Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial.

PURPOSE: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients. MATERIAL AND METHODS: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life. RESULTS: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520). CONCLUSION: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020. GOV IDENTIFIER: NCT04549922.

Real-world Effectiveness of original BNT162b2 mRNA COVID-19 against symptomatic Omicron infection among Children 5-11 years of age in Brazil: a prospective test-negative design study.

OBJECTIVE: To estimate original wild-type BNT162b2 effectiveness against symptomatic Omicron infection among children 5-11 years of age. METHODS: This prospective test-negative, case-control study was conducted in Toledo, southern Brazil, from June 2022 to July 2023. Patients were included if they were aged 5-11 years, sought care for acute respiratory symptoms in the public health system, and were tested for SARS-CoV-2 using reverse transcription polymerase chain reaction. In the primary analysis, we determined the effectiveness of two doses of original wild-type BNT162b2 against symptomatic COVID-19. The reference exposure group was the unvaccinated. RESULTS: A total of 757 children were enrolled; of these, 461 (25 cases; 436 controls) were included in the primary analysis. Mean age was 7.4 years, 49.7% were female, 34.6% were obese, and 14.1% had chronic pulmonary disease. Omicron accounted for 100% of all identified SARS-CoV-2 variants with BA.5, BQ.1, and XBB.1 accounting for 35.7%, 21.4% and 21.4%, respectively. The adjusted estimate of two-dose vaccine effectiveness against symptomatic Omicron was 3.1% (95% CI, -133.7% to 61.8%) after a median time between the second dose and the beginning of COVID-19 symptoms of 192.5 days (interquartile range, 99 to 242 days). CONCLUSION: In this study with children 5-11 years of age, a two dose-schedule of original wild-type BNT162b2 was not associated with a significant protection against symptomatic Omicron infection after a median time between the second dose and the beginning of COVID-19 symptoms of 192 days, although the study may have been underpowered to detect a clinically important difference. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT05403307 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT05403307).

Temporal trends in respiratory pathogens following the COVID-19 pandemic and climate variables: A unicentric retrospective evaluation of 24 pathogens in a temperate subtropical region.

Temperature and humidity are studied in the context of seasonal infections in temperate and tropical zones, but the relationship between viral trends and climate variables in temperate subtropical zones remains underexplored. Our retrospective study analyzes respiratory pathogen incidence and its correlation with climate data in a subtropical zone. Retrospective observational study at Moinhos de Vento Hospital, South Brazil, aiming to assess seasonal trends in respiratory pathogens, correlating them with climate data. The study included patients of all ages from various healthcare settings, with data collected between April 2022 and July 2023. Biological samples were analyzed for 24 pathogens using polymerase chain reaction and hybridization techniques; demographic variables were also collected. The data was analyzed descriptively and graphically. Spearman tests and Poisson regression were used as correlation tests. Tests were clustered according to all pathogens, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza viruses, rhinovirus, and respiratory syncytial virus (RSV). Between April 2022 and July 2023, 3329 tests showed a 71.6% positivity rate. Rhinovirus and RSV predominated, exhibiting seasonal patterns. Temperature was inversely correlated with the viruses, notably rhinovirus, but SARS-CoV-2 was positively correlated. Air humidity was positively correlated with all pathogens, RSV, rhinovirus, and atmospheric pressure with all pathogens and rhinovirus. Our results showed statistically significant correlations, with modest effect sizes. Our study did not evaluate causation effects. Despite the correlation between climate and respiratory pathogens, our work suggests additional factors influencing transmission dynamics. Our findings underscore the complex interplay between climate and respiratory infections in subtropical climates.

Long term cognitive dysfunction among critical care survivors: associated factors and quality of life-a multicenter cohort study.

