I. Presentation of Current Case
A 4-year-old female patient complained of experiencing recurrent oral ulceration (about once per month) 1 year prior to our hospital admission; no due attention was given at the disease onset.
10 months ago, she developed fever and accompanied by painful erythema nodosum on the dorsum of the left foot, bilateral distal lower extremities, and right ankle. During this period, the patient also experienced a perianal ulcer once and occasionally complained of fatigue, however, there was no abdominal pain, diarrhea, or ocular malaise. She was admitted to local hospital, and her laboratory tests were as follows: white blood cell (WBC): 15.5 × 109/L, C-reactive protein (CRP): 124 mg/L, erythrocyte sedimentation rate (ESR): 83 mm/H; positive results were obtained for both influenza A virus antigen and influenza B virus antigen; no abnormalities in autoantibodies (antinuclear antibody, antinuclear antibodies, anti-neutrophil cytoplasmic antibodies), bone marrow cytology, electrocardiogram, or vascular ultrasound were noted. Minor signals of tricuspid regurgitation were detected in Color Doppler Echocardiography. She was initially treated medically with cephalosporin antibiotics and meropenem intravenous infusion therapy for over 20 days, without any improvement in the patient's symptoms. Subsequently, considering diagnose of "systemic inflammatory response syndrome", the child was given oral ibuprofen for 1 month (80mg each time, twice a day), during which the body temperature returned to normal, but oral ulcers and fatigue were still present.
5 months ago, during a visit for diarrhea, she was found a cardiac murmur from a doctor’s auscultation. Further examining revealed the levels of N-terminal pro brain natriuretic peptide (NT-proBNP) was increased (1270 pg/mL), and severe aortic insufficiency, massive aortic regurgitation, the leaflets were thickened was observed via echocardiography, accompanied by gradual left ventricular enlargement and left cardiac systolic function reductio, ejection fraction (EF) 47-62% (Figure 1). Coronary ultrasound: expansion of the left coronary trunk (3.2 Z =+2.72). Chest radiography revealed the fullness of the pulmonary arterial segment with a cardiothoracic ratio of 0.54. 24-hour ambulatory Electrocardiograph (ECG) disclosed paroxysmal sinus tachycardia (mean heart rate 101 bpm, maximum heart rate 173 bpm), frequent atrial premature beat, and occasional trigeminy.
Two weeks prior to hospitalization, the patient experienced recurrent hyperpyrexia again and visited our hospital. Physical examination revealed chromatosis in bilateral distal lower extremities, grade 3/6 rumbling diastolic murmur at the cardiac apex (Austin-Flint murmur), New York Heart Association (NYHA) heart failure Class 2, and negative pathergy test. Prior physical health, growth, and development of the patient were found to be normal, and a family history of rheumatic diseases, tumor, or cardiovascular disorder was denied.
Evaluating the patient’s medical history and the results of examination, a diagnosis of BD was considered (Diagnostic basis: 2 pt recurrent oral and perianal ulceration + 1 pt skin [erythema nodosum] + 1 pt vascular [coronary artery, cardiac valve] + others, including pyrexia and increased inflammatory indicators), in accordance with the 2013 The International Criteria for Behçet's Disease (ICBD)  and 2016 The Paediatric Behçet’s Disease (PEDBD) classification criteria . Taking into account the severe involvement of vital organs and progressive exacerbation, the patient was administered methylprednisolone tablets (1 mg/kg.d) and thalidomid oral, combined cyclophosphamide, infliximab (6 mg/kg) intravenous infusion therapy, while orally given diuretics for symptomatic treatment. After oral administration of glucocorticoids, the patient's body temperature returned to normal the next day; 1 week later, WBC, ESR, and CRP retests reverted to normal; whereas, 1 month later, NT-proBNP retest returned to normal. However, 2 months after regular treatment (the 14th month of the disease onset), echocardiography reports substantiated significant left cardiac enlargement, the posterior semilunar valve (non-coronary leaflets) prolapse, as well as damage to the anterior semilunar valve and right posterior semilunar valve (non-coronary leaflets) of the aortic valve, which signified a newly onset valvular impairment that was aggravating progressively. The patient underwent aortic valvuloplasty 15 months into the course of the disease. Following the operation, a significant decrease in aortic valve regurgitation was recorded (Figure 2). As of now, the patient has received regular treatment for 6 months, clinical symptoms disappeared, laboratory tests were all normal, and the patient's condition was stable.
II. Literature Review
A literature search of China national knowledge infrastructure (CNKI), Wanfang Data, and SinoMed (published before March 2021) with the keywords-"Behcet's", "cardiac", and "pediatric"- retrieved 1 relevant publication, reflecting 1 case of BD pediatric patient with comorbid multiple thrombi in the right cardiac chamber; There was currently no relevant reports on cardiac valvular involvement in pediatric BD.
With the search string "Behcet's, cardiac, pediatric", a literature search in Pubmed (published before March 2021) retrieved 55 publications. There were 13 publications closely related, all of which were published in the form of case reports. There were no large-scale case studies on cardiac involvement in pediatric BD.
A total of 14 cases of cardiac involvement in pediatric BD were summarized from 13 publications mentioned above. Among them, 13 males and 1 female, and the mean disease onset age was 11 ±3.40 years (3 patients were 14, 17, and 15 years old, respectively when medical advice was sought, but the ages of the disease onset were unknown; therefore, only 11 cases were summarized with the known age of onset). Of the 14 patients, the longest time to diagnosis was 9 years; cardiac involvement was observed at disease onset for 4 patients, 7 gradually developed cardiac symptoms during the course of the disease, while incidence time of cardiac involvement was not mentioned for 3. Two cases were misdiagnosed as infective endocarditis. Table 1 narrates details of clinical characteristics and other systemic involvement.
Among the 14 patients, cardiac involvement mainly reflected as: valvular lesions (2 cases), intracardiac thrombus (10 cases), coronary artery involvement (5 cases), myocardial infarction (2 cases), and ECG abnormality (2 cases); other comorbidities included ascending aortic aneurysm (2 cases), pulmonary artery involvement (4 cases), peripheral venous thrombosis (2 cases), and peripheral arterial thrombosis (1 case). Comorbid ECG abnormalities were reported in two cases, including 1 case with abnormal T waves and 1 case with successive ST changes, pathological Q wave, and inverted T waves. Pulmonary arterial hypertension was not reported. One case documented comorbid thrombosis in the superficial femoral vein, deep femoral vein, right hepatic vein, and inferior vena cava, 1 case reported comorbid superior vena cava thrombosis, and 1 case comorbid popliteal artery thrombosis (Table 2).
Glucocorticoids were given to all 14 patients, among them, 4 received pulse therapy. Twelve patients were treated with immunosuppressants, including cyclophosphamide (8 cases), colchicine (6 cases), mycophenolate mofetil (4 cases), azathioprine (3 cases), methotrexate (2 cases), and cyclosporin (1 case). Biologics, including infliximab (2 cases) and anakinra (1 case), were administered to three patients. Eight patients received surgical treatment, surgical resection of thrombus or aneurysm was conducted on 6 of them (5 patients recovered and the postoperative condition of one patient was unknown), and 1 underwent aortic valvuloplasty with autologous pericardium and recovered after 2 months. One patient underwent mitral valve repair and replacement as well as exclusion of aneurysms and catheter placement of occlusion devices in aneurysmal communications, however, the patient developed end stage heart failure. Orthotopic heart transplantation was performed, followed by maintenance therapy with cyclosporin, mycophenolate mofetil, and prednisone. The post-transplant course was complicated by periodic episodes of renal failure, recurrence of painful mouth ulcers, hypertension and several large pseudoaneurysms were found in the ascending aorta at the site of the surgical anastomosis. Emergency surgical re-anastomosis and exclusion of the aneurysm was performed without complication. The patient survived for > 2 years post-transplant at the time of the report, with no aneurysm regrowth . (Table 3).
As per our literature search, the current case demonstrated the youngest age of disease onset reported in literature among pediatric BD with cardiac involvement and was the only case with aortic valve damage as the main clinical manifestation.