ACUTE ASEPTIC MENINGITIS SECONDARY TO INTRAVENOUS IMMUNOGLOBULIN IN A PATIENT WITH KAWASAKI SYNDROME (1998)

Kawasaki syndrome is a multisystem, inflammatory vasculitis of infants and young children. Although the etiology is unknown, treatment with intravenous immunoglobulin (IVIG) reduces the frequency of the most serious sequelae, coronary artery abnormalities, from 18% to 4%.1 Since its introduction in the early 1980s, IVIG has been used to treat a variety of disorders and is generally considered safe. Aseptic meningitis has been reported as a rare complication of IVIG therapy, especially when given for immune thrombocytopenic purpura or neurologic disorders.2-4 However, to our knowledge this complication has not previously been reported in a patient being treated for Kawasaki syndrome. We report a 9-year-old boy with Kawasaki syndrome who developed acute aseptic meningitis with neutrophilic predominance after the administration of immune globulin. Case report. A 9-year-old boy was admitted to the hospital with fever and rash. He had been well until 2 weeks previously, when he developed fever, sore throat, vomiting and a tender submandibular lymph node. A Group A streptococcal antigen test of a throat swab was negative. On the fourth day of illness he was admitted to another hospital and treated with intravenous ceftriaxone for presumed bacterial adenitis. During that 7-day hospitalization and while being treated with ceftriaxone, he developed conjunctival injection, cracked lips, swelling of his hands and feet and a scarlatiniform rash. Although still febrile he was discharged without a diagnosis. His symptoms persisted, and 4 days after discharge (the 15th day of illness) he was referred by his primary physician to an adult infectious diseases specialist who suspected Kawasaki syndrome and arranged for admission to Vanderbilt Children's Hospital that same day. Physical examination demonstrated a temperature of 38.1°C, heart rate of 100 per min, blood pressure of 105/69 mm Hg and respiratory rate of 22 per min. The patient was comfortable. There was bilateral, nonpurulent conjunctival injection. The oropharynx was diffusely red and the lips were dry and cracked. There was no meningismus. A 4- by 4-cm nontender lymph node was palpated in the left submandibular area. He had nonpitting edema of the hands and feet, peeling of the skin around his distal fingers and toes and a patchy macular rash on the trunk. The peripheral leukocyte count was 17 500 cells/μl, with 65% neutrophils, 12% lymphocytes, 8% monocytes and 15% eosinophils. The platelet count was 805 000/μl, and the Westergren erythrocyte sedimentation rate was 38 mm/h. Aspirin 90 mg/kg/day in four divided doses was prescribed, and IVIG (Polygam®, Baxter Healthcare, Glendale, CA; distributed by the American Red Cross, Washington, DC) 2 g/kg was administered during a 14-h infusion. By the end of the IVIG infusion the patient was afebrile, and the conjunctivitis and rash were improved. Ten hours after completion of the IVIG infusion, severe frontal headache, nausea and vomiting developed. His temperature was 38.9°C. He was alert but photophobic. Physical examination revealed marked nuchal rigidity and positive Kernig and Brudzinski signs. A computed tomographic scan of the head was negative. Lumbar puncture revealed cloudy cerebrospinal fluid (CSF) with a closing pressure of 21 cm of water. There were 1515 nucleated cells/μl (99% neutrophils and 1% lymphocytes), and 50 red blood cells/μl. The glucose was 55 mg/dl, and the protein was 49 mg/dl. No organisms were seen on Gram-stained smear of CSF sediment. Serum liver enzymes were normal. Intravenous ceftriaxone was administered. After 72 h of incubation the CSF bacterial culture was negative, and ceftriaxone was discontinued. CSF viral cultures were also negative. During the next 24 h the patient's fever, photophobia and nuchal rigidity resolved. His headache resolved gradually over the next 5 days, and he was discharged on the seventh hospital day. Four weeks later the patient was doing well, and an echocardiogram was normal. Discussion. Aseptic meningitis was first reported as a possible side effect of IVIG in 1988.5 Since then at least 36 cases have been documented, either in the medical literature or as reported to the Food and Drug Administration.6 Most cases have occurred in patients treated for immune thrombocytopenic purpura2, 3 or, less commonly, immune-related neuromuscular diseases.3, 4 There are several reports of recurrent aseptic meningitis after rechallenge with IVIG in the same patient,6 suggesting a causal relationship. The mechanism by which IVIG causes aseptic meningitis is unknown, although several theories have been proposed. The possibility of an allergic hypersensitivity reaction caused by the direct entry of the preparation into the CSF is supported by the presence of eosinophils in the CSF of some of the reported cases.4 However, many patients have not demonstrated a CSF eosinophilia. Serum immunoglobulins, especially IgG, can cross the blood-brain barrier and may be another offending factor. IVIG is allogenic and may interact with antigenic determinants on the endothelial cells of the meningeal microvasculature.4 Soluble molecules