral abscesses, encephalitis, and meningitis). Compared to patients without stroke, those with stroke had a similar mean age (69 years) but were more frequently female (68.2% vs 63.7%, p = 0.04) and had a higher incidence of intracardiac complications (35% vs 30%, p = 0.01), surgical indication (69.9% vs 65.9%, p = 0.001), in-hospital mortality (40.9% vs 22.0%, p < 0.001), and 1-year mortality (46.2% vs 27.9%, p < 0.001). The following variables were independently associated with stroke: mitral location (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.34-1.8, p < 0.001), vascular phenomenon (OR = 2.9, 95% CI = 2.4-3.6, p = 0.0001), acute renal failure (OR = 1.2, 95% CI = 1.0-1.4, p = 0.021), septic shock (OR = 1.3, 95% CI = 1.1-1.6, p = 0.007), sepsis (OR = 1.3, 95% CI = 1.1-1.6, p = 0.005), surgery indicated but not performed (OR = 1.4, 95% CI = 1.2-1.7, p < 0.001), community-acquired IE (OR = 1.2, 95% CI = 1-1.4, p = 0.017), and peripheral embolization (OR = 1.6, 95% CI = 1.4-1.9, p < 0.001). Stroke was an independent predictor of in-hospital (OR = 2.1, 95% CI = 1.78-2.51, p < 0.001) and 1-year mortality (hazard ratio = 1.9, 95% CI = 1.6-2.5). CONCLUSION: One-fifth of patients with IE have concomitant stroke. Stroke is associated with mortality.

Epidemiology and Risk Factors of Mycotic Aneurysm in Patients With Infective Endocarditis and the Impact of its Rupture in Outcomes. Analysis of a National Prospective Cohort.

Background: Several aspects of the occurrence and management of mycotic aneurysm (MA) in patients with infective endocarditis (IE) have not been studied. Objectives: To determine the incidence and factors associated with MA presence and rupture and to assess the evolution of those initially unruptured MA. Methods: Prospective multicenter cohort including all patients with definite IE between January 2008 and December 2020. Results: Of 4548 IE cases, 85 (1.9%) developed MA. Forty-six (54.1%) had intracranial MA and 39 (45.9%) extracranial MA. Rupture of MA occurred in 39 patients (45.9%). Patients with ruptured MA had higher 1-year mortality (hazard ratio, 2.33; 95% confidence interval, 1.49-3.67). Of the 55 patients with initially unruptured MA, 9 (16.4%) presented rupture after a median of 3 days (interquartile range, 1-7) after diagnosis, being more frequent in intracranial MA (32% vs 3.3%, P = .004). Of patients with initially unruptured MA, there was a trend toward better outcomes among those who received early specific intervention, including lower follow-up rupture (7.1% vs 25.0%, P = .170), higher rate of aneurysm resolution in control imaging (66.7% vs 31.3%, P = .087), lower MA-related mortality (7.1% vs 16.7%, P = .232), and lower MA-related sequalae (0% vs 27.8%, P = .045). Conclusions: MA occurred in 2% of the patients with IE. Half of the Mas occurred in an intracranial location. Their rupture is frequent and associated with poor prognosis. A significant proportion of initially unruptured aneurysms result from rupture during the first several days, being more common in intracranial aneurysms. Early specific treatment could potentially lead to better outcomes.

Clinical presentation, microbiology, and prognostic factors of prosthetic valve endocarditis. Lessons learned from a large prospective registry.

BACKGROUND: Prosthetic valve endocarditis (PVE) is a serious infection associated with high mortality that often requires surgical treatment. METHODS: Study on clinical characteristics and prognosis of a large contemporary prospective cohort of prosthetic valve endocarditis (PVE) that included patients diagnosed between January 2008 and December 2020. Univariate and multivariate analysis of factors associated with in-hospital mortality was performed. RESULTS: The study included 1354 cases of PVE. The median age was 71 years with an interquartile range of 62-77 years and 66.9% of the cases were male. Patients diagnosed during the first year after valve implantation (early onset) were characterized by a higher proportion of cases due to coagulase-negative staphylococci and Candida and more perivalvular complications than patients detected after the first year (late onset). In-hospital mortality of PVE in this series was 32.6%; specifically, it was 35.4% in the period 2008-2013 and 29.9% in 2014-2020 (p = 0.031). Variables associated with in-hospital mortality were: Age-adjusted Charlson comorbidity index (OR: 1.15, 95% CI: 1.08-1.23), intracardiac abscess (OR:1.78, 95% CI:1.30-2.44), acute heart failure related to PVE (OR: 3. 11, 95% CI: 2.31-4.19), acute renal failure (OR: 3.11, 95% CI:1.14-2.09), septic shock (OR: 5.56, 95% CI:3.55-8.71), persistent bacteremia (OR: 1.85, 95% CI: 1.21-2.83) and surgery indicated but not performed (OR: 2.08, 95% CI: 1.49-2.89). In-hospital mortality in patients with surgical indication according to guidelines was 31.3% in operated patients and 51.3% in non-operated patients (p<0.001). In the latter group, there were more cases of advanced age, comorbidity, hospital acquired PVE, PVE due to Staphylococcus aureus, septic shock, and stroke. CONCLUSIONS: Not performing cardiac surgery in patients with PVE and surgical indication, according to guidelines, has a significant negative effect on in-hospital mortality. Strategies to better discriminate patients who can benefit most from surgery would be desirable.

