Nathaniel Hupert

Initial human transmission dynamics of the pandemic (H1N1) 2009 virus in North America.

Background  Between 5 and 25 April 2009, pandemic (H1N1) 2009 caused a substantial, severe outbreak in Mexico, and subsequently developed into the first global pandemic in 41 years. We determined the reproduction number of pandemic (H1N1) 2009 by analyzing the dynamics of the complete case series in Mexico City during this early period.

Modeling the Public Health Response to Bioterrorism: Using Discrete Event Simulation to Design Antibiotic Distribution Centers:

Background Post-exposure prophylaxis is a critical component of the public health response to bioterrorism. Computer simulation modeling may assist in designing antibiotic distribution centers for this task. Methods The authors used discrete event simulation modeling to determine staffing levels for entry screening, triage, medical evaluation, and drug dispensing stations in a hypothetical antibiotic distribution center operating in low, medium, and high disease prevalence bioterrorism response scenarios. Patient arrival rates and processing times were based on prior mass prophylaxis campaigns. Multiple sensitivity analyses examined the relationship between average staff utilization rate (UR) (i.e., percentage of time occupied in patient contact) and capacity of the model to handle surge arrivals. Results Distribution center operation required from 93 staff for the low-prevalence scenario to 111 staff for the high-prevalence scenario to process approximately 1000 people per hour within the baseline model assumptions. Excess capacity to process surge arrivals approximated (1-UR) for triage staffing. Conclusions Discrete event simulation modeling is a useful tool in developing the public health infrastructure for bioterrorism response. Live exercises to validate the assumptions and outcomes presented here may improve preparedness to respond to bioterrorism.

The Shifting Demographic Landscape of Pandemic Influenza

Background As Pandemic (H1N1) 2009 influenza spreads around the globe, it strikes school-age children more often than adults. Although there is some evidence of pre-existing immunity among older adults, this alone may not explain the significant gap in age-specific infection rates. Methods and Findings Based on a retrospective analysis of pandemic strains of influenza from the last century, we show that school-age children typically experience the highest attack rates in primarily naive populations, with the burden shifting to adults during the subsequent season. Using a parsimonious network-based mathematical model which incorporates the changing distribution of contacts in the susceptible population, we demonstrate that new pandemic strains of influenza are expected to shift the epidemiological landscape in exactly this way. Conclusions Our analysis provides a simple demographic explanation for the age bias observed for H1N1/09 attack rates, and suggests that this bias may shift in coming months. These results have significant implications for the allocation of public health resources for H1N1/09 and future influenza pandemics.

