Kawasaki Disease: Case: This is a 2 year old Japanese-Korean male presenting with 5 days of fever up to 39 degrees C (102.

2 degrees F). On the second day of illness, he developed red lips and an erythematous maculopapular rash over his torso. By the third day of illness, his conjunctivae were erythematous without exudates, his rash involved his extremities, and he developed a strawberry tongue. On the fourth day of illness, he had edema to his hands and feet with a diffuse red-purple discoloration over the palms and soles. His lips were now cracked and bleeding. He was noted to be irritable and fussy, with decreased oral intake. Examination: y y y y y           Vital Signs T 39.5 P 130 RR 40 BP 100/60 Weight and height are at the 25th percentile. He is alert and slightly fussy, but he consoles easily and he is not lethargic. Eyes: His bulbar conjunctivae are injected with limbal sparing (less injected around the limbus where the cornea fuses with the conjunctiva), but no exudates. Lips: red and cracked. His tongue is bright red. His neck is supple with bilateral small lymph nodes. Heart is slightly tachycardic, with no murmurs or gallop. Lungs are clear. Abdominal exam finds no abnormalities. He has some mild edema of his hands and feet with some red-purple discoloration of the palms and soles. He has a generalized deeply erythematous rash which is flat with irregularly shaped pink-red lesions ranging from 1 to 7 cm in diameter, with some areas coalescing. The lesions blanch. No joint swelling is noted. He moves all extremities well.

He is admitted to the hospital for further management and treatment of suspected Kawasaki Disease (KD). Lab:     CBC WBC 19,500 with 75% segs, 20% lymphs, 5% monos. Platelet count 475,000. Hgb 10.

   

AST 56, ALT 62, bilirubin 1.2, albumin 2.8. Urinalysis with WBC 5-10, no organisms, negative for protein, blood, leukocyte esterase or nitrites. Urine and blood cultures are obtained. Echocardiogram and EKG are both normal. He is treated with IVIG (IV gamma globulin) and aspirin. His fever subsides after 24 hours with improvement in his rash, lips, extremities and conjunctivae. He is discharged after the completion of IVIG treatment. Follow-up echocardiograms demonstrate no abnormalities.

Kawasaki Disease (KD) AKA mucocutaneous lymph node syndrome is an acute multisystem vasculitis that almost exclusively affects young children below the age of 5. Significant adverse cardiac effects were recognized in untreated patients, particularly the development of coronary artery aneurysms leading to myocardial infarction (thrombosis) and sudden death. The etiology of KD remains unknown. The acute, febrile, and self-limited nature of KD and its clinical manifestations of rash, meningeal, hepatic, joint, and mucous membrane inflammation strongly suggest an infectious etiology or trigger. Exaggerated T-cell response to an unknown antigen. The predominance of cases in children under 12 years of age and the occurrence of community-wide epidemics further suggest that the etiologic agent may be common and widely distributed. Despite lack of the identification of an etiologic agent, intravenous gamma globulin (IVIG) has been discovered as a remarkably effective treatment resulting in rapid clinical improvement and prevention of coronary artery sequelae. KD has a peak incidence in the first two years of life. Boys are affected more often than girls by a ratio of 1.5 to 1. Although classic symptoms can occur in children as young as several weeks old, diagnosis within the first 3 months of life is uncommon, perhaps because of passive protection from maternal antibodies or because these children tend to have atypical or mild clinical manifestations. KD occurs more frequently in the winter and the spring than in the summer and fall. Pathologically, KD is a multisystem vasculitis with a predilection for the coronary arteries. The acute phase (first 10 days of illness) is characterized by an intense inflammatory infiltrate in the vasa vasorum of the coronary arteries with infiltration and hypertrophy of the intima. Pancarditis may be present and the pericardium may also inflame, often with effusion. Some patients may develop congestive heart failure and myocardial dysfunction, but death during this phase is usually sudden and thought to be due to arrhythmia. During the convalescent phase (10-40 days after the onset of fever) the inflammatory infiltrate matures from predominantly polymorphonuclear leukocytes to a predominance of mononuclear cells. Fragmentation of internal elastic lamina and damage to the media can result in aneurysm formation. Coronary artery involvement is usually bilateral and most severe near the origin (proximal). Death is most frequently due to acute myocardial infarction due to acute coronary artery thrombosis during this stage.

