Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612

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Detecting spatial clusters of Taenia solium infections in a rural block in South India

M. Venkata Raghava a,∗, V. Prabhakaran b, T. Jayaraman b, J. Muliyil a, A. Oommen b, P. Dorny c,d, J. Vercruysse c,d, V. Rajshekhar b a Department of Community Health, Christian Medical College, 632 002, , India b Department of Neurological Sciences, Christian Medical College, Vellore, India c Department of Virology, Parasitology and Immunology, Ghent University, Belgium d Institute of Tropical Medicine, Antwerp, Belgium article info abstract

Article history: Neurocysticercosis (NCC) is a major cause of seizures/epilepsy in countries endemic for the Received 18 November 2009 disease. The objectives of this study were to spatially map the burden of active epilepsy Received in revised form 11 June 2010 (AE), NCC, taeniasis, seroprevalence for cysticercal antibodies and positivity to circulating Accepted 11 June 2010 cysticercal antigens in (approximately 100 villages comprising 100 000 Available online 17 July 2010 population) of and to detect spatial clusters of AE, NCC, taeniasis and sero- prevalence. Using geographic information system (GIS) techniques, all 21 study villages Keywords: with over 8000 houses (population of 38 105) were mapped. Clustering of different indices Cysticercosis clusters of Taenia solium infection was determined using a spatial scan statistic (SaTScan). There epilepsy was a primary spatial cluster of AE with a log likelihood ratio (LLR) of 10.8 and relative geographic information systems risk (RR) of 22.4; however, no significant clustering for NCC was detected. Five significant taeniasis spatial clusters of seropositivity for cysticercal antibodies, two clusters of seropositivity for cysticercal antigens and one for taeniasis were detected (LLR of 8.35 and RR of 36.67). Our study has demonstrated the use of GIS methods in mapping and identifying ‘hot spots’ of various indices of T. solium infection in humans. This spatial analysis has identified pockets with high transmission rates so that preventive measures could be focused on an intensive scale. © 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

1. Introduction biased since most available data are from hospital based populations.1 Taeniasis is an intestinal disease acquired by ingestion Human cysticercosis frequently affects the central ner- of viable Taenia solium metacestode larvae from pork, while vous system and is a major cause of acquired epilepsy.2–4 cysticercosis is acquired by the ingestion of T. solium eggs. In Asia and Africa, the subcutaneous form of cysticerco- Taenia solium infection is widely endemic in the rural areas sis which is concomitant with intracerebral infection is of developing countries in Asia, Africa, South and the Cen- the most common variety and accounts for more than tral Americas. In Asia, the exact geographic origin and the 30% of cases.5 Neurocysticercosis (NCC) is a major cause epidemiological factors associated with transmission are of seizures/epilepsy in countries endemic for the disease. In African countries, studies have shown that in about 30 to 50% of cases, epilepsy had been documented to T. ∗ 1 Corresponding author. Tel.: +91 416 228 4207; fax: +91 416 226 2268. solium infection. Earlier community based studies carried E-mail address: [email protected] (M.V. Raghava). out in Kaniyambadi block (a block is a sub district level

0035-9203/$ – see front matter © 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2010.06.002 602 M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612

