Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose

doi:10.1016/S0022-3476(97)70038-6

The Journal of Pediatrics

Volume 131, Issue 6, December 1997, Pages 888-893

https://doi.org/10.1016/S0022-3476(97)70038-6 Get rights and content

Abstract

The efficacy of intravenous gamma globulin (IVGG) for treatment of Kawasaki disease (KD) is clearly established. In a metaanalysis, we reviewed U.S. and Japanese multicenter, randomized controlled studies regarding the effect of various doses of IVGG with aspirin administered within the first 7 to 10 days of illness on the prevalence of coronary artery abnormalities in KD. We studied 1629 patients with acute KD from the six reported studies that included blinded echocardiographic assessments. In 868 Japanese patients treated with moderate-dose aspirin (30 to 50 mg/kg per day), the prevalence of coronary abnormalities at the subacute stage (illness day 30) was 26.8% with aspirin alone, 18.1% with total IVGG dose < 1 gm/kg, 17.3% with total IVGG of 1.0 to 1.2 g/kg, and 5.3% with total IVGG of 2 gm/kg; the corresponding prevalence at the convalescent stage of illness (illness day 60) was 17.5%, 13.5%, 9.8%, and 3.5%, respectively. In 761 U.S. patients treated with high-dose aspirin (80 to 120 mg/kg per day), the prevalence of coronary abnormalities at the subacute stage (2 to 3 weeks after enrollment) was 23.0% with aspirin alone, 9.0% with total IVGG of 1.0 gm/kg, 8.6% with total IVGG of 1.6 gm/kg, and 4.6% with total IVGG of 2.0 gm/kg; corresponding prevalence at the convalescent stage (6 to 8 weeks after enrollment) was 17.7%, 9.0%, 6.3%, and 3.8%, respectively. When all data for the 1629 patients were combined, the prevalence at the subacute stage was 25.8% with aspirin alone, 18.1% with IVGG < 1 gm/kg, 15.7% with IVGG of 1 to 1.2 gm/kg, 8.6% with IVGG of 1.6 gm/kg, and 4.8% with IVGG of 2 gm/kg (adjusted R² = 0.966, p = 0.0017); corresponding prevalence at the convalescent stage was 17.6%, 13.5%, 9.7%, 6.3%, and 3.8%, respectively (adjusted R² = 0.993, p = 0.0602). The prevalence of coronary abnormalities was inversely related to the total dose of IVGG and was independent of the aspirin dose. We conclude that 2 gm/kg IVGG combined with at least 30 to 50 mg/kg per day aspirin provides maximum protection against development of coronary abnormalities after KD. (J Pediatr 1997;131:888-93)

Section snippets

Methods

We identified 15 published multicenter controlled studies of IVGG treatment of acute KD written in English or Japanese since 1984.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 Because the evaluation of echocardiograms can be somewhat subjective, ideally they should be interpreted by readers unaware of the patient's treatment assignment to avoid bias. We selected 7 of the 15 studies for analysis of the effect of IVGG and aspirin on prevalence of CAA because they were multicenter,

Moderate-dose aspirin plus IVGG

Data for 868 Japanese patients treated with moderate-dose aspirin (30 to 50 mg/kg per day) in five multicenter trials (in three reports) were available for analysis.10, 15, 16 The prevalence of CAA at the subacute stage was 26.8% with aspirin alone, 18.1% with total IVGG dose < 1 gm/kg, 17.3% with total IVGG of 1.0 to 1.2 gm/kg, and 5.3% with total IVGG dose of 2 gm/kg; corresponding figures at the convalescent stage were 17.5%, 13.5%, 9.8%, and 3.5% respectively. The prevalence of CAA after

Discussion

The first published (in Japanese) preliminary report of IVGG treatment of KD in February 1983 was a series of five patients treated with 400 mg/kg for 5 days in an uncontrolled trial by Furusho et al.²⁰ The first controlled study of the effect of IVGG on KD was described in Japanese by Kondo et al.²¹ in July 1983. These investigators studied 41 patients with KD treated by the eighth illness day, comparing 19 patients who received a single infusion of 100 mg/kg intact IVGG plus aspirin with 22

Acknowledgements

We thank Edwin Chen, PhD, for statistical advice.

