Resistant Kawasaki Disease in an Infant Causing Giant Coronary Aneurysms with Thrombosis

A 13 month-old boy male infant admitted for fever, generalized polymorphous exanthema, hyperemic conjunctivae, and diarrhea. The onset of the disease was approximately 2 weeks before the admission with a generalized polymorphous exanthema for which he received antihistaminic treatment, but after 7 days he associated fever, hyperemic conjunctivae, and diarrhea being admitted in the regional hospital. The fever persisted despite the antibiotic and symptomatic treatment, and therefore he was transferred in our hospital. The clinical exam at the time of admission revealed influenced general status, generalized polymorphous exanthema, hyperemic pharynx, bilateral conjunctivitis, and approximately five diarrheic stools per day. The laboratory tests revealed leukocytosis (27,050/mL), with neutrophilia (19,900/mL), anemia (Hb 6.9 g/dL, Htc 19.7%, MEV 68.6 fL, MEH 24 pg), thrombocytosis (1,111,000/ mL), elevated inflammatory biomarkers (CRP An Abstract Giant coronary artery aneurysms that occur in 0.5 to 1% of patients with Kawasaki disease can be fatal if associated with thrombosis. Some patients may show persistent inflammation and fever despite treatment with repeated doses of intravenous immunoglobulin (IVIG), steroids, and aspirin. This report describes an infant boy with resistant Kawasaki disease who presented with extensive coronary artery involvement and coronary thrombosis. His inflammation was not controlled with multiple doses of IVIG, parenteral and oral steroids, or high-dose aspirin, and he finally needed infliximab, a monoclonal antibody against tumor necrosis factor alpha.

The onset of the disease was approximately 2 weeks before the admission with a generalized polymorphous exanthema for which he received antihistaminic treatment, but after 7 days he associated fever, hyperemic conjunctivae, and diarrhea being admitted in the regional hospital. The fever persisted despite the antibiotic and symptomatic treatment, and therefore he was transferred in our hospital.  high-dose aspirin, oral prednisolone, and warfarin. His platelet count rose to 1001 9 109 /l on day 28 of his illness. He had an erythrocyte sedimentation rate of 90 mm in first hour, and his C-reactive protein level was 90 mg/l. A loose mobile thrombus measuring 12 9 3 mm in the distal RAD responded to 24 h of abciximab infusion, with a marked reduction in thrombus size together with some reduction in the size of the right coronary artery aneurysm. The boy subsequently remained afebrile. He was discharged on fulldose aspirin together with clopidogrel, alternate-day prednisolone and warfarin to maintain an international normalized ratio (INR) of 2 to 3. 2 weeks after discharge. An echocardiogram showed a very small thrombus, with persistent dilation of the coronary arteries.
At the 9-month follow-up visit, the boy was receiving warfarin and low-dose aspirin and showed normal growth and development. At this writing, he is scheduled for coronary imaging after a year.

Discussion
Extremes of age represents, associated with male gender, prolonged fever and a delay in diagnosis or treatment an important risk factor for the development of giant coronary aneurysms, with thrombus noted in 0.5% to 1% of patients with Kawasaki's disease [1]. A coronary aneurysm is diagnosed when the internal lumen diameter of the coronary arteries is found to be >3 mm in children younger than 5 years or >4 mm in children older than 5 years on two-dimensional echocardiography. The American Heart Association has classified coronary aneurysms on the basis of their sizes as small (< 5 mm), medium (5-8 mm), and giant (>8 mm) [2]. Giant coronary aneurysms are less likely to regress, and they have the highest association with progression to stenosis and myocardial infarction [3]. With the evolution of newer computed tomography scanner technology, the radiation exposure from an ECG-gated cardiac CTA has declined to under 1 mSv. In addition, CTA allows visualization of mid and distal segments, which are common sites for aneurysm formation and are poorly seen on the ultrasound. CTA is also helpful in assessing the degree of stenosis, presence of calcifications, thrombosis, and findings of embolic myocardial infarction and serves as a tool for noninvasive follow-up imaging in selected patients [4]. The current American Heart Association guideline favors low-dose aspirin for aneurysms up to 6 mm for a period of 8 weeks or until the aneurysms regress in size. Long-term antiplatelet treatment in patients with aneurysm more than 6 mm is recommended to avoid catastrophic sequel of myocardial infarction and death [5]. Intravenous immune globulin (IVIG), the cornerstone of therapy, can reduce the risk of coronary-artery aneurysms to 4%. However, among the therapies tested so far that have been found to be effective against IVIG-resistant Kawasaki's disease, the best choice remains a subject of controversy [6]. Kawasaki's disease is characterized by a cytokine storm, with elevated levels of tumor necrosis factor (TNF) α, interleukin-6, granulocyte colonystimulating factor, interleukin-1β, and interleukin-17.1 [7].
However, the boy's fever recurred despite infliximab, thereby necessitating prolonged oral steroid use. Extensive coronary artery aneurysms with thrombosis warranted the use of abciximab, another murine monoclonal antibody against platelet glycoprotein 2b/3a receptor [8]. Abciximab may promote vascular remodeling and could lead to regression of coronary aneurysms. If coronary thrombosis leads to myocardial infarction, thrombolytics may have a role [9]. Coronary angiography is needed to document regression of coronary artery lesions that may occur in 50% to 67% of aneurysms, often within the first 1 or 2 years [10]. Regression of aneurysms is more likely in young infants and in cases with smaller aneurysms, a fusiform aneurysm morphology, and a location in a distal coronary segment.

Conclusion
The present report illustrates a rare case of Kawasaki disease with a delayed presentation at 13 months of age, giant coronary aneurysms, and an accompanying coronary arterial thrombus that was detected by two-dimensional echocardiography. Where Kawasaki disease is refractory to intravenous immunoglobulin therapy, methylprednisolone and infliximab may be used to reduce acute vascular inflammation.