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Distribution of paracoccidioidomycosis: determination of ecologic correlates through spatial analyses

LVIO ALENCAR MARQUES$ & EDUARDO BAGAGLI* ES*, SI LIGIA BARROZO SIMO ncias, and $Departamento de Dermatologia e *Departamento de Microbiologia e Imunologia, Instituto de Biocie ncias, Universidade Estadual Paulista/UNESP, Universidade Estadual Paulista/UNESP, Botucatu, Radioterapia, Instituto de Biocie SP, Brazil

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Paracoccidioidomycosis (PCM) is endemic in Latin America and in countries like Brazil it carries a high mortality rate. The fungus habitat has not been precisely determined. The present study aims to identify ecologic correlates based on PCM distribution in a hyper-endemic area in southeastern Brazil. The Geographic Information System (GIS) and spatial statistics were used to associate environmental attributes, human population density and, PCM distribution. By means of the Pearson r correlation coefficient, the highest statistically significant associations with prevalence density were the percent area (by county) of: basaltic rocks (r 0 0.63; P B 0.0001), Podzolic soils (r 0 ( 0.48; P B 0.001), Latosol soils (r 0 0.40; P B 0.01), mean annual precipitation between 1500 and 1600 mm (r 0 0.46; P B 0.001) and, mean precipitation during the wet season between 940 and 1040 mm (r 0 ( 0.44; P B 0.01). Soil texture and precipitation analyzed together reached r 0 0.61 (P B 0.000002) for fine-textured soils with annual precipitation above 1400 mm. Environmental correlates indicate that moisture availability plays an important role in PCM distribution.
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Keywords ecological factors, Geographic Information System, Paracoccidioides brasiliensis , Paracoccidioidomycosis

Introduction
Paracoccidioidomycosis (PCM), caused by the fungus Paracoccidioides brasiliensis, represents the most important systemic mycosis in Latin America [1]. PCM is endemic from Mexico (238N) to Argentina (358S), with the largest number of occurrences in Brazil, Venezuela and Colombia [2]. Because PCM is not a notifiable disease, it is not possible to calculate its real prevalence and incidence [3]. It is the systemic mycosis with the highest mortality rate among immunocompetent patients in Brazil [4]. Overall nationwide mortality per area during the period 1980 /1995 was 3.73/10 000 km2

Received 25 July 2003; Accepted 27 November 2003 Correspondence: Eduardo Bagagli, Departamento de Microbiologia e Imunologia, Instituto de Biocie ncias, Faculdade de Medicina, Universidade Estadual Paulista/UNESP, Rubia o Jr, s/n 18618-000, CP 510, Botucatu, SP, Brazil. Tel.: '/55 14 3811 6058; Fax: '/55 14 3815 3744; E-mail: bagagli@ibb.unesp.br

with non-homogeneous distribution throughout the country. The mortality rate is higher than that of leishmaniasis, and it is the eighth most common cause of death among the chronic/recurrent infectious and parasitic diseases in Brazil [4]. Furthermore, the disease is now emerging in new areas. Recent environmental and socioeconomic changes in the Brazilian Amazon, for example, have been associated with new occurrences of PCM-infection in Amerindian populations [5]. As the mucocutaneous lesions are relatively frequent, during a certain time it has been claimed that people in rural areas could have acquired PCM by the common habit of placing vegetable material in the mouth and chewing it. Nevertheless, there is strong evidence indicating that the principal route of infection is the respiratory tract by inhalation of airborne propagules [6,7], similar to other systemic mycoses caused by the dimorphic pathogenic fungi Blastomyces dermatitidis , Coccidioides immitis (C. posadasii ) and Histoplasma capsulatum . Although the infection of some of these
DOI: 10.1080/13693780310001656795

