Maarten H. Biezeveld

Association of mannose-binding lectin genotype with cardiovascular abnormalities in Kawasaki disease

Kawasaki disease is an acute vasculitis of possible infectious cause, which in particular affects the coronary arteries. Young children rely mostly on their innate immune system for protection against invading microorganisms, of which mannose-binding lectin is an important component. We aimed to investigate the possible role of the gene for this molecule (MBL) in white Dutch patients with Kawasaki disease. In 90 patients, frequency of mutations in the MBL gene was higher than in healthy children. In children younger than 1 year, those with mutations were at higher risk of development of coronary artery lesions than were those without (odds ratio 15.7, 95% CI 1.4-176.5, p=0.026). Our findings suggest that the innate immune system contributes differently to pathophysiology of Kawasaki disease at various ages.

Effect of dexamethasone on tracheal viral load and interleukin-8 tracheal concentration in children with respiratory syncytial virus infection

Background. Lower respiratory tract infection caused by respiratory syncytial virus (RSV) is in part an immune-mediated disease. For that reason corticosteroids might be effective, especially in patients with severe RSV lower respiratory tract infection. Our aim was to assess the effect of dexamethasone on tracheal viral load and airway inflammation in patients with RSV infection. Methods. Mechanically ventilated children with proven RSV infection were randomized to receive dexamethasone (0.6 mg/kg/day in four doses for 48 h) or placebo. Daily tracheal aspirates were analyzed for viral load (by quantitative polymerase chain reaction), interleukin (IL)-8 and white blood cell count. Results. The RSV RNA concentrations decreased in a similar manner from baseline in the dexamethasone (9 patients) and in the placebo group (13 patients). IL-8 decreased from baseline in the dexamethasone group but increased in the placebo group during the first 48 h [change from baseline at 24 h, –2.3 vs. 0.9 ln ng/ml (95% confidence interval for difference, −4.2 to 0.3, P = 0.02) and at 48 h, –4.2 vs. 0.4 ln mg/ml (95% confidence interval for difference, −5.3 to –0.3; P = 0.03), respectively], without effect on the tracheal white blood cell count. Conclusion. Dexamethasone does not cause an impaired decline of tracheal RSV but lowers IL-8 of children mechanically ventilated for RSV lower respiratory tract infection, potentially leading to less inflammation and reduced phagocyte activation.

The involvement of Fc gamma receptor gene polymorphisms in Kawasaki disease.

Kawasaki disease is an acute febrile syndrome in infancy, characterized by vasculitis of medium‐sized arteries. Without treatment the disease can lead to coronary artery lesions (CAL) in approximately 25% of the children. Therapy consists of intravenous immunoglobulins (IVIG), leading to a decrease of complications to 5–16%. Little is known about the working mechanisms of IVIG. In this study we evaluated the involvement of Fcγ receptors (FcγRs) in Kawasaki disease by the determination of the frequency of known single nucleotide polymorphisms (SNPs) in the genes coding for the FcγRs and compared this with frequencies in a cohort of healthy controls. There was no difference in the distribution of the functionally relevant genotypes for FcγRIIa‐131H/R, FcγRIIb‐232I/T, FcγRIIIa‐158 V/F and FcγRIIIb‐NA1/NA2 between the patient group and the healthy controls. Furthermore, there were no polymorphisms linked to the disease severity as indicated by the absence or development of CAL during the disease. Altered transcription or expression of FcγR on specific cell types of the immune system may still play a role in susceptibility and treatment success, but at a level different from the functional SNPs in FcγR genes tested in this study.

