Kawasaki disease
• Although KD or mucocutaneous lymph node syndrome it is a self-limited condition, with fever and manifestations of.
• Acute inflammation lasting for an average of 12 days without therapy.
• Diagnosed by clinical criteria not histology or angiography.
Kawasaki disease
• 80% to 90% of >fifth birthday.
• 1.5% of untreated children died from KD.
• More than 140,837 cases of KD have been registered in Japan since its initial description in 1967.
Kawasaki disease
• susceptibility of different ethnic groups to KD
• Genetic factors,
• polymorphisms of chemokines
• and TNF receptors
• variations in HLA haplotypes
• Overall, Asians are affected 5 to 10 times as frequently as whites;
• blacks and Hispanics have an intermediate risk
The cause of KD remains unknown.
Criteria for diagnosis of Kawasaki disease
• Fever lasting 5 days or more (4 days if treatment with IVIG
• eradicates fever) plus at least four of the following clinical signs
• not explained by another disease process
Modified from Centers for Disease Control. Revised diagnostic criteria
for Kawasaki disease. MMWR Morb Mortal Wkly Rpt 1990;
39(No. 44-13):27–8.
1. Bilateral conjunctival injection (80%–90%)
2. Changes in the oropharyngeal mucous membranes (including
one or more of the following symptoms: injected or fissured
lips, strawberry tongue, injected pharynx) (80%–90%)
3. Changes in the peripheral extremities, including erythema
or edema of the hands and feet (acute phase) or periungual
desquamation (convalescent phase) (80%)
4. Polymorphous rash, primarily truncal; nonvesicular (N 90%)
5. Cervical lymphadenopathy: anterior cervical lymph note at
least 1.5 cm in diameter (50%)
Pathologically, however, KD seems to be unique:
• Macrophages and IgA-producing plasma cells in the vessel walls, features recognized in no other conditions.
• Many aspects of KD suggest that it is caused by a transmissible agent.
• A synthetic monoclonal IgA antibody was found to bind to an unidentified cytoplasmic.
• Component of macrophages within the coronary arteries of 9 of.
• 12 fatal cases of KD but in none of 10 controls.
Kawasaki disease
• Similar binding to the respiratory epithelium of proximal bronchi was noted in 77% of fatal cases, never in controls.
• One interpretation is that a particular respiratory pathogen may be associated with KD.
Kawasaki disease
Many epidemiologic data also support the.
theory that KD is triggered by a transmissible.
agent or agents;
• Boys > 50% more commonly than girls, a feature typical of infectious diseases.
• The average age of children with KD is.
• about 2 years, and occurrence beyond late childhood is extremely rare.
nonetheless
• viruses (eg, Epstein–Barr virus, parvovirus, HIV-2) or bacterial toxins (eg, streptococcal erythrogenic toxin, staphylococcal toxic shock toxin) account for the majority of cases have not been substantiated
• Thus, many researchers now believe that KD represents a final common pathway of immune-mediated vascular inflammation following a variety of inciting infections.
Clinical manifestations
• Guidelines for the diagnosis of KD were established by Tomisaku Kawasaki 1967.
• Diagnosis requires the presence of fever lasting 5 days or more without any other explanation, combined with at least four of five manifestations of mucocutaneous inflammation.
• Children who do not meet the criteria may have an incomplete or atypical form of KD.
• at least 10% of children who develop coronary artery aneurysms never meet criteria for KD
• Fever is probably the most consistent manifestation of KD.
• It reflects elevated levels of proinflammatory cytokines such as TNF and interleukin (IL)-1 that are also thought to mediate the underlying vascular inflammation.
• The fever is typically hectic, minimally responsive to antipyretic agents, and remains > 38.58C during most of the illness.
• Bilateral nonexudative conjunctivitis is present in as many as 90% of cases.
Bulbar injection
• Begins within days of the onset of fever, and the eyes have a brilliant erythema that spares the limbus.
• Children are also frequently photophobic, and anterior uveitis may develop.
• Slit-lamp examination may be helpful in ambiguous cases; the presence of uveitis.
Cracked, red lips
• Cracked, red lips and a strawberry tongue are characteristic.
• caused by sloughing of filiform papillae and denuding of the inflamed glossal tissue.
