Kawasaki Disease Analysis

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Introduction

Kawasaki disease is described as an acute febrile illness. KD patients have inflammation which is usually small or medium-sized blood vessels throughout their body, in specific, in the coronary arteries such as the blood vessels around the heart [1]. It was first described in Japan in 1967 by the pediatrician Dr. Tomisaku Kawasaki and initially was designated as the mucocutaneous lymph node syndrome [2]. KD is described as an immune-mediated vasculitis with limited clinical course and unknown etiology. Without therapy, manifestations of acute inflammation and fever may last for about 12 days [1]. The disease gets complicated when the development of aneurysms occurs in coronary arteries which can lead to myocardial ischemia or infarction (MI). However, untreated KD patient usually develops coronary artery aneurysms. Recent research has concluded that with early detection of the disease and punctual initiation of medication with either aspirin or intravenous immune globulin (IVIG), the death rate has reduced drastically with the prevalence of coronary artery aneurysms being approximated as 5 percent [3].

Epidemiology

It has been established that children of Asian descent whether in Asia or those scattered in the world possess a greater incidence of KD. Reported statistics show that over 80% of KD cases are of children under the age of 5 years with a considerable peak of 1-2 years of age. However, Kawasaki disease is relatively uncommon in children under the age of six months of age, children in their late childhood age, and adults. In addition, KD is more prevalent in boys than girls. Japan is the most affected with Kawasaki disease and about 100,000 cases have been reported since its first described case in 1967. In Japan, 100 per 100,000 cases of KD are usually reported every year. However, the incidence of KD is increasing as a well-presented study in 14 years from 1987 to 2000 indicated [4]. China and Taiwan have also high reported KD cases reaching up to 66 per 100,000 annually [5]. In another survey in Beijing hospitals, an increase in Kawasaki disease has been reported from 41/100,000 in the year 2000 to about 51/100,000 in 2004 [6]. In the United States, a high incidence rate of KD was noted among the Asians and Pacific Islanders, Hispanics, and non-Hispanics [7]. The increase was moderate compared to the Asian countries.

Etiology

The etiology of KD remains unknown. Several theories have been linked to its cause. However, the most likely cause of KD remains through infectious organisms which cause problems to a certain group of individuals.

Immunologic response

The abnormalities of the immune system have been associated with KD. The damage of the blood vessel leads to endothelial cell injury and vessel wall damage [8]. KD is unique compared to another vasculitis in that it involves macrophages more prominently [8]. Children with KD are associated with Humoral factors such as antiendothelial cell antibodies or circulating immune complexes [9, 10]. In a recent study, plasma cells producing IgA have been suggested to be present in the walls of children with KD [11]. A synthetic monoclonal IgA antibody was found to bind to the cytoplasm of macrophages in the coronary arteries of 9 of 12 fatal cases of KD. In the same study, a similar binding was noted in the respiratory epithelium of proximal bronchi in 10 of 13 fatal cases examined. The earliest pathologic evidence of vasculitis in KD remains the neutrophilic infiltrate. These types of cells are usually activated by antineutrophil cytoplasm antibodies. The case of neutrophilic was confirmed by a study of gene-expression patterns using DNA microarrays [12]. During the early stages, expression of genes associated with neutrophilic and inflammatory which included adrenomedullin, grancalcin, and granulin was extremely high. In addition, children with untreated KD have elevated levels of calcium-binding protein S100A12 (also called p6 or calgranulin C), a ligand for the receptor for advanced glycation end products and a mediator of inflammation [13].

Infectious etiology

Infectious diseases are caused by bacteria or bacterial superantigens (particularly Streptococcus pyogenes) or virus [14]. Since Kawasaki disease is rarely seen in adults, it has been suggested that adults may have developed immunity to the causative agent [15]. Support for this theory is derived from several observations which include the following; most of the clinical features are similar to those of other infectious diseases such as adenovirus infection and scarlet fever [1], there is an increase in KD during winter and summer in many geographical areas, boys being more susceptible than girls, the disease often occurs in epidemics as well as the fact that the disease is usually common in children under 5 years of age [16]. However, these circumstantial data supporting an infectious etiology for KD have not been substantiated [17]. A possible association of new coronavirus and Kawasaki disease was reported in 2005 by a group of researchers in New Haven [18]. In the study, HCoV-NH was isolated from 8 of 11 cases compared with 1 of 22 control subjects using RT-PCR [18]. Since this result could not be duplicated, many investigators continue to believe that KD represents a final common pathway of immune-mediated vascular inflammation [19, 20].

