Areas Of Co-endemicity Research Articles

Wuchereria bancrofti infection is associated with progression to clinical visceral leishmaniasis in VL- endemic areas in Muzaffarpur, Bihar, India.

Co-endemicity of neglected tropical diseases (NTDs) necessitates that these diseases should be considered concomitantly to understand the relationship between pathology and to support disease management and control programs. The aims of the study were to assess the prevalence of filarial infection in asymptomatic Leishmania donovani infected individuals and the correlation of Wuchereria bancrofti infection with progression to clinical visceral leishmaniasis (VL) in Bihar, India. Within the Muzaffarpur-TMRC Health and Demographic Surveillance System (HDSS) area, a cohort of Leishmania seropositive (n = 476) or seronegative individuals (n = 1130) were sampled annually for three years for filarial infection and followed for progression to clinical VL. To corroborate the results from the cohort study, we also used a retrospective case-control study of 36 VL cases and 71 controls selected from a subset of the HDSS population to investigate the relationship between progression to clinical VL and the prevalence of filarial infection at baseline. Our findings suggest a higher probability of progression to clinical VL in individuals with a history of filarial infection: in both the cohort and case-control studies, progression to clinical VL was higher among filaria infected individuals (RR = 2.57, p = 0.056, and OR = 2.52, p = 0.046 respectively). This study describes that progression to clinical VL disease is associated with serological evidence of prior infection with W. bancrofti. The integration of disease programs for Leishmania and lymphatic filariasis extend beyond the relationship of sequential or co-infection with disease burden. To ensure elimination targets can be reached and sustained, we suggest areas of co-endemicity would benefit from overlapping vector control activities, health system networks and surveillance infrastructure.

Major Burden of Severe Anemia from Non-Falciparum Malaria Species in Southern Papua: A Hospital-Based Surveillance Study

The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia. Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81-9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16-9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44-9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49-9.57]); p-value for all comparisons <0.001. Severe anemia (hemoglobin <5 g/dl) was present in 8,151 (3.7%) patients. Compared to patients without malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99-3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00-2.23), 1.87 (95% CI 1.74-2.01), and 2.18 (95% CI 1.76-2.67), respectively, p<0.001. Overall, 12.2% (95% CI 11.2%-13.3%) of severe anemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%-16.3%) for P. falciparum monoinfections. Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17-6.50]; p<0.001). Not all patients had a hemoglobin measurement, thus limitations of the study include the potential for selection bias, and possible residual confounding in multivariable analyses. In Papua P. vivax is the dominant cause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity.

Long term impact of large scale community-directed delivery of doxycycline for the treatment of onchocerciasis

BackgroundAnti-Wolbachia treatment with doxycycline is effective in sterilising and killing adult Onchocerca volvulus nematodes, proving superior to ivermectin and of great potential as an alternative approach for the treatment and control of onchocerciasis, particularly in areas of Loa loa co-endemicity. Nevertheless, the length of the required treatment poses potential logistical problems and risk of poor compliance, raising a barrier to the use of doxycycline in Mass Drug Administration (MDA) strategies. In 2007 and 2008 a feasibility trial of community-directed treatment with doxycycline was carried out in two health districts in Cameroon, co-endemic for O. volvulus and L. loa. With 17,519 eligible subjects, the therapeutic coverage was 73.8% with 97.5% compliance, encouraging the feasibility of using doxycycline community-directed delivery in restricted populations of this size. The current study evaluated the effectiveness of this community-directed delivery of doxycycline four years after delivery.FindingsInfection with O. volvulus was evaluated by skin biopsy and nodule palpation. Of the 507 subjects recruited, 375 had completed the treatment with doxycycline followed by one or two rounds of annual ivermectin MDA and 132 received one or two rounds of annual ivermectin MDA alone. Statistically significant lower microfilarial prevalence (17.0% [doxycycline plus ivermectin group], 27.0% [ivermectin only group], p = 0.014) and load (p = 0.012) were found in people that had received doxycycline followed by ivermectin compared to those who received ivermectin only.ConclusionsThis study demonstrates the long-term effectiveness of doxycycline treatment delivered with a community-directed strategy even when evaluated four years after delivery in an area of ongoing transmission. This finding shows that a multi-week course of treatment is not a barrier to community-delivery of MDA in restricted populations of this size and supports its implementation to compliment existing control strategies for onchocerciasis, where needed.

