OPEN ACCESS

Jacobs Journal of Pediatrics

Clinical Investigation of Kawasaki Disease in Patients aged Five years or Older at OnsetEiichi Yamamoto, MD1, Takashi Higaki, MD*2, Takeshi Nakano, MD1, Ryusuke Watanabe, MD1, Kyoko Konishi, MD3, Yoshihiro

Takahashi, MD4, Yasushi Ishida, MD1, Eiichi Ishii, MD2

1 Department of pediatrics, Ehime prefectural Central Hospital, Matsuyama, Japan 2Department of pediatrics, Ehime University Graduate School of Medicine, Toon, Japan 3Department of pediatrics, Matsuyama Shimin Hospital, Matsuyama, Japan 4Department of pediatrics, Uwajima City Hospital, Uwajima, Japan

*Corresponding author: Dr. Takashi Higaki, MD, Department of Pediatrics, Ehime University Graduate School of Medicine,

Shitsukawa, Toon, Ehime 791-0295, Japan , Tel: +81-89-960-5320; Fax: +81-89-960-5941; Email: higaki@m.ehime-u.ac.jp

Received: 12-24-2017

Accepted: 12-27-2017

Published: 12-31-2017

Copyright: © 2017 Takashi Higaki

Abstract

Introduction

Kawasaki disease (KD) is a systemic vasculitic syndrome which commonly develops under age 5. Older age at onset is one of the risk factors for cardiovascular complications.

Objective and Methods

We retrospectively analyzed 200 patients with diagnosis of KD in the Ehime prefectural Central Hospital in Japan between 2008 and 2014. The clinical characteristics of the patients with an onset age of 5 years or older (older age group: n=21) were compared with those with an onset age of less than 5 years (control group; n=179).

Results

In the older group, none demonstrated erythema around BCG scar, and more patients were initially diagnosed with a disease other than Kawasaki disease (p<0.05), particularly 33% of the older group were primarily diagnosed as cervical lymphade-nitis significantly higher than in the control group (4.2%, p<0.001). The required time for diagnosis (p=0.071) and the start date of the starting day of intravenous injection of immunoglobulin (IVIG) (p<0.05) tend to be late in the older group. There were no significant differences in their coronary artery sequelae incidence between two groups, this may have been because treatment was started earlier.

Conclusions

The prompt diagnosis is warranted for even older patients, just because there was equal chance to prevent coronary artery aneurysms by early intervention of high-dose IVIG (2 g/kg).

Keywords: Kawasaki Disease; Older-Onset; Clinical Characteristics, Cervical Lymphadenitis; High-Dose IVIG

Original Article

Cite this article: Takashi Higaki. Clinical Investigation of Kawasaki Disease in Patients aged Five years or Older at Onset. J J Pedia. 2017, 4(2): 012.

Research Article

10.5% of the total subjects recruited for the study. Figure 1 shows the age distribution in our hospital. For comparison, Figure 2 shows the age distribution in Japan. It was a similar trend.

Figure 1. Histogram of the onset age of KD in our hospital from Jan-uary 1.2008 to January 31.2014. There were 21 patients in the older group of 5 years of age or older, which included 10.5% of the total subjects recruited for the study.

Table 1 shows the comparison of the patients characteris-tics for both groups. The ages of patients in the older group ranged from 5 years to 12 years 6 months (mean, 6 years 8 months). The ages of patients in the control group ranged from 2 months to 4 years 11 months (mean, 1 year 11 months). The older group included a significantly higher number of girls.

Figure 2. Histogram of the onset age of KD in Japan from January 1.2009 to December 31.2012. The national survey shows the age and the sex distribution in Japan. (Japan Kawasaki Disease Research Cen-ter: Results of the 22nd Kawasaki Disease National Survey. 2013.9 [In Japanese] )

Introduction

Kawasaki disease (KD), first reported 47 years ago, is a vascu-litis of still unknown etiology. Approximately 10,000 patients are diagnosed with KD every year in Japan, and this number is gradually increasing [1]. The disease most commonly develops during infancy and early childhood (up to 4 years old), and its incidence peaks around 1 year. The most debilitating feature is the development or persistence of coronary artery damage during the acute phase. Coronary artery dilation or coronary aneurysm developed in approximately 10% of these patients.