Genetic factors

Genetic factors have been associated with patients from Japan, Asia, and Asian-American descent [1, 21, 22]. These groups are affected regardless of where they live in the world. In most diagnosed cases, genetic factors are popular especially in those families with KD histories. Several genes described below have been associated with KD. The gene is known as nucleotide polymorphism (SNP) of the inositol 1, 4, 5-trisphosphate 3-Kinase C (ITPKC) have been reported to be associated with the increased susceptibility to KD [23]. A single nucleotide polymorphism (SNP) of the inositol 1, 4, 5-trisphosphate 3-Kinase C (ITPKC) gene on chromosome 19q13.2 was linked with increased risk of KD in children from both Japan and the U.S [23]. This allelic change also increased the risk of coronary artery lesions in patients with KD. Additionally, HLA genes include B5, B44, Bw51, DR3, and DRB3*0301 in Caucasians; B54, Bw15, and Bw35 in Japan, as well as Bw51 Israelites, have been linked to Kawasaki disease [24]. The susceptibility of KD has also been influenced by genetic variations in the chemokine receptor CCR5 and its major ligand CCL3L1 [25]. In addition, a small possible link with carpet shampoo or living near a body of stagnant water is thought to cause KD although neither of these theories has yet been established.

Clinical Manifestation

The clinical signs of KD include; systematic inflammation manifested by fever, bilateral non-exudative conjunctivitis, erythema of the lips, oral mucosa, rash as well as lymphadenopathy [26]. The most consistent manifestation of KD is fever. Fever reflects increased levels of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 which are suggested to mediate vascular inflammation. Bilateral nonexudative conjunctivitis is present in more than 90 percent of patients [27]. The presence of uveitis provides substantial evidence for further diagnosis of KD as it is more often seen in KD than in other diseases [28]. Mucositis often becomes evident as KD progresses. The major symptoms of mucositis are cracked red lips and a strawberry tongue. The onset of rash begins as peripheral erythema and desquamation which is followed by macular, extremities, and morbilliform [29]. In some cases, KD may trigger a psoriasiform eruption in children with no history of psoriasis. Extremities changes are typically the last manifestation to develop in KD cases. Such changes include indurated edema of the dorsum on their hands and feet as well as diffused erythema on their palms and soles. These symptoms are usually the diagnostic criteria for Kawasaki disease. It is worthwhile to note that, the signs and symptoms of KD occur at different times, and therefore only repeated medical examination can establish the diagnosis of KD.

Laboratory findings

The most common characteristic of KD is systematic inflammation. Generally, this refers to the elevation of acute phase reactants or erythrocyte sedimentation rate, leukocytosis, and a left-shift in the white blood cell count. Mild to moderate elevation of transaminases is common in some patients because of intrahepatic congestion.

Diagnostic Criteria

Until today, there is no specific laboratory test for diagnoses of Kawasaki disease. The diagnosis is however established by meeting the diagnostic criteria in the table below.

Fever persists for at least 5 days

Fever is high and reaching up to 40⁰C or higher
The patient does not respond to antibiotics
Fever may persist for 1-2 weeks or longer duration

In addition to fever, the following conditions are met

Changes in hands and feet involve swelling and redness. In some cases, the increase in fever usually results in the peeling of toes and fingertips.

If fever remains high for a week, the rash tends to appear on most parts of the body.

The mouth is characterized by a red tongue referred to as strawberry tongue as well as dry broken lips.

In most KD cases patients have red eyes.

Lymph glands in the neck become enlarged, and unilateral (about 50-70% of cases reported).