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mycoses may be associated with extreme winds and earthquakes, the prolonged periods of latency and the lack of outbreaks of PCM do not allow correlating the infection with sporadic climatic events. Despite the continuous efforts by several research groups, little is known about the habitat of P. brasiliensis [3]. Some authors have suggested that the fungus has its natural habitat in soil or in the vegetation present in disease-endemic area [6,8]. However, the fungus has been rarely isolated from soil and related materials [9]. Frequent migration of the inhabitants within the disease-endemic area, among other factors, increases the difficulties in finding the fungus microniche in nature [8]. Epidemiologic and ecologic studies on PCM have shown that the disease is widely distributed throughout an ecologically diverse continental area. Several authors have pointed out some environment preferences where PCM is highly endemic, which are: temperature between 17 /248C; mild winters; mean annual precipitation from 500 to 2500 mm; height from 500 to 2000 m; proximity of water courses; clayey, fertile and acid soils [2,6,10 /14]. However, most of previous works have been derived from descriptive studies [10,12,14 /17], others have been supported by statistically oriented approaches, such as logistical regression methods [18] and multivariate analyses [19] or using armadillos as animal sentinels [20]. Due to the spatial character of this epidemiologic and ecologic issue, fine scale studies are needed to help to identify hot spots in the disease-endemic areas. Remote sensing and Geographic Information Systems (GIS) have been successfully applied to other epidemiologic problems, mainly to vector-borne diseases, such as malaria [21,22], Rift Valley fever [23], Lyme disease [24], African trypanosomiasis [25], and infectious diseases such as coccidioidomycosis [26], among others. Following this approach we present here a study on ecologic correlates of PCM distribution in its endemic region in Southeastern Brazil, through GIS and spatial analyses. Although there are no control measures that may be applied to prevent this disease [27], ecologic correlates are important findings to design epidemiologic risk maps. These maps could then be used to increase awareness among clinicians, tourists and the people living in rural areas where PCM is endemic.

(UH-UNESP), located in Botucatu County, Sa o Paulo State, from 1970 to 1999. Three surveillance measures were calculated based on the 30 years of data: cases by county of residence, cases by county per 10 000 inhabitants and prevalence density (cases by county per area of the county). This approach favors the spatial distribution of occurrences and the distribution of the etiologic agent in the environment [4,28]. Average population density (people/km2) by county for the period was also calculated based on census data produced by the Brazilian Institute of Geography and Statistics and the Foundation for Data Analyses System of Sa o Paulo State. The study area was based on patients residence (Fig. 1), which largely coincides with the Botucatu hyper-endemic area of PCM, previously described [14].

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Spatial data
Data were prepared taking into consideration the boundaries of the 44 studied counties as indicated in the 1:250 000 scale topographic maps of the region [29]. Elevation data were digitized at the same scale. Geologic, geomorphologic, and soils data [30 /32] were digitized at a scale of 1:500 000. Carta Linx software was used to digitize and edit the spatial databases, which were processed and analyzed using IDRISI32 GIS software [33]. From the digitized elevation data, it was possible to interpolate height values and generate a Digital Elevation Model (DEM) for the study area. Triangulated Irregular Networks (TIN) modeling was performed to create the DEM [33]. Daily rainfall statistics were obtained by using the data from 68 rain gauges that was recorded from 1970 through 1999, georeferenced and submitted to geostatistical analyses [34]. Precipitation data were interpolated through ordinary kriging and three maps subsequently derived: average annual precipitation, mean precipitation in the wet season (October through March) and mean precipitation in the dry season (April through September). Temperature data were calculated for the same 68 stations using a regression equation [35] that related elevation, latitude and temperature for Sa o Paulo State.

Results
From 1970 through 1999, 377 confirmed human cases of PCM were registered at the Department of Dermatology of UH-UNESP. Among those, 159 of the cases came from 33 of the 44 (75%) counties of residence in the study area. Over the 30 years of data, the
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Material and methods

Human cases data and study area
Human PCM data corresponded to the cases seen in the Dermatologic Sector of the University Hospital

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Fig. 1 Prevalence density of PCM by county (cases/thousand km2) in the study area.

distribution of PCM cases by county varied from 0 to 32. Mean incidence rate was 4.27 per 10 000 inhabitants, varying from 0 to 57.9 in each of the 44 counties in the study area. Mean prevalence density was 8.26 cases/1000 km2, varying from 0 to 41.32 in each of the 44 counties in the study area. Population density ranged from 4.92 to 176.28 inhabitants/km2 in each of the 44 counties in the study area. Spatial statistics can measure the likelihood that an apparent pattern was produced merely by chance. Spatial autocorrelation allows for hypotheses testing about pattern values of a single variable at different locations [36]. Morans I [37] and Gearys C [38] were applied to measure spatial autocorrelation [39]. Morans I ranges from (/1 to '/1, and equals 0 when there is no spatial autocorrelation (no effect of distance on
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the distribution of a variable). Gearys C varies from 0 to 2 and when it equals 1, indicates random distribution of values. Interpretation of Morans I and Gearys C , reveal a strong positive autocorrelation when I /0 and 0 B/C B/1 and, a strong negative autocorrelation when I B/0 and C /1. Standardized normal variables, Z (I ) and Z (C ), were derived from the Morans I and the Gearys C values for each variable considered to evaluate statistical significance. For a two-tailed test, the critical values are 9/z0.025 0/ 9/1.96, at the 5% significance level. Spatial autocorrelation analyses indicated significant spatial clustering of counties according to population density, cases by county of residence, cases per 10 000 inhabitants and prevalence density (Table 1). Surveillance measures indicated spatial autocorrela-

