• View in gallery

    Effect of half-yearly diethylcarbamazine treatment on microfilaremia (dashed lines) and circulating filarial antigenemia (solid lines) in individuals who were microfilaria and circulating filarial antigen positive, respectively, before start of treatment in Masaika, Tanzania (A and B) and Kingwede, Kenya (C and D). A and C indicate prevalence and B and D indicate geometric mean intensity (GMI). Results are expressed as the percent of pre-treatment levels. Only individuals who attended all treatment rounds and follow-up surveys are included. Arrows indicate treatments.

  • View in gallery

    Annual transmission potential (upper graph) and the percent of mosquitoes with infective larvae (lower graph) in Masaika, Tanzania and Kingwede, Kenya before (Year 1) and after (Year 2 and 3 for Masaika and Year 2 for Kingwede) the start of half-yearly mass treatment with diethylcarbamazine. L3 = third-stage (infective) larvae.

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THE EFFECT OF REPEATED HALF-YEARLY DIETHYLCARBAMAZINE MASS TREATMENT ON WUCHERERIA BANCROFTI INFECTION AND TRANSMISSION IN TWO EAST AFRICAN COMMUNITIES WITH DIFFERENT LEVELS OF ENDEMICITY

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  • 1 Danish Bilharziasis Laboratory, Charlottenlund, Denmark; Division of Vector Borne Diseases, Ministry of Health, Nairobi, Kenya; National Institute for Medical Research, Dar es Salaam, Tanzania; Department of Medical Microbiology, College of Health Sciences, Nairobi, Kenya; Department of Infectious Diseases Epidemiology, Imperial College School of Medicine, London, United Kingdom

The effect of repeated half-yearly mass treatment with diethylcarbamazine (DEC, 6 mg/kg body weight) on infection and transmission of Wuchereria bancrofti was assessed and compared in communities with high and low endemicity in eastern Africa, with pretreatment microfilaria (mf) and circulating filarial antigen (CFA) prevalences of 29.4% and 53.2% in the high endemicity community and 3.1% and 18.7% in the low endemicity community, respectively. Human infection was monitored by repeated cross-sectional surveys, and transmission by weekly light trap collection of vector mosquitoes in selected houses in each community. Treatments resulted in a progressive decrease in microfilaremia and circulating antigenemia in both communities, with relative reductions being considerably higher for mf than for CFA. Among pretreatment mf-positive individuals, more than 60% were diagnosed as mf negative and mean mf intensities were reduced by 99% in both communities after two treatment rounds. In contrast, only moderate reductions were seen in circulating antigenemia among pretreatment CFA-positive individuals, with mean intensities still being 24–39% of pretreatment values after two treatment rounds. Among the pretreatment mf/CFA-positive individuals, clearance to a CFA-negative status was negligible. Complete CFA clearance was only observed among pretreatment CFA-positive but mf negative individuals who also had much lower initial mean CFA levels than the mf-positive individuals. After treatment, the intensity of transmission decreased in the high-endemicity community, but this appeared mainly to be a consequence of a drought-induced reduction in vector density rather than to reduced mf load in the human population, since the proportion of mosquitoes carrying infective larvae was not reduced. No change in transmission or mosquito infectivity was observed after treatment in the low-endemicity community. Implications of these observations for the control of Bancroftian filariasis are discussed.

INTRODUCTION

Bancroftian filariasis, which results from infection with the mosquito-borne filarial nematode Wuchereria bancrofti, is a widespread and debilitating disease affecting millions of people in tropical developing countries. Recent significant advances in understanding of the disease and its control, combined with a realization of its profound contribution to poverty and suffering in affected endemic areas, has within recent years changed the position of Bancroftian filariasis from being one of the great neglected diseases to one of major concern and concerted action. Thus, in 1997 the World Health Assembly called for a strengthening of activities towards its elimination as a public health problem. This was soon followed by initiation of the now very active Global Program to Eliminate Lymphatic Filariasis.1,2

Mass chemotherapy is the primary measure for control of Bancroftian filariasis, and the classic and best known drug for this purpose is diethylcarbamazine (DEC). It has been shown in eastern Africa3,4 and elsewhere5–9 that a single treatment with DEC (6 mg/kg body weight) given at half-yearly or yearly intervals can dramatically reduce the microfilarial load, whereas it has a more limited effect on adult worms. Although infection is not completely cleared from the individual, it is assumed that a reduction in population microfilarial load will lead to a simultaneous reduction, or even interruption, of transmission.1,2 The few studies that have addressed this issue have lent support to optimism,8–12 although generally the reported decrease in transmission has not been comparable to the dramatic reduction in human microfilarial load. However, transmission characteristics vary considerably from one endemic area to the other, with different vector species and endemicity levels prevailing, which mathematical models of filariasis control suggest may affect the intensity and duration of mass treatment required.13 Thus, a deeper understanding of how chemotherapy affects infection and transmission patterns in the varied endemic settings is vital for making qualified decisions on the most optimal control strategy for a given area.13

We have previously reported from our investigations on the link between transmission intensity and community pattern of Bancroftian filariasis in coastal eastern Africa.14,15 In these, the pattern of infection, disease, and specific antibody responses were analyzed and compared in two communities with high and low endemicity. Overall community microfilarial prevalences were used as initial criteria for selecting the study communities as indirect indicators of community transmission intensity. Intense entomologic surveillance has confirmed that the average exposure to infective larvae was more than 10 times higher in the high-endemicity community than in the low-endemicity community. After an initial pretreatment year with parasitologic, serologic, clinical, and transmission studies, half-yearly mass treatment with DEC commenced in each community. Here we report on the effect of treatment on infection and transmission in the two communities.

