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Serum alanine aminotransferase level and intravenous immunoglobulin resistance in patients with kawasaki disease

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Abstract

Introduction/objectives

Serum alanine aminotransferase (ALT) elevation is considered a risk factor for resistance to initial intravenous immunoglobulin (IVIG) treatment in patients with Kawasaki disease (KD). However, serum ALT levels change dramatically during acute KD illness. We tested the hypothesis that risk assessment for initial IVIG resistance based on serum ALT elevation may differ by examination day after KD onset.

Methods

We analyzed 18,492 population-based patients who developed KD throughout Japan. First, we epidemiologically evaluated the serum ALT variation at 1‒10 days after disease onset. Second, we conducted multivariable logistic regression to determine the association between serum ALT level and initial IVIG resistance according to timing of initial hospital visit by stratifying the patients into an early group (1‒5 days after onset) and a late group (6‒10 days after onset).

Results

Serum ALT rapidly increased after KD onset, peaked at day 4 of illness, and then declined regardless of IVIG responsiveness. The adjusted odds ratio (OR) increased with increasing serum ALT in the early group (adjusted OR [95% CI]: 1.44 [1.25–1.66], 1.94 [1.65–2.28], and 2.22 [1.99–2.48] for serum ALT 50–99, 100–199, and ≥ 200 IU/L, respectively; reference ALT level: 1–49 IU/L). No significant association was observed in the late group.

Conclusions

The findings indicate that risk assessment for initial IVIG resistance based on serum ALT level may only be reliable for patients with KD who visit hospitals during early illness, specifically 1–5 days after disease onset.

Key Points

  • Serum alanine aminotransferase level differed markedly according to examination days after Kawasaki disease onset.

  • Serum alanine aminotransferase level declined toward normal range after day 5 of illness regardless of intravenous immunoglobulin responsiveness.

  • Elevated serum alanine aminotransferase level was no longer a significant risk factor for initial intravenous immunoglobulin resistance when measured on delayed hospital visits.

  • Risk assessment for initial intravenous immunoglobulin resistance based on serum alanine aminotransferase level may only be reliable for patients who visit hospitals during early illness, specifically 1–5 days after disease onset.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

References

  1. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H (1974) A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics 54:271–276

    Article  CAS  Google Scholar 

  2. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, Baker AL, Jackson MA, Takahashi M, Shah PB, Kobayashi T, Wu MH, Saji TT, Pahl E (2017) Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation 135:e927–e999. https://doi.org/10.1161/cir.0000000000000484

    Article  PubMed  Google Scholar 

  3. Burns JC, Glodé MP (2004) Kawasaki syndrome. Lancet 364:533–544. https://doi.org/10.1016/s0140-6736(04)16814-1

    Article  PubMed  Google Scholar 

  4. Travaline JM, Hamilton SM, Ringel RE, Laschinger JC, Ziskind AA (1991) Cardiac transplantation for giant coronary artery aneurysms complicating Kawasaki disease. Am J Cardiol 68:560–561. https://doi.org/10.1016/0002-9149(91)90801-q

    Article  CAS  PubMed  Google Scholar 

  5. Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, Glode MP, Mason WH, Reddy V, Sanders SP et al (1986) The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 315:341–347. https://doi.org/10.1056/nejm198608073150601

    Article  CAS  PubMed  Google Scholar 

  6. Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, Tamura T, Hirose O, Manabe Y, Yokoyama T et al (1984) High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 2:1055–1058. https://doi.org/10.1016/s0140-6736(84)91504-6

    Article  CAS  PubMed  Google Scholar 

  7. Ae R, Makino N, Kosami K, Kuwabara M, Matsubara Y, Nakamura Y (2020) Epidemiology, treatments, and cardiac complications in patients with Kawasaki disease: the nationwide survey in Japan, 2017–2018. J Pediatr 225:23-29.e2. https://doi.org/10.1016/j.jpeds.2020.05.034

    Article  PubMed  Google Scholar 

  8. Wallace CA, French JW, Kahn SJ, Sherry DD (2000) Initial intravenous gammaglobulin treatment failure in Kawasaki disease. Pediatrics 105:E78. https://doi.org/10.1542/peds.105.6.e78

