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Cardiac death in mucocutaneous lymph node syndrome
CASE REPORTS
Cardiac Death in Mucocutaneous Lymph Node Syndrome
STANLEY M . KEGEL, MD, FACC THOMAS J . DORSEY, MD MARSHALL ROWEN, MD WILLIAM F . TAYLOR, MD Los Angeles and Irvine, California
A 12 year old boy had 4 symptom-free years after hospitalization for acute febrile mucocutaneous lymph node syndrome before he died suddenly from extensive myocardial infarction. Current evidence suggests that many patients with this syndrome have coronary artery disease and that those with significant cardiac findings should be studied with coronary angiography . Serial studies are recommended because of the danger of sudden death .
Since Kawasaki' first described the clinical findings in acute febrile, mucocutaneous lymph node syndrome in 1967, more than 6000 cases have been reported in Japan . 2 Only recently have cases of this syndrome been reported in the United States and Canada . 3-13 Sudden death occurs in 2 percent of reported cases, generally as a result of myocardial infarction or cardiac arrhythmia and occurring in the third or fourth week of the illness. 2 " 14-20 Because most survivors have no symptoms of cardiovascular disease, a good prognosis is usually given to children surviving the acute illness. However, at least six deaths occurring 1 to 8 years after the onset of the illness have now been reported in Japan . 18-21 This paper describes a boy who first showed symptoms of coronary artery disease 4 years after recovering from mucocutaneous lymph node syndrome and died suddenly while awaiting scheduled coronary arterial surgery. Case Report
From the Departments of Cardiology, Radiology and Pathology, Children Hospital of Orange County, the Department of Pediatrics (Cardiology), University of California, Los Angeles, and Departments of Pediatrics, Radiology and Pathology, University of California, Irvine, California . Manuscript received March 15, 1977, Accepted April 6, 1977 .
Address for reprints : Marshall Rowan, MD, Children Hospital of Orange County, 1109 West La Veta Avenue, Orange, California, 92668 .
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An 8 year old Nisei boy was in good health until January 1972, when he presented with acute pharyngitis and was treated with orally administered clindomycin after throat cultures grew beta hemolytic streptococci Two weeks later, he manifested fever and swelling of the right side of the neck that failed to respond to penicillin and methicillin . Because of increased fever and cervical swelling, he was admitted to a local hospital with a fever of 103°F and leukocytosis (white blood count 35,000, with 80 percent neutrophils and 9 percent stab cells) . He was treated with intravenously administered penicillin and cephaloridine but continued to have a spiking fever as well as a scarlatiniform rash of the face and hands, severe hemorrhagic conjuctivitis and dry red edema of the lips . Chest and abdominal pain, mild jaundice and a mucous diarrhea were also present . Antibiotic drugs were changed to gentamycin sulfate (Garamycin ®), chloramphenicol and tetracycline without response . Biopsy of an enlarged node in the neck revealed necrosis and fibrosis, and cultures were sterile . The fever persisted 14 days, and peeling of the skin of the fingertips followed, He was discharged 3 weeks after admission . During the following week he frequently complained of chest pain but did not consult his physician . Positive laboratory studies during the illness included sedimentation rate 68 mm in 1 hour, gamma M globulin 320 mg percent, hemoglobin 8 .9 g/100 ml, hematocrit 27 percent, reticulocytes 9 .4 percent, bilirubin, direct 2 .6 mg/100 ml, and indirect 1 .1 mg/10oml . Thymol turbidity was 12 units ; cephalin flocculation 3+, serum glutamic oxaloacetic transaminase 195 units, alkaline phosphatase
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FIGURE 2 . Electrocardiogram demonstrating 'poor R wave progression' in the precordial leads with almost complete absence of the R wave in V 4 suggesting anterior myocardial infarction . There are diffuse nonspecific T wave abnormalities and an unusual but nondlagnostic P wave configuration in lead II .
FIGURE 1 . Radiograph of the chest showing mild generalized cardiac enlargement and normal pulmonary vascularity .
