CHAPTER 61

Febrile Nonhemolytic Transfusion Reactions

Irina Maramica, MD, PhD, MBA

Febrile nonhemolytic transfusion reactions (FNHTRs) are common, occurring

with 1–3% of transfusions. FNHTR manifests as fever and/or chills without hemolysis
occurring in the patient during or within 4 hours of transfusion cessation. Diagnosis
is made by excluding other causes of fever. Most common causes are passively trans-
fused proinflammatory cytokines or recipient antibodies reacting with donor leuko-
cytes. Most reactions are easily managed. FNHTRs are mitigated through prestorage
leukoreduction.

Clinical Presentation:  FNHTR is defined as occurring during or within 4 hours of

cessation of transfusion, with fever (≥38°C and change of ≥1°C) from pretransfusion or
chills/rigors. Fever may be absent due to antipyretic premedication. One-third of reac-
tions are severe, resulting in rigors, temperature elevation of >2°C, dyspnea, headache,
nausea, and vomiting.

Diagnosis:  FNHTR is diagnosis of exclusion, as no specific tests are available.

Differential diagnosis includes hemolysis, sepsis and TRALI, or fever due to medi-
cations or medical conditions. Hemolytic transfusion reaction is excluded thorough
transfusion reaction workup, including clerical check, ABO confirmation of product
and recipient, and serological workup. Transfusion-associated sepsis usually presents
with high increase in fever and hypotension. Gram stain and culture of patient and unit
support excluding septic transfusion reactions. TRALI typically presents with fever,
dyspnea, and hypotension. Review of patient’s record can rule out fevers due to under-
lying disease or medications, such as beta-lactam antibiotics, procainamide, isoniazid,
barbiturates, quinidine, and diphenylhydantoin.

Incidence:  FNHTRs are the most common acute transfusion reactions. Prestorage
leukocyte reduction has dramatically decreased its incidence to <0.2% for both RBCs
and platelets, with higher incidence using active versus passive reporting. Certain
patient populations are considered to be at a higher risk, including patients with hema-
tologic diseases, who maybe HLA alloimmunized from frequent transfusions, or more
sensitive to infused cytokines due to baseline inflammatory state.

Platelets:  FNHTRs’ incidence varies with platelet product type; higher (0.4%–2.2%
of transfusions) with nonleukoreduced or bedside leukocyte-reduced products ver-
sus 0.1%–0.15% with prestorage leukoreduced platelet products. More reactions are
observed when nonprestorage leukoreduced 4–5 days old platelet concentrates are
transfused, due to increase in cytokine levels: 1.1% with ≤3 day versus 4.6% > 3 day
platelets. Use of platelet additive solution decreased FNHTR rate with apheresis plate-
lets from 0.50% to 0.17%.

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386 Irina Maramica, MD, PhD, MBA

Red Blood Cells:  FNHTR incidences also vary with leukoreduction: nonleu-
koreduced 0.33%–0.34% to leukoreduced 0.18%–0.19%.

Plasma:  FNHTRs rarely occur with plasma products: incidence of 0.02% of trans-
fusions. Recent systematic review showed that methylene blue–treated Fresh Frozen
Plasma (FFP) led to fewer FNHTRs than FFP.

Pathophysiology:  Fever in FNHTRs is triggered by several different mechanisms,

resulting in release of cytokines, including IL-1β, IL-6, and TNF- α from activated
monocytes and macrophages. These cytokines induce production of prostaglandin E2,
which acts on the hypothalamus to increase body temperature. Immune and nonim-
mune mechanisms have been implicated its pathophysiology:
1. One immune-mediated mechanism is a result of recipient white blood cell
alloantibodies reacting with donor white blood cells to release cytokines. Both
granulocyte and HLA antibodies can stimulate donor’s white blood cells.
Immune-mediated FNHTRs are most commonly seen in previously transfused
or pregnant patients who are receiving nonleukocyte-reduced products, thus are
prevented with leukoreduction.
2. Second immune mechanism is when cytokines are produced and released
by recipient’s macrophages, stimulated by immune complexes formed
between recipient’s antibody and donor cell (leukocyte or platelet) antigens.
Leukoreduction is effective only in preventing reactions mediated by antibody
interaction with donor leukocytes but not platelets. Antibody interaction with
donor platelets provides possible explanation for febrile reactions in alloimmu-
nized recipients of prestorage leukocyte-reduced platelets. Repeat FNHTRs may
indicate development of refractoriness to platelet transfusions, as these same
antibody interactions with transfused platelets can lead to their clearance.
3. Nonimmune mechanism is due to passive transfer of proinflammatory cytokines
accumulated in plasma portion of product during storage at room temperature.
This mechanism is not dependent on leukocyte antibody presence. Leukocyte-
derived cytokines have been demonstrated in supernatant plasma of stored
platelet products, and their levels correlate with storage duration and prestorage
leukocyte number. Cytokines do not accumulate in sufficient quantities during
refrigerated RBC storage.
Bedside leukocyte reduction does not prevent these reactions. Prestorage leukocyte
reduction is effective, although it does not eliminate these reactions completely, pos-
sibly due to platelet-derived mediators that are not removed by leukoreduction filters.
Proinflammatory cytokines released by storage-induced platelet microparticles have
been demonstrated in supernatants of leukoreduced platelet concentrates and apheresis
platelets, including platelet factor 4 (PF-4), transforming growth factor β1 (TGF-β1),
β-thromboglobulin (β-TG) and soluble CD40 ligand (sCD40L). Notably, these are
removed by nonplatelet-sparing RBC leukoreduction filters.

