Kawasaki Disease

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Article initiated by:

Justin Fichtner, Michael A. Puente, MD

All contributors:

Ghazala D. O'Keefe, MD, S. Grace Prakalapakorn, MD, MPH, Marissa Larochelle, MD, Michael A. Puente, MD, Ujwala S Saboo, MBBS

Assigned editor:

Marissa Larochelle, MD, Ujwala S Saboo, MBBS

Review:

Assigned status Update Pending

 by Ujwala S Saboo, MBBS on February 25, 2024.

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Contributing Editors:	add

Kawasaki Disease

Bilateral non-exudative bulbar conjunctivitis in a 7-year-old boy with Kawasaki disease

ICD-10

[1]30.3

OMIM

611775

Kawasaki disease is the most common cause of acquired heart disease in children in developed countries, and ocular inflammation is an important early clinical sign. Though long-term ocular morbidity is rare, the systemic manifestations of Kawasaki disease can be fatal.

Disease Entity

Kawasaki disease (KD) is predominantly a vasculitis of childhood, though it rarely can occur in adults. Signs include ≥5 days of fever plus the presence of conjunctivitis, mucositis, skin rash, extremity changes, and cervical lymphadenopathy.

The disease was first described in Japan by a Japanese pediatrician named Tomisaku Kawasaki in 1967. It was approximately three years later when physicians began describing the various cardiac sequelae of the disease which are a leading cause of pediatric acquired heart disease worldwide.

Epidemiology

The incidence of KD varies geographically, with the highest incidence in Japan of approximately 265 cases per 100,000 children under 5 years of age, followed by 134 and 83 cases per 100,000 in Korea and Taiwan respectively. In the United States, the annual incidence of KD is about 18 per 100,000. Boys are more commonly affected than girls, and the vast majority of cases occur between the ages of 6 months and 5 years. Incidence tends to be higher during winter months.

Etiology

While the etiology of KD remains unknown, the leading theory is that exposure to a pathogen (most likely viral) triggers an inflammatory cascade resulting in immune system dysregulation in a genetically susceptible child. Evidence that some individuals have a genetic predisposition include varying incidence among different ethnicities, higher incidence in children with a family history of KD, and single-nucleotide polymorphisms in a variety of genes that have been implicated through genome-wide association studies. There is currently no evidence to suggest that the disease is associated with administration of routine vaccines.

Pathophysiology

Kawasaki Disease is a medium vessel vasculitis of childhood which typically affects muscular arteries, often with a predilection for the coronary arteries. It is thought that respiratory or gastrointestinal exposure to an unknown pathogen results in activation of B-cells within the associated lymphoid tissue, which then differentiate into IgA-producing plasma cells. These plasma cells enter circulation and along with T-cells, neutrophils, macrophages, and eosinophils, cause infiltrative damage of arterial walls. Aberrant activation of these infiltrating cells potentiates the inflammatory response within arterial walls leading to compromised structural integrity, vessel dilation, and aneurysms.

The systemic inflammatory response that occurs in KD can affect various ocular tissues including the conjunctiva, cornea, sclera, uvea, vitreous, retina, optic nerve, extraocular muscles, and any vasculature in or around the eye. In one study, acute bilateral conjunctivitis was directly correlated with presence of a skin rash, and this was thought to be due to overlap between inflammatory pathways present in the conjunctiva and skin. Histology of conjunctival swabs taken from patients in the acute phase of the disease sometimes shows abundant neutrophils surrounding conjunctival epithelial cells referred to as “neutrophilic rosetting.”

Diagnosis

Diagnosis is based on a specific set of clinical findings that often follow an expected timeline. The Kawasaki Disease Research Committee and the American Heart Association have both developed guidelines for diagnosing KD. While the AHA guidelines specify that a fever must last at least 5 days, the Japanese guidelines suggest that KD can be diagnosed in the absence of a fever.