180 mg/100 cc, prothrombin time 37 percent and antistreptolysin-0 titer 333 units. Pyuria was present, but cultures were sterile. Acute and convalescent serum titers were negative for influenza A and B, adenovirus, psittacosis, Q fever, mycoplasma, typhoid H and 0, paratyphoid A and B, proteus ox-19 and ox-2, brucella, Australian antigen, toxoplasmosis and leptospirosis . Skin tests were negative for tuberculosis, catscratch fever, coccidioidomycosis and histoplasmosis . Serial blood, urine, throat and stool cultures were negative as were heterophile, lupus erythematosus preparation, rheumatoid arthritis latex fixation and antinuclear antibody studies . During this admission, electrocardiograms and chest roentgenograms were normal . The patient was healthy for the next 4 years except for occasional epistaxis and increased diaphoresis with exercise . In January 1976, two hours after playing soccer, he vomited and complained of chest pain. Pulse rate was 120/min . The following morning his local pediatrician obtained an electrocardiogram and referred him for cardiac evaluation . Physical examination revealed a mildly obese 12 year old Japanese boy in no distress. Blood pressure was 106/68 mm Hg . A grade II short mid-diastolic rumbling murmur was heard at the apex . There was no evidence of Marfan's syndrome, Ehler-Danlos syndrome or other connective tissue disorder . Hemoglobin was 12 .5 g/100 ml, hematocrit 38 .3 percent, leukocytes 8200 with normal differential . Radiographs of the chest (Fig . 1) showed mild cardiac enlargement and normal vascularity . Echocardiogram revealed a dilated left ventricle with decreased percent fractional shortening, flat to paradoxical septa) motion and decreased mitral valve velocity and excursion . The electrocardiogram demonstrated an old anteroseptal myocardial infarction (Fig . 2) . Frank and cube vectorcardiograms revealed marked loss of anterior forces with initial forces to the left, typical of an-
teroseptal myocardial infarction . Treadmill exercise studies were attempted but were discontinued after 1 minute of jogging at 4 .5 miles/hour because of short runs of ventricular tachycardia . Right and left cardiac catheterization demonstrated a left ventricular end-diastolic pressure of 35 mm Hg increasing to 50 mm Hg after angiocardiography. Left ventricular angiograms revealed an extremely dilated left ventricle that contracted poorly. The entire anterior wall of the left ventricle was akinetic, and there was slow emptying . Left coronary angiograms revealed a 15 mm aneurysmal dilatation of the left main coronary artery immediately distal to its origin, complete occlusion of the anterior descending artery with poor collateral circulation, 95+ percent narrowing of the luminal diameter of a large diagonal artery and distal disease in the circumflex system (Fig. 3) . Right coronary angiograms demonstrated complete occlusion of the right coronary artery immediately distal to the origin of a conus branch artery . Most of the distal right coronary arterial distribution was supplied by the left coronary artery through atria) and circumflex collateral vessels (Fig. 3C), The boy was scheduled for coronary bypass surgery, but was found dead in bed 1 week before the scheduled operation . At autopsy, the heart weighed 700 g, and all chambers were dilated . The left ventricle showed marked dilatation and was red and flabby- Numerous pericardial adhesions were present . The apex of the left ventricle was thinned and contained marked fibrosis. There was severe endocardial sclerosis throughout, greatest on the ventricular septum . The heart valves were normal, and there was no evidence of congenital heart disease. The coronary orifices were normally placed . A 13 mm aneurysm containing thrombus was present in the proximal left coronary artery (Fig . 4) . The left anterior descending, circumflex and right coronary arteries were thickened and the lumens narrowed . The proximal right coronary artery was totally obstructed early in its course . Careful examination of the aorta and carotid, cerebral, renal, mesenteric and iliac arteries demonstrated no evidence of vasculitis or atherosclerosis . The trachea and bronchi contained copious mucus . The lungs were heavy . There was no evidence of aspiration.
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FIGURE 3. Coronary angiograms . A, left coronary arteriogram (right anterior oblique view) demonstrates a 15 mm aneurysmal dilatation of the left main coronary artery and smaller aneurysms in the left anterior descending coronary artery. B, left coronary arteriogram (left anterior oblique view) demonstrates the left main coronary arterial aneurysm with extensive left to distal right collateral vessels . There is no significant filling of the left anterior descending coronary artery . C, right coronary arteriogram demonstrates a proximal aneurysm with complete occlusion of the right coronary artery and epicardlal collateral vessels reconstituting some of the distal right coronary artery .
Microscopic examination of the left coronary aneurysm demonstrated thickening of the media, subintimal fibrosis with marked hyalinization, and extensive calcification, and the lumen contained a recent thrombus (Fig . 4) . The adjacent circumflex artery showed the same findings without calcification . The right coronary artery, 1 cm from its orifice, was completely obliterated by subintimal fibrous proliferation . Surrounding this obstructed artery were small collateral arterioles. More distal sections through all coronary arteries revealed no detectable abnormalities . All sections of myocardium showed severe nuclear hypertrophy and fibrosis . The left ventricular septum demonstrated severe endocardial sclerosis . Microscopic examination of arteries from all other organs was normal.
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Review of the cervical lymph node obtained in 1972 showed obliteration of nodal architecture and severe fragmentation . The majority of cells were mature lymphocytes and frequent immunoblasts . Within the fragmented lymphoid tissue were several small foci of fibrinoid material containing nuclear debris and occasional neutrophils. No nuclear or cytoplasmic inclusions were present . The foci were smaller and less suppurative than those usually found in cat-scratch fever .
