Pediatric Annals

Special Issue Article 

Intravenous Immunoglobulin for the Treatment of Kawasaki Disease

Stanford T. Shulman, MD

Abstract

Standard first-line therapy for Kawasaki disease (KD) consists of intravenous immunoglobulin (IVIG) and aspirin. Current guidelines recommend 2 g/kg of IVIG and 80 to 100 mg/kg of aspirin administered within the first 10 days of illness. This regimen has marked efficacy in preventing the development of coronary artery aneurysms. Approximately 15% to 20% of treated patients require a second dose of IVIG to control the inflammatory process. The role of adjunctive corticosteroid therapy with IVIG and aspirin is evolving, with Japanese studies showing a clear benefit in those patients at highest risk for development of coronary disease. The challenge in North America has been reliable identification of the highest-risk patients, which still eludes us because the Japanese scoring systems are ineffective in multiethnic populations. Despite its efficacy, the precise mechanism of IVIG's effect in KD is unclear but probably relates to its ability to down-regulate aspects of the up-regulated inflammatory response in patients with KD. [Pediatr Ann. 2017;46(1):e25–e28.]

Abstract

Standard first-line therapy for Kawasaki disease (KD) consists of intravenous immunoglobulin (IVIG) and aspirin. Current guidelines recommend 2 g/kg of IVIG and 80 to 100 mg/kg of aspirin administered within the first 10 days of illness. This regimen has marked efficacy in preventing the development of coronary artery aneurysms. Approximately 15% to 20% of treated patients require a second dose of IVIG to control the inflammatory process. The role of adjunctive corticosteroid therapy with IVIG and aspirin is evolving, with Japanese studies showing a clear benefit in those patients at highest risk for development of coronary disease. The challenge in North America has been reliable identification of the highest-risk patients, which still eludes us because the Japanese scoring systems are ineffective in multiethnic populations. Despite its efficacy, the precise mechanism of IVIG's effect in KD is unclear but probably relates to its ability to down-regulate aspects of the up-regulated inflammatory response in patients with KD. [Pediatr Ann. 2017;46(1):e25–e28.]

Kawasaki disease (KD) was first identified in the 1960s by Dr. Tomasaku Kawasaki at the Japan Red Cross Hospital in Tokyo.1 In 1967, Dr. Kawasaki's initial article described 50 children with what he recognized as a new disease.1 Within a few years it became clear that some children with KD developed coronary artery inflammation that led to aneurysms, and in the most severe cases to coronary thrombosis and myocardial infarcts, some of which were fatal.2

In 1970, Japanese pediatric health authorities established diagnostic criteria for KD, which have survived basically intact to the present (Table 1).3 All health care providers who care for children with fever need to be familiar with these criteria, because the diagnosis of KD and treatment with intravenous immunoglobulin (IVIG) and aspirin by the 10th day of illness (onset of fever = day 1) reduces the risk of developing coronary abnormalities by approximately 90%.3


            Kawasaki Disease Criteria

Table 1.

Kawasaki Disease Criteria

The diagnostic criteria for typical or classic KD include at least 5 days of fever (although the diagnosis by experienced providers can be established before illness day 5) and at least 4 of the 5 classic criteria: (1) polymorphic (but not vesicular or bullous) rash, primarily truncal; (2) swollen erythematous hands and/or feet; (3) bilateral bulbar conjunctival injection, usually nonexudative and with limbic-sparing rash; (4) oral mucosal changes including red and swollen cracked lips, strawberry tongue, inflamed oral mucosa (especially anteriorly); and (5) cervical lymphadenopathy at least 1.5 cm in diameter, generally unilateral with mild or no tenderness, usually without erythema, and rarely if ever becoming fluctuant.3

As physicians' experience with KD increased, there was increased recognition that incomplete (or atypical) cases of KD are common. An incomplete case refers to children with at least 5 days of fever and 2 or 3 (but not 4 or 5) of the classic features of KD. Recognition that incomplete KD patients are at essentially the same risk for developing coronary abnormalities as are those who fulfill the criteria for complete or typical KD, and that standard therapy is effective in preventing coronary changes (as discussed below), has made it imperative to diagnose and treat these patients as well.3

Mechanism of Action of Intravenous Immunoglobulin

The exact mechanism(s) of action by which IVIG mediates its dramatic therapeutic effect in KD patients remains uncertain. It is most likely that the high dose of IVIG required for its efficacy in KD signifies that an immunomodulatory effect, rather than neutralization of an infectious agent or toxic product, is the mechanism of action. IVIG has many potential immunomodulatory mechanisms, some or all of which may be operative in KD, including Fc-gamma receptor blockade, stimulation of the inhibitory Fc-gamma RIIb receptor, induction of neutrophil apoptosis, binding of activated complement components C3b and C4b, neutralization of or enhancement of anti-idiotype antibodies, neutralization of cytokines, and effects on chemokines, metalloproteinases, or others.

