Rapid Prediction of Hematologic Acute Radiation Syndrome in Radiation Injury Patients Using Peripheral Blood Cell Counts.

Rapid clinical triage of radiation injury patients is essential for determining appropriate diagnostic and therapeutic interventions. We examined the utility of blood cell counts (BCCs) in the first three days postirradiation to predict clinical outcome, specifically for hematologic acute radiation syndrome (HARS). We analyzed BCC test samples from radiation accident victims (n = 135) along with their clinical outcome HARS severity scores (H1-4) using the System for Evaluation and Archiving of Radiation Accidents based on Case Histories (SEARCH) database. Data from nonirradiated individuals (H0, n = 132) were collected from an outpatient facility. We created binary categories for severity scores, i.e., 1 (H0 vs. H1-4), 2 (H0-1 vs. H2-4) and 3 (H0-2 vs. H3-4), to assess the discrimination ability of BCCs using unconditional logistic regression analysis. The test sample contained 454 BCCs from 267 individuals. We validated the discrimination ability on a second independent group comprised of 275 BCCs from 252 individuals originating from SEARCH (HARS 1-4), an outpatient facility (H0) and hospitals (e.g., leukemia patients, H4). Individuals with a score of H0 were easily separated from exposed individuals based on developing lymphopenia and granulocytosis. The separation of H0 and H1-4 became more prominent with increasing hematologic severity scores and time. On day 1, lymphocyte counts were most predictive for discriminating binary categories, followed by granulocytes and thrombocytes. For days 2 and 3, an almost complete separation was achieved when BCCs from different days were combined, supporting the measurement of sequential BCC. We found an almost complete discrimination of H0 vs. irradiated individuals during model validation (negative predictive value, NPV > 94%) for all three days, while the correct prediction of exposed individuals increased from day 1 (positive predictive value, PPV 78-89%) to day 3 (PPV > 90%). The models were unable to provide predictions for 10.9% of the test samples, because the PPVs or NPVs did not reach a 95% likelihood defined as the lower limit for a prediction. We developed a prediction model spreadsheet to provide early and prompt diagnostic predictions and therapeutic recommendations including identification of the worried well, requirement of hospitalization or development of severe hematopoietic syndrome. These results improve the provisional classification of HARS. For the final diagnosis, further procedures (sequential diagnosis, retrospective dosimetry, clinical follow-up, etc.) must be taken into account. Clinical outcome of radiation injury patients can be rapidly predicted within the first three days postirradiation using peripheral BCC.

Comparison of established and emerging biodosimetry assays.

Rapid biodosimetry tools are required to assist with triage in the case of a large-scale radiation incident. Here, we aimed to determine the dose-assessment accuracy of the well-established dicentric chromosome assay (DCA) and cytokinesis-block micronucleus assay (CBMN) in comparison to the emerging γ-H2AX foci and gene expression assays for triage mode biodosimetry and radiation injury assessment. Coded blood samples exposed to 10 X-ray doses (240 kVp, 1 Gy/min) of up to 6.4 Gy were sent to participants for dose estimation. Report times were documented for each laboratory and assay. The mean absolute difference (MAD) of estimated doses relative to the true doses was calculated. We also merged doses into binary dose categories of clinical relevance and examined accuracy, sensitivity and specificity of the assays. Dose estimates were reported by the first laboratories within 0.3-0.4 days of receipt of samples for the γ-H2AX and gene expression assays compared to 2.4 and 4 days for the DCA and CBMN assays, respectively. Irrespective of the assay we found a 2.5-4-fold variation of interlaboratory accuracy per assay and lowest MAD values for the DCA assay (0.16 Gy) followed by CBMN (0.34 Gy), gene expression (0.34 Gy) and γ-H2AX (0.45 Gy) foci assay. Binary categories of dose estimates could be discriminated with equal efficiency for all assays, but at doses ≥1.5 Gy a 10% decrease in efficiency was observed for the foci assay, which was still comparable to the CBMN assay. In conclusion, the DCA has been confirmed as the gold standard biodosimetry method, but in situations where speed and throughput are more important than ultimate accuracy, the emerging rapid molecular assays have the potential to become useful triage tools.