Kawasaki disease (KD) is an acute and self-limited vasculitis that particularly affects children under 5 years, leading to coronary arteries alterations in about 15%−25% of cases if not promptly treated [1
]. The disease has been reported worldwide with different incidences in different countries [1
], but it is known to be more common in East Asianpopulations with a peak of 309/100,000 cases for children under 5 years of age in Japan [2
]. In Europe, the incidence of KD is variable from 5 to 16 cases per 100,000 children under 5 years of age. A recent Italian study [3
] reports the incidence under 5 years of age in the Emilia-Romagna region as equal to 16.4 cases over the 2011 to 2013 period, with a peak in winter to early spring and a fall in the summer. The etiology of KD seems to be multifactorial, with some infectious trigger on genetically predisposed children playing an important role. Recent epidemiological studies have focused on some potential environmental risk factors for KD and the analyses have correlated the incidence of KD cases in Japan, Hawaii, and San Diego with tropospheric wind currents originating from northeastern China, which suggests that a wind-borne agent could trigger the illness [4
Burns et al. [6
] have studied the seasonal patterns of KD over the globe in the years 1970–2012 in 25 countries. In the Northern Hemisphere extra-tropics, the cases of KD cases were higher from January to March than from August to October, while in the tropics and the Southern Hemisphere extra-tropics, the maximum incidence of KD was between May to June and was lower between February, March, and October. Their results also support the hypothesis that an environmental trigger could have a role in determining the seasonality of KD cases worldwide [7
]. In particular, a recent study has shown that large scale tropospheric wind patterns could be associated with fluctuations in KD cases: Rodò et al. [4
] hypothesized the existence of a KD trigger agent spread by means of direct airborne sampling conducted over Japan. In 2014, the same authors conducted a detailed analysis of nucleic acids extracted from aerosolized atmospheric samples trapped on filters collected at selected altitudes, finding a different microbiota of the tropospheric aerosols during KD seasons, with Candida as the dominant fungus [5
]. Besides, Chilean peaks of incidence have been related with air masses that originated in the northern Atacama desert [10
]. All these results are consistent with the presence of an external environmental trigger for KD interplaying with a genetic susceptibility.
Recently, some studies examined the association between KD onset and exposure to specific air pollutants, such as carbon monoxide (CO), nitrogen dioxide (NO2
), ozone (O3
), particulate matter PM10 and PM 2,5 and sulfate dioxide (SO2
]. No relation was found by Zeft et al. [11
] and Lin et al. [12
], while Jung et al. [13
] found a relation between KD onset frequency and exposure to high level density of O3
in Taiwan. Finally, a recent study by Yorifuji et al. [14
] showed that prenatal exposure to high levels of particulate matter may significantly increase the risk of KD occurrence in child from 6 to 30 months of age in Japan.
The purpose of the present study is to describe the correlations between KD onsets in Emilia-Romagna, a region of Northern Italy, and the variability of local climate in terms of wind direction and intensity, surface temperature, precipitation and local density of environmental pollutants, like urban and rural air concentration of particulate matter, detected at local air quality, and meteorological stations. This study represents a novel contribution to the field since KD European data has never been correlated with local meteorological or environmental variability except for a recent study conducted in Spain, where no significant associations have been found between KD and regional Weather Types, although a possible relevance of some environmental factors in disease onset has been suggested [15
Study subjects include a total of 516 patients affected by KD in Emilia-Romagna between 1 January 2000 and 31 December 2017: 329 (71%) patients in Emilia and 187 (29%) in Romagna; 299 were male (58%) and 217 female (43%),and the disease was more prevalent in girls by ≈ 1.3:1. Median age (months) at onset was 34 ± 30 standard deviation (SD) and 113 patients (22%) were younger than 12 months.
a shows the number of KD onsets per month, averaged over the period 2000−2017 over Emilia-Romagna, Emilia, and Romagna, normalized to 100,000 children. KD onset of the disease is less likely to occur from May to September. No significant difference can be observed in the mean monthly frequency of KD onsets over the full period in the two subareas of the region.
