EPIDEMIOLOGY OF MALARIA IN AN AREA OF LOW TRANSMISSION IN CENTRAL INDIA

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1 Am. J. Trop. Med. Hyg., 75(5), 2006, pp Copyright 2006 by The American Society of Tropical Medicine and Hygiene EPIDEMIOLOGY OF MALARIA IN AN AREA OF LOW TRANSMISSION IN CENTRAL INDIA NEERU SINGH,* S. K. CHAND, A. K. MISHRA, PRAVEEN K. BHARTI, M. P. SINGH, T. P. AHLUWALIA, AND A. P. DASH National Institute of Malaria Research, Field Station, Jabalpur, Madhya Pradesh, India; Division of Reproductive Health and Nutrition, Indian Council of Medical Research, Ansari Nagar, New Delhi, India; National Institute of Malaria Research, Delhi, India Abstract. A longitudinal study on malaria was carried out from 2003 to 2005 in an area of unstable malaria in the Panna district in central India. Both Plasmodium vivax and P. falciparum were prevalent; however, the risk of P. falciparum malaria was 31.6% (95% confidence interval [CI] %), which is four times higher compared with that of P. vivax malaria (7.8%, 95% CI 6.7 9%). An increasing trend was recorded in malaria prevalence from 30.2% in 2003 to 46.6% in 2004 (odds ratio [OR] 2.0, 95% CI ) that increased to 58.6% in 2005 (OR 1.6, 95% CI ). This increase was statistically significant ( , degrees of freedom 2, P < ). Anopheles culicifacies was the dominant vector of malaria and showed partial (< 50%) resistance to DDT, which indicated that DDT can still be used. Improved access to treatment facilities, combination therapy, and vector control appears to be the most promising method for controlling malaria in this region. INTRODUCTION Malaria is a major public health problem in India and its dynamics vary from place to place. 1 In areas where malaria is highly endemic (high transmission), severe malaria most commonly occurs in young children. 2 Where malaria transmission is low or unstable (sporadic or periodic) as has been described in southeast Asia, natural immunity is slow to develop, all age groups are affected, and incidence often increases with age. 3,4 Plasmodium falciparum malaria is a life-threatening disease for individuals with low immunity 5 and although only a small proportion of patients with malaria develop severe manifestations, these patients require the most urgent and intensive care. Although the burden of malaria in stable areas is welldocumented, data from unstable transmission areas are scarce because too few subjects are affected to be able to conduct systematic surveys during non-epidemic years. Furthermore, in areas of stable transmission, the pattern of transmission remains relatively unchanged from year to year, whereas areas with unstable malaria are characterized by considerable variation in the intensity of transmission between years. Malaria in central India (Madhya Pradesh) is complex because of the vast tracts of forest with tribal settlement. Furthermore, socioeconomic status, cultural characteristic, health care infrastructure, and degree of mobility of population also differ between locations and populations, and contribute to the diversity of malaria characteristics in the region. Scientists at the National Institute of Malaria Research Field Station at Jabalpur are conducting a multidisciplinary study for the last two decades on malaria in a tribal forested belt of Mandla District, which has the highest number of malaria cases in the state (25%). 6 However, in Panna District, which is approximately 400 km from Mandla, malaria was not a problem until recently. 7 A focal outbreak of malaria including deaths was recorded in Jabalpur district in May June 2003 in a labor population who went to forests of Panna District (Figure 1), approximately 300 km from Jabalpur for collection of forest produce. 