Decreasing fertility rate correlates with the chronological increase and geographical variation in incidence of Kawasaki disease in Japan

Abstract

Background: Kawasaki disease (KD) is a common cause of acquired paediatric heart disease in developed countries. KD was first identified in the 1960s in Japan, and has been steadily increasing since it was first reported. The aetiology of KD has not been defined, but is assumed to be infection-related. The present study sought to identify the factor(s) that mediate the geographical variation and chronological increase of KD in Japan.

Methods and findings: Based upon data reported between 1979 and 2010 from all 47 prefectures in Japan, the incidence and mean patient age at the onset of KD were estimated. Using spatial and time-series analyses, incidence and mean age were regressed against climatic/socioeconomic variables. Both incidence and mean age of KD were inversely correlated with the total fertility rate (TFR; i.e., the number of children that would be born to one woman). The extrapolation of a time-series regressive model suggested that KD emerged in the 1960s because of a dramatic decrease in TFR in the 1940s through the 1950s.

Conclusions: Mean patient age is an inverse surrogate for the hazard of contracting the aetiologic agent. Therefore, the observed negative correlation between mean patient age and TFR suggests that a higher TFR is associated with KD transmission. This relationship may be because a higher TFR facilitates sibling-to-sibling transmission. Additionally, the observed inverse correlation between incidence and TFR implies a paradoxical "negative" correlation between the incidence and the hazard of contracting the aetiologic agent. It was hypothesized that a decreasing TFR resulted in a reduced hazard of contracting the agent for KD, thereby increasing KD incidence.

Figure 1. Percentage of hospitals that responded to national surveillance and the diagnostic guideline revisions.

Definitions of revisions 3, 4 and 5 are available in Text S1.

Figure 2. Total fertility rate (TFR), incidence, and mean age of Kawasaki disease, 1979–2010.

Prefectures were classified based upon annual incidence (/100,000 children between 0 and 4 years) (a), crude mean patient age (years) (b), and TFR (c). TFR was also presented in reverse order (d). The similarity between (a) and (d), and that between (b) and (d) implied negative correlations between incidence and TFR, and between mean patient age and TFR, respectively. The cut-off values were selected by natural breaks classification algorithm. Only the main islands are presented.

Figure 3. Fitness (R²) of the time-series regression model, time lag (G), and smoothing radius (W).

Incidence (a), and crude mean patient age (b) of Kawasaki disease were regressed against the TFR estimated for a specific combination of G (time lag) and W (smoothing radius). The G and W are defined in eq. 6.

Figure 4. The relationship of Kawasaki disease incidence and mean patient age to Total fertility rate (TFR).

KD incidence (/100,000 children between 0 and 4 years) (a), and crude mean patient age (b) were plotted against the TFR with the time lag (G) and smoothing radius (W) that provided the largest R². Each dot represents an annual record from a prefecture.

Figure 5. Temporal change in Total Fertility Rate (TFR) and Kawasaki disease incidence and mean patient age.

KD incidence in children of 0–4 years (b) and crude mean patient age (c) were reconstructed based on the TFR in Japan (a). The reconstruction used a univariate time-series model based on Kawasaki disease data recorded either between 2000 and 2010 or between 1979 and 2010.

Figure 6. The proportion of age-stratified number of Kawasaki disease cases.

Number of Kawasaki disease cases in each age category was divided by the population of children between 0 and 4 years (a, b, c). The percentage of patients in each age category was smoothed using the Lowess spline procedure (dashed line) (d, e, f).