Only about 12% of all patients develop this disease after the age of 5 years [2]. The clinical course of patients with onset at an older age differs from that of patients with onset at a young-er age in terms of clinical symptoms and responsiveness to treatment, and later onset is considered an independent risk factor for a higher incidence of cardiovascular sequelae [3-6]. The frequency with which symptoms appear varies in patients with onset at an older age, and the first symptoms to appear may not be those described in the diagnostic guidelines. This often makes late-onset KD difficult to diagnose. A proper understanding of the difference between these 2 groups is very important, because appropriate diagnosis and treatment strategy for patients with KD onset at an older age may sig-nificantly reduce the incidence of cardiovascular sequelae. We investigated and reported on the clinical presentations, treat-ment courses, and sequelae in patients with KD aged ≥5 years. Materials and Methods

We studied 200 patients with Kawasaki disease who were treated in our hospital between January 1, 2008 and January 31, 2014. We compared those who developed the disease at ≥5 years of age (older group) with those who developed the disease at ≤5 years of age (control group).

We carried out a retrospective investigation of clinical symp-toms, disease severity, test results, treatment, and coronary artery complications in both patient groups. Cardiac com-plications (acute coronary artery lesions) were investigated separately and defined as: dilation resolved within 1 month; sequelae in which dilation persisted for more than 1 month; and coronary aneurysms in which dilation was present after more than 1 year. Dilation was defined as ≥3 mm at all ages. A decrease in cardiac ejection fraction to ≤60% or mitral in-sufficiency with cardiac strain was representative of myocar-dial damage. We also compared our results with those of the 22nd National Survey of Kawasaki Disease. Statistical analy-sis was performed with SPSS ver. 22 for a χ2 test, t-test, and Mann-Whitney test, with p < 0.05 regarded as significant.

Results

There were 21 patients in the older group, which included

Jacobs Publishers 2

Table 2 shows the incidences of major symptoms of Kawasaki disease patients. In the older group of our hospital, fever was noted in 100% of patients; polymorphous rash, in 81%; lip and mouth-related symptoms, in 95.2%; bulbar conjunctival injection, in 95.2%; lesions of the extremities, in 85.7%; and cervical lymph node swelling, in 81%.

Figure 3 shows each symptom’s incidence compared to the incidence in the control group. There was no difference in the incidence of any of the 6 major symptoms between the groups. No member of the older group exhibited redness and swelling at the Bacillus Calmette-Guérin vaccination site, a com-paratively specific subcriterion for Kawasaki disease. There was no significant difference between the groups regarding the number of patients with incomplete Kawasaki disease (exhibited ≤4 of the major symptoms) (Table 1).

Table 1. Patients Characteristics

Additonally, Table 2 compares incidence of symptoms in the patients at our institution to incidences reported by other in-stitutions and the national survey. The incidences of symptoms were similar [7]. Nonpurulent cervical lymph node swelling was generally noted less frequently than other symptoms [8], but its incidence was similar to that of other symptoms in the older group (81%). Cervical lymph node swelling and fever are the first symptoms to appear, and purulent cervical lymph-adenitis was diagnosed and treatment for this condition was started in 33% (7/21) patients in the older group, a signifi-cantly higher proportion than the 4.2% (10/179) in the con-trol group (p < 0.001) (Table 3). Nine of 21 patients in the older group and 26 of 179 patients in the control group were initially diagnosed with a disease other than Kawasaki disease.

Again, we observed a significantly higher proportion of mis-taken diagnoses in the older children (p < 0.05). It was a mat-ter of course, the antibiotics was not effective in all cases in both groups.

