Calibration and validation of the Pneumonia Shock Score in critically ill patients with SARS-CoV-2 infection, a multicenter prospective cohort study.

Background: Prognostic tools developed to stratify critically ill patients in Intensive Care Units (ICUs), are critical to predict those with higher risk of mortality in the first hours of admission. This study aims to evaluate the performance of the pShock score in critically ill patients admitted to the ICU with SARS-CoV-2 infection. Methods: Prospective observational analytical cohort study conducted between January 2020 and March 2021 in four general ICUs in Salvador, Brazil. Descriptive statistics were used to characterize the cohort and a logistic regression, followed by cross-validation, were performed to calibrate the score. A ROC curve analysis was used to assess accuracy of the models analyzed. Results: Six hundred five adult ICU patients were included in the study. The median age was 63 (IQR: 49-74) years with a mortality rate of 33.2% (201 patients). The calibrated pShock-CoV score performed well in prediction of ICU mortality (AUC of 0.80 [95% Confidence Interval (CI): 0.77-0.83; p-value < 0.0001]). Conclusions: The pShock-CoV score demonstrated robust discriminatory capacity and may assist in targeting scarce ICU resources during the COVID-19 pandemic to those critically ill patients most likely to benefit.

A prospective comparison between multidisciplinary healthcare providers' clinical examination and a validated pain scale.

Introduction: Unrecognized pain in the Intensive Care Unit (ICU), due to inadequate assessment and therapeutic management, is associated with increased morbidity and mortality. Despite the availability of validated pain monitoring tools, such as the Critical-Care Pain Observational Tool (CPOT), these scales are not commonly used in clinical practice, with healthcare professionals often relying on their clinical impression. Our study aims to determine the agreement between the pain examination performed by ICU professionals and the CPOT. Methods: Prospective cohort study that included critically ill patients and physicians, nurses and physiotherapists from an ICU in Bahia, Brazil. During bedside clinical rounds, the CPOT score was applied to assess the pain of hospitalized patients, and health professionals were interviewed to ascertain their perception of the patient's pain for a maximum of five consecutive days. Correlations were assessed using the Spearman rank tests. Hierarchical cluster analysis was employed to show the results of CPOT score and pain assessment by healthcare professionals at each study time. And the Kappa statistic was calculated to assess the agreement between the CPOT score vs. the pain assessment by healthcare providers. Results: One hundred one patients were included in the study with median age of 74 years (IQR 61.5-83.5), a predominance of women (55.4%) and a median SAPS 3 score of 45 (IQR 39.5-53.0). The correlation between the professional's pain assessment and the CPOT were mostly statistically significant, ranged from negligible to weak, being the highest index obtained in the evaluation of nurses on day 5 (Kappa index = 0.43, p = 0.005). Physician assessments were significant only in day 1. On the presence of pain, the professionals' assessments and CPOT revealed mild to a moderate agreement. Conclusion: Healthcare professional's pain assessment displayed a weak positive correlation with a validated pain scale and poor agreement amongst members of the ICU team, particularly when the pain was felt to be absent. Thus, this study highlights the importance of routine tools for pain assessment in the ICU for all members of multidisciplinary teams.

The impact of body mass index on the prognostic performance of the Simplified Acute Physiology Score 3: A prospective cohort study.

Objective: To assess the Simplified Acute Physiology Score 3 (SAPS3) prognostic score performance across different body mass index categories. Methods: A retrospective cohort study in a general ICU in Brazil. A secondary analysis of medical records was performed with clinical and epidemiological data. Patients were stratified according to their body mass index (BMI) category, and a binary logistic regression was then performed to identify factors independently associated with mortality. SAPS3 accuracy was determined using the area under the receiver operating characteristics curve and the Hosmer-Lemeshow test. A modified Kaplan-Meyer plot was employed to evaluate death probability according to BMI. ICU mortality was evaluated as the primary outcome. Results: A total of 2,179 patients (mean age of 67.9 years and female predominance (53.1%)) were enrolled. SAPS3 was found accurate in all groups except in the underweight (AUC: 0.694 95% CI 0.616-0.773; HL = 0.042). The patients in the underweight group tended to be older, have longer hospital stay, have worse functional status, and have a higher value on prognostic scores. After the adjustments, no statistically significant difference between the BMI groups was noted in relation to mortality, except for the low weight that presented a likelihood of death of 3.50 (95% CI, 1.43-8.58, p = 0.006). Conclusion: This research showed that SAPS3 had poor accuracy in predicting ICU mortality in underweight patients. This group was shown to be an independent risk factor for worse clinical outcomes.

