Coronary Artery Aneurysms and Thrombosis in Kawasaki Disease

Kawasaki disease (KD) is an acute vasculitis of unknown etiology occurring in infants and young children and affecting medium-sized muscular arteries. It is a systemic disease, with possibly morbid to mortal manifestations in the cardiovascular system, including lymphocytic myocarditis and acute vasculitis associated with thrombosis and/or aneurysm formation. In regards to aneurysm formation, coronary artery involvement occurs in up to 40% of patients and can range from transient, mild dilatation or ectasia to giant coronary artery aneurysm. Treatment with aspirin and intravenous immunoglobulin (IVIG) therapy greatly reduces the occurrence of coronary artery aneurysm. Patients with large or giant coronary artery aneurysms are especially at risk for cardiac events including coronary artery thrombosis or stenosis, myocardial infarction, arrhythmias, and death (1).

A 7-month-old male infant was brought to the hospital after being found by his foster parents to be inconsolable and crying. He was up-to-date on his immunizations and met all his developmental milestones. Significant birth history included intrauterine exposure to methamphetamine, with a positive methamphetamine drug screen at birth, and subsequent removal from his mother and placement with a foster family.

A month earlier, he presented to an emergency department with symptoms of diarrhea for one week, loss of appetite, fever, pink eye, and rash on his entire body. A pediatrician diagnosed him with gastroenteritis secondary to adenovirus, he was treated with intravenous fluids, and he was released three days later with instructions to continue with oral rehydration with Pedialyte.

He continued to have intermittent loss of appetite and diarrhea, change of personality from being a happy baby to one with low energy, and significant weight loss. Worried, his foster parents brought him to the emergency department.

At the emergency department, he became tachycardic, displayed decreased capillary refill, and had episodes of apnea necessitating bag-mask ventilation. A complete blood count showed the white blood cell count was elevated, but without profound left-shift, and he had mild anemia. While in the pediatric intensive care unit, an emergency bedside echocardiogram was done that showed markedly dilated coronary arteries consistent with Kawasaki disease. Despite aggressive management, he had multiple episodes of respiratory arrest without loss of pulse and was pronounced dead.

Autopsy examination revealed a pale infant with pale organs and an enlarged heart with thrombosed giant coronary artery aneurysms involving the proximal portions of the right coronary and the entire left anterior descending arteries (Image 1A). Both kidneys had multiple wedge-shaped acute cortical infarcts. Histopathologically, there were thrombosed aneurysms of the coronary arteries along with panvasculitis of the coronary arterial wall (Images 1B and 1C), lymphocytic epicarditis, lymphocytic myocarditis, and multifocal contraction band necrosis (Image 1D). An interlobular aneurysm with thrombus formation was identified with panarteritis was seen in one of the kidneys (Image 1E).

Image 1A:

Enlarged heart with giant coronary artery aneurysms of the right coronary and left anterior descending arteries.

Image 1B:

Coronary artery with aneurysm, thrombus and panvasculitis (H&E, x20).

Image 1C:

Higher magnification of thrombus with lymphocytic panvasculitis and surrounding epicarditis (H&E, x100).

Image 1D:

Myocardium with contraction band necrosis (H&E, x400).

Image 1E:

Kidney with thrombus in arcuate artery and associated vasculitis (H&E, x20).

The cause of death was determined to be complications of Kawasaki disease and the manner of death was natural.

The clinical diagnosis of Kawasaki disease, or mucocutaneous lymph node syndrome, requires the presence of a fever lasting for five or more days, accompanied by four out of five principal clinical findings including bilateral conjunctival congestion, oral changes such as strawberry tongue and cracked and erythematous lips, acute non-purulent cervical lymphadenopathy, extremity changes such as erythema or palm and sole desquamation, and polymorphous rash. Incomplete (atypical) Kawasaki disease occurs in patients with fevers lasting five or more days and with less than four of the clinical findings. A clinical diagnosis of Kawasaki disease can be made in patients with the incomplete form when coronary artery disease is detected by coronary angiography or two-dimensional echocardiography (2). Histologic descriptions are largely based on the most severe cases, as they reflect findings at the time of autopsy (1).

Prompt and early diagnosis within ten days of illness is imperative, so treatment with aspirin and intravenous immunoglobins can be initiated. In nearly 15 to 25% of untreated patients, coronary artery aneurysms develop. If treated properly, the incidence of coronary artery aneurysm decreases to approximately 5% and development of giant coronary aneurysms to 1% (2). Giant coronary artery aneurysms are defined as aneurysms that measure greater than 8 mm in diameter. This finding is strongly associated with poor patient outcome as the large aneurysm size increases the risk of thrombosis, rupture, stenosis, myocardial infarction, and sudden death (3, 4).

Diagnosis of Kawasaki disease can be challenging as it mimics other common illnesses and drug reactions, and thus diagnosis is often delayed. Infants presenting with incomplete (atypical) Kawasaki disease are at a heightened risk for delayed diagnosis and the development of coronary artery aneurysms (5, 6). Risk factors for development of coronary artery aneurysms, particularly giant coronary artery aneurysms, include young infants, males, persistent fevers, laboratory signs of inflammation, Asian ancestry, Hispanic children (intermediate risk), longer interval to diagnosis and treatment, and recurrent disease (7 –10). Giant coronary artery aneurysm confers a high risk for thrombosis, as was seen in this patient (3, 4).

There is a progression to the histopathology findings in the coronary arteries in Kawasaki disease that mirrors patient risk and disease state. Coronary arteritis is first seen six to eight days after the onset of disease. Beginning at day ten, the arterial walls are infiltrated by lymphocytes and macrophages with subsequent panvasculitis and damage of the internal elastic lamina and medial smooth muscle cells. Around day 12, aneurysms start to form, if the damage is severe, and thrombosis may occur since blood pools in the aneurysms. Inflammatory infiltrates continue to be present until the 25th day of the disease, and then will gradually decrease and be almost completely gone by day 40. Scars from the inflammation will remain (11). Lymphocytic myocarditis is commonly found in Kawasaki disease and can be responsible for cardiac dysfunction (12).

Kawasaki disease is an infrequent entity seen in the medical examiner setting. Delay in clinical diagnosis can lead to coronary artery aneurysm and thrombosis and sudden death. Mortality/morbidity due to sequelae of persistent/remodeled cardiac damage can be seen in the adult population (13).

Authors

Linda J. Szymanski DO, Los Angeles County Department of Medical Examiner-Coroner

Roles: Project conception and/or design, data acquisition, analysis and/or interpretation, manuscript creation and/or revision, approved final version for publication, accountable for all aspects of the work, principal investigator of the current study.

Julie Huss-Bawab MD, Los Angeles County Department of Medical Examiner-Coroner

Roles: Project conception and/or design, data acquisition, analysis and/or interpretation, manuscript creation and/or revision, approved final version for publication, accountable for all aspects of the work, writing assistance and/or technical editing.

James K. Ribe MD, Los Angeles County Department of Medical Examiner-Coroner

Roles: Project conception and/or design, data acquisition, analysis and/or interpretation, manuscript creation and/or revision, approved final version for publication, accountable for all aspects of the work, general supervision, writing assistance and/or technical editing.