Abstract

Key Points

• Kawasaki disease is a life-threatening disorder in children for which the incidence in China has increased over the past decades.

• Children with KD experience a considerable burden of illness leading to functional impairment in various aspects of life following the acute disease episode.

• The limited existing literature has not documented the long-term impact on HRQOL in children with acute KD-related CAAs well.

• This case-control retrospective study estimated the long-term HRQOL using both child self-reported and parent-proxy–reported formats in a large sample of children diagnosed with CAAs during acute KD.

• Patients with a history of CAAs should be identified and closely monitored using routine out-patient HRQOL screening to reduce the risk of long-term disability.

Abbreviations

CAA

coronary artery aneurysm

HRQOL

health-related quality of life

KD

Kawasaki disease

PedsQL

Pediatric Quality of Life Inventory

Introduction

Kawasaki disease (KD) is an acute, self-limited form of vasculitis with an intense inflammatory process that accounts for the most common cause of acquired heart disease in children, especially in children younger than 5 years of age.¹ Epidemiological surveys from China have reported an increasing trend in the incidence of KD of approximately 46.3 to 55.1 per 100,000 population in patients younger than 5 years of age over the past few decades.² Diagnosing KD is challenging because of the variety of associated clinical symptoms, which creates difficulties and delays clinical treatment.³ During the disease's acute phase, the patient is susceptible to cardiovascular complications, including valvulitis, myocarditis, pericarditis, and KD syndrome. Approximately 15% to 25% of patients will develop coronary artery aneurysms (CAAs) in the subacute to convalescent phase, leading to serious long-term consequences, including aneurysm, arterial thrombotic occlusion, or even sudden death if left untreated.^4,5 Rapid infusion of high-dose intravenous immunoglobulin within the first 10 days of illness, however, was reported to reduce the rate of aneurysm to 3% to 5%.⁶ In addition to cardiac complications, extreme irritability, seizures, hemiplegia, facial palsy, and aseptic meningitis were reported during the disease's acute phase. Kawasaki disease can therefore substantially impair patients’ function in a variety of aspects of life, from the first episode of disease onward. Although the majority of patients recover after the acute phase, some children who have poor coronary artery outcomes may have to face a long-term daily impairment in health-related quality of life (HRQOL) resulting from potentially serious cardiovascular sequelae. The limited existing literature, however, has not documented the impact of KD-related CAAs on the long-term HRQOL of surviving children well.

This study hypothesized that patients with KD-related CAAs exhibited poorer QOL because of the uncertain long-term prognosis of coronary artery lesions. This case-control retrospective study was designed to compare the long-term HRQOL reported by children and their parent proxies in a cohort of patients with KD-related CAAs with patients diagnosed with pneumonia or arterio-arterial fistula during contemporary hospitalization in the Nanjing region of China using a large sample.

Patients and Methods

Results

Figure 1 illustrates the design of the retrospective trial. Of the 164 patients included in the study, 12 were lost to follow-up because of unavailable questionnaires, including 6 patients in the pneumonia group, 2 patients in the small or medium-sized aneurysms group, and 4 patients in the arterio-arterial fistula group. Table I shows the participants’ baseline characteristics. The mean (SD) age at the time of diagnosis was 3.73 (1.93) years (range, 2.12-12.19 years).

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TABLE I.Baseline Demographics and Clinical Characteristics

