Kawasaki Disease

Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome or infantile polyarteritis, is a medium-sized necrotizing febrile vasculitis that affects children < 5 years of age. Multiple systems are involved but the most serious is the predilection of the coronary arteries. Management involves intravenous immunoglobulin and high-dose aspirin. Follow-up requires serial echocardiograms to monitor for coronary artery aneurysm.

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Epidemiology and Etiology

Epidemiology

  • One of the most common vasculitides of childhood
  • Boys are more commonly affected than girls.
  • 80%–90% of cases in children younger than 5 years of age.
  • Geographic variation
    • Highest incidence in children who live in East Asia or are of Asian ancestry living in other parts of the world
    • Overall annual incidence of 20 per 100,000 children younger than 5 years in the United States
  • ¼ of adult cases occur in patients with HIV.

Etiology

The etiology of Kawasaki disease (KD) is unknown. There are several theories:

  • Immunologic response theory
    • Inflammatory cells are found infiltrating medium-sized arteries: neutrophils, CD8+ T cells, eosinophils, IgA plasma cells, macrophages.
    • Inflammatory gene expression via adrenomedullin, grancalcin, and granulin is high during the acute phase of illness.
    • The stimulus for this gene expression and inflammatory infiltration is unknown.
  • Infection theory
    • Similarities with other pediatric infectious conditions: febrile exanthem with lymphadenitis and mucositis, incidence during winter and summer, occurs in epidemics, boys > girls, incidence in younger children
    • Viral: adenovirus, cytomegalovirus, rotavirus
    • Bacterial: mycoplasma
  • Genetic predisposition theory
    • Pleomorphism of plasma-activating factor acetylhydrolase in resistance to immunoglobulins
    • Genes implied: single nucleotide polymorphisms (SNPs) of ITPKC (inositol 1,4,5-trisphosphate 3-kinase C) gene (a negative regulator of T-cell activation)
  • Environmental factors theory
    • Mercury, dust mites, rug shampoo, and pollen release have been hypothesized to be a trigger for KD but lack supporting evidence.

Pathophysiology

  • Kawasaki disease is a systemic, inflammatory illness that affects medium-sized arteries, especially the coronary arteries.
  • Multiple organs and tissues are involved but long-term sequelae occur only in arteries.
  • Blood vessel damage results from inflammatory cell infiltration into vascular tissues.
    • Early-stage: vascular media and endothelium become edematous
    • Late-stage: an influx of neutrophils followed by proliferation of IgA plasma cells and CD8+ T cells
      • Eosinophils and macrophages can also be prominent.
      • Multiple cytokines and matrix metalloproteinases are secreted by inflammatory cells that result in vascular damage.
      • Fibrous connective tissue within the vascular wall can develop and cause a thickening of the intima, narrowing of the vessel lumen, and formation of a thrombus.
      • Destruction of elastin and collagen fibers can cause a loss of structural integrity of the arterial wall leading to dilation and aneurysm formation.

Clinical Presentation

Commonly presenting symptoms

  • Fever (most consistent manifestation of KD)
  • Rash
  • Malaise
  • Bilateral nonexudative conjunctivitis
  • Erythema of the lips and oral mucosa (“strawberry tongue”)
  • Extremity changes (e.g., swelling and/or erythema on palms and soles, periungual desquamation)
  • Cervical lymphadenopathy (least consistent manifestation of KD)
  • Nonspecific prodrome of respiratory or gastrointestinal (GI) symptoms

Less common manifestations

SystemManifestations
GastrointestinalDiarrhea, abdominal pain, vomiting, liver dysfunction, pancreatitis, hydrops gallbladder, ascites, splenic infarction
MusculoskeletalPolyarthritis, arthralgia
Cardiovascular systemMyocarditis, pericarditis, tachycardia, valvular heart disease
GenitourinaryUrethritis, prostatitis, cystitis, interstitial nephritis, nephrotic syndrome
Central nervous systemLethargy, seminoma, aseptic meningitis, sensorineural deafness
RespiratoryShortness of breath, influenza-like illness, pleural effusion, cough, rhinorrhea
SkinErythema and induration at BCG (bacille Calmette-Guérin) vaccination site, Beau’s lines, finger gangrene
GeneralIrritability, decreased PO intake, lethargy

Diagnosis

Diagnostic criteria

  • Fever lasting ≥ 5 days AND at least 4 of the following:
    • Bilateral, non-exudative conjunctiva
    • Oral mucosal changes: fissured lips, strawberry tongue, injected pharynx
    • Peripheral extremity changes: erythema of palms/soles, edema of hands/feet, periungual desquamation
    • Erythematous polymorphous rash
    • Cervical lymphadenopathy: at least 1 node > 1.5 cm in diameter
  • If only 2–3 criteria → atypical Kawasaki, supplement with laboratories below
The diagnostic algorithm for Kawasaki disease

Diagnostic algorithm for children with fever/diagnosis of Kawasaki disease

Image by Lecturio.

