Use of Electronic Clinical Data to Track Incidence and Mortality for SARS-CoV-2-Associated Sepsis.

Importance: Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis. Objective: To describe the incidence and outcomes of SARS-CoV-2-associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria. Design, Setting, and Participants: This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022. Exposures: SARS-CoV-2-associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2-associated sepsis). Main Outcomes and Measures: Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2-associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models. Results: This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2-associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2-associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2-positive hospitalizations confirmed electronic health record (EHR)-based SARS-CoV-2-associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity). Conclusions and Relevance: In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2-associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2-associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.

Risk of Misleading Conclusions in Observational Studies of Time-to-Antibiotics and Mortality in Suspected Sepsis.

BACKGROUND: Influential studies conclude that each hour until antibiotics increases mortality in sepsis. However, these analyses often (1) adjusted for limited covariates, (2) included patients with long delays until antibiotics, (3) combined sepsis and septic shock, and (4) used linear models presuming each hour delay has equal impact. We evaluated the effect of these analytic choices on associations between time-to-antibiotics and mortality. METHODS: We retrospectively identified 104 248 adults admitted to 5 hospitals from 2015-2022 with suspected infection (blood culture collection and intravenous antibiotics ≤24 h of arrival), including 25 990 with suspected septic shock and 23 619 with sepsis without shock. We used multivariable regression to calculate associations between time-to-antibiotics and in-hospital mortality under successively broader confounding-adjustment, shorter maximum time-to-antibiotic intervals, stratification by illness severity, and removing assumptions of linear hourly associations. RESULTS: Changing covariates, maximum time-to-antibiotics, and severity stratification altered the magnitude, direction, and significance of observed associations between time-to-antibiotics and mortality. In a fully adjusted model of patients treated ≤6 hours, each hour was associated with higher mortality for septic shock (adjusted odds ratio [aOR]: 1.07; 95% CI: 1.04-1.11) but not sepsis without shock (aOR: 1.03; .98-1.09) or suspected infection alone (aOR: .99; .94-1.05). Modeling each hour separately confirmed that every hour of delay was associated with increased mortality for septic shock, but only delays >6 hours were associated with higher mortality for sepsis without shock. CONCLUSIONS: Associations between time-to-antibiotics and mortality in sepsis are highly sensitive to analytic choices. Failure to adequately address these issues can generate misleading conclusions.

Incidence and Outcomes of Non-Ventilator-Associated Hospital-Acquired Pneumonia in 284 US Hospitals Using Electronic Surveillance Criteria.