8 At the same time, however, there were increasing * Address correspondence to Neeru Singh, National Institute of Malaria Research, Field Station, RMRCT (ICMR) Complex, Nagpur Road, Garha, Jabalpur Madhya Pradesh, India. neeru.singh@gmail.com 812 reports of focal outbreaks of malaria in Panna. The outbreak provided an opportunity for a case study on mosquito and malaria prevalence. The main objective was to determine the pattern of malaria in an area of unstable malaria caused by each species of Plasmodium encountered because effective measures to reduce the burden of malaria in unstable transmission settings would differ from those recommended for high-transmission areas. MATERIALS AND METHODS Study site. Panna District (area 7,135 km 2 ) consists of five blocks (administrative units) with a total population of 0.9 million (15% ethnic tribes). Pawai block has 200 villages (population 175,267). There is only one primary health center (PHC) in Pawai block and this is responsible for providing health facility to all 200 villages spread over 1,218 km 2. Pawai PHC is close to the forest where migrants came for collection of forest produce from various districts in March April The terrain in Pawai PHC is highly undulating and hilly (mean altitude meters above sea level) and 57% area is under forest cover. The forest is tropical deciduous. The houses are made of mud and thatch and are often located near a stream or its tributary in the forest. Houses are dark and damp, even during summer. Windows are seldom provided. These villages were not sprayed since 1997 with indoor residual insecticide. This study was carried out from July 2003 to December Parasitologic and entomologic monitoring. Parasitologic and entomologic cross-sectional surveys were carried out during all seasons, i.e., a hot dry summer, monsoon, and autumn. Parasitologic surveys were conducted in 20 villages within a 30-km radius and included a population (Gond ethnic tribe) of mainly low socioeconomic status. Blood smears were made from all fever cases and cases with history of fever in past 14 days. Blood smears were stained with Jaswant Singh, and Bhattacharji (JSB) stain 9 examined in the field to provide prompt malaria treatment as per the National Vector Borne Disease Control Program, i.e., 1,500 mg of chloroquine (CQ) over a three-day period (600 mg, 600 mg, and 300 mg) and 45 mg of primaquine (PQ) as a single dose to adult patients with P. falciparum infection. 600 mg CQ followed by 15 mg PQ/ day for 5 days to adult cases of P. vivax infection and pro-

2 EPIDEMIOLOGY OF MALARIA IN LOW TRANSMISSION AREA 813 FIGURE 1. District. Map of India showing Madhya Pradesh and the Panna portionally smaller doses for children, according to age. Patients not responding to CQ were administered alternative treatment, i.e., Fansidar (F. Hoffmann-La Roche, Basel, Switzerland) (1,500 mg of sulfadoxine plus 75 mg of pyrimethamine), and 45 mg of PQ for adults and proportionately less for children as per national guidelines. Pregnant women and infants were not given PQ. Parasites were counted against 200 white blood cells and converted into counts per microliter assuming an average count of 8,000/ L. Mosquito collections were made in three villages. Anophelines resting inside four fixed houses located in different parts of the villages (two human dwellings and two cattle sheds) were sampled during early morning (6:00 AM) for 15 minutes in each place as per standard techniques. 10 The same collectors caught mosquitoes with flashlights and mouth aspirators in each village. Insecticide susceptibility tests were carried out only on field-collected Anopheles culicifacies using World Health Organization test kits and standard techniques. Anopheles culicifacies were exposed for one hour to paper impregnated with 4% DDT, for one hour to paper impregnated with 5% malathion, and for 30 minutes to papers impregnated with 0.05% deltamethrin, 0.1% propoxur, and 0.1% bendiocarb. Mortality of adult mosquitoes were recorded after 24 hours post-exposure and a corrected percent mortality was calculated using Abbott s formula. Anopheles fluviatilis and other species were found in small numbers during limited periods of the year; thus, the insecticide susceptibility test was not performed with this species. The climate is characterized by a hot dry summer (March June), a monsoon/rainy season (July October), and a cool autumn (November February). Rainfall in Panna in 2002, 2003, 2004, and 2005 was 1,301 mm, 1,026.4 mm, 1,961.6 mm, and 1,250.3 mm, respectively. Before undertaking this investigation, data from previous years ( ) of the district were obtained from District Malaria Officer in Panna. Past epidemiologic situation. For analysis of epidemiologic trends, secondary data pertaining to annual parasite incidence (API) were used because age-specific records were not available. Estimates for for the district are based on data pooled for