Continuing Medical Education
from Clinical Update, Summer 2004
Kawasaki Disease
Charles R. Woods, M.D., M.S.
Department of Pediatrics (Infectious Diseases)
This Continuing Medical Education activity is sponsored by Wake Forest University School of Medicine.
Educational Objectives: 1) Describe the primary components of the case definition of Kawasaki disease; 2) Recognize other manifestations of Kawasaki disease and understand issues surrounding atypical cases; 3) Discuss the approach to making the diagnosis of Kawasaki disease; 4) Describe treatment and follow-up of children with Kawasaki disease.
Abstract: Kawasaki disease is the leading cause of acquired heart disease in children in developed countries. Most cases are seen in children under 5 years old. It is a generalized vasculitis associated with an intense inflammatory state that can lead to aneurysms of the coronary arteries, complicated sometimes by thrombosis, myocardial infarction and death. The specific etiology remains unknown. There is no specific diagnostic test, but a case definition helps to make the diagnosis. Timely recognition of typical and atypical cases is essential as treatment with large doses of IVIG within the first 10 days of illness greatly reduces risk of coronary artery aneurysms.
Introduction
Kawasaki disease is a febrile, multi-system illness that occurs worldwide, primarily in young children. The most feared complication is myocardial infarction and death due to thrombosis of coronary artery aneurysms. It is the leading cause of acquired heart disease in children in many developed countries. [1] Kawasaki disease also is known as mucocutaneous lymph node syndrome. Atypical cases have been increasingly recognized, especially in older children, in recent years.
The disease was first recognized as a clinical entity in 1961 among Japanese children. [2] It is seen worldwide and almost all cases occur in childhood, with 80% to 85% of cases occurring in children <5 years old. Kawasaki disease is more common in Asian populations. In Japan, annual rates exceed 100 cases/100,000 children <5 years compared to 9 to 19 per 100,000 in the U.S. Cases occur year-round but are more common during winter and spring months. Local and regional epidemics have been seen in the U.S. National epidemics have occurred in Japan. [1, 3]
The male-to-female case ratio is 1.5:1. Males also have greater risk of coronary artery disease. The peak age of occurrence in the United States is 18 to 24 months of age. In the current treatment era, mortality rates in the U.S. are about 0.2% overall—0.1% for children <10 years old, and 1.4% among those 10 years old. The higher rate among older children reflects the difficulty in timely diagnosis of atypical cases. Although a genetic predisposition for Kawasaki disease is suspected, to date no specific HLA gene or other host factor has been confirmed to be a risk factor for the disease. The disease recurs in <4% of cases, usually within 2 years of the initial episode. Siblings are rarely affected. [1,3,4]
Pathophysiology and Etiologic Considerations
The pathologic hallmark of Kawasaki disease is a generalized vasculitis that is most severe in the extraparenchymal sections of medium-sized musculoelastic arteries, especially the coronary arteries. The primary cause of death is myocardial infarction due to acute thrombosis of inflamed coronary arteries. Coronary artery stenosis can occur and result in death years after the acute illness. Aneurysms can occur in any major artery. Phlebitis occurs but is not of clinical significance.
An initial mixed neutrophil and mononuclear cell infiltrate into arterial walls and rapidly give way to a predominantly mononuclear cell presence. In severe cases, edema and smooth muscle necrosis occur in the media, with inflammation also seen in the intima and adventia (panarteritis). Elastin and collagen fibers become fragmented such that structural integrity of the vessel wall is lost, leading to aneurysm. [5] Fibrosis and intimal proliferation occur over time, causing vessel walls to become stiff and stenotic. Luminal occlusion may occur by stenosis or thrombosis. [6]
The mononuclear infiltrate consists of activated T cells (CD8 cytotoxic and suppressor T cells more than CD4 helper T cells), macrophages and IgA-producing plasma cells. [1,7,8] The immune system is highly activated in Kawasaki Disease, with extensive production of many cytokines: interleukins (IL)1, 2, 4, 6, 8, and 10; tumor necrosis factor a, interferon y, and solulable IL-2 receptor. Endothelial cells are activated with up-regulation of leukocyte adhesion molecules and other surface markers. There is systemic polyclonal activation of B cells with increased antibody production of all classes. Antiendothelial cells and other autoantibodies have been reported, but their precise roles, if any, in pathogenesis remain unclear. The accumulated evidence suggests that immune cascades triggered in Kawasaki disease lead to autoimmune vascular damage that is mediated by cytokine-induced expression of various endothelial cell surface antigens (i.e., receptor proteins). [1,9]
