Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study.

Background: The emergence of COVID-19 variants with immune scape and the waning of primary vaccine schemes effectiveness have prompted many countries to indicate first and second booster COVID-19 vaccine doses to prevent severe COVID-19. However, current available evidence on second booster dose effectiveness are mostly limited to high-income countries, older adults, and mRNA-based vaccination schemes scenarios. We aimed to investigate the relative vaccine effectiveness (rVE) of the fourth dose compared to three doses for severe COVID-19 outcomes in Brazil; and compare the rVE of a fourth dose with an mRNA vaccine compared to adenovirus-based product in the same settings. Methods: We performed a target emulated trial using a population-based cohort of individuals aged 40 years or older who have received a homologous primary scheme of CoronaVac, ChAdOx1, or BNT162b2, and any third dose product and were eligible for the fourth dose in Brazil. The primary outcome was COVID-19 associated hospitalization or death. We built Cohort A matching individuals vaccinated with a fourth dose to individuals who received three doses to estimate the rVE of the fourth dose. We built Cohort B, a subset of Cohort A, matching mRNA-based (mRNA) to adenovirus-based fourth dose vaccinated individuals to compare their relative hazards for severe COVID-19. Findings: 46,693,484 individuals were included in Cohort A and 6,763,016 in Cohort B. 45% of them were aged between 40 and 60 years old, and 48% between 60 and 79 years old. In Cohort A, the most common previous series was a ChAdOx1 two-dose followed by BNT162b2 (44%), and a CoronaVac two-dose followed by a BNT162b2 (36%). Among those fourth dose vaccinated, 36.9% received ChAdOx1, 32.7% Ad26.COV2.S, 25.8% BNT162b2, and 4.7% CoronaVac. In Cohort B, among those who received an adenovirus fourth dose, 53.7% received ChAdOx1 and 46.3% received Ad26.COV2.S. The estimated rVE for the primary outcome of four doses compared to three doses was 44.1% (95% CI 42.3-46.0), with some waning during follow-up (rVE 7-60 days 46.8% [95% CI 44.4-49.1], rVE after 120 days 33.8% [95% CI 18.0-46.6]). Among fourth dose vaccinated individuals, mRNA-based vaccinated individuals had lower hazards for hospitalization or death compared to adenovirus-vaccinated individuals (HR 0.81, 95% CI 0.75-0.87). After 120 days, no difference in hazards between groups was observed (HR 1.35, 95% CI 0.93-1.97). Similar findings were observed for hospitalization and death separately, except no evidence for differences between fourth dose brands for death in Cohort B. Interpretation: In a heterogeneous scenario of primary and first booster vaccination combinations, a fourth dose provided meaningful and durable protection against severe COVID-19 outcomes. Compared to adenovirus-based booster, a fourth dose wild-type mRNA vaccine was associated with immediate lower hazards of hospitalization or death unsustained after 120 days. Funding: None.

Are hematopoietic cell transplant recipients with Gram-negative bacteremia spending more time outpatient while on intravenous antibiotics? Addressing trends over 10 years at a single center.

INTRODUCTION: The increasing proportion of outpatient allogeneic hematopoietic cell transplants (HCTs) coupled with increased access of once-daily broad-spectrum antibiotics and evidence that outpatient antibiotic treatment may be safer and less costly than inpatient treatment, suggest that allogeneic HCT recipients with Gram-negative rod bacteremia (GNRBs) are increasingly being treated in ambulatory care settings. METHODS: Using data from the first GNRB event that occurred within the first 100 days posttransplantation among allogeneic HCT recipients transplanted at a single center between 2007 and 2016, we estimated the temporal trends in GNRB incidence and treatment management of GNRBs and identified if patient or infection characteristics impacted observed trends. RESULTS: A total of 11% (238/2165) of the observed allogeneic HCT recipients experienced ≥1 GNRB with available resistance data and contributed antibiotic treatment time. Patients, on average, received 55.1% of their antibiotic treatment in an outpatient setting and we observed a significant decline in the proportion of treatment time spent outpatient (crude: -3.3% [95% confidence interval: -5.0, -1.6%]). We observed similar declines in the proportion of treatment time spent outpatient among patients with similar GNRB and pretransplant complexity factors but not among patients with similar posttransplant complications (p value: .165). CONCLUSION: These results suggest that, despite increased availability of outpatient suitable treatment options, allogeneic HCT recipients with GNRBs received less treatment in outpatient settings. However, among patients with similar posttransplant complications, the lack of significant decline suggests that treatment location decisions remained consistent for patients with similar posttransplant complications. These findings suggest the need for additional interventions targeting outpatient antibiotic treatment among allogeneic HCT recipients with GNRBs.

