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KAWASAKI     DISEASE mucocutaneous lymph node syndrome Tomisaku Kawasaki Definition • An acute febrile eruptive disease occurring most commonly in infants and children under 5 years of age. • Vasculitis, especially involving coronary arteries, is a serious complication.

Clinical features Fever for five or more days without other explanation plus at least 4 of the following: Nonexudative bulbar conjunctival injection Oropharyngeal changes (e.g., injected or fissured lips, injected pharynx, strawberry tongue) Extremity changes (e.g., erythema of palms or soles, edema of hands or feet, periungual desquamation) Polymorphous rash Acute nonsuppurative cervical lymphadenopathy

Diagnostic Criteria for Kawasaki Syndrome A diagnosis of atypical Kawasaki syndrome can be made with less than four criteria if coronary artery aneurysms are present

HISTORY First case; Japan 1961; Original paper; Tomisaku Kawasaki 1967.

EPIDEMIOLOGY Nationwide survey of KD, Japan; December 1996; 140,837 cases 102.6 cases per 100,000 children of <5 years Recurrent cases 3–5% Peak age; 1 year 80–85% of cases < 5 years Male to female ratio is 1.5:1

fatality Fatality rate < 1974 1.0–2.6%, > 1975 and at present 0.08–0.1%. M/F ratio of those who died 3:1

Epidemiology No difference between urban and rural areas USA middle class and above Japan any background. No difference between breast-fed and formula-fed children.

Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997 408 cases  - 81% typical KD annual incidence 13.6 per 100,000 <5yo yrs males vs. females of 1.73

Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997 Relative risk by race (vs. Caucasian); Asian 5.3, Black 3.5, Hispanic 1.2 and other 1.3. Seasonal peak between November and February, with a smaller peak in June and July. 92%  treated with IVGG (94% treated within 10 days of fever onset; 10% received more than 1 dose).

Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997 Coronary artery involvement included ectasia 35% giant aneurysms (>8 mm) 1.4% non-giant aneurysms 9% ventricular dysfunction 2.7%

Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997 Aneurysms were noted in 6% of cases treated with IVGG within 10 days of fever onset, 29% if treated later Aneurisms;  <1 yr of age 15% 1 to 4 yrs 9%  5 to 9 yrs 6% 10 to 14 yrs 13%

Kawasaki Syndrome Surveillance, United States, 1994-1997 Continued preventive efficacy of IVIG treatment ; Coronary artery ectasia 8.2% Before the use of IVIG 19.6%

epidemics of KD In Japan three nationwide epidemics of KD: • December 1978 – June 1979 • January    1982 – June 1982 • November 1985 – May 1986

epidemics In 1979, began in southwest Japan and in 4 months moved to the northernmost part. In the 1982 epidemic no movement. The 1986 outbreak started in the Tokyo moved northward, and in 4 months had spread throughout the country

Epidemics 2 No clear evidence of person-to-person transmission. In sibling cases (1–2% of the total)  50% occurred 7 days after the first sibling

Reports from Hawaii, KD in all racial descents but particularly Oriental origin, especially Japanese Lowest rate in Caucasian children. Black, Hawaiian children, and mixed ancestry, midway between these extremes

CLINICAL FEATURES The symptoms - two categories: principal symptoms  (Criteria) and other significant symptoms Three phases: Acute: subacute: convalescence

Principal Symptoms abrupt onset high fever, with or without prodromal symptoms remittent or continuous fever ranging from 38–40°C and lasting 1–2 weeks. Could lasts 3–4 weeks; more than 4 weeks is rare When gammaglobulin is given, the fever subsides within a few days. Steroid with aspirin is also often effective in helping the fever to subside. Within 2–4 days of onset, conjunctival congestion occurs.

lips and oral cavity Changes occur 2–5 days after onset. Dryness, redness and fissuring of lips, and in some cases bleeding and crust formation. Oral cavity and pharyngeal mucosa show diffuse reddening. No vesicle, aphtha or pseudomembrane formation. Frequently, strawberry tongue These changes subside within 2 weeks, although the reddening of the lips will often continue for 3–4 weeks.

lymphadenopathy Painful cervical lymphadenopathy may appear 1 day before or simultaneously with the onset of fever. Swelling is a firm, nonfluctuant mass >1.5cm in diameter. Bilateral swelling is often misdiagnosed as mumps.