The Gunma score [9] was used to predict resistance to treat-ment and to compare disease severity. In the older group, 11 patients (52.4%) scored ≥5 points, compared to 74 patients (41.6%) in the control group. The difference was not signifi-cant (p = 0.344).

Table 2. Incidence of the Symptom.

Table 4 shows a comparison of blood examination results. Patients in the older group had significantly higher neutro-phil percentages and lower platelet counts. The levels of sIL-2R were significantly higher in the control group (1544 U/ml vs 2338 U/ml, p <0.001); however, there were no significant differences between the older group and the control group in terms of White blood cell (WBC), C-reactive protein (CRP), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), albumin, total bilirubin, sodium, Brain natriuretic pep-tide (BNP), urinary β2microgloburin (β2MG), or ferritin levels.

Table 3. Diagnostic Difficulty in Older group.

Jacobs Publishers 3

Coronary angiography 1 year later found no coronary artery lesions in any patient. Myocardial damage occurred in 2 pa-tients (9.5%) in the older group and in 22 (12.3%) in the con-trol group, but this difference was not significant (p = 0.823).

Discussion

According to the 22nd National Survey of Kawasaki Disease in Japan, Kawasaki disease patients aged ≥5 years accounted for 1,469 of a total 12,774 patients (11.5%) in 2011; of these, 120 were aged ≥10 years. In 2012, 1,701 of 13,917 patients (12.2%) were aged ≥ 5 years; of these, 134 were aged ≥10 years.

Until the 22nd Kawasaki Disease Survey, this older patient group has accounted for around 10% of patients annually, meaning that recent years have seen an increasing proportion of older patients.

This trend suggests that susceptibility to Kawasaki disease may be expanding to encompass older children, although this tendency was not evident at our hospital (Figure 4). Children who develop Kawasaki disease at an older age are believed to have an increased risk of coronary artery sequelae, and, as shown in Figure 5, the national survey in Japan showed that the incidence of cardiac damage at age 10 stratified by age and sex was extremely high.

One reason for this increased risk may be the delay in start-ing treatment. In an older study from overseas, Pannaraj found that more than half of general pediatricians and a quarter of infectious disease specialists did not suspect Kawasaki disease in children 8 years or older, [11] largely because older-onset Kawasaki disease symptoms are nonspecific. Jannet et al. even reported a case of an older child who underwent laparotomy

Although there was no significant difference between the 2 groups in the number of days from onset to diagnosis (5.33 days in the older group vs. 4.32 days in the control group, p = 0.14), diagnosis of the older group tended to be somewhat de-layed. Twenty patients in the older group and 174 in the con-trol group required administration of γ-globulin.

Table 4. Blood Examination

There was also no significant difference when the 2 groups were divided into patients diagnosed within 5 days or >5 days [6 patients (30.0%) in the older group vs 25 (14.4%) in the control group, p = 0.071]. In this case, too, diagnosis of the older group tended to be somewhat delayed. A comparison of these patients showed that administration began after 5.2 days for those in the older group, significantly later than the 4.29 days for those in the control group (p < 0.05) (Table 3).

There was no difference in the proportion of patients who were resistant to γ-globulin treatment (those who required administration of additional drugs) between the groups [5 pa-tients (23.8%) in the older group vs 65 (36.3%) in the control group, p = 0.256]. At our hospital, γ-globulin-resistant patients [10] were mainly treated with additional γ-globulin or with the administration of ulinastatin or cyclosporine A.

We compared these treatment methods for resistant patients between groups and found no significant difference in the use of either ulinastatin [2 patients (10%) in the older group vs 30 (17.1%) in the control group, p = 0.538] or cyclosporine A [2 patients (10%) in the older group vs 24 (13.7%) in the control group, p = 0.999].

In terms of cardiac complications, acute lesions were present in 4 patients (19%) in the older group and in 16 (8.9%) in the control group. Sequelae were present in 0 patients in the older group and in 11 (6%) in the control group, but these differenc-es were not significant (p = 0.202).

