Pediatric Dennatology Vol. 9 No. 4 335-337
Kawasaki Syndrome: A 1992 Update Marian E. Melish, M.D. Johrt A. Burns School of Medicine of the University of Hawaii at Manoa, Kapiolani Medical Center for Women and Children, Honolulu, Hawaii Kawasaki syndrome (KS) was first described as mucocutaneous lymph node syndrome by Tomisaku Kawasaki of Japan in 1967. Dr. Kawasaki's enduring contributions have been the recognition of a new clinical disease entity and the development of the diagnostic criteria that form the mainstay of diETIOLOGY The microbial etiology of KS remains unknown. The epidemiology is characterized by virtual restriction to young children, the occurrence of communitywide outbreaks in three- to six-year intervals, and wide geographic distribution in different climactic zones. These features suggest that KS might be caused by a common agent that is widely transmitted, causing disease and/or immunity by age 8 years, that it is widely distributed, and probably is primarily associated with humans rather than animals or insect vectors. To date, although several theories have been put forward and numerous microbial agents have been recovered, no specific microbial-host relationship has been discovered. Interest in a Propionibacterium acnes toxin or a retrovirus as possible etiologic agents has waned because initial promising studies were not confirmed. Nunierous immunologic alterations can be documented in acute KS: Many of these suggest disordered immune regulation and excessive production of cytokines characteristic of the presence of an agent with superantigen properties. In collaboration with Donald Leung and Jun Abe and in our own laboratory we recently obtained more direct evidence of superantigen activity. We discovered that the repertoire of the variable p chain (Vp) region of the T cell receptor is altered in acute KS, resulting in overrepresentation of V32 and V38 expression in the acute stage, with a return to normal in convalescence. This expansion of one or two particular Vp
chains on T helper cells is characteristic of superantigen effect. Superantigens have become an intense area of investigation since their definition in 1989. Currently, a few bacterial exotoxins including the toxic shock syndrome toxin 1, the staphylococcal enterotoxins A through E, the streptococcal pyrogenic exotoxins A, B, and C, a Mycoplasma toxin, and some retroviruses have been found to have the property of binding to the major histocompatibiiity locus on monocytes and macrophages, and then being able to bind to specific regions on particular Vp chains of the T cell receptor. This lateral hingelike binding results in activation of both monocytes and T cells with resultant massive cytokine release. It also selectively stimulates proliferation of particular clones of T cells. An important characterisfic of superantigen reactions is their ability to engage a very high proportion of immunologically reactive cells compared with the limited number involved in classic antigen antibody reactions. PATHOLOGY Originally termed benign mucocutaneous lymph node syndrome, it was recognized in the early 1970s that some children died unexpectedly, generally between the third and sixth weeks after onset. The pathologic findings have been grouped into four stages corresponding to the duration of illness at death. It can be appreciated that KS is a selflimited, inflammatory vasculitis. Patients dying during the first week of illness show acute inflammation in the vasa vasorum of the aorta and coronary vessels, with severe intimal and adventitial inflammation. The coronary arteries are patent, but breaks in the internal elastic lamina can be noted. Death is usually secondary to arrhythmia with inflammatory changes in the atrioventricular conduction system. In addition, an inflammatory pancardi-
335
336 Pediatric Dermatology Vol. 9 No. 4 December !992
tis affects the valves, myocardium, and pericardium. Stages II and III from 10 days to 40 days after onset show a progressive decrease in inflEunmation of vessels and myocardium. The coronary arteries are aneurysmally dilated with evidence of medical destruction. The cause of death is acute coronary thrombosis. Patients dying in stage VI (after 40 days) generally have no acute inflammation but have evidence of abnormal coronary arteries with acute or chronic ischemic myocardial changes secondary to coronary thrombosis or stenosis. Although vessel damage is always most severe in the coronary vessels, some patients develop aneurysms in peripheral arteries, generally the axillary, iliac, and femoral arteries. These may occur in the third and fourth weeks of illness as pulsatile masses in the axiUae or femoral areas. Regression of aneurysms of both coronary arteries is known to occur over one to two years after onset. Repeat echocardiography or angiography may show restoration of a nonnal lumen size, but exercise and dipyridamole angiography demonstrated that Eireas of aneurysmal regression are not nonnal since these sections are no longer elastic, pulsatile, or able to respond to exercise with nonnal dilation. Persistent and large aneurysms have a pronounced tendency to develop stenosis.