References (27)

ST Shulman et al.
Kawasaki disease
Pediatr Clin North Am
(1995)
K Furusho et al.
High-dose intravenous gamma globulin for Kawasaki disease
Lancet
(1984)
M Nagashima et al.
High-dose gamma globulin therapy for Kawasaki disease
J Pediatr
(1987)
KS Barron et al.
Treatment of Kawasaki syndrome: a comparison of two dosage regimens of intravenously administered immune globulin
J Pediatr
(1990)
M Marasini et al.
Late intravenous gamma globulin treatment in infants and children with Kawasaki disease and coronary artery abnormalities
Am J Cardiol
(1991)
T Kawasaki
Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]
Arerugi
(1967)
M Matsushima et al.
A controlled study of gamma globulin treatment for Kawasaki disease [in Japanese]
J Jpn Pediatr Soc
(1986)
JW Newburger et al.
The treatment of Kawasaki syndrome with intravenous gamma globulin
N Engl J Med
(1986)
K Furusho et al.
Japanese gamma globulin trials for Kawasaki disease
H Ogino et al.
High-dose gamma globulin therapy for Kawasaki disease; trial of 200 mg/kg/day for 3 days [in Japanese]
J Jpn Pediatr Soc
(1987)

M Ogawa et al.

High-dose gamma globulin therapy for Kawasaki disease [in Japanese]

J Jpn Pediatr Soc

(1987)

Z Onouchi et al.

Multicenter randomized controlled study of intravenous immunoglobulin in Kawasaki disease [in Japanese]

J Jpn Pediatr Soc

(1988)

MA Engle et al.

Clinical trial of single-dose intravenous gamma globulin in acute Kawasaki disease

Am J Dis Child

(1989)

Cited by (306)

