Finite Supplies of Cytokines Will Require Strategic Deployment

The detonation of a nuclear device in a large city could result in hundreds of thousands of people with mechanical blast trauma and/or thermal burn injuries, hundreds of thousands with significant radiation exposure, and tens of thousands with combined radiation-trauma-burn injuries.Reference Knebel, Coleman and Cliffer ¹¹ These numbers of injured people will result in a scarce-resources environment where the need for healthcare resources will far exceed local availability.Reference Casagrande, Wills and Kramer ¹² Triage will be essential to prioritize care so that limited resources can do the “greatest good for the greatest number.”Reference Coleman, Weinstock and Casagrande ¹

Although hospitals typically maintain small quantities of cytokines for routine use, these inventories are inadequate for responding to a nuclear detonation. Cytokines can be deployed to requesting jurisdictions in a national nuclear public health emergency. However, the number of people at risk for ARS will likely exceed the number treatable by cytokine inventory that can be mobilized, deployed, and administered early in the response.

Standard clinical recommendations for the treatment of ARS include administering cytokines as soon as possible after whole body or significant partial body exposure to radiation doses above 2 Gy.Reference Reeves ^{13 ,} Reference Dainiak, Gent and Carr ¹⁴ The triage protocol for crisis standards of care developed by the ASPR Scarce Resources Project working groupReference Coleman, Knebel and Hick ¹⁵ prioritizes giving cytokines to people with radiation doses between 2 and 6 Gy and minimal or no mechanical trauma or burn injury, i.e., those who could benefit most when resources are scarce.Reference Coleman, Weinstock and Casagrande ¹ This triage protocol excludes people who received low enough doses of radiation that they could adequately recover without cytokines, as well as those who have received such high doses of radiation that recovery is unlikely without intensive care. While only a fraction of survivors will fit this criterion, this group could still number in the thousands to tens of thousands.Reference Knebel, Coleman and Cliffer ¹¹ In the chaotic aftermath of a nuclear detonation, identifying these people will be challenging, yet they must be identified as quickly and efficiently as possible to promote effective use of a limited supply of cytokines. Timely radiation dose estimation will therefore be critical.

Strategic Cytokine Deployment Requires the Ability to Estimate Radiation Dose With Tools That Are Simple, Yet Robust

Methods to identify eligibility for cytokines must be robust enough to screen out people with radiation exposures that are too low or too high to benefit substantially from cytokines and should be simple enough to be performed by people with no prior experience with radiation symptoms. Ideally, effective screening methods should have high throughput with a rapid turnaround time, can be administered at the point of care, and require minimal expertise to perform and interpret. Current methods for accurately and reliably estimating radiation exposure (dicentric chromosome assay and micronuclei assay) are lab-based, low-throughput, and require time and expertise. While useful for a small-scale radiation incident, these methods will be of limited use for rapidly screening the great number of nuclear detonation survivors for cytokine eligibility in the initial days of the response. Serial complete blood counts (CBCs) to measure lymphocyte depletion kinetics can provide a preliminary estimation of radiation dose; however, to expect widespread availability of CBCs for rapid, high-throughput screening soon after a nuclear detonation is unrealistic. Several radiation exposure screening tools are in the development pipeline,Reference Abend, Blakely, Ostheim, Schuele and Port ^{16 –}Reference Lacombe, Summers and Khanishayan ¹⁸ including point-of-care assays based on biodosimetry algorithms that require only limited hematological data; however, no firm pathway or timeline is currently in place to support FDA approval for these tools. Even if these tools were imminently available, challenges remain around deploying them for fair and effective use in a nuclear detonation response.

In the absence of a high-throughput, point-of-care diagnostic test, the methods available to rapidly assess radiation exposure dose and cytokine eligibility for tens of thousands of people are geographic assessment, clinical symptoms, and blood cell counts. The EAST tool provides a framework based on these three factors for determining cytokine eligibility in a resource-poor environment.Reference Hick, Bader and Coleman ³ While simple, the EAST tool provides a methodology that can be fairly and consistently applied and is appropriately more discriminating than a first-come, first-served approach to cytokine eligibility. Guidance suggests performing at least one CBC, and ideally serial CBCs, whenever possible, to guide triage and clinical management of the patient.Reference Hick, Bader and Coleman ^{3 , 19 – 22} However, CBCs are unlikely to be available for widespread, rapid screening early in the response.