Importance: Non-ventilator-associated hospital-acquired pneumonia (NV-HAP) is a common and deadly hospital-acquired infection. However, inconsistent surveillance methods and unclear estimates of attributable mortality challenge prevention. Objective: To estimate the incidence, variability, outcomes, and population attributable mortality of NV-HAP. Design, Setting, and Participants: This cohort study retrospectively applied clinical surveillance criteria for NV-HAP to electronic health record data from 284 US hospitals. Adult patients admitted to the Veterans Health Administration hospital from 2015 to 2020 and HCA Healthcare hospitals from 2018 to 2020 were included. The medical records of 250 patients who met the surveillance criteria were reviewed for accuracy. Exposures: NV-HAP, defined as sustained deterioration in oxygenation for 2 or more days in a patient who was not ventilated concurrent with abnormal temperature or white blood cell count, performance of chest imaging, and 3 or more days of new antibiotics. Main Outcomes and Measures: NV-HAP incidence, length-of-stay, and crude inpatient mortality. Attributable inpatient mortality by 60 days follow-up was estimated using inverse probability weighting, accounting for both baseline and time-varying confounding. Results: Among 6 022 185 hospitalizations (median [IQR] age, 66 [54-75] years; 1 829 475 [26.1%] female), there were 32 797 NV-HAP events (0.55 per 100 admissions [95% CI, 0.54-0.55] per 100 admissions and 0.96 per 1000 patient-days [95% CI, 0.95-0.97] per 1000 patient-days). Patients with NV-HAP had multiple comorbidities (median [IQR], 6 [4-7]), including congestive heart failure (9680 [29.5%]), neurologic conditions (8255 [25.2%]), chronic lung disease (6439 [19.6%]), and cancer (5,467 [16.7%]); 24 568 cases (74.9%) occurred outside intensive care units. Crude inpatient mortality was 22.4% (7361 of 32 797) for NV-HAP vs 1.9% (115 530 of 6 022 185) for all hospitalizations; 12 449 (8.0%) were discharged to hospice. Median [IQR] length-of-stay was 16 (11-26) days vs 4 (3-6) days. On medical record review, pneumonia was confirmed by reviewers or bedside clinicians in 202 of 250 patients (81%). It was estimated that NV-HAP accounted for 7.3% (95% CI, 7.1%-7.5%) of all hospital deaths (total hospital population inpatient death risk of 1.87% with NV-HAP events included vs 1.73% with NV-HAP events excluded; risk ratio, 0.927; 95% CI, 0.925-0.929). Conclusions and Relevance: In this cohort study, NV-HAP, which was defined using electronic surveillance criteria, was present in approximately 1 in 200 hospitalizations, of whom 1 in 5 died in the hospital. NV-HAP may account for up to 7% of all hospital deaths. These findings underscore the need to systematically monitor NV-HAP, define best practices for prevention, and track their impact.

Electronic surveillance criteria for non-ventilator-associated hospital-acquired pneumonia: Assessment of reliability and validity.

OBJECTIVE: Surveillance of non-ventilator-associated hospital-acquired pneumonia (NV-HAP) is complicated by subjectivity and variability in diagnosing pneumonia. We compared a fully automatable surveillance definition using routine electronic health record data to manual determinations of NV-HAP according to surveillance criteria and clinical diagnoses. METHODS: We retrospectively applied an electronic surveillance definition for NV-HAP to all adults admitted to Veterans' Affairs (VA) hospitals from January 1, 2015, to November 30, 2020. We randomly selected 250 hospitalizations meeting NV-HAP surveillance criteria for independent review by 2 clinicians and calculated the percent of hospitalizations with (1) clinical deterioration, (2) CDC National Healthcare Safety Network (CDC-NHSN) criteria, (3) NV-HAP according to a reviewer, (4) NV-HAP according to a treating clinician, (5) pneumonia diagnosis in discharge summary; and (6) discharge diagnosis codes for HAP. We assessed interrater reliability by calculating simple agreement and the Cohen κ (kappa). RESULTS: Among 3.1 million hospitalizations, 14,023 met NV-HAP electronic surveillance criteria. Among reviewed cases, 98% had a confirmed clinical deterioration; 67% met CDC-NHSN criteria; 71% had NV-HAP according to a reviewer; 60% had NV-HAP according to a treating clinician; 49% had a discharge summary diagnosis of pneumonia; and 82% had NV-HAP according to any definition according to at least 1 reviewer. Only 8% had diagnosis codes for HAP. Interrater agreement was 75% (κ = 0.50) for CDC-NHSN criteria and 78% (κ = 0.55) for reviewer diagnosis of NV-HAP. CONCLUSIONS: Electronic NV-HAP surveillance criteria correlated moderately with existing manual surveillance criteria. Reviewer variability for all manual assessments was high. Electronic surveillance using clinical data may therefore allow for more consistent and efficient surveillance with similar accuracy compared to manual assessments or diagnosis codes.

Ultra-Short-Course Antibiotics for Suspected Pneumonia With Preserved Oxygenation.