A bibliometric analysis of Kawasaki disease from 1974 to 2022
2024, Heliyon
To analyse the research history, development trends and current status of relevant literature in the field of Kawasaki disease, and to provide the basis for future directions in Kawasaki disease (KD) research.
Literature on Kawasaki disease published between January 1974 and December 2022 was searched for in the Web of Science database, and CiteSpace was used to perform visual analyses.
The search yielded a total of 6950 articles. The number of publications related to Kawasaki disease showed an increasing trend. A collaborative network analysis revealed that the United States, Japan and mainland China were the most influential countries in this field. The University of California system contributed the most publications and the journal with the most publications was Circulation. JW Newburger was an authoritative author in this field. “Coronary artery lesion”, “Intravenous immunoglobulin” (IVIG) and “Risk factor” were three prominent keywords. Keyword bursts changed from “TNF” and “IVIG”, which focused on aetiology and treatment, to “Long term management”, which emphasized the recovery period, and to “Kawasaki-like disease” and “Multisystem inflammatory syndrome” during the novel coronavirus pandemic. Trends of highly cited references indicated that landmark articles in different periods focused on Kawasaki disease guidelines, gene polymorphisms and multisystem inflammatory syndrome caused by the novel coronavirus.
The aetiology of Kawasaki disease remains unclear, but viral infection is likely to play an important role. The combination of evolving sequencing technologies, large-scale epidemiological investigations and prospective cohort studies is likely to be important in exploring Kawasaki disease and improving its prognosis in future.
Kawasaki disease in children with Bacillus Calmette-Guérin scar reactivity: Focus on coronary outcomes
2023, Journal of the Formosan Medical Association
/Purpose: Reactivity at the Bacillus Calmette-Guérin (BCG) scar is a pathognomonic feature of Kawasaki disease (KD). However, its value in predicting KD outcomes has not been emphasized. This study explored the clinical significance of BCG scar redness with respect to coronary artery outcomes.
This retrospective study collected data on children with KD from 13 hospitals in Taiwan during 2019–2021. Children with KD were categorized into four groups based on the KD type and BCG scar reactivity. Risk factors of coronary artery abnormalities (CAA) were analyzed in all groups.
BCG scar redness occurred in 49% of 388 children with KD. BCG scar redness was associated with younger age, early intravenous immunoglobulin (IVIG) treatment, hypoalbuminemia, and CAA at the first echocardiogram (p < 0.01). BCG scar redness (RR 0.56) and pyuria (RR 2.61) were independent predictors of any CAA within 1 month (p < 0.05). Moreover, pyuria (RR 5.85, p < 0.05) in children with complete KD plus BCG scar redness was associated with CAA at 2–3 months; first IVIG resistance (RR 15.2) and neutrophil levels ≥80% (RR 8.37) in children with complete KD plus BCG scar non-redness were associated with CAA at 2–3 months (p < 0.05). We failed to detect any significant risk factors of CAA at 2–3 months in children with incomplete KD.
BCG scar reactivity contributes to diverse clinical features in KD. It can be effectively applied to determine the risk factors of any CAA within 1 month and CAA at 2–3 months.
French national diagnostic and care protocol for Kawasaki disease
2023, Revue de Medecine Interne
Kawasaki disease (KD) is an acute vasculitis with a particular tropism for the coronary arteries. KD mainly affects male children between 6 months and 5 years of age. The diagnosis is clinical, based on the international American Heart Association criteria. It should be systematically considered in children with a fever, either of 5 days or more, or of 3 days if all other criteria are present. It is important to note that most children present with marked irritability and may have digestive signs. Although the biological inflammatory response is not specific, it is of great value for the diagnosis. Because of the difficulty of recognising incomplete or atypical forms of KD, and the need for urgent treatment, the child should be referred to a paediatric hospital as soon as the diagnosis is suspected. In the event of signs of heart failure (pallor, tachycardia, polypnea, sweating, hepatomegaly, unstable blood pressure), medical transfer to an intensive care unit (ICU) is essential. The standard treatment is an infusion of IVIG combined with aspirin (before 10 days of fever, and for a minimum of 6 weeks), which reduces the risk of coronary aneurysms. In case of coronary involvement, antiplatelet therapy can be maintained for life. In case of a giant aneurysm, anticoagulant treatment is added to the antiplatelet agent. The prognosis of KD is generally good and most children recover without sequelae. The prognosis in children with initial coronary involvement depends on the progression of the cardiac anomalies, which are monitored during careful specialised cardiological follow-up.
La maladie de Kawasaki (MK) est une vascularite aiguë ayant un tropisme particulier pour les artères coronaires. La MK touche préférentiellement les enfants âgés de 6 mois à 5 ans, avec une prédominance masculine. Le diagnostic est clinique, basé sur les critères internationaux de l’American Heart Association, et doit être posé systématiquement chez les enfants présentant une fièvre depuis 5 jours ou plus, ou depuis 3 jours si tous les critères sont présents. Il est important de noter que la plupart des enfants présentent une irritabilité marquée et parfois des signes digestifs. Une inflammation biologique marquée, bien que non spécifique, est d’une grande valeur pour le diagnostic. En raison des difficultés à reconnaître la MK dans les formes incomplètes ou atypiques, et de l’urgence du traitement, l’enfant doit être référé à un hôpital pédiatrique dès que le diagnostic est simplement suspecté. En cas de signes d’insuffisance cardiaque (pâleur, tachycardie, polypnée, sueurs, hépatomégalie, instabilité tensionnelle), un transfert en soins intensifs est indispensable. Le traitement de référence repose sur les IgIV associée à l’aspirine, (avant 10 jours de fièvre, et pour une durée minimale de 6 semaines), ce qui réduit le risque d’anévrisme coronarien. En cas d’atteinte coronarienne, les antiagrégants peuvent être maintenus à vie. En cas d’anévrisme géant, les anticoagulants sont ajoutés aux antiagrégants. Le pronostic de la MK est généralement bon, la majorité des enfants se rétablissant sans séquelles. En cas d’atteinte coronarienne initiale, le pronostic dépend de l’évolution de l’atteinte cardiaque telle qu’elle est définie au cours d’un suivi cardiologique rapproché.
Cost-effectiveness analysis of infliximab for the treatment of Kawasaki disease refractory to the initial treatment: A retrospective cohort study
2022, Journal of Cardiology
Citation Excerpt :
However, CAA can be prevented by suppressing inflammation early in acute phase treatment. Initiation of intravenous immunoglobulin (IVIG) (2 g/kg) within 10 days of fever onset has been confirmed to reduce the risk of CAA by approximately 20% (from 25% to <5%) [4–8]. High-dose IVIG (2 g/kg) or combination with steroid therapy as 1st line treatment has reduced rates of cardiac sequelae in Japan [9].
Infliximab (IFX) treatment is approved in Japan for health insurance coverage in patients with Kawasaki disease (KD). This study aimed to compare the cost-effectiveness of IFX and other therapeutic strategies for KD refractory to initial treatment, including intravenous immunoglobulin (IVIG), steroids, immunosuppressants, and plasma exchange therapy.
This multicenter, retrospective cohort study utilized data from the public medical insurance system of Japan. The target population included those who received treatment for KD between April 2012 and March 2019. Eligibility criteria were as follows: 1) initial onset of KD, 2) age < 15 years at onset, and 3) administration of 3rd line treatment if the 1st line treatment was IVIG alone or 2nd line treatment if the 1st line treatment was a combination of IVIG and steroids, in accordance with Japanese guidelines (2012). Those with KD-related cardiovascular complications before admission and those with congenital cardiac disease were excluded. The primary outcome was cost-effectiveness, which was calculated based on the number of admission events per annum divided by medical expenses per annum (times/10,000 US dollars). The Wilcoxon test was applied to analyze the difference in cost-effectiveness between patients who had received IFX and those who had not.
Among 1267 patients with KD, 25 received IFX treatment, while 206 received another treatment after the disease was designated refractory to initial treatment. The frequency of steroid use during initial IVIG treatment (a predictor of severity) was higher in the non-IFX group than in the IFX group (70.4% vs. 32.0%, p < 0.001) but became comparable after propensity-score matching. Our analysis indicated that IFX was more cost-effective than other treatments [1.04 (0.86, 1.34) vs. 1.38 (1.03, 1.79) (times/10,000 US dollars), p = 0.006].
IFX treatment may be more cost-effective than non-IFX treatment for patients with KD that is refractory to initial treatment.
Autoimmune Encephalitis: Distinguishing Features and Specific Therapies
2022, Critical Care Clinics
Treatment and Coronary Artery Aneurysm Formation in Kawasaki Disease: A Per-Day Risk Analysis
2022, Journal of Pediatrics
To assess whether ‘treatment day’ is a significant predicting factor in Kawasaki disease and imposes a risk for coronary artery aneurysms (CAAs) in a per-day analysis. CAA formation can be reduced from 25% to 10% when treated with intravenous immunoglobulin (IVIG).
Patient data from (n = 1016) a single center were collected for an observational cohort study. After exclusions, we retrospectively analyzed 776 patients in total. A multivariate analysis was performed with treatment day as a continuous variable (n = 691). Patients were categorized as no enlargement, small CAA, medium CAA, and giant CAA.
Late treatment per-day was a significant predicting factor for the development of larger CAAs. ORs for medium and giant CAAs per delayed day were 1.1 (95% CI 1.1-1.2) P < .05 and 1.2 (95% CI 1.1-1.2) P < .05, respectively.
We showed that every day of delay in treatment of patients with Kawasaki disease inherently carries a risk of medium and giant aneurysm formation. There was no cut-off point for treatment day that could mark a safe zone.