all 12 months of a year. These estimates are primarily based on active case detection (where a malaria worker goes into a community and takes blood smears from suspected malaria cases) with minor contribution from passive case detection (where blood smears were made from suspected malaria cases among patients visiting a health center or a hospital). The API from 1986 to 2002 was low in Panna (Figure 2), despite a good annual blood examination rate (ABER). Data analysis. Fever was defined as an axillary temperature 37.5 C. Average parasite density was defined as arithmetic mean of asexual parasitemia per microliter of blood. The API was defined as the annual number of malarial parasite positive cases per 1,000 subjects. The ABER was defined as the annual number of fever cases providing blood samples for examination. The slide positivity rate (SPR) refers to the proportion of malaria-positive blood smears among all smears. The slide P. falciparum/p. vivax rate (SFR/SVR) was the total number of blood smears found positive for P. falciparum and P. vivax in the total number of blood smears examined. Mixed infections of P. vivax and P. falciparum were treated as P. falciparum cases because P. falciparum is the predominant in terms of prevalence. Differences in parasite prevalence between different age groups, seasons, and years were analyzed by the chi-square test. Differences in mean parasite density between different age groups and differences in human-hour density between years and seasons were analyzed by analysis of variance. RESULTS The only two Plasmodium species encountered were P. falciparum and P. vivax (Table 1). Analysis of age-specific data on malaria prevalence from study villages showed that the slide P. falciparum rate increased from 12.6% to 26.9% in children 1 year of age (infants) to 35.6% in those > 1 4 years of age to 39.4% in those > 4 8 years of age, and then decreased to 31.3% in those > 14 years of age ( , degrees of freedom [df] 4, P < ). Ten deaths in children and three in adults caused by P. falciparum were also observed among subjects in the cross-sectional surveys. Gametocytes of P. falciparum were detected in 2.7%, 7.1%, 9.1%, 12.7%, and 7.6% of subjects 1,>1 4,>4 8,>8 14, and > 14 years of age. The differences in prevalence of gametocyte carriage between age groups were statistically significant ( , df 4, P 0.005). However, slide P. vivax rate increased from 9% in the youngest subjects to 12.6% in those > 1 4 years of age and then showed a steady FIGURE 2. Annual blood slide examination rate and annual parasite incidence in Panna, India ( ). Source: State Health, Madhya Pradesh Bhopal.

3 814 SINGH AND OTHERS TABLE 1 Age and season wise distribution of malaria infection (95% CI) in Panna District, India, * Plasmodium falciparum cases Seasons P. vivax cases Seasons Age group (years) Indices Autumn Monsoon Dry Autumn Monsoon Dry BSE/n 13/3 54/7 44/4 13/1 54/5 44/4 0 1 (23.1) (13.0) (9.1) (7.7) (9.3) (9.1) 95% CI BSE/n 61/32 73/16 119/20 61/4 73/13 119/15 > 1 (52.5) (21.9) (16.8) (6.6) (17.8) (12.6) 95% CI BSE/n 83/60 98/26 117/20 83/6 98/13 117/12 >4 8 (72.3) (26.5) (17.1) (7.2) (13.3) (10.3) 95% CI BSE/n 84/62 131/39 100/23 84/5 131/17 100/8 >8 14 (73.8) (29.8) (23.0) (6.0) (13.0) (8.0) 95% CI > 14 BSE/n 335/ / /60 335/19 495/29 392/20 (50.1) (31.1) (15.3) (5.7) (5.9) (5.1) 95% CI *CI confidence interval, BSE blood slides examined; n no. positive for malaria. decrease to 10.4% in those > 4 8 years of age to 9.5% in those >8 14 years of age to 5.6% in those > 14 years of age ( , df 4, P < 0.001). Mixed infections of P. vivax and P. falciparum were recorded in all age groups except infants. Further analysis showed that although P. falciparum was the dominant infection, there were considerable variations in the prevalence of P. vivax and P. falciparum by season. The overall parasite prevalence among the subjects investigated during the dry hot season was 24.1% when 68.3% of the infections were P. falciparum and remaining 31.7% were P. vivax. During the monsoon season, the parasite prevalence was 37.5% when 75.9% of the infections were P. falciparum, and the highest malaria prevalence was recorded during autumn (62.5%) when 90.3% of the infections were P. falciparum. The differences in seasonal prevalence of the SFR was statistically significant ( , df 2, P < ); however the difference in the SVR was not statistically significant ( 2 4.2, df 2, P > 0.05). Gametocytes of P. falciparum were recorded in 3.8%, 8.3%, and 14.1% of the subjects in hot dry, monsoon, and post-monsoon (autumn) seasons, respectively. The differences in the prevalence of P. falciparum gametocyte carriage between seasons were significant statistically ( , df 2, P < ). Figure 3 shows yearly malaria prevalence (all age groups combined). An increasing trend was recorded from 30.2% in 2003 to 46.6% in 2004 (odds ratio [OR] 2.0, 95% confidence interval [CI] ) and to 58.6% in 2005 (OR 1.6, 95% CI ). This increase was statistically significant ( , df 2, P < ). The mean ± SD parasite density of P. vivax was ± 2.3 parasites/ L, but was not statistically significant (t 1.7, P > 0.05) when compared with that of P. falciparum (861.7 ± 5.2 parasites/ L). Furthermore, the differences in mean parasite densities between different age were not statistically significant (F 1.07, P > 0.05). Data were log transformed and extreme values were excluded during this analysis. Twenty-seven case with P. falciparum malaria cases were enrolled in a seven-day in vivo test for the determination of CQ resistance (9 cases < 10 years of age and 18 cases 10 years of age). One young girl (parasitemia 79,000 parasites/ L) died even after taking the first dose of CQ (excluded from the analysis). Mean parasitemia was 10,082 parasites/ L at the time of enrollment. Of 26 enrolled cases, only 10 showed an asexual parasitemia on days 3 and 7. Seven cases (71% < 10 years of age and 29% 10 years of age) showed early therapeutic failure and three cases on day 7 (67% < 10 years of age and 33% 10 years of age) showed asexual parasitemias ( 2 8.9, P < ). Because of the high number of malaria cases in the community and the death of one study subject, it was not possible to conduct follow-up after day 7 and the study was terminated because of many operational problems. Thus, it is possible that some recrudescent infections did not become apparent until after seven days, which was the cut-off value we used to estimate the RI level. Entomologic monitoring. The results of indoor-resting collections identified 10 anopheline species, of which two were vectors, i.e., An. culicifacies and An. fluviatilis. Anopheles culicifacies showed the highest indoor-resting density in nearly all surveys followed by An. subpictus, but An. fluviatilis was rarely observed (Table 2). Two rounds of malathion (2 grams/ m 2 ) were sprayed in 2004, but this spraying was discontinued in Analysis of variance showed that catches were greater in 2003 compared with 2004 and 2005, An. culicifacies FIGURE 3. Slide positivity rate and slide Plasmodium falciparum rate in Panna, India,

4 EPIDEMIOLOGY OF MALARIA IN LOW TRANSMISSION AREA 815 Anophelines species TABLE 2 Human hour density of indoor-resting Anophelines in villages of Pawai, Panna District, India Mean ± SD Year Mean ± SD Season F statistics (between and within groups) Autumn Hot dry Monsoon F statistics (between and within groups) An. culicifacies 47.1 ± ± ± * 17.3 ± ± ± * An. subpictus 22.1 ± ± ± ± ± ± An. fluviatilis 0.6 ± ± ± ± An. annularis 2.1 ± ± ± ± ± ± Total anophelines 71.8 ± ± ± ± ± ± * P < P < P < was the predominant species, catches were greater in the monsoon season compared with other months. Insecticide susceptibility test. Results of insecticide susceptibility tests with An. culicifacies females showed that mortality of adults was > 50% to 4% DDT, > 80% to 5% malathion, and 100% to deltamethrin, propoxur, and bendiocarb (Table 3). DISCUSSION The epidemiology of malaria is the product of complex interaction between host, vector, and parasite factors that are specific to each location in which malaria occurs. 11 Agespecific analysis of the data indicated that all age groups showed a high positivity for malaria, particularly for P. falciparum infection. Furthermore, all age groups had gametocytes, including infants as previously reported. 