The Use of Artemether-Lumefantrine for the Treatment of Uncomplicated Plasmodium vivax Malaria

The long-standing dearth of knowledge surrounding Plasmodium vivax, the most widely distributed of the malaria species, merits urgent attention. A growing awareness of the true burden of this parasite and its potential to cause severe disease, and the identification of increasing parasite resistance in many areas of the world to chloroquine, the mainstay of vivax treatment, underscores the need to identify new and effective treatment strategies. Artemisinin-based combination therapies (ACTs) have been widely adopted as first-line treatment for P. falciparum malaria and would offer logistic benefits in areas of co-endemicity. However, while ACTs show high and similar efficacy against the blood stages of P. vivax, neither ACTs nor chloroquine are active against vivax hypnozoites and must be complemented with a full course of primaquine to eradicate dormant vivax hypnozoites and prevent relapses. Artemether-lumefantrine (AL), the most commonly deployed ACT, has shown rapid clearance of P. vivax parasitemia and fever. The relatively short half-life of lumefantrine would appear beneficial in terms of reducing risk of resistance when compared to other ACTs. However, it has a shorter capability to suppress vivax relapses or prevent de novo infections, which generally translates into comparatively lower in vivo short-term measures of efficacy (e.g., day 28 or day 42 uncorrected cure rates). Assuming that the different artemisinin derivatives have equivalent efficacy against vivax, differences between AL and other ACTs may be restricted to the duration of plasma therapeutic levels of the partner drug, a variable of limited clinical relevance, particularly in regions with low vivax transmission rates or in cases where primaquine is added to the regimen to prevent relapses. More rigorous assessment of the use of ACTs in general, and AL in particular, for the treatment of P. vivax infections, either alone or in combination with primaquine, is merited. In the meantime, AL treatment of vivax malaria may be a pragmatic choice for areas with chloroquine-resistant P. vivax, and in co-endemic areas where AL is already used routinely against P. falciparum and parasitological differentiation is not routinely performed or only clinical diagnosis is used.

Bayesian geostatistical modelling of malaria and lymphatic filariasis infections in Uganda: predictors of risk and geographical patterns of co-endemicity

BackgroundIn Uganda, malaria and lymphatic filariasis (causative agent Wuchereria bancrofti) are transmitted by the same vector species of Anopheles mosquitoes, and thus are likely to share common environmental risk factors and overlap in geographical space. In a comprehensive nationwide survey in 2000-2003 the geographical distribution of W. bancrofti was assessed by screening school-aged children for circulating filarial antigens (CFA). Concurrently, blood smears were examined for malaria parasites. In this study, the resultant malariological data are analysed for the first time and the CFA data re-analysed in order to identify risk factors, produce age-stratified prevalence maps for each infection, and to define the geographical patterns of Plasmodium sp. and W. bancrofti co-endemicity.MethodsLogistic regression models were fitted separately for Plasmodium sp. and W. bancrofti within a Bayesian framework. Models contained covariates representing individual-level demographic effects, school-level environmental effects and location-based random effects. Several models were fitted assuming different random effects to allow for spatial structuring and to capture potential non-linearity in the malaria- and filariasis-environment relation. Model-based risk predictions at unobserved locations were obtained via Bayesian predictive distributions for the best fitting models. Maps of predicted hyper-endemic malaria and filariasis were furthermore overlaid in order to define areas of co-endemicity.ResultsPlasmodium sp. parasitaemia was found to be highly endemic in most of Uganda, with an overall population adjusted parasitaemia risk of 47.2% in the highest risk age-sex group (boys 5-9 years). High W. bancrofti prevalence was predicted for a much more confined area in northern Uganda, with an overall population adjusted infection risk of 7.2% in the highest risk age-group (14-19 year olds). Observed overall prevalence of individual co-infection was 1.1%, and the two infections overlap geographically with an estimated number of 212,975 children aged 5 - 9 years living in hyper-co-endemic transmission areas.ConclusionsThe empirical map of malaria parasitaemia risk for Uganda presented in this paper is the first based on coherent, national survey data, and can serve as a baseline to guide and evaluate the continuous implementation of control activities. Furthermore, geographical areas of overlap with hyper-endemic W. bancrofti transmission have been identified to help provide a better informed platform for integrated control.

