Report on - World Health Organization · Partnerships for malaria control: engaging the formal and...

Report on

10-12 May 2005Geneva, Switzerland

www.who.int/tdr

TDR/SWG/05

Scientific Working Group

TDR/SWG/05

Report on Lymphatic Filariasis

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Partnerships for malaria control: engaging the formal and informal private sectors: a review / commissioned by the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), in collaboration with the Working Group on Financing and Resources of the Roll Back Malaria Partnership, chaired by The World Bank.

“TDR/GEN/06.1”.

1.Malaria - prevention and control. 2.International cooperation. 3.Intersectoral cooperation. I.UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. II.Global Partnership to Roll Back Malaria. Working Group on Financing and Resources. III.World Health Organization.

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Report of the Scientific Working Group meeting on Lymphatic Filariasis

Geneva, 10–12 May, 2005

TDR/SWG/05

Copyright © World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases, 2005All rights reserved.

The use of content from this health information product for all non-commercial education, training and information purposes is encouraged, including translation, quotation and reproduction, in any medium, but the content must not be changed and full acknowledgement of the source must be clearly stated. A copy of any resulting product with such content should be sent to TDR, World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland. TDR is the World Health Organization (WHO) executed UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.

This information product is not for sale. The use of any information or content whatsoever from it for publicity or advertising, or for any commercial or income-generating purpose, is strictly prohibited. No elements of this information product, in part or in whole, may be used to promote any specific individual, entity or product, in any manner whatsoever.



The views expressed in this health information product are those of the authors and do not necessarily reflect those of WHO, including TDR.

WHO, including TDR, and the authors of this health information product make no warranties or representations regarding the content, presentation, appearance, completeness or accuracy in any medium and shall not be held liable for any damages whatsoever as a result of its use or application. WHO, including TDR, reserves the right to make updates and changes without notice and accepts no liability for any errors or omissions in this regard. Any alteration to the original content brought about by display or access through different media is not the responsibility of WHO, including TDR, or the authors.

WHO, including TDR, and the authors accept no responsibility whatsoever for any inaccurate advice or information that is provided by sources reached via linkages or references to this health information product.

Design: Lisa SchwarbLayout by Inís: www.inis.ie

Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05 iii

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Contents

Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Goals, .objectives .and .expected .outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Effect of mass drug administration on lymphatic filariasis transmission . . . . . . . . 5modellinG .lymphatic .filariasis .transmission .and .the .effects .of .mass .druG .administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7tools .for .monitorinG .mass .druG .administration .proGrammes . . . . . . . . . . . . . . . . . . 7social .science .and .factors .influencinG .the .success .of .mass .druG .administration . . 8

Lymphatic filariasis related morbidity and disability . . . . . . . . . . . . . . . . . . . . . . . . 11acute .dermatolymphanGioadenitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11lymphedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11hydrocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12effect .of .mass .druG .administration .on .filarial .morbidity . . . . . . . . . . . . . . . . . . . . 12

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Annex 1. AGENDA: Scientific Working Group on Lymphatic Filariasis . . . . . . . . . . . 17

Annex 2. LIST OF PARTICIPANTS: Scientific Working Group on Lymphatic Filariasis . 21

Annex 3. WORKING PAPER: Towards a strategic plan for research to support the global programme to eliminate lymphatic filariasis . . . . . . . . . . . . . . . . . . . . . . . 27appendix .a .– .lymphatic .filariasis .forum: .prioritized .research .needs . . . . . . . . . . . . 33appendix .b .– .participants .and .WorKinG .Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Annex 4. WORKING PAPERS: Impact of mass drug administration . . . . . . . . . . . . . 434a: .impact .of .mass .druG .administration .on .CULEX-transmitted .lymphatic .filariasis .in .india . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444b: .impact .of .mass .druG .administration .on .AEDES-transmitted .filariasis .in .the .pacific . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524c: .lonG-term .impact .of .mass .druG .administration .on .bancroftian .filariasis .in .dreiKiKir, .papua .neW .Guinea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584d: .impact .of .mass .druG .administration .on .ANOPHELES-transmitted .filariasis .in .africa: .emerGinG .data .from .Ghana .and .mali . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624e: .impact .of .mass .druG .administration .on .infection .and .transmission .of .lymphatic .filariasis .in .eGypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Annex 5. WORKING PAPER: Advances and challenges in predicting the impact of lymphatic filariasis elimination programmes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05iv

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s Annex 6. WORKING PAPER: Diagnostic tools for filariasis elimination programmes . 85appendix .– .primer: .diaGnostic .options .for .monitorinG .the .effects .of .mass .druG .administration .in .proGrammes .for .elimination .of .lymphatic .filariasis . . . . . . . . . 90

Annex 7. WORKING PAPER: Morbidity management in the global programme to eliminate lymphatic filariasis: a review of the scientific literature . . . . . . . . . . 95

Annex 8. WORKING PAPER: Social and behavioural issues of mass drug administration and morbidity management in the programme to eliminate lymphatic filariasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05 1

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Executive summary

WHA resolution 50.29 catalysed the development of the Global Programme to Eliminate Lymphatic Filariasis (GPELF). Implementation of the GPELF over the past five years has been extraordinarily successful. Exponential growth has occurred both in the number of participating countries and in the number of persons receiving combination therapy through mass drug administration (MDA). Data are accumulating that document the impact of the programme, both on the filarial parasite and on intestinal parasites that are also targeted by the drugs. At this early stage of the programme, it is important to critically evaluate the strategies upon which the global programme is based. Is GPELF achieving its objectives? Specifically: •Is there evidence that transmission of lymphatic filariasis (LF) is eliminated by five years of

MDA?•Are disability prevention efforts alleviating the suffering of those with disease?

The Lymphatic Filariasis Scientific Working Group (SWG) was convened by WHO/TDR to review the current state of knowledge regarding the GPELF and to recommend research priorities that could best address the questions facing this global programme. More than 30 experts from around the world participated in the discussions, 10–12 May 2005, in Geneva. Working papers prepared in advance of the meeting summarized the available evidence with respect to the effectiveness of MDA in different epidemiologic settings, the status of the disability prevention programme, and the state of art of diagnostic and modelling tools to support the global programme (see annexes 3–8). These working papers represented the starting point for in-depth discussions at the SWG meeting. In addition, the SWG was able to capitalize on recent meetings at which LF research had been reviewed in detail. At the LF Research Forum held in December 2003, scientists were asked to summarize research needs and opportunities for research on LF. The products of these deliberations were published as a journal supplement.1 Furthermore, in November 2004, WHO sponsored an informal consultation to discuss issues arising out of five years of programme implementation.

Review of the latest evidence for impact of MDA, largely from TDR-funded studies, showed that MDA has resulted in dramatic declines in microfilaraemia everywhere the programme has been implemented. However, the impact on transmission (i.e. on infection in mosquitoes) is variable, ranging from complete interruption of transmission, as in one site in Papua New Guinea where four rounds of treatment were applied,2,3 through a significant reduction in transmission by A. funestus in Ghana and Mali after three rounds of MDA, to an area in Pondicherry, India, where low-level residual transmission remains after nine rounds of treatment4,5 (but in this latter area there is comparatively low compliance by the population). The SWG concluded that in many settings, more than 4–6 years of MDA will be required to

Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/052

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s achieve elimination of transmission. This conclusion has significant implications, both for GPELF operations and for the LF research agenda.

The SWG used all of the available information, including many unpublished studies, to discuss research priorities related to the effect of MDA on LF transmission and to prevention and treatment of LF-related disability. In plenary sessions, the SWG tried to synthesize the recommendations emanating from different working groups into a single list of overarching priorities. It was recognized that the research needs of GPELF at this early stage of programme implementation are great and that a strong research effort will increase the likelihood of GPELF success. At the same time, limitations in human and financial resources must be considered, so the research agenda must be prioritized to focus on issues of greatest importance to GPELF. After a great deal of deliberation, priority research needs were defined by the SWG. These include:•Fundamental socio-behavioural research on reasons for compliance and noncompliance, as

well as studies on how to augment compliance.•Development of the evidence base and tools for stopping MDA for major vector/parasite

complexes.•Establishment of the evidence base for implementing and scaling up disability prevention

programmes.•Research to improve implementation of MDA in urban settings and where opportunities exist

for integration.


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Background

Research support from TDR and other funding agencies played a critical role in developing the tools that spawned the Global Programme to Eliminate Lymphatic Filariasis (GPELF). Key studies sponsored by TDR in the late 1980s and early 1990s established the safety and efficacy of single-dose treatment with diethylcarbamazine (DEC) and ivermectin and led to field trials that demonstrated the utility of annual treatment for filariasis control at the community level.6 With the advent of sensitive and specific antigen tests for Wuchereria bancrofti, mapping the distribution of bancroftian filariasis became operationally feasible.7 It was these two advances that gave rise to the idea that elimination of lymphatic filariasis was attainable as a public health goal. Following on the heels of the World Health Assembly resolution (50.29) that called for elimination of LF as a public health programme, three additional events catalysed an exponential increase in the number of persons treated for LF: 1) the donation of albendazole by SmithKlineBeecham (now GlaxoSmithKline); 2) the donation of ivermectin by Merck; and 3) a US$ 20 million grant from the Bill & Melinda Gates Foundation for LF elimination.

From the beginning of the GPELF, it has been clear that the success of this programme hinges on the ability of country programmes to adapt operations to local circumstances, i.e. on “learning by doing”. To accomplish this, it is critical to have an active and engaged research community, and TDR and partners have been responsible for stimulating operational research and disseminating the results of this research to LF programme managers. As a prelude to the current meeting of the SWG, two earlier meetings established a framework for relating filariasis research to the needs of GPELF. The first meeting addressed the research needs of the global programme and focused on four research areas: 1) tools and measurements of programme success; 2) efforts to enhance programme effectiveness; 3) improving clinical management for persons with LF disease; and 4) protecting the LF programme by monitoring the development of drug resistance and developing new drugs. Specific recommendations from this meeting were published as a journal supplement.1

The second meeting, in November 2004, considered issues arising out of five years of programme implementation, and recommended that TDR convene a scientific meeting of “tool-makers”, modellers, epidemiologists, entomologists, and sampling statisticians, to define and develop strategies and protocols for assessing whether the “transmission threshold” has been reached in different settings, to assess transmission using different “tools”, and to carry out prospective studies of tool performance. These recommendations set the stage for the current meeting of the SWG.


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s Goals, .objectives .and .expected .outcomes .

The goal of the SWG was to:•Recommend research priorities for addressing the questions facing GPELF in the next five

years.

The objectives of the SWG were to: •Review the current state of knowledge regarding the global programme (GPELF).•Identify the major research priorities for lymphatic filariasis. •Develop a strategic plan for lymphatic filariasis research.


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sExperience with mass treatment to interrupt LF is building rapidly as the programme grows. In reviewing the available evidence, both published and unpublished, the SWG focused on multiyear (three years or more of MDA) studies that docu-mented changes in infection in both humans and vectors (see Table 1 for key studies). In most set-tings, MDA has led to significant reductions in key measures of LF infection (as determined by microfilaraemia and antigenaemia) and trans-mission (as assessed by antifilarial antibody and vector infection); however, interruption of trans-mission has only been observed in settings with favourable combinations of programmatic and epidemiologic factors. For example, despite high levels of initial microfilaria prevalence, four years of MDA in Papua New Guinea appears to have eliminated transmission based on the absence of microfilaraemia recrudescence and of new infections in children several years after MDA ceased.2,3 The ease with which transmis-sion has been interrupted in these villages may reflect facilitation – the process by which trans-mission by Anopheles mosquitoes becomes less efficient as parasite numbers decline. Success has also been observed in Egypt, where Culex is the vector. Five years of high MDA coverage with DEC and albendazole has decreased microfila-raemia and antigenaemia and, in addition, dra-matic declines in antibody responses to Bm14, a marker of filarial exposure, have been observed among sentinel populations.8 These data suggest that new infections are not being observed fol-lowing MDA.

In other settings, there is evidence of ongoing transmission even after five or more years of MDA. In one of the best studied examples, after 8–10 annual cycles of MDA with ivermectin or DEC alone in Pondicherry, India, microfila-raemia prevalence remained above the thresh-old (1%) established by the global programme for initiating MDA.4,5 Similarly, five years of

DEC and albendazole in Leogane, Haiti, failed to interrupt transmission of LF or reduce micro-filaria prevalence below 1% in two of four sen-tinel sites.9 In both programmes, compliance issues were considered to represent potential explanations for continued transmission.10,11 Vec-tor-specific issues may also play a role in the per-sistence of LF. In the South Pacific where LF is transmitted by Aedes mosquitoes, historical evi-dence indicates that a microfilaria prevalence of less than 1% was reached in Samoa, only to see a rebound in microfilaria prevalence several years later.12

Based on this work, the ease with which trans-mission can be interrupted is related to: 1) MDA coverage; 2) initial microfilaria prevalence; and 3) the parasite vector. In some settings with high treatment compliance and other favourable con-ditions (e.g. low baseline infection rates, ineffi-cient vectors), 4–5 rounds of MDA can reduce microfilaria prevalence to near zero. However, in other areas, MDA alone may not be suffi-cient to eliminate LF due to poor compliance and other factors. This raises many research ques-tions about how to improve the impact of MDA. Potential options include: improving treatment coverage through appropriate social mobiliza-tion; increasing the frequency of MDA; and sup-plementing MDA with adjunct measures such as vector control, insecticide-treated bed nets (ITN), and/or DEC-salt.

In sub-Saharan Africa, GPELF is faced with another critical issue. Serious adverse events (SAE), including neurologic changes and coma, have been linked temporally with mass treat-ment with ivermectin for onchocerciasis in Loa-endemic areas.13 As a result, mass treatment for lymphatic filariasis (LF) in Loa-endemic areas has been halted. This has prevented implemen-tation of LF elimination programmes in several African countries. New approaches to treat LF in

Effect of mass drug administration on lymphatic filariasis transmission


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Tabl

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ass .drug

.adm

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and .its .im

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ansm

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ntigen

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. .larva

l .stage

.3


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scommunities with Loa loa infection are urgently needed.

Priority research needs identified by the Scientific Working Group:

Field studies and cost-efficacy analyses of additional measures (such as vector control, ITN, and/or DEC-salt) in different vector–par-asite situations. Strategies for eliminating LF in areas that are co-endemic for loiasis.

modellinG .lymphatic .filariasis .transmission .and .the .effects .of .mass .druG .administration

Mathematical models provide useful tools to pre-dict programme trends and, in principle, could facilitate decision-making by programme man-agers. Two models have been developed – Epi-fil and Lymfasim; when tested against data, they give comparable predictions.14,15 The mod-els for Culex quinquefasciatus have been stud-ied most extensively. This work has generated findings that are important for all ongoing pro-grammes; specifically, the number of rounds of MDA required for elimination is likely to exceed 4–6, the number used as the basis of programme implementation by many countries. As noted above, predictions about the intensity of control efforts (with respect to coverage and duration) strongly depend on the efficacy of the drugs and the pre-control prevalence of microfilaria. New information is needed to refine these models, and efforts to validate them should be undertaken. Such a process would be facilitated by creating a common database for MDA programmes that includes both research and national programme monitoring data.

The overall transmission dynamics strongly

•

•

depend on the dynamics at both interfaces, i.e. transmission from man to mosquito and from mosquito to man. A proper calibration of the model(s) requires data from mosquito feeding experiments. Therefore mosquito-feeding studies are needed for major vectors where existing data are insufficient. It is important to generate these data to improve the utility of the models for pre-dicting programme outcomes.

Refining and validating existing models is likely to be an iterative process. Throughout these efforts, there is a critical need to evaluate the utility of the models as tools for decision-mak-ing. Therefore, available models should be used to make predictions on several important issues:

Definition of endpoints for stopping mass treat-ment based on results from available diagnostic tests (see below) for different vector/parasite combinations. Definition of optimal control strategies, i.e. optimal coverage for defined endpoints and pre-control prevalence rates, and definition of whether the cost-effectiveness of control strat-egies can be improved by changing the fre-quency of treatment, the choice of drugs, or implementing vector control in the early or late phases of a programme. Identification of cost-effective strategies for monitoring during and after control.Analysis of the efficacy of drug combinations on microfilaria and adult worms, especially at low levels of infection intensity.

tools .for .monitorinG .mass .druG .administration .proGrammes

A number of excellent tools have been devel-oped in recent years for use in LF programmes. Briefly, these include tests for detecting circulat-ing filarial antigen (bancroftian filariasis), assays

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s for IgG4 antibodies to recombinant filarial anti-gens (indicating infection or exposure), and methods for detecting filarial DNA in mosqui-toes. These new tools complement the traditional diagnostic methods of detecting microfilaria and dissecting mosquitoes. However, there is no con-sensus on the comparative value of the new tools for documenting the endpoints for MDA pro-grammes (i.e. when MDA can safely be discon-tinued with minimal risk of recrudescence).

The SWG endorsed one of the recommenda-tions in the Essential Tools and Diagnostics sec-tion of the LF Research Forum Report.1 Briefly, this calls for studies to “define the comparative accuracy of available diagnostic strategies for monitoring the progress of LF elimination pro-grammes and for deciding both when to stop MDA and how to initiate surveillance to detect potential recrudescence”. Such studies should include “longitudinal studies using all diagnostic tools concurrently in both high- and low- prev-alence areas where LF elimination programmes are under way”. The studies should be closely linked to research scientists with interest and expertise in mathematical modelling for human filariasis.

There is also no consensus on sampling tech-niques for monitoring LF programmes or for post-MDA surveillance. Therefore, the group also endorsed the recommendation from the LF Research Forum to “validate sampling strategies for testing both vector and human populations for LF infection or exposure to infection”.

Improved tools (single-dose combination therapy and antigen detection tests) were important for the conceptualization and initiation of GPELF. Additional research is required to improve the existing tools and to develop new tools to sup-port GPELF.

Priority research needs identified by the Scientific Working Group:

improve .and .test .existing .tools .Use existing tools to test guidelines for when to stop MDA.Validate antibody testing as a monitoring and evaluation tool for use by both brugian and bancroftian filariasis programmes. Further streamline filarial DNA assays and antibody tests to make them more user-friendly and accessible to endemic country laboratories.

develop .new .tools .Develop a sensitive W. bancrofti antibody assay for use in sub-Saharan Africa; there should be no cross-reactivity with sera from patients with loiasis or onchocerciasis. Develop a molecular assay for the specific detection of filarial infective larvae in mosqui-toes. Develop and validate a new rapid-format filar-ial antigen detection test.

social .science .and .factors .influencinG .the .success .of .mass .druG .administration

Models predict and experience confirms that population coverage is a key determinant of the success of LF programmes. Use of the term ‘cov-erage’ implies that each person who receives the drugs actually takes them (i.e. they are compli-ant), but in several countries, most notably India, a gap between coverage and compliance has been observed.16 Intensified social mobilization can narrow this gap, at least to a degree; however, even in programmes where treatment is observed, compliance is not uniform. Unpublished surveys conducted after 3–5 rounds of MDA in Haiti and elsewhere have identified persons who are sys-tematically noncompliant.10,11 The contribution

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sof these persons to transmission is unknown, but systematic noncompliance may represent a potential threat to LF elimination. Despite the obvious importance of this issue, rigorous studies of compliance that are based on sound social sci-ence have not been conducted, perhaps because social scientists have been under-represented in the community of LF researchers. In order to understand why some people do not take the drugs during MDA, it is important first to under-stand why other people do take them. Systematic studies are needed to identify the perceived ben-efits of MDA from the community perspective. From this vantage point, it will be possible to study noncompliance and to define the most cost-effective strategies for social mobilization (e.g. communication for behavioural impact [COMBI] or others).

Other key operational research issues that have not been addressed have been identified by pro-gramme managers. Most LF programmes have been initiated, with great success, in rural com-munities, but a few programmes have extended into urban environments, in part because of con-cerns about the suitability of the MDA strategy for urban areas. Research is needed to determine whether new social mobilization and implemen-tation strategies are in fact needed in urban areas. Similarly, the extent to which population migra-tion impacts on MDA coverage, interruption of transmission and morbidity management is not clear. What are the social and epidemiological determinants of migration and how should these be addressed at the programme level?

Health system strengthening is a prerequisite to achieving health related goals; stronger health systems are key to achieving improved health outcomes. The evidence base to support efforts to strengthen health systems is very weak however, particularly when it comes to the effects that dis-ease-specific programme may potentially have on

these systems. The concerns are human resource shortages, constraints to scaling up health serv-ices, health financing, equity, human rights for disabled LF patients, to list but a few. Are MDA campaigns the best strategy for the health sys-tem? Research is needed to develop health sys-tem assessment tools and to measure the impact of the LF elimination programmes on health sys-tems. In addition, as ministries of health move increasingly towards integration of programmes for neglected tropical diseases, what are the advantages and disadvantages of integration of LF programmes with other disease specific pro-grammes?

The Scientific Working Group identified the following priorities for research:

Systematic studies to identify cross-cutting fac-tors affecting compliance and noncompliance from a comparative perspective. Determination of the best strategies for MDA and morbidity management in urban and con-flict settings.Description of the effects/impact of LF elimi-nation programmes on national health systems.

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sManagement and prevention of LF-related mor-bidity is an important component of the global programme. SWG discussions focused on four major areas: acute dermatolymphangioadenitis (“acute attacks”), lymphedema, hydrocele, and the impact of MDA on filarial morbidity.

acute .dermatolymphanGio-adenitis .

Research during the last decade has confirmed the importance of acute dermatolymphangioaden-itis (ADLA) as a public health problem in filaria-sis endemic areas. Although some debate about the pathogenesis of ADLA continues, the central role of bacteria is generally accepted.17 Dramatic decreases in ADLA incidence have been noted following implementation of simple programmes of hygiene and skin care.18,19,20,21 Uncertainties remain about the role of inflammatory mediators or other triggers of ADLA, environmental risks factors, and best treatment practices.

lymphedema .

The current lymphedema management strat-egies of the GPELF are based on the central role of bacterial ADLA as a trigger for lymphe-dema progression. Simple intervention packages have been developed and are being used in many countries, although optimization of the compo-nents of these packages would benefit from fur-ther research. These interventions have resulted in dramatic reductions in ADLA rates in sev-eral studies. The key challenge now for GPELF in lymphedema management is how best to scale up, monitor, and evaluate programmes at the national level. Morbidity management pro-grammes are generally in pilot project phase, with limited comparability among them. At least four different strategies are being employed or considered in different settings:

Dissemination of information and reliance on patient self-motivation through the distribution of patient education booklets during MDA. This strategy has not been evaluated for effec-tiveness or impact because of funding limita-tions. Community-based care supervised by non-governmental organizations (NGOs), local health centres, or home-based disability pre-vention programmes. This strategy emphasizes care by patients, with support and assistance from family members and community health workers. This strategy appears to work well in areas where there is a low prevalence of lymphedema.Outpatient clinics open to lymphedema patients. This strategy depends on patient self-referral and allows for more thorough assess-ment of lymphedema severity and co-morbidity by doctors or nurses. In principle, such an approach permits collection of pre-intervention baseline data as well as follow-up assessments.Integrated approaches to general hygiene and health education for entire communities. This strategy attempts to encompass health edu-cation messages for control of other diseases such as trachoma, diarrhoeal diseases, soil-transmitted helminthiasis, and schistosomiasis.

These four strategies should be evaluated in dif-ferent settings to determine the feasibility and efficiency of implementation, the degree of patient compliance, the factors that influence compliance, and the impact and cost of the inter-ventions. In countries with over-stretched health services, it also may be useful to evaluate new strategies for delivering care and to assess the potential of alternate caregivers and support groups to improve access of patients to appropri-ate treatment. Finally, it is important to assess the impact of interventions in terms of quality of life of affected persons.

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s hydrocele .

Of the clinical manifestations targeted by the disability alleviation component of the GPELF, hydrocele has been the focus of the least atten-tion. Basic information is lacking on the effec-tiveness, complications, and risk of recurrence following hydrocele surgery in filariasis endemic areas. Similarly, there is little understanding of the social costs of hydrocele. The group iden-tified two strategies that should be assessed to improve morbidity due to hydrocele:

Short intensive surgical programmes several times a year, with hands-on training of local doctors by national specialists.Routine surgeries through local hospitals throughout the year.

These strategies should be evaluated to assess surgical outcomes (including post-surgical infec-tions, recurrence, and quality of life), the cost of surgery, and secondary benefits, e.g. improved compliance with MDA.

effect .of .mass .druG .administration .on .filarial .morbidity .

Data on the impact of MDA on filarial morbidity are inconsistent (Table 2). Several studies report reductions in adenolymphangitis, lymphedema, and/or hydrocele following MDA, but others report no such association. An overarching prob-lem in interpreting these data is the lack of stand-ardized case definitions. Assessing the public health impact of mass treatment with antifilarial drugs is an important issue for programme advo-cacy and for morbidity control strategies.

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The Scientific Working Group identified the following priorities for research:

Standardization of definitions (e.g. for ADLA, lymphedema, and hydrocele) and criteria for staging disease severity.Determination of how best to scale up morbid-ity management programmes.Definition of the impact of MDA on morbidity.

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s* . . decrease .from .5% .to .4% .prevalence** . placebo-controlled*** .2 .of .8 .hydroceles .resolved+ . decrease .noted .(not .necessarily .statistically .significant)– . no .decrease .noted .(or .if .noted, .not .considered .significant .by .authors) . . not .evaluated, .or .extremely .small .numbersdec .diethylcarbamazineiv . ivermectinalb . albendazole

Table 2 summary .of .studies .assessing .the .effect .of .antifilarial .drug .treatment .on .the .clinical .manifestations .of .acute .attacks .or .lymphangitis, .hydrocele, .and .lymphedema .

Source Acuteattacks

Hydrocele Lymph-edema

Drug Delivery Follow-up interval

bockarie . + . .+ .* dec, .dec+iv mass 5 .years

partono + . + dec . mass 11 .years

march + + + dec .monthly mass 10 .years

fan . - - dec mass .(salt) 16–19 .years

bernhard . - . dec mass, .plusclinical .trial .**

1 .year

meyrowitch . + + dec mass, .salt 2 .years

. - . mass, .salt 4 .years

beye - - - dec mass, .selective 16 .months

simonsen . . . . . . .- .*** . dec mass 1 .year

ciferri + . - - dec mass 2 .years

malecela, .macKenzie(pers . .communication)

+ . + iv .+ .alb mda 1–2 .years

pani . . - dec . clinical .trial 1 .year

Kerry . . + dec clinical .trial 1–3 .months

moore . . + dec case .report 1 .week–7 .months


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Conclusions

In order to execute the ambitious research agenda defined by the SWG, additional resources will be needed, both human and financial. Human resources must be developed at the country level through research capacity strengthening activi-ties that complement parallel efforts to address other neglected tropical diseases. With the severe constraints on financial resources available to support LF research, renewed efforts to advo-cate for research on tropical diseases are needed. Also, greater coordination of research activi-ties would help to diversify the research portfo-lio and increase the contribution of LF research to programmatic goals. Ultimately, the success of GPELF as a disease elimination programme requires a strong and engaged research commu-nity. Priorities identified by the SWG establish a framework that will help guarantee the success of GPELF.


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References

1 Towards a strategic plan for research to sup-port the global program to eliminate lym-phatic filariasis. American Journal of Tropical Medicine and Hygiene, 2004, 71:Suppl.

2 Bockarie MJ et al. Mass treatment to elim-inate filariasis in Papua New Guinea. New England Medical Journal, 2002, 347:1841–1848.

3 Kazura J et al. Unpublished observations. 4 Ramaiah KD et al. The effect of six rounds

of single dose mass treatment with diethyl-carbamazine or ivermectin on Wuchere-ria bancrofti infection and its implication for lymphatic filariasis elimination. Tropi-cal Medicine and International Health, 2002, 7:767–774.

5 Ramaiah KD et al. The impact of six rounds of single dose mass administration of diethyl-carbamazine or ivermectin on the trans-mission of Wuchereria bancrofti by Culex quinquefasciatus and its implications for lym-phatic filariasis elimination programmes. Tropical Medicine and International Health, 2003, 8:1082–1092.

6 Reviewed in: Horton et al. An analysis of the safety of the single dose, two drug regimens used in programmes to eliminate lymphatic filariasis. Parasitology, 2000, 121 (Suppl): S147–160.

7 Weil GJ, Lammie PJ, Weiss N. The ICT Filariasis Test: A rapid format antigen test for diagnosis of bancroftian filariasis. Parasitol-ogy Today, 1997, 13:401–404.

8 Weil GJ, Ramzy R. Unpublished observations.

9 Beau de Rochars et al. Unpublished observations.

10 Vanamail P et al. Patterns of community compliance with spaced, single-dose, mass administrations of diethylcarbamazine or ivermectin, for the elimination of lymphatic filariasis from rural areas of southern India. Annals of Tropical Medicine and Parasitol-ogy, 2005, 99:237–242.

11 Mathieu E et al. Trends in participation in three consecutive mass drug administrations in Leogane, Haiti (in press).

12 Reviewed in: Burkot T, Ichimori K. The PacELF programme: will mass drug admin-istration be enough? Trends in Parasitology, 2002, 18:109–115.

13 Reviewed in: Twum-Danso NA. Loa loa encephalopathy temporally related to iver-mectin administration reported form onchocerciasis mass treatment programs from 1989 to 2001: implications for the future. Filaria Journal, 2003, 2 Suppl 1:S7.

14 Chan MS et al. Epifil: a dynamic model of infection and disease in lymphatic filariasis. American Journal of Tropical Medicine and Hygiene, 1998, 59:606–614.

15 Stolk WA et al. Prospects for elimination of bancroftian filariasis by mass drug treat-ment in Pondicherry, India: a simulation study. Journal of Infectious Diseases, 2003, 188:1371–1381.

16 Ramaiah KD et al. A programme to elimi-nate lymphatic filariasis in Tamil Nadu state, India: compliance with annual single-dose DEC mass treatment and some related opera-tional aspects. Tropical Medicine and Interna-tional Health, 2000, 12:842–847.

17 Dreyer G et al. Pathogenesis of lymphatic disease in bancroftian filariasis: a clini-cal perspective. Parasitology Today, 2000, 16:544–548.

18 Shenoy RK. Management of disability in lymphatic filariasis – an update. Journal of Communicable Diseases, 2002, 34:1–14.

19 Suma TK, Shenoy RK, Kumaraswami V. Efficacy and sustainability of a footcare programme in preventing acute attacks of adenolymphangitis in Brugian filariasis. Trop-ical Medicine and International Health, 2002, 7:763–766.

20 Kerketta AS, et al. A randomized clinical trial to compare the efficacy of three treatment regimens along with footcare in the morbidity management of filarial lymphoedema. Tropi-cal Medicine and International Health, 2005, 10:698–705.

21 Addiss et al. Unpublished observations.



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17Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05

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Annex 1 AGENDA: Scientific Working Group on Lymphatic Filariasis

18 Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05

Day 1, Tuesday 10 May 2005

Time Item Speaker

09 .00–09:30 Welcome .addressintroduction .of .participants

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dr .a . .asamoa-baah, .assistant .director-General, .communicable .diseases .(adG/cds)dr .r . .ridley, .director .unicef/undp/World .bank/Who .special .programme .for .research .and .training .in .tropical .diseases .(tdr)dr .h . .endo, .director .strategy .development .and .monitoring .for .eradication .and .elimination .(cpe)

09:30–09:45 meeting .objectives .and .process• dr .j .h .f . .remme, .tdr

09:45–10:15 Global .lymphatic .filariasis .(lf) .elimination .programme: .progress .and .challenges• dr .G . .biswas, .cpe

10:15–10:30 current .strategic .emphases .for .lf .research .in .tdr• dr .j .h .f . .remme

10 .30–11 .00 Coffee break

11:00–11:30 .research .needs .of .national .lf .elimination .programmes• national .programme .managers: .drs . .Gyapong, .hernandez, .joshi, .Kyelem, .milord

11 .30–12 .00 .needs .and .opportunities .for .research .on .lymphatic .filaraisis: .summary .of .the .lf .research .forum

• dr .e . .ottesen

12:00–12 .30 impact .of .mass .drug .administration .(mda) .on .lf .transmission: .Culex-transmitted, .india

• dr .K .p . .ramaiah/dr .r .rajendran

12 .30–14 .00 Lunch break

14:00–14 .20 .impact .of .mda .on .lf .transmission: .Aedes-transmitted, .pacific• dr . .r . .speare

14 .20–14 .40 impact .of .mda .on .lf .transmission: .Anopheles-transmitted, .papua .new .Guinea• dr .j . .Kazura

15 .00–15 .20 .impact .of .mda .on .lf .transmission: .Anopheles-transmitted, .africa• 1 . .prof .s .f . .traore2 . .dr .j . .Gyapong

15:20–15:40 impact .of .mda .on .lf .transmission, .egypt• dr . .ramzy


16 .00–16 .20 modelling .lf .elimination .strategies• dr .W . .stolk

16 .20–16 .40 tools .for .measuring .impact .of .filariasis .control• prof .G . .Weil

16 .40–17 .00 .morbidity .management: .current .status .and .research .needs• dr .d .G . .addis

17 .00–17 .20 .social .and .behavioural .aspects .of .mda .and .morbidity .management• dr .b .v . .babu

Day 2, Wednesday 11 May

08 .30–10 .30 Working .groups .(WG)•


11 .00–12 .30 Working .groups: .continued•


14 .00–15:00 Working .groups: .continued•


15 .30–16 .10 plenary .report: .Working .Group .i• WG .rapporteur .(presentation .and .discussion)

16 .10–16 .50 plenary .report: .Working .Group .ii• WG .rapporteur .(presentation .and .discussion)

16 .50–17 .30 plenary .report: .Working .Group .iii• WG .rapporteur .(presentation .and .discussion)

1�Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05

Day 3, Thursday 12 May

08 .30–10 .30 .small .group .to .review .the .overall .prioritization, .harmonize .the .recommendations, .and .outline .a .strategic .plan

• small .group: .sWG .chair .and .plenary .rapporteurs, .Who .secretariat

Working .groups .to .finalize .reports• WGs


11 .00–12 .30 small .group .report .to .the .plenary .meeting .on .overall .priorities .and .draft .strategic .planplenary .rapporteurs .to .finalize .the .sWG .draft .conclusions .and .recommendations

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sWG .chairperson/rapporteurs


14 .00–15 .30 plenary .discussion .and .amendment .of .conclusions, .recommendations .and .draft .strategic .plan

• all .


16 .00–16 .30 continuation .of .discussion .on .conclusions, .recommendations .and .draft .strategic .planany .other .business

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all

16 .30–17 .00 concluding .remarksclosure .of .the .meeting

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chairperson, .director .tdr

1 .unable .to .attend2 .shift .in .presentation .period .between .drs .seaman .(section .ii) .and .Ganguly .(section .iii)3 .tdr .definition .of .category .i .disease: .epidemiological .situation .getting .worse, .and .incidence .of .infection .and .disease .increasing .



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Annex 2 LIST OF PARTICIPANTS: Scientific Working Group on Lymphatic Filariasis


Dr David G. AddissCenters for Disease Control & PreventionDivision of Parasitic DiseasesMS F-22, Bldg 1024770 Buford Highway NortheastAtlanta, GA 30341-3724USATel: 1 404 488 7750 or 4240Fax: 1 404 488 7794 or 770 488 7761Email: [email protected]

Dr Rama BaruCentre for Social Medicine and Community HealthSchool of Social SciencesJawaharlal Nehru UniversityNew Delhi 110067INDIATel: 91 11 267 04489Email: [email protected]

Dr Bontha V. BabuRegional Medical Research CentreIndian Council of Medical ResearchSE Rly Project ComplexBhubaneshwar, Orissa 751023INDIATel: 91 674 230 3002Fax: 91 674 230 1352Email: [email protected]

Dr Daniel Adjei BoakyeUniversity of Ghana, Noguchi Memorial Institute for Medical Research

P.O. Box LG 581Accra, Legon, GHANATel: 233 21 500374/501178/24Fax: 233 21 502 182Email: [email protected]

Dr Hans-Peter DuerrDepartment of Medical BiometryUniversity of TübingenWestbahnhofstr. 5572070 TübingenGERMANYEmail: [email protected]

Dr John Owusu GyapongMinistry of HealthHealth Research UnitGhana Health ServiceP.O. Box GP-184, Adabraka PolyclinicAccra, GHANATel: 233 21 67 93 23 or 68 11 09Fax: 233 21 22 67 39Email: [email protected]

Dr Margaret GyapongMinistry of HealthHealth Research UnitP.O. Box 184Accra, GHANATel: 233 21 230220Fax: 233 21 226739Email: [email protected]

Dr Leda M. HernandezDepartment of HealthCommunicable Disease Control ServiceSan Lazaro CompoundP.O. Box 612, Rizal AvenueSanta Cruz, ManilaTHE PHILIPPINESTel: 63 2 711 6804 or 6808 or 6699Fax: 63 2 711 6808Email: [email protected]

Professor Achim HoeraufUniversity of BonnInstitute of Medical Parasitology Faculty of Medicine Sigmund Freud Str. 2553105 Bonn, GERMANYTel: +49 228 287-5673Fax: +49 228 287-9573Email: [email protected]

*Dr P.L. JoshiDirector, National Vector Borne Disease Control Programme

22 Shamnath MargDelhi 110 054, INDIATel: +91 (11) 2391 8576Fax: +91 (11) 2396 8329Email: [email protected]

* unable to attend


Professor James W. KazuraCase Western Reserve UniversitySchool of Medicine, W137Division of Geographic Medicine10900 Euclid AvenueCleveland OH 44106-4983USATel: 1 216 368 4810 or 4818Fax: 1 216 368 4825Email: [email protected]

Dr Dominique KyelemProgramme Manager LF01 BP 2935Ouagadougou 01BURKINA FASOTel: 226 50 30 87 90Fax: 226 50 50 32 63 35Email: [email protected]

Dr Patrick J. LammieCenters for Disease Control & PreventionDivision of Parasitic DiseasesP.O. Box F13, 4770 Buford Highway NEAtlanta, GA 30341-3724USATel: 1 (770) 488 4054 /7750/4240Email: [email protected]

Dr Sabine MandUniversity of BonnInstitute of Medical ParasitologyFaculty of MedicineSigmund Freud Str. 2553105 BonnGERMANYTel: 49 228 287 1387Fax: 49 228 287 9573Email: [email protected]

Dr Edwin MichaelDepartment of Infectious Disease Epidemiology, Division of Primary Care & Population Health Science,

Faculty of Medicine, St Mary’s Campus, London SW7 2AZ, UKTel: 020 7595 3946Email: [email protected]

Dr Marie-Denise MilordDirectrice de la Section RechercheHopital Ste CroixCoordinator, PELF HaitiDebussy 32, Port-au-PrinceHAITITel: +509 (-245) -4276;509 554 1287Email: [email protected]

Dr Eric A. OttesenEmory UniversityEmory Lymphatic Filariasis Support Center, Dept. of International HealthRobert W. Woodruff Health Sciences1518 Clifton Road, Atlanta GA 30322, USAEmail: [email protected]

Dr R. RajendranCentre for Research in Medical Entomology, 127 Periyar Nagar, Cuddalore Main RdVriddhachalam, Tamil Nadu 606001INDIATel: 91 452 253 0746Fax: 91 452 253 0660Email: [email protected]

Dr Kapa Dasaradha RamaiahVector Control Research CentreMedical Complex, Indira NagarPondicherry, Tamil Nadu 605006INDIATel: 91 413 272 396 or 397Fax: 91 413 272 041Email: [email protected]; [email protected]

Professor C.P. RamachandranGlobal Programme for the Elimination of Lymphatic Filariasis

c/o 8A-4-4 Belvedere, 1/63 off Jalan Tunku, Bukit, Tunku50 480 Kuala Lumpur, MALAYSIATel: 603 2698 7275Fax: 603 2698 6152Email: [email protected]

Dr Reda RamzyAin Shams UniversityResearch and Training Center on Vectors of DiseasesAbassia SquareCairo 11566, EGYPTTel/Fax: 20 2 683 9622Email: [email protected]


Dr David ReeveJames Cook UniversitySchool of Public Health, Tropical Medicine & Rehabilitation SciencesTownsville, Queensland 4810AUSTRALIATel: 617 4781 6175Fax: 617 4781 5254Email: [email protected]

*Dr. Shampa NagNational Vector Borne Disease Control Programme 22 Shamnath MargDelhi, INDIAFax No.: 91-11-23968329Mobile: 91-9811757524E-mail: [email protected]

*Dr. S.C. SharmaDepartment of MedicineRam Manohar Lohia HospitalNew Delhi, INDIAMobile: 91-9811629462Fax: 91-11-23365081Email: [email protected]

Dr Paul Erik SimonsenDanish Bilharziasis LaboratoryJaegersborg Alle 1DDK-2920 CharlottenlundDENMARKTel: 45 77 32 77 32Fax: 45 77 32 77 33Email: [email protected]

Dr Wilma StolkErasmus University RotterdamDepartment of Public HealthP.O. Box 17383000 DR RotterdamTHE NETHERLANDSTel: 31 10 408 7985 or 7714Fax: 31 10 408 9449Email: [email protected]

Dr M. SudomoMinistry of Health, National Inst. of Health Research and Development

Health Ecology Research CentreP.O. Box 226, Jl Percetaken Negara 1JakartaINDONESIAEmail: [email protected]

Professeur Sekou Fantamady TraoreMalaria Research and Training CenterDepartment of Parasitic DiseasesB.P. 1805, BamakoMALITel: 223 22 52 77/75 33 94Fax: 223 22 49 87Email: [email protected]

Professor Gary J. WeilWashington UniversitySchool of MedicineInfectious Disease DivisionCampus Mailbox Box 8051660 S. Euclid AvenueSt Louis MO 63110USATel: 314 454 7782Fax: 314 454 5066 or 5293Email: [email protected]

Professor Steven A. WilliamsSmith College, Clark Science CenterFilarial Genome Project Resource Center, Dept of Biological SciencesNorthampton, MA 01063, USATel: 413 585 3826 or 3857Fax: 413 585 3786Email: [email protected]

* unable to attend


Dr Mark Bradley, Manager Scientific SupportLymphatic Filariasis, Global Community Partnerships,GlaxoSmithKline plc, 980 Great West Road, Brentford,Middlesex, TW8 9GS, UK Tel: 44 (0)208 047 [email protected]

*Dr Bernhard Liese, Onchocerciasis Coordination Unit, African Region, World Bank,

Room J8-009, MSN J8-800, Washington DC 20433, USATel: 1-202-458-4491Fax: 1-202-522-3157Fax: [email protected]

*Professor David H. Molyneux, Liverpool School of Tropical Medicine, Dept. for International

Development, Lymphatic Filariasis Programme,Pembroke Place, Liverpool L3 5QA, UKTel: 44 1 51 708 9393, ext. 2261Fax: 44 1 51 707 0155Email: [email protected]

Dr Nana A.Y. Twum Danso, MectizanR Donation Program (MDP), 750 Commerce Drive,

Suite 400, Decatur, Georgia 30030, USATel: 1 404 371 1460Fax: 1 404 371 1138Email: [email protected]

Observers

WHO Secretariat

Dr Robert Ridley, Director UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)

Dr Gautam Biswas, Medical Officer (filariasis), Strategy Development and Monitoring for Communicable Disease Eradication and Elimination (CDS/CPE/CEE)

Dr Hans Remme, Coordinator, Science Strategy & Knowledge (TDR/SSK)

Dr Nevio Zagaria, Coordinator CDS/CPE/CEE Dr Jane Kayondo Kengeya, Coordinator, Implementation, Research and Methods (TDR/IRM)

Dr Janis Lazdins, Acting Coordinator, Product Development & Evaluation (TDR/PDE)

Dr Ayo Oduola, Coordinator, Strategic & Discovery Research (TDR/SDR)

Dr Fabio Zicker, Coordinator, Research Capability Strengthening (TDR/RCS)

Dr Johannes Sommerfeld, TDR/SDRDr Francesco Rio, CDS/CPE/CEEDr Pierre Brantus, CDS/CPE/CEEDr Sergio Yactayo, CDS/CPE/CEEDr Mike Nathan, Strategy Development and Monitoring for Parasitic Diseases and Vector Control (CDS/CPE/PVC)

Dr Annette Kuesel, TDR/PDE Dr Boakye Boatin, AIDS Medicines and Diagnostics Service (HTM/HIV/AMD)

* unable to attend



“TDR/GEN/06.1”.