Guidelines for the diagnosis of KD were established by Tomisaku Kawasaki in 1967 [1]. Differential diagnoses considered include scarlet fever, toxic shock syndrome as well as juvenile idiopathic arthritis [30, 31]. Diagnosis establishment of KD is illustrated in the flow chart below;

Complications

Most complications primarily reflect cardiac sequelae that include coronary artery aneurysms. In addition, non-cardiac complications may also be present.

Cardiac

Cardiac complications are estimated to occur in approximately 25% of those individuals who do not receive treatment [32]. Most KD complications are associated with coronary artery aneurysms while others occur with decreased myocardial contractility [33, 34], coronary arteritis without aneurysms [34], mild valvular regurgitation, and pericardial effusion [35]. These abnormalities for KD are helpful in diagnostic criteria of incomplete KD.

Others

Other complications include dehydration, limited mobility from joint inflammation, urinary and renal diseases, gastrointestinal abnormalities as well as macrophage activation syndrome.

Incomplete KD

Children suspected of having KD who do not fulfill diagnostic criteria may have incomplete or atypical KD [1]. The children manifest the typical clinical features of KD but simply lack a sufficient number of signs to fulfill the diagnostic criteria of KD. The incidence of incomplete KD is unknown. An established case in Japan had 242 children with KD treated at a single center for over 9 year period. However, 10 percent of patients were diagnosed with incomplete KD [36]. Incomplete KD is most common in infants below 6 months of age [1]. This was concluded after a retrospective review of 44 children with KD, 5 of 11 infants (45%) had incomplete disease compared with 4 of 33 (12%) older children [7].

Management

Aspirin

Aspirin is used to treat KD because of its anti-inflammatory and anti-platelet effects. A high dose is usually recommended although a low dose is administered for its anti-platelet action. Other alternatives include anti-inflammatory agents such as ibuprofen which may be used for prolonged cases of arthritis [37].

IV Immune Globulin

Although the beneficial effect of IVIG remains unknown, it appears to have a typical inflammatory effect with a reduction of fever and acute markers of inflammation. The application of IVIG requires several mechanisms. Some of the mechanisms are regulation of antibody production; regulation of cytokine synthesis, the elevation of T-cell suppressors as well as neutralization of bacteria antigens [38]. In addition, IVIG remains the most cost-effective therapy for KD.

Glucocorticoid

Glucocorticoids also called corticosteroids, have been reported to be the most beneficial in a patient with KD who fails to respond to IVIG during their first therapy [39]. However, further research failed to establish the clinical benefit of Glucocorticoid during the initial treatment of KD [39].

Prognosis

Recent research has shown that children without cardiovascular abnormalities detected in the acute and subacute phase appear to be clinically asymptomatic 10 to 21 years later [39]. However, the long-term effect on cardiovascular health is unknown and it is unclear whether these patients will be at increased risk for atherosclerotic heart diseases as adults compared to those with no histories of KD [1].

Follow up

To authenticate the effectiveness of KD treatment, an echocardiogram should be obtained during the sixth week immediately after the onset of the disease. Patients are also recommended to take repeated clinical evaluations during the first two months following the diagnosis of KD to detect disorders such as arrhythmias, heart failure, valvular insufficiency, or myocarditis [39].

Vaccination

Measles and varicella vaccines should be postponed in children who have been treated with IVIG. This is because passively acquired antibodies persist for an extended period of up to 11 months following IVIG administration and tend to interfere with vaccine immunogenicity [38]. In addition, children above 6 months of age who require long-term aspirin therapy should receive yearly influenza immunization because of the increased risk of Reye syndrome [40].

Summary of important points

When a patient fulfills the criteria for KD or incomplete KD, treatment should be given because of cardiovascular complications that result in significant morbidity and mortality. IVIG should be administered during the onset period of KD to avoid the development of aneurysms [38]. Aspirin should be administered in the acute stage. However, treatment with glucocorticoids remains unclear whether the addition to IVIG therapy is beneficial inpatient with KD. To evaluate incomplete KD, it is recommended for one to use the American Heart Association (AHA) and the American Academy Pediatrics (AAP) guidelines [1, 39].

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