Accuracy of Screening for Inhalational Anthrax after a Bioterrorist Attack

Context In the event of a bioterrorist attack, it may be difficult to distinguish inhalational anthrax from viral respiratory tract disease. Contribution This synthesis compares reported symptoms of 28 patients with inhalational anthrax and 4694 patients with viral respiratory tract illnesses. Fever and cough were common in both infections. Mental confusion or loss of consciousness, shortness of breath, and nausea and vomiting more often indicated anthrax, whereas sore throat and runny nose more often indicated viral infection. Implications Several symptoms, including neurologic and gastrointestinal symptoms and shortness of breath, may help distinguish inhalational anthrax from respiratory viral illness. The Editors The 2001 anthrax attacks in the United States, in which 11 people developed the inhalational form of the disease and 5 died, exposed a weakness in the U.S. medical response to bioterrorism (1). Despite heroic efforts on behalf of the victims, physicians were largely unprepared to recognize the early symptoms and signs of this extremely rare and rapidly progressive infection in ambulatory patients (2). Initially, 4 of the 11 patients were sent home after being seen as outpatients or in an emergency department with diagnoses that included viral syndrome, bronchitis, and gastroenteritis (3, 4). Physicians first considered a diagnosis of anthrax in 2 of these patients (both postal workers) on their second visits to the emergency department and then only after hearing media reports of illness among other postal employees (3). Inhalation of anthrax spores leads to clinical disease from elaboration of two toxins, a calmodulin-dependent adenylate cyclase known as edema factor and a zinc metalloproteinase called lethal factor, by phagocytosed bacteria in the mediastinal lymph nodes and bloodstream (5). Classic pathologic findings include hemorrhagic mediastinitis and hemorrhagic meningitis; primary anthrax pneumonia is rare (6, 7). Without prompt treatment, death occurs rapidly from a combination of shock and respiratory compromise. Anthrax has been classified by the U.S. Centers for Disease Control and Prevention as one of six category A bioterrorist agents posing the greatest risk to civilian populations (8). A large-scale anthrax attack has the potential to cause casualties on a scale that would quickly overwhelm local and regional health care treatment capacity (6). The emergency response to such an attack would probably include the establishment of multiple mass prophylaxis centers physically distinct from hospital emergency departments (to prevent overcrowding and potential contamination) for rapid dispensing of prophylactic antibiotics to exposed populations and for identifying individuals suspected of having inhalational anthrax (9). Presumptive cases would be transferred to established or temporary medical care facilities for rapid definitive testing and initiation of combination antimicrobial treatment, which may improve outcomes (10-12). Efficient management of this limited medical care capacity is an important secondary goal of outpatient triage during a bioterrorism response (13, 14). Screening and triage protocols used in these settings would need to rely on presenting symptoms and signs because laboratory or radiographic testing will probably not be feasible in high-volume mass prophylaxis centers (15). We sought to establish an evidence base for developing a screening protocol for inhalational anthrax. The utility of such a protocol, which improves both case detection and case exclusion, would also extend beyond the immediate mass prophylaxis setting because large numbers of individuals outside the exposure zone will probably seek reassurance from health care providers for symptomatic illnesses in the aftermath of a major attack. Providing scientific evidence on which to base these discussions may decrease postattack anxiety and inappropriate utilization of health care resources (16). Methods Clinical data on the 11 inhalational anthrax cases of 2001 are now widely available (3, 4, 17-20). Because of the small number of cases in the contemporary attack, we performed a systematic literature review to identify additional original case reports of inhalational anthrax in the English-language medical literature. We searched two computerized databases (MEDLINE and Web of Science) for adult human case reports of anthrax infection between 1960 and 2000 using the keywords anthrax and case report. This yielded 44 references; 4 contained sufficient clinical data on inhalational anthrax to permit comparison with the 11 contemporary cases (21-24). Tracing bibliographies of these articles and a recent review article (25) produced an additional 7 articles that were appropriate for inclusion, for a total of 11 reports on 17 cases (26-32). Two of the cases involved patients from outside of the United States (22, 24). We interpreted lack of mention of a specific symptom or abnormal sign in these reports as indicating the absence of that finding from the patients clinical presentation. We compared proportions of symptoms and signs in historical and contemporary cases using the Fisher exact test; clinical features that had consistent prevalence rates in earlier and contemporary cases were candidates for comparison with viral respiratory tract disease. Viral respiratory tract infections, such as with influenza, respiratory syncytial virus (RSV), parainfluenza, and rhinoviruses or coronaviruses, are appropriate comparison conditions for this study because of their prevalence and potential similarity to inhalational anthrax (15, 33). We searched MEDLINE for descriptive epidemiologic reports of presenting clinical features of laboratory-confirmed influenza and noninfluenza viral respiratory illnesses in ambulatory adults; we found five published studies that met the search criteria (34-38). We did not include studies that describe samples of mixed influenza and noninfluenza cases (39-42) or that present data already reported in these five studies (43). We did not compare anthrax cases with asymptomatic persons (because they would not present a screening dilemma) or with acutely ill patients (because they would probably not participate in mass screening). Since there are no reports of inhalational anthrax in pediatric patients, we limited our comparison sample to adult patients. Finally, we also compared anthrax cases to ambulatory patients with community-acquired pneumonia to highlight the difficulty of distinguishing these two conditions (44). We calculated positive likelihood ratios with 95% CIs for the presence of selected signs and symptoms in inhalational anthrax versus influenza, influenza-like illness, and ambulatory community-acquired pneumonia. The positive likelihood ratio is defined here as the prevalence of a symptom or sign among inhalational anthrax cases divided by the prevalence of the same symptom or sign in the influenza, influenza-like illness, or pneumonia comparison groups. The positive likelihood ratio is the multiplicative factor that increases or decreases the odds of having inhalational anthrax as opposed to one of these comparison diseases, given the presence of a clinical finding (45). Therefore, the post-test probability of having inhalational anthrax is influenced by both the magnitude of the positive likelihood ratio and the pretest probability of having the disease (46). In the appropriate clinical setting (that is, when the pretest probability of having the target disease is not zero), likelihood ratios greater than 3 or less than 0.3 are considered clinically important (47). The general approach used heredeveloping diagnostic algorithms for rare diagnoses by using likelihood ratios and by establishing hypothetical comparison groups populated by common medical conditionshas been previously described (46, 48, 49). The study sponsors had no role in the design, conduct, and reporting of the data or in the decision to submit the manuscript for publication. Results Presenting symptoms and signs and radiographic results for the 11 deliberately infected contemporary cases and 17 occupationally or environmentally infected historical cases were similar, although contemporary patients reported significantly more fever/chills and fatigue or malaise (Table 1). All but 1 of the 28 patients (including 100% of the contemporary patients) had fever, chills, or cough on presentation. (The single exception was a patient who presented with impending shock, which limited the ability to record a complete history.) Other symptoms that affected more than half of all patients included dyspnea (68%), chest discomfort or pain (61%), and nausea or vomiting (61%). More than half of current case-patients and 43% of the combined sample presented with neurologic symptoms other than headache, including confusion, blurred vision, and dizziness. Only a few patients with inhalational anthrax reported sore throat (18%) or rhinorrhea (14%). Table 1. Summary of Symptoms and Signs at Initial Presentation: Historical versus Contemporary Patients with Inhalational Anthrax Eighty-one percent of patients presented with abnormalities on lung auscultation, including rales or rhonchi (65%) and dullness or decreased breath sounds (58%). Respiratory symptoms often did not match findings on lung physical examination. Four of the five patients with no respiratory symptoms had positive findings (rales), whereas 8 of the 23 patients with respiratory symptoms had no abnormality on lung examination. Outcomes differed significantly between historical and contemporary patients: 16 of the 17 historical patients died compared with only 5 of the 11 contemporary patients. The presenting clinical features of the 28 patients can be divided into nine symptom complexes involving respiratory; gastrointestinal; ear, nose, and throat; and nonheadache neurologic problems (Figure 1). The single most common presentation was a combination of respirato

