Current address: Centre for Neglected Tropical Diseases, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Conceived and designed the experiments: GJW WK SJL SAW CLK JWK MJB. Performed the experiments: GJW WK MS SJL CLK MJB. Analyzed the data: GJW WK MS SJL SAW MJB. Contributed reagents/materials/analysis tools: GJW SJL SAW. Wrote the paper: GJW WK SJL CLK JWK MJB.
The filariasis antigen card test used in this study uses reagents licensed from Barnes-Jewish Hospital, an affilation of Gary J. Weil. All royalties from the sales of this test are donated to the Barnes-Jewish Hospital Foundation, a registered not-for-profit organization. This statement is made in the interest of full disclosure, and not because the authors consider this to be a conflict of interest.
This study employed various monitoring methods to assess the impact of repeated rounds of mass drug administration (MDA) on bancroftian filariasis in Papua New Guinea, which has the largest filariasis problem in the Pacific region.
Residents of rural villages near Madang were studied prior to and one year after each of three rounds of MDA with diethylcarbamazine plus albendazole administered per World Health Organization (WHO) guidelines. The mean MDA compliance rate was 72.9%. Three rounds of MDA decreased microfilaremia rates (Mf, 1 ml night blood by filter) from 18.6% pre-MDA to 1.3% after the third MDA (a 94% decrease). Mf clearance rates in infected persons were 71%, 90.7%, and 98.1% after 1, 2, and 3 rounds of MDA. Rates of filarial antigenemia assessed by card test (a marker for adult worm infection) decreased from 47.5% to 17.1% (a 64% decrease) after 3 rounds of MDA. The filarial antibody rate (IgG4 antibodies to Bm14, an indicator of filarial infection status and/or exposure to mosquito-borne infective larvae) decreased from 59.3% to 25.1% (a 54.6% decrease). Mf, antigen, and antibody rates decreased more rapidly in children <11 years of age (by 100%, 84.2%, and 76.8%, respectively) relative to older individuals, perhaps reflecting their lighter infections and shorter durations of exposure/infection prior to MDA. Incidence rates for microfilaremia, filarial antigenemia, and antifilarial antibodies also decreased significantly after MDA. Filarial DNA rates in
MDA had dramatic effects on all filariasis parameters in the study area and also reduced incidence rates. Follow-up studies will be needed to determine whether residual infection rates in residents of these villages are sufficient to support sustained transmission by the
Lymphatic filariasis (LF) is a deforming and disabling disease that is caused by parasitic worms that are transmitted by mosquitoes. While a number of countries have initiated LF elimination programs based on mass drug administration (MDA), relatively little good information is available on the impact of MDA on filariasis prevalence and incidence rates in populations. This study assessed the impact of three rounds of MDA (with single doses of diethylcarbamazine and albendazole) on filariasis infection rates in villages in Papua New Guinea, which has the largest filariasis problem in the Pacific region. MDA dramatically reduced rates for all filariasis infection markers tested. These included microfilaremia (parasites in blood that are necessary for transmission of the infection), filarial antigenemia (a marker for adult worm infection), anti-filarial antibodies (which indicate infection or heavy exposure to the parasite), and parasites in mosquitoes that transmit the infection. In addition to curing existing infections, MDA also reduced new infection rates in the study population to very low levels. These results suggest that it should be possible to eliminate LF in Papua New Guinea if MDA can be effectively delivered to endemic populations.
Lymphatic filariasis (LF) is a deforming and disabling infectious disease that causes elephantiasis and hydroceles. The infection affects some 120 million people in an estimated 83 countries in tropical and subtropical regions, with an estimated 1.2 billion individuals at risk
Bancroftian filariasis is a major public health problem in Papua New Guinea
Several studies conducted over the past 10 years have assessed the impact of MDA on LF infection parameters in Papua New Guinea. For example, a study performed in 14 villages in East Sepik Province found that four rounds of MDA with DEC plus ivermectin or with DEC alone (drug regimens that have been superseded by the current WHO recommendation of single dose DEC plus albendazole) dramatically decreased microfilaremia (Mf) prevalence rates and transmission parameters in areas with high and moderate baseline infection and transmission rates
The study was performed in 4 villages in the Usino-Bundi district, Madang Province, Papua New Guinea. The villages are located approximately 40 km southwest of the provincial capital, Madang town. The study villages were located at least 2 km from untreated filariasis-endemic villages. This is the estimated flight range of the local mosquito vector
Field teams comprised of trained nurses and field technicians met with community leaders and held outdoor community education sessions to inform people about the health significance and biology of LF, the planned MDA program, and the importance of blood tests for monitoring the impact of MDA. Annual follow-up meetings were held to communicate preliminary results and to provide community members with opportunities to ask questions about the project.