b describes the time series of the number of KD onset per year per 100,000 children in Emilia, Romagna, and Emilia-Romagna as a function of time (years). Mean numbers over the period are close to 15 onsets per year, which is in agreement with the literature, and greater than the mean number of onsets per year in northern European countries [20
]. During the period, the number of KD onsets per year changed substantially, with two outbreaks of the disease in 2005 and 2013, when it reached values up to 30 onsets per 100,000 children. Over the considered period, inter-annual variability also had similar amplitude in the two areas, with peaks in the number of onsets occurring in different years depending on the area.
and Table 2
show the values of correlation between the KD onset frequency and temperature indices over the two areas. All monthly temperature indices present a statistically significant anti-correlation with the number of onsets of KD per month, due to the presence of an opposite seasonality in the two indices, explaining most of their respective monthly variance: temperatures reach maximum (minimum) values in the summer (winter) when KD is at its minimum (maximum). This anti-correlation disappears when seasonality is removed from both time series (anomalies). The only significant correlation that is still present in the anomaly time series is that between a higher (lower) monthly 90th percentile of minimum temperature (Tmin
90th p) in Emilia and a higher (lower) number of KD onsets. No significant correlation was found between KD onsets and day-time maximum temperature in Emilia or between KD onsets and temperature (minimum or maximum) in Romagna or between annual indices.
Correlation values between monthly frequency of KD onsets and monthly precipitation or precipitation averaged over the three months ending at the end of the month considered were computed for both areas (values not shown for brevity). No significant correlation was found in all cases, indicating that the KD outbreaks are not sensitive either to the momentarily increase in humidity or to the improvement in air quality connected with precipitation occurrence, nor are they sensitive to the persistence of such conditions up to three months.
and Table 4
shows the correlation values between the frequency of KD onsets and wind indices depending on direction and intensity for the two areas. Correlations are computed for the time series of monthly values, for their correspondent monthly anomalies with respect to monthly climate, and for annual mean indices.
In Emilia, significant correlation values between KD indices and monthly wind indices or monthly anomalies of wind indices are only found for the frequency of southerly wind events, which are typically associated with high values of night-time temperatures (high values of Tmin
90th p). Figure 4
shows the covariance between the monthly wind anomaly index and the Z500 monthly anomalies for the wind calm and for the southerly wind indices for Emilia, both in terms of Z500 anomalies (shaded fields) and associated full fields (contours). As can be seen, a local monthly anomaly of southerly wind in Emilia (b) is related to a change in the general circulation anomalies favoring the extension of the Atlantic tropospheric jet into the Euro-Mediterranean area and a related high frequency of synoptic transients coming from the Atlantic over the area. On the contrary, during months characterized by a high frequency of wind calm days (a), high values of Z500 are more likely to occur. This correlation is consistent with the previously described presence of a significant correlation, at monthly time scales, between KD onset frequency and the Tmin
90th panomaly index in the same area. The presence of a barely significant correlation between monthly anomalies of KD onset and easterly wind event frequencies might instead be connected to the fact that these last wind regimes are more typical of months when the KD onset is less likely to occur (specifically January, April, and July). The strong seasonality in the variability of the two indices may lead to a borderline significant value of correlation between the two time series.
Finally, the Emilia annual index of KD onset frequency was significantly correlated only with south-westerly wind regimes, indicating a general similarity between the long-term variability of the two time-series, as can be seen in Figure 5
b. In particular, it is possible to appreciate that the KD outbreak in the second half of 2013 in this part of the region was associated with particularly high frequencies of south-westerly winds, reaching an overall mean peak in this year. This wind regime is significantly related to general milder night-time temperatures, but has no correlation with day time temperature (Tmax
) like the monthly southerly regime.
a can help one to appreciate the relevance of the seasonal component of variability of wind regimes frequency, which can be seen in particular in the calm index, presenting a significant correlation with the number of KD onsets at seasonal time scales (5 month running mean), but not at monthly nor at annual time-scales. Calm of wind frequency has a significant seasonal component, with its maximum in summer months when KD is at its minimum. Interestingly, the periods with a persistently reduced number of KD onsets are sometimes characterized by a greater than average persistence in wind calms.
