Kawasaki Disease
Kawasaki disease is an acute, self-limited febrile vasculitis of medium-sized arteries predominantly affecting children under five years old, with a particular predilection for the coronary arteries.
Kawasaki Disease (KD) — Mucocutaneous Lymph Node Syndrome (川崎症)
Kawasaki disease (KD) is an acute, self-limiting systemic vasculitis that predominantly affects small- to medium-sized muscular arteries throughout the body, with a striking predilection for the coronary arteries [1][2].
Let's break the older eponym down:
- "Mucocutaneous" = mucous membranes (lips, tongue, conjunctivae) + cutaneous (skin) → tells you the hallmark target tissues
- "Lymph node syndrome" = cervical lymphadenopathy is a cardinal feature
The disease was first described in 1967 by Dr Tomisaku Kawasaki in Japan.
Key conceptual points:
- It is a self-limiting condition: without treatment, the acute febrile illness lasts an average of 12 days and resolves spontaneously [1][2].
- However, the reason we care deeply about KD is not the fever itself — it is the coronary artery abnormalities (CAA): 20–25% of untreated children develop coronary artery abnormalities, but < 5% of children treated with IVIG develop CAA [2]. This is why early recognition and treatment are paramount.
- KD is the most common cause of acquired heart disease in children in developed countries [1][2], having surpassed acute rheumatic fever in this role.
High Yield
KD has replaced rheumatic heart disease as the #1 cause of acquired heart disease in children in the developed world. The entire management strategy revolves around preventing coronary artery aneurysms.
2. Epidemiology
| Population | Approximate Annual Incidence (per 100,000 children < 5 y) |
|---|---|
| Japan | ~300–350 (highest worldwide) |
| South Korea | ~200 |
| Hong Kong / Taiwan | ~70–80 |
| USA (Asian descent) | ~30–50 |
| USA (non-Hispanic white) | ~10–20 |
| Europe | ~5–15 |
- Age: 80–90% of cases occur in children < 5 years of age [2], with a peak at ~2–3 years [1]. Rare in neonates (< 3 months) and in children > 8 years.
- Why the age restriction? The prevailing theory is that the immature immune system in young children responds to the unknown trigger with exuberant inflammation; older children and adults have immunological maturity that tempers this response.
- However, "incomplete" or "atypical" KD is more common at the extremes of age (infants < 6 months and children > 5 years) — and these are paradoxically the groups at highest risk for coronary complications because diagnosis is often delayed.
- Sex: Males > Females (approximately 1.5:1) [1][2].
- Recurrence: ~3% recurrence rate, most within 2 years of the first episode.
- Family clustering: Siblings have a 10-fold increased risk; if one twin is affected, concordance in the other twin is ~13%.
- Seasonal peak in winter and spring in temperate climates [1].
- In Hong Kong, peaks tend to occur in spring/summer.
- Epidemics have been described, further supporting an infectious trigger.
| Risk Factor | Explanation |
|---|---|
| Asian ethnicity (especially Japanese, Korean, Chinese) | Genetic susceptibility — highest incidence worldwide |
| Age 6 months – 5 years | Immature immune response to unknown trigger |
| Male sex | Unknown mechanism; possibly X-linked immunoregulatory factors |
| Family history of KD | Genetic predisposition (see below) |
| Siblings of affected child | 10× increased risk |
3. Anatomy & Function: Why the Coronary Arteries?
To understand why KD is so dangerous, you need to understand what it does to coronary artery walls.
The coronary arteries are medium-sized muscular arteries with three layers:
- Tunica intima — endothelial cells + subendothelial connective tissue
- Tunica media — smooth muscle cells + elastic laminae (internal and external elastic lamina)
- Tunica adventitia — connective tissue, vasa vasorum, nerves
The exact reason is unknown, but the leading hypothesis is:
- KD causes a pan-vasculitis — inflammation of all three layers (intima, media, adventitia).
- In the acute phase, neutrophilic infiltration and edema affect the vessel wall.
- This is followed by CD8+ T-cell and macrophage-predominant infiltration of the media and adventitia.
- Destruction of the internal elastic lamina (IEL) and smooth muscle cell necrosis in the media are the key pathological events. Once the IEL is destroyed, the structural integrity of the arterial wall is lost → the wall balloons outward under arterial pressure → aneurysm formation.
- The coronary arteries are particularly susceptible because:
- They are exposed to high pulsatile pressures (directly off the aortic root).
- They have relatively thin walls for the hemodynamic stress they bear.
- They have a rich vasa vasorum that facilitates inflammatory cell infiltration.
| Artery | Territory Supplied |
|---|---|
| Left main coronary artery (LMCA) → LAD + LCx | LAD: anterior wall, anterior septum, apex. LCx: lateral wall, posterior wall (in left-dominant) |
| Right coronary artery (RCA) | Inferior wall, RV, SA node, AV node (in right-dominant) |
- Proximal segments of coronary arteries (especially the proximal LAD and proximal RCA) are the most commonly affected in KD.
- Coronary artery aneurysms are classified by size (see Classification section).
4. Etiology & Pathophysiology
4.1 Etiology: The Unknown Trigger
The etiology of KD remains unknown. Theories suggest there may be an immunological, infectious, and genetic component in the pathogenesis. [2]
Despite decades of research, no single causative agent has been identified. The current best understanding is a multifactorial model:
Evidence supporting an infectious trigger [1]:
- Seasonal peaks in winter/spring
- Epidemics (waves of cases in Japan)
- Peak incidence in toddlers (6m–5y) — consistent with first exposure to a common pathogen
- Clinical similarity to known infectious diseases (scarlet fever, adenovirus, measles)
- Rarity in infants < 3 months (protected by maternal antibodies) and adults (prior immunity)
Candidate agents that have been investigated (none proven): coronaviruses, adenoviruses, parvovirus B19, EBV, retroviruses, bacterial superantigens (staphylococcal / streptococcal), Mycoplasma pneumoniae, etc.
Superantigen theory: One prominent hypothesis is that a superantigen (a protein that non-specifically activates large numbers of T cells by cross-linking TCR Vβ chains to MHC-II molecules) triggers the massive immune activation seen in KD. This would explain the polyclonal T-cell activation and cytokine storm.
Increased risk among family members [1]. Suggested susceptibility genes include [1]:
- ITPKC (inositol-trisphosphate 3-kinase C) — a negative regulator of T-cell activation; polymorphisms lead to unchecked T-cell activation
- FCGR2A — encodes Fc gamma receptor IIA (involved in IgG-mediated immune responses)
- BLK (B lymphocyte kinase) — involved in B-cell signalling
- CD40 — a costimulatory molecule on antigen-presenting cells critical for T-cell activation
- CASP3 (caspase 3) — involved in apoptosis of immune cells
The genetic component explains why KD is 10–20× more common in Japanese children than in European children, even when they live in the same country.
The final common pathway regardless of trigger is an aberrant immune response:
- The unknown agent activates innate and adaptive immunity.
- Massive cytokine release (TNF-α, IL-1, IL-6, IFN-γ) → systemic inflammation.
- Activation of endothelial cells → upregulation of adhesion molecules → inflammatory cell infiltration of vessel walls.
Here is the stepwise pathophysiological cascade:
Phase-by-phase vascular pathology:
| Phase | Timing | Vascular Pathology |
|---|---|---|
| Stage I | Days 0–9 | Perivasculitis of small arteries, arterioles, venules, capillaries. Pericarditis, myocarditis, endocardial inflammation. Coronary arteries show neutrophilic infiltration of media/adventitia. |
| Stage II | Days 12–25 | Pan-vasculitis of medium-sized arteries including coronaries. Destruction of IEL and media → aneurysm formation. Thrombosis may occur within aneurysms. |
| Stage III | Days 28–31 | Granulation tissue formation. Waning acute inflammation. |
| Stage IV | Weeks–Years | Scar formation, intimal thickening (myofibroblastic proliferation), stenosis. Giant aneurysms may persist. |
Understanding why each clinical feature occurs is the key to remembering them:
| Feature | Pathophysiological Basis |
|---|---|
| High fever | Massive cytokine release (IL-1, IL-6, TNF-α) resets the hypothalamic thermostat upward. Antipyretics often fail because the inflammatory drive is overwhelming. |
| Bilateral conjunctival injection | Vasculitis of conjunctival blood vessels → hyperemia. Non-exudative because it is vascular inflammation, not infection. |
| Perilimbal sparing | The limbus (junction of cornea and sclera) has a different blood supply (avascular cornea); the bulbar conjunctival vessels are inflamed while limbal vessels are relatively spared → characteristic clear ring around the iris. |
| Oral mucosal changes (strawberry tongue, cracked lips) | Vasculitis of mucosal and submucosal vessels → edema, erythema. Papillae hypertrophy on the tongue → strawberry appearance. Lips dry and crack from mucosal inflammation. |
| Cervical lymphadenopathy | Reactive lymph node hyperplasia from systemic immune activation. Usually unilateral (≥1.5 cm), unlike the bilateral symmetric lymphadenopathy of most viral infections. |
| Extremity changes (edema → desquamation) | Acute: vasculitis of dermal/subcutaneous vessels → increased capillary permeability → non-pitting edema and erythema of hands/feet. Subacute: once inflammation subsides, the epidermis that was damaged desquamates, starting periungually (around the nails). |
| Polymorphous rash | Vasculitis of dermal vessels → variable skin eruptions. Characteristically NOT vesicular (no blisters). |
| Irritability | Likely due to aseptic meningitis — CSF shows pleocytosis with normal glucose and protein, suggesting meningeal inflammation without bacterial infection. |
| Coronary artery aneurysms | See above: destruction of IEL and media → loss of wall integrity → dilation under arterial pressure. |
| Thrombocytosis (subacute) | Reactive thrombocytosis from acute inflammation (IL-6 stimulates thrombopoietin production). Platelet counts may reach 700,000–1,000,000/μL in the subacute phase. |
5. Classification
5.1 By Clinical Criteria: Complete vs. Incomplete (Atypical) KD
Defined by the AHA 2017 criteria (updated from 2004):
- Fever ≥ 5 days PLUS ≥ 4 of 5 principal clinical features (see Clinical Features below)
- OR fever ≥ 5 days + < 4 features BUT coronary artery abnormalities on echocardiography
The 5 principal clinical features (mnemonic: "CRASH and Burn" — Conjunctivitis, Rash, Adenopathy (cervical), Strawberry tongue / oral mucosal changes, Hand and foot changes + Burn = Fever)
- Patients (especially infants < 6 months and children > 5 years) who have prolonged unexplained fever ≥ 5 days and 2–3 of the principal features
- These patients are at HIGHER risk for coronary artery complications because diagnosis is delayed.
- The AHA algorithm uses supplementary laboratory criteria and echocardiography to support the diagnosis (detailed in Diagnostic section — next response).
Exam Trap
"Incomplete KD" does NOT mean a milder form of the disease. It means the patient does not meet full diagnostic criteria but still has KD. These patients are actually at HIGHER risk of coronary complications due to delayed diagnosis. Never dismiss a child with prolonged unexplained fever just because they don't tick all 5 boxes.
| Classification | Coronary Artery Internal Diameter (Z-score) | Description |
|---|---|---|
| No involvement | Z-score < 2 | Normal |
| Dilation only | Z-score 2 to < 2.5; or initial Z < 2 with ↓ in Z-score ≥ 1 | Mild dilation |
| Small aneurysm | Z-score ≥ 2.5 to < 5 | |
| Medium aneurysm | Z-score ≥ 5 to < 10; or absolute dimension 5–8 mm | |
| Giant aneurysm | Z-score ≥ 10; or absolute dimension ≥ 8 mm | Highest risk of thrombosis, MI, death |
Z-scores are used because absolute coronary artery dimensions vary with body surface area (BSA). A Z-score normalizes the measurement to the child's BSA.
| Phase | Timing | Key Features |
|---|---|---|
| Acute febrile phase | Weeks 1–2 | High fever, all principal clinical features present, myocarditis, pericarditis |
| Subacute phase | Weeks 2–4 | Fever resolves, periungual desquamation, thrombocytosis, highest risk of coronary aneurysm formation and sudden death |
| Convalescent phase | Weeks 4 to 6–8 | Clinical signs resolve, ESR normalises, Beau's lines may appear on nails |
High Yield
The subacute phase (weeks 2–4) is the most dangerous period — this is when coronary artery aneurysms develop, thrombocytosis peaks, and the risk of MI/sudden death is greatest. If you only remember one thing about timing, remember this.
6. Clinical Features
6.1 Diagnostic (Principal) Clinical Features
These are the 5 cardinal features used for diagnosis. Below I detail each with its inline pathophysiological basis.
- Description: Bilateral, painless, non-exudative (no pus, no crusting) injection of the bulbar conjunctivae (the white of the eye) with characteristic perilimbal sparing (a clear zone around the iris) [1][2].
- Pathophysiology: Small vessel vasculitis in the conjunctiva → hyperemia. Non-exudative because this is a sterile inflammatory process, not an infectious conjunctivitis. The limbal region is relatively avascular (the cornea has no blood vessels) → sparing.
- Timing: Begins shortly after fever onset; resolves in the subacute phase.
- DDx clue: Exudative (purulent) conjunctivitis suggests bacterial infection, NOT KD. Anterior uveitis (detected on slit lamp) can also occur in KD.
- "Strawberry tongue": Erythematous, oedematous tongue with prominent fungiform papillae (looks like a strawberry) — due to vasculitis of lingual vessels and papillae hypertrophy.
- Dry, red, cracked (fissured) lips: Mucosal vasculitis → desiccation and erythema → fissuring.
- Diffuse oropharyngeal erythema: Erythema of the oral and pharyngeal mucosa.
- Pathophysiology: Vasculitis of mucosal/submucosal arterioles → edema, erythema, epithelial disruption.
- Note: No oral ulcers or pharyngeal exudates — if you see ulcers, think of other diagnoses (e.g., HSV, Stevens-Johnson syndrome, Behçet's disease).
- Description: Variable morphology — can be maculopapular, diffuse erythroderma, erythema multiforme-like, or scarlatiniform. Often accentuated in the perineal area (groin/diaper area). Never vesicular or bullous [1].
- Pathophysiology: Dermal vasculitis → variable patterns of skin inflammation.
- Timing: Usually appears within 5 days of fever onset.
- Special sign: BCG scar erythema/induration (BCGitis) [1] — erythema and induration at the site of previous BCG vaccination. This is relatively specific for KD, especially in populations where BCG vaccination is routine (like Hong Kong). Mechanism: cross-reactive immune activation against mycobacterial heat-shock proteins expressed at the BCG scar site during the KD immune response.
High Yield – BCGitis in Hong Kong
BCG scar erythema/induration is an important and somewhat specific early sign of KD, especially relevant in Hong Kong where BCG is given at birth. If you see a febrile child with a red, swollen BCG scar — think KD!
Acute phase:
- Erythema of palms and soles + firm, fusiform (non-pitting) swelling/induration of hands and feet [1][2].
