Response of Refractory Kawasaki Disease to Pulse Steroid and Cyclosporin a Therapy

We describe a child with aggressive and protracted Kawasaki disease with coronary aneurysms, myocarditis, pericarditis and valvular insufficiency, despite repeated administration of intravenous immunoglobulin. After a transient response to pulse corticosteroids, his disease ultimately subsided with combination therapy with pulse and high dosage corticosteroids and cyclosporin A. Aggressive immunosuppressive therapy with high dosage corticosteroids and cyclosporin A may be beneficial in patients with refractory Kawasaki disease. Kawasaki disease is the most common pediatric vasculitic disorder, targeting the coronary vessels and posing a serious risk of morbidity and mortality to those affected. A single dose of intravenous immunoglobulin (IVIG) at 2 g/kg given within 10 days of disease onset is effective in preventing progression to coronary artery dilatation in 85% or more of patients with Kawasaki disease. 1 Although many who fail to respond to the first dose of IVIG respond to a second IVIG infusion, 2 a few prove resistant to this therapy. Patients in the latter group who continue to have signs and symptoms of active Kawasaki disease are especially at risk for developing coronary aneurysms and contribute disproportionately to disease-related morbidity and mortality. These patients may be candidates for aggressive immunosuppressive therapeutic modalities commonly reserved for other vasculitides. Support for such an approach has been provided by a recent report documenting the response of four such patients to pulse corticosteroid therapy. 3 In this report we describe a child with refractory Kawasaki disease who had recrudescent disease despite repeated IVIG infusions and a trial of pulse corticosteroid therapy. His disease responded to combination therapy with sustained high dosage corticosteroids and cyclosporin A. Case report. A 3-year-old Caucasian boy was admitted with a 12-day history of daily fever up to 38.9°C, followed by conjunctival injection, red cracked lips and tongue, diffuse erythematous macular rash, cervical adenopathy, bilateral hand swelling, diffuse arthralgia and anorexia. The history was unremarkable for infectious or tick exposure or for recent travel. The physical examination at admission was remarkable for an ill-appearing boy, with the aforementioned findings. Cardiac examination revealed tachycardia with a regular rhythm, normal heart sounds and no murmur, rub or gallop. His liver was normal in size, and he had no evidence of arthritis. The initial white blood cell (WBC) count was 17 500/mm 3 with 15% band forms and 76% neutrophils. He had mild normocytic anemia, an elevated platelet count at 560 000/mm 3 and an erythrocyte sedimentation rate (ESR) of 59 mm/h. He had a negative throat culture, anti-streptolysin O and blood culture. A diagnosis of Kawasaki disease was made based on the presence of fever and all five CDC criteria. 4 He was given IVIG at 2 g/kg and started on high dosage aspirin (Fig. 1).Fig. 1: Schematic representation of clinical course and response to specific interventions.On the 14th day of illness tachycardia worsened, and he developed a nonproductive cough, an S3 gallop and hepatomegaly with the liver edge palpable 3 cm below the right costal margin. Chest radiogram showed cardiomegaly with diffuse interstitial infiltrates consistent with congestive heart failure. An electrocardiogram showed normal sinus rhythm and possible left ventricular hypertrophy. An echocardiogram showed moderate tricuspid regurgitation, moderate-severe mitral regurgitation, pulmonary insufficiency and a dilated left ventricle with normal systolic function, with normal sized coronary vessels. Digoxin and diuretics were started. Fever recurred 2 days later, prompting a second dose of IVIG of 2 g/kg, which resulted in defervescence and resolution of his gallop rhythm. The echocardiogram showed improvement in mitral regurgitation. However, he now had coronary artery dilatation, with the left anterior descending artery (LAD) at 5.8 mm, left circumflex artery (LCA) at 4 mm and right coronary artery (RCA) at 4 mm. He was discharged receiving intermediate dose aspirin. He was readmitted on the 26th day of illness, with fever of 39.1°C, tachycardia, diaphoresis and increased left cervical adenopathy. Aspirin had been increased to 100 mg/kg/day before readmission. He had a firm, tender left cervical lymph node 3 by 4 cm in diameter and a normal cardiac examination. Laboratory studies now showed a WBC count of 22 900/mm 3 with neutrophil predominance, and a platelet count of 819 000/mm 3. The ESR was unchanged. Chest radiogram showed a normal heart size and no pulmonary infiltrates. Neck ultrasound showed no suppuration and Epstein-Barr virus titers were negative. In the ensuing days he developed signs of recurrence of Kawasaki disease, with fever, mucocutaneous involvement, swelling of hands and feet and arthralgia. Signs of congestive heart failure recurred, with an S3 gallop, a 3/6 systolic murmur and hepatomegaly. His echocardiogram showed a small pericardial effusion and worsened coronary dilatation, with LAD 7.5 mm, LCA 5 mm and RCA 5.5 mm. He was given a third dose of IVIG 2 g/kg, but the clinical stigmata of Kawasaki disease persisted. His cardiovascular status worsened as manifested by increased pericardial effusion, T wave inversion in leads V4–6 and diffuse ST-T changes. Given the severity of his coronary involvement, extracoronary vascular inflammation was excluded by magnetic resonance angiography of the descending aorta down to the iliac arteries. He had no evidence of other systemic vasculitides with a negative antinuclear antibody, anti-double stranded DNA and antineutrophil cytoplasmic antibody. Because of the potential for coronary artery thrombosis in large aneurysms, anticoagulation with heparin was initiated. Immunologic studies at this stage of his disease revealed evidence of intense polyclonal B cell activation, with striking increase in the percentage of