CLB-08970; No. of pages: 7; 4C: Clinical Biochemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
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Article history: Received 4 September 2014 Received in revised form 20 February 2015 Accepted 21 February 2015 Available online xxxx
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Keywords: Kawasaki Biomarkers Diagnosis NT-proBNP
Faculty of Science, McMaster University, Hamilton, ON, Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada c College of Medicine, Howard University, Washington DC, USA d Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada e Department of Pediatrics, McMaster Children's Hospital, Hamilton, ON, Canada b
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Kawasaki disease (KD) is a major cause of acquired heart disease among children and increases the risk of myocardial infarction. While the biochemical basis of the disease is unclear, the evidence suggests interplay between a microbial infection and a genetic predisposition in the development of the disease. Diagnosis of KD based on clinical observation is not completely reliable and is problematic due to the time-sensitive nature of the disease. Hence, identification of inflammatory, proteomic, and genetic biomarkers may assist in earlier and more effective diagnosis and treatment. This review of observational studies and clinical trials analyzes biomarkers in recent research that may be used to establish a gold standard test for KD diagnosis. 65 articles in the literature are assessed to investigate these new biomarkers in addition to biomarkers presently in use. ESR ≥ 40 mm/h, leukocyte count ≥16 ∗ 109/L and increased WBC count are together suggestive of the presence of KD. Among proteomic biomarkers, elevated NT-proBNP and differing levels of several other proteomic biomarkers such as iNOS in monocytes and neutrophils have been observed in KD patients. Genetic polymorphisms of six HLA class I genes have also been linked with the disease, alongside MICA alleles A4 and A5.1. The results suggest that NT-proBNP is currently a very promising biomarker for future investigation; further research is warranted to allow for accurate and early detection of the disease using this biomarker. © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
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Contents . . . . . . . . . . . . . .
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Introduction . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . Inflammatory biomarkers . . . . . . Proteomic biomarkers . . . . . . . Genetic polymorphisms as biomarkers Discussion . . . . . . . . . . . . . . . Conclusion & future perspective . . . . . Executive summary . . . . . . . . . . . Competing financial interests . . . . . . Contributions . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . Acknowledgments . . . . . . . . . . . References . . . . . . . . . . . . . . .
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Pavithra Parthasarathy a,c,d, Arnav Agarwal b, Karan Chawla a, Taraneh Tofighi b, Tapas K. Mondal e,⁎
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Upcoming biomarkers for the diagnosis of Kawasaki disease: A review
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Introduction
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⁎ Corresponding author at: 3A-Health Sciences Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. Fax: +1 9055217914 . E-mail address: [email protected] (T.K. Mondal).
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Kawasaki disease (KD) is an acute pediatric multisystem vasculitis 57 primarily affecting individuals between the ages of 6 months and 58 5 years [1–3], and is the primary cause of acquired heart disease within 59
http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013 0009-9120/© 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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Two searches were conducted on PubMed to pool results addressing diagnostic biomarkers relevant to the KD. The search terms “(kawasaki [Title/Abstract]) AND biomarker [Title/Abstract]”, and “(kawasaki [Title/ Abstract]) AND diagnosis [Title/Abstract]”, were used to identify potentially relevant literature in the first and second searches, respectively. The searches were not limited by date of publication or any other criteria to ensure their comprehensiveness, especially given the significant amount of evidence available prior to 2000. The searches yielded a pooled total of 789 results. The following inclusion criteria was established for eligibility assessment of the combined search results: a) published in the English language; b) conducted in human pediatric sample(s) and/or aiming to identify relationships with direct relevance to the pediatric human population; c) directly addressing one or more biological markerrelated aspects of KD; and d) reporting a prospective or retrospective observational study, randomized controlled trial, or other form of clinical trial (i.e. primary article). As KD is most prevalent in pediatric patients less than five years of age, and presents the highest risk factors in this population, this study aimed to examine diagnostic biomarkers in a population under five years of age, otherwise defined as a pediatric population. Articles discussing biomarkers for coronary artery involvement in relation to KD were included. Articles solely pertaining to diagnostic technologies or methods of biomarker assessment without a major focus on one or more biomarkers were excluded. Title-and-abstract screening was conducted in duplicate by a pair of blinded screeners (AA, TT). A total of 129 articles were identified to be included for full-text screening following application of the inclusion criteria, primarily excluding duplicate hits, non-English articles, case reports and case series, and other studies beyond the aforementioned accepted designs. Full-text screening was conducted in duplicate by a pair of blinded screeners (PP, AA, TT, KC) based on the same criteria as during title-and-abstract screening. Following this second stage of screening, articles were selected to be included in the review, and were combined after the screening. Article classification by age of study sample (i.e. division as per adult and child-related articles, with pediatric being defined by mean/median subject age being below five years, or declaration by authors as pediatric study), by sample size (considered for inclusion if involving more than 30 participants), and by grouping of biomarker (i.e. inflammatory, genetic, proteomic) was conducted to stratify the articles to be included in the review.
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Table 1 Clinical features as criteria for diagnosis of Kawasaki disease [2,5].
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complementary clinical diagnosis; the time sensitivity of this disease necessitates the continuation of clinical diagnosis until a gold standard laboratory test with high specificity and sensitivity is established. Despite the significance of laboratory biomarkers to KD diagnosis and optimal management, the literature in the area is disparate and few attempts have been made to synthesize the available evidence (Table 2). The purpose of this study is to explore proteomic and genetic biomarkers indicative of KD and associated coronary artery damage.