- Pathophysiology: Vasculitis of dermal and subcutaneous vessels → increased vascular permeability → interstitial edema. The swelling is firm because it is within the relatively tight fascial compartments of the hands and feet.
Subacute phase (characteristic):
- Periungual desquamation — skin peeling beginning around the fingernails and toenails, then spreading to the palms and soles [1][2].
- Pathophysiology: The acutely inflamed epidermis undergoes necrosis during the vasculitic phase; as the inflammation subsides, the dead superficial layers slough off, starting at the nail folds where skin turnover is highest.
- Timing: Typically occurs 10–21 days after fever onset.
- Description: Usually unilateral, ≥ 1.5 cm diameter, firm, non-fluctuant, mildly tender [1][2].
- Pathophysiology: Reactive lymph node hyperplasia from regional and systemic immune activation. The predilection for unilateral cervical nodes (rather than diffuse lymphadenopathy) may relate to the drainage pattern from the oropharynx, which is heavily involved in KD inflammation.
- Note: This is the least common of the 5 cardinal features and is sometimes the feature that causes "incomplete" KD to be missed.
6.2 Non-Principal Clinical Features (Multi-System Involvement)
KD is a systemic vasculitis; virtually any organ can be involved. These features are not part of the diagnostic criteria but are very commonly present and may be the presenting complaint.
This is the most important system involvement:
- Pericarditis, myocarditis, endocarditis [1] — a "pan-carditis" similar to rheumatic fever.
- Myocarditis (present in ~50–70% during acute phase): cytokine-mediated and direct inflammatory infiltration of myocardium → decreased contractility → heart failure (tachycardia, gallop rhythm, poor feeding).
- Pericarditis: pericardial inflammation → small pericardial effusion (usually not hemodynamically significant).
- Valvulitis: usually mitral regurgitation (most common valve lesion).
- Coronary artery abnormalities: dilations/aneurysms — THE major complication (detailed in Complications section).
- Dysrhythmias: 1st degree AV block, PR prolongation.
- Diarrhea, vomiting, abdominal pain — from mesenteric vasculitis and mucosal inflammation.
- Hepatitis — mild transaminitis; hepatic vasculitis.
- Pancreatitis — pancreatic duct vasculitis.
- Hydrops of the gallbladder [1] — gallbladder distension without calculi, seen on ultrasound. Due to vasculitis of the gallbladder wall and cystic duct → obstruction and edema → acalculous cholecystitis. This is a fairly specific finding and can be the presenting complaint.
- Pneumonitis — vasculitis of pulmonary vessels → interstitial lung inflammation.
- Cough, rhinorrhea (may mimic a viral URI and delay diagnosis).
- Extreme irritability — this is very characteristic and present in the majority of KD patients. Far more pronounced than expected for the degree of fever. Likely due to aseptic meningitis (CSF: lymphocytic pleocytosis, normal glucose, mildly elevated protein) and/or cerebral vasculitis.
- Sensorineural hearing loss (SNHL) [1] — vasculitis of cochlear vessels. Usually reversible but can be permanent.
- Facial nerve palsy (rare).
- Urethritis / meatitis — sterile pyuria (WBCs in urine without bacterial growth) is common. This reflects urethral mucosal inflammation, not UTI. Can mislead clinicians into treating for UTI.
- Arthritis / arthralgia — affects small joints (hands) in the first week; larger joints (knees, hips) in the second week. Due to synovial vasculitis.
- BCGitis (BCG scar erythema/induration) — see above.
- Hemophagocytic lymphohistiocytosis (HLH) — KD is a recognized trigger for secondary HLH (macrophage activation syndrome) due to the massive cytokine storm. Presents with persistent fever, cytopenias, hyperferritinemia, hepatosplenomegaly [2].
- Anterior uveitis — slit-lamp exam may reveal mild non-granulomatous anterior uveitis.
| Phase | Timing | Symptoms | Signs |
|---|---|---|---|
| Acute febrile phase | Week 1–2 | High fever (often > 39°C, unresponsive to antipyretics), extreme irritability, poor feeding, diarrhea, vomiting, abdominal pain, joint pain | All 5 principal features (conjunctival injection, oral changes, rash, extremity swelling, cervical LN), BCGitis, tachycardia, gallop (if myocarditis), hepatomegaly |
| Subacute phase | Week 2–4 | Fever resolves, irritability improves | Periungual desquamation, thrombocytosis (platelets may exceed 1,000,000/μL), coronary artery aneurysms develop (highest risk of sudden death) |
| Convalescent phase | Week 4 to 6–8 | Asymptomatic | Deep transverse grooves on nails (Beau's lines), ESR normalises, CRP normalises (CRP normalises before ESR) |
| Symptom | Frequency | Pathophysiological Basis |
|---|---|---|
| High fever (> 39°C, often > 40°C) persisting ≥ 5 days, unresponsive to antibiotics and poorly responsive to antipyretics | 100% (by definition) | IL-1, IL-6, TNF-α reset hypothalamic set point. Unlike infectious fevers that often respond partially to paracetamol/ibuprofen, the overwhelming cytokine drive in KD means antipyretics only transiently and partially reduce fever. |
| Irritability (often extreme, inconsolable) | ~80–90% | Aseptic meningitis (meningeal vasculitis → CSF pleocytosis → meningeal irritation) and/or cerebral vasculitis. |
| Poor oral intake / feeding | Common | Oral pain from cracked lips and strawberry tongue; systemic malaise. |
| Diarrhea, vomiting, abdominal pain | ~60% | Mesenteric vasculitis, intestinal mucosal inflammation, gallbladder hydrops. |
| Arthralgia / joint swelling | ~30% | Synovial vasculitis → inflammatory arthritis. |
| Dysuria / urethral discharge | ~20% | Urethritis from mucosal vasculitis → sterile pyuria. |
| Cough, rhinorrhea | ~35% | Respiratory mucosal inflammation. Can mimic URTI and delay KD diagnosis. |
| Sign | Description | Pathophysiological Basis |
|---|---|---|
| Fever | Sustained high-grade (remittent), ≥ 5 days | Cytokine-mediated (see above) |
| Bilateral non-exudative conjunctival injection with perilimbal sparing | Red eyes without discharge; clear rim around iris | Conjunctival vasculitis; limbus avascular → spared |
| Strawberry tongue | Erythematous tongue with prominent papillae | Lingual vessel vasculitis → papillae hypertrophy + erythema |
| Dry, cracked, erythematous lips | Fissured, bleeding lips | Labial mucosal vasculitis → desiccation, epithelial cracking |
| Polymorphous rash (never vesicular) | Maculopapular, erythema multiforme-like, scarlatiniform; perineal accentuation | Dermal vasculitis → variable inflammation patterns |
| Erythema/edema of hands and feet | Non-pitting, fusiform swelling of dorsum of hands/feet; erythema of palms/soles | Subcutaneous/dermal vasculitis → increased vascular permeability → edema |
| Periungual desquamation | Skin peeling starting around nails (subacute phase) | Necrosis of epidermis during acute vasculitic phase → shedding during recovery |
| Unilateral cervical lymphadenopathy (≥ 1.5 cm) | Firm, non-suppurative, mildly tender | Regional reactive hyperplasia from oropharyngeal inflammation |
| BCG scar erythema / induration | Red, swollen BCG scar | Cross-reactive immune activation at site of mycobacterial antigen deposition |
| Tachycardia, gallop rhythm | Signs of myocardial dysfunction | Myocarditis → decreased contractility |
| Pericardial friction rub (rare) | Pericarditis | Pericardial inflammation |
| Hepatomegaly | Mild hepatic enlargement | Hepatic vasculitis / hepatitis |
| Hydrops of gallbladder (on USS) | RUQ mass / tenderness in young child | Vasculitis of gallbladder wall / cystic duct → acalculous cholecystitis |
- BCG vaccination is given at birth in Hong Kong → BCGitis is a useful early clue.
- Incidence is intermediate between Japan (highest) and Western countries — estimated ~70–80 per 100,000 children < 5 years.
- Ethnicity: Chinese children have a genetic predisposition similar to (but lower than) Japanese children. ITPKC polymorphisms have been confirmed in Chinese populations.
- KD is a notifiable disease in Hong Kong — physicians are required to report cases to the Centre for Health Protection (CHP).
- The local treatment protocol follows AHA guidelines (IVIG + aspirin — to be detailed in Management section).
| Concept | Detail |
|---|---|
| Most common acquired heart disease in children (developed world) | KD — surpassed rheumatic fever |
| Peak age | 6 months – 5 years (peak 2–3 years) |
| Incomplete KD = HIGHER risk | Delayed diagnosis → more coronary damage |
| Giant aneurysm cutoff | ≥ 8 mm or Z-score ≥ 10 |
| Most dangerous phase | Subacute (weeks 2–4): coronary aneurysms + thrombocytosis |
| Classic triad of labs in subacute phase | Thrombocytosis, elevated ESR, elevated CRP |
| Non-exudative conjunctivitis + perilimbal sparing | Almost pathognomonic for KD in a febrile child |
| Coronary artery involvement (untreated) | ~20–25% |
| Coronary artery involvement (IVIG-treated) | < 5% |
| KD can cause MI in children | Thrombosis within coronary aneurysm |
High Yield Summary
Kawasaki Disease — Key Points for Exams:
-
Definition: Acute, self-limiting systemic vasculitis of small-to-medium arteries, predilection for coronary arteries. Most common cause of acquired heart disease in children in the developed world.
-
Epidemiology: Peak age 6m–5y (peak 2–3y), M > F (1.5:1), highest in Asians (Japan #1, HK ~70–80/100k), seasonal (winter/spring).
-
Etiology: Unknown — likely an aberrant immune response to an unknown (? infectious) trigger in genetically susceptible children. Key susceptibility genes: ITPKC, FCGR2A, BLK, CD40.
-
Pathophysiology: Immune activation → cytokine storm → endothelial activation → pan-vasculitis → destruction of internal elastic lamina & medial smooth muscle → coronary artery aneurysm formation.
-
5 Cardinal Features (CRASH and Burn): Conjunctivitis (bilateral, non-exudative, perilimbal sparing), Rash (polymorphous, never vesicular, perineal accentuation), Adenopathy (cervical, unilateral, ≥ 1.5 cm), Strawberry tongue + oral changes (cracked lips, oropharyngeal erythema), Hands/feet changes (edema → desquamation) + Burn (fever ≥ 5 days).
-
Phases: Acute (wk 1–2: fever + principal features), Subacute (wk 2–4: desquamation, thrombocytosis, HIGHEST risk of coronary aneurysm/MI/death), Convalescent (wk 4–8: ESR normalises, Beau's lines).
-
Multi-system involvement: CVS (pancarditis, coronary aneurysms), GI (hydrops of GB, hepatitis), CNS (irritability, aseptic meningitis, SNHL), Resp (pneumonitis), UG (sterile pyuria), MSK (arthritis), BCGitis, HLH.
-
Incomplete KD: Fever ≥ 5 days + 2–3 features → higher risk of coronary complications due to delayed diagnosis. More common in infants < 6m and children > 5y.
-
Untreated: 20–25% develop coronary artery abnormalities. Treated with IVIG: < 5%.
-
BCGitis is a useful early sign, particularly relevant in Hong Kong where BCG is given at birth.
Active Recall - Kawasaki Disease (Definition to Clinical Features)
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf, Section 6.3.3 Kawasaki Disease (p.242) [2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, Section on Kawasaki Disease (p.295) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, Section on Coronary Artery Disease — Non-atherosclerotic CAD (p.384, p.395) [4] Senior notes: Maksim Medicine Notes.pdf, Section 1.3 Ischaemic Heart Disease — Vasculitis causes (p.7) [5] Lecture slides: GC 147. Heart failure and cyanosis in children acyanotic and cyanotic congenital heart disease - Part 1.pdf [6] Lecture slides: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf
Differential Diagnosis of Kawasaki Disease
Kawasaki disease is a clinical diagnosis with no confirmatory laboratory test [1][2]. This means you diagnose it by recognising a pattern of clinical features — and the key challenge is distinguishing KD from the many other conditions that can produce fever + rash + mucocutaneous inflammation in a young child. Getting the DDx wrong has real consequences:
- Miss KD → delayed IVIG → coronary artery aneurysms (20–25% untreated)
- Overdiagnose KD → unnecessary IVIG (expensive, carries small risk of anaphylaxis, transfusion reactions)
The approach is systematic: you consider conditions that mimic each of the cardinal features of KD, then look for the distinguishing features that separate them.
The DDx of KD essentially maps onto the DDx of a febrile child with rash and mucocutaneous inflammation. Felix Lai's pediatrics notes organise this beautifully into three main categories [2]:
Differential diagnosis of KD [2]:
- Viral illnesses (Measles / Echovirus / Adenovirus / EBV) — share many signs of mucocutaneous inflammation but generally lack extremities changes seen in KD
- Toxin-mediated illness (Scarlet fever / Toxic shock syndrome: GAS infection) — generally lack ocular and articular involvement seen in KD
- Drug reactions (Stevens-Johnson syndrome) — inflammatory markers are usually normal or mildly elevated
Let me expand this framework into a comprehensive, exam-ready differential.
