Hematopoietic progenitor umbilical cord blood cells (HPC-cord) have a reported infusion reaction rate ranging from 4 to 65%.1, 2, 3, 4.Cardiovascular symptoms (hypertension, bradycardia) are most common, followed by nausea and vomiting, chest tightness, desaturation and headache.1, 3.Severe reactions, characterized by prominent cardiopulmonary involvement, are considered relatively rare, with most known cases occurring in adults (7/8; Table 1).5, 6, 7, 8, 9.Herein, we report a severe anaphylactic cord cell infusion in a pediatric patient.This is the second severe reaction in a pediatric patient and is the third attributed to dextran in the cryopreservation and/or dilution solutions5, 7.The patient was initially seen at the age of 5 mo for neutropenia.He was diagnosed with Kostmann syndrome, displaying severe neutropenia, immature myeloid hyperplasia with maturation arrest on bone marrow biopsy, and mutations in neutrophil elastase (ELANE) and the intracellular domain of the G-CSF receptor (G-CSFR).By age 1 yr, he was managed with daily G-CSF treatment with ANC>1500/μL.However, his subsequent medical history was significant for multiple infections and hospitalizations, chronic fungal sinusitis, asthma and Asperger's syndrome.In addition, the patient was highly atopic with seasonal allergies, eczema, severe blistering contact dermatitis (tape) and documented anaphylactoid/anaphylactic reactions to rubber, latex, contrast dye, codeine, vancomycin, levaquin, cephalexin and cefaclor.At the age of 13 years, the patient was evaluated for allogeneic hematopoietic cell transplantation (HCT) due to increasing resistance to exogenous G-CSF treatment and an increasing frequency of infections (∼1-2 per mo), requiring hospitalization and IV antibiotics.Several family members were evaluated as potential hematopoietic cell donors, including parents, grandparents, uncle and two siblings.His father was identified as a potential donor (7/8 HLA-match).His mother subsequently gave birth to a younger brother, who was an ABO-incompatible (donor A+/patient O+), 10/10 HLA-match.Umbilical cord blood from the brother had been frozen but was insufficient to support allogeneic HCT.After discussion, the parents opted to delay transplantation until the sibling donor reached at least 20-25 kg body weight to permit an allogeneic bone marrow harvest.At age 16 years, the patient was tentatively scheduled for allogeneic HCT.His 3-yr-old brother underwent a G-CSF-stimulated, bone marrow harvest under general anesthesia without complications.As a precaution, the marrow harvest was scheduled in advance and cryopreserved due to the significant weight discrepancy between the donor (20.2 kg) and patient (weight 75 kg).A total of 370 mL was harvested, with a final yield of 9.5 × 109 WBC and 4.05 × 108 CD34+ cells.The marrow was plasma- and RBC-depleted prior to cryopreservation.The final post-processing counts were 1.2 × 108 WBC/kg, 5.5 × 106 CD34+ cells/kg and 34.8% hematocrit.The marrow was split into three units and cryopreserved in 10% DMSO.The patient was admitted to undergo allogeneic HCT 6 wk after the harvest.He underwent myeloablative conditioning with busulfan (3.2 mg/kg, days -5,-4,-3), fludarabine (40 mg/m2, days -5,-4,-3) and anti-thymocyte globulin (1.5 mg/kg, days -3,-2,-1).GvHD prophylaxis was tacrolimus (0.03 mg/kg IV beginning day -1) and methotrexate (5 mg/m2 days +1,+3,+6,+11 post-HCT).On the day of HCT, the patient was premedicated with 100 mg hydrocortisone and 50 mg diphenhydramine.All the available product was used to ensure engraftment given the size discrepancy.The first unit infused was the HPC-cord.The unit was thawed in a 37 °C water bath, and then diluted 1:3 (vol/vol) with a chilled solution of 5% human serum albumin and 8% dextran 40 per the dilutional washout method.2, 10 Within 5 min of starting the cord infusion, the patient became flushed with hives, coughing, agitation and complaints of chest tightness.His vital signs showed increased heart rate (102-138 b.p.m.), blood pressure (119/59-158/70 mm Hg) and respiratory rate (24 per min).On phys. examination, he was noted to have poor air movement with prominent wheezing.He was placed on 4 L of supplemental O2 (%O2=98%) and given three albuterol treatments over the next 30 min.He also received addnl. hydrocortisone (100 mg IV), diphenhydramine (50 mg IV), famotidine (20 mg IV) and ativan (1 mg IV) for agitation.His symptoms resolved and supplemental O2 was discontinued after 1 h.Given the severe reaction, the infusion of cryopreserved bone marrow was deferred until the following day.A transfusion reaction evaluation showed no clerical errors and there was no evidence of hemolysis.The patient did not have IgA deficiency (IgA 209 mg/dL) and had no prior blood transfusions before HPC-cord infusion.The HPC-cord unit was RBC-depleted, containing 5.85 × 108 total nucleated cells, 3.55 × 106 CD34 and 4.5% nucleated RBC.The unit was cryopreserved in 10% DMSO and 10% dextran 40 (2.25 mL) and diluted with an addnl. 