INTRODUCTION
The primary purpose of the elimination program for lymphatic filariasis (LF) is to interrupt transmission of the parasite through annual mass treatment with either ivermectin or diethylcarbamazine (DEC), in combination with albendazole. Combination therapy offers important therapeutic advantages to the global program to eliminate lymphatic filariasis, in terms of the additive benefit of two drugs in reducing microfilaremia.1–3 The use of two drugs with different mechanisms of action also reduces the likelihood that filarial parasites will develop drug resistance as a consequence of mass treatment.
The drug combinations used for LF also offer important public health benefits through their effects on intestinal helminths. Intestinal helminth infections in children are a leading cause of morbidity and are associated with nutritional deficiency, anemia, growth stunting, and cognitive deficits.4,5 Clinical studies done in many countries have shown that children infected with intestinal worms experience height and weight gains following de-worming with mebendazole or albendazole.6–9 Although DEC by itself has only a limited impact on intestinal helminths, ivermectin does decrease intestinal worm burdens; thus, drug combinations that include albendazole provide de-worming and nutritional benefit.10–12 For Trichuris infections, the additive benefits of albendazole and ivermectin are greater than when either drug is used alone.10
Mass treatment of filariasis is known to reduce intestinal helminth burdens, at least transiently, but it is not clear whether these reductions can be sustained at the community level.11,12 Therefore, we investigated the impact of mass treatment with DEC and albendazole on intestinal helminth infections in the context of a mass treatment program for LF in Leogane, Haiti.
MATERIALS AND METHODS
Study setting.
The study was conducted in Leogane, Haiti as part of a demonstration project to eliminate LF. Annual mass drug administration (MDA) with DEC (6 mg/kg) and albendazole (400 mg in a single dose) was first conducted in October 2000. The DEC for the program was provided by the World Health Organization (WHO) and albendazole was donated by GlaxoSmithKline (Middlesex, UK). Children less than two years of age and pregnant women were excluded from treatment as per WHO guidelines. At the request of the Ministry of Health, women of child-bearing potential were treated with DEC alone in 2000 and 2001.13
Sentinel sites.
For the Leogane project, we selected four communities (Masson/Mathieu, Barrier Jeudi, Mapou, and Leogane town) as sentinel sites for intensive data collection. These sites represented discrete areas of larger towns or small villages inhabited by 1,000–1,500 persons. Research activities in the sentinel sites were reviewed and approved by the Centers for Disease Control and Prevention and Notre Dame Institutional Review Boards, and the Ethics Committee of Hopital Ste. Croix.
Stool collection.
Stools were collected from consenting persons in each of the four sentinel sites in the summer and fall of 2000, before the first MDA. Specimens were collected again nine months after MDA. In 2001, after the first MDA, stool samples were collected from only two of the four sentinel sites (Mapou and Barrier Jeudi) as a cost-saving measure; however, all four sites were sampled in 2002, nine months after the second MDA. At the time that this study was conducted, local schools were not routinely de-worming school children.
Stool processing.
Specimen containers were left with families and collected the following morning. After specimens were transported to the laboratory at Hopital Ste. Croix, a measured quantity of stool was preserved in 10% formalin. Samples were concentrated by the formalin-ethyl acetate technique, diluted in 10% formalin to 2 mL, and a measured quantity (50 μL) of this concentrated sample was examined for helminth eggs and protozoa as previously described.10 Egg counts were multiplied by 40 to generate an estimate of the number of eggs per gram.
Data analysis.
Poisson regression using Proc Genmod (SAS, Cary, NC) and controlling for the effect of villages was used to calculate adjusted risk ratios of post-treatment prevalence rates relative to a pre-treatment baseline for Ascaris, Trichuris, and hookworm infection. Because the same persons were generally followed over a three-year period, the regression implemented the generalized estimating equations (GEEs) procedure to adjust for the lack of independence between observations.