Figure 1. Map of the study area in the state of Tamilnadu, south India. organization of rural areas under the Community Devel- studies have reported the application of GIS to study the opment Programme of the Government of India and clustering of cysticercosis or taeniasis. Lescano et al.24 comprises of approximately 100 villages and 100 000 pop- used GIS to study swine cysticercosis risk gradient sur- ulation), a rural development block in Vellore district of rounding human tapeworm carriers in Peru. They also the state of Tamil Nadu in India have demonstrated active studied human cysticercosis seroprevalence gradient and and continuous transmission of cysticercosis. This is evi- cysticercosis related seizures surrounding tapeworm car- dent from the high prevalence of NCC as a cause of over riers using GIS techniques.25 The objectives of this study a third of all cases of active epilepsy (AE).6 The preva- were: to spatially map the burden of AE, NCC, taeniasis lence of taeniasis in the community, as diagnosed by and seroprevalence of cysticercal antibodies and positivity using a coproantigen assay, was 30.2 per 1000 population to circulating cysticercal antigens in Kaniyambadi block; (Raghava et al., unpublished data). A high seroprevalence and to detect and map spatial clusters of AE, NCC, taenia- of cysticercal antibodies at 17.7% in the seizure-free gen- sis, seroprevalence of cysticercal antibodies and positivity eral population in the same community also indicates high rates for circulating antigens. exposure to cysticercal antigens.7 This provided an impetus for us to study the spatial distribution of the disease in this community. 2. Methods In the last decade, geographical information systems (GIS) have provided a powerful tool to display epidemi- Kaniyambadi block is located in Vellore district of Tamil ological data in a spatial format in the form of maps. Not Nadu State in India, spanning a geographic area of 184 km2 only is a spatial display of the distribution of a disease pos- with a population of 106 000 (current updated census, sible, but also it is possible to perform statistical analyses 2006, of the Community Health Department of Christian to determine whether there is a disproportionate con- Medical College (CMC), Vellore). There are 82 settlements centration of disease in some pockets of the geographical distributed across 33 revenue villages (three or four settle- areas surveyed. These clusters or ‘hot spots’ may provide ments grouped for administrative and revenue purposes) a target for surveillance and control strategies. Studies in the block. The study area is bordered by Vellore town on using GIS have been done mainly to study clustering of the northeastern side, block on the western side patients with various types of cancers.8–13 A few stud- and Arani block on the southern part of the study area and ies involving infectious diseases such as cholera, malaria, situated between 12◦40Nto12◦55N latitudes and 79◦0E leprosy, tuberculosis and giardiasis have been reported in to 79◦15E longitudes (Figure 1). The adult literacy in this recent years.14–22 Efforts are under way to develop GIS and block is 79% and the primary occupation is agriculture. The remote sensing based models for various parasitic diseases population under study was selected from 21 randomly including schistosomiasis, which are now being expanded selected settlements from the block and is representative to include widespread infectious diseases.23 Only a few of the state of Tamil Nadu. M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612 603

Figure 2. GIS map of Kaniyambadi block in Vellore district showing the villages and study clusters.

We used data from the following sources for our study: Detection of cysticercal antibodies in serum was by an EITB using lentil lectin specific T. solium glycoproteins as Master Health Census collected with geo-locations antigens, standardized in our laboratory.28 A sample was sourced from Community Health Department of CMC, Vel- considered positive for cysticercal antibodies by the crite- lore. ria of Tsang et al.,26 i.e. reaction to one or more T. solium GIS data pertaining to the block, its villages, and people glycoproteins of molecular weights 50, 38–42, 24, 21, 18, from the existing Geodatabase of the Department of Com- 14 and 13 kDa. munity Health, CMC, Vellore. Circulating T. solium metacestode antigens were assayed in all sera by an ELISA using monoclonal antibodies 2.1. Study population to excretory/secretory products of T. saginata metaces- todes established by Brandt et al.29 and modified by Dorny The study population covered 38 105 people between et al.30 The ELISA is 94% sensitive for cysticercosis with the ages of 2 and 60 yrs who had been screened for AE no cross reactivity with sera of other parasitic infec- from 16 randomly selected rural clusters. Rural clusters tions. A sample was considered positive for cyst antigens in the study are village panchayats (settlements of peo- above the Mean+3 SD absorbance of 6 negative control ple with local self-governance). Figure 2 shows the spatial sera assayed with the study samples on each microtitre location of all the village settlements and the study clusters plate. in Kaniyambadi block. Each case in the block was linked with the master Cen- sus database using a unique identification number and 2.2. Epidemiological survey the geographic coordinates (latitude, longitude) extracted from this database. Twenty households were randomly The survey methods and screening tools used for deter- selected from each study cluster and 729 early morning mining the AE rates have been published previously.6 stool samples were collected from the study population Briefly, patients with AE were identified using a validated aged between 2 and 60 years and tested for the presence questionnaire administered, in a door-to-door survey, by of coproantigens.31,32 The same households provided 960 health workers. Clinicians evaluated those identified in serum samples which were tested for cysticercal antibod- a hospital setting and those finally determined to have ies and antigens to determine the prevalence rates. While AE were advised to undergo a contrast enhanced CT scan the presence of cysticercal antibodies in the serum indi- after informed consent was obtained. All patients with AE cates exposure to the larval antigens but not necessarily undergoing CT scan were also tested for the presence of infection, the presence of cysticercal antigens in the serum cysticercal antibodies and antigens in their blood using indicates the presence of a viable cyst in the patient and enzyme-linked immunoelectrotransfer blot assay (EITB) active infection which may or may not cause symptoms. and ELISA techniques, respectively.26,27 Cluster analyses were performed using SatScan software 604 M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612