Printed in Italy




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Annex 3 WORKING PAPER: Towards a strategic plan for research to support the global programme to eliminate lymphatic filariasis

Appendix A .lymphatic .filariasis .forum: .prioritized .research .needs . . . . . . . . . . . . . . . . . . . . . 33

Appendix B participants .and .working .groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36


3: DEVELOPING A STRATEGIC PLAN FOR RESEARCH TO SUPPORT THE GLOBAL PROGRAMME TO ELIMINATE LYMPHATIC FILARIASIS

STEP 1: THE LYMPHATIC FILARIASIS RESEARCH FORUM

Eric A Ottesen US LF Support Center Task Force on Child Survival and Development Decatur, Georgia, USA

1. BACKGROUND

1.1 The need for a research agenda

It was the dramatic research success in developing effective tools and strategies during the 1980s and 1990s that provided the foundation and rationale for the Global Programme to Eliminate Lymphatic Filariasis (GPELF). Yet, ironically, despite great prog-ress in ‘scaling up’ this programme (currently active in 38 of the 80 endemic countries), or perhaps even because of this progress, one critical element for ulti-mate programme success – research – is increasingly being neglected.

It is widely appreciated that a mark of all successful public health programmes is the continuing involve-ment of an active research community capable of providing solutions both to programme problems as they arise and to anticipated problems or barri-ers that might arise during programme activities. Indeed, such research must be especially vigorous and focused in programmes (like the lymphatic fil-ariasis [LF] programme) with a time-limited goal of disease elimination. In addition, for diseases like LF – the neglected ‘10/90 diseases’ of poverty – where research funds are particularly limited, it is espe-cially critical that research needs and research initia-tives be clearly identified and effectively prioritized. A strategic plan based on these identified needs is essential not only for the GPELF to develop cost-effective solutions to the problems it faces, but also for scientists to identify important research oppor-tunities and for funding agencies to understand exactly how their investments fit into the overall horizon of LF research needs.

1.2 The three-step path to developing a strategic plan

In 2003, a progressive three-step process to develop a strategic plan for LF research was begun.

Step 1, the ‘brainstorming’ effort, was designed to provide an optimal opportunity for the filaria-sis scientific, research and public health communi-ties first to explore, as freely and widely as possible, the research needs of the Global Programme (both today and in the future), then to identify the oppor-tunities to meet those needs, and finally to prioritize the efforts required to pursue those opportunities. It culminated in the ‘LF Research Forum’1 (appen-dix a).

Step 2, the period of reflection and focusing, was designed to allow analysis and debate of the many recommendations and opportunities identified through the brainstorming efforts in order to iden-tify those research issues that would most help the Programme achieve its targets and goals, particu-larly in the near term but in the longer term as well. The conclusions have been captured in the report of an Informal consultation on issues arising out of five years of programme implementation.2

Step 3 in this process of developing a strategic plan was perhaps the most important in that it required WHO/TDR to convene a scientific working group on lymphatic filariasis, first to reaffirm or improve on the conclusions from steps 1 and 2, and then to complete a strategic plan for LF research that would include not only recommendations, but also a real, viable action plan and funding strategy to ensure the strategic plan’s implementation.

2. STEP 1: DEVELOPING THE LYMPHATIC FILARIASIS RESEARCH FORUM

2.1 Approach and goals

The ‘ideal’ LF research forum was envisioned as one that would include all research-oriented members of the LF community from both the scientific and programmatic disciplines, with subgroups being formed to define the issues relevant to their disci-plines. From these components, an overall research agenda could subsequently be developed. To come as close to this ideal as possible, the LF Research Forum was held in Philadelphia, USA (December 2003), at the time of two other activities where large numbers of filariasis-oriented researchers were con-gregating – the centennial meeting of the American Society of Tropical Medicine and Hygiene and a


filariasis ‘research summit’ where international sci-entists were convened for in-depth presentation and discussion of key, cutting-edge filariasis research issues.

During the LF Forum meeting, subgroups of researchers focused on defining the clinical, epide-miological and other scientific research issues most important to lymphatic filariasis, public health and the GPELF. These issues included pathogenesis, dis-ease management, infection in children, drug utiliza-tion, drug development, diagnostic tools, strategies for employing these tools, modelling to define crit-ical epidemiological endpoints, vector biology and others. Significantly omitted however (solely for reasons of logistics), were in-depth considerations of research needs related to social science, health eco-nomics, health systems and filarial genomics. (Since the latter two issues had been the subjects of other recent meetings of experts, they were also included in the final report from the LF Research Forum.1)

2.2 Participants and funding

The inclusiveness of researchers participating in the Forum was limited only by the funds avail-able to support people’s necessary travel expenses. Therefore, individuals (and their home institutions) were asked to support themselves if at all possible, with the remaining costs to be covered by a pool of funds from external donors.

Sixty-four senior scientists and experts in filaria-sis from 21 different countries participated in the LF Forum (appendix b). Another 24 invited partici-pants from 11 countries (all but two represented by other attendees) were unable to attend but agreed to have an input into the process through review of the draft documents. A further list of nine potential invitees from five different countries (only one not otherwise represented) was developed but not acted upon because of budgetary constraints.

Instead of seeking a single donor to underwrite the costs of the Forum, it was decided to request smaller sums (US$ 5000 to US$ 20 000) from multiple orga-nizations, both to decrease the burden on these organizations and to broaden the Forum’s support base. Indeed, eight organizations (three commer-cial, four non-governmental, and one governmental agency) contributed to its support.* In addition, of the 64 participants, 42 investigators from 26 different

* Ellison Medical Foundation; The Geneva Foundation for Diseases of the Tropics; GlaxoSmithKline; Health and Development International; Merck & Company, Inc.; New England Biolabs; The US National Institute of Allergy and Infectious Diseases; The Wellcome Trust.

organizations supported their own costs for meet-ing participation.

2.3 Organization

Initially an organizing committee represent-ing six institutions (including the World Health Organization unit on Strategy Development and Monitoring for Eradication and Elimination [WHO/CEE] and WHO/TDR) identified ten sub-topics cov-ering the range of scientific issues addressable at this Forum. These were the following: (1) chemother-apy, (2) LF infection and drug trials, (3) LF disease and treatment trials, (4) pathogenesis, (5) diag-nostics, (6) epidemiology and parasite biology, (7) programme implementation, (8) programme moni-toring and evaluation, (9) protective immunity, (10) vector biology.

Prior to the Forum, each participant was asked to select two of these sub-topics on which to focus in working groups at the Forum. Once the groups were constituted, a chairperson was designated who then contacted the working group members prior to the Forum itself.

During the two-day Forum, the ten working groups (6–15 individuals per group) met twice in five parallel sessions to determine the most important research-able questions in their topic areas and the priority that these questions should have with respect not only to the Global Programme but to other aspects of science and public health as well. Conclusions from all ten working groups were reviewed in ple-nary, and subsequently summaries of the sub-topics and conclusions were prepared by the group chair-persons and assembled into a draft document that was reviewed by all the Forum participants, invitees and others before finalization for publication.

3. STEP 1: PRINCIPAL OUTCOMES OF THE LYMPHATIC FILARIASIS RESEARCH FORUM’S ‘BRAINSTORMING’

The structure of the Forum allowed both issue prep-aration in advance of the meeting and ‘small-group’ informal interactions among experts during the meeting, all focused on specific topics and without severe time constraints. As a result, ample oppor-tunity was provided for identification of the prin-cipal research needs, and the rationales underlying each of these needs could be defined and outlined in detail (see LF Forum final report1 and appendix a). As the organization of the meeting was by disci-pline, there was a measure of overlap in the research needs identified. Overall, however, the conclusions


of the LF Research Forum could be generalized, as follows.

3.1 Operational research

To ensure success of the Global Programme, the operational research identified as being most impor-tant focused on finding solutions to four essential Programme needs.

The need to establish the tools and measures for programme success

This to be addressed by: • Comparative evaluation of the diagnostics and

sampling strategies available both in humans and in vectors.

• Testing the endpoints for defining transmission interruption.

• Creating/testing sets of indicators developed to monitor:– morbidity-control/disability-prevention efforts– multi-disease integrated programme activities– the GPELF impact on national health systems.

The need to enhance current programme effectiveness

This to be addressed by:• Identifying adjunctive measures that could

reduce the number of mass drug administrations (MDAs) required to achieve success (e.g. vector control, modified regimens of available drugs).

• Refining predictive models for decision-making.• Improving methods and tools to treat difficult

populations (especially urban and Loa-endemic communities).

• Integrating LF programmes with others having cost-effective complementarities.

• Optimizing social mobilization techniques.• Developing creative advocacy and fundraising

strategies.

The need to ensure good clinical/morbidity management

This to be addressed by: • Standardizing clinical terminology and technical

approaches to patient assessment.• Establishing best practices for home-based care

for lymphoedema, surgical care for hydrocele/lymphocele, and treatment for individuals with LF infection.

• Assessing reversibility of clinical/subclinical LF disease, especially in children.

The need to protect effectiveness of drug-based programmes for elimination of lymphatic filariasis

This to be addressed by:• Establishing a definition for diminished drug

sensitivity.• Developing parasite repositories and surveillance

for genotypic signs of drug resistance.• Continuing new and alternative drug

development.

3.2 Basic, upstream research

In addition to these essential operational research issues, the need for ‘basic’ upstream research was also recognized as being critical for maintaining a strong science base for the GPELF. Not only might there be potential scientific ‘breakthroughs’ from these efforts that could entirely short cut the cur-rent LF elimination strategy but, just as importantly, such research activity will help ensure the exis-tence of a cadre of knowledgeable investigators to serve as scientific ‘problem-solvers’ available even for assisting with the operational research needs of the Programme. The issues of particular importance for this upstream research study were identified as those defining: • The effect of LF co-infections on clinical expres-

sion of other diseases and on responsiveness to routine vaccines.

• The mechanisms that determine the pathogenesis of lymphatic disease and its clinical expression.

• The susceptibility and resistance (immunity) to LF and the effect of MDA on natural immunity to LF in treated populations.

• The genomics and proteomics of filarial parasites.

4. DEFINING THE STRATEGIC PLAN AND AN ACTION PLAN TO IMPLEMENT IT

4.1 Step 3: Completion of the strategic plan for research to support the GPELF

It is essential that the WHO/TDR Scientific Working Group on Lymphatic Filariasis, responsible for step 3 of the process to develop a strategic plan, reviews all of the conclusions from steps 1 and 2 of this pro-cess and fills the gaps (particularly in the areas of social science and vector biology) that still remain. Once these gaps have been filled, the list of research needs must be thoughtfully distilled and prioritized in terms of both relevance to programme implemen-tation and overall feasibility. Specific goals, targets and time frames can then be established.


4.2 The action plan

Having a strategic plan for LF research is an impor-tant step towards meeting the needs of the Global Programme, but without a concomitant action plan its value is much diminished. For LF research, how-ever, the greatest barrier to developing a realis-tic action plan is not identifying what needs to be done or who can be engaged to do it, but rather, it is the critical lack of available funds to support the research. Therefore, the action plan needs to focus at least as much on implementing a funding strategy as it does on implementing research activities!

The traditional funding mechanisms are not now meeting the research needs of the LF community even as well as they did in the past. While one can hope that these traditional mechanisms (i.e. TDR support from its annual budget, investigator-initi-ated grants from national governments, international agencies or foundations) will begin to contribute again to a greater funding stream, it is clear that new approaches to stimulate funding of operational research for GPELF (and other global health initia-tives) must be devised. Two obvious needs can be readily identified for developing new approaches to research funding – advocacy and leadership.

Advocacy really means making sure that the pub-lic and its decision-makers recognize the importance of the research that needs to be funded. From the humanitarian point of view, the efforts of GPELF and the research required to support it clearly address the poverty reduction, productivity and health objec-tives of the Millennium Development Goals. From a less humanitarian, practical point of view, decision-makers need to be made aware of the fact that soci-ety has already invested literally tens of millions of dollars in the Global Programme to Eliminate LF, and it is very much in the interests of protecting this investment that those hurdles (or potential hurdles) to the Programme’s achieving success be overcome through the necessary research efforts. Both these lines of advocacy (the humanitarian and the practi-cal) are compelling, and it is important that they be disseminated as widely as possible.

Leadership must take on new attributes to meet the challenges of developing new funding strategies for LF and other ‘neglected’ tropical diseases. Many sci-entific funding institutions simply do not recognize how much of a difference support for the needed research for LF (and other similar diseases) would make to global health. Indeed, much of the research needed is relatively inexpensive. For a small propor-tion of the total budgets invested in the operational research needs of the LF Programme (and similar

global health initiatives), the lives of an enormous number of the most underserved individuals in the developing world could be entirely transformed. Leadership in articulating such opportunities and in presenting both their cost-effectiveness and human-itarian implications is essential.

4.3 The challenge

But who will provide this leadership?

“Fundraising is everybody’s business.” Yet, still, it is WHO/TDR that has the most distinguished and enviable track record for understanding and invest-ing wisely in research to overcome tropical diseases. Furthermore, it has the international convening authority and ‘honest broker’ image that make it an ideal candidate for the leadership role in pursuing a new, aggressive funding strategy.

It is fitting, therefore, to propose that TDR develops a portfolio describing the essential research needs for success of the LF elimination programme and simi-lar global health initiatives, and that this includes the cost-benefit implications of the funded research. Convening a multinational council of research insti-tutions and agencies, where specific research needs and their potential importance and value could be presented and debated, would ensure greater aware-ness of the global health community’s urgent needs for the real-world solutions that the supported research activities would generate. Establishing such a council would, moreover, foster a sense of global community partnership and a shared under-standing among research institutions and agencies from different parts of the world (as well as provide an important forum for lobbying efforts), and it is likely that once the societal value of such research is recognized, a greater proportion of international research budgets would be devoted to it.

It is important that the strategic plan for LF research be completed by the SWG (step 3 of the three-step process), but it is just as important that an action plan for both implementation and funding of the identified research be generated. It is clear that the success of the Global Programme to Eliminate LF will require success of the action plan to implement the essential elements of the research agenda, and, in turn, this implementation will require the success of a new, aggressive funding strategy to generate the necessary funds to support it. For all of these chal-lenges, WHO/TDR is in the best position to provide again that same measure of leadership and guid-ance that has led to its extraordinary success of the past 30 years.


References

1. Filariasis Community of Scientists. Towards a strategic plan for research to support the Global Program to Eliminate Lymphatic Filariasis. American Journal of Tropical Medicine and Hygiene, 2005, 71 (Supplement):1–46.

2. WHO/TDR. Issues arising out of five years of pro-gramme implementation (report of an informal consulta-tion). www.filariasis.org, 2005.


Appendix A

LYMPHATIC FILARIASIS FORUM: PRIORITIZED RESEARCH NEEDS 1. RESEARCH DIRECTLY LINKED WITH GPELF ACTIVITIES (OPERATIONAL RESEARCH)

1.1 Essential tools: diagnostics

P.J. Lammie

Prioritized research needs• Develop effective, practical strategy for defining

in field settings the areas and individuals with levels of Loa loa microfilaraemia so high as to be dangerous if MDA for concurrent LF were to be initiated (? novel tool; ? novel approach with available tools).

• Define the comparative accuracy of available diagnostics (antigen, antibody, DNA) and strat-egies for monitoring the progress of LF elimina-tion programmes and for deciding both when to stop MDAs and how to initiate surveillance to detect potential recrudescence:– determine limits of sensitivity and specificity

of available tests– carry out longitudinal studies using all diag-

nostic tools concurrently and in both high and low prevalence areas where LF elimination programmes are under way.

• Take advantage of new technologies to improve user-friendliness and efficiency of the LF diag-nostics currently available (e.g. isothermal PCR, ‘multiplex’ antibody or PCR kits, use of oral flu-ids or urine for diagnostic tests).

• Validate sampling strategies for testing both vec-tor and human populations for LF infection or exposure to infection.

1.2 Essential tools: drugs and clinical drug trials

M.H. Bradley & V. Kumaraswami

Prioritized research needs• Create a framework for monitoring for potential

development of drug resistance, including:– defining criteria for the phenotype of reduced

responsiveness and resistance– establishing a repository of microfilariae and/

or adult worms to provide base-line data on the occurrence of drug-resistant genotypes

– initiating a surveillance system for diminished responsiveness to antifilarial drugs.

• Initiate clinical trials of available antifilarial drugs in order to:– enhance microfilaria (mf) reduction (through

alternative dosages, frequency regimens, etc.)– enhance adulticidal effectiveness – define ways to minimize patient treatment

reactions at a population level– define a ‘standard treatment’ for individuals

with LF.• Ensure the safety of coordinated administration

of drugs in ‘linked’ public health programmes (e.g. albendazole, ivermectin, azithromycin, pra-ziquantel, etc.) or in other medical settings (e.g. used with HIV/AIDS or TB multidrug-therapy regimens).

• Establish a framework for seeking a macrofilaricide.

• Pursue discovery of anti-Wolbachia agent suitable for MDA and/or individual treatment.

• Develop broadly applicable implementation strategies for use of DEC-fortified salt (with or without concurrent albendazole administration).

• Evaluate use of moxidectin for LF.

1.3 Lymphatic Filariasis disease: clinical management

D.G. Addiss & C Mackenzie

Prioritized research needs• Investigate effects of MDA alone on progression

or reversal of LF disease (LE, filaricele, ADL).• Evaluate comparative studies of ‘filaricele’ sur-

gical techniques for: a) relapse rates, b) sur-gical costs and duration, c) post-operative complications.

• Refine and standardize (through a consensus conference) clinical definitions of LF disease, and describe epidemiology of LF disease with these new definitions.

• Improve differential diagnosis of paediatric LF disease, and initiate studies to define measures to prevent its progression.

• Investigate the value of traditional medicine approaches to lymphoedema and urogenital disease.

• Increase understanding of the skin barrier func-tion, ‘entry lesions’, and ways of preventing the bacterial complications of LF disease.

• Define epidemiology, risk factors, complications and optimal management of chyluria.

1. 4 Programme implementation

M. Malecela-Lazaro & N. Twum-Danso

Prioritized research needs• Define the duration and coverage of MDA


necessary to achieve interruption of transmission in different epidemiologic/entomologic settings.

• Determine the effect of the rate of upscaling on:– duration of MDA necessary to achieve inter-

ruption of transmission– cost of the programme in the short and long

term. • Identify the most effective social mobilization

strategies for MDA in different settings.• Optimize MDA strategies for urban areas with

low prevalence of infection.• Determine the duration and coverage of DEC–

salt administration necessary to interrupt transmission.

• Identify safe strategies for LF elimination in L .loa endemic areas.

• Assess the impact of LF elimination programmes on health systems.

• Identify the complementarities of specific tar-geted disease programmes that can promote link-ages among the programmes for coordinated implementation, monitoring and evaluation.

• Review outcomes and ‘best practices’ both from ongoing LF elimination programmes and from other, similar targeted disease programmes.

• Develop novel means of resource mobilization for upscaling national programmes.

1.5 Monitoring and evaluation

J.O. Gyapong

Prioritized research needs• Initiate multicentre, longitudinal studies to

define the relationship and comparative effec-tiveness of the available diagnostic monitor-ing tools (Ag, Ab, PCR) used in human or vector populations, to determine:– when to stop MDA– how to perform surveillance to ensure absence

of resurgence– how to verify absence of transmission.

• Use data from this multicentre study to refine predictive models.

• Study the role of mobility and migration both in populations and by modelling to define their effects on LF transmission dynamics.

• Investigate the effects of non-compliance on the LF elimination programme, and the sociological reasons underlying non-compliance.

• Refine and validate tools for monitoring morbid-ity management programmes.

• Develop guidelines for monitoring multi-pro-gramme effectiveness and outcome in situations where LF elimination is coordinated (integrated) with other public health interventions (e.g. with onchocerciasis, intestinal parasite, trachoma

or malaria control; and/or with vector control activities).

1.6 Epidemiology, parasite biology, modelling

K.Y. Dadzie, M.-G. Basanez & F. Richards

Prioritized research needs• Define transmission dynamics for the various

vector–parasite complexes, including the esti-mated reproductive lifespan of the adult worms.

• Determine end points at which MDA can be stopped with low probability of recrudescence, under different epidemiologic settings and using different diagnostic tests.

• Develop mathematical models to support deci-sion-making on the duration of local MDA pro-grammes in different epidemiological situations (e.g. initial endemicity, coverage rates, migration patterns, drug combinations).

• Define the comparative effectiveness of available tools and indicators for monitoring the progress of LF elimination programmes and for modelling to decide when to stop MDA and how to initiate surveillance to detect recrudescence.

1.7 Vectors

T. Burkot & M. Bockarie

Prioritized research needs• Refine and evaluate the new tools for determin-

ing LF infection rates in mosquitoes.• Develop and evaluate new tools for estimating

the rate of contact between human and mosquito populations.

• Evaluate vector control strategies based on knowledge of vector biology for impact on LF transmission, including:– the effect of insecticide-impregnated mosquito

nets on LF transmission by Anopheles and Culex vectors

– breeding site reduction strategies on LF trans-mission by Aedes vectors

– polystyrene beads and Bacillus sphaericus on LF transmission by Culex vectors.

• Conduct operational research on how to inte-grate successful vector control strategies for LF into ongoing programmes for other vector borne diseases (e.g. malaria, dengue).

1.8 Health systems

D.A. McFarland & L.C. Barrett

Prioritized research needs• Test the current LF/health systems assessment

tool (matrix) in a variety of endemic countries


to determine if the data necessary for each pro-posed indicator can be feasibly acquired.

• Identify which health system function represents the best opportunity for assessing LF impact.

• Determine baselines for health systems perfor-mance in endemic countries at each level where the LF programme is likely to have an impact.

• Identify ways to disaggregate the health systems effects of the LF programme from those of other concurrent disease control programmes.

2. UPSTREAM (BASIC) RESEARCH TO SUPPORT THE GPELF

2.1 Pathogenesis

C.L. King & J.W. Kazura

Prioritized research needs• Develop a revised, standardized set of definitions

for lymphatic and urogenital pathology seen with LF.

• Utilize animal models and clinical studies to define the influence of LF parasites, molecules, endosymbionts and host-induced factors on lym-phatic endothelium.

• Define the role of co-infections (local bacterial or systemic TB, HIV/AIDS, etc) in pathogenesis of LF disease.

• Define effects of the LF-altered host responsive-ness on reactions to vaccines or to other infec-tious agents (malaria, HIV/AIDS, TB, etc).

• Explore roles of innate and adaptive immune responses to LF in the initiation, progression or reversal of lymphatic disease and disease of other organs.

• Define the role of the host immune response in the mechanism of action of the common antifilar-ial drugs (especially DEC).

• Define differential host susceptibility to devel-opment of disease caused by genetic, endo-crinologic, nutritional and other types of heterogeneity.

2.2 Protective immunity: vaccines

A. Hoerauf & C. Steel

Prioritized research needs• Define the changes to protective immunity

among populations undergoing MDA pro-grammes (requires longitudinal cohort studies in newborn infants and adults, the identification of markers of protective immunity [sterile and con-comitant], and parallel observations in experi-mental animal models).

• Assess the impact of MDA-induced alteration of antifilarial immunity on efficacy of ‘routine’ vac-cines and on co-infections with other helminths,

malaria, TB and HIV/AIDS.• Work towards an LF vaccine (as a tool for use

post-2010) through: – identification of protective antigens and their

product development– identification of the mechanisms underlying

protective immunity– ‘piggy-backing’ observations on the anti-hook-

worm vaccine currently under development.

2.3 Filarial genomics

S. A. Williams

Prioritized research needs• Collect materials:

– before the opportunity is lost to preserve their genomes, collect geographically representative isolates of the various species and strains of human filarial parasites.

• Construct libraries: – construct updated and additional genomic and

cDNA libraries to represent completely the dif-ferent stages and species of filarial parasites.

• Sequencing:– expand EST sequencing from cDNA of a

greater diversity of life cycle stages and para-sites than currently available

– complete the sequencing and annotation of the B. malayi genome

– expand the sequencing of the W. bancrofti and O. volvulus genomes

– complete the sequencing of the Wolbachia genome from B. malayi and the mitochondrial genomes from B. malayi and O. volvulus.

• Technical development: – develop transgenic methods useful for filarial

parasites– utilize RNAi techniques for functional genom-

ics studies – expand microarray assessments of gene

expression with B. malayi and other filariae.• Repositories:

– develop and maintain all collections of genomes, libraries, sequences, microarrays, etc. in central repositories accessible to all inter-ested investigators within and outside the fila-riasis research community.


Appendix B

PARTICIPANTS AND WORKING GROUPSREPORT CONTRIBUTORS**

1.1 Diagnostics

FischerFontesHoustonKlion*LammieMelroseNoordinOttesenRamzyRavindranWeilWeerasooriyaWilliams

1.2 Intervention tools: chemotherapy

*BradleyBrandling-BennettBrownBuettnerCoyneHoeraufKronLazdins-HeldsMcCallPrichardRajan

1.2 Clinical drug trials

AlexanderBasanezBradleyBrownCoyneKazuraKron*KumaraswamiLazdins-HeldsMandMcCallNoordin

RamzySaahStolkTaylorWeerasooriya

1.3 LF disease: clinical management trials

*AddissBuettnerDreyerMackenzieNoroesRyanSeimShenoy

1.4 Programme implementation

BagnallBalducci-SilanoBiswasDadzieEhrenbergKyelemLammie*Malecela-LazaroPrichardRichardsStreit*Twum-Danso

1.5 Monitoring and evaluation

BockarieBurkotDasEl SetouhyFischerFontes*GyapongHabbema

HoustonIchimoriLamMathieuMelroseOttesenSunWeilWilliams

1.6 Epidemiology, parasite biology, modelling

AlexanderBalducci-SilanoBasanezBiswas*DadzieEhrenbergEl SetouhyGyapongHabbemaKyelemLamLustigmanMathieuRichardsStolkSunTwum-Danso

1.7 Vectors

BoakyeBockarie*BurkotDasIchimoriStreit

1.8 Health systems †

2.1 Pathogenesis

AbrahamAddissDreyer*Kazura*KingKleiKumaraswamiMackenzieMalacelaMandNoroesNutmanRyanSeimShenoySteelTaylor

2.2 Protective immunity: vaccines

Abraham*HoeraufKingKleiKlionLustigmanNutmanRajanRavindran*Steel

2.3 Filarial genomics ††

* Working group chairperson and/or report section author

** Additional contributors: C. Curtis, London, U.K.; D Durrheim, Townsville, Australia; E. Michael, London, U.K.; P. Pani, Pondicherry, India; A. Rocha, Recife, Brazil; P. Simonsen, Copenhagen, Denmark

† Compiled by L. Barrett and D. McFarland based on a meeting in Crewe, U.K., January 2003 (see attendees in appendix b)

†† Section compiled by S.A. Williams


Abraham, David Thomas Jefferson University233 S 10th StreetPhiladelphia, PA 19107 [email protected]

Addiss, DavidCenters for Disease Control4770 Buford HighwayBldg. 102; Room 1320Atlanta, GA 30341-3724 [email protected]

Alexander, NealInfectious Disease EpidemiologyLondon School of Hygiene and Tropical MedicineKeppel StreetLondon WC1E [email protected]

Bagnall, Brian G.GlaxoSmithKlinePhiladelphia, PA [email protected]

Balducci-Silano, PinaDirector, Evaluation and ResearchInternational Trachoma Initiative441 Lexington Avenue, 16th FloorNew York, NY [email protected]

Basanez, Maria-GloriaDepartment of Infectious Disease EpidemiologyImperial College School of MedicineNorfolk PlaceLondon W2 [email protected]

Biswas, GautamWorld Health Organization20, Avenue Appia, CH-1211 Geneva 27, [email protected]

Boakye, DanielNoguchi Memorial Institute forMedical Research, Parasitology UnitP.O. Box LG581Legon Accra, [email protected]

Bockarie, MosesPNG Inst of Medical ResearchP.O Box 378 MadangPAPUA NEW [email protected]

Bradley, MarkGlaxoSmithKlineGSK House, Floor C 12980 Great West RoadBrentford, Middlesex, TW8 [email protected]

Brandling-Bennett, DavidBill and Melinda Gates FoundationP.O Box 23350Seattle, WA [email protected]

Brown, KenMerck Emeritus8111 Winston RoadPhiladelphia, PA 19118 USAmkg33@verizon,net

Buettner, DietrichBernhard Nocht Institute for Tropical MedicineBernhard-Nocht-Strasse 74D-20359 Hamburg [email protected]

Burkot, ThomasCenters for Disease Control4770 Buford HighwayMailstop F-13Atlanta, GA 30341-3724 [email protected]

LYMPHATIC FILARIASIS FORUM: PARTICIPANTS


Coyne, PhilipNIH/NIAID Parasitic & International Programs Branch, Division of Microbiology & Infectious Diseases6700B Rockledge DriveBethesda, MD 20892-7630 [email protected]

Dadzie, K. YankumPO Box 01905OSUAccra [email protected]

Das, P.K.VCRC (Indian Council of Medical Research)Medical ComplexIndira NagarPondicherry, 605006 [email protected]

Dreyer, GerusaNGO Amaury CoutinhoRua Gomes Coutinho, Grupo 49Casa 96, TamarineiraRecife, PE, [email protected]

Durrheim, DavidSchool of Public Health and Tropical MedicineJames Cook University7 Kendell StreetTownsville Queensland, [email protected]

Ehrenberg, John P.PAHO, Organizacion Panamericana de la SaludOrganizacion Mundial de la Salud525 23rd Street, NWWashington, DC 20037-2895 [email protected]

El Setouhy, Maged AProfessor, Public Health DepartmentFaculty of MedicineAIN Shams UniversityAbbasiaCairo, [email protected]

Fischer, PeterDepartment of HelminthologyBernhard Nocht Institute for Tropical MedicineBernhard Nocht Str. 74D-20359 [email protected]

Fontes, GilbertoUniversidade Federal de AlagoasCentro de Ciencias BiologicasDepartamento de PatologiaMaceio, [email protected]

Gyapong, JohnHealth Research UnitMinistry of HealthPO Box 184Accra [email protected]

Habbema, J.D.F.Center for Decision Sciences inTropical Disease ControlDepartment of Public Health, Erasmus University PO 17383000 DR RotterdamThe [email protected]

Hoerauf, AchimDirector, Institute of Medical ParasitologyFaculty of MedicineUniversity of BonnSigmund Freud Str. 2553105 Bonn [email protected]

Houston, Robin9455 Big GulchBozeman, MT 59715 [email protected]

Ichimori, KazuyoOffice of the WHO RepresentativeLevel 4 Provident Plaza OneDowntown Blvd 33 Ellery St.Suva, [email protected]


Kazura, James W.Case Western Reserve UniversitySchool of Medicine10900 Euclid AvenueCleveland, OH 44106-4983 [email protected]

King, ChristopherCase Western Reserve University School of Medicine10900 Euclid AvenueCleveland, OH 44106-4983 USA [email protected]

Klei, Thomas R.Associate Dean for Research and Advanced StudiesSchool of Veterinary MedicineLouisiana State UniversityBaton Rouge, LA 70803 [email protected]

Klion, AmyNational Institutes of HealthBldg 4, Room 1269000 Rockville PikeBethesda, MD 20892 [email protected]

Kron, MichaelDivision of Infectious DiseasesMichigan State UniversityB323 Life Science BuildingEast Lansing, MI 48824 [email protected]

Kumaraswami, VasanthapuraTuberculosis Research CentreSpur Tank RoadChennai, [email protected]

Kyelem, DominiqueMinistry of Health01 BP 2935Ougadougou, 1BURKINA [email protected]

Lam, Nguyen NgocEpidemiologist and Physician Clinical & EpidemiologicalResearch UnitInstitute Louis MalardeBP 30 Papeete – [email protected]

Lammie, PatrickCenters for Disease Control4770 Buford HighwayMailstop F-13Atlanta, GA 30341-3724 [email protected]

Lazdins-Helds, Janis K.World Health Organization20, Avenue Appia, CH-1211 Geneva, 27 [email protected]

Lustigman, SaraMolecular ParasitologyLindsley F. Kimball Research InstituteNew York Blood Center310 East 67th StreetNew York, NY 10021 [email protected]

Mackenzie, CharlesMichigan State University11649 Jarvis HighwayDiamondale, MI, 48821 [email protected]

Malecela-Lazaro, Mwele NtuliNational Institute for Medical ResearchOcean Road PO Box 9653Dar es Salaam, [email protected]

Mand, SabineFaculty of Medicine, University of BonnSigmund Freud Str. 2553105 [email protected]

Mathieu, ElsCenters for Disease Control & Prevention4770 Buford Highway, NE MS-F-22Atlanta, GA 30341 [email protected]

McCall, John W.University of GeorgiaDept of ParasitologyCollege of Veterinary MedicineAthens, GA 30602 [email protected]


Melrose, WayneSchool of Public Health and Tropical MedicineJames Cook UniversityTownsville, QLD [email protected]

Noordin, RahmahDept. of Microiology & ParasitologySchool of Medical SciencesUniversity Sains Malaysia16150 Kubang Kerian, [email protected]

Noroes, JoaquimUPFEAve. Moraes Reso s/nCampus UniversitarioRecife, [email protected]

Nutman, Thomas B.National Institutes of HealthLaboratory of Parasitic DiseasesBuilding 4 Room 126Bethesda, MD 20892-0425 [email protected]

Ottesen, Eric A.Rollins School of Public HealthEmory University1518 Clifton Road, NE 7th FloorAtlanta, GA 30322 [email protected]

Prichard, RogerMcGill University21 111, Chemin LakeshoreSte-Anne-deBellevueQuebec, H9X [email protected]

Rajan, T.V.University of ConnecticutDept. of Pathology, Health CenterRm L-1008 MC 3105Farmington, CT 06030-3105 USA [email protected]

Ramzy, Reda21 El Tayef St DokkiCairo 12311 [email protected]

Ravindran, BalachandranDivisioin of ImmunologyRegional Medical Research Centre (ICMR) Bhubaneswar 751023 [email protected]

Richards, FrankCenters for Disease Control4770 Buford HighwayBldg 102Atlanta, GA 30342-3724 USA [email protected]

Ryan, TerranceOCHRAD44 London RoadHeadington Oxford, OX3 7PDUK [email protected]

Saah, AlfredMerck & Co. Inc.Blue Bell, PA 19422 [email protected]

Seim, AndersHealth & Development InternationalFAGERSTRAND Brygge 1454Fagerstrand [email protected]

Shenoy, R. KrishnaT.D. Medical College HospitalAlleppeyKerala, INDIA [email protected]

Steel, CathyNIH/NIAID/LPD9000 Rockville PikeBldg. 4 Room 126Bethesda, MD 20892-0425 [email protected],gov


Stolk, WilmaDepartment of Public HealthErasmus University Medical CenterPO Box 17383000 DR RotterdamThe [email protected]

Streit, TomHaiti ProgramUniversity of Notre DameSouth Bend, [email protected]

Sun, De-JianChinese Academy of Preventive Medicine207 Rui Jin Er LuShanghai, 200035PR [email protected]

Taylor, Mark J.Liverpool School of Tropical MedicinePembroke PlaceLiverpool, [email protected]

Twum-Danso, NanaTask Force for Child Survival & Development750 Commerce Drive, Ste. 400Decatur, GA [email protected]

Weil, GaryWashington School of MedicineBarnes-Jewish Hospital (N)216 South Kingshighway Blvd.St. Louis, MO 63110 [email protected]

Weerasooriya, MiraniDepartment of ParasitologyFaculty of MedicinePO Box 70Galle, SRI [email protected]

Williams, Steven A.Smith College/Dept. of Bio SciencesClark Science CenterNorthampton, MA [email protected]

CREWE HALL MEETING PARTICIPANTS

Baah, Asamoa World Health Organization, CH 1211 Geneva 27, Switzerland (Wednesday 28th January only) Tel: 22 791 4388Fax: 22 791 4752Email: [email protected]

Bagnall, Brian Chair Advocacy and Fundraising Task Force, 1708 E. Lancaster Ave #286, Paoli, PA 19301-1553, USA Tel: 215 870 0701Fax: 610 296 0381 Email: [email protected]

Bagrey, Ngwira (Rapporteur)Lymphatic Filariasis Support Centre, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK Tel: 0151 705 3242Fax: 0151 709 0354Email: [email protected]

Barrett, Laura Department of International Health, Rollins School of Public Health, Emory University, 1518 Clifton Rd., Atlanta, GA 30322, USA Email: [email protected]

Biritwum, Richard Ghana Medical School, Box 4236, Accra, Ghana Tel: 233-21-665101Email: [email protected]

Dadzie,Yankum (Chairperson)PO Box 01905, Osu, Accra, Ghana Tel: 233 21 401353 Fax: 233 21 246154Email: [email protected]

Gyapong, Margaret Health Research Unit, Ministry of Health, PO Box 184, Accra, Ghana Tel: 233 21 230 220Fax: 233 21 226 739Email: [email protected]

Jacoby, Ann Department of Primary Care, Liverpool University, Whelan Building, The Quadrangle, Brownlow Hill, Liverpool L69 3GB, UKTel: 0151 794 5602


Kyelem, DominiqueLF Elimination Program Manager, Ministry of Health, 01 BP 2935, Ougadougou 01, Burkina FasoTel: 226 (30) 8790 Email: [email protected]

McFarland, Deborah Department of International Health, Rollins School of Public Health, Emory University, 1518 Clifton Rd., Atlanta, GA 30322, USA Tel: 404 727 7849Fax: 404 727 4590Email: [email protected]

McQuide, Pam School of Nursing, Emory University, 1520 Clifton Rd., Atlanta, GA 30322, USATel: 404 727 8489Fax: 404 727 4645Email: [email protected]

Molyneux, David Lymphatic Filariasis Support Centre, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK Tel: 0151 705 3145Fax: 0151 709 0354Email: [email protected]

Mzige, Ali Director Preventive Services, PO Box 9083, Dar es Salaam, Tanzania Tel: 255 22 213676Fax: 255 22 2123676Email: [email protected]

Ottesen, Eric Emory LF Support Center, Department of International Health, Rollins School of Public Health, 1518 Clifton Rd., Atlanta, GA 30322, USA Tel: 404 712 9263Fax: 404 727 5530Email: [email protected]

Toe, FernandDirection General de la Sante, 03 BP 7009, Ougadougou 03, Burkina Faso Tel: (226) 32 44 52Fax: (226) 31 54 40Email: [email protected]

Whitehead, Margaret Department of Public Health, Liverpool University, Liverpool L69 3GB, UK Tel: 0151 794 5280Email: [email protected]

Wright, Andy GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UKTel: 0208 047 5515Fax: 0208 047 0684Email: [email protected]

Zagaria, Nevio World Health Organization, CH 1211 Geneva 27, Switzerland Tel: 22 791 2534Fax: 22 791 4777Email: [email protected]


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Annex 4 WORKING PAPERS: Impact of mass drug administration

4a . impact .of .mass .drug .administration .on .Culex-transmitted . .lymphatic .filariasis .in .india . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

4b . impact .of .mass .drug .administration .on .Aedes-transmitted . .filariasis .in .the .pacific . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

4c . long-term .impact .of .mass .drug .administration .on .bancroftian .filariasis .in .dreikikir, .papua .new .Guinea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

4d . impact .of .mass .drug .administration .on .Anopheles-transmitted .filariasis .in .africa: .emerging .data .from .Ghana .and .mali . . . . . . . . . . . . . . . . . . . . . 62

4e . impact .of .mass .drug .administration .on .infection .and .transmission .of .lymphatic .filariasis .in .egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68


4A: IMPACT OF MASS DRUG ADMINISTRATION ON CULEX-TRANSMITTED LYMPHATIC FILARIASIS IN INDIA

K.D. Ramaiah1 and R. Rajendran2

1 Vector Control Research Centre (ICMR), Medical Complex, Indira Nagar, Pondicherry, India 605006

2 Centre for Research in Medical Entomology (ICMR), Sarojini Street, Chinna Chokkikulam, Madurai, Tamil Nadu, India 625002

1 INTRODUCTION

With more than 40% of its one billion population liv-ing in endemic areas and 48 million infected peo-ple (TDR, 1994), India accounts for 40% of the global lymphatic filariasis (LF) burden. Nearly 95% of the 48 million filarial infections in India are caused by Wuchereria bancrofti and transmitted by Culex quin-quefasciatus, the tropical house mosquito. The other 5% of the infections are caused by Brugia malayi transmitted by Mansonia species.

Vector control combined with detection and treat-ment of people with microfilariae formed the core of the National Filaria Control Programme (NFCP) in India, which began in 1955 (NFCP, 1995). Its activi-ties were confined to some urban areas with 11% of the total endemic population. Following the World Health Assembly resolution in 1997 calling for steps towards eliminating LF as a public health problem, India initiated a mass drug administration (MDA) programme. This programme was first implemented in 11 districts with a population of 32 million in 6 states; in 2001 it was extended to 20 more districts.

