Kawasaki Disease in Children
1. Dr. Osmonova Gulnaz Zhenishbaevna
2. Tamboliya Shyam Kanjibhai
3. Salman Ali
(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
2. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
3. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
Abstract
Kawasaki disease (KD) has become the most common cause of acquired heart disease in children and can lead to severe, potentially fatal cardiovascular complications, with coronary artery aneurysms carrying the most serious consequences. Extensive research has been conducted on various aspects of KD. This article briefly reviews representative studies and current limitations in the fields of epidemiology, etiology, pathological basis, diagnosis, treatment, and prognosis of KD, aiming to expand knowledge and better guide clinical practice and basic research.
Etiology
The etiology of KD is still unknown. Most researchers believe it results from the interaction of genetic susceptibility and environmental factors.
2.1 Genetic factors
Epidemiological data showing different susceptibilities across ethnic groups suggest a genetic role in KD pathogenesis. Accordingly, genome-wide and candidate-gene studies have been conducted worldwide. Onouchi et al. performed the first genome-wide linkage analysis of KD in 2007, studying 78 Japanese families and identifying the strongest association on chromosome 12q24. A study of 392 Chinese Han patients showed that ADAM17 variants are closely associated with KD susceptibility and coronary artery aneurysm formation. Subsequent studies have identified many genes linked to KD susceptibility in specific populations, such as BLK (associated in Japanese, Taiwanese, Korean, and some European populations) and ITPKC (first linked to aneurysm risk in Japanese and American children). In Japanese populations, ITPKC rs28493229 and Caspase 3 rs113420705 are associated with intravenous immunoglobulin (IVIG) resistance and coronary aneurysms, but these associations do not hold in Taiwanese populations. Genes in the transforming growth factor-β (TGF-β) pathway (TGF-β2, TGF-βR2, SMAD3), which participates in inflammation and T-cell activation, have also been linked to aneurysm formation. MicroRNAs such as miRNA-200c and miRNA-371-5p have likewise been investigated. Although these genes are associated with KD, studies are limited to specific populations and lack universality. Multi-ethnic cross-validation studies are needed to clarify the genetic characteristics of KD.
2.2 Viruses
The seasonal clustering, regional outbreaks, and lack of response to antibiotics in KD have led researchers to suspect viral involvement. Fukuda et al. reported KD in monozygotic twins following adenovirus infection. Rowley et al. identified an unnamed RNA virus capable of inducing KD and damaging coronary arteries in some children; this virus shares structural domains with hepatitis C virus. In recent years, respiratory viruses have been detected by PCR in more than half of KD patients, but no single virus has been consistently identified across cases.
2.3 Bacteria
Superantigens such as toxic shock syndrome toxin-1 (TSST-1) from Staphylococcus aureus, streptococcal pyrogenic exotoxin C (SPEC), and Yersinia pseudotuberculosis-derived mitogen (TPM) have been implicated in some KD cases, producing similar symptoms (fever, rash, elevated inflammatory cytokines). TSST-1 can activate vascular endothelial cells; given KD’s selective arterial involvement, the role of endothelial cells as superantigen-presenting cells merits further study. In basic research, Lactobacillus casei cell-wall extract is widely used to establish animal models of KD coronary arteritis.
2.4 Fungi
Fungal research is relatively limited, but water-soluble extracts of Candida albicans have been used to create coronary arteritis models showing granulomatous and proliferative inflammation, intimal thickening, and elastic lamina destruction—histological features similar to human KD. Manlhiot et al. found that seasonal winds carrying fungal particles were strongly associated with local KD incidence. Whether fungi act as pathogens requires more experimental evidence.
Pathological Basis
The vasculitis process in KD progresses through several stages. It begins with acute vasculitis originating in the vessel lumen, characterized by neutrophilic infiltration without full-thickness involvement. This is followed by subacute/chronic vasculitis marked by lymphocytic and macrophage infiltration. Activated cells release inflammatory cytokines and proteases (e.g., elastase, matrix metalloproteinases), causing collagen degradation and elastic lamina disruption, which leads to aneurysm formation. Concurrently, myofibroblast proliferation occurs; fibroblasts from the adventitia and smooth-muscle cells from the media undergo phenotypic transformation, proliferate, form thrombi and granulation tissue, and cause partial or complete coronary occlusion, resulting in myocardial infarction.
