Elimination of visceral leishmaniasis in Nepal: pipe-dreams and possibilities.

INTRODUCTION: Visceral Leishmaniasis (VL) re-emerged in the Indian subcontinent in the mid-1970s after an almost complete absence in the previous fifteen or so years. The disease was first noted in Nepal in 1978 and, since 1980, it has been reported regularly in increasing numbers. Elimination of visceral leishmaniasis by 2015 has been identified as regional priority program in the level of high political commitment. OBJECTIVE: The objectives of this study are the comprehensive assessment of information related to VL on the basis of past research studies conducted in Nepal, and an assessment of the prospects of control measures. MATERIALS AND METHODS: This was time line comprehensive VL epidemiological assessment study based on the research conducted by main author during the past ten years. During the period the studies were conducted using cross sectional, case control and exploratory study design. The statistical analysis was done using qualitative and quantitative methods. RESULTS: In our study in the visceral leishmaniasis endemic district, Siraha, in the population of 112,029, a total of 996 clinically suspected cases were reported (with fever of long duration and splenomegaly, with no malaria) during 1998-2002. In all, 283 subjects were found positive for visceral leishmaniasis by rK39 and 284 had positive bone marrow. There was no detectable difference in the density of Phlebotomus argentipes between high, and moderate incidence village development committees (VDC: the smallest administrative unit), but collections in the low incidence areas (in winter) were negative. P. argentipes was never numerous (maximum 4.4 females collected per man-hour), and was much less common than P. papatasi. Peaks of abundance were recorded in the March and September collections. We have found that the numbers of reported cases of visceral leishmaniasis in Nepalese villages was unaffected by indoor residual spray (IRS) indicated by parallel trends in case numbers by time series analysis in treated and untreated villages. A series of maps through ten years clearly showed that the infection can move rapidly between villages, and it is impossible to predict where transmission will occur from year to year. CONCLUSION: If maximum benefit in relation to cost is the goal, it may be preferable to put all possible efforts into active case detection (ACD) with free treatment. ACD should involve the network of Village Health Workers or Female Community Health Volunteers and the rK39 dipstick test at health centre level. Surveillance of disease and vector, communication for behavioural impacts and insecticide spraying should be important component of elimination program. If IRS is to be a part of the intervention, it is essential that it is carried out effectively, both in areas where the disease has been reported and in neighbouring areas. Integrated vector management need to be monitored for its application and effectiveness for VL elimination.

C-reactive protein, interleukin-6, and tumor necrosis factor-alpha levels in overweight and healthy adults.

This study aimed to 1) compare levels of high sensitivity c-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) between overweight Thais and apparently healthy controls, and 2) investigate the association between serum hs-CRP, IL-6, and TNF-alpha levels and other biochemical parameters. A total of 180 health-conscious adults aged 25-60 years, who resided in Bangkok, participated in this study. No significant difference was found in age and sex between the overweight subjects and controls. Serum levels of hs-CRP, IL-6, TNF-alpha, glucose, lipid profile, body mass index (BMI), waist circumference (WC), hip circumference (HC) and waist hip ratio (WHR) were determined in these volunteers. The mean levels of white blood cells (WBC), uric acid, total cholesterol (TC), triglyceride (TG), and hs-CRP were significantly higher in the overweight subjects than those in the controls, whereas high density lipoprotein-cholesterol (HDL-C) values were significantly higher in the controls than the overweight subjects (p < 0.05). Hs-CRP levels were significantly positively correlated with levels of TG, BMI, WC, HC and WHR. HDL-C levels were significantly negative correlated with hs-CRP levels. In conclusion, the prevalence of elevated serum hs-CRP levels was higher in overweight subjects than controls. However, more data in larger and other population groups are needed to confirm this study.

Temporal trends of dengue fever/dengue hemorrhagic fever in Bangkok, Thailand from 1981 to 2000: an age-period-cohort analysis.

The aim of this study was to examine the effects of age, time period, and birth cohorts with dengue fever/dengue hemorrhagic fever (DF/DHF) in Bangkok, Thailand over the period 1981-2000. The age group at greatest risk for DF/DHF was 5-9 years old. The period effect shows a remittent pattern, with significant increases in 1986-1990 and 1996-2000. The birth cohort group showed a significant decreasing trend from the 1961-1965 group to the 1991-1995 group (R2 = 0.7620) with a decreasing rate of 0.1. We concluded that the temporal trend of DF/DHF is decreasing; especially for DHF.

