Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report.

As COVID-19 continues, an increasing number of patients develop long COVID symptoms varying in severity that last for weeks, months, or longer. Symptoms commonly include lingering loss of smell and taste, hearing loss, extreme fatigue, and "brain fog." Still, persistent cardiovascular and respiratory problems, muscle weakness, and neurologic issues have also been documented. A major problem is the lack of clear guidelines for diagnosing long COVID. Although some studies suggest that long COVID is due to prolonged inflammation after SARS-CoV-2 infection, the underlying mechanisms remain unclear. The broad range of COVID-19's bodily effects and responses after initial viral infection are also poorly understood. This workshop brought together multidisciplinary experts to showcase and discuss the latest research on long COVID and chronic inflammation that might be associated with the persistent sequelae following COVID-19 infection.

The NIAID/RNCP Biodosimetry Program: An Overview.

Established in 2004, the Radiation and Nuclear Countermeasures Program (RNCP), within the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health has the central mission to advance medical countermeasure mitigators/therapeutics, and biomarkers and technologies to assess, triage, and inform medical management of patients experiencing acute radiation syndrome and/or the delayed effects of acute radiation exposure. The RNCP biodosimetry mission space encompasses: (1) basic research to elucidate novel approaches for rapid and accurate assessment of radiation exposure, (2) studies to support advanced development for US Food and Drug Administration (FDA) clearance of promising triage or treatment devices/approaches, (3) characterization of biomarkers and/or assays to determine degree of tissue or organ dose that can predict outcome of radiation injuries (i.e., organ failure, morbidity, and/or mortality), and (4) outreach efforts to facilitate interactions with researchers developing cutting edge biodosimetry approaches. Thus far, no biodosimetry device has been FDA cleared for use during a radiological/nuclear incident. At NIAID, advancement of radiation biomarkers and biodosimetry approaches is facilitated by a variety of funding mechanisms (grants, contracts, cooperative and interagency agreements, and Small Business Innovation Research awards), with the objective of advancing devices and assays toward clearance, as outlined in the FDA's Radiation Biodosimetry Medical Countermeasure Devices Guidance. The ultimate goal of the RNCP biodosimetry program is to develop and establish accurate and reliable biodosimetry tools that will improve radiation preparedness and ultimately save lives during a radiological or nuclear incident.

Radiation-induced gastrointestinal and cutaneous injuries: understanding models, pathologies, assessments, and clinically accepted practices.

PURPOSE: A U. S. and European joint effort fostering the development of medical countermeasures (MCMs) operable in case of radiological or nuclear emergencies. METHODS: Based on the joint engagement between the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the French Institut de Radioprotection et de Sûreté Nucléaire (IRSN), a Statement of Intent to Collaborate was signed in 2014 and a series of working group meeting were established. In December 2022, the NIAID and IRSN hosted a five-day, U.S./European meeting titled 'Radiation-Induced Cutaneous and Gastrointestinal Injuries: Advances in Understanding Pathologies, Assessment, and Clinically Accepted Practices' in Paris, France. The goals of the meeting were to bring together U.S. and European investigators to explore new research avenues for the medical management of skin and gastrointestinal injuries, including specific diagnostics for each organ system, animal models, and promising medical countermeasures (MCMs) to mitigate radiation damage. There was also an emphasis on exploring additional areas of medicine and response to understand best practices from other emergency scenarios, which could be leveraged to improve radiation preparedness, and the importance of accurate dosimetry in preclinical work. RESULTS: Subsequent to the workshop, seven collaborative projects, funded by both organizations, were established on topics ranging from MCMs and predictive biomarkers, and using physical methods to assess cutaneous radiation injuries, to mechanistic studies to understand radiation-induced damage in multiple organ systems. The importance of accurate dosimetry in preclinical works was highlighted and two recently published U.S./European commentaries that focus on the need for dosimetry standardization in the reported literature had their origins in this meeting. This commentary summarizes the workshop and open discussions among academic investigators, industry researchers, and U.S. and IRSN program representatives. CONCLUSIONS: Given the substantive progress made due to these interactions, both groups plan to expand out these meetings by incorporating high-level investigators from across the globe, while endeavoring to maintain the informal setting that was conducive to in-depth scientific discussion and enhanced the state of the science in radiation research.

Radiation-induced multi-organ injury.