IVIG is produced from pooled immunoglobulin G (IgG) that has been purified from plasma obtained from more than 1,000 donors. The chemical processes used to purify IgG are harsh enough to inactivate any virus that might potentially contaminate plasma donor pools. Various IVIG preparations differ in manufacturing processes and in composition, such as the proportion of IgG monomers and polymers, and the presence of proteins other than IgG (such as IgA). These factors can affect adverse reaction rates among products, but clinical efficacy does not seem to vary. One exception is that IVIG prepared with beta-propiolactone, which can affect the function of the Fc portion of IVIG, is less effective in KD, but such products are no longer available.3

Intravenous Immunoglobulin in Kawasaki Disease

IVIG, together with aspirin, has been the mainstay of therapy for KD for the past 30 years despite the fact that its mechanism of action in this illness remains somewhat unclear. Furusho et al.4 first reported that IVIG might be beneficial in the treatment of KD. Their original hypothesis was that KD was likely mediated by immune complexes, and that exogenous IVIG would result in blockade of deposition of those immune complexes. This does not appear to be the mechanism of action, but a reduction in coronary abnormalities was observed. Subsequent multicenter randomized controlled trials of IVIG,5,6 particularly in North America, clearly demonstrated its efficacy in reducing the incidence of coronary aneurysms. Initially, a regimen of 4 once-daily doses (400 mg/kg per dose) plus high-dose aspirin was shown to be superior to aspirin alone,5 and subsequently 1 large (2 g/kg) IVIG dose was clearly demonstrated to be superior to the 4-dose regimen with respect to rapidity of defervescence, normalization of acute phase reactants, and prevention of coronary abnormalities.6

Current North American guidelines recommend that all patients diagnosed with classic or incomplete KD should receive IVIG at 2 g/kg plus aspirin (80–100 mg/kg per day) whenever possible within 10 days of the onset of KD as determined by the day of fever onset (Table 2).3


            Treatment of Kawasaki Disease

Table 2.

Treatment of Kawasaki Disease

Because few data exist regarding the management of patients with KD diagnosed later than the 10th day of illness, and because coronary abnormalities are commonly detected by echocardiogram by illness day 10, the therapeutic goal is to institute IVIG therapy by the 10th illness day whenever possible. Patients treated after day 10 of illness who are still febrile with elevated inflammatory markers may still benefit from IVIG and aspirin therapy, but the ability to prevent coronary changes is less certain. Those diagnosed after illness day 10 who are afebrile and asymptomatic are unlikely to benefit from IVIG therapy. IVIG and aspirin have been demonstrated specifically to prevent the development of giant coronary aneurysms,7 which are the most serious aneurysms, and also to have direct benefits on cardiac function.8

The issue of whether treatment with IVIG and aspirin prior to the 5th day of illness in KD leads to better or poorer outcomes compared to those patients treated on the 5th to 10th illness day is still controversial. A major confounding factor is that KD patients diagnosed and treated on illness days 3 or 4 are generally sicker than those diagnosed and treated later in their illness, and thus they may be at greater risk for developing coronary complications.

It also appears that IVIG prevents coronary artery abnormalities, including aneurysms, in a dose-response fashion. Terai and Shulman,9 in a meta-analysis, showed that the incidence of coronary abnormalities at 30 and 60 days after treatment was inversely proportional to the total dose per kilogram of IVIG administered over the range of 1 to 2 g/kg of total dose, but was independent of the aspirin dose administered. This is also part of the rationale for giving a second dose of 2 g/kg of IVIG to those KD patients who have persistent or recurrent fever 36 or more hours after the end of the initial IVIG dose.3 Approximately 15% to 20% of patients require a second dose of IVIG (2 g/kg), and patients should remain hospitalized until they have been afebrile for at least 24 hours to ensure they are available for a second dose if necessary.3

Adjunctive Therapy

The RAISE study10 (efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease) used a scoring system developed by one of the investigators (Kobayashi) based on demographic and laboratory features to define KD patients at highest risk for development of coronary abnormalities. These high-risk patients were randomized to receive standard IVIG and aspirin with or without intravenous methylprednisolone at a dose of 2 mg/kg per day followed by a 2- to 3-week course of tapering oral prednisolone as primary KD therapy. An approximate 80% reduction in frequency of coronary abnormalities was observed in the steroid group.10 Unfortunately, the Kobayashi and other scoring systems do not reliably identify high-risk KD patients in ethnically diverse populations such as those in North America. However, one identifiable population that clearly includes patients at higher risk for coronary abnormalities are infants younger than age 6 to 9 months. It is possible that this population would benefit from the addition of a steroid to IVIG and aspirin as primary KD therapy.

Cautions when Treating with Intravenous Immunoglobulin

Because passive administration of antibody to varicella, measles, or other viruses can impair the active immune response to these live virus vaccines, they should be deferred for 11 months after administration of IVIG.3

A classic but uncommon adverse reaction to the administration of IVIG, occurring in approximately 2% to 3% of patients with KD, is the development of aseptic meningitis with fever, headache, and/or vomiting within 12 to 36 hours of IVIG infusion.3 This resolves quickly without neurologic sequelae.