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Table 1 Spatial autocorrelation for PCM distribution, measured by Morans I and Gearys C coefcients and their derived standard normal variables, Z(I ) and Z(C ) Variable Population density Cases by county of residence Cases per 10 000 inhabitants Prevalence density
/

I 0.53 0.69 0.48 0.71

Z (I) 7.25 9.36 6.73 9.6

C 0.46 0.37 0.51 0.28

Z ( C) 7.01 8.04 5.91 9.33

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tion, which makes it appropriate to analyze environmental patterns that appear to overlay the distribution of PCM. By means of Pearsons r correlation, prevalence density by county was associated with the percent area of each of the environmental variables by county over the 44 counties. Geologic and soil features, as well as precipitation were found to be significant environmental correlates. The results are shown in Table 2 and below. The Mesozoic basaltic rocks of the Serra Geral Formation were the only geologic unit to show a

significant correlation with prevalence density. In fact, this was the highest correlation found amongst any environmental variable (r 0/0.63; P B/0.0001). Associations with soil types were calculated between prevalence density and soil order and suborder, with nine and 57 types, respectively. From the nine main types of soils in the study area, four different types showed statistical correlations. Because of their extensions, two of these types are noteworthy. Calculating all Latosol data (LV and LVA types) r 0/0.40 (P B/0.003). Podzolic soils together (PV and PVA types) did not change the negative correlation (r 0/ (/0.48; P B/0.0003). Soil texture was also analyzed. The 57 soil types were grouped according to their texture, based on percent clay content, as follow: sand ( B/15% clay), medium (15 /35% clay), clay ( /35% clay). Sand and clay soil textures correlated statistically with prevalence density (r 0/ (/0.40, P B/0.003; r 0/0.34, P B/0.02, respectively). Adding medium and clay soil textures, the correlation increased to r 0/0.40 (P B/0.003). Statistical analyses of precipitation indexes showed

Table 2 Signicant statistic correlates of PCM prevalence density by county with percent area of soil (order, suborder and texture), precipitation, soil texture plus precipitation and geologic types by county (n 0/44) r Soil order Red Latosol (LV) Red-Yellow Podzolic (PVA) Lithosol (RL) Red Nitosol (NV) Percent area of each soil suborder by county Red Latosol (LV1) Red Nitosol (NV1) Red-Yellow Podzolic (PVA10) Red Nitosol (NV3) Red-Yellow Latosol (LVA52) Soil texture Sand ( B/15% clay) Clay ( /35% clay) Medium'/clay ( /15% clay) Precipitation Mean annual precipitation (1300 /1400 mm) Mean annual precipitation (1500 /1600 mm) Mean precipitation in the wet season (940 /1040 mm) Mean precipitation in the wet season (above 1040 mm) Soil texture'/precipitation Sand, B/1400 mm Sand, /1400 mm Medium, B/1500 mm Medium, /1500 mm Clay, /1400 mm Medium'/clay, /1400 mm Geology Mesozoic basaltic rocks of the Serra Geral Formation P -value

0.40 (/0.48 (/0.28 0.29 0.62 0.31 (/0.29 0.35 0.34 (/0.40 0.34 0.40 (/0.40 0.46 (/0.44 0.40 (/0.29 (/0.27 (/0.28 0.44 0.61 0.53 0.63

B/0.003 B/0.0003 B/0.05 B/0.04 B/0.0000008 B/0.03 B/0.04 B/0.02 B/0.02 B/0.003 B/0.02 B/0.003 B/0.01 B/0.001 B/0.01 B/0.004 B/0.04 B/0.05 B/0.05 B/0.002 B/0.000002 B/0.00006 B/0.0001

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that mean annual precipitation above 1400 mm and, in the wet season, a minimum mean precipitation of 1040 mm, increased prevalence density rates. In the study area, median temperature (from 19.3 to 22.58C), minimum temperature (from 13.1 to 15.98C) and maximum temperature (from 25.4 to 29.18C) did not reveal significant association with prevalence density, nor did height (varying from 450 to 950 m above sea level), present significant correlation.