scarlatiniform erythroderma and occasionally by an erythema marginatum rash. The rash has a variable distribution pattern, being most often generalized, but sometimes more prominent on the trunk and in other cases more peripherally distributed. In some patients the rash is accentuated in the perineal area. Changes in the hands and feet are distinctive, consisting of firm, indurative edema with diffuse red-purple discoloration of the palms and soles. In convalescence a characteristic desquamation begins at the fingertips and toe tips and frequently involves the entire palm and sole. The sixth of the major diagnostic criteria, lymphadenopathy, occurs in only 50% of patients. It is typically unilateral and cervical, with a firm node mass measuring over 1.5 cm in diameter, sometimes with overlying erythema. A spectrum of cardiovascular abnormalities accompanies KS. Mjiny series showed that 15% to 25% of patients have coronary artery abnormalities detectable by echocardiogram at eight weeks after onset. The children at greatest risk for serious complications of myocardial infarction, myocardial ischemia, and sudden death are those with giant coronary aneurysms measuring over 8 mm. Some of these patients have developed such severe coronary disease that coronary artery bypass surgery has been necessary.
CLINICAL FEATURES
The disease begins suddenly with high fever generally ranging between 38° and 4 r C . Unless treated with intravenous gamma globulin (IVIG), the fever lasts for a mean of eight days (range 5-35 days). Duration of over 14 days is associated with a higher frequency of cardiac complications. Within one to three days after the onset of fever other diagnostic features emerge. The characteristic changes in the eyes are discrete vascular injection so that each smdl scleral vessel is apparent. There is a zone of clearing around the hmbus. The absence of exudate and cornea! ulceration helps to differentiate the eye findings of KS from those of measles and Stevens-Johnson syndrome. Changes in the mouth consist of redness of the lips followed by cracking and fissuring, diffuse oropharyngeal erythema without ulceration or exudate, and a strawberry tongue. The rash of KS takes several forms both in its character and distribution. Most commonly it consists of raised, irregular, erythematous plaques that are pniritic and not fixed. Maculopapular rash is seen in about 30% of patients, followed by diffuse
COMPLICATIONS
A rare complication of KS that has been newly recognized is peripheral gangrene, described in 11 patients to date. AU patients were less than 6 months of age. Nine had giant coronary aneurysms and only one had normal coronaries; eight had peripheral artery aneurysms. Only three had received I VIG within the first 10 days of illness. Signs of ischemia developed 15 to 30 days after onset of illness. The patients ultimately developed gangrene of the digits or distal extremities. Peripheral arterial inflammation, proximal compromise of blood flow due to proximal arteritis, and poor perfusion due to myocardial compromise were implicated. Therapy includes IVIG and aspirin, prostaglandin F,,,, pulsed corticosteroids in high dosages, sympathetic blockade, anticoagulants, and thrombolytic agents. The relative value, if any, of these interventions is unknown. DIAGNOSIS
Based as it is on clinical criteria, the diagnosis of KS may present problems. "Incomplete" or formes
Melish: Kawasaki Syndrome: A 1992 Update
frustes of KS undoubtedly occur. Children under 6 months of age are particularly likely to have incomplete diagnostic features or to show them in a mild form such as transient or faint rashes, mild erythema of palms and soles, and minimal conjunctival vascular injection. Lymphadenitis that is especially severe or appears as an early or first manifestation creates another diagnostic dilemma. A definite diagnosis of bacterial lymphadenitis is made, antibiotics are begun, and adl subsequent manifestations (i.e., rash, conjunctival injection) are either ignored or attributed to drug hypersensitivity. Patients with prominent lymphadenopathy tend to be older, with a mean age of 4 years. Enlargement of the lymph nodes is usually dramatic and may even cause deviation of the esophagus and larynx. The lymphadenitis does not become suppurant and resolves rapidly. The diagnosis is sometimes missed because a child is perceived to be of the "wrong" ancestry or resides in the wrong geographic area. The syndrome is most prevalent among children of Japanese and Korean ancestry but it occurs on all continents among children of all races. It is frequently overlooked and underdiagnosed in areas inhabited primarily by people of European ancestry. Finally, measles or rubeola may be confounding factor. Some cases of measles do resemble KS. Careful attention to the differences in conjunctival involvement with exudate, prominent photophobia, and diffuse suffusion, and the presence of discrete macules on the palms and soles in measles rather than diffuse erythema in KS may be helpful. In measles the erythrocyte sedimentation rate, white blood count, and platelet count are usually low, whereas all are usually elevated in KS.