A more recent adverse reaction, reported primarily from Canada, is the development of Coombs-positive hemolytic anemia after IVIG, especially in those with blood type A.11

Conclusion

IVIG therapy for KD represents an unusual circumstance in which a highly effective therapy has a yet unproven mechanism of action. However, its safety and efficacy are without question in this important pediatric disorder, which is the most common cause of acquired heart disease in children in developed countries with little incidence of acute rheumatic fever.

References

  1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi. 1967;16(3):178–222.
  2. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54(3):271–276.
  3. Newburger JW, Takahashi M, Gerber MA, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki DiseaseCouncil on Cardiovascular Disease in the YoungAmerican Heart Association; American Academy of Pediatrics. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747–2771. doi:10.1161/01.CIR.0000145143.19711.78 [CrossRef]
  4. Furusho K, Kamiya T, Nakano H, et al. High dose intravenous gammaglobulin for Kawasaki disease. Lancet. 1984;2(8411):1055–1058. doi:10.1016/S0140-6736(84)91504-6 [CrossRef]
  5. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki sundrome with intravenous gamma globulin. N Engl J Med. 1986;315(6):341–347. doi:10.1056/NEJM198608073150601 [CrossRef]
  6. Newburger JW, Takashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324(23):1633–1639. doi:10.1056/NEJM199106063242305 [CrossRef]
  7. Rowley AH, Duffy CE, Shulman ST. Prevention of giant coronary artery aneurysms in Kawasaki disease by intravenous gammaglobulin. J Pediatr. 1988;113:290–294. doi:10.1016/S0022-3476(88)80267-1 [CrossRef]
  8. Newburger JW, Sanders SP, Burns JC, et al. Left ventricular contractility and function in Kawasaki syndrome. Effect of intravenous gamma-globulin. Circulation. 1989;79:1237–1246. doi:10.1161/01.CIR.79.6.1237 [CrossRef]
  9. Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr. 1997;131(6):888–893. doi:10.1016/S0022-3476(97)70038-6 [CrossRef]
  10. Kobayashi T, Saji T, Otani T, et al. RAISE study group investigators. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomized, open-label, blinded-endpoints trial. Lancet. 2012;379(9826):1613–1620. doi:10.1016/S0140-6736(11)61930-2 [CrossRef]
  11. Yeung RS, Almeida F, Khajoee V, et al. Intravenous immunoglobulin-associated hemolysis in Kawasaki disease. Circulation. 2015;131(Suppl 2):Abstract O.48.

Kawasaki Disease Criteria

At least 5 days of fever    Plus At least 4 of the following 5 criteria <list-item>

Bilateral bulbar conjunctival injection, usually nonexudative, with limbic-sparing

</list-item><list-item>

Polymorphous rash especially on the trunk, often with perineal accentuation, not vesicular or bullous

</list-item><list-item>

Swollen erythematous hands and/or feet

</list-item><list-item>

Oral mucosal changes including red and swollen cracked lips, strawberry tongue, inflamed anterior oral mucosa

</list-item><list-item>

Cervical lymphadenopathy ≥1.5 cm in diameter, usually unilateral with mild or no overlying erythema and without fluctuance

</list-item>

Treatment of Kawasaki Disease

Acute and Subacute Stages <list-item>

IVIG 2g/kg infusion over 10–12 hours

</list-item><list-item>

   Plus

</list-item><list-item>

Aspirin 80–100 mg/kg per day in 4 divided doses (until 10th–14th illness day and patient is afebrile at least 3–4 days), then change to 3–5 mg/kg once daily for 6–8 weeks

</list-item><list-item>

IVIG may be repeated if fever persists or recurs with at least 1 classic sign of Kawasaki disease and/or elevated C-reactive protein level (see text for alternative “rescue therapies”)

</list-item>
Convalescent Stage <list-item>

No coronary abnormalities: no therapy

</list-item><list-item>

Transient coronary abnormalities: aspirin 3–5 mg/kg once daily at least until resolution of coronary abnormalities

</list-item><list-item>

Persistent small or medium coronary aneurysms: aspirin 3–5 mg/kg once daily

</list-item><list-item>

Giant or multiple small coronary aneurysms: aspirin 3–5 mg/kg once daily, with or without 1 mg/kg per day of clopidogrel, with warfarin or low molecular-weight heparin for most patients

</list-item><list-item>

Coronary obstruction: thrombolytic therapy, surgical or interventional procedures

</list-item>
Authors

Stanford T. Shulman, MD, is the Virginia H. Rogers Professor of Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine; and the Division Head Emeritus, Pediatric Infectious Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago.

Address correspondence to Stanford T. Shulman, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Avenue, Chicago, IL 60611; email: SShulman@luriechildrens.org.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/19382359-20161212-01

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