Using Biomarkers to Predict Unresponsiveness to Initial Immunoglobulin for Kawasaki Disease Patients

Kawasaki disease (KD) is an inflammatory disorder of unknown etiology that is characterized by medium-sized vessel vasculitis and is the leading cause of pediatric acquired heart disease in developed countries. Development of coronary arterial aneurysms is the most important complication of this disease, because it may result in myocardial ischemia or acute coronary syndrome. Pathologically, panarteritis is reported to be seen by the 9th day of illness, and disruption and dissociation of internal elastic laminae can be seen by the 10th day of panarteritis. Vascular walls are infiltrated with neutrophils followed by macrophages, T lymphocytes and B lymphocytes. Consequently, aneurysmal change starts within 12 days of illness.¹ These findings suggest that the treatment strategy to control inflammation by the 10th day is reasonable.

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Intravenous immunoglobulin (IVIG) is the standard of care in the treatment of KD. However, approximately 15–20% of patients show resistance to IVIG, and resistance to IVIG may increase the risk of coronary arterial aneurysm. To solve this problem, attempts have been made to reduce the proportion of refractory cases by strengthening the initial treatment regimen. The addition of intravenous methylprednisolone to IVIG as the 1st-line treatment for “non-risk-stratified” KD patients showed no improvement compared with standard IVIG therapy.² On the other hand, the RAISE study showed that the addition of prednisolone to conventional IVIG as the 1st-line treatment improved the incidence of non-responders to primary treatment, patients needing additional therapy and the incidence of coronary arterial aneurysm in Japanese patients.³ The reasons for these different results were explained by the timing of the 1st-line therapy, duration of corticosteroid administration and the patient selection. For Japanese patients, a scoring system that predicts the unresponsiveness to initial IVIG therapy has been developed.⁴ In the RAISE study, only patients highly predicted to be non-responders to initial IVIG therapy were enrolled and this risk stratification increased the statistical power. Using the risk stratification method by scoring system, the KAICA trial showed that the addition of cyclosporin to the initial IVIG treatment for high-risk KD patients improved the incidence of non-responders to primary therapy and the incidence of coronary arterial abnormalities in Japanese patients, although the relapse rate to primary therapy was higher in the IVIG+cyclosporin group compared with the IVIG group.⁵ As a result, recent Japanese guidelines on acute stage KD treatment describe enhanced initial treatment based on risk classification using a scoring system.⁶ Although these scoring systems are well utilized in Japan, there is a problem that they are not applicable to ethnicities other than Japanese. Therefore, finding biomarkers that accurately predict unresponsiveness to initial IVIG is one of the most urgent issues in the management of KD.

Serum levels of granulocyte colony-stimulating factor,⁷ and tumor necrosis factor-α⁸ before IVIG have been reported as potential biomarkers to predict response to IVIG, and microarray analysis comparing the transcript abundance profiles of whole-blood RNA between IVIG responders and non-responders revealed that higher matrix metalloproteinase-8, S100A8, S100A9 and CEACAM1 transcript levels were associated with unresponsiveness to IVIG.⁹ In addition to these factors, other candidate biomarkers have been reported in recent years (Table).^10–14

Table. Recently Reported Potential Biomarkers for IVIG Resistance

Biomarker	Study type	No. of KD patients analyzed	Age	1st line therapy	Definition of resistance to initial treatment	Reference
Tenascin C (serum)	Retrospective	111	2–84 months	IVIG+aspirin	Patients needing 2nd-line therapy	Okuma et al,10 2016
NT-pro BNP (serum)	Prospective cohort	393	1–125 months	IVIG+aspirin	Fever >36 h after end of IVIG treatment	Shao et al,11 2019
sCD163 (serum)	Retrospective	87	1–121 months	IVIG+aspirin	Persistent or recrudescent fever (>37.5℃) at 48 h after IVIG infusion and requiring additional therapies	Azuma et al,12 2020
Procalcitonin (serum)	Retrospective	127	0.2–12.0 years	IVIG+aspirin	Persisting or recurrent pyrexia >24 h after IVIG, necessitating 2nd-line treatment	Nakamura et al,13 2020
Pentraxin 3 (plasma)	Prospective cohort	75	3–114 months	IVIG+aspirin	Persistent or recrudescent fever ≥24 h after completion of the initial IVIG infusion	Kitoh et al,14 2021

BNP, B-type natriuretic peptide; IVIG, intravenous immunoglobulin; KD, Kawasaki disease.