Discussion Clinical features : Acute febrile mucocutaneous lymph node syndrome or Kawasaki's disease is a febrile illness of children occurring almost exclusively before
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age 10 years and usually before age 2 years . In 1972, the Japanese Mucocutaneous Lymph Node Syndrome Research Committee formulated the following guidelines for its diagnosis 18 : ( 1) Fever for 5 days or more with no response to antibiotics ; (2) bilateral congestion of ocular conjuctiva ; (3) changes in the peripheral limbs including indurative peripheral edema and erythema of the palms and feet followed later in the illness by a membranous desquamation of the fingertips ; (4) changes in the lips and mouth including dry red fissured lips, strawberry tongue and red oral and pharyngeal mucosa ; and (5) a polymorphous exanthema of the trunk without crusts or vesicles . The Research Committee requires that criterion 1 and at least three of criteria 2 to 5 be met for the diagnosis to be accepted . Other frequent findings are acute nonpurulent cervical lymphadenopathy greater than 1 .5 cm, mild diarrhea, arthritis or arthralgia, proteinuria and pyuria, leukocytosis with neutrophilic shift to the left, increased erythrocyte sedimentation rate and positive C-reactive protein . Evidence of aseptic meningitis, mild jaundice, increase in serum transaminase and alpha-2 globulin and evidence of carditis may also occur . Clinically, the disease is usually misdiagnosed as scarlet fever, Stevens-Johnson syndrome, juvenile rheumatoid arthritis or infantile periarteritis nodosa . Sudden death has occurred in 1 .4 to 2 .5 percent of all reported cases . Cardiac causes account for 85 percent of all deaths, noncardiac causes for 6 percent and unknown causes for 9 percent . 1 $ The majority of deaths have occurred in the third or fourth week of the illness . Postmortem examination in fatal cases has uniformly revealed coronary arterial aneurysms with occlusion due to thromboendarteritis . 17,18 Other findings have included rupture of coronary arterial aneurysms, severe mitral insufficiency and intractable congestive heart failure due to papillary muscle dysfunction and pancarditis . The cardiac pathologic findings are identical with those previously reported in infantile periarteritis nodosa . 19,22 Review of cases of coronary arterial aneurysms in infancy reported in the United States reveals that a majority of cases were diagnosed as infantile periarteritis nodosa . In many of these cases, an initial illness identical to mucocutaneous lymph node syndrome is described 2 Tanaka 22 reviewed 44 well documented cases of infantile periarteritis nodosa and found 18 cases clinically identical with mucocutaneous lymph node syndrome and 11 cases strongly suggestive of that illness . It appears likely that this syndrome has existed in the United States for many years but has been diagnosed as periarteritis nodosa, Stevens-Johnson syndrome or other illnesses . Incidence of cardiac abnormalities : The Research Committee, supported by the Ministry of Health and Welfare of the Japanese government, reports an incidence of carditis of 4 percent . 78 However, Onouchi et al . 14 and Asai et al . 1 i report electrocardiographic abnormalities or cardiac enlargement in almost all cases in the acute stage. Takao et al .'s studied 72 cases of the syndrome from a cardiologic viewpoint and found significant electrocardiographic abnormalities in 74 per-
FIGURE 4 . Section through the left coronary aneurysm and widened
circumflex artery shows attenuation and hyalinization of muscular layers . Fragmentation and duplication of external and internal elastic lamellae were demonstrated with elastic stain . More than 50 percent of the wall thickness is composed of hyalinized fibrous tissue internal to the internal elastic lamellae . Calcium deposits are numerous and limited to the hyalinized tissue. The aneurysm contains attached and organizing thrombus (hematoxylin-eosin X 5, reduced by 28 percent) .
cent. Retrograde aortography and coronary angiography were performed in 17 of these cases with aneurysm of the coronary arteries, narrowing, tortuosity and obstruction present in 14 (82 percent) . Eight of these infants (11 percent) developed papillary muscle dysfunction with mitral insufficiency and progressive congestive heart failure . Only one infant died, death occurring during the fourth week of illness . It appears likely that the estimated 4 percent incidence rate of cardiovascular abnormalities is too low . Prognosis : Most reports have suggested an excellent prognosis in children surviving the acute phase of the illness. However, Kato et al ., 15 studying serial coronary angiograms in four patients, found regression of the coronary arterial lesions in only two, and evidence of significant coronary artery disease as late as 2 years after the onset of the syndrome in the others . Several cases of late death from coronary artery disease and extensive myocardial infarction I to 8 years after the onset of the illness have been reported . 20,22,23 Kitamura et al . 28 described a 4 year old boy who had a myocardial infarction 10 months after the acute illness and underwent aortocoronary bypass grafting 5 months later . Theirs is the only reported case of bypass surgery .* Our patient was awaiting scheduled bypass surgery when he died of severe coronary arterial lesions 4 years after the acute illness . The etiology of the mucocutaneous lymph node syndrome is not established . 29 Rickettsia-like bodies in patients with this syndrome have been observed in Japan° and England . 31 Some authors 18,20 have suggested an autoimmune response similar to periarteritis ' Editor's note: Except for the cases reported in this issue of the Journal by Kitamura et al . (p . 156-164)
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nodosa. Other causes such as abnormal host reaction to a variety of infections and allergic reaction to chemical detergents have also been postulated . 2,31 Therapeutic implications : Although 98 percent of infants with the mucocutaneous lymph node syndrome survive, the state of the coronary arteries in the majority of these children is not known . Late coronary arterial death in patients without obvious cardiac involvement does occur, and the long-term prognosis of children recovering from the acute illness is not known . It is imperative that all children with this syndrome have extensive cardiac evaluation during the acute illness, including serial electrocardiograms, enzyme studies,
chest X-ray films and echocardiograms . It is not known if antimyocardial antibody studies would be helpful in this disease, but evaluation of this new study appears warranted . 32 We consider that coronary angiography is indicated in all children with evidence of significant cardiac involvement . All patients with proved coronary artery aneurysm or obstruction should have serial studies . Until more evidence is available, a guarded prognosis should be given to any child with coronary arterial abnormalities after the mucocutaneous lymph node syndrome . If surgery is indicated, it should be expeditiously accomplished because of the danger of sudden death as demonstrated in our case.
