Multiple models for outbreak decision support in the face of uncertainty.

Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Heterologous vaccination interventions to reduce pandemic morbidity and mortality: Modeling the US winter 2020 COVID-19 wave.

COVID-19 remains a stark health threat worldwide, in part because of minimal levels of targeted vaccination outside high-income countries and highly transmissible variants causing infection in vaccinated individuals. Decades of theoretical and experimental data suggest that nonspecific effects of non-COVID-19 vaccines may help bolster population immunological resilience to new pathogens. These routine vaccinations can stimulate heterologous cross-protective effects, which modulate nontargeted infections. For example, immunization with Bacillus Calmette-Guérin, inactivated influenza vaccine, oral polio vaccine, and other vaccines have been associated with some protection from SARS-CoV-2 infection and amelioration of COVID-19 disease. If heterologous vaccine interventions (HVIs) are to be seriously considered by policy makers as bridging or boosting interventions in pandemic settings to augment nonpharmaceutical interventions and specific vaccination efforts, evidence is needed to determine their optimal implementation. Using the COVID-19 International Modeling Consortium mathematical model, we show that logistically realistic HVIs with low (5 to 15%) effectiveness could have reduced COVID-19 cases, hospitalization, and mortality in the United States fall/winter 2020 wave. Similar to other mass drug administration campaigns (e.g., for malaria), HVI impact is highly dependent on both age targeting and intervention timing in relation to incidence, with maximal benefit accruing from implementation across the widest age cohort when the pandemic reproduction number is >1.0. Optimal HVI logistics therefore differ from optimal rollout parameters for specific COVID-19 immunizations. These results may be generalizable beyond COVID-19 and the US to indicate how even minimally effective heterologous immunization campaigns could reduce the burden of future viral pandemics.

The Immunologists' Guide to Pandemic Preparedness.

Immunologists are central to fighting any pandemic. From pathogenesis to disease modeling, pharmaceuticals to vaccines, immunologists play a crucial role in translating basic science into effective response strategies. This article describes our view on how lessons from the coronavirus disease 2019 (COVID-19) pandemic can be developed into an immunologists' guide for preparedness for future pandemics.

Systematic Review of Hospital Treatment Outcomes for Naturally Acquired and Bioterrorism-Related Anthrax, 1880-2018.

BACKGROUND: Bacillus anthracis can cause anthrax and is a potential bioterrorism agent. The 2014 Centers for Disease Control and Prevention recommendations for medical countermeasures against anthrax were based on in vitro data and expert opinion. However, a century of previously uncompiled observational human data that often includes treatment and outcomes is available in the literature for analysis. METHODS: We reviewed treatment outcomes for patients hospitalized with anthrax. We stratified patients by meningitis status, route of infection, and systemic criteria, then analyzed survival by treatment type, including antimicrobials, antitoxin/antiserum, and steroids. Using logistic regression, we calculated odds ratios and 95% confidence intervals to compare survival between treatments. We also calculated hospital length of stay. Finally, we evaluated antimicrobial postexposure prophylaxis (PEPAbx) using data from a 1970 Russian-language article. RESULTS: We identified 965 anthrax patients reported from 1880 through 2018. After exclusions, 605 remained: 430 adults, 145 children, and 30 missing age. Survival was low for untreated patients and meningitis patients, regardless of treatment. Most patients with localized cutaneous or nonmeningitis systemic anthrax survived with 1 or more antimicrobials; patients with inhalation anthrax without meningitis fared better with at least 2. Bactericidal antimicrobials were effective for systemic anthrax; addition of a protein synthesis inhibitor(s) (PSI) to a bactericidal antimicrobial(s) did not improve survival. Likewise, addition of antitoxin/antiserum to antimicrobials did not improve survival. Mannitol improved survival for meningitis patients, but steroids did not. PEPAbx reduced risk of anthrax following exposure to B. anthracis. CONCLUSIONS: Combination therapy appeared to be superior to monotherapy for inhalation anthrax without meningitis. For anthrax meningitis, neither monotherapy nor combination therapy were particularly effective; however, numbers were small. For localized cutaneous anthrax, monotherapy was sufficient. For B. anthracis exposures, PEPAbx was effective.

Clinical Features of Patients Hospitalized for All Routes of Anthrax, 1880-2018: A Systematic Review.