Exanthema On the trunk and/or on the extremities within 1–5 days of onset. Polymorphous: morbilliform, urticarial, or erythema multiform-like lesions can be seen. Scarlatiniform exanthema should be differentiated from scarlet fever. The exanthema disappears when fever subsides.

Skin and mucous membranes Reddening of the palms and soles and indurative edema. Symptoms disappear when the fever subsides. Membranous desquamation on the fingertips sometimes extending to the wrists, can be seen 10–15 days from onset.

cardiovascular The most significant complications acute phase > 80% mild or severe carditis Severe cases - heart murmur, gallop rhythm, distant heart sounds ECG; prolonged PR-QT intervals, abnormal Q wave, low voltage ST-T changes, arrhythmias.

cardiovascular Cardiomegaly (due to myocarditis or pericarditis) on chest X-ray. Two-dimensional echocardiography shows coronary artery changes such as dilatation or aneurysms. In cases of angina pectoris or myocardial infarction, coronary angiography is necessary. In rare cases, peripheral arteries such as axillary, subclavicular and iliac arteries, show aneurysms. Also very rare is necrosis of fingers and toes.

STRUCTURE AND FUNCTION The primary changes in KD are systemic vasculitis, especially involving coronary arteries, or inflammation of organs such as carditis and hepatitis.

systemic vasculitis The most important element in the pathologic process of KD Particularly the development of coronary artery changes including aneurysms. In the acute phase; vasculitis in the medium-sized arteries Acute inflammation lasting about 7 weeks, with or without mild fibrinoid necrosis. .

Other arteries mesenteric organs,  kidneys The angiitis can also be seen in the internal arteries of the heart, skin, kidneys and tongue, as well as in the veins. Myocarditis involving the conduction system, pericarditis, endocarditis, cholecystitis, cholangitis, pancreatic ductitis, sialoadenitis, meningitis and lymphadenitis are often seen.

Gastrointestinal In the acute phase; diarrhea, vomiting, abdominal pain, Mild jaundice due to hydrops of the gall bladder. Paralytic ileus, Slight increase of serum transaminase due to hepatitis.

irritability Spinal tap; mild pleocytosis of mononuclear cells 30–40% of cases febrile convulsion In rare cases; facial palsy and paralysis of the extremities Loss of consciousness due to encephalitis or encephalopathy

Other complications include: Slight proteinuria and slight increase of leukocytes in urine sediment; Occasional aseptic small pustules on the elbows, knees and/or buttocks; Transverse furrows of the fingernails seen 2–3 months after onset; Upper respiratory signs; sneezing and coughing, chest X-rays = do not indicate pneumonia; Arthritis in about 20–30% of cases, with involvement of small and large joints.

HLA No specific laboratory test currently exists to diagnose this illness  HLA-Bw22 and Bw22J2

laboratory findings The following are suggestive of KD: leukocytosis with shift to the left increased ESR positive CRP thrombocytosis; 2-3 weeks after onset negative ASLO negative throat culture and blood culture pleocytosis in cerebrospinal fluid slight increase of serum transaminase activity Hypoalbuminemia

Immunological findings in Kawasaki disease Clin Exp Rheumatol 1997 Nov-Dec;15(6):685-9 in a cohort of 34 Italian children with KD circulating immune complexes 66% anticardiolipin 30% antineutrophil cytoplasmic antibodies 8% anti-endothelial cells 26%