circulating B cells (57%; normal, 4 to 23%), and elevation of serum IgM at 398 mg/dl. This was associated with low serum concentrations of complement components C3 and C4, at 62 and 6.5 mg/dl, respectively, consistent with complement consumption. Given the clinical and laboratory evidence of ongoing inflammation and immune activation and the severity of coronary artery involvement, he was treated with pulse steroid therapy, with methylprednisolone at 30 mg/kg/day for 3 days, and a fourth dose of IVIG (Fig. 1). Fever, gallop rhythm and hepatomegaly resolved, whereas coronary dilatation remained unchanged. The steroid dosage was lowered to 2 mg/kg/day divided for twice a day administration. Three days later low grade fever returned, and a prominent pericardial friction rub was audible. The WBC count was further elevated at 34 700/mm 3, with persisting elevations in platelet count, ESR and C-reactive protein. As a result of the worsening pericardial effusion, another 3-day course of methylprednisolone was given, starting on the 37th day of illness with the addition of cyclosporin A at 3 mg/kg/day divided for administration three times a day. By the 44th day of illness the patient had complete defervescence with resolution of pericardial effusion and signs of congestive heart failure. The WBC count and C-reactive protein values became normal, followed by a gradual fall in ESR. Complement components exhibited a rapid rise after immunosuppressive therapy and then returned to normal. The steroid dosage was tapered to 1 mg/kg/day at discharge and treatment was continued with cyclosporin A, digoxin, aldactazide and intermediate dose aspirin. After discharge he had no signs of recrudescence of disease, and laboratory indices of systemic inflammation normalized. At follow-up the echocardiogram showed resolution of LCA and RCA dilatation, and persistent dilatation of LAD at 7.5 mm. Low dosage aspirin was initiated once the platelet count returned to normal, and digoxin, prednisone and cyclosporin A were discontinued or tapered off. A recent echocardiogram 7 months after the illness shows isolated aneurysmal dilatation of the left anterior descending artery at 7.5 mm. He continued to receive low dosage aspirin as his only medication. Discussion. The patient we describe was challenging with regard to both the rapid worsening of his cardiac status and the persistence of signs of active inflammation despite aggressive immunosuppressive therapy. He had several criteria predictive of poor outcome with a score of 11 on the modified Asai score (score >6 associated with increased risk of coronary aneurysms). 5 Signs of myocardial dysfunction, pericarditis and early signs of ischemia, as seen in our patient, have been associated with a fatal outcome in this disease. The maximal internal diameter of his coronary vessels approached the 8-mm mark that is used to describe giant coronary aneurysms, which are at greatest risk for coronary thrombosis, stenosis, myocardial infarction and rupture. This patient exhibited several findings of intense immune activation, particularly exaggerated polyclonal B cell activation and marked hypocomplementemia, which mirrored the severity of his clinical manifestations and foreshadowed the refractoriness of his disease to conventional therapy. Hypocomplementemia is a recognized feature of patients with severe Kawasaki disease, 6 reflecting a process of immune complex deposition, although an increase in complement components such as C4d may be seen in the acute phase. His predominance of B cells and elevated total IgM would support the hypothesis that this is an antibody-mediated process caused by IgM antiendothelial antibodies, which are believed to be complement-fixing. 7 It has been hypothesized that high dose IVIG exerts its effect by inhibiting complement activation and/or complement attachment to the antiendothelial antibodies. The initial favorable response to high dosage steroids in this patient with regard to resolution of fever and overt signs of congestive heart failure was encouraging, especially in light of the ongoing controversy regarding their use in this disease. Studies dating before the introduction of IVIG therapy have reported conflicting results on the efficacy of steroids in treating Kawasaki disease. Kato et al. 8 showed a higher prevalence of coronary aneurysms among patients treated with steroids. However, this study was based on a small sample of patients and did not analyze the data based on age and other risk factors. The oral dose used may also have been insufficient and given at varying times in disease course, thus making it difficult to assess their true impact. A subsequent study showed a beneficial effect of pulse steroid therapy with decrease in the number of vessels affected and regression of coronary artery dilatation. 9 A more recent report showed a favorable response to 1–3 days of pulse corticosteroid therapy in 4 patients who had failed earlier treatments with IVIG. 3 Therefore a large controlled study to compare the efficacy of high dosage steroids with readministration of IVIG in the management of refractory Kawasaki disease is warranted. The addition of cyclosporin A was prompted by the recurrence of pericardial effusion following the first round of pulse and high dose maintenance steroids, indicative of ongoing disease. His clinical picture at this juncture was more reminiscent of classical vasculitic syndromes, with inflammation targeting the coronary vessels and causing a rapidly progressive and life-threatening myopericarditis. Based on his immunologic studies it is proposed that cyclosporin A targets T cell-dependent B cell activation, thus diminishing autoantibody production. Alternatively it may effectively inhibit T cell proliferation at the site of tissue injury, analogous to the proposed mechanism in other forms of vasculitis, such as Wegener’s granulomatosis. The beneficial effect of cyclosporin A in preventing disease relapses in antineutrophil cytoplasmic antibody-associated vasculitides has been well-described. 10