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Adverse Events Associated With Hematopoietic Progenitor Cell Product Infusion
Adverse events associated with hematopoietic progenitor cell (HPC) product infusion can vary depending on the type of product infused ( Table 88.1 ). The Center for Disease Control National Health Safety Network provides a Biovigilance Component Hemovigilance Module Surveillance Protocol that provides definitions for blood transfusion reactions. Similarly, the Circular of Information for the Use of Cellular Therapy Products also provides descriptions of the known side effects and hazards associated with HPC infusions. This chapter focuses on the common types of clinically significant reactions that can occur during or within hours after HPC infusion, and the strategies to mitigate and treat adverse reactions.
Table 88.1
Adverse Reactions to Stem Cell Infusions
| Nonimmunologic Complications | Immunologic Complications |
|---|---|
| Dimethyl sulfoxide toxicity | Acute/delayed hemolytic reaction |
| Septic transfusion reaction | Febrile, nonhemolytic reaction |
| Fat emboli | Allergic reaction |
| Bleeding from excessive anticoagulant | Transfusion-related acute lung injury |
| Circulatory/volume overload | Graft-versus-host disease |
| Hypothermia | |
| Nonimmunologic hemolysis | |
| Transmission of infectious disease or disease agent |
Incidence
The incidence of adverse reaction to HPC infusion varies depending on the sources of graft obtained (e.g., bone marrow, peripheral blood, or umbilical cord), HPC product condition (e.g., fresh/thawed/washed), and the infusion volume. Complex host factors (e.g., patient demographics, primary diagnoses, infection status, or responses to conditional regiments) can also modulate the recipients’ immune responses that lead to abnormal clinical signs and symptoms during the HPC infusion. Recently, Mulay et al. reported that roughly 50% of HPC infusions are associated with infusion-related adverse reactions. In the pediatric cohort, another study with over 200 patients described an HPC infusion adverse event incidence of 55%–62% within 24 hours of infusion.
Cryopreserved products have different risks than fresh products. Although the HPCs survive the freeze–thaw process and the effect of DMSO, granulocytes and RBCs lyse because of their particular susceptibility to osmotic stress. Postthaw washing eliminates the cell debris and DMSO. With postthaw nonwashed HPC product infusions (i.e., bedside thaws), the frequency of adverse events is associated with the number of granulocytes in the product at the time of graft harvest. Host factors, such as recipient age and sex, have been associated with infusion-related toxicity, with more side effects occurring in female patients. It was also observed that pediatric patients with lower body weight (<10 kg) might have a slightly higher incidence of adverse events. The exact etiology of these findings has not yet been elucidated. It is hypothesized that recipients with smaller body surface area and lower intravascular volume per body weight may receive relatively higher DMSO and/or cellular debris concentrations during HPC infusion.
With the exception of umbilical cord blood HPC transplants, allogeneic transplants are generally infused to the recipient shortly (within 48 hours) after collection from the donors. In the interim, the allogeneic grafts are maintained either at room temperature (bone marrow HPC product) or refrigerated temperature (peripheral blood HPC product). The rate of adverse events during the infusion of noncryopreserved products is significantly lower than that of cryopreserved products, with reported rates ranging from 0% to 26.8%.
Nonimmunologic Complications
Circulatory Overload
Circulatory or volume overload occurs when the intravenous infusion of an HPC product acutely raises the central venous hydrostatic pressure, resulting in fluid extravasation and subsequent pulmonary edema. Female, pediatric/elderly, and renal insufficiency patients are reported to be more susceptible. For those recipients with increased susceptibility, slowing the infusion rate, splitting the total HPC infusion volume into multiple infusions, or using diuretics before and in between infusions should be considered.
Septic Transfusion Reaction
Bacterial contamination can occur during any step in the process, including HPC collection, processing, and infusion. The reported HPC product contamination rate varies among institutions and by product type, ranging from 1% to 6%. Skin flora and environmental organisms are the predominant bacteria identified in contaminated HPCs, with coagulase negative Staphylococcus species accounting for the majority of positive cultures. Rarely, fungal contamination is detected. Fortunately, in vitro microbial growth in the HPC product may not correlate with a clinical septic reaction. The risk can be extrapolated from studying human transfusable platelet products where at least 100,000 CFU/mL microbial activity in a product is associated with clinical sepsis. Fortunately, bacterial contamination can be significantly reduced by the cryopreservation and thawing/washing processes.
Unlike the more common blood components and products, microbial-contaminated HPCs are not readily replaceable. When an HPC product is determined to be culture-positive, the clinical transplant team must be immediately notified. The possibility of replacing or discarding the contaminated HPC product should be considered, especially when the recipient is receiving a fully myeloablative conditioning regimen or when additional noncontaminated aliquots of HPC are available. Alternatively, the transplant team may decide to infuse the product with prophylactic antimicrobial therapy targeting the bacterial species identified. Before HPC infusion, many of the immune-compromised HPC recipients would already be receiving a broad-spectrum prophylactic antimicrobial regimen. Overall, patients who receive culture-positive products do not have increased mortality compared with patients receiving culture-negative products. When a septic reaction is suspected, it is important to evaluate the infectious etiologies both for the recipient (e.g., underlying infection or infected vascular access) and HPC product (e.g., donor or processing contamination) level during the treatment and investigation.
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