Limits of the Glasgow Coma Scale When Assessing for Sepsis in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: The well-documented association between acute mental status changes and sepsis development and progression makes acute mental status an attractive factor for sepsis screening tools. However, the usefulness of acute mental status within these criteria is limited to the frequency and accuracy of its capture. The Glasgow Coma Scale (GCS) score-the acute mental status indicator in many clinical sepsis criteria-is infrequently captured among allogeneic hematopoietic cell transplant recipients with suspected infections, and its ability to serve as an indicator of acute mental status among this high-risk population is unknown. OBJECTIVE: We evaluated the GCS score as an indicator of acute mental status during the 24 hours after suspected infection onset among allogeneic hematopoietic cell transplant recipients. METHODS: Using data from the first 100 days posttransplant for patients transplanted at a single center between September 2010 and July 2017, we evaluated the GCS score as an indicator of documented acute mental status during the 24 hours after suspected infection onset. From all inpatients with suspected infections, we randomly selected a cohort based on previously published estimates of GCS score frequency among hematopoietic cell transplant recipients with suspected infections and performed chart review to ascertain documentation of clinical acute mental status within the 24 hours after suspected infection onset. RESULTS: A total of 773 patients had ≥1 suspected infections and experienced 1,655 suspected infections during follow-up-625 of which had an accompanying GCS score. Among the randomly selected cohort of 100 persons with suspected infection, 28 were accompanied with documented acute mental status, including 18 without a recorded GCS. In relation to documented acute mental status, the GCS had moderate to high sensitivity and high specificity. DISCUSSION: These data indicate that, among allogeneic hematopoietic cell transplant recipients with suspected infections, the GCS scores are infrequently collected and have a moderate sensitivity. If sepsis screening tools inclusive of acute mental status changes are to be used, nursing teams need to increase measurement of GCS scores among high sepsis risk patients or identify a standard alternative indicator.

Development and Validation of a Machine Learning Model to Estimate Bacterial Sepsis Among Immunocompromised Recipients of Stem Cell Transplant.

Importance: Sepsis disproportionately affects recipients of allogeneic hematopoietic cell transplant (allo-HCT), and timely detection is crucial. However, the atypical presentation of sepsis within this population makes detection challenging, and existing clinical sepsis tools have limited prognostic value among this high-risk population. Objective: To develop a full risk factor (demographic, transplant, clinical, and laboratory factors) and clinical factor-specific automated bacterial sepsis decision support tool for recipients of allo-HCT with potential bloodstream infections (PBIs). Design, Setting, and Participants: This prognostic study used data from adult recipients of allo-HCT transplanted at the Fred Hutchinson Cancer Research Center, Seattle, Washington, between June 2010 and June 2019 randomly divided into 70% modeling and 30% validation data sets. Tools were developed using the area under the curve (AUC) optimized SuperLearner, and their performance was compared with existing clinical sepsis tools: National Early Warning Score (NEWS), quick Sequential Organ Failure Assessment (qSOFA), and Systemic Inflammatory Response Syndrome (SIRS), using the validation data set. Data were analyzed between January and October of 2020. Main Outcomes and Measures: The primary outcome was high-sepsis risk bacteremia (culture confirmed gram-negative species, Staphylococcus aureus, or Streptococcus spp bacteremia), and the secondary outcomes were 10- and 28-day mortality. Tool discrimination and calibration were examined using accuracy metrics and expected vs observed probabilities. Results: Between June 2010 and June 2019, 1943 recipients of allo-HCT received their first transplant, and 1594 recipients (median [interquartile range] age at transplant, 54 [43-63] years; 911 [57.2%] men; 1242 individuals [77.9%] identifying as White) experienced at least 1 PBI. Of 8131 observed PBIs, 238 (2.9%) were high-sepsis risk bacteremia. Compared with high-sepsis risk bacteremia, the full decision support tool had the highest AUC (0.85; 95% CI, 0.81-0.89), followed by the clinical factor-specific tool (0.72; 95% CI, 0.66-0.78). SIRS had the highest AUC of existing tools (0.64; 95% CI, 0.57-0.71). The full decision support tool had the highest AUCs for PBIs identified in inpatient (0.82; 95% CI, 0.76-0.89) and outpatient (0.82; 95% CI, 0.75-0.89) settings and for 10-day (0.85; 95% CI, 0.79-0.91) and 28-day (0.80; 95% CI, 0.75-0.84) mortality. Conclusions and Relevance: These findings suggest that compared with existing tools and the clinical factor-specific tool, the full decision support tool had superior prognostic accuracy for the primary (high-sepsis risk bacteremia) and secondary (short-term mortality) outcomes in inpatient and outpatient settings. If used at the time of culture collection, the full decision support tool may inform more timely sepsis detection among recipients of allo-HCT.

Predictive Value of 3 Clinical Criteria for Sepsis (Quick Sequential Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and National Early Warning Score) With Respect to Short-term Mortality in Allogeneic Hematopoietic Cell Transplant Recipients With Suspected Infections.