Jacobs Publishers 4

before being diagnosed [12].

Figure 3. The symptom’s incidence compared to the incidence in the control group. There was no difference in the incidence of any of the 6 major symptoms between the groups. No member of the older group exhibited redness and swelling at the Bacillus Calmette-Guerin vac-cination site, a comparatively specific subcriterion for kawasaki dis-ease.

Figure 4 . This trend suggests that susceptibility to Kawasaki disease may be expanding to encompass older children, although this tenden-cy was not evident at our hospital.

Nakata reported cases of older children with Kawasaki disease who were initially diagnosed with peritonsillitis or appendi-citis; further, all patients aged ≥8 years reported by Bresson et al. were first diagnosed with other conditions, resulting in starting Kawasaki disease treatment, on average, 11.2 days af-ter onset [13]. Our own results also showed that older children were diagnosed somewhat later—generally ≥6 days after on-set. One patient was not diagnosed until day 10, and several patients were diagnosed with and treated for cervical lymph-adenopathy for some days [14-20]. Older children with Kawa-saki disease may initially exhibit symptoms other than those listed in diagnostic guides, including gastrointestinal symp-toms, joint pain, headache, sore throat, and muscle pain.

Ultrasonography has been reported to be useful for differenti-ating cervical lymph node swelling [21].

Figure 5. Age-specific prevalence of cardiac lesions and sequelae of KD in Japan. The national survey showed that the incidence of cardiac damage at age 10stratified by age and sex was extremely high. (Yosikazu Nakamura: Epidemiologic Features of Kawasaki Disease in Japan:Results of the 2009–2010 Nationwide Survey)

In lymph node swelling due to Kawasaki disease, several swol-len lymph nodes form a grape-cluster-like mass that can be palpated like a single lymph node. In purulent lymphadeni-tis, on the other hand, isolated lymph nodes become swollen. This finding alone is insufficient grounds on which to base a differential diagnosis, but taken in conjunction with other fac-tors, such as response to antibiotic therapy, it may be helpful for early diagnosis. In the older child who is not predilection age of the Kawasaki disease, the onset of main symptom is slow, and it is difficult to diagnose it with Kawasaki disease at the time with a little main symptom of the early period of illness. It is necessary for the principal symptom of the guide of the diagnosis to be met more in comparison with a control group so that Kawasaki disease is diagnosed. This does not have the significant difference, but it is a similar reason to tend with a less frequency of the incomplete type of Kawasa-ki disease and shows that the Kawasaki disease is hard to be diagnosed at the stage when a symptom is not progressed. Table 3 shows the difficulty of diagnosing Kawasaki disease in older patients. Delay in diagnosis, delays administration of γ-globulin, which may result in a higher incidence of cardiovas-cular sequelae. A good understanding of the clinical character-istics of older patients is crucial for earlier diagnosis and treat-ment. In this study, we did not find any difference in coronary artery sequelae incidence between the older group and the control group, but this may have been because treatment was started earlier for control group subjects. Our findings indicate that early diagnosis of Kawasaki disease and improved diag-nostic capabilities in primary care are important for improving the prognosis of patients with Kawasaki disease. Considering Kawasaki disease in the differential diagnosis is key to its early diagnosis.

Jacobs Publishers 5

Figure.3 The symptom’s incidence

in the older group compared to the incidence in the control group

おｌｄ

発熱 発疹 口唇 眼球充血 四肢の変化 頚部リンパ節 BCG

年長児 対照

＊

(%)

＊

20

40

60

80

100

P=0.99 P=0.488 P=0.322 P=0.701 P=0.771 P=0.359

Older group（n=21） VS Control group（n=179）

control

Fever Skin rash Conjunctival Extremities change

Mucosal change of oropharynx

Cervical Lymph-adenopathy

injection

P<0.01

older

BCG

Figure.4 This trend suggests that susceptibility to Kawasaki disease may be expanding to encompass older children, although this tendency was not evident at our hospital.

