Kawasaki Disease: A Clinical Guide
Definition
Kawasaki Disease (KD), historically known as Mucocutaneous Lymph Node Syndrome, is an acute, self-limiting systemic vasculitis of unknown aetiology (1, 2). The term "vasculitis" refers to inflammation of blood vessels, and in KD, this process predominantly targets medium-sized muscular arteries. While the inflammation can affect any organ system, it has a dangerous and unexplained predilection for the coronary arteries, which supply blood to the heart muscle (1, 4). "Self-limiting" means the acute febrile phase of the illness will eventually resolve on its own; however, the vascular damage that occurs during this phase can be permanent and life-threatening. It is the leading cause of acquired heart disease in children in developed nations, and its diagnosis is based on a constellation of clinical signs, as no specific diagnostic test exists (3, 4).
Epidemiology
In Malaysia, the incidence of Kawasaki Disease appears to be rising, consistent with trends in other Asian countries. A retrospective study from a major Malaysian teaching hospital (HCTM) noted a significant incidence among the Malay ethnicity, though this finding may differ from other local studies and highlights the importance of considering KD across all ethnic groups in our diverse population (5). This contrasts with some earlier reports suggesting higher rates in the Chinese population, underscoring the need for ongoing local surveillance.
Globally, KD shows a strong predilection for children of Northeast Asian descent, with Japan reporting the world's highest incidence, exceeding 260 cases per 100,000 children under five (6). This provides compelling evidence for a genetic predisposition, with studies identifying specific gene variants, such as in the ITPKC gene, that may impair the "off-switch" for T-cell activation, leading to hyperinflammation (8). The disease primarily affects young children, with approximately 80% of cases occurring in those under five years of age and a peak incidence between 6 and 24 months (1). This age distribution strongly suggests a common infectious trigger to which most adults have immunity, with infants protected by waning maternal antibodies. A consistent male predominance is observed globally, with a male-to-female ratio of about 1.5:1 (5, 7). In temperate climates, a seasonal peak in winter and spring is often observed, mirroring the circulation of many respiratory viruses and further supporting an infectious trigger (7).
Pathophysiology
The exact cause of KD remains unknown, but the leading hypothesis involves an environmental trigger, likely a common and possibly airborne infectious agent, in a genetically susceptible child (2). This trigger incites a dysregulated, hyperinflammatory immune response. Instead of a controlled reaction, there is massive activation of the innate and adaptive immune systems, leading to a "cytokine storm" (8). Key pro-inflammatory cytokines, such as Tumour Necrosis Factor-alpha (TNF-α), Interleukin-1 (IL-1), and IL-6, are released in massive quantities.
This cytokine cascade causes widespread inflammation of medium-sized arteries. Neutrophils, macrophages, and lymphocytes infiltrate the vessel wall, disrupting its normal architecture. This inflammatory infiltrate leads to enzymatic degradation of elastin and collagen within the tunica media, the muscular layer of the artery (2, 8). This structural weakening causes the vessel wall to lose its integrity, leading to dilation (ectasia) and, in severe cases, the formation of saccular or fusiform coronary artery aneurysms (CAA)—the most feared complication of the disease. The damaged endothelium and turbulent blood flow within these aneurysms create a prothrombotic state, increasing the risk of clot formation, which can lead to coronary artery stenosis or complete occlusion, resulting in myocardial infarction (2).
Clinical Presentation
The diagnosis of classic (or complete) KD is based on the American Heart Association (AHA) criteria, requiring fever lasting for at least five days plus at least four of the five principal clinical features. It is crucial to remember these features may appear sequentially, so a thorough history of symptoms that may have already resolved is vital (3).
Diagnostic Clues: Profound, inconsolable irritability is a classic "soft sign." This is not typical toddler fussiness; it is an extreme, unrelenting misery, often described by parents as their child being "unrecognizable." It is thought to be due to aseptic meningitis and should significantly raise your index of suspicion (9).
Common Symptoms & Signs:
Bilateral bulbar conjunctival injection: (~90%) This is a painless, bilateral redness of the whites of the eyes. Crucially, it is non-exudative (no pus or discharge) and typically demonstrates "limbic sparing," meaning there is a clear halo of uninvolved sclera immediately surrounding the iris (3).
