Red Cell Alloimmunization Is Associated with Higher Treatment Costs and Poor Health Outcomes Among Hemoglobin S-Beta Thalassemia Patients
Authors: Gehrie Eric , Viayna Elisabet , Blanchette Christopher , Meny Geralyn , Noumsi Ghislain , Huber Maria , Runken M. Chris 
Published: November 2021

Abstract
Hemoglobin S (HbS) beta thalassemias (thal) are types of sickle cell disease (SCD) that result from the inheritance of one HbS gene and one β thalassemia gene. Red Blood Cell (RBC) alloimmunization is believed to be a major complication of transfusion therapy for HbS-thal patients. Indeed, among SCD patients generally, alloimmunization not only complicates the procurement of blood, but can also lead to life threatening delayed hemolytic transfusion reactions, and can be associated with a host of negative health outcomes including a higher risk of death. It is generally accepted that some alloimmunization events can be prevented via donor-recipient antigen matching, although this strategy is associated with higher costs and utilization of scarce resources (i.e.. antigen negative RBC units). The present study aimed to assess the clinical and economic implications of alloimmunization in HbS-thal patients.
The Premier Hospital chargemaster dataset was used to perform a cross-sectional study matching alloimmunized and non-alloimmunized patients based on sex, age, date of admission, and type of visit (outpatient vs. inpatient). All outpatient and inpatient discharges from Jan 2015 to Jun 2019 were included in the study. Because there is not a specific laboratory code to designate alloimmunization, presence of both "antiglobulin crossmatch" and "RBC antibody identification" codes in a record was used as a surrogate for alloimmunization. Accuracy of this approach was validated by comparing the frequency of these codes among the hereditary hemorrhagic telangiectasia (HHT) and myelodysplastic syndromes (MDS) populations within the Premier dataset to the reported rates of alloimmunization for these entities in the medical literature (Zheng Transfusion. 2018;58(3):775-780, Singhal Haematologica. 2017;102(12):2021-2029). This comparison predicted a 16.8% alloimmunization rate in the HHT population (similar to the 15.3% reported in the literature) and an 11.5% alloimmunization prevalence in the MDS population (similar to the 11% reported in the literature).
HbS-thal patients were identified based on diagnostic coding (ICD-10 code D57.4). Demographic, clinical and billing characteristics were retrieved. Cost per outpatient and inpatient discharge, hospital and intensive care unit (ICU) length of stay (LoS) and inpatient mortality were assessed for both alloimmunized and non-alloimmunized HbS-thal patients. Bivariate comparisons were performed, assuming a two-tailed test of significance and an α level of 0.05. Multivariable regression models adjusting for diagnosis-related groups with ≥1% incidence were performed.
This approach permitted a total of 999 discharges corresponding to alloimmunized HbS-thal patients (cases) to be matched to 550 HbS-thal controls. Mean (SD) age was 35.1 (18.8) and 30.1 (18.6) for cases and controls, respectively. The percentage of females was slightly higher within the alloimmunized group (63.66% vs. 57.45%), and higher rates of inpatient visits were observed for the alloimmunized population compared to controls (67.9% vs. 33.1%).
The multivariate models showed that alloimmunized HbS-thal patients presented significantly worse economic and clinical outcomes compared to their non-alloimmunized controls through all variables assessed. Median cost per discharge was $5,313 (p&lt;0.0001) higher for alloimmunized inpatients and $1,014 (p&lt;0.0001) higher for alloimmunized outpatients, compared to non-alloimmunized controls. Alloimmunized HbS-thal patients also experienced a 63% increase in hospital LoS (4.5 vs 7.4 days;; p&lt;0.0001) and nearly over a 2.5-fold increase in ICU LoS (4.2 vs 10.0 days; p=0.0257). Alloimmunization in this population was also associated with a 3-fold increased risk of admission to intensive care (p=0.0032), longer stays in the ICU (p-0.0257), and a 3-fold increase in inpatient death (p&lt;0.0001) (Table 1).
The present study reveals that alloimmunization is associated with significantly longer hospitalizations and ICU stays, higher risk of ICU admission, greater inpatient death, and higher healthcare costs among patients with ICD-10 diagnosis of HbS-thal. These data seem to support the incremental costs and resource allocation decisions required to provide prophylactic antigen matching to HbS-thal patients, in an effort to diminish the risk of alloimmunization.
Figure 1 Figure 1.

Disclosures
Gehrie: Grifols SSNA: Consultancy, Honoraria. Viayna: Grifols S.A.: Current Employment. Blanchette: Grifols SSNA: Consultancy; Novo Nordisk Inc.: Current Employment. Meny: Grifols SSNA: Current Employment. Noumsi: Grifols SSNA: Current Employment. Huber: Grifols SSNA: Current Employment. Runken: Grifols SSNA: Current Employment.