Sejung Sohn

Infliximab Treatment for Refractory Kawasaki Disease in Korean Children

Background and Objectives This was a multicenter study to evaluate the usefulness of the tumor necrosis factor-alpha (TNF-α) blocker infliximab for treatment of Korean pediatric patients with refractory Kawasaki disease (KD). Subjects and Methods Data from 16 patients throughout Korea who were diagnosed with refractory KD and received infliximab were collected retrospectively. Results Complete response to therapy with cessation of fever occurred in 13 of 16 patients. C-reactive protein (CRP) concentrations decreased following infliximab infusion in all 14 patients in whom it was measured before and after treatment. There were no infusion reactions or complications associated with infliximab except in 1 case with acute hepatitis occurring during treatment followed by calculous cholecystitis 4 months later. Fifteen patients had coronary artery (CA) abnormalities before infliximab therapy. Three had transient mild dilatation and 9 had CA aneurysms, with subsequent normalization in 4 patients, persistent mild dilatation in 3, persistent aneurysm in 2, and there were 3 cases (2 with CA aneurysm, 1 with mild CA dilatation) without follow-up echocardiography. Conclusion The results of this study suggest that infliximab may be useful in the treatment of refractory KD, and it appears that there is no significant further progression of CA lesions developing after infliximab treatment. Multicenter trials with larger numbers of patients and long-term follow-up are necessary to assess the clinical efficacy and safety of infliximab in refractory KD.

Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion in kawasaki disease.

Background and Objectives The pathogenesis of hyponatremia (serum sodium <135 mEq/L) in Kawasaki disease (KD) remains unclear. We investigated the clinical significance of hyponatremia, and the role of interleukin (IL)-6 and IL-1β in the development of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) in KD. Subjects and Methods Fifty KD patients were prospectively enrolled and analyzed for clinical and laboratory variables according to the presence of hyponatremia or SIADH. Results Thirteen KD patients (26%) had hyponatremia and 6 of these had SIADH. In patients with hyponatremia, the percentage of neutrophils (% neutrophils), C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were higher than in those without hyponatremia, while serum triiodothyronine (T3) and albumin were lower. Patients with hyponatremia had a higher incidence of intravenous immunoglobulin-resistance but this was not statistically significant. No differences existed between patients with and without SIADH with regard to clinical or laboratory variables and the incidence of IVIG-resistance. Serum sodium inversely correlated with % neutrophils, CRP, and NT-proBNP, and positively correlated with T3 and albumin. Serum IL-6 and IL-1β levels increased in KD patients and were higher in patients with hyponatremia. Plasma antidiuretic hormone increased in patients with SIADH, which tended to positively correlate with IL-6 and IL-1β levels. Conclusion Hyponatremia occurs in KD patients with severe inflammation, while increased IL-6 and IL-1β may activate ADH secretion, leading to SIADH and hyponatremia in KD.

Mycoplasma pneumoniae infection in patients with Kawasaki disease

Purpose Kawasaki disease (KD) is the main cause of acquired heart disease in children. In addition to cardiovascular involvement, many complications have been recognized in KD. However, respiratory complications have been rarely reported. We investigated the differences in clinical characteristics, laboratory findings, radiography findings, and echocardiography findings of Mycoplasma pneumoniae infection and other types of pneumonia in KD patients. Methods Among 358 patients with KD, 54 developed concurrent pneumonia. Among the 54 patients, 12 (22.2%) with high titers of anti-M. pneumoniae antibody (AMA) (>1:640) were grouped in the M. pneumoniae group and 42 were included in the control group. Serum AMA was measured in each patient. Clinical laboratory findings and total duration of fever were analyzed. Results The duration of fever, serum hemoglobin, white blood cell count, platelet count, erythrocyte sedimentation rate, C-reactive protein level, albumin level, and the incidence of coronary arterial lesions showed no statistical difference in the 2 groups. Neutrophil count was significantly higher in the M. pneumoniae group than in the control group. Among various radiography findings observed in pneumonia, consolidation and pleural effusion were more frequent in the M. pneumoniae group than in the control group. On the other hand, parahilar peribronchial opacification, diffuse interstitial lesion, and normal findings prevailed in the control group. Conclusion KD patients can have concurrent infections, especially pulmonary symptoms. The cause of KD is likely to be associated with M. pneumoniae infection. Thus, immediate treatment of M. pneumoniae infection in KD patients is very important.

