Public Health Journal 25 (2014) by Bayer Vector Control

Public Health Journal No. 25

INSECTICIDE RESISTANCE IN MALARIA VECTORS

Widespread exposure to pyrethroids used in long-lasting insecticide-treated nets (LNs) and indoor residual spraying (IRS) has led to steadily increasing resistance to these and similar-acting classes of insecticides. This is compromising their use in these interventions and increases risk of control failure. The recent introduction of the carbamate insecticide bendiocarb (Ficam®) has provided an opportunity to continue successful implementation of IRS in many countries. Ficam® plays an important role in malaria control, integrated into strategic vector m anagement, as recommended by the WHO.

June 2014

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k e y fa c t s

(

IN S E C T IC IDE R ES I S TA N C E M A N A G E M EN T IN IRS ( INDOOR RES IDU AL S P RAYING)

Malaria in mid-Northern Uganda

Promoting socioeconomic stability

Rotational use of non-cross-resistant chemical classes

by John Bosco Rwakimari

Malaria and insecticide resistance in Mali

Using Ficam® to control pyrethroid-resistant mosquitoes

ORGANOCHLORINES e.g. DDT • One of the four classes of insecticides recommended by WHOPES • Cross-resistance with pyrethroids can impact efficacy • Usage is required to be reported under the Stockholm Convention

ORGANOPHOSPHATES e.g. pirimiphos-methyl, malathion

• One of the four classes of insecticides recommended by WHOPES • Generally shorter residual activity than pyrethroids • Same mode of action as carbamates • Organophosphates cause non-reversible acetyl-cholinesterase inhibition • Acetyl cholinesterase monitoring is usually required in spray operators

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CARBAMATES

by Mamadou B. Coulibaly

e.g. bendiocarb

• One of the four classes of insecticides recommended by WHOPES • Generally shorter residual activity than pyrethroids • Same mode of action as organophosphates • Carbamates cause reversible acetyl cholinesterase inhibition (monitoring in spray operators not required)

R O T A T I O N

NE G L ECTE D T R O P I C A L D I S E A S E S

Tungiasis

A debilitating but neglected parasitic skin disease by Hermann Feldmeier

NGO

Catholic Relief Services

PYRETHROIDS e.g. deltamethrin, alpha-cypermethrin, lambda-cyhalothrin

• One of the four classes of insecticides recommended by WHOPES • Usage on both long-lasting nets and in IRS is contributing to wide spread resistance development • Relatively cheaper compared to other insecticide modes of action

Compassion for the very poorest NOTE S

Book review: All you ever wanted to know about Anopheles mosquitoes Malaria deaths: Numbers halved since 2000 Football World Cup in Brazil: Threat of dengue Financial crisis in Greece: Return of tropical diseases Climate change: Malaria moves to higher altitudes Resistance management: Recurring theme UNITAID: Malaria Vector Control Report 52 History West Nile Virus CD-ROM

Available as poster on the enclosed Public Health CD-ROM

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Cover photo: Stevo Oruma Abalo & Peris Agengo (With permission of USAID/PMI) PUBLIC HEALTH JOURNAL 25/2014

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Editorial Editor’s note Insecticide resistance management

Essential for successful vector control

by Gerhard Hesse cover story

Insecticide resistance in African malaria mosquitoes

Looking to the future

by Hilary Ranson

History of Ficam®

Bendiocarb revived as prime insecticide

by Justin McBeath

C A SE ST U D I ES RES I ST A NCE M A N A G E M ENT

Malaria vector control and insecticide resistance in Sudan

Keeping check on susceptibility

by Hmooda Toto Kafy

Introducing bendiocarb for IRS in Senegal

Restoring sensitivity by Konaté Lanssana, Diop Abdoulaye, Dia Ibrahima, SY Mamadou Demba, Diagne Moussa, Gadiaga Lebasse, Julie Thwing, Elleen Dotson, Faye Ousmane

Indoor residual spraying in Zambia

Prioritizing resistance monitoring by Mulenga Musapa 2

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Malaria in mid-Northern Uganda