PURPOSE: Natural history studies have been informative in dissecting radiation injury, isolating its effects, and compartmentalizing injury based on the extent of exposure and the elapsed time post-irradiation. Although radiation injury models are useful for investigating the mechanism of action in isolated subsyndromes and development of medical countermeasures (MCMs), it is clear that ionizing radiation exposure leads to multi-organ injury (MOI). METHODS: The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases partnered with the Biomedical Advanced Research and Development Authority to convene a virtual two-day meeting titled 'Radiation-Induced Multi-Organ Injury' on June 7-8, 2022. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. RESULTS: This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. CONCLUSIONS: Understanding the mechanisms that lead to radiation-induced MOI is critical to advancing candidate MCMs that could mitigate the injury and reduce associated morbidity and mortality. The observation that some of these mechanisms associated with MOI include systemic injuries, such as inflammation and vascular damage, suggests that MCMs that address systemic pathways could be effective against multiple organ systems.

Sex differences in radiation research.

PURPOSE: The Sex Differences in Radiation Research workshop addressed the role of sex as a confounder in radiation research and its implication in real-world radiological and nuclear applications. METHODS: In April 2022, HHS-wide partners from the Radiation and Nuclear Countermeasures Program, the Office of Research on Women's Health National Institutes of Health Office of Women's Health, U.S. Food and Drug Administration, and the Radiological and Nuclear Countermeasures Branch at the Biomedical Advanced Research and Development Authority conducted a workshop to address the scientific implication and knowledge gaps in understanding sex in basic and translational research. The goals of this workshop were to examine sex differences in 1. Radiation animal models and understand how these may affect radiation medical countermeasure development; 2. Biodosimetry and/or biomarkers used to assess acute radiation syndrome, delayed effects of acute radiation exposure, and/or predict major organ morbidities; 3. medical research that lacks representation from both sexes. In addition, regulatory policies that influence inclusion of women in research, and the gaps that exist in drug development and device clearance were discussed. Finally, real-world sex differences in human health scenarios were also considered. RESULTS: This report provides an overview of the two-day workshop, and open discussion among academic investigators, industry researchers, and U.S. government representatives. CONCLUSIONS: This meeting highlighted that current study designs lack the power to determine statistical significance based on sex, and much is unknown about the underlying factors that contribute to these differences. Investigators should accommodate both sexes in all stages of research to ensure that the outcome is robust, reproducible, and accurate, and will benefit public health.

Radiation and Chemical Program Research for Multi-Utility and Repurposed Countermeasures: A US Department of Health and Human Services Agencies Perspective.

Although chemical and radiological agents cause toxicity through different mechanisms, the multiorgan injuries caused by these threats share similarities that convene on the level of basic biological responses. This publication will discuss these areas of convergence and explore "multi-utility" approaches that could be leveraged to address common injury mechanisms underlying actions of chemical and radiological agents in a threat-agnostic manner. In addition, we will provide an overview of the current state of radiological and chemical threat research, discuss the US Government's efforts toward medical preparedness, and identify potential areas for collaboration geared toward enhancing preparedness and response against radiological and chemical threats. We also will discuss previous regulatory experience to provide insight on how to navigate regulatory paths for US Food and Drug Administration (FDA) approval/licensure/clearance for products addressing chemical or radiological/nuclear threats. This publication follows a 2022 trans-agency meeting titled, "Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures," sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health (NIH). Discussions from this meeting explored the overlapping nature of radiation and chemical injury and spurred increased interest in how preparedness for one threat leads to preparedness for the other. Herein, subject matter experts from the NIAID and the Biomedical Advanced Research and Development Authority (BARDA), a part of the Administration for Strategic Preparedness and Response (ASPR), summarize the knowledge gained from recently funded biomedical research, as well as insights from the 2022 meeting. These topics include identification of common areas for collaboration, potential use of biomarkers of injury to identify injuries caused by both hazards, and common and widely available treatments that could treat damage caused by radiological or chemical threats.

Making connections: the scientific impact and mentoring legacy of Dr. John E. Moulder.

PURPOSE: The intent of this mini review is to pay homage to Dr. John E. Moulder's long and successful career in radiation science with the Medical College of Wisconsin. This effort will be done from the perspective of his history of U.S. Government funding for research into the biological pathways involved in radiation-induced normal tissue injuries, especially damage to the kidneys and heart, and pharmacological interventions. In addition, the impact of his steady guidance and leadership in the mentoring of junior scientists, and the development of meaningful collaborations with other researchers will be highlighted. CONCLUSION: Dr. John E. Moulder's contributions to the field of radiation research, through his strong character and reputation, his consistent and dedicated commitment to his colleagues and students, and his significant scientific advances, have been critical to moving the science forward, and will not be forgotten by those who knew him personally or through publications documenting his important work.

