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