MATERIALS AND METHODS

Study design.

The study was carried out in two rural communities located approximately 80 km apart within the same eastern African W. bancrofti transmission focus, namely Masaika village in the Pangani District (Tanga Region) of Tanzania, and Kingwede village in the Kwale District (Coastal Province) of Kenya. The study areas and populations have been previously described.14 Preliminary surveys had indicated that these communities had high and low endemicity, respectively, for Bancroftian filariasis. This was confirmed during cross-sectional surveys carried out in July–August 1998 among all consenting inhabitants ≥ 1 year of age, which showed overall population microfilaria (mf) and circulating filarial antigen (CFA) prevalences of 24.9% and 52.2% in Masaika and 2.7% and 16.5% in Kingwede, respectively.14

Simultaneously with the initial surveys in 1998, continuous weekly surveillance for vectors and transmission of Bancroftian filariasis commenced in 50 selected houses in each village. After a full year of pre-intervention entomologic surveillance, the human cross-sectional surveys were repeated in July–August 1999. This was followed immediately by a first round of mass-treatment of the human populations with DEC. The 1999 cross-sectional surveys are therefore taken as the baseline human surveys for the present analyses of the effects of drug intervention.

Mass treatment with DEC was repeated half a year later (round 2) in January–February 2000. Another cross-sectional survey was carried out in July–August 2000 and was followed immediately by DEC mass treatment (round 3). Project activities thereafter ceased in Kingwede (low-endemicity community). In Masaika (high-endemicity community), activities continued for another year with DEC mass treatment (round 4) in January 2001 and a human cross-sectional survey followed by DEC mass treatment (round 5) in July 2001. The entomologic surveillance continued throughout the whole period of the study. Thus, for Kingwede the data set for the present analyses comprises one pre-intervention and one post-intervention year, whereas in Masaika it comprises one pre-intervention and two post-intervention years.

Oral informed consent to participate in the study was obtained from adults and from parents or guardians of individuals less than 15 years old. The study was reviewed and approved by the Medical Research Co-ordinating Committee of the National Institute for Medical Research, Tanzania, the Kenyatta National Hospital Ethical and Research Committee, Kenya, and the Central Scientific-Ethical Committee, Denmark.

Demography.

Among the 950 and 1,013 individuals reported and registered as village inhabitants ≥ 1 year of age in the 1998 surveys in Masaika and Kingwede, respectively14 192 and 197 were not met during any of the 1998–2001 annual village surveys (each lasting about two weeks) or were reported during the 1999 surveys to have moved away from the villages (most appeared to have been visitors in 1998) or to have died. These missing individuals were therefore deleted from the original lists of village inhabitants, leaving populations of 758 and 816, respectively, for the present study. Newcomers (immigrants and newborns) were not included in the study, and this resulted in a gradual increase in age of the study populations. Thus, the study populations were ≥ 2 years of age in 1999, ≥ 3 years of age in 2000, and ≥ 4 years of age in 2001.

Examination of the human populations.

Methods and procedures for examination of blood for mf and CFA are described in detail elsewhere.14 Briefly, 100-μL finger prick blood samples were collected in heparinized capillary tubes at night between 9:00 pm and midnight. The blood was transferred to plastic vials containing 0.9 mL of 3% acetic acid. Later, in the laboratory, specimens were transferred to a counting chamber, and mf were counted under a microscope.16

Immediately after finger prick blood sampling, 5 mL of venous blood was collected in plain vacutainer tubes (BD Vacutainer Systems, Plymouth, United Kingdom). More individuals refused venous blood sampling than finger prick sampling, thus making coverages in CFA surveys lower than in mf surveys. After overnight clotting in a refrigerator, serum was separated by centrifugation and stored at −80°C. The specimens were later tested for CFA by using the TropBio enzyme-linked immunosorbent assay kit for detection and quantification of circulating W. bancrofti antigen in serum (catalog no. 03-010-01; TropBio, Ltd., Pty., Townsville, Australia) according to instructions of the manufacturer and as described.17 Serum specimens responding ≥ standard 2 (≥ 32 antigen units) were considered positive for CFA, and specimens responding ≥ standard 7 were assigned a fixed value of 32,000 antigen units.

Entomologic surveillance.