Optimizing tactics for use of the U.S. antiviral strategic national stockpile for pandemic influenza.

In 2009, public health agencies across the globe worked to mitigate the impact of the swine-origin influenza A (pH1N1) virus. These efforts included intensified surveillance, social distancing, hygiene measures, and the targeted use of antiviral medications to prevent infection (prophylaxis). In addition, aggressive antiviral treatment was recommended for certain patient subgroups to reduce the severity and duration of symptoms. To assist States and other localities meet these needs, the U.S. Government distributed a quarter of the antiviral medications in the Strategic National Stockpile within weeks of the pandemics start. However, there are no quantitative models guiding the geo-temporal distribution of the remainder of the Stockpile in relation to pandemic spread or severity. We present a tactical optimization model for distributing this stockpile for treatment of infected cases during the early stages of a pandemic like 2009 pH1N1, prior to the wide availability of a strain-specific vaccine. Our optimization method efficiently searches large sets of intervention strategies applied to a stochastic network model of pandemic influenza transmission within and among U.S. cities. The resulting optimized strategies depend on the transmissability of the virus and postulated rates of antiviral uptake and wastage (through misallocation or loss). Our results suggest that an aggressive community-based antiviral treatment strategy involving early, widespread, pro-rata distribution of antivirals to States can contribute to slowing the transmission of mildly transmissible strains, like pH1N1. For more highly transmissible strains, outcomes of antiviral use are more heavily impacted by choice of distribution intervals, quantities per shipment, and timing of shipments in relation to pandemic spread. This study supports previous modeling results suggesting that appropriate antiviral treatment may be an effective mitigation strategy during the early stages of future influenza pandemics, increasing the need for systematic efforts to optimize distribution strategies and provide tactical guidance for public health policy-makers.