3. Differential Diagnosis — Detailed Breakdown
3.1 Viral Infections
These are the most common mimics because viral exanthems in children are far more prevalent than KD.
| Feature | Measles | KD | Why Different |
|---|---|---|---|
| Rash | "Brick-red" maculopapular rash starting on face/behind ears → spreads craniocaudally (head → trunk → extremities) [3] | Polymorphous rash, perineal accentuation, no cephalocaudal spread | Measles rash follows a strict craniocaudal progression due to viremia seeding skin in a wave; KD rash is vasculitis-driven and randomly distributed |
| Conjunctivitis | Present — but exudative (watery/mucopurulent) | Non-exudative, perilimbal sparing | Measles virus directly infects conjunctival epithelium → secretions; KD is sterile vasculitis |
| Pathognomonic sign | Koplik's spots (tiny white/blue-grey papules on buccal mucosa opposite molars) | Strawberry tongue, cracked lips | Koplik's spots are pathognomonic for measles — look for them on the buccal mucosa |
| Cough / Coryza | Prominent — the classic "3 Cs" (Cough, Coryza, Conjunctivitis) | Respiratory symptoms less prominent (~35%) | Measles virus has tropism for respiratory epithelium |
| Extremity changes | Absent — no hand/foot swelling or desquamation | Edema → periungual desquamation | This is a key distinguishing feature [2] |
| Epidemiology | Now rare in HK due to vaccination (MMR); think of unvaccinated / travellers | Year-round, no vaccine |
Exam Clue
The presence of Koplik's spots essentially rules IN measles and rules OUT KD. If you see hand/foot swelling and periungual desquamation, that strongly favours KD over measles.
| Feature | Adenovirus | KD | Why Different |
|---|---|---|---|
| Conjunctivitis | Often exudative (pharyngoconjunctival fever); can be follicular | Non-exudative, perilimbal sparing | Adenovirus directly infects conjunctival epithelium → pus |
| Pharyngitis | Prominent exudative pharyngitis / tonsillitis | Diffuse oropharyngeal erythema without exudate | |
| Rash | Maculopapular, often mild and transient | Polymorphous, perineal accentuation | |
| Extremity changes | Absent | Present | Key distinguisher [2] |
| Fever duration | Usually < 5 days; self-limiting | ≥ 5 days by definition | |
| GI symptoms | Prominent (vomiting, diarrhea — "adeno-enteric") | GI involvement in ~60% but with hydrops of GB, hepatitis |
| Feature | EBV/IM | KD | Why Different |
|---|---|---|---|
| Age | Older children / adolescents (typically > 5y) | 6m–5y (peak 2–3y) | EBV infection in young children is usually subclinical; IM is an adolescent disease |
| Lymphadenopathy | Generalised, especially posterior cervical + epitrochlear [5] | Unilateral anterior cervical ≥ 1.5 cm | KD lymphadenopathy overlies the SCM; EBV involves posterior cervical chain and is bilateral |
| Splenomegaly | Present in 50–60% [5] | Not a feature | |
| Rash | Maculopapular, especially if given ampicillin/amoxicillin ("ampicillin rash") [5] | Polymorphous, perineal accentuation | |
| Atypical lymphocytes | Present on PBS (> 10%) | Absent (leucocytosis with neutrophilia) | |
| Extremity changes | Absent | Present | [2] |
| Diagnosis | Monospot test (heterophile antibodies) or EBV-specific serology (VCA IgM) | Clinical diagnosis |
| Feature | HFMD | KD | Why Different |
|---|---|---|---|
| Oral lesions | Vesicles / ulcers on palate, buccal mucosa, tongue | Cracked lips, strawberry tongue — no ulcers, no vesicles | HFMD causes epithelial cytolysis → vesicle → ulcer; KD causes vasculitis → erythema without vesicle formation |
| Rash | Vesicular — hands, feet, buttocks | Never vesicular | This is a critical distinction [1] |
| Fever | Low-grade, usually < 5 days | High-grade, ≥ 5 days | |
| Conjunctivitis | Usually absent | Bilateral, non-exudative |
Key Distinguishing Feature
KD rash is NEVER vesicular or bullous [1]. If you see vesicles, think HFMD, HSV, or VZV — not KD.
| Feature | Roseola | KD | Why Different |
|---|---|---|---|
| Fever pattern | High fever for 3–4 days → rash appears AFTER fever resolves [3] | Fever persists WITH rash (rash appears during febrile phase) | In roseola, the rash is a post-viral exanthem that emerges as T-cells clear the virus; in KD, vasculitis-driven rash appears while inflammation is ongoing |
| Rash | Maculopapular, starts on trunk → spreads peripherally, spares face [3] | Polymorphous, perineal accentuation | |
| Extremity changes | Absent | Present | |
| Age | 6m–2y (same overlap with KD) | 6m–5y | |
| Seizures | Febrile seizures common (high fever in young infant) | Irritability, but seizures uncommon |
| Feature | Parvovirus B19 | KD | Why Different |
|---|---|---|---|
| Rash | "Slapped cheek" appearance → reticular (lace-like) maculopapular rash on arms/trunk [3] | Polymorphous, never "slapped cheek" pattern | Parvovirus directly infects erythroid precursors and the facial rash is immune-complex mediated |
| Conjunctivitis | Absent | Present | |
| Extremity changes | Absent | Present | |
| Arthritis | Common in adults, less so in children | Possible (~30%) | |
| Aplastic crisis | Risk in sickle cell disease / chronic hemolytic anemia patients | Not a feature |
3.2 Bacterial / Toxin-Mediated Illnesses
This is a very important DDx in Hong Kong (GAS pharyngitis is common in children).
| Feature | Scarlet Fever | KD | Why Different |
|---|---|---|---|
| Strawberry tongue | Present (shared feature!) [3] | Present | Both cause strawberry tongue — cannot distinguish on this feature alone |
| Rash | Sandpaper-textured, blanching, erythematous; Pastia's lines (linear petechiae in skin creases, e.g. antecubital fossae) | Polymorphous; perineal accentuation | Scarlet fever toxin (SpeA/SpeC) causes diffuse capillary damage in a uniform pattern; KD vasculitis is patchy |
| Conjunctivitis | Usually absent | Bilateral, non-exudative | Key distinguisher [2]: "toxin-mediated illness generally lacks ocular and articular involvement" |
| Extremity changes | Desquamation (late) — can overlap with KD | Edema → periungual desquamation | Scarlet fever desquamation is more diffuse ("peeling sunburn"), less periungual |
| Pharyngitis | Exudative tonsillopharyngitis (pus on tonsils) | Diffuse erythema — no exudate | GAS directly invades tonsillar tissue; KD is vasculitis of mucosal vessels |
| Periorbital pallor | Classic sign (circumoral pallor) | Not a feature | |
| Diagnosis | Throat culture +ve for GAS, rapid strep antigen test +ve, elevated ASO titre | Clinical diagnosis; throat swab typically negative | |
| Response to antibiotics | Fever resolves within 24–48h of penicillin | Unresponsive to antibiotics [1] |
High Yield — Scarlet Fever vs KD
Both scarlet fever and KD cause strawberry tongue and desquamation. The key distinguishing features are: (1) conjunctivitis — present in KD, absent in scarlet fever; (2) exudative pharyngitis — present in scarlet fever, absent in KD; (3) response to antibiotics — scarlet fever responds rapidly, KD does not; (4) extremity edema — present in KD, absent in scarlet fever.
| Feature | Staphylococcal TSS | KD | Why Different |
|---|---|---|---|
| Pathogenesis | Staphylococcal exotoxins (TSST-1) act as superantigens → massive T-cell activation → cytokine storm → shock [7] | Unknown trigger → immune activation → vasculitis | Both involve superantigen-like massive immune activation — this is why TSS is a close mimic |
| Fever | High, acute onset | High, ≥ 5 days | |
| Rash | Diffuse erythroderma ("sunburn-like"), followed by desquamation (palms + soles) [7] | Polymorphous, perineal accentuation | TSS rash is more uniformly erythrodermal |
| Hypotension / Shock | Defining feature — sBP ≤ 90 mmHg; multi-organ failure | Hypotension is NOT typical (may occur with severe myocarditis, but uncommon) | This is THE key distinguisher — TSS causes frank shock; KD typically does not |
| Conjunctivitis | Can occur (mucous membrane hyperemia) | Bilateral, non-exudative, perilimbal sparing | Overlap exists |
| Strawberry tongue | Can occur | Present | Overlap |
| Coronary aneurysms | Not a feature | Hallmark complication | |
| Source | Often identifiable (wound, tampon, nasal packing) [7] | No identifiable source | |
| Course | Rapid deterioration → shock within hours | Gradual onset, self-limiting over days–weeks |
| Feature | SSSS | KD | Why Different |
|---|---|---|---|
| Age | Primarily < 6 years [7] — overlaps with KD | 6m–5y | |
| Skin | Generalized erythema → flaccid bullae → Nikolsky sign positive (gentle lateral pressure causes skin to shear off) | Polymorphous rash — never bullous | SSSS is caused by exfoliative toxins A/B that cleave desmoglein 1 in the superficial epidermis → intra-epidermal split; KD is vasculitis without epidermal cleavage |
| Mucous membrane | NOT involved [7] | Prominently involved (lips, tongue, pharynx) | This is the key distinguisher |
| Conjunctivitis | Usually absent | Present | |
| Biopsy | Split beneath stratum corneum (superficial) | Not biopsied in typical KD |
- Relevant in HK (exposure to contaminated water, especially after typhoons/heavy rain)
- Fever, conjunctival suffusion (redness without exudate — can mimic KD), myalgia, jaundice
- Distinguishing: jaundice prominent, renal failure (Weil's disease), exposure history, leptospira serology/PCR positive
- Lacks extremity changes and strawberry tongue
3.3 Drug Hypersensitivity Reactions
| Feature | SJS/TEN | KD | Why Different |
|---|---|---|---|
| Drug history | Almost always drug-related (antiepileptics, allopurinol, sulfonamides, NSAIDs) | No drug exposure required | |
| Skin | Target lesions (atypical) → vesicles/bullae → epidermal detachment (Nikolsky +) | Polymorphous — never vesicular/bullous | SJS/TEN: full-thickness epidermal necrosis; KD: vasculitis without epidermal necrosis |
| Mucous membranes | Severely involved — oral, ocular, genital erosions (painful) | Involved (cracked lips, strawberry tongue) but no erosions/ulcers | SJS/TEN mucositis is erosive and extremely painful; KD mucositis is erythematous without ulceration |
| Inflammatory markers | Usually normal or mildly elevated [2] | Markedly elevated (CRP, ESR) | This is explicitly stated in the notes as a distinguishing feature [2] |
| Skin pain | Severe — out of proportion to findings | Not a prominent feature | |
| Fever | Present but often lower grade | High-grade, ≥ 5 days | |
| Conjunctivitis | Present — but purulent, with pseudomembrane formation | Non-exudative, perilimbal sparing |
- Fever + rash + eosinophilia + internal organ involvement (hepatitis, nephritis)
- Drug exposure 2–8 weeks prior (antiepileptics, allopurinol, sulfonamides)
- Distinguishing: prominent eosinophilia, drug history, facial edema, hepatitis dominant, no coronary artery involvement
- Fever, urticaria / erythema multiforme-like rash, arthralgia — typically 1–3 weeks after drug exposure (commonly cefaclor in children)
- Distinguishing: drug history, urticarial component, normal inflammatory markers, self-limiting after drug withdrawal
3.4 Other Inflammatory / Autoimmune Conditions
| Feature | sJIA | KD | Why Different |
|---|---|---|---|
| Fever pattern | Quotidian (daily spike to ≥ 39°C with return to baseline or below) — characteristically "spiking" with double quotidian pattern | Sustained/remittent high fever | sJIA has a very characteristic fever pattern: high spikes 1–2× daily with return to normal between spikes |
| Rash | Evanescent salmon-pink macular rash (appears during febrile spikes, disappears when afebrile) | Polymorphous, persistent | sJIA rash is transient and Koebner-positive; KD rash persists |
| Arthritis | Prominent — polyarticular, often symmetric | May have arthritis but less prominent | |
| Lymphadenopathy | Generalised | Unilateral cervical | |
| Hepatosplenomegaly | Common | Uncommon | |
| Serositis | Pericarditis, pleuritis | Pericarditis possible | |
| Ferritin | Markedly elevated (often > 10,000 → consider MAS) | Mildly elevated | |
| Duration | Chronic (weeks–months) | Self-limiting (~12 days untreated) |
- A medium-vessel vasculitis (same Chapel Hill category as KD) [4]
- Can cause fever, rash (livedo reticularis, purpura, nodules), myalgia, neuropathy, renal involvement, GI ischemia
- Distinguishing: PAN affects older children/adults, causes cutaneous nodules along arteries, hypertension (renal artery involvement), peripheral neuropathy — features NOT seen in KD
- PAN is NOT associated with ANCA [4]; diagnosed by biopsy or angiography showing micro-aneurysms
| Feature | HSP | KD | Why Different |
|---|---|---|---|
| Rash | Palpable purpura — symmetrical, buttocks + extensor surfaces of lower limbs [6] | Polymorphous — not purpuric | HSP: IgA immune-complex deposition in dermal vessels → leucocytoclastic vasculitis → purpura; KD: non-purpuric vasculitis |
| Abdominal pain | Colicky — intussusception risk [6] | May have abdominal pain (hydrops of GB, pancreatitis) | |
| Renal | Glomerulonephritis (IgA nephropathy) | Not typically renal | |
| Arthritis | Present | Present | |
| Coronary involvement | Not a feature | Hallmark |
This is a critically important modern DDx that emerged post-COVID-19.
| Feature | MIS-C | KD | Why Different |
|---|---|---|---|
| Temporal association | 2–6 weeks after SARS-CoV-2 infection / exposure | No known infectious association | |
| Age | Older — median 8–9 years (school-age) | Peak 2–3 years | |
| Ethnicity | Disproportionately affects Black / Hispanic children | Disproportionately affects Asian children | |
| Cardiac involvement | LV dysfunction / shock far more prominent; coronary dilation less common than in KD | Coronary artery aneurysms are the hallmark; LV dysfunction less common | |
| GI symptoms | Very prominent — vomiting, diarrhea, abdominal pain (often the presenting complaint) | GI in ~60% but less dominant | |
| Shock / Hypotension | Common — many require ICU for vasopressor support | Uncommon | |
| Lab | Markedly elevated ferritin, D-dimer, troponin, BNP; lymphopenia | Elevated ESR/CRP; thrombocytosis; less prominent ferritin/D-dimer elevation | |
| COVID-19 link | SARS-CoV-2 PCR or serology positive | Negative | |
| Overlap with KD | ~50% of MIS-C patients meet KD criteria → "KD-like" phenotype | MIS-C can look identical to KD; COVID-19 testing is essential |
High Yield — MIS-C vs KD
MIS-C is a crucial modern DDx. Key differences: MIS-C affects older children, causes more prominent shock/LV dysfunction, has markedly elevated ferritin and D-dimer, and has a temporal link to SARS-CoV-2. Always check COVID-19 serology/PCR in suspected KD, especially in children > 5 years with prominent shock features.
| Feature | Favours KD | Favours Alternative Diagnosis |
|---|---|---|
| Non-exudative conjunctivitis with perilimbal sparing | ✅ KD | Exudative → measles, adenovirus; purulent → bacterial; absent → scarlet fever |
| Extremity changes (edema → desquamation) | ✅ KD | Absent in most viral illnesses [2] |
| Strawberry tongue | KD or scarlet fever | Need other features to distinguish |
| Vesicles / bullae | Never in KD | HFMD, HSV, VZV, SJS/TEN, SSSS |
| Oral ulcers | Not KD | HFMD, HSV, Behçet's, SJS/TEN |
| Response to antibiotics | KD does not respond [1] | Scarlet fever rapidly responds to penicillin |
| Koplik's spots | Not KD | Measles (pathognomonic) |
| Hypotension / shock | Rarely KD (unless severe myocarditis) | TSS, MIS-C |
| Normal / mildly elevated inflammatory markers | Not typical KD | SJS/TEN [2] |
| BCGitis | Strongly suggestive of KD | Not seen in other conditions |
| Coronary artery abnormalities on echo | KD (or MIS-C) | Not seen in infections or drug reactions |
| Drug exposure | Not KD | SJS/TEN, DRESS, serum sickness |
| SARS-CoV-2 positive | MIS-C |
When you encounter a febrile child with rash and mucocutaneous features, use this systematic approach:
Step 1: Duration of fever
- < 5 days → likely viral exanthem; monitor
- ≥ 5 days → must consider KD (and MIS-C) [8]
Step 2: Check for the 5 cardinal features of KD
- If ≥ 4/5 + fever ≥ 5 days → likely complete KD; treat
- If 2–3/5 + fever ≥ 5 days → consider incomplete KD; pursue labs + echo
Step 3: Look for features that EXCLUDE KD
- Vesicles/bullae → NOT KD (think HFMD, HSV, VZV, SJS/TEN)
- Oral ulcers → NOT KD (think HFMD, HSV, Behçet's)
- Exudative pharyngitis → think scarlet fever, adenovirus, EBV
- Frank shock / hypotension → think TSS or MIS-C
- Drug exposure → think SJS/TEN, DRESS
Step 4: Directed investigations to rule out mimics
- Throat swab / rapid strep → scarlet fever
- Monospot / EBV serology → EBV
- Viral PCR (respiratory panel) → adenovirus, enterovirus, measles
- Blood culture → bacterial sepsis / TSS
- COVID-19 PCR + serology → MIS-C
- Skin biopsy (if vesicles/bullae) → SJS/TEN, SSSS
Step 5: Echocardiography
- If KD is suspected (even incomplete) → echo for coronary artery abnormalities
- Finding coronary dilation/aneurysms essentially confirms KD
"VITAMINS" for fever + rash DDx in children:
| Letter | Category | Examples |
|---|---|---|
| V | Viral | Measles, adenovirus, EBV, enterovirus, HHV-6, parvovirus B19 |
| I | Inflammatory | sJIA, PAN, HSP/IgA vasculitis |
| T | Toxin-mediated | Scarlet fever (GAS), TSS (staph/strep), SSSS |
| A | Autoimmune / Allergic | SLE, drug reactions (SJS/TEN, DRESS) |
| M | MIS-C | Post-COVID multisystem inflammatory syndrome |
| I | Idiopathic | KD itself! |
| N | Neoplastic | Leukaemia, lymphoma (consider if fever > 1 week) |
| S | Serum sickness | Serum sickness-like reaction |
High Yield Summary
Differential Diagnosis of Kawasaki Disease — Key Points:
-
Three main categories of KD mimics [2]: Viral illnesses (lack extremity changes), Toxin-mediated illness (lack ocular/articular involvement), Drug reactions (normal/mildly elevated inflammatory markers).