Figure 3. The study methodology.

(Information Management Services Inc., Silver Spring, These were then downloaded using GPS utility 4.10.4 (GPS MD, USA) and GIS maps were created using ArcGIS 9.1 Utility Ltd., Southampton, UK) and mapped using ArcView software (Environmental Systems Research Institute Inc., GIS 9.1 software. Redlands, CA, USA). The study methodology is illustrated To explore the spatial distribution of AE, seropreva- in Figure 3. lence of cysticercal antibodies, positivity rates of circulating cysticercal antigens, taeniasis and to identify significant 2.3. Statistical analysis spatial clusters, if any, spatial scan statistic implemented in SaTScan 7.0.1 software program was used. The unit of anal- Data were entered in Microsoft ExcelTM 2002 (Microsoft ysis was considered to be a case of either AE or taeniasis or Corp.1985—2001) and statistical analysis was done using a seropositive individual. Statistical Package for Social Sciences v. 12 (SPSS Inc., SaTScan needs three input files: one population file, Chicago, IL, USA)33 software. Prevalence rates of AE, NCC, one case file and one coordinate file. The case file could taeniasis and seroprevalence for cysticercal antibodies be single or aggregated data. Thus, in our study the case and rates of positivity to circulating cysticercal antigens file consisted of the number of active epileptics or patients were calculated for each of the clusters and at the block with taeniasis in the study area, and thus the data is level. aggregated at the block level in our case. The population file carries the population of the block, and the coor- 2.4. Spatial mapping and analysis dinate file contains the coordinates of the individuals.34 SaTScan operates by passing a circle over the study region. Garmin GPS V (Garmin International Inc., Olathe, KS, The software moves a circular window systematically USA) was used for collecting waypoints (latitude, longi- over a geographic area to detect significant spatial clus- tude) of the people who did not have existing co-ordinates. ters. The radius of the window may vary from zero to M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612 605

Figure 4. (a) Prevalence of Active Epilepsy in the study clusters. (b) Prevalence of Neurocysticercosis in the study clusters. (c). Prevalence of positivity rates to serum cysticercal antigens in the study clusters. (d) Prevalence of seropositivity rates to cysticercal antibodies in the study clusters. (e) Prevalence of taeniasis in the study clusters. a user-defined upper limit. The centroids (mathematical the size of the circle until the user-defined threshold is or geographical center point of a polygon or the mid- reached. The circle moves from one centroid to another point of a line, described as an x, y coordinate35) of some until all the centroids within the study region are covered. individuals will lie within the circle. SaTScan tests if the Once this testing is done, generating a large number of number of cases in the ‘within circle’ region outstrips the random permutations of the dataset tests the test statis- expected number of cases, within that region. It increases tic. 606 M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612

Figure 4. (Continued)