BACKGROUND: Suspected pneumonia is the most common indication for antibiotics in hospitalized patients but is frequently overdiagnosed. We explored whether normal oxygenation could be used as an indicator to support early discontinuation of antibiotics. METHODS: We retrospectively identified all patients started on antibiotics for pneumonia in 4 hospitals with oxygen saturations ≥95% on ambient air, May 2017-February 2021. We propensity-matched patients treated 1-2 days vs 5-8 days and compared hospital mortality and time to discharge using subdistribution hazard ratios (SHRs). Secondary outcomes included readmissions, 30-day mortality, Clostridioides difficile infections, hospital-free days, and antibiotic-free days. RESULTS: Among 39 752 patients treated for possible pneumonia, 10 012 had median oxygen saturations ≥95% without supplemental oxygen. Of these, 2871 were treated 1-2 days and 2891 for 5-8 days; 4478 patients were propensity-matched. Patients treated 1-2 vs 5-8 days had similar hospital mortality (2.1% vs 2.8%; SHR, 0.75 [95% confidence interval {CI}, .51-1.09]) but less time to discharge (6.1 vs 6.6 days; SHR, 1.13 [95% CI, 1.07-1.19]) and more 30-day hospital-free days (23.1 vs 22.7; mean difference, 0.44 [95% CI, .09-.78]). There were no significant differences in 30-day readmissions (16.0% vs 15.8%; odds ratio [OR], 1.01 [95% CI, .86-1.19]), 30-day mortality (4.6% vs 5.1%; OR, 0.91 [95% CI, .69-1.19]), or 90-day C. difficile infections (1.3% vs 0.8%; OR, 1.67 [95% CI, .94-2.99]). CONCLUSIONS: One-quarter of hospitalized patients treated for pneumonia had oxygenation saturations ≥95% on ambient air. Outcomes were similar with 1-2 vs 5-8 days of antibiotics. Normal oxygenation levels may help identify candidates for early antibiotic discontinuation. Prospective trials are warranted.

Sjögren's Syndrome Associated Dry Eye: Impact on Daily Living and Adherence to Therapy.

Sjögren's syndrome-related dry eye disease (SS-DED) often involves more severe dry eye symptoms than people with non-SS dry eye disease (DED). This cross-sectional study employed an anonymous self-administered questionnaire to understand the experience of people living with SS-DED and to identify factors affecting adherence to DED self-care. Participants reported difficulty with visual tasks such as driving, and diminished enjoyment in daily activities due to DED symptoms. Almost 80% reported being worried about a reduced quality of life due to DED, and over 50% reported fear of blindness. The most common reasons for non-adherence were cost of therapy and forgetting to instill drops. Drop rationing to reduce cost of therapy was endorsed by 83% of respondents. Only 3% of respondents had private insurance for non-prescription agents required to treat DED. A quarter of respondents reported they would not disclose non-adherence to their eye care provider. Multiple regression analysis revealed age was a significant contributor to missing drops. This is the first study to report on the financial burden experienced by SS-DED patients in Canada. This paper identified strategies used by patients to reduce the cost of therapy and its impact on adherence to treatment. Patients may be reluctant to disclose challenges regarding adherence to DED therapy, as well as fears of worsening quality of life.

Prevalence of Clinical Signs Within Reference Ranges Among Hospitalized Patients Prescribed Antibiotics for Pneumonia.

