In March 2017, a 5-year-old female (body weight 19.5 kg, Chinese, Chaoxian ethnicity) who presented with prolonged intermittent fever and a giant right coronary Valsalva sinus aneurysm was admitted to our department. Nine months before this admission, in July 2016, she had a fever (T-max 38.5 C) that lasted for 5 days without any precipitating factors. The fever was accompanied by oral vesicles and mild facial edema, and there are no other pertinent findings on history or physical exams. She was brought to local hospital A and found to have elevated inflammatory markers, alanine aminotransferase (ALT), and cardiac enzymes. Her presentations at that time raised concern for IM, and serological tests specific for EBV were sent, which demonstrated positives of EBV-viral capsid antigen (VCA)-IgM and EBV-early antigen (EA)-IgG, negatives of EBV-VCA-IgG, and EBV-nuclear antigen (NA)-IgG. The load of EBV-DNA detected by real-time polymerase chain reaction (PCR) was 3.2 x 105 copies/mug DNA in peripheral blood. Therefore, she was diagnosed with IM with liver injury. After treatment with ganciclovir, her fever and facial edema improved, EBV-VCA-IgM turned negative, and EBV-VCA-IgG and EBV-NA-IgG turned positive, and then she was discharged.
After discharge, the patient continued to have intermittent fever with a peak temperature of 38 C, accompanied by progressive facial edema. Monitoring of inflammatory markers showed persistently elevated C-reactive protein (CRP) of 2.4 mg/dl and white blood cell count (WBC) of 12.8 x 103/mul. In January 2017 (3 months before admission to our department), the patient was admitted to hospital B for persistently elevated inflammatory markers and fever. Laboratory evaluation was significant for negative EBV-VCA-IgM, with positives of EBV-NA-IgG, EBV-VCA-IgG, and EBV-EA-IgG, and the load of EBV-DNA was 3.66 x 105 copies/mug DNA. Autoimmune panels showed negative ANCA and ANA. Her echocardiography showed a widened aortic sinus, with the widest site measuring 33.4 mm. Additionally, there was widened left and right coronary artery inner diameter. Coronary artery computed tomography angiography (CCTA) showed bilateral coronary aneurysms and giant right coronary sinus aneurysm measuring 22 mm x 25 mm; no coronary-pulmonary artery fistula was found. Carotid ultrasonography showed a slightly thickened tunica media. Duplex ultrasonography of renal artery, superior vena cava, superior mesenteric artery, and aorta were all negative for aneurysm or dilation. Due to persistent fever and elevated inflammatory markers, a bone marrow biopsy was also obtained, which showed hyperplasic bone marrow without leukemic cells.
The patient was diagnosed with Kawasaki disease remission stage with giant coronary sinus aneurysm and EBV infection (due to a lack of clinical information, a Z-score was not obtained). Given the large total number of aneurysms and involvement of multiple branches, she was determined to be at elevated risks of coronary artery thrombosis. Thus, she was treated with antiviral therapy with intravenous ganciclovir, dual-antiplatelet therapy with aspirin and dipyridamole (as no currently available drug information about clopidogrel usage in children with Kawasaki disease in China), and systemic anticoagulation therapy with oral warfarin. Due to no improvement of facial edema and intermittent fever, she was transferred to our hospital. This patient had a contact history of tuberculosis 3 months prior to admission without other significant past medical history and family history. Physical examination was pertinent for non-pitting facial edema, generalized lymphadenopathy, and hepatosplenomegaly.
On admission, the following laboratory results were obtained: elevated neutrophils of 55.6%, elevated CRP of 2.47 mg/dl, elevated AST of 93 U/L, and ALT of 67.8 U/L. Other serum values included WBC that was within normal limits. EBV serologic tests revealed negative EBV-VCA-IgM and positives EBV-VCA-IgG, EBV-EA-IgG, and EBV-NA-IgG. The load of EBV DNA was 1.05 x 105 copies/mug DNA. Her ECG showed a second-degree atrioventricular block. Transthoracic echocardiography (TTE) revealed moderate mitral valve and tricuspid regurgitation, mild aortic regurgitation, giant sinus of Valsalva (SoV) aneurysms, particularly of the right coronary sinus (RCS) (Figure 1A), and a left main coronary artery (LMCA) aneurysm with the broadest diameter being about 7.9 mm (Figure 1B). A further computed tomographic angiogram (CTA) was obtained, which demonstrated multiple arterial aneurysms involving SoV, as well as LMCA (Figures 1C,D), aorta, and its major branches (Figures 1E-G). Dilated aneurysms could lead to venous hypertension with severe inflow restriction, and thus, multiple collateral vessels were produced. A lymph node biopsy for histopathological evaluation of EBV-infected cells was recommended but declined by the patient's family.
Based on her clinical manifestations, increased EBV-DNA, and positive EBV antibodies, we diagnosed this patient with CAEBV with multiple giant coronary artery aneurysms. Given the risk stratification as above, she was given 8 days of dual-antiplatelet therapy (aspirin 50 mg daily, dipyridamole 25 mg TID), systemic anticoagulation (warfarin 1 mg daily), and myocardial protection therapy (metoprolol 6.25 mg Q12H, captopril 6.25 mg Q12H). Spironolactone 5 mg Q12H and hydrochlorothiazide 6.25 mg Q12H were added for 2 days. Due to the parents' request, she was discharged after her parents were informed of discharge risks, and outpatient follow-up was scheduled to monitor disease progression, coronary artery aneurysms' size, and possible myocardial ischemia. Unfortunately, the patient did not follow up and died at home 15 months after the onset of the disease for unknown reasons. The clinical course is summarized in Table 1.