Is overtriage associated with increased mortality? Insights from a simulation model of mass casualty trauma care.

PURPOSE To examine the relationship between overtriage and critical mortality after a mass casualty incident (MCI) using a simulation model of trauma system response. METHODS We created a discrete event simulation model of trauma system management of MCIs involving individual patient triage and treatment. Model variables include triage performance, treatment capability, treatment time, and time-dependent mortality of critically injured patients. We model triage as a variable selection process applied to a hypothetical population of critically and noncritically injured patients. Treatment capability is represented by staffed emergency department trauma bays with associated staffed operating rooms that are recycled after each use. We estimated critical and noncritical patient treatment times and time-dependent mortality rates from the trauma literature. RESULTS In this simulation model, overtriage, the proportion of noncritical patients among all of those labeled as critical, has a positive, negative, or variable association with critical mortality depending on its etiology (ie, related to changes in triage sensitivity or to changes in the prevalence and total number of critical patients). In all of the modeled scenarios, the ratio of critical patients to treatment capability has a greater impact on critical mortality than overtriage level or time-dependent mortality assumption. CONCLUSIONS Increasing overtriage may have positive, negative, or mixed effects on critical mortality in this trauma system simulation model. These results, which contrast with prior analyses describing a positive linear relationship between overtriage and mortality, highlight the need for alternative metrics to describe trauma system response after MCIs. We explore using the relative number of critical patients to available and staffed treatment units, or the critical surge to capability ratio, which exhibits a consistent and nonlinear association with critical mortality in this model.

Vaccination against 2009 pandemic H1N1 in a population dynamical model of Vancouver, Canada: timing is everything

BackgroundMuch remains unknown about the effect of timing and prioritization of vaccination against pandemic (pH1N1) 2009 virus on health outcomes. We adapted a city-level contact network model to study different campaigns on influenza morbidity and mortality.MethodsWe modeled different distribution strategies initiated between July and November 2009 using a compartmental epidemic model that includes age structure and transmission network dynamics. The model represents the Greater Vancouver Regional District, a major North American city and surrounding suburbs with a population of 2 million, and is parameterized using data from the British Columbia Ministry of Health, published studies, and expert opinion. Outcomes are expressed as the number of infections and deaths averted due to vaccination.ResultsThe model output was consistent with provincial surveillance data. Assuming a basic reproduction number = 1.4, an 8-week vaccination campaign initiated 2 weeks before the epidemic onset reduced morbidity and mortality by 79-91% and 80-87%, respectively, compared to no vaccination. Prioritizing children and parents for vaccination may have reduced transmission compared to actual practice, but the mortality benefit of this strategy appears highly sensitive to campaign timing. Modeling the actual late October start date resulted in modest reductions in morbidity and mortality (13-25% and 16-20%, respectively) with little variation by prioritization scheme.ConclusionDelays in vaccine production due to technological or logistical barriers may reduce potential benefits of vaccination for pandemic influenza, and these temporal effects can outweigh any additional theoretical benefits from population targeting. Careful modeling may provide decision makers with estimates of these effects before the epidemic peak to guide production goals and inform policy. Integration of real-time surveillance data with mathematical models holds the promise of enabling public health planners to optimize the community benefits from proposed interventions before the pandemic peak.

Predicting hospital surge after a large-scale anthrax attack: a model-based analysis of CDC's cities readiness initiative prophylaxis recommendations.

