Andrea L. DiCarlo

Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation.

A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses >2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network.

Medical Countermeasures for Radiation Combined Injury: Radiation with Burn, Blast, Trauma and/or Sepsis. Report of an NIAID Workshop, March 26–27, 2007

Abstract DiCarlo, A. L., Hatchett, R. J., Kaminski, J. M., Ledney, G. D., Pellmar, T. C., Okunieff, P. and Ramakrishnan, N. Medical Countermeasures for Radiation Combined Injury: Radiation with Burn, Blast, Trauma and/or Sepsis. Report of an NIAID Workshop, March 26–27, 2007. Radiat. Res. 169, 712–721 (2008). 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.

Medical Countermeasures against Nuclear Threats: Radionuclide Decorporation Agents

Abstract Cassatt, D. R., Kaminski, J. M., Hatchett, R. J., DiCarlo, A. L., Benjamin, J. M. and Maidment, B. W. Medical Countermeasures against Nuclear Threats: Radionuclide Decorporation Agents. Radiat. Res. 170, 540–548 (2008). 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 individuals 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.

Radiation combined injury: overview of NIAID research.

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.

Animal models and medical countermeasures development for radiation-induced lung damage: report from an NIAID Workshop.

Since 9/11, there have been concerns that terrorists may detonate a radiological or nuclear device in an American city. Aside from several decorporation and blocking agents for use against internal radionuclide contamination, there are currently no medications within the Strategic National Stockpile that are approved to treat the immediate or delayed complications resulting from accidental exposure to radiation. Although the majority of research attention has focused on developing countermeasures that target the bone marrow and gastrointestinal tract, since they represent the most acutely radiosensitive organs, individuals who survive early radiation syndromes will likely suffer late effects in the months that follow. Of particular concern are the delayed effects seen in the lung that play a major role in late mortality seen in radiation-exposed patients and accident victims. To address these concerns, the National Institute of Allergy and Infectious Diseases convened a workshop to discuss pulmonary model development, mechanisms of radiation-induced lung injury, targets for medical countermeasures development, and end points to evaluate treatment efficacy. Other topics covered included guidance on the challenges of developing and licensing drugs and treatments specific to a radiation lung damage indication. This report reviews the data presented, as well as key points from the ensuing discussion.

Aging in the context of immunological architecture, function and disease outcomes