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the pediatric population of industrialized nations [4,5]. While KD causes vascular inflammation in various parts of the body, the main concern is its effect on the coronary arteries. Dilatations, aneurysms, and fistulae of the coronary arteries associated with KD can lead to myocardial infarction and death, emphasizing the need for immediate diagnosis and treatment [5]. KD occurs in males and females with a 1.6:1 ratio and shows marked ethnicity- and age-based patterns of occurrence [5]. Though the first few cases of KD were described in Japan, it has since been diagnosed with increasing frequency in numerous other countries. Current accounts of international diagnoses indicate incidence rates in Japanese, Korean, and Taiwanese ethnicities being as high as 20 times the incidence rates in European-Caucasian, Australian, and New Zealander populations [6]. In a study by Salo et al., Nordic residents of Japanese descent showed earlier onset than their ethnic Nordic counterparts: more than 85% of Japanese patients were younger than 5 years of age, compared to only approximately 68% of Nordic patients (p b 0.001) [7]. While the underlying biochemical basis for KD is unknown, microbiological data suggests a pathogenic component to the origin of the disease [5]. However, given that some genetic groups are more susceptible, a microbial infection compounded by a genetic predisposition is currently accepted as the likely cause [5]. The unclear etiology of KD only allows for symptomatic treatments focused on fever and inflammation and therefore treatments that do not address the underlying cause. A single dose of intravenous immunoglobulin (IVIG) of 2 g/kg between days 5 to 7 of the illness causes marked decreases in coronary artery abnormalities and the duration of the febrile period [8]. Acetylsalicylic acid (aspirin) is co-administered with IVIG in four daily doses adding up to 80–100 mg/kg; together, IVIG and aspirin have an additive anti-inflammatory effect [2]. Other treatments such as corticosteroid and pentoxifylline administration for KD have also been evidenced in past literature, but recent data regarding their efficacy is inconclusive, or altogether insufficient, respectively [3]. Current treatments for KD have proven to be potentially financially burdensome [9]. The current gold standard clinical diagnosis of KD is based on the presentation of a collection of clinical manifestations: a prolonged fever — usually above 39 °C — persisting for more than five days, coupled with a minimum of four out of a set of five clinical features (see Table 1) [2,5,10]. A febrile patient showing two or three of the clinical features is diagnosed as presenting with incomplete KD following evaluation with an echocardiogram [2]. As the coronary effects of KD can be long-lasting and detrimental [3], it is important that accurate laboratory diagnoses are developed for early recognition of the disease. A laboratory diagnosis will serve as the universal gold standard test, as it may not depend upon the outward manifestation of the disease, unlike present clinical diagnoses that may fail to properly identify atypical cases of disease. A comparison of early and late diagnoses of KD indicated that delayed diagnosis was correlated with increased risk of the development of coronary artery aneurysms (CAAs) [11]. Current laboratory markers cannot diagnose KD without a
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Prolonged fever Usually above 39 °C, lasting for ≥5 days Minimum of 4 of the following in complete KD
Bilateral non-exudative, non-purulent conjunctival injection Polymorphous, erythematous rash Inflammation of the oral cavity Injected pharynx and lips, non-exudative fissuring of the lips, strawberry tongue Erythematous changes to extremities Peripheral oedema, peripheral erythema, periungual desquamation Cervical lymphadenopathy
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122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159
From a literature search which yielded 796 articles, a final 65 articles 161 satisfied the inclusion criteria following title-and-abstract and full-text 162 screening and were included in this review (see Fig. 1). 163 Inflammatory biomarkers
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A variety of acute inflammatory biomarkers presently comprise a significant portion of the laboratory analysis for KD patients. Largely non-specific, these markers are used in conjunction with the clinical diagnosis for KD. Erythrocyte sedimentation rate (ESR), white blood cell (WBC)/leukocyte count, platelet count, and C-reactive protein (CRP) values above their respective normal ranges help to confirm KD
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Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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P. Parthasarathy et al. / Clinical Biochemistry xxx (2015) xxx–xxx t2:1 t2:2 t2:3 t2:4 Q1
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Table 2 List of several KD diagnostic biomarkers commonly cited in literature, as well as newly mentioned biomarkers of potential use for KD diagnosis. Supplementary Table A is a complete list of all biomarkers extracted from the 65 final articles reviewed. Biomarker
Change (compared to controls)
Indication of/occurs during
References
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Erythrocyte sedimentation rate White blood cell/leukocyte count Platelet count C-Reactive protein CD69 + CD8T cell proportion in CD8T cell count CD8T cell count NT-proBNP Apolipoprotein B Haptoglobin Serum cTnI Creatine kinase-MB iNOS expression (in neutrophils, monocytes) Fibrinogen-related plasma protein levels Immunoglobulin free light chains Apolipoprotein A–I levels Plasma clusterin (apolipoprotein J) PI3K signaling (in B cells & T cell receptor signaling pathway) CXCL10 (IP-10) and CXCR3 HLA class I gene polymorphisms HLA-B35 frequency HLA-B75 frequency
↑ ↑ ↑ ↑ ↑ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↓ ↑ ↑ ↑
[12–17] [14–16,18–21] [12–15,17,22–25] [14,15,17,21,25–29,63] [30] [30] [18,31,32] [23] [23,43] [33] [33] [29] [25] [25] [23] [34] [35] [79] [36] [36]
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HLA-Cw09 frequency HLA-DRB1*11 frequency HLA-DRB1*04 frequency HLA-A26 frequency Allele A5 frequency Allele A5.1 frequency Allele A4 frequencies
↑ ↑ ↑ ↓ ↑ ↓ ↓
SNP itpkc_3 SNP rs7251246
↑ (Presence) ↑ (Presence)
Acute inflammation Acute inflammation Thrombocytosis; coronary artery disease development Prediction of cardiac sequelae, age-dependent prognosis Acute KD (early activation) Acute KD Acute KD, atypical clinical characteristics Acute KD Acute KD (ratio greater than 2; ROC curve) Myocyte injury; inflammation Not heart-specific Acute KD (neutrophils); CAL presence (neutrophils & monocytes) Acute KD KD Acute KD (ratio greater than 2; ROC curve) CAL sequelae Acute KD Acute KD KD presence KD presence; exclusively in KD patients without coronary complications KD presence KD presence with coronary complications KD presence without coronary complications KD presence without coronary complications KD presence with aneurysm KD presence Phenotypic & genotypic frequency decrease in KD with aneurysm vs. KD without aneurysm; lower phenotypic frequency in KD with aneurysm than in healthy controls CAL risk CAL formation
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Proteomic biomarkers
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As a result of the active research into proteomic biomarkers for KD, various peptides showing significant relationships with different
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diagnosis in the presence of inflammation, while serum albumin levels below normal range values were correlated with coronary artery abnormalities [27]. Six of the included studies indicated increased ESR in patients with KD in comparison to control groups without KD [12–17]. In a retrospective study comparing patients with KD and controls with differential diagnoses for KD, Chaiyarak et al. reported the average value of ESR in KD patients as being significantly higher than controls; in the same study, receiver operating curve analysis was used to conclude that with an ESR ≥ 40 mm/h, a patient suspected of having KD was 2.72 times more likely to have KD [12]. An ESR-based cut-off value for KD exclusion was not reported in this study. WBC/leukocyte count was also frequently noted to be significantly elevated in KD patients when compared against non-KD controls [14–16,18–21]. WBC count elevations were particularly high in patients with delayed diagnoses of KD compared to early diagnoses of KD [19], and were associated with left ventricular systolic dysfunction [16]. Koyanagi et al. additionally noted a positive relationship between a leukocyte count ≥ 16 ∗ 109/L and cardiac sequelae [20]. CRP was measured in many studies and was significantly elevated in KD patients with CAAs [27], or coronary artery lesions (CALs) [29], versus KD patients without such coronary complications. There have also been observed alterations involving CD8T cells in KD patients compared to control subjects. Ehara et al. have shown that not only do KD patients show a decrease in the number of CD8T cells, but they also experience an increase in the proportion of CD69+CD8T cells [30]. The study has shown that CD69+CD8T cells could play a role as a marker for KD progression, treatment response, and convalescence in acute KD [30].