Primary verification: is the TRISS appropriate for Thailand?

The Trauma and Injury Severity Score (TRISS) is a well-accepted model used to evaluate the quality of trauma care in the US. This research aims to study whether TRISS can be applied to evaluate trauma care and classify outcomes of road traffic injury patients in Thailand. A retrospective study was used to review the Thailand's Injury Surveillance System database from the 1st January to the 31st of December 1996. The study subjects were severe road traffic injury patients with blunt injuries. The TRISS model was applied to compute the survival probability for each patient. The chi-square goodness-of-fit was used to compare the survival probability distribution between the American Major Trauma Outcome of Study (MTOS) and the road traffic injuries in Thailand. The accuracy, sensitivity and specificity of the survival prediction by TRISS were evaluated. The distribution of survival probability between American trauma patients and Thai road traffic injury patients was significantly different (p-value < 0.00001). The TRISS model had high accuracy and sensitivity, but low specificity, in predicting the survival of Thai road traffic injuries. The MTOS and Thai road traffic injuries had different distributions for various factors such as the Revised Trauma Score (RTS), Injury Severity Score (ISS), and ages which effect injury survival. Due to these factors the distribution of survival probability between MTOS and Thai road traffic injuries was also significantly different. By applying TRISS, the survival prediction of Thai road traffic injuries resulted in a high number of false positives.

Mapping soil-transmitted helminths in Southeast Asia and implications for parasite control.

Establishing the current status and distribution of soil-transmitted helminths is essential for developing and implementing parasite control. Although Southeast Asia is known to have a high prevalence of infection, a precise estimate of the total disease burden has not been fully described. Here, we use Geographical Information Systems (GIS) to collate and map recent published surveys on soil-transmitted helminth epidemiology and distribution for this region. Distinct geographical variation was observed, which is suggested to reflect climatic variation, as well as behavioral differences. However, for much of the region few data are available, and therefore it proved necessary to generate predictions of the distribution of soil-transmitted helminths using remotely sensed (RS) satellite sensor environmental variables. A significant finding was the importance of land surface temperature in influencing the distribution of Ascaris lumbricoides and Trichuris trichiura. Spatial analyses using RS satellite sensor data were then used to generate predictive maps of infection risk. This information provided the basis for an estimate of the population at risk of infection and the numbers requiring treatment. These applications of GIS and remote sensing provide a good basis for developing control of soil-transmitted helminths in the region.

Effect of primaquine standard dose (15 mg/day for 14 days) in the treatment of vivax malaria patients in Thailand.

Primaquine (8-aminoquinoline), the only effective drug to prevent relapses of the persistent liver forms of Plasmodium vivax and Plasmodium ovale, can induce hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The severity varies considerably among affected individuals. Three hundred and sixty-four Plasmodium vivax cases (342 G6PD-normal and 22 G6PD-deficient) were given a 3-day course of chloroquine (total dose 1,500 mg) followed by primaquine 15 mg a day for 14 days and completed a 28-day follow-up. All G6PD-deficient patients were male; there were no relapses or serious adverse events during the study. Although a significant decrease in hematocrit levels and an increase in the percent reduction of hematocrit levels were observed on day 7 (34.9+/-5.0 vs 26.7+/-5.4; (-1.2)+/-14.4 vs (-24.5) +/-13.9 respectively) and on day 14 (35.7+/-4.3 vs 30.9+/-3.1; 1.6+/-17.8 vs (-11.0) +/-19.3 respectively) blood transfusion was not required. Daily doses of 15 mg of primaquine for 14 days following a full course of chloroquine when prescribed to Thai G6PD deficient patients where Mahidol variant is predominant, are relatively safe.

Clinical trial of halofantrine with modified doses for treatment of malaria in the hospital for tropical diseases.

The spread of falciparum malaria resistant to chloroquine all over Southeast Asian continent has led to increasing use of alternative antimalarial drugs. Halofantrine has been shown to be effective against multidrug resistant Plasmodium falciparum. One hundred and twenty falciparum malaria cases were randomly assigned to one of three different halofantrine regimes. Group I (HA1) received 500 mg three times daily for 3 days (total dose: 4,500 mg), group II (HA2) received 500 mg three times daily for the first and the third day (total dose: 3,000 mg) and group III (HA3) received 500 mg three times for one day followed by 500 mg once daily for 7 days (total dose: 4,500 mg). No significant difference in the cure rate was observed among the three regimes (cure rate: 89%, 73%, 97% respectively). However, the cure rate was significantly higher in the HA3 group when compared to the HA2 group. There were no overt cardiac problems seen in this study. Thus, halofantrine has high efficacy in the recommended treatment dose of 500 mg three times after meals on the first day followed by 500 mg once a day after a meal for 7 days (total dose: 4,500 mg).