Geometric means of egg per gram prior to and after two years of MDA were calculated on log-transformed data. A value of one was added to each egg count to permit calculation of the logarithm when the egg count was 0. Multivariate linear regression (using the GEE procedure) taking into account the effect of villages and age of patient was used to compare log-transformed egg counts per gram at baseline and two years after MDA. Statistical significance was set at P = 0.05.
RESULTS
More than 2,700 stools were collected and examined from participating households in the four sentinel sites before the first MDA (Table 1). In subsequent years, fewer specimens were collected, both as a cost saving measure and to reduce demands on laboratory staff. The population sampled is skewed toward women and girls and the median age decreased slightly from 2000 to 2002.
At baseline, the age specific prevalence of Ascaris and Trichuris was highest in 6–10-year-old children, reaching 35.5% and 47.1%, respectively (Figure 1A). Infection levels decreased sharply in adults. In contrast, hookworm prevalence increased gradually and did not vary much with age in adults. The pre-intervention infection prevalence of the intestinal helminths differed significantly by sentinel site (Table 2). Infection levels in the two more rural communities, Masson/Mathieu and Mapou, were higher than in the more urban settings of Barrier Jeudi and Leogane town. Mapou had the highest infection prevalence for each intestinal helminth infection: 37% for Ascaris, 61.6% for Trichuris, and 21% for hookworm. Strongyloides was detected in only five persons; these persons were offered treatment with ivermectin following the MDA. No other helminth infections were detected by stool examination.
Changes in overall infection prevalence before and after the two rounds of MDA are plotted in Figure 2. Nine months after the first MDA, we observed modest, but significant decreases in Ascaris (P = 0.027), Trichuris (P = 0.001), and hookworm prevalence (P < 0.001) among treated persons; however, infection prevalence among untreated persons was unchanged from baseline for each of the helminths (Table 3). Nine months after the second MDA, significant decreases in prevalence were noted for all three parasites (P < 0.001); decreases in hookworm prevalence were especially striking. Of persons who provided samples in 2002 after the second MDA, only 60 had not been treated in the second MDA. Helminth infection prevalence was lower among these persons, significantly so for Trichuris; however, it is not possible to attribute these reductions in infection prevalence to reduced transmission because some of the persons who did not participate in the second MDA were treated during the first MDA.
The age-specific prevalence nine months after the second MDA is plotted in Figure 1B. Although infection prevalence was lower than at baseline, the pattern was similar. Ascaris and Trichuris infection were most prevalent in children while hookworm infections continued to be most common in adults.
We also analyzed the impact of treatment on the intensity of helminth infections. Most helminth infections were light before treatment. After two rounds of MDA, significant decreases in the intensity of infection were observed for all three parasites (Table 4).
As noted in the Materials and Methods, women of child-bearing potential were treated with DEC, but not albendazole, for the first two rounds of MDA. All other persons who were eligible for treatment received both drugs. To analyze the effect of the different exclusion criteria on treatment outcome, we considered that women between the ages of 15 and 44 years were of child-bearing potential. A differential outcome was observed following the first round of MDA (Table 5). The prevalence of Trichuris infection decreased significantly among children and men, but not among women. Following the second round of MDA, the decrease in Trichuris infection prevalence was comparable for women and children and men.
DISCUSSION
Ultimately, the success of the LF elmination program will be judged by its impact on microfilaria prevalence and intensity. Although the program is still in its infancy, it is clear that mass treatment leads to significant reductions in filarial infection level and in transmission.14 In Leogane, where DEC and albendazole are used, the program has dramatically reduced microfilaria prevalence in the four sentinel sites (Beau de Rochars M and others, unpublished data). Demonstrating collateral public health benefits, such as reductions in the burden of filarial disease or intestinal helminth infections, is also important for building political and social support for the LF elimination effort. Here, we present the first evidence that MDA for lymphatic filariasis also led to significant and sustained reductions in Ascaris, Trichuris, and hookworm prevalence at the population level.