[36] [36] [36] [36] [37] [37] [37]
[77] [78]
aspects of KD have been identified. Plasma clusterin, also known as apolipoprotein J, has been recognized as a prognostic biomarker for CAL sequelae in KD [34]. In a study by Yu et al., a plasma clusterin level lower than 12 mg/L was associated with CAL occurrence in KD patients [34]. Another study in 2009 indicated that fibrinogen-related plasma protein (fibrinogen, alpha-1-antitrypsin, clusterin and CD5L) levels are highly elevated during acute KD in KD patients, while immunoglobulin free light chain levels are lower [25]. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was a molecule found to be elevated in the acute phase of KD [18,32] in comparison to febrile controls [31]. McNeal-Davidson et al. reported that the molecule showed subtle myocardial involvement in KD patients during the acute phase of the disease [32]. Huang et al. published an evaluation of several ‘acute-phase reactants’ [23] and their involvement in KD diagnosis. This study compared KD patients with controls having other febrile illnesses, and found that KD patients showed marked elevation in apolipoprotein B and haptoglobin levels, along with a significant decrease in apolipoprotein A–I levels [23]. Two biomarkers, serum cardiac troponin I (cTnI) and creatinine kinase (CK)-MB, were increased in KD patients in comparison to agematched, non-KD control patients [33]. cTnI was highlighted to be of particular interest by Kim and Kim, as its presence indicated myocyte injury and/or inflammation prior to clinical presentation of other KD symptoms, allowing for earlier diagnosis of acute myocarditis accompanying KD [33]. Nitric oxide synthases (iNOS) expression by neutrophils and monocytes has also been identified as a promising biomarker to follow the progression of KD by Yu et al. [29]. In neutrophils of KD patients, iNOS expression was strong during acute KD, at levels significantly higher than those found in control patients, and then normalized with progression of the disease [29]. Additionally, KD patients with CALs presented iNOS expression in neutrophils that was much higher than the nonCAL KD patients' level of expression, although only before intravenous
Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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Records identified through PubMed (n = 789)
Identification
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Fig. 1. Review process diagram. From database searching to final selection of articles for inclusion, various screening and eligibility factors were enforced, leaving 65 articles to be reviewed out of the 789 available articles.
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Genetic polymorphisms as biomarkers
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Polymorphisms of various alleles within the HLA class I genes have shown several associations with KD, as demonstrated in a paper by Oh et al. [36]. Within the polymorphisms of the HLA-A alleles, the frequency of HLA-A26 was decreased in KD patients without coronary complications, in comparison to healthy patients [36]. Secondly, for the polymorphisms of the HLA-B alleles, significant increases in frequencies of polymorphisms -B35 and -B75 were noted in KD patients compared to the healthy control group [36]. In subgroup analysis, KD patients
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gammaglobulin (IVGG) treatment [29]. After treatment, both patient groups exhibited rapid decline in iNOS expression in their neutrophils [29]. In monocytes, while initial tests showed KD patients and controls as having normal iNOS expression, after 2 weeks of IVGG treatment, iNOS expression peaked in KD patients. As well, KD patients with CALs had higher expression after 2 weeks of disease onset, when lesion presence also was at its highest [29]. Another important finding is presented in a study by Ling et al., in which it is shown that phosphoinositide 3-kinase (PI3K) signaling is significantly down regulated in the B cells and in the T cell receptor signaling pathway of patients with acute KD, compared to febrile controls [35]. A recent cytokine study by Ko et al. has provided further insight into the use of cytokines as biomarkers for KD[79]. Ko et al. reported that CXCL10 (IP-10) levels were significantly increased in KD patients, and there was IP-10 receptor CXCR3 activation in T cells of the acute KD cohort [79].