In a significant development, the MDA programme was expanded to include as many as 202 districts in 2004 (Sharma, 2004). The programme in India, except in a few districts, uses single-drug dieth-ylcarbamazine (DEC) therapy. The merits of com-bination therapy with DEC + albendazole (ALB), recommended by WHO for use in LF elimination programmes, are being evaluated in pilot studies.

During the last decade, several studies have been initiated in India to address various issues that are directly or indirectly related to LF elimination, with more focus on MDA impact and process evaluation.

2 IMPACT OF MASS DRUG ADMINISTRATION

2.1 Impact on microfilaraemia

Longitudinal community-level trials in South Indian rural communities provided an insight into the potential of MDA to clear microfilaraemia in human populations. In one trial, five communities each received 8–9 cycles of DEC or ivermectin (IVM) mass administration at 12–15 month intervals over a period of 10 years. In these communities, nine cycles of DEC administration to 54%–75% of the population, except children under 15 kg body weight, resulted in a remarkable decrease in the microfilaria reser-voir. The initial six cycles of treatment reduced the proportion of people with microfilariae from 13.2% to 1.9% (Ramaiah et al., 2002); three more cycles reduced the proportion from 1.9% to 0.8% (Ramaiah et al., unpublished). During the initial six-cycle duration, the geometric mean number of microfilar-iae declined from 0.66 to 0.06. During the seventh to ninth cycles, the mean number declined from 0.06 to 0.03. Thus, six cycles of treatment reduced the pro-portion of people with microfilariae and the geo-metric mean number of microfilariae by 86% and

Figure 1. .pattern .of .decline .of .microfilaraemia .with .nine .cycles .of .mass .dec .treatment


91% respectively. Clearance of the remaining 15% microfilaria-positive infections was slow; it was not complete with three more cycles of treatment (fig. 1) and seems to require disproportionately more cycles of treatment. How many more cycles of treatment are required is unclear. Only 0.5% of children aged 1–15 years were positive for microfilariae after nine cycles of DEC treatment compared to 10.5% prior to the intervention.

With the other antifilarial drug, IVM, the results were slightly less impressive. Eight cycles of IVM administration decreased the proportion of subjects with microfilariae from 14.5% to 3.1%, and the geo-metric mean intensity of microfilariae from 0.62 to 0.07. Discontinuation of IVM administration after eight cycles led, within one year, to an increase in the microfilaria prevalence rate from 3.1% to 4.9%, and an increase in microfilaria intensity from 0.07 to 0.1 (Ramaiah et al., unpublished). Elsewhere also, an increase in the microfilaria-positive rate, from 1.81% to 4.74%, was observed one year after the cessation of two cycles of DEC + IVM mass administration (Sunish et al., 2002).

Villages may not respond uniformly to MDA. We observed variations in the microfilaria positive rate between villages after a given number of treatments. For example, after nine cycles of treatment, the micro-filaria positive rate varied from 0% to 3.8% in the five treated communities. In another investigation, vector evaluation in 40 villages of a primary health centre (PHC) that received 5 cycles of MDA showed that 11 villages (28%) had a zero infection rate, that another 3 villages (8%) had a <1% infection rate, and that the remaining 64% villages had a 1%–19% infec-tion rate. There are indications that smaller or low endemic villages show greater decreases in micro-filaria positive rate and that larger or high endemic villages show lesser decreases. If these results are extrapolated to a district, which is an intervention unit in India and consists of more than one thou-sand villages with a population of 1.5 to 2.0 million, hundreds of endemic villages may become free from microfilaria positive infections after 6–10 treatments while others may require more cycles of treatment to decimate the microfilaria reservoir. In such a sit-uation, it may be economical to ‘phase out’ the ‘suc-cessful’ villages from MDA over a period of time. Such a ‘phase out’ exercise appears to be complex because of uncertainties over: (i) the threshold cri-teria for stopping MDA; (ii) the threshold indicators and their measurement; and (iii) the sampling meth-odology for MDA impact assessment in an inter-vention unit with more than 1000 villages. These issues were recently elaborated by Lammie (2004) and Gyapong (2004).

With MDA alone and with 54% to 75% (or less than the recommended 80% of the population) under-going treatment, 15% of microfilaria carriers con-tinued to be microfilaria positive after six cycles of DEC treatment and 6% remained positive after nine cycles of treatment. Although the decrease in proportion of people with microfilariae is directly related to the number of treatments (Ramaiah et al., 2002), some people may not be able to clear micro-filaraemia even after repeated treatments. For exam-ple, 1.6% of those who received 7–8 DEC treatments continued to show microfilaria in their blood. Thus, persistence of microfilaria carriers after 6–9 cycles of treatment may occur on two accounts: (i) treatment coverage of 54%–75% is inadequate; and (ii) though the efficacy of the drug is excellent, it falls slightly short of clearing microfilaraemia in all treated peo-ple. Therefore, improvement in peoples’ participa-tion in treatment and some measures to improve the effectiveness of MDA seem to be necessary to achieve a zero per cent microfilaria positive rate in a 6–10 year time frame in large-scale or district-level elimination programmes, where treatment com-pliance is often much below 80% (Ramaiah et al., 2000).

Post-MDA microfilaria carriers and recrudes-cence of infection

Recrudescence of infection was shown to be a major threat to the control of Aedes transmitted LF in islands of the South Pacific. Recrudescence of infec-tion is possible because of the persistence of micro-filaria carriers in the community despite MDA. In some communities in our studies, 0.4% to 3.8% of the population continued to be microfilaria posi-tive after nine cycles of treatment. These microfi-laria positive people may be of two types: (i) those with intact infections owing to total non-compliance or poor compliance with treatment, as a result of semi-systematic treatment compliance patterns in their communities (Vanamail et al., 2005), and (ii) those left with what we call ‘residual microfilarae-mia’ (or low density microfilaria carriers) resulting from the inability of the drug to clear 100% of the parasitaemia in every person (Eberhard et al., 1997). The number of such post-MDA microfilaria carri-ers, detectable using the blood smear technique, is expected to be approximately five in a village with a population of 1000 and a 10% microfilaria posi-tive rate prior to MDA and a 0.5% positive rate after MDA. The microfilaria count of such carriers ranged from 1 to 38, and 60% of them had <5 microfilaria per 60 cu. mm of blood. The dangerous potential of these microfilaria carriers to perpetuate transmis-sion and cause recrudescence of infection in humans is well documented in Aedes-transmitted LF (Esterre


et al., 2001), but such information is scanty for Culex-transmitted LF. Studying the viability of adult worms in the two categories of microfilaria carriers may yield important information.

Microfilaria carriers with intact infections are likely to be an important source of infection to mosqui-toes, at least for a few years. Hence it is necessary to ensure their treatment to prevent them contributing to transmission. Some information is available on the contribution of low density microfilaria carriers to transmission. A low density microfilaria carrier (1–6 microfilaria per ml of blood) can contribute to 0–15 infective stage larvae (L3) per year (McGreevy et al., 1982). Infected mosquitoes were also found in villages with zero or very low microfilaria positive rates (0.16% and 0.72%), estimated using the blood smear technique (Jayasekara et al., 1991; Ramaiah et al., 2003[a]). These studies clearly suggest that low level transmission is possible in the presence of residual microfilaraemia carriers in the communi-ties. It is, however, not known whether this low level transmission is sufficient to cause recrudescence of infection in Culex-transmitted LF. In India, the pro-portion of subjects with microfilaria rose only mar-ginally, from 0% to 0.03%, seven years after cessation of a DEC-fortified salt administration programme (G.S. Reddy, personal communication), indicating that recrudescence of microfilaraemia is not a seri-ous problem. Partono (1978) is of the opinion that low levels of microfilaraemia detectable by the mem-brane filtration technique do not contribute to trans-mission. Some evidence for resurgence of infection was reported by Harb et al. (1993). Overall, the risk of recrudescence of infection in Culex-transmitted LF may not be as serious as in Aedes-transmitted LF. Some of the ongoing studies may provide opportu-nities to examine the ‘recrudescence’ issue.

2.2. Effect on transmission

The decline of transmission in treated communi-ties was along expected lines, following the reduc-tion of microfilaraemia prevalence and intensity in the human population. After six cycles of mass DEC administration, the annual infective biting rate (AIBR) per person fell from the pre-MDA level of 735 to 93, and the annual transmission potential (ATP) fell from 2514 to 125 (Ramaiah et al., 2003[a]), which is equivalent to reductions of 87% and 95% respectively. Monitoring of the resting vector pop-ulation confirmed what we observed with microfil-araemia – residual parasitaemia persists even after nine cycles of MDA (fig. 2) (K.D. Ramaiah, unpub-lished). About 2% of resting mosquitoes were found with infection and 0.06% with L3 larvae after nine cycles of DEC treatment, compared to 18% and 1% respectively before the start of the study. This is equivalent to a 90% reduction in the infection rate and 94% in the infectivity rate. The transmis-sion intensity index (resting vector density x pro-portion of mosquitoes with L3 x average number of L3/infective mosquito) declined by 97%. After nine cycles of MDA, while mosquitoes with micro-filariae or first or second stage larvae were found in four out of five villages, mosquitoes with infective stage larva (L3) were found in only one out of five villages. Persistence of mosquitoes with infection was relatively higher in villages with high micro-filaria positive rates. Intensive searches in a couple of villages where no mosquitoes with L3 had been found during routine evaluation for four consecu-tive years led to the detection of a single mosquito with L3 in one village. It is debatable whether MDA should be continued or withdrawn in those villages without (or with only ‘stray’) infective mosquitoes but with mosquitoes containing pre-L3 stage par-asites. The decline in vector infection rate is simi-lar to that observed with the microfilaria prevalence rate – it was consistent initially but meagre during

Figure 2. pattern .of .decline .of .vector .infection .rates .with .nine .cycles .of .mass .dec .treatment .


the seventh to ninth cycles of treatment. The impact of MDA on transmission intensity was also greater in smaller/low endemic villages compared to larger/highly endemic villages.

Mass IVM administration led to equally good results. Eight cycles of mass IVM administration led to a decline in resting vector infection rate from the pre-intervention value of 18.7% to 2.8%, and to a decline in infectivity rate from 1.71% to 0.31%, reductions of 85% and 82% respectively. Withdrawal of IVM administration led to a surge in infection rate from the reduced level of 2.8% to 5.1%, and in infectivity rate from 0.31% to 0.74, within one year (Ramaiah et al., unpublished). Sunish et al. (2002) reported an increase in ATP from 21 to 632 when administration of DEC + IVM was stopped after two treatments.

The possibility of recrudescence of infection in MDA-implemented communities is partly deter-mined by the ‘limitation’ and ‘facilitation’ phenom-ena observed in vector species. Culex and Aedes exhibit limitation, in which transmission efficiency of the vector increases at low microfilaria densities; this is often seen after MDA programmes. Anopheles vectors however exhibit facilitation – they sustain transmission at higher densities of microfilariae than Culex (Southgate, 1992). As the critical density of microfilariae required to sustain transmission in Culex is less than in Anopheles, more efficient control of microfilaraemia is necessary in Culex vector areas than in Anopheles vector areas.

2.3. Effect on antigenaemia

The level of circulating filarial antigen indicates the burden of infection with adult or pre-adult worms, and assessment of antigenaemia after MDA is use-ful for finding out if transmission is totally inter-rupted. However, in large-scale MDA programmes the timing of antigenaemia assessment appears to be important – it may depend on the efficiency of the programme in terms of compliance with treat-ment. With poor or moderate treatment compli-ance (40% to 60%), some amount of transmission is always possible during the initial cycles (1–4) of MDA. For example, we estimated the total trans-mission during the first to fourth cycles of MDA to be 524 infective bites per person. This may explain the presence of antigenaemia in as many as 18.9% of children in the 0–5 year age group after six cycles of DEC treatment, compared to 22.4% in placebo vil-lages (p>0.05) (Ramaiah et al., 2003[b]). These results suggest that a significant effect of MDA on the anti-genaemia positive rate is possible only with very high levels of (>80%) treatment compliance from the beginning of the programme.

2.4. Impact on acute and chronic disease

Community level trials suggest that up to four cycles of mass administration of DEC or IVM will have no impact on incidence of the acute form of the disease (Das et al., 2001), which is a significant health prob-lem in endemic communities. This confirms earlier findings that foot care combined with local appli-cation of antibiotic and antifungals is more impor-tant for containing the incidence of ADL episodes than treatment with antifilarial drugs (Shenoy et al., 1998).

Studies carried out in India showed a dramatic impact of MDA on frequency of hydrocele, which constitutes about 60% of the total chronic disease burden (TDR, 1994). The proportion of people with hydrocele was 20.5% prior to intervention, com-pared to 5.1% (= 75% reduction) after seven cycles of DEC mass administration. The impact was more appreciable in the <40-year age group, in which the frequency of hydrocele cases declined from 13.6% to 1.5% (= 90% reduction). In villages adminis-tered seven cycles of IVM, the overall frequency of hydrocele decreased from 23.9% to 10.4% (= 56% reduction) and the frequency in the <40-year age group decreased from 15.8% to 6.0% (= 62% reduc-tion). However, these optimistic results need to be viewed in the light of the 47% (20.4%–10.9%) and 48% (13.5%–7.1%) reductions observed in placebo villages in the entire population and <40-year age group respectively (Vector Control Research Centre, annual report 2003). Meyrowitsch et al. (1996) and Bockarie et al. (2002) also reported a very apprecia-ble impact of MDA on prevalence of hydrocele. It is not known if a few more cycles of MDA or bet-ter treatment compliance would further reduce the prevalence of hydrocele, or if MDA caused ‘cure’ of hydrocele is irreversible. Because of the close asso-ciation between the chronic and acute disease, such a drastic reduction in the proportion of people with hydrocele should also lead to some relief for the patients from acute disease episodes.

MDA is unlikely to provide much relief to lymph-oedema patients in the Indian situation. The pre-intervention lymphoedema frequencies of 3.7% in the population administered with DEC and 4.6% in the population administered with IVM remained almost unchanged after seven cycles of treatment (Vector Control Research Centre, annual report 2003). Hence, the importance of a foot-care-based morbidity-management strategy for lymphoedema patients assumes greater significance for the Indian programme.


3. COMBINATION THERAPY VERSUS SINGLE DRUG THERAPY

Data are now available from four research studies on the impact of combination therapy (DEC + alben-dazole) on microfilaria prevalence and geometric mean number of microfilaria. In all four studies, combination therapy yielded greater reduction in the microfilaria positive rate than single drug (DEC) therapy. Two to three cycles of mass administration of DEC + ALB decreased the proportion of microfi-laria positive subjects by 37%–61%, and DEC alone decreased the proportion by 3%–42%. The differ-ence in microfilaraemia clearance rate between the two regimens was in the range 11%–34% (p>0.05) (Rajendran et al., 2004; Ramaiah et al., unpublished; Vector Control Research Centre, annual report 2003). There was a difference in impact on geometric mean microfilaria count between the two regimens – two studies showed only a marginal difference, while the other two studies showed that a 27%–61% greater reduction in the count is possible with com-bination therapy. Comparable data on the effect of the two regimens on the antigenaemia positive rate is available only from one study – the rate decreased from 23.8% to 10.1% in the population treated with three cycles of combination therapy and from 17.0% to 16.3% in the population treated with sin-gle drug therapy, equivalent to 57% and 4% respec-tively (p<0.05) (Rajendran et al., unpublished). As expected, the combination therapy was very effec-tive against intestinal helminths – 76% of the popu-lation became free from infection, compared to 15% with DEC alone, after two cycles of MDA. The inten-sity of infection was reduced by 98% with combi-nation therapy compared to 58% with DEC alone (Mani et al., 2004), and these reductions are sustain-able for one year in the people treated with DEC + ALB (Rajendran et al., 2003).

After six rounds of MDA, the impact of DEC + IVM combination on microfilaraemia and transmission was found to be almost similar to that of DEC alone (Ramaiah et al., unpublished).

4. COST–BENEFIT AND COST–EFFECTIVENESS ANALYSES

Recent analyses suggest that benefits to the com-munity expected to accrue from the use of MDA far outweigh its costs. Prevention of chronic disease by spending US$ 8.41 leads to savings of 58 working days per case per annum, equivalent to US$ 449 over a period of 11 years, the duration of productive life lost by a patient. This gives a cost–benefit ratio of 0.019 (Ramaiah and Das, 2004). Cost–effectiveness analysis revealed that the predicted cost per DALY

averted with DEC-medicated salt, MDA and vector control is US $ 3.3, 8.1 and 84.3 respectively (Remme and Ramaiah, unpublished). These studies clearly suggest that MDA is a very cost-effective option.

5. OPERATIONAL ISSUES

Experience from large-scale MDA programmes sug-gests that, with reasonable efforts, LF drugs could be distributed to >80% of the population. However, based on some strong beliefs, 1/3 to 1/4 of the pop-ulation is reluctant to consume the drug (Ramaiah et al., 2000; Babu and Kar, 2004); this is one of the most important issues for the Indian programme. Changing the behaviour of the reluctant, and sustain-ing the interest of the willing, through appropriate community mobilization strategies – notwithstand-ing the costs – is a major challenge, particularly in the wake of the severe side reactions and even some deaths attributed to MDA (Ramaiah et al., 2005[a]). Failure to do this will have significant negative implications for the duration and impact of the LF elimination programme. A social mobilization strat-egy to improve people’s participation in MDA pro-grammes yielded some positive results (Ramaiah et al., unpublished).

Some workers question the rationale of adopting a district (Sabesan et al., 2005), which consists of 30–50 PHCs and more than 1000 villages, or an entire urban area as an ‘intervention unit’ because of the sheer size and variation in endemicity level; these workers argue for a ‘stratification’ approach. Studies in urban areas suggest that LF is steadily decreas-ing, particularly in higher income groups, owing to better health care and awareness and use of ‘self protection’ measures against the mosquito nui-sance (primarily the LF vector C. quinquefasciatus) in almost all households (Snehalatha et al., 2003). It is not clear whether such groups should be included in MDA at all (Ramaiah et al., 2005[b]).

The quality of drugs has become a major issue after allegations of death due to DEC in the southern state of Tamil Nadu (Ramaiah et al., 2005[a]).

6. CONCLUSIONS

• Evidence suggests that nine cycles of mass DEC administration are able to: (a) clear microfilarae-mia in 94% of subjects; (b) cut down transmission very drastically; (c) prevent incidence of new infections; (iv) appreciably reduce the propor-tion of cases with hydrocele in Culex-transmit-ted LF. These remarkable results were achieved with less than the recommended 80% treatment compliance.


• Microfilaria prevalence declines consistently from a level of >10% to 1–2% with the initial cycles of treatment. Further decline to zero per cent appears to be slow and possible only with multiple cycles of MDA.

• After nine cycles of treatment, in most villages the microfilaria positive rate declines to <1% with virtually no infective mosquitoes. However, most of these villages are likely to have a few microfilaria carriers, many people with antigen-aemia, and mosquitoes with infection, making it uncertain whether the villages qualify for stop-ping MDA.

• The outcome of MDA and the number of cycles of treatment required is likely to vary with the endemicity and population size of the village. Low endemic villages are more amenable and require fewer cycles of treatment to reduce the proportion of people with microfilaraemia to zero per cent.

• Combination therapy achieves better clearance of microfilaraemia than single drug therapy, as well as appreciable reduction in intestinal helminth infections.

• Evidence from large-scale programmes suggests that a considerable proportion of people accept the drugs but are reluctant to consume them.

7. RESEARCH NEEDS

• Assess critically the potential of the last few and persistent microfilaria carriers to cause recru-descence of infection in communities that have progressed to a near zero rate of microfilaria positivity.

• Explore various options such as vector control, new treatment regimens, and DEC-medicated salt, to improve the effectiveness of MDA in elim-inating the residual microfilaria reservoir with fewer cycles of treatment.

• Determine the threshold indicator to be used in LF elimination programmes and define the threshold levels for stopping MDA with no prob-ability of transmission and recrudescence of infection.

• Develop user-friendly and cheaper molecular tools for health workers to monitor the impact of MDA at PHC level and facilitate decision-making about stopping or continuing MDA.

• Develop and validate sampling strategies to: (a) monitor the impact of MDA, (b) stop MDA, and (c) monitor the recrudescence of infection.

• Develop and test strategies to bridge the gap between receiving and consuming the drug in MDA programmes.

• Investigate the collateral benefits of MDA.• Define the socioeconomic and epidemiological

criteria for excluding low-risk populations in urban areas from active MDA programmes, and assess the advantages and disadvantages of their exclusion.


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4B: IMPACT OF MASS DRUG ADMINISTRATION ON AEDES-TRANSMITTED FILARIASIS IN THE PACIFIC

Burkot TR,1 Melrose WD,2 Durrheim DN,2,3 Speare R,2 Ichimori K4

1 Centers for Disease Prevention and Control, Atlanta, Georgia, USA

2 WHO Lymphatic Filariasis Collaborating Center, James Cook University, Townsville, Australia

3 Hunter New England Population Health, Newcastle, New South Wales, Australia

4 PacELF, Suva, Fiji

OVERVIEW OF LYMPHATIC FILARIASIS CONTROL / ELIMINATION IN THE REGION

Vector control was the primary tool for controlling filariasis in the Pacific when effective antifilarial drugs were unknown and, even after effective antifi-larials became available, was preferred because mass drug administration (MDA) campaigns were con-sidered too labour intensive (Burkot and Ichimori, 2002). Beginning in the 1950s, various diethylcar-bamazine (DEC)-based population treatment strate-gies were undertaken to control lymphatic filariasis (details below). These campaigns often succeeded in achieving significant reductions in microfilar-iae (mf) rates and densities. However, mf rates fre-quently rebounded due to: (1) poor compliance; (2) inadequate duration of campaigns; and (3) failure of DEC to completely kill or sterilize adult Wuchereria bancrofti in all people treated, despite repeated administration (Chow, 1974).

The present Pacific Programme for the Elimination of Lymphatic Filariasis (PacELF) relies on repeated annual mass drug administration (MDA) of diethylcarbamazine (DEC) and alben-dazole, with nearly universal coverage of affected populations. Evidence that the present DEC/albendazole combi-nation will be more successful than monotherapy with DEC against adult worms is supported by falling adult worm antigen levels and clinical reac-tions in infected humans receiving the drug combination (Ottesen, Ismail and Horton, 1999). A number of the PacELF countries have now completed five

annual rounds of MDA but their impact has not yet been fully evaluated. There is, however, evidence from Samoa and French Polynesia where Aedes poly-nesiensis is an important vector that, despite high coverage with MDA campaigns, transmission was not interrupted by the DEC-based campaigns as there were increases in microfilaria (mf) prevalence after the campaigns. There may well be a need for adjunct control measures, including vector control, to accomplish disease elimination where mf levels are not adequately suppressed by MDA alone.

VECTOR CONTROL AS AN ADJUNCT TO MDA FOR LYMPHATIC FILARIASIS ELIMINATION

Success in the control and elimination of filariasis based only on anti-vector activities has been demon-strated in the Pacific. In Papua New Guinea and the Solomon Islands, where species of Anopheles are the vectors of malaria and filariasis, filariasis was elim-inated from areas where DDT spraying campaigns to control malaria were undertaken (Bockarie, 1994; Webber 1977, 1979). Similarly, W. bancrofti was elim-inated from Australia, primarily by sanitation cam-paigns against C. quinquefasciatus (Boreham and Marks, 1986). Comparable vector control based suc-cesses in the areas where Ae. polynesiensis is the vec-tor do not exist. Ae. polynesiensis is a notoriously efficient vector due to ‘limitation’, a characteristic whereby the efficiency of transmission increases with decreasing densities of mf (Pichon, 2002).

In areas where W. bancrofti is subperiodic, lymphatic filariasis (LF) transmission can be complex due to the presence of multiple vectors; in the region from Fiji

Table 1. reported .Aedes .vectors .of .lymphatic .filariasis .in .the .pacific

Vector Countries where found

Aedes cooki niue

Aedes fijiensis fiji

Aedes horrensces fiji

Aedes kochi papua .new .Guinea

Aedes marshallensis Kiribati

Aedes oceanicus tonga

Aedes polynesiensis (burnett .Gf, .1960[a]) .

american .samoa, .samoa, .cook .islands, .tokelau, .tuvalu, .french .polynesia, .Wallis .and .futuna, .fiji

Aedes pseudoscutellaris fiji

Aedes rotumae rotuma .island .in .fiji

Aedes samoanus samoa

Aedes tabu tonga

Aedes tutuilae samoa .

Aedes upolenis samoa

Aedes vigilax new .caledonia, .fiji


to French Polynesia, there are 14 reported Aedes vec-tors (six LF vectors are found in Fiji) (table 1). With the exception of Ae. polynesiensis and Ae. vigilax, lit-tle is known about the ecology of these mosquitoes and there is almost no documentation of attempts to control them. Ae. polynesiensis is believed to pose the greatest challenge to LF elimination and is the most important Aedes LF vector in the Pacific, and is thus the focus of this manuscript.

VECTOR CONTROL STRATEGIES FOR AEDES

Mosquito surveillance and control is an integral part of filariasis elimination plans in many Pacific islands. Among these island countries, larval sur-veys for filariasis vectors are often advocated with environmental sanitation to reduce mosquito breed-ing sites, as are bednets and ultra-low-volume (ULV) spraying against adult mosquitoes. Unfortunately, the effectiveness of these interventions at the popu-lation level has rarely been evaluated. For example, many studies on controlling Ae. aegypti for dengue have shown that treating rainwater drums with lar-vicides dramatically reduces the numbers of mos-quitoes breeding in these drums, but there are only

a few studies showing the impact that elimination of drums has on the number of adult mosquitoes.

There have not been any studies on controlling Ae. vigilax in the Pacific. The long flight range of this vector means that focal larviciding is unlikely to be feasible or cost-effective. However, as Ae. vigi-lax breeds in salt marshes, runnels (ditches designed to allow flushing of salt marshes by tides) had some impact on larval numbers in Australia (Dale et al., 1993). Unfortunately, the impact on biting rates was not measured in this study.

More operational research for control of Ae. polyne-siensis at population level has been conducted in the Pacific (table 2). Mesocyclops aspericornis reduced by 98% the number of Ae. polynesiensis larvae in treated crab holes. However, despite treating more than 14 000 crab holes on one French Polynesian island, no measurable impact on the number of biting Ae. polynesiensis was demonstrated (Lardeux et al., 1992). Insecticide fogging and spraying campaigns have had minimal impacts on Ae. polynesiensis biting rates, with reductions of less than 64% in three trials (Suzuki and Stone,1976; Chow, 1974; Wharton and Jachowski, 1980).

Table 2. .summary .of .field .trials .for .controlling .Aedes .in .the .pacific

Vector* Breeding site Country Control method % Reduction in Reference

breeding .sites mosquitoes

Ae. polynesiensis tree .holes fiji destroying .tree .holes 87% ? burnett .Gf, .1960[a] .

Ae. polynesiensis crab .holes fiji 1% .lindane .and .plugging .of .crab .holes

? 0% .on .biting burnett .Gf, .1960[a] .

Ae. polynesiensis all .types french .polynesia

breeding .site .elimination .within .100 .yd . .of .village

? 80% .to .90% Kessel .jf, .1965 .


breeding .site .elimination .within .100 .yd . .of .village

? 90% .of .larvae laigret .j, .1958 .


breeding .site .elimination; .vegetation .control

? 81% .biting byrd .ee, .st .amant .ls, .1959 .

Ae. polynesiensisand .Ae. samoanus

all .types samoa ddt .spray .of .breeding .site .and .fogging .of .houses/bush

? 64% .biting suzuki .t, .stone .f, .1976 .

Ae. polynesiensisand .Ae. samoanus

not .known samoa abate .larvicide .and .malathion .fog

? 60% chow .cy, .1974 .

Ae. polynesiensis not .available american .samoa

ddt .house .spraying; .aerial .spraying .every .14 .days

not .available 0% .at .14 .days Wharton .and .jachowski, .1980 .

Ae. aegypti and .Ae. samoanus

cisterns, .wells, .drums

french .polynesia

integrated .control .(abate, .sealing .drums, .polystyrene .beads, .Poecillia reticulata)

94% 84% lardeux .f .et .al, .2002(a) .

Ae. polynesiensis crab .holes french .polynesia

Mesocyclops aspericornis 98% .of .larvae0% .of .adults

lardeux .f .et .al, .1992 .

Ae. polynesiensis crab .holes french .polynesia

insecticide .impregnated .crab .bait

86% . lardeux .f .et .al, .2002(b) .

* .references .in .the .literature .to .Ae. pseudoscutellaris .prior .to .1960 .are .believed .to .be Ae. polynesiensis .and .are .listed .as .Ae. polynesiensis. Ae. polynesiensis was .described .by .marks .as .a .separate .species .in .1955 . .


The effectiveness of larval source-reduction cam-paigns against Ae. polynesiensis has been repeat-edly demonstrated in French Polynesia (Kessel, 1965; Laigret, 1965), particularly when integrated with other measures (Lardeux et al., 2002[a]) includ-ing removal of vegetation to facilitate discovery of breeding sites (Byrd and St Amant, 1959). However, the sustainability of source reduction is unproven. A Fijian study documented the rapidity with which breeding sites reappear after clean-up campaigns. Within 4.5 months, 3906 destroyed containers were replaced with 2040 new breeding sites and 2544 destroyed tree holes were replaced with 388 new tree holes demonstrating breeding (Burnett, 1960[b]). These efforts are labour-intensive. Hairston (1973) estimated that one man-month of work was needed to eliminate breeding sites around each village, and that only 77% of breeding sites were amenable to destruction.

Targeted source reduction of Ae. polynesiensis will only be possible if we have more complete knowl-edge on the importance of different breeding sites. Although studies show that Ae. polynesiensis will breed in a large variety of man-made (storage drums, tyres, rain gutters) and natural (crab holes, tree holes, leaf axils, rat-damaged coconuts) con-tainers, their relative importance in different areas is not known. Specific local studies are required to guide control efforts. In American Samoa, for exam-ple, Lambdin (Masters in Public Health [MPH] the-sis, Emory University, unpublished) found that almost 70% of Ae. polynesiensis pupae were present during the wet season in five container categories (drums, tyres, buckets, ice cream containers, folded plastic sheets). Similar results were obtained during the dry season, with 66% of Ae. polynesiensis pupae produced in buckets and plastic containers (Burkot, unpublished) although buckets and plastic contain-ers were only 27% of all containers surveyed.

Anti-dengue campaigns worldwide are now pri-marily based on larval source reduction and, while important behavioural differences exist between Aedes aegypti and Ae. polynesiensis, there are suffi-cient similarities between the two species (both bite in the daytime and breed in containers) to allow us to draw some lessons from the anti-Ae. aegypti campaigns for Ae. polynesiensis control. Of partic-ular importance is the need for local information on breeding sites and community practices prior to the implementation of health education campaigns aimed at encouraging the community to reduce the number of breeding sites.

There are very few data on control strategies tar-geting adult Ae. polynesiensis mosquitoes. A trial is

being conducted in Fiji to evaluate the impact of insecticide-treated curtains and bednets on trans-mission by Ae. polynesiensis (Koroivueta, Ichimori and Burkot, personal communication). There is clearly a need to investigate the potential of addi-tional personal protection measures, including nat-urally occurring botanical extracts, as components of an integrated Ae. polynesiensis control strategy. University of Kentucky researchers are conducting trials using Wolbachia-induced cytoplasmic incom-patibility for Ae. polynesiensis elimination (Dobson, personal communication).

From the above review, it is clear that much of our understanding of Aedes behaviour and transmis-sion of W. bancrofti is based on studies conducted many decades ago, and that there has been limited investment in recent years in operational research to guide an integrated approach to LF control and elimination.

IMPACT OF MASS DRUG ADMINISTRATION ON TRANSMISSION

Prior to the 1950s, LF control in the Pacific relied almost exclusively on vector control. With the dis-covery of the anti-microfilaricidal activity of DEC, emphasis shifted to MDA campaign-based con-trol. These campaigns, particularly in Samoa and French Polynesia, achieved significant reductions in mf rates and densities (Ichimori, 2001; Esterre et al, 2001; Laigret et al,1980). In Samoa, five extensive campaigns using DEC, including 12–18 month treat-ments in 1966 and 1971, and single annual doses in 1982, 1983 and 1986, reduced the mf rate from 21% in 1964 to 2.3% in 1987. Mf rates declined to 0.14% in 1974, following the second DEC campaign, but rebounded to 2.1% within two years (Ichimori, 2001).

In French Polynesia, since 1955 but excluding the years 1960–67 and 1970–74, twice yearly DEC che-motherapy (6 mg/kg) was administered to an aver-age of 85% of the population on Maupiti island (Esterre et al, 2001). In addition, mosquito control using DDT (1955–1957) and larval breeding source destruction (1955–1970) were implemented. Despite these efforts, a comprehensive survey in 2000 found that 0.4% of residents had mf and 4.6% had antigen-aemia (Esterre et al, 2001).

After cessation of the MDA campaigns in Samoa and French Polynesia, mf rates increased (Kimura et al., 1985; Ichimori, 2001). While the extensive campaigns succeeded in minimizing filariasis as a public health


problem by significantly reducing the number of clinical cases of the disease, elimination of the par-asite was not achieved. A subsequent analysis of LF positives on Maupiti suggests that residual positives may have persistently not complied with the MDA programme (Nguyen, personal communication).

Under the PacELF MDA programme, annual administration of DEC and albendazole has been undertaken in the following countries where Aedes species are important vectors: American Samoa, Cook Islands, Fiji, French Polynesia, Niue, Samoa, Tokelau, Tonga, Tuvalu, and Wallis and Futuna. By the end of 2005, five rounds of MDA will have been completed in the Cook Islands, French Polynesia, Niue, Samoa and Tonga. Samoa is the only country to have completed its prevalence assessment after five rounds of MDA, with annual coverage ranging from 57% to 90%, but the results of this assessment are not yet available.

FEASIBILITY OF TERMINATING TRANSMISSION BY MDA OR OTHER INTERVENTIONS, AND RISK OF RECRUDESCENCE

Despite phenomenal progress in the Pacific towards elimination of LF, several major challenges remain. Firstly, we do not know the exact level of suppres-sion of mf that needs to be achieved in order for elimination to be realized. This obstacle is even more vexing where Aedes is the vector. The implications of Pichon’s (2002) ‘limitation’ models have been ver-ified by observations on mf rates following MDA campaigns with DEC in Samoa. Despite reducing mf rates to less than 0.33% between 1972 and 1974, LF rates rose afterwards. It is likely that ‘pockets of infection’ capable of initiating resurgence of LF will remain and that relatively low levels of micro-filaraemia may permit resurgence and pose a for-midable challenge to traditional survey techniques. New surveillance tools will certainly be necessary where Aedes mosquitoes are the vectors if MDA is used alone for elimination of LF.

A second significant challenge is the mobility of Pacific islanders; migration is particularly com-mon in many of the Pacific islands where Aedes is an important LF vector. More Cook Islanders live in New Zealand than on the main island of Rarotonga, and thus may have missed annual MDA treatment. Frequent travel back to the Cook Islands carries with it the possibility of reintroduction of LF. Similarly, Samoans frequently travel between Samoa and American Samoa for economic opportunities and to visit relatives and friends living in the neighbouring

country. Thus, the PacELF regional approach to LF in the Pacific is appropriate but migration between the various Pacific countries, including Australia and New Zealand, must be taken into consideration.

A third challenge is the presence of individuals whose behaviour places them at risk of infection or who do not regularly participate in MDA, placing their communities at risk of ongoing transmission (Gyapong et al., 1996). Merely increasing the num-ber of years of MDA campaigns will not reach these individuals, but a better understanding of their per-ceptions and priorities will allow tailoring of mes-sages and interventions so that they are locally appropriate and acceptable (Durrheim et al., 2004).

A fourth challenge is the potential for W. bancrofti to develop resistance to either DEC or albendazole. Albendazole resistance is already common amongst helminths of veterinary importance. Although there is currently no evidence of resistance to DEC or albendazole in areas where LF elimination pro-grammes are under way, no reliable assay system is currently available to allow assessment of resis-tance. Resistance is more likely to appear late in an MDA programme when success appears feasible.

These challenges can be reduced by integrating vec-tor control with MDA for LF elimination (Burkot et al., 2002). A country-wide vector control pro-gramme can: suppress LF transmission without the need for identifying all individual ‘pockets of infec-tion’; minimize the risk from imported mf positives; and reduce the spread of any DEC or albendazole resistant W. bancrofti. Furthermore, control mea-sures targeting Aedes vectors may also decrease the risk of dengue transmission. Vector control strate-gies as adjuncts to the MDA campaigns are certainly needed in the next five years to ensure success of the elimination efforts.

IMPACT OF MDA ON DISEASE, AND ELIMINATION OF LF AS A PUBLIC HEALTH PROBLEM

Clinical presentations, now known to be consistent with LF infection, were first reported in Polynesia by early European explorers, including Captain Cook. In recent years there have been relatively few cross-sectional surveys on prevalence of LF disease; however, overt pathology was seen to diminish con-currently with previous widespread DEC-based MDA. The most recent data available from Pacific countries in Aedes transmission areas include:


– In Samoa in 1954, an elephantiasis rate of 3.6% and a lymphadenitis rate of 15%–20% were reported (Sasa, 1976).

– In Tonga in 1977, a 0.39% prevalence of elephan-tiasis and a 2.4% prevalence of hydrocele were found.

– In Tuvalu in 1928, 23% of men surveyed had hydroceles and there was an 8.1% elephantiasis rate (Sasa, 1976).

– In Tokelau during a 1994 survey, a single case of elephantiasis was found (Tokelau country report to the PacELF annual meeting, Apia, Somoa, 1994).

– In Niue in 1960, a clinical survey found 5.5% of the population with symptoms of LF (Ichimori, unpublished).

– In French Polynesia, the most recent data report a 1.3% prevalence of elephantiasis (Sasa, 1976).

– In Fiji between 1991 and 1995, a countrywide clinical survey of 18 253 people found 16% of people had lymph node enlargement, 0.9 % had hydrocele, and 0.2% had elephantiasis (Fiji MOH, unpublished).

– In the Cook Islands during 1965, a survey found that 3.8% of 498 people examined had elephanti-asis (Sasa, 1976).

SUMMARY OF THE MAJOR REMAINING UNCERTAINTIES, RESEARCH QUESTIONS AND SUGGESTIONS FOR SPECIFIC STUDIES

The ability of Ae. polynesiensis to sustain LF trans-mission at low mf levels demands an integrated approach to control that is sensitive to local vector and human characteristics and behaviour. The fol-lowing conclusions may be drawn from the limited number of population-based studies of Aedes con-trol strategies:• The contribution of human behaviour and per-

ceptions to achieving and sustaining adequate MDA coverage, and to placing individuals at risk of infection, needs to be better understood and probably poses the biggest threat to achieving elimination of LF.

• As well as benefits in eliminating LF transmis-sion, Ae. polynesiensis control strategies offer potential in preventing and controlling dengue through their concurrent impact on Ae. aegypti.

• Source reduction of Ae. polynesiensis breeding sites has demonstrated the most consistent suc-cess in reducing Ae. polynesiensis numbers.

• When source reduction is integrated with other control measures, for example use of insecticide-treated crab baits where crab holes are the major

breeding sites, then the impact on biting rates and possibly transmission is enhanced.

• While insecticide-treated bednets have been shown to effectively control filariasis where it is transmitted by anophelines, their impact on the day-time biting Aedes vectors in the Pacific is unknown. It may be that insecticide-treated materials, including curtains, could have a signif-icant impact in either killing vectors or repelling vectors from houses.

• Insecticides have not been effective in reducing adult Ae. polynesiensis populations when used alone.

• The demonstrated ability of LF to rebound in Ae. polynesiensis transmission areas, even at very low mf rates, and the high mobility of Pacific island peoples makes recrudescence a real threat:– surveillance systems are needed to promptly

detect mf positive individuals – vector control can reduce the risk of LF

resurgence. • Little is known about the impact of the PacELF

MDAs on the prevalence of LF disease.

RECOMMENDATIONS FOR SPECIFIC STUDIES

• As a large number of countries with Aedes vec-tors of LF have completed five rounds of MDA, there is an urgent need for population-based tri-als of Aedes control strategies for implementa-tion as adjunct measures to MDA. Strategies that deserve further evaluation include:– novel biological, chemical and mechanical

source reduction measures, including the use of crab baits impregnated with insecticides

– use of insecticide-treated materials, including clothing and curtains

– personal protection measures.• Control strategies that integrate a combination of

approaches consistent with the ecology of local vectors should be encouraged.

• Simple survey methods for trapping adult Aedes that can be implemented at local level need to be evaluated, as standard traps are not effective.

• Pupal surveys need to be undertaken to iden-tify the most productive containers for producing adult Aedes.

• Qualitative studies are required to pro-vide a better understanding of human behav-ioural and perceptual contributions to ongoing transmission.

• Surveys of remaining LF pathology are needed to determine the impact of the MDA strategy where Aedes species are the vectors.


References

Bockarie, M. Can lymphatic filariasis be eradicated in Papua New Guinea? Papua and New Guinea Medical Journal, 1994, 37:61–64.

Boreham PFL, Marks EN. Human filariasis in Australia: Introduction, investigation and elimination. Proceedings of the Royal Society of Queensland, 1986, 97:23–52.

Burkot TR, Ichimori K. The Pacific program for the elimination of lymphatic filariasis: Will mass drug administration be enough? Trends in Parasitology, 2002, 18:109–115.

Burkot TR et al. Initial progress towards and challeng-es to filariasis elimination in Pacific island communi-ties. Annals of Tropical Medicine and Parasitology, 2002, 96(Suppl 2):S61–S69.

Burnett GF, Filariasis research in Fiji, 1957–1959, parts I, II and III. Journal of Tropical Medicine and Hygiene, 1960[a], 63:156–162, 181–192, 208–215.

Burnett GF. Filariasis research in Fiji, 1957–59. Journal of Tropical Medicine and Hygiene, 1960[b], 63:156–162.

Byrd EE, St Amant LS. Studies on the epidemiology of filariasis on Central and South Pacific Islands. South Pacific Commission Technical Paper, 1959, 125:52–55.

Chow CY. Filariasis vectors and their control in the South Pacific. 4th Joint WHO/SPC seminar on Filariasis and Vector Control. Apia, W. Samoa, WPR/Fil/12. Manila, World Health Organization, 1974.

Dale PER et al. Runnelling to control saltmarsh mosquitoes: long term efficacy and environmen-tal impacts. Journal of the American Mosquito Control Association, 1993, 9:174–181.