שקופית 34

Kawasaki Disease (n=22) Age 3.1 ± 2.8  (3 months- 8 y) Male: Female 7/22 diagnosis >10 days from onset 3/22 –giant aneurysm (>8 mm) 4/22 <5 criteria

שקופית 36

Kawasaki Disease (n=22)

DIFFERENTIALS Drug Eruptions Erythema Multiforme Measles (Rubeola) Scarlet Fever Staphylococcal Scalded Skin Syndrome Stevens-Johnson Syndrome Epidermal Necrolysis Toxic Shock Syndrome

Other Problems to be Considered: Acrodynia (Mercury Toxicity) Group A Beta-hemolytic Streptococcal infection Infantile Polyarteritis Nodosum Juvenile Rheumatoid Arthritis Leptospirosis Rocky Mountain Spotted Fever Staphylococcal or Streptococcal Scarlet Fever Viral Exanthems

ETIOLOGY The etiology of KD is unknown. Microorganisms may initially act as a trigger for abnormal immunologic activation and/or suppression. Various hypotheses have been proposed, some supporting an infectious and some a noninfectious etiology.

Immunologic Patterns The initial vascular lesion is associated with endothelial cell activation, accompanied by infiltration by activated CD4 and CD8 T cells as well as monocytes and macrophages. elevated serum levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, soluble interleukin-2 receptor, macrophage colony stimulating factor, and soluble E-selectin.  Peripheral blood mononuclear cells from patients with acute, but not convalescent, disease spontaneously produce high levels of IL-1-beta, TNF-alpha, and IL-6, which elicit proinflammatory and prothrombotic responses.

Immunologic Patterns In the acute phase  - circulating antibodies that are cytotoxic against vascular endothelial cells prestimulated with IL-1-beta, TNF-alpha, or gamma-interferon Elevated anticardiac myosin autoantibodies may be involved in myocardial damage

ETIOLOGY A number of bacteria (e.g. Propioni bacterium acnes, Streptococcus sanguis), and several viruses (Epstein–Barr virus, retroviruses), have been suspected etiologic agents. The noninfectious etiological agents which have been proposed include detergents, mercury, and mites. none of them has been confirmed.

bacterial toxins act as superantigens Staphylococcal enterotoxin B (SEB) and C (SEC), toxic shock syndrome toxin 1 (TSST-1), and streptococcal pyrogenic exotoxins Binding directly to conserved amino acid residues outside the antigen-binding groove on MHC class II molecules, Selectively stimulate T cells expressing specific T-cell receptor (TCR) BV (previously called V-beta) chains. Conventionally processed peptide antigens tend to require all five variable elements of a TCR (VJ-alpha and VDJ-beta) of the TCR contribute much less to the recognition process.

Superantigen role ; pathogeny An infectious cause is presumed. Coronaritis in some toxic shock syndrome Immunity against HSP65 and 63 in blood of Kawasaki disease patients Tissue lesions are due to activation of an immune cascade and mediated by a lot of inflammatory cytokines

superantigens A skewed T-cell receptor response (VB2T) in the myocardium and coronary arteries Immunohistochemical staining shows an inflammatory infiltrate of predominantly CD4+ (helper-induced) T-lymphocytes and CD13 macrophages, but no CD20 B cells Increased Tumor Necrosis Factor-alpha is found in the epidermis and on blood vessel walls, HLA-DR (class II MHC molecules) are expressed by keratinocytes and endothelial cells. Hypothesis of proinflammatory cell-mediated immune reactions possibly triggered by a superantigen or conventional antigen

toxic shock syndrome Has now been associated with coronary artery abnormalities similar to those seen in Kawasaki syndrome. Kawasaki syndrome and toxic shock syndrome are overlapping entities with a common microbial trigger. The final clinical phenotype may depend on the host's age and unidentified genetic and environmental factors