-
Features that EXCLUDE KD: Vesicles/bullae (→ HFMD, HSV, VZV, SJS/TEN), oral ulcers (→ HFMD, Behçet's, SJS/TEN), exudative pharyngitis (→ GAS, adenovirus), Koplik's spots (→ measles), frank shock (→ TSS, MIS-C).
-
Features highly suggestive of KD over mimics: Non-exudative conjunctivitis with perilimbal sparing, extremity edema → periungual desquamation, BCGitis, coronary artery abnormalities on echo.
-
Scarlet fever is the closest bacterial mimic (both have strawberry tongue + desquamation). Distinguish by: conjunctivitis (KD yes, scarlet fever no), exudative pharyngitis (scarlet fever yes, KD no), response to penicillin (scarlet fever yes, KD no).
-
MIS-C is a critical modern DDx: older age, more shock/LV dysfunction, high ferritin/D-dimer, SARS-CoV-2 link. Always check COVID-19 serology in suspected KD.
-
KD is a clinical diagnosis — the DDx is worked through by pattern recognition and directed investigations to exclude mimics, not by a single confirmatory test.
Active Recall - Kawasaki Disease Differential Diagnosis
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf, Section 6.3.3 Kawasaki Disease (p.242–243) [2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, Section on Kawasaki Disease — Differential Diagnosis and Clinical Features (p.295–297) [3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, Section on Fever and Rash — Differential Diagnosis (p.86–89) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, Section on Vasculitis — Chapel Hill Classification (p.1763) [5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, Section on Infectious Mononucleosis — Physical Examination (p.1812) [6] Senior notes: Maksim Surgery Notes.pdf, Section 3.3 Paediatric Surgical Abdomen — HSP (p.336) [7] Senior notes: Ryan Ho Rheumatology.pdf, Section on SSSS and Staphylococcal TSS (p.133) [8] Paediatrics reference: Fever without a source in children 3 to 36 months of age — UpToDate (2026)
Diagnostic Criteria, Algorithm & Investigations for Kawasaki Disease
Kawasaki disease is a clinical diagnosis! [1]
There is no single pathognomonic laboratory test, no specific biomarker, and no confirmatory investigation for KD. You diagnose it by recognising the clinical pattern — fever plus the cardinal mucocutaneous features — and by excluding mimics. Laboratory tests and echocardiography serve two purposes: (1) supporting the diagnosis when features are incomplete, and (2) assessing for complications (especially coronary artery abnormalities).
This is worth understanding from first principles: KD is caused by an unknown trigger, so we have no antigen to test for, no specific antibody, and no PCR target. The diagnosis therefore rests entirely on pattern recognition — which is exactly why understanding the criteria and algorithm is so critical for exams and clinical practice.
2. Diagnostic Criteria
Presence of fever ≥ 5 days AND at least 4/5 of the following physical findings [2]:
| # | Cardinal Feature | Frequency | Key Details |
|---|---|---|---|
| 1 | Bilateral non-exudative bulbar conjunctival injection | > 75% | Usually with typical perilimbal sparing [2]. No discharge, no crusting. |
| 2 | Oral mucosal membrane changes | 90% | Injected or fissured lips ("lipstick sign") [1], injected pharynx, strawberry tongue [2]. No ulcers, no exudate. |
| 3 | Peripheral extremity changes | 50–85% | Acute: erythema of palms/soles, edema of hands/feet [2]. Subacute: periungual desquamation in fingers and toes (week 2–3) [2]. |
| 4 | Polymorphous rash | 70–90% | Maculopapular, diffuse erythroderma, or erythema multiforme–like [1]. Perineal accentuation. Never vesicular. |
| 5 | Cervical lymphadenopathy | 25–70% | At least one lymph node > 1.5 cm in diameter, usually unilateral [2]. |
Important nuances:
- "Fever ≥ 5 days" — this is by convention. In practice, experienced clinicians may diagnose and treat KD before day 5 if all 4/5 features are present and the clinical picture is classic, because waiting until day 5 risks delaying treatment and increases coronary risk. The AHA 2017 statement explicitly allows this.
- The order of appearance of features is variable. Fever is always first. The other features may appear sequentially over the first week — a child examined on day 2 may only have fever + conjunctivitis and then develop the remaining features by day 4–5. Serial examination is essential.
- Periungual desquamation is a SUBACUTE finding — it appears in weeks 2–3, so it is a retrospective confirmation rather than a feature that helps you diagnose KD in the acute phase.
Exam Trap
Don't wait for desquamation to diagnose KD! Desquamation occurs in the subacute phase (weeks 2–3). If you wait for it, you've already missed the treatment window. The other 4 features (conjunctivitis, oral changes, rash, lymphadenopathy) should prompt diagnosis in the acute febrile phase.
2.2 Incomplete Kawasaki Disease [1][2]
This is where the diagnostic algorithm becomes critical. Incomplete KD is defined as:
Fever ≥ 5 days with < 4 principal clinical features [2]
- This does NOT mean a milder disease — recall from previous sections that incomplete KD is more common in infants < 6 months and children > 5 years and carries a higher risk of coronary complications due to delayed diagnosis.
- The AHA algorithm uses supplementary laboratory criteria and echocardiographic findings to support the diagnosis when clinical features alone are insufficient [1][2].
If ≥ 3 of the following 6 criteria are met, treat before echocardiography [2]:
| # | Laboratory Criterion | Threshold | Pathophysiological Basis |
|---|---|---|---|
| 1 | Anaemia | For age | Anaemia of chronic inflammation (hepcidin-mediated iron sequestration from cytokine drive) |
| 2 | Leucocytosis | WBC ≥ 15 × 10⁹/L [2] | Neutrophilia from systemic inflammatory response (IL-6 / G-CSF driven marrow release) |
| 3 | Thrombocytosis | Platelet after D7 ≥ 450 × 10⁹/L [2] | Reactive thrombocytosis from IL-6-stimulated thrombopoietin production; characteristically peaks in subacute phase |
| 4 | Hypoalbuminaemia | Albumin ≤ 30 g/L [2] | Increased vascular permeability from vasculitis → albumin leaks into interstitium; also negative acute-phase reactant (hepatic synthesis ↓ during inflammation) |
| 5 | Elevated ALT | Above upper limit of normal | Hepatic vasculitis / hepatitis |
| 6 | Sterile pyuria | Urine ≥ 10 WBC/HPF [2] | Urethritis from mucosal vasculitis → WBCs in urine without bacterial growth. Important: this is best detected on catheterised or midstream specimen, NOT bag urine |
High Yield
The supplementary lab criteria for incomplete KD are very commonly examined. Memorise the 6 criteria and their thresholds. The key concept: if ≥ 3/6 are met in a child with fever ≥ 5 days + 2–3 cardinal features, you should treat as KD even BEFORE echocardiography [2].
Any 1 of the following 3 is considered a positive echocardiogram [2]:
| # | Echo Criterion | Detail |
|---|---|---|
| 1 | Z-score of LAD or RCA ≥ 2.5 [2] | Z-score normalises coronary dimension to body surface area; ≥ 2.5 = small aneurysm territory |
| 2 | Coronary arteries meet Japanese Ministry of Health criteria [2] | > 3 mm in children < 5 years; > 4 mm in children ≥ 5 years; or diameter of a segment ≥ 1.5× adjacent segment [2] |
| 3 | Presence of ≥ 3 other suggestive features [1][2] | Z-score of LAD or RCA > 2 but < 2.5; perivascular brightness; lack of tapering; pericardial effusion; mitral regurgitation; decreased LV function [2] |
Why these echo findings matter:
- Z-score ≥ 2.5 = the coronary artery is abnormally dilated for the child's body size — this essentially confirms the diagnosis even if clinical criteria are borderline.
- Perivascular brightness = echogenic halo around the coronary artery on ultrasound, reflecting perivascular inflammatory edema/oedema — an early sign of coronary arteritis BEFORE luminal dilation occurs.
- Lack of tapering = normal coronary arteries gradually narrow as they course distally; in KD, inflammation causes uniform calibre (loss of normal taper) — another early sign.
- Pericardial effusion, MR, ↓LV function = evidence of pan-carditis (pericarditis, endocarditis/valvulitis, myocarditis) — supportive of KD as the underlying cause.
Atypical KD is reserved for those with features that are NOT usually present in KD [2], such as renal impairment, macrophage activation syndrome (MAS/HLH), or other unusual organ involvement.
- This is distinct from incomplete KD — "incomplete" means fewer cardinal features; "atypical" means unusual features that make you question the diagnosis.
- In practice, atypical KD should prompt you to reconsider alternative diagnoses while still keeping KD on the differential [1].
This is the critical decision-making pathway for evaluating a child with suspected KD. The algorithm is especially important for incomplete KD, which is the scenario most commonly examined.
Algorithm walk-through, step by step:
- Start: Any child with fever ≥ 5 days and no clear alternative explanation.
- Count cardinal features: If ≥ 4 of 5 → complete KD → treat immediately + baseline echo.
- If 2–3 features → suspect incomplete KD → check inflammatory markers (CRP, ESR).
- CRP ≥ 30 mg/L or ESR ≥ 40 mm/h?
- No → KD less likely. Observe. But if fever persists or desquamation develops → reassess.
- Yes → proceed to the 6 supplementary lab criteria.
- ≥ 3 of 6 supplementary criteria?
- Yes → treat as KD even before echocardiography [2].
- No → obtain echocardiogram.
- Echo positive (any 1 of 3 criteria above)? → treat as KD.
- Echo negative + < 3 lab criteria → KD unlikely → observe, but if fever persists → repeat assessment.
High Yield — The Key Decision Points
The two pivotal branch points in the algorithm are:
- CRP/ESR screening: if both are normal, KD is very unlikely (strong negative predictive value).
- ≥ 3/6 supplementary lab criteria: if met, treat empirically without waiting for echo — because delays in treatment increase coronary risk.
Special scenario: Infants < 6 months with prolonged fever
- The AHA recommends a lower threshold for echo and lab evaluation in infants with ≥ 7 days of unexplained fever, even with 0–1 cardinal features, because incomplete KD is especially common and dangerous in this age group.
4. Investigation Modalities
Investigations in KD serve three purposes:
- Support the diagnosis (especially for incomplete KD)
- Exclude mimics (infections, drug reactions)
- Assess for complications (coronary, cardiac, systemic)
4.1 Blood Tests
| Test | Expected Finding | Interpretation / Pathophysiology |
|---|---|---|
| CRP | Markedly elevated (often > 30 mg/L, can exceed 100) | Acute-phase reactant produced by hepatocytes in response to IL-6. Rises early (within 6–12h) and normalises before ESR during convalescence. |
| ESR | Markedly elevated (often > 40 mm/h, can exceed 100) | Reflects increased fibrinogen and immunoglobulins causing RBC rouleaux formation → faster sedimentation. ESR normalises later in the convalescent phase (6–8 weeks) [1]. Caveat: IVIG itself elevates ESR (due to immunoglobulin loading), so ESR is unreliable for monitoring response to treatment — use CRP instead. |
| Procalcitonin | Mildly elevated (usually < 2 ng/mL) | Useful to distinguish KD from bacterial sepsis: PCT > 2 suggests bacterial infection; mildly elevated PCT (0.5–2) is common in KD |
Clinical Pearl
After IVIG, use CRP (not ESR) to monitor treatment response. IVIG artificially elevates ESR for weeks because you've infused a large load of immunoglobulin that increases rouleaux formation. CRP reflects the actual inflammatory state.
| Parameter | Expected Finding | Pathophysiology |
|---|---|---|
| Haemoglobin | Normochromic normocytic (NcNc) anaemia [1] | Anaemia of chronic inflammation: IL-6 → hepcidin ↑ → iron sequestration in macrophages → ↓ iron available for erythropoiesis. Also: ↓ EPO response and ↓ RBC survival. |
| WBC | Leucocytosis [1], often with neutrophilia and left shift | Neutrophil-predominant response driven by IL-6 / G-CSF from systemic inflammation. WBC ≥ 15 × 10⁹/L is one of the supplementary criteria [2]. |
| Platelets | Normal in acute phase → reactive thrombocytosis in subacute phase [1] | IL-6 → hepatic thrombopoietin → megakaryocyte proliferation → thrombocytosis. Characteristically peaks in week 2–3 (platelet after D7 ≥ 450 × 10⁹/L [2]), can exceed 1,000 × 10⁹/L. Important: thrombocytosis is NOT present at diagnosis — it develops later. Thrombocytopenia at presentation is ominous and suggests possible MAS/HLH. |
| Parameter | Finding | Pathophysiology |
|---|---|---|
| Albumin | Hypoalbuminaemia (≤ 30 g/L) [1][2] | Two mechanisms: (1) albumin is a negative acute-phase reactant → hepatic synthesis ↓ during inflammation; (2) vasculitis → increased capillary permeability → albumin leaks into interstitial space |
| ALT / AST | Elevated [1] | Hepatic vasculitis → hepatocyte inflammation/necrosis. Usually mild (2–5× ULN). |
| Bilirubin | Mildly elevated [1] | Hepatic dysfunction from vasculitis |
| GGT | Elevated [1] | Cholestatic component — bile duct/canalicular vasculitis and gallbladder hydrops causing biliary stasis |
| Parameter | Finding | Pathophysiology |
|---|---|---|
| Sodium | Hyponatraemia [1] | Likely SIADH-like mechanism from systemic inflammation + third-spacing from vasculitis. Also: poor oral intake in unwell febrile child. |
| Creatinine | Usually normal | Renal involvement is uncommon in classic KD (if present, consider "atypical KD") |
| Finding | Explanation |
|---|---|
| Abnormal plasma lipids [1] | ↓HDL, ↑triglycerides — typical "inflammatory lipid profile". Cytokines inhibit lipoprotein lipase and alter hepatic lipid synthesis. This is transient and resolves in convalescence. |
- Should be sent to exclude bacteraemia / sepsis as a mimic.