Durrheim DN et al. Lymphatic filariasis endemic-ity – an indicator of poverty? Tropical Medicine and International Health, 2004, 9:1–3.

Esterre P et al. The impact of 34 years of massive DEC chemotherapy on Wuchereria bancrofti infection and transmission: the Maupiti cohort. Tropical Medicine and International Health, 2001, 6:190–195.

Gyapong M et al. Filariasis in Northern Ghana: Some cultural beliefs and practices and their implications for disease control. Social Science and Medicine, 1996, 43:235–242.

Hairston N. Assessment of filariasis in Western Samoa. Assignment report. Manila, World Health Organization, 1973.

Ichimori K. Entomology of the filariasis control pro-gramme in Samoa, Aedes polynesiensis and Ae. samoa-nus. Medical Entomology and Zoology, 2001, 52:11–21.

Kessel JF. Combined control methods in filariasis. Manila, World Health Organization, unpublished report, 1965 (FIL/WP/16.65).

Kimura E et al. The efficacy of annual single-dose treatment with diethycarbamazine citrate against diur-nally subperiodic bancroftian filariasis in Samoa. Bulle-tin of the World Health Organization, 1985, 63:1097–1106.

Laigret J. La lutte contre la filariose lympatique aperi-odique en Polynesie francaise. Bulletin de la Societe de pathologie exotique, 1965, 58:895–916.

Laigret J et al. Chimiotherapie de masse par la diethylcarbamazine end doses espacees : effets obte-nus a Tahiti sur la microfilaremie a Wuchereria bancrof-ti, var. pacifica. Bulletin of the World Health Organization, 1980, 58:779–783.

Lardeux F et al. Release of Mesocyclops aspericornis (Copepoda) for control of larval Aedes polynesiensis (Diptera: Culicidae) in land crab burrows on an atoll of French Polynesia. Journal of Medical Entomology, 1992, 29:571–576.

Lardeux F et al. Integrated control of peridomestic lar-val habitats of Aedes and Culex mosquitoes of French Polynesian Atolls. Journal of Medical Entomology, 2002[a], 39:493–498.

Lardeux F et al. Evaluation of insecticide impregnated baits for control of mosquito larvae in land crab bur-rows on French Polynesian Atolls. Journal of Medical Entomology, 2002[b], 39:658–661.

Ottesen EA, Ismail MM, Horton J. The role of alben-dazole in programmes to eliminate lymphatic filaria-sis. Parasitology Today, 1999, 15:382–386.

Pichon G. Limitation and facilitation in the vectors and other aspects of the dynamics of filarial trans-mission: the need for vector control against Anopheles transmitted filariasis. Annals of Tropical Medicine and Parasitology, 2002, 96:S143–S152.

Sasa, M. Human Filariasis. University Park Press, Baltimore, 1976.

Suzuki T, Stone F. Laboratory and field tests of insecti-cides against vector mosquitos of subperiodic filariasis in Western Samoa. Unpublished report to WHO, 1976.

Webber RH. The natural decline of Wuchereria bancrofti infection in a vector control situation in the Solomon Islands. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1977, 71:396–400.

Webber RH. Eradication of Wuchereria bancrofti infec-tion through vector control. Transactions of the Royal So-ciety of Tropical Medicine and Hygiene, 1979, 73:722–724.

Wharton and Jachowski. In: Zahar, King and Chow. A review and annotated bibliography on subperiod-ic bancroftian filariasis with special reference to its vec-tors in Polynesia, South Pacific. Manila, World Health Organization, 1980.


4C: LONG-TERM IMPACT OF MASS DRUG ADMINISTRATION ON BANCROFTIAN FILARIASIS IN DREIKIKIR, PAPUA NEW GUINEA

James W. Kazura2 and Moses J. Bockarie1

1 The Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea

2 Case Western Reserve University School of Medicine, Cleveland, USA

INTRODUCTION

A crucial unresolved issue in chemotherapy-based elimination programmes against bancroftian fila-riasis is the level to which the parasite population density must be reduced in order to stop the inter-vention with minimal risk of recrudescence. In eco-logical terms, the goal is local, and ultimately global, extinction of lymphatic filariasis (LF). Mass drug administration (MDA) programmes that are too short in duration, interrupted, have inadequate pop-ulation coverage, or in which drug resistance arises, will eventually lead to parasite population recovery and recrudescence. On the other hand, MDA given for too long a period of time is wasteful of financial

and human resources, and inappropriate since indi-viduals will be given drugs that are not indicated for personal or public health reasons.

EARLIER MDA STUDIES IN DREIKIKIR, PAPUA NEW GUINEA

From 1993 to 1998, we examined the impact of four annual single doses of MDA (block randomization of DEC alone [6 mg per kg body weight] vs. DEC + ivermectin [400 μg per kg]) on anopheline-trans-mitted W. bancrofti in Dreikikir, East Sepik Province, Papua New Guinea. These data have been pub-lished.1,2 The key findings were that: a) transmission by Anopheles punctulatus and An. koliensis, the major vectors of LF in Papua New Guinea, was reduced by 96.7% in the low transmission zone one year after the fourth cycle of MDA; b) the human microfilaria+ (mf+) rates were reduced by 86%–98% one year after the fourth cycle of MDA; c) there was no significant difference in reduction of transmission and human infection after the third cycle of MDA; d) the impact of MDA on mosquito and human infection levels was greatest in areas where the pre-treatment level of transmission was moderate (annual transmission potential [ATP] 45–404 L3/person/year) vs. areas where transmission was relatively higher (ATP 704–2518 L3/person/year). Salient data supporting these claims are presented in table 1 and figure 1.

MASS TREATMENT FOR LYMPHATIC FILARIASIS

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antifilarial drugs, 19 percent received one dose, 21 per-cent received two doses, 24 percent received threedoses, and 35 percent received all four doses. Fifty per-cent of the episodes of noncompliance were not ran-dom (e.g., half the subjects who did not take the med-ication in 1997 also did not do so in 1995 and 1996).There were no significant differences between thenumber of doses of diethylcarbamazine plus ivermec-tin that were taken and the number of doses of diethyl-carbamazine alone that were taken.

Adverse Reactions

No severe reactions were observed. Minor reactionswere reported after the first treatment by 20 percentof subjects who took diethylcarbamazine plus ivermec-tin (93 of 472) and 11 percent of subjects who tookdiethylcarbamazine alone (53 of 494) (

x

2

=14.3, P<0.01). Seven hundred fifty-four of these subjects tookthe medications the following year. Nine of 146 sub-jects who had minor side effects after the first treat-ment (6 percent) declined to take the second annualdose, as compared with 111 of 608 who did not havean adverse reaction after the first treatment (18 per-cent) (

x

2

=11.9, P<0.01).

Effect of Treatment on the Reservoir of Microfilariae

Annual treatment reduced the reservoir of microfi-lariae (Table 1). The initial decrease was greatest intreatment units with a moderate rate of transmissionwhose inhabitants were randomly assigned to receivediethylcarbamazine plus ivermectin. Forty-seven per-cent of such subjects were positive for microfilariae

before the initial treatment, as compared with 1 per-cent one year after the fourth treatment (

x

2

=475.9,P<0.001). In units with a high rate of transmission,the rate of positivity for microfilariae decreased from77 percent to 5 percent during the same period (

x

2

=287.5, P<0.001). In units whose inhabitants were ran-domly assigned to receive diethylcarbamazine alone,the rates decreased from 42 percent before the initialtreatment to 2 percent one year after the fourth treat-ment in areas with a moderate rate of transmission andfrom 76 percent to 11 percent in areas with a high rateof transmission.

A generalized estimating equation was used to ac-count for the correlation of observations clusteredwithin various treatment units. The model to estimatethe odds of microfilarial infection included the drugregimen, the estimated transmission potential beforetreatment, the year of observation, and an interactionterm for year and treatment regimen that was based ona logit link and an independent working correlationstructure. The efficacy of diethylcarbamazine plus iver-mectin was greater than that of diethylcarbamazinealone one year after the first, second, and third annualtreatments (Fig. 2). For example, after the third treat-ment, residents of sites randomly assigned to receivediethylcarbamazine alone were 3.3 times as likely tobe positive for microfilariae as those who lived in areaswhere diethylcarbamazine plus ivermectin was given(95 percent confidence interval, 1.04 to 10.57; P=0.04), and the odds of being positive for microfilar-iae were 3.5 times as great for residents of areas witha high rate of transmission as for residents of areas

*Four treatment units with a moderate transmission rate were randomly assigned to receive diethylcarbamazine plus ivermectin, and four were assignedto receive diethylcarbamazine alone; three treatment units with a high transmission rate were randomly assigned to receive diethylcarbamazine plus iver-mectin, and three were assigned to receive diethylcarbamazine alone.

†P<0.001 for the comparison with all other years.

T

ABLE

1.

E

FFECT

OF

F

OUR

A

NNUAL

T

REATMENTS

WITH

D

IETHYLCARBAMAZINE

PLUS

I

VERMECTIN

OR

D

IETHYLCARBAMAZINE

A

LONE

ON

THE

R

ESERVOIR

OF

M

ICROFILARIAE

IN

T

REATMENT

U

NITS

WITH

A

M

ODERATE

R

ATE

OF

T

RANSMISSION

AND

T

REATMENT

U

NITS

WITH

A

H

IGH

R

ATE

OF

T

RANSMISSION

, A

CCORDING

TO

Y

EAR

.*

T

REATMENT

AND

V

ARIABLE

M

ODERATE

T

RANSMISSION

R

ATE

H

IGH

T

RANSMISSION

R

ATE

1994 1995 1996 1997 1998 1994 1995 1996 1997 1998

Diethylcarbamazine plus ivermectin

No. of subjects examined 797 756 790 819 750 281 318 311 303 266No. of microfilariae-positive

subjects (%)376 (47)† 156 (21) 45 (6) 8 (1) 7 (1) 216 (77)† 101 (32) 74 (24) 33 (11) 14 (5)

Geometric mean no. ofmicrofilariae/ml

9.6 0.9 0.3 0.3 0.5 49.8 2.9 2.6 0.6 0.3

Diethylcarbamazine alone

No. of subjects examined 903 815 802 692 639 243 192 253 257 165No. of microfilariae-positive

subjects (%)381 (42)† 238 (29) 121 (15) 47 (7) 10 (2) 185 (76)† 98 (51) 107 (42) 56 (22) 18 (11)

Geometric mean no. ofmicrofilariae/ml

8.8 2.6 0.9 0.3 0.5 55.2 13.1 7.8 1.4 0.5

Copyright © 2002 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by N NINA MATTOCK on May 1, 2006 .

Table 1. effect .of .four .annual .treatments .with .diethylcarbamazine .plus .ivermectin .or .diethylcarbamazine .alone .on .the .reservoir .of .microfilariae .in .treatment .units .with .a .moderate .rate .of .transmission .and .treatment .units .with .a .high .rate .of .transmission, .according .to .year*

reprinted .from: .bockarie .mj .et .al .2 . .copyright .© .2002 .massachusetts .medical .society . .all .rights .reserved . .


UNPUBLISHED ANALYSES OF IMPACT OF MDA FOLLOWING CESSATION OF SYSTEMATIC DRUG DISTRIBUTION

Formal studies of LF ceased in the Dreikikir area in 1998 because of financial constraints. Antifilarial drugs, bednets and other potential interventions have not been available to the population from either the investigators or the Papua New Guinea Ministry of Health. We have however been able to initiate work that will enable us to assess the long-term effects of the MDA trial to aid in planning for future interventions.

CHILDHOOD INFECTION

In order to determine the immediate impact of MDA on infection in persons with limited exposure to L3, we measured Og4C3 antigen levels of under-10-year-old children one year after the fourth cycle of MDA (1998). Three hundred and twenty-four chil-dren were examined, and 89 (27%) were infected (titre group ≥4). The distribution of infection accord-ing to age and antigen level scored as ‘low’ or ‘high’ (titre group 4–5 and 6–7, respectively) are shown in table 2. Of children 4–6 years of age, born at most two years before initiation of MDA in 1994 and therefore unlikely to have been infected prior to the initiation of the study, 24 of 67 (36%) were antigen positive. These data suggest that transmission con-tinued following initiation of MDA.

A subset of 36 children in this group was examined again in 2003 in order to assess whether ‘new’ infec-tions might have been established after cessation of MDA six years earlier. In 1998, 28 children were antigen negative and 8 were antigen positive. All 36 were antigen negative in 2003.

Figure 1. odds .of .microfilariae-positive .infection .over .the .five-year .study .period .among .subjects .in .treatment .areas .with .moderate .and .high .rates .of .transmission .randomly .assigned .to .receive .diethylcarbamazine .plus .ivermectin .or .diethylcarbamazine .alone . . . . .the .first .annual .dose .of .each .drug .regimen .was .given .immediately .after .the .determination .of .microfilarial .status .in .1994 . .the .odds .of .microfilariae-positive .infection .were .less .than .0 .1 .in .1998, .regardless .of .the .drug .regimen .or .the .base-line .transmission .potential .

Table 2. og4c3 .antigen .status .of .children .one .year .after .the .fourth .cycle .of .mda

Age 4 Age 5 Age 6 Age 7 Age 8 Age � Age 10

antigen .positive .(low, .high)* 1(0,1) 5(3,2) 18(9,9) 16(10,6) 21(14,7) 21(11,10) 7(3,4)

antigen .negative 2(66%) 18(78%) 23(56%) 31(65%) 54(72%) 61(74%) 46(86%)

total .number 3 . 23 41 . .47 . .75 . 82 . 53

* .numbers .in .parentheses .indicate .number .of .children .with .low .or .high .antigen .levels .

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with a moderate rate of transmission (95 percent con-fidence interval, 1.30 to 9.09; P=0.02). After thefourth treatment, however, the odds of microfilariae-positive infection decreased to less than 0.1, regard-less of whether subjects lived in an area with a mod-erate or a high rate of transmission and regardless ofwhether they were given diethylcarbamazine plus iver-mectin or diethylcarbamazine alone.

Effect of Treatment on Transmission

Before treatment, there were 24 to 167 bites frommosquitoes containing infective larvae per person peryear in treatment units with a moderate rate of trans-mission and 224 to 742 infective bites per person peryear in units with a high rate of transmission; the re-spective ranges for the transmission potential were 45to 404 and 704 to 2518 infective larvae inoculatedper person per year. Detailed entomologic indexes intwo treatment units where diethylcarbamazine plusivermectin was used are presented in Figure 3.

In the unit with a moderate rate of transmission, theoverall transmission potential decreased by 97 percent(from 704 to 23 infective larvae inoculated per per-son per year). The effect of treatment was less marked

in the unit with a higher rate of transmission. The pre-treatment transmission potential of 1485 infective lar-vae inoculated per person per year decreased to 234infective larvae inoculated per person per year the yearafter the third annual treatment (84 percent reduc-tion). The pattern of exposure to infective mosqui-toes also differed according to the pretreatment rateof transmission. In units with a moderate rate of trans-mission before treatment, after treatment there wasan average of 0 bites from infective mosquitoes perperson per month during 11 months of the year. Incontrast, in units with a high rate of transmission be-fore treatment, rates remained moderate to high (1 tomore than 30 bites from infective mosquitoes per per-son per year) for five to seven months per year aftertreatment was initiated.

To estimate the effect of mass treatment on the es-tablishment of new infections, we compared the prev-alence of microfilariae-positive infections in previouslyuntreated cohorts of five-to-six-year-old children fromeach year of the study for the treatment regimens com-bined. Before the initial treatment, 28 of 64 children(44 percent) were positive for microfilariae. A total of9 percent were positive for microfilariae in 1995 (3 of32), 11 percent in 1996 (8 of 71), 2 percent in 1997(1 of 42), and 6 percent in 1998 (3 of 52) (

x

2

=12.9for the comparison between the pretreatment valueand the value in 1998, P<0.001).

Effect on Filarial Antigen Level

Estimates of the levels of circulating filarial antigenalone, independent of the blood level of microfilari-ae, are thought to reflect the burden of pre-adult andadult worms.

23-25

Antigen levels were monitored be-tween 1994 and 1997 in residents of two treatmentunits (Table 2). Fewer than 20 percent of subjects whowere antigen-positive before the trial began were an-tigen-negative one year after the third annual treat-ment, though mean antigen levels decreased by 79percent. There was no significant difference in theseproportions between the two drug regimens. Chang-es in antigen status and level did not correlate with thenumber of treatments a subject received. No subjectswho were identified as antigen-negative before thetrial began were antigen-positive in subsequent years,and in no case did the antigen level increase relativeto the pretreatment value.

Effect of Treatment on Hydrocele and Leg Lymphedema

The proportion of male subjects with advanced hy-drocele who were at least 16 years old was 15 percent(110 of 726) before the trial began and 5 percent (27of 563) one year after the fourth treatment (x2=35.8,P<0.001). There was no significant difference in thefrequency or odds of hydrocele between the two drugregimens, after adjustment for the clustering of treat-

Figure 2. Odds of Microfilariae-Positive Infection over the Five-Year Study Period among Subjects in Treatment Areas with Mod-erate and High Rates of Transmission Randomly Assigned toReceive Diethylcarbamazine plus Ivermectin or Diethylcarbam-azine Alone.The first annual dose of each drug regimen was given immedi-ately after the determination of microfilarial status in 1994. Theodds of microfilariae-positive infection were less than 0.1 in 1998,regardless of the drug regimen or the base-line transmissionpotential.

4

0

1

2

3

19981994 1995 1996 1997

Year of Study

Od

ds

of

Mic

rofi

lari

al In

fect

ion

Diethylcarbamazine + ivermectin,mhigh transmission rateDiethylcarbamazine alone,mhigh transmission rateDiethylcarbamazine + ivermectin,mmoderate transmission rateDiethylcarbamazine alone,mmoderate transmission rate

Copyright © 2002 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by N NINA MATTOCK on May 1, 2006 .

1

reprinted .from: .bockarie .mj .et .al .2 .copyright .© .2002 .massachusetts .medical .society . .all .rights .reserved .

.


COMMUNITY INFECTION RATES SIX YEARS AFTER CESSATION OF MDA

We obtained blood samples in 2003 from 538 resi-dents of three moderate transmission villages that were part of the MDA trial. The prevalence of mf+ samples (mf quantified after nucleoprotein filtra-tion of 1 ml blood obtained between 22.00 hrs and 02.00 hrs) had been 34% prior to initiation of MDA (1993–4), and 0.4% one year after the final year of four annual treatments with MDA. Upon re-exam-ination in 2003, only three of the 538 individuals (0.5%) were mf+. Two of the three mf+ persons had not participated in the MDA programme and had never received antifilarial drugs (although recorded as residents of the villages, they were absent when distribution of the drugs occurred). The remaining mf+ individual was an immigrant from a surround-ing area where MDA had not been used.

Og4C3 assays have been completed for 132 study participants from whom plasma was available in 1998 and 2003 (the assays were performed on matched samples using the same plate). As indi-cated in table 3, among individuals who were anti-gen positive in 1998, 23% remained positive six years later. Only one individual who was antigen negative in 1998 was antigen positive in 2003. When antigen status was examined as a continuous variable, 98% of individuals who were antigen positive in 1998 had lower or undetectable levels in 2003.

Table 3. long-term .effect .of .mda .on .infection .as .determined .by .filarial .antigenaemia

Number Antigen positive six

years post-MDA

antigen .negative .one .year .after .final .mda .71 .1 .(1 .4%)

antigen .positive .one .year .after .final .mda .61 .14 .(23 .0%)

Taken together, these data suggest that human LF infection remained reduced with no evidence of recrudescence six years after cessation of MDA and in the absence of other systematic interventions against LF.

ENTOMOLOGICAL INDICATORS OF LF TRANSMISSION

In order to assess the long-term impact of the four cycles of MDA on entomological indictors of trans-mission, Anopheles punctulatus and An. koliensis mos-quitoes attempting to feed on human volunteers between 18.00 hrs and 06.00 hrs were captured and the proportion infected with any larval stage or L3 enumerated. Table 4 below presents results for the pre-treatment period (1993/4), selected years dur-ing the MDA study, and for 2003/4, six years after cessation of MDA in the three villages where mf and Og4C3 antigen levels were determined. Following reductions in the proportions of infected and infec-tive mosquitoes after the first and second cycles of MDA, these values continued to decrease with no recrudescence six years after cessation of MDA. Only one infected mosquito and no mosquitoes with L3 were identified in 2003/4. These results par-allel those for human infection indicators, suggest-ing that LF transmission may be extinguished by the four cycles of MDA completed six years earlier.

Table 4. Anopheles .mosquitoes .containing .any .larval .stage .and .l3 .in .three .study .villages

Year No. dissected

No. infected

(%)

No. with L3 (%)

Months with

MTP>0

1993/4 1195 89 .(7 .50) 22 .(1 .8) 8

1994/5 1500 14 .(0 .93) 2 .(0 .13) 1

1995/6 1172 8 .(1 .68) 3 .(0 .26) 1

2003/4 .(aug .03–jan .04) 764 1 .(0 .10) 0 .(0 .00) 0

mtp .– .monthly .transmission .potential


POINTS FOR DISCUSSION

• Evaluation of villages where pre-treatment trans-mission intensities are higher than those exam-ined to date is necessary to evaluate more fully the impact of these earlier MDA studies con-ducted in Papua New Guinea.

• The promising results of our earlier MDA trial suggest that additional interventions such as insecticide-impregnated bednets may be useful to accelerate reduction of transmission and pos-sibly eradication of LF in areas where anopheline mosquitoes are the primary or exclusive vectors.

• The importance of facilitation in the vector–para-site relationship may account in part for the sus-tained reduction in transmission observed to date.

• Variables such as population coverage with MDA and pre-existing transmission level may influ-ence the success of LF control in Papua New Guinea and other areas of anopheline-transmit-ted filariasis. Deterministic and stochastic models may be helpful in this context.

• These earlier studies in Papua New Guinea used single annual doses of DEC alone or DEC + iver-mectin, combinations that predated the current recommendation of DEC plus albendazole. It will be useful to determine the potential added bene-fit of albendazole to DEC in future work.

References

1. Bockarie MJ et al. Randomised community-based trial of annual single-dose diethylcarbamazine with or without ivermectin against Wuchereria bancrofti infec-tion in human beings and mosquitoes. Lancet, 1998, 351:162–168.

2. Bockarie MJ et al. Mass treatment to eliminate filariasis in Papua New Guinea. New England Journal of Medicine, 2002, 347(23):1841–1848.


4D: IMPACT OF MASS DRUG ADMINISTRATION ON ANOPHELES-TRANSMITTED FILARIASIS IN AFRICA: EMERGING DATA FROM GHANA AND MALI

Gyapong JO,1 Boakye DA2 and Traore SF3 1 Health Research Unit, Ghana Health Service, Accra,

Ghana2 Noguchi Memorial Institute for Medical Research,

University of Ghana, Legon, Ghana3 Faculty of Medicine, Pharmacy and Dentistry of

Bamako Malaria Research & Training Centre, Bamako, Mali

INTRODUCTION

Recent evidence suggests that anopheline transmit-ted lymphatic filariasis can be eliminated world-wide because of the phenomenon of facilitation. This hypothesis indicates that, at low microfilaria densi-ties, Anopheles vectors of filariasis are less efficient in transmitting Wuchereria bancrofti. This has been borne out by observations in Papua New Guinea where the vector is Anopheles punctulatus (Bockarie et al., 1998). However, it may not be practical to gen-eralize this observation worldwide since the thresh-old levels of microfilaraemia needed for elimination of anopheline transmitted W. bancrofti lymphatic filariasis (LF) might differ from species to species (Southgate, 1992[a], 1992[b]; Southgate and Bryan, 1992). For example, results from earlier studies in sub-Saharan Africa, on the quantitative relation-ship between transmission intensity and microfilar-ial reservoir, indicated variation among members of the An. gambiae complex and An. funestus (Bryan and Southgate, 1988[a], 1988[b]); McGreevy et al., 1982; Bryan, McMahon and Barnes, 1990).

In Ghana, several sympatric Anopheles species are vectors of Wuchereria bancrofti (Dzodzomenyo et al., 1999); these species are likely to differ in their vectorial role and capacity to transmit low den-sity microfilaraemia. For example, Appawu et al. (2001) observed that no An. arabiensis (a member of the An. gambiae complex) was positive for W. ban-crofti although this species formed 9%–14% of An. gambiae s.l. Furthermore, analysis of pooled data for Anopheles mosquitoes from a recent study by Boakye et al. (2004) indicated presence of the ‘limitation’ process, although larger samples need to be investi-gated to determine whether this process occurs only

in An. gambiae s.l. or An. funestus or in both of these taxa.

Although the impact of treatment on transmission of LF has not been studied in Ghana, there have been some transmission studies and investigations on the efficacy of different treatment regimes (Appawu et al., 2001; Dunyo et al., 2000). Concerning treatment efficiency, Dunyo and Simonsen (2002) observed that re-treatment of Wuchereria bancrofti microfila-raemia with a combination of ivermectin and alben-dazole resulted one year later in an overall mean reduction in microfilarial intensity of 76.2%. The efficacy of the combination treatment thus appeared to be largely independent of the type of primary treatment given and was multiplicative when used repeatedly. Gyapong (2000) evaluated the impact of a single dose of ivermectin in six communities in Ghana after two years (due to unavailability of the drug for re-treatment in the second year); this showed the community microfilaraemia prevalence and intensity to be reduced, respectively, by only 25.5% and 39.5% of pre-treatment levels.

Although LF has been known in Mali since 1912 (Thiroux), only a few studies have been aimed at determining disease burden and transmission pat-terns (Touré, 1979; Keita, 1979). The data show, how-ever, that the LF infection rate increases from the northern to the southern part of the country, and they confirm the nocturnal periodicity of W. ban-crofti. Entomological data have identified the gam-biae and funestus complexes as the main vectors of LF in Mali. Recently Coulibaly (2002) reported a sur-vey carried out 20 years after a previously reported study in the same endemic area (savannah area). The data show a significant decrease of infection rate in both human and vector in the absence of any control measures. Data from Keita (2002) however, on the prevalence of elephantiasis in the country, show that LF is a major public heath problem in Mali.

The Ministry of Health (MOH) coordinating group undertook mapping of LF in eight regions of the country in 2002, and in Bamako, the capital city, in 2004 (supported by WHO). In the eight regions, the infection rate by the immunochromatographic card test (ICT) ranged from 1% in Timbuktu (north-ern part) to 18.6% in Sikasso (southern part) with a mean infection rate of 7.07% (n = 100 per commu-nity). In the capital city (six communes), the average infection rate was 1.5% (n = 5990); four communes were found positive using ICT.

The Lymphatic Filariasis Elimination Programme of the Ghana Health Service and the Malian MOH are undertaking elimination of LF using mass drug


administration (MDA) with ivermectin and albenda-zole. The elimination programmes have been set up in both countries as part of the Global Programme to Eliminate Lymphatic Filariasis using the follow-ing strategies:• Information, education and communication

(IEC).• Mass drug administration to the populations at

risk.• Prevention of disabilities. • Integration into other programmes at opera-

tional, intermediate and central levels.

This provides the opportunity to investigate the impact of MDA on transmission by members of the An. gambiae complex and An. funestus group.

CURRENT STATE OF KNOWLEDGE AND AVAILABLE EVIDENCE ON IMPACT OF MDA ON TRANSMISSION

These studies were organized as multicountry stud-ies with the aim of evaluating the effect of commu-nity-based mass chemotherapy on the transmission of LF. The specific objectives were to:• Determine the infection rates in mosquitoes after

two rounds of community-based mass treatment. • Determine the prevalence of W. bancrofti infection

and associated clinical signs after one round of community-based mass treatment.

• Identify and determine the prevalence of adverse events (side effects) associated with mass treat-ment with albendazole–ivermectin.

• Determine the trend of major entomological and parasitological parameters after two rounds of treatment.

In Ghana, the study sites included eight villages in a district with a record of filariasis endemicity where there had not been any community-wide treatment but which had been earmarked for treatment with ivermectin and albendazole. A census was carried out in all eight villages: all houses were enumerated and demographic data of the inhabitants recorded, including the use of bednets. In Mali, similar base-line data were collected using a common protocol.

Entomological studies (assessing transmission)

Mosquito collection

Each village was divided into four sections and one house per section selected randomly for over-night mosquito collection using the man-landing catch method. Four houses were sampled in each village per night (from July to December, from 2001 to 2004); the mosquitoes were later dissected in the laboratory.

Parasitological studies

Inhabitants surveyed for W. bancrofti infection were randomly selected by computer. The first preva-lence survey was conducted during February 2002 before mass treatment of the inhabitants (in March 2002). Subsequent surveys were done in 2003, 2004 and 2005. Each time, the surveys preceded MDA in the communities.

Results

Ghana

The average coverage by MDA in the three years for the eight villages was around 66% (table 1). The low-est coverage was 13.9% in the village of Fawomanye in 2002; this situation improved to 62% and 65% in subsequent years (2003 and 2004, respectively). At the time of writing, treatment had been completed at all sites for 2005 and data were being collected.

Community 2002 2003 2004

obiri 90 .3 65 58

hwida 87 .4 79 73

dego 85 60 51

ayensuano 78 .3 97 86

fawomanye 13 .9 62 65

Kyiren 75 .8 52 79

amanful 76 .5 62 58

mampong - 55 63

% Mean coverage 63.4 66.5 66.625

Table 1. mass .drug .administration .treatment .coverage .(%) .with .ivermectin .and .albendazole .in .the .study .communities .(Ghana)


Parasitological examination of blood smears has shown a decrease in proportion of positive individ-uals in the population. In 2002, the proportion was 4.6%; in the most recent survey, in January 2005, this had declined to 0.9% (fig. 1 and table 2).

Final analysis of the entomological data for 2005 is being compiled. Data for the first three years showed an overall decreasing trend in the annual transmission potential (ATP) (from 356.2 in 2001, through 296.6 in 2002, to 229.4 in 2003) (fig. 2). However, when this was broken down to the contri-butions made by different Anopheles species, it was realized that, while the ATP of An. funestus had sig-nificantly decreased, that for An. gambiae had not. A critical examination of the data indicated that the ATP is being influenced by collections from one site (Mampong); the current analysis will take this into account. The ATP is mirrored in the annual infective biting rate (fig. 3).

Figure 1. mean .prevalence .of .microfilaraemia .over .a .four-year .period .(Ghana)

Table 2. .2001–2004: .blood .sampling .results .for .infections .with .W. bancrofti (Ghana) .

VILLAGE NUMBER EXAMINED NUMBER POSITIVE RANGE OF DENSITIES (mf/ml)

2001 2002 2003 2004 2001 2002 2003 2004 2001 2002 2003 2004

G . .mamponG 50 33 25 63 7 1 1 0 .20–550 310 80 0

Kyeren 120 58 54 161 0 0 0 0 0 0 0 0

amanful 44 30 43 61 0 0 0 0 0 0 0 0

faWomanyo 53 28 36 66 2 0 0 0 .30–140 0 0 0

obiri 80 38 48 70 0 0 1 0 0 0 1 0

hWida 100 47 50 88 12 2 4 2 10–3230 600–1500 20–990 5–21

daGo 442 112 105 228 21 1 4 4 10–5010 10 10–980 1–4

ayensuano 52 34 36 69 1 3 2 1 60 30 100–670 4

941 380 397 806 43 7 12 7

proportion 0 .046 0 .018 0 .030 0 .009

Figure 3. annual .infective .biting .rate .(aibr) .trends .for .the .main .Anopheles .vector .species .from .2001 .to .2004 .(Ghana)

Figure 2. annual .transmission .potential .(atp) .trends .for .the .main .Anopheles .vector .species .from .2001 .to .2004 .(Ghana)


Mali

The treatment coverage based on total study popu-lation was 67% with 0.6% having side effects in 2002, and 69.4% with 0.4% having side effects in 2003.

PARASITOLOGICAL AND CLINICAL STUDIES

• 2001 sample size: 1141 people, with 29.7% loss to follow-up in 2004.

• Average infection rate: 9.3% reduction between 2002 and 2004 (fig 4).

• Geometric mean parasitaemia: 19.5% between 2001 and 2004.

• Side effects: 0.6% in 2002 and 0.4% in 2003.

ENTOMOLOGICAL STUDIES

• Main vectors: An. gambiae s.l. (>86%) and An. funestus (table 3).

• Infection rate: 73.8% reduction between 2001 and 2004 (after two MDAs) (fig 5).

• Infectivity rate: 94.8% reduction between 2001 and 2004 (after two MDAs) (fig 5).

• Man-biting rate: not affected by the treatment (after two MDAs) (fig 6).

• Annual transmission potential: 97.25% reduction between 2001 and 2004 (fig 7).

Figure 4. parasitological .data .variation .before .and .after .treatment .(mali) .

Table 3. species .composition .(mali) .

Mali: An. funestus An. gambiae s.1

Total no. of mosquitoes examined

2001 9 .9% 90 .1% 23 .265

2002 14 .0% 86 .0% 12 .986

2003 3 .1% 96 .9% 18 .394

2004 9 .2% 90 .8% 13 .021

Figure 5. vector .infection .and .infectivity .rates, .2001–2004 .(mali)

Figure 6. vector .man-biting .rates .(mbr) .and .entomological .inoculation .rates .(eir), .2001–2004 .(mali)

Figure 7. vector .annual .transmission .potential, .2001–2004, . .expressed .in .number .of .infective .bites .per .man .per .year


SUMMARY OF THE MAJOR REMAINING UNCERTAINTIES AND RESEARCH QUESTIONS, AND SUGGESTIONS FOR SPECIFIC STUDIES

The observation that Anopheles-transmitted W. ban-crofti in the Bongo area of Ghana shows the process of limitation (Boakye et al. 2004) indicates that the situation needs clarification in terms of the species involved in transmission. A similar study to look at specific Anopheles species is necessary.

The study on trends in transmission after MDA in the eight communities in Ghana indicates that some of the vectors (An. gambiae s.s.) are able to pick up the infection and transmit infective larvae at very low levels of microfilaraemia in humans. Although the 2004 entomological analysis is yet to be completed, it may be necessary to consider continuing the study for longer than the five years of MDA planned by the national programme. As now planned, the study will end after four years of MDA, but this may not be enough to arrive at a definite conclusion.

Pichon (2002) postulated that low level prevalence and intensity of microfilaraemia may increase the

mean lifespan of some of the local Anopheles spe-cies and may worsen the problem posed by malaria. How this increase in mean lifespan affects the transmission of W. bancrofti has not, however, been examined.

Issues to be addressed to increase the chances of eliminating lymphatic filariasis by mass drug administration

• Treatment coverage required to have maximum impact and reduce the duration of intervention.

• Untreated people (persistent refusals, migration) as a source of vector infection.

• IEC for better involvement of the population.• Vector control as an adjunct to MDA.

Suggestions for specific studies

• Impact of insecticide-treated nets on LF transmis-sion: effect of intense use during MDA in high, middle and low transmission areas.

• Finding a good macrofilaricidal drug: other drugs (e.g. if combined with antibiotics) with effects on adult worm (as deduced by sono-graphic assessment).


References

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Boakye DA et al. Vector competence, for Wuchereria bancrofti, of the Anopheles populations in the Bongo district of Ghana. Annals of Tropical Medicine and Parasitology, 2004, 98:501–508.

Bryan JH, McMahon P, Barnes A. Factors affecting transmission of Wuchereria bancrofti by anopheline mosquitoes. 3. Uptake and damage to ingested micro-filariae by Anopheles gambiae, An arabiensis, An. merus and An. funestus in East Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1990, 84:265–268.

Bryan JH, Southgate BA. Factors affecting transmis-sion of Wuchereria bancrofti by anopheline mosqui-toes. 1. Uptake of microfilariae. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1988[a], 82(1):128–137.

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Bockarie MJ et al. Randomised community-based trial of annual single-dose diethylcarbamazine with or without ivermectin against Wuchereria bancrofti infec-tion in human beings and mosquitoes. Lancet, 1998, 351(9097):162–168.

Coulibaly YI. Etude des aspects parasitologiques, cli-niques, entomologiques de la transmission de la filariose lymphatique en zone de savane soudanienne au Mali (vil-lage de Banambani et de Sirakoro Niaré). FMPOS thèse de Médecine Bamako, 2002.

Dunyo SK, Nkrumah FK, Simonsen PE. A randomized double-blind placebo-controlled field trial of ivermec-tin and albendazole alone and in combination for the treatment of lymphatic filariasis in Ghana. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000, 94:205–211.

Dunyo SK, Simonsen PE. Ivermectin and albendazole alone and in combination for the treatment of lym-phatic filariasis in Ghana: follow-up after re-treatment with the combination. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2002, 96:189–192.

Dzodzomenyo M et al. Bancroftian filariasis in an irri-gation project community in southern Ghana. Tropical Medicine and International Health, 1999, 4:13–18.

Gyapong JO. Impact of single-dose ivermectin on community microfilaria load in bancroftian filaria-sis infection: two years post treatment. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000, 94:434–436.

Keïta MF. Aspects épidémiologiques des filarios-es à Onchocerca volvulus, Wuchereria bancrofti et Tetrapetalonema perstans. Etude de leur association au Mali. Bamako, thèse de Médecine, Ecole Nationale de Médecine et de Pharmacie du Mali, 1979.

Keita F. Etude de la prise en charge de l’étiologie filarienne des grosses jambes non tumorales et des hydrocèles non infectieuses au Mali. Thèse Nº22 de Pharmacie FMPOS, Bamako, Mali, 2002.

McGreevy PB et al. Ingestion and development of Wuchereria bancrofti in Culex quinquefasciatus, Anopheles gambiae and Aedes aegypti after feeding on humans with varying densities of microfilariae in Tanzania. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1982, 76(3):288–296.

Pichon G. Limitation and facilitation in the vectors and other aspects of the dynamics of filarial transmis-sion: the need for vector control against Anopheles-transmitted filariasis. Annals of Tropical Medicine and Parasitology, 2002, 96:S143–152.

Southgate BA. The significance of low density micro-filaraemia in the transmission of lymphatic filari-al parasites. Journal of Tropical Medicine and Hygiene, 1992[a], 95:78-86.

Southgate BA. Intensity of transmission and develop-ment of microfilaraemia and disease: their relation-ship to lymphatic filariasis. Journal of Tropical Medicine and Hygiene, 1992[b], 95:1-12.

Southgate BA, Bryan JH. Factors affecting transmis-sion of Wuchereria bancrofti by anopheline mosquitoes. 4. Facilitation, limitation proportionality and their epidemiological significance. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1992, 86:523–530.

Thiroux A. Les filarioses embryonnaires du sang des indigènes de l’Afrique Occidentale Française 1912. Bulletin de la Societe de Pathologie Exotique, 1912, 5:438–450.

Touré YT. Bio-écologie des anophèles (Diptera, culcidea) dans une zone rurale de savane soudanienne au Mali (vil-lage de Banambani). Incidence sur la transmission du paludisme et de la filariose de bancroft. Mali, Bamako, thèse de 3ème cycle, Centre Pédagogique Supérieur, 1979.


4E: IMPACT OF MASS DRUG ADMINISTRATION ON INFECTION AND TRANSMISSION OF LYMPHATIC FILARIASIS IN EGYPT

Ramzy RMR,1 El Setouhy M,1 Helmy H,1 Ahmed ES,1 Abdel Aziz K,1 Farid HA,1 Weil GJ2

1 Research and Training Center on Vectors of Diseases, Ain Shams University, Cairo, Egypt

2 Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri, USA

ABSTRACT

Egypt was among the first countries to implement a national filariasis elimination programme based on annual mass drug administration (MDA) with dieth-ylcarbamazine (DEC) and albendazole (target popu-lation about 2.5 million in 181 endemic towns and villages). We evaluated the impact of four rounds of MDA in four sentinel villages. Circulating filar-ial antigen (CFA, immunochromatographic card test [ICT]), microfilaraemia (mf) prevalence rates and levels, and MDA coverage were assessed in ran-domly selected households before and 6–8 months after each round of MDA. Mf testing (by membrane filtration of night blood) was limited to those with positive CFA tests. MDA coverage rates were 86.7%, 95.5%, 90.1% and 88.8% for rounds 1 to 4, respec-tively, in our study villages. Pretreatment infection rates varied significantly among the study villages. Overall mf prevalence decreased 98%, from 8.0% to 0.16%, after four MDA rounds. Mf/ml/popu-lation fell 96.9%, from 13.0 to 0.4. CFA prevalence decreased 86.4%, from 15.7% to 2.3%. The smaller reduction in CFA prevalence (compared to mf) may indicate survival of adult worms in some subjects who cleared mf. We also assessed antibody preva-lence rates (IgG4 to Bm14) in primary school chil-dren in study villages before and after MDA. Antibody rates decreased from 20.6% before MDA to 2.7% six months after the fourth round of MDA. Indoor-resting mosquitoes were collected before and after MDA at night, pooled by house, and infection rates assessed by the Ssp1-PCR assay. The overall minimum mosquito infection rate (assuming that a positive mosquito pool contained one infected mos-quito) decreased 90.8%, from 2.8% before MDA to 0.26% after four rounds of MDA. Elimination tar-gets were achieved more quickly in the villages with low rates. Since most of the 181 localities included in the MDA programme had low baseline infection

parameters, our results suggest that filariasis would be eliminated in most endemic villages of Egypt by five rounds of MDA.

INTRODUCTION

Bancroftian filariasis, a deforming and disabling parasitic disease caused by the filarial nematode Wuchereria bancrofti, is endemic in some 80 coun-tries with an estimated 100 million infected people (TDR, 1997). In 2000, the World Health Organization (WHO) initiated a Global Programme for Elimination of Lymphatic Filariasis (GPELF), which is based on repeated annual cycles of mass drug administration of single-dose drug combinations to at-risk popu-lations. By such an approach, the GPELF aims to interrupt transmission of filariasis by attacking the reservoir of microfilariae (mf) and thereby reduc-ing the uptake of parasites by mosquitoes. Recent reports indicate that the programme has expanded rapidly to cover approximately 60 million people in 34 countries in 2002 (Molyneux and Zagaria, 2002).

Nocturnally periodic lymphatic filariasis caused by Wuchereria bancrofti has been endemic in Egypt for a long time (Harb et al, 1993). Culex pipiens is the main mosquito vector responsible for transmission of filariasis in Egypt (Southgate, 1979). Filariasis has a highly focal distribution in Egypt with most cases in the densely populated governorates in the Nile Delta. There are also foci of infection in Giza and Asiut governorates in Upper Egypt (Harb et al, 1993). Recent spot surveys (Weil et al., 1999) have shown that mf prevalence rates and intensity of infection are low.

