Incomplete Kawasaki disease in a patient with chronic granulomatous disease

Abstract

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency characterized by microbicidal dysfunction due to a defect in nicotinamide adenine dinucleotide phosphate oxidase in neutrophils. Patients with CGD have abnormalities in cytokine production and apoptosis leading to prolonged inflammation, which is related to the susceptibility to autoimmune or inflammatory diseases such as sarcoidosis, Crohn's disease, systemic lupus erythematosus, Behçet's disease, and Henoch–Schönlein purpura.1 Meanwhile, Kawasaki disease (KD) is a febrile illness characterized by systemic vasculitis including coronary arteritis. It is considered that immunoregulatory disturbances in activated monocyte/macrophages, CD4+T-helper cells and B cells are responsible for the development of KD.2 There have been reports that KD has occurred in patients with immunodeficiency disorders including Wiskott–Aldrich syndrome,3 hyperimmunoglobulin E syndrome,4 HIV infection,5 and CGD.6 These associations suggest that these patients with immunodeficiency disorders had susceptibilities to KD. We herein present a notable case of a 2-year-old boy with CGD who developed incomplete KD with left coronary artery aneurysm (CAA). A 2-year-old boy was admitted to our hospital because of fever and painful right-sided cervical lymphadenopathy. The present patient was diagnosed as having CGD at 4 months of age because he had severe suppurative and disseminated reaction after bacillus Calmette–Guerin (BCG) vaccination according to the Japanese vaccination schedule. Genetic analysis revealed the mutation of the gp91-phox gene. The superoxide production in neutrophils was reduced below 1% (normal range, 70–100%) by flow cytometry. The patient was given prophylactic medications of an oral antibiotic agent (sulfamethoxazole-trimethoprim) and subcutaneous interferon-gamma. His clinical course from admission is shown in Figure 1. On the second day of the illness, laboratory examination showed a white blood cell count (WBC) of 10 300/mm3 (61% of neutrophils and 29% of lymphocytes), hemoglobin concentration of 11.6 g/dL, platelet count of 188 000/mm3 and serum C-reactive protein (CRP) concentration of 3.84 mg/dL. Intravenous administration of wide-spectrum antibiotic agents was started under the diagnosis of suppurative cervical lymphadenitis. On the 4th day of illness, fever and cervical lymphadenopathy subsided with the decreased serum CRP level of 1.02 mg/dL. On the 6th day of illness, however, he had high fever again with bloodshot eyes and reddish lips. The site of BCG vaccination was not reactivated at that time. Laboratory examination showed WBC, platelet count and serum CRP concentration were 10 090/mm3, 314 000/mm3, and 3.55 mg/dL, respectively. Thereafter, fever continued, however cervical lymphadenopathy, bloodshot eyes and reddish lips subsided. On the 11th day of illness, the reactivation of the BCG site was noted. Echocardiography performed on the 18th day of illness showed the dilatation of the left main coronary artery at a maximum diameter of 4 mm. He was diagnosed as having incomplete KD because he fulfilled four of six major symptom criteria according to the Japanese KD guidelines, and intravenous gamma-globulin (2 g/kg) was subsequently given. Fever discontinued with improved laboratory data including WBC count and CRP concentration. Coronary angiography performed on the 39th day of illness revealed that the left main coronary artery was saccularly dilated at a maximum diameter of 6 mm (Fig. 2). The patient was given oral aspirin and dipyridamole. On the 54th day of illness, he had a fever and mild lymphadenopathy without other KD signs such as bloodshot eyes or reddish lips. He was treated with additional intravenous gamma-globulin (1 g/kg/day for 2 days) following defervescence. He has been followed up carefully in the outpatient clinic with medications. He has never suffered from chest pain or hemodynamic incompetence. Clinical course in a patient with chronic granulomatous disease who developed incomplete Kawasaki disease (KD). The patient showed a prolonged course of KD with atypical manifestation. Serum tumor necrosis factor (TNF)-α, interleukin (IL)-6 and procalcitonin concentrations were measured at individual time points. BCG, bacillus Calmette–Guerin; CRP, C-reactive protein; Plt, platelet; WBC, white blood cell count. Selective coronary angiogram showed coronary artery aneurysm in the left coronary artery with a diameter of 6 mm. Serum cytokines of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor-α were measured by BD Cytometric Bead Array Biosciences (BD Biosciences, San Jose, CA, USA) using a flow cytometer (EPICS XL; Beckman Coulter, Fullerton, CA, USA) on the 2nd, 16th and 49th days of illness. Serum IL-6 was increased to 82.0 and 28.5 pg/mL on the 16th and 49th days of illness, respectively, but other cytokines were not detected. We present a notable case of a 2-year-old boy with CGD who developed incomplete KD associated with CAA. To our knowledge, there has been only one case report by Yamazaki-Nakashimada et al. who described a 1-year-old boy with CGD who developed KD.6 There seem to be some clinical similarities between their patient and the patient in the present case. Both of the KD patients with CGD showed incomplete KD manifestations, prolonged disease courses and development of CAA. Although it is unclear how neutrophils contribute to the pathophysiology of KD, several reports suggest the role of neutrophils in KD. Takahashi et al.7 suggested that neutrophils were mainly infiltrating in CAA during the very early phase of KD. It was also reported that serum levels of a granulocyte colony-stimulating factor were higher in KD patients with CAA than those without it.2 Actually, an inhibitor of neutrophilic elastase (ulinastatin) was considered as an additional treatment of KD. These findings suggest that activated neutrophils play an important role in eliciting vasculitis in KD. With regard to neutrophilic superoxide, Niwa et al.8 demonstrated that superoxide production was increased in the early phase of KD, which indicated its importance in the pathophysiology of KD. Because both of the patients with CGD developed incomplete clinical manifestations of KD, we considered that the lacking of superoxide production might influence or attenuate the clinical manifestation of KD in the early phase of illness to some extent. It was interesting that both of the patients with CGD developed CAA as a complication of KD. Niwa et al.8 suggested that superoxide production was higher in patients with CAA than in those without it. However, their report included too few KD patients with CAA to show its significance. As both of the KD patients with CGD developed CAA, it is not likely that superoxide production plays a major role in the formation of CAA. Although several reports have indicated the pathophysiological relationship between the function of neutrophils and the formation of CAA in KD, inflammatory responses other than superoxide production may contribute to the formation of CAA. Recent reports have indicated that incomplete KD itself is associated with the development of CAA.9,10 Because incomplete clinical manifestation makes the definitive diagnosis of KD difficult, vascular damage can progress before the treatment. The predisposition to bacterial infection in CGD patients also leads to a delay in the diagnosis of KD. These factors may contribute to the occurrence of CAA in KD patients with CGD. This rare association of CGD and KD yields a novel clinical implication in the relationship between superoxide production and development of KD. It is likely that the lack of superoxide production is related to the incomplete clinical manifestation of KD but not essential in the formation of CAA.