References 1 . Kawasaki T: Mucocutaneous lymph node syndrome: clinical observations in 50 cases . Jpn J Allerg 16 :178-222, 1967 (in Japanese) 2 . Kawasaki T, Kosald F, Okawa S, et al : A new infantile acute febrile mucocutaneous lymph node syndrome (KILNS) prevailing in Japan . Pediatrics 54:271-276, 1974 3 . Fetterman GH, Hashida Y : Mucocutaneous lymph node syndrome (MLNS) : A disease widespread in Japan which demands our attention. Pediatrics 54 :268-270, 1974 4 . Goldsmith RS, Grlbetz D, Strauss L : Mucocutaneous lymph node syndrome (MLNS) in the continental United States . Pediatrics 57:431-434, 1976 5 . Mallsh ME, Hicks AM, Larson EJ : Mucocutaneous lymph node syndrome in the United States . Am J Dis Child 130 :599-607, 1976 6 . Redford DJ, Sondhekner HM, Williams GJ, st al : Mucocutaneous lymph node syndrome with coronary artery aneurysm . Am J Dis Child 130 :599-607, 1976 7 . Lauer BA, Bruin FW, Todd JK, of al : Mucocutaneous lymph node syndrome in Denver . Am J Dis Child 130 :610-612, 1976 8 . John TJ, DeBenedetti CD, Zee ML: Mucocutaneous lymph node syndrome in Arizona. Am J Dis Child 130 :613-614, 1976 9 . Walker 5H, OuIntero BA, Hekkich FJ : Mucocutaneous lymph node syndrome . Am J Dis Child 130 :1164, 1976 10 . Brown JS, Blllmeler GJ, Cox F, at al : Mucocutaneous lymph node syndrome in the continental United States . J Pediatr 88 :81-86, 1976 11 . Darby CP, Kyong CU: Mucocutaneous lymph node syndrome . JAMA 236 :2295-2297, 1976 12 . Bernhardt I : Mucocutaneous lymph node syndrome with encephalopathy in the continental United States . West J Med 125 :230233, 1976 13 . Russell AS, Zaragoza AJ, Shea R : Mucocutaneous lymph node syndrome in Canada. Can Med Assn J 112 :1210-1211, 1975 14 . Onouchi Z, Tomizawa N, Goto M, at al : Cardiac involvement and prognosis in acute mucocutaneous lymph node syndrome . Chest 68 :297-301, 1976 15 . Kalo H, Koike S, Yamamoto M, at al : Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome . J Pediatr 86:892-898, 1975 16 . Takao A, Kusakawa S, Hamada I, et al : Cardiovascular lesions of mucocutaneous lymph node syndrome (abstr). Circulation 50 : Suppl 111 :111-39, 1974 17 . Asal T, Klguchl H, Nagal Y, et al : Analysis of cardiac involvement
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in 29 cases with mucocutaneous lymph node syndrome . Jpn J Pediatr 26 :824-830 1973 (in Japanese) 18. Tanaka N, Selklmoto K, Naoe 5 : Kawasaki disease . Relationship with infantile periarteritis nodosa . Arch Pathol Lab Mod 100 :81-86, 1976 19 . Yanagisawa M, Kobayashl N, Matsuya S : Myocardial infarction due to coronary thromboarteritis following acute mucocutaneous lymph node syndrome in an infant . Pediatrics 54 :277-281, 1974 20. Hamada 1, Takao A, Mined S, at al : Cardiovascular complications of mucocutaneous lymph node syndrome . Jpn J Clin Pediatr 21 : 163, 1973 (in Japanese) 21 . Koizumi Y, Hoshino S, Harazawa T, et al : Autopsy findings in a patient dying from MCLS 7 years after the onset . J Pediatr Practice 38:615-621, 1975 (in Japanese) 22 . Tanaka N: Comments on fatal cases of MLNS . Relationship between MLNS and infantile periarteritis nodosa . Acts Pediatr Jpn 76:699, 1972 (in Japanese) 23. Roberts FB, Fetterman GH : Periarteritis nodose in infancy . J Pediatr 63 :519-529,1963 24. Munro-Faure H: Necrotizing arteritis of the coronary arteries in infancy . Pediatrics 23 :914-926, 1959 25. Glanz S, Blttner SJ, Berman MA, et al : Regression of coronary artery aneurysms in infantile periarteritis nodosa . N Engl J Med 294 :939-940, 1976 26. McMartin DE, Stone AJ, French RH : Multiple coronary artery aneurysms in a child with angina pectoris . N Engl J Med 290 :669-670, 1974 27. Crocker DW, Sobin S, Thomas WC : Aneurysms of the coronary arteries . Am J Pathol 33 :819-843, 1957 28. Kitamura S, Kawashima Y, Fujita T, et al : Aortocoronary bypass graft in a child with coronary artery obstruction due to mucocutaneous lymph node syndrome . Circulation 53:1035-1040, 1976 29 . Mortimer EA: Mucocutaneous lymph node syndrome : the epidemiologic approach toward finding its causation . Am J Dis Child 130 :593-594, 1976 30 . Hamashima Y, Klshl K, Tasaka K : Rickettsia-like bodies in infantile acute febrile mucocutaneous lymph node syndrome . Lancet 2 :42, 1973 31 . Carter RF, Haynes ME, Morlon J: Rickettsia-like bodies and splenitis in Kawasaki disease . Lancet 2 :1254-1255, 1976 32 . Bauer H, Waters TJ, Talano JV, at al : Anti-myocardial antibodies in the diagnosis and prognosis of coronary artery disease (abstr). Circulation 42 :Suppl 111 :111-155, 1970
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Cardiac Death in Mucocutaneous Lymph Node Syndrome
STANLEY M . KEGEL, MD, FACC THOMAS J . DORSEY, MD MARSHALL ROWEN, MD WILLIAM F . TAYLOR, MD Los Angeles and Irvine, California
A 12 year old boy had 4 symptom-free years after hospitalization for acute febrile mucocutaneous lymph node syndrome before he died suddenly from extensive myocardial infarction. Current evidence suggests that many patients with this syndrome have coronary artery disease and that those with significant cardiac findings should be studied with coronary angiography . Serial studies are recommended because of the danger of sudden death .