Macrofilaricidal Activity after Doxycycline Only Treatment of Onchocerca volvulus in an Area of Loa loa Co-Endemicity: A Randomized Controlled Trial

BackgroundThe risk of severe adverse events following treatment of onchocerciasis with ivermectin in areas co-endemic with loiasis currently compromises the development of control programmes and the treatment of co-infected individuals. We therefore assessed whether doxycycline treatment could be used without subsequent ivermectin administration to effectively deliver sustained effects on Onchocerca volvulus microfilaridermia and adult viability. Furthermore we assessed the safety of doxycycline treatment prior to ivermectin administration in a subset of onchocerciasis individuals co-infected with low to moderate intensities of Loa loa microfilaraemia.MethodsA double-blind, randomized, field trial was conducted of 6 weeks of doxycycline (200 mg/day) alone, doxycycline in combination with ivermectin (150 µg/kg) at +4 months or placebo matching doxycycline + ivermectin at +4 months in 150 individuals infected with Onchocerca volvulus. A further 22 individuals infected with O. volvulus and low to moderate intensities of Loa loa infection were administered with a course of 6 weeks doxycycline with ivermectin at +4 months. Treatment efficacy was determined at 4, 12 and 21 months after the start of doxycycline treatment together with the frequency and severity of adverse events.ResultsOne hundred and four (60.5%) participants completed all treatment allocations and follow up assessments over the 21-month trial period. At 12 months, doxycycline/ivermectin treated individuals had lower levels of microfilaridermia and higher frequency of amicrofilaridermia compared with ivermectin or doxycycline only groups. At 21 months, microfilaridermia in doxycycline/ivermectin and doxycycline only groups was significantly reduced compared to the ivermectin only group. 89% of the doxycycline/ivermectin group and 67% of the doxycycline only group were amicrofilaridermic, compared with 21% in the ivermectin only group. O. volvulus from doxycycline groups were depleted of Wolbachia and all embryonic stages in utero. Notably, the viability of female adult worms was significantly reduced in doxycycline treated groups and the macrofilaricidal and sterilising activity was unaffected by the addition of ivermectin. Treatment with doxycycline was well tolerated and the incidence of adverse event to doxycycline or ivermectin did not significantly deviate between treatment groups.ConclusionsA six-week course of doxycycline delivers macrofilaricidal and sterilizing activities, which is not dependent upon co-administration of ivermectin. Doxycycline is well tolerated in patients co-infected with moderate intensities of L. loa microfilariae. Therefore, further trials are warranted to assess the safety and efficacy of doxycycline-based interventions to treat onchocerciasis in individuals at risk of serious adverse reactions to standard treatments due to the co-occurrence of high intensities of L. loa parasitaemias. The development of an anti-wolbachial treatment regime compatible with MDA control programmes could offer an alternative to the control of onchocerciasis in areas of co-endemicity with loiasis and at risk of severe adverse reactions to ivermectin.Trial RegistrationControlled-Trials.com ISRCTN48118452

Spatial co‐distribution of neglected tropical diseases in the East African Great Lakes region: revisiting the justification for integrated control

To determine spatial patterns of co-endemicity of schistosomiasis mansoni and the soil-transmitted helminths (STHs) Ascaris lumbricoides, Trichuris trichiura and hookworm in the Great Lakes region of East Africa, to help plan integrated neglected tropical disease programmes in this region. Parasitological surveys were conducted in Uganda, Tanzania, Kenya and Burundi in 28 213 children in 404 schools. Bayesian geostatistical models were used to interpolate prevalence of these infections across the study area. Interpolated prevalence maps were overlaid to determine areas of co-endemicity. In the Great Lakes region, prevalence was 18.1% for Schistosoma mansoni, 50.0% for hookworm, 6.8% for A. lumbricoides and 6.8% for T. trichiura. Hookworm infection was ubiquitous, whereas S. mansoni, A. lumbricoides and T. trichiura were highly focal. Most areas were endemic (prevalence >or=10%) or hyperendemic (prevalence >or=50%) for one or more STHs, whereas endemic areas for schistosomiasis mansoni were restricted to foci adjacent large perennial water bodies. Because of the ubiquity of hookworm, treatment programmes are required for STH throughout the region but efficient schistosomiasis control should only be targeted at limited high-risk areas. Therefore, integration of schistosomiasis with STH control is only indicated in limited foci in East Africa.