The aging immune system demonstrates a reduced capacity to mount a robust immune response (immunosenescence), thereby increasing the susceptibility to various infectious agents, cancers and diseases in elderly individuals. Defects in immune response that develop with advanced age also result in diminished vaccine efficacy, creating a major public health burden. In addition, radiation and chemical exposure and certain disease states can accelerate the progression of immunosenescence. An area of recent clinical focus is the development of vaccine strategies that would be effective across all age groups and would afford some degree of protection to older individuals to emerging or antibiotic-resistant pathogens. Further elucidation of the mechanisms underlying immunosenescence and identification of the most crucial age-related defects in immune response will lead to more effective strategies to boost immune function in the elderly. To discuss these and other research areas, the US–Japan Cooperative Medical Science Program (US Department of State), in conjunction with the National Institute of Allergy and Infectious Diseases, the National Institute of Aging, the Radiation Effects Research Foundation, the Ministry of Foreign Affairs and the Ministry of Education, Culture, Sports, Science and Technology of Japan, hosted a meeting in June 2008 in San Francisco. Topics discussed at the workshop included relative contributions of age-related defects in the function of T cells, B cells and various innate immune cells to the immunosenescent phenotype. Presentations also explored ways to offset the deleterious effects of aging through immune reconstitution and novel vaccination strategies. Although this meeting was limited to US and Asian researchers, articles within this special issue have been written by investigators throughout the world, including Europe, Australia, Asia and North America. Within this single topic issue of Trends in Immunology are 12 papers that represent highlights of many presentations from the June meeting. This special issue also adds to this body of knowledge by exploring topics not fully discussed at the meeting, such as the evolutionary context of aging.Due to the ‘baby boomers’ and health care advances, the US population is aging [1xSee all References][1] (Figure 1Figure 1). Similar trends are also occurring in Europe [2xSee all References][2] and elsewhere. Therefore, diagnosis and treatment of diseases in the elderly is becoming an ever greater priority, translating into a need to better understand immunological dysfunction and its contribution to disease. For example, Mark Weksler (United States) and colleagues from Europe discuss the high prevalence of certain diseases in elderly patients including shingles, Alzheimers and atherosclerotic heart disease. The authors emphasize that additional investigation of immune responsiveness (or lack thereof) and progression and severity of these diseases is essential for the development of effective therapies.Figure 1Number of people age 65 and over, by age group, selected years 1900–2006 and projected 2010–2050 (US population). Source US Census Bureau, Decennial Census, Population Estimates and Projections. Courtesy of www.agingstats.gov.View Large Image | Download PowerPoint SlideHartmut Geiger and colleagues (United States) discuss how the process of hematopoiesis is impacted by age-related alterations in the frequency and function of hematopoietic stem cell (HSC) precursor pools. The relative contributions of extrinsic factors (from the microenvironment or systemic circulation) or cell-intrinsic factors (telomere dysfunction and/or accumulation of macromolecular and cellular damage) to alterations in phenotypes of aged HSCs is considered. These alterations affect the differentiation potential of B and T cells, as well as effectors of innate immunity including granulocyte and macrophage lineages, and all are adversely affected with aging. For example, aging B cells show decreased gene expression in the areas of lineage commitment and differentiation, resulting in reduced clonotypic diversity. Indeed, Michael Cancro (United States) and colleagues suggest that it is important to consider molecular, cellular and population level changes to fully understand the impact of aging on humoral immunity. Age-related deficits in T-cell function and resultant impairment in vaccination responses also represents an area of active research interest. Laura Haynes and colleagues (United States) have developed mouse models to investigate mechanisms underlying CD4+ and CD8+ T-cell defects. In addition, Nan-Ping Weng (United States) and colleagues suggest that loss of CD28+ T cells and the concomitant accumulation of CD28− T cells underlie an important age-associated decline in immune function. In other areas of T-cell research, Mark Dowling and colleagues (Australia) argue that thymic involution might have evolved to minimize autoimmunity in young adults while at the same time, optimizing the T-cell repertoire available to recognize pathogens and protect the individual from infections. With advancing age, the naive T-cell repertoire becomes dominated by a restricted set of large T-cell clones, primarily as a result of thymic involution and T-cell death. This constriction of the repertoire contributes greatly to the inability of an individual to respond to a variety of pathogens and is therefore largely responsible for the development of immunosenescence.According to Marcelo Sztein (United States) and colleagues, information on mechanisms responsible for diminished vaccination responses in the elderly is incomplete due to the small number of clinical studies conducted with elderly subjects. Nevertheless, the Centers for Disease Control and Prevention has estimated vaccine efficacy in young adults to be 70–90%, whereas in the elderly, it is estimated to be only 17–53%; therefore, more potent vaccine formulations will be required [3xAntibody response to influenza vaccination in the elderly: a quantitative review. Goodwin, K. et al. Vaccine. 2006; 24: 1159–1169Crossref | PubMed | Scopus (543)See all References][3]. Another potentially useful approach will be to target specific immune compartments such as the intestinal mucosa. Kohtaro Fujihashi and colleagues (Japan) therefore discuss the age-related changes in mucosal immunity, including reductions in the size of gut-associated lymphoid tissues and lack of oral tolerance induction. Furthermore, they present data from both experimental and human studies suggesting that nasal vaccination might represent a more effective route of mucosal vaccination in the elderly due the slower rate of immunosenescence of this tissue compartment, a finding that could have important clinical implications. The articles by Elizabeth Kovacs (United States) and Alexander Panda (United States) and colleagues discuss the impact of aging in innate cellular immunity including the function of neutrophils, monocytes, macrophages and other cells. Recent studies have shown that age-associated changes in cell number and function can result in initiation and/or progression of infections. Reversing the multiple immune defects of immunosenescence is the ultimate goal of therapy, and indeed, Gregory Sempowski (United States) and colleagues provide experimental evidence that thymic involution, at least, could be reversible. These studies provide hope that it might be possible to intervene in the activation or suppression of developmental pathways and thereby rejuvenate the thymus and restore thymic output and function, reconstituting the aged immune system. Finally, Daryl Shanley and colleagues (United Kingdom) discuss the modern evolutionary theory of aging as it relates to the aged immune system. This theory proposes that genes that confer a selective advantage in early life survival might have detrimental effects in later life, leading to such conditions as a chronic inflammatory state (so-called inflamm-aging), which exacerbates the progression of various age-related pathologies and increased autoimmunity. We hope that you enjoy reading this authoritative issue on aging and immunosenescence, which provides guidance for future research and development in this field.

