Classic Eds Diagnostic Criteria

[Zada Odome]

Thereare standard diagnostic criteria for definite, probable and possible sporadic CJD cases. There are separate diagnostic criteria for cases that may be iatrogenic and those that may be familial. This page outlines the clinical criteria needed to meet each of these definitions.

Kawasaki disease is an acute, systemic vasculitis that predominantly affects patients younger than five years. It represents the most prominent cause of acquired coronary artery disease in childhood. In the United States, 19 per 100,000 children younger than five years are hospitalized with Kawasaki disease annually. According to U.S. and Japanese guidelines, Kawasaki disease is a clinical diagnosis. Classic (typical) Kawasaki disease is diagnosed based on the presence of a fever lasting five or more days, accompanied by four out of five findings: bilateral conjunctival injection, oral changes such as cracked and erythematous lips and strawberry tongue, cervical lymphadenopathy, extremity changes such as erythema or palm and sole desquamation, and polymorphous rash. Incomplete (atypical) Kawasaki disease occurs in persons with fever lasting five or more days and with two or three of these findings. Transthoracic echocardiography is the diagnostic imaging modality of choice to screen for coronary aneurysms, although other techniques are being evaluated for diagnosis and management. Treatment for acute disease is intravenous immunoglobulin and aspirin. If there is no response to treatment, patients are given a second dose of intravenous immunoglobulin with or without corticosteroids or other adjunctive treatments. The presence and severity of coronary aneurysms and obstruction at diagnosis determine treatment options and the need, periodicity, and intensity of long-term cardiovascular monitoring for potential atherosclerosis.

Kawasaki disease, also known as mucocutaneous lymph node syndrome, is an acute, systemic vasculitis of small- and medium-sized arteries that predominantly affects patients younger than five years. It represents the most prominent cause of acquired coronary artery disease in childhood.1,2

Kawasaki disease was first described in 19671; the causative factors are unknown. Pathologic changes theoretically result from an exaggerated immune response to a pathogen in patients with genetic susceptibility.3 Aberrant production of tumor necrosis factor α (TNF-α), interleukin-6, and other inflammatory cytokines purportedly promote leukocyte-endothelial cell interactions that cause endothelial damage.3

The annual incidence of hospitalizations of U.S. patients with Kawasaki disease (19 per 100,000 children younger than five years) has not changed significantly over the previous 20 years.4 Asian and black Americans are 2.5 and 1.5 times more likely to develop Kawasaki disease than whites, respectively, suggesting a genetic link.4,5 Approximately 75% to 80% of cases in the United States occur in children younger than five years; the median age at diagnosis is 1.5 years, and the male-to-female ratio is approximately 1.5:1.4 Peak incidence occurs between January and March, suggesting an environmental contribution.4,6

In some cases, patients do not fulfill the classic criteria for Kawasaki disease and are classified as having incomplete (atypical) disease. A recent Australian study estimates that this occurs in 9.6% of cases.11 More common in younger infants and older children, incomplete disease is suspected when patients have a fever for at least five days with only two or three of the principal clinical features (eFigure A).7 As a result, it is important to consider the diagnosis of Kawasaki disease and the possible need for echocardiography in all infants younger than six months who have an unexplained fever lasting at least seven days with laboratory evidence of systemic inflammation.7

Transthoracic echocardiography is the imaging modality of choice to detect coronary aneurysms and other cardiac artery abnormalities in Kawasaki disease, and it should be obtained as soon as the patient's symptoms suggest the diagnosis.7 If needed, other imaging modalities may provide additional information. Three-dimensional echocardiography has been used to localize coronary anomalies such as thrombi, although they are more difficult to perform in smaller children with higher heart rates. Radionuclide imaging is useful in evaluating the presence and severity of coronary artery disease, but it is reserved for the evaluation of cardiac perfusion in those with persistent coronary changes.8 Magnetic resonance coronary angiography is helpful after treatment for acute disease to visualize coronary artery stenosis, thrombi, and intimal hyperplasia in difficult-to-image locations like the circumflex and more distal arteries.8