Community liaison personnel mobilized village residents to participate in the study. Children <2 years of age, children who weighed <10 kg, pregnant women, and people with severe chronic illness or acute illness with fever were excluded from the study. We reassessed eligibility for treatment each year. For example, women who were pregnant in year 1 were eligible for the study in later years if they were not pregnant. Survey teams enrolled subjects in the late afternoon by obtaining oral informed consent from adults and recording demographic information. Enrollment of children required their assent and consent from at least one parent. The population was surveyed twice prior to the first round of MDA. The first pre-MDA survey (pre-MDA-A, which collected day blood samples for antigen and antibody testing only without microfilaria testing) was performed approximately 2 years prior to the first round of MDA. The second pre-MDA survey (pre-MDA-B, with blood for Mf, antigen, and antibody testing) was performed together with the first round of MDA (with blood collection just prior to treatment).
MDA comprised the WHO-recommended regimen of a single oral dose of diethylcarbamazine citrate (6 mg/kg body weight) with albendazole (400 mg regardless of weight). This was repeated once per year for a total of three years. Project staff directly observed ingestion of antifilarial medications. Some people agreed to receive MDA but refused to provide blood samples. MDA compliance rates were estimated by dividing the number of people who ingested DEC with albendazole by the number of village residents in the census who were at least 2 years of age. This is similar to “observed coverage” in GPELF guidelines
All tests were performed in the Papua New Guinea Institute of Medical Research Laboratories near Madang. Microfilaremia was assessed by membrane filtration of 1 ml of venous blood collected between 9 p.m. and 12 midnight
Circulating filarial antigenemia (CFA) was assessed with a rapid-format antigen card test (Filariasis Now, Binax Inc., Portland, Maine, USA)
Mosquitoes were collected with CDC light traps (without dry ice) placed in houses (1 night per house) in study villages over 4 months period before MDA commenced and for 4 months starting 6 to 9 months following each round of MDA. Two pre-MDA mosquito collections were conducted. The first (pre-MDA-A) was conducted approximately 12 to 18 months prior to the first round of MDA; the second (pre-MDA-B) was 1 to 5 months prior to the first round of MDA.
Blood-engorged, gravid, or semi-gravid
Data entry was performed with Visual FoxPro software with field limits and double data entry. We used the SPSS v.14 software package (SPSS, Chicago, IL) for statistical analysis. The chi-square test was used to assess the significance of differences in proportions.
This study (including the oral consent process) was reviewed and approved by institutional review boards at Washington University School of Medicine and Case Western Reserve University and the Medical Research Advisory Committee of the Papua New Guinea Department of Health. The sponsor of the study (Division of Microbiology and Infectious Diseases, NIAID, NIH, Bethesda, MD) also reviewed the study protocol to ensure compliance with GCP standards. Study personnel informed prospective study participants about the study by reading them a consent document in the local language. Oral consent was documented on case report forms. Participation by children required consent from at least one parent and the child's assent. As noted above, some subjects agreed to take anti-filarial medications but refused blood tests.
Age Range | Mf (%) | CFA (%) | Bm14 (%) |
3/125 (2.4) | 22/120 (18.3) | 43/120 (35.8) | |
7/90 (7.8) | 25/87 (28.7) | 40/87 (46.0) | |
13/60 (21.7) | 27/60 (45) | 37/60 (61.7) | |
31/131 (24.4) | 78/128 (60.9) | 95/129 (73.6) | |
24/80 (30.0) | 52/79 (65.8) | 54/79 (68.4) | |
24/49 (29.2) | 34/47 (72.3) | 37/48 (77.1) | |
13/37 (35.1) | 27/37 (73.0) | 26/37 (70.3) | |
106/571 (18.6) | 265/558 (47.5) | 332/560 (59.3) |
Abbreviations: Mf, microfilaremia; CFA, circulating filarial antigenemia; Bm14, antibodies to recombinant filarial antigen Bm14.
Data shown are the number of positive tests and the total number of tests performed (% positive).
Gender | Mf Prev (%) | CFA Prev (%) | Bm14 (%) |
2/89 (2.2) | 15/87 (17.2) | 33/87 (37.9) | |
8/126 (6.3) | 32/120 (26.7) | 50/120 (41.7) | |
0.28 | 0.15 | 0.69 | |
32/182 (17.6) | 99/181 (54.7) | 117/181 (64.6) | |
64/174 (36.8) | 119/170 (70) | 132/172 (76.7) | |
<0.001 | 0.005 | 0.02 | |
34/271 (12.5) | 114/268 (42.5) | 150/268 (56.0) | |
72/300 (24.0) | 151/290 (52.1) | 182/292 (62.3) | |
0.001 | 0.024 | 0.126 |
Abbreviations: Mf, microfilaremia; CFA, circulating filarial antigenemia; Bm14, antibodies to recombinant filarial antigen Bm14.
