Delayed Hemolytic Transfusion Reaction/Hyperhemolysis Syndrome in Children With Sickle Cell Disease Julie-An M. Talano, MD*ʈ; Cheryl A. Hillery, MD*§ʈ; Jerome L. Gottschall, MD‡§ʈ; Diane M. Baylerian, BS, MT§ʈ; and J. Paul Scott, MD*§ʈ ABSTRACT. Objective. Alloimmunization in patients lower than it was at the time of original transfusion, with sickle cell disease (SCD) has a reported incidence of suggesting the hemolysis of the patient’s own RBCs in 5% to 36%. One complication of alloimmunization is addition to hemolysis of the transfused RBCs; a negative delayed hemolytic transfusion reaction/hyperhemolysis DAT and reticulocytopenia are often present. Severe (DHTR/H) syndrome, which has a reported incidence of complications including acute chest syndrome, conges- 11%. In patients with SCD, clinical findings in DHTR/H tive heart failure, pancreatitis, and acute renal failure syndrome occur approximately 1 week after the red were associated with DHTR/H syndrome in our patients. blood cell (RBC) transfusion and include the onset of DHTR/H in the pediatric sickle cell population is a seri- increased hemolysis associated with pain and profound ous and potentially life-threatening complication of RBC anemia. The hemoglobin (Hb) often drops below pre- transfusion. It is important to avoid additional trans- transfusion levels. In many reported adult cases, the di- fusions in these patients, if possible, because these may rect antiglobulin test (DAT) remains negative and no exacerbate the hemolysis and worsen the degree of new alloantibody is detected as the cause for these trans- anemia. DHTR/H syndrome must be included in the fusion reactions. To date, few pediatric cases have been differential of a patient who has SCD and vaso-occlusive reported with this phenomenon. The objective of this crisis who has recently had a transfusion. Pediatrics study was to describe the clinical and laboratory findings 2003;111:e661–e665. URL: http://www.pediatrics.org/cgi/ of a case series in children who had SCD and experi- content/full/111/6/e661; delayed hemolytic transfusion re- enced a DHTR/H syndrome at our institution. action/hyperhemolysis, sickle cell disease. Methods. An 11-year retrospective chart review of pa- tients with discharge diagnosis of SCD and transfusion reaction was performed. DHTR/H syndrome was defined ABBREVIATIONS. SCD, sickle cell disease; RBC, red blood cell; as the abrupt onset of signs and symptoms of accelerated DHTR/H, delayed hemolytic transfusion reaction/hyperhemoly- sis; Hb, hemoglobin; DAT, direct antiglobulin test; IVIg, intrave- hemolysis evidenced by an unexplained fall in Hb, ele- nous immunoglobulin. vated lactic dehydrogenase, elevated bilirubin above baseline, and hemoglobinuria, all occurring between 4 and 10 days after an RBC transfusion. Patient character- hildren with sickle cell disease (SCD) com- istics, time from transfusion, symptoms, reported DAT, monly require red blood cell (RBC) transfu- new autoantibody or alloantibody formation, laboratory sions to manage complications including ane- abnormalities, and complications were recorded. Patients C mia, acute chest syndrome, stroke, and splenic with acute transfusion reactions were excluded. sequestration. Alloimmunization in patients who Results. We encountered 7 patients who developed 9 episodes of DHTR/H syndrome occurring 6 to 10 days have SCD and have had a transfusion has a reported after RBC transfusion. Each presented with fever and incidence of 5% to 36% in the United States and hemoglobinuria. All but 1 patient experienced pain ini- Europe.1–3 One serious complication of alloimmuni- tially ascribed to vaso-occlusive crisis. The DAT was zation has been termed the delayed hemolytic trans- positive in only 2 of the 9 episodes. The presenting Hb fusion reaction/hyperhemolysis (DHTR/H) syn- was lower than pretransfusion levels in 8 of the 9 events. drome.3,4 In patients with SCD, clinical findings in Severe complications were observed after the onset of DHTR/H occur approximately 1 week after the RBC ؍ ؍ DHTR/H: acute chest syndrome, n 3; pancreatitis, n transfusion and include the onset of increased hemo- ,and acute renal failure ;1 ؍ congestive heart failure, n ;1 lysis associated with pain and profound anemia. The ؍ n 1. hemoglobin (Hb) often drops below pretransfusion Conclusions. DHTR/H syndrome occurs in pediatric SCD patients, typically 1 week posttransfusion, and pre- levels. In many reported adult cases, the direct anti- sents with back, leg, or abdominal pain; fever; and he- globulin test (DAT) remains negative and no new moglobinuria that may mimic pain crisis. Hb is often alloantibody is detected as the cause for the transfu- sion reactions. The DHTR/H syndrome is thought to occur after From the Departments of *Pediatrics and ‡Pathology, Medical College of alloimmunization to an RBC antigen(s) after a trans- Wisconsin, Milwaukee, Wisconsin; §The Blood Center of Southeastern Wis- consin Inc, Milwaukee, Wisconsin; and ʈThe Children’s Hospital of Wiscon- fusion. Over time, the patient’s antibody levels fall to sin, Milwaukee, Wisconsin. undetectable levels. Subsequent reexposure of the Received for publication Oct 15, 2002; accepted Feb 19, 2003. recipient to RBCs that possess the antigen triggers an Reprint requests to (J.