Association of early social environment with the onset of pediatric Kawasaki disease

Abstract

Purpose

The purpose of this study was to investigate the association of early social environment with Kawasaki disease (KD).

Methods

We analyzed the data of children aged up to 10 years derived from the 21st Century Longitudinal Survey in Newborns (n = 41,872) in Japan. Parental education, total household income, and family size were obtained via a questionnaire at 0.5 years after birth. Physician's diagnosis of KD during the past year was surveyed via a questionnaire for caregiver with children aged up to 10 years. We used Cox proportional hazards modeling to examine the risk factors for KD onset.

Results

Children born in households with an annual income of JPY 10 million or more were 1.76 times more likely to have KD onset compared with children born in households with an income of less than JPY 4 million (hazard ratio: 1.76, 95% confidence interval [CI]: 1.15–2.69). Children born in households with three or less persons were 1.62 times more likely to have KD onset compared with those born in households with six or more persons (95% CI: 1.10–2.40). The children who were born in urban municipalities also showed higher risk of KD onset compared with those born in rural municipalities (hazard ratio: 1.55, 95% CI: 1.06–2.26).

Conclusions

Higher household income, smaller family size, and urbanization at birth were associated with increased KD incidence. This study, however, did not find a significant association between lack of exposure to infection in early life and onset of KD.

Introduction

Kawasaki disease (KD) is a form of acute febrile systemic vasculitis [1], [2], which is a leading cause of childhood acquired cardiac disease [3]. One of the most serious complications of KD is coronary artery dilatation and/or aneurysm, which can be fatal [4], [5]. In Japan, around one in 150 children is diagnosed with KD by the age of 10 years [3], and the most recent estimate of KD incidence in 2012 was one in 75 children by the age of 5 years [6]. Although more than 40 years have passed since the first reported case series of the disease [1], [2], the etiology of KD remains obscure. The pathogenesis of KD is characterized by massive immune dysregulation, including hyperinflammatory cytokinemia, marked activation of multilineage T-cell subsets, and systemic vasculitis.

Both genetic and environmental factors are believed to be involved in the etiology of immune dysregulatory disorders. Asia has the highest incidence of KD in the world, and genome-wide association studies have implicated multiple novels and functionally related susceptibility loci for KD [7]. Infectious agents such as bacteria [8], [9], [10], [11], fungi [12], and viruses [13], [14], [15], as well as microbe-derived factors such as superantigens [16], [17], fungi-related components [18], and seasonal variation [19] have attracted major attention as disease-triggering pathogens, as antibodies of these agents were more likely to be isolated from KD patients. A recent epidemiologic report found evidence for rising KD incidence in developed northeast Asian countries such as Japan and South Korea [19], but low levels of risk among indigenous Australians [20], although racial difference in susceptibility for KD might explain the difference of KD incidence [21].

Because KD has a peak onset age of around 10–11 months, early life course circumstances are likely to be relevant to its etiology. The hygiene hypothesis states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (e.g., gut flora), and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system [22], [23]. According to this theory, factors that lower early life course exposure to infectious agents, such as economic development, urbanization, and higher household income, should cause an increase in the risk of allergic diseases. Conversely, factors that elevate the risk of early exposure to microbes, such as residential overcrowding, should lower the risk of allergic disease.

Previous studies have suggested higher socioeconomic status (SES) [24], [25] and urbanization [26] to be associated with KD. To our knowledge, however, few studies [21], [27] have focused on early life course circumstances, which can be determined by early social environments such as household income, parental education, family size, and urban/rural difference at infancy as risk factors for KD onset. Thus, the hygiene hypothesis was proposed as an etiology of KD [28], [29]. In the present study, we analyzed the data from a nationwide birth cohort of 47,015 children aged up to 10 years, with the specific aim of testing the hygiene hypothesis in the etiology of KD. The data collected in this study allowed to directly test the association between history of infectious disease in early life and the onset of KD.