BACKGROUND: Anthrax is a toxin-mediated zoonotic disease caused by Bacillus anthracis, with a worldwide distribution recognized for millennia. Bacillus anthracis is considered a potential biowarfare agent. METHODS: We completed a systematic review for clinical and demographic characteristics of adults and children hospitalized with anthrax (cutaneous, inhalation, ingestion, injection [from contaminated heroin], primary meningitis) abstracted from published case reports, case series, and line lists in English from 1880 through 2018, assessing treatment impact by type and severity of disease. We analyzed geographic distribution, route of infection, exposure to anthrax, and incubation period. RESULTS: Data on 764 adults and 167 children were reviewed. Most cases reported for 1880 through 1915 were from Europe; those for 1916 through 1950 were from North America; and from 1951 on, cases were from Asia. Cutaneous was the most common form of anthrax for all populations. Since 1960, adult anthrax mortality has ranged from 31% for cutaneous to 90% for primary meningitis. Median incubation periods ranged from 1 day (interquartile range [IQR], 0-4) for injection to 7 days (IQR, 4-9) for inhalation anthrax. Most patients with inhalation anthrax developed pleural effusions and more than half with ingestion anthrax developed ascites. Treatment and critical care advances have improved survival for those with systemic symptoms, from approximately 30% in those untreated to approximately 70% in those receiving antimicrobials or antiserum/antitoxin. CONCLUSIONS: This review provides an improved evidence base for both clinical care of individual anthrax patients and public health planning for wide-area aerosol releases of B. anthracis spores.

Heterologous vaccine interventions: boosting immunity against future pandemics.

While vaccines traditionally have been designed and used for protection against infection or disease caused by one specific pathogen, there are known off-target effects from vaccines that can impact infection from unrelated pathogens. The best-known non-specific effects from an unrelated or heterologous vaccine are from the use of the Bacillus Calmette-Guérin (BCG) vaccine, mediated partly through trained immunity. Other vaccines have similar heterologous effects. This review covers molecular mechanisms behind the heterologous effects, and the potential use of heterologous vaccination in the current COVID-19 pandemic. We then discuss novel pandemic response strategies based on rapidly deployed, widespread heterologous vaccination to boost population-level immunity for initial, partial protection against infection and/or clinical disease, while specific vaccines are developed.

Extreme immunotherapy: emergency immunology to defeat pandemics.

The ongoing global COVID-19 pandemic has thrown into sharp relief the gap between modern biology's ability to investigate and respond to a novel pathogen and modern medicine's ability to marshal effective front-line interventions to limit its immediate health impact. While we have witnessed the rapid development of innovative vaccines against SARS-CoV-2 using novel molecular platforms, these have yet to alter the pandemic's long-term trajectory in all but a handful of high-income countries. Health workers at the clinical front lines have little more in their clinical armamentarium than was available a century ago-chiefly oxygen and steroids-and yet advances in modern immunology and immunotherapeutics suggest an underuse of extant and effective, if unorthodox, therapies, which we now call "Extreme Immunotherapies for Pandemics (EIPs)."

Development and Performance of a Checklist for Initial Triage After an Anthrax Mass Exposure Event.

Background: Population exposure to Bacillus anthracis spores could cause mass casualties requiring complex medical care. Rapid identification of patients needing anthrax-specific therapies will improve patient outcomes and resource use. Objective: To develop a checklist that rapidly distinguishes most anthrax from nonanthrax illnesses on the basis of clinical presentation and identifies patients requiring diagnostic testing after a population exposure. Design: Comparison of published anthrax case reports from 1880 through 2013 that included patients seeking anthrax-related care at 2 epicenters of the 2001 U.S. anthrax attacks. Setting: Outpatient and inpatient. Patients: 408 case patients with inhalation, ingestion, and cutaneous anthrax and primary anthrax meningitis, and 657 control patients. Measurements: Diagnostic test characteristics, including positive and negative likelihood ratios (LRs) and patient triage assignation. Results: Checklist-directed triage without diagnostic testing correctly classified 95% (95% CI, 93% to 97%) of 353 adult anthrax case patients and 76% (CI, 73% to 79%) of 647 control patients (positive LR, 3.96 [CI, 3.45 to 4.55]; negative LR, 0.07 [CI, 0.04 to 0.11]; false-negative rate, 5%; false-positive rate, 24%). Diagnostic testing was needed for triage in up to 5% of case patients and 15% of control patients and improved overall test characteristics (positive LR, 8.90 [CI, 7.05 to 11.24]; negative LR, 0.06 [CI, 0.04 to 0.09]; false-negative rate, 5%; false-positive rate, 11%). Checklist sensitivity and specificity were minimally affected by inclusion of pediatric patients. Sensitivity increased to 97% (CI, 94% to 100%) and 98% (CI, 96% to 100%), respectively, when only inhalation anthrax cases or higher-quality case reports were investigated. Limitations: Data on case patients were limited to nonstandardized, published observational reports, many of which lacked complete data on symptoms and signs of interest. Reporting bias favoring more severe cases and lack of intercurrent outbreaks (such as influenza) in the control populations may have improved test characteristics. Conclusion: A brief checklist covering symptoms and signs can distinguish anthrax from other conditions with minimal need for diagnostic testing after known or suspected population exposure. Primary Funding Source: U.S. Department of Health and Human Services.

