Nine years have passed since the first announcement of the Italian Guidelines for diagnosis and management of Kawasaki disease (KD) in a national journal, but recently many novel data and publications have become available in relationship with this acute systemic vasculitis of childhood [
1]. According to the 2012 “Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides” [
2], KD involves small and medium-sized vessels in each organ and tissue. The first KD cases were observed in Japan in 1962, and described by dr. Tomisaku Kawasaki in the article “
Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the finger and the toes in children” in the 1967 journal
Arerugi [
3]. In general terms, we can consider KD as a self-limited heterogeneous disease with unknown etiology, which mostly affects infants and children under 5 years of age.
The most significant complications in KD are coronary artery aneurysms (CAA), but their overall incidence has been consistently reduced by treatment with intravenous immunoglobulin (IVIG) within 10 days of fever onset [
4,
5]. Diagnosis of KD is merely clinic, based on the diagnostic clinical criteria, but may be supported by the results of various blood and instrumental exams. Actually, no clinical findings or tests can be considered specific for KD, and this circumstance makes diagnosis especially challenging. Diagnostic difficulties depend on several causes, such as the different times at which clinical findings might appear, difficult discrimination with other infectious and non-infectious illnesses, protean clinical expression of the disease, occurrence of non-typical clinical findings, incomplete forms of the disease, absence of specific laboratory data, and even association with low acute phase reactants. Concurrently, a prompt recognition of KD is essential as its prognosis depends on the rapidity of treatment decision.
Goal of these guidelines is to recommend the best practice in both diagnosis and management of children with KD, based on the most actual scientific evidence, and improve the overall prognosis of this disease. These guidelines have been created for pediatricians working in hospital, family pediatricians, and general practitioners or nurses managing children affected by KD and for families of KD patients.
Epidemiology of Kawasaki disease
Epidemiologic data for KD are mainly available for Asia, Europe and North America, but there are also estimates for Australia, South America, Middle East, along with few data also from Africa [
7‐
11]. The latest Italian data were produced in 1984 [
12]. Studies on the spread of the disease have shown considerable differences between different geographical areas (Table
3), with incidence from 3.4 up to 218.6 cases per 100.000 children less than 5 years [
7‐
13]. The overall incidence in Asia is, on average, at least 3–4 times higher in certain countries (Japan, Korea, China, Taiwan) rather than other (India, Thailand); these differences are even more significant in comparison with Europe and USA. It is likely that these differences are due to ethnic factors combined with environmental factors, but the different ability to recognize and report the disease should also be taken into account [
11,
14,
15]. In fact, KD incidence in the Japanese population living in Hawaii is similar to those living in Japan [
11]. The incidence of KD is different according to gender, as males are more prone to develop the disease, with a M:F ratio of 1,4-1,9:1 emerging from many studies [
7‐
14].
Table 3
Incidence rates of Kawasaki disease in Asia, Europe, and North-America
Asia |
Japan | 2011–2012 | 243.1–264.8 | National survey | |
Japan | 2007–2008 | 215.3–218.6 | National survey | Nakamura et al. 2010 [ 39] |
Korea | 2009–2011 | 115.4–134.4 | National survey | |
Corea | 2006–2008 | 113.1 | National survey | |
Taiwan | 2003–2006 | 69.0 | National Health System database | |
China |
-Bejing | 2004 | 55.1 | Beijing’s Hospitals survey | |
-Shanghai | 2007 | 53.3 | Pediatric ward survey | |
-Hong Kong | 1997–2000 | 39.0 | Retrospective and perspective analysis | |
- Sichuan | 2001 | 9.81 | Hospital survey | |
India | 2007 | 4.5 | Retrospective analysis in Chandigarh, Northern India | |
Thailand | 2002 | 3.4 | KD National Register | Durongpisitkul et al. 2006 [ 46] |
North America |
Hawaii | 1996–2006 | 50.4 | Hawaii State Inpatient Database | |
Canada | 2004–2006 | 26.2 | Clinical records’ Review in Ontario | |
South America |
Chile | 2001–2007 | 6.8 | National survey | Borzutzky et al. 2012 [ 49] |
Australia |
Western Australia | 1980–1989 | 2.82 | ICD-9 review in Referral Hospital | Saundankar et al. 2014 [ 9] |
1990–1999 | 7.96 |
2000–2009 | 9.34 |
Middle- East |
Israel | 1996–2009 | 6.4 | National Health System database | |
Europe |
United Kingdom | 1998–2003 | 8.4 | Hospitals’ data | |
Ireland | 1996–2000 | 15.2 | Ireland’s Hospital In-Patient Enquiry database | |
Finland | 1992 | 7.2 | Recovery register | |
Denmark | 1999–2004 | 4.9 | Danish National Hospital Register | |
Sweden | 1990–1992 | 6.2 | Clinical records | Schiller et al. 1995 [ 54] |
France | 2005–2006 | 9.0 | Perspective survey in pediatric ward of Northen France | |
Italy | 1981–1982 | 14.7 | Clinical records’ Review and families’interview in Northen Italy | Tamburlini et al. 1984 [ 12] |
Recent epidemiologic data showed an increased incidence of KD during the last decades, both into Western and Asiatic countries [
7‐
9,
11,
13,
16,
17]: this is probably due to an improved ability for practitioners to recognize and diagnose KD, especially in its incomplete form [
11,
18]. For instance, in Australia the incidence has increased from 2.82 cases for 100.000 children of age < 5 years during the decade 1980–1989 up to 9.34 cases during the decade 2000–2009 [
9]. Due to this improvement, KD has become the leading cause of acquired heart disease in children living in developed countries [
1,
11,
14].