OBJECTIVES: To identify the prevalence and associated factors of cognitive dysfunction, 1 year after ICU discharge, among adult patients, and it´s relation with quality of life. METHODS: Multicenter, prospective cohort study including ICUs of 10 tertiary hospitals in Brazil, between May 2014 and December 2018. The patients included were 452 adult ICU survivors (median age 60; 47.6% women) with an ICU stay greater than 72 h. RESULTS: At 12 months after ICU discharge, a Montreal Cognitive Assessment (tMOCA) telephone score of less than 12 was defined as cognitive dysfunction. At 12 months, of the 452 ICU survivors who completed the cognitive evaluation 216 (47.8%) had cognitive dysfunction. In multivariable analyses, the factors associated with long-term (1-year) cognitive dysfunction were older age (Prevalence Ratio-PR = 1.44, P < 0.001), absence of higher education (PR = 2.81, P = 0.005), higher comorbidities on admission (PR = 1.089; P = 0.004) and delirium (PR = 1.13, P < 0.001). Health-related Quality of life (HRQoL), assessed by the mental and physical dimensions of the SF-12v2, was significantly better in patients without cognitive dysfunction (Mental SF-12v2 Mean difference = 2.54; CI 95%, - 4.80/- 0.28; p = 0.028 and Physical SF-12v2 Mean difference = - 2.85; CI 95%, - 5.20/- 0.50; P = 0.018). CONCLUSIONS: Delirium was found to be the main modifiable predictor of long-term cognitive dysfunction in ICU survivors. Higher education consistently reduced the probability of having long-term cognitive dysfunction. Cognitive dysfunction significantly influenced patients' quality of life, leading us to emphasize the importance of cognitive reserve for long-term prognosis after ICU discharge.

Mortality predictors in patients with suspected sepsis in the emergency department of a tertiary care hospital: a retrospective cohort study.

BACKGROUND: Sepsis remains a worldwide major cause of hospitalization, mortality, and morbidity. To enhance the identification of patients with suspected sepsis at high risk of mortality and adverse outcomes in the emergency department (ED), the use of mortality predictors is relevant. This study aims to establish whether quick sofa (qSOFA) and the severity criteria applied in patients with suspicion of sepsis in a monitored ED are in fact predictors of mortality. METHODS: We performed a retrospective cohort study among adult patients with suspicion of sepsis at the ED of a tertiary care hospital in Brazil between January 1st, 2019 and December 31, 2020. All adult patients (ages 18 and over) with suspected sepsis that scored two or more points on qSOFA score or at least one point on the severity criteria score were included in the study. RESULTS: The total of patients included in the study was 665 and the average age of the sample was 73 ± 19 years. The ratio of men to women was similar. Most patients exhibited qSOFA ≥ 2 (58.80%) and 356 patients (53.61%) scored one point in the severity criteria at admission. The overall mortality rate was 19.7% (131 patients) with 98 patients (14.74%) having positive blood cultures, mainly showing Escherichia coli as the most isolated bacteria. Neither scores of qSOFA nor the severity criteria were associated with mortality rates, but scoring any point on qSOFA was considered as an independent factor for intensive care unit (ICU) admission (qSOFA = 1 point, p = 0.02; qSOFA = 2 points, p = 0.03, and qSOFA = 3 points, p = 0.04). Positive blood cultures (RR, 1.63;95% CI, 1.10 to 2.41) and general administration of vasopressors at the ED (RR, 2.14;95% CI, 1.44 to 3.17) were associated with 30-day mortality. The administration of vasopressors at the ED (RR, 2.25; CI 95%, 1.58 to 3.21) was found to be a predictor of overall mortality. CONCLUSIONS: Even though an association was found between qSOFA and ICU admission, there was no association of qSOFA or the severity criteria with mortality. Therefore, patients with a tendency toward greater severity could be identified and treated more quickly and effectively in the emergency department. Further studies are necessary to assess novel scores or biomarkers to predict mortality in sepsis patients admitted to the ED's initial care.

Impact on pulmonary, cardiac, and renal function and long-term quality of life after hospitalization for acute respiratory distress syndrome due to COVID-19: Protocol of the Post-COVID Brazil 3 study.

