Pharmacologic interventions for Kawasaki disease in children: A network meta-analysis of 56 randomized controlled trials
Wei-Te Lei,
Ling-Sai Chang,
Bing-Yan Zeng,
Yu-Kang Tu,
Ritei Uehara,
Yutaka J. Matsuoka,
Kuan-Pin Su,
Pi-Chang Lee,
Joao L. Cavalcante,
Brendon Stubbs,
Pao-Yen Lin,
Yi-Cheng Wu,
Chih-Wei Hsu,
Tien-Yu Chen,
Yen-Wen Chen,
Pin-Yang Yeh,
Cheuk-Kwan Sun,
Ping-Tao Tseng,
Yu-Hsuan Kao
Affiliations
Wei-Te Lei
Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Ling-Sai Chang
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
Bing-Yan Zeng
Department of Internal Medicine, E-DA Dachang Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
Yu-Kang Tu
Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
Ritei Uehara
Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Yutaka J. Matsuoka
Former Division Chief of Health Care Research, Center for Public Health Sciences, National Cancer Center Japan, Tokyo, Japan; Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
Kuan-Pin Su
Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan
Pi-Chang Lee
Section of Cardiology, Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
Joao L. Cavalcante
Minneapolis Heart Institute - Abbott Northwestern Hospital, Minneapolis, MN, United States; Valve Science Center - Minneapolis Heart Institute Foundation, Minneapolis, MN, United States
Brendon Stubbs
Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK; Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, UK; Positive Ageing Research Institute, Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK
Pao-Yen Lin
Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
Yi-Cheng Wu
Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan
Chih-Wei Hsu
Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
Tien-Yu Chen
Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
Yen-Wen Chen
Prospect Clinic for Otorhinolaryngology and Neurology, Number 252, Nanzixin Road, Nanzi District, Kaohsiung 811, Taiwan
Pin-Yang Yeh
Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
Cheuk-Kwan Sun
Department of Emergency Medicine, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan
Ping-Tao Tseng
Prospect Clinic for Otorhinolaryngology and Neurology, Number 252, Nanzixin Road, Nanzi District, Kaohsiung 811, Taiwan; Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Corresponding author at: Prospect Clinic for Otorhinolaryngology and Neurology, Number 252, Nanzixin Road, Nanzi District, Kaohsiung 811, Taiwan.
Yu-Hsuan Kao
Section of Immunology, Rheumatology, and Allergy, Department of Pediatrics, Mackay Memorial Hospital, Number 92, Section 2, Zhong-shan N. Rd, Taipei 10449, Taiwan; Corresponding author.
Summary: Background: Although the current consensus recommends a standard treatment of high-dose intravenous immunoglobulin with high-dose aspirin to manage Kawasaki disease (KD), the use of different adjunctive therapies remains controversial. The aim of the current network meta-analysis (NMA) was to compare the efficacy and tolerability of different existing interventions for the initial and refractory stages of KD. Methods: An NMA of randomised controlled trials (RCTs) was conducted using the frequentist model applied after electronic searches in PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, and Web of Science. The main outcomes were reduced fever duration/diminished severity of fever subsided. The initial stage of KD was defined as the first stage to treat patients with KD; the refractory stage of KD represents KD patients who failed to respond to standard KD treatment. The cut-off points for intravenous immunoglobulin (IVIG) were low (100–400 mg), medium (1 g), and high (at least 2 g). Findings: A total of fifty-six RCTs with 6486 participants were included. NMA demonstrated that the medium-dosage IVIG + aspirin + infliximab [mean difference=−1.76 days (95% confidence intervals (95% CIs): −3.65 to 0.13 days) compared to high-dosage IVIG + aspirin] exhibited the shortest fever duration; likewise, the medium-dosage IVIG + aspirin + infliximab [odds ratio (OR)=0.50, 95% CIs: 0.18–1.37 compared to high-dosage IVIG + aspirin] exhibited the smallest incidence of coronary artery lesion (CAL) in the initial-stage KD. In the refractory-stage KD, the high-dosage IVIG + pulse steroid therapy (OR=0.04, 95% CIs: 0.00–0.43 compared to the high-dosage IVIG only) had the best rate of decline of fever; likewise, the high-dosage IVIG + ciclosporin [OR=0.05 (95% CIs: 0.00–1.21) compared to the high-dosage IVIG only] exhibited the smallest incidence of CAL. Infliximab significantly improved resolution compared to the high-dosage IVIG only group (OR=0.20, 95%CIs: 0.07–0.62) in refractory-stage KD. Interpretation: The NMA demonstrated that the combination therapy with the standard therapy of IVIG and aspirin might have an additional effect on shortening the duration of fever and lowering the CAL incidence rate in patients with acute KD. Moreover, the combination therapy with high-dose IVIG and pulse steroid therapy or cyclosporine therapy might have an additional effect on improving the rate of decline of fever and lowering the incidence rate of CAL in children with refractory KD. Because some of the findings of this NMA should be considered hypothesis-generating rather than confirmatory, further evidence from de novo randomised trials is needed to support our results. Funding: None.
