Irene M. Kuipers

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.

A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation

Kawasaki disease (KD) is an acute inflammatory vasculitis that predominantly occurs in children under 5 years of age.1 It is associated with the development of coronary artery aneurysms (CAA) in 15–25% of untreated cases.2 Standard treatment consists of high-dose intravenous immunoglobulins (IVIG) along with aspirin.3 About 15% of patients do not respond to a single dose of IVIG and need retreatment.4 When ongoing signs of active disease are present, methylprednisolone pulses are often administered.5 If there is a lack of response, alternative anti-inflammatory medication such as infliximab or plasmapheresis have been suggested in individual case series.6 ,7 We report, for the first time, the beneficial use of an interleukin-1 receptor antagonist (IL-1RA) in relapsing KD. A 2-year-old boy was presented with persistent fever, coughing and swollen cervical lymph nodes. The boys condition had not improved with empirical antibiotic treatment. He developed a rash, conjunctivitis and swollen extremities. Upon admission the …

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case–control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3–CCR2–CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5‐Δ32 was observed with an allele frequency of 10·7% in the control population compared to 6·5% in the KD patients (P = 0·04). Two haplotypes of the CCR3–CCR2–CCR5 gene‐cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene‐cluster CCR3–CCR2–CCR5 was observed.

Cardiac magnetic resonance imaging for noninvasive assessment of cardiovascular disease during the follow-up of patients with Kawasaki disease.

Background— Kawasaki disease (KD) is the most common cause of acquired coronary artery disease in childhood. In KD, the American Heart Association recommends echocardiography for routine coronary artery surveillance and nuclear perfusion scans and conventional coronary angiography in select patients. Cardiac MRI (CMRI) may be a noninvasive and radiation-free alternative. We applied CMRI during the follow-up of patients with KD and assessed the performance of CMRI compared with echocardiography. Methods and Results— Patients with KD aged ≥8 years were consecutively included. Sixty-three patients (median age, 14.6 years; 74.6% male sex) underwent a comprehensive CMRI protocol including adenosine stress testing to evaluate coronary artery anatomy, ischemia, and myocardial infarction. All patients underwent CMRI without significant complications. On CMRI, 23 coronary artery aneurysms (CAAs) were identified in 15 patients. CMRI detected thrombus formation in 6 CAAs in 4 patients, wall motion disturbances and ischemia in 4 patients, and delayed hyperenhancement indicating myocardial infarction in 5 patients. Wall motion and perfusion abnormalities were noted in territories supplied by affected coronary arteries. CMRI results were compared with recent echocardiography findings. In 6 of the 15 patients with CAAs on CMRI, CAAs were not detected by echocardiography. Conclusions— A comprehensive CMRI protocol including adenosine stress testing is feasible to identify coronary artery pathology, ischemia, and myocardial infarction in former patients with KD and compares favorably with echocardiography. CMRI may be used as a noninvasive and radiation-free imaging method for coronary artery surveillance during the long-term follow-up of patients with KD.

Five years of Kawasaki disease in the Netherlands a national surveillance study

Background: The aim of this study was to evaluate the incidence, disease presentation, treatment and cardiac outcome of Kawasaki disease (KD) in The Netherlands. Methods: The national Dutch Pediatric Surveillance Unit was used to prospectively register new KD cases from 2008 through 2012. Questionnaires were sent to pediatricians to obtain clinical information. Results: Nationwide 341 cases were reported during the 5-year study period, of which 319 questionnaires (93.0%) were returned. The mean incidence of KD was estimated to be 5.8/100,000 children <5 years of age. The median age at disease onset was 2.4 years (range 0.1–14.6 years) and 79.2% of cases were <5 years of age. The male-to-female ratio was 1.5 to 1. Incomplete KD was diagnosed in 22.3% of cases and these cases were significantly younger than complete cases [median: 1.1 (0.1–13.7) vs. 2.8 (0.2–14.6) years, P < 0.001]. In total, 308 patients (96.6%) received intravenous immunoglobulins (IVIG). Retreatment with IVIG was given in 71 (23.1%) and additional steroid treatment in 17 patients (5.5%). During the acute phase, coronary artery aneurysms developed in 43 cases (13.5%). Multivariate logistic regression analysis showed that male gender, delay of treatment (>10 days) and IVIG retreatment were independent risk factors for coronary artery aneurysms development. Conclusions: This prospective study of KD in The Netherlands revealed a mean annual incidence of 5.8/100,000 children <5 years of age. Clinicians should consider the diagnosis of KD in young (male) children with persistent inexplicable fever to start IVIG treatment within 10 days to prevent development of coronary artery aneurysms.

Aerobic Exercise Influences Quality of Life of Children and Youngsters With Congenital Heart Disease: A Randomized Controlled Trial

PURPOSE To evaluate effects of an exercise program on health-related quality of life (HRQoL) in children and adolescents with tetralogy of Fallot (ToF) or a Fontan circulation. METHODS Stratified, randomized, controlled intervention study conducted in five participating centers of pediatric cardiology in The Netherlands. In total, 93 patients, aged 10-25 years, with surgical repair for tetralogy of Fallot or with a Fontan circulation for single-ventricle physiology were included. They were randomly allocated with a ratio of 2:1 to: (1) a 12-week period with an exercise program for 3 times per week or (2) to a control group. Randomization was stratified by age, gender, and cardiac diagnosis. At baseline and follow-up after 12 weeks, all participants completed Web-based age-appropriate HRQoL questionnaires. Primary analyses involved change in HRQoL during follow-up. Secondary analyses concerned influence of cardiac diagnosis and comparison with normative data. RESULTS Forty-eight (86%) and 32 (86%) patients in the exercise-group and control-group respectively completed all questionnaires at baseline and follow-up. Compared with the control-group, children, aged 10-15 years, in the exercise-group improved significantly on self-reported cognitive functioning, p < .05, r = .30, and parent-reported social functioning, p < .05, r = .30. Youngsters aged 16-25 years did not change their HRQoL. Cardiac diagnosis had no influence on pre/post changes. Children and youngsters in this study reported comparable or better HRQoL than norm groups. CONCLUSIONS Participation in an exercise program improved HRQoL of children with ToF or a Fontan circulation, especially in those with low baseline QoL.