Egypt was among the first countries to join the WHO global efforts and develop a national programme to eliminate LF (NPELF) as a public health problem. The NPELF has a major goal: to interrupt transmis-sion by decreasing mf prevalence rates to less than 0.1% by MDA of an annual dose of DEC (6 mg/kg) in combination with albendazole (400 mg). A total of 181 villages (implementation units) with mf smear or filarial antigen prevalence rates of 1% or more are included in the programme. To be successful, the NPELF aims to achieve an MDA coverage rate of about 80% of the at-risk population in the target villages. However, children below two years of age and pregnant women are excluded from MDA.

Although several studies have documented the effects of community-based single-dose DEC on microfilaria prevalence rates and levels (Ramzy et al., 2002), so far studies to evaluate the effects of MDA based on combined regimens are lacking. Over the last decade, our group has been actively


involved in developing and evaluating various epi-demiological tools for monitoring the effect of treat-ment on infection rate and transmission parameters. These include detecting serological markers such as circulating filarial antigen (CFA) by the ICT (Weil et al., 1997; Ramzy et al., 1999) and Bm14-IgG4 anti-bodies by the ELISA, and a molecular marker, the Ssp1-PCR assay, for detecting W. bancrofti DNA in the mosquito vector (Ramzy et al., 1997).

As of October 2004, the NPELF had completed five cycles of MDA in 161 endemic villages (and 1 to 4 cycles of MDA in an additional 20 villages) cover-ing over 2.5 million people. Consequently, the pres-ent study was designed to assess the impact of these MDA rounds in four different sentinel villages from two governorates, and to compare different meth-ods for monitoring the effects of MDA on infection rate and transmission. In particular, we assessed CFA by the ICT, mf prevalence rates and levels, and MDA coverage in randomly selected households before and 8–10 months after each round of MDA. Furthermore, as a marker of exposure to infection, we compared antibody prevalence rates (IgG4 to Bm14) in primary schoolchildren in the study vil-lages before and after MDA. In addition, for monitor-ing transmission, mosquito infection as determined by the Ssp1-PCR assay were compared in indoor-resting mosquitoes collected at night before and after MDA.

MATERIALS AND METHODS

To achieve the objectives of the present study, three types of survey were conducted in four sentinel villages representing two governorates (Giza and Qalyubia). These included a village survey to assess MDA coverage, CFA prevalence, and mf prevalence rates and levels; a school survey to measure Bm14-IgG4 antibodies in primary schoolchildren; and a vector survey to determine mosquito infection rates before and after each round of MDA.

The study was approved by institutional review boards at Ain Shams University in Cairo and Barnes-Jewish Hospital in St. Louis.

Village surveys

Two (Kafr Tahoria [KT] and Tahoria [TH]) of the four study villages are located approximately 35 km north-east of Cairo, in Shebin El Kanatar District, Qalubyia Governorate. These villages had low mf prevalence and intensity of infection prior to MDA and are typical for endemic villages in Egypt. The other two villages (Kafr El Bahary [KB] and Kafr El Qebly [KQ]) are located approximately 40 km

south-west of Cairo, in El Badrasheen District, Giza Governorate; they had relatively high mf prevalence and intensity of infection prior to MDA.

Annual surveys were performed in 10% of ran-domly selected households; a different household sample was tested each year. Surveys were per-formed before the first round of MDA and approx-imately 6–8 months following each round of MDA. Field teams, comprised of a physician, a technician, and a local health worker, visited houses at night (21.00–23.00 hrs). After obtaining informed consent, the teams recorded demographic and MDA infor-mation on pre-printed forms. Finger prick blood samples were collected for performance of the ICT filariasis (antigen) test according to the manufactur-er’s instructions. Note that AMRAD ICT cards were used for three cycles (before MDA and after the first and second MDA rounds), and Binax ICT cards for the last survey. If a card test turned positive, then venous blood samples were collected for mf detec-tion by membrane filtration of 1 ml blood.

Mosquito study

The prevalence of infected mosquitoes was also assessed in the same study houses. Houses were visited late at night and indoor-resting mosqui-toes collected by aspiration by trained field work-ers. Fed and gravid Culex pipiens mosquitoes were pooled by house, and mosquito pools were stored at –70oC until tested for W. bancrofti DNA by poly-merase chain reaction (PCR) with primers specific for the SspI repeat, as previously described (Ramzy et al., 1997). Details of the mosquito survey methods are reported elsewhere (Farid et al., manuscript in preparation).

School study

To assess the prevalence of IgG4 antibodies to the recombinant filarial antigen Bm14, finger prick blood samples (approximately 300 μl) were collected, in Eppendorf tubes containing 30μl EDTA, from all children in grades 1 and 5 at primary schools in the study villages. Plasma samples were separated and tested by ELISA as previously described (Ramzy et al., 1995).

DATA ANALYSIS

Data management and statistical analysis were per-formed using a statistical software package (SPSS, Chicago, IL). Proportions were compared by chi-square or Fisher’s exact test (two-tailed). The Kruskal-Wallace test was used to assess the signifi-cance of group differences for continuous variables.


Tests were two-tailed and a p-value of less than 0.05 was considered significant.

RESULTS

Mass drug administration coverage rates

The overall MDA coverage rates in our study pop-ulation were, relative to the target population and for the four rounds respectively, 86.7%, 95.5% 90.1% and 88.8% (table 1). These coverage rates were rela-tively high and exceeded the MDA target (80%) of the elimination programme. In general, our cover-age rates were not different from those rates esti-mated by the national programme for the entire governorates of our study villages (table 1).

Impact of four rounds of MDA on microfilaraemia rate and level

Pretreatment mf rates ranged between 13.1% and 0.75% in the study villages (fig.1). Note that eligi-ble residents of the village with the lowest mf prev-alence (approximately 75% of subjects aged over four years and not pregnant) were treated with DEC in 1998. Pretreatment age-specific mf rates increased with age, reached a peak (13.3%) in the 21–30 year age group, then declined thereafter (table 2). Pretreatment microfilaraemia was significantly higher in males than females (X2 = 4.29, p = 0.038). This was also true following the first (X2 = 4.12, p = 0.04) and second (X2 = 4.15, p = 0.04) rounds of MDA.

Table 1: estimated .percentage .coverage .rates1 .of .four .rounds .of .mass .drug .administration .among .the .study .villages

LocalityYear one Year two Year three Year four

our .estimate moph2 our .estimate moph our .estimate moph our .estimate moph

Giza gov.K . .bahary 89 .5 91 .8 96 .3 93 .7 90 .7 92 .1 88 .4 94 .5K . .Qebly 81 .8 90 .2 86 .3 83 .4

QalyubiaK . .tahoria 82 .0 85 .7 98 .5 95 .2 89 .9 96 .9 90 .6 92 .4

tahoria 91 .3 98 .6 93 .4 93 .7

total 86 .7 86 .8 95 .5 96 .6 90 .1 95 .9 88 .8 94 .3

1 .these .coverage .rates .are .in .relation .to .the .target .population . .2 .moph .estimated .coverage .rate .is .the .mean .for .the .entire .governorate .

Figure 1. pretreatment .prevalence .rates .of .microfilaraemia .(a) .and .antigenaemia .(b) .in .Kafr .el .bahary .(Kb) .and .Kafr .el .Kebly .(KK) .villages .(Giza .governorate), .and .tahoria .(th) .and .Kafr .tahoria .(Kt) .(Qalyubia .governorate)


The overall mf prevalence decreased significantly (98%), from 8% to 0.16%, after four MDA rounds (X2=146.6, p<0.001). Microfilaraemia prevalence rates decreased in all study villages after each MDA round, and no mf carriers were identified in KT, TH and KB after the first, second and third MDA rounds respectively (fig. 2).

The overall median mf/ml in mf-positive cases were: 42 (pretreatment), 19 (year 1), 9 (year 2), 23.5 (year 3) and 35 (year 4). Mf/ml/population decreased sig-nificantly in all study villages (fig. 3), with an over-all mf/ml/population decrease of 99.5% (from 13 to 0.07) (fig. 4).

Impact of four rounds of MDA on circulating filarial antigen prevalence rate

Pretreatment CFA rates ranged between 23.4% and 13.0% in the study villages (fig. 1). CFA prevalence rates decreased in all study villages after each round of MDA. The overall CFA prevalence rate decreased significantly (86.4%), from 16.9% to 2.3%, after the four MDA rounds (X2 = 230.48, p<0.001). The reduc-tion in CFA prevalence relative to the baseline was

Figure 2. impact .of .four .rounds .of .mda .on .microfilaraemia .rates .

Figure 3. impact .of .four .rounds .of .mda .on .the .microfilaraemia .rate, .prevalence .rate .of .circulating .filarial .antigen .(cfa), .and .levels .of .microfilaraemia .

data .from .the .two .highly .endemic .villages .in .Giza .were .combined .for .the .analysis .in .this .figure, .which .shows, .relative .to .the .pretreatment .level: .mf .prevalence .rate .and .mf/ml/population .(a), .and .antigenaemia .prevalence .(b) . .

Figure 4. impact .of .four .rounds .of .mda .on .microfilaraemia .counts .(mf/ml/population)

Table 2: pretreatment .age-specific .microfilaraemia .and .antigenaemia .prevalence .rates .

Age group

Female Male

numberexamined

mf .rate cfa .rate number .examined

mf .rate

cfa .rate

<10 108 1 .9 10 .2 111 0 .9 9 .9

11–20 345 6 .1 13 .9 307 7 .2 17 .9

21–30 239 10 .5 17 .6 138 18 .1 31 .2

31–40 125 6 .4 16 .0 124 12 .2 20 .2

41–50 93 7 .5 18 .3 74 8 .1 24 .3

51–60 58 5 .2 12 .0 65 9 .2 16 .9

>60 41 4 .9 4 .9 49 14 .3 16 .3

total 1009 6 .7 14 .6 868 9 .4 19 .7

mf .= .microfilariacfa .= .circulating .filarial .antigen


less dramatic after each MDA than that observed for mf prevalence (fig. 3). This may suggest that the treatment employed for MDA is more effective against mf than against adult worms.

Impact of four rounds of MDA on anti-Bm14 antibody rate in schoolchildren

Results from schools in the two Giza villages were pooled and compared to results from schools in the two Qaylubia villages. Pretreatment antibody rates were higher in Giza (23.8%) than Qalyubia schools (10.15%) (X2=35.19, p<0.001), and higher in grade five (25.2%) than grade one (15.4%) (X2=20.24, p<0.001) (fig. 5). The overall antibody rates decreased (86.9%) from 20.6% before MDA to 2.7% after the fourth round of MDA. Antibody prev-alence in Qaylubia schools grade one declined to zero after two MDA rounds. The antibody preva-lence rate in Giza schools grade one (GS1) decreased significantly after each MDA round, and four MDA rounds reduced the antibody rate in GS1 signifi-cantly (94.1%), from 18% to 1% (fig. 5).

The overall mean antibody level decreased from 80.5 units (range 15–263 units, median 81.1 units) to 59 units (range 15.6–380.0 units, median 44.6 units) after four MDA rounds (Z=-3.725, p<0.001).

Impact of MDA on W. bancrofti infection of wild caught mosquitoes

Indoor-resting mosquitoes were collected each year from the four study villages, and pooled by house-hold. The minimum infection rate before MDA,

assuming that a positive mosquito pool contained only one infected mosquito, ranged from 2.3% to 4.0%. The overall minimum infection rate decreased significantly (90.8%), from 2.8% before MDA to 0.26% after four MDA rounds. The mosquito data are reported elsewhere in detail (Farid et al., manu-script in preparation).

DISCUSSION

The present study was designed to evaluate the impact of four rounds of MDA in four different sen-tinel villages selected from two governorates. Two of our study villages (in Giza governorate) represent the most highly filariasis-endemic villages, whereas the other two (in Qalyubia governorate) have rel-atively low prevalence and intensity of infection and are typical of most filariasis-endemic villages in Egypt.

Our data strongly suggest that filariasis has been eliminated, with interruption of transmission, in the two study villages in Qalyubia governorate. This is supported by the absence of microfilaria carriers (by the stringent membrane filtration test) (fig. 3), the absence of antifilarial antibodies in first grade children (fig. 5), and the absence of positive mos-quito pools by PCR (data not shown) after four rounds of MDA. Four rounds of MDA also resulted in dramatic decreases in infection and transmission parameters in the two study villages in Giza gover-norate. Such findings suggest that residual infection and transmission rates in the 181 localities included in the NPELF programme are likely to be very low

Figure 5. impact .of .four .mda .rounds .on .anti-bm14 .antibody .rates .in .primary .schoolchildren . .children .who .live .in .the .two .villages .of .each .governorate .attend .the .same .schools . .antibody .data .are .presented .for .Giza .school .grade .1 .(Gs1), .Qalyubia .school .grade .1 .(Qs1) .and .Qalyubia .school .grade .5 .(Qs5) . .note .that .children .in .Grade .5 .were .not .studied .after .the .first .round .of .mda .


following the four rounds of MDA. The goal of fil-ariasis elimination has probably been achieved in many treated villages. However, additional stud-ies, with broader sampling, are needed to determine whether filariasis has been eliminated in Egypt by five rounds of MDA.

Our independent assessments confirmed the govern-ment claims of high coverage rates in the MDA pro-gramme. High MDA coverage rates (>85%) achieved for the four implemented rounds have greatly con-tributed to the clearance and significant reduction in mf intensity and prevalence rates. Computer-based models have indicated that the number of treatment rounds necessary to achieve elimination depends to a large extent on treatment coverage, drug effi-cacy, and disease endemicity level. Predictions based on simulation analysis suggest that 90% cov-erage is required to achieve the goal of elimination with five annual rounds of DEC-based MDA (Das and Subramanian, 2002). It is likely that the reported coverage rate (>85%) for the NPELF programme would be sufficient to achieve LF elimination with five annual MDA rounds using the more efficient combination treatment (DEC + albendazole) rather than DEC alone, especially as levels of endemicity are low.

A second goal of the present study was to compare different methods for monitoring the effects of MDA on infection rate and transmission. Microfilaraemia was assessed by a stringent test, membrane fil-tration of 1ml blood, which showed low residual mf counts (median 35) in less than 1% of subjects tested after MDA. It is more likely that such sub-jects, with relatively low mf counts by membrane filtration (<100 mf/ml), would be free of mf by the thick blood smear (20–50 μl blood), a method usually used for routine surveys. Data from a pre-vious study by our group (Farid et al., 2003) have suggested that filariasis elimination programmes should aim to achieve mf smear rates of zero. This is because few mf were ingested, and very few L3 were produced, by mosquitoes which had been fed on infected subjects who were amicrofilaraemic by the 50 μl thick smear. Additional studies are needed to further establish the relationship between low mf count by membrane filtration and the thick blood smear after MDA.

As anticipated, the overall decrease in the CFA prev-alence rate (86.4%), as measured by the ICT, was smaller than the overall reduction in mf preva-lence rate (98%). The single-dose combination reg-imen (DEC + albendazole) is known to be effective for reducing the blood mf count; however, it is only partially effective at killing adult W. bancrofti. For

such methods (as assessment of CFA prevalence by the ICT) to be cost effective, we believe they should be employed at wider intervals than those used for mf assessment. For surveillance of elimination pro-grammes, we suggest assessing CFA prevalence by the ICT before MDA to obtain baseline rates, then repeating the assessment after every three rounds of MDA.

As a marker for interruption of transmission, we used a xenomonitoring approach to assess the pres-ence of W. bancrofti DNA by PCR in indoor-resting mosquitoes. The SspI-PCR method has gained much attention as a powerful epidemiological tool (Farid et al., 2001) and was proposed as a useful means for monitoring of filarial transmission during con-trol campaigns (Ramzy, 2002). Data from the present study provided empirical proof for this proposal. However, considering that, as the elimination pro-gramme progresses, the parasitic load in treated populations will decrease to a level where transmis-sion will be interrupted, few mf will be available for ingestion by mosquitoes. Consequently, thousands of female mosquitoes would need to be collected for active surveillance of elimination programmes. In such cases, collecting blood-fed resting mosqui-toes may not provide enough mosquitoes to esti-mate the vector infection rate after multiple rounds of MDA; additional studies are required to deter-mine whether other methods for mosquito collec-tion (Service, 1993) would fulfil such a need.

We measured antibody prevalence in primary schoolchildren (first and fifth grades) as another marker for interruption of transmission. Antibody rates in adults may reflect exposure or infection prior to the initiation of the MDA programme; it may take many years for antibody rates to fall in adults even after effective MDA. We favoured sampling of schoolchildren, assuming that their exposure to infective mosquitoes reflects the transmission sta-tus in their communities after MDA. The dramatic reduction in antibody prevalence in Giza schools grade 1 following four MDA rounds (94.1%) vali-dates our assumption and indicates that transmis-sion in our study areas became very low consequent to MDA. Such a finding renders this approach – suc-cessive assessment of specific antifilarial antibodies in primary schoolchildren – to be the most appropri-ate and valuable strategy for monitoring elimination programmes.

We conclude that four rounds of MDA have dramat-ically decreased filariasis infection rates, infection intensity, and transmission in our study villages. The method of choice to evaluate interruption of transmission is assessment of antibody in primary,


preferably first grade, schoolchildren. If our study villages are representative of the 181 localities included in the MDA programme, our results sug-gest that the five-year programme may lead to elim-ination of filariasis as a public health problem in Egypt.

References

Das PK, Subramanian S. Modelling the epidemiolo-gy, transmission and control of lymphatic filariasis. Annals of Tropical Medicine and Parasitology, 2002, 96: (S2)S135–S164.

Farid HA et al. Detection of Wuchereria bancrofti in mosquitoes by the polymerase chain reaction: a poten-tially useful tool for large-scale control programs. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2001, 95:29–32.

Farid HA et al. Relationships between Wuchereria ban-crofti microfilaria counts in human blood and parasite uptake and maturation in Culex pipiens, with observa-tions on the effect of diethylcarbamazine treatment on these parameters. American Journal of Tropical Medicine and Hygiene, 2003, 68:286–293.

Harb M et al. The resurgence of lymphatic filariasis in the Nile Delta. Bulletin of the World Health Organization, 1993, 71:49–54.

Molyneux DH, Zagaria N. Lymphatic filariasis elim-ination: progress in global programme development. Annals of Tropical Medicine and Parasitology, 2003, 96:S15–S40.

Ramzy RMR et al. Field evaluation of a recombinant antigen-based antibody assay for diagnosis of ban-croftian filariasis in Egypt. Annals of Tropical Medicine and Parasitology, 1995, 89:443–446.

Ramzy RMR et al. A polymerase chain reaction-based assay for detection of Wuchereria bancrofti in human blood and its mosquito vector in Egypt. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1997, 91:156–160.

Ramzy RMR et al. Field evaluation of a rapid-for-mat-kit for diagnosis of bancroftian filariasis in Egypt. Eastern Mediterranean Health Journal, 1999, 5:880–887.

Ramzy RMR. Field application of PCR-based assays for monitoring Wuchereria bancrofti infection in Africa. Annals of Tropical Medicine and Parasitology, 2002, 96:(S2) S55–S59.

Ramzy RMR et al. Impact of single dose diethylcar-bamazine treatment of filariasis in a low endemicity area in Egypt. American Journal of Tropical Medicine and Hygiene, 2002, 67:196–200.

Service MW. Mosquito ecology. Field sampling methods, 2nd Edn. London, Elsevier Applied Science, 1993.

Southgate B. Bancroftian filariasis in Egypt. Tropical Diseases Bulletin, 1979, 76:1045–1068.

TDR. Prospects for elimination: Chagas disease, Leprosy, Lymphatic filariasis, Onchocerciasis. Geneva, UNDP/World Bank/WHO Special Programme for Research and Training in Tropical diseases (TDR), 1997 (TDR/Gen /97.1).

Weil GJ, Lamie PJ, Weiss N. The ICT filariasis test: A rapid-format antigen test for diagnosis of bancroftian filariasis. Parasitology Today, 1997, 13:401–404.

Weil GJ et al. A longitudinal study of bancroftian filariasis in the Nile Delta of Egypt: Baseline data and one-year follow-up. American Journal of Tropical Medicine and Hygiene, 1999, 6:53–58.


Lym

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Annex 5 WORKING PAPER: Advances and challenges in predicting the impact of lymphatic filariasis elimination programmes


5: ADVANCES AND CHALLENGES IN PREDICTING THE IMPACT OF LYMPHATIC FILARIASIS ELIMINATION PROGRAMMES

Wilma A. Stolk, Sake J. de Vlas, J. Dik F. Habbema Department of Public Health, Erasmus University Medical Center, Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.

INTRODUCTION

Lymphatic filariasis is a mosquito-borne parasitic disease and an important cause of chronic morbidity in tropical countries. In 1998, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was ini-tiated, aiming at worldwide elimination of this par-asitic disease as a public health problem.1 The main strategy in the global programme is to interrupt transmission by annual population treatment with antifilarial drugs (diethylcarbamazine or ivermectin plus albendazole). In addition, morbidity manage-ment should reduce the suffering of patients who have chronic manifestations. Thirty-two countries had started elimination programmes in 20022 and this number is still growing.

The goal of elimination is ambitious. Past mass treat-ment programmes had varying degrees of success. In some areas transmission was apparently inter-rupted.3 In other areas elimination was not achieved, in spite of long-term control programmes.4,5 How strategic choices, and operational or biological fac-tors, contribute to success or failure is poorly under-stood. It is unknown what coverage and duration of mass treatment (and possible additional mea-sures) are required to achieve elimination and how this depends on the vector and parasite strain, ende-micity level, and drugs used. Mathematical mod-els can help to clarify these issues and application of such models is considered important for support of GPELF.6

Mathematical models have been used widely in parasitology. They help to understand the complex transmission dynamics of parasitic diseases and are useful tools for planning and evaluating control pro-grammes.7,8 Models have also played an important role in lymphatic filariasis research.9,10 Targeted mod-els, which consider part of the processes involved in transmission, helped, for example, to clarify the role of acquired immunity11,12 and the macrofilaricidal

effects of treatment.13,14 This paper concentrates on so-called ‘full transmission models’, which relate the rate of transmission to the intensity and distribution of infection in a human population and can be used to predict the impact of interventions on transmis-sion and the probability of elimination.

To our knowledge, three full transmission mod-els have been described in the literature. The first was specifically developed for the evaluation of a vector control programme and is not considered here.15 The two other models, called EPIFIL16,17 and LYMFASIM,18 are both being used for planning and evaluation of elimination programmes. After a brief introduction of the processes involved in transmis-sion and control of lymphatic filariasis, we describe the basic structure of these models, compare and discuss some critical model predictions, and outline future research priorities.

PROCESSES IN LYMPHATIC FILARIASIS TRANSMISSION AND CONTROL

Models for lymphatic filariasis control basically describe the main biological processes involved in transmission (fig. 1). To study the dynamics of trans-mission and how intervention affects transmission, it is specifically important to take account of density dependence and heterogeneities.19–21

Density dependence means that the outcome of a process depends on the abundance of the parasite stages involved. Several limitation mechanisms may reduce transmission when the average worm bur-den increases. For example, the proportion of micro-filariae (mf) that develop into infectious L3 larvae saturates in Culex quinquefasciatus when the mf intake is higher, limiting the transmission of infec-tion.22,23 Further, the survival probability of mosqui-toes is reported to reduce with their infection load.24 Acquired immunity may limit infection intensity in the human host. Different mechanisms for this have been proposed,28 but evidence for the operation of such immunity is inconclusive.11,25 These limita-tion mechanisms all negatively affect the impact of interventions, because transmission becomes rela-tively more efficient when infection levels are lower. Density dependence, however, may also occur in the opposite direction (called facilitation). The prob-ability that a female worm mates with a male worm increases with higher worm burdens. Further, in some anopheline mosquito species, larval develop-ment might increase with higher mf intake.22 It is unknown whether density dependence, either limi-tation or facilitation, occurs in parasite establishment


and survival in humans, their fertility, and mf survival.

The term heterogeneity points at variation between individuals. Individuals differ for example in genetic background, nutritional status and behaviour, which may cause differences in exposure to mosquitoes, susceptibility to infection, and survival, matura-tion and fecundity of parasites. Therefore individ-uals may be predisposed to heavy or light infection, leading to an aggregated or overdispersed distri-bution of parasites (with a few hosts harbouring the majority of the parasites). Individuals also dif-fer in compliance and responsiveness to treatment, which may also contribute to aggregation of par-asites.13,14 This aggregation enhances transmission because it increases the probability that female and male worms mate. Heterogeneity may also occur in the parasite population, e.g. with respect to the lifes-pan and resistance to treatment.

AVAILABLE MODELS

The two available models for lymphatic filariasis transmission and control, EPIFIL and LYMFASIM, mainly differ in the amount of detail included. Specific variants of both models have been devel-oped for Wuchereria bancrofti transmitted by Culex quinquefasciatus, using data from an integrated vector management control programme carried out in Pondicherry, India, 1981–1985.17,26 These ‘Pondicherry model variants’ are described below. Table 1 gives the quantification of several key bio-logical parameters of the models. Figure 2 illustrates the good fit of both models to the precontrol (1981) data from Pondicherry.

Figure 1. transmission .cycle .of .lymphatic .filariasis .with .density .dependent .mechanisms . .this .figure .shows .the .life .cycle .of .Wuchereria bancrofti, .the .main .parasitic .cause .of .lymphatic .filariasis . .the .adult .worms .(macrofilariae) .are .located .in .the .lymphatic .system .of .the .human .host, .where .they .live .for .5–10 .years .26,35 .after .mating .with .male .worms, .female .worms .can .produce .millions .of .microfilariae .(mf), .which .can .be .found .in .the .bloodstream .and .have .a .lifespan .of .6–24 .months .13 .a .mosquito .that .takes .a .blood .meal .may .engorge .some .mf . .inside .the .mosquito, .mf .develop .in .about .12 .days .into .l3 .stage .larvae .(l3), .which .are .infectious .to .humans . .When .the .mosquito .takes .another .blood .meal, .the .l3 .can .enter .the .human .body .and .some .will .migrate .to .the .lymphatic .system .and .develop .into .mature .adult .worms . .the .immature .period .lasts .about .6–12 .months .39 .mf .cannot .develop .into .adult .worms .without .passing .through .the .developmental .stages .in .the .mosquito . .larval .development .and .mosquito .survival .are .density .dependent .23,24 .two .possible .mechanisms .of .acquired .immunity .are .shown .11


EPIFIL LYMFASIM a

anti-l3 .immunity

anti-fecundity .immunity

Parasite lifecycle

average .adult .worm .lifespan .in .years .(type .of .distribution) . 8 .b 10 .2 .c 11 .8 .c

average .mf .lifespan .in .months .(type .of .distribution) 10 .b 10 .b .

premature .period .in .months - 8 .

Exposure variation by age

exposure .at .age .zero .as .fraction .of .maximum .exposure 0 0 .26 0 .40

age .in .years .at .which .maximum .exposure .is .achieved 9 19 .1 21 .3

Density dependence in mosquitoes

maximum .number .of .l3 .larvae .that .can .develop .in .mosquitoes .at .high .mf .intensities

6 .d 6 .6 .e

Acquired immunity

duration .of .acquired .immunity .in .years lifelong 9 .6 .f 11 .2 .f

Other parameters

monthly .biting .rate 5760 2200

proportion .of .l3 .larvae .in .mosquitoes .that .enter .the .human .host .when .a .mosquito .bites

0 .414 .x .0 .32 .= .0 .13

0 .1

proportion .of .inoculated .l3 .larvae .that .develop .successfully .into .adult .worms .(x103)

0 .113 1 .03 .g 0 .42

mf .production .per .worm 2 0 .61 .h 4 .03 .h,i

Table 1. Quantification .of .several .key .biological .parameters .in .the .epifil .and .lymfasim .model .variants .for .pondicherry, .where .Wuchereria bancrofti is .transmitted .by .Culex quinquefasciatus

– .not .considered .in .the .modela .When .only .one .number .is .given, .this .is .the .same .for .both .model .variants .

b .assuming .a .negative .exponential .distribution .c . .assuming .a .Weibull .distribution .with .shape .parameter=2 .

d .exponential .saturating .function .with .initial .increase .when .mf .intake .increases .from .zero .= .0 .047

e .hyperbolic .saturating .function .with .initial .increase .when .mf .intake .increases .from .zero .= .0 .09

f . .this .parameter .defines .the .period .in .which .the .strength .of .the .immune .response .is .halved .in .the .absence .of .boosting

g . .in .the .absence .of .anti-l3 .immunityh . .in .the .presence .of .at .least .one .male .worm, .scaled .to .the .number .of .mf .per .20 .μl .peripheral .blood

i . .in .the .absence .of .anti-fecundity .immunity

Figure 2. comparison .of .model .predictions .with .microfilaraemia .prevalence .by .age .observed .before .the .start .of .vector .control .in .pondicherry, .india, .in .1981 . .(a) .lymfasim .predictions .for .models .with .anti-l3 .immunity .(solid .line), .anti-fecundity .immunity .(dashed .line), .and .a .model .variant .without .immunity .(dot-dashed .line); .the .latter .model .does .not .fit .the .data .and .was .therefore .rejected .26 .(b) .epifil .predictions .of .a .model .with .acquired .immunity .17 .symbols .in .both .graphs .indicate .the .observed .prevalence .levels .with .corresponding .confidence .intervals . .

adapted .from: .subramanian .s .et .al . .the .dynamics .of .Wuchereria bancrofti infection: a model-based analysis of longitudinal data from Pondicherry, India. Parasitology, .2004, .128:467–482, .with .permission .from .cambridge .university .press .

adapted .from: .norman .ra .et .al . .epifil: .the .development .of .an .age-structured .model .for .describing .the .transmission .dynamics .and .control .of .lymphatic .filariasis . .Epidemiology and Infection, .2000, .124:529–541, .with .permission .from .cambridge .university .press .

mf .p

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1 .(%

)

18

16

14

12

10

8

6

4

2

0

age .(years)

0 . 10 . 20 . 30 . 40 . 50 . 60 . 70

mf .p

reva

lenc

e .in .198

1 .(%

)

16

14

12

10

8

6

4

2

0

age .(years)

0 . 10 . 20 . 30 . 40 . 50 . 60 . 70


EPIFIL

EPIFIL simulates the average course of infection over age and time in a human population by a set of differential equations. The human population is constant in size and age-structure. Limitation in the transmission of infection by culicine mosquitoes is taken into account, so that the number of infec-tious L3 larvae that can develop in mosquitoes satu-rates at higher mf intensities. Acquired immunity is included as a second limitation mechanism: it is trig-gered by incoming L3 larvae and reduces the prob-ability that new larvae develop into adult worms. Heterogeneity is only included by age-related expo-sure to mosquitoes, i.e. the risk of infection increases with age, until a maximum level is reached at the age of 9 years. The mf prevalence is calculated using a negative binomial distribution, assuming a certain amount of aggregation of parasites in the human population.

The model can be used to simulate the impact of vector control or mass treatment. Vector control is assumed to reduce the mosquito biting rate. Mass treatment leads to killing of a proportion of adult worms or mf and to temporal infertility of worms, depending on the proportion of the population that receives treatment and characteristics of the treat-ment regimen.

The design of this population-based, deterministic model is based on a general differential equation framework describing the dynamics of macropara-sitic infections.19,27,28

LYMFASIM

LYMFASIM simulates the acquisition and loss of worms over age and time in a discrete number of human individuals, using stochastic microsimula-tion. Individuals interact through biting mosquitoes and together they form a dynamic population of which the size and age-structure may change over time. Like EPIFIL, LYMFASIM takes account of limi-tation in the proportion of engorged mf that develop into L3 larvae inside the mosquito and of acquired immunity in human hosts. Two model variants were developed for Pondicherry, which differed with respect to the type of acquired immunity: ‘anti-L3’ immunity is triggered by incoming L3 larvae and reduces the probability of successful adult worm establishment; ‘anti-fecundity’ immunity is trig-gered by the presence of adult worms and reduces the rate of mf production by female worms. By con-sidering individual worms in individual hosts, the model automatically takes account of the declin-ing mating probability of female and male worms

with lower average infection intensities. Age-depen-dent exposure is included, assuming that exposure increases until a maximum is reached at about 20 years of age. Other factors contributing to heteroge-neity are variation in exposure to infection within age groups, inclination to participate in treatment programmes, the response to treatment, and the ability to develop immune responses. Parasites may vary with respect to their lifespan (about ten years on average). Individual mf intensities are translated into the number of mf that would be counted in a 20 μl blood smear, taking account of random variabil-ity in these counts and reduced sensitivity of diag-nostic tests at lower mf densities. The mf prevalence and (geometric or arithmetic) mean mf intensity can be directly calculated from the smear counts, using data from all simulated individuals or specific subgroups.

Similar to EPIFIL, LYMFASIM simulates the impact of vector control by reducing the mosquito biting rate. Treatment takes place at the individual level, and results in killing (part) of adult worms or mf and a temporal or permanent reduction in the fertil-ity of female worms. Selective or mass treatment can be simulated.

This individual-based model uses the technique of stochastic microsimulation, which was earlier applied in the modelling of onchocerciasis transmis-sion and control.29,30

COMPARISON OF MODEL PREDICTIONS

Both EPIFIL and LYMFASIM have been used to pre-dict the impact of control measures.9,10,31,32 In this report, we focus on predictions of the coverage and duration of annual mass treatment programmes that will be required for elimination. All published pre-dictions were based on the Pondicherry variants of the model, although acquired immunity was left out of the model in the EPIFIL predictions. From the predictions of both models we can conclude that it is possible to eliminate lymphatic filariasis by yearly mass treatment, but the number of treatment rounds largely depends on coverage, precontrol mf preva-lence, and the macrofilaricidal effects of drugs. This is illustrated in tables 2 and 3, and figure 3. Often the required number of yearly treatment rounds is pre-dicted to be higher than 4–6, which was hoped to be sufficient when GPELF was initiated. As an alter-native to longer programmes, one might consider more frequent mass treatment (e.g. half-yearly) or applying vector control in addition to mass treat-ment (fig. 4).


Table 2. lymfasim: .predicted .number .of .annual .rounds .of .mass .drug .treatment .required .to .achieve .elimination .in .99% .of .the .simulation .runs .in .an .area .like .pondicherry, .for .four .different .drugs .or .drug .combinations .and .two .coverage .levels . .predictions .are .based .on .the .anti-l3 .variant .of .the .model .for .pondicherry, .with .a .precontrol .microfilaraemia .prevalence .of .8 .5% . .elimination .is .defined .as .zero .microfilaraemia .prevalence .40 .years .after .the .start .of .treatment .32 .

Assumed treatment effects (proportion

killed)

Predicted number of rounds required

for elimination with coverage of:

Drug (combination)

adult .worms

micro-filariae

65% 80%

ivermectin .+ .albendazole

35% 100% 10 6

diethylcarbamazine 50% 70% 8 5

diethylcarbamazine .+ .albendazole

65% 70% 6 4

doxycycline 80% 0% 6 4

* .reprinted .from: .stolk .Wa, .de .vlas .sj, .habbema .jdf . .anti-Wolbachia .treatment .for .lymphatic .filariasis . .The Lancet, .2005, .365:2067–2068, .with .permission .from .elsevier . .

Table 3. prediction .of .number .of .yearly .mass .treatment .rounds .required .to .reach .a .0 .5% .microfilaraemia .prevalence .threshold, .using .a .combination .of .diethylcarbamazine .plus .albendazole .in .relation .to .endemicity .and .coverage . .the .combination .treatment .is .assumed .to .kill .55% .of .all .adult .worms .and .95% .of .the .microfilariae, .and .to .interrupt .microfilaria .production .for .six .months . .epifil .simulations .were .published10 .and .concerned .a .model .without .acquired .immunity . .lymfasim .results .from .the .model .with .anti-l3 .immunity .were .added .for .comparison .for .an .average .pretreatment .microfilaraemia .prevalence .of .10% . .

pretreatment .mf .prevalence

Coverage

60% 70% 80% 90%

epifil

. 2 .5% 7 6 5 4

. 5% 9 7 6 5

10% 10 8 7 6

. 15% 12 9 8 7

lymfasim .a

10% 10 8 6 5

a . .based .on .the .average .trend .in .microfilaraemia .prevalence .of .100 .simulation .runs .

Figure 3. lymfasim: .prediction .of .the .duration .of .yearly .mass .treatment .with .ivermectin .required .to .reach .elimination .(zero .microfilaraemia .prevalence .40 .years .after .the .start .of .treatment) .with .99% .certainty, .in .relation .to .coverage . .ivermectin .is .assumed .to .permanently .sterilize .77% .of .female .worms .and .to .kill .all .microfilariae . .results .are .shown .for .two .variants .of .the .lymfasim .model .for .pondicherry .that .differ .in .the .type .of .acquired .immunity .assumed, .assuming .a .precontrol .microfilaraemia .prevalence .of .8 .5% . .the .‘drop .lines’ .(i .e . .the .intersecting .horizontal .and .vertical .lines) .indicate .the .number .of .treatment .rounds .that .would .be .necessary .to .achieve .a .99% .probability .of .elimination .when .the .population .coverage .is .65% .31 .

reprinted .from: .stolk .Wa .et .al . .prospects .for .elimination .of .bancroftian .filariasis .by .mass .drug .treatment .in .pondicherry, .india: .a .simulation .study . .The Journal of Infectious Diseases, 2003, .188:1371–1381, .with .permission .from .the .university .of .chicago .press . .

Figure 4. epifil: .the .impact .of .different .control .strategies .on .the .mean .microfilaraemia .prevalence .in .an .endemic .community .with .precontrol .prevalence .of .10% . .the .plot .shows .the .impact .of .mass .treatment .alone .(five .rounds .of .annual .mass .treatment .with .diethylcarbamazine .+ .albendazole, .with .a .coverage .of .80%), .vector .control .alone .(assuming .a .90% .reduction .in .biting .rate .during .five .years), .and .the .combination .of .the .two . .

reprinted .from: .michael .e .et .al . .mathematical .modelling .and .the .control .of .lymphatic .filariasis . .The Lancet Infectious Diseases, .2004, .4:223–234, .with .permission .from .elsevier .

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The predictions of EPIFIL and LYMFASIM cannot be compared directly because the original publica-tions reported results for different treatment regi-mens, with different assumptions on efficacy of the drugs, and different precontrol mf prevalence lev-els. Further, different criteria for elimination were used: in EPIFIL elimination was assumed to occur if the mf prevalence after treatment was below 0.5%; in LYMFASIM elimination was defined as a zero mf prevalence 40 years after the start of control in 99% of the runs. To allow better comparison of the mod-els, we did a series of additional simulations with LYMFASIM for mass treatment with the combina-tion of diethylcarbamazine plus albendazole, using the same assumptions on drug efficacy and the same criterion for elimination as in published EPIFIL pre-dictions (table 3). Simulations were done with the anti-L3 variant of the LYMFASIM model.

It is reassuring that both models come to compara-ble conclusions regarding the number of treatment rounds required to achieve elimination, although LYMFASIM predictions are slightly more optimis-tic than EPIFIL predictions when population cover-age is high. This finding of nearly equal predictions is not straightforward. The LYMFASIM model con-tains several assumptions and mechanisms, which, relative to EPIFIL, limit the impact of the interven-tion on transmission: 1) a longer adult worm lifespan (about 10 years vs. 8 years); 2) acquired immunity; 3) heterogeneities in exposure to mosquitoes, com-pliance to mass treatment, and adult worm lifespan. However, the limiting effect of these assumptions and mechanisms on the impact of mass treatment is apparently counteracted by the enhancing effect of a reduced mating probability of worms at lower aver-age worm burdens in LYMFASIM.

CRITERIA FOR ELIMINATION

EPIFIL predictions were based on the assump-tion that transmission will not continue when the mf prevalence falls below 0.5%. The choice for this threshold is somewhat arbitrary in the absence of evidence from the field. Given its individual-based structure, LYMFASIM is more suitable for examin-ing in how many runs infection is ‘truly’ eliminated, as indicated by zero mf prevalence 40 years after the start of control. For example, in the runs with 10% precontrol prevalence, 8 rounds were required to bring the average mf prevalence below 0.5% (table 3). However, in only 87% of the runs did this result in zero mf prevalence 40 years after the start of con-trol. It is clear that to be 99% certain of elimination (as was the criterion in table 2), much longer contin-uation of mass treatment would be required.

More extensive simulation studies are required to determine a more precise threshold level below which elimination would occur. This threshold level (or threshold levels) will depend on local transmis-sion dynamics and mosquito biting rates, inmigra-tion of parasite carriers or infected mosquitoes, but also on heterogeneities and population size in view of the stochastic processes involved.

APPLICATION OF MODELS FOR OTHER REGIONS

The existing model variants were all quantified for transmission of W. bancrofti by Culex quinquefasci-atus and tested against data from Pondicherry.17,26 The basic structure of the models is generalizable to other areas, but various model parameters may take different values. Most importantly, this con-cerns the relationship between mf density in the human blood and the number of L3 larvae devel-oping in mosquitoes. Unfortunately, few data are available to quantify this relationship for the differ-ent mosquito species involved.33 Especially for the anopheline mosquito species responsible for trans-mission in large parts of Africa, more field research is needed. Other parameters that may need requan-tification relate to the composition of the human population, mosquito biting rates and heterogene-ity in exposure, and operational characteristics of interventions.

Biological parameters are not expected to vary much between regions. However, our understanding of the biology of infection (in spite of in-depth model-based analysis of the Pondicherry data) is incomplete and there is uncertainty about the quantification of several key parameters, such as the parasite lifespan or role of acquired immunity. Therefore, it is cru-cial to continue testing the validity of existing and new model variants against epidemiological data. Testing models against age-specific data may help to determine the role of acquired immunity or other processes.34 Trends during vector control are espe-cially informative about the adult worm lifespan.26,35 Trends during mass treatment may give informa-tion about the effects of drugs on worm survival and productivity. And trends after cessation of con-trol may help to determine whether density-depen-dent mechanisms have appropriately been included in the model. Better information on all these aspects should eventually come from field research: using combinations of available diagnostic tests (mf and antigen detection, ultrasound to visualize adult worms), it may be possible to further increase the validity of our existing models.

