Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology described by Tomisaku Kawasaki in 1967. It affects predominantly toddlers and children under 5 years old and is the second most common childhood vasculitis in frequency after IgA vasculitis.

KD is a self-limited inflammatory process, but potentially life threatening depending on the extent of cardiac involvement. Diagnosis is based on clinical criteria that include fever, exanthema, conjunctivitis, changes in the extremities, erythema of oral mucosa and lips and cervical lymphadenopathy. An early recognition of the disease is important in order to establish early treatment and to lower the risk of cardiac complications.

The etiology of KD is still unknown, although clinical, laboratory and epidemiological features suggest an infectious origin or trigger.1 However, many studies so far failed to identify a unique etiological infectious agent and the disease has not been proved either to be related to exposure to any drug or to occur as a response to a superantigen.1,2 On the contrary, activation of the immune system is an evident characteristic of KD, and concentrations of many proinflammatory cytokines and chemokines are being studied in patients with KD, which may lead to improved anti-inflammatory therapy in the future.3,4 Due – among other patterns – to the clustering of cases in space and/or time, a reasonable – but still disputed – hypothesis is that KD may be caused by a trigger (probably an infectious agent) that produces disease or elicits response in only genetically predisposed individuals, particularly Asians.

Recent research5,6 has suggested that the causative agent of KD may be an environmental agent carried on trophospheric winds from agricultural sources, possibly a toxin from a fungus. In Japan, burden of cases is seen to be often linked to wind currents originating in a densely cultivated cereal croplands of northeastern China.

To test for a similar predominance of patients from rural areas in other regions of the world where the disease is present, we present a population-based study on the incidence of KD in Catalonia (Spain), focusing on differences between patients in rural and non-rural areas of the region.

Catalonia is an autonomous region in the north-east of Spain in the north-western Mediterranean area. It covers an area of 32,108km2 with a population of 7.5 million inhabitants in 2015, of which non-Spanish immigrants represent about 19% and about 1 million inhabitants with less than 16 years old. Catalonia has a diverse climate and topography. The most populated areas lying by the coast in Tarragona, Barcelona and Girona. The provinces feature a Mediterranean climate and their economy is based on industry, tourism and the tertiary sector. The inland part (including the Lleida province and the inner part of Barcelona province) show a mostly continental climate and agriculture and livestock economies are predominant. The Pyrenean peaks have an Alpine climate at the highest summits, while the valleys have an oceanic climate. Economy is also based on agriculture although tourism plays an important role.

During 2004–2014, a total of 399 KD cases were diagnosed in Catalonia. Data from all 33 hospitals with pediatric units in Catalonia was collected, involving the whole Catalonian territory. Of the total 399 patients, 233 (58.4%) had complete KD, 159 (39.8%) incomplete KD and 7 (1.7%) were considered atypical KD. Mean annual incidence was 8/100,000 children<5yo. CAAs were present in 25 patients (6.3%) and a significant difference (p<0.001) between the percentages of ethnic groups was found, the disease being more common in Asian and North African patients.

Among the total KD patients, 353 (88.5%) lived in non-rural areas and 46 (11.5%) in rural areas. A significant difference (p<0.001) was observed toward the percentage of patients living in rural areas (11.5%) versus the expected 5% for Catalan population according to national census.

Conversely, no differences were found regarding age, ethnic group, sex, KD subtype, presence of classical criteria symptoms at the beginning of the disease, risk of CAAs or day of administration of IVIG first dose between children living in rural and non-rural areas. Baseline characteristics of the patients are shown in Table 1.

Distribution of cases during the study period, corrected for total population, is shown in Fig. 1. Despite most of the cases being concentrated in the most densely populated areas around Barcelona, there is a significant relatively higher number of cases in regions less densely populated like rural areas of Lleida and Girona.

Figure 1.

Catalonia land use map denoting location and number of KD cases. Colors for diamonds are as follows: white: more than 50 cases; blue: 11–25 cases; light green: 2–10 cases and black: 1 case. For land use, green denotes forests, clearings and humid vegetation, gray denotes sand, snow and poor soils, yellow indicates crops and in red, urban and industrial centers (base data for land use obtained from the Generalitat de Catalunya. Department of Environment and Housing).

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To the best of our knowledge, this is the first population-based epidemiological study on KD that introduces the possibility of differences in KD incidence between non-rural and rural areas. Among our population, it was found that there is a significant difference (p<0.001) towards the percentage of patients living in rural areas (11.5%) versus the expected 5% for Catalan population according to epidemiological data based on census from IDESCAT.7

It is important to highlight that the study that we present includes KD patients from all over the Catalan territory due to the public health access in our country and the collaboration of all 33 hospitals with pediatric units in Catalonia.

The relationship between other so-called autoimmune diseases and a major incidence in rural areas has also been described in the past. For instance, in primary systemic vasculitis (PSV), a study held in the UK by Lane et al.,8 found that farming during working lifetime was significantly associated with the risk of PSV. Other studies were not able to establish this association in Spain9 or Japan10 and found no differences between incidences on PSV between rural and urban areas. On the contrary, a German study11 found that giant cell arteritis was more prevalent in urban than in rural areas of Germany. In the case of sarcoidosis, some reports suggest that the exposure to bio-aerosols or insecticides could be associated with higher sarcoidosis frequency in the US.12 Another study held in Switzerland13 found association between the regional frequency of sarcoidosis and the presence of vast areas of bread grain and potatoes crops.

The differences between KD incidence in rural and non-rural areas could also be related to the presence of extensive areas of intensive farming,6 sociocultural and household income differences14 or other unidentified environmental or genetic factors that may play an additive role.

A recent study by Rodó et al.6 postulates that a possible wind-borne agent of KD in the form of an environmental toxin could came from the densely cultivated region of north-eastern China. This conclusion was obtained after inferring sources for all days with high KD incidence, obtained by means of daily atmospheric particle backwards simulations. A study performed in the Sichuan province,15 one of the major agricultural production bases of China, found a KD incidence of 7.1/100,000 children, which is lower than incidences described in urban regions of China16,17 or in Japan.18 It remains unclear if this lower incidence is real or if it may reflect less access to medical services in this area. An epidemiologic study performed in Korea between 2006 and 2008,19 found a significant difference on KD incidence according to region, with the highest proportion of cases in the Kangwon province, located in the north-east part of the country, and the lowest on Jeju island, located in the south of the peninsula. Both regions are supported by primary industry (agriculture and fishing). On the contrary, another study about epidemiology of KD in the Netherlands,20 found that the incidence of KD was higher in the provinces with a higher density of population and less agriculture-based economies.

To our knowledge, few other studies describe differences on KD incidence rates between rural and non-rural areas. Inference of air masses provenance at the precise times and locations where the KD kids lived at the times of disease onsets will also be needed to check for consistency with former studies suggesting an agricultural-based etiology. Future larger epidemiological studies are needed to establish the causes of these differences between rural and non-rural areas, to study possible pathogenic etiologies and to establish possible clinical implications for health awareness and policies.

This is the first population-based study showing significant differences in KD incidence rates between rural and non-rural areas. In this study, KD was found to be more frequent among children living in non-urban areas than expected. Further studies are needed to establish the exact causes of these differences.

No external funding has been obtained for the realization or publication of the article.

The authors of the article state that they don’t have conflict of interest to disclose. They are not shareholding in a company, they have not received any grant or consultancy fee from a company whose product features in the submitted manuscript or manufactures a competing product.