The Spectrum of Cardiovascular Lesions Requiring Intervention in Adults After Kawasaki Disease.

OBJECTIVES: The aim of this study was to characterize the range of management issues raised by adults with cardiovascular sequelae from Kawasaki disease (KD) in childhood. BACKGROUND: Aneurysms resulting from vascular inflammation associated with KD in childhood may remain clinically silent until adulthood. Adults with large aneurysms, unstable angina, or myocardial infarction following KD in childhood present unique challenges to interventional cardiologists and cardiothoracic surgeons. METHODS: In an observational study of adults with histories of KD in childhood, data were collected regarding the medical histories and outcomes of 154 adult KD patients, of whom 21 underwent either percutaneous interventions or surgery. RESULTS: Of the 21 subjects with interventions, 11 had been diagnosed with KD in childhood, and 10 had histories of KD-compatible illnesses. Seventeen subjects were asymptomatic until experiencing acute cardiovascular symptoms: acute myocardial infarction (n = 12), angina (n = 2), end-stage congestive heart failure requiring cardiac transplantation (n = 1), and claudication (n = 2). CONCLUSIONS: Cardiovascular complications in these subjects illustrate the following points: 1) even small to moderate-sized aneurysms that "normalize" on echocardiography in childhood can lead to stenosis and thrombosis decades after the acute illness; 2) coronary interventions without intravascular ultrasound may result in clinically significant underestimation of vessel luminal diameter; 3) failure to assess the extent of calcification may lead to suboptimal procedural outcomes; and 4) patients with symptomatic peripheral aneurysms may benefit from endarterectomy or resection. Interventional cardiologists should be aware of the potential challenges in treating this growing population of adults.

Axillary, Oral and Rectal Routes of Temperature Measurement During Treatment of Acute Kawasaki Disease.

BACKGROUND: Important therapeutic decisions are made based on the presence or absence of fever in patients with Kawasaki disease (KD), yet no standard method or threshold exists for temperature measurement during the diagnosis and treatment of these patients. We sought to compare surface and internal (rectal or oral) routes of temperature measurement for the detection of fever as a marker of treatment resistance. METHODS: From a randomized, placebo-controlled trial of infliximab as an adjunct to primary intravenous immunoglobulin treatment for acute KD, we collected concurrent (within 5 minutes) axillary and internal temperature measurements and performed receiver-operating characteristic and Bland-Altman analyses. We also determined the ability of surface temperatures to detect treatment resistance defined by internal temperature measurements. RESULTS: Among 452 oral-axillary and 439 rectal-axillary pairs from 159 patients, mean axillary temperatures were 0.25 and 0.43 °C lower than oral and rectal temperatures and had high receiver-operating characteristic areas under curves. However, axillary temperatures ≥ 38.0 °C had limited sensitivity to detect fever defined by internal temperatures. Axillary thresholds of 37.5 and 37.2 °C provided maximal sensitivity and specificity to detect oral and rectal temperatures ≥ 38.0 °C, respectively. CONCLUSIONS: Axillary temperatures are an insensitive metric for fevers defining treatment resistance. Clinical trials should adopt temperature measurement by the oral or rectal routes for adjudication of treatment resistance in KD.

Galectin-3 is a marker of myocardial and vascular fibrosis in Kawasaki disease patients with giant aneurysms.

BACKGROUNDS: Galectin-3 (Gal-3) is a multifunctional matricellular protein associated with heart failure and cardiovascular events. Gal-3 is required for transforming growth factor-ß pathway-mediated myofibroblast activation that is a key process in coronary artery aneurysm formation in Kawasaki Disease (KD). Autopsies from young adults late after KD onset (AKD) have demonstrated bridging fibrosis throughout the myocardium and arteries. In this study, we postulated that Gal-3 may participate in the pathogenesis of myocardial and vascular fibrosis and the remodeling of coronary artery aneurysms following acute KD. METHODS AND RESULTS: We measured plasma Gal-3 levels in 63 pediatric KD (PKD) and 81 AKD subjects. AKD subjects with giant aneurysms had significantly higher Gal-3 levels compared to the other adult groups (all p<0.05). All PKD groups had significantly higher Gal-3 levels than pediatric healthy controls (HC) (all p<0.05). Histological and immunohistochemical staining was performed on tissues from 10 KD autopsies and one explanted heart. Gal-3 positive staining was detected associated with acute inflammation and in spindle-shaped cells in the myocardium and arterial wall in KD subjects with giant aneurysms. CONCLUSIONS: AKD subjects with giant aneurysms and PKD subjects had significantly higher plasma Gal-3 levels than HC and Gal-3 expression was increased in the myocardium of KD subjects who died with either acute inflammation or marked myocardial fibrosis. Gal-3 may be a clinically useful biomarker that identifies a subset of KD patients at highest risk of myocardial and vascular fibrosis, and may be an attractive therapeutic target to prevent myocardial dysfunction in this subset.

