Sometimes called simply (and incorrectly) “febrile reactions,” nonhemolytic febrile reactions occur in about 1% (range, 0.5-5.0%) of all transfusions, more commonly in multiply transfused patients.

Leukoagglutinin reaction. The most common variety of nonhemolytic febrile reaction and the most common of any transfusion reaction is a febrile episode during or just after transfusion due to patient antibodies against donor leukocytes (leukoagglutinins). Before leukoagglutinins were recognized, these episodes were included among the pyrogenic reactions (discussed later). Fever may be the only symptom but there may be others, such as chills, headache, malaise, confusion, and tachycardia. In a small number of cases a syndrome known as transfusion-related acute lung injury is produced. It includes febrile reaction symptoms plus dyspnea and tachycardia; the chest x-ray film has a characteristic pattern described as numerous hilar and lower lobe nodular infiltrates without cardiac enlargement or pulmonary vessel congestion. In some cases the clinical picture includes marked hypoxemia and also hypotension and thus strongly resembles the adult respiratory distress syndrome. However, symptoms usually substantially improve or disappear in 24-48 hours (81% of patients in one report), but the radiologic abnormalities may persist for several days. Some patients have eosinophilia, but others do not. The syndrome has been called “noncardiac pulmonary edema,” a somewhat unfortunate term since pulmonary edema is not present, although many clinical findings simulate pulmonary edema. Most cases with leukoagglutinin lung involvement follow transfusion of whole blood. At least some of these reactions have been traced to histocompatibility leukocyte antigen (HLA) system incompatibility.

Most patients produce leukoagglutinins due to previous transfusion or from fetal antigen sensitization in pregnancy. The more transfusions, the greater the likelihood of sensitization.

Reactions due to leukoagglutinins are usually not life threatening but are unpleasant to the patient, physician, and laboratory. Since clinical symptoms are similar to those of a hemolytic reaction, each febrile reaction must be investigated to rule out RBC incompatibility, even if the patient is known to have leukoagglutinins. Leukoagglutinin reactions may be reduced or eliminated by the use of leukocyte-poor packed RBC, washed RBC, frozen RBC, or best, use of a special leukocyte-removal filter (Chapter 10). There are specialized tests available that are able to demonstrate leukoagglutinin activity, but most laboratories are not equipped to perform them. The diagnosis, therefore, is usually a presumptive one based on history and ruling out hemolytic reaction.

Washed or frozen RBCs contain fewer white blood cells (WBCs) than the average leukocyte-poor packed cell preparation. However, since washed or frozen RBCs must either be transfused within 24 hours after preparation or be discarded, one must be certain that a need for transfusion exists sufficient to guarantee that the blood will actually be administered before these blood products are ordered. In contrast, leukocyte filtration can be done at the patient’s bedside as part of the transfusion.

Pyrogenic reactions. These result from contamination by bacteria, dirt, or foreign proteins. One frequently cited study estimates that nearly 2% of donor blood units have some degree of bacterial contamination, regardless of the care taken when the blood was drawn. Symptoms begin during or shortly after transfusion and consist of chills and fever; the more severe cases often have abdominal cramps, nausea, and diarrhea. Very heavy bacterial contamination may lead to shock. Therefore, in a patient with transfusion-associated reaction that includes hypotension, a Gram-stained smear should be made from blood remaining in the donor bag without waiting for culture results.