Clinical presentation and systemic manifestations:

KD is a clinical diagnosis classically characterized by ≥5 days of fevers (which cannot be explained by any other disease), plus four or more of the following physical exam findings:

1. Conjunctivitis, typically bilateral, bulbar, and nonexudative
2. Mucositis causing cracked red lips and/or “strawberry tongue”
3. Polymorphous widespread rash
4. Extremity changes including erythema, desquamation, and swelling of the hands and feet
5. Cervical lymphadenopathy, which is often absent and is the least common feature

There are no confirmatory lab tests that can be used to diagnose Kawasaki Disease, though there are several characteristic lab findings often present:

• Elevated positive acute phase reactants (ESR >40mm/h, CRP >3g/dL, Ferritin above normal range, thrombocytosis which typically peaks in the third week)
• Decreased albumin (< 3g/dL)
• Leukocytosis >15,000 per mm3 with neutrophilia and left shift
• Low hemoglobin (often normocytic normochromic anemia)
• Hyponatremia
• Elevated ALT and/or GGT
• CSF showing mononuclear pleocytosis with normal glucose and protein

Clinical features omitted from the diagnostic criteria include uveitis, perineal and periungual desquamation, irritability, sterile pyuria, peripheral arthritis, hydropic gallbladder, myocarditis, interstitial pneumonitis, hepatitis, and pancreatitis. Prodromal symptoms of diarrhea, vomiting, abdominal pain, cough, rhinorrhea, and decreased oral intake are common 7-10 days prior to the onset of fever and mucocutaneous features.

KD can cause a variety of acquired pediatric cardiovascular diseases including coronary artery dilation and aneurysms, decreased coronary artery compliance, ischemic heart disease/ myocardial infarction, myocarditis, pericarditis, pericardial effusions, valvular disease, aortic root dilation, arrythmias, and sudden cardiac death. These complications affecting the coronary arteries, myocardium, cardiac contractility, and overall cardiac function can occur acutely at the time of presentation or many years after resolution of the acute disease.

KD can also present with an atypical or incomplete presentation, in which some but not all diagnostic criteria are met, often making it harder for clinicians to diagnose at an initial encounter. Patients that present with atypical KD are at increased risk of coronary artery aneurysms and long term cardiac complications due to a higher rate of missed diagnosis and delays in treatment. It is therefore essential that the diagnosis of Kawasaki disease be considered on the differential in any patient with prolonged fever and 1 or more of the common clinical features.

Ocular manifestations

Over 90% of patients with KD develop ocular abnormalities. The following list outlines the various ocular manifestations and relevant considerations for each finding:

• Conjunctivitis is the most common (90%) and is bilateral, bulbar, nonexudative, limbic sparing, and typically present within a few days of fever onset. It is directly correlated with the presence of skin rash.
• Anterior uveitis is present in up to 70% of patients and usually arises within a week of fever onset. It is characteristically Grade 1+ or 2+ and bilateral, and sometimes associated with keratic precipitates. Presence of uveitis early in the acute phase can help establish the diagnosis particularly in cases of incomplete KD. Uveitis was shown in at least one study to be significantly correlated with coronary artery dilation. Intermediate uveitis has also less commonly been reported.
• Posterior segment changes can include papilledema, papillitis, vitreous opacities, vitritis, retinitis, and retinal ischemia from inflammatory damage or thrombosis of retinal vasculature.

The time course of eyelid ptosis in a 3-year-old boy with KD. A the 1st day of admission; B the 3rd day of admission; C the 6th day of admission; and D: the 14th day of admission

• Ptosis can rarely be observed 1 to 4 weeks after the onset of symptoms. In reported cases, ptosis has been self-limited, resolving anywhere from 5 days to 4 weeks after onset. Elevated levels of acetylcholine receptor antibodies can be seen, suggesting a myastheniform condition. Proposed pathophysiology of ptosis in KD includes destruction of arteries supplying the levator muscles, myositis, or immune-mediated nerve involvement.
• Palsies of the oculomotor nerve, abducens nerve, and facial nerve have been reported.
• Myopia is more common in patients with a history of KD. A population-based cohort study conducted in Taiwan in 2017 found a statistically significant increase in myopia in a cohort of 532 KD patients compared to a cohort of 2128 non-KD patients. It is thought that myopic shift is induced by ocular inflammation.