Can treatment of P. vivax lead to a unexpected appearance of falciparum malaria?

Of 994 patients admitted to the Bangkok Hospital for Tropical Diseases for P. vivax malaria, 104 (10.5%) experienced appearance of Plasmodiumfalciparum following drug treatment for P. vivax . In all patients, P. falciparum parasites were not found by microscopic examination upon admission. The mean time for P. falciparum appearance was 12.6 days after the commencement of chloroquine treatment. Patients experiencing appearance of P. falciparum had significantly lower hematocrit, and greater initial P. vivax parasite counts. We use a mathematical model to explore the consequences of chloroquine treatment of such mixed infections. Both clinical results and features of the model suggest that such "hidden infections" may be quite common, and that the appearance of P. falciparum may be stimulated by treatment of P. vivax.

A randomized clinical trial of combinations of artesunate and azithromycin for treatment of uncomplicated Plasmodium falciparum malaria in Thailand.

Recently, a combination of artesunate and mefloquine has proved effective, although is contraindicated in early pregnancy and young children. Azithromycin, a widely used antibiotic and has antimalarial effects, replace mefloquine as a new alternative antimalarial regimen. Two hundred and two uncomplicated falciparum malaria patients were randomly assigned to 1 of 3 regimens. Patients in group I (n = 68) received artesunate 200 mg once daily for 3 days, group II (n = 67) received artesunate 200 mg together with mefloquine 10 mg/kg on the first 2 days and artesunate 200 mg together with mefloquine 5 mg/kg on the third day, and group III (n = 67) received artesunate 200 mg together with azithromycin 50 mg once daily for 3 days. The 28 day cure rates were 44, 98 and 56%, respectively. The median time to recrudescence was significantly longer in group III. In conclusion, a combination of artesunate and azithromycin might be useful in treating children in whom bacterial and malarial infections may be concomitant. However, further work is required in order to enhance its clinical efficacy.

The situation of malaria along the Vietnam-Lao PDR border and some related factors.

This was a descriptive cross sectional study. It was done in 4 communes along the Vietnam-Lao PDR border of two mountainous provinces: Sonla and Nghean. The cluster multistage sampling technique was applied to choose the study sites. The results of the study show: Among the 2,441 persons given blood tests to find malaria parasites, 0.7% of them carry malaria parasite, of whom 0.6% carry P. falciparum and 0.1% carry P. vivax. The malaria morbidity in the year was 6.9%. The mortality due to malaria is 1.59 per 100,000 population per year. Among the 106 hamlet motivators being interviewed, only 75.5% knew that malaria is transmitted by mosquitos, 71.7% knew that malaria patients are a source of transmission, over 50% of the motivators have mistaken understanding about the living environment of malaria mosquitos. Most of them have had mistakes in diagnosis, treatment of malaria, mosquito-killing spraying. Among the 729 adults being interviewed, 59.0% did not know about the causes of malaria, 30.7% did not take part in malaria control activities. Only 69.3% of the adults regularly sleep inside mosquito nets, 68% of adults buy medicine to cure malaria, 39.9% referred patients to health facilities for cure, and 25% use forest herbs to cure malaria. The factors that increased the malaria morbidity in communes along Vietnam-Lao PDR border have been identified.

Hidden Plasmodium falciparum infections.

Mixed infection of P. vivax and P. falciparum malaria frequently recorded in field survey. However mixed infection was frequently misdiagnosed as single infection due to low parasite density, difficult species identification and procedure error of microscopic examination. Our previous report showed high rates (32-33%) of P vivax infection following treatment of previously assumed to be only P. falciparum infection. In a study of 992 patients with initial presentation with P. falciparum, we found that 104 (10.5%) of patients had P. falciparum appearing during 28 days in the hospital (ranged 1-28 days) following chloroquine treatment for P. vivax. The potential for P. falciparum appearing following elimination of P. vivax must be considered in malaria treatment.

Malaria in tree crop plantations in south-eastern and western provinces of Thailand.

