Efficacy of Immunoglobulin Plus Prednisolone in Prevention of Coronary Artery Abnormalities in Kawasaki Disease
The Raise Study
Nina Shapiro
Findings from our randomized study show that combination treatment with intravenous immunoglobulin plus prednisolone is better than that with intravenous immunoglobulin alone in prevention of coronary artery abnormalities, reducing the need for additional rescue treatment, and rapid resolution of fever and inflammatory markers in Japanese patients with severe Kawasaki disease.
--Kobayashi ET AL.
Research Question: Does addition of prednisolone to conventional treatment with intravenous immunoglobulin (IVIG) and aspirin reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease?
Funding: Japanese Ministry of Health, Labour, and Welfare.
Year Study Began: 2008
Year Study Published: 2012
Study Location: 74 hospitals in Japan.
Who Was Studied: Children with severe Kawasaki disease, who received a Kobayashi risk score 3 of 5 points or higher (see Boxes 1.1 and 1.2), indicating a high risk of nonresponse to immunoglobulin therapy and subsequent coronary artery involvement.
Box 1.1 JAPANESE GUIDELINES FOR DIAGNOSIS OF KAWASAKI DISEASE
Infants and children under the age of 5 should satisfy either 5 of the principal symptoms of Kawasaki disease or 4 of the principal symptoms plus coronary aneurysm or dilatation.
Principal Symptoms:
1. Fever persisting ≥ 5 days
2. Fever for ≤ 4 days shortened by early intravenous immunoglobulin therapy
3. Bilateral conjunctival congestion
4. Changes of lips and oral cavity (reddening of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosa)
5. Polymorphous exanthema
6. Changes of peripheral extremities (initial stage: reddening of palms and soles, indurative edema; convalescent stage: membranous desquamation from fingertips)
7. Acute nonpurulent cervical lymphadenopathy
Box 1.2 KOBAYASHI RISK SCORES WERE CALCULATED USING THE FOLLOWING CRITERIA
• 2 points each for:
• Serum sodium concentration ≤ 133 mmol/ L
• Illness of ≤ 4 days at diagnosis
• Aspartate aminotransferase concentration of ≥ 100 U/ L
• % neutrophils ≥ 80%
• 1 point each for:
• Platelet count ≤ 30Å ~ 104/ μL
• C-reactive protein concentration of ≥ 100 mg/ L
•Age ≤ 12 months
Who Was Excluded: Children with a prior history of Kawasaki disease or coronary artery disease before study enrollment, those who were diagnosed with Kawasaki disease 9 or more days after onset of illness, those who were afebrile before study enrollment, those who received steroids or IVIG within 30 days or 180 days respectively, and those with coexisting severe medical disorders or suspected infectious disease were excluded from the study.
How Many Patients: 248
Study Overview: See Figure 1.1 for a summary of the study design. Figure 1.1 Summary of Study Design.
The Raise Study
Nina Shapiro
Findings from our randomized study show that combination treatment with intravenous immunoglobulin plus prednisolone is better than that with intravenous immunoglobulin alone in prevention of coronary artery abnormalities, reducing the need for additional rescue treatment, and rapid resolution of fever and inflammatory markers in Japanese patients with severe Kawasaki disease.
--Kobayashi ET AL.
Research Question: Does addition of prednisolone to conventional treatment with intravenous immunoglobulin (IVIG) and aspirin reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease?
Funding: Japanese Ministry of Health, Labour, and Welfare.
Year Study Began: 2008
Year Study Published: 2012
Study Location: 74 hospitals in Japan.
Who Was Studied: Children with severe Kawasaki disease, who received a Kobayashi risk score 3 of 5 points or higher (see Boxes 1.1 and 1.2), indicating a high risk of nonresponse to immunoglobulin therapy and subsequent coronary artery involvement.
Box 1.1 JAPANESE GUIDELINES FOR DIAGNOSIS OF KAWASAKI DISEASE
Infants and children under the age of 5 should satisfy either 5 of the principal symptoms of Kawasaki disease or 4 of the principal symptoms plus coronary aneurysm or dilatation.
Principal Symptoms:
1. Fever persisting ≥ 5 days
2. Fever for ≤ 4 days shortened by early intravenous immunoglobulin therapy
3. Bilateral conjunctival congestion
4. Changes of lips and oral cavity (reddening of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosa)
5. Polymorphous exanthema
6. Changes of peripheral extremities (initial stage: reddening of palms and soles, indurative edema; convalescent stage: membranous desquamation from fingertips)
7. Acute nonpurulent cervical lymphadenopathy
Box 1.2 KOBAYASHI RISK SCORES WERE CALCULATED USING THE FOLLOWING CRITERIA
• 2 points each for:
• Serum sodium concentration ≤ 133 mmol/ L
• Illness of ≤ 4 days at diagnosis
• Aspartate aminotransferase concentration of ≥ 100 U/ L
• % neutrophils ≥ 80%
• 1 point each for:
• Platelet count ≤ 30Å ~ 104/ μL
• C-reactive protein concentration of ≥ 100 mg/ L
•Age ≤ 12 months
Who Was Excluded: Children with a prior history of Kawasaki disease or coronary artery disease before study enrollment, those who were diagnosed with Kawasaki disease 9 or more days after onset of illness, those who were afebrile before study enrollment, those who received steroids or IVIG within 30 days or 180 days respectively, and those with coexisting severe medical disorders or suspected infectious disease were excluded from the study.