Other reported ocular manifestations include:

• Superficial punctate keratitis
• Disciform keratitis
• Periorbital vasculitis associated with eyelid edema
• Subconjunctival hemorrhage
• Dacryocystitis

Differential diagnosis

The broad differential diagnosis of KD includes viral infections (adenovirus, echovirus, EBV, and measles), bacterial infections (scarlet fever, acute rheumatic fever, Rocky Mountain spotted fever, and leptospirosis), toxin-mediated illnesses (staphylococcal scalded skin syndrome and toxic shock syndrome), hypersensitivity reactions (e.g. Stevens-Johnson syndrome), rheumatic disease (juvenile idiopathic arthritis, polyarteritis nodosa, and reactive arthritis), and multisystem inflammatory syndrome in children (MIS-C) that is associated with the SARS-CoV-2 virus.2 Children with KD may have a concurrent viral or bacterial infection.

MIS-C is a severe presentation of COVID-19 and can feature many of the same ocular manifestations as KD including conjunctivitis, eyelid edema, anterior uveitis, retinitis, cotton wool spots, and optic neuritis.

Adenovirus infection and Stevens-Johnson syndrome are more likely to cause an exudative (membranous or pseudomembranous) conjunctivitis. This finding in conjunction with the absence of prolonged fever and other clinical manifestations of KD should steer clinicians toward an alternative diagnosis. Conjunctivitis is typically absent in streptococcal scarlet fever and juvenile idiopathic arthritis, though uveitis is often present in the latter.

Management

Echocardiography to assess for coronary artery dilation is mandatory, and is usually performed at the time of diagnosis, prior to discharge, and at 2 week and 6 week follow up appointments.

Ophthalmologists are often consulted during the patient’s hospital admission to assess for surface pathology, anterior chamber inflammation, and posterior segment changes.

Systemic treatment

Initial therapy includes intravenous immunoglobulin (IVIG), whichhas been shown to reduce the risk of developing coronary artery lesions if administered within 10 days of symptom onset.

Aspirin is often used for its anti-inflammatory and antiplatelet activity, though it has not been shown to reduce the risk of developing coronary artery lesions. Aspirin should be avoided in KD patients with potential concurrent influenza or varicella infection due to the possibility of precipitating Reye syndrome.

Additional agents including glucocorticoids and tumor necrosis factor inhibitors (Infliximab) can be added in patients whose fever is refractory to IVIG 36 hours after administration.

Ocular treatment

Ocular inflammation in Kawasaki disease is almost always self-limited, resolving over a course of a few days to 8 weeks. Symptomatic ocular inflammation can be treated with topical corticosteroids. Cycloplegic agents can be added to reduce pain and photophobia and to prevent the formation of posterior synechiae.

Complications

Usually, ocular manifestations of KD resolve after treatment and do not cause long term problems. However, patients who have recovered from KD do commonly develop a myopic shift.

Retinal damage from vasculitis or thrombus formation within the branches of the ophthalmic artery can cause permanent visual impairment.

Dacrycystitis and conjunctival scarring are rarely reported long term complications of KD.

The reported cases of neuromuscular abnormalities (e.g. ptosis, cranial nerve palsies) during the acute and subacute phase of KD were self-limited and did not require long term follow-up.

Prognosis

Mortality from Kawasaki Disease is very low, estimated to be about 0.1 to 0.3% of patients. Fatal outcomes are usually the result of myocardial infarction, arrhythmia, or ruptured coronary aneurysm. Persistent ocular pathology is rare, and most patients do not require consistent follow up with an ophthalmologist outside of recommended annual exams.