Changes in lips and oral cavity: (~90%) Look for intensely erythematous, dry, cracked, and often bleeding lips. The tongue develops a "strawberry" appearance, with prominent, reddened papillae on a bright red background. There is also a diffuse, deep red injection of the oropharyngeal mucosa. The absence of discrete oral ulcers (as in herpangina) or pharyngeal exudates (as in strep throat) is a key negative finding (3, 7).
Polymorphous exanthem (rash): (~90%) The rash is non-specific in its form and can be maculopapular (like measles), scarlatiniform (like scarlet fever), or even resemble erythema multiforme. It typically begins within the first few days of fever, often starting in the perineal area where it can be associated with early peeling, and then spreads to the trunk and limbs. Vesicular (blistering) or bullous rashes are not characteristic of KD (3). Inflammation, redness, and induration at a previous BCG inoculation site is a highly specific, though less common, cutaneous finding (5).
Changes in the extremities: (~75%) These findings evolve. In the acute phase (week 1-2), there is painful erythema (deep red or purplish discoloration) of the palms and soles, accompanied by a tense, indurative oedema of the dorsum of the hands and feet. This can be so painful that the child refuses to walk, crawl, or even hold objects (3, 7). In the subacute phase (week 2-3), as the swelling subsides, a highly characteristic desquamation begins. This peeling typically starts in the periungual region (at the very tips of the fingers and toes) and can extend to involve the entire palm and sole in large sheets.
Cervical lymphadenopathy: (~50-60%) This is the least common criterion, and its absence should not dissuade you from the diagnosis. When present, it is typically a single, unilateral lymph node in the anterior cervical chain, measuring >1.5 cm in diameter. The node is characteristically firm, somewhat tender, and non-suppurative (not fluctuant or draining pus) (3).
⚠️ Red Flag Signs & Symptoms:
Persistent fever >5 days despite appropriate antibiotics. This is a cardinal sign that a typical bacterial infection is not the cause.
Signs of haemodynamic instability or shock (Kawasaki Disease Shock Syndrome - KDSS): This includes hypotension, tachycardia unresponsive to fluids, and poor peripheral perfusion. KDSS is a severe presentation with a very high risk of CAA.
Extreme, inconsolable irritability suggesting significant meningeal or systemic inflammation.
Any patient, especially an infant <1 year old, with prolonged unexplained fever (≥7 days) and only 2-3 of the above criteria. This presentation is highly suspicious for Incomplete KD, which carries a higher risk of CAA because diagnosis and treatment are often delayed.
Complications
The most significant complications are cardiovascular and can be devastating if treatment is delayed.
Coronary Artery Aneurysms (CAA): Occurs in up to 25% of untreated children. These weakened, bulging sections of the coronary arteries are prone to thrombosis (clotting), which can lead to stenosis (narrowing) and myocardial infarction (heart attack), even years later (1).
Myocarditis and Pericarditis: Inflammation of the heart muscle and surrounding sac is common in the acute phase. This can manifest as tachycardia disproportionate to the fever, a gallop rhythm on auscultation, and can lead to heart failure or arrhythmias (2).
Valvular Regurgitation: Inflammation can affect the heart valves, most commonly causing the mitral valve to leak (2).
Kawasaki Disease Shock Syndrome (KDSS): A rare but life-threatening complication characterized by hypotension and end-organ hypoperfusion, requiring intensive care support.
Prognosis
With timely treatment, the prognosis is excellent for the majority of patients. Intravenous immunoglobulin (IVIG) therapy administered within the first 10 days of illness is a game-changer, reducing the risk of CAA from 25% to less than 5% (1). Children who do not develop aneurysms generally have no long-term sequelae and can be discharged from cardiology follow-up after their final normal echocardiogram at 4-6 weeks. The prognosis for those with giant aneurysms (Z-score ≥10 or absolute dimension >8mm) is more guarded, requiring lifelong cardiology follow-up, anticoagulation therapy, and carrying a significant risk of late cardiovascular events (10).
Differential Diagnosis
Scarlet Fever is a key differential due to the presence of fever, rash, and strawberry tongue. However, the rash in scarlet fever is typically a fine, sandpaper-like (sandpapery) erythema with prominent Pastia's lines (linear petechiae in skin folds). It is also often associated with a prominent pharyngeal exudate and a positive rapid strep test or culture, which are absent in KD (7).