LR11 is a member of the low-density lipoprotein receptor family and is markedly expressed in atherosclerotic lesions, especially in intimal smooth muscle cells. In this issue of the Journal, Watanabe et al¹⁵ report that serum soluble LR11 (sLR11) before 1st-line IVIG treatment was significantly higher in IVIG responders compared with non-responders, which suggested that sLR11 might be a biomarker of unresponsiveness to IVIG. Many of the serum inflammatory mediators reported as potential biomarkers decrease after the first IVIG, whereas Watanabe et al report that elevated serum sLR11 levels were sustained until convalescence. Investigation of the time-dependent expression of sLR11 in the vascular lesions of KD may elucidate the underlying cause of this dynamic and enable a more in-depth look at vasculitis in KD.

One of the problems with the reported potential biomarkers is the different definition of resistance to initial treatment. As shown in the Table, there are substantial differences in the definition of resistance to initial treatment among the studies.^10–14 These differences may affect the sensitivity and specificity of the biomarkers to predict unresponsiveness to IVIG and this makes it difficult to compare the superiority or inferiority of the proposed biomarkers. Another problem is the lack of validation. Confirmation by large-scale prospective study and confirmation of efficacy outside of the reported cohorts and ethnicities are necessary to establish biomarkers. Because the establishment of biomarkers will lead to a deeper understanding of the pathogenesis of KD, the discovery of new therapeutic targets and improved treatment outcomes, further research is desirable.

Disclosures

The author declares there are no conflicts of interest.

References

• 1.   Takahashi K, Oharaseki T, Naoe S, Wakayama M, Yokouchi Y. Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr Int 2005; 47: 305–310.
• 2.   Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007; 356: 663–675.
• 3.   Kobayashi T, Saji T, Otani T, Takeuchi K, Nakamura T, Arakawa H, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): A randomised, open-label, blinded-endpoints trial. Lancet 2012; 379: 1613–1620.
• 4.   Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 2006; 113: 2606–2612.
• 5.   Hamada H, Suzuki H, Onouchi Y, Ebata R, Terai M, Fuse S, et al. Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): A randomised controlled, open-label, blinded-endpoints, phase 3 trial. Lancet 2019; 393: 1128–1137.
• 6.   Miura M, Ayusawa M, Ito S, Ikeda S, Kanai T, Kobayashi T, et al. The guidelines on acute stage Kawasaki disease treatment. Pediatr Cardiol Card Surg 2020; 36: S1.1–S1.29.
• 7.   Abe J, Ebata R, Jibiki T, Yasukawa K, Saito H, Terai M. Elevated granulocyte colony-stimulating factor levels predict treatment failure in patients with Kawasaki disease. J Allergy Clin Immunol 2008; 122: 1008–1013.e1008.
• 8.   Wang Y, Wang W, Gong F, Fu S, Zhang Q, Hu J, et al. Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease. Arthritis Rheum 2013; 65: 805–814.
• 9.   Fury W, Tremoulet AH, Watson VE, Best BM, Shimizu C, Hamilton J, et al. Transcript abundance patterns in Kawasaki disease patients with intravenous immunoglobulin resistance. Hum Immunol 2010; 71: 865–873.
• 10.   Okuma Y, Suda K, Nakaoka H, Katsube Y, Mitani Y, Yoshikane Y, et al. Serum tenascin-C as a novel predictor for risk of coronary artery lesion and resistance to intravenous immunoglobulin in Kawasaki disease: A multicenter retrospective study. Circ J 2016; 80: 2376–2381.
• 11.   Shao S, Luo C, Zhou K, Hua Y, Wu M, Liu L, et al. The role of age-specific N-terminal pro-brain natriuretic peptide cutoff values in predicting intravenous immunoglobulin resistance in Kawasaki disease: A prospective cohort study. Pediatr Rheumatol Online J 2019; 17: 65.
• 12.   Azuma Y, Suzuki Y, Okada S, Matsuguma C, Wakiguchi H, Ohnishi Y, et al. Utility of soluble CD163 in the clinical management of patients with Kawasaki disease. Front Pediatr 2020; 8: 148.
• 13.   Nakamura N, Muto T, Masuda Y, Numoto S, Kodama S, Miyamoto R, et al. Procalcitonin as a biomarker of unresponsiveness to intravenous immunoglobulin for Kawasaki disease. Pediatr Infect Dis J 2020; 39: 857–861.
• 14.   Kitoh T, Ohara T, Muto T, Okumura A, Baba R, Koizumi Y, et al. Increased pentraxin 3 levels correlate with IVIG responsiveness and coronary artery aneurysm formation in Kawasaki disease. Front Immunol 2021; 12: 624802.
• 15.   Watanabe K, Suzuki H, Jiang M, Tsukano S, Kataoka S, Ito S, et al. Soluble LR11 as a novel biomarker in acute Kawasaki disease. Circ J 2022; 86: 977–983.