1 Under the current strategy of the National Vector Borne Disease Control Program, much emphasis is given to early detection and prompt treatment (EDPT) of fever cases. Consequently, malaria workers were posted for EDPT in affected villages. In addition, two rounds of malathion were sprayed in 2004, but this spraying was discontinued in However, malaria particularly that caused by P. falciparum, showed a steady increasing trend. The problem is compounded by a moderate level of resistance to CQ. Although there are limitations in the interpretation of our results because of the small sample size, it is possible that we may have underestimated the true incidence of CQ-resistant malaria in the population. However, these results provide information that may be relevant for future studies. The epidemiologic consequence of CQ resistance can be assessed because during the hot dry season when the prevalence of P. TABLE 3 Susceptibility test of Anopheles culicifacies to different insecticideimpregnated paper in villages of Pawai, Panna Disctict, India* Insecticide No. exposed (replicates) No. dead (post 24 hours) Mortality Control mortality Corrected mortality DDT (4%) 90 (6) Malathion (5%) 90 (6) Deltamethrin (0.05%) 45 (3) Propoxur (0.1%) 45 (3) Bendiocarb (0.1%) 45 (3) * PHC primary health center. falciparum infection would be expected to be low, 12 it was the predominant infection (68%) and 3.8% of the subjects had gametocytes. This is an impressive burden despite intensified surveillance and treatment because transmission of malarial parasites from humans to mosquitoes depends on the availability of mature infectious gametocytes in peripheral blood. 13 Therefore, gametocyte carriage can be used as an estimate of transmission potential of malaria parasites from human to mosquitoes. Malaria transmission may be reduced either by the removal of gametocytes from the circulation or by reducing the infectivity of mosquitoes. Such a reduction can be achieved by the use of PQ 14 or by anti-vector intervention. Anopheles culicifacies was the only vector species found in all seasons and in all villages. This species was reported to be responsible for approximately 60% of the total transmission in India. 15 It has been reported that this species maintains unstable malaria with epidemic potential in most areas. 16 However, in central India, which is second most malarious state in the country, areas with An. culicifacies-transmitted malaria are always very difficult to control without specific intensive control measures. 6 DDT is still partially effective in Panna, unlike in most parts of Madhya Pradesh where An. culicifacies shows nearly 100% resistance to DDT. 1,16,17 Antivector intervention should focus on indoor residual spraying because this method can most rapidly reduce the danger of infectious mosquitoes as well as reduce the longevity of those mosquitoes that might otherwise become infectious. There are only a few alternative insecticides to DDT. Malathion and synthetic pyrethroids are approximately 2.5-fold more expensive than DDT per house treatment per year. 15 Furthermore, it has been reported that even where a standard World Health Organization test showed only 11.5% mortality of An. culicifacies, spraying still had some effect on malaria. 18 The major environmental concern of using DDT and evidence of toxicity of DDT to non-target organisms arose when great quantities were used in open fields in the 1950s and 1960s. 19 There is little evidence for toxicity when DDT is used indoors against Anopheles mosquitoes. 20,21 Therefore, DDT can be used in Panna in residual spraying for malaria control as long as it is effective. The results of our study have several implications for malaria control in central India. Past epidemiologic data showed that there has been a sudden increase in number of malaria cases in Panna, particularly in the Pawai PHC. The hypothetical picture that emerges from this study and earlier studies in this area is that people working outside the villages in forests brought malaria into the villages. 8 Ever present anophelines