BACKGROUND: Sepsis disproportionately affects allogeneic hematopoietic cell transplant (HCT) recipients and is challenging to define. Clinical criteria that predict mortality and intensive care unit end-points in patients with suspected infections (SIs) are used in sepsis definitions, but their predictive value among immunocompromised populations is largely unknown. Here, we evaluate 3 criteria among allogeneic HCT recipients with SIs. METHODS: We evaluated Systemic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) in relation to short-term mortality among recipients transplanted between September 2010 and July 2017. We used cut-points of ≥ 2 for qSOFA/SIRS and ≥ 7 for NEWS and restricted to first SI per hospital encounter during patients' first 100 days posttransplant. RESULTS: Of the 880 recipients who experienced ≥ 1 SI, 58 (6.6%) died within 28 days and 22 (2.5%) within 10 days of an SI. In relation to 10-day mortality, SIRS was the most sensitive (91.3% [95% confidence interval {CI}, 72.0%-98.9%]) but least specific (35.0% [95% CI, 32.6%-37.5%]), whereas qSOFA was the most specific (90.5% [95% CI, 88.9%-91.9%]) but least sensitive (47.8% [95% CI, 26.8%-69.4%]). NEWS was moderately sensitive (78.3% [95% CI, 56.3%-92.5%]) and specific (70.2% [95% CI, 67.8%-72.4%]). CONCLUSIONS: NEWS outperformed qSOFA and SIRS, but each criterion had low to moderate predictive accuracy, and the magnitude of the known limitations of qSOFA and SIRS was at least as large as in the general population. Our data suggest that population-specific criteria are needed for immunocompromised patients.

A Targeted Screening Program for Latent Tuberculosis Infection Among Hematopoietic Cell Transplant Recipients.

BACKGROUND: US hematopoietic cell transplantation (HCT) recipients have a low prevalence of latent tuberculosis infection (LTBI), but if latently infected they are at risk for progression to active tuberculosis. At our center, all HCT recipients underwent LTBI testing pretransplant by tuberculin skin testing (TST) until 2013 when we implemented a targeted screening program. Our objective was to assess the utility of our screening program that incorporated a pretransplant LTBI questionnaire to target TST and QuantiFERON TB Gold (QFT) testing. METHODS: We performed a retrospective cohort study of HCT recipients undergoing first transplant from 2014 to 2016. Patients with positive, indeterminate, and a subset with negative QFT results underwent electronic medical record (EMR) review to assess TST results and risk factors for LTBI. RESULTS: Among 1290 eligible recipients, 457 (35%) had at least 1 risk factor for LTBI on the pretransplant questionnaire; nonwhites were more likely to undergo LTBI testing (P < .0001). Overall, 16 of 1290 (1.2%) had at least 1 positive LTBI test. Of those screened by QFT, 14 of 457 (3%) were positive and 52 (11%) were indeterminate. Among those undergoing EMR review, 123 of 267 (46%) had TST records; 4 of 123 (3%) positive by both TST and QFT, and 2 (2%) by TST alone. Two or more risk factors were reported among the majority of LTBI-positive patients (15 of 16 [94%]). All patients with at least 1 positive test for LTBI (n = 16) were evaluated, and 11 of 16 (69%) were recommended to receive treatment. CONCLUSIONS: Incorporating a pretransplant LTBI questionnaire allowed for an approximate 65% reduction in LTBI testing when compared with universal testing among this low prevalence population.

Ventilator-associated events, not ventilator-associated pneumonia, is associated with higher mortality in trauma patients.

BACKGROUND: Ventilator-associated events (VAE), using objective diagnostic criteria, are the preferred quality indicator for patients requiring mechanical ventilation (MV) for greater than 48 hours. We aim to identify the occurrence of VAE in our trauma population, the impact on survival, and length of stay, as compared to the traditional definition of ventilator-associated pneumonia (VAP). METHODS: This retrospective review included adult trauma patients, who were Washington residents, admitted between 2012 and 2017, and required at least 3 days of MV. Exclusions included patients with Abbreviated Injury Scale head score greater than 4 and burn related mechanisms of injury. We matched trauma registry data with our institutional, physician-adjudicated, and culture-confirmed ventilator event database. We compared the clinical outcomes of ventilator-free days, intensive care unit length of stay, hospital length of stay, and likelihood of death between VAE and VAP. RESULTS: One thousand five hundred thirty-three trauma patients met criteria; 124 (8.1%) patients developed VAE, 114 (7.4%) patients developed VAP, and 63 (4.1%) patients met criteria for both VAE and VAP. After adjusted analyses, patients with VAE were more likely to die (hazard ratio [HR], 2.86; 95% confidence interval [CI], 1.44-5.68), than those with VAP, as well those patients with neither diagnosis (HR, 2.83; 95% CI, 1.83-4.38). Patients with VAP were no more likely to die (HR, 1.55; 95% CI, 0.91-2.68) than those with neither diagnosis. Patients with VAE had fewer ventilator-free days than those with VAP (HR, -2.71; 95% CI, -4.74 to -0.68). CONCLUSION: Critically injured trauma patients who develop VAE are three times more likely to die and utilize almost 3 days more MV than those that develop VAP. The objective criteria of VAE make it a promising indicator on which quality indicator efforts should be focused. Future studies should be aimed at identification of modifiable risk factors for VAE and their impact on outcome, as these patients are at high risk for death. LEVEL OF EVIDENCE: Retrospective cohort study, level III.