Mathematical models incorporate various data sources and advanced computational techniques to portray real-world disease transmission and translate the basic science of infectious diseases into decision-support tools for public health. Unlike standard epidemiologic methods that rely on complete data, modeling is needed when there are gaps in data. By combining diverse data sources, models can fill gaps when critical decisions must be made using incomplete or limited information. They can be used to assess the effect and feasibility of different scenarios and provide insight into the emergence, spread, and control of disease. During the past decade, models have been used to predict the likelihood and magnitude of infectious disease outbreaks, inform emergency response activities in real time (1), and develop plans and preparedness strategies for future events, the latter of which proved invaluable during outbreaks such as severe acute respiratory syndrome and pandemic influenza (2-6). Ideally, modeling is a multistep process that involves communication between modelers and decision-makers, allowing them to gain a mutual understanding of the problem to be addressed, the type of estimates that can be reliably generated, and the limitations of the data. As models become more detailed and relevant to real-time threats, the importance of modeling in public health decision-making continues to grow.

Background Preclinical studies on irradiated animals show that thrombocytopenia can play a role in radiation mortality, particularly in animals receiving minimal supportive care. These findings are consistent with anecdotal evidence from the atomic bombings, where bleeding complications were noted often in patients. Objective To evaluate the role of thrombocytopenia and hemorrhage in radiation-induced mortality, a review was conducted of publicly available pathology reports of patients who died following radiation exposure. Of the 42 reports identified with reasonably complete information, exposures resulted from nuclear detonation, contact with improperly disposed sources, radiotherapy, or industrial accidents. Results Consistent with animal data, a high incidence of bleeding was noted in the autopsy reports of the victims. Also presented is a review of animal model data on the use of various forms of thrombopoietin (TPO) as a treatment for hematopoietic acute radiation syndrome (ARS). Although animal studies suggested these approaches would increase platelet levels following lethal irradiation, their clinical development was halted due to lack of significant efficacy for chemotherapy-induced thrombocytopenia and safety concerns. Conclusion Because there is currently no approved treatment stockpiled for radiation-induced thrombocytopenia, second-generation TPO mimetics and other novel platelet-promoting agents should be developed for this indication.

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Following the attacks of 11 September 2001, emergency preparedness within the U.S. Department of Health and Human Services, as well as at the Department of Defense and other federal agencies, received higher visibility, new mandates and increased funding. Emergency deployment teams increased the frequency of drills to enable better response to the health consequences of mass-casualty incidents. Interagency coordination has also continued to increase to more efficiently and effectively leverage federal resources toward emergency medical preparedness for both civilian and military populations.

The term "radiation combined injury" (RCI) is used to describe conditions where radiation injury is coupled with other insults such as burns, wounds, infection, or blunt trauma. A retrospective account of injuries sustained following the atomic bombing of Hiroshima estimates that RCI comprised approximately 65% of all injuries observed. Much of the research that has been performed on RCI was carried out during the Cold War and our understanding of the clinical problem RCI presents does not reflect the latest advances in medicine or science. Because concerns have increased that terrorists might employ radiological or nuclear weapons, and because of the likelihood that victims of such terrorism would experience RCI, the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health sponsored a meeting in 2007 to explore the state of the research in this area, identify programmatic gaps, and establish priorities for future research. As a follow-up to that meeting, in 2008 NIAID sponsored an initiative on RCI, leading to the award of several exploratory/developmental grants, the goals of which are to better understand biological synergy involved in RCI-induced damage, develop improved animal models for various type of RCI, and advance identification and testing of potential countermeasures to treat injuries that would be expected following a radiological or nuclear event. This program has already yielded new insight into the nature of combined injuries and has identified a number of novel and existing compounds that may be effective treatments for this condition.

The National Institute of Allergy and Infectious Diseases (NIAID) Radiation/Nuclear Medical Countermeasures Development Program has developed an integrated approach to providing the resources and expertise required for the research, discovery, and development of radiation/nuclear medical countermeasures (MCMs). These resources and services lower the opportunity costs and reduce the barriers to entry for companies interested in working in this area and accelerate translational progress by providing goal-oriented stewardship of promising projects. In many ways, the radiation countermeasures program functions as a "virtual pharmaceutical firm," coordinating the early and mid-stage development of a wide array of radiation/nuclear MCMs. This commentary describes the radiation countermeasures program and discusses a novel business model that has facilitated product development partnerships between the federal government and academic investigators and biopharmaceutical companies.

Mass exposure to radiation does not occur frequently but such events, when they do occur, present tremendous challenges to affected communities. With the concerns of recent years about nuclear or radiological terrorism, it would also appear that the risk of deliberate mass exposures to radiation has increased. Nuclear power plant accidents leading to the release of radioactive materials could cause widespread environmental contamination with a variety of radionuclides. This chapter summarizes the prompt and delayed effects of fission explosions in the range of energy yields expected from an improvised nuclear device. The acute radiation syndrome (ARS) encompasses a set of complex pathophysiological processes precipitated by exposure to high doses of radiation. The major determinant of clinical outcome following an acute radiation exposure is the dose received by the affected individual. Estimating this dose (in a process termed biodosimetry) thus becomes a critical part of clinical management of such individuals.

