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Fatal Kawasaki Disease With Coronary Arteritis and No Coronary Aneurysms

1998; American Academy of Pediatrics; Volume: 101; Issue: 1 Linguagem: Inglês

10.1542/peds.101.1.108

1098-4275

Allen Burke, Renu Virmani, Lowell W. Perry, Ling Li, Theodore M. King, John E. Smialek,

Cardiovascular Issues in Pregnancy

Cardiac complications of Kawasaki disease occur in approximately 25% of patients who receive no treatment.1 The initial phase of cardiac involvement is a pancarditis with the subsequent formation of epicardial coronary aneurysms. It is well-appreciated that aneurysms may progress to stenosis, and that segmental stenoses are not uncommon in the healed forms of disease. However, diffuse narrowing of epicardial coronary arteries by a healed vasculitis has rarely been reported, and has generally been described as mild.2We report two cases of fatal coronary vasculitis, one patient with clinical Kawasaki disease and the other without classic clinical features of mucocutaneous lymph node syndrome. In both cases death was due to diffuse fibrointimal proliferation involving all epicardial arteries resulting in >75% luminal narrowing throughout the coronary system.A 4-year-old white boy had a 7-month history of multiple hospital admissions for fever and abdominal pain. The child was well until an episode of a severe cold at age 3, which was characterized by fever, conjunctivitis, pharyngitis, rash, and mild lymphadenopathy. The illness and fever subsided within 2 weeks, but soon thereafter intermittent severe abdominal pain, with episodes lasting 5 to 20 minutes, occurred. The pain resolved for several months and recurred. At this the patient was evaluated, and Coombs positive autoimmune hemolytic anemia and an erythrocyte sedimentation rate of 50 mm/hour were found. A gastrointestinal evaluation revealed an absence of gallstones, and a tentative diagnosis of ulcerative colitis was made. A diagnosis of Kawasaki disease was not considered, and a cardiac evaluation was never undertaken.The patient's physical and mental growth and development were normal. A family history was remarkable only for a maternal aunt with juvenile rheumatoid arthritis.Two weeks before death he was admitted for abdominal pain, circumoral cyanosis, and apnea. During this admission, the white blood cell count was 21 400/mm3 (70% lymphocytes, 0.5% eosinophils); platelet count 153 000/mm3; sedimentation rate 55 mm/h; and hemoglobin was 11.4 g/dL. Evaluations for porphyria, heavy metal poisoning, and toxicologic screening were negative. A neurologic evaluation was essentially negative, and the discharge diagnosis was seizure of unknown etiology and possible inflammatory bowel disease, with a planned upper gastrointestinal series with small bowel follow-through as an outpatient. On the day of death, he complained of abdominal pain while at a party, went to lie down, and became unresponsive. Resuscitative efforts were unsuccessful.At autopsy, the heart weighed 155 g (normal 53–115 g for body weight of 17 kg). The left ventricular lateral wall was 6 mm thick with gross evidence of fibrosis or necrosis. The foramen ovale was closed and the valves and endocardium were grossly unremarkable. The coronary arteries were diffusely thickened and the adventitial surfaces a dull whitish gray (Fig 1). On sectioning, the lumina of the three major epicardial arteries and their epicardial branches were diffusely constricted, with cross-sectional luminal narrowing ranging from 75% to 95% (Fig2). The aortic root and aortic arch were normal grossly and histologically. Other vessels were grossly unremarkable, but histologic examination was not performed.Histologically, there was diffuse fibrointimal proliferation, with focal destruction of the media and scattered inflammatory infiltrates in the intima, media and adventitia. There was focal acute and organizing thrombus. The inflammation consisted of lymphocytes, macrophages, and scattered giant cells. By immunohistochemical stains (avidin-biotin method), the lymphocytes were predominantly T cells (CD3-positive, 1:250 dilution, DAKO Corp, Indianapolis IN), which stained with anti-CD4 (CD3-positive T cells). There were occasionally CD8 positive lymphocytes (OPD8, 1:50 dilution, DAKO Corp) and rare B cells (anti-L26, 1:200 dilution, DAKO Corp), which were predominantly in the adventitia. The macrophages and giant cells stained with anti-KP-1 (macrophage marker, 1:500 dilution, DAKO Corp). T-cells were diffusely strongly positive for HLA-DR (1:100 dilution, DAKO Corp) with focal staining in macrophages.A 20-month-old white boy was well until age 8 months, when he experienced fever, pharyngitis, and conjunctivitis, and palpable submandibular, axillary, inguinal, and occipital adenopathy that was not tender. There was a question of a strawberry tongue, but no skin rash. The sedimentation rate was 94 mm/h and the platelet count 946 000. The diagnosis of Kawasaki disease was made, and the patient was given hyper immune gamma globulin therapy (2 g/kg) on approximately days 12 and 28 of illness and aspirin in therapeutic (100 mg/kg/day) and subsequent antiplatelet dose (80 mg/day). Despite therapy, his course over the next year was marked by persistent low grade temperature elevation, persistent leukocytosis (13 400–32 000/mm3, an elevated sedimentation rate up to 150 mm/h, thrombocytosis (666 000–1 073 000/mm3) and anemia (hematocrit 