-A.M.T.) Medical College of Wisconsin, Department of anamnestic response and subsequent hemolysis. Ac- Pediatric Hematology/Oncology, MACC Fund Research Center, 8701 Wa- tertown Plank Rd, Milwaukee, WI 53226. E-mail: [email protected]. celerated hemolysis results in profound anemia and 5 PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Acad- hyperbilirubinemia. The diagnosis of antibody-me- emy of Pediatrics. diated RBC hemolysis is usually confirmed by a pos- http://www.pediatrics.org/cgi/content/full/111/6/Downloaded from www.aappublications.org/newse661 by guestPEDIATRICS on October 2,Vol. 2021 111 No. 6 June 2003 e661 itive DAT and identification of a new red cell anti- DAT results, new autoantibody or alloantibody formation, other body directed against a specific red cell antigen in laboratory abnormalities, complications, and treatment. the patient. However, in the patient who has SCD and DHTR/H syndrome, the DAT is often negative Statistical Analysis and no antibody can be detected in the serum.4,6,7 Changes in laboratory results were compared using paired Student t test. P Ͻ .05 was considered statistically significant. Therefore, this syndrome poses a significant diagnos- Before the data collection, the study was approved by the Institu- tic challenge. tional Review Board. Cox et al6 reported a prevalence of recognized DHTR/H syndrome of 4% in their patients with RESULTS SCD. Nevertheless, the syndrome may go unrecog- Each year, our center transfuses approximately nized and may have a much higher incidence. Petz et 1000 units of RBCs to a population of 162 pediatric al8 described 8 severe cases of DHTR/H syndrome patients with SCD. Using the criteria described in and defined a sickle cell transfusion reaction syn- “Methods,” we identified 7 patients with 9 episodes drome with a characteristic constellation of findings. of DHTR/H. None of the patients was on a chronic These characteristics include sickle cell pain crisis, transfusion program. Clinical characteristics of these laboratory manifestations of hemolysis, life-threaten- episodes are depicted in Table 1. ing anemia more severe than before the transfusion, One patient had 3 separate episodes of DHTR/H and reticulocytopenia. The DAT can be negative (UPN 7.1, 7.2, 7.3). The second and third episodes of (50% of the time in Petz’s series), and identification DHTR/H in this specific patient occurred when ad- of a new red cell antibody is often absent. The afore- ditional transfusions were given approximately 6 mentioned series were adult patients; there are few and 12 months after the original DHTR/H. The orig- reports of DHTR/H in children with SCD. inal DHTR/H was managed with transfusion of a In this retrospective chart review, we report 7 pe- completely phenotypically matched unit of RBC diatric patients who had SCD and developed evi- without additional complications. The 7.2 and 7.3 dence of accelerated hemolysis 6 to 10 days after an events were managed conservatively, and the pa- RBC transfusion. Each of these patients previously tient’s Hb recovered spontaneously without the need had a transfusion. In this report, we describe the for additional transfusions. clinical and laboratory characteristics of 9 episodes of As depicted in Table 1, 6 patients had Hb SS and 1 DHTR/H syndrome in 7 children with SCD. patient had Hb SC disease. Their ages ranged from 6 to 18 years. There were 5 girls and 2 boys. Of note, all METHODS patients presented with fever and hemoglobinuria. Before 1995, all patients who had SCD and received a transfu- All but 1 episode presented with symptoms of pain sion at our center received RBCs matched only for Rh D and ABO. that was initially ascribed to vaso-occlusive crisis (in Since 1995, patients with a diagnosis of SCD have received units of RBCs that are partially phenotype matched for the Rh (C, E, c, e) the back, abdomen, and/or legs). The number of and Kell antigens in addition to routine blood bank cross-match- days after transfusion to presentation ranged from 6 ing protocols. to 10 days with a median of 6 days. As shown in We performed a retrospective chart review of patients at the Table 2, the bilirubin increased from baseline in all Children’s Hospital of Wisconsin who had SCD from 1990 to 2001 ϭ with the discharge International Classification of Diseases, Ninth patients (P .003) and the peak bilirubin ranged Revision code of Sickle Cell Disease and transfusion reaction. Pa- from 1.7 mg/dL to 10.1 mg/dL with a median of 4.2 tients who experienced an acute transfusion reaction were ex- mg/dL. The LDH increased from baseline in all pa- cluded.