Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome, is an acute self-limited vasculitis that primarily affects medium-sized arteries, especially the coronary arteries. It is the leading cause of acquired heart disease in children in developed countries and can be potentially fatal, leading to myocardial infarction and sudden death.
Epidemiologically, it peaks around 1 year of age and is more common in infants and children under 4 years, with a slight male predominance. The incidence is highest in Asian populations, particularly in Japan and South Korea. An epidemiological survey in Shanghai showed that the incidence of Kawasaki disease in children under 5 years increased from 30.3 per 100,000 in 2008 to 107.3 per 100,000 in 20167).
In untreated cases, 15–25% develop coronary artery aneurysms (CAA), but early IVIG treatment can reduce this to less than 5% 1). About 9% of patients experience acute cardiac complications, and approximately 3% have permanent cardiac sequelae.
Ocular symptoms are one of the major initial manifestations of Kawasaki disease, and ophthalmologists often have the first opportunity to examine patients. Accurately identifying ocular findings and making an early diagnosis is extremely important for timely life-saving intervention.
Neonatal Kawasaki disease (NKD) is extremely rare but has been reported; in a Japanese nationwide survey (2001–2012), 23 out of 130,323 cases (0.02%) were neonates 2). Neonatal cases are often incomplete (68.4%) and have a high frequency of coronary artery lesions (89.5%), requiring more careful follow-up 2).
Ocular symptoms appear during the acute phase of Kawasaki disease and are usually bilateral and limited to the anterior segment of the eye.
Ocular findings are observed in 80% of cases and serve as clues for early diagnosis.
Anterior Segment Findings
Bilateral bulbar conjunctival congestion: The most representative finding. No exudate. Often appears on the 3rd to 7th day after onset.
Limbic sparing: A characteristic pattern where congestion is less around the limbus. Considered characteristic of Kawasaki disease.
Anterior uveitis: Iridocyclitis. Peaks on days 5–8 of illness. Common in children aged 2 years and older1).
Punctate keratitis: Punctate lesions on the corneal epithelium.
Posterior segment and other
Vitreous opacity: Rare but reported. Important as evidence of posterior segment involvement.
Optic disc edema-like findings: May occur in older children. Sometimes accompanied by retinal vascular dilation and tortuosity.
Retinitis and retinal detachment: Extremely rare (only 7 documented cases). Reported in severe, atypical cases and adults.
Chronic complications: Ocular surface diseases such as dry eye (keratoconjunctivitis sicca) and blepharitis.
There are important distinguishing points. Conjunctival injection in Kawasaki disease is not accompanied by exudate (discharge), whereas adenovirus causes conjunctival exudate. Additionally, toxic shock syndrome (TSS) and scarlet fever do not have the ocular and joint involvement seen in Kawasaki disease. If purulent conjunctivitis or exudative pharyngitis is present, consider a diagnosis other than Kawasaki disease.
The etiology of Kawasaki disease remains unknown, but it is thought that individuals with genetic predisposition develop the disease upon exposure to environmental triggers (infectious agents, possibly wind- or water-borne factors). Infectious agents may overactivate the innate immune system, leading to endothelial damage in medium-sized arteries.
The following factors are known to increase the risk of coronary artery aneurysms.
In Japan, as in Shanghai, the incidence of Kawasaki disease is increasing. It is particularly high in children under 5 years old, with a male-to-female ratio of approximately 1.7:17).
Genetic factors are also involved; the risk of developing the disease in affected siblings is 10 times higher than in the general population, and the risk in children of parents with a history of Kawasaki disease is 2 times higher4).
There is no single definitive diagnostic test for Kawasaki disease; it is a clinical diagnosis.
