Kawasaki disease

Author: Doctor Alfred Mahr1 Creation date: June 2001 Update: June 2004

Scientific Editor: Professor Loïc Guillevin

1Service de médecine interne, CHU Hôpital Cochin, 27 Rue du Faubourg Saint-Jacques, 75014 Paris France. [email protected].

Abstract Key words Disease name and synonyms Excluded diseases Diagnostic criteria/definition Epidemiology Clinical description Management including treatment Etiology Diagnostic methods Unresolved questions References

Abstract Mucocutaneous , or (KD), is an infantile of medium- and small-sized arteries. It is a disorder affecting predominantly children younger than 4 years and more frequently subjects of Asian origin. KD is an illness characterized by high , , oral mucosal changes, cheilitis, cervical lymph nodes, , and reddening of the palms and soles with subsequent . The disease generally resolves spontaneously within several days. However, approximately 20% of all untreated patients develop coronary that are potentially life- threatening. As there is no specific laboratory test, KD is diagnosed based on clinical criteria and, possibly, on the detection of coronary aneurysms by or by coronary . Treatment of KD combines a single course of intravenous immunoglobulins and . Instituted during the acute phase of the illness, this treatment reduces the frequency of coronary artery-lesions to less than 5%. Some patients unresponsive to this treatment may receive Infliximab as alternative therapy. The etiology of KD remains unknown but might be infectious. Nevertheless, no specific agent has yet been recognized.

Key words Kawasaki disease, Kawasaki syndrome, mucocutaneous lymph node syndrome, vasculitis, coronary aneurysms, acquired ischemic disease of childhood

Disease name and synonyms can be retained in the presence of fever lasting Kawasaki disease (KD), Kawasaki syndrome, for more than 5 days in association with 4 of the mucocutaneous lymph node syndrome following 5 criteria: 1) polymorphous rash; Excluded diseases 2) bilateral nonexudative conjunctivitis; Infantile 3) changes of the oral mucosa (cheilitis and/or "strawberry" and/or pharyngitis); Diagnostic criteria/definition 4) non-purulent cervical Diagnostic guidelines for KD were established by (at least 1.5 cm); the Japanese Kawasaki Disease Research 5) changes of the and feet Committee [1]. Accordingly, the diagnosis of KD ( on the palms or soles and/or

Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004: http://www.orpha.net/data/patho/GB/uk-kawasaki.pdf 1 indurative and/or desquamation from the disease incidence has been reported, with peak fingertips). occurrence in the spring and winter months. When coronary abnormalities are present, KD can be diagnosed in patients with fever and only Clinical description 3 of the other diagnostic criteria. However, Clinical presentation. KD is an acute-onset because these diagnostic guidelines are not illness characterized by high fever with entirely specific to KD, other diseases with mucocutaneous changes and . Fever is similar symptoms have previously to be a constant feature of KD and generally the first excluded. A small subset of children present with symptom of the disease; it ranges between 38° "atypical" or "incomplete" KD, as defined by the and 40°C and frequently has irregular spikes; it presence of fever and fewer than 4 of the other is often abrupt in onset and unresponsive to features. Atypical cases are more difficult to therapy. Mucocutaneous changes are recognize and, unfortunately, at greatest risk for seen in approximately 90% of the patients and coronary disease [2-4]. they coincide with the onset of fever or within the hours or days thereafter. The mucosal signs Differential diagnosis variably include intense bilateral non-exudative The differential diagnosis of KD encompasses a conjunctivitis predominantly involving the bulbar multitude of diseases including bacterial conjunctivae; cheilitis with crusting, lips; (toxic syndrome, staphylococcal "strawberry" tongue; or diffuse erythema of the scalded skin syndrome, , oropharynx. The skin involvement includes a rickettsiosis, , yersinia), viral rash, and changes of the hands and feet exanthema (, adenovirus, Epstein-Barr associating a clearly delimited erythema of the virus, cytomegalovirus, parvovirus, retrovirus), palms and soles, whereas the dorsa of the drug-induced skin reaction (Stevens - Johnson hands and feet and the fingers and become syndrome), connective disease (systemic swollen and indurated. The rash has a onset juvenile rheumatoid , Reiter's remarkably polymorphous presentation and can syndrome) or other vasculitides (infantile be morbilliform, scarlatiniform or multiform. It is polyarteritis nodosa) [2-5]. widespread over the body, affecting the face, the trunk and limbs. However, in some cases, and Epidemiology especially in and young children, the rash Since the initial description in 1967 by the may preferentially involve the perineal area. Japanese pediatrician T. Kawasaki [6], more Lymphadenitis is less frequent, occurring in than 170,000 children have been diagnosed with approximately 50 - 60% of the patients. Most KD in Japan. Recently, series from European frequently, the adenitis presents as a large, firm, countries such as the UK and Italy have been unilateral lymph node of the cervical or published [23]. In 80%, the affected individuals submandibular area; in some cases, it may are 4 years old with a peak incidence between 6 become the most prominent feature of the months and 2 years [2-4]. KD is uncommon disease [2-4, 12]. before 3 months and in children over 4 years, Associated manifestations. In addition to the even if it has also been observed occasionally in previously cited major signs, many other children older than 10 years [7] or in young features have been observed in association with adults [8]. Although described in subjects of all KD: aseptic , , , gall ethnic origins, the incidence of KD is highest in bladder hydrops, sterile , , Asians or individuals of Asian ancestry. In or arthritis, and/or [2-4, 12]. Japan, the estimated incidence rate exceeds (out of proportion to the degree of fever 1,000/1,000,000 under 5 years old [9]. In the or other signs) is present in the majority of United States, an annual incidence of up to children with KD that can be related to aseptic 150/1,000,000 children under 5 years old has meningitis. been reported, with the highest incidence among Asian Americans (333/1,000,000) followed by Disease course black (234/1,000,000) and white Americans KD has a typically triphasic course. (127/1,000,000) [10]. The incidence in Europe is The acute phase is self-limited with the fever and compatible to that in USA. Occurrence in siblings the other acute signs of inflammation subsiding is rare, at approximately 2% [11]. KD epidemics spontaneously after 1 - 2 weeks. have been recorded in many countries with, in The following subacute phase lasts 1-2 weeks particular, 3 large-scale outbreaks in Japan in and is characterized by the desquamation of the 1979, 1982 and 1986. KD recurrences are and feet with peeling starting at the tips of uncommon, occurring in only about 1-3% of the the fingers and toes and subsequently involving patients [3]. KD is more common in males, with a the entire hands and feet. The conjunctivitis may M:F ratio of 1.5:1. Seasonal variation in the persist during this phase.

Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004: http://www.orpha.net/data/patho/GB/uk-kawasaki.pdf 2

The convalescent phase starts when all clinical within the first 10 days of disease onset [2-4, 17]. signs have resolved and end when the It has been demonstrated in several therapeutic laboratory abnormalities have returned to studies that, compared to aspirin alone, this normal, usually 4 - 6 weeks after disease onset. treatment shortens the duration of the acute Beau's lines, corresponding to transverse signs of the disease and reduces the occurrence grooves of the fingernails, may develop 1 - 2 of coronary aneurysms and the frequency of months after KD onset [2-4, 12]. long-term coronary abnormalities [18, 19]. Among the various protocols that have been Cardiovascular complications tried, a single, high dose of IVIG (2 g/kg) Initially described as a harmless disease [6], it appeared to be the most efficacious regimen rapidly became evident that KD was fatal for 1- [20]. Aspirin was the first widely used 2% of the affected individuals with death most to treat KD. Although it has never been proven commonly attributed to ischemic heart disease that this drug has a preventive effect on the [12]. KD was subsequently recognized as a coronary abnormalities, it continues to be given of small- and medium-sized for its anti-inflammatory and anti-thrombotic arteries with a marked predilection for the properties. Most commonly, aspirin is [13]. During the acute phase of administered at an anti-inflammatory dose (80- the disease, the spectrum of cardiovascular 100 mg/kg/d in four divided doses) until the fever manifestations comprises , valvulitis, subsides and is subsequently reduced to an anti- or . However, cardiac platelet aggregation dose (3 - 10 mg/kg/d) until involvement during this stage is most commonly being discontinued by 6 weeks after disease asymptomatic but rarely is manifested by onset unless coronary abnormalities persist [2- congestive . The most characteristic 4]. Thus, the efficacy of the standard treatment feature of cardiovascular involvement in KD is with IVIG and aspirin has only been studied for the formation of coronary aneurysms that may administration within the first 10 days of illness occur during the subacute phase of the disease and, although the precise mechanism of this and thus when the acute clinical symptoms have therapy remains unknown, it is unlikely that it already subsided. may still be beneficial when the inflammatory Aneurysms develop in approximately 20% of response has already subsided [3, 17]. untreated patients [14]. Angiographic studies With regard to the atypical presentation in some showed that the aneurysms, which are patients and the importance of early initiation of principally located in the proximal portions of the therapy, this combined treatment should be coronary arteries, are commonly associated with given to all patients for whom a high index of other abnormalities, such as vessel dilatation, suspicion exists and other diagnoses have been or . The most severe reasonably excluded [2-4]. In about 10% of the coronary lesions are giant aneurysms, which are patients, the fever persists or recurs after the defined by an internal lumen of more than 8 mm completion of the initial therapy with IVIG and [15]. More rarely, aneurysms involve aspirin. The management of these patients is not extracoronary arteries, and approximately 2% of well defined, but most authors have the patients present with aneurysms in the recommended treating again with 1 g/kg of IVIG axillary, iliac, renal and/or intermammarian [17]. Steroids have been abandoned for the arteries [14]. The may treatment of KD since it was advanced that they lead to fatal myocardial or rupture of would favor the formation of coronary aneurysms an , with most of the deaths occurring [21]. More recently, however, the use of steroids within the first 2 months following disease onset has been reconsidered in selected patients, e.g. [14]. Peripheral ischemia is a rare but severe for patients with IVIG-refractory disease [22]. of KD that leads either to death or Other include anticoagulants that [16]. It is unclear what factors account should be given to patients with giant coronary for the occurrence of severe cardiovascular aneurysms. Inotropic agents may be required for disease in some patients. Male gender, age of congestive heart failure. The long-term follow-up less than 1 year at disease onset, prolonged of children with KD mainly depends on the fever duration and highly elevated laboratory presence or not of persistent coronary markers of inflammation have been cited as aneurysms beyond the convalescent phase. predictors of the occurrence of coronary Small- to medium-sized aneurysms may aneurysms [2-4]. completely regress within 1-2 years, whereas giant aneurysms generally do not resolve or Management including treatment progress to stenotic lesions and may ultimately The current standard of treatment of KD necessitate percutaneous or surgical combines high-dose intravenous . In developed countries, KD has immunoglobulins (IVIG) and aspirin administered

Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004: http://www.orpha.net/data/patho/GB/uk-kawasaki.pdf 3 become the major cause of acquired heart reactivity of T cells between epitopes of disease of childhood [2-4]. mycobacterial and human heat shock proteins, is Recently, a patient unresponsive to treatment the development of erythema and induration at with IVIG and high dose aspirin was treated with sites of BCG immunization [23] Two-dimensional infliximab. After the first dose, reduction of fever echocardiography may show coronary artery was observed and his laboratory measures aneurysms which are a highly suggestive but improved [24]. delayed finding as they generally become visible only during the subacute phase of the illness. Etiology During the acute phase, echocardiography may Despite intense investigation, the etiology of KD detect coronary dilatation, pericardial effusion, remains unknown. The young age at onset, the mitral insufficiency and/or left ventricular clinical presentation and the occurrence of insufficiency. Because of the high sensitivity of outbreaks would point to an infectious, and, in two-dimensional echocardiography in detecting particular, a viral origin. However, none of the proximal coronary aneurysms [2], coronary various viruses (, Epstein - Barr angiography is generally reserved for patients virus, human herpesvirus 6 or other with large or multiple aneurysms on Herpesviruses, retrovirus, measles virus) that echocardiograms, in order to fully investigate the have been incriminated as potential causative extent of the coronary involvement [4]. agents could be clearly correlated to KD. Toxin- Consequently, the diagnosis of KD relies, for the producing bacteria were implicated because of most part, on clinical criteria and, in particular, clinical similarities with the on the major features that have been outlined by and because of immunological evidence that the Japanese Kawasaki Disease Research would suggest an underlying - Committee [1]. However, with regard to the mediated mechanism. However, further existence of atypical presentations, the investigation provided conflicting results, and diagnosis should be considered in all children could not confirm the immunological findings or with an undiagnosed febrile illness presenting the relationship between staphylococcal or with any of the diagnostic criteria of KD [2, 4]. streptococcal and KD. An interesting hypothesis refers to the role of IgA plasma cells: Unresolved questions these have been found in the vascular walls of The long-term consequences of KD are a matter KD patients, and an oligoclonal pattern has been of debate. The results of several studies tend to demonstrated, consistent with an antigen-driven support that arteries with resolved aneurysms immune response [25]. Pro-inflammatory remain functionally impaired, but it is unclear if cytokines have been shown to play a role in the these abnormalities predispose to accelerated disease pathogenesis, and a recent study has atherosclerosis. Further investigation should also provided preliminary evidence for an increased be undertaken to define the optimal frequency of alleles associated with elevated management of immunoglobulin-refractory TNF- levels [26]. Autoantibodies in KD have disease. Finally, the development of a diagnostic not been found consistently except anti- test and a specific treatment awaits the endothelial cell (AECA) [27]. A discovery of the etiological agent of KD. genetic factor conferring susceptibility to KD would be supported by the higher incidence in References children of Asian ancestry but no particular 1. The Japanese Kawasaki Disease Research phenotype (HLA) could Committee: Diagnostic guidelines of Kawasaki be identified. Furthermore, different disease, 4th edition, 1984. environmental risk factors have been identified in 2. Laupland KB, Dele Davies H: Epidemiology, affected children such as a significantly higher etiology, and management of Kawasaki disease: exposure to carpet cleaning and proximity to state of the art. Pediatr Cardiol 1999; 20: 177-83. septic water, but the significance of these results 3. Rowley AH, Shulman ST: Kawasaki remains unknown [2-4]. syndrome. Pediatr Clin North Am 1999; 46: 313- 29. Diagnostic methods 4. Mason WH, Takahashi M: Kawasaki No specific test is available to diagnose KD. syndrome. Clin Infect Dis 1999; 28: 169-87. Laboratory findings mainly reflect an intense 5. Bligard CA: Kawasaki disease and its immune response with leukocytosis, highly diagnosis. Pediatr Dermatol 1987; 4: 75-84. elevated erythrocyte sedimentation rate and C- 6. Kawasaki T: Acute febrile mucocutaneous reactive protein level, and thrombocytosis. A syndrome with lymphoid involvement with mild elevation of liver enzymes and sterile pyuria specific desquamation of the fingers and toes in are also commonly observed [2-4]. An children (in Japanese). Arerugi 1967; 16: 178- interesting finding, possibly related to a cross 222.

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Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004: http://www.orpha.net/data/patho/GB/uk-kawasaki.pdf 5