Measles also presents with the three 'C's (cough, coryza, conjunctivitis) and fever, followed by a rash. However, measles is distinguished by the presence of Koplik's spots (pathognomonic white spots on the buccal mucosa) during the prodrome, a purulent conjunctivitis, and a rash that starts on the face and moves downwards. The child is often less irritable than in KD (7).
Toxic Shock Syndrome (TSS), caused by staphylococcal or streptococcal toxins, can present with fever, rash, and multisystem involvement. TSS is distinguished by the presence of profound hypotension early in the course, a rash that is more likely to be a diffuse, blanching erythroderma, and often a clear source of infection (e.g., a wound, abscess, or tampon use) (2).
Stevens-Johnson Syndrome (SJS) is another important differential. While it shares features of fever, rash, and mucositis, SJS is characterized by severe, painful, and often haemorrhagic crusting of the lips and oral mucosa, along with targetoid skin lesions. It is almost always triggered by a medication, a crucial point to elicit in the history.
Investigations
Investigations are crucial to support the diagnosis, assess for inflammation, and screen for cardiac complications.
Immediate & Bedside Tests
ECG: This is mandatory to immediately screen for evidence of myocarditis (e.g., sinus tachycardia, prolonged PR interval, low-voltage QRS), ischaemia, or arrhythmias (the action), which can be fatal complications of the acute vasculitic process (the rationale) (3).
Diagnostic Workup
First-Line Investigations: The initial blood work is essential for providing supportive evidence of systemic inflammation and risk stratification.
Full Blood Count (FBC): This is performed to identify a characteristic leukocytosis (>15,000/μL) with a neutrophilic predominance and a "left shift" in the acute phase, followed by a reactive thrombocytosis (platelets often >450,000/μL) in the subacute phase (the rationale). This platelet surge is a classic inflammatory response that strongly supports the diagnosis (the action) (5, 7).
C-Reactive Protein (CRP) & Erythrocyte Sedimentation Rate (ESR): Ordering these markers is critical as a CRP ≥3.0 mg/dL or ESR ≥40 mm/hr provides strong supportive evidence for KD, especially in incomplete cases (the rationale). A very high CRP can also predict a higher risk of IVIG resistance, helping to justify the initiation of and potential escalation of therapy (the action) (3).
Liver Function Tests (LFTs) & Serum Albumin: These are ordered to detect mild transaminitis (elevated ALT) and hypoalbuminaemia (albumin <3.0 g/dL) (the rationale). A low albumin level is a very significant marker of severe inflammation and capillary leak; it is one of the strongest predictors for both the development of coronary aneurysms and resistance to IVIG therapy (the action) (3, 5).
Gold Standard:
Transthoracic Echocardiogram: This is the definitive imaging modality and is mandatory in all patients with suspected KD. It is performed to establish a baseline and detect coronary artery abnormalities (the rationale). Measurements are converted to Z-scores, which adjust for the child's body surface area, to accurately classify vessel size. The presence of aneurysms (defined by a Z-score ≥2.5) confirms the diagnosis and dictates the intensity of long-term management and follow-up (the action) (3, 10).
Monitoring & Staging
Serial Echocardiograms: Follow-up echocardiograms are performed at 1-2 weeks and 4-6 weeks after treatment (the action) to monitor the evolution of any coronary artery changes, as some aneurysms may only develop or progress after the acute phase has subsided (the rationale). Patients with evolving aneurysms will require more frequent monitoring (3).
Management
The management of KD is time-sensitive and focuses on rapidly reducing inflammation to prevent coronary artery damage.
Management Principles
The management of this condition focuses on rapid suppression of systemic inflammation with IVIG and aspirin, preventing coronary artery aneurysm formation, and mitigating thrombosis risk.
Acute Stabilisation (The First Hour)
While most children are haemodynamically stable, those presenting with Kawasaki Disease Shock Syndrome require immediate resuscitation.
Circulation: Secure two large-bore IV cannulas and administer a stat fluid bolus of IV Normal Saline 20mL/kg (the action) to correct hypotension and restore vital organ perfusion in the setting of profound vasodilation and capillary leak (the rationale). These patients often require vasopressor support and admission to a high-dependency or intensive care unit.