without coronary complications showed significantly higher frequencies of HLA-B35 and HLA-B75, compared to the control group [36]. Additionally, this analysis demonstrated that between KD patients with and without coronary complications, HLA-B75 was found exclusively in the group without coronary complications [36]. Thirdly, for HLA-C, the HLA-Cw09 allelic frequency was higher in KD patients [36]. By way of subgroup analysis, Oh et al. ascertained that HLA-Cw09 frequency in KD patients without coronary complications was higher than in control subjects [36]. Finally, polymorphisms of the HLA-DRB1 alleles indicated that KD patients with coronary complications had higher frequencies of the HLA-DRB1*11 allele than healthy controls; KD patients without coronary complications had higher frequencies of the HLADRB1*04 allele than healthy controls [36]. MHC-class-I-chain-related gene A (MICA) alleles have been associated with KD as post-treatment biomarkers, for evaluating coronary aneurysm development in patients post treatment with aspirin and IVGG [37]. Lower phenotypic and genotypic frequencies of MICA allele A4 were seen in KD patients with aneurysms than in KD patients without aneurysms, and the phenotypic frequencies observed in KD patients with aneurysms was lower than in healthy controls overall [37]. Higher genotypic frequencies for allele A5 were witnessed in KD patients with aneurysms versus control patients [37]. Contrarily, allele A5.1 showed a negative association with KD occurrence [37]. The inositol 1,4,5-triphosphate 3-kinase C (ITPKC) gene has also been studied for its potential relationship to KD [53,77,78]. Onouchi et al. identified a functional single nucleotide polymorphism (itpkc_3) in this gene as being significantly correlated with KD susceptibility
Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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Conclusion & future perspective
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At present, KD is the single most prominent cause for pediatric acquired heart disease in the industrialized world, but a gold standard laboratory diagnosis does not exist for its identification [5]. This review of the literature indicated ESR and NT-proBNP as useful and promising as components of a diagnostic toolkit for KD. At present, many non-specific inflammatory biomarkers are used in conjunction with clinical diagnosis, such as ESR, CRP, and WBC/leukocyte count [12,16]. While non-specific biomarkers are helpful in further substantiating a diagnosis, literature search does show reports wherein despite validation with a KD diagnosis, these values have shown no difference from the data of control patients [12]. Nevertheless, analysis of ROC curves of inflammatory biomarkers (ESR, platelet count, T-cell subgroups, and CRP levels) in KD patients has shown that ESR has the highest sensitivity, specificity, and AUC among these biomarkers, making it a useful component for diagnosis [17]. Presently, given ESR's role as a non-specific inflammatory biomarker, it is advisable not to rely on it alone for the diagnosis of KD, but rather include it in a range of laboratory tests that will supplement a clinical diagnosis. While KD presents a variety of symptoms, its most adverse effects are coronary complications. Naturally, as the cardiovascular implications of KD are profound, research has been directed into finding biomarkers indicative of cardiac or coronary injury. The study of proteins such as plasma clusterin, NT-proBNP, cTnI, iNOS, IP-10 and fibrinogenrelated proteins, which indicate relationships with various coronary aspects, is a testament to this [18,29,31–34,79]. It is important to note that while one study [25] indicates increased clusterin levels in acute KD, another study notes its decrease as an indicator of the occurrence of CALs [34]. More investigation with larger sample sizes needs to be performed, and results with higher statistical power need to be obtained, before clusterin can be established as a useful biomarker for KD diagnosis. Additionally, the genetic polymorphisms focused upon in recent literature — HLA alleles, MICA alleles, and ITPKC single nucleotide polymorphisms — are also associated with coronary effects [36,37,77, 78]. In evaluating all of these new proposed biomarkers, we focus on NT-proBNP as, despite being newly identified and described in the literature, NT-proBNP has been investigated by multiple research groups and has produced significant positive associations, in contrast to biomarkers whose investigation is limited to one study. Elevated levels of NT-proBNP in the acute phase of KD, in comparison to febrile controls, were noted with statistical significance in three different studies [18,31,32]. Based on this review, we believe that NT-proBNP seems to be a very promising new biomarker for KD diagnosis. Further investigation is warranted to substantiate its integration into a gold standard panel of tests for KD. This review represents one of the first efforts to examine non-clinical symptoms with specific attention to proteomic and genetic markers, which may serve crucial to the immediate and accurate laboratory diagnosis of KD, and for KD management. Lastly, the lack of a year of publication limitation in this review's search and screening inclusion criteria allows for the integration of old and new evidence, allowing for the comparison of findings pertaining to biomarkers across different studies over time. The limitations of this study include the use of only one database in the search, which might limit the scope of the review in terms of the identification of all the relevant literature available. Furthermore, the automatic exclusion of several full-text articles which were nonEnglish, and not accessible through the student library permissions via McMaster University or through associated institutions (although such a situation was highly uncommon), compromises the comprehensiveness of this review, potentially preventing the identification and
While non-specific inflammatory markers have supplemented KD diagnosis in the past, more recent articles have focused upon genetic polymorphisms and protein expression as possible biomarkers for KD detection [29,30,36,37]. These are promising avenues for research, given the numerous technological tools that have been developed in recent years that allow for fast, inexpensive investigations. It is important to note, however, that currently, laboratory biomarkers are insufficient for the establishment of a solely laboratory-based diagnosis; clinical diagnosis should continue as they are more relevant at this stage. With the lack of biomarkers that can isolate KD without differential diagnosis, clinical diagnosis should be depended upon to address this time-sensitive disease. The need for laboratory data to corroborate solely clinical KD diagnosis is being increasingly recognized by the scientific community, as it would allow for earlier treatment, and thus, prevention of its most adverse effects. This will certainly propel further research for KD biomarkers, especially those indicating coronary effects, so that a gold standard for KD identification can be established. NT-proBNP, among the many other biomarkers, should be investigated thoroughly so its association with KD can be wholly understood for diagnosis. NT-proBNP and ESR levels could both be incorporated into a gold standard test. Future research must be directed towards establishment of a robust gold standard — the biomarker(s) involved, their threshold values for reliable KD diagnosis, and cost-effective methods of testing. Executive summary
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• There is a need for a gold standard test to reliably detect and treat cases of Kawasaki disease in affected children. • Elevations in inflammatory markers such as ESR, WBC/leukocyte count, platelet count can assist in confirming KD diagnosis. • Increased proportions of CD69+CD8T cells suggest KD progression and can be used to detect treatment response and convalescence in acute KD. • Proteomic biomarker NT-proBNP is elevated in the acute KD phase and holds great promise in allowing accurate laboratory-based KD diagnosis. • apoB, Hp, apoA-I, cTnI, CK-MB, and iNOS are also proteomic biomarkers, among others, that are altered during KD. • Genetic polymorphisms in six HLA class I alleles and two MICA alleles have been found to be associated with KD occurrence. • Further studies in these and other biomarkers will allow for early diagnosis of KD and avoidance of adverse coronary complications.
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and CAL risk in Japanese and American pediatric populations [77]. In another study, Kuo et al. noted that the single nucleotide polymorphism rs7251246 in the ITPKC gene correlates significantly with CAL formation [78].