Evaluation of ELISA-Based Multiplex Peptides for the Detection of Human Serum Antibodies Induced by Zika Virus Infection across Various Countries.

Zika virus (ZIKV) is a mosquito-borne Flavivirus with a positive-sense RNA genome, which are generally transmitted through the bite of an infected Aedes mosquito. ZIKV infections could be associated with neurological sequelae that, and otherwise produces similar clinical symptoms as other co-circulating pathogens. Past infection with one member of the Flavivirus genus often induces cross-reactive antibodies against other flaviruses. These attributes complicate the ability to differentially diagnose ZIKV infection from other endemic mosquito-borne viruses, making it both a public health issue as well as a diagnostic challenge. We report the results from serological analyses using arbovirus-specific peptides on 339 samples that were previously collected from 6 countries. Overall, we found that our multiplexed peptide-based ELISA was highly efficient for identifying ZIKV antibodies as early as 2 weeks post infection, and that it correlates with microneutralization, plaque reduction neutralization tests (PRNTs) and commercial tests for ZIKV in previously characterized samples. We observed that seropositivity varied by patient cohort, reflecting the sampling period in relation to the 2015-2016 ZIKV outbreak. This work evaluates the accuracy, specificity, and sensitivity of our peptide-based ELISA method for detecting ZIKV antibodies from geographically diverse regions. These findings can contribute to ongoing serological methods development and can be adapted for use in future studies.

Pragmatic Recommendations for the Management of Anticoagulation and Venous Thrombotic Disease for Hospitalized Patients with COVID-19 in Low- and Middle-Income Countries.

New studies of COVID-19 are constantly updating best practices in clinical care. Often, it is impractical to apply recommendations based on high-income country investigations to resource limited settings in low- and middle-income countries (LMICs). We present a set of pragmatic recommendations for the management of anticoagulation and thrombotic disease for hospitalized patients with COVID-19 in LMICs. In the absence of contraindications, we recommend prophylactic anticoagulation with either low molecular weight heparin (LMWH) or unfractionated heparin (UFH) for all hospitalized COVID-19 patients in LMICs. If available, we recommend LMWH over UFH for venous thromboembolism (VTE) prophylaxis to minimize risk to healthcare workers. We recommend against the use of aspirin for VTE prophylaxis in hospitalized COVID-19 and non-COVID-19 patients in LMICs. Because of limited evidence, we suggest against the use of "enhanced" or "intermediate" prophylaxis in COVID-19 patients in LMICs. Based on current available evidence, we recommend against the initiation of empiric therapeutic anticoagulation without clinical suspicion for VTE. If contraindications exist to chemical prophylaxis, we recommend mechanical prophylaxis with intermittent pneumatic compression (IPC) devices or graduated compression stockings (GCS) for hospitalized COVID-19 patients in LMICs. In LMICs, we recommend initiating therapeutic anticoagulation for hospitalized COVID-19 patients, in accordance with local clinical practice guidelines, if there is high clinical suspicion for VTE, even in the absence of testing. If available, we recommend LMWH over UFH or Direct oral anticoagulants for treatment of VTE in LMICs to minimize risk to healthcare workers. In LMIC settings where continuous intravenous UFH or LMWH are unavailable or not feasible to use, we recommend fixed dose heparin, adjusted to body weight, in hospitalized COVID-19 patients with high clinical suspicion of VTE. We suggest D-dimer measurement, if available and affordable, at the time of admission for risk stratification, or when clinical suspicion for VTE is high. For hospitalized COVID-19 patients in LMICs, based on current available evidence, we make no recommendation on the use of serial D-dimer monitoring for the initiation of therapeutic anticoagulation. For hospitalized COVID-19 patients in LMICs receiving intravenous therapeutic UFH, we recommend serial monitoring of partial thromboplastin time or anti-factor Xa level, based on local laboratory capabilities. For hospitalized COVID-19 patients in LMICs receiving LMWH, we suggest against serial monitoring of anti-factor Xa level. We suggest serial monitoring of platelet counts in patients receiving therapeutic anticoagulation for VTE, to assess risk of bleeding or development of heparin induced thrombocytopenia.

Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV.

Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.

The Interplay Between Systemic Inflammation, Oxidative Stress, and Tissue Remodeling in Tuberculosis.