Considerations of Medical Preparedness to Assess and Treat Various Populations During a Radiation Public Health Emergency.

During a radiological or nuclear public health emergency, given the heterogeneity of civilian populations, it is incumbent on medical response planners to understand and prepare for a potentially high degree of interindividual variability in the biological effects of radiation exposure. A part of advanced planning should include a comprehensive approach, in which the range of possible human responses in relation to the type of radiation expected from an incident has been thoughtfully considered. Although there are several reports addressing the radiation response for special populations (as compared to the standard 18-45-year-old male), the current review surveys published literature to assess the level of consideration given to differences in acute radiation responses in certain sub-groups. The authors attempt to bring clarity to the complex nature of human biology in the context of radiation to facilitate a path forward for radiation medical countermeasure (MCM) development that may be appropriate and effective in special populations. Consequently, the focus is on the medical (as opposed to logistical) aspects of preparedness and response. Populations identified for consideration include obstetric, pediatric, geriatric, males, females, individuals of different race/ethnicity, and people with comorbidities. Relevant animal models, biomarkers of radiation injury, and MCMs are highlighted, in addition to underscoring gaps in knowledge and the need for consistent and early inclusion of these populations in research. The inclusion of special populations in preclinical and clinical studies is essential to address shortcomings and is an important consideration for radiation public health emergency response planning. Pursuing this goal will benefit the population at large by considering those at greatest risk of health consequences after a radiological or nuclear mass casualty incident.

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin.

PURPOSE: To summarize presentations and discussions from the 2022 trans-agency workshop titled "Overlapping science in radiation and sulfur mustard (SM) exposures of skin and lung: Consideration of models, mechanisms, organ systems, and medical countermeasures." METHODS: Summary on topics includes: (1) an overview of the radiation and chemical countermeasure development programs and missions; (2) regulatory and industry perspectives for drugs and devices; 3) pathophysiology of skin and lung following radiation or SM exposure; 4) mechanisms of action/targets, biomarkers of injury; and 5) animal models that simulate anticipated clinical responses. RESULTS: There are striking similarities between injuries caused by radiation and SM exposures. Primary outcomes from both types of exposure include acute injuries, while late complications comprise chronic inflammation, oxidative stress, and vascular dysfunction, which can culminate in fibrosis in both skin and lung organ systems. This workshop brought together academic and industrial researchers, medical practitioners, US Government program officials, and regulators to discuss lung-, and skin- specific animal models and biomarkers, novel pathways of injury and recovery, and paths to licensure for products to address radiation or SM injuries. CONCLUSIONS: Regular communications between the radiological and chemical injury research communities can enhance the state-of-the-science, provide a unique perspective on novel therapeutic strategies, and improve overall US Government emergency preparedness.

A Trans-Agency Workshop on the Pathophysiology of Radiation-Induced Lung Injury.

As of January 2021, the U.S. Food and Drug Administration has approved four radiation exposure medical countermeasures (MCMs) to treat hematological acute effects, but no MCM is yet approved for radiation-induced lung injury (RILI). MCM approval for RILI and other subsyndromes utilizes the FDA Animal Efficacy Rule (Animal Rule), that requires demonstration of MCM efficacy in animal models with well-characterized pathophysiology, therefore, allowing translation to human use. A good animal model replicates the clinical condition and natural history of the disease, while allowing for studying the mechanism of action of the applied MCM and exhibiting clear benefits in terms of primary and secondary endpoints. However, there is much conversation regarding the advantages and limitations of individual models, and how to properly apply these models to demonstrate MCM efficacy. On March 20, 2019, the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID), Food and Drug Administration (FDA), and the Biomedical Advanced Research and Development Authority (BARDA) sponsored a workshop to identify critical research gaps, discuss current clinical practices for different types of pulmonary diseases, and consider available animal models for RILI.

Development of Biomarkers for Radiation Biodosimetry and Medical Countermeasures Research: Current Status, Utility, and Regulatory Pathways.