- Expected result in KD: negative.
- If positive → reconsider the diagnosis (? infective endocarditis, ? bacterial sepsis, ? TSS).
| Finding | Detail | Pathophysiology |
|---|---|---|
| Sterile pyuria (WBC ≥ 10/HPF) [1][2] | WBCs in urine WITHOUT bacterial growth on culture | Urethritis from mucosal vasculitis → WBCs shed into urine. This is NOT a UTI. Best detected on catheterised specimen because bag urine is often contaminated. Important: standard dipstick detects leukocyte esterase from neutrophils — may be misleadingly positive and prompt unnecessary antibiotic treatment for "UTI". |
Exam Trap
Sterile pyuria in KD can be misdiagnosed as UTI. If a febrile child with "UTI" on dipstick does not respond to antibiotics and has any other KD features — think KD, not UTI! Always send urine culture to confirm sterility.
| Finding | Detail |
|---|---|
| Pleocytosis [1] | Lymphocytic predominance (mononuclear cells) |
| Normal glucose | Rules out bacterial meningitis |
| Normal to mildly elevated protein | Consistent with aseptic meningitis |
- LP is not routinely performed for KD diagnosis. It may be done if the child presents with marked irritability/meningism and meningitis is being excluded.
- Finding aseptic meningitis (pleocytosis + normal glucose) in a febrile child with mucocutaneous features should prompt consideration of KD.
| Finding | Significance | Pathophysiology |
|---|---|---|
| Arrhythmias [1] | Usually benign (sinus tachycardia is most common) | Myocarditis and/or pericarditis |
| Prolonged PR interval (1st degree AV block) [1] | Suggests conduction system involvement | Inflammatory oedema of AV node region (myocarditis affecting the conduction system) |
| Non-specific ST/T wave changes [1] | Diffuse ST depression / T wave inversion | Myocarditis, pericarditis, or coronary ischaemia (if aneurysm with thrombosis) |
| Low voltage QRS | If pericardial effusion present | Pericardial fluid attenuates electrical signals |
- ECG is performed at baseline and serially. ST elevation in a coronary territory in a child with KD is ominous — suggests MI from coronary artery thrombosis.
4.5 Echocardiography — The Key Investigation
Echocardiography is the single most important investigation in KD because it directly visualises coronary artery abnormalities, which determine prognosis and guide long-term management.
Echocardiogram performed at least 3 times [1]:
- At time of diagnosis
- At 2 weeks
- At 6–8 weeks
- → Consider discharge if all 3 are normal (low risk)
For high-risk patients (coronary anomalies, ventricular dysfunction, IVIG resistance):
More frequent echo until no further progression [1]
Why this schedule?
- Baseline: establish whether coronary changes are already present (some children present late).
- 2 weeks: this is the subacute phase — the peak time for aneurysm development. If the baseline was normal, this is when you'd first detect evolving coronary dilation.
- 6–8 weeks: convalescent phase. If still normal → low risk → can discharge with reassurance. If abnormalities detected → ongoing follow-up.
Coronary arteries:
| Finding | Z-Score Classification | Clinical Significance |
|---|---|---|
| No involvement | Z-score < 2 | Normal |
| Dilation only | Z-score 2–2.5 | Mild; often transient and resolves |
| Small coronary artery aneurysm (CAA) | Z-score 2.5–5 | Requires follow-up; low risk of thrombosis |
| Medium CAA | Z-score 5–10, absolute dimension < 8 mm [1] | Moderate risk; requires antiplatelet ± anticoagulation |
| Large (Giant) CAA | Z-score > 10, OR absolute dimension ≥ 8 mm [1] | Highest risk of thrombosis, MI, rupture, sudden death |
Most common sites of CAA: proximal LAD > proximal RCA > LMCA > LCx > distal RCA [1]
Why proximal segments? The proximal coronary arteries branch directly off the aortic root and are exposed to the highest pulsatile wall stress. They also have the richest vasa vasorum (small nutrient vessels in the adventitia), which facilitates inflammatory cell infiltration during vasculitis.
Other echo findings suggestive of KD [1][2]:
| Finding | Reflects |
|---|---|
| Perivascular brightness | Perivascular inflammatory oedema — an early sign of coronary arteritis before luminal dilation |
| Lack of tapering | Loss of normal progressive narrowing of coronary artery distally — uniform calibre due to diffuse mural oedema |
| Pericardial effusion | Pericarditis |
| Mitral regurgitation (MR) | Valvulitis (endocarditis component of pan-carditis); also papillary muscle dysfunction from myocarditis |
| Decreased LV function | Myocarditis — reduced contractility (↓ ejection fraction, ↓ fractional shortening) |
For patients with persistent coronary aneurysms, especially medium or large:
Stress echocardiography, stress MRI, stress nuclear medicine (rMPI), or PET [1]
These are used to detect functional ischaemia — i.e., whether the coronary abnormalities are actually causing reduced myocardial perfusion during exercise or pharmacological stress.
| Modality | When Used | Advantages | Limitations |
|---|---|---|---|
| CT coronary angiography | Non-invasive assessment of coronary anatomy in follow-up | Excellent spatial resolution for calcification, stenosis | Radiation exposure in children; motion artefact |
| Cardiac MRI | Assessment of myocardial perfusion, viability, and function | No radiation; excellent soft tissue characterisation | Longer acquisition time; sedation may be needed in young children |
| Invasive coronary angiography | Gold standard for coronary anatomy; considered for giant aneurysms or when intervention planned | Direct visualisation + option for catheter-based intervention (PCI) | Invasive; risk of arterial damage; radiation |
For children with any coronary involvement, ongoing cardiovascular risk factor monitoring is recommended:
BP, fasting lipid profile, BMI, waist circumference, diet and physical activity assessment [1]
This is because children with KD-related coronary abnormalities are at lifelong risk of accelerated atherosclerosis — the damaged and fibrosed coronary segments serve as a nidus for plaque formation in adulthood.
| Investigation | Purpose |
|---|---|
| Throat swab / rapid strep antigen | Exclude scarlet fever (GAS) |
| Blood culture | Exclude bacteraemia, infective endocarditis |
| Viral serology / PCR panel | Exclude measles, adenovirus, EBV (monospot), enterovirus |
| COVID-19 PCR + serology | Exclude MIS-C |
| ANA, complement | If SLE or other autoimmune condition suspected |
| Peripheral blood smear | Atypical lymphocytes (→ EBV); blast cells (→ leukaemia) |
| Ferritin | If markedly elevated (> 10,000 ng/mL) → consider MAS/HLH as complication |
| Finding | Significance |
|---|---|
| Hydrops of gallbladder | Acalculous cholecystitis from gallbladder wall vasculitis / cystic duct oedema. Can be the presenting feature, especially in children taken to surgery for suspected "acute abdomen" |
| Hepatomegaly | Hepatic vasculitis |
Understanding who is at highest risk guides the intensity of monitoring:
Risk factors for CAA [1]:
- Prolonged fever > 14 days
- Prolonged elevated ESR
- Age < 1 year or > 9 years
- Poor response to treatment (IVIG resistance)
- Male sex
Why these factors?
- Prolonged fever / elevated ESR = more intense / sustained inflammation → more vascular damage
- Age < 1y or > 9y = these are the "incomplete KD" age groups where diagnosis is often delayed → longer untreated inflammation
- IVIG resistance = the disease is inherently more severe / aggressive
- Male sex = unknown mechanism; possibly hormonal or X-linked immunoregulatory factors
When you suspect KD, here is your systematic workup:
| Category | Investigations |
|---|---|
| Inflammatory markers | CRP, ESR |
| Blood | CBC with differential, LFT (albumin, ALT, AST, GGT, bilirubin), RFT (Na, Cr), lipid profile, blood culture |
| Urine | Urinalysis (look for sterile pyuria ≥ 10 WBC/HPF), urine culture |
| Cardiac | ECG (PR interval, ST/T changes), Echocardiogram (coronary arteries, LV function, pericardial effusion, MR) |
| To exclude mimics | Throat swab, viral PCR panel, COVID-19 PCR + serology, monospot/EBV serology |
| If LP performed | CSF analysis (cell count, glucose, protein, Gram stain, culture) |
| If abdominal symptoms | Abdominal USS (gallbladder hydrops, hepatomegaly) |
| Follow-up (if CAA) | Serial echo, stress testing, CT coronary angiography / cardiac MRI / invasive angiography, CV risk assessment |
High Yield Summary
Diagnosis of KD — Key Exam Points:
-
KD is a clinical diagnosis — no confirmatory test [1].
-
Complete KD: fever ≥ 5 days + ≥ 4/5 cardinal features (conjunctivitis, oral changes, rash, extremity changes, cervical LN).
-
Incomplete KD: fever ≥ 5 days + 2–3 features → check CRP/ESR → if elevated → check 6 supplementary lab criteria (anaemia, WBC ≥ 15, platelets ≥ 450 after D7, albumin ≤ 30, ↑ALT, urine ≥ 10 WBC/HPF) → if ≥ 3/6: treat before echo [2].
-
Echo positive criteria (any 1 of 3): Z-score ≥ 2.5 of LAD/RCA; Japanese MoH criteria ( > 3 mm if < 5y, > 4 mm if ≥ 5y, or segment ≥ 1.5× adjacent); or ≥ 3 other suggestive features (Z > 2 but < 2.5, perivascular brightness, lack of tapering, pericardial effusion, MR, ↓LV function).
-
Echo schedule: at diagnosis → 2 weeks → 6–8 weeks (minimum 3 times). More frequent if high-risk.
-
CAA risk factors: prolonged fever > 14d, prolonged ↑ESR, age < 1y or > 9y, IVIG resistance, male sex.
-
After IVIG: monitor with CRP (not ESR) because IVIG itself elevates ESR.
-
Sterile pyuria can mimic UTI — always correlate with culture and clinical features.
Active Recall - KD Diagnostic Criteria, Algorithm & Investigations
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf, Section 6.3.3 Kawasaki Disease (p.242–243) [2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, Section on Kawasaki Disease — Diagnosis (p.295–297) [8] Paediatrics reference: Fever without a source in children 3 to 36 months of age — UpToDate (2026) [9] Senior notes: Ryan Ho Rheumatology.pdf, Section 3.6 Vasculitis (p.93)
Management of Kawasaki Disease
Before diving into specific treatments, understand the strategic goals. Everything in KD management serves one (or both) of two purposes:
- Suppress the acute systemic inflammation → reduce vascular damage → prevent coronary artery abnormalities (CAA)
- Prevent thrombotic complications in patients who do develop coronary dilation/aneurysms
The entire treatment paradigm is built on one landmark finding: 20–25% of untreated children develop CAA, but < 5% of children treated with IVIG develop CAA [1][2]. That ~80% relative risk reduction with a single intervention (IVIG) is one of the most dramatic treatment effects in pediatrics — and it is why early recognition and prompt treatment are the cornerstones of KD management.
3. First-Line Treatment: IVIG + Aspirin
3.1 Intravenous Immunoglobulin (IVIG)
IVIG = "Intra" (into) + "venous" (vein) + "immunoglobulin" (antibodies). It is a pooled preparation of polyclonal IgG antibodies derived from thousands of blood donors.
ALL patients with acute KD should be treated with 2 g/kg of IVIG [2]
| Parameter | Detail |
|---|---|
| Dose | 2 g/kg as a single infusion |
| Route | Intravenous (slow infusion over 10–12 hours) |
| Timing | Within 10 days of disease onset, and ideally as soon as possible after diagnosis [2] |
Why a single high dose of 2 g/kg? The landmark RAISE trial and meta-analyses demonstrated that a single 2 g/kg dose is superior to divided doses (e.g., 400 mg/kg/day × 4 days). The single high dose achieves a more sustained high serum IgG level, which provides more effective immunomodulation.
Why within 10 days? The peak window for coronary artery damage is during the acute and early subacute phases (days 7–25). Treating within the first 10 days of illness significantly reduces CAA incidence. However, if a child presents after day 10 and still has active inflammation (persistent fever, elevated CRP), IVIG should still be given — the 10-day window is not an absolute cutoff.
IVIG's mechanism in KD is not fully understood, but multiple immunomodulatory effects are proposed:
| Mechanism | Explanation |
|---|---|
| Fc receptor blockade | Infused IgG saturates Fc receptors on macrophages and other immune cells → reduces phagocytosis and ADCC (antibody-dependent cellular cytotoxicity) |
| Anti-idiotypic antibodies | Pooled IgG contains antibodies against pathogenic autoantibodies → neutralisation |
| Complement modulation | Binds C3b/C4b → reduces complement-mediated tissue damage |
| Cytokine modulation | Downregulates pro-inflammatory cytokines (TNF-α, IL-1, IL-6) and upregulates anti-inflammatory cytokines (IL-10) |
| Endothelial protection | May directly protect endothelial cells from immune-mediated damage |
| Adverse Effect | Mechanism | Management |
|---|---|---|
| Infusion reactions (fever, chills, headache, myalgia, hypotension) | Complement activation, cytokine release from immune complex formation | Slow infusion rate; premedicate with paracetamol ± diphenhydramine; stop infusion if severe |
| Anaphylaxis (rare) | IgE-mediated hypersensitivity (especially in IgA-deficient patients who have anti-IgA antibodies) | Stop infusion; epinephrine, IV fluids, steroids |
| Aseptic meningitis | Unknown — possibly direct irritation of meninges by immunoglobulin or cytokine-mediated | Supportive; self-limiting (48–72h) |
| Haemolytic anaemia | Anti-A and anti-B isoagglutinins in pooled IgG cause haemolysis (especially in non-O blood types) | Monitor Hb; Coombs test if anaemia develops post-IVIG |
| Thrombotic events (rare) | Hyperviscosity from high-dose immunoglobulin; possible procoagulant IgG antibodies | Ensure adequate hydration; caution in patients with pre-existing thrombotic risk |
| Elevated ESR (artefact) | Infused immunoglobulin increases rouleaux formation → falsely elevated ESR for weeks | Use CRP (not ESR) to monitor treatment response |
| Contraindication | Reason |
|---|---|
| Severe IgA deficiency (with anti-IgA antibodies) | Risk of anaphylaxis. Use IgA-depleted IVIG preparations if available. |
| Volume overload / heart failure | 2 g/kg is a large volume load; in patients with myocarditis/LV dysfunction, infuse slowly with diuretic cover and cardiac monitoring |
Varicella vaccination is a live vaccine and should be administered 11 months after IVIG infusion [2]
Why? IVIG contains antibodies against varicella (and other common pathogens). These passively transferred antibodies neutralise the live attenuated vaccine virus, rendering the vaccination ineffective. You must wait until the passive antibodies have waned (~11 months) before giving live vaccines (varicella, MMR, live intranasal influenza).