RATIONALE: Evidence about long-term sequelae after hospitalization for acute respiratory distress syndrome due to COVID-19 is still scarce. PURPOSE: To evaluate changes in pulmonary, cardiac, and renal function and in quality of life after hospitalization for acute respiratory distress syndrome secondary to COVID-19. METHODS: This will be a multicenter case-control study of 220 participants. Eligible are patients who are hospitalized for acute respiratory distress syndrome due to COVID-19. In the control group, individuals with no history of hospitalization in the last 12 months or long-term symptoms of COVID-19 will be selected. All individuals will be subjected to pulmonary spirometry with a carbon monoxide diffusion test, chest tomography, cardiac and renal magnetic resonance imaging with gadolinium, ergospirometry, serum and urinary creatinine, total protein, and urinary microalbuminuria, in addition to quality-of-life questionnaires. Patients will be evaluated 12 months after hospital discharge, and controls will be evaluated within 90 days of inclusion in the study. For all the statistical analyses, p < 0.05 is the threshold for significance. RESULTS: The primary outcome of the study will be the pulmonary diffusing capacity for carbon monoxide measured after 12 months. The other parameters of pulmonary, cardiac, and renal function and quality of life are secondary outcomes. CONCLUSION: This study aims to determine the long-term sequelae of pulmonary, cardiac, and renal function and the quality of life of patients hospitalized for acute respiratory distress syndrome due to COVID-19 in the Brazilian population.

Unmasking the hidden aftermath: postintensive care unit sequelae, discharge preparedness, and long-term follow-up.

A significant portion of individuals who have experienced critical illness encounter new or exacerbated impairments in their physical, cognitive, or mental health, commonly referred to as postintensive care syndrome. Moreover, those who survive critical illness often face an increased risk of adverse consequences, including infections, major cardiovascular events, readmissions, and elevated mortality rates, during the months following hospitalization. These findings emphasize the critical necessity for effective prevention and management of long-term health deterioration in the critical care environment. Although conclusive evidence from well-designed randomized clinical trials is somewhat limited, potential interventions include strategies such as limiting sedation, early mobilization, maintaining family presence during the intensive care unit stay, implementing multicomponent transition programs (from intensive care unit to ward and from hospital to home), and offering specialized posthospital discharge follow-up. This review seeks to provide a concise summary of recent medical literature concerning long-term outcomes following critical illness and highlight potential approaches for preventing and addressing health decline in critical care survivors.

Predictors of bleeding and thrombotic events among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the ACTION randomized clinical trial.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.

Anticipating ICU discharge and long-term follow-up.

PURPOSE OF REVIEW: This review aims to summarize recent literature findings on long-term outcomes following critical illness and to highlight potential strategies for preventing and managing health deterioration in survivors of critical care. RECENT FINDINGS: A substantial number of critical care survivors experience new or exacerbated impairments in their physical, cognitive or mental health, commonly named as postintensive care syndrome (PICS). Furthermore, those who survive critical illness often face an elevated risk of adverse outcomes in the months following their hospital stay, including infections, cardiovascular events, rehospitalizations and increased mortality. These findings underscore the need for effective prevention and management of long-term health deterioration in the critical care setting. While robust evidence from well designed randomized clinical trials is limited, potential interventions encompass sedation limitation, early mobilization, delirium prevention and family presence during intensive care unit (ICU) stay, as well as multicomponent transition programs (from ICU to ward, and from hospital to home) and specialized posthospital discharge follow-up. SUMMARY: In this review, we offer a concise overview of recent insights into the long-term outcomes of critical care survivors and advancements in the prevention and management of health deterioration after critical illness.

Assessing the cost-effectiveness of capnography for end-tidal CO2 monitoring during in-hospital cardiac arrest: A middle-income country perspective analysis.