337
TREATMENT Despite the fact that the etiology of KS is unknown, effective therapy has been discovered. Using similar methodology, the United States multicenter Kawasaki syndrome study group carried out two trials testing the efficacy of intravenous gamma globulin for this disorder. The first study demonstrated that IVIG 400 mg/ kg/day over four days plus aspirin 100 mg/kg/day caused a fivefold reduction in coronary artery abnormalities compared with aspirin alone. In the second study, a single large dose of IVIG 2 g/kg plus aspirin was superior to the four-day schedule in reducing fever, the acute phase reactants, and the frequency and severity of coronary artery abnormalities. We are currently performing an interim analysis of a study comparing low- {3-8 mg/kg/day) with high-dose (100 mg/kg/day) aspirin as an adjunct to IVIG 2 g/kg. High-dose aspirin resulted in faster resolution of fever with no significant increase in adverse effects or hepatic abnormalities. Therefore at this time the treatment of choice for KS is IVIG 2 g/kg given over 10 to 12 hours plus aspirin 100 mg/ kg/day in four divided doses. On day 14 of illness, if fever is controlled, the aspirin dosage should be decreased to 40 to 80 mg/day (3-8 mg/kg) and continued for two months. Echocardiograms should be performed at the time of diagnosis and three to four weeks after therapy, and more frequently if abnormalities are found. If coronary arteries are normal four weeks after onset, no further follow-up is indicated. From experience with over 900 patients studied, within one week, three to four weeks, and eight weeks we determined that new abnormalities on echocardiogram do not develop beyond four weeks after onset.
Kawasaki Syndrome: A 1992 Update Marian E. Melish, M.D. Johrt A. Burns School of Medicine of the University of Hawaii at Manoa, Kapiolani Medical Center for Women and Children, Honolulu, Hawaii Kawasaki syndrome (KS) was first described as mucocutaneous lymph node syndrome by Tomisaku Kawasaki of Japan in 1967. Dr. Kawasaki's enduring contributions have been the recognition of a new clinical disease entity and the development of the diagnostic criteria that form the mainstay of diETIOLOGY The microbial etiology of KS remains unknown. The epidemiology is characterized by virtual restriction to young children, the occurrence of communitywide outbreaks in three- to six-year intervals, and wide geographic distribution in different climactic zones. These features suggest that KS might be caused by a common agent that is widely transmitted, causing disease and/or immunity by age 8 years, that it is widely distributed, and probably is primarily associated with humans rather than animals or insect vectors. To date, although several theories have been put forward and numerous microbial agents have been recovered, no specific microbial-host relationship has been discovered. Interest in a Propionibacterium acnes toxin or a retrovirus as possible etiologic agents has waned because initial promising studies were not confirmed. Nunierous immunologic alterations can be documented in acute KS: Many of these suggest disordered immune regulation and excessive production of cytokines characteristic of the presence of an agent with superantigen properties. In collaboration with Donald Leung and Jun Abe and in our own laboratory we recently obtained more direct evidence of superantigen activity. We discovered that the repertoire of the variable p chain (Vp) region of the T cell receptor is altered in acute KS, resulting in overrepresentation of V32 and V38 expression in the acute stage, with a return to normal in convalescence. This expansion of one or two particular Vp