Some work has already been done to prepare


models for use in other areas. The LYMFASIM model has been applied to age-patterns observed in an area of South-East India that has the same vec-tor-parasite combination and presumably the same transmission dynamics as Pondicherry. This led to the development of new model variants with less strong or no immunity (Subramanian, unpublished data). Comparison of predictions from the new LYMFASIM model variant and EPIFIL with observed trends during mass treatment in this region indi-cated that assumptions regarding efficacy of drugs or possibly coverage and compliance patterns had to be adapted (Subramanian, unpublished data).10 Using published data of uptake and development of mf in Anopheles mosquitoes,22,36–38 LYMFASIM was adapted for transmission in Africa (Stolk, unpub-lished data). Model parameters were adapted so that the predicted age-prevalence reflects the observed data from this region.25

CHALLENGES IN THE EVALUATION OF CURRENT ELIMINATION PROGRAMMES

The available models soon have to face new chal-lenges in the ongoing programmes for elimination of lymphatic filariasis. Predictions of the number of treatment rounds required for elimination were only a first step. However, specific programmes also need to be monitored and evaluated. For example, the observed results can be compared with model predictions to see whether progress is as expected. If results lag behind, programmes can be adapted. Also, the models could help to determine when mass treatment can be stopped with low risk of recrudescence, taking account of the specific local conditions, local coverage and compliance levels, and the achieved reduction in mf prevalence and intensity. Analogously, models can help to deter-mine cost-effective surveillance strategies for early detection of recrudescence of infection after cessa-tion of control, and measures to be taken to stop this recrudescence.

To address the discussed issues on monitoring and surveillance, the models must be extended to include the results of antigen detection, which is widely used in monitoring and surveillance by ongoing control programmes. Other possibly useful extensions of the model include migration of para-site carriers and infected mosquitoes and develop-ment of resistance to available drugs.

Although discussion until now focused on the elim-ination of transmission, this goal may be difficult to achieve in some areas. In some situations focus may

shift to reducing the public health problem with-out explicitly eliminating infection. To address this with the models, more attention is required for the development of disease. Simple mechanisms of dis-ease development are included in both models, but this has received little attention in published work until now.

CONCLUSIONS

There are currently two models for lymphatic fil-ariasis transmission and control, LYMFASIM and EPIFIL, that have been used in predicting the impact of mass treatment programmes. These models give more or less similar predictions on the number of treatment rounds that will be required for elimi-nation, at least in Pondicherry-like situations. The models differ however in defining when elimina-tion occurs, which leads to different advice on the duration of mass treatment. In view of current elim-ination programmes, it is crucial to obtain better criteria for when to stop control, taking account of stochasticity in the eventual outcome of elimination. Antigen tests should be included in the model, and the disease part of the models may need more atten-tion. Model variants that are adjusted to local situ-ations are powerful tools to aid decision-making in current control programmes.


References

1. Molyneux DH, Zagaria N. Lymphatic filariasis elimination: progress in global programme develop-ment. Annals of Tropical Medicine and Parasitology, 2002, 96(Suppl 2):S15–40

2. WHO. Lymphatic filariasis – Progress report on the Programme in 2002. Weekly Epidemiological Record, 2003, 78:171–179.

3. Schlemper BR Jr. et al. Elimination of bancroftian filariasis (Wuchereria bancrofti) in Santa Catarina state, Brazil. Tropical Medicine and International Health, 2000, 5:848–854.

4. Esterre P et al. The impact of 34 years of massive DEC chemotherapy on Wuchereria bancrofti infec-tion and transmission: the Maupiti cohort. Tropical Medicine and International Health, 2001, 6:190–195.

5. Vector Control Research Centre. Annual report 2003. Pondicherry, India, VCRC, 2003

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9. Das PK, Subramanian S. Modelling the epidemiol-ogy, transmission and control of lymphatic filariasis. Annals of Tropical Medicine and Parasitology, 2002, 96:S153–S164.

10. Michael E et al. Mathematical modelling and the control of lymphatic filariasis. Lancet Infectious Diseases, 2004, 4:223–234.

11. Michael E, Bundy DA. Herd immunity to filarial infection is a function of vector biting rate. Proceedings of the Royal Society of London. Series B, Biological Sciences, 1998, 265:855–860.

12. Michael E et al. Transmission intensity and the immunoepidemiology of bancroftian filariasis in East Africa. Parasite Immunology, 2001, 23:373–388.

13. Plaisier AP et al. Efficacy of ivermectin in the treat-ment of Wuchereria bancrofti infection: a model-based analysis of trial results. Parasitology, 1999, 119:385–394.

14. Stolk WA et al. Effects of ivermectin and diethylcar-bamazine on microfilariae and microfilaria production in bancroftian filariasis. (submitted for publication.)

15. Rochet MJ. A simple deterministic model for ban-croftian filariasis transmission dynamics. Tropical Medicine and Parasitology, 1990, 41:225–233.

16. Chan MS et al. Epifil: a dynamic model of infec-tion and disease in lymphatic filariasis. American Journal of Tropical Medicine and Hygiene, 1998, 59:606–614.

17. Norman RA et al. EPIFIL: the development of an age-structured model for describing the transmis-sion dynamics and control of lymphatic filariasis. Epidemiology and Infection, 2000, 124:529–541.

18. Plaisier AP et al. The LYMFASIM simulation pro-gram for modeling lymphatic filariasis and its control. Methods of Information in Medicine, 1998, 37:97–108.

19. Anderson RM, May RM. Infectious diseas-es of humans: dynamics and control. Oxford: Oxord University Press, 1991.

20. Duerr HP, Dietz K, Eichner M. Determinants of the eradicability of filarial infections: a conceptual approach. Trends in Parasitology, 2005, 21:88–96.

21. Churcher TS, Ferguson NM, Basáñez M-G. Density dependence and overdispersion in the transmission of helminth parasites. Parasitology, 2005, 131:1–12.

22. Southgate BA, Bryan JH. Factors affecting trans-mission of Wuchereria bancrofti by anopheline mos-quitoes. 4. Facilitation, limitation, proportionality and their epidemiological significance. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1992, 86:523–530.

23. Subramanian S et al. The relationship between microfilarial load in the human host and uptake and development of Wuchereria bancrofti microfilariae by Culex quinquefasciatus: a study under natural condi-tions. Parasitology, 1998, 116:243–255.

24. Krishnamoorthy K et al. Vector survival and par-asite infection: the effect of Wuchereria bancrofti on its vector Culex quinquefasciatus. Parasitology, 2004, 129:43–50.

25. Stolk WA et al. Meta-analysis of age-prevalence patterns in lymphatic filariasis: no decline in micro-filaraemia prevalence in older age groups as predicted by models with acquired immunity. Parasitology, 2004, 129:605–612.

26. Subramanian S et al. The dynamics of Wuchereria bancrofti infection: a model-based analysis of longitu-dinal data from Pondicherry, India. Parasitology, 2004, 128:467–482.

27. Anderson RM, May RM. Helminth infections of humans: mathematical models, population dynamics, and control. Advances in Parasitology, 1985, 24:1–101.


28. Woolhouse ME. A theoretical framework for the immunoepidemiology of helminth infection. Parasite Immunology, 1992, 14:563–578.

29. Habbema JD et al. The microsimulation approach to epidemiologic modeling of helminthic infections, with special reference to schistosomiasis. American Journal of Tropical Medicine and Hygiene, 1996, 55:165–169.

30. Plaisier AP et al. ONCHOSIM: a model and com-puter simulation program for the transmission and control of onchocerciasis. Computer Methods and Programs in Biomedicine, 1990, 31:43–56.

31. Stolk WA et al. Prospects for elimination of bancroftian filariasis by mass drug treatment in Pondicherry, India: a simulation study. The Journal of Infectious Diseases, 2003, 188:1371–1381.

32. Stolk WA, de Vlas SJ, Habbema JDF. Anti-Wolbachia treatment for lymphatic filariasis. [discus-sion.] Lancet, 2005, 365:2067–2068.

33. Snow LC, Michael E. Transmission dynamics of lymphatic filariasis: density-dependence in the uptake of Wuchereria bancrofti microfilariae by vector mos-quitoes. Medical and Veterinary Entomology, 2002, 16:409–423.

34. Duerr HP, Dietz K, Eichner M. On the interpre-tation of age-intensity profiles and dispersion pat-terns in parasitological surveys. Parasitology, 2003, 126:87–101.

35. Vanamail P et al. Estimation of the fecund life span of Wuchereria bancrofti in an endemic area. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1996, 90:119–121.

36. Bryan JH, Southgate BA. Factors affecting trans-mission of Wuchereria bancrofti by anopheline mos-quitoes. 1. Uptake of microfilariae. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1988, 82:128–137.

37. Bryan JH, Southgate BA. Factors affecting trans-mission of Wuchereria bancrofti by anopheline mosqui-toes. 2. Damage to ingested microfilariae by mosquito foregut armatures and development of filarial lar-vae in mosquitoes. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1988, 82:138–145.

38. Boakye DA et al. Vector competence, for Wuchereria bancrofti, of the Anopheles populations in the Bongo district of Ghana. Annals of Tropical Medicine and Parasitology, 2004, 98:501–508.

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Annex 6 WORKING PAPER: Diagnostic tools for filariasis elimination programmes

Appendix .primer: .diagnostic .options .for .monitoring .the .effects .of .mass .drug .administration .in .programmes .for .elimination .of .lymphatic .filariasis . . . . . . . . . . . . . . . . . . . . . . 90


6: DIAGNOSTIC TOOLS FOR FILARIASIS ELIMINATION PROGRAMMES

Gary J. Weil Washington University School of Medicine, St. Louis, MO 63110, USA

INTRODUCTION

In the not so distant past, diagnostic tools for filaria-sis were limited to clinical diagnosis (insensitive for active infections, low specificity), detection of micro-filariae (mf) (insensitive for infection, impractical in many areas), and detection of antibodies to crude native antigen preparations (poor specificity). These tools were inadequate for answering basic questions that are crucial to programmes for elimination of lymphatic filariasis (PELFs). There have been sig-nificant advances in diagnostic tools in recent years. It is obvious that the thoughtful use of these tools may be more important than their intrinsic prop-erties. The Japanese PELF succeeded with mf test-ing alone as an assessment tool. It is also possible to cut a piece of wood in two with a hammer! The pur-pose of this working paper is to critically review the current state of filarial diagnostics as they apply to PELFs. This review summarizes the work of many scientists (much of which is unpublished). I have inserted a primer on diagnostic options as an appen-dix to help bring the non-specialist reader up to speed in this important area.

Different tools may be needed for key stages in ELF programmes. I have used the metaphor of a ship sailing from her home port to a distant destination to illustrate this point.

STARTING POINT

Obviously, a navigator needs to know the point of origin to properly plan the journey. The first stage of a PELF requires a sensitive, specific, and convenient method for detecting filariasis endemicity that can be used to map endemic areas for inclusion in the pro-gramme. Overdiagnosis that includes nonendemic areas can greatly increase programme expenses and decrease the chances for success. Underdiagnosis and exclusion of endemic areas is also not accept-able. There are several viable diagnostic options for this early stage. Some programmes have used traditional mf testing (usually with thick blood smears collected at night). This method is insensi-tive for active infections; it misses people with low

mf counts and those with amicrofilaraemic infec-tions that have the potential to contribute to future transmission. Thus, reliance on mf testing may lead to underdiagnosis and exclusion of areas with sus-tainable LF transmission from PELFs. It is tempting for programme managers to focus on the poten-tial advantages of mf testing, namely that it is spe-cific, inexpensive, and low tech (low infrastructure requirement). I have emphasized ‘potential’ because, in practice, mf testing may not have any of these desirable features. It is often very difficult to obtain representative samples of night blood from endemic communities for mf testing. Specificity requires proper staining procedures and skilled microsco-pists with good equipment to differentiate mf from artefacts and to distinguish different filarial species. These attributes are not inexpensive to implement or maintain. Any money saved by reliance on tech-nically poor mf testing to classify implementation units early in a PELF is lost with interest paid later in the programme when the ostrich withdraws from its hole to find untreated endemic areas.

Antibody detection and molecular xenomonitoring could easily be used for identifying areas that are endemic for bancroftian filariasis. However, these tools have not been widely used for this purpose to date. This is probably because they have not been widely available in a convenient, user-friendly for-mat. This conclusion is supported by experience with antigen detection for filariasis (reviewed below and in the appendix).

Several laboratories described methods for detect-ing soluble filarial antigens in human blood in the late 1970s and early 1980s.1 However, no filarial anti-gen test was sensitive or convenient enough to be practically useful outside the developer’s home lab-oratory until the Weil laboratory developed a mono-clonal antibody-based ELISA (using monoclonal antibody AD12) for detecting circulating W. bancrofti antigen in 1984.2 Early studies with this test showed that it was more sensitive for active infection than mf tests, specific for W. bancrofti infection, and that serum antigen levels decreased following treatment with diethylcarbamazine (DEC).3 Although this ELISA was a useful research tool, it was not prac-tical for use by public health programmes. (This is also largely true of the TropBio CELISA for W. bancrofti antigenaemia that was marketed in the early 1990s. The TropBio kit has been widely used in research projects,4 but it has not caught on as a tool for mapping or monitoring ELF programmes.) This situation changed in 1997 with the introduction of a lateral flow, rapid-format card test for detect-ing filarial antigenaemia (the ICT Filariasis Test).5 It took a few years for this test to gain acceptance.


However, by 2000 the ICT test was recommended by international authorities as the diagnostic method of choice for mapping the distribution of bancroftian filariasis, and this test is now widely used around the world for this purpose in ELF programmes.6 Its virtues are that it is quick (ten minutes), minimally invasive (100 μl blood from a finger prick), easy to perform, and widely available. The last points are particularly important, because these features freed filarial antigen testing from the confines of research laboratories so that it could be used in field sites around the world. Please see the appendix for more information on this test.

Options for mapping areas with Brugian filariasis

Despite the limitations of mf testing listed above, lack of a sensitive antigen test for Brugia infections means that good quality mf testing is still a very useful option for identifying Brugia-endemic areas. Parasite DNA detection (either in mosquitoes or in human blood samples) and antibody testing could also be used for this purpose.7,8,9Antibody test kits (a dip-stick and a cassette test) based on recombi-nant antigen BmR1 have recently become commer-cially available. These tests have been reported to be sensitive for Brugia (malayi and timori) infection/exposure.10,11 They have not yet been validated as tools for mapping the distribution of brugian fila-riasis for PELFs; in my opinion, additional studies would be needed to determine how antibody prev-alence rates correspond to mf rates that merit inclu-sion in PELFs.

MONITORING PROGRESS DURING AN ELF PROGRAMME

Let us assume that baseline information was ade-quate for our ELF ship to leave port pointed in the correct direction. We cannot expect a ship to reach its destination without periodic navigational readings en route. These are important to show that we are on course, and also important for identifying problems that can be solved by mid-course corrections. The same can be said of ELF programmes. Interim mea-surements of progress may be crucially important for identifying problems that can be solved while funding is available and also for securing resources needed to complete the programme.

Considerations for tools for this purpose are somewhat different from those used for map-ping endemicity. For example, consider mf testing. Microfilaraemia rates and intensities typically fall shortly after initiation of MDA programmes, and this is gratifying to programme managers. While we

would agree that this is a positive change and evi-dence of good MDA coverage, it can also be mis-leading. This is because decreases in mf rates can be transient if the treatment regimens employed are either not highly macrofilaricidal (consider changes in mf rates that would occur a few months after a first round of MDA with ivermectin alone) or do not interrupt transmission of the infection for a period that is longer than the lifespan of most adult filar-ial worms. In addition to the limitations of mf test-ing mentioned above, this method does not provide much information on changes in filariasis transmis-sion during an ELF programme. Therefore, while mf testing will be employed in many areas for historical or practical reasons, it is not recommended as a sin-gle tool for monitoring ELF programmes (author’s opinion). While I endorse the use of antigen testing for mapping endemicity, this may not be an optimal tool for interim assessments of ELF programmes (especially early on). This is because antigen rates tend to fall relatively slowly following effective MDA, and antigen testing, in isolation, will tend to underestimate the effects of MDA on microfilarae-mia and transmission. However, antigen prevalence rates do fall sharply after several rounds of effective MDA. We have seen rates (card test) fall from 19% to ~2% after only four years of MDA. If very low resid-ual antigen rates are achieved, the risk that filariasis will reappear in an area should be very low (assum-ing no reintroduction due to migration). Therefore, I believe that antigen monitoring is preferable to mf testing as a monitoring tool. Either method is clearly preferable to no monitoring at all. Antigen monitor-ing in the context of PELFs should not be done more frequently than every two years (author’s opinion).

ALTERNATIVES TO ANTIGEN MONITORING

Recent studies in Egypt and Papua New Guinea have shown the value of antibody testing and molec-ular xenomonitoring (MX) as monitoring tools for interim assessment of ELF programmes. These tests are sensitive to changes that occur during a success-ful ELF programme that indicate the programme is on course. They provide information on changing rates of filariasis transmission and the potential risk of transmission, respectively.

However, these tests are now where antigen testing was before the ICT card test appeared – interesting research tools not quite ready for broad programme use. There is a ‘Catch 22’ situation here. While it is true that antibody testing will not be widely practiced until commercial kits become available, kits will not appear until enough people become


convinced that antibody testing is useful for wide-scale use.

The situation is somewhat different for MX, because it is a breakthrough technology that does not depend on availability of commercial kits; it is very unlikely that commercial kits will be developed for filarial MX. Despite the excitement and potential value of this technology, MX has not been a practical choice for use by endemic countries for monitoring ELF programmes to date; no government’s national ELF programme uses this method for monitoring at this time. Again the issue is accessibility. However, we believe that recent technical advances have made MX a realistic choice for practical field use in mon-itoring large-scale ELF programmes. These include use of traps for more efficient collection of mosqui-toes (gravid traps for Culex, light traps for Anopheles), improved methods for isolating DNA from mos-quito pools, software (Poolscreen2) for calculat-ing mosquito infection rates from qualitative PCR results,12 and real-time PCR (Dr R. Rao, unpublished data) for specific amplification of parasite DNA and detection of amplified DNA product. Real-time PCR is more sensitive than conventional PCR; other advantages are higher throughput, reduced risk of contamination in the laboratory, and the ability to perform other tests (e.g. HIV viral loads) with the same instrument. The cost per test for real-time PCR is comparable to conventional PCR (apart from the initial cost of the equipment).

More research is needed to determine the relative value of antibody and MX testing as monitoring tools. Each has advantages, and the two approaches are complementary. Antibody monitoring of senti-nel populations provides information on the cumu-lative lifetime exposure of the sampled cohort to filarial infection. This method requires collection of finger-prick blood from a representative sample (often primary school children). MX is based on the ability of mosquitoes to collect human blood, which these flying syringes do this for a living. MX pro-vides information on the point prevalence of filar-ial parasites in mosquitoes in the area of interest. In practice, most parasite DNA detected by MX in mosquitoes is from pre-infective stages. Therefore, MX should be thought of as a means of efficiently sampling endemic populations for the presence of microfilariae. It is not a measure of infectivity or cur-rent rates of transmission.

On the horizon: molecular assays for infectivity

Bedbugs probably ingest mf during blood meals, but filarial DNA rates in bedbugs (and even mosquitoes)

would provide a cloudy picture of filariasis trans-mission in a community. This is because mf cannot not develop to the infective L3 stage in bedbugs, and bedbugs cannot transmit the parasite. Thus, bedbugs may be infected, but they are not infective. Entomologists and modellers are looking for better information on infectivity of mosquitoes. Pilot stud-ies performed by Dr. Steven Williams’ group suggest that this is feasible by using reverse transcriptase PCR (RT-PCR) to amplify messenger RNA for genes preferentially expressed by L3. This work is ongo-ing, and it remains to be seen whether this tool will be practical and useful for use in ELF programmes.

ENDPOINTS FOR PELFs AND EARLY DETECTION OF RESURGENCE

More information is needed on how to use antigen, antibody, and MX tests to inform decisions on when it is safe to discontinue MDA. There is no consensus on this issue at this time. We (Weil and Egyptian col-leagues) favour an evidence-based approach to this question rather than adoption of arbitrary targets. In particular, we do not agree with the target some-times mentioned of reducing mf prevalence rates to below 0.1% or the current WHO recommendation to require implementation units to undertake addi-tional rounds of MDA if 1 in 3000 children born after the initiation of MDA have positive antigen tests.13 We believe that these targets are well beyond what is needed to eliminate LF (or reduce transmission to unsustainable levels (at least in areas with transmis-sion by Culex or Anopheles mosquitoes).

It is difficult to demonstrate the absolute absence of infection or transmission. The assessment tools are not perfect, and financial constraints place lim-its on the number of samples that can be collected and tested. Therefore, we favour using statistical cri-teria for targets: sample sizes should be calculated to provide 95% certainty that the true rate is less than the target rate (with power = 0.8). Target rates do not need to be zero; they should be rates that are below those needed for sustained transmission of LF. A few new cases can be accepted if the incidence rate is well below the natural attrition rate for LF infections.

Data from Egypt are again helpful in this regard. Seven per cent of our sample from localities with high baseline infection prevalence rates denied tak-ing DEC/albendazole in any of the first four rounds of MDA. As expected, antigen and mf prevalence rates in these people were significantly higher than in people who reported taking at least one round of DEC/albendazole. However, infection rates in the systematically noncompliant people were about


75% lower than baseline rates in the same popula-tion prior to MDA. We believe that these data indi-cate that effective MDA programmes have a herd treatment effect (analogous to herd immunity seen in vaccine programmes) in that they benefit those who fail to participate in the programme. If trans-mission is greatly reduced by MDA, old infections die out at a much faster rate than new infections can be established. This should be obvious to any-one who has thought about MDA in LF, but we were happy to see actual data to support this hypothesis.

Returning to targets, we favour adoption and testing of targets derived from population-based studies of PELFs. For example, our studies in Egypt suggest targets for treated populations following four years of effective MDA: < 2% for antigenaemia (or < 1% to be conservative), < 2% for antibody prevalence in first year primary school children, and < 0.25% infection rates by PCR/Poolscreen. We are about to initiate a study that will test whether communities that have achieved these targets have reduced trans-mission below sustainable levels. Different targets may be needed in different areas, depending on vec-tor species, seasonal transmission patterns, biting rates, drugs used for MDA, etc. How can we deter-mine targets for different areas?

We favour the use of antibody testing and MX as surveillance tools for early detection of resurgent transmission. Fairly large samples are needed to show statistically significant increases in these mea-sures when baseline rates post-cessation of MDA are very low. There is no consensus at this time on how these or other tests should be used for post-MDA surveillance. Research is required to provide data on this important question.

ADVANCED DATA ANALYSIS AND MODELLING

Modelling studies have the potential to help the navigator by clearly defining the destination and by developing tools that can tell the captain when the ship has reached the destination (ideally with a pre-defined, finite degree of certainty). While it has been useful, we will now leave the ship metaphor behind and speak seriously about modelling.

Research projects and ELF programmes around the world are generating reams of data on events in spe-cific villages, regions, and countries. Mathematical analysis and modelling efforts are needed to iden-tify patterns in the data so that we can move from the specific to the general. Dr. Wilma Stolk (personal communication) has commented on this situation as follows: “While field studies are useful, there are

few good ones, and even the best of them are limited in scale and time by budget constraints. Moreover, it is not possible to test every intervention in every sit-uation. Modelling can help overcome these limita-tions by intelligently predicting outcomes of studies that have not been conducted”.

I believe that modelling has the potential to be very helpful for people in the real world who are respon-sible for making tough decisions about PELFs. Models should have practical outputs so that they can help ELF programme managers to manage. Managers need guidance on criteria for including areas in MDA programmes, on when it is reasonable to stop MDA, on how to look for early evidence of LF re-emergence, and on options for managing this unhappy situation if it happens.

Modelling studies depend on the quality of the data available for analysis, and this has been a sig-nificant limitation in some prior modelling efforts for LF (author’s opinion). Existing models should now be refined by incorporating new types of data (antigenaemia, antibody rates, mosquito infection rates) to analyse relationships between infection and transmission parameters. While it may not be possi-ble to do this for every combination of vector, par-asite, and environment, I think that this should be done with real data from several of the major epi-demiological situations for LF transmission. The hope is that improved models will be able to use these new variables (alone and in combination) to improve understanding of the effects of MDA on fil-ariasis transmission and to develop practical targets for ELF programmes.

�0 Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05

Appendix

PRIMER: DIAGNOSTIC OPTIONS FOR MONITORING THE EFFECTS OF MASS DRUG ADMINISTRATION IN PROGRAMMES FOR ELIMINATION OF LYMPHATIC FILARIASIS

Several options are available:

Disease rates

Disease rates (prevalence rates for hydrocele, lymph-edema, or elephantiasis) are not useful for this pur-pose because most clinically evident filariasis is chronic and develops over a period of many years. Chronic filariasis, like a layer of coloured stone on the face of a cliff, reflects events from many years past. Thus, disease prevalence rates are not sensi-tive indicators of changes in infection prevalence or transmission following MDA.

Microscopic detection of microfilariae (mf testing)

This provides data on infection prevalence and par-asite density, both of which should fall following effective MDA programmes. However, mf testing is labour-intensive and requires collection of blood at night in many endemic areas. It is not very sensi-tive for active infections, and is impractical in some settings. Thus, while membrane filtration of venous blood is more sensitive than thick smears for detect-ing mf,14 this method requires expensive materials and unpopular venipuncture. In addition, relatively large population samples are needed to demonstrate that mf prevalence rates are below the very low tar-gets suggested for ELF programmes. On top of these problems, it is very difficult to obtain large, repre-sentative samples in night blood surveys in filaria-sis-endemic areas.

Despite these limitations, mf testing has certain advantages (it is low tech and inexpensive) and a long track record. Unfortunately, the availability of high quality mf testing is often taken for granted, although it is often not done well. It is a dying (or dead) art in many areas. Mf detection requires lots of work, training, and attention to detail (M. Sasa is a good resource on this15). Proper sampling of populations, preparation of smears, staining and microscopy is very labour intensive. Despite these

challenges, there may well be situations where mf testing could and should be the method of choice for assessment. If programmes choose this approach, they should not focus on young schoolchildren for sampling, because mf rates are often very low in this group even in the setting of ongoing transmission prior to MDA.

More information is needed to determine residual mf prevalence rates that correspond to interruption of transmission in different situations (i.e. reduc-tion of incidence rates to well below rates of spon-taneous clearance of filarial infections). These may vary in different epidemiological settings. If the mf threshold rate of < 1% reported from China16 is not completely accepted, is there any evidence that a mf rate of under 0.5% can sustain transmission in non-Aedes areas? If we accept a mf target of < 0.5%, this is much easier to demonstrate (because of sample size requirements) than < 0.1%.

Detection of filarial antigenaemia

Sensitive immunological tests (the original AD12 ELISA and a commercial test based on monoclo-nal antibody Og4C3 and marketed as the TropBio Filariasis Antigen CELISA) and a lateral flow card test based on mAB AD12.1 (now marketed as the Filariasis Now ICT Test by Binax) detect antigens released by living adult W. bancrofti worms in sera/plasma/whole blood from infected subjects.2,4,5 These tests do not detect antigenaemia in sera from subjects infected with other parasites including other filarial species. While positive tests may be seen in subjects with other parasitic infections if they have a history of residence in an area that is endemic for bancroftian filariasis, positive tests should not occur with sera from people with no history of exposure to W. bancrofti. Antigen tests have sensitivities of 95% or higher in untreated subjects with W. bancrofti microfilaraemia, and they also detect infections in subjects with amicrofilaraemic infections.

Several lines of evidence support the notion that amicrofilaraemic subjects with positive antigen tests are truly infected: their sera contain the same 200 kDa parasite antigen (detectable by Western blot) that is present in sera from mf carriers; their very high antifilarial antibody prevalence rates are com-parable to those seen in mf carriers; their antigen levels decrease or disappear following treatment; they are at increased risk of developing microfila-raemia relative to antigen-negative subjects in the same community; like mf carriers, mf-negative men with positive filarial antigen tests often have motile adult worms in scrotal lymphatic vessels that are visible by ultrasound.17,18,19,20 In contrast, most

�1Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05

amicrofilaraemic subjects with clinical filariasis have negative filarial antigen tests and no motile worms visible by ultrasound; we believe that such subjects are no longer infected with adult filarial worms.

The sensitivity of antigen tests in subjects with per-sistent microfilaraemia following treatment is lower than in untreated subjects (in the range of 85% for the card test relative to membrane filtration with higher sensitivity in persons with mf detected by thick smear).21,22 Prior studies have shown that mf prevalence rates (by thick smear) are much lower than filarial antigen prevalence rates in untreated populations (ratio mf rate/antigen rate approxi-mately 0.5).23 This ratio tends to decrease to 0.25 or lower following several rounds of MDA (which is more effective against mf than adult worms). More data are needed on the relationship between antigen and mf prevalence rates in treated populations.

Antigen testing has certain advantages over mf test-ing for detecting active filarial infections: (1) it is more sensitive than mf detection, and (2) blood col-lected by finger prick during the day or night can be used. Based on data from filarial infections in ani-mals, filarial antigen levels are believed to be related to the number of adult filarial worms in the human host.24,25

Unfortunately, antigen testing alone is not very good for monitoring progress in the first few years of ELF efforts based on MDA. This is because many infected subjects remain antigen-positive for years after treatment, even if they achieve sustained clearance of microfilaraemia.21,26 Thus, major early changes in mf prevalence and density, and decreases in filariasis transmission, are likely to be missed by monitoring programmes that are based solely on antigen testing. Antigen rates do however decrease sharply to levels that can approach zero following several rounds of effective MDA. While amicrofil-araemic, treated subjects with persistent antigen-aemia are theoretically at some risk of redeveloping microfilaraemia and potentially reinitiating trans-mission in the future, the magnitude of this risk is unknown. The risk that mf might reappear follow-ing MDA is likely to depend on the drug combina-tion used and the number of rounds of treatments taken. The author considers this question (rates of recurrence of microfilaraemia in subjects with per-sistent antigenaemia following MDA) to be a high research priority.

Additional notes on filariasis antigen card tests

The card test was transferred from AMRAD ICT to Binax, Inc. in 2000. The Binax Filariasis Now test

has generally performed very well, although tech-nical problems with certain test lots caused an inter-ruption in availability of the test in early 2005. Binax officials have told the author that they have solved the problem and are scheduled to resume sales of the test in May 2005. It is very important to read the Binax card test result at ten minutes. Falsely positive tests can occur if the tests are read after the recom-mended time point, and this problem increases with time (with up to 50% false positives after several hours). Simonsen and Magesa recently reported* that late false positive lines can be distinguished from true positive tests.27 Late-appearing false posi-tive lines tend to be grey instead of purple, and they have indistinct margins that are strongest on the lat-eral edges of the nitrocellulose membrane (in con-trast to true positive lines that are purple, sharp, and fairly uniform across the membrane). In our expe-rience, it is sometimes difficult to distinguish late false positive tests from weak true positive tests when the cards are read one or more days after test performance.

Detection of filarial parasites in mosquitoes

One commonly used traditional method is dissec-tion of host-seeking mosquitoes (collected with CO2/light traps) to look at changes in infection (any filarial larvae present) and infectivity (infective lar-vae present) rates over time. Mosquitoes can also be collected with human bait to estimate annual trans-mission potential; this method was used to docu-ment dramatic decreases in filariasis transmission after MDA with DEC and ivermectin in villages in Papua New Guinea.28 Unfortunately, human bait studies are labour intensive, and some have ques-tioned the ethics of this mosquito collection method. In addition, dissection of mosquitoes collected by any method is insensitive for detection of parasites in areas with very low mosquito infection rates fol-lowing MDA. Molecular xenodiagnosis (MX) detects filarial DNA in mosquitoes by PCR.29 MX is much more sensitive for detecting filarial parasites in mos-quitoes than dissection. Unfortunately, MX by PCR is beyond the capabilities of many laboratories in fil-ariasis-endemic countries.

However, recent advances in mosquito collection strategies, DNA isolation, and DNA detection have the potential to change MX from a research tool to a monitoring tool that can be used by PELFs around the world. Because of high infrastructure require-ments, we favour the model of establishing regional

* Simonsen PE, Magesa SM. Observations on false positive reactions in the rapid NOW Filariasis card test. Tropical Medicine and International Health, 2004, 9:1200–1202.


reference laboratories for high throughput MX test-ing by real-time PCR.

Antibody monitoring

Early antibody diagnostic tests for LF were plagued by poor specificity. Our group achieved greatly improved specificity by testing for IgG4 antibod-ies to a recombinant filarial antigen, Bm14 (ORF 459 bp, expressed in pGex as a GST fusion). This anti-gen is similar to Bm SXP-1 reported by Piessens’s group.30 Numerous studies have shown that the Bm14 antibody test is sensitive for infection with (or heavy exposure to) B. malayi and W. bancrofti (gen-erally positive in over 90% of mf carriers).31 A recent blinded multicentre study confirmed this finding.8 Primates produce antibodies to Bm14 a few weeks after they are infected with Brugia (i.e. during the pre-patent period). Humans with pre-patent infec-tions also have antibodies to Bm14; a prospective study showed that antibody to Bm14 was a signifi-cant risk factor for incidence of microfilaraemia over the next year.32 While a positive antibody test does not prove current infection, this test is specific for infection or heavy exposure to filarial parasites (i.e. no false-positive tests are seen with sera from people with or without other nematode infections who have not been exposed to filarial parasites). Prior studies have shown that antibody prevalence rates are much higher than mf and antigen prevalence rates in low-prevalence settings (pre-MDA Egyptian villages),32 but these three measures of filariasis activity varied in parallel in untreated populations. Antibody rates also tend to be much higher in young children in areas with low-level LF transmission than antigen or mf rates. For this reason, mf and filarial antigen tests are not as useful as antibody testing of sentinel chil-dren for assessing changes in LF transmission fol-lowing MDA; preliminary studies have shown that antibody rates in young children fall fairly rapidly in the years following initiation of effective MDA programmes.

Antibody testing is complementary to molecular xenomonitoring as a tool for monitoring changes in LF transmission during and after ELF programmes. MX typically tests mosquitoes collected over a short period of time (sometimes from a single night per sampling site). This is not a problem, because MX is primarily a method that uses mosquitoes to detect mf in the human population; it is not used to mea-sure transmission rates. Even so, mosquito popula-tions vary with weather and season in many areas, and sometimes conditions are not suitable for collec-tion of representative samples of fed or gravid mos-quitoes preferred for MX studies. On the other hand, antibody responses in a child reflect or integrate

the child’s lifetime exposure to LF infection, and antibody testing can be performed in any season. Antibody testing is also useful in locations where MX is not feasible because of technical difficulties in collecting mosquitoes or lack of laboratory facilities.

One limitation of the Bm14 antibody test is that it often gives weak positive results with sera from patients with loiasis and onchocerciasis.8 This lim-its the utility of the test in areas of sub-Saharan Africa where LF is co-endemic with these infections. Unfortunately, the WHO AFRO region contains as much as 40% of the world’s LF burden.

Therefore, we consider development of a LF-specific antibody test for use in sub-Saharan Africa to be a high research priority.

While this review has concentrated on Bm14, anti-gens such as Bm5, Bm serpin, Bm shp-1, BmR1, and others have been reported to have potential as diag-nostic reagents.7,33,34 Of these, only BmR1 has been studied extensively. Numerous studies have shown that antibody tests based on BmR1 are sensitive for Brugia infections.9,10,11 The sensitivity of BmR1 for W. bancrofti infection (generally low to middling) has been reported to vary with sera from different areas.8 BmR1 antibody assays have less cross-reac-tivity with sera from subjects with loiasis or oncho-cerciasis than Bm14 antibody assays.


References

1. Weil GJ. Parasite antigenemia in lymphatic filaria-sis. (Short survey.) Experimental Parasitology, 1990, 71:353–356.

2. Weil GJ et al. A monoclonal antibody-based enzyme immunoassay for detecting parasite anti-genemia in bancroftian filariasis. Journal of Infectious Diseases, 1987, 16:350–355.

3. Weil GJ et al. Persistence of parasite antigenemia following diethylcarbamazine therapy of bancroft-ian filariasis. American Journal of Tropical Medicine and Hygiene, 1988, 38:589–95.

4. Turner P et al. A comparison of the Og4C3 antigen capture ELISA, the Knott test, an IgG4 assay and clin-ical signs, in the diagnosis of Bancroftian filariasis. Tropical Medicine and Parasitology, 1993, 44:45–8.

5. Weil GJ, Lammie PJ, Weiss N. The ICT Filariasis Test: A rapid-format antigen test for diagnosis of ban-croftian filariasis. Parasitology Today, 1997, 13:401–404.

6. Gyapong JO et al. The use of spatial analysis in mapping the distribution of bancroftian filariasis in four West African countries. Annals of Tropical Medicine and Parasitology, 2002, 96:695–705.

7. Chandrashekar R et al. Molecular cloning of Brugia malayi antigens for diagnosis of lymphatic filaria-sis. Molecular and Biochemical Parasitology, 1994, 64:261–274.

8. Lammie P et al. Recombinant antigen based assays for the diagnosis and surveillance of lymphatic filaria-sis – a multicenter trial. Filaria Journal, 2004, 3:9.

9. Rahmah N et al. Specificity and sensitivity of a rapid dipstick test (Brugia Rapid) in the detection of Brugia malayi infection. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2001, 95:601–4.

10. Jamail M et al. Field validation of sensitivity and specificity of rapid test for detection of Brugia malayi infection. Tropical Medicine and International Health, 2005, 10:99–104.

11. Fischer P et al. Detection of filaria-specific IgG4 antibodies and filarial DNA for the screening of blood spots for Brugia timori. Annals of Tropical Medicine and Parasitology, 2005, 99:53–60.

12. Helmy H et al. Test strip detection of Wuchereria bancrofti amplified DNA in wild-caught Culex pipiens and estimation of infection rate by a PoolScreen algo-rithm. Tropical Medicine and International Health, 2004, 9:158–163.

13. WHO. Preparing and implementing a national plan to eliminate lymphatic filariasis (in countries where onchocerciasis is not co-endemic). Geneva, World Health Organization, 2000:65.

14. Desowitz RS, Hitchcock JC. Hyperendemic ban-croftian filariasis in the Kingdom of Tonga: the appli-cation of the membrane filter concentration technique to an age-stratified blood survey. American Journal of Tropical Medicine and Hygiene, 1974, 23:877–9.

15. Sasa M. Human filariasis. A global survey of epide-miology and control. Baltimore, University Park Press, 1976:513, 549, 672, 673.

16. Xu B et al. Studies on the transmission potential in controlled areas of Henan Province. Chinese Medical Journal, 1997, 110:807–810.

17. Weil GJ et al. Parasite antigenemia without micro-filaremia in bancroftian filariasis. American Journal of Tropical Medicine and Hygiene, 1996, 55:333–337.

18. Weil GJ et al. A longitudinal study of bancroft-ian filariasis in the Nile delta of Egypt: baseline data and one year follow-up. American Journal of Tropical Medicine and Hygiene, 1999, 61:53–58.

19. McCarthy J et al. Clearance of circulating parasite antigen as a measure of the macrofilaricidal activity of diethylcarbamazine in Wuchereria bancrofti infection. Journal of Infectious Diseases, 1995, 172:521–526.

20. Faris R et al. Bancroftian filariasis in Egypt: Visualization of adult worms and subclinical lymphat-ic pathology by scrotal ultrasound. American Journal of Tropical Medicine and Hygiene, 1998, 59:864–867.

21. El Setouhy M et al. A randomized clinical trial comparing single- and multi-dose combination ther-apy with diethylcarbamazine and albendazole for treatment of bancroftian filariasis. American Journal of Tropical Medicine and Hygiene, 2004, 70:191–196.

22. Ramzy RM et al. Field evaluation of a rapid-for-mat kit for the diagnosis of bancroftian filariasis in Egypt. Eastern Mediterranean Health Journal, 1999, 5:880–7.

23. Faris R et al. Community diagnosis of bancroft-ian filariasis. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1993, 87:659–661.

24. Weil G et al. Monoclonal antibodies to parasite antigens found in the serum of Dirofilaria immitis-infected dogs. Journal of Immunology, 1985, 134:1185–1191.

25. Weil G et al. Circulating parasite antigen in Brugia pahangi-infected jirds. Journal of Parasitology, 1990, 76:78–84.

26. Ismail MM et al. Long-term efficacy of single-dose combinations of albendazole, ivermectin, and diethyl-carbamazine for the treatment of lymphatic filariasis. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2001, 95:332–335.


27. Simonsen PE, Magesa SM. Observations on false positive reactions in the rapid NOW Filariasis card test. Tropical Medicine and International Health, 2004, 9:1200–1202.

28. Bockarie MJ, Kazura JW. Lymphatic filariasis in Papua New Guinea: prospects for elimination. Medical Microbiology and Immunology, 2003, 192:9–14.

29. Williams S et al. Development and standardiza-tion of a rapid PCR-based method for the detection of Wuchereria bancrofti in mosquitoes for xenomonitoring the human prevalence of bancroftian filariasis. Annals of Tropical Medicine and Parasitology, 2002, 96:S41–46.

30. Dissanayake S, Xu M, Piessens W. A cloned anti-gen for serological diagnosis of Wuchereria bancrofti microfilaremia with daytime blood samples. Molecular and Biochemical Parasitology, 1992, 56:269–277.

31. Ramzy R et al. Evaluation of a recombinant anti-gen-based antibody assay for diagnosis of bancroft-ian filariasis in Egypt. Annals of Tropical Medicine and Parasitology, 1995, 89:443–446.

32. Weil GJ et al. A longitudinal study of Bancroftian filariasis in the Nile Delta of Egypt: baseline data and one-year follow-up. American Journal of Tropical Medicine and Hygiene, 1999, 61:53–58.

33. Zang X et al. The serpin secreted by Brugia malayi microfilariae, Bm-SPN-2, elicits strong, but short-lived, immune responses in mice and humans. Journal of Immunology, 2000, 165:5161–5169.

34. Noordin R, Aziz MA, Ravindran B. Homologs of the Brugia malayi diagnostic antigen BmR1 are present in other filarial parasites but induce different humoral immune responses. Filaria Journal, 2004, 3:10.


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Annex 7 WORKING PAPER: Morbidity management in the global programme to eliminate lymphatic filariasis: a review of the scientific literature


7: MORBIDITY MANAGEMENT IN THE GLOBAL PROGRAMME TO ELIMINATE LYMPHATIC FILARIASIS: A REVIEW OF THE SCIENTIFIC LITERATURE

David G. Addiss,1,2 Molly A. Brady3

1 Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

2 WHO Collaborating Center for Control and Elimination of Lymphatic Filariasis in the Americas

3 Lymphatic Filariasis Support Center, Rollins School of Public Health, Emory University, Atlanta, Georgia

SUMMARY

The goal of this review is to assess the state of sci-entific knowledge regarding current management of filariasis-associated morbidity within the Global Programme to Eliminate Lymphatic Filariasis (GPELF). The review focuses on four major areas: acute inflammatory episodes (principally acute der-matolymphangioadenitis); lymphoedema; hydro-cele; and the impact of mass drug administration on filarial morbidity.