During the past three decades almost half of the existing natural tropical forests in Thailand were destroyed and replaced by cash crops, rubber, coffee, fruit orchards (durian, rambutan, mangosteen) and other commercial plantations. In order to determine the proportion of malaria cases contracted from such commercial plantations, an epidemiological study was conducted between June 1996 to May 1997 in two districts, one in Pong Nam Ron, located in a south-eastern province near the Cambodian border and another in Sai Yok, in a western province along the Myanmar border. Data were collected by passive case detection from patients attending the existing malaria clinics and active case detection by monthly malariometric survey in selected villages. All malaria cases were thoroughly investigated and classified according to exposure to different ecotypes prior to onset of malaria symptoms in the preceding two weeks. Malaria cases acquired from commercial plantations accounted for 35.2% and 11.2% in Pong Nam Ron and in Sai Yok districts respectively. In such plantations, most of the malaria cases were contracted from fruit orchards and to a lesser extent from rubber and teak plantations. From this study it is evident that commercial plantations provide a significant site of malaria transmission in addition to the forest and foothills areas in Southeast Asia where efficient vectors such as An. dirus and An. minimus are prevalent and have adapted to such changed ecosystems.

Evaluation of direct agglutination test (DAT) as an immunodiagnostic tool for diagnosis of visceral leishmaniasis in Nepal.

Before field application of the direct agglutination test (DAT) for leishmaniasis, it was assessed as a diagnostic tool. Fifteen confirmed visceral leishmaniasis cases (bone marrow aspiration positive), 120 tuberculosis, 58 leprosy, 15 malaria, 26 intestinal parasitic infection cases, 24 endemic healthy controls from adjacent to the study area, and 18 controls from Kathmandu (who had never visited the VL endemic areas) were tested for anti-leishmanial antibody agglutination titers. Two of the tuberculosis cases were positive for anti-leishmanial agglutinating antibodies at 1:800. All the visceral leishmaniasis confirmed cases were reactive to anti-leishmanial antibody at > or = 1:3,200. Other specimens were negative for serology. The sensitivity of the direct agglutination test was 100% and the specificity was 99.2%. The direct agglutination test had positive and negative predictive values of 100% and 99.2% respectively. The direct agglutination test has been found to be simple, rapid, reliable, economic, safe and adaptable to micro-techniques using microtiter plates. It is specific and sensitive. The direct agglutination test is simple enough for it to be performed in a field laboratory.

Mekong malaria. Malaria, multi-drug resistance and economic development in the greater Mekong subregion of Southeast Asia.

This monograph brings together national malaria databases for 1996, 1997 and 1998 from the 6 countries comprising the Greater Mekong Subregion of Southeast Asia: Cambodia, China (southern provinces), Lao People's Democratic Republic, Myanmar, Thailand, Viet Nam. The objective is to create a regional perspective in what is a global epicenter of drug resistant falciparum malaria, so to enhance the information flow required to improve malaria control on a regional basis in the context of economic and social change. Geographical Information Systems technology has been applied to the regional mapping of total reported malaria cases, malaria incidence, confirmed cases, parasite species distribution. There is great diversity in disease patterns in the 6 countries and at subnational administrative unit area level in each country, so that in the region as a whole there is marked asymmetry in disease distribution, with many areas of high endemicity. Focal expansion of maps in the vicinity of international border areas delineates the differential trans-border malaria distribution that presents a challenge for disease control. The malaria pattern is also depicted in environmental context against regional elevation and forest cover profiles, which affect mosquito breeding site distribution and agricultural activity. Data on resistance of falciparum malaria to a range of anti-malarial drugs summarise the historical and recent context of resistance development and spread in terms of geography and time frame. Data on population movement across international borders identify the magnitude of a major factor in the dispersal of malaria, including resistant parasite strains. Malaria control involves consideration of microeconomic capacity and operates in the broader context of macroeconomic policy: economic and social profiles of the region are included to provide this perspective. So too are maps depicting major economic development projects in the region, projects that have and will continue to have profound, dynamic impacts on malaria epidemiology. The geographic collation of regional malaria databases is thus placed in overall geographic, health, environmental and economic perspective. This beginning can form a basis for the development of an effective regional malaria surveillance system in the context of rapidly evolving social and infrastructural change, leading eventually to a multi-disease surveillance network.

Factors influencing malaria endemicity in Yunnan Province, PR China (analysis of spatial pattern by GIS). Geographical Information System.