Late changes (>40 days) involve healing and fibrosis in the coronary arteries. There may be organizing thrombosis within aneurysms with recanalization, calcification and stenosis. Fibrosis can also occur in the myocardium from old myocardial infarction. Death during this stage most often occurs from acute myocardial infarction or chronic myocardial ischemia. The immunologic mechanisms causing KD vasculitis are partially understood involving abnormalities of T cells, B cells, cytokines, autoantibodies, macrophages, monocytes, and blood vessel associated matrix metalloproteinases. There is no pathognomonic diagnostic test for Kawasaki syndrome. The diagnostic criteria for the diagnosis of KD as established by Dr. Kawasaki have stood the test of time and are listed in Table 1 and described in detail below. Diagnostic Criteria for Kawasaki Disease 1. Fever 2. Conjunctival vascular injection (non purulent) 3. Mouth changes:    Erythema, cracking and bleeding of lips Strawberry tongue Oropharyngeal erythema

4. Polymorphous erythematous rash 5. Changes in the hands and feet consisting of:    Indurative edema Diffuse erythema of the palms and soles Convalescent desquamation of skin after day 10

6. cervical lymphadenopathy

Clinical Course: The onset of illness is often abrupt with fever as the initial sign. The fever is typically persistent and high ranging between 38 and 41 degrees C (101 to 106 degreesF). Initially the criteria stated that fever should exceed 5 days before making the diagnosis. With recognition of serious sequelae if therapy is delayed, we now stress making the diagnosis as early as possible, disregarding the 5 day provision. In untreated patients, the mean duration of fever is 11 days with a range of 5 to 33 days. Within 2 to 5 days of fever onset, the child develops the other diagnostic signs of KD. These children are often exceedingly fussy or irritable. The eye involvement consists of discrete vascular injection of the bulbar conjunctiva most marked in the periphery with relative sparing around the limbus (known as limbic or perilimbic sparing). Exudate is absent while photophobia may be present. Mild

anterior uveitis may be present. Mouth changes include initial bright red erythema of the lips (progressing to swelling, cracking and bleeding), prominent papillae on the tongue with erythema (strawberry tongue), and diffuse erythema of the oropharynx without vesicles, ulcers or erosion. The rash can takes many forms (which is why the term "polymorphous" is used) but it is never vesicular or bullous. The most common form is deeply erythematous with papules varying from 2-3 mm to large, coalescent plaques covering several centimeters. Frequently it is pruritic and appears urticarial. A diffuse maculopapular measles-like rash is also commonly seen. Rash distribution is variable. It frequently involves the face, often coalescent and mask-like around the eyes, nose and mouth. It can involve the perineum with later peeling. It may be distributed more prominently on the trunk or the extremities. The rash is not fixed and can clear then reappear in new areas. It may be more prominent with high fever. Changes in the hands and feet consist of firm, indurative edema with diffuse redpurple discoloration of the palms and soles, usually with sharp demarcations at the wrists and sides of the hands and feet. In early convalescence (10-20 days after onset of fever), desquamation starts just under the nails and progresses to involve the entire palms and soles, with skin peeling in sheets. Cervical lymph node involvement occurs in approximately 50 % of patients, characterized by a sudden onset of unilateral firm swelling measuring more that 1.5 cm in diameter. Occasionally the cervical adenopathy can be diffuse and massive, even causing tracheal shift. It can be moderately tender, with or without erythema, and non-fluctuant. Associated findings include aseptic meningitis with CSF pleocytosis in 25% of patients. CSF counts range between 50-150 per cubic mm (mostly mononuclear). CSF protein levels are normal to slightly elevated, with normal glucose. Urethritis and sterile pyuria are present in approximately 60% of patients. Some hematuria may be seen, but urinary protein is usually normal. A small meatal ulcer or meatitis (redness) of the urethra is often seen in males. Prior to the use of IVIG, approximately one third of patients developed arthritis. During the first week of illness, arthritis was usually polyarticular of large and small joints. Oligoarthritis of large weight bearing joints was noted more in the second week of illness. Late onset arthritis has been virtually eliminated with the use of IVIG. Severe abdominal pain, often associated with diarrhea can be seen in the first few days of illness. Occasionally it may present as an acute abdomen. Amylase and lipase levels may be elevated, suggesting an acute pancreatitis. Liver involvement occurs in 40% of patients, including liver enzyme and bilirubin elevations. The direct fraction of bilirubin can be elevated suggesting a primarily obstructive pattern. Gallbladder hydrops can be seen with elevated bilirubin levels and findings of a right upper quadrant mass. Ultrasonography can confirm the diagnosis. This is usually a self-limited complication and does not require surgery, resolving within 2 weeks with IVIG and aspirin therapy. A wide spectrum of cardiac abnormalities has been identified. Many children have tachycardia. Some develop signs of congestive heart failure ranging from mild pulmonary vascular congestion and a gallop rhythm to cardiogenic shock. About a third of patients may have pericardial effusions during the first week of illness. Mitral and tricuspid insufficiency have also been noted. Echocardiography may demonstrate some degree of myocardial involvement in the majority of patients. Prolongation of the PR interval and first-degree heart block are common, but more significant arrhythmias are rare. Many of these abnormalities resolve rapidly after IVIG therapy.