Influenza and varicella vaccination are recommended [2] — but varicella vaccine timing must be deferred. Inactivated influenza vaccine can be given at any time.
3.2 Aspirin (Acetylsalicylic Acid)
Aspirin — "acetyl" (acetyl group) + "salicylic" (from Salix, the willow tree) — has dose-dependent pharmacological effects that are exploited in two phases of KD treatment:
| Phase | Dose | Effect | Mechanism |
|---|---|---|---|
| Acute phase (high-dose) | 80–100 mg/kg/day divided Q6H [2] | Anti-inflammatory | At high doses, aspirin irreversibly inhibits both COX-1 and COX-2 → ↓ prostaglandin synthesis → ↓ inflammation, fever, and vasculitis |
| Subacute/Convalescent phase (low-dose) | 3–5 mg/kg/day as a single dose [2] | Anti-thrombotic (antiplatelet) | At low doses, aspirin selectively inhibits COX-1 in platelets → ↓ thromboxane A₂ (TXA₂) → ↓ platelet aggregation. Platelets are anucleate and cannot resynthesise COX-1, so the effect lasts the platelet's entire lifespan (~7–10 days) |
80–100 mg/kg/day divided Q6H until patient is afebrile for ≥ 48 hours [2]
- Given simultaneously with IVIG.
- Once the child has been afebrile for ≥ 48 hours, step down to low-dose aspirin.
- Note on the AHA 2017 update: Some centres (especially in Japan and increasingly in North America) use moderate-dose aspirin (30–50 mg/kg/day) instead of high-dose (80–100 mg/kg/day). Evidence suggests that the coronary outcome is driven primarily by IVIG, and high-dose aspirin adds anti-inflammatory benefit but does not independently reduce CAA incidence. The lower dose has fewer side effects (GI, hepatotoxicity, Reye syndrome risk). However, the standard teaching for HKUMed exams remains 80–100 mg/kg/day per the senior notes [2].
3–5 mg/kg/day as a single dose for 8 weeks [2]
Discontinue in patients who have normal echocardiography findings throughout the course of illness during the designated echo follow-up [2]
Patients with CAA should continue with aspirin and may even require anticoagulation depending on the degree of coronary dilation [2]
1. Reye Syndrome
Cautious with Reye syndrome (viral illness + aspirin use) [2]
Reye syndrome = acute hepatic failure + encephalopathy in children given aspirin during a viral illness (especially influenza and varicella). The mechanism involves mitochondrial dysfunction in hepatocytes.
Monitoring for recurrence of fever and withhold or decrease dosage of aspirin in cases of suspected viral illnesses [2]
Practical approach:
- If a child on aspirin for KD develops chickenpox or influenza symptoms → hold aspirin, switch to alternative antipyretic (paracetamol), and resume aspirin once viral illness resolves.
- This is why influenza and varicella vaccination are recommended [2] — to reduce the risk of these viral illnesses occurring while the child is on aspirin.
2. Drug Interactions
Avoid using ibuprofen since it will decrease the antiplatelet function of aspirin [2]
Why? Ibuprofen is a reversible COX inhibitor that competes with aspirin for the COX-1 active site on platelets. If ibuprofen is taken first, it transiently occupies the active site and blocks aspirin's access. When ibuprofen eventually dissociates (it is reversible), the aspirin effect is lost because the aspirin molecule has already been metabolised. The net result = attenuated antiplatelet effect of aspirin.
Avoid antacids (generally not required) since it may decrease efficacy of aspirin [2]
Why? Antacids alkalinise the gastric environment. Aspirin is a weak acid (pKa ~3.5) that is best absorbed in the acidic stomach (where it exists in its unionised, lipid-soluble form). Alkalinising the stomach ionises aspirin → ↓ absorption → ↓ efficacy.
3. Contraindications to High-Dose Aspirin
Can be omitted in the acute phase if there are contraindications including bleeding tendency or aspirin-induced asthma [2]
- Bleeding tendency: aspirin inhibits platelet function → ↑ bleeding risk. If the child has thrombocytopenia (e.g., from MAS/HLH complicating KD), high-dose aspirin may worsen bleeding.
- Aspirin-induced asthma (aspirin-exacerbated respiratory disease, AERD): COX-1 inhibition shunts arachidonic acid metabolism toward the lipoxygenase pathway → ↑ leukotrienes → bronchoconstriction.
High Yield — Aspirin in KD
Remember the two doses and their effects: High-dose (80–100 mg/kg/day) = anti-inflammatory (acute phase, until afebrile ≥ 48h); Low-dose (3–5 mg/kg/day) = antiplatelet (8 weeks minimum, longer if CAA). Avoid ibuprofen (antagonises antiplatelet effect) and antacids (reduce absorption). Monitor for Reye syndrome during viral illnesses.
4. IVIG-Resistant (Refractory) KD
IVIG resistance = persistent or recurrent fever (≥ 36h after completion of initial IVIG infusion) despite first-line therapy.
- Occurs in approximately 10–20% of patients.
- These patients are at higher risk of coronary artery complications.
The first step for IVIG-resistant KD is straightforward:
Second dose of IVIG 2 g/kg (identical to the first dose)
- Rationale: some patients simply did not achieve adequate immunomodulation with the first dose. A second dose may push the immune system past the tipping point.
- Approximately 50–70% of IVIG-resistant patients will respond to a second dose.
4.3 Salvage Therapy: Corticosteroids
Corticosteroids are indicated as adjuvant therapy or salvage therapy when patients respond suboptimally to IVIG and aspirin [2]
Considered in patients with persistent or recurrent fever after receiving ≥ 4 g/kg of IVIG [2] (i.e., after two full doses)
| Phase | Drug | Dose | Duration |
|---|---|---|---|
| Pulse | IV Methylprednisolone | 30 mg/kg over 2–3 hours daily | 1–3 days [2] |
| Oral taper | PO Prednisolone | 2 mg/kg/day | Until day 7 or until CRP normalises, then wean over 2–3 weeks [2] |
Why corticosteroids?
- Corticosteroids are the most potent broad-spectrum anti-inflammatory agents available. They suppress:
- NF-κB → ↓ transcription of pro-inflammatory cytokines (TNF-α, IL-1, IL-6)
- Phospholipase A₂ → ↓ arachidonic acid release → ↓ prostaglandins AND leukotrienes
- Adhesion molecule expression → ↓ inflammatory cell recruitment to vessel walls
- In KD, the concern with steroids was historically that they might increase CAA risk (from early observational studies). However, the RAISE trial (2012) and subsequent meta-analyses showed that adjunctive corticosteroids reduce CAA risk in IVIG-resistant patients and possibly in high-risk patients as primary adjunctive therapy.
- The AHA 2017 scientific statement and the 2024 Japanese KD management guidelines suggest that primary adjunctive corticosteroids (given with IVIG + aspirin from the start) may benefit high-risk patients (those predicted to be IVIG-resistant based on risk scores, e.g., the Kobayashi score in Japan).
- This is not yet universal standard practice but is increasingly adopted in Asian centres including Hong Kong.
- The Kobayashi risk score (used predominantly in Japanese populations) predicts IVIG resistance based on: day of illness ≤ 4, CRP ≥ 80 mg/L, age ≤ 1 year, platelet count ≤ 300 × 10⁹/L, AST > 100 IU/L, neutrophils ≥ 80%, Na ≤ 133 mmol/L.
4.4 Third-Line / Refractory Therapies
For patients who remain febrile after 2 doses of IVIG + corticosteroids:
- "Inflixi-mab": "inflixi" = chimeric (mouse/human) antibody targeting TNF-α; "-mab" = monoclonal antibody.
- Dose: 5 mg/kg IV single infusion.
- Mechanism: TNF-α is a key cytokine driving vascular inflammation in KD. Infliximab binds and neutralises both soluble and membrane-bound TNF-α → rapid suppression of inflammation.
- Evidence: Small RCTs and case series show effectiveness in IVIG-resistant KD; included in AHA 2017 as a reasonable option.
- Contraindications: Active TB or latent TB (screen first), active serious infection, decompensated heart failure.
- Mechanism: Calcineurin inhibitor → blocks T-cell activation (inhibits IL-2 transcription via NFAT pathway).
- Rationale: KD involves T-cell-mediated vasculitis; cyclosporine directly targets the effector cells.
- Evidence: The KAICA trial (Japan, 2019) showed benefit as primary adjunctive therapy in high-risk KD.
- Cautions: Nephrotoxicity, hypertension, tremor. Requires drug level monitoring.
- Blocks IL-1 signalling (a key cytokine in the KD inflammatory cascade).
- Emerging evidence from case series and the KD-CAAP trial.
- Used primarily in specialist centres for truly refractory cases.
- Removes circulating cytokines, immune complexes, and autoantibodies.
- Reserved for the most severe/refractory cases with life-threatening complications.
- Logistically challenging in small children.
This is guided by the coronary artery risk stratification from echocardiography:
| CAA Category | Z-Score | Antithrombotic Regimen | Rationale |
|---|---|---|---|
| No involvement | < 2 | Low-dose aspirin for 8 weeks → discontinue if echo normal | No thrombus risk once inflammation resolves |
| Dilation only | 2–2.5 | Low-dose aspirin until dilation resolves (repeat echo) | Mild risk; usually transient |
| Small aneurysm | 2.5–5 | Low-dose aspirin indefinitely (until regression documented) | Small aneurysms may regress but warrant ongoing protection |
| Medium aneurysm | 5–10 | Low-dose aspirin + consider adding clopidogrel (dual antiplatelet) or low-dose anticoagulation | Larger aneurysms → more turbulent flow → higher thrombotic risk |
| Giant aneurysm | ≥ 10 or ≥ 8 mm | Low-dose aspirin + warfarin (target INR 2–3) or LMWH [2] | Highest risk of thrombosis, MI, and death. Giant aneurysms have extremely turbulent flow and stasis within the aneurysm sac → thrombus formation. Warfarin is preferred for its proven efficacy in preventing low-flow thrombosis. |
Patients with CAA should continue with aspirin and may even require anticoagulation depending on the degree of coronary dilation [2]
Why warfarin for giant aneurysms? In a giant aneurysm (≥ 8 mm or Z ≥ 10), the lumen is so dilated that blood flow becomes slow and turbulent within the sac. This creates conditions similar to those in the left atrium during atrial fibrillation — low flow / stasis. Under Virchow's triad, stasis + endothelial damage (from vasculitis) + hypercoagulable state (reactive thrombocytosis) = high thrombotic risk. Warfarin (vitamin K antagonist) inhibits the coagulation cascade (factors II, VII, IX, X) and is more effective than antiplatelet agents alone in preventing red thrombi (fibrin-rich clots) that form under low-flow conditions.
| Measure | Detail |
|---|---|
| Fluid management | Ensure adequate hydration — IVIG is a large protein load that can cause osmotic diuresis; also children are often dehydrated from fever and poor intake |
| Cardiac monitoring | Continuous ECG monitoring during acute phase if myocarditis suspected; observe for arrhythmias |
| Pain management | Paracetamol for fever/pain as adjunct (note: avoid ibuprofen!) |
| Nutritional support | Encourage oral intake; NG feeding rarely needed |
| Skin care | Emollients for desquamating skin; no specific treatment needed |
7. Follow-Up & Monitoring
Assessment for inducible myocardial ischaemia: stress echo, stress MRI, stress nuclear medicine, PET [1] Further imaging: CT coronary angiography, cardiac MRI, invasive angiography [1] Cardiovascular risk assessment: BP, fasting lipid, BMI, waist circumference, diet and activity assessment [1]
Why lifelong CV risk assessment? Even if coronary aneurysms regress, the vessel wall is never truly normal. Histologically, there is intimal myofibroblastic proliferation and fibrosis at the aneurysm site. This structurally abnormal segment is prone to accelerated atherosclerosis in adulthood — essentially, these children carry a lifelong CAD risk factor. Therefore, aggressive primary prevention (healthy diet, exercise, lipid monitoring, BP control, weight management) is essential.
| Treatment | Indication | Dose / Protocol | Mechanism | Key Cautions |
|---|---|---|---|---|
| IVIG | ALL acute KD | 2 g/kg single infusion, within 10 days | Immunomodulation (Fc receptor blockade, cytokine modulation) | Anaphylaxis (IgA deficiency), haemolytic anaemia, aseptic meningitis, volume overload. Defer live vaccines 11 months. |
| High-dose aspirin | ALL acute KD (given with IVIG) | 80–100 mg/kg/day ÷ Q6H → until afebrile ≥ 48h | Anti-inflammatory (COX-1+2 inhibition) | Reye syndrome, bleeding, aspirin-induced asthma. Avoid ibuprofen and antacids. |
| Low-dose aspirin | All KD after acute phase | 3–5 mg/kg/day × 8 weeks (minimum) | Antiplatelet (COX-1 inhibition → ↓ TXA₂) | Reye syndrome with concurrent viral illness. Continue indefinitely if CAA. |
| Repeat IVIG | IVIG-resistant (fever ≥ 36h post-1st IVIG) | 2 g/kg single infusion | Same as above | Same as above |
| IV Methylprednisolone → PO Prednisolone | Persistent fever after ≥ 4 g/kg IVIG | 30 mg/kg IV × 1–3 days → 2 mg/kg/day PO → taper 2–3 weeks | Broad immunosuppression (NF-κB, PLA₂ inhibition) | Immunosuppression, hyperglycaemia, hypertension, GI bleeding |
| Infliximab | Refractory to IVIG + steroids | 5 mg/kg IV single dose | Anti-TNF-α | Screen for TB; avoid in active infection or severe HF |
| Cyclosporine A | Refractory / high-risk adjunctive | Per protocol | Calcineurin inhibitor → T-cell suppression | Nephrotoxicity, hypertension, drug level monitoring |
| Warfarin / LMWH | Giant aneurysm (Z ≥ 10 or ≥ 8 mm) | Warfarin: target INR 2–3 | Vitamin K antagonist → ↓ factors II, VII, IX, X | Bleeding risk, INR monitoring, drug/food interactions |
| Clopidogrel | Medium–giant aneurysm (adjunct) | 0.2–1 mg/kg/day | P2Y₁₂ receptor antagonist → ↓ ADP-mediated platelet activation | Bleeding risk |
High Yield Summary
Management of KD — Key Exam Points:
-
First-line: IVIG 2 g/kg single infusion + high-dose aspirin (80–100 mg/kg/day ÷ Q6H) within 10 days of illness onset [2].
-
High-dose aspirin = anti-inflammatory (COX-1+2 inhibition). Switch to low-dose (3–5 mg/kg/day) once afebrile ≥ 48h [2].