In Romagna, no significant correlation was present at monthly time scales, while at yearly time-scales, only the westerly wind regime frequency presents a significant anti-correlation value with the yearly KD occurrence frequency, with KD frequency decreasing as the frequency of westerly wind increases. These winds are associated with an increase in the 10th percentile of both minimum and maximum temperature, indicating milder temperature conditions, although none of these relations emerged from the analysis presented earlier of the connections between the local temperature indices and KD onset frequency.
b presents the time series of these indices together with their five months running mean, showing a clear anti-correlation in the long term variability. In Figure 6
a, it is shown that in Romagna, the relation between the frequency of calm of wind and the KD onsets is weaker than in Emilia, which is probably due to a weaker seasonal component of the indices.
Finally, in Table 5
and Table 6
, the relation between KD onset frequency and the air quality is investigated, of which the variability is represented by the PM10 monthly indices. These indices are generally indicative of the mean air quality during a specific month, with high PM10 values pointing towards high air pollution. The presence of the correlation for monthly values, monthly anomalies with respect to the index climate, and annual mean values are evaluated. Both rural and urban conditions are considered.
In Emilia, the monthly times series of rural and urban PM10 are both significantly correlated due to the presence of a strong similar seasonality of the two indices. The absence of a correlation between the correspondent monthly anomaly series seems to indicate the absence of a direct relation between the intensity of local air pollution and KD onset frequencies. The presence of a negative, but not statistically significant, relation between the PM10 indices and KD annual indices is related to the fact that the south-westerly wind annual mean index is the only one that is negatively correlated with the PM10: upper air south westerly wind regimes cause higher chance of rainy conditions and lower values of local pollutants in the air. Although this is a general condition during the occurrence of this specific wind regime and a significant relation has been identified between KD onset frequency and the frequency of S-W wind regimes at an annual scale, there is no direct relation between KD onsets and local PM10.
In Romagna, the correlation values seem to indicate a similar connection between KD onset and local air pollution, although less pronounced and with smaller statistical significance than in Emilia.
This study suggests the presence of a correlation between the frequency of KD onsets and environmental factors and shows that KD onset in Emilia and in Romagna have similar general characteristics. The frequency of onsets per 100,000 children observed in Emilia-Romagna is similar to those observed in other European countries, although it seems higher than Northern European incidences [20
]. As described in the literature [2
], KD onsets are more likely to occur from October to April, in particular from late autumn to early spring. The lower frequency of KD onsets during summer seems to exclude that the disease is related to an increase in pollen or spores concentrations, like Stemphylium or Alternaria, and to increases in aerosols generated by agriculture linked to nitrate fertilizers distribution, with typical climatological maximum during summer months. Sources for both of these air pollutants are present in the region considered.
During the study period, the number of onsets per year has changed quite substantially from year to year and it is possible to identify at least two outbreaks of the disease, characterized by a number of onsets more than double the average over the other years. Furthermore, analyzing the time series of KD onset frequency, it is shown that the inter-annual variability over the two areas is slightly different with a similar amplitude and peaks of KD onset in different years. This seems to indicate the presence of a different link with some environmental factors in Emilia and in Romagna.
The presence of a significant correlation value in Emilia between the monthly 90th percentile of Tmin
and the KD onset number seems to suggest that KD onset is more likely to occur during particularly mild periods, with the minimum temperature (night-time temperatures) occasionally reaching values significantly warmer than average. This is in agreement with Rypdal et al. [8
] who found a correlation between KD clusters onsets and occurrence of circulation anomalies associated with warmer night-time temperatures. No correlation was found between monthly and annual precipitations and KD onsets, as described in literature.