Importance: Antibiotics are frequently prescribed for suspected pneumonia, but overdiagnosis is common and fixed regimens are often used despite randomized trials suggesting it is safe to stop antibiotics once clinical signs are normalizing. Objective: To quantify potential excess antibiotic prescribing by characterizing antibiotic use relative to patients' initial clinical signs and subsequent trajectories. Design, Setting, and Participants: An observational cohort study was conducted in 2 tertiary and 2 community hospitals in Eastern Massachusetts. All nonventilated adult patients admitted between May 1, 2017, and July 1, 2018 (194 521 hospitalizations), were included. Main Outcomes and Measures: Identification of all antibiotic starts for possible community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP) per clinicians' stated indications. Potential excess antibiotic prescribing was quantified by characterizing the frequency of patients in whom all clinical signs were within reference ranges on the first day of antibiotic therapy and by how long antibiotic therapy was continued after all clinical signs were normal, including postdischarge antibiotics. Results: Among 194 521 hospitalizations, 9540 patients were treated for possible CAP (4574 [48.0%] women; mean [SD] age, 67.6 [17.0] years) and 2733 for possible HAP (1211 [44.3%] women; mean [SD] age, 66.7 [16.2] years). Temperature, respiratory rate, oxygen saturation, and white blood cell count were all within reference ranges on the first day of antibiotics in 1779 of 9540 (18.6%) episodes of CAP and 370 of 2733 (13.5%) episodes of HAP. Antibiotics were continued for 3 days or longer after all clinical signs were normal in 3322 of 9540 (34.8%) episodes of CAP and 1050 of 2733 (38.4%) episodes of HAP. Up to 24 978 of 71 706 (34.8%) antibiotic-days prescribed for possible pneumonia may have been unnecessary. Conclusions and Relevance: In this study, almost one-fifth of hospitalized patients treated for pneumonia did not have any of the cardinal signs of pneumonia on the first day of treatment and antibiotics were continued for 3 days or longer after all signs were normal in more than a third of patients. These observations suggest substantial opportunities to improve antibiotic prescribing.

Women's decision-making power and undernutrition in their children under age five in the Democratic Republic of the Congo: A cross-sectional study.

Undernutrition in children remains a major global health issue and the prevalence of undernutrition in children under age five in the Democratic Republic of the Congo (DRC) is among the highest in the world. Both biological and socioeconomic factors contribute to undernutrition, and the literature reports an association between women's empowerment and lower rates of child undernutrition in sub-Saharan Africa. However, the relationship between women's decision-making power and child undernutrition is less understood. The objective of this study was to evaluate the association between women's decision-making power and stunting/wasting in their children under age five in the DRC. This study used cross-sectional data from the 2013-2014 DRC Demographic and Health Survey, from which a sample of 3,721 woman-child pairs were identified. Women were classified as having decision-making power in five decision-making dimensions if they participated in the decision either alone or jointly with their husband or partner or someone else. Child height-for-age and weight-for-height Z-scores were used to determine stunting and wasting, respectively, according to the World Health Organization Child Growth Standards. Multivariate regression analyses demonstrated that none of the five dimensions of decision-making power were associated with stunting or wasting in children. Further research that evaluates women's decision-making power with more detailed, relevant and context-specific measures is warranted to more accurately investigate women's decision-making power and undernutrition in children.

Development and Assessment of Objective Surveillance Definitions for Nonventilator Hospital-Acquired Pneumonia.