Mechanical ventilation in patients with cardiogenic pulmonary edema: a sub-analysis of the LUNG SAFE study.

BACKGROUND: Patients with acute respiratory failure caused by cardiogenic pulmonary edema (CPE) may require mechanical ventilation that can cause further lung damage. Our aim was to determine the impact of ventilatory settings on CPE mortality. METHODS: Patients from the LUNG SAFE cohort, a multicenter prospective cohort study of patients undergoing mechanical ventilation, were studied. Relationships between ventilatory parameters and outcomes (ICU discharge/hospital mortality) were assessed using latent mixture analysis and a marginal structural model. RESULTS: From 4499 patients, 391 meeting CPE criteria (median age 70 [interquartile range 59-78], 40% female) were included. ICU and hospital mortality were 34% and 40%, respectively. ICU survivors were younger (67 [57-77] vs 74 [64-80] years, p < 0.001) and had lower driving (12 [8-16] vs 15 [11-17] cmH2O, p < 0.001), plateau (20 [15-23] vs 22 [19-26] cmH2O, p < 0.001) and peak (21 [17-27] vs 26 [20-32] cmH2O, p < 0.001) pressures. Latent mixture analysis of patients receiving invasive mechanical ventilation on ICU day 1 revealed a subgroup ventilated with high pressures with lower probability of being discharged alive from the ICU (hazard ratio [HR] 0.79 [95% confidence interval 0.60-1.05], p = 0.103) and increased hospital mortality (HR 1.65 [1.16-2.36], p = 0.005). In a marginal structural model, driving pressures in the first week (HR 1.12 [1.06-1.18], p < 0.001) and tidal volume after day 7 (HR 0.69 [0.52-0.93], p = 0.015) were related to survival. CONCLUSIONS: Higher airway pressures in invasively ventilated patients with CPE are related to mortality. These patients may be exposed to an increased risk of ventilator-induced lung injury. Trial registration Clinicaltrials.gov NCT02010073.

Infective Endocarditis in Diabetic Patients: A Different Profile with Prognostic Consequences.

Background. Infective Endocarditis (IE) is a severe condition. Diabetes mellitus (DM) has been associated with a poor prognosis in other settings. Our aim was to describe the profile and prognosis of IE with and without DM and to analyze the prognostic relevance of DM-related organ damage. Methods. Retrospective analysis of the Spanish IE Registry (2008−2020). Results. The cohort comprises 5590 IE patients with a mean age of 65.0 ± 15.5 years; 3764 (67.3%) were male. DM was found in 1625 patients (29.1%) and 515 presented DM-related organ damage. DM prevalence during the first half of the study period was 27.6% vs. 30.6% in the last half, p = 0.015. Patients with DM presented higher in-hospital mortality than those without DM (521 [32.1%] vs. 924 [23.3%], p < 0.001) and higher one-year mortality (640 [39.4%] vs. 1131 [28.5%], p < 0.001). Among DM patients, organ damage was associated with higher in-hospital (200 [38.8%] vs. 321 [28.9%], p < 0.001) and one-year mortality (247 [48.0%] vs. 393 [35.4%], p < 0.001). Multivariate analyses showed an independent association of DM with in-hospital (odds ratio [OR] = 1.34, 95% confidence interval [CI]: 1.16−1.55, p < 0.001) and one-year mortality (OR = 1.38, 95% CI: 1.21−1.59, p < 0.001). Among DM patients, organ damage was independently associated with higher in-hospital (OR = 1.37, 95% CI: 1.06−1.76, p = 0.015) and one-year mortality (OR = 1.59, 95% CI = 1.26−2.01, p < 0.001) Conclusions. The prevalence of DM among patients with IE is increasing and is already above 30%. DM is independently associated with a poor prognosis, particularly in the case of DM with organ damage.

