European Medical Consensus for the Clinical Management of ARS

In 2006, a European consensus conference on the medical management of mass radiation casualties was convened in France by the EBMT, the Institute for Radiation Protection and Nuclear Safety (IRSN), and the University of Ulm, Germany.Reference Gorin, Fliedner and Gourmelon⁸ This conference, which focused on diagnosis and treatment strategies in cases of accidental overexposure to ionizing radiation, brought together a working group of 65 medical practitioners, emergency medicine specialists, surgeons, and representatives of national health authorities of 25 European and international member states. The participants came from a wide field of competences, including leading European experts in hematology, radiopathology, and radiation dosimetry, which ensured a comprehensive approach to addressing the challenges of clinical management of radiation injuries.

The participants reached a consensus, still considered a benchmark, for the triage of radiation casualties. It was based on a two-step strategy with a primary medical triage in the field and a secondary triage at a hospital. Primary scoring should be performed by recording clinical symptoms on a date and hour-stamped chart within the first 48 hours. This strategy allows to identify individuals who did not receive any clinically significant radiation exposure, who will be scored as “RC0” (Response Category, RC) to avoid saturation of hospital capacities. Further, there was an agreement that, to facilitate the initial emergency triage performed by first responders in the context of mass casualties, a simplified three-level transitory scoring system would be sufficient. In this system, a score of “RC1” would indicate patients who can be managed on an outpatient basis or through a day care hospital setting; a score of “RC2” would denote patients requiring intensive medical intervention for rescue; and a score of “RC3” would represent patients anticipated to develop multiple organ failure beyond the scope of any curative therapeutic measures. For a more granular assessment at the admission of patients in the hospital, it was agreed that the existing MEdical TREatment ProtocOLs for Radiation Accident Victims—METREPOLReference Fliedner, Friesecke and Beyrer⁶ grading system is appropriate. This scoring system builds on the principles of “clinical dosimetry,” which integrates exposure history, clinical symptoms, and systematic repetitive full blood counts (“sequential diagnostics”) and allows decision-making regarding hospitalization or specific therapy and prognosis orientation already at an early stage and in an overwhelming mass casualty disaster.

The consensus underscores that physicians ideally should not defer medical management until physical radiation dosimetry data becomes available. Such dosimetry data, requiring environmental and individual monitoring and measurements, involving reconstruction of individual doses using anthropomorphic phantoms loaded with dosimeters, dose reconstruction based on the use of Monte Carlo software using a modeling approach, biological cytogenetic dosimetry, or electron paramagnetic resonance measurements on biological samples, may help to evaluate dose distribution within the body in case of heterogeneous radiation exposure. However, these methods remain time-consuming, requiring special expertise and equipment, as well as typically limited by low throughput capacity. This means that dosimetric methods should be reserved for patients presenting with the more complex and severe clinical picture.

The consensus emphasizes that the principles of “supportive therapy” for managing hematopoietic failure in irradiated victims are like those required for other haematological patients with pancytopenia. There are important experiences gained from patients with various forms of acute leukemia and severe aplastic anemia managed with advanced hematologic intensive care in, e.g., approximately 3000 hospitals by 10,000+ hematologists in Europe linked to the 550 EBMT BMT Centers.⁹ Given that radiation-injured patients may undergo a phase of granulocytopenia, which heightens the risk of bacterial and fungal infections, supportive care should encompass reverse barrier nursing techniques, including permanent sterile environments and mobile isolation units to equip standard hospital rooms. For the most severe cases, controlling infection during the critical neutropenic phase is a major limiting factor for successful outcome. Fluoroquinolones have been used extensively for prophylaxis in neutropenic patientsReference Benderitter, Herrera-Reyes and Gigov¹⁰ and prophylactic treatment with fluconazole and acyclovir was reported in the literature for ARS-H patients.

There was a consensus regarding the implementation of a “stimulation therapy” for managing hematopoietic failure in patients with severe overexposure to radiation. Key products for addressing hematopoietic syndrome include cytokines-growth factors that promote the proliferation of progenitor blood cells, facilitate myeloid maturation, protect against apoptosis, and enhance cellular function. Consensus supports the use of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), erythropoietin (EPO), and thrombopoietin (TPO) agonists. Treatment should be initiated as early as possible (if possible, during the 24-48 hours window after radiation exposure) and maintained for a duration of 14-21 days.Reference Gorin, Fliedner and Gourmelon^{8, 9} If severe aplasia persists for 14-21 days despite cytokine treatment, and if there is no evidence of irreversible organ damage in a patient fulfilling basic regular age and health requirements, a hematopoietic stem cell (HSC) transplantation may well be considered. Such transplantation is not an emergency in such a clinical situation. If severe aplasia persists under cytokines for more than 14-21 days, the possibility of an HSC is discussed. HSC is not indicated in case of residual hematopoiesis on bone marrow biopsy, other irreversible organ damage, and untreated or uncontrolled infection, if present. ARS may be associated with difficult-to-treat cutaneous or localized radiation injuries or combined injuries (trauma and radiation exposure, for example), requiring complementary clinical specialties such as reconstructive surgery, stem cell therapy, and rehabilitation. Effective pain therapy may not be neglected.