Importance: Hospital-acquired pneumonia is the most common health care-associated infection in the United States. Most cases occur in nonventilated patients, but many hospitals track hospital-acquired pneumonia only in ventilated patients because of the complexity and subjectivity of conducting surveillance for large numbers of nonventilated patients. Objective: To propose and assess potentially objective, efficient, and reproducible surveillance definitions for nonventilator hospital-acquired pneumonia (NV-HAP) using routine clinical data stored in electronic health record systems. Design, Setting, and Participants: This cohort study was conducted in 2 tertiary referral and 2 community hospitals in Massachusetts between May 31, 2015, and July 1, 2018. All nonventilated patients aged 18 years or older who were admitted to these hospitals were included (N = 310 651). Exposures: Ten candidate definitions for NV-HAP based on clinically meaningful combinations of 6 potential surveillance criteria were proposed: worsening oxygenation, temperature higher than 38 °C (fever), abnormal white blood cell count of less than 4000/µL or more than 12 000/µL, performance of chest imaging, submission of respiratory specimen for culture, and 3 or more days of new antibiotics. Main Outcomes and Measures: Incidence rates, lengths of stay, hospital mortality rates, and odds ratios (ORs) for time to discharge and mortality compared with those of matched controls were calculated for each candidate definition. The ORs were adjusted for demographics, clinical service, comorbidities, and severity of illness. Results: The study analyzed 310 651 patients with 489 519 admissions, including 205 054 patients with 311 484 admissions of 3 or more days. Among the patients with 311 484 admissions, the mean (SD) patient age was 58.3 (19.3) years and 176 936 (56.8%) were of women. Incidence rates for candidate definitions per 100 admissions ranged from 3.4 events for worsening oxygenation alone to 0.9 event for worsening oxygenation and at least 3 days of new antibiotics to 0.6 event for worsening oxygenation, at least 3 days of new antibiotics, fever, abnormal white blood cell count, and performance of chest imaging. Crude mortality rates ranged from 16.1% (n = 2643) for patients with worsening oxygen alone to 27.7% (n = 868) for patients with worsening oxygenation, at least 3 days of antibiotics, fever or abnormal white blood cell count, and chest imaging. Patients who met NV-HAP candidate definitions remained in the hospital for twice as long as their matched controls (adjusted ORs ranged from 1.8 [95% CI, 1.7-1.8] to 2.1 [95% CI, 2.0-2.1]) and were 4 to 6 times as likely to die in the hospital (adjusted ORs ranged from 3.8 [95% CI, 3.5-4.0] to 6.5 [95% CI, 5.2-8.2]). Agreement between candidate definitions and clinical diagnoses was fair (κ = 0.33). Conclusions and Relevance: These findings suggest that objective surveillance for NV-HAP using electronically computable definitions that incorporate common clinical criteria is feasible and generates incidence, mortality, and adjusted ORs for hospital mortality similar to estimates from manual surveillance. These definitions have the potential to facilitate widespread, automated surveillance for NV-HAP and thus inform the development and evaluation of prevention programs.

Zika Virus Persistently and Productively Infects Primary Adult Sensory Neurons In Vitro.

Zika virus (ZIKV) has recently surged in human populations, causing an increase in congenital and Guillain-Barré syndromes. While sexual transmission and presence of ZIKV in urine, semen, vaginal secretions, and saliva have been established, the origin of persistent virus shedding into biological secretions is not clear. Using a primary adult murine neuronal culture model, we have determined that ZIKV persistently and productively infects sensory neurons of the trigeminal and dorsal root ganglia, which innervate glands and mucosa of the face and the genitourinary tract, respectively, without apparent injury. Autonomic neurons that innervate these regions are not permissive for infection. However, productive ZIKV infection of satellite glial cells that surround and support sensory and autonomic neurons in peripheral ganglia results in their destruction. Persistent infection of sensory neurons, without affecting their viability, provides a potential reservoir for viral shedding in biological secretions for extended periods of time after infection. Furthermore, viral destruction of satellite glial cells may contribute to the development of Guillain-Barré Syndrome via an alternative mechanism to the established autoimmune response.

Patterns of species range evolution in Indo-Pacific reef assemblages reveal the Coral Triangle as a net source of transoceanic diversity.

The Coral Triangle in the Indo-Pacific is a region renowned for exceptional marine biodiversity. The area could have acted as a 'centre of origin' where speciation has been prolific or a 'centre of survival' by providing refuge during major environmental shifts such as sea-level changes. The region could also have acted as a 'centre of accumulation' for species with origins outside of the Coral Triangle, owing to it being at a central position between the Indian and Pacific oceans. Here, we investigated support for these hypotheses using population-level DNA sequence-based reconstructions of the range evolution of 45 species (314 populations) of Indo-Pacific reef-associated organisms. Our results show that populations undergoing the most ancient establishment were significantly more likely to be closer to the centre of the Coral Triangle than to peripheral locations. The data are consistent with the Coral Triangle being a net source of coral-reef biodiversity for the Indo-Pacific region, suggesting that the region has acted primarily as a centre of survival, a centre of origin or both. These results provide evidence of how a key location can influence the large-scale distributions of biodiversity over evolutionary timescales.