Study objective: To evaluate the cost-effectiveness of EtCO2 monitoring during in-hospital cardiorespiratory arrest (CA) care outside the intensive care unit (ICU) and emergency room department. Design: We performed a cost-effectiveness analysis based on a simple decision model cost analysis and reported the study using the CHEERS checklist. Model inputs were derived from a retrospective Brazilian cohort study, complemented by information obtained through a literature review. Cost inputs were gathered from both literature sources and contacts with hospital suppliers. Setting: The analysis was carried out from the perspective of a tertiary referral hospital in a middle-income country. Participants: The study population comprised individuals experiencing in-hospital CA who received cardiopulmonary resuscitation (CPR) by rapid response team (RRT) in a hospital ward, not in the ICU or emergency room department. Interventions: Two strategies were assumed for comparison: one with an RRT delivering care without capnography during CPR and the other guiding CPR according to the EtCO2 waveform. Main outcome measures: Incremental cost-effectiveness rate (ICER) to return of spontaneous circulation (ROSC), hospital discharge, and hospital discharge with good neurological outcomes. Results: The ICER for EtCO2 monitoring during CPR, resulting in an absolute increase of one more case with ROSC, hospital discharge, and hospital discharge with good neurological outcome, was calculated at Int$ 515.78 (361.57-1201.12), Int$ 165.74 (119.29-248.4), and Int$ 240.55, respectively. Conclusion: In managing in-hospital CA in the hospital ward, incorporating EtCO2 monitoring is likely a cost-effective measure within the context of a middle-income country hospital with an RRT.

Long-Term Mortality and Health-Related Quality of Life After Continuous Versus Intermittent Renal Replacement Therapy in ICU Survivors: A Secondary Analysis of the Quality of Life After ICU Study.

Purpose: We assessed long-term outcomes in intensive care unit (ICU) survivors with acute kidney injury (AKI) submitted to intermittent or continuous renal replacement therapy (RRT) for comparisons between groups. Methods: The multicenter prospective cohort study included 195 adult ICU survivors with an ICU stay >72 h in 10 ICUs that had at least one episode of AKI treated with intermittent RRT (IRRT) or continuous RRT (CRRT) during ICU stay. The main outcomes were mortality and health-related quality of life (HRQoL). Hospital readmissions and physical dependence were also assessed. Results: Regarding RRT, 83 (42.6%) patients received IRRT and 112 (57.4%) received CRRT. Despite the similarity regarding sociodemographic characteristics, pre-ICU state of health and type of admission between groups, the risk of death (23.5% vs 42.7%; P < .001), the prevalence of sepsis (60.7%) and acute respiratory distress syndrome (17%) were higher at ICU admission among CRRT patients. The severity of critical illness was higher among CRRT patients, regarding the need for mechanical ventilation (75.0% vs 50.6%, P = .002) and vasopressors (91.1% vs 63.9%, P < .001). One year after ICU discharge, 67 of 195 ICU survivors died (34.4%) and, after adjustment for confounders, there were no significant differences in mortality when comparing IRRT and CRTT patients (34.9% vs 33.9%; P = .590), on HRQoL in both physical (41.9% vs 42.2%; P = .926) and mental dimensions (57.6% vs 56.6%; P = .340), and on the number of hospital readmissions and physical dependence. Conclusions: Our study suggests that among ICU survivors RRT modality (IRRT vs CRRT) in the ICU does not impact long-term outcomes after ICU discharge.

Cardiovascular Safety of Azithromycin in Patients Hospitalized With COVID-19: A Prespecified Pooled Analysis of the COALITION I and COALITION II Randomized Clinical Trials.

The cardiovascular safety from azithromycin in the treatment of several infectious diseases has been challenged. In this prespecified pooled analysis of 2 multicenter randomized clinical trials, we aimed to assess whether the use of azithromycin might lead to corrected QT (QTc) interval prolongation or clinically relevant ventricular arrhythmias. In the COALITION COVID Brazil I trial, 667 patients admitted with moderate COVID-19 were randomly allocated to hydroxychloroquine, hydroxychloroquine plus azithromycin, or standard of care. In the COALITION COVID Brazil II trial, 447 patients with severe COVID-19 were randomly allocated to hydroxychloroquine alone versus hydroxychloroquine plus azithromycin. The principal end point for the present analysis was the composite of death, resuscitated cardiac arrest, or ventricular arrhythmias. The addition of azithromycin to hydroxychloroquine did not result in any prolongation of the QTc interval (425.8 ± 3.6 ms vs 427.9 ± 3.9 ms, respectively, mean difference -2.1 ms, 95% confidence interval -12.5 to 8.4 ms, p = 0.70). The combination of azithromycin plus hydroxychloroquine compared with hydroxychloroquine alone did not result in increased risk of the primary end point (proportion of patients with events at 15 days 17.2% vs 16.0%, respectively, hazard ratio 1.08, 95% confidence interval 0.78 to 1.49, p = 0.65). In conclusion, in patients hospitalized with COVID-19 already receiving standard-of-care management (including hydroxychloroquine), the addition of azithromycin did not result in the prolongation of the QTc interval or increase in cardiovascular adverse events. Because azithromycin is among the most commonly prescribed antimicrobial agents, our results may inform clinical practice. Clinical Trial Registration: NCT04322123, NCT04321278.