Extracardial Vasculopathy After Kawasaki Disease: A Long‐Term Follow‐up Study

Background Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysm (CAA) as a major complication. Controversy exists about cardiovascular risk later in life. The aim of our study was to evaluate whether KD patients are at increased risk, as assessed by carotid intima‐media thickness (cIMT). Methods and Results We measured cIMT over 15 years by B‐mode ultrasonography in KD patients during follow‐up and in unaffected controls (mostly siblings). A multilevel, repeated‐measures, linear mixed‐effects model was used to evaluate the association between KD and cIMT. A total of 319 patients with 528 measurements were compared with 150 controls. In KD patients, the mean cIMT was increased compared with controls (0.375 mm [95% CI 0.372–0.378 mm] versus 0.363 mm [95% CI 0.358–0.368 mm]; P<0.001). Furthermore, mean cIMT of CAA‐negative patients was 0.373 mm (P<0.01 compared with controls), of patients with small–medium CAA was 0.374 mm (P<0.05 compared with controls), and of patients with giant CAA was 0.381 mm (P<0.01 compared with controls). Compared with controls, CAA‐negative participants started with an increased cIMT (+0.0193±0.0053 mm, P<0.001) but showed slower progression (−0.0014±0.0006 mm/year, P=0.012). Patients with giant CAA showed a trend toward increased cIMT progression (0.0013±0.0007 mm/year, P=0.058). Conclusions We observed a positive correlation between cIMT and KD severity of coronary arteritis at the acute stage. Although initially increased, the cIMT in CAA‐negative patients normalized at a later age. In contrast, patients with a history of KD complicated by giant CAA showed a trend toward persistently increased cIMT. These patients may need cardiovascular counseling and follow‐up beyond the heart.

Facial nerve palsy in a thirteen-year-old male youth with Kawasaki disease.

A 13-year-old male youth was hospitalized with Kawasaki disease. In the course of the disease he developed a facial nerve palsy and an aneurysm of the right coronary artery. After treatment with immunoglobulins both complications disappeared within 10 days and 1 month, respectively.

Association of FC Γ Receptor Polymorphisms in Kawasaki Disease

Introduction: Inadequate handling or clearance of microbial antigens is one of the explanations for the beneficial effect of IVIG in Kawasaki Disease. In case of antigen clearance by IgG, Fcγ-receptor (FcγR)-dependent mechanisms were logical targets for study. There are various FcγR types, each with a different expression pattern among leukocytes. Relevant amino acid substitutions or polymorphisms are known in the FcγRIIa, FcγRIIIA and FcγRIIIB genes, which define receptor affinity for IgG. Materials and Methods: Gene polymorphisms were determined by PCR techniques using specific primers for the FcγRIIA, FcγRIIIA and FcγRIIIB alleles. Results: In a cohort of Caucasian KD patients (n=106), FcγR polymorphisms showed differences in genotype distribution compared to a group of 87 healthy controls. A clear shift towards FcγRIIIA-158F/F was seen in our group compared to the control (41% versus 32%, p=0.08). No such differences in the genotype distribution of FcγRIIA-131R/H and FcγRIIIB-NA (1,2) were detected. A relation to IVIG efficacy and the occurrence of CAA was not found. The FcγRIIIA is expressed on Natural Killer cells and macrophages. The FcγRIIIA-158F isoform is known to have a lower affinity for IgG (1, 3, 4 subclasses) than the FcγRIIIA-158V isoform. Overexpression of this isoform might therefore result in a less effective handling of endogenous IgG or IVIG and a higher risk for the development of KD.

A Novel Marker for Disease Activity in Kawasaki Disease

A previous study on Kawasaki Disease (KD) revealed an interesting new marker to monitor disease activity: human neutrophil elastase (HNE). HNE is released by granulocytes, and their plasma levels are a good representation of the activity of those cells in vivo. Materials and Methods: A cohort of patients was screened prospectively. Blood was collected at sequential time-points, starting before IVIG administration. We determined plasma HNE and CRP, as routine inflammatory marker, by ELISA. Results: Preliminary data showed an increase of HNE levels in all KD patients in the acute phase of the disease. These levels remained high for a period of weeks only slowly returning to normal. Levels of HNE were 1155 ng/ml [95% C.I.: 703-1607 ng/ml] before IVIG administration. After 1 week, 6 weeks and 3 months the levels were 475 ng/ml [95% C.I.: 210-740 ng/ml], 300 ng/ml [95% C.I.: 158-442 ng/ml] and 386 ng/ml [95% C.I.: 69-702 ng/ml] respectively. Levels below 50 ng/ml are considered normal for children. Levels of CRP were only elevated until 1 week thereafter: 113 mg/L [95% C.I.: 70-157 mg/L] and 25 ng/ml [95% C.I.: 6.7-44 mg/L] respectively. After 6 weeks and 3 months the levels had normalized: 2.3 mg/L [95% C.I.: 0.1-4.8 mg/L] and 2.7 ng/ml [95% C.I.: 0.1-5.9 mg/L] (Normal value <5.0 mg/L). Conclusion: Human neutrophil elastase appears to be useful to monitor the acute phase of the disease activity. This finding indicates that inflammation proceeds for a longer period than has been suggested previously. A relation between prolonged inflammation and premature atherosclerosis warrants further evaluation.