Surveys for vectors and transmission of Bancroftian filariasis were carried out once every week throughout the study period in 50 specially representative randomly sampled houses in each study community. Briefly, communities were divided geographically into 50 clusters with approximately equal numbers of houses, and one household with two or more inhabitants was randomly selected from each cluster. During the day of mosquito collection, all beds in the catching houses were provided with unimpregnated bed nets and a Centers for Disease Control light trap was placed in the sleeping room beside one of the nets. The traps operated 6:00 PM to 6:00 AM. All caught mosquitoes were carried to the field laboratory and identified on morphologic criteria, and live female mosquitoes were dissected for infection and infectivity with larvae of W. bancrofti. In a few of the houses catching had to cease before the end of the study, either because inhabitants moved away and abandoned their house or because inhabitants refused further catching.

Treatment with DEC.

Mass treatment with DEC (6 mg/kg body weight; 50-mg tablets produced by Pharmamed Ltd., Zejtun, Malta) was carried out in Masaika and Kingwede immediately after the July–August 1999 cross-sectional survey, and was repeated at half-yearly intervals from then on. Swallowing of the DEC tablets was supervised and the information was recorded in registers by the project staff.

Data analysis.

The mf intensities were adjusted for sampling time by multiplying the counts with a time-specific factor, as described previously.18 Geometric mean intensities (GMIs) of microfilaramia and antigenemia were calculated as antilog [(Σ log x + 1)/n] − 1, with x being the number of mf/mL and number of CFA units, respectively, and n the number of individuals included. Vector biting rates and transmission potentials were calculated based on the formulas originally given by Walsh and others19 and by using a conversion factor of 1.5 for the light traps.20 Thus, the annual biting rate (ABR) was calculated as (total yearly catch × days in year × conversion factor)/(number of catching days × number of light traps), and the annual transmission potential (ATP) was calculated as (ABR × number of infective larvae in dissections)/(number of mosquitoes dissected).

RESULTS

Characteristics of the study population and the overall 1999 baseline prevalences and mean intensities of mf and CFA are shown in Table 1. All infection indices were statistically significantly higher in Masaika than in Kingwede. The male-to-female ratio was also significantly higher in Masaika than in Kingwede, mainly because many young males had left Kingwede for employment elsewhere.

Effect of treatment on microfilaraemia in the community.

Among the 758 and 816 individuals in Masaika and Kingwede, respectively, 622 and 642 were examined for mf at the baseline surveys and 29.4% and 3.12% of these were mf positive (Table 2). One year after the start of treatment (two treatment rounds), the mf prevalence had decreased to 11.9% in Masaika and 1.24% in Kingwede, corresponding to reductions of 59.5% and 60.3%, respectively, in relation to baseline. Over the same period, the baseline mf GMI among all examined individuals in Masaika (5.69 mf/mL) and Kingwede (0.191 mf/mL) was reduced by 84.3% and 67.0%, respectively, and the baseline mf GMI among mf-positive individuals in Masaika (638 mf/mL) and Kingwede (270 mf/mL) was reduced by 66.6% and 49.6%, respectively.

At two years after the start of treatment (four treatment rounds), the mf prevalence in Masaika had decreased to 4.8% (i.e., 83.7% reduction in relation to baseline). Over the same period, the baseline mf GMI was reduced by 95.1% when calculated for all examined individuals and by 74.8% when calculated for mf-positive individuals only (Table 2).

Effect of treatment on antigenemia in the community.

Among 546 and 598 examined individuals in Masaika and Kingwede, respectively, 289 (52.9%) and 112 (18.7%) were positive for CFA at baseline (Table 2). Among mf-positive individuals, 98.6% in Masaika and 100.0% in Kingwede were also CFA positive. Treatment with DEC obviously had less effect on circulating antigenemia than on microfilaremia. One year after start of treatment (two rounds) the CFA prevalence had decreased to 48.4% in Masaika and 15.0% in Kingwede, corresponding to reductions of only 8.5% and 19.8%, respectively. Over the same period, the baseline CFA GMIs among all examined individuals in Masaika (265 units) and Kingwede (30.9 units) were reduced by 53.6% and 15.5%, and the CFA GMIs among CFA-positive individuals in Masaika (2,772 units) and Kingwede (298 units) were reduced by 67.1% and 36.6%, respectively.

At two years after the start of treatment (four rounds), the CFA prevalence in Masaika had decreased to 43.3% (i.e., 18.1% reduction in relation to baseline). Over the same period, the baseline CFA GMI was reduced by 71.0% when calculated for all examined individuals and by 82.5% when calculated for CFA-positive individuals only (Table 2).

Treatment coverage and attendance pattern.

The coverage for each of the half-yearly treatments for the two communities is indicated in Table 2. In the first round, 81.7% and 78.7% of the populations in Masaika and Kingwede were treated. Apart from a slight increase in coverage from round 1 to 2 in Masaika, a gradual reduction in coverage was seen from round to round. This was partly due to individuals who moved away or died, and partly to increasing numbers refusing examination and treatment in subsequent surveys. The average number of treatments given per person after one year (two rounds) was 1.68 for Masaika and 1.49 for Kingwede. After two years (four rounds), it was 3.07 in Masaika.