Background . After a major bioterrorism attack, the US Centers for Disease Control and Prevention (CDC) Cities Readiness Initiative (CRI) calls for dispensing of medical countermeasures to targeted populations within 48 hours. The authors explore how meeting or missing this 48-hour goal after a hypothetical aerosol anthrax attack would affect hospital surge, in light of the multiple uncertainties surrounding anthrax-related illness and response. Design . The authors created a discrete-time state transition computer model representing the dynamic interaction between disease progression of inhalational anthrax and the rate of dispensing of prophylactic antibiotics in an exposed population. Results . A CRI-compliant prophylaxis campaign starting 2 days after exposure would protect from 86% to 87% of exposed individuals from illness (assuming, in the base case, 90% antibiotic effectiveness and a 95% attack rate). Each additional day needed to complete the campaign would result in, on average, 2.4% to 2.9% more hospitalizations in the exposed population; each additional days delay to initiating prophylaxis beyond 2 days would result in 5.2% to 6.5% additional hospitalizations. These population protection estimates vary roughly proportionally to antibiotic effectiveness but are relatively insensitive to variations in anthrax incubation period. Conclusion . Delays in detecting and initiating response to large-scale, covert aerosol anthrax releases in a major city would render even highly effective CRI-compliant mass prophylaxis campaigns unable to prevent unsustainable levels of surge hospitalizations. Although outcomes may improve with more rapid epidemiological identification of affected subpopulations and increased collaboration across regional public health and hospital systems, these findings support an increased focus on prevention of this public health threat.

Mechanical ventilators in US acute care hospitals.

OBJECTIVE The supply and distribution of mechanical ventilation capacity is of profound importance for planning for severe public health emergencies. However, the capability of US health systems to provide mechanical ventilation for children and adults remains poorly quantified. The objective of this study was to determine the quantity of adult and pediatric mechanical ventilators at US acute care hospitals. METHODS A total of 5,752 US acute care hospitals included in the 2007 American Hospital Association database were surveyed. We measured the quantities of mechanical ventilators and their features. RESULTS Responding to the survey were 4305 (74.8%) hospitals, which accounted for 83.8% of US intensive care unit beds. Of the 52,118 full-feature mechanical ventilators owned by respondent hospitals, 24,204 (46.4%) are pediatric/neonatal capable. Accounting for nonrespondents, we estimate that there are 62,188 full-feature mechanical ventilators owned by US acute care hospitals. The median number of full-feature mechanical ventilators per 100,000 population for individual states is 19.7 (interquartile ratio 17.2-23.1), ranging from 11.9 to 77.6. The median number of pediatric-capable device full-feature mechanical ventilators per 100,000 population younger than 14 years old is 52.3 (interquartile ratio 43.1-63.9) and the range across states is 22.1 to 206.2. In addition, respondent hospitals reported owning 82,755 ventilators other than full-feature mechanical ventilators; we estimate that there are 98,738 devices other than full-feature ventilators at all of the US acute care hospitals. CONCLUSIONS The number of mechanical ventilators per US population exceeds those reported by other developed countries, but there is wide variation across states in the population-adjusted supply. There are considerably more pediatric-capable ventilators than there are for adults only on a population-adjusted basis.

Modeling and public health emergency responses: lessons from SARS.

Abstract Modelers published thoughtful articles after the 2003 SARS crisis, but had limited if any real-time impact on the global response and may even have inadvertently contributed to a lingering misunderstanding of the means by which the epidemic was controlled. The impact of any intervention depends on its efficiency as well as efficacy, and efficient isolation of infected individuals before they become symptomatic is difficult to imagine. Nonetheless, in exploring the possible impact of quarantine, the product of efficiency and efficacy was varied over the entire unit interval. Another mistake was repeatedly fitting otherwise appropriate gamma distributions to times to event regardless of whether they were stationary or not, particularly onset-isolation intervals whose progressive reduction evidently contributed to SARS control. By virtue of their unknown biology, newly-emerging diseases are more challenging than familiar human scourges. Influenza, for example, recurs annually and has been modeled more thoroughly than any other infectious disease. Moreover, models were integrated into preparedness exercises, during which working relationships were established that bore fruit during the 2009 A/H1N1 pandemic. To provide the most accurate and timely advice possible, especially about the possible impact of measures designed to control diseases caused by novel human pathogens, we must appreciate the value and difficulty of policy-oriented modeling. Effective communication of insights gleaned from modeling SARS will help to ensure that policymakers involve modelers in future outbreaks of newly-emerging infectious diseases. Accordingly, we illustrate the increasingly timely care-seeking by which, together with increasingly accurate diagnoses and effective isolation, SARS was controlled via heuristic arguments and descriptive analyses of familiar observations.