chains on T helper cells is characteristic of superantigen effect. Superantigens have become an intense area of investigation since their definition in 1989. Currently, a few bacterial exotoxins including the toxic shock syndrome toxin 1, the staphylococcal enterotoxins A through E, the streptococcal pyrogenic exotoxins A, B, and C, a Mycoplasma toxin, and some retroviruses have been found to have the property of binding to the major histocompatibiiity locus on monocytes and macrophages, and then being able to bind to specific regions on particular Vp chains of the T cell receptor. This lateral hingelike binding results in activation of both monocytes and T cells with resultant massive cytokine release. It also selectively stimulates proliferation of particular clones of T cells. An important characterisfic of superantigen reactions is their ability to engage a very high proportion of immunologically reactive cells compared with the limited number involved in classic antigen antibody reactions. PATHOLOGY Originally termed benign mucocutaneous lymph node syndrome, it was recognized in the early 1970s that some children died unexpectedly, generally between the third and sixth weeks after onset. The pathologic findings have been grouped into four stages corresponding to the duration of illness at death. It can be appreciated that KS is a selflimited, inflammatory vasculitis. Patients dying during the first week of illness show acute inflammation in the vasa vasorum of the aorta and coronary vessels, with severe intimal and adventitial inflammation. The coronary arteries are patent, but breaks in the internal elastic lamina can be noted. Death is usually secondary to arrhythmia with inflammatory changes in the atrioventricular conduction system. In addition, an inflammatory pancardi-
335
336 Pediatric Dermatology Vol. 9 No. 4 December !992
tis affects the valves, myocardium, and pericardium. Stages II and III from 10 days to 40 days after onset show a progressive decrease in inflEunmation of vessels and myocardium. The coronary arteries are aneurysmally dilated with evidence of medical destruction. The cause of death is acute coronary thrombosis. Patients dying in stage VI (after 40 days) generally have no acute inflammation but have evidence of abnormal coronary arteries with acute or chronic ischemic myocardial changes secondary to coronary thrombosis or stenosis. Although vessel damage is always most severe in the coronary vessels, some patients develop aneurysms in peripheral arteries, generally the axillary, iliac, and femoral arteries. These may occur in the third and fourth weeks of illness as pulsatile masses in the axiUae or femoral areas. Regression of aneurysms of both coronary arteries is known to occur over one to two years after onset. Repeat echocardiography or angiography may show restoration of a nonnal lumen size, but exercise and dipyridamole angiography demonstrated that Eireas of aneurysmal regression are not nonnal since these sections are no longer elastic, pulsatile, or able to respond to exercise with nonnal dilation. Persistent and large aneurysms have a pronounced tendency to develop stenosis.
scarlatiniform erythroderma and occasionally by an erythema marginatum rash. The rash has a variable distribution pattern, being most often generalized, but sometimes more prominent on the trunk and in other cases more peripherally distributed. In some patients the rash is accentuated in the perineal area. Changes in the hands and feet are distinctive, consisting of firm, indurative edema with diffuse red-purple discoloration of the palms and soles. In convalescence a characteristic desquamation begins at the fingertips and toe tips and frequently involves the entire palm and sole. The sixth of the major diagnostic criteria, lymphadenopathy, occurs in only 50% of patients. It is typically unilateral and cervical, with a firm node mass measuring over 1.5 cm in diameter, sometimes with overlying erythema. A spectrum of cardiovascular abnormalities accompanies KS. Mjiny series showed that 15% to 25% of patients have coronary artery abnormalities detectable by echocardiogram at eight weeks after onset. The children at greatest risk for serious complications of myocardial infarction, myocardial ischemia, and sudden death are those with giant coronary aneurysms measuring over 8 mm. Some of these patients have developed such severe coronary disease that coronary artery bypass surgery has been necessary.