• Discrete oral lesions, such as vesicles or ulcers, as well as tonsillar exudate, suggest a viral or bacterial.
cutaneous manifestations
• Polymorphous rash typically begins as perineal erythema and desquamation,
• followed by macular, morbilliform,
• or targetoid lesions of the trunk and extremities.
• Vesicular or bullous lesions are rare.
Changes in the extremities
• generally the last manifestation of KD to develop.
• an indurated edema of the dorsum of the hands and feet and.
• a diffuse erythema of the palms and soles.
The convalescent phase of KD
• sheetlike desquamation that begins in the periungual region of the hands and feet and by linear nail creases (Beau’s lines).
The convalescent phase of KD
• one third of children have arthritis.
• The arthritis is typically a small joint polyarthritis during the first week of illness, followed by a large joint pauciarthritis.
• It never persists beyond 1 to 2 months, nor is it erosive.
Cervical lymphadenopathy
• is the least consistent.
• absent in as many as 50% of children with the disease.
• involve primarily the anterior cervical nodes overlying the sternocleidomastoid muscle.
• Children suspected of having KD who have fewer than four signs of mucocutaneous inflammation may have incomplete or atypical KD.
• most incomplete and atypical in the youngest patients.
• In a retrospective review of 45 cases of KD,
• 5 of 11 infants (45%) had atypical disease,
• compared with 4 of 33 older children (12%)
• Coronary artery complications occurred in 64% infants compared with 9% older children (and occurred in all five infants with incomplete disease).
Japanese nationwide survey of KD in 1995 and 1996
• Infants < 1 year of age had an odds ratio of 1.54 for developing cardiac sequelae.
• Similarly, in a recent retrospective survey, the rate of treatment failure was 8.5% in patients under 12 months of age.
• compared with a 1.8% incidence of coronary artery abnormalities in those at > 12 months of age.
Japanese nationwide survey of KD in 1995 and 1996: 140,837
• The incidence rates per 100,000 children of <5 years old were 102.6.
• Recurrent cases 3–5%.
• Peak age of incidence 1 year of age.
• 80–85% of cases < 5 years.
• Male to female ratio is 1.5:1.
Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997
• 408 cases - 81% typical KD
• annual incidence (per 100,000) by age was 13.6 in <5 yrs
• males vs. females of 1.73
Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997
• Coronary artery involvement included ectasia in 35%.
• non-giant aneurysms in 9%.
• giant aneurysms (>8 mm) in 1.4%.
• with ventricular dysfunction noted in 2.7%.
Laboratory
• Elevation of acute phase reactants (eg, CRP, ESR, and alpha-1 antitrypsin),
• Leukocytosis, and a left shift.
• By the second week of illness, platelet counts > 1,000,000/mm3 in the most severe cases.
• Normocytic, normochromic anemia;
• urinalysis - white blood cells on microscopic.
• The pyuria is of urethral origin and therefore will be missed on urinalyses obtained by bladder tap or catheterization.
• Renal involvement may occur in KD but is uncommon.
• elevated transaminase levels or mild hyperbilirubinemia caused by intrahepatic congestion
• Cerebrospinal fluid (CSF) typically displays a mononuclear pleocytosis without hypoglycorrhachia or elevation of CSF protein.
• Review of 46 children with KD found that 39% had elevated CSF white cell counts
• Obstructive jaundice from hydrops of the gallbladder.
Differential diagnosis
• KD is most commonly confused with infectious exanthems of childhood
• Measles, echovirus, and adenovirus may share many of the signs of mucocutaneous
Differential diagnosis
• Toxin-mediated illnesses, especially b hemolytic streptococcal infection and toxic shock syndrome,
• Rocky Mountain spotted fever and leptospirosis
• Drug reactions such as Stevens–Johnson syndrome or serum sickness
• Systemic-onset juvenile idiopathic arthritis
• Mercury hypersensitivity reaction (acrodynia)
Therapy
IVIG and aspirin.
Markers of increased risk of developing coronary artery aneurysms,
• age under 1 year,
• signs of severe systemic inflammation
• consumptive coagulopathy,
• Aspirin was the first medication used for treatment of KD because of its antiinflammatory and antithrombotic effects
• Therapy within the first 10 days of illness reduces the incidence of coronary artery aneurysms by more than 70%
• IVIG therapy also largely eliminates the
– development of giant coronary artery aneurysms (more than 8 mm in diameter), which are associated with the highest risk of morbidity and mortality,
– and rapidly restores disordered lipid metabolism and depressed myocardial contractility to normal
• Aspirin traditionally is given initially in relatively high doses to achieve an anti-inflammatory effect; doses of 30 mg/kg/day to more than 80 mg/kg/day in four divided doses have been used during the acute phase of illness.