After two cycles of MDA, Ascaris, Trichuris and hookworm prevalences in the four sentinel sites were reduced by 24.9%, 55.3%, and 82.1%, respectively (Figure 2). Comparable or greater decreases in infection intensity also occurred (Table 4). Decreases were noted in all age groups (Figure 1) and in both urban and rural settings. We did not quantify the nutritional benefit of DEC-albendazole treatment as part of this study; however, in our previous studies of school children in Haiti with similar intestinal parasite burdens, we observed increased height and weight gains following treatment (Beach MJ and others, unpublished data).10 This experience leads us to conclude that children who participated in the MDA were likely to have experienced a period of increased growth as a result of treatment.
The de-worming effect of treatment of filariasis is perceived as a benefit by people in the community and serves as an important factor in promoting compliance. Knowledge, attitude and perception surveys and anecdotal reports suggest that this contributes to the acceptance of the program (Streit TG and others, unpublished data). To date, these de-worming benefits of treatment have not been emphasized as part of our social mobilization strategy, in part, because of our concerns that once a year treatment might not produce a long-term reduction in intestinal helminth infection. The results of the present study lead us to conclude that increased emphasis on de-worming is appropriate and would benefit the LF program in Haiti and elsewhere.
It is important to recognize that the reductions in helminth infection that we detected in the sentinel sites are likely to be somewhat greater than those that we would have observed in the community at-large. The MDA coverage in the sentinel sites was higher than in the commune overall (78% versus 73% for year 1 and 88% versus 52% for year 2) and this may limit the generalizability of our results.15 In addition, persons who provided stool specimens are more compliant than other persons in the community. Conversely, the reduction in helminth infection that we did observe would have been greater if women had received albendazole as part of the first two years of MDA in 2000 and 2001. When the protocol for the filariasis project was developed initially, the Ministry of Health and Population requested that we exclude women of child-bearing potential from albendazole treatment. This recommendation was based on their concern that women in Leogane would not be able to reliably answer questions regarding pregnancy and the date of their last menstrual periods. Consequently, women of child-bearing potential received DEC, but not albendazole, for the first two years of the MDA. As a result of this policy, the prevalence of Trichuris infection did not decrease as much for women as it did for children and for men following the first round of MDA (Table 5). Our sample size was not large enough to detect a difference in outcome for either Ascaris or hookworm infection. In any event, women did not receive the direct benefits of albendazole treatment. This is a public health concern, especially in communities where hookworm is common because of the association between hookworm infection and maternal anemia and low birth weight.16,17 It is important to note that the Haitian Ministry of Health and Population approved a change in exclusion criteria, prior to the third MDA, to permit non-pregnant women of child-bearing age to receive albendazole.
Current efforts to control intestinal helminth infection through mass treatment largely are focused on chemotherapy targeted to specific risk groups, e.g., school children. Although it is clear that school-based de-worming programs can reduce the morbidity of helminth infections in children, the indirect benefits of this targeted treatment to younger children and adults who reside in the community but are untreated may be limited, depending on the proportion of infected persons who are treated.18,19 As the proportion of treated persons increases, untreated persons begin to benefit through a reduction in transmission intensity and decreased infection.20,21 Our study was not designed to address this question; however, it is interesting that the decline in Trichuris infection prevalence in women following two rounds of MDA was comparable to that of children and men, despite the fact that women did not receive albendazole (Table 5). This observation supports the conclusion that transmission of intestinal helminth infections did decrease and that even untreated persons derived benefit from MDA. In addition, it is clear that treatment targeted to school children, at least in Haiti, would miss populations that would benefit from treatment. Hookworm infections in particular, are more prevalent in adults than young children. Pre-school-age children also have substantial levels of Ascaris and Trichuris infection. In the Haitian context where school attendance is not universal, a significant proportion of school-age children also would be missed by school-based de-worming programs. Since LF programs are based on mass treatment, all age groups are expected to benefit from MDA regimens that include albendazole.