Significance: Excessive and prolonged proinflammatory responses are associated with oxidative stress, which is commonly observed during chronic tuberculosis (TB). Such condition favors tissue destruction and consequently bacterial spread. A tissue remodeling program is also triggered in chronically inflamed sites, facilitating a wide spectrum of clinical manifestations. Recent Advances: Since persistent and exacerbated oxidative stress responses have been associated with severe pathology, a number of studies have suggested that the inhibition of this augmented stress response by improving host antioxidant status may represent a reasonable strategy to ameliorate tissue damage in TB. Critical Issues: This review summarizes the interplay between oxidative stress, systemic inflammation and tissue remodeling, and its consequences in promoting TB disease. We emphasize the most important mechanisms associated with stress responses that contribute to the progression of TB. We also point out important host immune components that may influence the exacerbation of cellular stress and the subsequent tissue injury. Future Directions: Further research should reveal valuable targets for host-directed therapy of TB, preventing development of severe immunopathology and disease progression. Antioxid. Redox Signal. 34, 471-485.

Derivation and Validation of a Novel Severity Scoring System for Pneumonia at Intensive Care Unit Admission.

BACKGROUND: Severity stratification scores developed in intensive care units (ICUs) are used in interventional studies to identify the most critically ill. Studies that evaluate accuracy of these scores in ICU patients admitted with pneumonia are lacking. This study aims to determine performance of severity scores as predictors of mortality in critically ill patients admitted with pneumonia. METHODS: Prospective cohort study in a general ICU in Brazil. ICU severity scores (Simplified Acute Physiology Score 3 [SAPS 3] and Sepsis-Related Organ Failure Assessment [qSOFA]), prognostic scores of pneumonia (CURB-65 [confusion, urea, respiratory rate, blood pressure, age] and CRB-65 [confusion, respiratory rate, blood pressure, age]), and clinical and epidemiological variables in the first 6 hours of hospitalization were analyzed. RESULTS: Two hundred patients were included between 2015 and 2018, with a median age of 81 years (interquartile range, 67-90 years) and female predominance (52%), primarily admitted from the emergency department (65%) with community-acquired pneumonia (CAP, 80.5%). SAPS 3, CURB-65, CRB-65,and qSOFA all exhibited poor performance in predicting mortality. Multivariate regression identified variables independently associated with mortality that were used to develop a novel pneumonia-specific ICU severity score (Pneumonia Shock score) that outperformed SAPS 3, CURB-65, and CRB-65. The Shock score was validated in an external multicenter cohort of critically ill patients admitted with CAP. CONCLUSIONS: We created a parsimonious score that accurately identifies patients with pneumonia at highest risk of ICU death. These findings are critical to accurately stratify patients with severe pneumonia in therapeutic trials that aim to reduce mortality.

Pragmatic Recommendations for the Management of COVID-19 Patients with Shock in Low- and Middle-Income Countries.

As some patients infected with the novel coronavirus progress to critical illness, a subset will eventually develop shock. High-quality data on management of these patients are scarce, and further investigation will provide valuable information in the context of the pandemic. A group of experts identify a set of pragmatic recommendations for the care of patients with SARS-CoV-2 and shock in resource-limited environments. We define shock as life-threatening circulatory failure that results in inadequate tissue perfusion and cellular dysoxia/hypoxia, and suggest that it can be operationalized via clinical observations. We suggest a thorough evaluation for other potential causes of shock and suggest against indiscriminate testing for coinfections. We suggest the use of the quick Sequential Organ Failure Assessment (qSOFA) as a simple bedside prognostic score for COVID-19 patients and point-of-care ultrasound (POCUS) to evaluate the etiology of shock. Regarding fluid therapy for the treatment of COVID-19 patients with shock in low-middle-income countries, we favor balanced crystalloids and recommend using a conservative fluid strategy for resuscitation. Where available and not prohibited by cost, we recommend using norepinephrine, given its safety profile. We favor avoiding the routine use of central venous or arterial catheters, where availability and costs are strong considerations. We also recommend using low-dose corticosteroids in patients with refractory shock. In addressing targets of resuscitation, we recommend the use of simple bedside parameters such as capillary refill time and suggest that POCUS be used to assess the need for further fluid resuscitation, if available.

Pragmatic Recommendations for Therapeutics of Hospitalized COVID-19 Patients in Low- and Middle-Income Countries.