Definitive Therapy
This should be started as soon as the diagnosis is suspected, ideally within the first 10 days of illness onset. Treatment after day 10 is still indicated if there is persistent fever or evidence of ongoing inflammation.
First-Line Treatment:
Intravenous Immunoglobulin (IVIG): Administer a single high-dose infusion of 2 g/kg over 10-12 hours (1, 3). This is the cornerstone of therapy. IVIG is a pooled antibody product that is thought to work by providing anti-idiotypic antibodies, neutralizing toxins, and downregulating the production of pro-inflammatory cytokines (the rationale), thereby dramatically reducing the risk of developing coronary artery aneurysms (the action).
Aspirin: Initially, give a high (anti-inflammatory) dose of 30-50 mg/kg/day divided every 6 hours (local Malaysian practice may favour this lower range over the 80-100mg/kg/day suggested in some US guidelines) (3, 5). Once the patient is afebrile for 48-72 hours, reduce to a low (anti-platelet) dose of 3-5 mg/kg once daily (the action). This is continued for at least 6-8 weeks to inhibit platelet aggregation and prevent thrombosis in potentially inflamed or aneurysmal coronary arteries (the rationale) (3).
Second-Line/Escalation (for Refractory KD):
Approximately 10-20% of patients have persistent or recrudescent fever ≥36 hours after completing the first IVIG infusion. This is IVIG-resistant KD. These patients require prompt escalation of therapy as they are at the highest risk for CAA (11).
The standard second-line treatment is a second dose of IVIG 2 g/kg (11).
If the patient remains febrile, a course of intravenous methylprednisolone (e.g., 30 mg/kg for one dose or 2 mg/kg/day for several days) is typically the next step. For cases resistant to steroids, biologic agents like Infliximab (a TNF-α inhibitor) are used to more directly target the inflammatory cascade. Consultation with a paediatric specialist or infectious disease physician is mandatory at this stage (11).
Supportive & Symptomatic Care
Analgesia/Antipyretics: Paracetamol can be used for fever and discomfort. Avoid NSAIDs like ibuprofen as they may interfere with the antiplatelet effect of aspirin.
Hydration & Nutrition: Maintain hydration with IV fluids if oral intake is poor due to painful mucositis. Encourage soft foods and cool liquids.
Skincare: Apply unscented emollients or lip balm to cracked lips and peeling skin to alleviate discomfort.
Key Nursing & Monitoring Instructions
Strict hourly monitoring of vital signs until afebrile and stable for at least 24 hours.
Maintain a strict input/output chart to monitor hydration status.
Inform the medical team immediately if fever recurs ≥36 hours after IVIG completion.
Inform the medical team if systolic BP drops, tachycardia worsens, or signs of shock develop.
Long-Term Plan & Patient Education
Follow-up is coordinated by the primary paediatric team and paediatric cardiology. Educate parents on the importance of adherence to low-dose aspirin and the follow-up echocardiogram schedule. A crucial point for discharge counselling is the delay of live virus vaccines (MMR, Varicella) for 11 months after receiving IVIG, as the high concentration of antibodies in IVIG can neutralize the live vaccine virus and interfere with the development of a protective immune response (7). For patients with persistent aneurysms, education on long-term anticoagulation, activity restrictions, and the lifelong need for cardiac follow-up is essential.
When to Escalate
A house officer must know when to seek senior help.
Call Your Senior (MO/Specialist) if:
The diagnosis is suspected, to confirm the management plan and ensure timely initiation of IVIG.
The patient remains febrile or has recurrent fever ≥36 hours after the first dose of IVIG is completed (this is refractory KD and requires immediate action).
The patient develops any signs of shock or haemodynamic instability (e.g., hypotension, tachycardia unresponsive to fluids, prolonged capillary refill time).
The initial echocardiogram shows evidence of medium (Z-score 5 to <10) or giant (Z-score ≥10) coronary artery aneurysms, as this requires intensification of antithrombotic therapy.
Referral Criteria:
All patients with a confirmed diagnosis of Kawasaki Disease must be co-managed with a Paediatric Cardiologist for their initial and long-term echocardiographic surveillance and cardiovascular risk management.
References
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American Heart Association. (2024). Update on Diagnosis and Management of Kawasaki Disease: A Scientific Statement From the American Heart Association. Circulation. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001295
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