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.

Many cases of human exposures to high-dose radiation have been documented, including individuals exposed during the detonation of atomic bombs in Hiroshima and Nagasaki, nuclear power plant disasters (e.g., Chernobyl), as well as industrial and medical accidents. For many of these exposures, injuries to the skin have been present and have played a significant role in the progression of the injuries and survivability from the radiation exposure. There are also instances of radiation-induced skin complications in routine clinical radiotherapy and radiation diagnostic imaging procedures. In response to the threat of a radiological or nuclear mass casualty incident, the U.S. Department of Health and Human Services tasked the National Institute of Allergy and Infectious Diseases (NIAID) with identifying and funding early- to mid-stage medical countermeasure (MCM) development to treat radiation-induced injuries, including those to the skin. To appropriately assess the severity of radiation-induced skin injuries and determine efficacy of different approaches to mitigate/treat them, it is necessary to develop animal models that appropriately simulate what is seen in humans who have been exposed. In addition, it is important to understand the techniques that are used in other clinical indications (e.g., thermal burns, diabetic ulcers, etc.) to accurately assess the extent of skin injury and progression of healing. For these reasons, the NIAID partnered with two other U.S. Government funding and regulatory agencies, the Biomedical Advanced Research and Development Authority (BARDA) and the Food and Drug Administration (FDA), to identify state-of-the-art methods in assessment of skin injuries, explore animal models to better understand radiation-induced cutaneous damage and investigate treatment approaches. A two-day workshop was convened in May 2019 highlighting talks from 28 subject matter experts across five scientific sessions. This report provides an overview of information that was presented and the subsequent guided discussions.

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 threat of a large-scale radiological or nuclear (R/N) incident looms in the present-day climate, as noted most recently in an editorial in Scientific American (March 2021). These large-scale incidents are infrequent but affect large numbers of people. Smaller-scale R/N incidents occur more often, affecting smaller numbers of people. There is more awareness of acute radiation syndrome (ARS) in the medical community; however, ionising radiation-induced injuries to the skin are much less understood. This article will provide an overview of radiation-induced injuries to the skin, deeper tissues, and organs. The history and nomenclature; types and causes of injuries; pathophysiology; evaluation and diagnosis; current medical management; and current research of the evaluation and management are presented. Cutaneous radiation injuries (CRI) or local radiation injuries (LRI) may lead to cutaneous radiation syndrome, a sub-syndrome of ARS. These injuries may occur from exposure to radioactive particles suspended in the environment (air, soil, water) after a nuclear detonation or an improvised nuclear detonation (IND), a nuclear power plant incident, or an encounter with a radioactive dispersal or exposure device. These incidents may also result in a radiation-combined injury; a chemical, thermal, or traumatic injury, with radiation exposure. Skin injuries from medical diagnostic and therapeutic imaging, medical misadministration of nuclear medicine or radiotherapy, occupational exposures (including research) to radioactive sources are more common but are not the focus of this manuscript. Diagnosis and evaluation of injuries are based on the scenario, clinical picture, and dosimetry, and may be assisted through advanced imaging techniques. Research-based multidisciplinary therapies, both in the laboratory and clinical trial environments, hold promise for future medical management. Great progress is being made in recognising the extent of injuries, understanding their pathophysiology, as well as diagnosis and management; however, research gaps still exist.

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.

With the end of the Cold War in 1991, U.S. Government (USG) investments in radiation science and medical preparedness were phased out; however, the events of 11 September, which involved a terroristic attack on American soil, led to the re-establishment of funding for both radiation preparedness and development of approaches to address injuries. Similar activities have also been instituted worldwide, as the global threat of a radiological or nuclear incident continues to be a concern. Much of the USG’s efforts to plan for the unthinkable have centred on establishing clear lines of communication between agencies with responsibility for triage and medical response, and external stakeholders. There have also been strong connections made between those parts of the government that establish policies, fund research, oversee regulatory approval, and purchase and stockpile necessary medical supplies. Progress made in advancing preparedness has involved a number of subject matter meetings and tabletop exercises, publication of guidance documents, assessment of available resources, clear establishment of anticipated concepts of operation for multiple radiation and nuclear scenarios, and identification/mobilization of resources. From a scientific perspective, there were clear research gaps that needed to be addressed, which included the need to identify accurate biomarkers and design biodosimetry devices to triage large numbers of civilians, develop decorporation agents that are more amenable for mass casualty use, and advance candidate products to address injuries caused by radiation exposure and thereby improve survival. Central to all these activities was the development of several different animal constructs, since efficacy testing of these approaches requires extensive work in research models that accurately simulate what would be expected in humans. Recent experiences with COVID-19 have provided an opportunity to revisit aspects of radiation preparedness, and leverage those lessons learned to enhance readiness for a possible future radiation public health emergency.