The most common clinical feature of KD was conjunctival injection (95.7%), followed by rash (93.9%), mucous membrane changes (91.4%), extremity changes (75.8%) and unilateral cervical lymphadenopathy ≥1.5 cm (32.3%); these findings were consistent with prior literature.1 A total of 325 of 392 (82.9%) patients were classified as responders. The vast majority of subjects (85.5%) were treated within 10 days of disease onset, 6.1% were readmitted and 2.8% presented with KDSS.
In comparing complete and incomplete groups, 313 subjects met criteria for cKD and 79 (20.2%) subjects met criteria for iKD (Table 1). Patients with iKD were statistically more likely to have lower hemoglobin, lower albumin, ectasia or aneurysm on initial echo, echo meeting AHA criteria for KD involvement, ectasia or aneurysm at any time point and giant aneurysms. They were also more likely to have KDSS and longer duration of illness before treatment with IVIG compared with subjects with cKD (Table 1). The rates of treatment with IVIG within 10 days of illness onset were not statistically different between groups.
Responders accounted for the majority of subjects (325, 82.9%), with 67 (17.1%) subjects classified as nonresponders. Nonresponders were more likely to be Black, have higher ESR and CRP, AHA echo positivity and ectasia or aneurysm compared with responders (Table 1). In addition, nonresponders were more likely to require intensive care and readmission (Table 1).
Compared with non-Black, Black subjects (95, 23.2%) were more likely to have higher ESR, lower hemoglobin and lower albumin (Table 2). Black subjects were also more likely to be nonresponders. There was no significant difference in rates of initial positive echo, ectasias, or aneurysms between the groups (Table 2).
In the overall population, ectasia or aneurysm was present on 22.7% of initial echo and 27.0% of subjects had ectasia or aneurysm present on at least 1 echo. CAAs occurred in 7.4% and giant coronary aneurysms in 2.3%. Echos were followed for a period of 2 years and compared by responder status and racial subgroups. A total of 200 children developed an abnormal echo (any cardiac involvement, including full AHA criteria) and 98% were followed for at least 2 years. Normalization of echo abnormalities occurred in 76.5% (150/196) at 1 year. Responders were more likely to achieve echo normalization by 1 year than nonresponders (81.3% vs. 60.9%, P = 0.002). Black subjects trended toward slower normalization overall compared with non-Black subjects (67.4% vs. 79.6%, P = 0.08). This was driven by the Black nonresponder subgroup, which had the slowest normalization compared with non-Black responders (52.9% vs. 83.1%, P = 0.004). Black nonresponders took a median of 13 weeks post-IVIG to normalize (95% CI: 3.42–40.00) compared with 7.7 weeks (95% CI: 5.14–22.43) in Black responders, 5.6 weeks (95% CI: 3.71–6.71) in non-Black responders and 9.4 weeks (95% CI: 3.0–52.29) in non-Black nonresponders (P = 0.01; Fig. 3A).
A total of 111 children developed echo abnormalities meeting AHA criteria (echo positive)16; 82% (91/111) of these children had pseudonormalization of their coronary arteries by 1 year. Responders were more likely to pseudonormalize than nonresponders (87.2% vs. 69.7%, P = 0.03). No racial differences were appreciated in pseudonormalization rates (Black subjects 86.7% vs. non-Black subjects 80.3%, P = 0.58), including among racial subgroups of nonresponders (non-Black nonresponders 65% vs. Black nonresponders 76.9%, P = 0.47). Similarly, there was no statistically significant racial subgroup difference in pseudonormalization rate by 2 years (P = 0.10, Fig. 3B).
In this 14-year, single-center, retrospective study of US children with KD, we uniquely identified Black race as a risk factor for nonresponse to a single dose of IVIG. We also noted elevated inflammatory markers were associated with nonresponse, consistent with prior studies.7 , 25 , 26 Interestingly, nonresponders in our cohort did not trend toward age extremes, male gender or delayed IVIG treatment—all of which have previously been shown as risk factors for cardiac involvement in KD.6–8 , 12 The frequency of nonresponse (17.1%) is within the 10%–20% rate of previously reported studies5 , 7 , 27 and is only slightly higher compared with the Pediatric Health Information System database (16.3%).28 Nonresponders in our study were more likely to develop and have more severe coronary abnormalities, with 20.9% of nonresponders having a CAA detected on echo compared with 4.6% of responders, consistent with other published studies.5 , 17 , 29 , 30 Nonresponders required more intensive care and were readmitted at higher rates. Our data support that nonresponders are at high risk for presenting with severe disease and developing CAAs. Further studies to identify these children and different targeted treatment modalities are needed.