    Article  CAS  PubMed  Google Scholar 

  9. Burns JC, Capparelli EV, Brown JA, Newburger JW, Glode MP (1998) Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group. Pediatr Infect Dis J 17:1144–1148. https://doi.org/10.1097/00006454-199812000-00009

    Article  CAS  PubMed  Google Scholar 

  10. Ae R, Abrams JY, Maddox RA, Schonberger LB, Nakamura Y, Kuwabara M, Makino N, Matsubara Y, Matsubara D, Kosami K, Sasahara T, Belay ED (2020) Outcomes in Kawasaki disease patients with coronary artery abnormalities at admission. Am Heart J 225:120–128. https://doi.org/10.1016/j.ahj.2020.04.019

    Article  PubMed  Google Scholar 

  11. Masuda H, Ae R, Koshimizu TA, Matsumura M, Kosami K, Hayashida K, Makino N, Matsubara Y, Sasahara T, Nakamura Y (2021) Serum sodium level associated with coronary artery lesions in patients with Kawasaki disease. Clin Rheumatol 41:137–145. https://doi.org/10.1007/s10067-021-05881-7

    Article  PubMed  Google Scholar 

  12. Kim MK, Song MS, Kim GB (2018) Factors predicting resistance to intravenous immunoglobulin treatment and coronary artery lesion in patients with Kawasaki disease: analysis of the Korean nationwide multicenter survey from 2012 to 2014. Korean Circ J 48:71–79. https://doi.org/10.4070/kcj.2017.0136

    Article  CAS  PubMed  Google Scholar 

  13. Maggio MC, Corsello G, Prinzi E, Cimaz R (2016) Kawasaki disease in Sicily: clinical description and markers of disease severity. Ital J Pediatr 42:92. https://doi.org/10.1186/s13052-016-0306-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Park HM, Lee DW, Hyun MC, Lee SB (2013) Predictors of nonresponse to intravenous immunoglobulin therapy in Kawasaki disease. Korean J Pediatr 56:75–79. https://doi.org/10.3345/kjp.2013.56.2.75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Uehara R, Belay ED, Maddox RA, Holman RC, Nakamura Y, Yashiro M, Oki I, Ogino H, Schonberger LB, Yanagawa H (2008) Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan. Pediatr Infect Dis J 27:155–160. https://doi.org/10.1097/INF.0b013e31815922b5

    Article  PubMed  Google Scholar 

  16. Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, Martin DD, Newburger JW, Burns JC (2008) Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 153:117–121. https://doi.org/10.1016/j.jpeds.2007.12.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, Kogaki S, Hara J (2007) Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr 166:131–137. https://doi.org/10.1007/s00431-006-0223-z

    Article  CAS  PubMed  Google Scholar 

  18. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, Kobayashi T, Morikawa A (2006) Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 113:2606–2612. https://doi.org/10.1161/circulationaha.105.592865

    Article  PubMed  Google Scholar 

  19. Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, Matsuishi T (2006) Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr 149:237–240. https://doi.org/10.1016/j.jpeds.2006.03.050

    Article  CAS  PubMed  Google Scholar 

  20. Nakamura Y, Yashiro M, Uehara R, Watanabe M, Tajimi M, Oki I, Ojima T, Sonobe T, Yanagawa H (2004) Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease. Pediatr Int 46:33–38. https://doi.org/10.1111/j.1442-200X.2004.01840.x

    Article  PubMed  Google Scholar 

  21. Koyanagi H, Nakamura Y, Yanagawa H (1998) Lower level of serum potassium and higher level of C-reactive protein as an independent risk factor for giant aneurysms in Kawasaki disease. Acta Paediatr 87:32–36. https://doi.org/10.1080/08035259850157831

    Article  CAS  PubMed  Google Scholar 

  22. Ae R, Abrams JY, Maddox RA, Schonberger LB, Nakamura Y, Kuwabara M, Makino N, Matsubara Y, Kosami K, Sasahara T, Belay ED (2020) Corticosteroids added to initial intravenous immunoglobulin treatment for the prevention of coronary artery abnormalities in high risk patients with Kawasaki disease. J Am Heart Assoc 9:e015308. https://doi.org/10.1161/JAHA.119.015308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tremoulet AH (2018) Adjunctive therapies in Kawasaki disease. Int J Rheum Dis 21:76–79. https://doi.org/10.1111/1756-185x.13208