The precise mechanism of coronary aneurysm formation remains unclear. Current research focuses on oxidative stress and endoplasmic reticulum stress in vascular endothelium, macrophage- and neutrophil-mediated inflammation, and myofibroblast-like cells in the media. These cells secrete structurally abnormal collagen, recruit inflammatory cells, and release IL-17 and matrix metalloproteinases, further damaging arterial walls and promoting aneurysms. Pathological studies of KD remain a research hotspot, with investigators exploring multiple mechanisms to identify key pathogenic pathways.
Diagnosis
Current KD diagnosis relies on clinical criteria: fever, bilateral non-exudative conjunctival injection, oral mucosal changes (red/cracked lips, strawberry tongue), polymorphous rash, cervical lymphadenopathy, and extremity changes (edema, erythema, desquamation). However, many children present with incomplete or atypical features—sometimes only one or two criteria—making diagnosis challenging and increasing the risk of missed cases. In addition, numerous conditions (measles, adenovirus infection, scarlet fever, etc.) mimic KD’s rash and fever. When KD coexists with infection, diagnosis becomes even more difficult. Sensitive and specific laboratory markers are urgently needed to assist diagnosis.
Traditional inflammation markers
White blood cell count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) rise markedly in the acute phase and serve as important diagnostic references. Platelet indices (absolute count, mean platelet volume, platelet distribution width) help predict aneurysm risk. A Japanese retrospective study showed that platelet counts >450 × 10⁹/L within 3–4 days of onset increase aneurysm risk, while a rapid drop to <150 × 10⁹/L by days 6–7 in IVIG non-responders also predicts higher risk. Limitations exist: ESR loses value after IVIG administration and cannot monitor treatment response. These markers also lack specificity, as they rise in many infectious diseases.
Other indicators
Immunological markers (CD8⁺ T cells, Th1/Th2 cells) and cytokines (TGF-β, TNF-α, VEGF, IL-6) fluctuate during different KD phases and correlate with coronary lesions. Cardiovascular markers such as NT-proBNP show diagnostic utility: levels of 96–260 pg/mL yield 66 %–98 % sensitivity for KD recognition, while 515–1300 pg/mL offer 73 %–95 % sensitivity and 61 %–85 % specificity for aneurysms and predict IVIG non-response. However, these findings are based on small cohorts and require validation in larger studies.
IVIG non-responders
Most patients defervesce after a single high-dose IVIG infusion, but 10 %–20 % remain febrile or relapse within 36 hours and are classified as IVIG non-responders; they face a markedly higher risk of coronary abnormalities. Predictive scoring systems include EGAMI, HARADA, KOBAYASHI, and FORMOSA scores. A Turkish study identified high white blood cell count and low hematocrit as risk factors for coronary artery involvement, while elevated γ-glutamyl transferase was an independent predictor of IVIG resistance. These scoring systems are limited by geographic and ethnic specificity and require further refinement.
Treatment and Prognosis
KD management follows established guidelines; adherence yields favorable outcomes. In a survey of 1 487 patients, aneurysm incidence was 4.9 % with guideline-concordant treatment versus 9.9 % with non-standard care. The natural history of KD vascular lesions remains unclear: some regress completely, while others develop fibrosis or obstruction. Even apparently normal vessels may harbor irreversible damage that predisposes to later myocardial infarction. A Japanese retrospective study found that adults with a history of KD develop acute coronary syndrome at lower risk scores and younger ages than the general population. This underscores the need for cautious acute management and lifelong follow-up.
Children are the hope of the nation and society. Coronary damage from KD persists into adulthood and elevates long-term cardiovascular risk. Advances in science have produced many new insights into KD etiology, diagnosis, and treatment, deepening our understanding. Nevertheless, many unanswered questions remain, and continued exploration is essential.
References
1. Robert A. Good - Known as one of the "fathers of modern immunology"; performed the first successful bone marrow transplant for immunodeficiency.
2. Max D. Cooper - Discovered B and T lymphocytes; major contributor to understanding immune system disorders.
3.H. Buckley - Pioneer in treating Severe Combined Immunodeficiency (SCID) in children.
4. Luigi D. Notarangelo - Leading expert in primary immunodeficiency and genetic immune disorders.
5. Jean-Laurent Casanova - Known for research on genetic causes of childhood infectious diseases.
6. Alain Fischer - Key figure in gene therapy for pediatric immunodeficiency.
7. Charlotte Cunningham-Rundles - Expert in primary immune deficiency diseases.
8. Hans D. Ochs - Known for research on Wiskott-Aldrich syndrome and pediatric immune disorders