Coronary artery abnormalities can be detected by echocardiography at the end of the first week to the second week of illness (range 7-28 days after onset of illness). Progressive dilatation and aneurysm formation may occur with a peak incidence and severity at approximately 1 month after the onset of disease. Prior to the use of IVIG therapy, about 18-25% of patients developed coronary artery aneurysms, with the highest risk in males and children under the age of 1 year. Transient coronary artery dilatation is even more common affecting at least 60%. Regression of aneurysms is common for all but giant aneurysms. Approximately 2/3 of children with aneurysms at 8 weeks post onset have regression by 1 year on echocardiography. Although the aneurysm may appear to have regressed by echo, the vessel walls are not normal and no longer dilate in response to exercise or drugs. These patients may still develop stenosis, tortuosity, and coronary artery thrombosis. Some of these children will develop giant coronary aneurysms (>8mm). Children with coronary abnormalities are at high risk for myocardial infarction, sudden death, coronary thrombosis, and myocardial ischemia within the first year after onset and have a higher lifetime risk in the long term. Giant aneurysms (greater than 8 mm or the diameter of the aorta) pose a most severe problem. These occur in 3% to 7% of untreated patients, are correlated with duration of fever >2 weeks and have a poor prognosis. Children with giant coronary aneurysms are at the highest risk for early myocardial infarctions and sudden death due to coronary thrombosis or rupture. Progression to significant coronary stenosis with resultant myocardial ischemia occurs in a very high percentage over the next 20 years. Some patients may have more severe vasculitis with acute KD. Aneurysms in vessels other than the coronary arteries, such as axillary, mesenteric, and renal arteries have been noted in severe cases. Some cases develop peripheral gangrene due to severe vasculitis and thrombosis. In infants, fatal KD is indistinguishable from infantile polyarteritis nodosa. Laboratory findings in KD are nonspecific but consistent with significant inflammatory indices. There is no diagnostic test for Kawasaki disease. Erythrocyte sedimentation rate, C-reactive protein, and alpha1-antitrypsin are elevated. White blood cell count (WBC) is often elevated with a polymorphonuclear cell predominance and sometimes, a left shift. The WBC rises through the first two weeks of illness, peaking between 7-12 days. By day 5 of illness, 50% of patients have platelet counts greater than 450,000 per cubic mm. By day 10, nearly all have elevated platelet counts which may peak at 650,000 to 2,000,000 per cubic mm between days 10 and 20. Mild to moderate anemia is common. Liver enzymes are moderately elevated (over twice the upper limit of normal) in 40% of patients in the first week. Bilirubin may be elevated in 10% of patients. Hypoalbuminemia is common. Urinalysis shows sterile pyuria in 60%. Work up of patients suspected of KD should include the above lab studies, and a cardiovascular evaluation including EKG, echocardiography, and chest x-ray. The differential diagnosis for KD includes staphylococcal and streptococcal toxic shock syndromes, streptococcal scarlet fever, staphylococcal scalded skin syndrome, measles, febrile viral exanthems, adenovirus infection, hypersensitivity reactions (including Stevens-Johnson syndrome, erythema multiforme minor and serum sickness), and systemic onset juvenile rheumatoid arthritis. When KD is