Non-clinical human radiation exposure events such as the Hiroshima and Nagasaki bombings or the Chernobyl accident are often coupled with other forms of injury, such as wounds, burns, blunt trauma, and infection. Radiation combined injury would also be expected after a radiological or nuclear attack. Few animal models of radiation combined injury exist, and mechanisms underlying the high mortality associated with complex radiation injuries are poorly understood. Medical countermeasures are currently available for management of the non-radiation components of radiation combined injury, but it is not known whether treatments for other insults will be effective when the injury is combined with radiation exposure. Further research is needed to elucidate mechanisms behind the synergistic lethality of radiation combined injury and to identify targets for medical countermeasures. To address these issues, the National Institute of Allergy and Infectious Diseases convened a workshop to make recommendations on the development of animal models of radiation combined injury, possible mechanisms of radiation combined injury, and future directions for countermeasure research, including target identification and end points to evaluate treatment efficacy.

Exposure to radionuclides disseminated by a radiological dispersion device or deposited as fallout after a nuclear power plant accident or detonation of an improvised nuclear device could result in internal contamination of a significant number of individuals. Internalized radionuclides may cause both acute and chronic radiation injury and increase an individual's risk of developing cancer. This damage and risk can be mitigated by the use of decorporation agents that reduce internal contamination. Unfortunately, most effective agents decorporate only a limited range of radionuclides, and some are formulated in ways that would make administration in mass casualty situations challenging. There is a need for new radionuclide decorporation agents, reformulations of existing agents, and/or expansion of the labeled indications for existing treatments. Researchers developing novel or improved decorporation agents should also understand the regulatory pathway for these products. This workshop, the first in nearly half a century to focus exclusively on radionuclide decorporation, brought together researchers and scientific administrators from academia, government and industry as well as senior regulatory affairs officers and U.S. Food and Drug Administration personnel. Meeting participants reviewed recent progress in the development of decorporation agents and contemplated the future of the field. (C) 2008 by Radiation Research Society.

Untoward events involving radioactive material, either accidental or intentional, are potentially devastating. Hematologists and oncologists are uniquely suited to help manage radiation victims, as myelosuppression is a frequent complication of radiation exposure. In the aftermath of a large event, such as a nuclear detonation, there may be a national call for surge capacity that involves hematologists/oncologists across the country in the disaster response. In preparation, the National Marrow Donor Program and American Society for Blood and Marrow Transplantation have established the Radiation Injury Treatment Network (RITN), a voluntary consortium of transplant centers, donor centers, and umbilical cord blood banks. RITN is partnered with the Office of the Assistant Secretary for Preparedness and Response in the United States Department of Health and Human Services to develop treatment guidelines, educate healthcare professionals, coordinate situation response, and provide comprehensive evaluation and care for radiation injury victims. We outline the current plans for event response and describe scenarios, including catastrophic events that would require extensive support from hematologists/oncologists across the country. In addition, we highlight important reference resources and discuss current efforts to develop medical countermeasures against radiation toxicity. Practitioners and institutions across the country are encouraged to become involved and participate in the planning.

Nonpharmaceutical interventions (NPIs) intended to reduce infectious contacts between persons form an integral part of plans to mitigate the impact of the next influenza pandemic. Although the potential benefits of NPIs are supported by mathematical models, the historical evidence for the impact of such interventions in past pandemics has not been systematically examined. We obtained data on the timing of 19 classes of NPI in 17 U.S. cities during the 1918 pandemic and tested the hypothesis that early implementation of multiple interventions was associated with reduced disease transmission. Consistent with this hypothesis, cities in which multiple interventions were implemented at an early phase of the epidemic had peak death rates ≈50% lower than those that did not and had less-steep epidemic curves. Cities in which multiple interventions were implemented at an early phase of the epidemic also showed a trend toward lower cumulative excess mortality, but the difference was smaller (≈20%) and less statistically significant than that for peak death rates. This finding was not unexpected, given that few cities maintained NPIs longer than 6 weeks in 1918. Early implementation of certain interventions, including closure of schools, churches, and theaters, was associated with lower peak death rates, but no single intervention showed an association with improved aggregate outcomes for the 1918 phase of the pandemic. These findings support the hypothesis that rapid implementation of multiple NPIs can significantly reduce influenza transmission, but that viral spread will be renewed upon relaxation of such measures.

