Kawasaki disease

Key Points at a Glance

Key Points at a Glance

• Kawasaki disease is a medium-vessel vasculitis primarily affecting children, first reported by Tomisaku Kawasaki in 1967.
• It is the most common cause of acquired heart disease in children in developed countries (risk of coronary artery aneurysms and myocardial infarction).
• Ocular abnormalities occur in over 90% of patients, with conjunctivitis (90%) and anterior uveitis (up to 70%) being particularly common.
• Ocular symptoms are often self-limiting and resolve within days to 8 weeks.
• The incidence is highest in Japan (approximately 265 per 100,000 children under 5 years), with a male predominance.
• Intravenous immunoglobulin (IVIG) therapy within 10 days of onset reduces the risk of coronary artery lesions.
• Incomplete Kawasaki disease meets only some diagnostic criteria and carries a high risk of coronary complications.

1. What is Kawasaki Disease?

Kawasaki disease (KD) is a medium-vessel vasculitis primarily occurring in childhood, typically affecting muscular arteries, with a predilection for the coronary arteries. It rarely occurs in adults.

First reported in 1967 by Japanese pediatrician Tomisaku Kawasaki, it has since been recognized as a major cause of acquired heart disease in children worldwide. The International Classification of Diseases (ICD-10) code is M30.3.

Epidemiology

Incidence varies significantly by region.

Region	Incidence per 100,000 children under 5 years
Japan	Approximately 265 people
South Korea	134 people
Taiwan	83 people
United States	Approximately 18 people

Boys are more likely to be affected than girls, and most cases occur between 6 months and 5 years of age. Incidence tends to be higher in winter.

Q What causes Kawasaki disease?

A

The cause remains unknown. A leading theory is that exposure to a pathogen (possibly a virus) triggers an inflammatory cascade, leading to immune system dysregulation in genetically susceptible children. Evidence includes differences in incidence among ethnic groups, higher rates in children with a family history, and genetic predisposition identified by genome-wide association studies.

2. Main symptoms and clinical findings

Subjective symptoms

Kawasaki disease begins with systemic symptoms, mainly fever, and is accompanied by eye symptoms.

• Fever: High fever persisting for 5 days or more (central to diagnostic criteria)
• Ocular symptoms: Conjunctival injection, eye pain (generally mild)
• Mucous membrane symptoms: Redness and cracking of lips, “strawberry tongue”
• Skin rash: Widespread polymorphous rash
• Extremity changes: Erythema and swelling of hands and feet, membranous desquamation
• Prodromal symptoms: Diarrhea, vomiting, abdominal pain, cough, rhinorrhea 7–10 days before fever onset

Clinical Findings

Kawasaki disease is a clinical diagnosis, made when fever persists for 5 days or more and at least 4 of the following major criteria are present:

1. Bilateral, bulbar, non-exudative conjunctivitis (with limbal sparing)
2. Mucous membrane changes (redness and cracking of lips, strawberry tongue)
3. Polymorphous rash
4. Extremity changes (erythema, swelling, membranous desquamation)
5. Cervical lymphadenopathy

Details of ocular symptoms (present in >90% of patients)

Conjunctivitis

Frequency: Most common (approximately 90%)

Characteristics: Bilateral, bulbar conjunctival, non-exudative. Characterized by limbal sparing.

Timing: Appears within a few days after fever onset. Directly correlates with the presence of rash.

Pathology: Neutrophilic rosette formation (observed in conjunctival scrapings).

Anterior Uveitis

Frequency: Up to 70%

Characteristics: Bilateral, Grade 1+ or 2+. Sometimes accompanied by keratic precipitates.

Timing: Occurs within one week after fever onset.

Note: Its presence in the early acute phase helps confirm the diagnosis of incomplete Kawasaki disease. At least one study has shown a significant correlation with coronary artery dilation.