Treatment:  Transfusion should be discontinued immediately and antipyretics admin-

istered. Acetaminophen (adult dose: 325–650 mg orally, pediatric dose: 10–15 mg/kg
Febrile Nonhemolytic Reactions 387

orally or rectally) is preferred because aspirin and nonsteroidal antiinflammatory agents

are contraindicated in patients receiving platelet transfusions. Patients who develop
rigors are commonly given meperidine (25–50 mg intravenously) to control severe
shaking that can significantly increase oxygen demand. This drug should be avoided in
patients with renal failure or on MAO inhibitor therapy. These are self-limited reactions
without long-term consequences.
Recent retrospective analysis of FNHTR management and outcomes demonstrated
postreaction clinical activity represents substantial burden on hospital and patient care:
>40% of implicated products were incompletely transfused, one-fourth of patients
underwent chest imaging and majority had microbial cultures, patients had exposure
to unplanned medications, and 15% had disposition escalation. Based on these con-
siderations, authors provided estimates of FNHTR management of $160 per patient.

Prevention:  Both pre- and poststorage leukoreduction, are effective in preventing

antibody-mediated reactions to RBCs and platelets. Poststorage leukoreduction is not
effective in preventing reactions to platelets that are mediated by accumulation of cyto-
kines released from leukocytes during storage. These reactions can be prevented by
prestorage filtration, which is not effective in removing platelet-derived mediators, and
some patients experience repeat reactions to prestorage leukoreduced blood products.
Decreasing cytokine levels in platelet products by removal of stored supernatant plasma
effectively lowers FNHTR rate to 0.6% compared with poststorage (20%) leukoreduc-
tion. However, this method is not superior to prestorage leukoreduction and required
additional centrifugation step compromises platelet function. Using leukoreduced
apheresis, platelets stored in PAS decreased FNHTRs with relative risk of 0.336 in rela-
tion to platelets stored in 100% plasma. Prestorage leukoreduction remains most prac-
tical and efficient way of preventing FNHTRs.
Routine premedication with antipyretics is commonly used to prevent FNHTRs in
high-risk patients and those with recurrent reactions. Two prospective, randomized, con-
trolled trials examined effectiveness of acetaminophen and diphenhydramine in prevent-
ing reactions. 51 patients with hematological malignancies experienced 12 febrile and 3
allergic reactions when transfused with 98 prestorage leukoreduced apheresis platelets.
Overall rate of reactions was similar in the treatment arm (15.4%) and the placebo arm
(15.2%), but FNHTRs were more common in the treatment arm (15.4%) compared with
placebo arm (8.7%). The second study of 315 patients receiving poststorage leukoreduced
products also failed to demonstrate effectiveness of premedication on preventing NHTR,
with the overall rate of reactions of 1.44% of transfusions in treatment group and 1.51%
in placebo group (FNHTR rate: 0.35% vs. 0.64%, P = .8). Use of premedication to pre-
vent FNHTRs should be evaluated with consideration of its costs and potential toxicities,
potential risk that antipyretics could mask fever due to more serious reasons, and signifi-
cantly reduced FNHTR rates associated with leukoreduced components.

Further Reading
Cohen, R., Escorcia, A., Tasmin, F., et al. (2017). Feeling the burn: The significant bur-
den of febrile nonhemolytic transfusion reactions. Transfusion, 57, 1674–1683.
Cohn, C. S., Stubbs, J., Schwartz, J., et al. (2014). A comparison of adverse reaction rates
for PAS C versus plasma platelet units. Transfusion, 54, 1927–1934.
388 Irina Maramica, MD, PhD, MBA

Dzik, W. H., Anderson, J. K., O’Neill, E. M., et al. (2002). A prospective, randomized
clinical trial of universal WBC reduction. Transfusion, 42, 1114–1122.
Heddle, N. M., Blajchman, M. A., Meyer, R. M., et al. (2002). A randomized controlled
trial comparing the frequency of acute reactions to plasma-removed platelets and
prestorage WBC-reduced platelets. Transfusion, 42, 556–566.
Kennedy, L. D., Case, L. D., Hurd, D. D., Cruz, J. M., & Pomper, G. J. (2008). A prospec-
tive, randomized, double-blind controlled trial of acetaminophen and diphenhydr-
amine pretransfusion medication versus placebo for the prevention of transfusion
reactions. Transfusion, 48(11), 2285–2291.
Pagliano, J. C., Pomper, G. J., Fisch, G. S., et al. (2004). Reduction of febrile but not
allergic reactions to RBCs and platelets after conversion to universal leukoreduction.
Transfusion, 44, 16–24.
Rogers, M. A. M., Rohde, J. M., & Blumberg, N. (2016). Haemovigilance of reactions
associated with red blood cell transfusion: Comparison across 17 countries. Vox Sang,
110, 266–277.
Sadaah, N., van Hout, F. M. A., Schipperius, M. R., et al. (2017). Comparing transfusion
reaction rates for various plasma types: A systemic review and meta-analysis/regres-
sion. Transfusion, 57, 2104–2114.