In Emilia, the monthly frequency of KD onsets is shown to be significantly correlated with monthly weather regimes associated with local southerly winds. Southerly wind regimes are sometimes related to the occurrence of Apenninic föhn events, to a greater boundary layer mixing, and, more often than not, to rainy conditions and mild night temperatures. All these conditions favor mixing of otherwise colder surface air parcels with milder upper air ones. In this way, the significant relation of KD onset frequency in Emilia with milder night temperature and southerly local wind regimes are two sides of the same phenomenon.
In the same area, at the annual level, there is a significant correlation between the frequency of KD onsets and south-westerly regimes. At the annual level, the wind index is significantly correlated with milder night temperature. It is possible that the longer averaging process highlights the relevance of this wind direction, which is more related with upper-air large scale conditions prevailing during local southerly wind events. So, in the end, this significant correlation value also points towards the same class of environmental conditions. During these events, the greater air mixing and the greater likeness of rainy conditions lead to lower air pollution values, as suggested by the PM10 index. This results in a general negative, not statistically significant correlation between PM10 yearly index and KD onsets, showing no direct relation between the two indices, in accordance with what was found by Zeft et al. [11
] and Lin et al. [12
].Conversely, all these different results point towards the possibility that the KD onset is mostly associated with the occurrence of particular weather regimes associated with upper air wind of a specific direction, which can be responsible for the transport of environmental agents, ultimately triggering the disease in susceptible patients, as suggested in the literature [4
In Romagna, the only significant relation between KD onset and meteorological indices is the anti-correlation with the annual westerly index. This index, which is not directly related to the type of events favoring the KD onsets in Emilia, is related to generally mild conditions in Romagna, both in the day and in the night. The information collected from the environmental indices considered is not sufficient to identify the reason for the presence of such anti-correlation in this area. It is possible that the difficulty in obtaining consistent results in Romagna for all environmental indices is also linked to the paucity of the number of clinical cases in this part of the region, leading to a greater difficulty in identifying statistically significant relations between the disease onset and environmental factors. On the other hand, it is possible that in this area, the relation with the environment is harder to identify for other unknown reasons due to a more complex relation between the environmental trigger of the disease and weather regimes.
The present work has considered only some of the possible factors that could possibly affect KD onset. In particular, in the absence of specific observational data, it was not possible to verify if high concentrations of carbon monoxide (CO), nitrogen dioxide (NO2
), ozone (O3
), PM 2,5, and sulfate dioxide (SO2
) favor the occurrence of KD onset as described in the literature [11
]. Additionally, no data was available to confirm a recent study by Yorifuji et al. [14
], which showed that prenatal exposure to high levels of particulate matter may significantly increase the risk of KD occurrence.
This study has several limitations. Firstly, the small number of cases related to the low incidence of KD in our region and, more generally, in Europe. Secondly, we considered the exposure at hospital location rather than individual exposure. Despite these limitations, the results seem encouraging and encourage an extension of this study to other regions in Italy and in Europe and a more detailed investigation of the correlation between climate factors and possible environmental triggers in air samples, such as spores and microorganisms.
This study represents a novel contribution to the investigation of the possible correlation between KD onset and climate factors in Europe, including wind patterns and air pollutants.
According to our results, in Emilia, KD onsets are more likely to occur in periods characterized by weather events with substantially warmer night-time temperatures, as previously described [8
]. This finding can be related to the significant correlation found between southerly winds (on a monthly scale) and south-westerly winds (on an annual scale) in Emilia, which are associated with the occurrence of warmer night-time temperatures.
Conversely, it is not possible to obtain consistent results in Romagna, probably due to the paucity of the number of clinical cases in this part of the region.
Our study supports the hypothesis of an environmental agent carried by the wind from a specific direction that can trigger KD in patients who are genetically susceptible. No correlations between PM10 index and KD onsets were found.
This is the first study in Europe that is consistent with a possible correlation between KD and wind-born agents. Further investigation is needed to find environmental trigger agents and to confirm a similar relation between KD onsets and climate anomalies in other Italian regions. Collaboration between European nations may help to increase the number of KD cases included and to compare results for regions with different climate conditions and variabilities.