IVIG prevents the development of coronary aneurysms in a dose-dependent fashion. A single dose of 2 g per kg is administered within 10 days of illness or later if a patient has persistent fever, aneurysms, or inflammation. This approach reduces development of coronary artery abnormalities from approximately 25% to less than 5%; development of giant aneurysms is reduced to 1%.7,13 The mechanism of action of IVIG is unknown, but effects may be from its modulation of cytokine production, influence on T-cell activity, and suppression of antibody synthesis.7,17

Approximately 10% of patients have refractory disease that does not respond to initial therapy (i.e., fever persists or recurs 36 hours after initial IVIG dose). These patients usually receive a second infusion of IVIG at 2 g per kg. The AHA guideline states that the relative roles of repeated use of IVIG and other adjunctive therapies (e.g., corticosteroids, TNF-α antagonists, plasma exchange, cyclophosphamide) are uncertain,7 although additional evidence has emerged since the last update. A retrospective study (n = 359) found that adding corticosteroids to IVIG for refractory Kawasaki disease decreased the number of patients whose condition did not respond to therapy (adjusted OR = 0.16; 95% CI, 0.09 to 0.31) and lowered the risk of coronary artery abnormalities at one month (adjusted OR = 0.40; 95% CI, 0.27 to 0.90).18

TNF-α antagonists have also been used for disease that does not respond to IVIG. An open-label trial demonstrated resolution of inflammatory markers and symptoms in 18 of 20 patients given infliximab (Remicade) after IVIG was ineffective.19 A retrospective cohort study found that patients given infliximab (n = 20) had faster resolution of fever and similar coronary outcomes compared with IVIG retreatment (n = 86).20 A phase 3 randomized controlled study of infliximab for the primary treatment of Kawasaki disease (n = 196) found that although it decreased fever duration and some inflammatory markers, it did not improve treatment response over IVIG and aspirin alone.21

A case series of 125 patients with Kawasaki disease refractory to IVIG who were later treated with plasma exchange found that patients without coronary artery abnormalities at the start of therapy remained lesion free during follow-up, whereas 12 of 14 patients with coronary dilatation and two of six patients with aneurysms at the start of exchange experienced symptom resolution.22

Patients with mild to moderate aneurysms are treated with aspirin alone or in combination with other anti-platelet agents, such as clopidogrel (Plavix) or dipyridamole (Persantine). Heparin and warfarin (Coumadin) are reserved for treating larger aneurysms, and coronary thrombosis is treated with thrombolytic agents in conjunction with aspirin and heparin.7

Data Sources: A PubMed search was completed using the keyword and medical subject heading (MeSH) Kawasaki disease. The search included randomized controlled trials, meta-analyses, clinical trials, systematic reviews, clinical practice guidelines, and review articles. Also searched were Essential Evidence Plus, the National Guideline Clearinghouse, and the Cochrane Database of Systematic Reviews. Search dates: November 2013 through September 2014.

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Molecular diagnostic strategies should rely on NGS technologies, which offer the potential for parallel sequencing of multiple genes. Targeted resequencing of a panel of genes is a time- and cost-effective approach. When no mutation (or in the case of an autosomal recessive condition only one mutation) is identified, this approach should be complemented with a copy number variant (CNV) detection strategy to identify large deletions or duplications.

A final diagnosis requires confirmation by molecular testing. More than 90% of those with cEDS have a heterozygous mutation in one of the genes encoding type V collagen (COL5A1 and COL5A2). Rarely, specific mutations in the genes encoding type I collagen can be associated with the characteristics of cEDS. Classical EDS is inherited in the autosomal dominant pattern.

Skin is hyperextensible if it can be stretched over a standardized cut off in the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbow and knees; 1 cm on the volar surface of the hand (palm).

Abnormal scarring can range in severity. Most with cEDS have extensive atrophic scars at a number of sites. A minority are more mildly affected. The relevance of surgical scars should be considered with caution in classical EDS, they can appear normal in patients with classical EDS if well managed. Atrophic surgical scars can be found in the general population due to mechanical factors and the site of the incision.

Joint hypermobility is evaluated according to the Beighton score; a Beighton score of >5 is considered positive for the presence of generalized joint hypermobility. Since joint hypermobility decreases with age, patients with a Beighton score

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