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A total of 152 PedsQL questionnaires were available, including 114 child self-reported questionnaires and 38 parent-proxy–reported questionnaires. The median (IQR) follow-up time was 5.64 (3.81-7.47) years (range, 1.03-10.67 years). At baseline, in the KD-related CAAs cohort‚ which included the small or medium-sized and the giant aneurysms groups, children reported a total mean (SD) score of 48.63 (16.60), while parents reported a mean (SD) score of 46.76 (14.77). In the pneumonia group, children reported a mean (SD) score of 63.60 (18.82), and parents reported a mean (SD) score of 62.71 (17.72), both of which were statistically significantly higher than those of the KD-related CAAs cohort (children, P = .028; parents, P = .042). Among children with arterio-arterial fistula before treatment, the mean (SD) total scores of both formats were comparable to those of the KD-related CAAs cohort (child self-report, 50.80 [13.16], P = .97; parent-proxy–reported, 52.73 [13.34], P = .96). No statistically significant difference for the matched arterio-arterial fistula groups was observed for either child or parent reports at baseline in the detailed scores from the PedsQL 4.0 functional assessment subscales. In contrast, statistically significant differences were observed between the matched pneumonia group in multiple specific domains of emotional, social, and school-related functioning by parent-proxy report or child self-report (as provided in Table II). Starting at baseline, the total HRQOL scores improved over time in the total sample. Within each subgroup, as well, scores improved statistically significantly over time. At the time of long-term follow-up, children in the small or medium-sized aneurysms group reported a mean (SD) total score of 81.61 (19.50), which was comparable with children in the arterio-arterial fistula group (83.32 [18.24]; P = .54), though it was 9.51 points lower (95% CI, 2.02-16.98) than the mean total score in the pneumonia group (P =.014) and 9.70 points higher (95% CI, 2.22-17.18) than the mean total score in the giant aneurysms group (P = .012). Parents in the small or medium-sized aneurysms group also reported a comparable mean (SD) score of 81.03 (12.57) vs 83.30 (15.17) in the arterio-arterial fistula group (P = .53), scores that were statistically significantly higher than those in the giant aneurysms group (65.93 [13.69]; P = .009). The score reported by parents in the small or medium-sized aneurysms group, however, was statistically significantly worse (-9.9 points [95% CI, −17.27 to −2.53]) than the mean total score reported by parents in the pneumonia group (P = .010). Analysis of the 4 functional PedsQL subscales revealed that patients in the giant aneurysms group reported the lowest scores for both the child self-reported and parent-proxy–reported formats, while the matched pneumonia control group showed the highest scores. Mean scores, however, did not differ in a statistically significant way between patients in the small or medium-sized aneurysms group and the matched arterio-arterial fistula control group. Sensitivity analysis yielded results that were consistent with the primary findings of the long-term HRQOL scores using multiple imputation data (Table II).

TABLE II.Change in PedsQL Scores From Baseline to Follow-Up Among Patients With KD-Related CAAs vs Control Patients, Before and After Multiple Imputation

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Discussion

Although the incidence of KD in the Nanjing region of China remains uncertain because of the lack of accurate population statistics and a centralized database, to the authors’ knowledge, the study hospital is the largest referral center for the treatment of coronary artery sequelae of KD and has admitted the vast majority of patients in the Nanjing region over the past few decades. Studies investigating the long-term HRQOL consequences of cardiovascular sequelae of KD on children were nevertheless scarce. The study's results established comprehensive comparisons of long-term QOL between children with KD-related CAAs and 2 control patients during their contemporary hospitalization period. The study found that coronary artery sequelae indeed had a negative influence on a patient's life: The long-term HRQOL in children with a history of giant aneurysms during acute KD was substantially impaired.

Since it was first described in Japan in 1967 by Tomisaku Kawasaki,¹² KD has surpassed acute rheumatic fever as the leading cause of acquired heart disease among young children. The cause of KD remains poorly understood; it appears to be an interplay of genetic susceptibility and an infectious trigger followed by an abnormal immune response, mainly resulting in multisystemic vasculitis that shows a predilection for the coronary arteries.¹³ Possible delays in diagnosis and treatment occur in many children because of the disease's lack of typical manifestations, which challenges young children and their parents with the physical and psychological consequences of having a serious disease of unknown etiology and future outcome.³ Extreme irritability was described as a common symptom during the acute phase; children described an overwhelming range of emotions that had a heavy negative influence on their life.¹⁴ Previous data compared caregivers’ perceptions of their child with KD's health with the perceptions of caregivers of patients with other common childhood diseases and found that HRQOL plummeted after hospital admission as a result of the acute KD episode.¹⁵ The current study's results illustrate that children with CAAs during acute KD showed deteriorating HRQOL compared with the matched cohort of patients with similar serious cardiac problems, such as arterio-arterial fistula, while their PedsQL scores on admission were statistically significantly worse than those of the matched pneumonia cohort, findings that were consistent with those of 2 similar trials.^16,17 In turn, children with highly variable clinical presentations during the acute phase of KD experienced greater disability related to physical, social, emotional, and school-related functioning than children with acute pneumonia in the present study. Patients with KD-related CAAs experienced more substantial deterioration of HRQOL during the acute phase of KD than did patients with other common diseases, such as pneumonia, which potentially explains the profound decline of HRQOL at illness onset.