Since Kawasaki' first described the clinical findings in acute febrile, mucocutaneous lymph node syndrome in 1967, more than 6000 cases have been reported in Japan . 2 Only recently have cases of this syndrome been reported in the United States and Canada . 3-13 Sudden death occurs in 2 percent of reported cases, generally as a result of myocardial infarction or cardiac arrhythmia and occurring in the third or fourth week of the illness. 2 " 14-20 Because most survivors have no symptoms of cardiovascular disease, a good prognosis is usually given to children surviving the acute illness. However, at least six deaths occurring 1 to 8 years after the onset of the illness have now been reported in Japan . 18-21 This paper describes a boy who first showed symptoms of coronary artery disease 4 years after recovering from mucocutaneous lymph node syndrome and died suddenly while awaiting scheduled coronary arterial surgery. Case Report
From the Departments of Cardiology, Radiology and Pathology, Children Hospital of Orange County, the Department of Pediatrics (Cardiology), University of California, Los Angeles, and Departments of Pediatrics, Radiology and Pathology, University of California, Irvine, California . Manuscript received March 15, 1977, Accepted April 6, 1977 .
Address for reprints : Marshall Rowan, MD, Children Hospital of Orange County, 1109 West La Veta Avenue, Orange, California, 92668 .
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An 8 year old Nisei boy was in good health until January 1972, when he presented with acute pharyngitis and was treated with orally administered clindomycin after throat cultures grew beta hemolytic streptococci Two weeks later, he manifested fever and swelling of the right side of the neck that failed to respond to penicillin and methicillin . Because of increased fever and cervical swelling, he was admitted to a local hospital with a fever of 103°F and leukocytosis (white blood count 35,000, with 80 percent neutrophils and 9 percent stab cells) . He was treated with intravenously administered penicillin and cephaloridine but continued to have a spiking fever as well as a scarlatiniform rash of the face and hands, severe hemorrhagic conjuctivitis and dry red edema of the lips . Chest and abdominal pain, mild jaundice and a mucous diarrhea were also present . Antibiotic drugs were changed to gentamycin sulfate (Garamycin ®), chloramphenicol and tetracycline without response . Biopsy of an enlarged node in the neck revealed necrosis and fibrosis, and cultures were sterile . The fever persisted 14 days, and peeling of the skin of the fingertips followed, He was discharged 3 weeks after admission . During the following week he frequently complained of chest pain but did not consult his physician . Positive laboratory studies during the illness included sedimentation rate 68 mm in 1 hour, gamma M globulin 320 mg percent, hemoglobin 8 .9 g/100 ml, hematocrit 27 percent, reticulocytes 9 .4 percent, bilirubin, direct 2 .6 mg/100 ml, and indirect 1 .1 mg/10oml . Thymol turbidity was 12 units ; cephalin flocculation 3+, serum glutamic oxaloacetic transaminase 195 units, alkaline phosphatase
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FIGURE 2 . Electrocardiogram demonstrating 'poor R wave progression' in the precordial leads with almost complete absence of the R wave in V 4 suggesting anterior myocardial infarction . There are diffuse nonspecific T wave abnormalities and an unusual but nondlagnostic P wave configuration in lead II .
FIGURE 1 . Radiograph of the chest showing mild generalized cardiac enlargement and normal pulmonary vascularity .