Laboratory studies

  • CBC with differential: elevated WBC and platelet counts, anemia
  • Liver function tests (LFTs): elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), low albumin
  • Acute phase reactants: elevated c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
  • Urinalysis: sterile pyuria
  • Echocardiography:
    • Increased size of left anterior descending or right coronary artery, coronary artery aneurysm observed, decreased left ventricular function, mitral regurgitation, pericardial effusion
    • Should be performed in all patients with KD
    • Establish a reference point for longitudinal follow-up 
    • Determine treatment efficacy
  • Angiography: 
    • Used to observe aneurysms already detected via echocardiogram
    • Not used for initial detection or diagnosis

Mnemonic

CRASH and Burn:

Conjunctivitis
Rash
Adenopathy
Strawberry tongue
Hands and feet
Burn: fever

Management

  • Kawasaki disease is self-limited!
  • Treatment is aimed at preventing complications and reducing symptoms.
  • Mainstay of treatment:
    • Intravenous immunoglobulin (IVIG): 
      • 2 g/kg administered as a single infusion over 8–12 hours
      • Started within 10 days of fever onset, it reduces the risk of coronary artery aneurysms.
      • Observe for 24 hours following completion of IVIG infusion to confirm fever resolution.
      • Patients at high risk for IVIG resistance are additionally treated with systemic glucocorticoids.
    • Aspirin: 
      • 30–50 mg/kg daily divided into 4 doses
      • Anti-inflammatory and antiplatelet effects
      • Prevents thrombus in coronary arteries
  • Follow-up with serial echocardiograms at 2 and 6 weeks
Table: Other medications that can be used
MedicationIndication
Cyclophosphamide, dipyridamole, and other antiplatelet drugsIf there is involvement of the coronary arteries and a high risk for thrombus formation
Low-molecular-weight heparin, warfarin, and other anticoagulantsPatients with a high risk of thrombus formation and aneurysm
InfliximabRefractory cases with coronary aneurysm
CorticosteroidsPatients who do not respond to standard treatments and therapies or are at risk for IVIG resistance
Ulinastatin (a neutrophil elastase inhibitor)Patients suffering from circulatory shock or pancreatitis; however, it is under clinical trials.

Complications

  • Shock: KD shock syndrome (KDSS) is sustained systolic hypotension or clinical signs of poor perfusion. Accompanying thrombocytosis, younger age, and coronary artery abnormalities are highly suggestive of KDSS.
  • Cardiac complications: Coronary artery dilation, aneurysm, and/or stenosis, ventricular dysfunction, valvular regurgitation, and pericardial effusions are all complications seen in KD. Monitor with serial echocardiograms. 
  • Macrophage activation syndrome: activation and proliferation of macrophages and T cells. Can lead to life-threatening complications such as disseminated intravascular coagulopathy, cytopenias, and thrombosis.
  • Ischemia, gangrene: Peripheral arterial obstruction can lead to ischemia of viscera and gangrene of limbs.
  • Urinary abnormalities: Sterile pyuria is common in KD, while acute interstitial nephritis, mild proteinuria, and acute kidney injury are uncommon manifestations.
  • GI abnormalities: Hydrops of the gallbladder is a common finding during KD’s acute phase but rapidly resolves upon IVIG administration.
  • Central nervous system: Irritability is a common feature of KD’s acute phase and is thought to be related to the cerebral spinal fluid pleocytosis seen in 40% of children with KD.
  • Sensorineural hearing loss: Can occur in KD’s acute phase but rarely persists.

Differential Diagnosis

  • Scarlet fever: a disease that occurs as a result of a group A streptococcus infection, also known as Streptococcus Pyogenes. Signs and symptoms include sore throat, fever, headaches, swollen lymph nodes, a characteristic rash (red and sandpaper-like), and red/bumpy tongue. The exudative pharyngitis in KD can be confused with streptococcal pharyngitis.
  • Measles: infection by the paramyxovirus that presents with fever, conjunctivitis, desquamations, and a polymorphous rash that is highly contagious. Discrete intraoral lesions of KD can be confused with Koplik spots of measles. Diagnosis is made by viral polymerase chain reaction (PCR), and management involves isolation and supportive treatment.
  • Lyme disease: Also known as borreliosis, an infectious disease caused by Borrelia burgdorferi, which spreads by ticks. The most common sign is erythema migrans that appear at the site of a tick bite about a week after it occurred. Other symptoms are joint pain, severe headache, neck stiffness or heart palpitations, etc.
  • Rocky Mountain spotted fever: A bacterial infection that spreads by a bite from an infected tick. Symptoms include vomiting, a sudden high fever around 39.0°C–39.5°C (102°C–103°F), headache, abdominal pain, rash, and muscle aches.
  • Rotavirus: Rotavirus is a common cause of severe gastroenteritis. The nonspecific prodrome of gastrointestinal (GI) symptoms such as diarrhea, abdominal pain, and vomiting that can be seen in KD can be confused with an infection due to rotavirus. 
  • Pneumonia: an acute or chronic inflammation of lung tissue caused by infection with bacteria, viruses, or fungi that is considered a routine childhood illness. The nonspecific prodrome of respiratory and GI symptoms of KD can be mistaken for pneumonia. 
  • Adenovirus: causes mild upper respiratory infections in young children. The prodrome of nonspecific respiratory symptoms and accompanying exudative conjunctivitis in KD can be mistaken for a common upper respiratory infection caused by adenovirus. 
  • Meningitis: inflammation of the meninges most commonly caused by bacteria and viruses. Irritability is a common manifestation of KD and meningitis. 
  • Stevens-Johnson syndrome (SJS): immune-complex mediated hypersensitivity reaction that can be triggered by infectious etiologies or the use of anticonvulsants, antibiotics, or other drugs. The syndrome is characterized by epidermal necrolysis, separation of the epidermis from the dermis, and the formation of skin blisters and bullae on the face, lips, throat, and extremities. The bullous or vesicular rash in KD can be mistaken for SJS.
  • Epstein-Barr virus: causes infectious mononucleosis and is associated with Burkitt’s lymphoma, hemophagocytic lymphohistiocytosis, and Hodgkin’s lymphoma. The generalized lymphadenopathy observed in KD can be mistaken for the generalized lymphadenopathy of infectious mononucleosis.

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