The following post contains excerpts from the 2017 AHA Guidelines on Kawasaki Disease [Resource (1)]:
Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause that predominantly affects children <5 years of age. When initially described, the potential for coronary artery complications was not appreciated. KD is now the most common cause of acquired heart disease in children in developed countries. In the absence of pathognomonic tests, the diagnosis continues to rest on the identification of principal clinical findings and the exclusion of other clinically similar entities with known causes. Timely initiation of treatment with intravenous immunoglobulin (IVIG) has reduced the incidence of coronary artery aneurysms defined from absolute luminal dimensions from 25% to ≈4%.
Key Points: Epidemiology
- The cause is unknown.
- The estimated incidence in North America is ≈25 cases per 100000 children <5 years of age per year.
- The highest relative risk is in Asian children, especially of Japanese ancestry.
- The ratio of males to females is ≈1.5:1.
- KD affects predominantly, but not exclusively, young children.
- It is most common in winter and early spring in North America.
- Predisposing factors have been reported inconsistently.
- Nonspecific symptoms are common in the 10 days before diagnosis.
- In Japan, the recurrence rate is ≈3%, and the relative risk in siblings is 10-fold higher.
- The case fatality rate is <0.1% in Japan.
- Coronary artery aneurysms from KD account for 5% of acute coronary syndromes (ACS) in adults <40 years of age.
CAUSES AND PATHOGENESIS
Despite 4 decades of investigation, the cause of KD remains unknown.
Although inflammation of the coronary arteries results in the most important clinical outcomes, KD is characterized by systemic inflammation in all the medium-sized arteries and in multiple organs and tissues during the acute febrile phase,71 leading to associated clinical findings: liver (hepatitis), lung (interstitial pneumonitis), gastrointestinal tract (abdominal pain, vomiting, diarrhea, gallbladder hydrops), meninges (aseptic meningitis, irritability), heart (myocarditis, pericarditis, valvulitis), urinary tract (pyuria), pancreas (pancreatitis), and lymph nodes (lymphadenopathy). Unfortunately, lymph node pathology is nonspecific and nondiagnostic. Intracytoplasmic inclusion bodies are commonly observed in ciliated bronchial epithelial cells in autopsied cases.67,68,72
Key Points: Pathology
- KD vasculopathy primarily involves muscular arteries and is characterized by 3 linked processes: (1) necrotizing arteritis; (2) subacute/chronic vasculitis; and (3) LMP.
- Large or giant coronary artery aneurysms ≥8 mm in diameter or with a Z score ≥10 do not “resolve,” “regress,” or “remodel.” They rarely rupture and virtually always contain thrombi (the oldest of which may calcify) that can become occlusive.
- Aneurysms with markedly damaged but partially preserved media may develop decreases in lumen diameter over time as the result of LMP or thrombi and can become progressively stenotic.
- Atherosclerotic features are not characteristic of KD vasculopathy even in late deaths or transplants.
- Pericarditis and myocarditis result from subacute/ chronic inflammation, which is usually concentrated around coronary arteries.
Principal Clinical Findings
The diagnosis of classic KD is based on the presence of ≥5 days of fever (first calendar day of fever is illness day 1) and the presence of ≥4 of the 5 principal clinical features (Table 3, Figure 2).1 In the presence of >4 principal clinical criteria, particularly when redness and swelling of the hands and feet are present, the diagnosis may be made with only 4 days of fever. Similarly, experienced clinicians who have treated many KD patients may make the diagnosis in rare instances with only 3 days of fever in the presence of a classic clinical presentation. Typically the clinical features are not all present at a single point in time, and it is generally not possible to establish the diagnosis very early in the course. Similarly, some clinical features may have abated in patients who present after 1 to 2 weeks of fever, and a careful review of prior signs and symptoms can help establish the diagnosis.
Changes in the extremities are distinctive. Erythema of the palms and soles and firm and sometimes painful induration of the hands or feet often occur in the acute phase. Desquamation of the fingers and toes usually begins in the periungual region within 2 to 3 weeks after the onset of fever and may extend to involve the palms and soles. At 1 to 2 months after fever onset, deep transverse grooves across the nails (Beau’s lines) may be noted.
An erythematous rash usually appears within 5 days of fever onset. Most commonly, this is a diffuse maculopapular eruption. Scarlatiniform erythroderma and erythema multiforme-like rashes are also common. Less commonly, urticarial or fine micropustular eruptions are observed. The rash is usually extensive, primarily involving the trunk and extremities, and accentuation in the groin with early desquamation is a characteristic feature.
Bilateral bulbar nonexudative conjunctival injection usually begins shortly after fever onset and often spares the limbus, an avascular zone around the iris.
Changes of the lips and oral cavity include (1) erythema, dryness, fissuring, peeling, cracking, and bleeding of the lips; (2) a “strawberry tongue,” with erythema and prominent fungiform papillae; and (3) diffuse erythema of the oropharyngeal mucosa. Oral ulcers and pharyngeal exudates are not consistent with KD.
Cervical lymphadenopathy is the least common of the principal clinical features. Lymph node swelling is usually unilateral, ≥1.5 cm in diameter, and confined to the anterior cervical triangle. In a small subset of patients, lymph node findings may be the most notable and sometimes only initial clinical finding, prompting a clinical diagnosis of bacterial lymphadenitis and significantly delaying KD diagnosis.84 In such cases, fever persists, and other typical KD features, such as rash and conjunctival injection, will follow. Imaging studies including ultrasound and computed tomography (CT) can be helpful in differentiating KD lymphadenopathy from bacterial lymphadenitis.