180 mg/100 cc, prothrombin time 37 percent and antistreptolysin-0 titer 333 units. Pyuria was present, but cultures were sterile. Acute and convalescent serum titers were negative for influenza A and B, adenovirus, psittacosis, Q fever, mycoplasma, typhoid H and 0, paratyphoid A and B, proteus ox-19 and ox-2, brucella, Australian antigen, toxoplasmosis and leptospirosis . Skin tests were negative for tuberculosis, catscratch fever, coccidioidomycosis and histoplasmosis . Serial blood, urine, throat and stool cultures were negative as were heterophile, lupus erythematosus preparation, rheumatoid arthritis latex fixation and antinuclear antibody studies . During this admission, electrocardiograms and chest roentgenograms were normal . The patient was healthy for the next 4 years except for occasional epistaxis and increased diaphoresis with exercise . In January 1976, two hours after playing soccer, he vomited and complained of chest pain. Pulse rate was 120/min . The following morning his local pediatrician obtained an electrocardiogram and referred him for cardiac evaluation . Physical examination revealed a mildly obese 12 year old Japanese boy in no distress. Blood pressure was 106/68 mm Hg . A grade II short mid-diastolic rumbling murmur was heard at the apex . There was no evidence of Marfan's syndrome, Ehler-Danlos syndrome or other connective tissue disorder . Hemoglobin was 12 .5 g/100 ml, hematocrit 38 .3 percent, leukocytes 8200 with normal differential . Radiographs of the chest (Fig . 1) showed mild cardiac enlargement and normal vascularity . Echocardiogram revealed a dilated left ventricle with decreased percent fractional shortening, flat to paradoxical septa) motion and decreased mitral valve velocity and excursion . The electrocardiogram demonstrated an old anteroseptal myocardial infarction (Fig . 2) . Frank and cube vectorcardiograms revealed marked loss of anterior forces with initial forces to the left, typical of an-
teroseptal myocardial infarction . Treadmill exercise studies were attempted but were discontinued after 1 minute of jogging at 4 .5 miles/hour because of short runs of ventricular tachycardia . Right and left cardiac catheterization demonstrated a left ventricular end-diastolic pressure of 35 mm Hg increasing to 50 mm Hg after angiocardiography. Left ventricular angiograms revealed an extremely dilated left ventricle that contracted poorly. The entire anterior wall of the left ventricle was akinetic, and there was slow emptying . Left coronary angiograms revealed a 15 mm aneurysmal dilatation of the left main coronary artery immediately distal to its origin, complete occlusion of the anterior descending artery with poor collateral circulation, 95+ percent narrowing of the luminal diameter of a large diagonal artery and distal disease in the circumflex system (Fig. 3) . Right coronary angiograms demonstrated complete occlusion of the right coronary artery immediately distal to the origin of a conus branch artery . Most of the distal right coronary arterial distribution was supplied by the left coronary artery through atria) and circumflex collateral vessels (Fig. 3C), The boy was scheduled for coronary bypass surgery, but was found dead in bed 1 week before the scheduled operation . At autopsy, the heart weighed 700 g, and all chambers were dilated . The left ventricle showed marked dilatation and was red and flabby- Numerous pericardial adhesions were present . The apex of the left ventricle was thinned and contained marked fibrosis. There was severe endocardial sclerosis throughout, greatest on the ventricular septum . The heart valves were normal, and there was no evidence of congenital heart disease. The coronary orifices were normally placed . A 13 mm aneurysm containing thrombus was present in the proximal left coronary artery (Fig . 4) . The left anterior descending, circumflex and right coronary arteries were thickened and the lumens narrowed . The proximal right coronary artery was totally obstructed early in its course . Careful examination of the aorta and carotid, cerebral, renal, mesenteric and iliac arteries demonstrated no evidence of vasculitis or atherosclerosis . The trachea and bronchi contained copious mucus . The lungs were heavy . There was no evidence of aspiration.
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FIGURE 3. Coronary angiograms . A, left coronary arteriogram (right anterior oblique view) demonstrates a 15 mm aneurysmal dilatation of the left main coronary artery and smaller aneurysms in the left anterior descending coronary artery. B, left coronary arteriogram (left anterior oblique view) demonstrates the left main coronary arterial aneurysm with extensive left to distal right collateral vessels . There is no significant filling of the left anterior descending coronary artery . C, right coronary arteriogram demonstrates a proximal aneurysm with complete occlusion of the right coronary artery and epicardlal collateral vessels reconstituting some of the distal right coronary artery .
Microscopic examination of the left coronary aneurysm demonstrated thickening of the media, subintimal fibrosis with marked hyalinization, and extensive calcification, and the lumen contained a recent thrombus (Fig . 4) . The adjacent circumflex artery showed the same findings without calcification . The right coronary artery, 1 cm from its orifice, was completely obliterated by subintimal fibrous proliferation . Surrounding this obstructed artery were small collateral arterioles. More distal sections through all coronary arteries revealed no detectable abnormalities . All sections of myocardium showed severe nuclear hypertrophy and fibrosis . The left ventricular septum demonstrated severe endocardial sclerosis . Microscopic examination of arteries from all other organs was normal.
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Review of the cervical lymph node obtained in 1972 showed obliteration of nodal architecture and severe fragmentation . The majority of cells were mature lymphocytes and frequent immunoblasts . Within the fragmented lymphoid tissue were several small foci of fibrinoid material containing nuclear debris and occasional neutrophils. No nuclear or cytoplasmic inclusions were present . The foci were smaller and less suppurative than those usually found in cat-scratch fever .