Community-directed delivery of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis in Cameroon

BackgroundSevere side effects following ivermectin treatment of onchocerciasis in areas of co-endemicity with loaisis have been an impediment for the work of the African Programme for Onchocerciasis Control (APOC) in forested regions of several countries. Doxycycline has been shown to be effective in the treatment of onchocerciasis and has the added advantages of killing adult Onchocerca volvulus but neither adult Loa loa nor their microfilariae. This drug therefore offers great potential for the treatment of onchocerciasis in areas of co-endemicity with loiasis. The limitation of use of this drug is the duration of treatment that may pose a potential problem with therapeutic coverage and compliance with treatment. To benefit from the advantages that doxycycline offers in the treatment of onchocerciasis, it will be necessary to establish an effective distribution system that can access remote communities. This study assessed the feasibility of a large-scale distribution of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis using a community-directed approach.MethodsThe study was carried out in 5 health areas co-endemic for Onchocerca volvulus and Loa loa which had no prior experience of the Community Directed Treatment with Ivermectin (CDTI). The community-directed delivery process was introduced using a cascade mechanism from the central health system that passed through the regional health delegation, health district and the health areas. Community health implementers (CHIs) were trained to deliver doxycycline to community members and, under the supervision of the health system, to monitor and document drug intake and side effects.ResultsThe community members adhered massively to the process. Of the 21355 individuals counted, 17519 were eligible for treatment and 12936 were treated with doxycycline; giving a therapeutic coverage of eligible population of 73.8%. Of the 12936 who started the treatment, 97.5% complied by the end of six weeks. No serious side effect was registered during the six week treatment.ConclusionThis study indicates that when empowered the community health implementers can successfully deliver doxycycline for six weeks for the treatment of onchocerciasis in areas of co-endemicity with loiasis. The therapeutic coverage and the compliance treatment rate achieved in this study coupled to the known efficacy of doxycycline on O. volvulus, are indicators that the strategy involving the mass administration of doxycycline can be used to control onchocerciasis in those areas of co-endemicity with loiasis where ivermectin may be contraindicated.

Short communication: Impact of long‐term (14 years) bi‐annual ivermectin treatment on Wuchereria bancrofti microfilaraemia

Ivermectin has been and continues to be extensively used to control onchocerciasis in areas of hyper and mesoendemicity within the African Programme of Onchocerciasis Control. As programmes to eliminate lymphatic filariasis (LF) caused by Wuchereria bancrofti expand, areas of coendemicity with onchocerciasis will be incorporated into LF programmes. This study reports that in villages which were hyperendemic for onchocerciasis after some 14 years of treatment with ivermectin, no W. bancrofti could be detected in a population of 1210 individuals whilst in adjacent villages a prevalence of around 3% was found. Despite the long period of ivermectin treatment Mansonella perstans did not appear to respond to ivermectin in this setting.

Mass ivermectin treatment for Onchocerciasis: Lack of evidence for collateral impact on transmission of Wuchereria bancroftiin areas of co-endemicity

There has long been interest in determining if mass ivermectin administration for onchocerciasis has 'unknowingly' interrupted lymphatic filariasis (LF) transmission where the endemicity of the two diseases' overlaps. We studied 11 communities in central Nigeria entomologically for LF by performing mosquito dissections on Anopheline LF vectors. Six of the communities studied were located within an onchocerciasis treatment zone, and five were located outside of that zone. Communities inside the treatment zone had been offered ivermectin treatment for two-five years, with a mean coverage of 81% of the eligible population (range 58–95%). We found 4.9% of mosquitoes were infected with any larval stage of W. bancrofti in the head or thorax in 362 dissections in the untreated villages compared to 4.7% infected in 549 dissections in the ivermectin treated villages (Mantel-Haenszel ChiSquare 0.02, P = 0.9). We concluded that ivermectin annual therapy for onchocerciasis has not interrupted transmission of Wuchereria bancrofti (the causative agent of LF in Nigeria).