Impact on pulmonary, cardiac, and renal function and long-term quality of life after hospitalization for acute respiratory distress syndrome due to COVID-19: Protocol of the Post-COVID Brazil 3 study / Impacto nas funções pulmonar, cardíaca e renal e na qualidade de vida a longo prazo após internação por síndrome do desconforto respiratório agudo por COVID-19: protocolo do Estudo 3 Pós-COVID Brasil

ABSTRACT Rationale: Evidence about long-term sequelae after hospitalization for acute respiratory distress syndrome due to COVID-19 is still scarce. Purpose: To evaluate changes in pulmonary, cardiac, and renal function and in quality of life after hospitalization for acute respiratory distress syndrome secondary to COVID-19. Methods: This will be a multicenter case-control study of 220 participants. Eligible are patients who are hospitalized for acute respiratory distress syndrome due to COVID-19. In the control group, individuals with no history of hospitalization in the last 12 months or long-term symptoms of COVID-19 will be selected. All individuals will be subjected to pulmonary spirometry with a carbon monoxide diffusion test, chest tomography, cardiac and renal magnetic resonance imaging with gadolinium, ergospirometry, serum and urinary creatinine, total protein, and urinary microalbuminuria, in addition to quality-of-life questionnaires. Patients will be evaluated 12 months after hospital discharge, and controls will be evaluated within 90 days of inclusion in the study. For all the statistical analyses, p < 0.05 is the threshold for significance. Results: The primary outcome of the study will be the pulmonary diffusing capacity for carbon monoxide measured after 12 months. The other parameters of pulmonary, cardiac, and renal function and quality of life are secondary outcomes. Conclusion: This study aims to determine the long-term sequelae of pulmonary, cardiac, and renal function and the quality of life of patients hospitalized for acute respiratory distress syndrome due to COVID-19 in the Brazilian population.

RESUMO Fundamento: As evidências acerca das sequelas a longo prazo após internação por síndrome do desconforto respiratório agudo por COVID-19 ainda são escassas. Objetivo: Avaliar alterações nas funções pulmonar, cardíaca e renal e na qualidade de vida após internação por síndrome do desconforto respiratório agudo secundária à COVID-19. Métodos: Trata-se de estudo multicêntrico, caso-controle, incluindo 220 participantes. Os casos serão definidos como pacientes hospitalizados por síndrome do desconforto respiratório agudo devido à COVID-19. No Grupo Controle, serão selecionados indivíduos sem histórico de hospitalização nos últimos 12 meses ou sintomas a longo prazo de COVID-19. Todos os indivíduos serão submetidos à espirometria pulmonar com teste de difusão pelo monóxido de carbono, tomografia de tórax, ressonância magnética cardíaca e renal com gadolínio, ergoespirometria, creatinina sérica e urinária, proteínas totais e microalbuminúria urinária, além de questionários de qualidade de vida. Os casos serão avaliados 12 meses após a alta hospitalar e os controles, 90 dias após a inclusão no estudo. Para todas as análises estatísticas, será assumido como significativo o valor p < 0,05. Resultados: O desfecho primário do estudo foi definido com a capacidade de difusão pulmonar aferida para o monóxido de carbono a partir de 12 meses. Os demais parâmetros das funções pulmonar, cardíacas e renal e da qualidade de vida foram definidos como desfechos secundários. Conclusão: Este estudo visa determinar as sequelas a longo prazo nas funções pulmonar, cardíaca e renal e na qualidade de vida de pacientes internados por síndrome do desconforto respiratório agudo devido à COVID-19 na população brasileira.