Acute dermatolymphangioadenitis

Research during the last decade has confirmed the importance of acute dermatolymphangioadenitis (ADLA) in filariasis-endemic areas. Although some debate continues, a central role for bacteria is gen-erally accepted. Evidence includes isolation of bac-teria and increased antibody titres to Streptococcal antigen; comparable data from the general lymph-oedema and dermatological literature; and dramatic decreases in ADLA incidence with hygiene and skin care, as well as with prophylactic antibiotics. Several studies document the economic burden of ADLA and its impact on quality of life.

Lymphoedema

The current strategies of the GPELF for lymphoe-dema management are based on the central role of bacterial ADLA as a trigger for lymphoedema pro-gression. Simple intervention packages have been developed and are being used in many countries, although optimization of the components of these packages would benefit from further research. These interventions have resulted in dramatic reductions in ADLA rates in several studies. Lymphoedema management has also been shown to reduce chronic

inflammatory cells in the skin and improve quality of life. During the past decade, the socioeconomic impact of lymphoedema in filariasis-endemic areas has received increasing attention. A key challenge for the GPELF is how best to scale up, monitor, and evaluate lymphoedema management programmes at the national level. Numerous operational research questions remain to be answered in this regard.

Hydrocele

Of the clinical manifestations targeted by the dis-ability alleviation component of the GPELF, hydro-cele has been the focus of the least attention. Basic information is lacking on the effectiveness and com-plications of hydrocele surgery and risk of post-operative hydrocele recurrence in filariasis-endemic areas. While there has been a steady increase in the number of papers addressing health-seeking behav-iour, beliefs, quality of life, and productivity losses to hydrocele, few have evaluated the impact of sur-gery on quality of life and productivity.

Effect of mass drug administration on filarial morbidity

Data on the impact of mass drug administration (MDA) on filarial morbidity are inconsistent. Several studies report reductions in acute inflammatory epi-sodes, lymphoedema, and/or hydrocele following MDAs, but a roughly equal number of studies report no such association. Many of these studies are lim-ited by inadequate or non-standardized case defini-tions and intermittent or incomplete follow-up. Few studies included control groups. Assessing the pub-lic health impact of mass treatment with antifilarial drugs is an important issue for programme advo-cacy and for morbidity control strategies.

1. BACKGROUND

The objectives of this review are to summarize the scientific basis for morbidity management within the Global Programme to Eliminate Lymphatic Filariasis (GPELF) and to identify priorities for research. Lymphatic filariasis causes a wide range of clini-cal signs and symptoms, including lymphoedema, hydrocele, lymph scrotum, chyluria, tropical pul-monary eosinophilia (TPE), adenopathy, haematu-ria, and various manifestations of worms in ectopic sites,1 among others. This document does not focus on the clinical management of individual patients with these various forms of filarial disease. Rather, it examines the scientific evidence for the morbidity management strategies that have been adopted by the GPELF to reduce the public health burden from the major forms of morbidity in persons with lym-phatic filariasis, both acute (inflammatory episodes)


and chronic (lymphoedema and hydrocele). The narrow focus of this paper should not be interpreted as an indication that other manifestations of lym-phatic filariasis (e.g. chyluria) lack public health significance, but rather, that no coordinated pub-lic health approach to these other problems has yet been established.

Our understanding of lymphatic filariasis mor-bidity has evolved considerably during the last 20 years,2–5 and this new understanding has led to the current strategies for morbidity management – especially for lymphoedema and adenolymphangi-tis. It seems clear that the clinical manifestations and factors leading to progression of so-called ‘filarial lymphoedema’ are similar, if not identical, to those for lymphoedema in non-filariasis-endemic areas. Indeed, given the absence of a diagnostic marker for ‘filarial lymphoedema’, as well as its multifacto-rial aetiology,4 some have argued that the use of this term should be avoided. The literature on manage-ment of lymphoedema in filariasis-endemic areas is relatively limited; considerably more is known about the pathogenesis, clinical management, and psychosocial impact of ‘non-filarial’ lymphoedema in Europe, Australia, and North America. It is out-side the scope of this document to systematically review the literature on lymphoedema and hydro-cele from non-endemic areas, but we will refer to this literature in passing.

The document is divided into three sections cor-responding to the three major clinical manifesta-tions to be addressed: acute inflammatory episodes, lymphoedema, and hydrocele. After a brief intro-duction, the available data are reviewed for the following topics: pathogenesis, epidemiology, eco-nomic and social impact, and treatment. A fourth section addresses the impact of mass treatment with antifilarial drugs on all three forms of morbidity.

2. ACUTE INFLAMMATORY EPISODES (ACUTE ATTACKS)

The aetiology of acute inflammatory episodes in lymphatic filariasis has long been a subject of debate and confusion. Indeed, a variety of terms have been used in the literature to describe them, including ‘adenolymphangitis (ADL)’, ‘acute attack’, ‘filarial attack’, and ‘endemic lymphangitis’, among others.6 As early as the 1920s, some scientists argued that bacterial infections were the primary cause of ‘filar-ial’ lymphangitis.7–9 In 1924, the British Filariasis Commission went so far as to state that “all the pathological manifestations” of lymphatic filaria-sis were caused by secondary bacterial infections.10 During World War II, clinical and pathologic studies

of soldiers with adenolymphangitis and other early clinical manifestations demonstrated the impor-tance of Wuchereria bancrofti adult worms or 4th-stage larvae.11 The debate continued after World War II, when the role of the immune system in trig-gering adenolymphangitis, as well as other forms of filarial pathology, was emphasized.12

One of the major factors contributing both to the debate and the confusion during the latter half of the 20th century was the relative lack of emphasis on careful clinical observation and case definitions. In 1999, Gerusa Dreyer and colleagues, working in Brazil, defined two distinct clinical syndromes: acute filarial lymphangitis (AFL), caused by death of the adult worm, and acute dermatolymphangioadenitis (ADLA), caused by secondary bacterial infection.13 AFL is characterized by lymphangitis that progresses distally or in a ‘retrograde’ fashion, along the lym-phatic vessel, producing a palpable ‘cord’. Rarely, AFL is accompanied by mild fever, headache, and malaise. Distal lymphoedema may occur, but is usu-ally mild and reversible, i.e. self-limited. In contrast, ADLA (a term used by Olszewski),14 develops in a reticular or circumferential pattern, and is clinically similar to erysipelas or cellulitis. Symptoms of local pain and swelling, as well as fever and chills, are present. In filariasis-endemic areas, ADLA occurs much more commonly than AFL.13

Although there is general agreement within the GPELF on the two syndromes as described by Dreyer et al., investigators have suggested that exposure to 3rd-stage filarial larvae also causes lym-phangitis and triggers the onset or progression of lymphoedema. A role for 3rd or 4th-stage larvae in lymphangitis or lymphoedema is supported by ani-mal studies, experimental infections,15 reports of disease in individual patients travelling from non-endemic areas,16 and epidemiologic observations that associate incidence of acute adenolymphangi-tis with filarial transmission intensity.17, 18 However, a case definition has not been established for larva-associated lymphangitis, which might distinguish it from either AFL or ADLA; this makes it difficult to count cases. Additional work is needed to clar-ify the incidence, possible mechanisms, and clinical expression of larva-associated filarial lymphangitis and to assess its public health importance in filaria-sis-endemic areas.

Recent speculation also has focused on a poten-tial role for Wolbachia in the pathogenesis of filaria-related disease.19 Lammie and colleagues have suggested that the pathogenesis of disease in lym-phatic filariasis is multifactorial, and have proposed


a model that involves the immune system and also allows for a variety of possible causes.3

Limited attention has been paid to the differences in pathogenesis and clinical manifestations of brugian and bancroftian filariasis. Obvious differences have been noted, such as the absence of male urogenital involvement and chyluria, and the much more fre-quent occurrence of abscesses at the site of lymph nodes in brugian filariasis. However, the reasons for these differences are poorly understood.

The following two sub-sections review the scientific data on ADLA and AFL.

2.1 Acute dermatolymphangioadenitis

2.1.1 Pathogenesis

Evidence for a bacterial aetiology of ADLA in filari-asis-endemic areas comes from the distinctive clini-cal signs and symptoms, isolation of bacteria at the time of the acute episode, and changes in antibody titres between acute and convalescent serum speci-mens.20–30 In India, the bacteria most frequently asso-ciated with ADLA are Group A Streptococcus. Other bacteria are often found in cultures, including those that are usually regarded as non-pathogenic.21, 23, 27

The role of the immune system in amplifying or modulating ADLA is not entirely clear. The rela-tive infrequency with which bacteria are isolated from patients with ADLA,21, 28, 31 as well as from per-sons with cellulitis in areas not endemic for lym-phatic filariasis,32, 33 suggests a role for inflammatory mediators.32–34

Little has been published on the antimicrobial sensi-tivity of bacteria isolated from persons with ADLA in filariasis-endemic areas. Available experience sug-gests that the organisms most commonly involved are sensitive to penicillin; thus, penicillin is usually recommended for treatment.35

The clinical description of ADLA in filariasis-endemic areas is remarkably similar – if not iden-tical – to that for erysipelas, about which much has been written in the dermatologic literature. Group A Streptococcus is the classical causative organism for erysipelas, and lymphoedema is a well-recognized risk factor for erysipelas and cellulitis in areas not endemic for lymphatic filariasis.34

2.1.2 Epidemiology

In the early 1990s, TDR sponsored a series of pop-ulation-based studies on the incidence of ‘acute attacks’ among the general population in filariasis-

endemic areas. These studies were done before the bacterial aetiology of ADLA was widely appreci-ated. However, the case definition – localized pain, lymphadenitis and/or lymphangitis and/or celluli-tis and local warmth, with or without systemic man-ifestations of fever, nausea, and vomiting (in some studies, lasting for at least three days) – is consis-tent with ADLA. In these studies, the overall inci-dence of ADLA ranged from 33 per 1000 per year to 97 per 1000 per year.36–39 A study from Papua New Guinea, which found an incidence of 31 attacks per 1000 population per year, included only cases with fever.40 The one such study in an area endemic for Brugia malayi, which also included only cases with fever, found an incidence of 371 episodes per 1000 people per year.41 It is unclear whether these epi-sodes were ADLA or AFL, or both. Taken as a group, these studies indicate that the rate of ADLA is higher in persons with chronic filarial disease, principally lymphoedema. Among lymphoedema patients in filariasis-endemic areas, the mean annual reported incidence of ADLA ranges from 0.5 to more than ten episodes per patient.14, 31, 38, 42–44

The duration of ADLA, primarily based on patient self-reporting, ranges from 3 to 11 days.20, 31, 36–39, 42, 43,

45–47 Recurrent ADLA episodes result in significant short-term disability (see section 2.1.3.2), and are of much greater concern to patients than is lymphoe-dema per se.48 Studies in Ghana indicate that patients with ADLA are incapacitated for 3 of the 5.1 days of ADLA duration;37 in Tanzania, patients are incapaci-tated for 3.7 of the 8.6 days of ADLA.36 In India, total disability from ADLA lasted no more than 3 days in an area with brugian filariasis area.41 However, pre-liminary data from Haiti42 and Togo49 suggest that the number of workdays lost may exceed the dura-tion of the acute ADLA episode itself.

Among persons with lymphoedema, risk factors for ADLA include increasing patient age,36–38 poor hygiene50 and illiteracy.51 Gender, lymphoedema severity, and the presence of entry lesions are addi-tional risk factors. Females tend to experience higher rates than males, although exceptions have been noted.38 The relationship between lymphoe-dema stage and incidence of ADLA is not consistent among all studies. It is complicated, in part, by the use of different systems to stage lymphoedema. Most studies show a positive association between lymph-oedema stage and observed or patient-reported inci-dence of ADLA.6, 13, 31, 44, 52–54 However, some studies – all of which relied on patient recall of ADLA inci-dence – found no such association.36, 37, 42, 43 Data from Brazil, India, and Guyana indicate that the pres-ence of interdigital skin lesions increases the risk of ADLA13, 50,55(G. Dreyer, personal communication).

��Report of the Scientif ic Working Group on Filariasis, 2005 • TDR/SWG/05

The epidemiologic association between ADLA fre-quency and stage, as well as extensive clinical experience from both filariasis-endemic and non-endemic areas, strongly suggest that ADLA episodes are a major – likely the most important – factor in lymphoedema progression, particularly in filariasis-endemic areas.

2.1.3 Economic and psychosocial impact

2.1.3.1 COST

Studies from India, Ghana and Haiti indicate that ADLA treatment costs to patients range from US$ 0.25 to US$ 1.62 per episode, as much as two days’ wages.42, 43, 47, 56–58 In Sri Lanka, Chandrasena reported costs of US$ 7.38 per episode for care from pri-vate practitioners, although most patients received free treatment at government clinics.59 These costs include direct costs of treatment, including self-med-ication, as well as travel. Two studies also included costs of food and accommodation.43, 57 In all cases, except for consultations with herbalists in Haiti, patients seeking care from health centres or private practitioners spent more money, primarily because these providers had higher consultation charges. In addition, payment is often provided in-kind when care is given by members of the extended family or traditional practitioners. At the upper end of the spectrum, Kron et al. calculated costs for personal expenses in the Philippines as high as US$ 25 per ADLA episode, excluding lost wages.45

2.1.3.2 PRODUCTIVITY

The true burden of ADLA comes not from treatment costs, but from indirect costs due to lost produc-tivity. ADLA episodes significantly affect patients’ abilities to carry out both economic (farming, mar-ket activities, building) and domestic (household chores, cooking, taking care of children) activities.36,

37, 41, 42, 48, 59, 60 ADLA episodes are more disabling than other febrile illnesses.39, 57 This incapacitation results in productivity losses; studies in India and Tanzania showed that patients undergoing ADLA spent an average of 2.7–3.6 hours less per day on economic activities than controls.36, 39, 47, 56

Studies indicate that ADLA episodes reduced potential community labour supply in Ghana by 0.79%57 and in Indian communities by approxi-mately 0.1%.39, 47 While these figures represent a much smaller loss than that from chronic filarial dis-ease (7% of potential labour lost), they do not ade-quately capture impact at the level of the household. Household-level effects, including time lost from work and school for caregivers, have not been stud-ied in detail.

Even with these modest estimates, the productiv-ity lost due to ADLA represents a significant loss of potential income. Sabesan estimated that US$ 160 000 per year was lost to ADLA among persons with lymphatic filariasis in Pondicherry, India,46 while other studies in India estimate a national fig-ure of US$ 60–85 million lost per year.43, 61 Kron esti-mated that US$ 38 million is lost annually due to ADLA in the Philippines.45

2.1.3.3 QUALITY OF LIFE

Most information collected on quality of life has not differentiated the effect of chronic disease from that of ADLA. A study of patients at a filariasis clinic in Haiti found that ADLA affected several quality of life indicators, including how much one thinks about the disease and the ability to work.48 A qual-itative study in the Dominican Republic found that the greatest physical and psychological dis-tress occurs during ADLA, regardless of stage of lymphoedema (B. Person, personal communica-tion). Ninety-six per cent of women interviewed in this study described distress not only from the pain and disability caused during the ADLA episode, but also from anticipation of future episodes. A study of the effect of lymphatic filariasis on schoolchildren in India found that ADLA led to common absenteeism and impaired performance.62

In another recent study, patients in India ranked ADLA higher than lymphoedema and hydrocele in terms of severity, with an average severity score of 25–27 on a scale of 0–28. Patients also cited ‘very severe problems’ in the domains of mobility, self-care, usual activities, pain, anxiety/depression and social participation on an extended EuroQol scal-ing system.63 They reported curtailing their activ-ities and interactions with others in an attempt to prevent other ADLA attacks from occurring. Other studies have remarked on the pain, restrictions and dependency that result from ALDA episodes, but have not translated this into standard quality-of-life indicators.64, 65

2.1.3.4 HEALTH CARE SEEKING BEHAVIOUR

Studies in India found that 49%-98% of lymphoe-dema patients sought treatment for ADLA during the previous 6–12 months, either by consulting gov-ernment or private health personnel or self treat-ing. Patients in urban areas were more likely to seek treatment.43, 47, 56, 58 In a study in rural Haiti, approx-imately 50% of people experiencing an ADLA episode sought treatment from health clinics, tradi-tional healers, or by self-treating.42 In rural Ghana, Gyapong et al. found that 55% of those suffering ADLA episodes sought care (with only 1% going


to government health facilities), compared to 88% of those with other febrile illnesses. Because of dis-tance to health facilities, difficult terrain, and the pain associated with ADLA, many patients do not seek treatment outside the home until the episode is almost over.57, 66 In addition, many patients believe that ADLA is not preventable, since it recurs even with treatment, so they stop seeking treatment.47, 56,

66, 67 Preliminary data from Togo confirm this impres-sion, and indicate that many patients have sought help in the past for ADLA from a wide variety of sources, but currently either self-medicate or do not seek help.49

Traditional practices for ADLA include herbal prep-arations which are smeared on the affected limb, scarification or cutting the skin, and analgesics bought from local drug peddlers.57, 65, 67, 68

2.1.4 Treatment and prevention

2.1.4.1 TREATMENT

Treatment recommendations for ADLA include rest, cooling the affected area to relieve pain and limit thermal-related damage to the skin, analgesics and antipyretics to relieve pain and fever, systemic anti-biotics, and elevation of the affected limb.26, 35 Little is known about the degree to which antibiotics shorten the duration of ADLA episodes, but as with erysipe-las and cellulitis in areas not endemic for lymphatic filariasis, antibiotic treatment is recommended.

2.1.4.2 PREVENTION

Basic lymphoedema management

An increasing number of studies have documented the effectiveness of basic lymphoedema manage-ment, as recommended by WHO,35, 51, 59, 69–71 in reduc-ing the incidence of ADLA episodes. In Guyana, McPherson found that none of 11 patients reported ADLA during the six months after hygiene educa-tion, whereas 10 had reported ADLA during the pre-ceding six months.70 A recent evaluation by WHO reported even more dramatic reductions in incidence of ADLA in Sri Lanka, Zanzibar (United Republic of Tanzania), and Madagascar.69 In India, several placebo-controlled studies have observed signifi-cant decreases in ADLA incidence among lymphoe-dema patients who only received instruction in foot care.29, 52, 53

Reductions in ADLA frequency can be maintained for several years through home-based care. In Haiti, the reported incidence of ADLA during the year before beginning treatment was 2.1 episodes per year; this decreased to 0.6 episodes after hygiene and skin care were emphasized.51 A follow-up

assessment 18 months after the patients ‘graduated’ from clinic visits, but continued lymphoedema care at home, showed an annual incidence of 0.5 ADLA episodes per year.48 Suma and colleagues reported sustained practice of self-care among patients in an area endemic for Brugian filariasis; some two years after patients had received ‘foot care’ education, 95.3% reported having fewer or less severe ADLA episodes, with a mean incidence of 2.8 acute attacks per year.31

Prophylactic antibiotics

For patients who continue to experience frequent episodes of ADLA despite basic measures of hygiene and skin care, prophylactic antibiotics are recom-mended.35 This practice is also recommended in non-endemic countries for patients with lymphoe-dema who have recurrent ADLA. The effectiveness of prophylactic antibiotics has been evaluated in sev-eral studies. Olszewski examined the effect of ben-zathine penicillin, given at three-week intervals for one year, on the incidence of ADLA, and reported a dramatic decrease, with recurrent episodes occur-ring only in 9% of patients.14 In a placebo-controlled trial in Vellore, India, lymphoedema patients who received prophylactic penicillin experienced greater decreases in ADLA incidence than those who only received training in foot care.29 In similar studies in Kerala, India, Shenoy and colleagues found that, for most patients, antibiotics provided little additional benefit if foot care was regularly practiced.25, 52, 53 Kerketta and colleagues, in Orissa, India, observed lower rates of ADLA among patients who were ran-domized to receive foot care and penicillin prophy-laxis than among patients not receiving penicillin, although the difference was not statistically signif-icant.71 A recent Cochrane review concluded that although penicillin and foot care appear to reduce the frequency of ADLA, further studies are needed to document the effectiveness of these measures.72

Antibiotic soap

An unpublished study from Haiti found that the inci-dence of ADLA in lymphoedema patients decreased to a similar extent (from 1.1 episodes to 0.4 episodes per year) in patients who washed with antimicrobial soap and those who received standard soap,54 sug-gesting that hygiene itself was more important than the antimicrobial content of the soap.

Participation in patient support groups

Participation in patient support groups has been shown to decrease the number of ADLA episodes and improve quality of life among lymphoedema patients in Haiti.73


Table 1. matrix .of .published .studies .on .acute .dermatolymphangioadenitis .(adla) .in .filariasis-endemic .areas

Study or publication Aetiology Epidemiology Socioeconomic impact of ADLA Impact of treatment

economic .impact .of .disease

Quality .of .life health .care .seeking .

behaviour

antibiotic .treatment

hygiene .and .foot .care

acton .19298 x

addiss .199951 x x

addiss .200354 x

ahorlu .199967 x

alexander .199940 x

ananthakrishnan .200450 x

badger .200572 x

baird .200228 x

babu .200347 x x x

chandrasena .200459 x x

coreil .199864 x

dahl .200148 x x x x

dreyer .199913 x

dreyer .20006 x

dreyer .200235 x x x

dunyo .199768 x

esterre .200024 x

Gasarasi .200036 x x

Grace .193174 x x

Grace .19327 x

Gyapong .199637 x x

Gyapong .199657 x x

Gyapong .199666 x

joseph .200429 x x x

Kanda .200442 x x x

Kessel .195760 x

Kerkatta .200571 x x

Krishnamoorthy .199943 x x x

Kron .200045 x x

Kumari .200563 x

mathieu .200549 x x

mcpherson .200370 x

mcpherson .200655 x x

nanda .200358 x x

olszewki .199422 x

olszewki .199614 x x

olszewki .199723 x

olszewki .199921 x

pani .198975 x x

Continues on next page


Risk of death

Fatal outcomes for ADLA are thought to be uncom-mon, but most programme managers and clinicians who care for patients with lymphoedema are aware of at least a few cases in which ADLA progressed to septicaemia and death. The actual incidence of fatal outcomes with ADLA is unknown, as are the risk factors for severe or fatal ADLA. The clinical expe-rience of Dreyer and others indicates that elderly patients, alcoholics, and patients with malnutrition, hypertension, diabetes, or chronic cardiac or pul-monary disease may be at increased risk of severe ADLA.35

Table 1 summarizes, in a matrix format, studies pub-lished on ADLA.

2.2 Acute filarial lymphangitis

2.2.1 Pathogenesis

As noted above, among persons born and raised in areas endemic for bancroftian filariasis, episodes of AFL, due to death of the adult worm or 4th-stage larva, are less severe and have less systemic involve-ment than ADLA. Systemic involvement may be greater in ‘immune-naïve’ immigrants to endemic areas. Classical AFL was described extensively in US and European soldiers during World War II.11, 78–

81 AFL has been reported widely following treatment with DEC; indeed, such reactions are considered evidence of the drug’s macrofilaricidal efficacy.82–84

AFL is commonly observed following mass treat-ment with DEC.85, 86

Study or publication Aetiology Epidemiology Socioeconomic impact of ADLA Impact of treatment

economic .impact .of .disease


behaviour

antibiotic .treatment

hygiene .and .foot .care

pani .199520 x x

pani .199544 x

ramaiah .199638 x

ramaiah .199856 x x

ramaiah .200039 x x

ramaiah .200061 x

ramaiah .200062 x

rao .198241 x x

sabesen .199246 x x

shenoy .199552 x x x

shenoy .199825 x x

shenoy .199953 x x x

shenoy .200226 x

suma .199730 x

shi .200017 x x

suma .200231 x x

suma .200365 x x

vagas .200376 x

vijayalakshmi .199727 x

Who .200469 x x

zongjun .200477 x x

TOTAL 18 30 16 5 10 8 14

Continued from previous page


2.2.2 Treatment

Treatment of AFL is supportive. Cold compresses, rest, and analgesics are recommended. Treatment with antifilarial drugs during acute inflammatory episodes used to be recommended, but now is con-sidered contraindicated.26, 35, 87

2.2.3 Acute filarial lymphangitis and clinical disease

The degree to which AFL triggers or hastens the development of hydrocele in bancroftian filariasis has been investigated by several authors. Norões and colleagues reported a 22% incidence of acute hydrocele following a single ‘scrotal nodule event’, whether spontaneous or induced by DEC.88 Overall, 5% of men with scrotal nodules (adult worm death) developed hydrocele that persisted for 18 months or longer. Similar findings were observed in Haiti following mass treatment with DEC and albenda-zole.89 Hussein and colleagues in Egypt found that 14 of 16 infected men developed detectable fluid in the tunica vaginalis cavity after treatment with DEC and albendazole, of whom three developed chronic hydrocele.90 It is unclear whether the life-time risk of acute or chronic hydrocele is increased by DEC treatment, or whether the drug merely syn-chronizes adult worm death and, therefore, result-ing hydrocele.

AFL appears to trigger the onset of lymphoedema less frequently, and persistent lymphoedema is unusual in the absence of other co-factors.5

3. LYMPHOEDEMA

The literature on lymphoedema in filariasis-endemic areas suffers from a lack of standardization, ter-minology, and agreed-upon criteria for diagnosis and case definition. Indeed, many authors use the term ‘elephantiasis’ for all forms of lymphoedema. Further, even in non-endemic areas, there is no one system for classifying or staging lymphoedema that is universally accepted.91 The lack of standardiza-tion limits our understanding of the epidemiology, prevalence, and severity of lymphoedema. Further, the prevalence of co-morbidity, especially venous disease, associated with lymphoedema in filariasis-endemic areas is unknown. An urgent need exists for standardization of terms and common case definitions, and for improved knowledge about co-morbidity and its effect on recommended treat-ment practices. For a matrix of studies published on lymphoedema in filariasis-endemic areas, see table 2.

3.1 Pathogenesis

The pathogenesis of lymphoedema in filariasis-endemic areas has been a matter of intense debate. For many years, it was believed that a shift in anti-filarial immunity triggered the onset of lymphoe-dema, before which time the asymptomatically infected host was ‘in harmony’ with the parasite.110,

114 Clinical observations and ultrasonographic and lymphoscintigraphic examinations demonstrated that lymphatic vessel dilatation and dysfunction commonly occur in the absence of lymphoedema. The molecules or processes that stimulate lymphatic vessel dilatation, and the mechanisms by which this process is maintained, are unknown. The clinical model proposed by Dreyer emphasizes that lymph-oedema in filariasis-endemic areas is a multifacto-rial process.4

Alternative models have been proposed. Epidemiologic associations between transmission intensity and the prevalence of lymphoedema have suggested to some investigators that third-stage lar-vae trigger lymphoedema.18, 108 This hypothesis is supported by observations of decreases in lymph-oedema prevalence and severity following mass treatment with antifilarial drugs.18 Although such reductions are not always observed, these findings suggest that mass drug administration could have therapeutic benefits on filarial morbidity (see section 4). Longitudinal studies showing that asymptomatic microfilaraemic persons are less likely than unin-fected persons to develop lymphoedema suggest an immunologic mechanism.124

3.2 Epidemiology

Globally, an estimated 15 million persons suffer from lymphoedema in filariasis-endemic areas of the world.112 Clinically, so-called filarial lymphoe-dema is often indistinguishable from lymphoedema of other causes, and there is no laboratory marker that proves, at the individual level, that the initial (or only) cause of lymphatic vessel dysfunction was damage associated with adult filarial worms.

The earliest onset of lymphoedema in filariasis-endemic areas is usually observed around the time of puberty, and the prevalence increases with age.116,

117, 128 In many areas where bancroftian filariasis is endemic, lymphoedema of the leg is more common in women than in men,97, 105, 109 although this finding is not universal,117 especially in areas with brugian filariasis.116 Gyapong and colleagues have reported an association between the prevalence of lymphoe-dema and that of microfilaraemia.106


Table 2. matrix .of .published .studies .on .lymphoedema .in .filariasis-endemic .areas .*

Study or publication Pathogenesis Epidemiology Socio-economic impact Impact of treatment

economic .impact


behaviour

beliefs .and .traditional .practices

treatment .and .prevention

addiss .199951 x

addiss .200354 x

ahorlu .199967 x x x x

amuyunzu .199792 . x x x

babu .200293 x x x

babu .200394 x

babu .200495 x

bandyopadhyay .199696 x x x

barry .197197 x

bockarie .200218 x x

carme .197998 x

casley-smith .199399 x

chandrasena .200459 x x

coreil .199864 x x

coreil .200373 x

dahl .200148 x x

das .2005100 x

dreyer .20004 x

dreyer .200235 x

dunyo .199768 x x

eberhard .1996101 x

evans .1993102 x

fox .2005103 x x

Giglioli .1960104 x

Gyapong .1994105 x

Gyapong .1996106 x

Gyapong .199666 x x x


hunter .1992107 x x

joseph .200429 x

Kanda .200442 x

Kazura .1997108 x x

Kerketta .200571 x

Kessel .195760 x

Kron .200045 x

Kumari .200563 x

lammie .1993109 x x

maizels .1991110 x

mcpherson .200370 x x



Little is known about what triggers the onset of clin-ical lymphoedema in filariasis-endemic areas, or about what factors cause lymphoedema, once trig-gered, to persist. Once lymphoedema is established, recurrent episodes of ADLA are thought to be the major factor associated with disease progression

(see section 2.1.2), although the role of other factors remains largely unexplored. Scarification of the skin, a traditional practice in many filariasis-endemic areas, is considered a risk factor for rapid progres-sion of filarial elephantiasis because of the increased risk of ADLA.68


economic .impact


behaviour


treatment .and .prevention

mcpherson .2003111 x

michael .1996112 x

nanda .200358 x x

nanda .2003113 x x x

ottesen .1984114 x

ramaiah .1996115 x

pani .198975 x x

pani .1990116 x

pani .1991117 x

ramaiah .1997118 x

ramaiah .1999119 x x

ramaiah .200039 x

ramaiah .2005120 x

ramu .1996121 x

rath .2005122 x x

rauyajin .1995123 x x x

ravindran .2003124 x

riji .1986125 x

schellekens .2005126 x x

shenoy .199552 x

shenoy .199953 x

shenoy .200226 x

shenoy .2003127 x x

srividya .1991128

suma .200231 x x

suma .200365 x x x x

vagas .200376 . x

Wendt .1999129 x x

Wilson .2004130 x

TOTAL � 11 � 23 14 20 1�

* .studies .on .pathogenesis .and .epidemiology .not .comprehensively .reviewed



3.3. Economic and psychosocial impact

3.3.1 Cost

Costs to patients for lymphoedema treatment, reported as both per-visit and per-year costs, vary greatly by study. A study in India reported an aver-age of US$ 0.56 per visit, more than half a day’s wages.58 A Ghanaian study reported costs for treat-ment of chronic disease (both lymphoedema and hydrocele) of US$ 0.87 per visit, equivalent to almost a day’s wages,57 and greater than costs incurred by controls with other chronic diseases. In India, the annual cost for lymphoedema treatment ranges from US$ 2.17 to US$ 8.70 per person.93, 119 Average treatment costs are often low; many patients who find potential treatment costs prohibitive either self-treat or do not seek treatment.113, 119

3.3.2 Productivity

Productivity losses from lymphoedema have been captured as lost working hours and as changes in individual output. Lymphoedema patients in India lose 0.55 to 1.61 hours per day in time at work; 11%-31% of workdays are lost annually.39, 119 These find-ings are similar to those of another study of both lymphoedema and hydrocele patients, which esti-mated 1.13 hours lost per day, for a total of 19% of workdays lost per year.93 In Ghana, female labour input loss due to lymphoedema was estimated at 1.5% per year, using the average percentage of lymphoedema patients unable to complete cer-tain activities and the local prevalence of lymphoe-dema.57 In general, many patients report changing to less strenuous occupations or giving up working altogether due to lymphoedema and ADLA.63, 65, 67

A study of male weavers in India with chronic dis-ease, 26% of whom had lymphoedema, found a 27% decrease in output versus controls.121

3.3.3 Quality of life

A few studies have quantified the impact of lymph-oedema on quality of life using standardized mea-sures. McPherson, using a 30-point Dermatology Life Quality Index in Guyana, found a mean base-line score for lymphoedema patients of 10.9 (compa-rable to patients with psoriasis and atopic eczema in the United Kingdom), with controls scoring 0.5.70 Six months after starting regular hygiene treatment, the scores improved significantly by an average of 6.8 points.111 In Haiti, Kanda compared different ways of measuring quality of life among rural people with lymphoedema.42 Using the EuroQol scale, he found that no respondents had extreme problems in mobil-ity or self-care, but more than half reported pain or discomfort. On a depression scale, the CES-D, these same patients had a mean score of 13.2 (16 and above

indicates depression). On the CDC Healthy Days questionnaire, Kanda found that 88% of patients ranked their health as fair or better; however, they also reported an average of 9.9 physically or mentally unhealthy days during the past month. Advanced age, advanced stage of illness, and low educational level were strongly associated with lower quality-of-life measures.42 In India, patients with lymphoe-dema scored from 9.2 to 12.4 on a 28-point scale of ‘health state severity’ using an extended EuroQol measuring system.63 Severity was associated with stage of lymphoedema; in higher stages, ‘severe or very severe problems’ were reported for the domains of usual activities, pain, anxiety/depression, cogni-tion and social participation.

3.3.3.1 STIGMA

Many studies mention the stigma surrounding lymphoedema, but they differ in the severity of stigma reported. Diminished marriage prospects and/or threat of divorce due to diminished eco-nomic productivity and attractiveness are often cited as problems for persons with lymphoedema, both by the patients themselves and by other com-munity members.60, 63–67, 96, 102, 107, 123 This effect appears to be dependent on age of lymphoedema onset and disease stage.64 In Haiti, patients reported that their children had the most difficulty coping, as they were often teased or embarrassed about the mothers’ lymphoedema.64 Following a series of ‘soap opera’ radio broadcasts in Haiti, which were intended to decrease social stigma associated with lymphoe-dema, patients reported improved self-efficacy and social support.129

3.3.3.2 IMPACT ON ACTIVITIES

A study in Ghana, which did not distinguish between lymphoedema and hydrocele, found that those with chronic filariasis were significantly less likely to be able to perform market and building activities than matched controls.57 Among patients in India who were visited at home during the course of a year, those with chronic filarial disease were found to be totally incapacitated at 22% of visits, compared to 13.4% for controls, a significant differ-ence.93 Another study in India found that lymph-oedema patients reported a negative impact on domestic activities (15%–33% of patients), economic activities (65%–83%), and movement (67%–78%).118 Lymphoedema patients in Haiti reported decreased ability to walk, difficulty in finding appropriate foot-wear, and sometimes inability to sell at the market or do household chores.64 Among those practicing lymphoedema self-care, 25% stated that lymphoe-dema limited their ability to work.48


3.3.3.3 EMOTIONAL IMPACT

Among filariasis clinic patients in Sri Lanka, 18% felt they were being shunned by society, although these data were collected after the patients had been enrolled in treatment.59 In other studies, almost all patients report negative feelings of frustration, iso-lation, and/or embarrassment resulting from their condition or their inability to find effective treat-ment.48, 64–66, 92, 96, 129 As lymphoedema progresses, the negative emotional and psychological impact often worsens. Patients in an Indian study expressed suicidal thoughts;63 anecdotal reports from sev-eral countries suggest that suicidal ideation and depression are not uncommon among persons with lymphoedema.

3.3.3.4 SOCIAL SUPPORT

A study in Haiti of patients enrolled in a lymph-oedema treatment clinic found that the odds of regularly practicing hygiene and skin care were 3.7 times greater among patients who believed that family members supported them than among those who didn’t mention family member sup-port.129 Participation in patient support groups was shown to decrease the number of ADLA episodes and improve quality of life among lymphoedema patients in Haiti.73 In Brazil, patient ‘Hope Clubs’ have been developed to provide ongoing opportu-nities for social and emotional support, problem-solving, and continued learning.131

3.3.4 Health care seeking behaviour

Studies in India and Ghana show that 46%–100% of persons with lymphoedema sought treatment from health care centres, local healers, or pharma-cies during the previous year.57, 58, 93, 119 Studies in Ghana show that modern medical care is avoided due to lack of interest from health care workers and a belief by patients in spiritual causes of lymphoe-dema (which require spiritual interventions).66, 107 Patients consult spiritualists and treat themselves with herbal preparations or analgesics, even though many believe lymphoedema cannot be prevented.67 In contrast, in areas of India with networks of pub-lic healthcare facilities, most patients seek care from modern medical practitioners, although a minority consult Ayurvedic doctors or use home remedies first.65, 113 Access to care is not necessarily univer-sal, however; young women in India may not seek treatment because of social constraints, such as the paucity of female doctors.96 Other barriers to care include distance to a health facility, lack of time, lack of child care, perceived severity of disease, and dissatisfaction with previous treatment.66, 92, 96 Even when patients seek treatment, health personnel

often will prescribe antifilarial or other drugs that are expensive and ineffective. Inadequate knowl-edge of lymphoedema management by health work-ers results in suboptimal patient care.113, 122, 126

3.3.5 Beliefs and traditional practices

Beliefs about the cause of lymphoedema include heredity, supernatural and spiritual causes, and nat-ural causes such as injury, standing in cold water, stepping on insects, and ingesting unhygienic food or drinks.45, 64, 66, 67, 92, 96, 98, 101, 104, 115, 123, 125 Beliefs about lymphatic filariasis and its transmission can be dif-ficult to alter. Few people in French Polynesia impli-cated mosquitoes in transmission, although there were ongoing health education programmes.98 Half of patients who had formerly been involved in a clinical trial in India were unaware of transmis-sion by mosquitoes.65 Ninety-two percent of women interviewed in an Indian study were unaware that mosquitoes transmitted filariasis, but 50% of the children interviewed knew about filariasis transmis-sion and prevention, which they learned at school or in health camps.96 Knowledge of transmission and prevention of lymphatic filariasis is associated with younger age, higher educational level and higher socioeconomic status.95, 100, 120, 123

In filariasis-endemic areas, people with lymphoe-dema seek help from traditional healers, herbal-ists, sorcerers, and pharmacies, or they self-treat. Traditional treatment for lymphoedema includes herbal preparations, burial of the leg, scrubbing the surface of the foot with ants, bloodletting, and scari-fication, among others.64, 66, 68, 92, 123 Even in areas with established clinics for lymphoedema management, where patients learn the importance of hygiene, skin care, elevation and proper footwear,59, 94, 129 many still hope for a permanent cure64 (B. Person, personal communication).

3.4 Treatment and prevention

Recognition of the importance of secondary bacte-rial infections (ADLA) in the progression of lymph-oedema has led to basic recommendations for the treatment of lymphoedema in filariasis-endemic areas. The cornerstones of this treatment include hygiene, skin care (early detection, treatment, and prevention of entry lesions), exercise, and elevation of the affected limb.26, 35, 76 In addition to the above measures, appropriate footwear is recommended, and prophylactic antibiotics are recommended for some patients (see section 2.1.4.2).

All of these recommendations are consistent with proper lymphoedema care in developed countries


where lymphatic filariasis is not endemic.132 However, in these areas, additional modalities are also used, including compressive bandages, com-pressive garments, and manual lymphatic drain-age.133, 134 These and other measures would no doubt be helpful for individual patients in filari-asis-endemic areas,76 but may require more train-ing, experience, or resources, and are therefore not included in the public health approach to managing lymphoedema adopted by the GPELF.

3.4.1 Effectiveness of treatment on acute dermatolymphangioadenitis

Relatively few studies have documented the effec-tiveness or impact of the basic package of lymphoe-dema management, and most of these have focused on ADLA. The available data indicate that such treatment is associated with a marked reduction in incidence of ADLA.29, 31, 51–54, 70 An unpublished study from Haiti reported that risk factors for continued ADLA include more advanced disease, ‘non-com-pliance’, and illiteracy.51

3.4.2 Effectiveness of treatment on leg volume

A few studies have documented changes in leg vol-ume or circumference in response to basic lymph-oedema management. Although an ‘objective’ measurement, leg volume can vary considerably with time of day, exercise, elevation, and other factors. In Orissa, India, Kerketta and colleagues reported significant reductions in leg circumference with all treatment regimens that included basic foot care.71 Pani and colleagues reported greater volume reductions in patients with oedema of recent onset than in those with lymphoedema of longer dura-tion.75 An unpublished study from Haiti, which ini-tially included compressive bandaging as one of its modalities, reported that 80% of 178 patients had a reduction in leg volume after two years when com-pared with pre-treatment measurements.51

3.4.3 Effectiveness of treatment on entry lesions

It is commonly observed that, with basic lymphoe-dema management, the prevalence and severity of entry lesions decrease.35

3.4.4 Effectiveness of treatment on odour

Reduction in offensive odour is commonly observed with regular hygiene. To our knowledge, there have been no studies focusing on reduction in odour as an outcome of lymphoedema treatment in filariasis-endemic areas, although anecdotally this improve-ment has an important effect on quality of life.

3.4.5 Effectiveness of treatment on stage of lymphoedema

Few studies have attempted to address the degree to which basic lymphoedema management results in regression of lymphoedema stage or grade. In part, this is because most staging systems have not been developed for this purpose. Thus, consider-able improvement in skin condition or even volume reduction is possible without regression in stage per se.

3.4.6 Effectiveness of treatment on limb flexi-bility and range of motion

Improved flexibility and a feeling of ‘lightness’ are commonly reported by patients, but few, if any, studies have documented the effectiveness of basic lymphoedema management on limb flexibility.

3.4.7 Effectiveness of treatment on quality of life

Several studies are currently under way that address the extent to which basic lymphoedema management in filariasis-endemic areas improves quality of life. One study, by McPherson and col-leagues in Guyana, documented highly significant improvement in quality of life as measured by the Dermatology Quality of Life Index.70 Similar work in non-endemic areas has shown substantial gains in quality of life with lymphoedema treatment. Patients who incorporate regular lymphoedema management into their daily routines have reported satisfaction with the results.48, 127

3.4.8 Effectiveness of treatment on chronic inflammation

A study in Haiti collected skin punch biopsy speci-mens from the lymphoedematous legs of 27 patients before and about 12 months after they initiated basic lymphoedema management.130 Follow-up biop-sies showed significant reductions in perivascu-lar mononuclear infiltrate in the superficial dermis (41% decrease in prevalence), in perivascular fibro-sis in the deep dermis (58% decrease), and in periad-nexal mononuclear infiltrate (53% decrease).