    Article  CAS  PubMed  Google Scholar 

  24. Kobayashi T, Saji T, Otani T, Takeuchi K, Nakamura T, Arakawa H, Kato T, Hara T, Hamaoka K, Ogawa S, Miura M, Nomura Y, Fuse S, Ichida F, Seki M, Fukazawa R, Ogawa C, Furuno K, Tokunaga H, Takatsuki S, Hara S, Morikawa A (2012) 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 379:1613–1620. https://doi.org/10.1016/s0140-6736(11)61930-2

    Article  CAS  PubMed  Google Scholar 

  25. Liu L, Yin W, Wang R, Sun D, He X, Ding Y (2016) The prognostic role of abnormal liver function in IVIG unresponsiveness in Kawasaki disease: a meta-analysis. Inflamm Res 65:161–168. https://doi.org/10.1007/s00011-015-0900-3

    Article  CAS  PubMed  Google Scholar 

  26. Chen CJ, Huang FC, Tiao MM, Huang YH, Lin LY, Yu HR, Yang KD, Huang YC, Chen CC, Chang WC, Kuo HC (2012) Sonographic gallbladder abnormality is associated with intravenous immunoglobulin resistance in Kawasaki disease. Sci World J 2012:485758. https://doi.org/10.1100/2012/485758

    Article  Google Scholar 

  27. Uehara R, Yashiro M, Hayasaka S, Oki I, Nakamura Y, Muta H, Ishii M, Matsuishi T, Sonobe T, Yanagawa H (2003) Serum alanine aminotransferase concentrations in patients with Kawasaki disease. Pediatr Infect Dis J 22:839–842. https://doi.org/10.1097/01.inf.0000086388.74930.0d

    Article  PubMed  Google Scholar 

  28. Nakamura Y, Yashiro M, Uehara R, Watanabe M, Tajimi M, Oki I, Ojima T, Yanagawa H (2003) Case-control study of giant coronary aneurysms due to Kawasaki disease. Pediatr Int 45:410–413. https://doi.org/10.1046/j.1442-200x.2003.01744.x

    Article  PubMed  Google Scholar 

  29. Tremoulet AH, Jain S, Chandrasekar D, Sun X, Sato Y, Burns JC (2011) Evolution of laboratory values in patients with Kawasaki disease. Pediatr Infect Dis J 30:1022–1026. https://doi.org/10.1097/INF.0b013e31822d4f56

    Article  PubMed  PubMed Central  Google Scholar 

  30. Jakob A, von Kries R, Horstmann J, Hufnagel M, Stiller B, Berner R, Schachinger E, Meyer K, Obermeier V (2018) Failure to predict high-risk Kawasaki disease patients in a population-based study cohort in Germany. Pediatr Infect Dis J 37:850–855. https://doi.org/10.1097/inf.0000000000001923

    Article  PubMed  Google Scholar 

  31. Chantasiriwan N, Silvilairat S, Makonkawkeyoon K, Pongprot Y, Sittiwangkul R (2018) Predictors of intravenous immunoglobulin resistance and coronary artery aneurysm in patients with Kawasaki disease. Paediatr Int Child Health 38:209–212. https://doi.org/10.1080/20469047.2018.1471381

    Article  PubMed  Google Scholar 

  32. Davies S, Sutton N, Blackstock S, Gormley S, Hoggart CJ, Levin M, Herberg JA (2015) Predicting IVIG resistance in UK Kawasaki disease. Arch Dis Child 100:366–368. https://doi.org/10.1136/archdischild-2014-307397

    Article  PubMed  Google Scholar 

  33. Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, Atz AM, Printz BF, Baker A, Vetter VL, Newburger JW (2011) Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr 158:831-835.e833. https://doi.org/10.1016/j.jpeds.2010.10.031

    Article  PubMed  Google Scholar 

  34. Makino N, Nakamura Y, Yashiro M, Sano T, Ae R, Kosami K, Kojo T, Aoyama Y, Kotani K, Yanagawa H (2018) Epidemiological observations of Kawasaki disease in Japan, 2013–2014. Pediatr Int 60:581–587. https://doi.org/10.1111/ped.13544

    Article  PubMed  Google Scholar 

  35. Research Committee of the Japanese Society of Pediatric Cardiology; Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease (2014) Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version). Pediatr Int 56:135–158. https://doi.org/10.1111/ped.12317