In conclusion, lymphatic filariasis elimination programs provide important collateral benefits through the reduction of intestinal helminth burdens. Because DEC has only a limited effect on intestinal parasites, greater health benefits are expected where albendazole is combined with ivermectin rather than DEC. To increase compliance as the LF program grows in Haiti and elsewhere, health educational messages should place greater emphasis on the de-worming benefits of the program.
Study population for stool surveys*
| Year | MDA number | No. | % Female participants | Median age (range),years |
|---|---|---|---|---|
| * For 2001 and 2002, stool specimens were collected nine months after the MDA that was conducted the previous year. MDA = mass drug administration. | ||||
| 2000 | Baseline | 2716 | 56.6 | 18.0 (2–88) |
| 2001 | 1 | 508 | 59.1 | 17.0 (2–77) |
| 2002 | 2 | 814 | 57.1 | 15.0 (2–87) |
Baseline infection prevalence (%) by community
| Community | No. | Ascaris* | Trichuris* | Hookworm* |
|---|---|---|---|---|
| * For each parasite, infection prevalence differs significantly by community. (P < 0.001, by chi-square test). | ||||
| Mapou | 438 | 37.2 | 61.6 | 21.0 |
| Masson/Mathieu | 906 | 24.3 | 37.3 | 12.0 |
| Barrier Jeudi | 924 | 15.0 | 19.4 | 8.6 |
| Leogane | 448 | 10.5 | 30.4 | 5.6 |
| Overall | 2716 | 20.9 | 34.0 | 11.2 |
Infection prevalence by treatment status
| Ascaris treated previous year | Year | Prevalence | RR* (95% CI) | P |
|---|---|---|---|---|
| No (baseline) | 2000 | 20.9 (556/2,664) | 1.00 | – |
| Yes | 2001 | 18.8 (70/372) | 0.79 (0.63, 0.97) | 0.027 |
| Yes | 2002 | 14.4 (108/749) | 0.67 (0.56, 0.81) | < 0.001 |
| No (baseline) | 2000 | 20.9 (556/2,664) | 1.00 | – |
| No | 2001 | 17.6 (23/131) | 0.76 (0.52, 1.11) | 0.159 |
| No | 2002 | 16.7 (10/60) | 0.79 (0.46, 1.34) | 0.380 |
| Trichuris treated previous year | Year | Prevalence | RR* (95% CI) | P |
|---|---|---|---|---|
| No (baseline) | 2000 | 34.1 (908/2,664) | 1.00 | – |
| Yes | 2001 | 27.6 (103/372) | 0.76 (0.64, 0.90) | 0.0013 |
| Yes | 2002 | 15.0 (112/748) | 0.44 (0.37, 0.52) | < 0.001 |
| No (baseline) | 2000 | 34.1 (908/2,664) | 1.00 | – |
| No | 2001 | 34.4 (45/131) | 0.99 (0.78, 1.25) | 0.933 |
| No | 2002 | 11.7 (7/60) | 0.33 (0.17, 0.64) | 0.010 |
| Hookworm treated previous year | Year | Prevalence | RR* (95% CI) | P |
|---|---|---|---|---|
| * Adjusted risk ratio (RR) (95% confidence interval [CI]) controlling for effect of community. Children < 2 years of age were not included in the analysis because they were not eligible for treatment. | ||||
| No (baseline) | 2000 | 11.1 (296/2,662) | 1.00 | – |
| Yes | 2001 | 3.0 (11/372) | 0.23 (0.13, 0.40) | < 0.001 |
| Yes | 2002 | 1.9 (14/748) | 0.17 (0.11, 0.29) | < 0.001 |
| No (baseline) | 2000 | 11.1 (296/2,662) | 1.00 | – |
| No | 2001 | 14.5 (19/131) | 1.14 (0.76, 1.73) | 0.527 |
| No | 2002 | 3.3 (2/60) | 0.32 (0.09, 1.05) | 0.060 |
Changes in intensity of helminth infection after two cycles of mass drug administration (MDA)
| Helminth | MDA | No. | Geometric mean egg count/gram | Arithmetic median (range) |
|---|---|---|---|---|
| * Significantly decreased from baseline (P < 0.0001). | ||||
| Ascaris | Baseline | 2,664 | 88.8 | 0 (0–34,680) |
| Ascaris | 2 | 749 | 56.8* | 0 (0–17,880) |
| Trichuris | Baseline | 2,664 | 150.4 | 0 (0–4,920) |
| Trichuris | 2 | 748 | 38.8* | 0 (0–1,280) |