The initiating etiology of Kawasaki disease remains unknown. Many organisms and exposures (e.g., chemical, heavy metals) have been offered up over the years, only to become discarded after subsequent studies. Recent theories that superantigen-producing microbes were causative also now seem unlikely. IgA-plasma cells infiltrating coronary artery walls are oligoclonal, consistent with response to a conventional antigen. [10] The process likely represents a post-infectious inflammatory state. The rarity of the disease in young infants and adults suggests a relatively ubiquitous infection may initiate the process. The disease likely is not new. Infantile polyarteritis nodosa, which appears identical to Kawasaki disease histopathologically and clinically, was recognized as early as 1871. [1,11]
Clinical Manifestations and Diagnosis
Typical Kawasaki disease has a well-characterized clinical course. The case definition requires the presence of fever greater than 101ºF for at least five days in association with at least four of the following signs: 1) bilateral bulbar conjunctival infection, 2) inflammatory changes of the lips (erythema, dryness, fissuring, peeling, cracking, bleeding) and mouth (“strawberry tongue” and diffuse erythema of the oral mucosa and pharynx), 3) generalized polymorphous rash, 4) bilateral redness and swelling of the hands and feet; and 5) cervical adenopathy with at least one node enlarged to more than 1.5 cm in diameter. The first four types of findings each occur in 80% of cases while lymphadenopathy occurs in 50% to 75%. Fever often precedes other signs, which may appear stepwise over several days. [1,12,13]
Children with Kawasaki disease generally are irritable and uncomfortable. Fever is usually high and spiking, exceeding 102ºF in almost all and 104ºF in many cases. Antipyretics have little impact. The febrile course persists as long as 3 to 4 weeks without definitive treatment. Conjunctival injection is more prominently bulbar than palpebral without associated exudates or ulceration. Mild anterior uveitis is often evident on slit lamp examination and resolves without sequelae. Oropharyngeal changes are seldom associated with ulcers or pharyngeal exudates. Nasal congestion is uncommon. Copious nasal discharge or prominent cough suggest a viral illness rather than Kawasaki disease.
The rash most commonly seen in Kawasaki disease is erythematous, diffuse and maculopapular. Urticaria, scarletiniform rash or diffuse erythroderma can occur. Perineal rash is common and often prominent. Perineal desquamation can occur early in the febrile course and is highly suggestive of Kawasaki disease. Extremity changes can be striking, with induration and erythema beginning abruptly at the wrists or ankles. Subsequent periungual, or even more extensive, desquamation occurs 2 to 3 weeks after onset of fever. Lymphadenopathy is usually unilateral. It may be present early and resolve by the fifth day of fever. Fluctuance and tenderness are rare. It occasionally is the dominant feature, such that Kawasaki disease should be considered, and other signs carefully sought, in children with acute cervical adenitis who do not respond to antibiotics and have no clear alternate diagnosis. [1,14]
Carditis is present to some degree in all cases of Kawasaki disease. The pericardium, myocardium and endocardium can be affected. Pericardial effusion is present in 20 to 40% of cases. Inflammation of the mitral or aortic valves can lead to valvular regurgitation. Physical examination is often normal but gallops or muffled heart sounds may be heard. Congestive heart failure occurs in about 5% of cases. Aneurysms will occur in 20% to 25% of patients if untreated, usually becoming evident 2 to 4 weeks after onset of illness but sometimes seen as early as within 7 days of illness.
Kawasaki disease has many other manifestations that reflect its systemic nature. Urethritis with sterile pyuria is present in 70% of cases. Mild hepatitis with 2-to-4-fold elevations of transaminases occurs in 40% of cases. Diarrhea, nausea or vomiting may be present, usually due to ileus or hepatic inflammation. Hydrops of the gallbladder occurs in <10% of cases and may cause severe right upper quadrant pain; cholecystectomy is not required. Arthritis or arthralgia are present in 10% to 20% of patients and often involve the small joints of the fingers and toes. When affected, large joints can have effusions that mimic septic arthritis with >100,000 white blood cells (WBC)/mm3. Aseptic meningitis occurs in up to 50% of patients but often is clinically silent. Facial nerve palsy can occur, most often in girls <2 years old. Resolution in 1 to 2 weeks is the rule. [1]
Differential Diagnosis and Atypical Kawasaki Disease
The Kawasaki disease criteria can be met by many other diseases. The most common processes that mimic Kawasaki disease are viral infections with exanthems (especially adenovirus and measles), acute streptococcal and staphylococcal infections, and drug hypersensitivity reactions. In adenovirus infections, conjunctivitis and pharyngitis usually are exudative, and perineal prominence of rash and distal extremity changes are unusual. Rocky Mountain Spotted fever, infectious mononucleosis and leptospirosis can have presentations suggestive of Kawasaki disease. [1,15]