The therapeutic options for COVID-19 patients are currently limited, but numerous randomized controlled trials are being completed, and many are on the way. For COVID-19 patients in low- and middle-income countries (LMICs), we recommend against using remdesivir outside of a clinical trial. We recommend against using hydroxychloroquine ± azithromycin or lopinavir-ritonavir. We suggest empiric antimicrobial treatment for likely coinfecting pathogens if an alternative infectious cause is likely. We suggest close monitoring without additional empiric antimicrobials if there are no clinical or laboratory signs of other infections. We recommend using oral or intravenous low-dose dexamethasone in adults with COVID-19 disease who require oxygen or mechanical ventilation. We recommend against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen. We recommend using alternate equivalent doses of steroids in the event that dexamethasone is unavailable. We also recommend using low-dose corticosteroids in patients with refractory shock requiring vasopressor support. We recommend against the use of convalescent plasma and interleukin-6 inhibitors, such as tocilizumab, for the treatment of COVID-19 in LMICs outside of clinical trials.

Are prognostic tools losing accuracy? Development and performance of a novel age-calibrated severity scoring system for critically ill patients.

OBJECTIVE: This study aimed to assess the performance of a commonly used ICU severity score (SAPS3) and determine whether an alternative scoring system may be more accurate across all age strata. METHODS: Retrospective cohort study in a general ICU in Brazil. A secondary analysis was performed with clinical and epidemiological data, present in the first 24 hours of unit admission. Then, a binary logistic regression, followed by cross-validation, was made to develop a novel prognostic tool. ICU mortality was the primary outcome evaluated. RESULTS: A total of 3042 patients were included over the study period between August 2015 and July 2018 with a median age of 67 ± 18.4 years. SAPS3 performed fairly in prediction of ICU mortality, particularly in the 80 years or older subset. Multivariable regression identified variables independently associated with mortality that were used to develop the Age Calibrated ICU Score (ACIS) tool that performed similarly to SAPS3 across age categories, being slightly superior in the very elderly population (AUC 0.80 vs 0.72). CONCLUSIONS: The ACIS offers a robust and simple tool to predict ICU mortality, particularly in an increasingly elderly critical care population.

Factors Associated with Mortality in Critically Ill Patients Diagnosed with Hospital Acquired Infections.

OBJECTIVE: Evaluate host and pathogen factors associated with mortality in those with hospital acquired infections (HAI) in a tertiary intensive care unit in Brazil. METHODS: Observational and analytical cohort single center study in a general intensive care unit (ICU) in Northeastern Brazil between January 2016 and August 2018, including those over 18 years of age admitted to the ICU found to have a HAI. RESULTS: A total of 165 patients were included, with a mean age of 72 years and male predominance (53.3%) and observed mortality of 46%. Mortality in those with HAI was significantly associated with older age, increased ICU length of stay and readmission to the ICU in univariate analysis. Multivariate analysis revealed that development of septic shock and obtundation during ICU admission was significantly associated with an increased risk of death (OR: 6.94, 95% CI 1.23-39.27, OR: 2.48, 95% CI 1.17-5.29, respectively). A trend towards mortality risk was noted in those with increased age and prior cardiovascular disease. Surprisingly, mortality risk was independent of site of infection, type of pathogen and antibiotic resistance. Furthermore, having more than one HAI over the course of the ICU admission did not impact mortality. CONCLUSION: Risk of death in those with HAI is associated with obtundation and septic shock, in addition to vasopressor use. Host factors, rather than pathogen-specific characteristics or infecting site, impact risk of death related to HAI in the ICU.

Comparison of a modified Sequential Organ Failure Assessment Score using RASS and FOUR.