Other Ocular Symptoms

• Posterior segment changes: Optic disc edema, papillitis, vitritis, retinitis, retinal ischemia (due to inflammatory damage or thrombosis)
• Ptosis: Rarely observed 1 to 4 weeks after symptom onset. Self-limiting, resolving within 5 days to 4 weeks. May be associated with elevated acetylcholine receptor antibodies.
• Cranial nerve palsy: Oculomotor, abducens, and facial nerve palsy
• Myopia: Myopia is more common in patients with a history of Kawasaki disease. A Taiwanese population-based study (532 cases vs. 2128 controls) showed a statistically significant increase in myopia.
• Punctate keratitis, disciform keratitis, subconjunctival hemorrhage, dacryocystitis (rare)

Timing of Ophthalmology Consultation

Ophthalmologists are often consulted during hospitalization to evaluate ocular surface lesions, anterior chamber inflammation, and posterior segment changes. In particular, early confirmation of anterior uveitis is useful to support the diagnosis of incomplete Kawasaki disease.

3. Causes and Risk Factors

Pathophysiology

In Kawasaki disease, exposure to an unknown pathogen via the respiratory or gastrointestinal tract is thought to activate B cells in associated lymphoid tissues, leading to differentiation into IgA-producing plasma cells. These plasma cells enter the circulation and, together with T cells, neutrophils, macrophages, and eosinophils, cause infiltrative damage to the arterial wall.

This process enhances the inflammatory response within the arterial wall, leading to loss of structural integrity, vasodilation, and aneurysm formation.

The systemic inflammatory response affects various ocular tissues, including the conjunctiva, cornea, sclera, uvea, vitreous, retina, optic nerve, extraocular muscles, and periorbital vasculature.

Risk Factors

• East Asian ethnic background (e.g., Japan, Korea, Taiwan)
• Age 6 months to 5 years (most common)
• Male sex
• Family history (sibling cases reported)
• Winter season

Prevention and Daily Care

The cause of Kawasaki disease is unknown, and there is no clear prevention method at present. If a child has an unexplained fever lasting more than 5 days combined with symptoms such as conjunctival injection and rash, seek immediate pediatric consultation. Early treatment can reduce the risk of coronary artery complications.

4. Diagnosis and Testing Methods

Clinical Diagnosis

There is no single clinical test that confirms Kawasaki disease. Diagnosis is based on a combination of specific clinical findings.

Characteristic laboratory findings (not required but helpful)

• Elevated acute-phase reactants (CRP >3 g/dL, ESR >40 mm/h, thrombocytosis peaking in the third week)
• Low albumin (<3 g/dL)
• Leukocytosis (>15,000/mm³) with neutrophilia and left shift
• Low hemoglobin (normocytic normochromic anemia)
• Hyponatremia
• Elevated ALT and γ-GTP
• Cerebrospinal fluid mononuclear pleocytosis (normal glucose and protein)

Echocardiography

Assessment of coronary artery dilation is essential and is usually performed at diagnosis, before discharge, and at 2 weeks and 6 weeks follow-up.

Differential Diagnosis

The broad differential diagnosis of Kawasaki disease includes:

• Viral infections (adenovirus, Epstein-Barr virus, measles): Important to differentiate because they cause exudative conjunctivitis. Adenovirus often causes membranous or pseudomembranous conjunctivitis.
• Bacterial infections (streptococcal scarlet fever, acute rheumatic fever): Scarlet fever usually does not present with conjunctivitis.
• Multisystem inflammatory syndrome in children (MIS-C, COVID-19 associated): Presents with ocular symptoms similar to Kawasaki disease (conjunctivitis, uveitis, retinitis, etc.).
• Stevens-Johnson syndrome: Characterized by exudative conjunctivitis.
• Juvenile idiopathic arthritis: Uveitis may be present, but conjunctivitis is usually absent.

Q What is incomplete Kawasaki disease?

A

A form that meets only part of the diagnostic criteria is called incomplete or atypical. Diagnosis is often delayed, and the risk of coronary artery aneurysms and long-term cardiac complications is high. If there is persistent fever and one or more typical symptoms, Kawasaki disease should be included in the differential diagnosis.

5. Standard Treatment

Systemic Treatment

Intravenous immunoglobulin therapy

The mainstay of initial treatment. Administration within 10 days of symptom onset has been shown to reduce the risk of developing coronary artery lesions.

Aspirin

Used for its anti-inflammatory and antiplatelet effects. However, it has not been shown to reduce the risk of developing coronary artery lesions.