As seen in Table 3, there was considerable individual variation in pattern of attendance to treatment. Thus, in Masaika only 49.7% received all four treatments whereas 3.2% received no treatments at all. Importantly, however, 96.8% of the population received at least one treatment. In Kingwede, 60.5% received both treatments, 88.6% received at least one treatment, and 11.4% were not treated at all.

Assessment of drug efficacy in infection-positive individuals.

The efficacy of the DEC treatment on microfilaremia was assessed in individuals from Masaika and Kingwede who were mf positive at the baseline survey and attended all treatment rounds and follow-up examinations (83 in Masaika and 11 in Kingwede; Table 4 and Figure 1). Among these, the proportion of mf positivity was reduced by 61.4% and 90.9%, respectively, at one year after start of treatment (two rounds). The reduction in mf GMI was even more marked, by 98.86% and 99.89%, respectively. Two years after start of treatment (four rounds), the proportion of mf-positive individuals in Masaika was reduced by 96.4%, and the mf GMI was reduced by 99.96%, in relation to baseline.

The efficacy of treatment on circulating antigenemia was assessed among individuals who were CFA positive at the baseline survey and attended all treatment rounds and follow-up examinations (137 in Masaika and 62 in Kingwede). Again, treatment clearly affected circulating antigenemia much less than microfilaremia (Table 5 and Figure 1). The relative reductions in CFA positivity were 9.5% and 25.8%, respectively, at one year after start of treatment, and the CFA GMIs were reduced by 76.2% and 61.2%, respectively. Two years after start of treatment (four rounds), the proportion of CFA-positive individuals in Masaika was reduced by 19.0%, whereas the CFA GMI was reduced by 90.2%, in relation to baseline.

Clearance of circulating antigenemia was mainly confined to the CFA-positive but mf-negative individuals, who also had considerably lower pretreatment CFA levels (Table 5). Thus, in the 76 and 51 individuals from Masaika and Kingwede, respectively, who were mf negative but CFA positive at baseline, the mean pretreatment levels of CFA were 1,108 and 193 antigen units. Among these, the proportion of CFA-positive individuals was reduced by 15.8% and 31.4%, respectively, at one year after the start of treatment. One year later (after four treatment rounds), the Masaika cohort had a 32.9% reduction in the proportion of CFA-positive individuals compared with baseline. In contrast, in 61 and 11 individuals from Masaika and Kingwede, respectively, who were mf and CFA positive at the baseline survey, the mean pretreatment levels of CFA were 6,641 and 1,959 units, respectively (Table 5). Among these, the effect on the proportion of CFA-positive individuals was negligible both at one (both communities) and two (Masaika) years after start of treatment.

Effect of treatment on transmission.

Mosquito collections were carried out for the full three-year period (one pretreatment and two treatment years) in 37 of the selected 50 houses in Masaika, and for the full two-year period (one pretreatment and one treatment year) in 49 of the selected 50 houses in Kingwede (Table 6). Only data from these 37 and 49 full-period catching houses are included in the present analyses. Three mosquito species, Anopheles gambiae s.l., An. funestus, and Culex quinquefasciatus, were vectors of Bancroftian filariasis, but their abundance and vectorial importance differed between the communities (Table 6). In Masaika, An. gambiae was the most abundant human biting mosquito and it contributed most to transmission, whereas in Kingwede, Cx. quinquefasciatus was most abundant and contributed most to transmission (Table 6).

In Masaika, the overall ATP decreased from 79.2 in the baseline year to 35.9 in year 2 and 31.0 in year 3 (Table 6 and Figure 2), corresponding to year 2 and 3 reductions of 54.7% and 60.9% in relation to the pretreatment year. Comparable reductions in ATP were seen for all three vector species. Paradoxically, this reduction in transmission was not a reflection of the vector infection rates, since the proportion of mosquitoes containing infective larvae actually increased from 0.63% in the pretreatment year to 0.90% in year 2 (P = 0.04, by chi-square test) and further to 1.13% in year 3 (P = 0.003 for year 1 versus year 3, by chi-square test) (Table 6 and Figure 2). The relative increase was most pronounced for An. funestus, followed by An. gambiae and Cx. quinquefasciatus (104%, 39%, and 32%, respectively, from year 1 to year 3). More likely, the reduction in transmission could be due to the marked decrease in mosquito density, since the mean number of mosquitoes per catch was reduced from 11.3 in year 1 to 4.1 in year 2 (P < 0.001, by t-test) and further to 2.2 in year 3 (P < 0.001 in relation to year 2, by t-test), causing corresponding decreases in the overall ABR from 6,184 in the pretreatment year to 2,222 in year 2 and 1,211 in year 3 (again with similar trends seen for all three vector species). The decrease in vector abundance most likely resulted from an extraordinary dry climate in the Masaika area in year 2 and 3, with rainfall during the long rains in 1999 and 2000 being less than 50% of that in 1998.

