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.

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).

• 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.

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.

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.

This is a very important DDx in Hong Kong (GAS pharyngitis is common in children).

• 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

• 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

• 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

If ≥ 3 of the following 6 criteria are met, treat before echocardiography ^[2]:

Any 1 of the following 3 is considered a positive echocardiogram ^[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.

• 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).

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:

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]:

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.

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]

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:

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.

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.

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.

• "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.

Develops in up to 25% of untreated patients in the 2nd to 3rd week of illness ^[1][2]

• With IVIG treatment: < 5% develop CAA (the entire rationale for treatment).
• Giant aneurysms (Z ≥ 10 or ≥ 8 mm) develop in ~1% of treated and ~5–8% of untreated patients.

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:

1. Pan-vasculitis → neutrophilic then lymphocytic/macrophage infiltration of all three vessel wall layers
2. Destruction of the internal elastic lamina (IEL) and medial smooth muscle cell necrosis → loss of structural integrity
3. Arterial blood pressure acting on the weakened wall → outward ballooning → aneurysm
4. The aneurysm sac fills with blood flowing in a turbulent, low-velocity vortex → creates a prothrombotic environment

Risk factors ^[1][2]:

• 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

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]

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