OBJECTIVE: ICU severity scores such as the Sequential Organ Failure Assessment (SOFA) determine neurologic dysfunction based on the Glasgow Coma Scale, a tool that may be limited in a critically ill population. It remains unknown whether alternative methods to assess for neurologic dysfunction, such as FOUR and RASS, are superior. This study aimed to determine the predictive performance of a modified SOFA tool in a large Brazilian ICU cohort. DESIGN: Prospective cohort single center study. SETTING: Mixed surgical and medical ICU in Salvador, Bahia, Brazil between August 2015 and December 2018. PATIENTS: All acutely ill ICU admissions, other than postoperative patients or those with insufficient data, were eligible for study inclusion. MEASUREMENTS AND MAIN RESULTS: 2147 patients were admitted to the ICU, of which 999 meeting inclusion criteria were included in the final analysis with a median age of 72 years (IQR 58-83) and a female predominance 545 (54%). The SOFA score using GCS, RASS and FOUR for the neurologic component performed marginally in the ability to predict general ICU mortality (SOFAGCS AUC 0.74 vs SOFARASS AUC 0.71 and SOFAFOUR AUC 0.67), with SOFAFOUR performing significantly lower compared to either SOFARASS and SOFAGCS (p<0.04, p<0.004 respectively). All three scores demonstrated decreased discriminate function in the mechanically ventilated population (SOFAGCS AUC 0.70 vs SOFARASS AUC 0.70 and SOFAFOUR AUC 0.55), though SOFAFOUR remained significantly worse when compared to SOFAGCS or SOFARASS (p = 0.034, p = 0.014, respectively).. Furthermore, performance was poor in a subset of patients with sepsis (n = 145) at time of admission (SOFAGCS AUC 0.66 vs SOFARASS AUC 0.55 and SOFAFOUR AUC 0.56). CONCLUSION: Modification of the neurologic component in the SOFA score does not appear to improve mortality prediction in the ICU.

Comparison of the New Oral Anticoagulants and Warfarin in Patients with Atrial Fibrillation and Valvular Heart Disease: Systematic Review and Meta-Analysis.

INTRODUCTION: New oral anticoagulants (NOACs) are approved for use in nonvalvular atrial fibrillation (AF). OBJECTIVES: This study aimed to evaluate the efficacy and safety of NOACs compared with warfarin in AF and valvular heart disease (VHD). METHODS: We identified randomized controlled trials (RCTs) and post-hoc analyses comparing NOACs and warfarin in AF and VHD, including biological and mechanical heart valves (MHV). Through systematic review and meta-analysis, with the aid of the "Rev Man" program 5.3, the primary effectiveness endpoints were stroke and systemic embolism (SE). The primary safety outcome was major bleeding, and the secondary outcome included intracranial hemorrhage. Data were analyzed using risk ratios (RRs) and 95% confidence intervals (CIs), and heterogeneity was assessed using the I2 statistic. RESULTS: Six RCTs were included, involving 13,850 patients with AF and VHD. NOACs significantly reduced the risk of stroke/SE (RR 0.78; 95% CI 0.66-0.91; P = 0.002) and intracranial hemorrhage (RR 0.51; 95% CI 0.33-0.79; P = 0.003) and lowered the risk of major bleeding (RR 0.77; 95% CI 0.58-1.02; P = 0.07) compared with warfarin. CONCLUSIONS: The efficacy and safety of NOACs as thromboprophylaxis for AF and VHD are similar to those of warfarin.

Rivaroxaban versus Warfarin in Patients with Mechanical Heart Valve: Rationale and Design of the RIWA Study.

INTRODUCTION: Mechanical heart valves (MHV) are extremely durable, but they require permanent use of anticoagulation to prevent thromboembolic events. The only approved therapeutic options are vitamin K antagonists (VKAs), such as warfarin. As a drug class, clinical management is difficult, therefore new alternatives need to be evaluated. METHODS: RIWA is a phase II/III, prospective, open-label, randomized, pilot study designed to investigate oral rivaroxaban 15 mg twice daily compared with dose-adjusted warfarin for the prevention of stroke (ischemic or hemorrhagic) and systemic embolism in patients with MHV, from August 2018 to December 2019. Patients will undergo transesophageal echocardiography at the beginning and the end of the study (follow-up time 90 days). On an explanatory basis, all events will be analyzed, including stroke, peripheral systemic embolism, valve thrombosis, significant bleeding and death. DISCUSSION: Warfarin and similar VKAs are standard therapy for patients with an MHV. Even with the appropriate use of therapy, the incidence of thromboembolic events is high at 1-4% per year. Furthermore, bleeding risk is significant, ranging from 2 to 9% per year. The new frontier to be overcome in relation to use of the new oral anticoagulants is undoubtedly in patients with MHV. A significant portion of people with MHV worldwide will benefit if noninferiority of these new agents is confirmed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03566303. Recruitment Status: Recruiting. First Posted: 25 June 2018. Last Update Posted: 25 June 2018.

Correction: Factors associated with tuberculosis treatment delay in patients co-infected with HIV in a high prevalence area in Brazil.

[This corrects the article DOI: 10.1371/journal.pone.0195409.].