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Supplementary data to this article can be found online at http://dx. 395 doi.org/10.1016/j.clinbiochem.2015.02.013. 396 Competing financial interests The authors declare no competing financial interests. Contributions
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T.M. conceived of the study; P.P., A.A., K.C., T.T. performed screening 400 analyses. T.M. supervised the study. P.P. wrote the manuscript with 401 valuable assistance from all co-authors. 402 Uncited references
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Article history: Received 4 September 2014 Received in revised form 20 February 2015 Accepted 21 February 2015 Available online xxxx
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Keywords: Kawasaki Biomarkers Diagnosis NT-proBNP
Faculty of Science, McMaster University, Hamilton, ON, Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada c College of Medicine, Howard University, Washington DC, USA d Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada e Department of Pediatrics, McMaster Children's Hospital, Hamilton, ON, Canada b
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Kawasaki disease (KD) is a major cause of acquired heart disease among children and increases the risk of myocardial infarction. While the biochemical basis of the disease is unclear, the evidence suggests interplay between a microbial infection and a genetic predisposition in the development of the disease. Diagnosis of KD based on clinical observation is not completely reliable and is problematic due to the time-sensitive nature of the disease. Hence, identification of inflammatory, proteomic, and genetic biomarkers may assist in earlier and more effective diagnosis and treatment. This review of observational studies and clinical trials analyzes biomarkers in recent research that may be used to establish a gold standard test for KD diagnosis. 65 articles in the literature are assessed to investigate these new biomarkers in addition to biomarkers presently in use. ESR ≥ 40 mm/h, leukocyte count ≥16 ∗ 109/L and increased WBC count are together suggestive of the presence of KD. Among proteomic biomarkers, elevated NT-proBNP and differing levels of several other proteomic biomarkers such as iNOS in monocytes and neutrophils have been observed in KD patients. Genetic polymorphisms of six HLA class I genes have also been linked with the disease, alongside MICA alleles A4 and A5.1. The results suggest that NT-proBNP is currently a very promising biomarker for future investigation; further research is warranted to allow for accurate and early detection of the disease using this biomarker. © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
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Introduction . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . Inflammatory biomarkers . . . . . . Proteomic biomarkers . . . . . . . Genetic polymorphisms as biomarkers Discussion . . . . . . . . . . . . . . . Conclusion & future perspective . . . . . Executive summary . . . . . . . . . . . Competing financial interests . . . . . . Contributions . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . Acknowledgments . . . . . . . . . . . References . . . . . . . . . . . . . . .
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⁎ Corresponding author at: 3A-Health Sciences Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. Fax: +1 9055217914 . E-mail address: [email protected] (T.K. Mondal).
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Kawasaki disease (KD) is an acute pediatric multisystem vasculitis 57 primarily affecting individuals between the ages of 6 months and 58 5 years [1–3], and is the primary cause of acquired heart disease within 59
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Two searches were conducted on PubMed to pool results addressing diagnostic biomarkers relevant to the KD. The search terms “(kawasaki [Title/Abstract]) AND biomarker [Title/Abstract]”, and “(kawasaki [Title/ Abstract]) AND diagnosis [Title/Abstract]”, were used to identify potentially relevant literature in the first and second searches, respectively. The searches were not limited by date of publication or any other criteria to ensure their comprehensiveness, especially given the significant amount of evidence available prior to 2000. The searches yielded a pooled total of 789 results. The following inclusion criteria was established for eligibility assessment of the combined search results: a) published in the English language; b) conducted in human pediatric sample(s) and/or aiming to identify relationships with direct relevance to the pediatric human population; c) directly addressing one or more biological markerrelated aspects of KD; and d) reporting a prospective or retrospective observational study, randomized controlled trial, or other form of clinical trial (i.e. primary article). As KD is most prevalent in pediatric patients less than five years of age, and presents the highest risk factors in this population, this study aimed to examine diagnostic biomarkers in a population under five years of age, otherwise defined as a pediatric population. Articles discussing biomarkers for coronary artery involvement in relation to KD were included. Articles solely pertaining to diagnostic technologies or methods of biomarker assessment without a major focus on one or more biomarkers were excluded. Title-and-abstract screening was conducted in duplicate by a pair of blinded screeners (AA, TT). A total of 129 articles were identified to be included for full-text screening following application of the inclusion criteria, primarily excluding duplicate hits, non-English articles, case reports and case series, and other studies beyond the aforementioned accepted designs. Full-text screening was conducted in duplicate by a pair of blinded screeners (PP, AA, TT, KC) based on the same criteria as during title-and-abstract screening. Following this second stage of screening, articles were selected to be included in the review, and were combined after the screening. Article classification by age of study sample (i.e. division as per adult and child-related articles, with pediatric being defined by mean/median subject age being below five years, or declaration by authors as pediatric study), by sample size (considered for inclusion if involving more than 30 participants), and by grouping of biomarker (i.e. inflammatory, genetic, proteomic) was conducted to stratify the articles to be included in the review.
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R
75 76
R
73 74
O
71 72
C
69 70
N
67 68
U
66
R O
Table 1 Clinical features as criteria for diagnosis of Kawasaki disease [2,5].
64 65
111 112
P
t1:1 t1:2
62 63
complementary clinical diagnosis; the time sensitivity of this disease necessitates the continuation of clinical diagnosis until a gold standard laboratory test with high specificity and sensitivity is established. Despite the significance of laboratory biomarkers to KD diagnosis and optimal management, the literature in the area is disparate and few attempts have been made to synthesize the available evidence (Table 2). The purpose of this study is to explore proteomic and genetic biomarkers indicative of KD and associated coronary artery damage.
