February, 1997


Granulocyte Transfusion

Donald L. Kelley, M.D. and Ileana Lopez-Plaza, M.D


Introduction

The risk of infection is increased in neutropenic patients, particularly in those with very low neutrophil counts (<500/uL). Serious infections may also be seen in those with qualitative abnormalities of neutrophils (e.g. chronic granulomatous disease). Transfusion of exogenous granulocytes (GTx) in such cases is theoretically attractive, but has not enjoyed widespread use due to a number of practical limitations.

Provision of granulocyte concentrates (GCs) is an involved process requiring selection, recruitment and scheduling of suitable donors, pretreatment of donors with corticosteroids to increase peripheral white blood cell count/granulocyte yield, collection by leukapheresis, and immediate transport to the transfusing facility. Clinical response correlates directly with the number of granulocytes transfused, and the quantity of granulocytes obtainable from normal donors may be only marginally effective in adults. Adverse reactions are common and can be severe.

 

Indications

Septic Neonates: Bacterial sepsis carries a high mortality in neonates, ranging from 20% up to 100% in premature infants with group B streptococcal sepsis. Factors contributing to this high mortality are depletion of granulocyte stores and a reduction in chemotactic and bactericidal response of neonatal granulocytes seen with severe infection. GTx should be considered in cases of bacterial sepsis with neutropenia (ANC <3,000/uL in first week of life, <1,000/uL thereafter) and depletion of marrow neutrophil stores (>70% circulating immature granulocytes).

Neutropenic Patients: Severely neutropenic patients (ANC <500/uL) with sepsis unresponsive to at least 48 hours of appropriate antimicrobial therapy and expected bone marrow recovery are candidates for GTx.

Improvement in survival has been demonstrated in gram-negative sepsis and would be expected in sepsis due to gram-positive bacteria, as well. The efficacy of GTx in treating disseminated yeast or fungal infection is less well established, but evidence from several case reports and animal studies suggest a beneficial effect.

The use of GTx prophylactically (in neutropenic patients with no evidence of infection) is not recommended.

Granulocyte Dysfunction: Severe disorders of granulocyte function are rare, and experience with GTx in these patients is, therefore, limited. Indications for transfusion are similar to those in neutropenic patients (except neutropenia, of course). Due to the potential for immunization to neutrophil antigens and the limitations that would impose on future GTx, this modality should be reserved for severe infections only in these patients.

 

Therapeutic Approach

Course Of Treatment: Daily GTx for at least four days is recommended, as studies have shown that improvement from gram-negative sepsis requires at least this number. Continuation of treatment is based upon clinical judgment and the response of the patient.

Dosage: The dose of granulocytes in adults should be as large as is practical. Current standards require a minimum of 1 x 1010 granulocytes per concentrate (~1.5 x 108/kg), and at least double this number is desirable.

Neonates may receive up to 1 x 109 granulo-cytes/kg/day.

Donor Selection: Due to the red cell content of the product, donors must be ABO compatible. Recipients known to be alloimmunized to leukocyte antigens (HLA or neutrophil-specific) may have poor responses and/or severe reactions to randomly selected donors and require HLA-matching.

Storage/Timing: GCs can be stored for up to 24 hours at room temperature without agitation, but show progressive loss of function with storage, and are, therefore, generally transfused as soon as possible after collection (usually within 6 hours). This necessitates that the transfusing physician accept products for transfusion on which viral testing has not yet been completed.

 

Adverse Effects

Transfusion Reactions: Reactions to transfused granulocytes are common and are predominantly of the febrile, non-hemolytic ("fever-chill") type. Mild to moderate reactions occur in 25-50% of transfusions and severe reactions in about 1%. Severity of reactions can be reduced by transfusing slowly and by treatment with antipyretics and intravenous hydrocortisone (50-100 mg), if severe. Administration of meperidine (50 mg IV) may be required for severe shaking chills.

Fatal pulmonary reactions have occurred. An association with concurrent Amphotericin B treatment was suspected, but this has not been confirmed. Nevertheless, when both therapies are indicated, times of administration should be staggered. (GTx should not be delayed.) Leukoagglutinating antibodies may also precipitate severe pulmonary reactions.

Disease Transmission: GCs carry the same risk of infectious disease transmission as other blood products. However, due to the necessity for transfusion prior to completion of viral testing, donors are generally selected who are known to have recent nonreactive test results, lessening the risk considerably. Donors for CMV seronegative patients should also be CMV negative, as use of leukoreduction filters is contraindicated.

Graft-Versus-Host Disease: Severely immuno-suppressed patients are at risk for development of fatal GVHD following transfusion of cellular blood products containing viable lymphocytes, including GCs. Products transfused to such patients should be irradiated.

 

New Technologies

The availability of hematopoietic growth factors, specifically G-CSF (Neupogen), has raised the possibility of stimulating normal donors, so that a more efficacious product may be obtained. Recent studies have shown that granulocyte collections from G-CSF stimulated donors have yields six times greater than those currently available and contain cells with enhanced function and increased adhesiveness.

Another potential future source of granulocytes for transfusion is production in the laboratory using ex-vivo culture. Widespread use of both of these techniques awaits further study and FDA approval.

 

Copies of the Transfusion Medicine Update can be obtained by contacting
Deborah Small, (412) 209-7320.