Our finding of Black race as a risk factor for IVIG nonresponse supports the recent Pediatric Health Information System (PHIS) epidemiologic study showing that hospitals in the highest quartile of IVIG nonresponse had a statistically significant higher number of Black children compared with those at the lowest quartile of IVIG nonresponse (26.5% vs. 20.1%; P < 0.01).28 Our multivariable logistic regression model showed a posterior Pr of 0.95 that the true OR for Black race was greater than 1, indicating for the first time that Black race is a risk factor for IVIG nonresponse. Thus, this higher risk racial subgroup may warrant consideration of adjunctive therapies in the initial treatment algorithm. This is particularly concerning given African American children are disproportionately affected by KD.3 , 31 , 32
Few studies have included a significant number of Black KD patients and those that did had conflicting conclusions. A Michigan State study (n = 189, 72% Black) found that Black children were more likely to be hospitalized for KD with trends toward higher rates of coronary involvement, though statistically insignificant.31 Conversely, a study at Children’s National Medical Center (n = 302, 54% Black) found that Black race may be protective against CAAs.33 Our study found no difference in the rate of coronary artery involvement in Black children when compared with non-Black children. However, Black nonresponders had delayed normalization of KD-related echo abnormalities at 1 year (52.9%, P = 0.02) with similar rates of CAA and ectasia pseudonormalization compared with non-Black nonresponders (76.9% vs. 65.0%, P = 0.47). Thus, Black race predisposes to IVIG nonresponse with a prolonged duration of cardiac involvement compared with other races. Additional studies with racially diverse populations are necessary to confirm our results.
The explanation for the racial disparity in IVIG response is unknown, but host genetics may play an important role. It has been suggested that African-descent is associated with decreased sialylation.34 , 35 Prior immunologic work has shown nonresponders have lower levels of sialylation of the Fc (fragment crystallizable) portion of their endogenous IgG, which has been shown to be important for response to IVIG.36 Secondly, hemoglobin values were lower in Black subjects compared with non-Black subjects, which may represent an increased inflammatory state. One proposed mechanism of anemia in KD is upregulation of toll-like receptors leading to an increase in the liver-derived protein hepcidin.37 Hepcidin is speculated to be elevated in Black subjects, and levels correlate with increased levels of CRP, which trended toward significant increases among Black subjects in our cohort.38 , 39 Hepcidin-induced anemia can occur by 3 mechanisms: (1) direct inhibitory suppression of erythropoiesis; (2) intracellular iron sequestration from interaction with ferroportin and (3) decreased intestinal iron absorption in the duodenum.37 Additional studies are needed to determine if hepcidin levels could be a biomarker for nonresponse and if these levels and/or hepcidin receptors are associated with racial disparities.
It is well established that children with KD who fail to respond to the first dose of IVIG are more likely to develop cardiac abnormalities, which can be detrimental long term.40 , 41 Our study confirmed these findings. Both normalization of any echo abnormality and pseudonormalization of coronary abnormalities diverged by responder status by 8 weeks and persisted until 2-year follow-up, favoring responders. Future studies powered to detect racial differences in cardiac involvement are necessary to better understand how Black race affects long-term cardiac sequelae of KD.
Predicting clinical and lab features of children at high risk for IVIG nonresponse is important for understanding which children need additional monitoring, treatment and parental counseling. Thus, some international KD working groups have developed predictive models for IVIG nonresponse based on clinical, laboratory and/or imaging criteria. Unfortunately, the vast majority of these studies evaluating risk factors were done in predominately Asian populations, with limited generalizability to and/or sensitivity among US children.5 , 29 , 42 , 43 In particular, a prior study showed reduced sensitivity of the Egami score25 in Black children13 and race is not part of the predictive model derived from the UCSD (University of California - San Diego) experience.6 Multicenter studies are needed to predict and validate a score for nonresponders that is applicable to the heterogeneous US population.