| Hookworm | Baseline | 2,662 | 25.2 | 0 (0–3,240) |
| Hookworm | 2 | 748 | 3.2* | 0 (0–600) |
Influence of albendazole exclusion criteria on treatment outcome
| Ascaris treated group | Year | Prevalence | RR* (95% CI) | P |
|---|---|---|---|---|
| Females, 15–44 years old | 2000 | 14.5 (104/717) | 1.00 | – |
| Females, 15–44 years old | 2001 | 10.6 (7/66) | 0.72 (0.40, 1.27) | 0.251 |
| Females, 15–44 years old | 2002 | 10.4 (15/144) | 0.72 (0.48, 1.07) | 0.101 |
| All others | 2000 | 23.3 (452/1,947) | 1.00 | – |
| All others | 2001 | 20.6 (63/306) | 0.77 (0.63, 0.96) | 0.019 |
| All others | 2002 | 15.4 (93/605) | 0.65 (0.55, 0.77) | < 0.001 |
| Trichuris treatment group | Year | Prevalence | RR* (95% CI) | P |
|---|---|---|---|---|
| Females, 15–44 years old | 2000 | 28.3 (203/717) | 1.00 | – |
| Females, 15–44 years old | 2001 | 28.8 (19/66) | 0.97 (0.67, 1.41) | 0.874 |
| Females, 15–44 years old | 2002 | 12.5 (18/144) | 0.44 (0.30, 0.64) | < 0.001 |
| All others | 2000 | 36.1 (705/1,947) | 1.00 | – |
| All others | 2001 | 27.5 (84/306) | 0.72 (0.60, 0.87) | 0.001 |
| All others | 2002 | 15.5 (94/604) | 0.44 (0.37, 0.52) | < 0.001 |
| Hookworm treatment group | Year | Prevalence | RR* (95% CI) | P |
|---|---|---|---|---|
| * Adjusted risk ratio (RR) (95% confidence interval [CI]) controlling for effect of community. Children < 2 years of age were excluded from analysis. | ||||
| Females, 15–44 years old | 2000 | 7.1 (51/717) | 1.00 | – |
| Females, 15–44 years old | 2001 | 0 (0/66) | – | – |
| Females, 15–44 years old | 2002 | 2.1 (3/143) | 0.30 (0.15, 0.60) | 0.001 |
| All others | 2000 | 12.6 (245/1,945) | 1.00 | – |
| All others | 2001 | 3.6 (11/306) | 0.25 (0.17, 0.36) | < 0.0001 |
| All others | 2002 | 1.8 (11/605) | 0.15 (0.11, 0.22) | < 0.0001 |
Age-specific prevalence of intestinal helminth before (A) and after (B) two rounds of mass treatment. The prevalence of infection (%) is plotted for the indicated age groups. Ascaris is plotted with a dotted line with diamonds, Trichuris with a solid line with squares, and hookworm with a dashed line and triangles.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 71, 4; 10.4269/ajtmh.2004.71.466
Age-specific prevalence of intestinal helminth before (A) and after (B) two rounds of mass treatment. The prevalence of infection (%) is plotted for the indicated age groups. Ascaris is plotted with a dotted line with diamonds, Trichuris with a solid line with squares, and hookworm with a dashed line and triangles.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 71, 4; 10.4269/ajtmh.2004.71.466
Age-specific prevalence of intestinal helminth before (A) and after (B) two rounds of mass treatment. The prevalence of infection (%) is plotted for the indicated age groups. Ascaris is plotted with a dotted line with diamonds, Trichuris with a solid line with squares, and hookworm with a dashed line and triangles.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 71, 4; 10.4269/ajtmh.2004.71.466
Intestinal helminth prevalence before and after mass treatment with diethylcarbamazine and albendazole. Overall prevalences (%) for Ascaris, Trichuris, and hookworm in the four sentinel sites are plotted at baseline, after one and two rounds of mass drug administration. Ascaris is represented by the cross-hatched bars, Trichuris by the stippled bars, and hookworm by the solid bars. Significant decreases from baseline infection level are indicated by an asterisk.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 71, 4; 10.4269/ajtmh.2004.71.466
