Headache, backache, flushing, chills, fever, and nausea are the most common side effects reported with infusions of intravenous immunoglobulin. The cause of these symptoms has not been determined, but the symptoms are often associated with the rapidity of the infusion and usually resolve spontaneously within 30 to 60 minutes after the infusion is stopped. The symptoms may occur with every infusion or may occur randomly and infrequently without regard to lot or manufacturer of the preparation. Because of the frequency of these relatively mild side effects, many physicians have elected to pretreat their patients with a nonsteroidal anti-inflammatory agent or even with corticosteroids. Rarely, true anaphylactic reactions occur, most often related to the infusion of intravenous immunoglobulin containing small amounts of IgA into congenitally IgA-deficient patients.

An aseptic meningitis syndrome associated with the use of intravenous immunoglobulin has been reported for many years [5-12], although not at the frequency reported by Sekul and colleagues. It has been hypothesized that the intravenous immunoglobulin-associated aseptic meningitis syndrome is part of a continuum of disease that begins with headache [13]. Several studies of this hypothesis are in progress. A preliminary analysis of an ongoing study showed that no changes have been noted on magnetic resonance imaging studies of the central nervous system, and cells apparently occur in the cerebrospinal fluid only with severe headache (Bussel J. Personal communication). However, it should be noted that Sekul and colleagues used 10 times the standard dose for the prophylaxis of primary immunodeficiencies (0.2 g/kg) and approximately twice the standard dose used for the treatment of idiopathic thrombocytopenic purpura (1 g/kg).

To delineate the potential for the aseptic meningitis syndrome that develops with intravenous immunoglobulin therapy, we queried the FDA MEDWatch system [14], a compendium of voluntary reports of adverse reactions associated with approved or licensed products. The MEDWatch program has received 22 reports of the aseptic meningitis syndrome associated with 6 different intravenous immune globulin products: Gamimune N 10% and 5% (Miles, Inc., West Haven, Connecticut), Gammagard (Baxter, Glendale, California), Gammar I.V. (Armour Pharmaceutical Co., Collegeville, Pennsylvania), Polygam (Baxter; distributed by American Red Cross, Washington, DC), Sandoglobulin (Central Laboratory of the Swiss Red Cross; distributed by Sandoz, Minneapolis, Minnesota), and Venoglobulin-I (Alpha Therapeutic Corp., Los Angeles, California).

The most common indication for administration of intravenous immunoglobulin in the 22 cases reported to MEDWatch was idiopathic thrombocytopenic purpura, an indication that requires large doses (1 g/kg) of intravenous immunoglobulin to be given over several hours. Symptoms and signs of the aseptic meningitis syndrome began 6 to 48 hours after infusion of intravenous immunoglobulin. The most prominent symptoms included severe headache, fever, vomiting, and signs of meningeal irritation such as nuchal rigidity and photophobia. Twenty of the reports indicated that lumbar punctures had been done. In 17 cases, cerebrospinal fluid cytologic analysis showed pleocytosis of as high as 3260 cells/mm³, predominantly from the neutrophil series. Cerebrospinal fluid protein levels were reported in 13 cases, and they were elevated as high as 566 mg/dL in 8 cases. Cerebrospinal fluid glucose levels were reported in only 8 cases and were normal to low. Resolution of the syndrome occurred in hours to days after discontinuation of therapy with intravenous immunoglobulin. No deaths were reported in association with the aseptic meningitis syndrome.

In one report, a 6-year-old boy developed two separate episodes of the aseptic meningitis syndrome within 24 hours of receiving intravenous immunoglobulin 3 weeks apart. This is the only positive rechallenge reported to the FDA, and it mirrors the published reports of this event [5, 6, 9-11].

Because of the voluntary nature of such reporting, a true incidence of intravenous immunoglobulin-associated aseptic meningitis syndrome cannot be computed. However, with the 6 cases reported by Sekul and colleagues, the 8 cases reported in the literature, and the 22 reports from MEDWatch, 36 cases of the aseptic meningitis syndrome have been documented in association with intravenous immunoglobulin. Although at least 8 cases of the aseptic meningitis syndrome have been associated with the treatment of neurologic diseases, Van der Meche and coworkers [15] have reported no cases of the syndrome in the 74 patients with the Guillain-Barre syndrome receiving somewhat lower doses of intravenous immunoglobulin (400 mg/kg daily for 5 days) in the Dutch Multi-Center Guillain-Barre Trial. However, as noted by Sekul and colleagues [4], Watson and coworkers [7], and Meiner and associates [11], because of the intensive study of very high doses of intravenous immunoglobulin for the treatment of autoimmune neurologic disorders in which some compromise of the blood-brain barrier may already exist and the increasing use of intravenous immunoglobulin by primary care physicians in their offices, it is important for all clinicians to be aware of the potential for aseptic meningitis to develop after the use of any intravenous immunoglobulin product.