Is high-dose aspirin necessary in the acute phase of kawasaki disease?

Background and Objectives We sought to determine whether high-dose aspirin is necessary for the acute therapy of Kawasaki disease (KD) in the intravenous immunoglobulin (IVIG) era. Subjects and Methods Two groups of KD patients treated during the different periods were included. Study group (n=51, treated with IVIG without concomitant use of aspirin in the acute phase) was compared with control group (n=129, treated with IVIG plus high-dose aspirin) with regard to the response to IVIG, duration of fever after IVIG completion, time to C-reactive protein (CRP) <3 mg/dL, and the incidence of coronary artery lesions (CALs). Results There was no difference between the groups in age, sex, and duration of fever before treatment. Pre-IVIG laboratory measures also did not differ from each other. IVIG-resistant cases were 8 (15.7%) in study group and 22 (17.1%) in control group (p=1.000). Mean duration of fever after IVIG completion in IVIG-responsive patients was 13.3±13.5 hours in study group compared to 6.2±8.3 hours in control group (p=0.000). The mean time to decrease in CRP was 4.0±1.7 days in study group and 4.1±2.2 days in control group (p=0.828). There were 2 (3.9%) patients with CALs in study group and 10 (7.8%) in control group (p=0.514). Conclusion Although high-dose aspirin shortens the duration of fever, treatment without aspirin in the acute phase has no influence on the response to IVIG, resolution of inflammation, or the development of CALs. In the IVIG era, high-dose aspirin may provide little benefit to the treatment in the acute phase of KD.

Infliximab as the First Retreatment in Patients with Kawasaki Disease Resistant to Initial Intravenous Immunoglobulin.

Forty-three patients with Kawasaki disease who were resistant to initial intravenous immunoglobulin (IVIG) were randomized to receive either a second dose of IVIG (n = 32) or an infliximab (n = 11). With IVIG retreatment 21 patients (65.6%) responded, and with infliximab 10 patients (90.9%) responded. The infliximab group had shorter duration of fever and fewer days of hospitalization. Coronary artery outcomes and adverse events were similar.

Accelerated Thrombotic Occlusion of a Medium-Sized Coronary Aneurysm in Kawasaki Disease by the Inhibitory Effect of Ibuprofen on Aspirin

The fate of coronary artery aneurysms (CAAs) caused by Kawasaki disease depends mainly on their initial size and shape. Small to medium-sized CAAs are known to regress to normal size or decrease in size, with a good outcome. A patient with Kawasaki disease is reported who had a medium-sized CAA prematurely occluded with thrombi during regression, resulting in myocardial ischemia. This event was probably due to simultaneous use of aspirin and ibuprofen. Thus, the concomitant use of ibuprofen should be avoided when aspirin is given as an antiplatelet agent because ibuprofen blocks the platelet inhibition induced by aspirin.

Clinical characteristics and serum N-terminal pro-brain natriuretic peptide as a diagnostic marker of Kawasaki disease in infants younger than 3 months of age

Purpose The incidence of Kawasaki disease (KD) is rare in young infants (less than 3 months of age), who present with only a few symptoms that fulfill the clinical diagnostic criteria. The diagnosis for KD can therefore be delayed, leading to a high risk of cardiac complications. We examined the clinical characteristics and measured the serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels of these patients for assessing its value in the early detection of KD. Methods We retrospectively reviewed the data of young infants diagnosed with KD from 2004 to 2012. The control group included 20 hospitalized febrile patients. Laboratory data, including NT-proBNP were obtained for each patient in both groups. Results Incomplete KD was observed in 21/24 patients (87.5%). The mean fever duration on admission was 1.36±1.0 days in the KD group. Common symptoms included erythema at the site of Bacille Calmette-Guerin inoculation (70.8%), skin rash (50.0%), changes of oropharyngeal mucosa (29.1%), and cervical lymphadenopathy (20.8%). The mean number of major diagnostic criteria fulfilled was 2.8±1.4. Five KD patients (20.8%) had only one symptom matching these criteria. The incidence of coronary artery complications was 12.5%. The mean serum NT-proBNP level in the acute phase, in the KD and control groups, were 4,159±3,714 pg/mL and 957±902 pg/mL, respectively, which decreased significantly in the convalescent phase. Conclusion Incomplete KD was observed in 87.5% patients. Serum NT-proBNP might be a valuable biomarker for the early detection of KD in febrile infants aged <3 months.