Contact among healthcare workers in the hospital setting: developing the evidence base for innovative approaches to infection control.

BACKGROUND: Nosocomial, or healthcare-associated infections (HAI), exact a high medical and financial toll on patients, healthcare workers, caretakers, and the health system. Interpersonal contact patterns play a large role in infectious disease spread, but little is known about the relationship between health care workers' (HCW) movements and contact patterns within a heath care facility and HAI. Quantitatively capturing these patterns will aid in understanding the dynamics of HAI and may lead to more targeted and effective control strategies in the hospital setting. METHODS: Staff at 3 urban university-based tertiary care hospitals in Canada completed a detailed questionnaire on demographics, interpersonal contacts, in-hospital movement, and infection prevention and control practices. Staff were divided into categories of administrative/support, nurses, physicians, and "Other HCWs" - a fourth distinct category, which excludes physicians and nurses. Using quantitative network modeling tools, we constructed the resulting HCW "co-location network" to illustrate contacts among different occupations and with locations in hospital settings. RESULTS: Among 3048 respondents (response rate 38%) an average of 3.79, 3.69 and 3.88 floors were visited by each HCW each week in the 3 hospitals, with a standard deviation of 2.63, 1.74 and 2.08, respectively. Physicians reported the highest rate of direct patient contacts (> 20 patients/day) but the lowest rate of contacts with other HCWs; nurses had the most extended (> 20 min) periods of direct patient contact. "Other HCWs" had the most direct daily contact with all other HCWs. Physicians also reported significantly more locations visited per week than nurses, other HCW, or administrators; nurses visited the fewest. Public spaces such as the cafeteria had the most staff visits per week, but the least mean hours spent per visit. Inpatient settings had significantly more HCW interactions per week than outpatient settings. CONCLUSIONS: HCW contact patterns and spatial movement demonstrate significant heterogeneity by occupation. Control strategies that address this diversity among health care workers may be more effective than "one-strategy-fits-all" HAI prevention and control programs.

Modeling Tool for Decision Support during Early Days of an Anthrax Event.

Health officials lack field-implementable tools for forecasting the effects that a large-scale release of Bacillus anthracis spores would have on public health and hospitals. We created a modeling tool (combining inhalational anthrax caseload projections based on initial case reports, effects of variable postexposure prophylaxis campaigns, and healthcare facility surge capacity requirements) to project hospitalizations and casualties from a newly detected inhalation anthrax event, and we examined the consequences of intervention choices. With only 3 days of case counts, the model can predict final attack sizes for simulated Sverdlovsk-like events (1979 USSR) with sufficient accuracy for decision making and confirms the value of early postexposure prophylaxis initiation. According to a baseline scenario, hospital treatment volume peaks 15 days after exposure, deaths peak earlier (day 5), and recovery peaks later (day 23). This tool gives public health, hospital, and emergency planners scenario-specific information for developing quantitative response plans for this threat.

Anthrax Cases Associated with Animal-Hair Shaving Brushes.

During the First World War, anthrax cases in the United States and England increased greatly and seemed to be associated with use of new shaving brushes. Further investigation revealed that the source material and origin of shaving brushes had changed during the war. Cheap brushes of imported horsehair were being made to look like the preferred badger-hair brushes. Unfortunately, some of these brushes were not effectively disinfected and brought with them a nasty stowaway: Bacillus anthracis. A review of outbreak summaries, surveillance data, and case reports indicated that these cases originated from the use of ineffectively disinfected animal-hair shaving brushes. This historical information is relevant to current public health practice because renewed interest in vintage and animal-hair shaving brushes has been seen in popular culture. This information should help healthcare providers and public health officials answer questions on this topic.