Discussion Clinical features : Acute febrile mucocutaneous lymph node syndrome or Kawasaki's disease is a febrile illness of children occurring almost exclusively before
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age 10 years and usually before age 2 years . In 1972, the Japanese Mucocutaneous Lymph Node Syndrome Research Committee formulated the following guidelines for its diagnosis 18 : ( 1) Fever for 5 days or more with no response to antibiotics ; (2) bilateral congestion of ocular conjuctiva ; (3) changes in the peripheral limbs including indurative peripheral edema and erythema of the palms and feet followed later in the illness by a membranous desquamation of the fingertips ; (4) changes in the lips and mouth including dry red fissured lips, strawberry tongue and red oral and pharyngeal mucosa ; and (5) a polymorphous exanthema of the trunk without crusts or vesicles . The Research Committee requires that criterion 1 and at least three of criteria 2 to 5 be met for the diagnosis to be accepted . Other frequent findings are acute nonpurulent cervical lymphadenopathy greater than 1 .5 cm, mild diarrhea, arthritis or arthralgia, proteinuria and pyuria, leukocytosis with neutrophilic shift to the left, increased erythrocyte sedimentation rate and positive C-reactive protein . Evidence of aseptic meningitis, mild jaundice, increase in serum transaminase and alpha-2 globulin and evidence of carditis may also occur . Clinically, the disease is usually misdiagnosed as scarlet fever, Stevens-Johnson syndrome, juvenile rheumatoid arthritis or infantile periarteritis nodosa . Sudden death has occurred in 1 .4 to 2 .5 percent of all reported cases . Cardiac causes account for 85 percent of all deaths, noncardiac causes for 6 percent and unknown causes for 9 percent . 1 $ The majority of deaths have occurred in the third or fourth week of the illness . Postmortem examination in fatal cases has uniformly revealed coronary arterial aneurysms with occlusion due to thromboendarteritis . 17,18 Other findings have included rupture of coronary arterial aneurysms, severe mitral insufficiency and intractable congestive heart failure due to papillary muscle dysfunction and pancarditis . The cardiac pathologic findings are identical with those previously reported in infantile periarteritis nodosa . 19,22 Review of cases of coronary arterial aneurysms in infancy reported in the United States reveals that a majority of cases were diagnosed as infantile periarteritis nodosa . In many of these cases, an initial illness identical to mucocutaneous lymph node syndrome is described 2 Tanaka 22 reviewed 44 well documented cases of infantile periarteritis nodosa and found 18 cases clinically identical with mucocutaneous lymph node syndrome and 11 cases strongly suggestive of that illness . It appears likely that this syndrome has existed in the United States for many years but has been diagnosed as periarteritis nodosa, Stevens-Johnson syndrome or other illnesses . Incidence of cardiac abnormalities : The Research Committee, supported by the Ministry of Health and Welfare of the Japanese government, reports an incidence of carditis of 4 percent . 78 However, Onouchi et al . 14 and Asai et al . 1 i report electrocardiographic abnormalities or cardiac enlargement in almost all cases in the acute stage. Takao et al .'s studied 72 cases of the syndrome from a cardiologic viewpoint and found significant electrocardiographic abnormalities in 74 per-
FIGURE 4 . Section through the left coronary aneurysm and widened
circumflex artery shows attenuation and hyalinization of muscular layers . Fragmentation and duplication of external and internal elastic lamellae were demonstrated with elastic stain . More than 50 percent of the wall thickness is composed of hyalinized fibrous tissue internal to the internal elastic lamellae . Calcium deposits are numerous and limited to the hyalinized tissue. The aneurysm contains attached and organizing thrombus (hematoxylin-eosin X 5, reduced by 28 percent) .
cent. Retrograde aortography and coronary angiography were performed in 17 of these cases with aneurysm of the coronary arteries, narrowing, tortuosity and obstruction present in 14 (82 percent) . Eight of these infants (11 percent) developed papillary muscle dysfunction with mitral insufficiency and progressive congestive heart failure . Only one infant died, death occurring during the fourth week of illness . It appears likely that the estimated 4 percent incidence rate of cardiovascular abnormalities is too low . Prognosis : Most reports have suggested an excellent prognosis in children surviving the acute phase of the illness. However, Kato et al ., 15 studying serial coronary angiograms in four patients, found regression of the coronary arterial lesions in only two, and evidence of significant coronary artery disease as late as 2 years after the onset of the syndrome in the others . Several cases of late death from coronary artery disease and extensive myocardial infarction I to 8 years after the onset of the illness have been reported . 20,22,23 Kitamura et al . 28 described a 4 year old boy who had a myocardial infarction 10 months after the acute illness and underwent aortocoronary bypass grafting 5 months later . Theirs is the only reported case of bypass surgery .* Our patient was awaiting scheduled bypass surgery when he died of severe coronary arterial lesions 4 years after the acute illness . The etiology of the mucocutaneous lymph node syndrome is not established . 29 Rickettsia-like bodies in patients with this syndrome have been observed in Japan° and England . 31 Some authors 18,20 have suggested an autoimmune response similar to periarteritis ' Editor's note: Except for the cases reported in this issue of the Journal by Kitamura et al . (p . 156-164)
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nodosa. Other causes such as abnormal host reaction to a variety of infections and allergic reaction to chemical detergents have also been postulated . 2,31 Therapeutic implications : Although 98 percent of infants with the mucocutaneous lymph node syndrome survive, the state of the coronary arteries in the majority of these children is not known . Late coronary arterial death in patients without obvious cardiac involvement does occur, and the long-term prognosis of children recovering from the acute illness is not known . It is imperative that all children with this syndrome have extensive cardiac evaluation during the acute illness, including serial electrocardiograms, enzyme studies,
chest X-ray films and echocardiograms . It is not known if antimyocardial antibody studies would be helpful in this disease, but evaluation of this new study appears warranted . 32 We consider that coronary angiography is indicated in all children with evidence of significant cardiac involvement . All patients with proved coronary artery aneurysm or obstruction should have serial studies . Until more evidence is available, a guarded prognosis should be given to any child with coronary arterial abnormalities after the mucocutaneous lymph node syndrome . If surgery is indicated, it should be expeditiously accomplished because of the danger of sudden death as demonstrated in our case.