0

5

10

15

20

25

30

35

40

45

2008 2009 2010 2011 2012 2013 2014

年長群総数

×

×

× ×

×

×

×

× rate of the older patients

(%)

number(％)

12.5

17.9

8.3 8.611.1 11.1

8.8

the older patientsall patients

The older group contained a higher proportion of patients not treated with γ-globulin than the younger group. Accord-ing to the 22nd Kawasaki Disease National Survey, γ-globulin was used in 91.2% of cases. For the older children, however, the rate of γ-globulin treatment tended to decline. The therapy was used in 84.8% of patients aged 8 years, 88.1% of patients aged 9 years, and 85% of patients aged ≥10 years. Older chil-dren have been known to develop hyperviscosity syndrome and headache as side effects of high doses of γ-globulin, and the appropriate dose per body weight and total γ-globulin dose in affected children of heavier weight are controver-sial. Yanagimoto et al. reported obtaining good therapeutic outcomes in patients with Kawasaki disease who weighed ≥25 kg using lower-than-recommended doses [22].On the other hand, Takahashi et al. reduced the recommended dose of 2 g/kg/day for older children, but subsequently found evident cor-onary artery dilation [23]. Kawamura et al. reported that coro-nary artery lesions persisted in 2 patients who were aged ≥10 years and treated with γ-globulin (1 g/kg) [24]. No coronary artery lesions, however, were evident in another patient at the same hospital who was treated with a dose of 2 g/kg. At our hospital, we treated 5 patients who weighed ≥25 kg with 1.74–2 g/kg γ-globulin. The maximum dose was 90 g (1 g/kg/day x 2 days) in a patient who weighed 45 kg. There was no differ-ence between the control and older groups in the proportion of patients who were resistant to γ-globulin treatment, and no coronary artery sequelae were observed. There were also no side effects such as headache, vomiting, respiratory distress, or embolism. This suggests that treating older patients who de-velop Kawasaki with 2 g/kg γ globulin may prevent coronary artery damage without adverse effects.

Conclusions

(1) We investigated clinical symptoms and responsiveness to treatment in patients older than 5 years who developed Kawa-saki disease and were treated at our hospital during the past 6 years. No patient developed persistent coronary artery lesions.

(2) The possibility of Kawasaki disease and appropriate treat-ment must be considered in cases of older children who are diagnosed with and treated for antibiotic-resistant cervical lymphadenitis

(3) Older children with Kawasaki disease have a higher risk of cardiovascular sequelae, and starting treatment with an ade-quate dose of intravenous immunoglobulin as soon as possible may improve their prognosis.

Conflict of Interest

The authors declare that there are no conflicts of interest.

Author contributions

Conception and design: EY, TH and YI Collection and assembly of data: EY, TH, TN, RW, KK, YT and YI

Data analysis and interpretation: EY, TH, YI and EI

Manuscript writing: EY and TH

Final approval of manuscript: All members (EY, TH, TN, RW, KK, YT, YI and EI)

References

1. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syn-drome(MCLS) prevailing in Japan. Pediatrics. 1974, 54(3): 271-276.

2. Japan Kawasaki Disease Research Center: Results of the 22nd Kawasaki Disease National Survey. 2013.9 [In Japanese]3. Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, et al. Epidemiologic Features of Kawasaki Disease in Japan : Re-sults of the 2009-2010 Nationwide Survey. J Epidemiol. 2010, 22(3): 216-221 .

4. Muta H, Ishii M, Sakaue T, Egami K, Furui J et al. Older age is a risk factor for the development of cardiovascular sequelae in Kawasaki disease. Pediatrics . 2004, 114(3): 751-754.

5. Cai Z, Zuo R, Liu Y. Characteristics of Kawasaki Disease in Older Children. Clin Pediatr (Phila). 2011. 50(10): 952-956. 6. Gomard-Mennesson E, Landron C, Dauphin C, Epaulard O, Petit C et al. Kawasaki disease in adults: report of 10 cases. Medicine (Baltimore). 2010, 89(3):149-158.

7. Higuchi S. Clinical study of Kawasaki disease patients in our department. Progress in Medicine 2012, 32(7):1412-1415 [In Japanese].

8. Oki I, Yashiro M, Ritei U. Comparison of Principal Symptoms of Kawasaki Disease between Early Stage (1971) and Recent (2003) Nationwide Survey, Journal of the Japan Pediatric Soci-ety. 2005, 109, 484-491[in Japanese] .

9. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006, 113(22): 2606-2612.

10. Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Dis-ease: Guidelines for medical treatment of acute Kawasaki dis-ease: Report of the Research Committee of the Japanese Soci-

Jacobs Publishers 6

ety of Pediatric Cardiology and Cardiac Surgery (2012 revised version); Pediatrics International. 2014, 56:135–158.

11. Pannaraj PS, Turner CL, Bastian JF, Burns JC. Failure to di-agnose Kawasaki disease at the extremes of the pediatric age range. Pediatr Infect Dis J. 2004 ,23(8): 789-791.

12. Stockheim JA, Innocentini N, Shulman ST. Kawasaki disease in older children and adolescents. J Pediatr. 2000,137(2): 250-252.

13. Nakata T. Clinical observation of older patients with Ka-wasaki disease. Japanese Journal of Pediatrics. 2013; 66(10): 2116-2121 [In Japanese] .

14. Kubota M, Usami I, Yamakawa M, Tomita Y, Haruta T. Ka-wasaki disease with lymphadenopathy and fever as sole initial manifestations. J Paediatr Child Health. 2008, 44(6): 359-362.

15. Nomura Y, Arata M, Koriyama C, Masuda K, Morita Y et al. A severe form of Kawasaki disease presenting with only fever and cervical lymphadenopathy at admission. J Pediatr. 2010, 156(5): 786-791.

16. Chiew-Y Y,Lung-Huang L, Nan-Koong W. An atypical presen-tation of Kawasaki disease: a 10-year-old boy with acute exu-dative tonsillitis and bilateral cervical lymphadenitis. CLINICS 2012, 67(6): 89-692 .

17. Burgner D, Festa M, Isaacs D. Delayed diagnosis of Kawa-saki disease presenting with massive lymphadenopathy and airway obstruction. BMJ. 1996, 312(7044): 1471-1472.

18. Yoskovitch A, Tewfik TL, Duffy CM, Moroz B. Head and neck manifestations of Kawasaki disease. Int J Pediatr Otorhinolar-yngol. 2000, 52(2):123-129.

19. Stamos JK, Corydon K, Donaldson J, Shulman ST et al. Lymphadenitis as the dominant manifestation of Kawasaki disease. Pediatrics. 1994, 93(3): 525-528.20. Kao HT, Huang YC, LinTY. Kawasaki disease presenting as cervical lymphadenitis or deep neck infection. Otolaryngol Head and Neck. 2001, 124: 468-470 .

21. Tashiro N, Matsubara T, Uchida M, Katayama K, Ichiyama T et al. Ultrasonographic Evaluation of Cervical Lymph Nodes in Kawasaki Disease, Pediatrics. 2002, 109(5): e77.

22. Kosuke Yanagimoto, Yuichi Nomura, Kiminori Masuda, Michiko Arata, Daisuke Hazeki et al.: Investigation of Kawasa-ki disease child patients with body weights twenty-five kilo-grams. Pediatric Cardiology and Cardiac Surgery. 2012, 28(3): 174-178.

23. Takahashi T. Investigation of γ-globulin doses for old-er Kawasaki disease child patients with body weights 30 kg and above. Pediatric Cardiology and Cardiac Surgery. 2008, 24(3):432[In Japanese].

24. Kawamura Y et al. Three cases of Kawasaki disease in 10-year-old patients. Journal of Pediatric Practice. 2003, 66(6): 1078-1081 [In Japanese].

Jacobs Publishers 7