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

Patients with severe COVID-19 often need mechanical ventilation to help them breathe and other types of intensive care. The outcome for many of these patients depends on how their immune system reacts to the infection. If the inflammatory response triggered by the immune system is too strong, this can cause further harm to the patient. One gene that plays an important role in inflammation is IFIH1 which encodes a protein that helps the body to recognize viruses. There are multiple versions of this gene which each produce a slightly different protein. It is possible that this variation impacts how the immune system responds to the virus that causes COVID-19. To investigate, Amado-Rodríguez, Salgado del Riego et al. analyzed the IFIH1 gene in 227 patients admitted to an intensive care unit in Spain for severe COVID-19 between March and December 2020. They found that patients with a specific version of the gene called TT experienced less inflammation and were more likely to survive the infection. Physicians typically treat patients with moderate to severe COVID-19 with corticosteroid drugs that reduce the inflammatory response. However, Amado-Rodríguez, Salgado del Riego et al. found that patients with the TT version of the IFIH1 gene were at greater risk of dying if they received corticosteroids. The team then applied the distribution of IFIH1 variants among different ethnic ancestries to data from a previous clinical trial, and simulated the effects of corticosteroid treatment. This 'mock' clinical trial supported their findings from the patient-derived data, which were also validated by laboratory experiments on immune cells from individuals with the TT gene. The work by Amado-Rodríguez, Salgado del Riego et al. suggests that while corticosteroids benefit some patients, they may cause harm to others. However, a real-world clinical trial is needed to determine whether patients with the TT version of the IFIH1 gene would do better without steroids.

Endoluminal tumor implant of a colorectal cancer in an anal fistula detected by FISH techniques: a case report.

Intraluminal shedding of tumor cells is a rare infrequent sporadic colorectal cancer (sCRC) mechanism of spreading. Less than 30 cases of sCRC metastasis into anal fistula have been reported. Here, we study a 72-year-old male with an adenocarcinoma arising in an anal fistula. Subsequent studies revealed another tumor in the rectum without distant metastatic disease; therefore, a curative-intent abdominoperineal resection was performed. The histologic study showed a moderately differentiated adenocarcinoma in both locations. No perineural or lymphovascular invasion was observed, and all the lymphatic nodes resected were negative for malignancy. Both tumors showed positive CK20 and negative CK7 immunostaining, but KRAS G12D mutation was only detected in the rectal tumor. After those conventional studies, a cytogenetic profile of both tumors was performed by interphase fluorescence in situ hybridization (iFISH) techniques. The FISH study displayed an identical genetic profile in both tumors, loss of the chromosomes 8 and 18q, and no alteration in chromosome 7 and 13q. Based on pathological and genetic findings, we established the same clonal origin of both tumors. Currently, the diagnosis of an intraluminal CRC metastasis relies on histologic and immunohistochemistry findings. We suggest that genetic studies at the individual cell level by FISH techniques may be useful in order to differentiate synchronous from intraluminal metastasis.

Evaluation of 16S rDNA Heart Tissue PCR as a Complement to Blood Cultures for the Routine Etiological Diagnosis of Infective Endocarditis.

Identification of the causative pathogen is required to optimize the effective therapy in infective endocarditis (IE). The aim of this study was to assess a 16S rDNA PCR to identify bacteria from heart valve tissues and to evaluate its usefulness as a complement to blood and removed valves cultures. A total of 266 patients diagnosed with IE from January 2015 to December 2019 were evaluated. Results between 16S rDNA PCR from heart valve tissues were compared with microbiological cultures. Blood cultures were positive in 83.5% of patients diagnosed with IE, while 39.6% and 71.8% of the evaluated heart valve samples were positive by culture and 16S rDNA PCR, respectively. For 32 (12%) patients, 16S rDNA tissue PCR provided valuable information supporting the results of blood cultures in the case of bacteria characteristic from the skin microbiota. Additionally, a microorganism was identified by using 16S rDNA PCR in 36% of blood culture-negative cases. The present study reveals that molecular diagnosis using 16S rDNA tissue PCR provides complementary information for the diagnosis of IE, and it should be recommended in surgical endocarditis, especially when blood cultures are negative.