In reply:We appreciate Dr. Casavant's suggestion about the importance of screening emergency department (ED) patients for radiologic contamination. Although early identification of radiologic contamination is key to effective treatment, as well as protection of personnel and facilities, a procedure that mandates screening of every person entering the ED would be problematic for several reasons, particularly in a high-volume facility. First, care for critical patients would be delayed, potentially resulting in worse outcomes, including unnecessary death. Second, resources would be diverted from triaging and treating other patients waiting for care in our nation's already crowded EDs and at time when we are experiencing a severe national nursing shortage. Finally, the process would likely be cost prohibitive for many institutions from the standpoints of equipment purchases and maintenance and of personnel time. If a portal monitor were used, it would require periodic calibration and maintenance and may not be wide enough to allow access to nonambulatory patients in wheelchairs or gurneys.1Smith JM, Spano MA. Interim guidelines for hospital response to mass casualties from a radiological incident: CDC radiation emergencies. Available at: http://www.bt.cdc.gov/radiation/pdf/masscasualtiesguidelines.pdf. Accessed July 29, 2005.Google ScholarIn some systems, first responders carry Geiger-Mueller counters to assess incident scenes for radiation, but this is not standard across the country, and many patients self-present to EDs after an event. Therefore, we cannot rely on radiologic decontamination at the scene. Although the ground shine concentration of radionuclides at a scene would be much easier to detect than the minimal amount on an individual casualty, EDs still need the capacity to detect radiation and decontaminate patients. For an explosion of uncertain cause, screening would be important, whereas for a patient with a simple ankle sprain, it would not make sense, and such widespread screening would be logistically impossible. As with every test we conduct, it should be medically indicated.If a hospital does choose to detect contaminated individuals entering its ED, there are ways of setting up computer-controlled area monitors in the interdoor vestibule that can accomplish this detection. The Armed Forces Radiobiology Research Institute has studied such techniques (D. Jarrett, oral communication, July 2005) and learned that the key points are that the detector system must be positioned correctly and be sufficiently sensitive to trigger occasional “false” positives (ie, patients who have undergone recent radionuclide therapy or even imaging). The ED must then have a rehearsed response drill for these positive cases.In summary, although it is critical to raise awareness of the potential for radiologic contamination and to not rely on consistent decontamination by out-of-hospital personnel, common sense should dictate which ED patients should be screened. It would likely be time consuming and frightening to patients if we started screening every baby with otitis media! As emphasized in our original manuscript, the key concept is ABCs first: life- and limb-threatening injuries and illnesses should always be treated before radiologic decontamination.2Koenig K.L. Goans R.E. Hatchett R.J. et al.Medical treatment of radiological casualties: current concepts.Ann Emerg Med. 2005; 45: 643-652Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar In reply: We appreciate Dr. Casavant's suggestion about the importance of screening emergency department (ED) patients for radiologic contamination. Although early identification of radiologic contamination is key to effective treatment, as well as protection of personnel and facilities, a procedure that mandates screening of every person entering the ED would be problematic for several reasons, particularly in a high-volume facility. First, care for critical patients would be delayed, potentially resulting in worse outcomes, including unnecessary death. Second, resources would be diverted from triaging and treating other patients waiting for care in our nation's already crowded EDs and at time when we are experiencing a severe national nursing shortage. Finally, the process would likely be cost prohibitive for many institutions from the standpoints of equipment purchases and maintenance and of personnel time. If a portal monitor were used, it would require periodic calibration and maintenance and may not be wide enough to allow access to nonambulatory patients in wheelchairs or gurneys.1Smith JM, Spano MA. Interim guidelines for hospital response to mass casualties from a radiological incident: CDC radiation emergencies. Available at: http://www.bt.cdc.gov/radiation/pdf/masscasualtiesguidelines.pdf. Accessed July 29, 2005.Google Scholar In some systems, first responders carry Geiger-Mueller counters to assess incident scenes for radiation, but this is not standard across the country, and many patients self-present to EDs after an event. Therefore, we cannot rely on radiologic decontamination at the scene. Although the ground shine concentration of radionuclides at a scene would be much easier to detect than the minimal amount on an individual casualty, EDs still need the capacity to detect radiation and decontaminate patients. For an explosion of uncertain cause, screening would be important, whereas for a patient with a simple ankle sprain, it would not make sense, and such widespread screening would be logistically impossible. As with every test we conduct, it should be medically indicated. If a hospital does choose to detect contaminated individuals entering its ED, there are ways of setting up computer-controlled area monitors in the interdoor vestibule that can accomplish this detection. The Armed Forces Radiobiology Research Institute has studied such techniques (D. Jarrett, oral communication, July 2005) and learned that the key points are that the detector system must be positioned correctly and be sufficiently sensitive to trigger occasional “false” positives (ie, patients who have undergone recent radionuclide therapy or even imaging). The ED must then have a rehearsed response drill for these positive cases. In summary, although it is critical to raise awareness of the potential for radiologic contamination and to not rely on consistent decontamination by out-of-hospital personnel, common sense should dictate which ED patients should be screened. It would likely be time consuming and frightening to patients if we started screening every baby with otitis media! As emphasized in our original manuscript, the key concept is ABCs first: life- and limb-threatening injuries and illnesses should always be treated before radiologic decontamination.2Koenig K.L. Goans R.E. Hatchett R.J. et al.Medical treatment of radiological casualties: current concepts.Ann Emerg Med. 2005; 45: 643-652Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar