Immunoglobulin resistance in Kawasaki disease with chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte dysfunction, which is caused by a defect in nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression in neutrophils and monocytes. This enzyme is necessary for the generation of reactive oxygen species (ROS). Kawasaki disease (KD) is an acute febrile systemic vasculitis of early childhood that affects the medium-sized arteries leading to conditions such as coronary arteritis. KD is characterized by prolonged fever, conjunctivitis, inflammation of the oropharynx, polymorphous rash, erythematous induration of the distal extremities, and cervical lymphadenopathy. This report describes a KD patient with CGD, and raises the hypothesis that phagocyte dysfunction in CGD may contribute to sustained inflammation in KD. A 10-month-old Japanese boy was admitted to the hospital on the first day of fever. His parents were not consanguineous. No cases of immunodeficiency were detected in the patient's family. The patient had been admitted to the hospital four times with febrile episode and increased C-reactive protein (CRP) concentration. The patient had undergone discission of recurrent perirectal abscess lesions at the age of 8 months. A physical examination revealed that his temperature was 39.0°C, his blood pressure was 113/50 mmHg and heart rate was 160 beats per min. His height and weight were −0.8 SD and −1.5 SD for Japanese standard, respectively. He had maculopapular rashes on the trunk and extremities, swollen palms, reddish lips, reddened pharyngeal mucosa, multiple cervical lymphadenopathies (0.5−1.5 cm in diameter), hepatosplenomegaly, and induration and erythema in the Bacillus Calmette–Guérin vaccination site. Laboratory tests revealed leukocytosis (16 000 cells/mm3, with 52.0% neutrophils, 38.6% lymphocytes, and 8.3% monocytes), mild anemia (9.7 g/dL), and thrombocytosis (466 000 /mm3). The level of CRP was highly elevated (17.1 mg/dL). The level of aspartate aminotransferase (AST) was slightly elevated (96 IU/L). The serum electrolytes, blood urea nitrogen, and serum creatinine were normal. Cultures of blood, urine and sputum were negative for bacteria, fungi and acid-fast bacteria. His chest radiograph showed no apparent infiltrates in the lungs. The initial echocardiography on the third day of illness showed no dilation of the coronary arteries and no pericardial effusion. A high-grade fever (39.2°C) persisted on the fourth day of the illness, and he was diagnosed with incomplete KD because he fulfilled four of the six major symptom criteria according to the Japanese KD guidelines, and high-dose intravenous immunoglobulin (IVIG) infusion (2 g/kg for 24 h) and flurbiprofen treatment (5 mg/kg daily) were initiated. He had a fever and mild cervical lymphadenopathy on the eighth day of illness, and the laboratory tests showed 11 600/mm3 leukocytes (66.5% neutrophils and 16.6% lymphocytes) and the level of CRP was 11.0 mg/dL. An echocardiogram showed no dilatation of the coronary artery. He was treated with additional IVIG infusion (1 g/kg/day for 12 h). In addition, meropenem hydrate, minocycline hydrochloride and itraconazole were initiated. His body temperature declined to within the normal range on the tenth day of illness, the cervical lymphadenopathy disappeared, and laboratory data, including leukocyte count and the CRP concentration, gradually decreased to within the normal range 3 weeks later. He was discharged with a prescription of 5 mg/kg of aspirin daily, and a follow-up echocardiogram remained normal 4 weeks after discharge. Serum cytokines of soluble tumor necrosis factor receptor (sTNFR)-1, interleukin (IL)-6, IL-8, interferon (IFN)-γ and soluble IL-2 receptor (sIL-2R) were measured serially using enzyme-linked immunosorbent assay. The sTNFR is an inhibitor and natural homeostatic regulator of the action of TNF-α, and its level, rather than that of TNF-α, reflects the true biological activity of TNF-α. As a result, the serum IL-8 and sIL-2R levels were increased consistently even after the disappearance of KD symptoms on the tenth day of illness (Table 1). The patient's history of recurrent infectious disease suggested immunodeficiency. H2O2 production in stimulated neutrophils was assessed 2 months after his discharge. The superoxide production in neutrophils was reduced below 1.9% (normal range, 70–100%), thus indicating a diagnosis of CGD. He was diagnosed as having X-linked CGD with a frameshift mutation in exon13 of the gp91phox gene (c. 1681 del G). Only two case reports have described patients with CGD who developed KD.1,2 The previously reported two cases showed incomplete KD. This case, however, eventually turned out to be complete KD, according to the Japanese diagnostic guidelines for Kawasaki disease. The symptom patterns of KD among the three cases were investigated; however, there were no specific patterns of any KD symptoms (Table 2). On the other hand, a notable point of similarity is that all of the KD patients with CGD showed poor responses to primary high-dose IVIG therapy. Various cytokines are elevated in patients during the acute stage of KD, including IL-2, IL-6, IL-8 and TNF-α.3 High-dose IVIG therapy is effective for reducing the incidence of coronary artery aneurysms, resulting in a reduction in their elevated cytokine production.4 In our case also, the symptoms improved and the values of inflammatory cytokine were decreased by the IVIG therapy. Even after the symptoms of KD disappeared, IL-8 and sIL-2R values above the normal range were sustained for a few weeks. It has been reported that even in the KD cases that were not resistant to IVIG therapy, TNF-α, IL-8, and sIL-2R remained at high values above the normal range for several weeks even after entering the recovery phase.5,6 Interestingly, in our case, the sIL-2R value continues to be high, at over 600 U/ml, more than 10 months after the onset of KD. There are no reports that the sIL-2R value keeps at a high value for over 6 months after the disappearance of KD symptoms. This suggests that the lymphocytes keep being activated in the background of this patient without the symptoms of KD. Recent investigations have implicated ROS generated by the cellular NADPH-oxidase as important signaling molecules in a variety of cell signaling systems. The reduction of ROS production reduces the capability to regulate the immune response and subsequently presents a general hyperinflammatory phenotype in response to multiple stimuli. Monocytes and neutrophils are in a hyperactivated state in CGD, which is demonstrated by enhanced production or diminished degradation of cytokines and chemokines, such as TNF-α, IL-8, IL-6 and IL-10 under stimulation.7,8 In addition, ROS derived from macrophages leads to the induction of regulatory T-cell induction to regulate T-cell mediated inflammation.9 A recent study suggested that the regulation of T-cell activation is a critical factor in determining susceptibility to and the severity of KD,10 and that the concentration of sIL-2R in serum, a marker of T-cell activation, is elevated significantly in KD patients resistant to IVIG therapy.6 This suggests that hyperinflammatory CGD lymphocytes might contribute to a poor response to primary high-dose IVIG therapy for KD. Further studies should be carried out.