Absent blood cell counts, the EAST tool and similar radiation dose estimation algorithms rely on clinical signs and geographic assessment. Time to onset and frequency of vomiting are frequently cited as the most useful symptoms for estimating radiation dose exposureReference Hick, Bader and Coleman ^{3 ,} Reference Flynn and Goans ^{4 ,} Reference Waselenko, MacVittie and Blakely ^{23 ,} Reference Demidenko, Williams and Swartz ²⁴; however, these symptoms are imprecise and not specific to radiation exposure. Sources differ on the incidence of vomiting, particularly at lower exposure doses; different sources correlate different times to onset and frequencies of vomiting with different radiation dose estimates.Reference Hick, Bader and Coleman ^{3 ,} Reference Flynn and Goans ^{4 ,} Reference Waselenko, MacVittie and Blakely ^{23 ,} Reference Demidenko, Williams and Swartz ²⁴

For geographic dose assessment, the EAST tool suggests the use of a map developed by the Interagency Modeling and Atmospheric Assessment Center (IMAAC), or similar “official 12-24 hour estimated dose map.”Reference Hick, Bader and Coleman ³ While the Radiation Emergency Medical Management website, operated by the U.S. Department of Health and Human Services, has a list of questions to ask survivors about location and sheltering, ²⁵ no methodology exists to use survivors’ answers to estimate exposure doses from prompt radiation and fallout, considering shelter quality and time spent sheltering in place. Currently, the National Atmospheric Release Advisory Center (NARAC) develops these maps for IMAAC in support of response to radiological/nuclear incidents. The NARAC products are designed primarily to help establish the timing of search-and-rescue activities, restricted or exclusion zones for human activity, and evacuation routes; these products are not intended to estimate exposure dose for determining health effects. ²⁶ Also, these maps show fallout dose and dose rates for people outside; they do not account for radiation exposure from prompt radiation, nor for shielding provided by different shelter types, which can significantly reduce both prompt radiation dose and fallout dose received during sheltering in place. ²⁷

The Solutions Lab is exploring alternative methodologies that build on the EAST tool and other radiation assessment tools, such as the Medical Treatment Protocols for Radiation Accident Victims (METREPOL)Reference Fliedner, Powles, Sirohi and Niederwieser ²⁸ and the Armed Forces Radiobiology Research Institute (AFRRI) Biodosimetry Assessment Tool (BAT),Reference Sandgren, Salter, Levine, Ross, Lillis-Hearne and Blakely ^{29 ,} Reference Blakely, Madrid and Sandgren ³⁰ to reduce the uncertainty of rapid, high-throughput radiation dose estimation with currently available technology. In addition, the Solutions Lab is engaging with other federal agencies to explore the development of additional maps that would be more useful for determining short-term health effects for survivors of a nuclear detonation.

Symptoms of ARS May Not Be Present at the Time of Medical Evaluation

Cytokine-eligible survivors may not exhibit symptoms of ARS at the time of screening for radiation exposure, and nearly all cytokine-eligible survivors will be ambulatory. Although vomiting is a widely cited symptom of radiation exposure, not everyone exposed to 2 to 6 Gy will vomit, especially at the lower end of this exposure range; the reported incidence of vomiting varies across references from 35 to 70 percent for 2 Gy and from 54 to 90 percent for 3 Gy.Reference Waselenko, MacVittie and Blakely ^{23 ,} Reference Anno, Baum, Withers and Young ^{31 , 32} For all exposure doses of interest, any vomiting experienced initially after exposure will have stopped within 24 hours. This trend is also seen for nausea and diarrhea.Reference Waselenko, MacVittie and Blakely ^{23 ,} Reference Anno, Baum, Withers and Young ³¹ Because they may appear well, cytokine-eligible survivors would not be prioritized for immediate care if nearby hospitals or medical centers are overwhelmed with providing acute care to survivors with serious trauma or burn injuries. Those who could benefit the most from early treatment with cytokines may be referred to a mass-care location such as an assembly center or community reception center. Assembly centers have been suggested as an alternate location for cytokine eligibility screening and administration.Reference Hick and Coleman ² The Solutions Lab is exploring the feasibility of administering cytokines to those who are eligible in austere, mass-care, nonhospital settings as a potential element of effective use of cytokines in a nuclear detonation response.

