Alloimmunization in sickle cell disease: changing antibody specificities and association with chronic pain and decreased survival

Abstract

Background: Alloimmunization remains a significant complication of transfusion and has been associated with multiple factors, including inflammation, an important pathophysiologic mechanism in sickle cell disease (SCD). We explored whether alloimmunization is associated with disease severity in SCD.

Study design and methods: Adult SCD patients were enrolled in a study of outcome-modifying genes in SCD. Historical records of patients with SCD at two participating institutions were reviewed for data on antigen phenotype and alloimmunization. Differences in demographic, clinical, and laboratory findings; end-organ damage; and overall disease severity were then compared between alloimmunized and nonalloimmunized patients.

Results: Of 319 patients, 87 (27%) were alloimmunized. Alloantibody specificities differed from those previously described, especially due to the significantly higher frequency of anti-S. Although alloimmunization was not associated with frequency of vasoocclusive episodes, a higher percentage of alloimmunized patients had chronic pain, as defined by daily use of short-acting narcotics (p = 0.006), long-acting narcotics (p = 0.013), or both (p = 0.03). Additionally, alloimmunized patients had poorer survival (hazard ratio, 1.92; p = 0.01) and were more likely to have avascular necrosis (p = 0.024), end-organ damage (p = 0.049), and red blood cell autoantibodies (p < 0.001), even after controlling for the effects of age, sex, and hemoglobin diagnosis. Alloimmunization was not associated with other SCD-related complications, such as acute chest syndrome or stroke.

Conclusion: Alloimmunization in SCD may be associated with chronic pain, risk of end-organ damage, and shorter survival. These novel findings suggest new directions for the investigation of immune response-mediated pathways common to alloimmunization and chronic pain.

Figure 1. Percent alloimmunized patients with specific hemoglobin diagnoses

Patients with HbSS and HbS-β⁰ thalassemia were alloimmunized significantly more often than were patients with HbSC or HbS β+ thalassemia.

Figure 2. Prevalence of having multiple alloantibodies among alloimmunized patients

Among patients who were alloimmunized, slightly less than 38% had only one alloantibody identified, while close to one-third had two or three alloantibodies, and nearly a third had four or more alloantibodies.

Figure 3. Relationship of overall disease severity and alloimmunization, based on a multi-organ chronic disease severity score

Scores were calculated based on the presence or absence of 1) pulmonary dysfunction 2) kidney dysfunction 3) CNS abnormality, 4) AVN of hips or shoulders, and 5) leg ulcers, for a total possible score of 5. The highest observed score for an individual patient, alloimmunized or non-alloimmunized, was 4 out of the possible 5. Alloimmunization was increasingly prevalent with increased disease severity (p=0.028). In addition, only 20% of alloimmunized patients had no organ damage, compared to 31% of non-alloimmunized patients and this difference was statistically significant (p=0.049, data not shown)).

Figure 4. Survival of alloimmunized and nonalloimmunized patients

Kaplan-Meier estimation of survival in patients with and without alloimmunization showed a median life expectancy of 65 years in nonalloimmunized patients but only 54 in alloimmunized patients.