-
Low-dose aspirin = antiplatelet (COX-1 → ↓ TXA₂). Continue for 8 weeks minimum; discontinue only if all echos are normal. Continue indefinitely if CAA present [2].
-
IVIG resistance (~10–20%): re-dose IVIG 2 g/kg → if still refractory → IV methylprednisolone 30 mg/kg pulse × 1–3 days → oral prednisolone taper [2].
-
Third-line: Infliximab (anti-TNF-α), cyclosporine, anakinra, plasma exchange.
-
Giant aneurysms (Z ≥ 10 or ≥ 8 mm): aspirin + warfarin (INR 2–3) or LMWH — highest thrombotic risk.
-
Avoid ibuprofen (antagonises aspirin's antiplatelet effect) and antacids (reduce aspirin absorption) [2].
-
Reye syndrome risk: monitor for viral illness; hold aspirin during varicella/influenza; vaccinate against both [2].
-
Defer live vaccines 11 months after IVIG (passive antibodies neutralise live vaccine virus) [2].
-
Long-term: lifelong CV risk factor monitoring for patients with any CAA history (diet, exercise, BP, lipids, BMI) [1].
Active Recall - KD Management
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf, Section 6.3.3 Kawasaki Disease (p.242–243) [2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, Section on Kawasaki Disease — Management (p.295, 301)
Complications of Kawasaki Disease
KD is self-limiting — the fever and mucocutaneous inflammation resolve spontaneously. The reason KD demands urgent treatment is entirely because of its complications, predominantly cardiovascular. Understanding the complications from first principles means tracing them back to the core pathology: pan-vasculitis of small-to-medium arteries with a striking predilection for the coronary arteries.
The complications can be organised into two categories:
- Cardiovascular complications — the dominant concern and the reason KD is the most common cause of acquired heart disease in children in developed countries
- Non-cardiovascular (systemic) complications — reflecting the multi-system nature of the vasculitis
2. Cardiovascular Complications
2.1 Coronary Artery Aneurysm (CAA) — The Cardinal Complication
Coronary artery aneurysm is the MOST common and serious complication of KD [2]
Located most commonly in proximal LAD and proximal right coronary arteries [1][2]
The full order of frequency [1]:
Proximal LAD > proximal RCA > LMCA > LCx > distal RCA
Why proximal segments? As explained in Part 1, the proximal coronary arteries are exposed to the highest pulsatile wall stress (directly off the aortic root) and have the richest vasa vasorum, facilitating inflammatory cell infiltration. The proximal LAD is the most commonly affected because it is the largest-calibre branch with the greatest hemodynamic stress.
The pathological sequence leading to aneurysm formation:
- Pan-vasculitis → neutrophilic then lymphocytic/macrophage infiltration of all three vessel wall layers
- Destruction of the internal elastic lamina (IEL) and medial smooth muscle cell necrosis → loss of structural integrity
- Arterial blood pressure acting on the weakened wall → outward ballooning → aneurysm
- The aneurysm sac fills with blood flowing in a turbulent, low-velocity vortex → creates a prothrombotic environment
- Male sex
- Age < 1 year
- Long duration of fever (> 14 days)
- Failure to respond to initial IVIG therapy manifested by persistent fever
- Late diagnosis and delayed treatment with IVIG
An additional factor from the notes [1]: prolonged elevated ESR and age > 9 years (the other extreme of age, where incomplete KD causes delayed diagnosis).
Why these factors increase risk:
- Male sex, age < 1y: likely inherent immune/vascular factors that predispose to more intense vasculitis.
- Prolonged fever / IVIG resistance: reflects more severe and sustained inflammation → more vascular damage.
- Delayed treatment: allows inflammation to continue unchecked during the critical window (days 7–25) when aneurysm formation peaks.
Prognosis [2]:
- Small aneurysm ≤ 8 mm: Low risk of MI and mortality
- Large aneurysm > 8 mm: High risk of aneurysmal rupture, thrombosis or stenosis with subsequent MI, arrhythmia and sudden death
| Aneurysm Size | Natural History | Long-term Outcome |
|---|---|---|
| Dilation (Z 2–2.5) | Usually regresses within 6–8 weeks | Excellent; normal long-term function |
| Small aneurysm (Z 2.5–5) | ~60% regress within 1–2 years (intimal myofibroblastic proliferation → lumen normalises) | Low risk; but regressed segments may have abnormal vasoreactivity and accelerated atherosclerosis in adulthood |
| Medium aneurysm (Z 5–10) | Variable; may regress, persist, or develop stenosis | Moderate risk of late ischaemia from stenosis |
| Giant aneurysm (Z ≥ 10 or ≥ 8 mm) | Rarely regress; tend to persist or develop calcification, stenosis, thrombosis | Highest risk of MI, arrhythmia, sudden death — lifelong cardiology follow-up mandatory |
Why do some aneurysms regress? After the acute inflammation subsides, myofibroblasts proliferate within the vessel wall and the intima thickens → the lumen diameter decreases → apparent "regression." However, the wall is never histologically normal — it has lost its elastic lamina and has fibrotic replacement of the media. This structurally abnormal segment is:
- Non-compliant (cannot dilate normally with demand) → abnormal vasoreactivity
- A nidus for atherosclerosis in later life (endothelial dysfunction + intimal fibrosis)
Consequence: rupture, thrombosis ± MI, arrhythmia, sudden death [1]
| Consequence | Mechanism | Timing |
|---|---|---|
| Coronary thrombosis | Turbulent/stagnant flow within aneurysm sac + damaged endothelium + reactive thrombocytosis (Virchow's triad) → thrombus formation → coronary occlusion | Subacute phase (weeks 2–4) = highest risk; but can occur at any time with persistent aneurysms |
| Myocardial infarction (MI) | Coronary thrombosis → complete occlusion → downstream myocardial necrosis | Subacute phase; also late (months–years) from stenosis |
| Coronary stenosis | Intimal myofibroblastic proliferation during healing → progressive luminal narrowing at the aneurysm inlet/outlet | Months to years after acute KD; can cause chronic stable angina in children/young adults |
| Aneurysm rupture | Extremely weakened wall at the aneurysm site → transmural rupture → haemopericardium → cardiac tamponade | Rare; usually only with giant aneurysms in the first few weeks |
| Arrhythmia | Myocardial ischaemia from coronary thrombosis/stenosis → re-entry circuits or automaticity → ventricular tachycardia / ventricular fibrillation | Acute or late |
| Sudden death | VF/VT from MI; cardiac tamponade from rupture; cardiogenic shock from massive MI | Any time if giant aneurysm present |
MI is evaluated by ECG; prevention of coronary artery thrombosis by aspirin; PCI or CABG may be indicated in selected cases [2]
PCI (percutaneous coronary intervention) or CABG (coronary artery bypass grafting) in children? Yes — in selected cases of KD with giant aneurysms and severe stenosis causing ischaemia:
- PCI with balloon angioplasty ± stenting is possible in older children/adolescents
- CABG using internal mammary artery grafts has been performed in children with severe multi-vessel coronary involvement — these children essentially have "coronary artery disease" as a childhood-onset condition
High Yield
KD is the most important non-atherosclerotic cause of MI in young people. Any young adult presenting with MI should have their childhood history reviewed for possible KD — they may have occult coronary aneurysms or stenosis from an episode of KD in childhood that was missed or inadequately followed up.
Myocarditis occurs in most patients with acute KD and manifests as tachycardia disproportionate to fever along with decreased LV systolic function [2]
- Prevalence: 50–70% of KD patients in the acute phase have some degree of myocardial inflammation (based on biopsy and functional studies).
- Mechanism: Direct inflammatory infiltration of the myocardium (lymphocytes, macrophages) + cytokine-mediated myocyte dysfunction. TNF-α, IL-1β, and IL-6 directly depress myocardial contractility.
- Clinical manifestation: Tachycardia out of proportion to fever, gallop rhythm, poor feeding, diaphoresis (signs of heart failure in an infant/toddler).
- Investigation: Echo shows ↓ ejection fraction, ↓ fractional shortening. BNP/NT-proBNP elevated.
KD Shock Syndrome (KDSS)
KD shock syndrome [2]:
- Present in cardiogenic shock with marked decreased LV function
- Sustained systolic hypotension or clinical signs of poor perfusion
- Potentially life-threatening complication
Why does KDSS occur? Severe myocarditis → markedly reduced cardiac output → cardiogenic shock. Additionally, the cytokine storm can cause distributive shock (similar to sepsis) with vasodilation and capillary leak. KDSS is essentially the overlap between KD and septic shock / MIS-C.
- Management: Volume resuscitation (cautious — the heart is failing), inotropes (milrinone, dobutamine), vasopressors if needed, IVIG + aspirin + corticosteroids.
- Prognosis: KDSS is associated with higher risk of CAA and IVIG resistance. These patients are often admitted to PICU.
Pericarditis associated with pericardial effusion [2]
- Mechanism: Inflammatory infiltration of the pericardium (part of the pan-carditis of KD).
- Clinical features: Chest pain (if child old enough to verbalise), pericardial friction rub (rare in young children), distant heart sounds (if significant effusion).
- Echo findings: Pericardial effusion — usually small and haemodynamically insignificant.
- Cardiac tamponade: Extremely rare in KD; effusions are typically small. However, should be monitored serially.
- Management: Resolves with treatment of the underlying KD (IVIG + aspirin). Pericardiocentesis virtually never required.
Mitral regurgitation (MR) secondary to valvulitis [2]
- Mechanism: Vasculitis-driven inflammation of the valve leaflets (endocardium) + papillary muscle dysfunction from myocarditis → failure of mitral valve coaptation → regurgitation.
- Most commonly affected valve: Mitral valve (similar to rheumatic fever, which also causes MR in the acute phase).
- Aortic regurgitation is less common but described.
- Prognosis: Usually mild and self-limiting; resolves as inflammation subsides. Chronic valvular disease is rare.
Arrhythmia evaluated by ECG [2]
| Arrhythmia | Mechanism | Significance |
|---|---|---|
| Sinus tachycardia | Fever + myocarditis + sympathetic drive | Most common; expected |
| 1st degree AV block (prolonged PR) | Inflammatory oedema of AV node | Usually benign; resolves |
| 2nd/3rd degree AV block | Severe AV node involvement | Rare; may require temporary pacing |
| Ventricular tachycardia / fibrillation | Myocardial ischaemia from coronary thrombosis → re-entry | Life-threatening; cause of sudden death |
| ST-T changes | Ischaemia (coronary involvement), pericarditis, or myocarditis | Must distinguish ischaemic from non-ischaemic causes |
- Prevalence: ~1–2% of KD patients; almost exclusively in those with giant aneurysms.
- Mechanism: Thrombosis within a coronary aneurysm → complete coronary occlusion → transmural myocardial necrosis.
- Clinical presentation: Sudden onset of distress, pallor, diaphoresis, chest pain (if verbalised), vomiting, shock. In infants, may present as sudden unexplained cardiovascular collapse.
- Diagnosis: ECG (ST elevation in affected territory), troponin/CK-MB elevated, echo (regional wall motion abnormality).
- Management: Thrombolysis (tPA), catheter-directed therapy, or CABG depending on clinical scenario. Supportive PICU care.
- Mortality: ~22% for first MI in KD; higher with subsequent MIs.
3. Non-Cardiovascular (Systemic) Complications
HLH (Macrophage activation syndrome) [1][2]:
- Potentially life-threatening complication
- Activation and proliferation of macrophages and T cells leading to DIC, coagulopathy, cytopenia and thrombosis [2]
Understanding HLH/MAS from first principles:
"Hemophagocytic" = "hemo" (blood) + "phago" (eating) + "cytic" (cell) — blood cells being eaten by phagocytes. "Lymphohistiocytosis" = "lympho" (lymphocytes) + "histio" (tissue macrophages/histiocytes) + "cytosis" (increased numbers).
In KD, the massive cytokine storm (especially IFN-γ, TNF-α, IL-18) can trigger uncontrolled macrophage activation. These activated macrophages phagocytose blood cells (RBCs, WBCs, platelets) in the bone marrow, spleen, and liver — hence "hemophagocytosis."
Clinical features of HLH complicating KD:
- Persistent high fever despite IVIG (important clue: HLH should be suspected if IVIG resistance + cytopenias)
- Cytopenias: falling Hb, WBC, platelets (paradoxically — you'd expect thrombocytosis in KD; if platelets are dropping, think HLH)
- Markedly elevated ferritin (often > 10,000 ng/mL) — activated macrophages release massive amounts of ferritin
- Elevated triglycerides — cytokine-mediated inhibition of lipoprotein lipase
- Elevated soluble IL-2 receptor (sCD25) — marker of T-cell activation
- Low/absent NK cell activity
- DIC — coagulopathy with elevated D-dimer, prolonged PT/aPTT, low fibrinogen
- Hepatosplenomegaly
Management: High-dose corticosteroids (often already given for IVIG-resistant KD), cyclosporine A, and in severe cases, etoposide-based HLH protocols.
Clinical Pearl
In a KD patient who is IVIG-resistant and has falling platelet counts (rather than the expected thrombocytosis), think HLH/MAS. Check ferritin urgently — if > 10,000 ng/mL, the diagnosis is very likely. This changes management significantly.
KD has definite but unexplained predilection for coronary arteries but all vascular beds can be affected including peripheral and visceral arteries such as peripheral arterial occlusion [2]
Axillary, popliteal, iliac or other arteries may become dilated which manifest as a localized pulsatile mass [2]
| Artery | Clinical Manifestation | Mechanism |
|---|---|---|
| Axillary artery | Pulsatile mass in axilla; limb ischaemia if thrombosed | Medium-vessel vasculitis → aneurysm |
| Femoral / popliteal artery | Pulsatile mass in groin/popliteal fossa; lower limb ischaemia | Same |
| Iliac artery | Abdominal pulsatile mass | Same |
| Renal artery | Hypertension (renovascular), renal infarction | Renal vasculitis → stenosis or thrombosis |
| Mesenteric artery | Abdominal pain, GI bleeding, bowel ischaemia | Mesenteric vasculitis |
| Hepatic artery | Hepatic dysfunction | Hepatic vasculitis |
- These non-coronary aneurysms are rarer but important to recognise, especially if a child with KD develops limb ischaemia or an unexplained pulsatile mass.
- Mechanism: Vasculitis of the cochlear arteries (labyrinthine artery and its branches) → ischaemia of the cochlea and organ of Corti → hair cell damage → SNHL.
- Prevalence: Reported in ~15–30% of KD patients (subclinical high-frequency loss detected on audiometry); clinically significant hearing loss is less common.
- Course: Usually reversible — hearing improves as inflammation resolves. However, permanent SNHL has been reported.
- Clinical relevance: Important to perform audiological follow-up, especially in children with speech delay after KD.