The cluster assessment is performed by comparing the Identification of spatial high clusters was done number of cases within the window with the number under the Bernoulli probability model assump- expected, if cases are randomly distributed in space. The tion using a maximum spatial cluster size of 5% of test of significance of the identified clusters is based on the total population. For statistical inference, 999 a likelihood ratio test whose P-value is obtained through Monte Carlo replications were performed. The null Monte Carlo testing. 34,36,37 hypothesis of no clustering was rejected when the M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612 607

Figure 4. (Continued)

simulated P-value was ≤ 0.05 for the primary clus- 3.2. Spatial distribution ters. Prevalence rates for AE varied within the study clus- ters and some of the clusters with high AE rates over 3. Results 3.04/1000 population were Salamanatham, Sathupalayam, Adukamparai, Pennathur and Virupakshipuram as shown 3.1. Prevalence of AE, and NCC, taeniasis and in Figure 4a. seropositivity for cysticercal antigens and antibodies The prevalence rates for NCC in the study clusters are shown in Figure 4b. Three clusters Salamanatham, The prevalence of AE in the surveyed population was Munjurpet and Mottupalayam had higher rates of both AE 3.04 per 1000 (116 cases out of a total population of and NCC as compared to other clusters. 6 38 105). The prevalence of AE in the individual clusters Two villages Nanjukondapuram and Kammasaudram ranged from 0.58 to 6.59/1000 population. Out of the 116 had the highest seroprevalence rates for cysticercal anti- patients with AE, a contrast enhanced CT scan was per- gens, measuring over 160 per 1000 population (Figure 4c) formed in 87% of the patients (101/116). In the remainder, and Salamanatham village had the highest seropreva- these tests could not be done for various reasons, the most lence rate for cysticercal antibodies of 390/1000 population common of which was refusal (6/15). The other reasons (Figure 4d). included severe physical or mental disability, patient work- The clusters with comparatively higher rates of taeni- ing or studying out of town, pregnancy, and history of asis in the study area were Mottupalayam, Sathupalayam, severe head injury. Using criteria described by del Brutto et Pennathur, Sathumadurai and Adukamparai as shown in 38 al. for the diagnosis of NCC, the prevalence of NCC in the Figure 4e. study population was 1.02 per 1000 population (39 cases out of a total population of 38 105). A diagnosis of NCC was made in 39 (38.6%) of the 101 AE patients undergo- 3.3. Spatial clustering ing a CT scan. The most common lesion identified on the CT scan was a solitary calcification; one or two calcifica- Cases of AE were distributed throughout the study area. tions were noted in 81.3% of the scans positive for NCC. GIS analysis revealed a significant high primary spatial clus- The prevalence of taeniasis in the community was 30.2 per ter of AE located at 12.8129 N, 79.1347 E in Kaniyambadi 1000 population (22/729 samples). The population sero- village with a log likelihood ratio (LLR) of 10.8, relative risk prevalence of cysticercus antibodies was 19.2% (184/960) (RR) of 22.4 and P value = 0.048 as shown in Figure 5. There and the positivity rate of cysticercal antigens was 4.8% were no significant spatial clusters noted for NCC in the (46/960). study area. 608 M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612

Figure 5. Spatial clustering of Active Epilepsy. A statistically significant ‘hotspot’ cluster seen in Kaniyambadi village.

Spatial analysis revealed five significant spatial clusters Nanjukondapuram, , Sholavaram and Dhar- for seropositivity to cysticercal antibodies. The most signif- mavaram villages as shown in Figure 6. icant one was located in Singirikoil village with a location Two ‘hot spot’ clusters were identified for positivity to id of 12.7641 N, 79.1236 E, LLR of 11.5, RR of 4.28 and P circulating cysticercal antigens located at Kammasaudram value = 0.007. The other significant clusters were located at village with a location id of 12.7770 N, 79.1849 E, LLR of

Figure 6. Spatial clustering of seropositivity to cysticercal antibodies. Five statistically significant ‘hotspot’ clusters are seen in different villages. M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612 609

Figure 7. Spatial clustering of seropositivity to cysticercal antigens. Two statistically significant ‘hotspot’ clusters are seen in Kammasaudram and Nan- jukondapuram villages.