Discussion
Our analyses depended mainly on patients with PCM admitted to the Dermatologic Sector of the UHUNESP, which treats about half of the cases seen in this center. We assume that the data from this center were representative of all areas within the region for the following reasons: (1) this is the oldest and the most traditional center for PCM diagnosis in the western portion of the state. The disease is not easily diagnosed, requiring specialized clinicians and laboratory support rarely found in other centers in the study area; (2) only recently has the disease been diagnosed in other centers and even in these cases, patients are sent to the UH-

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UNESP for treatment; and (3) finally, the center offers its services free of charge. Considering the difficulties found when attempting to identify areas where infection with P. brasiliensis occurs, current surveillance measures based on cases by county of residence is not sufficiently precise to identify risk areas of infection. On the other hand, prevalence density offered the best spatial clustering, measured by spatial autocorrelation, and was the unique surveillance measure that had significant ecologic correlates. As people are not equally exposed to risk due to the great variability in rural populations over the counties, and the infection is not contagious, this approach, standardizing by county area, emphasizes the location of the occurrences independently of the size of the population. As spatial autocorrelation exists, PCM distribution does not present a random pattern in the study area. This finding constitutes strong evidence in favor of some social or ecologic correlates explaining the presence of P. brasiliensis in the area. The results of this study show that there are important relationships among human PCM distribution and population density, basaltic rocks, Latosol soils and precipitation. Prevalence density is higher in areas with a larger percentage of Latosol soils. This can be explained by

Fig. 2 Soil texture, mean annual precipitation and prevalence density by county (cases/thousand km2).

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the fact that these soils, which in general present more than 35% clay and poor capacity for drainage, retain moisture. The four Latosol sub-order soils (LV1, NV1, NV3 and LVA52), which have clay texture and derived from the basaltic rocks of the Serra Geral Formation, also correlated positively. High incidence of PCM was also observed in clayey fertile soils derived from the Serra Geral Formation cropping out in the Rio Grande do Sul State, Southern Brazil [12]. Precipitation seems to play a role in the diseaseendemic regions, although its seasonality and geographic extent have yet not been properly studied. Mean annual precipitation range previously defined (500 /2500 mm) is too wide to contribute to develop risk models. Results indicate that precipitation distribution alone cannot completely explain the distribution of PCM in the study area. When soil texture and precipitation were analyzed together, the correlation increased to r 0/0.61 (P B/0.000002) for fine-textured soils ( /35% clay) with mean annual precipitation above 1400 mm. On the other hand, precipitation did not increase the association with coarse-textured soils ( B/15% clay), which presented r 0/ (/0.29 (P B/0.04) for precipitation below 1400 mm and r 0/ (/0.27 (P B/0.05) when precipitation was above 1400 mm. Actually, PCM distribution seems to be related to soilwater interactions, more specifically, to soil surface storage of water. Riparian forests and vegetation near watercourses have been strongly associated with infected armadillos [20] and even with human infection [19]. In the riparian zone, water table is high, favoring greater soil water availability. The soil water content varies with particle size, local drainage, and topographic and climatic characteristics. Available soil water is dependant on precipitation, evaporation rate and soil characteristics. For the same climatic conditions, fine-textured soils retain more water than coarsetextured soils due to the greater superficial area by mass unit of clay particles. Soil water availability in clayey soils is 1.56 greater than in sand soils [40], ranging from 75 mm/m of soil profile to 117 mm/m. At tropical latitudes, annual temperatures are less variable than in temperate areas and tend to exert a lesser effect on the development and limits of tolerance of a species than local hydrologic conditions [41]. Therefore, as temperature did not vary significantly in the study area, soil water-holding capacity and precipitation can partially explain PCM distribution (Fig. 2). Obviously, evaporation and evapotranspiration should also be considered to precisely define the water budget. In this case, land use has to be carefully analyzed. Through transpiration, plants have an active role in soil water use thus strongly conditioning the

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water balance [42]. Other conditions that reduce vegetative cover and compact the soil surface, such as the overgrazed pasture condition, cause infiltration to diminish [43] and, consequently, to decrease soil water availability. Ecologic correlates of PCM distribution indicate that moisture availability should be further investigated, since climate correlates have been extremely useful to develop models of suitable conditions to parasite habitats [44]. Prevalence density is higher in fertile clayey soils where intense agricultural activities generate great exposure to aerosols. Due to the small size of the clay particles, these soils are easily spread by the wind. On the other hand, poor soils are likely to be destined for grazing activities, being less aerated. It is still premature to conclude either that the fungus prefers fine-textured soils or that the high prevalence is associated with intense agricultural practices. Unfortunately, we still do not have a clear strategy to prevent future infections. An analyses including land use as a spatial variable would contribute to the understanding of the relationship among prevalence density, fungus autoecology and environmental risk factors for PCM.

Acknowledgements
The State of Sa o Paulo Research Foundation (FAPESP), grants 02/04489-0 (to LBS) and 02/00466-5 (to EB) supported this research. We thank Celia R. L. Zimback for her comments, Angela Restrepo for critically reviewing the manuscript and the two anonymous reviewers for their relevant suggestions.

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