CLINICAL FEATURES
The disease begins suddenly with high fever generally ranging between 38° and 4 r C . Unless treated with intravenous gamma globulin (IVIG), the fever lasts for a mean of eight days (range 5-35 days). Duration of over 14 days is associated with a higher frequency of cardiac complications. Within one to three days after the onset of fever other diagnostic features emerge. The characteristic changes in the eyes are discrete vascular injection so that each smdl scleral vessel is apparent. There is a zone of clearing around the hmbus. The absence of exudate and cornea! ulceration helps to differentiate the eye findings of KS from those of measles and Stevens-Johnson syndrome. Changes in the mouth consist of redness of the lips followed by cracking and fissuring, diffuse oropharyngeal erythema without ulceration or exudate, and a strawberry tongue. The rash of KS takes several forms both in its character and distribution. Most commonly it consists of raised, irregular, erythematous plaques that are pniritic and not fixed. Maculopapular rash is seen in about 30% of patients, followed by diffuse
COMPLICATIONS
A rare complication of KS that has been newly recognized is peripheral gangrene, described in 11 patients to date. AU patients were less than 6 months of age. Nine had giant coronary aneurysms and only one had normal coronaries; eight had peripheral artery aneurysms. Only three had received I VIG within the first 10 days of illness. Signs of ischemia developed 15 to 30 days after onset of illness. The patients ultimately developed gangrene of the digits or distal extremities. Peripheral arterial inflammation, proximal compromise of blood flow due to proximal arteritis, and poor perfusion due to myocardial compromise were implicated. Therapy includes IVIG and aspirin, prostaglandin F,,,, pulsed corticosteroids in high dosages, sympathetic blockade, anticoagulants, and thrombolytic agents. The relative value, if any, of these interventions is unknown. DIAGNOSIS
Based as it is on clinical criteria, the diagnosis of KS may present problems. "Incomplete" or formes
Melish: Kawasaki Syndrome: A 1992 Update
frustes of KS undoubtedly occur. Children under 6 months of age are particularly likely to have incomplete diagnostic features or to show them in a mild form such as transient or faint rashes, mild erythema of palms and soles, and minimal conjunctival vascular injection. Lymphadenitis that is especially severe or appears as an early or first manifestation creates another diagnostic dilemma. A definite diagnosis of bacterial lymphadenitis is made, antibiotics are begun, and adl subsequent manifestations (i.e., rash, conjunctival injection) are either ignored or attributed to drug hypersensitivity. Patients with prominent lymphadenopathy tend to be older, with a mean age of 4 years. Enlargement of the lymph nodes is usually dramatic and may even cause deviation of the esophagus and larynx. The lymphadenitis does not become suppurant and resolves rapidly. The diagnosis is sometimes missed because a child is perceived to be of the "wrong" ancestry or resides in the wrong geographic area. The syndrome is most prevalent among children of Japanese and Korean ancestry but it occurs on all continents among children of all races. It is frequently overlooked and underdiagnosed in areas inhabited primarily by people of European ancestry. Finally, measles or rubeola may be confounding factor. Some cases of measles do resemble KS. Careful attention to the differences in conjunctival involvement with exudate, prominent photophobia, and diffuse suffusion, and the presence of discrete macules on the palms and soles in measles rather than diffuse erythema in KS may be helpful. In measles the erythrocyte sedimentation rate, white blood count, and platelet count are usually low, whereas all are usually elevated in KS.
337
TREATMENT Despite the fact that the etiology of KS is unknown, effective therapy has been discovered. Using similar methodology, the United States multicenter Kawasaki syndrome study group carried out two trials testing the efficacy of intravenous gamma globulin for this disorder. The first study demonstrated that IVIG 400 mg/ kg/day over four days plus aspirin 100 mg/kg/day caused a fivefold reduction in coronary artery abnormalities compared with aspirin alone. In the second study, a single large dose of IVIG 2 g/kg plus aspirin was superior to the four-day schedule in reducing fever, the acute phase reactants, and the frequency and severity of coronary artery abnormalities. We are currently performing an interim analysis of a study comparing low- {3-8 mg/kg/day) with high-dose (100 mg/kg/day) aspirin as an adjunct to IVIG 2 g/kg. High-dose aspirin resulted in faster resolution of fever with no significant increase in adverse effects or hepatic abnormalities. Therefore at this time the treatment of choice for KS is IVIG 2 g/kg given over 10 to 12 hours plus aspirin 100 mg/ kg/day in four divided doses. On day 14 of illness, if fever is controlled, the aspirin dosage should be decreased to 40 to 80 mg/day (3-8 mg/kg) and continued for two months. Echocardiograms should be performed at the time of diagnosis and three to four weeks after therapy, and more frequently if abnormalities are found. If coronary arteries are normal four weeks after onset, no further follow-up is indicated. From experience with over 900 patients studied, within one week, three to four weeks, and eight weeks we determined that new abnormalities on echocardiogram do not develop beyond four weeks after onset.