3.4.9 Optimization of treatment protocols

Although there is general agreement as to the basic elements of lymphoedema management within the GPELF, considerable regional variation exists in the availability of supplies, including soap, water, and topical skin preparations (e.g. antiseptics, antifun-gal and antibacterial agents). These differences con-tribute to variation in approaches used in different regions. For example, in some countries, macer-ated interdigital lesions are treated with Whitfield


ointment, an inexpensive antifungal agent, on the presumption that dermatophytes are the primary pathogen. In Guyana, McPherson attempted to cul-ture fungi from these lesions and concluded that bacteria probably play a more important role.55 McPherson’s observations are consistent with studies of intertriginous lesions in non-endemic areas.135, 136

Controlled studies of how best to optimize the effec-tiveness of treatment, particularly for skin care, have not been published. Some investigators have argued for more widespread adoption of breathing exer-cises to mobilize lymph fluid, and for emollients to protect and rebuild the skin barrier function.76 These are issues that are amenable to basic, inexpensive clinical trials.

3.4.10 Programmatic challenges

Although there remains some debate about the opti-mal package of interventions for basic lymphoe-dema management in filariasis-endemic areas, the benefits of such treatment are generally recognized, and foci of activity in several countries have dem-onstrated success. However, relatively few persons with lymphoedema living in filariasis-endemic areas currently have access to treatment. Thus, the key programmatic issue is how best to ‘scale up’ basic lymphoedema management to state and national levels. The challenges can be considered in four major categories:• Finding patients and bringing them to treatment

(many are reluctant to seek care as discussed above).

• Education of patients and family members on the principles and practice of lymphoedema self-care.

• Encouragement and support to sustain daily self-care (this support may include improved access to supplies such as clean water, soap, antiseptics, topical antibacterial and antifungal agents, and oral antibiotics).

• Referral networks for management of ADLA and for patients with advanced lymphoedema or lymphoedema complicated by other diseases.

There is general agreement that most patients can manage their lymphoedema routinely at home, and that this is preferable and less costly than clinic-based care. WHO has developed training pack-ages for ‘informal caregivers’ to instruct patients on home-based care, and this approach has been adopted by most programmes. However, numer-ous key programmatic and operational research questions remain unanswered for each of the four major programme components. For example: 1) the

ability of untrained workers to recognize or diag-nose lymphoedema is unknown; 2) the frequency and intensity of education required for patients to become competent in lymphoedema self-care has not been evaluated; and 3) basic requirements for referral care, provider training, and clinical compe-tency have not been determined. The costs of treat-ment need to be better understood, as well as the benefits. These are areas in urgent need of investi-gation if the benefits of lymphoedema management are to reach those who most need it.

3.4.11 Prevention

Considerable anecdotal evidence suggests that the onset of chronic lymphoedema is triggered by the first or second episode of ADLA. Data from a filari-asis-endemic area of Haiti indicate that skin lesions between the toes, which could provide portals of entry for bacteria, are common in children, and are significantly more common in those who test posi-tive for circulating filarial antigenaemia.103 Similar findings have been observed in northeast Brazil (G. Dreyer, personal communication). The degree to which initial ADLA episodes, and therefore lymph-oedema, can be prevented through school-based education programmes focused on hygiene, skin care, and recognition and treatment of entry lesions is unknown.

4. HYDROCELE

Despite the greater public health burden of male urogenital disease in lymphatic filariasis, much more attention has been focused to date on man-agement of lymphoedema of the leg. This is begin-ning to change, as surgery programmes have been launched in several centres. However, many ques-tions remain about diagnosis, optimal management, and cost and benefits of intervention. For a matrix of studies published on hydrocele, see table 3.


Table 3. .matrix .of .published .studies .on .hydrocele .in .filariasis-endemic .areas .*


economic .impact


behaviour


treatment

acton .1930137 x

addiss .200189 x x

ahorlu .199967 x x

ahorlu .2001138 x x x x x

amuyunzu .199792 x x x

babu .200293 x

babu .200495 . x

bernhard .2001139 x

bockarie .200218 x

dandapat140 x

das .2005100 x

dreyer .1997141 x

dreyer .200235 x x

eberhard .1996101 x

evans .1993102 x x x x

fanasa .1983142 x x x

Gigliolo .1960104 x x



Gyapong .1998143 x

Gyapong .1998144 x


hunter .1992107 x

hussein .200490 x x

Kessel .195760 x x

Kumari .200563 x

lu .1988146 x x x x

michael .1996112 x

muhondwa .1983147 x x x

mwobobia .2000148 x x

nanda .200358 x x

noroes .200388 x x

partono .1981149 x

ramaiah .1996115 x

ramaiah .1997118 x

ramaiah .1999119 x x

ramaiah .200061 x

ramaiah .200039 x

ramaiah .200062 x



4.1 Pathogenesis

In many research papers written during the 1980s and 1990s on the epidemiology or immunology of lymphatic filariasis, all genital swelling in men was labelled as ‘hydrocele’. This was in contrast to detailed, even elegant, clinical descriptions of male urogenital disease by investigators in earlier decades.137, 142, 154, 155 Dreyer and colleagues recently emphasized the distinction between lymphoedema of the scrotal and penile skin, which has the same pathogenesis as lymphoedema of the limbs, and swelling due to increased fluid inside the tunica vaginalis.35 This fluid, which is usually considered to be ‘hydrocele’, actually is comprised of several distinct entities including true hydrocele and lym-phocele (including chylocele and hematochylocele). The term ‘filaricele’ has been suggested recently to include all of these manifestations.156

Norões and colleagues have shown that true filarial hydrocele is triggered by death of the adult worm, which produces an inflammatory nodule that occludes the lymphatic vessel. In this study, the inci-dence of acute hydrocele following a single ‘scro-tal nodule event’, whether spontaneous or induced by DEC, was 22%.88 Of these, 24% persist to become chronic. These data are similar to those of ultrasono-graphic and clinical studies from Egypt.90

Rupture of lymphatic vessels inside the scrotal cav-ity can lead to the presence of straw-coloured (lym-phocele) or milky (chylocele) fluid, sometimes with red blood cells. The implications for surgical man-agement and for risk of compromised testicular function for these conditions differ from those for hydrocele (Norões, personal communication). Little

is known about the relative frequency of these condi-tions in different filariasis-endemic areas, and tech-niques and markers to discriminate among them preoperatively are currently inadequate.

4.2 Epidemiology

An estimated 25 million men suffer from fluid accu-mulation in the tunica vaginalis (filaricele) in areas endemic for bancroftian filariasis.112 The prevalence of filaricele appears to be strongly associated with intensity of parasite transmission. Gyapong has documented a robust association at the community level between hydrocele prevalence and microfila-raemia prevalence in Ghana,143,144 and this associa-tion has been observed elsewhere. The prevalence of hydrocele increases with age.

Little is known about the natural history of hydro-cele in filariasis-endemic areas, although increas-ing (but as yet largely unpublished) evidence seems to suggest that it is much more “fluid” (forgive the pun) than previously realized. Recent observations from Brazil, Egypt, and Haiti demonstrate that many acute hydroceles resolve spontaneously.88–90

The epidemiology of the various forms of filaricele is unexplored.

4.3 Economic and psychosocial Impact

4.3.1 Costs for non-surgical treatment

Patient expenditures for hydrocele treatment are gen-erally low, as treatment other than surgery is found to be ineffective and most patients cannot afford to pay for surgery. Hydrocele patients in India paid from US$ 1.38 to US$ 4.29 per year for treatment;


economic .impact


behaviour


treatment

ramaiah .2005120 x

ramu .1996121 x

subrahmanyam .1980150 x

Wegesa .1979151 x

Wijers .1977152 x x

Who .2002153 x

TOTAL 5 10 14 15 12 13 �

* .studies .on .pathogenesis .and .epidemiology .not .comprehensively .reviewed



daily wages in the areas studied averaged less than US$ 1.58, 93, 119 A Ghanaian study found an average of US$ 0.87 a year (almost one day’s wages) spent for treatment of chronic filariasis, which included both hydrocele and lymphoedema – significantly more than was spent by patients with other chronic diseases.57 In general, treatment costs are difficult to collect accurately as much of treatment is paid in-kind or provided by traditional healers who are members of the extended family.

4.3.2 Costs for hydrocele surgery

Published costs to patients for hydrocele surgery range from US$ 5 to US$ 60, depending on the coun-try and source of care. The types of surgery per-formed and the parameters of costing are not known for all studies. Ramaiah reported costs of US$ 5–14 in government hospitals and US$ 14–57 in private hos-pitals in India,119 while Babu reported costs of US$ 44 in another Indian study.93 In Ghana, Gyapong reported surgery costs of US$ 30–35 at local hos-pitals57, 145 and Ahorlu reported surgery costs of US$ 30–60 for surgery sponsored by non-govern-mental organizations (NGOs).138 Interestingly, the patients in Ahorlu’s study estimated that surgery would have cost US$ 75–125 at local hospitals before the NGO programme was put in place. Ahorlu also reported other costs associated with surgery, includ-ing transport to hospital and food, estimated by patients at US$ 20–30, with an average hospital stay of 4–12 days.

4.3.3 Productivity

Early studies on hydrocele differed in their conclu-sion about the impact on productivity, and reduc-tions in productivity were not quantified.60, 102, 104, 152 In recent studies, the effect of hydrocele on produc-tivity has been quantified in three different ways:• Individual working hours. Studies in India have

shown that hydrocele patients work approxi-mately one hour less per day than matched con-trols.39, 93, 119 Lu et al. in the Philippines found that 30% of 22 males interviewed lost time from work due to hydrocele.146

• Individual output. A study of weavers with chronic filarial disease in India, 69% of whom had hydrocele, showed that those with disease produced 27% less cloth than matched controls.121

• National output. In India, 8% of potential male labour input was estimated lost due to hydrocele and lymphoedema119 and this loss was valued at US$ 704 million per year.61 In Ghana this fig-ure was similar, more than 7% of potential labour lost.57

There is almost no evidence on the degree to which

hydrocelectomy improves productivity, with only one study reporting qualitative data.138

4.3.4 Quality of life

Early studies described the socially unacceptable nature of hydrocele, but they were vague about the degree of associated stigma, its consistency across communities and cultures, and the psychosocial bur-den of hydrocele on those affected.60, 92, 102, 147 To date, research has not been carried out on quality of life in men with hydrocele in filariasis-endemic areas that would allow for comparison with other diseases, or with men who do not have hydrocele.

4.3.4.1 STIGMA

Hydrocele patients report both ‘enacted stigma’ (teasing, problems with marrying and divorce) and ‘felt stigma’ (ashamed to be part of community activ-ities).67, 138, 147 However, they often develop coping strategies to deal with the stigma.145 For example, men with hydrocele were less likely to admit that they avoided social events or suffered teasing than were unaffected people to report that they ill-treated men with hydrocele. The severity and visibility of hydrocele, as well as the relationship of patients to community members, seems to correlate with the degree of stigma.102 Gyapong et al. described gen-eral community acceptance of men with hydrocele, but reported that patients with advanced disease often feel ostracized and embarrassed.66 In Kenya, 36% of men with hydrocele interviewed responded that they were laughed at, while 29%, mostly patients with small hydrocele, reported no reaction from the community.92 When community members were asked about their reactions to men with hydro-cele, those who had family members with hydrocele expressed understanding and sympathy, while oth-ers tended to joke about it. In non-endemic villages in Ghana, considerable stigma was associated with hydrocele and lymphoedema, much more than in hyper-endemic villages.107

4.3.4.2 IMPACT ON ACTIVITIES

In rural India, 8%–10% of men with hydrocele reported a negative impact on domestic work, 53%–55% reported a negative impact on economic activ-ities, and 53%–63% reported decreased motility.118 A study in Ghana found that 10%–60% of persons with chronic filarial disease, which included both lymphoedema and hydrocele patients, were unable to perform certain daily activities and were less likely to perform market and building activities than matched controls who had other chronic dis-eases.57 Of 14 school-aged boys with hydrocele inter-viewed in India, one had dropped out of school as a


result of being stigmatized and six had high rates of absenteeism.62 An Indian study measuring the psy-chosocial and physical burden of hydrocele found that patients’ usual activities and social participa-tion were affected by hydrocele, especially for those with larger hydroceles. In addition, as noted in ear-lier studies,63, 147 many men had switched to less demanding occupations as a result of hydrocele.

4.3.4.3 EMOTIONAL IMPACT

Men with hydrocele often describe themselves as frustrated, losing hope and even suicidal.102, 141, 145, 146 In the Philippines, Lu reported that those in higher socioeconomic classes were less emotionally affected as they were aware of, and had access to, surgery.146

4.3.4.4 MALE IDENTITY AND SEXUAL FUNCTION

In Ghana, qualitative research found that men “whose hydrocele interfered with (this) concept of male identity were deeply frustrated”; they felt as if they were a burden to their families because of dif-ficulties in providing for their families.145 In Brazil, Dreyer and colleagues reported several concerns of men with urogenital disease, including genital elephantiasis, which ranged from lack of intimacy in marriage to thoughts of suicide.141 Hydrocele patients in India reported that hydrocele adversely affected their sexual functioning and caused ‘mod-erate problems’ with anxiety/depression, based on an extended EuroQol scale.63 In Ghana, both com-munity members and men with hydrocele reported that hydrocele impeded sexual intercourse, some-times leading to divorce.67, 145 In contrast, Evans sum-marized the existing literature in 1993 (two studies), which reported little impact on sexual activity or fertility.102

4.3.4.4 SOCIAL SUPPORT

While perceived social support is important for psychological well-being, we found no published studies that addressed the impact of hydrocele on patients’ social support networks or the impact of social support networks on recuperation after surgery.

4.3.5 Health care seeking behaviour

A wide range (25%–80%) of hydrocele patients seek treatment.57, 58, 119, 145 Patients seek treatment from local health centres, traditional healers, and through self-medication. In certain countries, the belief that hydrocele has a supernatural cause leads people to seek out traditional healers or sorcerers instead of modern medical care.66 While most studies describe treatment sought only during the previous year,

patients may have tried various remedies in the past but discontinued seeking care after the treatments were ineffective.66, 92, 145 Other reasons for not seek-ing treatment include problems with access, such as cost of surgery or medical treatment, distance from the health centre, inability to take time off work for recovery, and cultural issues such as fear of anaesthe-sia during surgery and stigma associated with hav-ing hydrocele.57, 102, 138, 146, 147 A study in coastal Kenya found that, in highly endemic districts, hydrocelec-tomies accounted for 23% of all major operations.148 Similarly, in Tanzania in 1976, 15% of operations in one district hospital were for hydrocele.151

4.3.6 Beliefs and traditional practices

Beliefs about the causes of hydrocele vary by cul-ture and geography, but can be grouped into super-natural causes (including witchcraft and sorcery), heredity, exposure to extreme hot or cold, exces-sive sexuality, and consumption of certain foods or drinks.66, 67, 92, 102, 146 Some studies also mention hard work or trauma as the cause of hydrocele.101, 104, 138 Few mention mosquitoes, even in regions where mass drug administration and health education has begun.95, 100–102, 115, 147 Only 2.5% of hydrocele patients in a study in rural South India believed that fila-riasis was transmissible.115 And the link between filarial infection, hydrocele and lymphoedema is often not understood. Only 1%–4% of people inter-viewed in an Indian study knew that filarial infec-tion was a major cause of hydrocele.120 In a study in Orissa, India, while less than half of respondents knew that mosquitoes contributed to the spread of hydrocele, about 70% named them as the cause of lymphoedema.95

Traditional remedies used to treat hydrocele include herbal preparations, sorcery spells and rites, and draining with hollow reeds.66, 67, 92 Perceptions of treatment efficacy vary greatly by region, with a majority of people naming surgery as a cure.66, 67, 95,

101, 147 However, 90% of persons with lymphoedema and/or hydrocele interviewed on the Kenyan coast believed their disease was incurable. This may have been influenced by the experience of two elderly men in the area who had a recurrence of hydrocele after surgery.92

4.4 Treatment

Surgery is the recommended intervention for hydro-cele, and if done properly, it is regarded as curative. Other techniques, such as aspiration of the fluid and injection of sclerosing substances, are less effective, have unacceptable side effects, and have not been adequately evaluated in filariasis-endemic areas.142,

157 Recently, Ryan has called for studies of other


measures, such as deep breathing, to reduce the size of hydrocele.158

A variety of surgical techniques are used for hydrocele in filariasis-endemic areas, although lit-tle is known about their relative frequency of use. Modifications of the ‘eversion’ technique are prob-ably most commonly used, in which part of the tunica vaginalis is excised and the remainder is everted. While this approach may be effective for non-filarial hydrocele or for ‘pure’ hydrocele in fil-ariasis-endemic areas, it is likely sub-optimal as a procedure for lymphocele, because dilated, leak-prone lymphatic vessels – the source of the excess fluid – are not removed. Thus, the risk of recur-rence may be substantial. Eversion techniques have also been associated with other more serious com-plications, including development of the debilitat-ing condition of lymph scrotum, for which surgical treatment is vastly more challenging than that for hydrocele.137 Thus, current WHO guidelines call for complete removal of the tunica vaginalis.153

Few studies have been published on the rates of complications and recurrence following hydrocele surgery in filariasis-endemic areas. A study from Wardha, India, reported a 26.7% incidence of wound infection or haematoma in cases considered filar-ial in aetiology, compared with 10.9% in non-filarial hydrocelectomies.159 Among 950 surgeries for large hydrocele in Orissa, India, post-operative infections and abscesses were seen in 28 (2.9%) cases, scro-tal haematoma in 12 (1.3%), and reversible penile oedema in 42 (4.4%).140 The paucity of data on out-comes makes it impossible to compare cost or effec-tiveness of one technique over another. Surgical outcomes are currently being evaluated in Brazil, India, Haiti, Nigeria, and West Africa.

Research is urgently needed in the following areas:• Evaluation of tools to distinguish the various

forms of ‘filaricele’ preoperatively.• Studies using various surgical techniques to

assess costs, resource requirements (e.g. time, anaesthesia, electricity), surgery duration, post-operative quality of life, and incidence of relapse and of infectious and other post-operative complications.

4.4.1 Impact of hydrocele surgery on quality of life

Ahorlu et al. interviewed hydrocele patients in Ghana 1.5 years after surgery. Patients reported that within three to six months post-surgery, they had experienced significant improvement in self esteem,

sexual function, and capacity for work, and they participated more in community activities.138

5. IMPACT OF ANTIFILARIAL DRUG TREATMENT ON ACUTE AND CHRONIC FILARIAL MORBIDITY

Data on the impact of treatment with antifilarial drugs on filarial morbidity are inconsistent. Several studies have reported reductions in acute attacks, lymphoedema, and/or hydrocele following MDA, but other studies report no such association (table 4). For most of these studies, the primary outcome of interest was microfilaraemia rather than clinical morbidity. Therefore, the studies are often limited by inadequate or non-standardized case definitions, inadequate sample sizes, and intermittent or incom-plete follow-up. Many studies have only evaluated the effect of drug treatment in persons with existing morbidity. Such an approach ignores the incidence of new cases, and could lead to an erroneous conclu-sion regarding the effect of the antifilarial drugs on disease incidence or prevalence.

Clinical studies have also produced inconsistent find-ings. A detailed case report of a US Peace Corps vol-unteer demonstrated dramatic clinical improvement in lymphoedema following DEC treatment,16 but a clinical trial by Das and colleagues in Pondicherry, India, found no change in limb volume or condi-tion.171 A study using lymphoscintigraphy in Recife, Brazil found no improvement in lymphatic mor-phology among patients with clinical or subclinical disease following treatment with DEC.174 A carefully designed placebo-controlled study by Bernhard and colleagues found no effect of DEC treatment (in the context of mass treatment) on hydrocele volume.139 As noted above, treatment with DEC can provoke both acute and chronic hydrocele in men with W. bancrofti infection.88, 90

Assessing the public health impact of mass treatment with antifilarial drugs is a critically important issue for programme advocacy and for planning morbid-ity control strategies. Studies on the impact of MDAs on the prevalence and incidence of acute inflamma-tory episodes, lymphoedema, and hydrocele are needed, using rigorous case definitions, close clin-ical assessment, and control groups. They should be conducted both in areas using DEC/albendazole and in areas using ivermectin/albendazole.

6. CONCLUSIONS

Morbidity control efforts within the GPELF have focused on: 1) basic lymphoedema management (hygiene, skin care, and simple physical measures)


to reduce the incidence of ADLA and prevent pro-gression of lymphoedema; and 2) surgical repair of hydrocele. Since the GPELF was launched in 1998, considerable research has documented the effective-ness of basic lymphoedema management and pro-vided a stronger scientific base for this intervention. Less work has been done to document the costs and benefits of hydrocele surgery in filariasis-endemic areas. Additional research is needed to support efforts to ‘scale up’ morbidity control and disability alleviation programmes at the national level, and to

document the extent to which antifilarial drug treat-ment influences the course of filariasis-associated disease.

Acknowledgements

The authors thank Dr. Gerusa Dreyer for helpful comments on an early draft of the manuscript and Ms. Tsu-Chin Wu for help in reviewing studies on the effect of antifilarial drug treatment on clinical morbidity.

Table 4. summary .of .studies .that .assessed .the .effect .of .antifilarial .drug .treatment .on .the .clinical .manifestations .of .lymphangitis .(acute .attacks), .hydrocele, .and .lymphoedema . .

Source Acuteattacks

Hydrocele Lymphoedema Drug Delivery Follow-up interval

ciferri .1969160 + . - - dec mda 2 .years

march .1960161 + + + dec . mda 10 .years

bernhard .2001139 . . . . - . dec mda, .clinical .trial .

1 .year

partono .1989162 + . + dec . mda, .selective 11 .years

beye .1952163 - - . - dec mda, .selective 16 .months

simonsen .1995164 . - .* . dec selective 1 .year

Kessel .1957165 + . . dec selective 1 .year

fan .1995166 . - - dec salt 16–19 .years

meyrowitch .1996167 . + . + dec salt 2 .years

meyrowitch .1998168 . + . dec salt 4 .years

meyrowitch .2004169 . + .¶ . dec mda, .salt 4 .years

hewitt .1950170 + + .¶ . + .¶ dec clinical .trial 8–14 .months

das .2003171 . . - dec . clinical .trial 1 .year

Kenney .1949172 . . + dec clinical .trial 1–3 .months

pani .198975 . . +‡ . dec clinical .trial† >1 .year

moore .199616 . . + dec case .report 1 .week–7 .months

bockarie .200218 . + + . dec, .dec .+ .iv mda 5 .years

dunyo .2000173 . - - iv .+ .alb mda 1 .year

malecela, .macKenzie(personal .communication)

+ . + iv .+ .alb mda 1–2 .years

* .2 .of .8 .hydroceles .resolved¶ .disease .progression .also .observed .‡ .reductions .seen .primarily .in .patients .with .early-stage .disease† .included .other .interventions, .but .improvement .related .to .number .of .dec .doses+ .decrease .noted .(not .necessarily .statistically .significant)– .no .decrease .noted .(or .if .noted, .inconsistent .or .not .considered .significant .by .authors) . . not .evaluated .or .extremely .small .numbersdec, .diethylcarbamazine; .iv, .ivermectin; .alb, .albendazolemda, .mass .drug .administration .using .dec .tablets


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152. Wijers D. Bancroftian filariasis in Kenya. I. Prevalence survey among adult males in the Coast province. Annals of Tropical Medicine and Parasitology, 1977, 71:313–331.

153. Global Programme for the Elimination of Lymphatic Filariasis. Surgical approaches to the uro-genital manifestations of lymphatic filariasis. Geneva, World Health Organization, 2002 (WHO/CDS/CPE/CEE/2002.33).


154. Lothrop HA, Pratt JH. A report of two cases of filariasis. American Journal of the Medical Sciences, 1900, 120(5):525–553.

155. Jachowski LA, Gonzales-Flores B, von Lichtenberg F. Filarial etiology of tropical hydroce-les in Puerto Rico. American Journal of Tropical Medicine and Hygiene, 1962, 11:220–233.

156. Ottesen EA, Weil GJ. Towards a strategic plan for research to support the Global Programme to Eliminate Lymphatic Filariasis. American Journal of Tropical Medicine and Hygiene, 2004, 71(5):S1:S46.

157. Addiss DG, Dreyer G. Treatment of lymphat-ic filariasis. In: Lymphatic filariasis. Nutman TB, ed. London: Imperial College Press, 2000:151–199.

158. Ryan T. Lymphatic filariasis and the International Society of Lymphology. Lymphology, 2004, 37(3):151–157.

159. Subrahmanyam M, Belokar WK. Filarial hydrocele – problems in diagnosis and management. The Clinician, 1980, 44(6):262–265.

160. Ciferri F et al. A filariasis-control program in American Samoa. American Journal of Tropical Medicine, 1969, 18(3):369–378.

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163. Beye HK et al. Preliminary observations on the prevalence, clinical manifestations, and control of filariasis in the Society Islands. American Journal of Tropical Medicine and Hygiene, 1952, 1:637–661.

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171. Das L, Subramanyam Reddy G, Pani S. Some observations on the effect of Daflon (micronized purified flavonoid fraction of Rutaceae aurantiae) in bancroftian filarial lymphoedema. Filarial Journal, 2003, 2(1):5.

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173. Dunyo SK, Nkrumah FK, Simonsen PE. Single-dose treatment of Wuchereria bancrofti infections with ivermectin and albendazole alone or in combination: Evaluation of the potential for control at 12 months after treatment. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000, 94:437–443.

174. Freedman DO et al. Lymphoscintigraphic assessment of the effect of diethylcarbamazine treat-ment on lymphatic damage in human bancroftian filariasis. American Journal of Tropical Medicine and Hygiene, 1995, 52:258–261.


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Annex 8 WORKING PAPER: Social and behavioural issues of mass drug administration and morbidity management in the programme to eliminate lymphatic filariasis


8: SOCIAL AND BEHAVIOURAL ISSUES OF MASS DRUG ADMINISTRATION AND MORBIDITY MANAGEMENT IN THE PROGRAMME TO ELIMINATE LYMPHATIC FILARIASIS

Babu BV Regional Medical Research Centre, Indian Council of Medical Research, Bhubaneswar 751 023, India.

Lymphatic filariasis (LF) is a major tropical dis-ease. Approximately 40 million people in 83 disease-endemic countries have clinical LF, and another 80 million people are infected, while more than 1000 million live in endemic areas and are at risk of becoming infected. Human infection with the par-asite leads to damage in the lymphatic vessels and then to a large range of temporary and permanent disabilities.

LF is particularly associated with grossly swollen limbs and genitals. The disease has been identified as an eradicable or potentially eradicable disease by the International Task Force for Disease Eradication.1 In 1997, the World Health Assembly passed a reso-lution that called for member states of the World Health Organization (WHO) to support the global elimination of LF as a public health problem. The programme to eliminate LF (PELF) has two princi-pal goals: (i) to interrupt transmission of infection, and (ii) to alleviate and prevent both the suffering and disability caused by the disease.

The most practical and feasible method of control-ling LF is to rapidly reduce the microfilarial load in the community by annual mass drug adminis-tration (MDA) of a single dose of antifilarial drugs, i.e. of diethylcarbamazine (DEC) or ivermectin with or without albendazole. MDA has been initiated in 36 of 83 endemic countries.2 Research has shown MDA to be an effective tool for the control of LF; 5–10 rounds of treatment with 75%–80% compliance could possibly eliminate the disease by reducing transmission to very low levels.3 Therefore the prin-cipal challenge before planners, programme man-agers and researchers is to develop effective and sustained drug delivery strategies to achieve higher treatment compliance, the importance of which has recently been highlighted.4 Studies on treatment compliance and other socio-behavioural issues of

implementation of large-scale MDA and other activ-ities under PELF are necessary for refining and reframing the PELF strategies to achieve desirable results. A few reviews are available on social and behavioural aspects of LF.5–7 This paper identifies areas where social and behavioural issues can con-tribute significantly to the success of PELF.

COVERAGE WITH MDA, COMPLIANCE, AND ASSOCIATED SOCIO-BEHAVIOURAL FACTORS

Studies on MDA indicate that compliance is rela-tively low in the majority of endemic areas. The per-centage of population covered by MDA is the most important factor in determining the success of mass control/elimination programmes.8 If the PELF is to be successful, it is essential that microfilaraemia is cleared, or at least reduced to very low levels, in almost all of those living in at-risk areas for at least five consecutive years. Both MDA coverage (the per-centage of population in a targeted district recorded as having ingested antifilarial drugs during MDA) and geographical coverage (the percentage of at-risk communities where MDA is regularly conducted) have to be kept high.9 Extension of geographical coverage usually depends on the operational feasi-bility and previously achieved treatment coverage or compliance with MDA. In many endemic coun-tries, coverage and compliance are not at the desired levels. Significant variations occur between reported coverage and actual compliance in many places due to several factors; data from some Indian states and Haiti show that failure of distributors to visit the community for treatment, and absenteeism of the people at the time of the distribution, are reasons for low coverage/compliance.10–13 Furthermore, as many as 25% of individuals fail to consume the drug after having received it, mostly due to behavioural reasons, particularly the fear of adverse reactions, forgetting to take the drug, losing the tablets, and feeling it unnecessary to take them.

People’s perception of the MDA programme as a whole is positive as they consider it a welfare pro-gramme; however, low level of knowledge about the disease and its treatment and prevention per-sist in all endemic areas. Poor awareness of the role of mosquitoes in LF transmission is reported in many endemic areas including Thailand,14,15 Ghana,16,17 Haiti,13,18 Malaysia,19 The Philippines,20 French Polynesia,21 and the states of Tamil Nadu,22 Orissa23,24 and Madhya Pradesh in India.25 In most of these areas, trauma to the testes is perceived to be the cause of hydrocele. In many areas where MDA is implemented, people link the programme


to prevention of elephantiasis but not of hydro-cele, though prevalence of the latter is expected to be significantly higher than prevalence of the for-mer. Achieving higher compliance with MDA and involving the community in the programme is pos-sible by strengthening their hands with adequate information.

In countries like India, annual MDA is an economic option26 and the existing government health care system is capable of operating the programme,10,11 although more inputs are required to achieve the desired levels of compliance. In African countries, community-directed treatment (ComDT), as devel-oped by TDR, is feasible and can achieve the high coverage needed for LF elimination. A multicountry study in India and Africa, undertaken with the sup-port of TDR, compared mass treatment of commu-nities through the public health system alone with mass treatment delivered through a community-directed system but with significant public health services involvement. In the latter system, the com-munities decided how to implement the treatment and selected their own drug distributors, who dis-tributed the drugs at the convenience of the commu-nity, while the health service’s role was to introduce the concept to the community, train the distributors, and help with monitoring and supervision. In Africa, the combined community-directed/health services system resulted in significantly greater treatment coverage than was achieved by the health services alone. ComDT was thus recommended as the drug delivery strategy for LF elimination in Africa.27,28 In India on the other hand, drug delivery by the combined health services/community approach achieved less coverage than delivery by the health services alone. However, this study showed that good coverage was associated with strong political and administrative commitment, with motivation and training of health workers, with more effec-tive communication between the health worker and community, and with greater involvement of the community. The most effective strategy in India was drug delivery through the regular health system but with active community involvement.29 However, a method to ensure that consumption of the drugs is supervised should be developed to minimize the gap between coverage and consumption.

ADVOCACY

Many factors associated with high/low coverage and compliance with MDA have been identified. In spite of the many issues related to the health system or policy which have influenced compliance with MDA, several obstacles have already overcome and MDA receives support at global and national levels.

Effective implementation protocols have been devel-oped30 and rationalization of programme activities has increased.31 The problems at planning level can be solved with proper mobilization of resources and advocacy through highlighting the benefits of the programme in relation to the social and economic costs. Data on the operational costs of MDA, effec-tiveness of MDA, epidemiology of disease, and economic loss due to the disease, are essential in this endeavour. A recent analysis based on data from South India concluded that elimination of LF through MDA is the most beneficial disease con-trol strategy in the annals of public health history.32 Advocating the feasibility and significant benefits of the programme at very low costs could be useful for sensitizing health authorities and donors, and for generating resources and commitment to the PELF.

Ottesen identified three potential benefits of the PELF: direct benefits, i.e. relief from suffering and disability, and prevention of economic loss; ancil-lary benefits with broad public health importance such as impact on intestinal helminth infection; and consequential benefits such as reinforcement of a new approach to the health problems of the devel-oping world.33 In spite of all this, a negative attitude and resultant low priority persist among many pro-gramme partners. A recent study in Orissa, India, on the attitudes of different programme partners, including peripheral level programme managers, health workers, private practitioners, key person-nel in the community, and non-governmental orga-nizations, indicated an undesirable level of attitude to the PELF.34 Some of these partners, particularly private practitioners and non-governmental orga-nizations, do not know the rationale and benefits of MDA. Even some health workers, who are expected to convince the community to consume the drugs, are not clear on the benefits of MDA. Similar infor-mation has to be obtained from other endemic areas undergoing MDA, and the rationale and benefits of MDA need to be integrated carefully in advocacy strategies. The PELF involves the committed part-nership of many, each bringing different strengths. If all programme partners have a good understand-ing of the programme and are eager to participate in it, the elimination of LF will be possible.

SOCIAL MOBILIZATION AND ENHANCEMENT OF COMMUNITY PARTICIPATION

In many endemic areas, not all community mem-bers receive the drugs, while some fail to consume the drug even though they received it. The reasons for this are mostly either operational or behavioural;


they can be corrected to achieve high coverage and compliance through IEC and social mobilization activities. The recently developed strategy of ‘com-munication for behavioural impact’ (COMBI), which has a sharp focus on expected behavioural results, i.e. on acceptance and swallowing of the tablets, has given good results in achieving the desired levels of MDA compliance. With the implementation of COMBI, MDA coverage in Sri Lanka increased from 65.4% in 2001 to 86% in 2002. In the same year, India covered about 53.5 million people with the backing of COMBI. The heart of this effort was a group of volunteers, mostly community members, who went from door to door, convincing people and deliver-ing the drugs. They were supported by a strong IEC campaign. To elevate the programme to high prior-ity among the community, IEC and community par-ticipation should be strengthened, as the best mass treatment strategies rely heavily on active commu-nity participation.35,36 The IEC should be culture spe-cific, and should involve endemic communities, particularly political and administrative figures who are respected by the community. The IEC activities should not remain exclusively in the hands of pro-gramme people. All types of communication tech-niques, advocacy tools and media outlets should be exploited, given that the most effective method of IEC depends on the local environment, health sys-tem, social structure, culture, population density and method of drug distribution.9

MANAGEMENT OF ADVERSE REACTIONS AS PART OF SOCIAL MOBILIZATION

Another important issue that affects coverage and compliance with MDA is the presence of adverse reactions to treatment. The severity of adverse reac-tions seen in endemic communities may be due to high levels of microfilariae.38 The problem of adverse reactions may subside as the programme progresses, given the reductions in microfilaria prevalence and adult filarial antigen level seen after each round of MDA with DEC and albendazole.39,40 In Papua New Guinea, adverse reactions were asso-ciated with increased rates of compliance in the fol-lowing year, possibly because the adverse reactions were perceived as indicators of the efficacy of treat-ment.41 These messages should be carefully incor-porated in IEC campaigns. In addition, an active surveillance system for managing adverse reactions during MDA should be developed.

SPECIFIC STRATEGIES FOR URBAN AREAS

Studies from India have shown that coverage is far below the expected level in all Indian states, and is significantly lower in urban than in rural areas.10,12 Comparative 2002 MDA data from urban and rural areas in Orissa, India, showed 45% coverage in urban areas and 76% in rural areas; similarly there was lower compliance in urban than rural areas, of 23% and 49% respectively.12 While a drug deliv-ery strategy, which is under continuous modifica-tion for refinement, has been developed for rural areas, no specific strategy exists for drug delivery in urban areas. More importantly, a well function-ing peripheral primary health care system as found in rural areas, where a strong network of periph-eral level health workers undertakes all preventive activities including LF elimination, is almost non-existent in urban areas. An ongoing TDR-initiated study, based on a partnership and community-par-ticipation approach, is an attempt to develop urban area specific strategies for MDA. Early results from the Orissa component of this study suggest that the approach is feasible and sustainable in urban areas of India; the approach succeeded in building part-nership and attaining compliance at least similar to that in rural areas. The approach can be scaled up to larger urban areas with necessary modifications through experimentation. More efforts need to be made to raise community-level awareness of: risk of getting the disease, the benefits of the programme, and the perceived health needs. Finally a revised strategy has to be integrated into the national programme.

SOCIAL AND BEHAVIOURAL ISSUES IN THE MANAGEMENT OF FILARIAL MORBIDITY

LF has been ranked as the second leading cause of disability worldwide.42 Chronic forms of LF, such as lymphoedema and hydrocele, have significant impact on the patient’s life.43–46 Acute attacks of lym-phangitis are also common, and in fact repeated acute episodes, which lead to progression of the dis-ease from lymphoedema to elephantiasis,49,50 are responsible for greater short-term disability and subsequent economic loss43,47,48 than the chronic manifestations.

The discovery that bacterial infection plays a key role in the occurrence of acute attacks and progres-sion of LF disease is very significant. It has become increasingly evident that regular hygiene prac-tices such as washing of the affected part, includ-ing simple exercises etc., may play an important role


in preventing progression of oedema and reduc-ing acute attacks. Shenoy et al. demonstrated how a programme of foot care can significantly decrease the frequency of acute adenolymphangitis (ADL) attacks and help alleviate LF disability.51 In such programmes, meticulous hygiene in treating the affected area needs to be incorporated along with the creation of hope and understanding among the patients, their care providers and the community as a whole.53 Dreyer et al. recommended washing of the affected limb regularly with soap and clean water to avoid progression of lymphoedema to ele-phantiasis.54 As foot care is the mainstay for mor-bidity control of LF,51,54 attempts should be made to promote foot care among lymphoedema patients. It is essential to assess current practices of foot care in the communities in light of the information from some endemic areas of India55–58 and Sri Lanka59 that the use of footwear, and foot hygiene, is not exten-sive. Since little information on foot care is available to patients, foot care measures are little practiced. A home-based morbidity management approach needs to be developed for lymphoedema patients; advocacy to promote foot care practices should be intensive and behaviourally driven.

Appropriate care in the early stages can help pre-vent or reverse progression of the disease. Hence peripheral level health institutions whose work-ers have the appropriate knowledge and technical skills to demonstrate foot care methods to patients, and to guide patients in the use of locally avail-able resources, should take the lead in encouraging patients to modify their behaviour and take up foot care practices. This activity should be undertaken during regular visits of health workers to the com-munity as well as during patients’ visits to health institutions.

Hydrocele patients should be encouraged to opt for surgery, and increased access to hydrocele sur-gery should be provided at peripheral level hospi-tals. Initially, large-scale surgeries at camps may be useful in endemic areas where there are large num-bers of patients with hydrocele, but there is a need for operational research to assess the feasibility and benefits of hydrocele surgery and home-based lymphoedema care, and to explore the possibili-ties of integrating these activities with other pro-grammes. Studies from Mali and Nigeria indicate that home-based morbidity management is possi-ble and, for all cases, the resource persons are the patients themselves and their families and neigh-bours.61 The pilot studies currently under way in Sri Lanka, Madagascar and Zanzibar, which involve treating lymphoedema patients, appear to show the method is feasible – there are indications of a

significant reduction in the occurrence of acute attacks.61 Another study has documented the ben-efits of support groups in teaching affected women the principles of lymphoedema self-care and moti-vating them to continue.62

Filarial patients visit primary health centres in rural areas as well as urban health centres for treatment of the various forms of LF.55,59,63 However, peripheral health workers should promote home-based foot care practices such as regular cleaning of affected parts with soap and water, use of antibiotics/anti-septics, limb elevation, and exercising. Optimal dis-ease prevention at the community level requires the development of simple, reliable and effective strate-gies to control secondary infections, as these infec-tions are essential cofactors in the development of filarial lymphoedema and the progression of ele-phantiasis.64 Although people living in endemic areas may be aware of elephantiasis, many fail to recognize the early stages of lymphoedema and fail to get treatment.24

A recent study from India revealed that many health workers are not aware of the concept of foot care and its importance in LF morbidity management.63 A similar study on physicians in Pondicherry, India, indicated that whereas 75% of physicians pre-scribed DEC for lymphoedema patients, only 10% gave advice about foot care.65 The medical and para-medical staff of these peripheral institutions should therefore be oriented as to recent developments in the clinical management of LF.

An area of research to be explored is the develop-ment of a measure or index to assess the severity of morbidity and/or quality of life among LF patients. This measure will be useful for assessing the impact of various interventions, and the results can be used in the up-scaling of activities. A few studies have attempted to utilize the widely used Dermatology Life Quality Index (DLQI) to assess the quality of life of lymphoedema patients.66,67 However, it can-not be concluded from the results that DLQI ade-quately fulfils this need.

CONCLUSIONS

This paper identifies areas where social and behav-ioural issues can contribute significantly to the suc-cess of the PELF. Coverage and compliance with MDA in many endemic areas are not at the desired levels; the reasons for this are behavioural, and could be due to poor knowledge of the disease. These are issues that can be redressed by providing communi-ties with correct and adequate information.


In African countries, community-directed treat-ment is in wide use; the method is feasible and can achieve higher compliance. In India however, where the government health system is capable of oper-ating MDA, care should be taken to minimize the gap between coverage and compliance. The atti-tudes of programme managers and other partners need to be studied and reoriented through advo-cacy campaigns. Similarly, community participa-tion has to be promoted through social mobilization; many community level factors for low compliance can be addressed through, for example, communica-tions for behavioural impact (COMBI). Research on developing specific strategies for urban areas needs to be continued given the promising results from the Orissa studies.

The second pillar of PELF, i.e. morbidity manage-ment, needs to be strengthened. As foot care is the mainstay in morbidity control, attempts should be made to promote hydrocele surgery and home-based lymphoedema care. Research to understand the current knowledge and practices of patients as well as of healthcare providers is therefore required. Behaviourally driven advocacy should be promoted.

Improvement of the DLQI index, to assess the sever-ity and or quality of life among lymphoedema patients, is also called for.

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Report on

10-12 May 2005Geneva, Switzerland

www.who.int/tdr

TDR/SWG/05

Scientific Working Group

TDR/SWG/05

Report on Lymphatic Filariasis

TDR/World Health Organization20, Avenue Appia1211 Geneva 27Switzerland

Tel: (+41) 22 791-3725Fax: (+41) 22 [email protected]/tdr



The Special Programme for Research and Training in Tropical Diseases(TDR) is a global programme of scientific collaboration established in1975. Its focus is research into neglected diseases of the poor, withthe goal of improving existing approaches and developing new waystoprevent, diagnose, treat and control these diseases. TDR is sponsoredby the following organizations:

World Bank

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