Data shown are the number of positive tests and the total number of tests performed (% positive). Numbers in the first column refer to age in years.
The mean MDA compliance rate over the 3 rounds of MDA was 72.9% (
Age (yr) | Round 1 | Round 2 | Round 3 | |||
Census | MDA Compliance % | Census | MDA Compliance % | Census | MDA Compliance % | |
147 | 29.9 | 146 | 39 | 130 | 23.1 | |
825 | 75.3 | 854 | 82.8 | 841 | 81.7 | |
972 | 68.4 | 1000 | 76.4 | 971 | 73.9 |
MDA had dramatic effects on all filariasis parameters examined (
Mf (%) | CMFL | CFA (%) | Bm14 (%) | ||
n/a | n/a | 334/627 (53.3) | 411/683 (60.2) | ||
106/757 (18.6) | 1.45 | 265/558 (47.5) | 332/560 (59.3) | ||
58/696 (8.3) | 0.44 | 243 692 (35.1) | 276/696 (39.7) | ||
24/714 (3.4) | 0.16 | 175/695 (25.2) | 337/693 (48.8) | ||
7/529 (1.3) | 0.03 | 93/543 (17.1) | 138/550 (25.1) | ||
n/a | n/a | 26/130 (20.0) | 52/137 (38.0) | ||
3/125 (2.4) | 22/120 (18.3) | 43/120 (35.8) | |||
1/138 (0.7) | 14/137 (10.1) | 17/138 (12.3) | |||
0/129 (0) | 3/124 (2.4) | 21/124 (16.3) | |||
0/129 (0) | 3/105 (2.9) | 9/109 (8.3) | |||
Data shown are the number of positive tests and the total number of tests performed (% positive).
The pre-MDA-A survey did not include Mf testing. CMFL was calculated for all ages only.
Pre-MDA-B values were used as the baseline for calculating % decrease for rates after MDA.
Abbreviations: Mf, microfilaremia; CMFL, community microfilarial load (see
CFA (%) | Bm14 (%) | |
98/104 (94.2) | 80/104 (76.9) | |
56/58 (96.6) | 41/58 (70.7) | |
21/23 (91.3) | 18/23 (78.3) | |
6/7 (85.7) | 6/7 (85.7) |
Data shown are the number of subjects with positive tests and the number of Mf-positive subjects tested (% positive) before the first round of MDA and approximately 12 months after each round of MDA.
Abbreviations: Mf, microfilaremia; CFA, circulating filarial antigenemia; Bm14, IgG4 antibodies to recombinant filarial antigen Bm14.
Seven of 529 subjects tested had Mf one year after the third round of MDA. Mf counts in these subjects ranged from 1–52 Mf/ml (mean 18.0±20.5; median 9). These subjects tended to have high Mf counts prior to MDA. Only one of the subjects with Mf detected after MDA round 3 had not received MDA; two had been treated once, one had been treated twice, and two had been treated three times.
Longitudinal Mf data were available for 104 subjects who were initially Mf positive and who had repeat Mf testing approximately one year after one or more rounds of MDA until Mf clearance was achieved. Mf clearance rates were 76% (79/107), 95.2% (99/104), and 98.1% (102/104) after 1, 2, or 3 rounds of treatment, respectively; 2 subjects had persistent microfilaremia after 3 rounds of treatment. Subjects with higher baseline Mf counts tended to require more rounds of MDA to completely clear Mf. The geometric mean and median Mf counts for 79 people who cleared Mf after one round of MDA were 64.8 and 89 (range, 1–3813); geometric mean and median Mf counts for 25 subjects who failed to clear Mf after one round of MDA were 604 and 833 (range 11–5279). The difference in baseline Mf counts between the two groups was statistically significant (
Microfilaria incidence rates in persons who were Mf-negative just prior to MDA were 1.7% (7/408), 0.4% (2/555), and 0.2% (1/472) after MDA rounds 1, 2, and 3, respectively. Note that Mf incidence data were not available for the period between the two pre-MDA surveys. Despite this, the decrease in Mf incidence rates after MDA was statistically significant (
Survey | Bm14 Incidence (rate, %) | CFA Incidence (rate, %) | |
21/154 (6.8) | 11/120 (4.6) | ||
5/164 (3.0) | 2/201 (1.0) | ||
7/213 (3.3) | 3/287 (1.0) | ||
3/181 (1.7) | 5/291 (1.7) | ||
14/83 (8.4) | 7/56 (6.3) | ||
4/98 (4.1) | 1/118 (0.8) | ||
4/131 (3.1) | 0/143 (0) | ||
3 /111 (2.7) | 3/155 (1.9) |
Incidence events for each test were defined as positive tests in people who had tested negative in the prior survey and who had never had a positive test in prior years. This analysis is restricted to persons with data available for consecutive years. The pre-MDA-B incidence data are for a 2 year interval (with annual incidence rates shown in parentheses). Other incidence data are for one year intervals. Annual incidence rates for the 2 year period between pre-MDA-A and pre-MDA-B were significantly higher than rates for the two years following the first round of MDA (
Abbreviations: CFA, circulating filarial antigenemia; Bm14, IgG4 antibodies to recombinant filarial antigen Bm14.