Non-HACEK gram negative bacilli endocarditis: Analysis of a national prospective cohort.

BACKGROUND: Infective endocarditis (IE) due to non-HACEK bacilli (Haemophilus species, Actinobacillus, Cardiobacterium, Eikenella, or Kingella) is uncommon and poorly described. The objectives of this study were to describe non-HACEK Gram-Negative Bacilli (GNB) IE cases and compare characteristic of IE produced by Enterobacterales and non-fermenting (NF) GNB. METHODS: From January 2008 to December 2018, 3910 consecutive patients with definitive IE diagnosis, defined with Modified Duke criteria, either clinical or pathological criteria (e.g. demonstration of non-HACEK GNB in valve culture)were prospectively included. RESULTS: A total of 104 IE cases were caused by non-HACEK GNB (2.6%). Compared to IE due to other microorganisms (excluding HACEK GNB), patients with non-HACEK GNB IE presented with higher age (71 years [IQR 62-78] vs 68 years [IQR: 57-77]; p = 0.026), higher proportion of women (52% vs 31.5%, p < 0.001), higher Charlson Index (5 [IQR: 4-8] vs 4 [IQR 3-7], p = 0.003) and higher in-hospital mortality (36.5% vs 27.1%, p = 0.034). Enterobacterales cases were more frequently associated with genitourinary focus (32.8% vs 5.0%, p = 0.001). NFGNB endocarditis more frequently affected right valves (20.0% vs. 6.3%, p = 0.033), had more common healthcare-related acquisition (67.5% vs. 43.7%, p = 0.030) and venous catheter as focus (40.0% vs. 17.2%, p = 0.019). In the multivariant model, factors related with hospital mortality were: age (OR 1.05, 95%CI 1.00-1.09, p = 0.042), prosthetic valve (OR 2.31, 95%CI 0.90-5.88, p = 0.080), and not performing surgery when indicated (OR 3.60, 95%CI 1.17-11.05, p = 0.025).Patients treated with quinolone combination had lower mortality (OR 0.29; 95%CI 0.09-0.96; p = 0.043). CONCLUSION: Non-HACEK GNB IE is a rare infection characterized by affecting elderly patients with high comorbidity, nosocomial acquisition and unfavorable outcome. Age, prosthetic valve and not performing surgery when indicated are associated with mortality.

In vitro activity of ceftaroline and ceftobiprole against clinical isolates of Gram-positive bacteria from infective endocarditis: are these drugs potential options for the initial management of this disease?

The in vitro activity of ceftaroline and ceftobiprole was assessed against 77 Gram-positive bacterial isolates recovered from patients diagnosed with infective endocarditis (IE). Our data confirm that these drugs are highly in vitro active against the most common agents of IE including methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, and Streptococcus spp., with no significant differences between them. Also, ceftaroline and ceftobiprole have demonstrated a good activity against Enterococcus faecalis (MIC90 0.75 µg/mL and 0.5 µg/mL, respectively). The spectrum of these drugs together with the in vitro and in vivo data on them related with IE published in the scientific literature places them as potential options for the initial management of this disease.

Tropheryma whipplei endocarditis in Spain: Case reports of 17 prospective cases.

Tropheryma whipplei endocarditis is an uncommon condition with very few series and <90 cases reported in the literature. The aim of the study was to analyze the epidemiological, clinical, and outcome characteristics of 17 cases of T. whipplei endocarditis recruited in our country from a multicentric cohort from 25 Spanish hospitals from the Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis infecciosa en España.From a total of 3165 cases included in the cohort, 14.2% were diagnosed of blood culture negative endocarditis (BCNE) and 3.5% of these had T. whipplei endocarditis. This condition was more frequent in men. The average age was 60.3 years. Previous cardiac condition was present in 35.3% of the cases. The main clinical manifestation was cardiac failure (76.5%) while fever was only present in the 35.3%. Ecocardiography showed vegetations in 64.7% of patients. Surgery was performed in all but 1 cases and it allowed the diagnosis when molecular assays were performed. A broad range rRNA 16S polymerase chain reaction was used for first instance in all laboratories and different specific targets for T. whipplei were employed for confirmation. A concomitant Whipple disease was diagnosed in 11.9% of patients. All patients received specific antimicrobial treatment for at least 1 year, with no relapse and complete recovery.T. whipplei endocarditis is an uncommon condition with an atypical presentation that must be considered in the diagnosis of BCNE. The prognosis is very good when an appropriate surgical management and antimicrobial-specific treatment is given.