25%-31%, hemoglobin 7.7–10.4 g/dL). Because of evidence of an ongoing inflammatory process, hematology-oncology evaluation was performed twice; bone marrow aspiration and abdominal ultrasound were obtained and were negative. Serum immunoglobulin G, immunoglobulin A, and immunoglobulin M, serum antinuclear antibody, and cardiac enzyme determination were normal. He was also seen on several occasions by infectious disease and rheumatology consultants because of the unusual clinical course. Blood cultures were normal on two occasions; throat cultures grew no significant pathogen; bone marrow cultures were negative for virus, fungus, Mycobacterium avium and bacteria (aerobic and anaerobic cultures). Near the middle of the clinical course, on urine culture was questionably positive with 50 000 colonies/mL enterococcus. Ophthalmology evaluation was within normal limits.Twelve echocardiograms were performed during the course of the illness on approximate day 12, 20, 31, 36, 40, 50, 69, 165, 225, 285, 300, and 345. The coronary arteries were visualized. In no instance did the right coronary artery, left main coronary artery, left anterior descending coronary artery or the circumflex coronary artery exceed 2 mm in diameter, although on day 345 it was remarked that the right coronary artery appeared somewhat more prominent than previously. Trace mitral regurgitation was noted on day 20, but this disappeared on the echocardiogram on day 33. On no occasion was a coronary aneurysm demonstrated by echocardiography. The ventricular contractility always appeared normal. There never was evidence for a pericardial effusion. The electrocardiogram on follow-up examination consistently was normal except for one instance of false-positive voltage criteria for left ventricular hypertrophy. There never was electrocardiographic evidence for a myocardial infarction.On approximately day 345 of illness, the patient experienced an episode of limpness, cyanosis, and unresponsiveness responsive to brief cardiopulmonary resuscitation and oxygen by mask. Drug screening, heavy metal screening, and skeletal films were negative.On the day of death (approximately 1 year after initial illness), the patient experienced another episode of cyanosis and limpness, from which he recovered. The morning after admission, he developed cardiac arrest while being evaluated by a neurologist and could not be resuscitated. Electrocardiograms from an outlying hospital subsequently were made available and showed slight ST segment elevation or depression in most leads in association with the cyanotic episodes. There was no electrocardiogram evidence for myocardial infarction and significant arrhythmia was never documented.At autopsy, the heart weighed 69 g (normal 33 −71 g for 10-kg boy). The foramen ovale was closed. The valves were normal, without developmental defect. The myocardium demonstrated diffuse mottling without scars, and the endocardium was without fibroelastosis. The coronary arteries demonstrated diffuse intimal thickening and mild ectasia (Fig 3), with pinpoint lumens of left main, ramus intermedius, left circumflex, right coronary, and posterior descending coronary arteries. There was mild thickening of the aortic wall with moderate to marked intimal thickening of the innominate and left common carotid and left subclavian arteries.Histologically, the coronary arteries demonstrated ongoing arteritis, with extensive fibrointimal proliferation (Fig4). There was a mixed inflammatory infiltrate which immunohistochemically resembled that of Case 1; as in Case 1, occasional giant cells were noted (Fig5). The infiltrate involved the intimal, media, and adventitia. Sections of the left subclavian artery and aorta showed ongoing arteritis, with numerous giant cells and lymphohistiocytic infiltrates, and a section of the pulmonary artery was normal. Histologic sections of the left ventricle demonstrate an acute subendocardial infarct in the lateral wall. Histologic sections of viscera demonstrated an arteritis of the hepatic and renal arteries. The arteritis was histologic identical to that of the coronary arteries, with lymphohistiocytic infiltrates of the media and adventitia, and concentric fibrointimal proliferation.Detailed pathologic studies of Japanese patients with Kawasaki disease have stressed the findings of coronary artery aneurysms, which occur in all but the earliest stages of disease.3-5Kawasaki disease begins as a pancarditis with vasculitis of small vessels (stage I), progressing to panvasculitis of the epicardial coronary arteries with proximal aneurysms (stage II), granulation of the aneurysms with disappearance of microvascular inflammation (stage III), and scarring of the coronary arteries with stenoses (stage IV).3The pathologic findings of Kawasaki disease in western Europe and the United States have been relatively poorly documented.6-8However, similar to autopsy studies from Japan, the presence of coronary aneurysms is stressed in these reports.9Fibrointimal proliferation in the absence of aneurysmal dilatation has been described in the coronary arteries of patients with a history of Kawasaki disease, but is generally mild.21011 In the healed stage of Kawasaki disease, aneurysms are absent in up to one third of cases in which mild fibrointimal proliferation with minimal stenoses are present.4 Severe diffuse narrowing resulting in cardiac ischemia is not a well-described form of coronary involvement, and