T
110
the pediatric population of industrialized nations [4,5]. While KD causes vascular inflammation in various parts of the body, the main concern is its effect on the coronary arteries. Dilatations, aneurysms, and fistulae of the coronary arteries associated with KD can lead to myocardial infarction and death, emphasizing the need for immediate diagnosis and treatment [5]. KD occurs in males and females with a 1.6:1 ratio and shows marked ethnicity- and age-based patterns of occurrence [5]. Though the first few cases of KD were described in Japan, it has since been diagnosed with increasing frequency in numerous other countries. Current accounts of international diagnoses indicate incidence rates in Japanese, Korean, and Taiwanese ethnicities being as high as 20 times the incidence rates in European-Caucasian, Australian, and New Zealander populations [6]. In a study by Salo et al., Nordic residents of Japanese descent showed earlier onset than their ethnic Nordic counterparts: more than 85% of Japanese patients were younger than 5 years of age, compared to only approximately 68% of Nordic patients (p b 0.001) [7]. While the underlying biochemical basis for KD is unknown, microbiological data suggests a pathogenic component to the origin of the disease [5]. However, given that some genetic groups are more susceptible, a microbial infection compounded by a genetic predisposition is currently accepted as the likely cause [5]. The unclear etiology of KD only allows for symptomatic treatments focused on fever and inflammation and therefore treatments that do not address the underlying cause. A single dose of intravenous immunoglobulin (IVIG) of 2 g/kg between days 5 to 7 of the illness causes marked decreases in coronary artery abnormalities and the duration of the febrile period [8]. Acetylsalicylic acid (aspirin) is co-administered with IVIG in four daily doses adding up to 80–100 mg/kg; together, IVIG and aspirin have an additive anti-inflammatory effect [2]. Other treatments such as corticosteroid and pentoxifylline administration for KD have also been evidenced in past literature, but recent data regarding their efficacy is inconclusive, or altogether insufficient, respectively [3]. Current treatments for KD have proven to be potentially financially burdensome [9]. The current gold standard clinical diagnosis of KD is based on the presentation of a collection of clinical manifestations: a prolonged fever — usually above 39 °C — persisting for more than five days, coupled with a minimum of four out of a set of five clinical features (see Table 1) [2,5,10]. A febrile patient showing two or three of the clinical features is diagnosed as presenting with incomplete KD following evaluation with an echocardiogram [2]. As the coronary effects of KD can be long-lasting and detrimental [3], it is important that accurate laboratory diagnoses are developed for early recognition of the disease. A laboratory diagnosis will serve as the universal gold standard test, as it may not depend upon the outward manifestation of the disease, unlike present clinical diagnoses that may fail to properly identify atypical cases of disease. A comparison of early and late diagnoses of KD indicated that delayed diagnosis was correlated with increased risk of the development of coronary artery aneurysms (CAAs) [11]. Current laboratory markers cannot diagnose KD without a
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2
Prolonged fever Usually above 39 °C, lasting for ≥5 days Minimum of 4 of the following in complete KD
Bilateral non-exudative, non-purulent conjunctival injection Polymorphous, erythematous rash Inflammation of the oral cavity Injected pharynx and lips, non-exudative fissuring of the lips, strawberry tongue Erythematous changes to extremities Peripheral oedema, peripheral erythema, periungual desquamation Cervical lymphadenopathy
113 114 115 116 Q6 117 118
122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159
From a literature search which yielded 796 articles, a final 65 articles 161 satisfied the inclusion criteria following title-and-abstract and full-text 162 screening and were included in this review (see Fig. 1). 163 Inflammatory biomarkers
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A variety of acute inflammatory biomarkers presently comprise a significant portion of the laboratory analysis for KD patients. Largely non-specific, these markers are used in conjunction with the clinical diagnosis for KD. Erythrocyte sedimentation rate (ESR), white blood cell (WBC)/leukocyte count, platelet count, and C-reactive protein (CRP) values above their respective normal ranges help to confirm KD
165
Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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3
Table 2 List of several KD diagnostic biomarkers commonly cited in literature, as well as newly mentioned biomarkers of potential use for KD diagnosis. Supplementary Table A is a complete list of all biomarkers extracted from the 65 final articles reviewed. Biomarker
Change (compared to controls)
Indication of/occurs during
References
t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25
Erythrocyte sedimentation rate White blood cell/leukocyte count Platelet count C-Reactive protein CD69 + CD8T cell proportion in CD8T cell count CD8T cell count NT-proBNP Apolipoprotein B Haptoglobin Serum cTnI Creatine kinase-MB iNOS expression (in neutrophils, monocytes) Fibrinogen-related plasma protein levels Immunoglobulin free light chains Apolipoprotein A–I levels Plasma clusterin (apolipoprotein J) PI3K signaling (in B cells & T cell receptor signaling pathway) CXCL10 (IP-10) and CXCR3 HLA class I gene polymorphisms HLA-B35 frequency HLA-B75 frequency
↑ ↑ ↑ ↑ ↑ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↓ ↑ ↑ ↑
[12–17] [14–16,18–21] [12–15,17,22–25] [14,15,17,21,25–29,63] [30] [30] [18,31,32] [23] [23,43] [33] [33] [29] [25] [25] [23] [34] [35] [79] [36] [36]
t2:26 t2:27 t2:28 t2:29 t2:30 t2:31 t2:32
HLA-Cw09 frequency HLA-DRB1*11 frequency HLA-DRB1*04 frequency HLA-A26 frequency Allele A5 frequency Allele A5.1 frequency Allele A4 frequencies
↑ ↑ ↑ ↓ ↑ ↓ ↓
SNP itpkc_3 SNP rs7251246
↑ (Presence) ↑ (Presence)
Acute inflammation Acute inflammation Thrombocytosis; coronary artery disease development Prediction of cardiac sequelae, age-dependent prognosis Acute KD (early activation) Acute KD Acute KD, atypical clinical characteristics Acute KD Acute KD (ratio greater than 2; ROC curve) Myocyte injury; inflammation Not heart-specific Acute KD (neutrophils); CAL presence (neutrophils & monocytes) Acute KD KD Acute KD (ratio greater than 2; ROC curve) CAL sequelae Acute KD Acute KD KD presence KD presence; exclusively in KD patients without coronary complications KD presence KD presence with coronary complications KD presence without coronary complications KD presence without coronary complications KD presence with aneurysm KD presence Phenotypic & genotypic frequency decrease in KD with aneurysm vs. KD without aneurysm; lower phenotypic frequency in KD with aneurysm than in healthy controls CAL risk CAL formation
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ITPKC gene
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MICA alleles
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199
Proteomic biomarkers
200
As a result of the active research into proteomic biomarkers for KD, various peptides showing significant relationships with different
180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197
201
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R
178 179
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177
N C O
175 176
U
173 174
C
198
diagnosis in the presence of inflammation, while serum albumin levels below normal range values were correlated with coronary artery abnormalities [27]. Six of the included studies indicated increased ESR in patients with KD in comparison to control groups without KD [12–17]. In a retrospective study comparing patients with KD and controls with differential diagnoses for KD, Chaiyarak et al. reported the average value of ESR in KD patients as being significantly higher than controls; in the same study, receiver operating curve analysis was used to conclude that with an ESR ≥ 40 mm/h, a patient suspected of having KD was 2.72 times more likely to have KD [12]. An ESR-based cut-off value for KD exclusion was not reported in this study. WBC/leukocyte count was also frequently noted to be significantly elevated in KD patients when compared against non-KD controls [14–16,18–21]. WBC count elevations were particularly high in patients with delayed diagnoses of KD compared to early diagnoses of KD [19], and were associated with left ventricular systolic dysfunction [16]. Koyanagi et al. additionally noted a positive relationship between a leukocyte count ≥ 16 ∗ 109/L and cardiac sequelae [20]. CRP was measured in many studies and was significantly elevated in KD patients with CAAs [27], or coronary artery lesions (CALs) [29], versus KD patients without such coronary complications. There have also been observed alterations involving CD8T cells in KD patients compared to control subjects. Ehara et al. have shown that not only do KD patients show a decrease in the number of CD8T cells, but they also experience an increase in the proportion of CD69+CD8T cells [30]. The study has shown that CD69+CD8T cells could play a role as a marker for KD progression, treatment response, and convalescence in acute KD [30].