Identifying Meningitis During an Anthrax Mass Casualty Incident: Systematic Review of Systemic Anthrax Since 1880.

BACKGROUND: Bacillus anthracis, the causative agent of anthrax, is a potential bioterrorism agent. Anthrax meningitis is a common manifestation of B. anthracis infection, has high mortality, and requires more aggressive treatment than anthrax without meningitis. Its rapid identification and treatment are essential for successful management of an anthrax mass casualty incident. METHODS: Three hundred six published reports from 1880 through 2013 met predefined inclusion criteria. We calculated descriptive statistics for abstracted cases and conducted multivariable regression on separate derivation and validation cohorts to identify clinical diagnostic and prognostic factors for anthrax meningitis. RESULTS: One hundred thirty-two of 363 (36%) cases with systemic anthrax met anthrax meningitis criteria. Severe headache, altered mental status, meningeal signs, and other neurological signs at presentation independently predicted meningitis in the derivation cohort and were tested as a 4-item assessment tool for use during anthrax mass casualty incidents. Presence of any 1 factor on admission had a sensitivity for finding anthrax meningitis of 89% (83%) in the adult (pediatric) validation cohorts. Anthrax meningitis was unlikely in the absence of any of these signs or symptoms (likelihood ratio [LR]- = 0.12 [0.19] for adult [pediatric] cohorts), while presence of 2 or more made meningitis very likely (LR+ = 26.5 [30.0]). Survival of anthrax meningitis was predicted by treatment with a bactericidal agent (P = .005) and use of multiple antimicrobials (P = .01). CONCLUSIONS: We developed an evidence-based assessment tool for screening patients for meningitis during an anthrax mass casualty incident. Its use could improve both patient outcomes and resource allocation in such an event.

Bringing a Structural Competency Framework to the (Simulated) Bedside: The Premature Discharge Objective Structured Clinical Exam.

PROBLEM: Structural competency is increasingly valued as a framework to address health equity within undergraduate medical education. As of academic year 2023-2024, the Liaison Committee on Medical Education (LCME) requires that medical schools have content regarding basic principles of structurally competent health care. Despite encouraging data about the effectiveness of structural competency curricula, most occur within the walls of a classroom and do not enter the authentic or simulated clinical space. APPROACH: From 2022 to 2023, an objective structured clinical exam (OSCE) focused on premature discharge, previously known as discharge against medical advice, was integrated into the required fourth-year Health Policy course at Weill Cornell Medical College, which uses the framework of structural competency. After a simulated clinical encounter, students completed a reflection assignment and participated in group debriefing to reflect on how policy coursework affected their simulated clinical experience. Students completed an evaluation about their OSCE experience, and OSCE checklist performance was analyzed. OUTCOMES: Of 82 students who participated in the curriculum, 68 completed a curricular evaluation, and 62 consented to have their OSCE performance evaluated for research. Mean overall OSCE checklist performance evaluating students' patient-centered communication skills, harm reduction skills, and discharge planning and counseling was 14.3/16 (89.6%; standard deviation 9.8%). Students reported it was valuable to focus on structural factors affecting care within the simulated clinical encounter by using the structural competency framework. NEXT STEPS: To the authors' knowledge, this is the first OSCE for medical students designed to deepen their understanding of structural competency by embedding the experience into an existing course using the framework. Future work should explore how this curriculum affects students' attitudes toward structurally vulnerable patients. With structural competency as an LCME requirement, the use of OSCEs may give educators a means to teach and assess fundamental concepts.

Association of COVID-19 Vaccinations With Flares of Systemic Rheumatic Disease: A Case-Crossover Study.