How Many Patients: 248
Study Overview: See Figure 1.1 for a summary of the study design. Figure 1.1 Summary of Study Design.
Figure 1.1 Summary of Study Design.
Study Intervention: Children diagnosed with severe Kawasaki disease were randomly assigned to receive either:
Follow-Up: Two-dimensional echocardiograms and laboratory data were obtained at baseline and at week 1 (6– 8 days after study enrollment), week 2 (12– 16 days after study enrollment), and week 4 (24– 32 days after study enrollment).
Endpoints: The primary endpoint was the incidence of coronary artery abnormalities on two-dimensional echocardiography during the study period. Secondary endpoints included coronary artery abnormalities at week 4 after study enrollment, need for additional rescue treatment, duration of fever after enrollment, serum concentrations of C-reactive protein at 1 and 2 weeks after enrollment, and serious adverse events.
RESULTS
The incidence of coronary artery abnormalities during the study period was significantly lower in the IVIG plus prednisolone group (3%) compared with the group receiving only IVIG (23%, P < 0.0001). At week 4 after study enrollment, patients in the IVIG plus prednisolone group also had significantly fewer coronary artery abnormalities, although the difference was less than that seen during the study period. Additionally, patients in the IVIG plus prednisolone group had more rapid fever resolution, lower incidence of rescue treatments, higher white blood cell counts and percentage neutrophils, lower aspartate aminotransferase concentration, higher serum sodium, higher total cholesterol, and lower concentrations of C-reactive protein.
Criticisms and Limitations: The RAISE study did not evaluate for many of the adverse effects of corticosteroids, though the study did identify an increase in the incidence of leukocytosis and high serum cholesterol in the group receiving prednisolone.
All study participants were of Japanese origin, and thus the results may not be generalizable to a more heterogeneous population. For example, the Kobayashi risk score was used to identify Japanese infants and children with severe Kawasaki disease that might be unresponsive to standard IVIG therapy, putting them at higher risk for coronary artery abnormalities. Yet, while this system predicted immunoglobulin nonresponse in Japanese patients, this scoring system has been found to have a low sensitivity for other populations, such as North Americans. Further study is required to address the efficacy of the RAISE treatment regimen in non-Japanese patients with severe Kawasaki disease.
Other Relevant Studies and Information: • The Pediatric Heart Network (PHN) study, “Randomized Trial of Pulsed Corticosteroid Therapy for Primary Treatment of Kawasaki Disease,” found no benefit of addition of pulsed high-dose intravenous methylprednisolone before conventional therapy with intravenous immunoglobulin with respect to coronary artery outcomes, reduction in adverse events, treatment time, or fever duration. This study evaluated the use of a single high-dose administration of corticosteroid in contrast to the RAISE study, which used low-dose corticosteroids over 15 days, but it highlights the controversy surrounding corticosteroid use in Kawasaki disease.
Summary and Implications: The RAISE study showed that the addition of prednisolone to standard of care treatment with IVIG and aspirin improved coronary artery outcomes, reduced the need for further treatment, and improved fever resolution in children with severe Kawasaki disease.
CLINICAL CASE: KAWASAKI DISEASE
Case History: A 4-year-old male presented with a 5-day history of fevers to 103 ° F. Physical exam demonstrated an ill-appearing child with conjunctival erythema; dry, chapped lips; a swollen, red tongue; bilateral anterior cervical adenopathy; and a diffuse cutaneous exanthem. Laboratory testing was most notable for a sodium concentration of 130 mmol/ L, C-reactive protein of 120, and a leukocytosis, with 85% neutrophils. Based on this study, what would be the treatment of choice for this child?
Suggested Answer: According to the RAISE study, children with a diagnosis of Kawasaki disease with a risk profile of > 5 benefit from treatment including IVIG, aspirin, and prednisolone. This child’s laboratory testing results included hyponatremia (2 risk profile points), elevated C-reactive protein (2 risk factor points), and neutrophil elevation (1 risk factor point), giving him a risk profile of 5, according to the RAISE study authors’ criteria. This risk profile puts him at higher risk for coronary aneurysms. Addition of prednisolone to the IVIG/ aspirin regimen in these high-risk patients gives them a significantly lower risk of developing coronary artery abnormalities, compared to children who received IVIG and aspirin alone.