[36] [36] [36] [36] [37] [37] [37]
[77] [78]
aspects of KD have been identified. Plasma clusterin, also known as apolipoprotein J, has been recognized as a prognostic biomarker for CAL sequelae in KD [34]. In a study by Yu et al., a plasma clusterin level lower than 12 mg/L was associated with CAL occurrence in KD patients [34]. Another study in 2009 indicated that fibrinogen-related plasma protein (fibrinogen, alpha-1-antitrypsin, clusterin and CD5L) levels are highly elevated during acute KD in KD patients, while immunoglobulin free light chain levels are lower [25]. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was a molecule found to be elevated in the acute phase of KD [18,32] in comparison to febrile controls [31]. McNeal-Davidson et al. reported that the molecule showed subtle myocardial involvement in KD patients during the acute phase of the disease [32]. Huang et al. published an evaluation of several ‘acute-phase reactants’ [23] and their involvement in KD diagnosis. This study compared KD patients with controls having other febrile illnesses, and found that KD patients showed marked elevation in apolipoprotein B and haptoglobin levels, along with a significant decrease in apolipoprotein A–I levels [23]. Two biomarkers, serum cardiac troponin I (cTnI) and creatinine kinase (CK)-MB, were increased in KD patients in comparison to agematched, non-KD control patients [33]. cTnI was highlighted to be of particular interest by Kim and Kim, as its presence indicated myocyte injury and/or inflammation prior to clinical presentation of other KD symptoms, allowing for earlier diagnosis of acute myocarditis accompanying KD [33]. Nitric oxide synthases (iNOS) expression by neutrophils and monocytes has also been identified as a promising biomarker to follow the progression of KD by Yu et al. [29]. In neutrophils of KD patients, iNOS expression was strong during acute KD, at levels significantly higher than those found in control patients, and then normalized with progression of the disease [29]. Additionally, KD patients with CALs presented iNOS expression in neutrophils that was much higher than the nonCAL KD patients' level of expression, although only before intravenous
Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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Records identified through PubMed (n = 789)
Identification
Titles-and-abstracts excluded (n = 623) Excluded for one or more of the following reasons:
Records after duplicates removed (n = 788)
• Not based on human samples • Not pertaining to diagnostic
T&A Screening
factors
• Case report/series/other (non-
Records screened (n = 788)
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review, non-observational, nonclinical trial)
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Full-texts excluded (n = 100)
Full-text articles reviewed for inclusion (n = 165)
Excluded for one or more of the following reasons:
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Eligibility
Inclusion
• Not primary study/clinical trial • Not pediatric population • Small sample size (n < 30) • Not biomarker-focused • Not in English
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Studies included in qualitative synthesis (n = 65)
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Fig. 1. Review process diagram. From database searching to final selection of articles for inclusion, various screening and eligibility factors were enforced, leaving 65 articles to be reviewed out of the 789 available articles.
251
Genetic polymorphisms as biomarkers
252
Polymorphisms of various alleles within the HLA class I genes have shown several associations with KD, as demonstrated in a paper by Oh et al. [36]. Within the polymorphisms of the HLA-A alleles, the frequency of HLA-A26 was decreased in KD patients without coronary complications, in comparison to healthy patients [36]. Secondly, for the polymorphisms of the HLA-B alleles, significant increases in frequencies of polymorphisms -B35 and -B75 were noted in KD patients compared to the healthy control group [36]. In subgroup analysis, KD patients
243 244 245 246 247 248
253 254 255 256 257 258 259
O
C
241 242
N
239 240
U
237 238
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249 250
gammaglobulin (IVGG) treatment [29]. After treatment, both patient groups exhibited rapid decline in iNOS expression in their neutrophils [29]. In monocytes, while initial tests showed KD patients and controls as having normal iNOS expression, after 2 weeks of IVGG treatment, iNOS expression peaked in KD patients. As well, KD patients with CALs had higher expression after 2 weeks of disease onset, when lesion presence also was at its highest [29]. Another important finding is presented in a study by Ling et al., in which it is shown that phosphoinositide 3-kinase (PI3K) signaling is significantly down regulated in the B cells and in the T cell receptor signaling pathway of patients with acute KD, compared to febrile controls [35]. A recent cytokine study by Ko et al. has provided further insight into the use of cytokines as biomarkers for KD[79]. Ko et al. reported that CXCL10 (IP-10) levels were significantly increased in KD patients, and there was IP-10 receptor CXCR3 activation in T cells of the acute KD cohort [79].