Lipoprotein particle concentrations in children and adults following Kawasaki disease.

OBJECTIVE: To test the hypothesis that children and adults with a history of Kawasaki disease (KD) are more likely to have abnormal lipoprotein particle profiles that could place them at increased risk for developing atherosclerosis later in life. STUDY DESIGN: Fasting serum samples were obtained from 192 children and 63 adults with history of KD and 90 age-similar healthy controls. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy (LipoScience Inc, Raleigh, North Carolina), and serum was assayed for total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) cholesterol (HDL-C). Low-density lipoprotein (LDL) cholesterol was estimated using the Friedewald formula. Data were analyzed in a least-square means model, with adjustment for age and sex and with the use of Holm correction for multiple comparisons. RESULTS: Compared with respective control groups, both adult and pediatric subjects with KD had significantly lower mean very low-density lipoprotein-chylomicron particles, intermediate-density lipoproteins, triglycerides, and TC concentrations. Pediatric subjects with KD had significantly lower LDL particle and LDL cholesterol concentrations and lower mean TC/HDL-C ratio (P < .001). In contrast, the adult subjects with KD had significantly lower HDL particle, small HDL particle, and HDL-C concentrations (P < .001), but HDL-C was within normal range. CONCLUSIONS: Nuclear magnetic resonance lipoprotein particle analysis suggests that pediatric and adult subjects with KD, regardless of their aneurysm status, are no more likely than age-similar, healthy controls to have lipid patterns associated with increased risk of atherosclerosis.

Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial.

BACKGROUND: Kawasaki disease, the most common cause of acquired heart disease in developed countries, is a self-limited vasculitis that is treated with high doses of intravenous immunoglobulin. Resistance to intravenous immunoglobulin in Kawasaki disease increases the risk of coronary artery aneurysms. We assessed whether the addition of infliximab to standard therapy (intravenous immunoglobulin and aspirin) in acute Kawasaki disease reduces the rate of treatment resistance. METHODS: We undertook a phase 3, randomised, double-blind, placebo-controlled trial in two children's hospitals in the USA to assess the addition of infliximab (5 mg per kg) to standard therapy. Eligible participants were children aged 4 weeks-17 years who had a fever (temperature ≥38·0°C) for 3-10 days and met American Heart Association criteria for Kawasaki disease. Participants were randomly allocated in 1:1 ratio to two treatment groups: infliximab 5 mg/kg at 1 mg/mL intravenously over 2 h or placebo (normal saline 5 mL/kg, administered intravenously). Randomisation was based on a randomly permuted block design (block sizes 2 and 4), stratified by age, sex, and centre. Patients, treating physicians and staff, study team members, and echocardiographers were all masked to treament assignment. The primary outcome was the difference between the groups in treatment resistance defined as a temperature of 38·0°C or higher at 36 h to 7 days after completion of the infusion of intravenous immunoglobulin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00760435. FINDINGS: 196 patients were enrolled and randomised: 98 to the infliximab group and 98 to placebo. One patient in the placebo group was withdrawn from the study because of hypotension before receiving treatment. Treatment resistance rate did not differ significantly (11 [11·2%] for infliximab and 11 [11·3%] for placebo; p=0·81). Compared with the placebo group, participants given infliximab had fewer days of fever (median 1 day for infliximab vs 2 days for placebo; p<0·0001). At week 2, infliximab-treated patients had greater mean reductions in erythrocyte sedimentation rate (p=0·009) and a two-fold greater decrease in Z score of the left anterior descending artery (p=0·045) than did those in the placebo group, but this difference was not significant at week 5. Participants in the infliximab group had a greater mean reduction in C-reactive protein concentration (p=0·0003) and in absolute neutrophil count (p=0·024) at 24 h after treatment than did those given placebo, but by week 2 this difference was not significant. At week 5, none of the laboratory values differed significantly compared with baseline. No significant differences were recorded between the two groups at any timepoint in proximal right coronary artery Z scores, age-adjusted haemoglobin values, duration of hospital stay, or any other laboratory markers of inflammation measured. No reactions to intravenous immunoglobulin infusion occurred in patients treated with infliximab compared with 13 (13·4%) patients given placebo (p<0·0001). No serious adverse events were directly attributable to infliximab infusion. INTERPRETATION: The addition of infliximab to primary treatment in acute Kawasaki disease did not reduce treatment resistance. However, it was safe and well tolerated and reduced fever duration, some markers of inflammation, left anterior descending coronary artery Z score, and intravenous immunoglobulin reaction rates. FUNDING: US Food and Drug Administration, Robert Wood Johnson Foundation, and Janssen Biotech.