573 pools of recently fed (blood fed, gravid, or semigravid) mosquitoes (3,729 mosquitoes) were tested for filarial DNA by PCR (
Survey | No. Pools | Mosq. per Pool (SD) | No. Mosquitoes Tested | Filarial DNA Rate (95% CI) |
97 | 6.8 (6.1) | 565 | 11.4 (10.87–21.25 | |
119 | 7.5 (7.3) | 892 | 15.1 (11.7–19.2) | |
118 | 6.2 (6.4) | 726 | 3.7 (2.2–5.6) | |
130 | 6.7 (6.8) | 926 | 4.8 (3.3–6.7) | |
100 | 6.2 (6.4) | 620 | 1.02 (0.4–2.2) | |
573 | 6.5 (6.6) | 3,729 |
Filarial DNA was detected in mosquitoes by PCR, and rates (maximum likelihood with 95% CI) were estimated by PoolScreen. The filarial DNA rate in mosquitoes collected in the MDA-3 survey (6 to 9 months after the third round of MDA) represented a 92.3% decrease from the rate in mosquitoes collected during the pre-MDA-B survey (just prior to the first round of MDA).
This is the first detailed report on the effects of repeated rounds of MDA with DEC and albendazole on filariasis infection parameters in an area with
The performance of the ICT antigen test and the Bm14 antibody test require some comment before we address the impact of MDA on filariasis parameters in this study. The ICT test detected filarial antigenemia in a high percentage of untreated Mf-positive subjects (detected by membrane filtration of 1 ml of venous blood), and this sensitivity was maintained after MDA. This is in contrast to a recent study from Kenya that reported decreased sensitivity of the ICT test in Mf carriers (detected by the counting chamber method with 0.1 ml of finger prick blood) after 2 rounds of MDA
Population MDA compliance rates were very good throughout the 3-year study period. However, this required a lot of effort, with multiple visits to the study villages and labor-intensive recruitment of village residents. It might be easier to achieve high compliance rates in a national MDA program that was not linked to collection of venous blood. MDA compliance rates were low in children <6 years of age. This may have reflected parents' concerns about blood tests in their young children. We believe that the national LF elimination program in Papua New Guinea will need to develop new strategies to achieve high MDA compliance in young children. Information campaigns should emphasize the dual benefits of MDA on LF and soil-transmitted helminth infections.
MDA dramatically reduced all filariasis infection parameters in the study villages. As in earlier studies, Mf rates in people and parasite DNA rates in mosquitoes fell more rapidly than CFA or antibody rates
CFA and anti-filarial antibody rates fell more rapidly after MDA in children <11 years of age than in the total study population; this may be because infection intensities and years of infection/exposure tend to be lower in young children than in older individuals. Although infection rates decreased in children after MDA, many young children had positive CFA and/or anti-filarial antibody tests after 3 rounds of MDA. Of course, these children had been exposed to the parasite for years prior to MDA. Children born after LF transmission has been interrupted should not have positive CFA or antibody tests
This study provided interesting longitudinal data on effects of MDA on Mf clearance in individuals and on incidence rates for different filariasis parameters. Mf clearance rates in this study after one or more annual doses of DEC with albendazole were higher than those reported from clinical trials performed in Sri Lanka and Egypt
The impact of three rounds of MDA in the current study was at least as impressive as that recently reported from Egypt (Giza governorate) with the same MDA regimen, although this “high prevalence” study area in Egypt had lower LF infection rates before MDA (11.5% Mf, 19.0% CFA, and 3.07% mosquito DNA) and higher MDA compliance rates than our study site in Papua New Guinea
The authors would like to thank the field teams (for community relations, MDA, and specimen collection) and laboratory staff (for entomology, parasitology, and serology work) of the Papua New Guinea Institute of Medical Research in Madang for diligent effort needed for this project. The project also benefited from administrative support provided by PNG IMR staff in Madang and Goroka. Special thanks go to Nandao Tarongka and Moses Biasor who led the field research teams and to Absalom Mai and Florence Bockarie who performed the antibody and antigen assays.