In Kingwede, there was no statistical difference in mean number of mosquitoes per catch (2.8 versus 2.9; P > 0.05, by t-test) or in the proportion of mosquitoes containing infective larvae (0.18% versus 0.15%; P > 0.05, by chi-square test) between the pre-intervention year and year 2. Thus, neither the ATP (5.7 versus 5.1) nor the ABR (1,447 versus 1,598) differed markedly between the two years (Table 6 and Figure 2). In this community, rainfall during the long rains in 1999 was of similar magnitude to that of 1998.

DISCUSSION

The eastern African coast has a long reputation of being endemic for Bancroftian filariasis, but the level of endemicity varies considerably from place to place.21–24 The present study was carried out in two communities with high and low endemicity, respectively, and assessed and compared the effect of repeated half-yearly mass treatment with DEC on infection and transmission.14 Knowledge on the effect of mass drug administration in areas with different endemicity levels and transmission characteristics are vital for the optimal design and implementation of control programs for the varied endemic settings.13

The effect of mass DEC treatment on infection in the human population was first analyzed at community level. Considerable reductions were observed in mf prevalences and mean mf intensities in both communities after treatment, being of the same magnitude as reported earlier for half-yearly DEC mass treatment in nearby communities.25,26 The relative reduction in community mean mf intensity at one year after the start of treatment (two rounds) was somewhat higher in the high-endemicity community than in the low-endemicity community. This was probably due to slightly higher treatment coverage in the former community than in the latter one. In agreement with other studies,27–29 DEC treatment also affected community antigenemia, but clearly to a much lesser degree than community microfilaremia. Moderate reductions were observed for community mean CFA intensities in both communities, but only a minor reduction was seen for CFA prevalences. It is noteworthy that after four rounds of treatment in Masaika, the prevalence of mf and CFA and the overall community mean mf and CFA intensities were still higher than these indices at pretreatment in Kingwede. Elimination of microfilaremia from areas with high endemicity would thus likely require longer durations of mass treatment, supporting recent simulation results obtained from mathematical models of filariasis control investigating this topic.13

Treatment coverage and attendance pattern are important determinants to consider when evaluating the effect and control potential of repeated mass drug administration.13,30 The coverage achieved in the different treatment rounds of the present study appeared reasonable in view of those generally reported from mass treatment programs, but a steady decrease in coverage occurred with increasing number of treatment rounds, despite intensive efforts to mobilize compliance of the population. It was, however, not the same individuals who missed treatment at every treatment round. Thus, despite coverage ranges of 68–87% in Masaika and 71–79% in Kingwede, 97% and 89% of individuals, respectively, received at least one treatment during the study period. Mathematical models of filariasis control have highlighted the vital contribution of coverage patterns to the success of mass treatment programs,31 and clearly indicate a key need for improved understanding of the causes, impact, and between-community variation in such patterns if better predictions of the long-term effect of mass drug control are to be made in endemic communities.

To eliminate the influence of treatment coverage and attendance pattern, and thereby getting a more accurate assessment of drug efficacy, groups of infected individuals from each of the two communities who attended all treatments and follow-up examinations were analyzed separately. Among pre-treatment mf-positive individuals, the relative reductions in mean mf intensities over the first year (two treatment rounds) were fairly similar in the two communities, thus conforming to an earlier study showing that DEC treatment has the same relative efficacy on microfilaremia in individuals with high and low infection burden.4 The proportion of mf-positive individuals also decreased in both groups, but reductions were less than for mf intensities, thus leaving a reservoir of low-density mf carriers to contribute to continued transmission.

In parallel to the observation at community level, the relative efficacy of DEC treatment on circulating antigenemia among pretreatment CFA-positive individuals was clearly lower than that on microfilaremia among pre-treatment mf-positive individuals. The pretreatment CFA-positive individuals who were also mf negative had considerably lower CFA levels than those who were mf positive, but DEC treatment resulted in comparable moderate reductions in CFA intensity in both of these groups. As a consequence, a proportion of individuals in the former low CFA intensity group reverted to a CFA-negative status after treatment, whereas the effect of treatment on CFA status in the later high CFA intensity group was negligible. The CFA response pattern to DEC treatment conformed well to the pattern previously reported,31 both in mf-positive and mf-negative individuals. The fact that the TropBio CFA test has an upper limit for measurement of CFA intensities (32,000 antigen units, see Materials and Methods) makes it difficult to more precisely compare the relative antigen reductions between groups, since even considerable reductions can remain unnoticed in highly antigenemic individuals. However, the continued reduction in mean CFA level seen during the second year of treatment in Masaika, and the CFA clearance observed in pretreatment CFA-positive but mf-negative individuals suggest that reversion to a CFA-negative status may also take place in the pretreatment mf-positive individuals after a longer treatment period. Further follow-up studies after more treatments should clarify this. The much slower elimination rate for CFA than for mf in the human population indicates that the potential for development of adult worm-induced pathology will persist for a considerably longer period than that required for elimination of the mf.