Precautions for Aspirin Use

In Kawasaki disease patients who may have concurrent influenza or varicella infection, aspirin should be avoided due to the risk of inducing Reye syndrome.

Additional treatment for cases unresponsive to intravenous immunoglobulin therapy

If fever persists 36 hours after intravenous immunoglobulin therapy, the following medications may be considered:

• Glucocorticoids (corticosteroids)
• Infliximab (tumor necrosis factor inhibitor)

Ophthalmic Treatment

Ocular inflammation in Kawasaki disease is often self-limiting and resolves over days to 8 weeks.

• Symptomatic ocular inflammation: Can be treated with steroid eye drops.
• Mydriatics (cycloplegics): May be added to relieve pain and photophobia and prevent posterior synechiae.

6. Pathophysiology and Detailed Mechanisms

Kawasaki disease is a vasculitis of medium-sized arteries, particularly affecting muscular arteries such as the coronary arteries. The core pathology is inflammatory infiltration of the arterial wall due to abnormal immune activation.

Molecular Mechanisms

Exposure to an unknown pathogen → B cell activation and differentiation into IgA-producing plasma cells → Plasma cells infiltrate the arterial wall → Interaction with T cells, neutrophils, macrophages, and eosinophils → Structural damage to the arterial wall, vasodilation, and aneurysm formation

Effects on Ocular Tissues

As part of systemic vasculitis, various ocular vascular and inflammatory pathways are affected. The direct correlation between conjunctivitis and rash suggests overlapping inflammatory pathways in the conjunctiva and skin.

Neutrophilic rosetting may be observed in conjunctival scrapings during the acute phase.

Proposed mechanisms for ptosis include destruction of the artery supplying the levator palpebrae superioris, myositis, and immune-mediated neuropathy.

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7. Latest Research and Future Prospects (Research Stage Reports)

For Patients: Please Read Carefully

The following content is currently in the research stage or under clinical trials, and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Research on Myopia Mechanisms

It has been shown that myopia is more common in patients with a history of Kawasaki disease, and research is advancing on the mechanism of myopic shift induced by ocular inflammation.

Relationship with Multisystem Inflammatory Syndrome in Children

Since COVID-19-related multisystem inflammatory syndrome in children presents clinical features similar to Kawasaki disease, research on the role of infectious triggers in the etiology of Kawasaki disease is accelerating.

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8. References

1. Smith LB, Newburger JW, Burns JC. Kawasaki syndrome and the eye. Pediatr Infect Dis J. 1989;8(2):116-118. PMID: 2468129
2. Rennebohm RM, Burke MJ, Crowe W, Levinson JE. Anterior uveitis in Kawasaki’s disease. Am J Ophthalmol. 1981;91(4):535-537. PMID: 7223826
3. Choi HS, Lee SB, Kwon JH, Kim HS, Sohn S, Hong YM. Uveitis as an important ocular sign to help early diagnosis in Kawasaki disease. Korean J Pediatr. 2015;58(10):374-379. PMID: 26576181
4. Shiari R, Jari M, Karimi S, et al. Relationship between ocular involvement and clinical manifestations, laboratory findings, and coronary artery dilatation in Kawasaki disease. Eye (Lond). 2020;34(10):1883-1887. PMID: 31900436
5. Jari M, Esmaeili H. Relationship between ocular manifestations, laboratory findings, echocardiographic findings, and intravenous immunoglobulin resistance in Kawasaki disease. Pediatr Rheumatol Online J. 2024;22(1):49. PMID: 38693550
6. Öztürk C, Yüce Sezen A, Savaş Şen Z, Özdem S. Bilateral Acute Anterior Uveitis and Corneal Punctate Epitheliopathy in Children Diagnosed with Multisystem Inflammatory Syndrome Secondary to COVID-19. Ocul Immunol Inflamm. 2021;29(4):700-704. PMID: 33856952
7. Lidder AK, Pandit SA, Lazzaro DR. An adult with COVID-19 kawasaki-like syndrome and ocular manifestations. Am J Ophthalmol Case Rep. 2020;20:100875. PMID: 32839740