Kawasaki Disease

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Chapter 160 Kawasaki Disease

Mary Beth F. Son, Jane W. Newburger

Kawasaki disease (KD), formerly known as mucocutaneous lymph node syndrome and infantile polyarteritis nodosa, is an acute febrile illness of childhood seen worldwide in all populations, with the highest incidence occurring in children of Asian background. KD is a vasculitis with a predilection for the coronary arteries, and approximately 20-25% of untreated patients experience coronary artery abnormalities, including aneurysms. KD is the leading cause of acquired heart disease in children in most developed countries, including the USA and Japan.

Etiology

The cause of KD remains unknown, but certain epidemiologic and clinical features support an infectious origin. These features include the young age group affected, epidemics with wavelike geographic spread of illness, the self-limited nature of the acute febrile illness, and the combination of clinical features fever, rash, enanthem, conjunctival injection, and cervical lymphadenopathy. Further evidence of an infectious trigger includes the infrequent occurrence of the illness in infants younger than 3 mo, likely the result of maternal antibodies, and the virtual absence of cases in adults, likely the result of prior exposures with subsequent immunity. Nonetheless, it is unusual to have multiple cases present at the same time within a family or daycare center. A genetic role in the pathogenesis of KD seems likely, as evidenced by the higher risk of KD in Asian children regardless of country of residence and in siblings and children of individuals with a history of KD. Furthermore, genome-wide association studies, including sibling pair analyses, have identified susceptibility loci.

A KD-associated antigen has been described in cytoplasmic inclusion bodies within ciliated bronchial epithelial cells from acute fatal cases. These inclusions appear consistent with viral protein aggregates and support the hypothesis of a respiratory portal of entry of the KD agent. However, no single infectious etiologic agent has been successfully identified, despite a comprehensive search.

Some of the features of KD, such as fever and diffuse rash, suggest superantigen activity, similar to that seen in toxin-mediated diseases like staphylococcal toxic shock syndrome. Studies of polyclonal activation of T cells, characteristic of superantigen-mediated processes, have yielded conflicting results in patients with KD. Similarly, the role of regulatory T cells, chemokines, and Toll-like receptors in KD has been studied, with inconclusive results. During the subacute phase of illness, levels of all immunoglobulins (Igs) are elevated, suggesting that a vigorous antibody response occurs. As in other forms of vasculitis, it is likely that a common environmental trigger leads to the phenotype of KD in genetically predisposed individuals.

Epidemiology

In 2000, the hospitalization rate for KD in the Kids Inpatient Database was reported to be 17.1/100,000 in children <5 yr of age. Asian and Pacific Islander children are at higher risk for KD; the same database yielded a hospitalization rate for KD of 39/100,000 children of Asian and Pacific Islander background, compared with 19.7/100,000 black, non-Hispanic children, 13.6/100,000 Hispanic children, and 11.4/100,000 white, non-Hispanic children. Between 2001 and 2006, the number of hospitalizations for KD in free-standing children’s hospitals participating in the Pediatric Health Information System increased by more than 30%. In Japan, >200,000 cases of KD have been reported since the 1960s. KD is an illness of early childhood, as the median age of illness is 2-3 yr and 80% of children are <5 yr old. KD may occur in adolescents.

Several risk stratification models have been constructed to determine which patients with KD are at highest risk for coronary artery abnormalities. Predictors of poor outcome include young age, male gender, and laboratory abnormalities including neutrophilia, thrombocytopenia, hepatic transaminase elevation, hyponatremia, hypoalbuminemia, and elevated C-reactive protein levels. Asian and Pacific Islander race and Hispanic ethnicity are also risk factors for coronary artery abnormalities. Prolonged fever is associated with the development of coronary artery disease.

Pathology

KD is a vasculitis that predominantly affects the medium-sized arteries, with a striking predilection for the coronary arteries. Pathologic examination of fatal cases in the acute or subacute stages reveals edema of endothelial and smooth muscle cells with intense inflammatory infiltration of the vascular wall, initially by polymorphonuclear cells but rapidly thereafter by macrophages, lymphocytes (primarily CD8+ T cells), and plasma cells. IgA plasma cells are particularly prominent in the inflammatory infiltrate. In the most severely affected vessels, inflammation involves all three layers of the vascular wall, with destruction of the internal elastic lamina. Loss of structural integrity weakens the vessel wall and results in dilation (ectasia) or saccular or fusiform aneurysm formation. Thrombi may form in the lumen and obstruct blood flow. Over time, the vascular wall can become progressively fibrotic with marked intimal proliferation, producing arterial stenosis or occlusion.

