Patients with SCD (Sickle Cell Disease) are more likely to have a severe COVID-19 disease course and a higher case-fatality rate in contrast to the general population. RBC (Red Blood Cell) transfusions are commonly given to patients with SCD and COVID-19. Hyperhemolysis syndrome (HHS) is an infrequent, severe hemolytic transfusion reaction primarily been described in patients with SCD (HbSS disease). HHS is characterized by rapid destruction of RBCs (red blood cells) from both donor and recipient, resulting in severe anemia to below pre-transfusion levels of hemoglobin and commonly reticulocytopenia. HHS can progress to multi-organ failure and death. The pathophysiology of HHS is not fully understood.
There are limited data to guide treatment of HHS, with avoidance of further transfusions and supportive care being the main therapies. Immunosuppressive therapy should be initiated promptly in patients with life-threatening hemolysis. More recent case reports have reported effective treatment outcomes with monoclonal antibodies such as rituximab, eculizumab, and tocilizumab. Tocilizumab, which blocks the interleukin-6 (IL-6) receptor and prevents macrophage response, has been used to treat various autoimmune conditions including macrophage activation syndrome (MAS), cytokine release syndrome (CRS), and most recently, patients with severe COVID-19 pneumonia. In June of 2021, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for the use of tocilizumab in the treatment of COVID-19 in hospitalized patients.
The ARC (American Red Cross) National Reference Lab for Blood Group Serology (NRLBGS) recently encountered a patient with a history of sickle cell disease complicated by prior vaso-occlusive crises and acute chest syndrome coupled with recent SARS-CoV-2 infection, leading to pneumonia. The patient’s antibody history included anti-Fya and a warm autoantibody. RBC antigen genotyping revealed the presence of the canonical mutation in the GATA binding site of the FY gene, resulting in loss of Fyb expression on RBCs. Per SCD matching policy, the blood bank provided this patient with multiple RBC units appropriate for transfusion. Fourteen days after the last transfusion, the patient was readmitted due to chest and back pain with a significant drop in hemoglobin. Anti-N was identified by the regional IRL (Immunohematology Reference Lab), and additional units were transfused with no improvement in the patient’s hemoglobin. NRLBGS later identified additional anti-FY3/5, anti-Lea and anti-Leb as well as an antibody to a KN system antigen. The patient developed multi-organ failure and was successfully treated with a single dose of tocilizumab.
Several case reports that have shown success in treating HHS with tocilizumab; our patient showed dramatic improvement after initiation of tocilizumab. Additionally, serology showed a decrease in reactivity after starting tocilizumab, declining two grades in the repeat antibody screen. While there have been no clinical trials on tocilizumab’s efficacy in the treatment of COVID-19 pneumonia specifically in SCD patients, several recent publications suggest tocilizumab is helpful in this population.
In conclusion, the relationship between SARS-CoV-2 infection and HHS is not well understood, however, it is likely that COVID-19 can augment risk factors associated with the onset of HHS. The anti-IL-6R agent tocilizumab also shows potential to be an effective treatment for patients with SCD that develop HHS, including patients with recent SARS-CoV-2 infection.
- Fuja C, Kothary V, Carll TC, Singh S, Mansfield P, Woo GD. Hyperhemolysis in a patient with sickle cell disease and recent SARS-CoV-2 infection, with complex auto- and alloantibody work-up, successfully treated with tocilizumab. Transfusion. 2022;62:1446 – 1471.
- De Luna G, Habibi A, Deux JF, et al. Rapid and severe Covid-19 pneumonia with severe acute chest syndrome in a sickle cell patient successfully treated with tocilizumab. Am J Hematol. 2020;95(7):876-878.