Logistics of Cytokine Administration Are Complex

Day-to-day use of cytokines for steady-state clinical indications (e.g., radiation-induced myelosuppression for transplants) under conventional care standards is managed by specialized healthcare providers, with close supervision of a patient’s health status. Treatment is initiated in a hospital or clinical setting, with options for follow-up treatment in a clinic or at home and under medical supervision. However, in the early days after a nuclear detonation, many cytokine-eligible survivors will be in mass-care settings, such as assembly centers or community reception centers. Frequent blood testing is unlikely to be available to guide treatment. As noted above, the Solutions Lab is exploring the feasibility of administering cytokines in mass-care, nonhospital settings as an approach to efficiently providing cytokines to those who are eligible within the window of efficacy for mitigating ARS. Logistics to consider for this approach include the delivery and cold storage of cytokines at austere, mass-care settings, personnel required for mass prescribing and dispensing of cytokines, administration of additional doses when needed, and patient monitoring and tracking.

Cytokines that could be used in a response must be refrigerated and administered as a subcutaneous injection, which requires training. ^{19 – 22} The ideal medical countermeasure for administering in a mass-care setting would be administered as a single dose, have a high therapeutic index, be approved for all populations, and have flexible storage conditions. Several promising candidates are in development, but the timeline to FDA approval and widespread availability is unclear.Reference Rosen, Day and Singh ³³ Whereas sargramostim requires daily dosing,Reference Zhong, Pouliot and Downey ¹⁰ pegfilgrastim can be used with only weekly dosing,Reference Hankey, Farese and Blaauw ⁷ and romiplostim requires only a single dose. A single dose of pegfilgrastim or romiplostim could suffice at least temporarily pending greater availability both of the medical countermeasures and of the resources to administer them, including sampling and laboratory monitoring of the results of administration. Additional hurdles to implementing the administration of cytokines in a mass-care setting include concerns about scope of practice laws and liability for personnel involved, lack of published planning and medical guidance for using cytokines in this context, and the logistics of providing patients with multiple doses of cytokines when needed. Lastly, patient tracking will be critical for effective cytokine administration activities and will be complicated by patient movement and limited access to electronic collection and storage options that may follow a nuclear incident. The Solutions Lab is connecting with other experts in federal agencies to examine potential solutions to these challenges, including the possible development of additional federal guidance documents, exercises, and coordination with state, tribal, territorial, and local partners to understand what capabilities are available for using cytokines for a nuclear detonation response.

Summary of Challenges

In the aftermath of a nuclear detonation, the effective administration of cytokines to radiation-injured survivors poses unique and diverse challenges. The appropriate population to receive cytokines must be quickly identified, and treatment must be initiated promptly in the context of scarce resources, disruptions to infrastructure, and potentially tens of thousands of patients needing care. Additional response factors, including the recommendation to shelter in place for 24 hours after detonation ²⁷ and time to evacuation, will carve into this window of time, making the need for rapid, effective selection for eligibility and initiation of treatment even more critical. While aspirational solutions to these challenges that involve new technology will inevitably improve our nation’s ability to respond in the future, development of solutions with current technology is imperative. The Solutions Lab aims to identify solutions based on alternative approaches to radiation screening and cytokine administration that can be incorporated into current planning and guidance at the federal, state/tribal/territorial, and local levels. These approaches include the enhancement of current methods to estimate radiation dose based on geographic assessment and clinical symptoms and the administration of cytokines in an austere, mass-care setting such as an assembly center or community reception center. Having a clear plan to use cytokines effectively and efficiently in the medical response to a nuclear detonation is a critical component of our nation’s radiological and nuclear preparedness to best redeem the value of the development, approval, and acquisition of these lifesaving medical countermeasures.