Coexistence of Ductal Constriction and Closure of the Foramen Ovale in Utero

We report a fetus with an unusual combination of a narrow ductus arteriosus (DA) and foramen ovale. A pregnant mother was referred at 26 weeks of gestation for fetal pericardial effusion. Fetal echocardiography showed pericardial effusion, right atrial enlargement, right ventricular hypertrophy, and tricuspid regurgitation. The DA looked tortuous with S-shaped kinking. The atrial septum primum bulged into the left atrium. Color Doppler did not show any flow across the atrial septum. Cesarean section was performed at 31 weeks of gestation. Admission to intensive care was required after delivery, but the infant gradually improved and was discharged home without any sequela.

A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease

Kawasaki disease (KD), a systemic vasculitis of infants and children, manifests as fever and mucocutaneous inflammation. Although its etiology is largely unknown, the epidemiological data suggest that genetic factors are important in KD susceptibility. To identify genetic variants influencing KD susceptibility, we performed a genome-wide association study (GWAS) and replication study using a total of 915 children with KD and 4553 controls in the Korean population. Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with KD susceptibility (P<1.0 × 10−5), including the previously reported BLK locus (rs6993775, odds ratio (OR)=1.52, P=2.52 × 10−11). The other two loci were newly identified: NMNAT2 on chromosome 1q25.3 (rs2078087, OR=1.33, P=1.15 × 10−6) and the human leukocyte antigen (HLA) region on chromosome 6p21.3 (HLA-C, HLA-B, MICA and HCP5) (rs9380242, rs9378199, rs9266669 and rs6938467; OR=1.33–1.51, P=8.93 × 10−6 to 5.24 × 10−8). Additionally, SNP rs17280682 in NLRP14 was associated significantly with KD with a family history (18 cases vs 4553 controls, OR=6.76, P=5.46 × 10−6). These results provide new insights into the pathogenesis and pathophysiology of KD.

An inhibitory effect of tumor necrosis factor-alpha antagonist to gene expression in monocrotaline-induced pulmonary hypertensive rats model

Purpose Tumor necrosis factor (TNF)-α is thought to contribute to pulmonary hypertension. We aimed to investigate the effect of infliximab (TNF-α antagonist) treatment on pathologic findings and gene expression in a monocrotaline-induced pulmonary hypertension rat model. Methods Six-week-old male Sprague-Dawley rats were allocated to 3 groups: control (C), single subcutaneous injection of normal saline (0.1 mL/kg); monocrotaline (M), single subcutaneous injection of monocrotaline (60 mg/kg); and monocrotaline + infliximab (M+I), single subcutaneous injection of monocrotaline plus single subcutaneous injection of infliximab (5 mg/kg). The rats were sacrificed after 1, 5, 7, 14, or 28 days. We examined changes in pathology and gene expression levels of TNF-α, endothelin-1 (ET-1), endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS), matrix metalloproteinase (MMP)2, and tissue inhibitor of matrix metalloproteinase (TIMP). Results The increase in medial wall thickness of the pulmonary arteriole in the M+I group was significantly lower than that in the M group on day 7 after infliximab treatment (P<0.05). The number of intra-acinar muscular arteries in the M+I group was lower than that in the M group on days 14 and 28 (P<0.05). Expression levels of TNF-α, ET-1, ERA, and MMP2 were significantly lower in the M+I group than in the M group on day 5, whereas eNOS and TIMP expressions were late in the M group (day 28). Conclusion Infliximab administration induced early changes in pathological findings and expression levels of TNF-α, and MMP2 in a monocrotaline-induced pulmonary hypertension rat model.