With regards to age, KD is mostly observed in children less than 5 years in over 80% of cases [
8,
15], with a peak incidence in the first 24 months of life [
11,
14]. However, there are also a few reports of KD in neonates, teenagers, and even in adults [
8,
14]. Such cases show a tendency to develop CAA [
15,
19], probably as a consequence of a late diagnosis.
Several studies demonstrate a seasonality pattern for KD, with a peak incidence in late winter and during the spring-summer period, though this link into different geographical areas is weak [
7,
8,
11,
20]. The study of 25 different countries related to a large number of KD patients has shown a significant increase of cases during wintertime in extra-tropical regions of the Boreal hemisphere, with no significant correlation in the Austral hemisphere [
21]. A recent theory suggests a link between tropospheric air currents and the epidemic diffusion of KD, due to the transportation of mycotoxins from China and other areas of the Asian continent [
22].
The average incidence for atypical and incomplete KD is between 15 and 36%, with a higher distribution at the ends of the age distribution curve (i.e. for children < 1 year and > 5 years) [
23,
24].
KD recurrence risk and incidence of familiar forms are well-documented in the Japanese medical literature and also in North-American studies [
25‐
31]. In Japan the risk of illness for a sibling of a patient with KD is increased by 10 times in comparison with the general population [
25], and the probability for children with KD to have a sibling with KD is between 0.17 and 1.6% [
26‐
28]. This percentage is increased up to 13% for twins [
29]; 50% of familiar cases occur, on average, up to 10 days later than the index case. Furthermore, 0.7% of Japanese cases with KD has at least one parent with a past history of KD [
27,
32]. In Japan and Korea the overall recurrence risk is 3% [
8,
27,
30], and the main risk factors are age < 3 years and existence of cardiac sequelae [
30].
In regards with KD complications, the incidence of CAA is approximately 15–25% in untreated patients and less than 5% in patients treated with IVIG within 10 days after the onset of fever [
11,
19,
33]. The risk of developing CAA is greater in children aged < 12 months and > 5 years, in males, and in the recurring forms of KD, as well as in the cases treated too late with IVIG [
19,
20,
34]. In particular, infants younger than 6 months can develop CAA up to 65% of cases, even if correctly treated with IVIG [
35]. The incidence of IVIG-resistant KD is 15–18% in relationship with the total number of cases and seems to have its main predictor in the presence of very high values of C-reactive protein (CRP) during KD acute phase [
34,
36,
37].
Death related to KD is mostly due to cardiac sequelae, both in the short-term, with a peak of mortality between 15 and 45 days after the onset of fever, and in the long-term, even in adulthood: the mortality rate in patients with KD in Japan was more than 1% up to 1974, and has decreased to 0.1 to 0.2% from 1974 to 1993, with a further reduction between 1993 and 2002 to 0.02–0.09% and down to 0.01% in the most recent cases [
6,
13,
38,
39]. A Japanese survey in patients who developed KD between 1982 and 1992, followed up until 2009, has documented that those patients without CAA have a standardized mortality rate equivalent to the general population. On the other hand, those patients with cardiovascular involvement have a significantly higher standardized mortality rate [
38].