Biomarkers are important indicators of biological processes in health or disease. For this reason, they play a critical role in advanced development of radiation biodosimetry tools and medical countermeasures (MCMs). They can aid in the assessment of radiation exposure level, extent of radiation-induced injury, and/or efficacy of a MCM. This meeting report summarizes the presentations and discussions from the 2020 workshop titled, "Biomarkers in Radiation Biodosimetry and Medical Countermeasures" sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID). The main goals of this meeting were to: 1. Provide an overview on biomarkers and to focus on the state of science with regards to biomarkers specific to radiation biodosimetry and MCMs; 2. Understand developmental challenges unique to the role of biomarkers in the fields of radiation biodosimetry and MCM development; and 3. Identify existing gaps and needs for translational application.

A Trans-Agency Workshop on the Pathophysiology of Radiation-Induced Lung Injury.

Research and development of medical countermeasures (MCMs) for radiation-induced lung injury relies on the availability of animal models with well-characterized pathophysiology, allowing effective bridging to humans. To develop useful animal models, it is important to understand the clinical condition, advantages and limitations of individual models, and how to properly apply these models to demonstrate MCM efficacy. On March 20, 2019, a meeting sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID) brought together medical, scientific and regulatory communities, including academic and industry subject matter experts, and government stakeholders from the Food and Drug Administration (FDA) and the Biomedical Advanced Research and Development Authority (BARDA), to identify critical research gaps, discuss current clinical practices for various forms of pulmonary damage, and consider available animal models for radiation-induced lung injury.

NIH Policies and Regulatory Pathways to U.S. FDA licensure: Strategies to Inform Advancement of Radiation Medical Countermeasures and Biodosimetry Devices.

The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases (NIAID), is tasked with the mandate of identifying biodosimetry tests to assess exposure and medical countermeasures (MCMs) to mitigate/treat injuries to individuals exposed to significant doses of ionizing radiation from a radiological/nuclear incident, hosted. To fulfill this mandate, the Radiation and Nuclear Countermeasures Program (RNCP), hosted a workshop in 2018 workshop entitled "Policies and Regulatory Pathways to U.S. FDA licensure: Radiation Countermeasures and Biodosimetry Devices." The purpose of the meeting was to facilitate the advancement of MCMs and biodosimetry devices by assessing the research devices and animal models used in preclinical studies; government policies on reproducibility, rigor and robustness; regulatory considerations for MCMs and biodosimetry devices; and lessons learned from sponsors of early stage MCM or biodosimetry devices. Meeting presentations were followed by a NIAID-led, open discussion among academic investigators, industry researchers and U.S. government representatives.

Animal Care in Radiation Medical Countermeasures Studies.

Animal models are necessary to demonstrate the efficacy of medical countermeasures (MCM) to mitigate/treat acute radiation syndrome and the delayed effects of acute radiation exposure and develop biodosimetry signatures for use in triage and to guide medical management. The use of animal models in radiation research allows for the simulation of the biological effects of exposure in humans. Robust and well-controlled animal studies provide a platform to address basic mechanistic and safety questions that cannot be conducted in humans. The U.S. Department of Health and Human Services has tasked the National Institute of Allergy and Infectious Diseases (NIAID) with identifying and funding early- through advanced-stage MCM development for radiation-induced injuries; and advancement of biodosimetry platforms and exploration of biomarkers for triage, definitive dose, and predictive purposes. Some of these NIAID-funded projects may transition to the Biomedical Advanced Research and Development Authority (BARDA), a component of the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services, which is tasked with the advanced development of MCMs to include pharmacokinetic, exposure, and safety assessments in humans. Guided by the U.S. Food and Drug Administration's (FDA) Animal Rule, both NIAID and BARDA work closely with researchers to advance product and device development, setting them on a course for eventual licensure/approval/clearance of their approaches by the FDA. In August 2020, NIAID partnered with BARDA to conduct a workshop to discuss currently accepted animal care protocols and examine aspects of animal models that can influence outcomes of studies to explore MCM efficacy for potential harmonization. This report provides an overview of the two-day workshop, which includes a series of special topic presentations followed by panel discussions with subject-matter experts from academia, industry partners, and select governmental agencies.

Meeting Report: A Poly-Pharmacy Approach to Mitigate Acute Radiation Syndrome.