Transmission of Bancroftian filariasis along the eastern African coast is facilitated by three different species of vectors. The relative contribution of these varies from place to place, and is dependent on the prevailing environmental conditions.21,23,32 In Masaika, the most abundant vector and the species contributing most to transmission was An. gambiae, whereas in Kingwede it was Cx. quinquefasciatus. During the baseline year, human exposure to infective larvae was more than 10 times higher in Masaika than in Kingwede. After the start of treatment, the intensity of transmission decreased in Masaika, but appeared unaffected in Kingwede. Most surprisingly, however, the proportion of mosquitoes carrying infective larvae showed no reduction in either of these communities, despite the substantial reductions in community mf intensities in both villages. A few individuals changed from CFA negative to CFA positive over the study period, namely, five in Masaika during the first year (2.5% incidence), one in Masaika during the second year (0.6% incidence), and five in Kingwede during the first year (1.3% incidence), thus confirming that transmission was still going on in the two communities.

Several factors may have contributed to the continued high vector infectivity rate despite the considerable reduction in human mf load. An immediate option is that mosquitoes were infected outside the study communities or took blood meals on microfilaremic visitors,33 but it appears unlikely that this contributed substantially to the continued transmission. More weighty explanations should probably be related to the dynamics of transmission between the residual pool of microfilariae in the villagers after treatment and the vector populations, and to the subsequent parasite development in the vectors. Uptake studies have shown that vector blood meals generally contain higher mf densities than those diagnosed in the blood of the human donors,34,35 and density-dependent processes operating during uptake and development of the parasites in the vectors do at least in some vector/filaria combinations (e.g., Cx. quinquefasciatus/W. bancrofti) lead to a relatively higher proportion of third-stage (infective) larval development in vectors with decreasing human mf burdens and vice versa, a phenomenon commonly referred to as limitation.34–36 Vector mortality may furthermore be reduced as the human mf load decreases, leading to increased transmission after mass chemotherapy. This phenomenon was recently pointed out by Picon to be of potential high relevance in relation to control of Anopheles transmitted filariasis in Africa.37

A third factor that may underlie the persistence of high vector infectivity rates following mass chemotherapy could be related to the observed natural decrease in vector abundance due to reduced rainfall in the Masaika area during years 2 and 3. Such fluctuations in mosquito numbers due to extrinsic density-independent climatic factors may by changing the age structure of mosquitoes in periods increase the infective rate of the surviving pool of vectors, indicating that the impact of mass chemotherapy on parasite transmission dynamics may be complicated by chance or systematic variations in prevailing abiotic micro-climatic factors that regulate the growth of local vector populations. Such a role for climatic variability in underlying the population dynamics of vector-borne diseases has recently been highlighted in the case of predicting malaria epidemics in eastern Africa.38 The mixed vector composition prevailing on the eastern African coast makes the unraveling of transmission dynamics before and after mass treatment in this region even more complex.

The present study thus highlights the importance of understanding and considering local transmission dynamics when attempting to predict the impacts of mass drug administration for filariasis control. We suggest that gaining such an understanding is now a priority because it will not only lead to a better understanding of the epidemiology of mass interventions, but also to more rational design and planning of control programs against this disease. For example, better understanding of density-dependent or density-independent regulation of filariasis transmission after mass treatment would allow the planning and implementation of counteracting measures to mitigate the adverse effects of such regulatory mechanisms on treatment efforts, such as the simultaneous application of vector control measures.12,39,40

Table 1

Characteristics of the study populations in Masaika, Tanzania and Kingwede, Kenya (high and low endemicity community, respectively) at the baseline survey in July–August 1999, immediately before the first round of mass treatment with diethylcarbamazine*

MasaikaKingwedeStatistics
* Mf = microfilaria; GMI = geometric mean intensity; CFA = circulating filarial antigen.
Study population
    No. of individuals ≥ 2 years old758816
    Male:female ratio1.050.85χ2 test, P = 0.038
Microfilaremia
    No. of individuals ≥ 2 years old examined622642
    No. positive (%)183 (29.4)20 (3.1)χ2 test, P < 0.001
    Mf GMI for mf positive, mf/mL638270t-test, P = 0.024
    Mf GMI for all examined, mf/mL5.690.19t-test, P < 0.001
Circulating filarial antigenemia
    No. of individuals ≥ 2 years old examined546598
    No. positive (%)289 (52.9)112 (18.7)χ2 test, P < 0.001
    CFA GMI for CFA positive, units2,772298t-test, P < 0.001
    CFA GMI for all examined, units26530.9t-test, P < 0.001
Table 2

Microfilaremia and circulating filarial antigenemia in Masaika, Tanzania and Kingwede, Kenya before and after mass treatment with diethylcarbamazine*