Infliximab treatment of pancreatitis complicating acute kawasaki disease.

Kawasaki disease can be associated with gastrointestinal complications, including pancreatitis. We describe a child in whom infliximab infusion for intravenous immunoglobulin-resistant Kawasaki disease coincided with marked clinical improvement of the patient's acute pancreatitis.

Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia.

BACKGROUND: Up to 25% of patients with untreated Kawasaki disease (KD) and 5% of those treated with intravenous immunoglobulin will develop coronary artery aneurysms. Persistent aneurysms may remain silent until later in life when myocardial ischemia can occur. We sought to determine the prevalence of coronary artery aneurysms suggesting a history of KD among young adults undergoing coronary angiography for evaluation of possible myocardial ischemia. METHODS AND RESULTS: We reviewed the medical histories and coronary angiograms of all adults <40 years of age who underwent coronary angiography for evaluation of suspected myocardial ischemia at 4 San Diego hospitals from 2005 to 2009 (n=261). History of KD-compatible illness and cardiac risk factors were obtained by medical record review. Angiograms were independently reviewed for the presence, size, and location of aneurysms and coronary artery disease by 2 cardiologists blinded to the history. Patients were evaluated for number of risk factors, angiographic appearance of their coronary arteries, and known history of KD. Of the 261 young adults who underwent angiography, 16 had coronary aneurysms. After all clinical criteria were assessed, 5.0% had aneurysms definitely (n=4) or presumed (n=9) secondary to KD as the cause of their coronary disease. CONCLUSIONS: Coronary sequelae of KD are present in 5% of young adults evaluated by angiography for myocardial ischemia. Cardiologists should be aware of this special subset of patients who may benefit from medical and invasive management strategies that differ from the strategies used to treat atherosclerotic coronary artery disease.

Calcium scoring in patients with a history of Kawasaki disease.

OBJECTIVES: The goal of this study was to assess coronary artery calcification in patients ≥10 years or age with a history of Kawasaki disease (KD). BACKGROUND: Patients with a history of KD and coronary artery aneurysms are at risk for late morbidity from coronary artery events. It is unknown whether patients with KD with acutely normal or transiently dilated coronary arteries also have increased risk of late coronary artery complications. Coronary calcium scoring using noncontrast computed tomography is a well-established tool for risk-stratifying patients with atherosclerotic coronary artery disease, but there are limited data on its role in evaluating patients with a history of KD. METHODS: We performed coronary artery calcium (CAC) volume scoring using a low radiation dose computed tomography protocol on 70 patients (median age 20.0 years) with a remote history of KD (median interval from acute KD to imaging 14.8 years). Forty-four (63%) patients had no history of coronary dilation, 12 (17%) had a history of transient dilation, and 14 (20%) had coronary aneurysms. RESULTS: All of the patients with normal coronary artery internal diameter during the acute phase of KD and 11 of 12 patients with transient dilation had CAC scores of zero. Coronary calcification was observed in 10 of the 14 patients with coronary aneurysms, with the degree of calcification ranging from mild to severe and occurring years after the patients' acute KD. CONCLUSIONS: Coronary calcification was not observed in patients with a history of KD and normal coronary arteries during the acute phase. Therefore, CAC scanning may be a useful tool to screen patients with a remote history of KD or suspected KD and unknown coronary artery status. Coronary calcification, which may be severe, occurs late in patients with coronary aneurysms. The pathophysiology and clinical implications of coronary calcification in patients with aneurysms are currently unknown and warrant further study.

Increased incidence and severity of Kawasaki disease among Filipino-Americans in San Diego county.

This study compared characteristics of Kawasaki disease (KD) in Filipino and non-Filipino children. Filipino KD patients had a higher coronary artery Z-score (P = 0.016) and aneurysm rate (P = 0.021) than KD patients of non-Filipino Asian and non-Asian descent.