Our study limitations include the retrospective design, in which clinical data were dependent on the physicians’ documentation and selection of laboratory studies was often not exhaustive. Additionally, recall bias may have affected the duration of illness, as well as the classification of children as cKD versus iKD. Sample size limited the power of our study and our ability to detect differences in long-term cardiac outcomes among racial subgroups.
KD is the most common cause of acquired cardiac abnormalities in American children, surpassing rheumatic fever.1 , 2 , 15 Current prediction modeling for IVIG nonresponse has limited sensitivity in the heterogeneous US population. Our study again confirms that nonresponders have higher rates and severity of coronary involvement than responders and require more intensive care and readmissions for ongoing therapy. Our study uniquely demonstrates Black race as a risk factor for IVIG nonresponse as well as for delayed resolution of any cardiac involvement at 1-year follow-up. Further studies in the United States are needed to elucidate which children are most likely to be nonresponders and to identify the optimal initial therapy for this high-risk group.
1. McCrindle BW, Rowley AH, Newburger JW, et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease
Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention. Diagnosis, treatment, and long-term management of Kawasaki disease
: a Scientific Statement for Health Professionals from the American Heart Association. Circulation. 2017;135:e927–e999.
2. Burns JC, Glodé MP. Kawasaki syndrome. Lancet. 2004;364:533–544.
3. Holman RC, Curns AT, Ermias D, et al. Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics. 2003;112:495–501.
4. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324:1633–1639.
5. Burns JC, Capparelli EV, Brown JA, et al. Intravenous gamma-globulin treatment and retreatment in Kawasaki disease
. US/Canadian Kawasaki Syndrome Study Group. Pediatr Infect Dis J. 1998;17:1144–1148.
6. Kitano N, Suzuki H, Takeuchi T, et al; Wakayama Kawasaki Disease
Study Group. Epidemiologic features and prognostic factors of coronary artery lesions associated with Kawasaki disease
based on a 13-year cohort of consecutive cases identified by complete enumeration surveys in Wakayama, Japan. J Epidemiol. 2014;24:427–434.
7. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin
in children with Kawasaki disease
. J Pediatr. 2008;153:117–121.
8. Nakamura Y, Fujita Y, Nagai M, et al. Cardiac sequelae of Kawasaki disease
in Japan: statistical analysis. Pediatrics. 1991;88:1144–1147.
9. Loomba RS, Raskin A, Gudausky TM, et al. Role of the Egami score in predicting intravenous immunoglobulin
resistance in Kawasaki disease
among different ethnicities. Am J Ther. 2016;23:e1293–e1299.
10. Sleeper LA, Minich LL, McCrindle BM, et al; Pediatric Heart Network Investigators. Evaluation of Kawasaki disease
risk-scoring systems for intravenous immunoglobulin
resistance. J Pediatr. 2011;158:831–835.e3.
11. Ashouri N, Takahashi M, Dorey F, et al. Risk factors for nonresponse to therapy in Kawasaki disease
. J Pediatr. 2008;153:365–368.
12. Muta H, Ishii M, Yashiro M, et al. Late intravenous immunoglobulin
treatment in patients with Kawasaki disease
. Pediatrics. 2012;129:e291–e297.
13. Nakamura Y, Oki I, Tanihara S, et al. Cardiac sequelae in recurrent cases of Kawasaki disease
: a comparison between the initial episode of the disease and a recurrence in the same patients. Pediatrics. 1998;102:E66.
14. Sonobe T, Kiyosawa N, Tsuchiya K, et al. Prevalence of coronary artery abnormality in incomplete Kawasaki disease
. Pediatr Int. 2007;49:421–426.
15. Witt MT, Minich LL, Bohnsack JF, et al. Kawasaki disease
: more patients are being diagnosed who do not meet American Heart Association criteria. Pediatrics. 1999;104:e10.
16. Newburger JW, Takahashi M, Gerber MA, et al; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease
, Council on Cardiovascular Disease in the Young, American Heart Association. Diagnosis, treatment, and long-term management of Kawasaki disease
: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease
, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114:1708–1733.
17. Yellen ES, Gauvreau K, Takahashi M, et al. Performance of 2004 American Heart Association recommendations for treatment of Kawasaki disease
. Pediatrics. 2010;125:e234–e241.
18. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–381.
19. Denby KJ, Clark DE, Markham LW. Management of Kawasaki disease
in adults. Heart. 2017;103:1760–1769.
20. Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease
. A 10- to 21-year follow-up study of 594 patients. Circulation. 1996;94:1379–1385.
21. Dhillon R, Clarkson P, Donald AE, et al. Endothelial dysfunction late after Kawasaki disease
. Circulation. 1996;94:2103–2106.
22. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease
shock syndrome. Pediatrics. 2009;123:e783–e789.
23. Hoffman MD, Gelman A. The No-U-Turn Sampler: adaptively setting path lengths in Hamiltonian Monte Carlo. J Mach Learn Res. 2014;15:1593–1623.
24. Salvatier J, Wiecki TV, Fonnesbeck C. Probabilistic programming in Python using PyMC3. PeerJ Computer Science. 2016;2:e55.
25. Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin
treatment in patients with Kawasaki disease
. J Pediatr. 2006;149:237–240.
26. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin
unresponsiveness in patients with Kawasaki disease
. Circulation. 2006;113:2606–2612.
27. Newburger JW, Sleeper LA, McCrindle BW, et al; Pediatric Heart Network Investigators. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease
. N Engl J Med. 2007;356:663–675.
28. Moffett BS, Syblik D, Denfield S, et al. Epidemiology of immunoglobulin resistant Kawasaki disease
: results from a large, national database. Pediatr Cardiol. 2015;36:374–378.
29. Chen S, Dong Y, Kiuchi MG, et al. Coronary artery complication in Kawasaki disease
and the importance of early intervention: a systematic review and meta-analysis. JAMA Pediatr. 2016;170:1156–1163.
30. Chen S, Dong Y, Yin Y, et al. Intravenous immunoglobulin
plus corticosteroid to prevent coronary artery abnormalities in Kawasaki disease
: a meta-analysis. Heart. 2013;99:76–82.
31. Abuhammour WM, Hasan RA, Eljamal A, et al. Kawasaki disease
hospitalizations in a predominantly African-American population. Clin Pediatr (Phila). 2005;44:721–725.
32. Gibbons RV, Parashar UD, Holman RC, Belay ED, Maddox RA, Powell KE, et al. An evaluation of hospitalizations for Kawasaki syndrome in Georgia. Archives of Pediatric and Adolescent Medicine. 2002;156:492–496.
33. Porcalla AR, Sable CA, Patel KM, et al. The epidemiology of Kawasaki disease
in an urban hospital: does African American race protect against coronary artery aneurysms
? Pediatr Cardiol. 2005;26:775–781.
34. Smith KG, Clatworthy MR. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol. 2010;10:328–343.
35. Mahan AE, Jennewein MF, Suscovich T, et al. Antigen-specific antibody glycosylation is regulated via vaccination. PLoS Pathog. 2016;12:e1005456.
36. Ogata S, Shimizu C, Franco A, et al. Treatment response in Kawasaki disease
is associated with sialylation levels of endogenous but not therapeutic intravenous immunoglobulin
G. PLoS One. 2013;8:e81448.
37. Huang YH, Kuo HC. Anemia in Kawasaki disease
: Hepcidin as a potential biomarker. Int J Mol Sci. 2017;18:820.
38. Karl JP, Lieberman HR, Cable SJ, et al. Randomized, double-blind, placebo-controlled trial of an iron-fortified food product in female soldiers during military training: relations between iron status, serum hepcidin, and inflammation. Am J Clin Nutr. 2010;92:93–100.
39. Smith EM, Alvarez JA, Martin GS, et al. Vitamin D deficiency is associated with anaemia among African Americans in a US cohort. Br J Nutr. 2015;113:1732–1740.
40. Hsu CH, Chen MR, Hwang FY, et al. Efficacy of plasmin-treated intravenous gamma-globulin for therapy of Kawasaki syndrome. Pediatr Infect Dis J. 1993;12:509–512.
41. Ephrem A, Misra N, Hassan G, et al. Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin
. Clin Exp Med. 2005;5:135–140.
42. Minich LL, Sleeper LA, Atz AM, et al; Pediatric Heart Network Investigators. Delayed diagnosis of Kawasaki disease
: what are the risk factors? Pediatrics. 2007;120:e1434–e1440.
43. Uehara R, Belay ED, Maddox RA, Holman RC, Y N, Yashiro M, et al. Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin
treatment among Kawasaki disease
patients in Japan. Pediatr Infect Dis J. 2008;27:155–160.