MicrofilaremiaCirculating antigenemia
CommunityPeriodNo. treated (%)No.examined (%)No. mf positive (%)GMI among all, mf/mlGMI among positives, mf/mlNo. examined (%)No. CFA positive (%)GMI among all, unitsGMI among positives, units
* The analyses are based on study populations of 758 and 816 individuals, respectively, ≥ 2 years old in July–August 1999. Mf = microfilaria; GMI = geometric mean intensity; CFA = circulating filarial antigen.
MasaikaJuly 1999619 (81.7)622 (82.1)183 (29.4)5.69638546 (72.0)289 (52.9)2652772
January 2000656 (86.5)
July 2000540 (71.2)555 (73.2)66 (11.9)0.893213417 (55.0)202 (48.4)123911
January 2001515 (67.9)
July 2001496 (65.4)24 (4.8)0.279161383 (50.5)166 (43.3)76.9484
KingwedeAugust 1999642 (78.7)642 (78.7)20 (3.12)0.191270598 (73.3)112 (18.7)30.9298
February 2000575 (70.5)
August 2000565 (69.2)7 (1.24)0.063136527 (64.6)79 (15.0)26.1189
Table 3

Mass diethylcarbamazine treatment attendance pattern in Masaika, Tanzania and Kingwede, Kenya*

No. of individuals (% of total in community)
No. of treatments receivedMasaika after 1 yearMasaika after 2 yearsKingwede after 1 year
* The analysis is based on the 758 and 816 individuals ≥ 2 years old during the baseline surveys in July–August 1999, respectively.
048 (6.3)24 (3.2)93 (11.4)
1145 (19.1)76 (10.0)229 (28.1)
2565 (74.5)97 (12.8)494 (60.5)
3184 (24.3)
4377 (49.7)
Total758 (100.0)758 (100.0)816 (100.0)
Table 4

Effect of half-yearly treatment with diethylcarbamazine on microfilaremia among individuals who were mf positive at the baseline surveys in July–August 1999 in Masaika, Tanzania and Kingwede, Kenya*

MasaikaKingwede
* Only individuals who attended all treatment rounds (4 in Masaika, 2 in Kingwede) and follow-up examinations (2 in Masaika, 1 in Kingwede) are included. Mf = microfilaria; GMI = geometric mean intensity (mf/mL) for those examined.
July–August 1999
    Number mf positive8311
    GMI505286
July–August 2000
    Number mf positive (% of examined)32 (38.6)1 (9.1)
    GMI (% of pretreatment)5.74 (1.14)0.32 (0.11)
July 2001
    Number mf positive (% of examined)3 (3.6)
    GMI (% of pretreatment)0.17 (0.037)
Table 5

Effect of half-yearly treatment with diethylcarbamazine on circulating filarial antigenemia among individuals from Masaika, Tanzania and Kingwede, Kenya who were CFA positive, mf positive/CFA positive, or mf negative/CFA positive at the baseline surveys in July–August 1999*

All pre-treatment CFA positivesPre-treatment mf positive/CFA positivePre-treatment mf negative/CFA positive
MasaikaKingwedeMasaikaKingwedeMasaikaKingwede
* Only individuals who attended all treatment rounds (4 in Masaika, 2 in Kingwede) and follow-up examinations (2 in Masaika, 1 in Kingwede) are included. CFA = circulating filarial antigen; mf = microfilaria; GMI = geometric mean intensity for those examined, in antigen units.
July–August 1999
    Number CFA positive1376261117651
    GMI2,4602916,6411,9591,108193
July–August 2000
    Number CFA positive (% of examined)124 (90.5)46 (74.2)60 (98.4)11 (100.0)64 (84.2)35 (68.6)
    GMI (% of pre-treatment)586 (23.8)113 (38.8)1932 (29.1)582 (29.7)225 (20.3)79.5 (41.2)
July 2001
    Number CFA positive (% of examined)111 (81.0)60 (98.4)51 (67.1)
    GMI (% of pre-treatment)241 (9.80)754 (11.4)96.5 (8.7)
Table 6

Vectors and transmission of bancroftian filariasis in Masaika, Tanzania and Kingwede, Kenya before and after mass treatment with diethylcarbamazine*