Development and Licensure of Medical Countermeasures to Treat Lung Damage Resulting from a Radiological or Nuclear Incident

Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure. Because some of these exposures may be high-dose, and yet heterogeneous, the expectation is that some victims will survive initial acute radiation syndromes (e.g. hematopoietic and gastrointestinal), but then suffer from potentially lethal lung complications. For this reason, efforts have concentrated on the development of animal models of lung irradiation damage that mimic expected exposure scenarios, as well as drugs to treat radiation-induced late lung sequelae including pneumonitis and fibrosis. Approaches targeting several pathways are under study, with the eventual goal of licensure by the United States Food and Drug Administration for government stockpiling. This Commentary outlines the status of countermeasure development in this area and provides information on the specifics of licensure requirements, as well as guidance and a discussion of challenges involved in developing and licensing drugs and treatments specific to a radiation lung damage indication.

Medical Countermeasures for Platelet Regeneration after Radiation Exposure

Abstract The events of September 11, 2001 and their aftermath increased awareness of the need to develop medical countermeasures (MCMs) to treat potential health consequences of a radiation accident or deliberate attack. The medical effects of lethal exposures to ionizing radiation have been well described and affect multiple organ systems. To date, much of the research to develop treatments for mitigation of radiation-induced hematopoietic damage has focused on amelioration of radiation-induced neutropenia, which has long been considered to be the primary factor in determining survival after an unintentional radiation exposure. Consistent with historical data, recent studies have highlighted the role that radiation-induced thrombocytopenia plays in radiation mortality, yet development of MCMs to mitigate radiation damage to the megakaryocyte lineage has lagged behind anti-neutropenia approaches. To address this gap and to foster research in the area of platelet regeneration after radiation exposure, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop on March 22–23, 2010 to encourage collaborations between NIAID program awardees and companies developing pro-platelet approaches. NIAID also organized an informal, open discussion between academic investigators, product development contractors, and representatives from the U.S. Food and Drug Administration (FDA) and other relevant government agencies about drug development toward FDA licensure of products for an acute radiation syndrome indication. Specific emphasis was placed on the challenges of product licensure for radiation/nuclear MCMs using current FDA regulations (21 CFR Parts 314 and 601) and on the importance of animal efficacy model development, design of pivotal protocols, and standardization of irradiation and animal supportive care.

NIAID/NIH radiation/nuclear medical countermeasures product research and development program.

One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. The U.S. Government has addressed these threats with a two-pronged strategy of preventing organizations from obtaining weapons of mass destruction and preparing in case an event occurs. The National Institute of Allergy and Infectious Diseases (NIAID) contributes to these preparedness efforts by supporting basic research and development for chemical, biological, radiological, and nuclear countermeasures for civilian use. The Radiation Countermeasures Program at NIAID has established a broad research agenda focused on the development of new medical products to mitigate and treat acute and long-term radiation injury, promote the clearance of internalized radionuclides, and facilitate accurate individual dose and exposure assessment. This paper reviews the recent work and collaborations supported by the Radiation Countermeasures Program.

Building the Strategic National Stockpile Through the NIAID Radiation Nuclear Countermeasures Program

The possibility of a public health radiological or nuclear emergency in the United States remains a concern. Media attention focused on lost radioactive sources and international nuclear threats, as well as the potential for accidents in nuclear power facilities (e.g., Windscale, Three Mile Island, Chernobyl, and Fukushima) highlight the need to address this critical national security issue. To date, no drugs have been licensed to mitigate/treat the acute and long‐term radiation injuries that would result in the event of large‐scale, radiation, or nuclear public health emergency. However, recent evaluation of several candidate radiation medical countermeasures (MCMs) has provided initial proof‐of‐concept of efficacy. The goal of the Radiation Nuclear Countermeasures Program (RNCP) of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) is to help ensure the government stockpiling of safe and efficacious MCMs to treat radiation injuries, including, but not limited to, hematopoietic, gastrointestinal, pulmonary, cutaneous, renal, cardiovascular, and central nervous systems. In addition to supporting research in these areas, the RNCP continues to fund research and development of decorporation agents targeting internal radionuclide contamination, and biodosimetry platforms (e.g., biomarkers and devices) to assess the levels of an individuals radiation exposure, capabilities that would be critical in a mass casualty scenario. New areas of research within the program include a focus on special populations, especially pediatric and geriatric civilians, as well as combination studies, in which drugs are tested within the context of expected medical care management (e.g., antibiotics and growth factors). Moving forward, challenges facing the RNCP, as well as the entire radiation research field, include further advancement and qualification of animal models, dose conversion from animal models to humans, biomarker identification, and formulation development. This paper provides a review of recent work and collaborations supported by the RNCP.