The prevalence of CAAs, especially giant CAAs, exposes patients to the risk of coronary arterial stenosis, obstruction, and thrombosis, which could lead to consequent angina pectoris or even myocardial infarction and sudden death.¹⁸ Although most patients have not been followed long enough to evaluate the long-term natural course of CAAs after the acute phase of KD, many CAAs were reported to regress to a normal diameter. The likelihood of regression seems to be highly dependent on the original size of the CAA.¹⁹ A large Japanese study showed that 55% to 60% of patients experienced regression of CAAs, typically within 1 to 2 years after the acute phase, by analyzing serial angiograms in those patients. None of the patients with giant aneurysms in their study showed regression.²⁰ A 2-center retrospective study with a large sample similarly found that CAA size at diagnosis was strongly associated with the prediction of CAA regression, with a low regression rate of 16% in patients with large or giant CAAs and a high regression rate of 85% in patients with small or medium-sized CAAs.²¹ Previous studies nevertheless emphasized that the long-term consequences of these changes were still largely unknown because even though many patients with KD-related CAAs regressed from aneurysmal dilatation, the coronary arteries remained abnormally thickened, and vessel-wall calcification was often detected.²² Chahal et al²³ reviewed the caregivers of children with KD-related CAAs and found that the principal reason for their persistent anxiety was the uncertainty of prognosis, which was implied by the degree of coronary artery lesions. Research on long-term HRQOL has accordingly demonstrated discrepant results between patients with only a remote history of KD and patients with KD-related CAAs.¹⁶ According to Iman Naimi's research,¹⁷ which first investigated the long-term impact of KD on HRQOL, children with KD experienced an acute impairment in HRQOL exceeding that of children with newly diagnosed pneumonia, but the scores returned to baseline at long-term follow-up. In that study, only 7 of 61 patients had persistent coronary aneurysms at 6-week follow-up.¹⁷ In contrast, the current study's results showed a statistically significant improvement in HRQOL over time in all cohorts, whereas a statistically significant difference in all domains of the PedsQL score was observed between the giant aneurysm group (17 patients) and the 2 matched pneumonia and arterio-arterial fistula groups at long-term follow-up. Long-term HRQOL scores between patients with small or medium-sized coronary aneurysms (47 patients) and control patients with arterio-arterial fistula undergoing transcatheter closure were comparable but were statistically significantly higher than the scores of patients diagnosed with pneumonia at contemporary hospitalization. All the previously mentioned results support the perspective that the majority of patients would recover fully and did not face long-term cardiac consequences after the acute phase, though 31% of patients struggled to meet their premorbid levels of age-appropriate function for weeks after presumed recovery. The presence of CAAs caused by KD, however, could add potentially serious cardiovascular sequelae, with a vague long-term prognosis. According to the current study's results, a long-term burden of CAAs after acute KD emerged if KD remained misdiagnosed or untreated or if optimal acute management was delayed. In addition, the presence of KD-related CAAs became a statistically significant contributory factor to possible long-term disabilities. It subsequently prolonged uncertainty as well as physical and psychological distress in relation to patients’ long-term HRQOL. These findings were consistent with the above-mentioned research that aimed to identify statistically significant changes in physical and psychological health, as perceived by the caregivers of children with chronic illness. Their results demonstrated a similar trend in which patients and their caregivers experienced considerable anxiety during the long-term follow-up period, despite having a mostly favorable prognosis. The current study's data therefore support its principal hypothesis because the longterm HRQOL findings indicated that a proportion of children with KD-related CAAs without complete recovery often encountered issues that disrupted their well-being during long-term follow-up. Considering these outcomes, a routine HRQOL screening in addition to monitoring for acquired heart disease could help reduce the risk of long-term disability in patients with KD-related CAAs following initial clinical improvement.

Conclusion

The results of the long-term HRQOL questionnaire in a cohort of children diagnosed with KD demonstrated that a proportion of these patients who had CAAs without complete recovery often encountered issues that disrupted their well-being during long-term follow-up, despite their HRQOL scores improving over time. Routine outpatient HRQOL screening may therefore be an appropriate support service to help identify patients with a history of KD-related CAAs during the disease's acute phase to eliminate the risk of long-term disability following initial clinical improvement.