Combined Utilisation of Rapid Assessment Procedures for Loiasis (RAPLOA) and Onchocerciasis (REA) in Rain forest Villages of Cameroon

BackgroundIndividuals with high microfilarial loads of Loa loa are at increased risk of neurologic serious adverse (SAE) events following ivermectin treatment against onchocerciasis. RAPLOA (Rapid Assessment Procedure for loiasis), a newly developed rapid assessment procedure for loiasis that relates the prevalence of key clinical manifestation of loiasis (history of eye worm) to the level of endemicity of the infection (prevalence of high intensity), is a very useful tool to identify areas at potential risk of L. loa post ivermectin treatment encephalopathy. In a perspective of treatment decision making in areas of co-endemicity of loiasis/onchocerciasis, it would be advantageous (both in time and cost savings) for national onchocerciasis control programmes to use RAPLOA and the Rapid epidemiologic assessment for onchocerciasis (REA), in combination in given surveys. Since each of the two rapid assessment tools have their own specificities, the workability of combining the two methods needed to be tested.MethodsWe worked in 10 communities of a forest area presumed co-endemic for loiasis and onchocerciasis in the North-West Province of Cameroon where the mass-treatment with ivermectin had not been carried out. A four-step approach was used and comprised: (i) generating data on the prevalence and intensity of loiasis and onchocerciasis in an area where such information is scarce; (ii) testing the relationship between the L. loa microfilaraemia prevalence and the RAPLOA prevalence, (iii) testing the relationship between the O. volvulus microfiladermia prevalence and the REA prevalence, (iv) testing the workability of combining RAPLOA/REA by study teams in which a single individual can perform the interview for RAPLOA and the nodule palpation for REA.ResultsThe microfilaraemia prevalence of loiasis in communities ranged from 3.6% to 14.3%. 6 (0.61%) individuals had L. loa microfilarial loads above 8000 mf/ml but none of them attained 30,000 mf/ml, the threshold value above which the risk of developing neurologic SAE after ivermectin treatment is very high. None of the communities surveyed had RAPLOA prevalence above 40%. All the communities had microfiladermia prevalence above 60%. The microfiladermia results could be confirmed by the rapid epidemiologic method (nodule palpation), with all the 10 communities having REA prevalence above 20%. For the first time, this study has demonstrated that the two rapid assessment procedures for loiasis and onchocerciasis can be carried out simultaneously by a survey team, in which a single individual can administer the questionnaire for RAPLOA and perform the nodule palpation for REA.ConclusionThis study has: (i) Revealed that the Momo valley of the North West province of Cameroon is hyperendemic for onchocerciasis, but is of lower level of endemicity for L. loa. (ii) Confirmed the previous relationships established between RAPLOA and the L. loa microfilaraemia prevalence in one hand and between the REA and the O. volvulus microfiladermia prevalence in another hand (iii) Shown that RAPLOA and REA could be used simultaneously for the evaluation of loiasis and onchocerciasis endemicity in areas targeted by the African Programme for onchocerciasis Control for community-directed treatment with ivermectin (CDTI).

Comparative study of the effects of artemether and artesunate on juvenile and adult Schistosoma mansoni in experimentally infected mice

Artemether and artesunate, derivatives of the antimalarial artemisinin, also exhibit antischistosomal properties. There is a need to assess comparatively the activity of both compounds against different developmental stages of schistosome parasites. Since artemisinin derivatives will be increasingly used to treat malaria, it is important to study the effects of 7-day monotherapy regimens on schistosome infections. We carried out experiments with mice, infected with juvenile or adult Schistosoma mansoni, and treated with artemether or artesunate at various doses and regimens including those currently used for monotherapy of malaria. Three doses of artemether, at concentrations of 150 or 300 mg/kg, administered to mice with juvenile S. mansoni resulted in worm reductions of 88–97%, which were significantly higher than the 67–77% obtained with artesunate ( P < 0·05). Total concentrations of 600 or 800 mg/kg artemether, administered over 2 or 4 consecutive days to mice with adult S. mansoni, reduced the worm burden significantly by 46–51% ( P < 0·05). The reduction of the worm burden observed with artesunate was considerably lower, 24–33%, and not significant when compared with untreated control mice. Seven-day monotherapy regimens of artemether or artesunate given at different concentrations to mice with adult S. mansoni showed total worm reductions of 53–61% or 34–49%, respectively. We conclude that artemether and artesunate are efficacious antischistosomal agents, with artemether displaying consistently higher activities. Our findings may contribute to the current strategic discussions on the effect and use of artemisinin derivatives against schistosomes when they are used in malaria chemotherapy in areas of co-endemicity of both parasites.