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.

Evaluation of Cardiac Function by Magnetic Resonance Imaging During the Follow-Up of Patients With Kawasaki Disease

Background—Although histopathologic studies suggest persistent myocardial abnormalities after Kawasaki disease (KD), the long-term effects on cardiac function remain to be revealed. We investigated biventricular volumes, function, and the presence of myocardial fibrosis by cardiac magnetic resonance imaging during long-term follow-up of KD. Methods and Results—Sixty patients with a history of KD (mean age, 16.9 years; 67% men; median interval after KD onset, 11.6 years) and 20 healthy control subjects (mean age, 17.9 years; 55% men) 12 to 24 years of age underwent cardiac magnetic resonance imaging. Biventricular end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction were determined. Volumetric measurements were indexed for body surface area. Late contrast enhancement was used to detect areas of myocardial fibrosis. Biventricular volumes and function did not differ significantly between patients and control subjects. There were also no significant differences between patients with and without a history of left ventricular dysfunction resulting from KD-associated myocarditis or between patients with and without coronary artery aneurysms. Only those with prior ischemic heart disease had a significantly lower left ventricular ejection fraction compared with unaffected KD cases (left ventricular ejection fraction, 51% versus 57%; P=0.012). Late contrast enhancement was observed in only 2 patients with severe coronary artery aneurysms and was typical for myocardial infarction. Conclusions—In this cardiac magnetic resonance imaging study evaluating the cardiac function of patients with KD at long-term follow-up, we did not observe a difference in cardiac function between KD patients and control subjects, except for a subgroup of patients with ischemic heart disease as a result of severe coronary artery pathology.

The effect of exercise training on cardiac remodelling in children and young adults with corrected tetralogy of Fallot or Fontan circulation: A randomized controlled trial

BACKGROUND Exercise can improve physical fitness in children and adults with congenital heart disease. We hypothesized that exercise training would not lead to adverse cardiac remodelling in this population. METHODS AND RESULTS This multi-centre randomized controlled trial included children and young adults (10 to 25 years) with either corrected tetralogy of Fallot or Fontan circulation. The exercise-group was enrolled in a 12 week standardized aerobic dynamic exercise training program. The control-group continued their life-style and received care as usual. Both groups underwent cardiopulmonary exercise testing, cardiac magnetic resonance imaging (MRI), echocardiography and neurohormonal assessment, within 2 weeks before and 2 weeks after the intervention period. Fifty-six patients were randomized to the exercise-group and 37 to the control-group. We assessed changes between the pre- and the post-intervention period for the exercise group compared to the changes in the control-group. Peak load increased significantly in the exercise-group compared to the control-group (exercise-group 6.9 ± 11.8 W; control-group 0.8 ± 13.9 W; p=0.047). There were no adverse events linked to the study. Ventricular systolic parameters, cardiac dimensions and neurohormonal markers during follow-up did not change in patients allocated to the exercise-group and control-group. Although there were some isolated minor changes in inflow parameters, there was no consistent pattern of changes, indicating a lack of true change in the diastolic function. CONCLUSION We demonstrated that no clinically relevant adverse cardiac remodelling occurred after 12 weeks of exercise training in patients with either corrected tetralogy of Fallot or Fontan circulation. CLINICAL TRIAL REGISTRATION www.trialregister.nl, identification NTR2731.

Cardiovascular imaging in children and adults following Kawasaki disease

AbstractKawasaki disease (KD) is a paediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. Two guidelines exist regarding the follow-up of patients after KD, by the American Heart Association and the Japanese Circulation Society. After the acute phase, CAA-negative patients are checked for cardiovascular risk assessment or with ECG and echocardiography until 5 years after the disease. In CAA-positive patients, monitoring includes myocardial perfusion imaging, conventional angiography and CT-angiography. However, the invasive nature and high radiation exposure do not reflect technical advances in cardiovascular imaging. Newer techniques, such as cardiac MRI, are mentioned but not directly implemented in the follow-up. Cardiac MRI can be performed to identify CAA, but also evaluate functional abnormalities, ischemia and previous myocardial infarction including adenosine stress-testing. Low-dose CT angiography can be implemented at a young age when MRI without anaesthesia is not feasible. CT calcium scoring with a very low radiation dose can be useful in risk stratification years after the disease. By incorporating newer imaging techniques, detection of CAA will be improved while reducing radiation burden and potential complications of invasive imaging modalities. Based on the current knowledge, a possible pathway to follow-up patients after KD is introduced. Key Points • Kawasaki disease is a paediatric vasculitis with coronary aneurysms as major complication. • Current guidelines include invasive, high-radiation modalities not reflecting new technical advances. • Cardiac MRI can provide information on coronary anatomy as well as cardiac function. • (Low-dose) CT-angiography and CT calcium score can also provide important information. • Current guidelines for follow-up of patients with KD need to be revised.