References
Study Intervention: Children diagnosed with severe Kawasaki disease were randomly assigned to receive either:
- Conventional treatment with intravenous immunoglobulin (2 g/ kg for 24 h) and aspirin (30 mg/ kg per day until afebrile and then 3-5mg/ day for at least 28 days after fever onset) or
- 2. The same regimen of intravenous immunoglobulin and aspirin just described plus prednisolone (2 mg/ kg per day over 15 days) and famotidine (0.5 mg/ kg per day), a histamine receptor antagonist, for gastric protection.
Follow-Up: Two-dimensional echocardiograms and laboratory data were obtained at baseline and at week 1 (6– 8 days after study enrollment), week 2 (12– 16 days after study enrollment), and week 4 (24– 32 days after study enrollment).
Endpoints: The primary endpoint was the incidence of coronary artery abnormalities on two-dimensional echocardiography during the study period. Secondary endpoints included coronary artery abnormalities at week 4 after study enrollment, need for additional rescue treatment, duration of fever after enrollment, serum concentrations of C-reactive protein at 1 and 2 weeks after enrollment, and serious adverse events.
RESULTS
The incidence of coronary artery abnormalities during the study period was significantly lower in the IVIG plus prednisolone group (3%) compared with the group receiving only IVIG (23%, P < 0.0001). At week 4 after study enrollment, patients in the IVIG plus prednisolone group also had significantly fewer coronary artery abnormalities, although the difference was less than that seen during the study period. Additionally, patients in the IVIG plus prednisolone group had more rapid fever resolution, lower incidence of rescue treatments, higher white blood cell counts and percentage neutrophils, lower aspartate aminotransferase concentration, higher serum sodium, higher total cholesterol, and lower concentrations of C-reactive protein.
Criticisms and Limitations: The RAISE study did not evaluate for many of the adverse effects of corticosteroids, though the study did identify an increase in the incidence of leukocytosis and high serum cholesterol in the group receiving prednisolone.
All study participants were of Japanese origin, and thus the results may not be generalizable to a more heterogeneous population. For example, the Kobayashi risk score was used to identify Japanese infants and children with severe Kawasaki disease that might be unresponsive to standard IVIG therapy, putting them at higher risk for coronary artery abnormalities. Yet, while this system predicted immunoglobulin nonresponse in Japanese patients, this scoring system has been found to have a low sensitivity for other populations, such as North Americans. Further study is required to address the efficacy of the RAISE treatment regimen in non-Japanese patients with severe Kawasaki disease.
Other Relevant Studies and Information: • The Pediatric Heart Network (PHN) study, “Randomized Trial of Pulsed Corticosteroid Therapy for Primary Treatment of Kawasaki Disease,” found no benefit of addition of pulsed high-dose intravenous methylprednisolone before conventional therapy with intravenous immunoglobulin with respect to coronary artery outcomes, reduction in adverse events, treatment time, or fever duration. This study evaluated the use of a single high-dose administration of corticosteroid in contrast to the RAISE study, which used low-dose corticosteroids over 15 days, but it highlights the controversy surrounding corticosteroid use in Kawasaki disease.
Summary and Implications: The RAISE study showed that the addition of prednisolone to standard of care treatment with IVIG and aspirin improved coronary artery outcomes, reduced the need for further treatment, and improved fever resolution in children with severe Kawasaki disease.
CLINICAL CASE: KAWASAKI DISEASE
Case History: A 4-year-old male presented with a 5-day history of fevers to 103 ° F. Physical exam demonstrated an ill-appearing child with conjunctival erythema; dry, chapped lips; a swollen, red tongue; bilateral anterior cervical adenopathy; and a diffuse cutaneous exanthem. Laboratory testing was most notable for a sodium concentration of 130 mmol/ L, C-reactive protein of 120, and a leukocytosis, with 85% neutrophils. Based on this study, what would be the treatment of choice for this child?
Suggested Answer: According to the RAISE study, children with a diagnosis of Kawasaki disease with a risk profile of > 5 benefit from treatment including IVIG, aspirin, and prednisolone. This child’s laboratory testing results included hyponatremia (2 risk profile points), elevated C-reactive protein (2 risk factor points), and neutrophil elevation (1 risk factor point), giving him a risk profile of 5, according to the RAISE study authors’ criteria. This risk profile puts him at higher risk for coronary aneurysms. Addition of prednisolone to the IVIG/ aspirin regimen in these high-risk patients gives them a significantly lower risk of developing coronary artery abnormalities, compared to children who received IVIG and aspirin alone.
References
- Kobayashi T, Saji T, Otani T, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. 2012;379( 9826): 1613– 1620.
- Ayusawa M, Sonobe T, Uemura S, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int. 2005;47( 2): 232– 234.
- Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006; 113( 22): 2606– 2612.
- Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr. 2011;158( 5): 831– 835.
- Etoom Y, Banihani R, Finkelstein Y. Critical review of: Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomized, open-label, blinded-endpoints trial. J Popul Ther Clin Pharmacol.
- Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, Atz AM, Li JS, Takahashi M, Baker AL, Colan SD, Mitchell PD, Klein GL, Sundel RP; Pediatric Heart Network Investigators. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med. 2007;356( 7): 663– 675.
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