Clinical Manifestations

Fever is characteristically high (≥101°F), unremitting, and unresponsive to antibiotics. The duration of fever without treatment is generally 1-2 wk but may persist for 3-4 wk. In addition to fever, the five principal clinical criteria of KD are: bilateral nonexudative bulbar conjunctival injection with limbal sparing; erythema of the oral and pharyngeal mucosa with strawberry tongue and dry, cracked lips; edema and erythema of the hands and feet; rash of various forms (maculopapular, erythema multiforme, or scarlatiniform) with accentuation in the groin area; and nonsuppurative cervical lymphadenopathy, usually unilateral, with node size >1.5 cm (Table 160-1; Figs. 160-1 to 160-4). Perineal desquamation is common in the acute phase. Periungual desquamation of the fingers and toes begins 1-3 wk after the onset of illness and may progress to involve the entire hand and foot (Fig. 160-5).

Table 160-1 CLINICAL AND LABORATORY FEATURES OF KAWASAKI DISEASE

EPIDEMIOLOGIC CASE DEFINITION (CLASSIC CLINICAL CRITERIA)*

Fever persisting at least 5 days ^†

Exclusion of other diseases with similar findings ^‡

OTHER CLINICAL AND LABORATORY FINDINGS

Cardiovascular findings:

Congestive heart failure, myocarditis, pericarditis, valvular regurgitation

Coronary artery abnormalities

Aneurysms of medium-sized noncoronary arteries

Raynaud phenomenon

Peripheral gangrene

Musculoskeletal system:

Arthritis, arthralgias

Gastrointestinal tract:

Diarrhea, vomiting, abdominal pain

Hepatic dysfunction

Hydrops of gallbladder

Central nervous system:

Extreme irritability

Aseptic meningitis

Sensorineural hearing loss

Genitourinary system:

Urethritis/meatitis

Other findings:

Erythema, induration at bacille Calmette-Guérin inoculation site

Anterior uveitis (mild)

Desquamating rash in groin

LABORATORY FINDINGS IN ACUTE KAWASAKI DISEASE

Leukocytosis with neutrophilia and immature forms

Elevated erythrocyte sedimentation rate (ESR)

Elevated C-reactive protein (CRP)

Abnormal plasma lipids

Hypoalbuminemia

Thrombocytosis after week 1 ^§

Elevated serum transaminases

Elevated serum gamma glutamyl transpeptidase

Pleocytosis of cerebrospinal fluid

Leukocytosis in synovial fluid

* Patients with fever at least 5 days and <4 principal criteria can be diagnosed with Kawasaki disease when coronary artery abnormalities are detected by two-dimensional echocardiography or angiography.

^† In the presence of ≥4 principal criteria, Kawasaki disease diagnosis can be made on day 4 of illness. Experienced clinicians who have treated many patients with Kawasaki disease may establish diagnosis before day 4.

^‡ See differential diagnosis (Table 160-2).

^§ Some infants present with thrombocytopenia and disseminated intravascular coagulation.

From Newburger JW, Takahashi M, Gerber MA, et al: Diagnosis, treatment, and long-term management of Kawasaki disease, Pediatrics 114:1708–1733, 2004.

Figure 160-1 Clinical symptoms and signs of Kawasaki disease. A summary of the clinical features from 110 cases of Kawasaki disease seen in Kaohsiung, Taiwan. LAP, lymphadenopathy in head and neck area; BCG, reactivation of bacille Calmette-Guérin inoculation site; CAD, coronary artery dilatation, defined by an internal diameter > 3 mm.

(From Wang CL, Wu YT, Liu CA, et al: Kawasaki disease: infection, immunity and genetics, Pediatr Infect Dis J 24:998–1004, 2005.)

Figure 160-2 Strawberry tongue in mucocutaneous lymph node syndrome (Kawasaki disease).

(Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical pediatric dermatology, ed 2, Philadelphia, 1993, WB Saunders.)

Figure 160-3 Congestion of bulbar conjunctiva in a patient with mucocutaneous lymph node syndrome (Kawasaki disease).

(Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical pediatric dermatology, ed 2, Philadelphia, 1993, WB Saunders.)

Figure 160-4

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