16.7, RR of 8.1 and P value = 0.001 and at Nanjukondapuram area the prevalence of the various indices vary consider- village with a location id of 12.7588 N, 79.0850 E, LLR of ably between the individual villages. Some of the villages 13.0, RR of 14.7 and P value = 0.002 as shown in Figure 7. with higher rates for seroprevalence of cysticercal antibod- One ‘hot spot’ cluster of taeniasis was observed in Kilval- ies, which indicate exposure either active or due to past lam village with a location id of 12.7545 N, 79.1521 E, LLR infection also demonstrated a higher positivity rates for of 8.35, RR of 36.67, P value of 0.02 as shown in Figure 8. cysticercal antigens, indicating that the exposure seems to be from a continuous source and could pose a hazard 4. Discussion to the people living in these clusters. Even though NCC contributed to 38.6% of AE in this region, there were no 4.1. Geographical information systems (GIS) significant clusters of NCC while significant spatial cluster- ing of AE was observed indicating that in this region, other Epidemiologists have long used maps to track the causes of AE could be important. spread of disease, and in the past decade, GIS technology Villages with high prevalence rates for taeniasis as has added a powerful new tool that helps reveal far more estimated by the coproantigen assay were geographically than simply the ‘where’ and ‘when’ of epidemics.39 Recent distributed over most of the study area and two villages also advances in GIS have allowed the application of disease had higher rates of AE but not of NCC. An interesting obser- mapping and spatial analysis, such as spatial clustering and vation from our study is that the clusters of positivity for cluster detection in epidemiological research.12,37,40 There circulating cysticercal antigens were different from that of are several important consequences of detecting clusters of taeniasis. Possible reasons for this anomaly are that taenia diseases. Efforts can be focused on these clusters to study carriers or carriers living in the vicinity of subjects positive the influence of potential causative factors of a disease or for cysticercal antigens have been missed in the sampling the modes of transmission of infectious diseases. The appli- process or that the individuals who are positive for cir- cation of GIS techniques in the field of health and disease culating cysticercal antigens acquired their infection from mapping has been on a gradual rise, however, its use with outside their area of residence, possibly while traveling. respect to neglected diseases such as cysticercosis has been In the study area and neighbouring blocks, the preva- minimal. lence of porcine cysticercosis as estimated by testing porcine sera for antibodies is 9.7% (Oommen et al., unpub- 4.2. Utility of this study lished data). Over the last 5 years or so, there has been a decline in pig rearing in this region mainly due to the ban- The results of our study demonstrate the application of ning of unorganized pig rearing by the state government, GIS techniques in mapping the indices of T. solium infec- and periodic state organized campaigns to kill free roam- tion. It could be seen that even in a small geographic study ing pigs whenever there are reports of small outbreaks of 610 M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612

Figure 8. Spatial clustering of taeniasis. A statistically significant ‘hotspot’ cluster is seen in Kilvallam village.