Intestinal helminth prevalence before and after mass treatment with diethylcarbamazine and albendazole. Overall prevalences (%) for Ascaris, Trichuris, and hookworm in the four sentinel sites are plotted at baseline, after one and two rounds of mass drug administration. Ascaris is represented by the cross-hatched bars, Trichuris by the stippled bars, and hookworm by the solid bars. Significant decreases from baseline infection level are indicated by an asterisk.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 71, 4; 10.4269/ajtmh.2004.71.466
Intestinal helminth prevalence before and after mass treatment with diethylcarbamazine and albendazole. Overall prevalences (%) for Ascaris, Trichuris, and hookworm in the four sentinel sites are plotted at baseline, after one and two rounds of mass drug administration. Ascaris is represented by the cross-hatched bars, Trichuris by the stippled bars, and hookworm by the solid bars. Significant decreases from baseline infection level are indicated by an asterisk.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 71, 4; 10.4269/ajtmh.2004.71.466
Authors’ addresses: Madsen Beau de Rochars, Hopital Ste. Croix, Leogane, Haiti, Telephione: 509-555-5246, Fax: 509-235-1845, E-mail: mbeauder@nd.edu. Abdel N. Direny, Hopital Ste. Croix, Leogane, Haiti, Telephone: 509-551-6445, Fax: 509-235-1845, E-mail: adireny@nd.edu. Jacquelin M. Roberts, Division of Parasitic Diseases, Mailstop F22, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341, Telephone: 488-7733, Faxs: 770-488-7794, E-mail: jmr1@cdc.gov. David G. Addiss, Division of Parasitic Diseases, Mailstop F22, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341, Telephone: 770-488-7770, Fax: 770-488-7761, E-mail: dga1@cdc.gov. Jeanne Rad-day, Division of Parasitic Diseases, Mailstop F22, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341, Telephone: 770-488-7538, Fax: 770- 488-7761, E-mail: jradday@hotmail.com. Michael J. Beach, Division of Parasitic Diseases, Mailstop F22, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341, Telephone: 770-488-7763, Fax: 770-488-7761, E-mail: mjb3@cdc.gov. Thomas G. Streit, Center for Tropical Diseases, University of Notre Dame, 351 Galvin Hall, Notre Dame, IN 46556, Telephone: 574-631-3273, Fax: 574-631-7413, E-mail: streit1@nd.edu. Desire Dardith, Hopital Ste. Croix, Leogane, Haiti. Jack Guy Lafontant, Hopital Ste. Croix, Leogane, Haiti, Telephone: 509-555-7692, Fax: 509-235-1845, E-mail: gastro@hospital-stecroix.org. Patrick J. Lammie, Division of Parasitic Diseases, Mail-stop F13, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341, Telephone: 770-488-4054, Fax: 770-488-4108, E-mail: pjl1@cdc.gov.
Acknowledgments: We thank the demonstration project staff in Leogane, the people living in the sentinel sites, and especially our colleagues at GlaxoSmithKline for their generous support for the LF program in Haiti and in other countries through their donation of albendazole.
Financial support: This study was supported by the Emerging Infections Program of the Centers for Disease Control and Prevention and by a grant from the Bill & Melinda Gates Foundation to the University of Notre Dame.
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