• Subsequently, aspirin is administered in low doses (3 to 5 mg/kg/day) for its antiplatelet action.
• No study has demonstrated long-term benefit from the use of aspirin, and a recent trial found no differences in outcomes between children treated with IVIG alone and those who also received aspirin
aspirin
• 100 mg/kg/day.
• Once fever resolves, patients receive a dose of 3 to 5 mg/kg/day.
• Treatment with aspirin is continued until laboratory studies (eg, platelet count and sedimentation rate) return to normal, unless coronary artery abnormalities are detected by echocardiography.
corticosteroids
• A retrospective survey of the records of almost 300 children treated with or without steroids between 1982 and 1998.
• and two open, randomized, prospective trials found that patients who received corticosteroids in addition to IVIG had shorter durations of fever and more rapid decrease in inflammatory markers than those in the standard-therapy group.
Corticosteroids
• In all reports, corticosteroid therapy has been well tolerated, with no significant adverse effects.
• At present, most clinicians who specialize in the care of KD use pulsed doses of intravenous methylprednisolone (IVMP) in children whose inflammation persists despite at least two doses of IVIG.
IVMP
• A trial supported by the National Institutes of Health comparing outcomes in children who received initial therapy with IVMP plus IVIG versus IVIG alone has completed enrollment.
• Results of this trial soon should supply definitive information concerning the potential role of steroids in the primary treatment of KD.
Re-treatment
• Fever persists or returns 48 hours after the start of initial treatment with IVIG in 10% to 15% of patients
• Persistent or recrudescent fever is particularly concerning, indicating ongoing vasculitis with increased risk of developing coronary artery aneurysms (12.2% versus 1.4% in one analysis)
• In another study, persistent fever was the only factor that predicted subsequent development of aneurysms
• It is extremely important not to dismiss mild temperature elevations in children with KD;
• Patients who remain febrile after the first dose of IVIG are usually treated with a second and perhaps even a third dose of IVIG, 2 g/kg
• This practice is based on the apparent dose–response effect of IVIG
• most specialists treat children who have not responded to IVIG and still have active KD with one to three daily doses of pulsed methylprednisolone (30 mg/kg)
• If this treatment is ineffective, a single dose of infliximab, 5 mg/kg, may be beneficial
Additional considerations
• An echocardiogram should be obtained early in the acute phase of illness and 6 to 8 weeks after onset to confirm the efficacy of treatment
• Children with coronary artery abnormalities receive long-term antithrombotic therapy with aspirin, dipyridamole, or other agents, as well as regular cardiac evaluations.
• Coronary artery dilatation of less than 8 mm regresses over time, and most smaller aneurysms fully resolve by echocardiogram.
• Healing is by fibrointimal proliferation, often accompanied by calcification, and vascular reactivity does not return to normal despite grossly normal appearance
• Children should thus be followed indefinitely after KD, a point highlighted by a report of the sudden death of a 3.5-year-old child 3 months after dilated coronary arteries had regained a normal echocardiographic appearance
• Autopsy revealed obliteration of the lumen of the left anterior descending coronary artery by fibrosis, with evidence of ongoing active inflammation in the epicardial arteries.
• Children with severe KD who develop coronary occlusion may experience myocardial infarction, arrhythmias, or sudden death, and those who develop peripheral artery occlusion may experience ischemia or gangrene.
• At least one report suggests a potential role for abciximab, a monoclonal antibody that inhibits platelet glycoprotein IIb/IIIa receptor.
• increased resolution of aneurysms in patients with KD who received abciximab compared with those who received conventional treatment.
• Overall, with modern treatment and cardiologic follow-up, the prognosis of children with KD is excellent.
• Long-term follow-up of children without persistent coronary artery abnormalities in Japan has demonstrated no increase in morbidity or mortality after 25 years.
• In fact, studies suggest that fear of a cardiac event is more disabling than actual medical problems in most children who have had KD.
• Thus, caregivers should be particularly careful to reassure families when appropriate.