Japanese encephalitis in the district. However, free roaming munity might be different from that which prevails in Peru. pigs are still visible in most villages. The vast majority of the The possible explanations for differences in transmission people in this region belong to the lower and middle socioe- dynamics could include differences in defecation practices, conomic strata and open field defecation is widespread. pig rearing practices, food habits and sources of water for This combined with poor sanitary and personal hygiene human consumption. provides a good setting for the transmission of cysticer- Our finding of a lack of clustering for NCC related AE cosis. cases is similar to that reported by Lescano et al.25 This reinforces the suggestion that patients with NCC related 4.3. Comparisons with other GIS studies on cysticercosis AE need not always be in the vicinity of a taenia carrier. As speculated by Lescano et al.,25 it is possible that patients Lescano et al.24,25 have recently demonstrated the util- with NCC related AE might have acquired the disease else- ity of GIS techniques in studying the clustering effect of where or that the adult worm within the taenia carriers cysticercosis. They found that while seroprevalence rates from whom the infection was acquired has died and hence were significantly correlated with the distance from a tae- these carriers were not diagnosed at the time of the survey. nia carrier, there was no such clustering of NCC related The latter hypothesis is based on the premise that the life seizures cases. Seroprevalence rates were highest among span of the adult worm is around 3–4 years, the time period the household members of the taenia carrier and decreased that is usually required for a patient with NCC to manifest in households within 1 to 50 metres of the carrier’s house. clinically with seizures. It declined further when the households were > 50 metres There are several difficulties in studying the relative from the taenia carrier’s residence.25 Interestingly, no such clustering of T. solium infection; while some are imposed by gradient was found with respect to NCC related seizure the life cycle of the parasite others stem from human activi- rates. The authors have three main explanations for this ties such as migration. Some of these issues, such as the 3–4 discrepancy: the life expectancy of a tapeworm, the latency year life expectancy of the adult worm, have been discussed between infection by the parasite and onset of seizures, and above. The transient nature of antibody response and even possible migration in and out of the region of the carrier and the antigen presence in the serum of those exposed to the patients with seizures. parasite eggs is yet another confounder.41 Our study was focused more on the determination of clustering of the different manifestations of the parasitic 4.4. Limitations of the study infection in humans rather than on elucidating a corre- lation between them. However, the presence of distinct The addition of geographical features such as the eleva- and spatially separated clusters of taeniasis, high preva- tion of villages, the direction of flow of rivers or streams lence rates of cysticercal antibodies and antigens and AE might have provided additional information. Since the suggests that the transmission of the disease in our com- study was conducted in a relatively small area, weather M.V. Raghava et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 601–612 611 patterns are unlikely to have played any role in disease 7. Prabhakaran V, Raghava MV, Rajshekhar V, Muliyil J, Oommen A. transmission. However, environmental factors such as the Seroprevalence of Taenia solium antibodies in Vellore district, south India. Trans R Soc Trop Med Hyg 2008;102:246–50. relative location of grounds used for defecation and the 8. Chen Y, Yi Q, Mao Y. Cluster of liver cancer and immigration: a geo- source of water supply could have possibly provided clues graphic analysis of incidence data for Ontario 1998–2002. Int J Health to disease transmission. Geogr 2008;7:28. 9. Joseph ST, DeChello LM, Kulldorff M, Gregorio DI, Gershman S, Mroszczyk M. The geographic distribution of breast cancer incidence 5. Conclusions in Massachusetts 1988 to 1997, adjusted for covariates. Int J Health Geogr 2004;3:17. 10. Kulldorff M, Feuer EJ, Miller BA, Freedman LS. 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The spatial Delhi and the Flemish Interuniversity Council, Belgium. distribution of leprosy in four villages in Bangladesh: an observa- tional study. BMC Infect Dis 2008;8:125. 23. Zhou XN, Lv S, Yang GJ, Kristensen TK, Bergquist NR, Utzinger J, et al. Conflicts of interest: The authors declare no conflict of Spatial epidemiology in zoonotic parasitic diseases: insights gained interest. at the 1st International Symposium on Geospatial Health in Lijiang, China, 2007. Parasit Vectors 2009;2:10. 24. Lescano AG, Garcia HH, Gilman RH, Guezala MC, Tsang VC, Ethical approval: The study was approved by the Insti- Gavidia CM, et al. Swine cysticercosis hotspots surrounding Tae- tutional Review Board of the Christian Medical College, nia solium tapeworm carriers. Am J Trop Med Hyg 2007;76: Vellore. 376–83. 25. Lescano AG, Garcia HH, Gilman RH, Gavidia CM, Tsang VC, Rodriguez S, et al. 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