In KD, multiple lymph nodes are enlarged, and retropharyngeal edema or phlegmon is common. In contrast, bacterial lymphadenitis is most frequently associated with a single node with a hypoechoic core.84 It has been increasingly recognized that cervical lymphadenopathy can be associated with deep neck inflammation leading to parapharyngeal and retropharyngeal edema and nonsuppurative phlegmon.84,85
Other Illnesses With Similar Features
Other illnesses with similar clinical features (Table 3) [Above]
should be considered before the diagnosis of KD is
made, because the principal clinical findings that fulfill
the diagnostic criteria are not specific.
Incomplete (Atypical) KD
Although the presence of fever for ≥4 days with 4 of the 5 other principal clinical findings establishes the diagnosis of complete KD, these criteria unfortunately do not identify all children with the illness. KD should be considered in the differential diagnosis of prolonged unexplained fever in childhood associated with any of the principal clinical features of the disease, and the diagnosis can be considered confirmed when coronary artery aneurysms are identified in such patients by echocardiography. However, coronary artery dilatation is generally not detected by echocardiography until after the first week of illness, and a normal echocardiogram in the first week of illness does not rule out the diagnosis of KD. Patients with incomplete KD, particularly those <6 months of age and those lacking eye or oral mucosal changes, may experience significant delays in diagnosis.92
Diagnosis of Incomplete KD
The diagnosis of incomplete (sometimes referred to as atypical) KD should be considered in any infant or child with prolonged unexplained fever, fewer than 4 of the principal clinical findings, and compatible laboratory or echocardiographic findings (Figure 3).
Key Points: Consider KD in the Differential Diagnosis of Certain Infants or Children
- Infants <6 months old with prolonged fever and irritability • Infants with prolonged fever and unexplained aseptic meningitis
- Infants or children with prolonged fever and unexplained or culture-negative shock
- Infants or children with prolonged fever and cervical lymphadenitis unresponsive to antibiotic therapy
- Infants or children with prolonged fever and retropharyngeal or parapharyngeal phlegmon unresponsive to antibiotic therapy
Laboratory tests, although nonspecific, provide support for a diagnosis of KD in patients with nonclassic but suggestive clinical features. Clinical experience suggests that KD is unlikely if the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet count are normal after day 7 of illness. In addition, low white blood cell count and lymphocyte predominance suggest an alternative diagnosis.
Leukocytosis is typical during the acute stage of illness, with a predominance of immature and mature granulocytes. Leukopenia and lymphocyte predominance suggest an alternative diagnosis. Anemia occurs commonly, is normochromic and normocytic, and resolves with resolution of inflammation. Elevation of acute-phase reactants such as ESR and CRP is nearly universal; the degree of elevation of ESR and CRP may be discrepant. . . .Finding of a minimally elevated ESR in the setting of severe clinical disease should prompt investigation for disseminated intravascular coagulation.55
Thrombocytosis is a characteristic feature of KD but generally does not occur until the second week, peaking in the third week (mean ≈700000 per mm3) and normalizing by 4 to 6 weeks after onset in most cases. Thrombocytopenia is rare but may occur in the first 1 to 2 weeks of illness. Thrombocytopenia can be a sign of disseminated intravascular coagulation and is a risk factor for the development of coronary artery abnormalities.
Cardiovascular manifestations can be prominent during the acute KD episode and are the leading cause of longterm morbidity and mortality. The pericardium, myocardium, endocardium including valves, and the coronary arteries all may be inflamed. . . . Valvar dysfunction occurs in ≈25% of patients regardless of coronary artery involvement and most often involves the mitral valve.111 Children with clinically important mitral regurgitation (MR) may have a pansystolic murmur heard best between the low left sternal border and the apex. A diastolic murmur associated with important aortic regurgitation (AR) is rare.
Approximately 5% of children with KD in the continental United States present with cardiovascular collapse and hypotension requiring the initiation of volume expanders, the infusion of vasoactive agents, or transfer to the intensive care unit. The presence of thrombocytopenia and coagulopathy in such cases is notable, and a diagnosis of bacterial sepsis is frequently suspected at the outset. In such cases, when bacterial cultures are negative and fever persists, the diagnosis of KD should be considered. Children with shock presentation appear to be at higher risk of IVIG resistance, coronary artery abnormalities, MR, and prolonged myocardial dysfunction.117–119
Evaluation for Cardiovascular Abnormalities
Echocardiography is the primary imaging modality for cardiac assessment because it is noninvasive and has a high sensitivity and specificity for the detection of abnormalities of the proximal coronary artery segments.134 The initial echocardiogram should be performed as soon as the diagnosis is suspected, but initiation of treatment should not be delayed by the timing of the study. Because detailed echocardiographic imaging is compromised if a child is uncooperative, sedation is frequently needed for those <3 years of age and may also be required in older, irritable children.135 If a poor-quality initial echocardiogram is obtained because sedation was not administered, a sedated study should be repeated as soon as possible within the 48 hours after diagnosis and initial treatment. This initial study establishes a baseline for longitudinal follow-up monitoring of coronary artery morphology, LV wall motion, valvular regurgitation, and pericardial effusion. An initial echocardiogram in the first week of illness is typically normal and does not rule out the diagnosis. [Emphasis Added]
(1) Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association [PubMed Abstract] [Full Text HTML] [Download Full Text PDF]. Circulation. 2017 Apr 25;135(17):e927-e999. doi: 10.1161/CIR.0000000000000484. Epub 2017 Mar 29.