Cardiovascular complications of Kawasaki disease
The most relevant complications in KD are represented by CAA, and different remodeling phenomena will affect their prognosis. The coronary artery dilation may start as ectasia, slight expansion (up to less than 5 mm in diameter), moderate dilation (from 5 to less than 8 mm) up to giant aneurysms (more than 8 mm in diameter). The majority of coronary artery aneurysms occur in the proximal segments and at the branch level. KD patients with normal coronary arteries or with mild ectasia at 6 weeks since disease onset have an overall good prognosis [
6,
89,
90]. On the contrary, patients with persistent aneurysms are at risk of stenosis and/or thrombosis of the same arteries. Giant coronary aneurysms do not revert to a normal morphology (see Tables
7 and
8 for details). The repair of affected vessels occur by wall remodeling without total “restitutio ad integrum”, but with progressive intimal hyperplasia and fibrosis, that lead to stenotic changes of the coronary artery, with risk of thrombosis, myocardial heart attack, and sometimes even sudden death. Rarely new aneurysms appear later in patients with pre-existing aneurysms and, if this occurs, they represent post-stenotic dilations. In rare cases aneurysms can develop in the axillary or celiac arteries. Other different cardiovascular complications may develop less frequently in patients with acute KD, and include myocarditis, pericarditis or pericardial effusion with myopericarditis, valvular insufficiency, and, rarely, arrhythmias. A specific treatment may be required for these manifestations as well as for cardiac dysfunction or heart failure [
91,
92] (see part II).
Investigations in Kawasaki disease
Diagnosis of KD is based on the sole clinical diagnostic criteria [
5,
6], because neither pathognomonic clinical features nor specific diagnostic tests exist. A prompt diagnosis is crucial because prognosis relies on the rapidity of treatment. Consequently, in case of suspected KD, it is important to recommend patient’s hospitalization to perform a thorough evaluation and confirm diagnosis. Unfortunately, laboratory tests are nonspecific, though they can support KD diagnosis (see Table
6) [
1,
6] in patients with suggestive clinical features of KD.
Table 6
Main laboratory abnormalities in patients with Kawasaki disease
BLOOD CELL COUNT |
white blood cells | ↑, maximal elevation of polymorphonuclear cells ↓ rarely |
red blood cells | ↓, normal mean corpuscular volume |
platelets | ↑, typically in the II and III week, normalization in 4–8 weeks if ↓ suspect disseminated intravascular dissemination |
INFLAMMATORY PARAMETERS |
erythro-sedimentation rate (ESR) | ↑, slow normalization |
C-reactive protein (CRP) | ↑, fast normalization |
LIVER FUNCTION TESTS |
transaminases | ↑ |
bilirubinemia | ↑ |
gamma-glutamyl transpeptidase | ↑ |
albuminemia | more severe and prolonged illness if ↓ |
OTHER LABORATORY TESTS |
urine | white blood cells > 10/high field powered |
cerebrospinal fluid | aseptic meningitis (presence of mononuclear cells, normal glucose/proteins) |
synovial fluid | purulent-appearing fluid, white blood cells 125.000–300.000/mm3, normal glucose level |
Laboratory findings
Leukocytosis is typical during the acute phase of this disease with predominance of immature and mature granulocytes. Anemia occurs commonly and is normochromic normocytic: it resolves with the resolution of inflammation. Elevation of acute-phase reactants as ESR and CRP is frequent, but sometimes they are only slightly increased. Moreover, ESR is elevated by IVIG therapy, and therefore, a decreased ESR during follow-up should not be used to assess response to treatment with IVIG. Thrombocytosis is characteristic in the second week of the disease, peaking in the third week 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. In patients with arthritis, arthrocentesis typically yields purulent-appearing fluid with a white blood cell count of 125,000 to 300,000 per mm3, a normal glucose level and negative culture tests. Mild to moderate elevations in serum transaminases or gamma-glutamyl transpeptidase occur in 40 to 60% of patients, and mild hyperbilirubinemia occurs in 10%. Hypoalbuminemia is common and associated with more severe and more prolonged acute disease. Urinalysis may show pyuria in up to 80% of children. In children who undergo lumbar puncture, 30% demonstrate pleiocytosis with a mononuclear cell predominance, normal glucose levels and generally normal protein levels.
Dyslipidemia and risk of atherogenesis in patients with Kawasaki disease
A disrupted lipid metabolism may characterize the acute phase of KD, and finally give a reduction of serum total cholesterol, particularly HDL, and increase of triglyceridemia. Some studies have reported that this altered lipid state might persist over a period of 3 years after KD diagnosis. The effect of dyslipidemia on the cardiovascular risk is not completely clear: while some studies proved early ultrasound signs of reduced elasticity and abnormal carotid intima-media thickness in young adults with history of KD, subsequent studies were not confirmatory [
99‐
102]. The presence of CAA seems also to correlate more significantly with lipid metabolism disorders, whereas this finding remains controversial in patients without CAA [
103].