OBJECTIVE: We aimed to determine the association of COVID-19 vaccination with flares of systemic rheumatic disease (SRD). METHODS: Adults with systemic rheumatic disease (SRD) in a single-center COVID-19 Rheumatology Registry were invited to enroll in a study of flares. COVID-19 vaccine information from March 5, 2021, to September 6, 2022, was obtained from chart review and self-report. Participants self-reported periods of SRD flare and periods without SRD flare. "Hazard periods" were defined as the time before a self-report of flare and "control periods" as the time before a self-report of no flare. The association between flare and COVID-19 vaccination was evaluated during hazard and control periods through univariate conditional logistic regression stratified by participant, using lookback windows of 2, 7, and 14 days. RESULTS: A total of 434 participants (mean ± SD age 59 ± 13 years, 84.1% female, 81.8% White, 64.5% with inflammatory arthritis, and 27.0% with connective tissue diseases) contributed to both the hazard and control periods and were included in analysis. A total of 1,316 COVID-19 vaccinations were identified (58.5% Pfizer-BioNTech, 39.5% Moderna, and 1.4% Johnson & Johnson); 96.1% of participants received at least one dose and 93.1% at least two doses. There was no association between COVID-19 vaccination and flares in the subsequent 2, 7, or 14 days (odds ratio [OR] 1.46, 95% confidence interval [CI] 0.86-2.46; OR 1.09, 95% CI 0.76-1.55; and OR 0.85, 95% CI 0.64-1.13, respectively). Analyses stratified on sex, age, SRD subtype, and vaccine manufacturer similarly showed no association between vaccination and flare. CONCLUSION: COVID-19 vaccination was not associated with flares in this cohort of participants with SRD. These data are reassuring and can inform shared decision-making on COVID-19 immunization.

Impact of the fall 2009 influenza A(H1N1)pdm09 pandemic on US hospitals.

BACKGROUND: Understanding how hospitals functioned during the 2009 influenza A(H1N1)pdm09 pandemic may improve future public health emergency response, but information about its impact on US hospitals remains largely unknown. RESEARCH DESIGN: We matched hospital and emergency department (ED) discharge data from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project with community-level influenza-like illness activity during each hospital's pandemic period in fall 2009 compared with a corresponding calendar baseline period. We compared inpatient mortality for sentinel conditions at high-surge versus nonsurge hospitals. RESULTS: US hospitals experienced a doubling of pneumonia and influenza ED visits during fall 2009 compared with prior years, along with an 18% increase in overall ED visits. Although no significant increase in total inpatient admissions occurred overall, approximately 10% of all study hospitals experienced high surge, associated with higher acute myocardial infarction and stroke case fatality rates. These hospitals had similar characteristics to other US hospitals except that they had higher mortality for acute cardiac illnesses before the pandemic. After adjusting for 2008 case fatality rates, the association between high-surge hospitals and increased mortality for acute myocardial infarction and stroke patients persisted. CONCLUSIONS: The fall 2009 pandemic period substantially impacted US hospitals, mostly through increased ED visits. For a small proportion of hospitals that experienced a high surge in inpatient admissions, increased mortality from selected clinical conditions was associated with both prepandemic outcomes and surge, highlighting the linkage between daily hospital operations and disaster preparedness.

Association between city-wide lockdown and COVID-19 hospitalization rates in multigenerational households in New York City.

BACKGROUND: City-wide lockdowns and school closures have demonstrably impacted COVID-19 transmission. However, simulation studies have suggested an increased risk of COVID-19 related morbidity for older individuals inoculated by house-bound children. This study examines whether the March 2020 lockdown in New York City (NYC) was associated with higher COVID-19 hospitalization rates in neighborhoods with larger proportions of multigenerational households. METHODS: We obtained daily age-segmented COVID-19 hospitalization counts in each of 166 ZIP code tabulation areas (ZCTAs) in NYC. Using Bayesian Poisson regression models that account for spatiotemporal dependencies between ZCTAs, as well as socioeconomic risk factors, we conducted a difference-in-differences study amongst ZCTA-level hospitalization rates from February 23 to May 2, 2020. We compared ZCTAs in the lowest quartile of multigenerational housing to other quartiles before and after the lockdown. FINDINGS: Among individuals over 55 years, the lockdown was associated with higher COVID-19 hospitalization rates in ZCTAs with more multigenerational households. The greatest difference occurred three weeks after lockdown: Q2 vs. Q1: 54% increase (95% Bayesian credible intervals: 22-96%); Q3 vs. Q1: 48% (17-89%); Q4 vs. Q1: 66% (30-211%). After accounting for pandemic-related population shifts, a significant difference was observed only in Q4 ZCTAs: 37% (7-76%). INTERPRETATION: By increasing house-bound mixing across older and younger age groups, city-wide lockdown mandates imposed during the growth of COVID-19 cases may have inadvertently, but transiently, contributed to increased transmission in multigenerational households.