The National Institute of Allergy and Infectious Diseases, Radiation and Nuclear Countermeasures Program, was tasked by the United States Congress and the U.S. Department of Health and Human Services to identify and fund early-to-mid-stage development of medical countermeasures (MCMs) to treat radiation-induced injuries. In developing MCMs to treat various sub-syndromes (e.g., hematopoietic, gastrointestinal, lung), it is important to investigate whether a poly-pharmacy approach (i.e., drug cocktails) can provide additive benefits to mitigate injuries arising from the acute radiation syndrome (ARS). In addition, potential drug-drug interactions must be examined. For this reason, a workshop was held, which centered on understanding the current state of research investigating poly-pharmacy approaches to treat radiation injuries. The first session set the stage with an introduction to the concept of operations or support available for the response to a nuclear incident, as this is the key to any emergency response, including MCM availability and distribution. The second session followed the natural history of ARS in both humans and animal models to underscore the complexity of ARS and why a poly-pharmacy approach may be necessary. The third session featured talks from investigators conducting current MCM poly-pharmacy research. The meeting closed with a focus on regulatory considerations for the development of poly-pharmacy approaches or combination treatments for ARS.

Study logistics that can impact medical countermeasure efficacy testing in mouse models of radiation injury.

PURPOSE: To address confounding issues that have been noted in planning and conducting studies to identify biomarkers of radiation injury, develop animal models to simulate these injuries, and test potential medical countermeasures to mitigate/treat damage caused by radiation exposure. METHODS: The authors completed an intensive literature search to address several key areas that should be considered before embarking on studies to assess efficacy of medical countermeasure approaches in mouse models of radiation injury. These considerations include: (1) study variables; (2) animal selection criteria; (3) animal husbandry; (4) medical management; and (5) radiation attributes. RESULTS: It is important to select mouse strains that are capable of responding to the selected radiation exposure (e.g. genetic predispositions might influence radiation sensitivity and proclivity to certain phenotypes of radiation injury), and that also react in a manner similar to humans. Gender, vendor, age, weight, and even seasonal variations are all important factors to consider. In addition, the housing and husbandry of the animals (i.e. feed, environment, handling, time of day of irradiation and animal restraint), as well as the medical management provided (e.g. use of acidified water, antibiotics, routes of administration of drugs, consideration of animal numbers, and euthanasia criteria) should all be addressed. Finally, the radiation exposure itself should be tightly controlled, by ensuring a full understanding and reporting of the radiation source, dose and dose rate, shielding and geometry of exposure, while also providing accurate dosimetry. It is important to understand how all the above factors contribute to the development of radiation dose response curves for a given animal facility with a well-defined murine model. CONCLUSIONS: Many potential confounders that could impact the outcomes of studies to assess efficacy of a medical countermeasure for radiation-induced injuries are addressed, and recommendations are made to assist investigators in carrying out research that is robust, reproducible, and accurate.

Acute Radiation Syndrome and the Microbiome: Impact and Review.

Study of the human microbiota has been a centuries-long endeavor, but since the inception of the National Institutes of Health (NIH) Human Microbiome Project in 2007, research has greatly expanded, including the space involving radiation injury. As acute radiation syndrome (ARS) is multisystemic, the microbiome niches across all areas of the body may be affected. This review highlights advances in radiation research examining the effect of irradiation on the microbiome and its potential use as a target for medical countermeasures or biodosimetry approaches, or as a medical countermeasure itself. The authors also address animal model considerations for designing studies, and the potential to use the microbiome as a biomarker to assess radiation exposure and predict outcome. Recent research has shown that the microbiome holds enormous potential for mitigation of radiation injury, in the context of both radiotherapy and radiological/nuclear public health emergencies. Gaps still exist, but the field is moving forward with much promise.

Commonalities Between COVID-19 and Radiation Injury.

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.

Metabolomics in Radiation Biodosimetry: Current Approaches and Advances.

Triage and medical intervention strategies for unanticipated exposure during a radiation incident benefit from the early, rapid and accurate assessment of dose level. Radiation exposure results in complex and persistent molecular and cellular responses that ultimately alter the levels of many biological markers, including the metabolomic phenotype. Metabolomics is an emerging field that promises the determination of radiation exposure by the qualitative and quantitative measurements of small molecules in a biological sample. This review highlights the current role of metabolomics in assessing radiation injury, as well as considerations for the diverse range of bioanalytical and sampling technologies that are being used to detect these changes. The authors also address the influence of the physiological status of an individual, the animal models studied, the technology and analysis employed in interrogating response to the radiation insult, and variables that factor into discovery and development of robust biomarker signatures. Furthermore, available databases for these studies have been reviewed, and existing regulatory guidance for metabolomics are discussed, with the ultimate goal of providing both context for this area of radiation research and the consideration of pathways for continued development.