Pro-inflammatory conditions and pro-coagulant activity of the peripheral blood in patients with Kawasaki disease
The formation of reactive oxygen and nitrogen species in KD is known to generate a systemic pro-oxidant status in the blood, which might lead to altered red blood cell and platelet homeostasis with propensity to develop a cascade of procoagulant complications and focal endothelial damage [
104‐
106]. Particularly, inflammation associated with systemic pro-oxidant state can play a key role in the pathogenesis and progression of KD. Reactive oxygen and nitrogen species (collectively called RONS) generate a pro-oxidant status in the blood that promote an oxidative and nitrative stress as well as a redox imbalance, leading to altered cell signaling and functions. Whole blood from patients with KD show increased levels of RONS, while scavenger activity of RONS might be significantly decreased during the acute phase of KD. Finally, thrombocytosis might result from a defect of cell death, as suggested by studies about annexin V positive and negative platelets, and the propensity to develop coronary damage may be associated with altered platelet homeostasis [
104‐
106].
Echocardiography
Echocardiography should be performed by a cardiologist with experience in the pediatric age, and the coronary artery districts to visualize include left coronary artery, descending coronary artery, circumflex artery, left anterior artery, right coronary artery, and posterior descending coronary artery. The presence of marked perivascular brightness, the absence of the physiological gradual reduction of coronary artery caliber, and a mild ectasia, if isolated, are not indicative of KD; however, these findings could be considered a positive echocardiographic sign when they are all three simultaneously present (expert opinion) to suggest KD diagnosis. Changes in the left ventricular function, presence of mild mitral or aortic regurgitation, and pericardial effusion may be present in the KD acute phase, though they should not be considered sufficient for confirming KD diagnosis [
111]. Stenosis and thrombosis might appear in later phases and/or in older patients, when the coronary arteries are more difficult to see on routine ultrasound investigations. Stress echo with the administration of drugs (dobutamine) is now widely used for the diagnosis and follow-up of secondary ischemic heart disease in patients with KD [
112,
113].
Recommendation 8
Persistently febrile non-responders KD patients with CAA, impaired left ventricular function, mild/moderate mitral regurgitation or significant pericardial effusion need a more frequent echocardiogram check-up (at least twice per week).
(VI - A)
The presence of marked perivascular brightness, the absence of the physiological gradual reduction of coronary artery caliber and mild ectasia, if isolated, are not indicative of KD. These findings could be considered a positive echocardiographic KD sign when they are all three simultaneously present (expert opinion). Changes in left ventricular function, presence of mild mitral or aortic regurgitation, pericardial effusion may be present in the KD acute stages but should not be considered sufficient for the diagnosis, as they can also be found in other inflammatory disease.
Moreover, pericarditis, mitral insufficiency, impairment of systolic function, indirect signs of inflammation, can be predictive of coronary lesions, which could be non permanent. Actually echocardiographic sensibility and specificity is not so clear in diagnosis of stenosis and thrombi.
These lesions appear usually in later phases and in older patients, when coronary arteries system is more difficult to see.
Echocardiography remains the instrument of choice to identify CAA during the acute phase of KD up to the first 6 weeks after onset. However, computed tomography (CT) or magnetic resonance (MR) angiography can be required for an accurate risk stratification via evaluation of the vascular system, especially in growing children. Advanced cardiovascular imaging techniques for a more specific assessment of cardiovascular sequelae in KD are CT and MR angiography. Multi-slice CT is an established tool for a less-invasive assessment of the cardiovascular system in adults: the diffusion of such a technique for coronary artery studies in children with KD is still limited. This is mainly due to radiation exposure issues, need for general anesthesia, need for beta-blockers (to obtain regular heart rates ideally lower than 65–70 beats per minute), and enhancement contrast infusion. A dual-source CT (DSCT) provides excellent quality images and low radiation doses for diagnosing KD-related CAA in infants and children [
114]. Moreover, DSCT is superior to echocardiography in the detection of CAA located in the peripheral parts of vessels [
115]. New generation scanners enable a very rapid body CT scan (less than 1 s), permit central/peripheral aneurysm detection, and reduce the need for general anesthesia [
116]. The majority of magnetic resonance (MR) angiography studies on KD have been performed using 1.5 Tesla magnets fully equipped for cardiac investigation with a set up for general anesthetic support, using a comprehensive scan protocol which includes functional imaging with breath-hold, ECG-gated, 2D steady-state free precession, contrast-enhanced study for whole body detection of central and peripheral aneurysmal dilations during intravenous infusion of contrast (gadolinium at a dose of 0.1 mmol/kg of body weight), or myocardial perfusion imaging at rest and after pharmacological stress [
117‐
119]. Advanced imaging studies with cardiovascular CT or MR may be reasonable in selected patients to help in the management decisions, as cardiac catheterization in the acute phase of KD has been associated with a greater incidence of adverse vascular events [
1]. Conversely, there are limited data regarding cardiac function after the acute phase of KD. Subclinical dysfunctions may be missed when assessing left ventricular systolic function using conventional echocardiography. Recently, speckle-tracking echocardiography is emerging as an effective tool for determining global longitudinal and circumferential strain and myocardial deformation in patients with KD, especially in mid-long term follow-up [
120].