References 1 . Kawasaki T: Mucocutaneous lymph node syndrome: clinical observations in 50 cases . Jpn J Allerg 16 :178-222, 1967 (in Japanese) 2 . Kawasaki T, Kosald F, Okawa S, et al : A new infantile acute febrile mucocutaneous lymph node syndrome (KILNS) prevailing in Japan . Pediatrics 54:271-276, 1974 3 . Fetterman GH, Hashida Y : Mucocutaneous lymph node syndrome (MLNS) : A disease widespread in Japan which demands our attention. Pediatrics 54 :268-270, 1974 4 . Goldsmith RS, Grlbetz D, Strauss L : Mucocutaneous lymph node syndrome (MLNS) in the continental United States . Pediatrics 57:431-434, 1976 5 . Mallsh ME, Hicks AM, Larson EJ : Mucocutaneous lymph node syndrome in the United States . Am J Dis Child 130 :599-607, 1976 6 . Redford DJ, Sondhekner HM, Williams GJ, st al : Mucocutaneous lymph node syndrome with coronary artery aneurysm . Am J Dis Child 130 :599-607, 1976 7 . Lauer BA, Bruin FW, Todd JK, of al : Mucocutaneous lymph node syndrome in Denver . Am J Dis Child 130 :610-612, 1976 8 . John TJ, DeBenedetti CD, Zee ML: Mucocutaneous lymph node syndrome in Arizona. Am J Dis Child 130 :613-614, 1976 9 . Walker 5H, OuIntero BA, Hekkich FJ : Mucocutaneous lymph node syndrome . Am J Dis Child 130 :1164, 1976 10 . Brown JS, Blllmeler GJ, Cox F, at al : Mucocutaneous lymph node syndrome in the continental United States . J Pediatr 88 :81-86, 1976 11 . Darby CP, Kyong CU: Mucocutaneous lymph node syndrome . JAMA 236 :2295-2297, 1976 12 . Bernhardt I : Mucocutaneous lymph node syndrome with encephalopathy in the continental United States . West J Med 125 :230233, 1976 13 . Russell AS, Zaragoza AJ, Shea R : Mucocutaneous lymph node syndrome in Canada. Can Med Assn J 112 :1210-1211, 1975 14 . Onouchi Z, Tomizawa N, Goto M, at al : Cardiac involvement and prognosis in acute mucocutaneous lymph node syndrome . Chest 68 :297-301, 1976 15 . Kalo H, Koike S, Yamamoto M, at al : Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome . J Pediatr 86:892-898, 1975 16 . Takao A, Kusakawa S, Hamada I, et al : Cardiovascular lesions of mucocutaneous lymph node syndrome (abstr). Circulation 50 : Suppl 111 :111-39, 1974 17 . Asal T, Klguchl H, Nagal Y, et al : Analysis of cardiac involvement
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in 29 cases with mucocutaneous lymph node syndrome . Jpn J Pediatr 26 :824-830 1973 (in Japanese) 18. Tanaka N, Selklmoto K, Naoe 5 : Kawasaki disease . Relationship with infantile periarteritis nodosa . Arch Pathol Lab Mod 100 :81-86, 1976 19 . Yanagisawa M, Kobayashl N, Matsuya S : Myocardial infarction due to coronary thromboarteritis following acute mucocutaneous lymph node syndrome in an infant . Pediatrics 54 :277-281, 1974 20. Hamada 1, Takao A, Mined S, at al : Cardiovascular complications of mucocutaneous lymph node syndrome . Jpn J Clin Pediatr 21 : 163, 1973 (in Japanese) 21 . Koizumi Y, Hoshino S, Harazawa T, et al : Autopsy findings in a patient dying from MCLS 7 years after the onset . J Pediatr Practice 38:615-621, 1975 (in Japanese) 22 . Tanaka N: Comments on fatal cases of MLNS . Relationship between MLNS and infantile periarteritis nodosa . Acts Pediatr Jpn 76:699, 1972 (in Japanese) 23. Roberts FB, Fetterman GH : Periarteritis nodose in infancy . J Pediatr 63 :519-529,1963 24. Munro-Faure H: Necrotizing arteritis of the coronary arteries in infancy . Pediatrics 23 :914-926, 1959 25. Glanz S, Blttner SJ, Berman MA, et al : Regression of coronary artery aneurysms in infantile periarteritis nodosa . N Engl J Med 294 :939-940, 1976 26. McMartin DE, Stone AJ, French RH : Multiple coronary artery aneurysms in a child with angina pectoris . N Engl J Med 290 :669-670, 1974 27. Crocker DW, Sobin S, Thomas WC : Aneurysms of the coronary arteries . Am J Pathol 33 :819-843, 1957 28. Kitamura S, Kawashima Y, Fujita T, et al : Aortocoronary bypass graft in a child with coronary artery obstruction due to mucocutaneous lymph node syndrome . Circulation 53:1035-1040, 1976 29 . Mortimer EA: Mucocutaneous lymph node syndrome : the epidemiologic approach toward finding its causation . Am J Dis Child 130 :593-594, 1976 30 . Hamashima Y, Klshl K, Tasaka K : Rickettsia-like bodies in infantile acute febrile mucocutaneous lymph node syndrome . Lancet 2 :42, 1973 31 . Carter RF, Haynes ME, Morlon J: Rickettsia-like bodies and splenitis in Kawasaki disease . Lancet 2 :1254-1255, 1976 32 . Bauer H, Waters TJ, Talano JV, at al : Anti-myocardial antibodies in the diagnosis and prognosis of coronary artery disease (abstr). Circulation 42 :Suppl 111 :111-155, 1970
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