MasaikaKingwede
TotalAnopheles gambiaeAnopheles funestusCulex quinquefasciatusTotalAnopheles gambiaeAnopheles funestusCulex quinquefasciatus
* Mosquitoes were caught by placing one light trap in each catching house once per week throughout the study period. Data from 37 and 49 catching houses in Masaika and Kingwede, respectively, are included in the present analysis (see Results). For these houses, the total number of catches in Masaika were 1,821, 1,838, and 1,622 (equal to a mean of 49.2, 49.7, and 43.8 per house) in year 1, 2, and 3, respectively, and the total number of catches in Kingwede were 2,447 and 2,421 (equal to 51.0 and 50.4 per house), in year 1 and 2, respectively. L3 = third-stage (infective) larvae of Wuchereria bancrofti; ABR = annual biting rate; ATP = annual transmission potential.
Year 1 (pretreatment)
    No. of mosquitoes caught (mean/catch)20,568 (11.3)9,180 (5.0)4,025 (2.2)7,363 (4.0)6,917 (2.8)828 (0.3)2,148 (0.9)3,941 (1.6)
    No. of mosquitoes dissected13,5826,5171,9535,1125,9497301,8013,418
        No. with L3 (% of dissected)86 (0.63)49 (0.74)21 (1.08)16 (0.31)11 (0.18)2 (0.27)7 (0.39)2 (0.06)
        No. of L31741042842223712
    ABR6,1842,7601,2102,2141,548185481882
    ATP79.244.017.318.25.70.81.93.1
Year 2 (treatment)
    No. of mosquitoes caught (mean/catch)7,461 (4.1)4,069 (2.2)1,971 (1.1)1,421 (0.8)7,066 (2.9)1,671 (0.7)1,957 (0.8)3,438 (1.4)
    No. of mosquitoes dissected6,1263,3421,4831,3015,9201,3641,6252,931
        No. with L3 (% of dissected)55 (0.90)28 (0.84)22 (1.48)5 (0.38)9 (0.15)3 (0.22)3 (0.18)3 (0.10)
        No. of L3995833819775
    ABR2,2221,2125874231,598378442777
    ATP35.921.013.12.65.11.91.91.3
Year 3 (treatment)
    No. of mosquitoes caught (mean/catch)3,587 (2.2)1,722 (1.1)842 (0.5)1,023 (0.6)
    No. of mosquitoes dissected3,1991,456774969
        No. with L3 (% of dissected)36 (1.13)15 (1.03)17 (2.20)4 (0.41)
        No. of L38243309
    ABR1,211581284345
    ATP31.017.211.03.2
Figure 1.
Figure 1.

Effect of half-yearly diethylcarbamazine treatment on microfilaremia (dashed lines) and circulating filarial antigenemia (solid lines) in individuals who were microfilaria and circulating filarial antigen positive, respectively, before start of treatment in Masaika, Tanzania (A and B) and Kingwede, Kenya (C and D). A and C indicate prevalence and B and D indicate geometric mean intensity (GMI). Results are expressed as the percent of pre-treatment levels. Only individuals who attended all treatment rounds and follow-up surveys are included. Arrows indicate treatments.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 70, 1; 10.4269/ajtmh.2004.70.63

Figure 2.
Figure 2.

Annual transmission potential (upper graph) and the percent of mosquitoes with infective larvae (lower graph) in Masaika, Tanzania and Kingwede, Kenya before (Year 1) and after (Year 2 and 3 for Masaika and Year 2 for Kingwede) the start of half-yearly mass treatment with diethylcarbamazine. L3 = third-stage (infective) larvae.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 70, 1; 10.4269/ajtmh.2004.70.63

Authors’ addresses: Paul E. Simonsen and Erling M. Pedersen, Danish Bilharziasis Laboratory, Jaegersborg Alle 1 D, 2920 Charlottenlund, Denmark. Dan W. Meyrowitsch, Institute of Public Health, Department of Epidemiology, University of Copenhagen, Blegdamsvej 2, 2200 Copenhagen N, Denmark. Dunstan Mukoko, John H. Ouma, and Naftal Masese, Division of Vector Borne Diseases, Ministry of Health, PO Box 20750, Nairobi, Kenya. Mwele N. Malecela-Lazaro and Rwehumbisa T. Rwegoshora, National Institute for Medical Research, PO Box 9653, Dar es Salaam, Tanzania. Walter G. Jaoko, Department of Medical Microbiology, College of Health Sciences, PO Box 19676, Nairobi, Kenya. Edwin Michael, Department of Infectious Diseases Epidemiology, Imperial College School of Medicine, Norfolk Place, London W2 1PG, United Kingdom.

Acknowledgments: We are grateful for the dedicated and skilled technical assistance provided by the staff of the Bombo Field Station (Joyce Kivugo, Charles Guzo, Megumi Yamakawa, Stephen David, Sudi Hassani, Mwanaisha Mganga, Benjamin Chambika, Peter Mhina, Maembe Mzee, and Robert Reuben), the Msambweni Field Station (Anthony Chome, Charles Nganga, Jackson Mwandi, Kepha Otieno, and Samuel Biego), Masaika Village (Abdul Ndamungu, Edward Winston, Mussa Mohamed, and Saidi Yahaya) Kingwede Village (Josephat Muthoka, Hassan Kilalo, and Bakari Mwanguku) and the Danish Bilharziasis Laboratory (Pernille Lund Strøm).

Financial support: The study was supported by the Program of International Cooperation with Developing Countries (INCO-DC) of the Commission of the European Communities (contract no. ERBIC18CT970257), the Danish Bilharziasis Laboratory, Denmark, and the Medical Research Council, United Kingdom.

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Author Notes

Reprint requests: Paul E. Simonsen, Danish Bilharziasis Laboratory, Jaegersborg Alle 1 D, 2920 Charlottenlund, Denmark, Telephone: 45-77-32-77-32, Fax: 45-77-32-77-33, E-mail: pes@bilharziasis.dk.
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