75 mL of 5% human serum albumin (HSA)-8% dextran prior to infusion, for a final volume of 104 mL.Given the immediate onset, phys. findings, response to therapy and the patient's extensive allergy history, it was felt that the patient had an anaphylactic reaction to dextran.5 The patient was infused with cryopreserved bone marrow the following day in the intensive care unit.Because the cryopreserved marrow units did not contain dextran, and concerns about potential cell loss with washing,10 it was decided to thaw marrow per routine without further manipulation.In preparation for HPC marrow, the patient continued to receive methylprednisolone (0.5 mg/kg IV every 6 h), famotidine (20 mg IV every 12 h) and diphenhydramine (25 mg IV every 6 h), followed by addnl. 100 mg hydrocortisone immediately prior to the infusion.All three units were infused over the course of 35 min with no adverse events except transient tachycardia and mild abdominal pain.The patient engrafted neutrophils on day +13 post HCT and platelets (> 50 K/μL unsupported by transfusion) on day +20 post HCT.He required transfusion with two units of RBCs and nine units of apheresis platelets over the course of transplant.He had one mild allergic reaction to platelets (hives) despite transfusion of plasma-reduced platelets.The clin. findings and rapid onset of symptoms following infusion of cryopreserved HPC-cord, but not cryopreserved bone marrow, support a severe allergic reaction to the dextran 40 present in HPC-cord cryopreservative and dilution solutionsThis is the second pediatric patient with an anaphylactic reaction due to dextran during infusion of an HPC-cord at our institution.Our first case occurred in a 16-yr-old girl who developed severe cardiopulmonary symptoms within minutes of HPC-cord infusion.5 Like the current case, the HPC-cord unit was RBC-depleted, cryopreserved in 10% DMSO and 10% dextran 40, and subsequently thawed and diluted 1:3 with a 5% HSA-8% dextran solutionThe patient was not atopic, but did have documented anaphylactoid reactions to Ambisome.She had no allergic reactions to blood transfusion prior to or during transplant.Ma et al.7 also reported severe reaction attributed to dextran in a 60-yr person who underwent a double-cord transplant.In contrast, a case of anaphylaxis in an adult Japanese allogeneic HCT patient cannot be ascribed to dextran as this patient was successfully infused with a second HPC-cord that had been washed and resuspended in HSA-dextran.6.To date, eight severe cardiopulmonary reactions have been reported in the literature.5, 6, 7, 8, 9.An investigation by the National Marrow Donor Program (NMDP) implicated infusion of older, unmanipulated, HPC-cord units containing a large bolus of lyzed RBC.8.As a consequence, it was recommended that RBC-replete, unmanipulated HPC-cord units undergo washing or dilution prior to infusion.As noted by Ma7 and Choi5, 6/7 evaluable patients received HPC-cord cryopreserved in DMSO-dextran and in 5/7, the HPC-cord was diluted with a dextran solution prior to infusion.It is estimated that 1/2000 individuals are sensitized to dextran, with severe grade III-V anaphylactoid reactions occurring in 0.01-0.6% patients and documented cases of acute renal failure, pulmonary toxicity, coronary vasospasm and Takotsubo or stress-induced cardiomyopathy.7, 11.In the majority (60-75%) of sensitized patients, symptoms occur within the first 5-10 min, indicating that only a few milliliters of dextran are necessary to precipitate a reaction.11.Premedication with dextran-1 (Promit), a monovalent hapten composed of low-mol. weight dextran (1 kD), can decrease the risk of severe reactions by 36-fold (<1/70 000) by binding dextran-specific antibodies.11, 12.Despite its proven efficacy, dextran-1 is no longer distributed in the USA but is available in other countries.Centers have also explored eliminating dextran in dilution and wash solutions, especially following recent manufacturing shortages.Limited published data suggest acceptable cell recoveries using a dextran substitute (hydroxyethyl-starch) or 5% HSA-plasmalyte solution,13, 14 although we observe 50% lower CD34+ cells recoveries when washing HPC-cords in the absence of dextran (unpublished data).Severe allergic and anaphylactic reactions with cryopreserved HPC products are considered uncommon and rarely reported.We previously reported mild allergic reactions (hives, pruritis) in 0.9% of peripheral blood HPC infusions, with the majority occurring with fresh allogeneic products.10.A 15-yr review of pediatric HPC-cord transplants at our institution found an overall infusion reaction rate of 52% (36/69 patients).Allergic reactions were identified in three patients (4.3%) and severe, anaphylactoid reactions in 2.9% patients and 3.3% (3/90) of HPC-cord products.This is significantly higher than the reported rate of anaphylactoid/anaphylaxis with transfusion of platelets (0.06% per unit) and warrants further investigation.15.