Atypical (incomplete) Kawasaki disease occurs when children develop coronary aneurysms without having met the full case definition. Atypical cases may comprise 20% to 60% of all cases, are difficult to recognize and occur most often in infants. Atypical Kawasaki disease should be considered in any infants or children with prolonged fever (≥7 days) with any signs of mucocutaneous inflammation (skin, eyes, mouth) and laboratory evidence of systemic inflammation (leukocytosis and elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)). Irritability, abdominal pain, diarrhea, vomiting and arthritis may be more common in atypical cases. Referral to physicians with considerable experience with Kawasaki disease is suggested when such cases are suspected. [1,16,17]
Evaluation and Laboratory Findings
There are no specific diagnostic tests. When the history and physical suggest Kawasaki disease, the initial evaluation should include a complete blood count, serum chemistries (including transaminases), urinalysis, ESR, CRP and echocardiogram. If there are concerns of bacterial infection (e.g., Group A streptococcus or Staphylococcus aureus), a blood culture should be obtained. WBC counts >15,000 and left shift of the differential count are very common. Eosinophilia is present in some cases. Platelet counts are usually normal early on. Thrombocytosis, with platelet counts often >1,000,000/mm3, is a hallmark of Kawasaki disease but usually does not occur until the second or third week of illness. Thrombocytopenia can occur but is uncommon and should cause alternate diagnoses to be entertained. Low serum albumin, anemia, marked thrombocytosis, marked leukocytosis, elevated band count, high ESR and persisting elevation of CRP—all of which indicate more severe or more prolonged inflammation—are associated with increased risk of coronary aneurysms. [1,16-18]
Chest radiographs are most often normal but may show cardiomegaly and, rarely, infiltrates. Electrocardiograms (ECG) can be normal but may show prolonged PR or QT intervals, Q-wave changes, ST-T wave changes or arrythmias. Echocardiograms may be normal in the first 7 to 10 days of illness or may show evidence of pericardial effusion, valvular insufficiency, coronary artery ectasia or decreased contractility. Eye exams should be considered for children who can undergo slit lamp evaluation. The presence of uveitis is largely confirmatory in a child who otherwise meets all or most of the criteria for Kawasaki disease. Other testing should be based on clinical findings suggestive of the presence of other disease processes or other manifestations of Kawasaki disease.
Treatment and Follow-up
Once the diagnosis of Kawasaki disease is reasonably certain, IVIG 2 g/kg should be infused over a 10 to 12 hour period. It is often appropriate to observe children for 1 to 2 days early in the course while trying to ascertain the diagnosis of Kawasaki disease. A trial of antistaphylococcal antibiotics is warranted in cases where bacterial infection is a concern. When IVIG is given within the first 10 days of illness, the frequency of coronary artery aneurysms is reduced from about 25% to 3%. Although efficacy is less, IVIG administration may provide some benefit even after the 10th day. [19,20] About 90% of children will have resolution of fever and other signs within 24-48 hours after the IVIG infusion is begun. Up to 10% of children may have a recrudescence of fever and other inflammatory signs and require a second dose of IVIG. When illness is refractory to a second dose, consultation with or transfer to a tertiary center for further management is advised. [1,21]
Aspirin alone does not impact the course of coronary artery disease, may help reduce inflammation and has been used in the clinical trials demonstrating benefit of IVIG. Aspirin is begun along with IVIG. In the U.S. many experts recommend 80 to 100 mg/kg/day until the patient has been afebrile for 3 to 4 days. Japanese clinicians (and some in the U.S.) use 30 to 50 mg/kg day. Once the patient is clearly afebrile, aspirin dosage is reduced to 3 to 5 mg/kg/day for antiplatelet effect to protect against arterial thrombosis 1) during the period of thrombocytosis (the magnitude of which is not impacted by IVIG or aspirin therapy) and 2) until coronary involvement has been ruled out.
Follow-up should be conducted by cardiologists experienced with Kawasaki disease. Echocardiography at 6 to 8 weeks after acute illness is essential. Need for long-term anti-platelet therapy and further cardiac follow-up decisions depend on these results. Most treated patients recover fully. Coronary aneurysms ≤8 mm in diameter usually resolve. Larger aneurysms often are associated with long-term complications and may result in disabilities or risk of cardiac events during sports or other activities with high cardiovascular demand. The American Heart Association developed guidelines for Kawasaki disease in 1994. [22] An updated version is in preparation.
Children on aspirin therapy during influenza season should be offered inactivated influenza vaccination. Live vaccines (measles-mumps-rubella and varicella) should be postponed for 11 months after IVIG as persisting neutralizing antibodies against the vaccine viruses may block immune response to the vaccines. [1]
References
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