Background
Intravenous immunoglobulin (IVIG) is a blood product that is widely used in the treatment of a number of medical conditions, including immunodeficiency disorders, inflammatory diseases, and autoimmune diseases.
Kawasaki disease (KD) is a self-limited systemic vasculitis syndrome of childhood that was first reported by Tomisaku Kawasaki in 1967 [
1]. Patients typically develop a fever, bulbar conjunctival injection, changes in the oropharyngeal mucosa and peripheral extremities, cervical lymphadenopathy, and a polymorphous rash. Coronary aneurysm and myocardial infarction are the most serious complications of this disease. In Japan, there are approximately 10,000 incident cases per year [
2]. The etiology of the disease is not well understood, but high-dose IVIG is known to prevent the coronary complications [
3,
4].
There have been a number of reports regarding IVIG-induced adverse reactions, including mild reactions such as tachycardia, headache, facial flushing, nausea, diarrhea, and rash, as well as serious adverse reactions such as anaphylaxis, acute renal failure, and thromboembolic events [
5]. Aseptic meningitis is a neurologic adverse event that can be caused by IVIG. Although there have been case reports describing IVIG-induced aseptic meningitis, few studies have described the characteristics of a group of such patients. In this study, we describe the clinical and laboratory characteristics of IVIG-induced aseptic meningitis in 4 patients with KD.
Discussion
Aseptic meningitis after IVIG was first reported in 1988 [
6]. Since then, there have been similar case reports of IVIG-induced meningitis in patients with medical conditions such as idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, and inflammatory demyelinating neuropathy [
7‐
9]. There has previously been only 1 case report describing this complication in a patient with KD [
10].
The rate of aseptic meningitis after IVIG was 1% (4 of 384) in this study, but the frequency varies widely, from 0% to 11%, in reports of patients with different underlying diseases [
11,
12]. It was also reported that the development of aseptic meningitis was not correlated with the patient age or the type of underlying neuromuscular disease [
12].
Hamrock reported that most patients who developed aseptic meningitis received 2 g/kg of IVIG, and that meningitis did not occur in any of their patients receiving a standard replacement dose of IVIG for a congenital immunodeficiency [
5]. All of our patients received high-dose IVIG at a dose of 1 or 2 g/kg. Our patients almost equally received sulfonated IVIG or PEG-treated IVIG, and 2 patients in each group (total 4) developed meningitis, thus indicating that there are no apparent differences in the effects of sulfaonated or PEG-treated IVIG with regard to the development of meningitis. In this study, patients were exposed to either sulfonated IVIG or PEG-treated IVIG, but not to products manufactured by other processes such as cold ethanol Cohn fractionation/ultrafiltration, ion exchange, or low-PH treatment. The inability to further explore the possible etiological factors related to specific IVIG brand or manufacturing lots may be a limitation of this study. There were no obvious differences of clinical and laboratory data, including the severity of KD on admission, day of initiating IVIG, or changes of inflammatory markers after IVIG between patients who developed meningitis and those who did not.
In the present study, aseptic meningitis developed within 25 to 40 hours after initiation of IVIG. In previous case reports, most patients also developed meningitis within 48 hours of beginning IVIG. Although all of our patients developed a fever and typical meningeal irritation signs, it may be possible that milder cases of aseptic meningitis could be misdiagnosed as IVIG- refractory KD, since the onset of fever after completion of IVIG therapy is often interpreted as recrudescence of KD. It is important to consider the possibility of IVIG-induced meningitis with careful physical examinations to avoid unnecessary therapies, such as additional IVIG, steroids, and infliximab.
CSF examinations revealed neutrophilic pleocytosis in 3 of our 4 patients, slight elevation of the protein level in 1 patient, and normal glucose levels in all 4 patients. These findings were similar to those of previous reports. The analysis of the CSF in patients with aseptic meningitis usually shows pleocytosis with neutrophil predominance, normal or slightly elevated protein, and normal glucose levels. It may therefore be difficult to differentiate IVIG-induced meningitis from viral meningitis by the CSF findings, as it has been reported that the CSF protein levels are normal to mildly elevated, glucose levels are normal to slightly depressed, and neutrophil predominance is also seen in pediatric patients with viral meningitis [
13,
14].
All of our patients recovered without developing any neurological complications. Two were treated with intravenous methylprednisolone, and the other 2 were monitored without medical treatment. Jayabose et al. reported that children with ITP who were given prednisone had a lower risk of neurological complications after IVIG [
15]. However, it has also been reported that such symptoms are self-limiting, and that there is no specific therapy that shortens the duration of symptoms. Thus, it may be advisable to carefully observe such patients and avoid systemic therapy [
5]. In our study, there were no obvious differences in the clinical courses between patients treated with intravenous methylprednisolone and those who received no medical treatment, which suggests that systemic steroid administration is not beneficial for IVIG-induced meningitis.
The mechanisms underlying IVIG-induced meningitis are not clear. One possible cause is an allergic hypersensitivity reaction caused by direct entry of the IVIG preparation into the CSF compartment. This is supported by the fact that CSF eosinophilia has been observed in some patients [
11]. In our study, one patient exhibited peripheral eosinophilia (11% of the total 5,800/μL white blood cells) but CSF eosinophilia was not observed in any of our patients. None of our patients developed exanthema after IVIG. Although our patients received no pre-treatment, it may be useful to give antihistamines prior to IVIG if allergic reaction is one of the mechanisms responsible for IVIG-induced meningitis. Recently, it was reported that there were increased levels of CSF monocyte chemoattractant protein-1 (MCP-1) in ITP patients with IVIG-induced meningitis, which suggests a role for monocytes in the inflammation of the meninges [
16]. On the other hand, Jarius et al. reported that aseptic meningitis was frequently associated with neutrophillic pleocytosis in the CSF and
in vivo activation of TNF-α-primed neutrophils by atypical antineutrophil cytoplasmic antibodies in IVIG might contribute to aseptic meningitis [
17]. In our present study, the CSF cytokines or chemokines were not measured.
Meningitis is also a known complication of KD. Dengler et al reported that one-third of patients with KD who underwent a lumbar puncture had CSF pleocytosis with mononuclear cell predominance [
18], which is in contrast to the polynuclear cell predominance observed in IVIG-induced meningitis. Meningitis as a complication of KD usually occurs early in the course of the disease and improves after KD treatment, which is mainly IVIG therapy [
19]. Table
4 shows a comparison between IVIG- and KD-induced meningitis. It is not difficult to differentiate IVIG-induced meningitis from aseptic meningitis complicating KD, as both the time of onset and CSF findings differ.
Table 4
A comparison between IVIG- and KD-induced meningitis
Appearance | Within 48 hrs after IVIG | Early in the stage, before IVIG |
Clinical findings | Typical meningeal signs | Can lack meningeal signs |
CSF findings | Polynuclear cell predominance | Mononuclear cell predominance |
Effective therapy | No special therapy | Therapy for KD |
Conclusions
In conclusion, IVIG-induced meningitis developed within 48 hours of initiating IVIG and resolved in a few days, without neurological complications, and systemic steroid administration was not beneficial in our patients. Further investigations of the pathophysiology of IVIG-induced meningitis, including a detailed analysis of the underlying mechanisms, are needed.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
YK contributed by taking care of the patients. All authors contributed to the analysis and interpretation of the data. All authors read and approved the final manuscript.