A diagnostic algorithm combining clinical and molecular data distinguishes Kawasaki disease from other febrile illnesses

<p>Abstract</p> <p>Background</p> <p>Kawasaki disease is an acute vasculitis of infants and young children that is recognized through a constellation of clinical signs that can mimic other benign conditions of childhood. The etiology remains unknown and there is no specific laboratory-based test to identify patients with Kawasaki disease. Treatment to prevent the complication of coronary artery aneurysms is most effective if administered early in the course of the illness. We sought to develop a diagnostic algorithm to help clinicians distinguish Kawasaki disease patients from febrile controls to allow timely initiation of treatment.</p> <p>Methods</p> <p>Urine peptidome profiling and whole blood cell type-specific gene expression analyses were integrated with clinical multivariate analysis to improve differentiation of Kawasaki disease subjects from febrile controls.</p> <p>Results</p> <p>Comparative analyses of multidimensional protein identification using 23 pooled Kawasaki disease and 23 pooled febrile control urine peptide samples revealed 139 candidate markers, of which 13 were confirmed (area under the receiver operating characteristic curve (ROC AUC 0.919)) in an independent cohort of 30 Kawasaki disease and 30 febrile control urine peptidomes. Cell type-specific analysis of microarrays (csSAM) on 26 Kawasaki disease and 13 febrile control whole blood samples revealed a 32-lymphocyte-specific-gene panel (ROC AUC 0.969). The integration of the urine/blood based biomarker panels and a multivariate analysis of 7 clinical parameters (ROC AUC 0.803) effectively stratified 441 Kawasaki disease and 342 febrile control subjects to diagnose Kawasaki disease.</p> <p>Conclusions</p> <p>A hybrid approach using a multi-step diagnostic algorithm integrating both clinical and molecular findings was successful in differentiating children with acute Kawasaki disease from febrile controls.</p

Hospitalisation with Infection, Asthma and Allergy in Kawasaki Disease Patients and Their Families: Genealogical Analysis Using Linked Population Data

Background: Kawasaki disease results from an abnormal immunological response to one or more infectious triggers. We hypothesised that heritable differences in immune responses in Kawasaki disease-affected children and their families would result in different epidemiological patterns of other immune-related conditions. We investigated whether hospitalisation for infection and asthma/allergy were different in Kawasaki disease-affected children and their relatives. Methods/Major Findings: We used Western Australian population-linked health data from live births (1970-2006) to compare patterns of hospital admissions in Kawasaki disease cases, age- and sex-matched controls, and their relatives. There were 295 Kawasaki disease cases and 598 age- and sex-matched controls, with 1,636 and 3,780 relatives, respectively. Compared to controls, cases were more likely to have been admitted at least once with an infection (cases, 150 admissions (50.8%) vs controls, 210 admissions (35.1%); odds ratio (OR) = 1.9, 95% confidence interval (CI) 1.4-2.6, P = 7.2×10-6), and with asthma/allergy (cases, 49 admissions (16.6%) vs controls, 42 admissions (7.0%); OR = 2.6, 95% CI 1.7-4.2, P = 1.3×10-5). Cases also had more admissions per person with infection (cases, median 2 admissions, 95% CI 1-5, vs controls, median 1 admission, 95% CI 1-4, P = 1.09×10-5). The risk of admission with infection was higher in the first degree relatives of Kawasaki disease cases compared to those of controls, but the differences were not significant. Conclusion: Differences in the immune phenotype of children who develop Kawasaki disease may influence the severity of other immune-related conditions, with some similar patterns observed in relatives. These data suggest the influence of shared heritable factors in these families

Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease.

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm-: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4 × 10(-5)) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation

Modulating effects of mannose binding lectin genotype on arterial stiffness in children after Kawasaki disease

Systemic arterial stiffness is increased in patients after Kawasaki disease (KD). Recently, associations between mannose-binding lectin (MBL) gene mutation and coronary complications in infants with KD and atherosclerosis in adults have been reported. We tested the hypothesis that MBL genotype modulates arterial stiffness in children after KD. Seventy-one KD patients (42 with and 29 without coronary aneurysms), aged 9.5 ± 3.7 y, and 41 age-matched controls were studied. We determined and compared their blood pressure, brachioradial arterial stiffness as determined by pulse wave velocity (PWV), fasting total cholesterol, serum MBL level, and MBL genotype. Additionally, the modulating effects of different MBL expression genotypes [high level (HL) versus intermediate or low level (IL/LL)] on arterial stiffness in different groups were assessed. The MBL genotype distributions did not differ between patients and controls (p = 0.41) or between patients with and without coronary aneurysms (p = 0.42). Patients with IL/LL expression genotypes had significantly faster PWV than those with HL expression genotypes (7.93 ± 1.38 m/s versus 6.67 ± 2.28 m/s, p = 0.027). This genotype-modulating effect is more pronounced in patients without (HL 8.86 ± 0.77 m/s versus IL/LL 6.48 ± 2.32 m/s, p = 0.02) than those with (HL 7.50 ± 1.41 m/s versus IL/LL 6.80 ± 2.28 m/s, p = 0.32) coronary aneurysms. Multiple linear regresion analysis identified age (β = 0.26, p = 0.012), being a Kawasaki patient (β = 0.22, p = 0.015), and MBL IL/LL genotype subgroup (β = 0.20, p = 0.03) as significant determinants of arterial stiffness in the entire cohort. In conclusion, MBL genotype modulates arterial stiffness, an important cardiovascular risk factor, in children after KD.link_to_subscribed_fulltex