This study is an initial attempt to apply disease mapping through Geographical Information System (GIS) with multiple regression analysis to determine the nature and extent of factors influencing malaria transmission in Yunnan Province, PR China, particularly in border areas. Secondary county-based data covering the period 1990 to 1996 were collected and analyzed. The malaria situation in Yunnan Province as a whole is influenced mainly by the combined effects of the physical environment, the presence of efficient vector species, and mobile population along international borders with Myanmar, Lao PDR and Vietnam.

Research on new antimalarial drugs and the use of drugs in combination at the Bangkok Hospital for Tropical Diseases.

With the emergence of multidrug resistant falciparum malaria in Thailand, various approaches have been taken. Research on new antimalarial drugs and the use of existing available drugs with modification are urgently needed. New drugs and drugs in combination such as pyronaridine, WR 238605, arteether, dihydroartemisinin, benflumetol atovaquone/proguanil are being evaluated. Drug combinations for the treatment of patients suffering from uncomplicated falciparum malaria include quinine-tetracycline for 7 days, or sequential treatment of artesunate (600 mg given over 5 days) followed by mefloquine (1,250 mg divided into 2 doses 6 hours apart) are recommended. The sequential treatment is highly recommended for those who failed other treatment regimens. Other combinations such as a short course sequential treatment of artesunate (300 mg given over 2.5 days) followed by a single dose of 750 mg mefloquine, or a combination of mefloquine 1,250 mg together with tetracycline 1 g per day or doxycycline 200 mg per day for 7 days are alternative treatment regimens with acceptable cure rates. The simultaneous administration of artesunate and mefloquine, in various doses and duration of treatment, is currently being investigated. Until proven otherwise, the drug combinations are still recommended for all adult patients suffering from acute uncomplicated falciparum malaria contracted in multidrug resistant areas. In severe malaria and malaria in children, the drug combinations need further investigation.

Comparison between microscopic examination, ELISA and quantitative buffy coat analysis in the diagnosis of falciparum malaria in an endemic population.

Monoclonal antibody-based ELISA and QBC (quantitative buffy coat analysis) were tested in two endemic areas with low and high incidence of malaria in Kanchanaburi Province, West Thailand with annual parasite incidence in 1992 of 119 and 5 per 1,000 population, respectively. The numbers of individuals positive by thick blood film examination (TBF) for P. falciparum with or without P. vivax, and P. vivax only were 82 and 69, respectively. The detection limit of ELISA was 10 parasites/10(6) red blood cells (RBC) (0.001% parasitemia). Of 1,095 individuals involved in the study at the beginning of the study, ELISA showed sensitivity, specificity, positive predictive value and negative predictive value of 78.1%, 94.9%, 72% and 98.1%, respectively. Nine of 18 (50%) TBF-positive but ELISA-positive individuals had parasitemia of less than 10 parasites/10(6) RBC. High and low incidence areas did not affect the validity of our result. Regression analysis showed good correlation between log parasitemia and ELISA percent OD increase (Y = 0 + 64.9*logX, r = 0.65), and agreement between TBF and ELISA results was 95.9%. In a fortnightly follow-up, in 82 TBF-positive individuals, both ELISA and TBF positive rates correlatively declined with agreement of 96.3%. With samples taken on the first day of the study, the TBF and QBC results were also correlated with agreement of 95.8% for P. falciparum, 95.6% for P. vivax. During 8 week follow-up involving altogether 191 samples, agreement between TBF and QBC results were 87.4% for P. falciparum. QBC detected more cases with P. falciparum infections but detected smaller number of cases with P. vivax infections.

Age-adjusted dengue haemorrhagic fever morbidity in Thailand 1983-1987.

Age-adjusted morbidity rates of Dengue Haemorrhagic Fever in Thailand during the period 1983-1987 were analysed. The 1983 data were used as standard baseline rates. The age-adjusted rates showed increasing trend in the disease morbidity, i.e., 60.2, 138.2, 159.6, 55.2 and 344.7 (per 100,000 capita) respectively. These rates were consistently higher than the crude rates. The Standardised Morbidity Ratios (SMRs) as compared with the baseline 1983 were 1.00, 2.30, 2.65, 0.92 and 5.73 respectively. Regional comparisons revealed annual increases in Bangkok areas, other Central provinces, the North and the Northeast with fluctuations observed in the South. The epidemic was most of the time higher in the Central provinces other than Bangkok areas. The authors suggest that age-adjusted rates (or possibly sex) should be applied in the study of DHF morbidity data, since there were discrepancies in the age distribution among different regions of the country.