The EBMT recommends the use of bone marrow, peripheral blood hematopoietic stem cells (whether depleted or not), or cord blood for grafting. The following priority for donor selection is advised according to current transplant criteria: human leucocyte antigen (HLA)-identical sibling, HLA-identical unrelated donor, cord blood (a minimum requirement of donor-recipient 4/6-loci HLA match), or haplo-identical donor. Minimum cell doses for grafting are specified as follows: at least 2 × 10Reference Fliedner, Friesecke and Beyrer⁶ CD34+ cells per kg for peripheral blood, 2 × 10Reference Gorin, Fliedner and Gourmelon⁸ nucleated cells per kg for bone marrow, and 3 × 10⁷ nucleated cells for cord blood. Conditioning regimens and prevention of graft-versus-host disease should adhere to current transplant guidelines, with a preference for reduced-intensity conditioning and avoidance of methotrexate. This medical consensus remains the state-of-the-art medical reference for ARS management and needs to be disseminated to the European medical community.

The primary units likely to care for patients with ARS are intensive care, burns, hematology, and cellular therapy, if available. The availability of mobile isolation units could enhance patient care in these settings. It was admitted that not all hospitals across Europe are adequately equipped or staffed to manage ARS patients.Reference Hashmi, Powles and Ma¹¹ Specific hospitals equipped to handle such emergencies should be designated with medical teams trained in this type of care and hematological departments equipped with sterile rooms. These hospitals, and other hospitals lacking these specific chambers, could benefit from mobile isolation units as used during the COVID-19 crisis in case of ARS patients’ afflux.

Without adequate preparation for such an exceptional scenario, healthcare providers will face significant pressure to determine appropriate responses and treatment options. Especially allocating scarce treatment resources in large-scale scenarios means to prioritize patients (pre-hospital damage control strategies) to allow medical regulation and allocate potential limited medical countermeasures to patients with the highest chance of remission. Consequently, it is crucial to develop standardized protocols to guide decision-making in these circumstances.

A unique European Medical Experience of Clinical Management of ARS

Details have been reported of operational medical management of a short series of ARS patients admitted in European hospitalsReference Benderitter, Herrera-Reyes and Gigov¹⁰ and highlight the still valid European medical consensus for ARS management in case of mass casualty event (MCE).Reference Gorin, Fliedner and Gourmelon⁸ In line with this medical consensus, the management of these patients with accidental radiation-induced myelosuppression primarily involved supportive care, with specific treatments as a first-line treatment based on hematopoietic growth factor injections. This clinical strategy was based on validated existence of residual hematopoietic function related to the characteristic heterogeneity of radiation exposure.Reference Gorin, Fliedner and Gourmelon⁸ Supportive care includes the administration of antimicrobial agents, antiemetic agents, antidiarrheal agents, fluids, electrolytes, analgesic agents, and topical burn creams. Rapid diagnosis at an early stage is crucial.Reference Fliedner, Friesecke and Beyrer^6, Reference Gorin, Fliedner and Gourmelon^{8, 12} Specific treatment is based on the administration of cytokines including in priority pegylated G-CSF (peg-filgrastim) at 6 mg every 14 days but also pegylated erythropoietin (darbepoetin alfa) at 500 IU once weekly, stem cell factor (SCF) at 20 μg/kg for 5 days, and romiplostim (TPO analogue) at 10 μg/kg once weekly, with various combinationsReference Benderitter, Herrera-Reyes and Gigov¹⁰ depending on the medical strategy implemented. Depending on the delay after radiation exposure, cytokines (Peg G-CSF) should be used as soon as possible, within 48 hours, as a mitigation treatment. If aplasia occurs, cytokine administration can be maintained up to 14 to 21 days post-radiation exposure, and this treatment strategy can be personalized based on the individual evolution of hematopoietic lineage and clinical characteristics of each patient. Daily blood counts were used to determine the initiation of G-CSF and SCF when granulocyte counts reached below 1000/mm³, TPO administration when platelet counts reached below 50,000/mm³, and EPO when hemoglobin levels fell below 80 g/L. The duration of treatment is guided by criteria for blood cell recovery. The recovery of bone marrow function following radio-induced myelosuppression was notably accelerated using this multi-cytokine therapy, particularly in cases of prolonged radiation exposure in dose ranges inducing severe myelosuppression (approximately 5-8 Gy), where hematopoietic stem cell transplantation was not indicated.

This medical European consensus remains the state-of-the-art medical reference for ARS management and needs to be disseminated to the European medical communities. Only a small fraction of practitioners has either training or experience in the field of radiation injury. A specific NAC group (Nuclear Accident Committee) was set up under the umbrella of the European Bone Marrow Transplantation Association to educate health care professionals and disseminate protocols for the diagnosis and treatment of ARS.

Pre-Hospital and Hospital Preparedness and Response in Europe

International healthcare organizations and associations should prepare for the potential scenarios of RN emergency, and further European harmonization on the capabilities required within teams responding at all levels of care needs to be fostered. With the war in Ukraine entering its third year, the country continues to face risks related to CBRN hazards. Preparedness for such a response needs to be planned in detail, well-coordinated, regularly exercised, and implemented by trained professionals. It must be based on three complementary levels: operational planning, training of health professionals, and provision of the equipment and health products necessary for the care of these patients. Substantial differences exist between European member states in the organizational responsibilities and mandates for CBRN response. However, technical capabilities needed to ensure the readiness of healthcare settings, referral pathways, and the health workforce capacity for an emergency response in case of NR mass causality are mandatory to save as many lives as possible by optimizing the use of available resources. Clinical management, even for a few ARS patients, can drain substantial resources of a health care facility and make it difficult to provide care in case of a mass-casualty emergency without a medical evacuation operation to designated European medical facilities.

Training programs for health professions across Europe remain fragmented, and EU-WHO and IAEA have a unique mandate to build on experiences of European countries, to provide European guidance, training materials, and planning tools adapted to experts of the European Civil Protection, emergency medical specialists, surgeons, or medical specialists (hematologists, gastroenterologists, etc.) of reference European hospitals. Initiatives were already implemented. The WHO Hospital emergency response checklist (an all-hazards tool for hospital administrators and emergency managers: WHO EURO, 2011)¹³ is designed to assist health facilities in evaluating their capacity to manage a mass-casualty event stemming from a radiation emergency, including hospital crisis management, triage and decontamination procedures, equipment and supply availability, clinical management protocols, and detailed operational procedures. Further on, Hospital Safety Index—HSI¹⁴ provides recommendations on safe operations of health care facilities in the areas affected by disasters, conflicts, and other emergencies. In addition to HSI, to bolster the preparedness of the national health systems for such risks, WHO is developing a hospital radiation emergency preparedness checklist that provides a list of actions and measures to be put in place to ensure the readiness to accept the patients after a mass-casualty radiation emergency. Both tools—HSI and Radiation Checklist are being piloted in health care facilities of WHO member states (in Ukraine in March 2024¹⁵ and in Lithuania in June 2024¹⁶), which allows to gather end-users’ feedback and fine-tuning of the tools. Comprehensive guides for medical care for radiation emergencies, covering specific aspects such as psychosocial support, organization of emergency response, and hospital preparedness planning, are provided in the EC.Reference Del Rosario Pérez, Carr and Rojas-Palma^17, Reference Rojas-Palma, Liland and Jerstad^{18, 19} For pre-clinical management, the Handbook on Triage, Monitoring and Treatment of People Following Malevolent Use of Radiation (TMT-Handbook) edited by European contributors is still a state-of-the-art reference. In particular, the publication outlines effective triage pathways for patients with trauma combined with radiation exposure.Reference Rojas-Palma, Liland and Jerstad¹⁸

European Stockpile of Medical Countermeasures for Radiological and Nuclear Threats

The WHO International Health Regulations (2005) require all countries to establish national capacity and secure resources for responding to health emergencies.²⁰ Facing NR threat, ARS is considered as one of the most life-threatening outcomes. In 2023, the WHO provided recommendations for national stockpiles for RN emergencies. G-CSF, pegylated G-CSF, GM-CSF, and romiplostim were consensually identified as MCM to be integrated into national stockpiles.²¹ These drugs were recently approved for ARS treatment by the US Food and Drug Administration.

Established in close collaboration with the Health Emergency Preparedness and Response Authority (HERA) and the Union Civil Protection Mechanism (UCPM), the creation of the CBRN stockpile including dedicated medical items and equipment, was implemented in order to face exceptional sanitary events (European Commission regulation 2022/2371 on serious cross-border threats to health). Since 2021, the Commission has financed medical countermeasures (MSMs) stockpiles maintained by several Member States with a €1200 million budget. The rescEU-CBRN strategic reserve stockpiles will provide additional support to Member States facing a sanitary crisis overwhelming their national capacities. These rescEU stockpiles contain isolated references or prepacked operational modules (trunks containing different items) readily available for emergency transport and use, in the field if need be. Prepositioning is a critical pillar of preparedness, allowing immediate response and saving of life. The European operational modules include specific medicines (for CBRN and medical emergencies in the field) complemented with general medical supplies so that the capacity does not need the use of additional ancillaries. More than 600 references are listed for NR threat, including medicines, medical devices, personal protective equipment (PPE), and support equipment. For some items stockpiled in large volume, a rotation strategy is implemented when feasible. Most recently, Europe has provided Ukraine with MCM and medical assistance to face CBRN threats, worth more than €50 million, including MCM (antidotes, potassium iodide tablets, bronchodilators, and other therapeutics), medical devices (oxygen concentrators and other intensive care unit equipment), and response equipment (e.g., for decontamination, PPE, and chemical detectors).

Setting up the financing and securing procurements in crisis situations, arrangements for storage, rotation, deployment, replenishment of stockpiles, as well as monitoring and evaluation of their use, need appropriate national legislation and supra-national recommendations.