such as human leukocyte antigens and cytokines may be the triggering agents.7 These factors may be present in the IVIG preparations, or their production may be triggered by the IVIG. Finally some authors speculate that the reaction could be caused by sensitivity to stabilizing agents within the IVIG. Because aseptic meningitis has recurred in the same patients who received different commercial preparations (containing different stabilizing agents), this mechanism is less likely.4 Signs and symptoms of aseptic meningitis such as fever, headache, vomiting, photophobia and nuchal rigidity begin abruptly 6 to 48 h after the IVIG infusion is complete.3, 6 CSF leukocyte counts as high as 3260 cells/μl have been reported,3 and most patients demonstrate a neutrophilic predominance.3, 4 CSF protein may be normal or elevated, and glucose may be normal or low.6 The incidence of aseptic meningitis after IVIG administration is not known but is likely to be underreported. Mild reactions to IVIG administration are common, occurring in 1 to 15% of recipients,8 and include headache, myalgia, fever, chills and nausea. Unlike the aseptic meningitis reaction these milder symptoms typically begin 30 to 60 min after the onset of the infusion and can usually be managed by slowing the rate or temporarily stopping the infusion.8 Because patients with mild reactions are unlikely to undergo lumbar puncture, it is uncertain whether their symptoms represent a milder form of the aseptic meningitis syndrome or some other process. Risk factors for developing aseptic meningitis after IVIG administration have not been elucidated, with the possible exception of migraine headaches. In one retrospective study of 54 consecutive patients with immune-related neuromuscular diseases treated at a tertiary research referral center, aseptic meningitis developed in 4 of 8 patients with a history of migraines and in 2 of 46 patients without such a history.4 Our patient had no past history or family history of migraine headaches. Resolution of symptoms occurs in hours to days. Whether or not empiric antimicrobial therapy is warranted until CSF bacterial cultures are negative is a subject of debate.7 We believe that empiric antimicrobial therapy is a rational approach when caring for a patient with clinical symptoms compatible with bacterial meningitis and a CSF neutrophilic predominance, regardless of recent exposure to IVIG. Central nervous system involvement, including aseptic meningitis, can be a presenting feature of Kawasaki syndrome itself. Approximately one-third to one-half of patients with Kawasaki syndrome who undergo lumbar puncture will have a CSF pleocytosis.9 Distinguishing between aseptic meningitis caused by IVIG and that occurring as a manifestation of Kawasaki syndrome may be difficult, particularly in an infant whose fever and irritability persist after the administration of IVIG. However, the symptoms of aseptic meningitis associated with IVIG administration tend to be more severe and more abrupt in onset. In addition CSF leukocyte counts are usually higher and with a greater percentage of neutrophils in IVIG-associated aseptic meningitis. In one series of 15 episodes of IVIG-associated aseptic meningitis, the median CSF leukocyte count was 451 cells/μl and the median neutrophil count was 87%.3 In contrast a series of children with aseptic meningitis as a manifestation of Kawasaki syndrome reported a median leukocyte count of 23 cells/μl with a median neutrophil count of 6%.9 Our patient met all the diagnostic criteria for Kawasaki syndrome.10 Because the diagnosis was not made until the 15th day of illness, some might question whether treatment with IVIG was indicated. Prospective studies of IVIG therapy for Kawasaki syndrome have included only those patients diagnosed within 10 days of the onset of fever. Thus there are no prospective data to suggest that IVIG is or is not effective in children treated after the 10th day of illness. In a retrospective study of 16 children with Kawasaki syndrome who had already developed coronary artery abnormalities, the authors compared the long term outcome among those who received IVIG (all after Day 10 of illness) to those who did not receive IVIG. All 7 of the children treated with IVIG had resolution of the coronary artery abnormalities (mean follow-up, 22 months) as compared with 4 of 9 untreated children (mean follow-up, 47 months).11 Because coronary artery aneurysms can develop up to 8 weeks after onset of symptoms, many experts recommend IVIG therapy in patients diagnosed after the 10th day of illness if there are signs of ongoing inflammation.12-14 Because our patient still had fever, conjunctival injection and an elevated erythrocyte sedimentation rate at the time of presentation, we believe that IVIG therapy was justified. IVIG therapy should not be withheld from a patient with suspected Kawasaki syndrome on the basis of this report. However, clinicians should be aware of the potential for aseptic meningitis in a patient receiving IVIG for any indication, including Kawasaki syndrome. Thomas G. Boyce, M.D. Paul Spearman, M.D. Department of Pediatrics; Division of Infectious Diseases; Vanderbilt University Medical Center; Nashville, TN