These are common (~60% of KD patients [1]) but usually self-limiting:
| Complication | Mechanism | Clinical Features |
|---|---|---|
| Hydrops of gallbladder | Vasculitis of gallbladder wall and cystic duct → oedema and obstruction → acalculous cholecystitis | RUQ pain/mass, USS shows distended gallbladder without stones. Usually resolves with KD treatment; surgery rarely needed. |
| Hepatitis | Hepatic vasculitis → hepatocyte inflammation | Elevated AST/ALT, jaundice (mild); resolves spontaneously |
| Pancreatitis | Pancreatic duct vasculitis | Elevated amylase/lipase, epigastric pain |
| Diarrhoea / vomiting | Mesenteric vasculitis, intestinal mucosal inflammation | Common in acute phase; supportive management |
| Intestinal pseudo-obstruction | Bowel wall oedema from vasculitis | Abdominal distension, absent bowel sounds; can mimic surgical abdomen |
| Complication | Mechanism | Features |
|---|---|---|
| Extreme irritability | Aseptic meningitis (meningeal vasculitis → CSF pleocytosis → meningeal irritation) | Present in majority; often the most distressing symptom for parents |
| Aseptic meningitis | Meningeal vasculitis | CSF: lymphocytic pleocytosis, normal glucose, mildly elevated protein |
| Facial nerve palsy | Vasculitis of vasa nervorum of CN VII | Unilateral facial weakness; rare; usually resolves |
| Cerebral infarction | Cerebral artery vasculitis or cardiogenic embolism | Hemiplegia, seizures; very rare |
| SNHL | See above |
- Arthritis/arthralgia (~30%): Synovial vasculitis → inflammatory arthritis. Small joints in week 1, larger joints in week 2. Usually self-limiting.
- Beau's lines: Transverse grooves on nails appearing during convalescent phase. These reflect temporary arrest of nail matrix growth during the acute illness. Not a complication per se but a useful retrospective sign.
- Usually mild: sterile pyuria (urethritis), mild proteinuria.
- Rarely: interstitial nephritis, haemolytic uraemic syndrome (HUS), or renal artery aneurysm.
- Significant renal impairment is "atypical" and should prompt reconsideration of the diagnosis [2].
| Treatment | Complication | Mechanism | Prevention / Management |
|---|---|---|---|
| IVIG | Haemolytic anaemia | Anti-A/B isoagglutinins in pooled IgG | Monitor Hb; direct Coombs test |
| IVIG | Aseptic meningitis | Unknown — immunoglobulin-mediated meningeal irritation | Self-limiting (48–72h); supportive |
| IVIG | Anaphylaxis | Anti-IgA antibodies in IgA-deficient patients | Use IgA-depleted preparations |
| High-dose aspirin | Reye syndrome | Mitochondrial dysfunction in hepatocytes during viral illness | Monitor for viral illness; hold aspirin if varicella/influenza; vaccinate |
| High-dose aspirin | GI bleeding | COX-1/2 inhibition → ↓ prostaglandins → ↓ gastric mucosal protection | Monitor for melaena; consider PPI if symptomatic |
| High-dose aspirin | Hepatotoxicity | Direct dose-dependent toxicity | Monitor LFTs; dose-adjust if transaminitis worsens |
| Corticosteroids | Immunosuppression, hyperglycaemia, hypertension | Well-known steroid side effects | Short course minimises risk; monitor glucose/BP |
| Warfarin | Bleeding | Excessive anticoagulation | INR monitoring; target 2–3 |
| Coronary Status | Long-Term Outcome |
|---|---|
| No CAA (vast majority with treatment) | Excellent prognosis; ≈ normal life expectancy; minimal long-term cardiac risk |
| CAA that regressed | Structurally abnormal vessel wall → abnormal vasoreactivity + nidus for accelerated atherosclerosis → lifelong CV risk factor monitoring recommended |
| Persistent small/medium CAA | Ongoing antiplatelet therapy; periodic stress testing; cardiology follow-up |
| Giant CAA | Lifelong anticoagulation + antiplatelet; periodic invasive angiography; may require PCI or CABG; risk of MI, arrhythmia, sudden death; ~1–2% mortality |
Key concept: Even patients with no detectable CAA on standard echo may have subclinical endothelial dysfunction in adulthood. Population-level studies show that KD survivors have mildly increased intima-media thickness and reduced flow-mediated dilation compared to controls. This is an area of ongoing research.
| System | Complication | Timing | Severity | Mechanism |
|---|---|---|---|---|
| CVS | Coronary artery aneurysm | Subacute (wk 2–3) | Most serious | Destruction of IEL + media → aneurysm |
| CVS | Coronary thrombosis → MI | Subacute–late | Life-threatening | Virchow's triad within aneurysm |
| CVS | Myocarditis → HF / KDSS | Acute | Severe | Inflammatory infiltration + cytokine depression of myocardium |
| CVS | Pericarditis | Acute | Usually mild | Pericardial vasculitis |
| CVS | MR (valvulitis) | Acute | Usually mild | Endocardial inflammation + papillary muscle dysfunction |
| CVS | Arrhythmia | Acute–late | Variable | Conduction system inflammation; ischaemia |
| Haem | HLH / MAS | Acute | Life-threatening | Uncontrolled macrophage activation → hemophagocytosis |
| Vascular | Non-coronary aneurysms | Acute–subacute | Variable | Medium-vessel vasculitis in axillary, popliteal, iliac, renal arteries |
| Neuro | SNHL | Acute–subacute | Usually reversible | Cochlear artery vasculitis |
| Neuro | Aseptic meningitis | Acute | Self-limiting | Meningeal vasculitis |
| GI | Hydrops of GB | Acute | Self-limiting | Gallbladder wall / cystic duct vasculitis |
| GI | Hepatitis, pancreatitis | Acute | Usually mild | Hepatic / pancreatic vasculitis |
High Yield Summary
Complications of KD — Key Exam Points:
-
Coronary artery aneurysm is the MOST common and serious complication — develops in 25% untreated, < 5% IVIG-treated. Most common site: proximal LAD > proximal RCA [1][2].
-
Giant aneurysms (≥ 8 mm or Z ≥ 10) carry the highest risk of rupture, thrombosis, MI, arrhythmia, and sudden death [2].
-
CAA consequences: thrombosis ± MI, stenosis (late), rupture (rare), arrhythmia, sudden death [1].
-
Myocarditis occurs in most acute KD patients — tachycardia disproportionate to fever + ↓LV function. KD shock syndrome (KDSS) = cardiogenic shock from severe myocarditis — life-threatening [2].
-
HLH/MAS: life-threatening complication — suspect if IVIG-resistant + falling platelets + ferritin > 10,000. Leads to DIC, coagulopathy, cytopenias [2].
-
Non-coronary aneurysms: axillary, popliteal, iliac, renal arteries can be affected → pulsatile mass, limb ischaemia, renovascular hypertension [2].
-
SNHL: cochlear artery vasculitis → usually reversible; perform audiological follow-up.
-
Risk factors for CAA: male sex, age < 1y, prolonged fever > 14d, IVIG resistance, delayed treatment.
-
Even regressed CAA leaves a structurally abnormal vessel wall → lifelong risk of accelerated atherosclerosis → CV risk factor monitoring essential.
-
Treatment complications: Reye syndrome (aspirin + viral illness), IVIG-induced haemolytic anaemia, aseptic meningitis post-IVIG.
Active Recall - KD Complications
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf, Section 6.3.3 Kawasaki Disease (p.242–243) [2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, Section on Kawasaki Disease — Complications (p.302)
High Yield Summary
Kawasaki Disease — Key Points for Exams:
-
Definition: Acute, self-limiting systemic vasculitis of small-to-medium arteries, predilection for coronary arteries. Most common cause of acquired heart disease in children in the developed world.
-
Epidemiology: Peak age 6m–5y (peak 2–3y), M > F (1.5:1), highest in Asians (Japan #1, HK ~70–80/100k), seasonal (winter/spring).
-
Etiology: Unknown — likely an aberrant immune response to an unknown (? infectious) trigger in genetically susceptible children. Key susceptibility genes: ITPKC, FCGR2A, BLK, CD40.
-
Pathophysiology: Immune activation → cytokine storm → endothelial activation → pan-vasculitis → destruction of internal elastic lamina & medial smooth muscle → coronary artery aneurysm formation.
-
5 Cardinal Features (CRASH and Burn): Conjunctivitis (bilateral, non-exudative, perilimbal sparing), Rash (polymorphous, never vesicular, perineal accentuation), Adenopathy (cervical, unilateral, ≥ 1.5 cm), Strawberry tongue + oral changes (cracked lips, oropharyngeal erythema), Hands/feet changes (edema → desquamation) + Burn (fever ≥ 5 days).
-
Phases: Acute (wk 1–2: fever + principal features), Subacute (wk 2–4: desquamation, thrombocytosis, HIGHEST risk of coronary aneurysm/MI/death), Convalescent (wk 4–8: ESR normalises, Beau's lines).
-
Multi-system involvement: CVS (pancarditis, coronary aneurysms), GI (hydrops of GB, hepatitis), CNS (irritability, aseptic meningitis, SNHL), Resp (pneumonitis), UG (sterile pyuria), MSK (arthritis), BCGitis, HLH.
-
Incomplete KD: Fever ≥ 5 days + 2–3 features → higher risk of coronary complications due to delayed diagnosis. More common in infants < 6m and children > 5y.
-
Untreated: 20–25% develop coronary artery abnormalities. Treated with IVIG: < 5%.
-
BCGitis is a useful early sign, particularly relevant in Hong Kong where BCG is given at birth.
High Yield Summary
Differential Diagnosis of Kawasaki Disease — Key Points:
-
Three main categories of KD mimics [2]: Viral illnesses (lack extremity changes), Toxin-mediated illness (lack ocular/articular involvement), Drug reactions (normal/mildly elevated inflammatory markers).
-
Features that EXCLUDE KD: Vesicles/bullae (→ HFMD, HSV, VZV, SJS/TEN), oral ulcers (→ HFMD, Behçet's, SJS/TEN), exudative pharyngitis (→ GAS, adenovirus), Koplik's spots (→ measles), frank shock (→ TSS, MIS-C).
-
Features highly suggestive of KD over mimics: Non-exudative conjunctivitis with perilimbal sparing, extremity edema → periungual desquamation, BCGitis, coronary artery abnormalities on echo.
-
Scarlet fever is the closest bacterial mimic (both have strawberry tongue + desquamation). Distinguish by: conjunctivitis (KD yes, scarlet fever no), exudative pharyngitis (scarlet fever yes, KD no), response to penicillin (scarlet fever yes, KD no).
-
MIS-C is a critical modern DDx: older age, more shock/LV dysfunction, high ferritin/D-dimer, SARS-CoV-2 link. Always check COVID-19 serology in suspected KD.
-
KD is a clinical diagnosis — the DDx is worked through by pattern recognition and directed investigations to exclude mimics, not by a single confirmatory test.
High Yield Summary
Diagnosis of KD — Key Exam Points:
-
KD is a clinical diagnosis — no confirmatory test [1].
-
Complete KD: fever ≥ 5 days + ≥ 4/5 cardinal features (conjunctivitis, oral changes, rash, extremity changes, cervical LN).
-
Incomplete KD: fever ≥ 5 days + 2–3 features → check CRP/ESR → if elevated → check 6 supplementary lab criteria (anaemia, WBC ≥ 15, platelets ≥ 450 after D7, albumin ≤ 30, ↑ALT, urine ≥ 10 WBC/HPF) → if ≥ 3/6: treat before echo [2].
-
Echo positive criteria (any 1 of 3): Z-score ≥ 2.5 of LAD/RCA; Japanese MoH criteria ( > 3 mm if < 5y, > 4 mm if ≥ 5y, or segment ≥ 1.5× adjacent); or ≥ 3 other suggestive features (Z > 2 but < 2.5, perivascular brightness, lack of tapering, pericardial effusion, MR, ↓LV function).
-
Echo schedule: at diagnosis → 2 weeks → 6–8 weeks (minimum 3 times). More frequent if high-risk.
-
CAA risk factors: prolonged fever > 14d, prolonged ↑ESR, age < 1y or > 9y, IVIG resistance, male sex.
-
After IVIG: monitor with CRP (not ESR) because IVIG itself elevates ESR.
-
Sterile pyuria can mimic UTI — always correlate with culture and clinical features.
High Yield Summary
Management of KD — Key Exam Points:
-
First-line: IVIG 2 g/kg single infusion + high-dose aspirin (80–100 mg/kg/day ÷ Q6H) within 10 days of illness onset [2].
-
High-dose aspirin = anti-inflammatory (COX-1+2 inhibition). Switch to low-dose (3–5 mg/kg/day) once afebrile ≥ 48h [2].
-
Low-dose aspirin = antiplatelet (COX-1 → ↓ TXA₂). Continue for 8 weeks minimum; discontinue only if all echos are normal. Continue indefinitely if CAA present [2].
-
IVIG resistance (~10–20%): re-dose IVIG 2 g/kg → if still refractory → IV methylprednisolone 30 mg/kg pulse × 1–3 days → oral prednisolone taper [2].
-
Third-line: Infliximab (anti-TNF-α), cyclosporine, anakinra, plasma exchange.
-
Giant aneurysms (Z ≥ 10 or ≥ 8 mm): aspirin + warfarin (INR 2–3) or LMWH — highest thrombotic risk.
-
Avoid ibuprofen (antagonises aspirin's antiplatelet effect) and antacids (reduce aspirin absorption) [2].
-
Reye syndrome risk: monitor for viral illness; hold aspirin during varicella/influenza; vaccinate against both [2].
-
Defer live vaccines 11 months after IVIG (passive antibodies neutralise live vaccine virus) [2].
-
Long-term: lifelong CV risk factor monitoring for patients with any CAA history (diet, exercise, BP, lipids, BMI) [1].
High Yield Summary
Complications of KD — Key Exam Points:
-
Coronary artery aneurysm is the MOST common and serious complication — develops in 25% untreated, < 5% IVIG-treated. Most common site: proximal LAD > proximal RCA [1][2].
-
Giant aneurysms (≥ 8 mm or Z ≥ 10) carry the highest risk of rupture, thrombosis, MI, arrhythmia, and sudden death [2].
-
CAA consequences: thrombosis ± MI, stenosis (late), rupture (rare), arrhythmia, sudden death [1].
-
Myocarditis occurs in most acute KD patients — tachycardia disproportionate to fever + ↓LV function. KD shock syndrome (KDSS) = cardiogenic shock from severe myocarditis — life-threatening [2].
-
HLH/MAS: life-threatening complication — suspect if IVIG-resistant + falling platelets + ferritin > 10,000. Leads to DIC, coagulopathy, cytopenias [2].
-
Non-coronary aneurysms: axillary, popliteal, iliac, renal arteries can be affected → pulsatile mass, limb ischaemia, renovascular hypertension [2].
-
SNHL: cochlear artery vasculitis → usually reversible; perform audiological follow-up.
-
Risk factors for CAA: male sex, age < 1y, prolonged fever > 14d, IVIG resistance, delayed treatment.
-
Even regressed CAA leaves a structurally abnormal vessel wall → lifelong risk of accelerated atherosclerosis → CV risk factor monitoring essential.
-
Treatment complications: Reye syndrome (aspirin + viral illness), IVIG-induced haemolytic anaemia, aseptic meningitis post-IVIG.