without coronary complications showed significantly higher frequencies of HLA-B35 and HLA-B75, compared to the control group [36]. Additionally, this analysis demonstrated that between KD patients with and without coronary complications, HLA-B75 was found exclusively in the group without coronary complications [36]. Thirdly, for HLA-C, the HLA-Cw09 allelic frequency was higher in KD patients [36]. By way of subgroup analysis, Oh et al. ascertained that HLA-Cw09 frequency in KD patients without coronary complications was higher than in control subjects [36]. Finally, polymorphisms of the HLA-DRB1 alleles indicated that KD patients with coronary complications had higher frequencies of the HLA-DRB1*11 allele than healthy controls; KD patients without coronary complications had higher frequencies of the HLADRB1*04 allele than healthy controls [36]. MHC-class-I-chain-related gene A (MICA) alleles have been associated with KD as post-treatment biomarkers, for evaluating coronary aneurysm development in patients post treatment with aspirin and IVGG [37]. Lower phenotypic and genotypic frequencies of MICA allele A4 were seen in KD patients with aneurysms than in KD patients without aneurysms, and the phenotypic frequencies observed in KD patients with aneurysms was lower than in healthy controls overall [37]. Higher genotypic frequencies for allele A5 were witnessed in KD patients with aneurysms versus control patients [37]. Contrarily, allele A5.1 showed a negative association with KD occurrence [37]. The inositol 1,4,5-triphosphate 3-kinase C (ITPKC) gene has also been studied for its potential relationship to KD [53,77,78]. Onouchi et al. identified a functional single nucleotide polymorphism (itpkc_3) in this gene as being significantly correlated with KD susceptibility
Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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Conclusion & future perspective
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Discussion
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At present, KD is the single most prominent cause for pediatric acquired heart disease in the industrialized world, but a gold standard laboratory diagnosis does not exist for its identification [5]. This review of the literature indicated ESR and NT-proBNP as useful and promising as components of a diagnostic toolkit for KD. At present, many non-specific inflammatory biomarkers are used in conjunction with clinical diagnosis, such as ESR, CRP, and WBC/leukocyte count [12,16]. While non-specific biomarkers are helpful in further substantiating a diagnosis, literature search does show reports wherein despite validation with a KD diagnosis, these values have shown no difference from the data of control patients [12]. Nevertheless, analysis of ROC curves of inflammatory biomarkers (ESR, platelet count, T-cell subgroups, and CRP levels) in KD patients has shown that ESR has the highest sensitivity, specificity, and AUC among these biomarkers, making it a useful component for diagnosis [17]. Presently, given ESR's role as a non-specific inflammatory biomarker, it is advisable not to rely on it alone for the diagnosis of KD, but rather include it in a range of laboratory tests that will supplement a clinical diagnosis. While KD presents a variety of symptoms, its most adverse effects are coronary complications. Naturally, as the cardiovascular implications of KD are profound, research has been directed into finding biomarkers indicative of cardiac or coronary injury. The study of proteins such as plasma clusterin, NT-proBNP, cTnI, iNOS, IP-10 and fibrinogenrelated proteins, which indicate relationships with various coronary aspects, is a testament to this [18,29,31–34,79]. It is important to note that while one study [25] indicates increased clusterin levels in acute KD, another study notes its decrease as an indicator of the occurrence of CALs [34]. More investigation with larger sample sizes needs to be performed, and results with higher statistical power need to be obtained, before clusterin can be established as a useful biomarker for KD diagnosis. Additionally, the genetic polymorphisms focused upon in recent literature — HLA alleles, MICA alleles, and ITPKC single nucleotide polymorphisms — are also associated with coronary effects [36,37,77, 78]. In evaluating all of these new proposed biomarkers, we focus on NT-proBNP as, despite being newly identified and described in the literature, NT-proBNP has been investigated by multiple research groups and has produced significant positive associations, in contrast to biomarkers whose investigation is limited to one study. Elevated levels of NT-proBNP in the acute phase of KD, in comparison to febrile controls, were noted with statistical significance in three different studies [18,31,32]. Based on this review, we believe that NT-proBNP seems to be a very promising new biomarker for KD diagnosis. Further investigation is warranted to substantiate its integration into a gold standard panel of tests for KD. This review represents one of the first efforts to examine non-clinical symptoms with specific attention to proteomic and genetic markers, which may serve crucial to the immediate and accurate laboratory diagnosis of KD, and for KD management. Lastly, the lack of a year of publication limitation in this review's search and screening inclusion criteria allows for the integration of old and new evidence, allowing for the comparison of findings pertaining to biomarkers across different studies over time. The limitations of this study include the use of only one database in the search, which might limit the scope of the review in terms of the identification of all the relevant literature available. Furthermore, the automatic exclusion of several full-text articles which were nonEnglish, and not accessible through the student library permissions via McMaster University or through associated institutions (although such a situation was highly uncommon), compromises the comprehensiveness of this review, potentially preventing the identification and
While non-specific inflammatory markers have supplemented KD diagnosis in the past, more recent articles have focused upon genetic polymorphisms and protein expression as possible biomarkers for KD detection [29,30,36,37]. These are promising avenues for research, given the numerous technological tools that have been developed in recent years that allow for fast, inexpensive investigations. It is important to note, however, that currently, laboratory biomarkers are insufficient for the establishment of a solely laboratory-based diagnosis; clinical diagnosis should continue as they are more relevant at this stage. With the lack of biomarkers that can isolate KD without differential diagnosis, clinical diagnosis should be depended upon to address this time-sensitive disease. The need for laboratory data to corroborate solely clinical KD diagnosis is being increasingly recognized by the scientific community, as it would allow for earlier treatment, and thus, prevention of its most adverse effects. This will certainly propel further research for KD biomarkers, especially those indicating coronary effects, so that a gold standard for KD identification can be established. NT-proBNP, among the many other biomarkers, should be investigated thoroughly so its association with KD can be wholly understood for diagnosis. NT-proBNP and ESR levels could both be incorporated into a gold standard test. Future research must be directed towards establishment of a robust gold standard — the biomarker(s) involved, their threshold values for reliable KD diagnosis, and cost-effective methods of testing. Executive summary
377
• There is a need for a gold standard test to reliably detect and treat cases of Kawasaki disease in affected children. • Elevations in inflammatory markers such as ESR, WBC/leukocyte count, platelet count can assist in confirming KD diagnosis. • Increased proportions of CD69+CD8T cells suggest KD progression and can be used to detect treatment response and convalescence in acute KD. • Proteomic biomarker NT-proBNP is elevated in the acute KD phase and holds great promise in allowing accurate laboratory-based KD diagnosis. • apoB, Hp, apoA-I, cTnI, CK-MB, and iNOS are also proteomic biomarkers, among others, that are altered during KD. • Genetic polymorphisms in six HLA class I alleles and two MICA alleles have been found to be associated with KD occurrence. • Further studies in these and other biomarkers will allow for early diagnosis of KD and avoidance of adverse coronary complications.
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inclusion of one or more relevant studies pertaining to KD diagnostic 351 biomarkers. 352
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and CAL risk in Japanese and American pediatric populations [77]. In another study, Kuo et al. noted that the single nucleotide polymorphism rs7251246 in the ITPKC gene correlates significantly with CAL formation [78].
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5
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379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394
Supplementary data to this article can be found online at http://dx. 395 doi.org/10.1016/j.clinbiochem.2015.02.013. 396 Competing financial interests The authors declare no competing financial interests. Contributions
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T.M. conceived of the study; P.P., A.A., K.C., T.T. performed screening 400 analyses. T.M. supervised the study. P.P. wrote the manuscript with 401 valuable assistance from all co-authors. 402 Uncited references
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[38,39,40,41,42,44,45,46,47,48,49,50,51,52,54,55,56,57,58,59,60,61, 404 62,64,65,66,67,68,69,70,71,72,73,74,75,76] 405
Please cite this article as: Parthasarathy P, et al, Upcoming biomarkers for the diagnosis of Kawasaki disease: A review, Clin Biochem (2015), http://dx.doi.org/10.1016/j.clinbiochem.2015.02.013
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We thank Dr. Anthony Chan, Reza Mirza and Melody Ren for kindly reviewing and editing the manuscript.
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