Treatment of KD Acute Phase Intravenous immune globulin, 2 gm/kg as a single 10-12-hr infusion Aspirin, 80-100 mg/kg/day in four divided doses until day 10 Convalescent Phase in Uncomplicated Cases Aspirin, 3-5 mg/kg once a day for 6-8 weeks Patients with Coronary Artery Disease Aspirin, 3-5 mg/kg once a day Dipyridamole, 1 mg/kg/day in selected patients Anticoagulant therapy or fibrinolytic therapy or both (as needed in patients with arterial thrombosis)

IVIG in different diseases

Mechanism of Intravenous Immune Globulin Therapy in Antibody-Mediated Autoimmune Diseases Its mechanism of action is not known  Block Fc receptors on phagocytes and on cellular effectors of antibody-dependent cytotoxicity The Fc region mediates the effector properties of the molecule but not its immunologic specificity

Mechanism of Intravenous Immune Globulin Therapy in Antibody-Mediated Autoimmune Diseases Various immunomodulatory properties have been attributed to pooled preparations of IgG  Including regulatory properties of antiidiotypic antibodies and effects on cytokine synthesis and on receptors for cytokines and complement. There is no persuasive evidence that any of these postulated mechanisms account for the therapeutic benefits

Mechanism of Intravenous Immune Globulin Therapy in Antibody-Mediated Autoimmune Diseases Mice with a targeted "knockout" of the gene encoding beta2-microglobulin, a subunit of the class I major-histocompatibility-complex protein, The low serum level of IgG in these mutant mice is attributed to the loss of a previously unrecognized transport receptor for IgG, named FcRn. Normally, IgG that enters cells through the process of pinocytosis is protected from catabolism by binding to FcRn.

FcRn The receptor was initially identified in neonatal intestinal epithelium (and is therefore called FcRn, for Fc receptor of the neonate), and beta2-microglobulin is a critical subunit of the receptor. IgG that is picked up by cells from plasma binds to a protective receptor in endocytotic vesicles and subsequently returns intact to the circulation  IgG binds maximally to its protective receptor — FcRn — in the acidic conditions of the endosome. Without this protective mechanism, IgG would pass to the lysosome and be degraded.

"In states of hypergammaglobulinemia," In states of hypergammaglobulinemia, this receptor is saturated, permitting the degradation of IgG to occur in proportion to its total concentration in plasma The IgG receptor known as FcRn is found in many adult tissues, including skin, muscle, and intestinal epithelium. Its high level of expression in vascular endothelial cells suggests that these cells are a major site of IgG catabolism. a human homologue of FcRn has been identified.

KD - Recurrences 3/22 within 1 month 1/22 –m 8 years? 4/22 needed a 2nd IVIG dose IV pulse methyl prednisolone in intractable KD (30 mg/kg/d X 3 days)

Coronary artery weekly two-dimensional echocardiography 4 weeks from onset. If coronary artery aneurysms are discovered low-dose aspirin (3–5mg/kg/day) treatment is continued until regression can be seen. If large or giant aneurysms are discovered, regression is difficult and there is the possibility of development of stenosis/and or obstruction. In this case, anticoagulant drugs, for example dipyridamole (5mg/kg), flurbiprofen (4mg/kg), or ticlopidin (5mg/kg), should also be administered.

Long-term management is not necessary in cases without coronary artery changes, but when these are present, angiography should be performed. Depending on the case, angiography should be repeated at 1–2 year intervals. For cases with infarction, ECG and thallium scintigraphy should be carried out. Some cases may call for bypass surgery.

Long-Term Management Many patients with arterial aneurysms will show angiographic regression within six months to two years of the onset  The likelihood of resolution is determined by the aneurysm's initial size. Giant aneurysms (with a maximum diameter exceeding 8 mm) carry the worst prognosis; nearly all late deaths from Kawasaki syndrome occur in this subgroup of patients. Some patients have required cardiac transplantation for severe ischemic heart disease

Options for Patients with Chronic Myocardial Ischemia Transluminal coronary angioplasty Coronary artery bypass graft surgery Cardiac transplantation