is not one of the recognized angiographic patterns.12Although there may be coronary narrowing without aneurysm in the acute phase of disease,9 the healed stages of coronary arteritis has not been reported to result in diffuse luminal narrowing. Sequential angiography of coronary aneurysms may demonstrate a reduction in luminal size due to thrombosis (so-called aneurysm regression), but autopsy studies have demonstrated persistence of the epicardial dimensions of the aneurysm.341314The currently reported cases demonstrate that localized aneurysmal dilatation of the coronary arteries is not a constant feature of fatal forms of Kawasaki disease. Diffuse fibrointimal proliferation has rarely been reported in coronary arteries in patients with Takayasu disease,15 an entity demonstrating considerable overlap pathologically with Kawasaki disease. The involvement of the aorta in Case 2 presented here, as well the presence of giant cells, are also features of Takayasu disease. However, the clinical presentation of Case 2 demonstrated features of mucocutaneous lymph node syndrome, and Case 1 did not demonstrate aortic involvement. Coronary involvement beyond the ostia is rare in Takayasu disease,16 which is virtually never diagnosed in children under age 10 years.1718 Histologic involvement of the aorta and the subclavian and carotid arteries has been described in Kawasaki disease,419 as have giant cells.2 Given the clinical and histologic constellation of the two cases described in this report, we believe that despite the unusual histologic findings, Kawasaki disease is the only tenable diagnosis.The febrile phase of Kawasaki disease generally lasts 1 to 3 weeks, and laboratory evidence of inflammation (sedimentation rate, thrombocytosis) generally subside within 6 to 8 weeks.52021 In these two patients, persistent fevers and elevations of the erythrocyte sedimentation rate led to the consideration of numerous diagnoses by a variety of consultants. The finding of autoimmune hemolytic anemia in Case 1 has been reported as a complication of Kawasaki disease.2223 These cases suggest a previously unrecognized form of Kawasaki disease with diffuse coronary narrowing associated with an unusually chronic and severe form of the illness. The presence of numerous activated lymphocytes expressing HLA-DR suggests that the severity of the illness reflected ongoing immune activation within the arterial walls. It remains to be seen whether such forms of Kawasaki disease are a continuing manifestation of superantigen involvement as has been described in a patient with acute illness.24The lack of aneurysmal dilatation of coronary arteries in these two hearts with severe ischemic changes demonstrates that echocardiography may not be a sensitive method for the detection of coronary in-volvement in Kawasaki disease without aneurysm formation. Selective coronary angiography would be contraindicated in cases such as these two because of the markedly compromised coronary lumina. Other diagnostic modalities have been used recently for the detection of coronary artery disease in children with a history of mucocutaneous lymph node syndrome. These include positron emission tomographic scanning with and without adenosine stress to assess myocardial flow25-27 and dobutamine stress echocardiography.28 Coronary sinus flow has been shown to be decreased and coronary vascular resistance to be increased during atrial pacing in a group of older children (mean, 14 years) who were status post Kawasaki disease without angiographic evidence of coronary involvement. Right ventricular biopsy in 8 patients demonstrated fibrosis and medial thickening of small coronary arteries without apparent coronary involvement.29 In older children, 9 to 11 years after onset of Kawasaki disease, up to 85% of branches and main coronary artery trunks had mildly thickened intimas with intravascular ultrasound.10Although coronary revascularization has been successfully achieved in children with Kawasaki disease by coronary bypass222330-32 or percutaneous balloon angioplasty,33 it is unlikely that either treatment would have been effective in the children reported here, because of the diffuse coronary involvement of proximal and distal coronary arteries and their branches.The cases presented here suggest that the clinical presentation of Kawasaki disease can be classified into at least four types, depending on the pathologic changes in the coronary tree. Type A Kawasaki disease is characterized by coronary aneurysm formation.1-5 Type B is represented by the two cases presented here, is characterized by prolonged clinical course with irreversible coronary arteritis with intimal thickening and death. Type C has no apparent cardiac involvement, but there is small coronary vessel involvement on the basis of abnormal perfusion scanning or intravascular ultrasound.25-29 Type D Kawasaki disease has no evidence of residual coronary arteritis by perfusion scanning and/or ultrasound.25-29In conclusion, our cases of coronary vasculitis, one of which occurred after an atypical episode of mucocutaneous lymph node syndrome, differ clinically and pathologically from typical Kawasaki disease. The lack of aneurysms in both cases may have hindered clinical recognition of cardiac involvement, and stresses the need for tests other than echocardiography in diagnosing coronary artery involvement in patients with a possible mucocutaneous lymph node syndrome.