5 816 SINGH AND OTHERS spread the disease rapidly. Favorable climatic and socioeconomic conditions have resulted in high transmission of malaria in the absence of effective vector control and treatment measures. Another cause of concern is the progressive return of endemicity in the area where control activities have succeeded in reducing or interrupting malaria transmission. This may have epidemiologically important implications in spreading malaria in neighboring districts. Our findings emphasize the dangers of basing malaria control programs solely on chemotherapy. Thus, reduction and elimination of malaria underscore the necessity of a broader approach that should include anti-vector intervention using effective insecticides. In conclusion, to maximize the effectiveness of limited resources, villages should be prioritized for spraying according to current information. It is likely that a combination of appropriate vector control measures in conjunction with continued prompt and effective treatment of clinical malaria will be necessary to achieve a marked reduction in malaria transmission. Received March 6, Accepted for publication June 8, Authors addresses: Neeru Singh, S. K. Chand, A. K. Mishra, Praveen K. Bharti, M. P. Singh, National Institute of Malaria Research, Field Station, RMRCT (ICMR) Complex, Nagpur Road, Garha, Jabalpur Madhya Pradesh, India, Telephone: , Fax: , neeru.singh@gmail.com. T. P. Ahluwalia, Division of Reproductive Health and Nutrition, Indian Council of Medical Research, Ansari Nagar, New Delhi, India, tejpaul2002@yahoo.com. and A. P. Dash, National Institute of Malaria Research, 22 Sham Nath Marg, Delhi, India, apdash2@rediffmail.com. REFERENCES 1. Pattanayak S, Sharma VP, Kalra NL, Orlov VS, Sharma RS, Malaria paradigms in India and control strategies. Indian J Malariol 31: Molineaux L, Gramiccia G, The Garki Project, Research on the Epidemiology and Control of Malaria in the Sudan Savanna of West Africa. Geneva: World Health Organization. 3. Theander TG, Unstable malaria in Sudan. The influence of the dry season. Trans R Soc Trop Med Hyg 92: Luxemburger C, Thwai KL, White NJ, Webster HK, Kyle DE, Maelankirn L, Chongsuphajaisiddhi T, Nosten F, The epidemiology of malaria in a Karen population on the western border of Thailand. Trans R Soc Trop Med Hyg 90: Worrall E, Rietveld A, Delacollett C, The burden of malaria epidemics and cost-effectiveness of interventions in epidemic situations in Africa. Am J Trop Med Hyg 71: Singh N, Nagpal AC, Saxena A, Singh MP, Changing scenario of malaria in central India, the replacement of Plasmodium vivax by Plasmodium falciparum ( ). Trop Med Int Health 9: Singh N, Saxena A, Usefulness of a rapid on site Plasmodium falciparum diagnosis (Paracheck Pf) in forest migrants and among the indigenous population at the site of their occupational activities in central India. Am J Trop Med Hyg 72: Singh N, Chand SK, Mishra AK, Nagpal AC, Migration malaria associated with forest economy in central India. Curr Sci 87: Singh J, Bhattacharji LM, Rapid staining of malaria parasites by a water soluble stain. Indian Med Gaz 79: World Health Organization, Manual on Practical Entomology in Malaria. Part II. Geneva; World Health Organization. Offset publication Bruce-Chwatt LJ, Malaria and its control: present situation and future prospects. Annu Rev Public Health 8: Singh N, Mishra SS, Singh MP, Sharma VP, Seasonality of Plasmodium vivax and P.falciparum in tribal villages in central India ( ). Ann Trop Med Parasitol 94: Akim NI, Drakeley C, Kingo T, Simon B, Senkoro K, Sauerwein RW, Dynamics of P. falciparum gametocytemia in symptomatic patients in an area of intense perennial transmission in Tanzania. Am J Trop Med Hyg 63: Roper MH, Rebeca S, Carrion T, Claudio G, Cava G, Ellen M, Andersen JS, Arambusa G, Carlos C, Allen WH, Alan JM, The epidemiology of malaria in an epidemic area of the Peruvian Amazon. Am J Trop Med Hyg 62: Raghavendra K, Subbarao SK, Chemical insecticides in malaria vector control in India. ICMR Bull 32: Gunasekaran K, Sahu SS, Jambulingam P, Das PK, DDT indoor residual spray, still an effective tool to control Anopheles fluviatilis transmitted Plasmodium falciparum malaria in India. Trop Med Int Health 10: Anonymous, Evaluation of the Impact of DDT and Malathion Indoor Residual Spraying Being Used in Malaria and Kala-Azar Control Programmes on the Disease Prevalence. Delhi: Malaria Research Centre (Indian Council of Medical Research). 18. Sharma VP, Upretty HC, Nutan N, Raina VK, Parida SK, Gupta VK, Impact of DDT spraying on malaria transmission in villages with resistant Anopheles culicifacies. Indian J Malariol 19: Curtis CF, Restoration of malaria control in the Madagascar highlands by DDT spraying. Am J Trop Med Hyg 66: Curtis CF, Lines JD, Should DDT be banned by international treaty? Parasitol Today 16: Longnecker MP, Invited commentary: why DDT matters now. Am J Epidemiol 162: