Clinical Investigation of Kawasaki Disease in Patients aged Five years or Older at Onset

Original Article
Clinical Investigation of Kawasaki Disease in Patients aged Five years or Older at Onset

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

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 lymphadenitis 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     

Introduction

Kawasaki disease (KD), first reported 47 years ago, is a vasculitis 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 atan older age differs from that of patients with onset at a younger 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 significantly reduce the incidence of cardiovascular sequelae. We investigated and reported on the clinical presentations, treatment 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 symptoms, disease severity, test results, treatment, and coronary artery complications in both patient groups. Cardiac complications (acute coronary artery lesions) were investigatedseparately 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 aftermore than 1 year. Dilation was defined as ≥3 mm at all ages. A decrease in cardiac ejection fraction to ≤60% or mitral insufficiency with cardiac strain was representative of myocardial damage. We also compared our results with those of the 22nd National Survey of Kawasaki Disease. Statistical analysis 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 included10.5% 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 January 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 characteristics 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 Center: Results of the 22nd Kawasaki Disease National Survey. 2013.9 [In Japanese] )

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 comparatively 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 institutions 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 lymphadenitis was diagnosed and treatment for this condition was started in 33% (7/21) patients in the older group, a significantly higher proportion than the 4.2% (10/179) in the control 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 mistaken diagnoses in the older children (p < 0.05). It was a matter of course, the antibiotics was not effective in all cases in both groups.

The Gunma score [9] was used to predict resistance to treatment 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 significant
(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 neutrophil 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 peptide (BNP), urinary β2microgloburin (β2MG), or ferritin levels.

Table 3. Diagnostic Difficulty in Older group.

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  delayed.  wenty patients in the older group and 174 in the control 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 patients (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  differences  ere not significant (p = 0.202).Coronary angiography 1 year later found no coronary artery lesions in any patient. Myocardial damage occurred in 2 patients (9.5%) in the older group and in 22 (12.3%) in the control 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 starting 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 laparotomybefore being diagnosed [12].

Figure 3. 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 . This trend suggests that susceptibility to Kawasaki disease may be expanding to encompass older children, although this tendency was not evident at our hospital.

Nakata reported cases of older children with Kawasaki disease who were initially diagnosed with peritonsillitis or appendicitis; 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 after onset [13]. Our own results also showed that older children were diagnosed somewhat later—generally ≥6 days after onset. One patient was not diagnosed until day 10, and several patients were diagnosed with and treated for cervical lymphadenopathy for some days [14-20]. Older children with Kawasaki disease may initially exhibit symptoms other than those listed in diagnostic guides, including gastrointestinal symptoms, joint pain, headache, sore throat, and muscle pain. Ultrasonography has been reported to be useful for differentiating cervical lymph node swelling [21].

Figure 5. Age-specific prevalence of cardiac lesions and sequelae of KD in Japan. The national survey showed that theincidence 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 swollen lymph nodes form a grape-cluster-like mass that can be palpated like a single lymph node. In purulent lymphadenitis, 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 factors, 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   t 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 Kawasaki 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 cardiovascular sequelae. A good understanding of the clinical characteristics of older patients is crucial for earlier diagnosis and treatment.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 diagnosticcapabilities 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.

The older group contained a higher proportion of patientsnot treated with γ-globulin than the younger group. According 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 children 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 controversial. 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 coronary artery dilation [23]. Kawamura et al. reported that coronary 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 difference
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 develop Kawasaki with 2 g/kg γ globulin may prevent coronary artery damage without adverse effects.

Conclusion

(1) We investigated clinical symptoms and responsiveness to treatment in patients older than 5 years who developed Kawasaki 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 treatment 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 adequate 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)

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