EClinicalMedicine · 2026
Predictive value for intravenous immunoglobulin resistance of Kobayashi and Kawanet scores in 722 children with Kawasaki disease across diverse ethnic backgrounds (KIWI study): an international cohort study.
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Mastrolia Maria Vincenza, Pandiarajan Vignesh, Cattalini Marco, Taddio Andrea, Vergnano Stefania, Anton Jordi, Sontichai Watchareewan, Sozeri Betul, Ozen Seza, Rosina Silvia, Sánchez-Manubens Judith, Haviv Ruby, Pal Priyankar, Fonseca Adriana Rodrigues, Gagro Alenka, Bagri Narendra Kumar, Verdoni Lucio, Montin Davide, Maggio Maria Cristina, Thangaraj Abarna, Pilania Rakesh, Mosquera Manuel, Calzada Joan, Sittiwangkul Rekwan, Ulu Kadir, Balik Zeynep, Bilginer Yelda, Garrone Marco, Patrone Elisa, Barbi Elisa, Ciacci Giulia, Barucci Andrea, Ruperto Nicolino, Simonini Gabriele
Аннотация
BACKGROUND: Intravenous immunoglobulin (IVIg) resistance affects 15-25% of children with Kawasaki disease (KD) and increases the risk of coronary artery abnormalities (CAA). The Kobayashi score has shown good predictive value in Japanese cohorts but limited accuracy in non-Asian populations. The Kawanet model was proposed as an alternative with improved applicability in non-Asian settings.
METHODS: A retrospective-prospective, observational, multicentre cohort study including children fulfilling the American Heart Association criteria for KD was conducted. The availability of all clinical and laboratory variables required to calculate both the Kobayashi and Kawanet IVIg-resistance scores was mandatory for inclusion (sodium, neutrophil percentage, AST, platelet count, CRP, age, illness days at first IVIg administration, ALT, hepatomegaly, lymphocyte count, time to treatment). All included patients were aged <18 years at the time of KD diagnosis. Prospectively enrolled patients (April 2022-January 2024) were combined with retrospective cases after Jan 1, 2015, from 19 paediatric rheumatology units in Europe (Italy, United Kingdom, Türkiye, Spain Croatia), South America (Brazil), and Asia (India, Thailand, Israel). The primary outcome was to assess the performance of Kobayashi and Kawanet scores and to identify predictors of IVIg resistance during the acute phase of KD in this multiethnic population. IVIg resistance was defined as persistent or recrudescent fever ≥48 h after infusion. This work is registered with ClinicalTrials.gov, NCT06305611.
FINDINGS: Among 722 patients (median age 2.4 years; 38.1% female), ethnicity was 59.4% Caucasian, 20.5% Indian, 14.3% other Asian, and 5.8% mixed. IVIg resistance occurred in 19.7% (n = 142), highest in mixed-ethnicity patients (33.3%), followed by Caucasian (21.2%), Indian (18.9%), and other Asian (9.7%). Independent predictors of IVIg resistance were prolonged fever (per day increase) (OR 1.09, 95% CI 1.06-1.13), cardiac involvement (OR 2.25, 95% CI 1.51-3.34), musculoskeletal involvement (OR 1.89, 95% CI 1.10-3.25), and macrophage activation syndrome (OR 4.14, 95% CI 1.13-15.13) while a complete KD phenotype resulted as a protective factor (OR 0.43, 95% CI 0.27-0.67). The Kobayashi score showed 71% sensitivity and 39% specificity (balanced accuracy 55%), whereas the Kawanet score showed 16% sensitivity and 90% specificity (balanced accuracy 53%), with no major ethnic differences.
INTERPRETATION: IVIg resistance was linked to ethnicity and phenotype. Both scores performed poorly, highlighting the need for inclusive, biomarker-based, adaptive models to guide early treatment intensification. Future research in larger, more ethnically balanced cohorts, with dedicated assessment of structural and sociodemographic determinants are required.
FUNDING: The 2020 Pediatric Rheumatology European Society/Paediatric Rheumatology International Trials Organisation grant.
METHODS: A retrospective-prospective, observational, multicentre cohort study including children fulfilling the American Heart Association criteria for KD was conducted. The availability of all clinical and laboratory variables required to calculate both the Kobayashi and Kawanet IVIg-resistance scores was mandatory for inclusion (sodium, neutrophil percentage, AST, platelet count, CRP, age, illness days at first IVIg administration, ALT, hepatomegaly, lymphocyte count, time to treatment). All included patients were aged <18 years at the time of KD diagnosis. Prospectively enrolled patients (April 2022-January 2024) were combined with retrospective cases after Jan 1, 2015, from 19 paediatric rheumatology units in Europe (Italy, United Kingdom, Türkiye, Spain Croatia), South America (Brazil), and Asia (India, Thailand, Israel). The primary outcome was to assess the performance of Kobayashi and Kawanet scores and to identify predictors of IVIg resistance during the acute phase of KD in this multiethnic population. IVIg resistance was defined as persistent or recrudescent fever ≥48 h after infusion. This work is registered with ClinicalTrials.gov, NCT06305611.
FINDINGS: Among 722 patients (median age 2.4 years; 38.1% female), ethnicity was 59.4% Caucasian, 20.5% Indian, 14.3% other Asian, and 5.8% mixed. IVIg resistance occurred in 19.7% (n = 142), highest in mixed-ethnicity patients (33.3%), followed by Caucasian (21.2%), Indian (18.9%), and other Asian (9.7%). Independent predictors of IVIg resistance were prolonged fever (per day increase) (OR 1.09, 95% CI 1.06-1.13), cardiac involvement (OR 2.25, 95% CI 1.51-3.34), musculoskeletal involvement (OR 1.89, 95% CI 1.10-3.25), and macrophage activation syndrome (OR 4.14, 95% CI 1.13-15.13) while a complete KD phenotype resulted as a protective factor (OR 0.43, 95% CI 0.27-0.67). The Kobayashi score showed 71% sensitivity and 39% specificity (balanced accuracy 55%), whereas the Kawanet score showed 16% sensitivity and 90% specificity (balanced accuracy 53%), with no major ethnic differences.
INTERPRETATION: IVIg resistance was linked to ethnicity and phenotype. Both scores performed poorly, highlighting the need for inclusive, biomarker-based, adaptive models to guide early treatment intensification. Future research in larger, more ethnically balanced cohorts, with dedicated assessment of structural and sociodemographic determinants are required.
FUNDING: The 2020 Pediatric Rheumatology European Society/Paediatric Rheumatology International Trials Organisation grant.