View all citing articles on Scopus

^☆: From the Department of Pediatrics, Northwestern University Medical School, Children's Memorial Hospital, Chicago, Illinois, and the Department of Pediatrics, School of Medicine, Chiba University, Chiba, Japan.

^☆☆: Reprints not available from author.

^★: 0022-3476/97/$5.00 + 0 9/21/81360

View full text

Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose☆,☆☆,★

Abstract

Section snippets

Methods

Moderate-dose aspirin plus IVGG

Discussion

Acknowledgements

Pediatr Clin North Am

Lancet

J Pediatr

J Pediatr

Am J Cardiol

Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]

Arerugi

A controlled study of gamma globulin treatment for Kawasaki disease [in Japanese]

J Jpn Pediatr Soc

The treatment of Kawasaki syndrome with intravenous gamma globulin

N Engl J Med

Japanese gamma globulin trials for Kawasaki disease

High-dose gamma globulin therapy for Kawasaki disease; trial of 200 mg/kg/day for 3 days [in Japanese]

J Jpn Pediatr Soc

High-dose gamma globulin therapy for Kawasaki disease [in Japanese]

J Jpn Pediatr Soc

Multicenter randomized controlled study of intravenous immunoglobulin in Kawasaki disease [in Japanese]

J Jpn Pediatr Soc

Clinical trial of single-dose intravenous gamma globulin in acute Kawasaki disease

Am J Dis Child