Kawasaki Disease

Etiology

The cause of KD remains unknown. Certain epidemiologic and clinical features support an infectious origin, including the young age-group affected, epidemics with wavelike geographic spread of illness, the self-limited nature of the acute febrile illness, and the clinical features of fever, rash, enanthem, conjunctival injection, and cervical lymphadenopathy. Further evidence of an infectious trigger includes the infrequent occurrence of the illness in infants <3 mo old, possibly the result of maternal antibodies, and the rarity of cases in adults, possibly the result of prior exposures with subsequent immunity. However, there are features that are not consistent with an infectious origin. For example, it is unusual to have multiple cases present at the same time within a family or daycare center. Furthermore, no single infectious etiologic agent has been successfully identified, despite a comprehensive search.

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, linkage studies and genome-wide association studies (GWAS) have identified significant potential associations between polymorphisms in the ITPKC gene, a T-cell regulator, with increased susceptibility to KD and more severe disease. Other candidate genes for KD identified by GWAS include CASP3, BLK, and FCGR2A. Lastly, associations of single nucleotide polymorphisms (SNPs) in the human leukocyte antigen class II region (HLA-DQB2 and HLA-DOB) with KD have been reported. The concordance rate among identical twins, however, is approximately 13%.

Epidemiology

For the majority of patients, KD is a disease of early childhood, and nearly all epidemiologic studies show a higher susceptibility to KD in boys. Data from the Kids Inpatient Database to study trends in KD hospitalizations in 2003, 2006, 2009, and 2012 reported that U.S. hospitalizations for KD seemed to decline significantly over the study period, with 6.68 per 100,000 children hospitalized for KD in 2006 vs 6.11 per 100,000 in 2012. Children age <5 yr had the highest annual hospitalization rates, and children of Asian and Pacific Islander ancestry had the highest rates among all racial groups. In other countries, such as the United Kingdom, South Korea, and Japan, the rate of KD seems to be increasing.

In Japan, nationwide surveys have been administered every 2 yr to monitor trends in KD incidence. In 2012 the highest recorded rate thus far of 264.8 per 100,000 children ages 0-4 yr was described, with the highest rate in young children ages 9-11 mo. Fortunately, the proportion of Japanese patients with coronary aneurysm and myocardial infarction has decreased over time, at 2.8% in the most recent survey.

Several risk stratification models have been constructed to determine which patients with KD are at highest risk for CAA. Predictors of poor outcome across several studies include young age, male gender, persistent fever, poor response to IVIG, and laboratory abnormalities, including neutrophilia, thrombocytopenia, transaminitis, hyponatremia, hypoalbuminemia, elevated levels of N-terminal–brain natriuretic protein and elevated C-reactive protein (CRP) levels. Asian and Pacific Islander race and Hispanic ethnicity are also risk factors for CAA. Three specific risk scores have been constructed by Japanese researchers; of these, the Kobayashi score is the most widely used and has high sensitivity and specificity. Unfortunately, application of these risk scores in non-Japanese populations does not appear to accurately identify all children at risk for IVIG resistance and CAA. Body surface area (BSA)–adjusted coronary artery dimensions on baseline echocardiography in the 1st 10 days of illness appear to be good predictors of involvement during follow-up. Accordingly, baseline z scores may provide a useful imaging biomarker.

Pathology

KD is a vasculitis that predominantly affects the medium-size arteries. The coronary arteries are most often involved, although other arteries (e.g., axillary, subclavian, femoral, popliteal, brachial) can also develop dilation. A 3-phase process to the arteriopathy of KD has been described. The 1st phase is a neutrophilic necrotizing arteritis occurring in the 1st 2 wk of illness that begins in the endothelium and moves through the coronary wall. Saccular aneurysms may form from this arteritis. The 2nd phase is a subacute/chronic vasculitis driven by lymphocytes, plasma cells, and eosinophils, which may last weeks to years and results in fusiform aneurysms. The vessels affected by the subacute/chronic vasculitis then develop smooth muscle cell myofibroblasts, which cause progressive stenosis in the 3rd phase. Thrombi may form in the lumen and obstruct blood flow ( Fig. 191.1 ).

Clinical Manifestations

Fever is characteristically high spiking (≥38.3°C [101°F]), remitting, and unresponsive to antipyretics. The duration of fever without treatment is generally 1-2 wk but may be as short as 5 days or may persist for 3-4 wk. In addition to fever, the 5 principal clinical criteria of KD are (1) bilateral nonexudative conjunctival injection with limbal sparing; (2) erythema of the oral and pharyngeal mucosa with strawberry tongue and red, cracked lips; (3) edema (induration) and erythema of the hands and feet; (4) rash of various forms (maculopapular, erythema multiforme, scarlatiniform or less often psoriatic-like, urticarial or micropustular); and (5) nonsuppurative cervical lymphadenopathy, usually unilateral, with node size >1.5 cm ( Table 191.1 and Figs. 191.2 to 191.5 ). Perineal desquamation is common in the acute phase. Periungual desquamation of the fingers and toes begins 2-3 wk after the onset of illness and may progress to involve the entire hand and foot ( Fig. 191.6 ).