suspected, appropriate testing for viral and bacterial infection are indicated in addition to laboratory testing described above. The diagnosis of KD relies primarily on clinical features and a pattern of non-specific laboratory tests. Since there is no specific diagnostic test available, patients who have a milder illness or an incomplete/atypical pattern of symptoms, may not be diagnosed with KD, but are still at risk for coronary artery disease. These "incomplete" cases are at risk for coronary complications, especially since they may not be diagnosed or treated with IVIG. Infants younger than 6 months of age, and older children are at particular risk. If a child has fever and 2 or 3 of the other criteria PLUS compatible laboratory findings KD should be considered and if needed, expert consultation sought. KD should also be considered in all younger children with fever of unknown origin. Patients with KD who present with fever and lymphadenitis as the first sign may also pose a diagnostic problem. These patients may be initially diagnosed with lymphadenitis and are treated with antibiotics. The subsequent development of rash, conjunctival injection, mouth, hand and feet changes, may be mistakenly attributed to antibiotic hypersensitivity. Laboratory tests can be very helpful in the diagnosis although none provide definitive answers. By day 5 of illness, most patients have WBC of 15,000 or more, significantly elevated sedimentation rate (ESR) and C reactive protein (CRP), and platelet count of >400,000. Sixty percent have sterile pyuria with >10 WBC/hpf and 40% have liver enzyme values equal to or greater than 2X the upper limit of normal. Most viral illnesses and serum sickness have normal or low WBC, and normal or near normal ESR and CRP values. Creatinine elevation is unusual in KD and usually suggests another diagnosis. Since the late 1980s multiple studies have shown that the use of high dose IVIG given in the first 10 days of illness has dramatically altered the clinical and pathologic course of the illness. Prompt clinical improvement follows IVIG: 60% become afebrile within 12 hours of IVIG, and 90% within 48 hours. The risk of coronary aneurysms has been lowered from 18-25% to 2-4%. Infants younger than 1 year of age have the highest risk of coronary abnormalities when untreated. Even with IVIG treatment, the risk of coronary abnormalities at 8 weeks is 15%. For all age groups treated with IVIG, the incidence and severity of any coronary disease and the frequency of giant aneurysms has been greatly reduced. Once a diagnosis of KD is made, therapy consists of intravenous infusion of IVIG 2 gm/kg given over 1012 hours. Heart rate and blood pressure should be monitored closely. Patients who remain febrile or have recurrent fevers 48 hours after the end of the initial IVIG infusion, may require an additional infusion. In our experience, approximately 10 % of children require second doses. Expert opinion should be sought for patients who are unresponsive to IVIG as this is the group who develop coronary disease. Aspirin therapy should be instituted on the day IVIG is given. In the United States, a dose of 100 mg/kg to a maximum of 4 grams per day is given until a few days after defervescence or until the 14th day of illness. This is followed by a daily dose of 3 to 10 mg/kg/day (one half to one 81 mg tablet) until the ESR and platelet counts return to normal, usually about 2-3 months after onset of illness. Aspirin has been shown to result in a more rapid defervescence, lower frequency of relapse of fever and shorter hospital

stay. Anti-coagulation with low dose aspirin therapy helps prevent the thrombosis in the setting of vascular inflammation and elevated platelet counts. Serum salicylate levels should be obtained if symptoms of salicylate toxicity develop. Aspirin therapy can be interrupted in children who develop varicella or influenza during the follow-up phase to decrease the risk of Reye syndrome. There is no data to guide therapy of patients suspected of having KD who present more than 10 days after onset of illness. If patients are still febrile or have other signs of active disease such as progressive coronary artery dilatation, IVIG therapy may result in prompt clinical improvement. Patients who have become afebrile and have normal coronary arteries by 3-4 weeks after illness onset are unlikely to benefit from IVIG and should be placed on low dose aspirin. In patients who have already developed coronary aneurysms without active inflammation, there appears to be no beneficial effect of IVIG. In summary, KD is a severe acute febrile exanthematous illness of young children, who are usually under the age of 6 years. Cardiovascular damage sustained during the acute and early convalescent phases of KD occurs in over 30% and may be serious, causing lifelong coronary abnormalities including premature myocardial infarction, coronary and myocardial insufficiency or coronary artery rupture. KD is fatal in 24% of undiagnosed and untreated patients. Early IVIG therapy results in prompt clinical improvement and prevents coronary artery damage and long term cardiovascular complications. Therefore KD must be recognized, diagnosed and treated early and aggressively. If there is any question about the diagnosis of KD or if a patient thought to have KD does not respond to IVIG and aspirin therapy within 48 hours, expert consultation with a local or national expert is indicated on an urgent basis.