The Impact of Repeated Rounds of Mass Drug Administration with Diethylcarbamazine Plus Albendazole on Bancroftian Filariasis in Papua New Guinea

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

Reduced Plasmodium vivax Erythrocyte Infection in PNG Duffy-Negative Heterozygotes

BACKGROUND: Erythrocyte Duffy blood group negativity reaches fixation in African populations where Plasmodium vivax (Pv) is uncommon. While it is known that Duffy-negative individuals are highly resistant to Pv erythrocyte infection, little is known regarding Pv susceptibility among heterozygous carriers of a Duffy-negative allele (+/−). Our limited knowledge of the selective advantages or disadvantages associated with this genotype constrains our understanding of the effect that interventions against Pv may have on the health of people living in malaria-endemic regions. METHODS AND FINDINGS: We conducted cross-sectional malaria prevalence surveys in Papua New Guinea (PNG), where we have previously identified a new Duffy-negative allele among individuals living in a region endemic for all four human malaria parasite species. We evaluated infection status by conventional blood smear light microscopy and semi-quantitative PCR-based strategies. Analysis of a longitudinal cohort constructed from our surveys showed that Duffy heterozygous (+/−) individuals were protected from Pv erythrocyte infection compared to those homozygous for wild-type alleles (+/+) (log-rank tests: LM, p = 0.049; PCR, p = 0.065). Evaluation of Pv parasitemia, determined by semi-quantitative PCR-based methods, was significantly lower in Duffy +/− vs. +/+ individuals (Mann-Whitney U: p = 0.023). Overall, we observed no association between susceptibility to P. falciparum erythrocyte infection and Duffy genotype. CONCLUSIONS: Our findings provide the first evidence that Duffy-negative heterozygosity reduces erythrocyte susceptibility to Pv infection. As this reduction was not associated with greater susceptibility to Pf malaria, our in vivo observations provide evidence that Pv-targeted control measures can be developed safely

Der Nahrungs- und Genußmittelverbauch im Bundesgebiet

BACKGROUND: In areas where malaria endemicity is high, many people harbour blood stage parasites without acute febrile illness, complicating the estimation of disease burden from infection data. For Plasmodium falciparum the density of parasitaemia that can be tolerated is low in the youngest children, but reaches a maximum in the age groups at highest risk of infection. There is little data on the age dependence of tolerance in other species of human malaria. METHODS: Parasite densities measured in 24,386 presumptive malaria cases at two local health centres in the Wosera area of Papua New Guinea were compared with the distributions of parasite densities recorded in community surveys in the same area. We then analyse the proportions of cases attributable to each of Plasmodium falciparum, P. vivax, and P. malariae as functions of parasite density and age using a latent class model. These attributable fractions are then used to compute the incidence of attributable disease. RESULTS: Overall 33.3%, 6.1%, and 0.1% of the presumptive cases were attributable to P. falciparum, P. vivax, and P. malariae respectively. The incidence of attributable disease and parasite density broadly follow similar age patterns. The logarithm of the incidence of acute illness is approximately proportion to the logarithm of the parasite density for all three malaria species, with little age variation in the relationship for P. vivax or P. malariae. P. falciparum shows more age variation in disease incidence at given levels of parasitaemia than the other species. CONCLUSION: The similarities between Plasmodium species in the relationships between parasite density and risk of attributable disease are compatible with the hypothesis that pan-specific mechanisms may regulate tolerance to different human Plasmodia. A straightforward mathematical expression might be used to project disease burden from parasite density distributions assessed in community-based parasitological surveys

Epitope-Specific Humoral Immunity to Plasmodium vivax Duffy Binding Protein

Erythrocyte invasion by Plasmodium vivax is completely dependent on binding to the Duffy blood group antigen by the parasite Duffy binding protein (DBP). The receptor-binding domain of this protein lies within a cysteine-rich region referred to as region II (DBPII). To examine whether antibody responses to DBP correlate with age-acquired immunity to P. vivax, antibodies to recombinant DBP (rDBP) were measured in 551 individuals residing in a village endemic for P. vivax in Papua New Guinea, and linear epitopes mapped in the critical binding region of DBPII. Antibody levels to rDBP(II) increased with age. Four dominant linear epitopes were identified, and the number of linear epitopes recognized by semiimmune individuals increased with age, suggesting greater recognition with repeated infection. Some individuals had antibodies to rDBP(II) but not to the linear epitopes, indicating the presence of conformational epitopes. This occurred in younger individuals or subjects acutely infected for the first time with P. vivax, indicating that repeated infection is required for recognition of linear epitopes. All four dominant B-cell epitopes contained polymorphic residues, three of which showed variant-specific serologic responses in over 10% of subjects examined. In conclusion, these results demonstrate age-dependent and variant-specific antibody responses to DBPII and implicate this molecule in partial acquired immunity to P. vivax in populations in endemic areas

Mass treatment to eliminate filariasis in Papua New Guinea.

BACKGROUND: The global initiative to eradicate bancroftian filariasis currently relies on mass treatment with four to six annual doses of antifilarial drugs. The goal is to reduce the reservoir of microfilariae in the blood to a level that is insufficient to maintain transmission by the mosquito vector. METHODS: In nearly 2500 residents of Papua New Guinea, we prospectively assessed the effects of four annual treatments with a single dose of diethylcarbamazine plus ivermectin or diethylcarbamazine alone on the incidence of microfilariae-positive infections, the severity of lymphatic disease, and the rate of transmission of Wuchereria bancrofti by mosquitoes. Random assignment to treatment regimens was carried out according to the village of residence, and villages were categorized as having moderate or high rates of transmission. RESULTS: The four annual treatments with either drug regimen were taken by 77 to 86 percent of the members of the population who were at least five years old; treatments were well tolerated. The proportion with microfilariae-positive infections decreased by 86 to 98 percent, with a greater reduction in areas with a moderate rate of transmission than in those with a high rate. The respective aggregate frequencies of hydrocele and leg lymphedema were 15 percent and 5 percent before the trial began, and 5 percent (P<0.001) and 4 percent (P=0.04) after five years. Hydrocele and leg lymphedema were eliminated in 87 percent and 69 percent, respectively, of those who had these conditions at the outset. The rate of transmission by mosquitoes decreased substantially, and new microfilariae-positive infections in children were almost completely prevented over the five-year study period. CONCLUSIONS: Annual mass treatment with drugs such as diethylcarbamazine can virtually eliminate the reservoir of microfilariae and greatly reduce the frequency of clinical lymphatic abnormalities due to bancroftian filariasis. Eradication may be possible in areas with moderate rates of transmission, but longer periods of treatment or additional control measures may be necessary in areas with high rates of transmission

Filariasis infection parameters by age in Usino villages just prior to the first round of mass drug administration.

<p>Abbreviations: Mf, microfilaremia; CFA, circulating filarial antigenemia; Bm14, antibodies to recombinant filarial antigen Bm14.</p><p>Data shown are the number of positive tests and the total number of tests performed (% positive).</p

Filarial antigenemia and Bm14 antibody rates in subjects with microfilaremia before and after mass drug administration (MDA).

<p>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.</p><p>Abbreviations: Mf, microfilaremia; CFA, circulating filarial antigenemia; Bm14, IgG₄ antibodies to recombinant filarial antigen Bm14.</p