  36. JCS Joint Working Group (2014) Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013). Digest version. Circ J 78:2521–2562. https://doi.org/10.1253/circj.cj-66-0096

  37. Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, Ishii M, Harada K (2005) Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int 47:232–234. https://doi.org/10.1111/j.1442-200x.2005.02033.x

    Article  PubMed  Google Scholar 

  38. Akagi T, Rose V, Benson LN, Newman A, Freedom RM (1992) Outcome of coronary artery aneurysms after Kawasaki disease. J Pediatr 121:689–694. https://doi.org/10.1016/s0022-3476(05)81894-3

    Article  CAS  PubMed  Google Scholar 

  39. Dionne A, Burns JC, Dahdah N, Tremoulet AH, Gauvreau K, de Ferranti SD, Baker AL, Son MB, Gould P, Fournier A, Newburger JW, Friedman KG (2019) Treatment intensification in patients with Kawasaki disease and coronary aneurysm at diagnosis. Pediatrics 143:e20183341. https://doi.org/10.1542/peds.2018-3341

    Article  PubMed  Google Scholar 

  40. Ae R, Abrams JY, Maddox RA, Schonberger LB, Nakamura Y, Shindo A, Kuwabara M, Makino N, Matsubara Y, Kosami K, Sasahara T, Belay ED (2020) Platelet count variation and risk for coronary artery abnormalities in Kawasaki disease. Pediatr Infect Dis J 39:197–203. https://doi.org/10.1097/inf.0000000000002563

    Article  PubMed  Google Scholar 

  41. de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger JW (1998) Coronary artery dimensions may be misclassified as normal in Kawasaki disease. J Pediatr 133:254–258. https://doi.org/10.1016/s0022-3476(98)70229-x

    Article  PubMed  Google Scholar 

  42. Burns JC, Hoshino S, Kobayashi T (2018) Kawasaki disease: an essential comparison of coronary artery aneurysm criteria. Lancet Child Adolesc Health 2:840–841. https://doi.org/10.1016/s2352-4642(18)30334-1

    Article  PubMed  Google Scholar 

  43. Belay ED, Maddox RA, Holman RC, Curns AT, Ballah K, Schonberger LB (2006) Kawasaki syndrome and risk factors for coronary artery abnormalities: United States, 1994–2003. Pediatr Infect Dis J 25:245–249. https://doi.org/10.1097/01.inf.0000202068.30956.16

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all the pediatricians who contributed to the nationwide survey on Kawasaki disease in Japan. We thank Alison Sherwin, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

The study was partially supported by grants and funding from a non-profit organization, the Japan Kawasaki Disease Research Center.

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Authors and Affiliations

  1. Division of Public Health, Center for Community Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi, Japan

    Hiroya Masuda, Ryusuke Ae, Koki Kosami, Nobuko Makino, Yuri Matsubara, Teppei Sasahara & Yosikazu Nakamura

  2. Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan

    Taka-aki Koshimizu

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  1. Hiroya Masuda
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Contributions

HM:Conceptualization, Formal analysis, Literature review, Investigation, Software, Writing—original draft.

RA:Conceptualization, Formal analysis, Literature review, Investigation, Software, Writing - original draft and review & editing.

TK:Formal analysis, Investigation, Methodology, Software.

KK:Formal analysis, Investigation, Methodology, Software.

NM:Data curation, Supervision.

YM:Data curation, Formal analysis.

TS:Data curation, Supervision.

YN:Funding acquisition, Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing—review & editing, Final approval.

Corresponding authors

Correspondence to Hiroya Masuda or Ryusuke Ae.

Ethics declarations

Ethics approval

The Jichi Medical University Clinical Research Ethics Committee approved the study and waived the requirement for informed consent from each participant (Approval ID: 18–070).

Consent for publication

All of the authors contributed significantly to the work, approved the manuscript, and agree with its submission and publication.

Conflict of interest

Dr. Nakamura has received grants and funding from a non-profit organization, the Japan Kawasaki Disease Research Center. The other authors have no conflicts of interest to declare.

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Ryusuke Ae contributed equally as the co-first author.

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Masuda, H., Ae, R., Koshimizu, Ta. et al. Serum alanine aminotransferase level and intravenous immunoglobulin resistance in patients with kawasaki disease. Clin Rheumatol 41, 3125–3133 (2022). https://doi.org/10.1007/s10067-022-06278-w

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