In Japan, Kawasaki disease is diagnosed when 5 of the following 6 main symptoms are present.
| Main Symptoms | Details |
|---|---|
| Fever | Fever of unknown cause lasting 5 days or more |
| Conjunctival injection | Bilateral bulbar conjunctival injection (no discharge) |
| Mucous membrane changes | Red lips, strawberry tongue, oropharyngeal mucosal erythema |
| Rash | Polymorphous rash |
| Changes in extremities | Acute phase: hard edema of hands and feet, erythema of fingertips. Convalescent phase: membranous desquamation from fingertips |
| Lymphadenopathy | Non-suppurative cervical lymphadenopathy in the acute phase |
Even if only 4 criteria are met, Kawasaki disease is diagnosed if coronary artery aneurysm is confirmed on cardiac imaging and other diseases are ruled out. Incomplete Kawasaki disease (IKD) is reported to account for more than 20% of all Kawasaki disease cases 2).
In atypical cases where diagnosis is difficult or cases unresponsive to antibiotics, Kawasaki disease should be actively suspected. Cases presenting with deep neck infection-like symptoms (retropharyngeal abscess-like) have been reported to be diagnosed as Kawasaki disease, and it should be considered in the differential diagnosis of febrile lymphadenopathy unresponsive to antibiotics1).
Adenovirus infection, enterovirus infection, measles, mononucleosis, scarlet fever, rheumatic fever, toxic shock syndrome (TSS), Stevens-Johnson syndrome, juvenile rheumatoid arthritis, sepsis, etc.
The goal of treatment for Kawasaki disease is to suppress inflammation in the acute phase and prevent coronary artery complications. The following are administered to all patients with a confirmed diagnosis.
For IVIG non-responders (persistent fever 48 hours after the second IVIG dose), the following treatments are considered.
For long-term ocular complications (dry keratoconjunctivitis, blepharitis), symptomatic treatment is given according to symptoms.
When a child with a genetic predisposition is exposed to environmental stimuli (infectious agents), the innate immune system becomes overactivated.
In the acute phase, activated T cells and macrophages release a large amount of various cytokines (such as IL-1β, IL-6, IL-8, TNF-α, and IFN-γ), leading to a state of hypercytokinemia (cytokine storm-like). These cytokines cause the following vascular endothelial changes.
As a result, inflammatory cells and mediators infiltrate the tunica media of medium-sized arteries (especially coronary arteries), leading to arteritis and aneurysm formation. Within the aneurysm, stenosis and thrombus formation occur, posing risks of myocardial infarction, rupture, and ischemic arrhythmias.
Inflammation in the eye is understood as a local manifestation of systemic vasculitis. Inflammatory cell infiltration into the small vessels of the bulbar conjunctiva causes conjunctival hyperemia, and extension of inflammation to the iris and ciliary body leads to anterior uveitis.
Histopathologically, granulomatous inflammation with neutrophil infiltration and destruction of the arterial media are observed; in the later stage, infiltration of lymphocytes, monocytes, and fibroblasts occurs, leading to arterial remodeling.
Regarding peripheral vascular lesions in Kawasaki disease, abnormalities in capillary morphology (dilation of arteriovenous diameter, increased intercapillary distance, decreased number of loops, and marked reduction in capillary blood flow velocity during the afebrile period) have been reported, which may be risk factors for peripheral vascular thrombosis 5).
Infliximab (anti-TNF-α antibody) has been reported to be effective for IVIG-resistant refractory Kawasaki disease. Its use has also been reported in neonatal cases, and it is attracting attention as an option for refractory cases 3).
In cases of Kawasaki disease complicated by peripheral artery thrombosis (25 reported cases), combinations of anticoagulation therapy (heparin, warfarin), thrombolytic therapy, and vasodilators (prostaglandins) have been attempted, suggesting that early intervention may improve prognosis 5). Hyperbaric oxygen therapy is also being considered as an adjunctive option, but it has not been used in the 25 reported cases of Kawasaki disease complicated by peripheral artery thrombosis, and further accumulation of knowledge is needed.
The optimal timing of IVIG administration is still under debate. The 2022 Chinese expert consensus recommends prompt administration after KD diagnosis, and early administration has been reported to be effective in preventing coronary artery lesions 7). Some reports indicate that differences in dose and method (2 g/kg/day single dose vs. 1 g/kg/day for 2 consecutive days) do not have a statistically significant impact on prognosis 7).