Promoting socioeconomic stability by John Bosco Rwakimari

Malaria and insecticide resistance in Mali

Using FicamÂŽ to control pyrethroid-resistant mosquitoes by Mamadou B. Coulibaly

NE G L ECTE D TRO P I C A L D I SE A SES

Tungiasis

A debilitating but neglected parasitic skin disease by Hermann Feldmeier

NGO

Catholic Relief Services

Compassion for the very poorest

NOTES

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editorial

Resistance easily comes to the minds of many of us when we reflect on the main threats to the concerted malaria control efforts in recent years. It has become an added enemy and challenge for the international community set to eradicate this vector-borne disease. Resistance management is a major focus of Bayer’s portfolio and innovation strategy, and the principal topic of this Public Health Journal. I am pleased that Hilary Ranson, Professor in Medical Entomology at the Liverpool School of Tropical Medicine and a leading expert in the field, has contributed to this edition by providing a detailed update on resistance and resistance management in the lead article. The threat to our ability to control the vectors of malaria and dengue goes hand in hand with alarming news about the development of resistances against the newer drugs for curative malaria treatment. Will this development threaten the successes of concerted malaria control efforts and of the consequent application of the principles of the Global Malaria Action Plan? Will future editions of the WHO World Malaria Report show an increase in malaria again? Will dengue hamper economic development in Asia, Latin America, and other parts of the world? The response needs to be NO, and Bayer will play a role in that answer. In this issue, we highlight ® the rotational use of bendiocarb (Ficam ) in indoor residual spraying (IRS) to mitigate resistance of ® impacted pyrethroids. Some years ago we made the conscious decision to defend Ficam – in anticipation of increasing pyrethroid and DDT resistance – although there was no longer a use for ® it in agriculture. Today, Ficam is the primary choice for pyrethroid resistance management for IRS, whereas pyrethroids are still the major insecticide for bednets. In this Public Health Journal, we look at several case studies from country programs in western Africa, southern Africa, eastern Africa, and particularly Sudan, which runs one of the biggest programs in Africa. Both in our cooperation with IVCC and in our own development efforts, we are striving to bring alternative modes of action and new chemical classes to the market, preferably before the end of ® this decade. And for the programs which can switch back to pyrethroids after having used Ficam , we can now offer a solution with K-Othrine Polyzone, which due to its unique polymer can extend the a ctivity of the spray treatment without increasing the dose rate. As the soccer World Cup is approaching and the world casts its eyes on Brazil, we look at Tungiasis (sand flea disease) – a neglected tropical disease that is most prominent in Brazil and causes serious skin inflammation of the feet. It is one, but clearly not the only threat to public health in the country. Sports fans and visitors should of course also take precautionary measures to protect themselves against dengue! I wish you pleasant reading.

Gunnar Riemann

Member of the Bayer CropScience Executive Committee and President of the Environmental Science Division Worldwide

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Editor’s note

Insecticide resistance management

Essential for successful vector control In this, the 25th edition of the Public Health Journal, we take the opportunity to review and discuss the status of insecticide resistance in malaria vectors. We receive insights from leading researchers in this field; see illustrations of what is being done on the ground in malaria indoor residual spraying programs and also reflect on the history of one of the insecticide active ingredients which is currently regarded as key for pyrethroid resistance management. We bring these accounts together in order to bring a holistic perspective to the topic; an approach which we believe is essential to ultimately solving the problems faced and reflecting our 360 degree approach to vector control.

esistance, in malaria vectors, to the currently available insecticides seems to be increasing at a dramatic rate and, indeed, threatens the gains made in the fight against malaria. In parallel, we are also observing the emergence of resistance to commonly used insecticides in dengue and Chagas vectors. Insecticide resistance management (IRM) must therefore be an essential component of integrated vector control against these diseases. A complicating factor in vector control (certainly a major difference compared to agriculture) is the small number of insecticide modes of action available, and the heavy reliance on pyrethroids for both indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LNs). Resistance to pyrethroids (and DDT) through the knock-down resistance (kdr) mechanism seems to be the most widespread of all resistance types.

The author: GERHARD HESSE Head of Global Partnering Vector Control, Bayer Environmental Science, Lyon, France

So what can be done about this worrying development? The WHO Global Malaria Pro gramme ‘Global Plan for Insecticide Resistance Management in malaria

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vectors’ issued in 2012, provides insight and suggestions to this question. It outlines the available strategies to manage resistance, but most importantly stresses the key message that insecticide resistance management is a shared responsibility for all relevant stakeholders. Given the involvement of Bayer in vector control for more than 50 years, we take our role, responsibility and contribution very seriously. As a result, we: • invest to defend existing insecticide classes; both in terms of regulatory position and also in terms of promoting proper use and stewardship • screen our library of insecticides to determine if there are novel ways other existing active ingredients could be put to use in vector control • invest in development of new modes of action (i.e. completely new insecticides) • improve formulations of existing insecticides to enhance cost-effectiveness and performance (e.g. through longer lasting formulations) Investing in defence of existing insecticides: Bendiocarb is an active ingredient within the carbamate class of insecticides which, in the last five years or so, has become increasingly important for malaria vector control. The story with this active ingredient (described in more detail in the article on page 16) illustrates perhaps one of the challenges faced by the insecticides manufacturing 5

Editor’s note

industry as a whole. A significant investment was made by Bayer to defend the regulatory position of bendiocarb a (relatively) long time before pyrethroid resistance became so widespread in malaria vectors and thus prior to its urgent need for IRM. The probability of a return on investment at that point in time was arguably quite low. The commitment was still made because of a firm belief that there would be a need for it in the future. Screening of existing insecticide libraries: As a rule, the newer insecticide classes being introduced into agriculture do not possess the same features as those desired for use in Public Health. Two of the most desirable properties of a public health insecticide (especially for use as an indoor residual spray) include a contact action and extended residual activity. These two features are not so desired in agriculture (less need for long residual activity on the plant surface and a contact action may be counter-productive to integrated pest management strategies which also rely on beneficial insects). So it might take a different approach and some creative thinking to apply these “newer classes” of insecticide and introduce them into Public Health. In 2013, coinciding with the MIM Conference in Durban, Bayer announced that it had committed to the development of a new mode of action for malaria vector control. This project has involved screening compounds with novel modes of action and examining how their activity might be modified in combination with other insecticides. The outcome will be a solution which is effective against multiple resistant strains of mosquitoes. This product concept went into early field trials in 2013 and launch of the product is expected within the coming three to four years, provided that preliminary data are confirmed and depending on the time needed for the WHOPES evaluation process. Investing into development of new modes of action: Bayer is working in collaboration with the IVCC (the Innovative Vector Control Consortium), to identify completely new insecticide classes which could be utilised in Public Health. This is a major undertaking, which involves screening a vast library of molecules (including past candidates which may 6

not have quite matched the profiles desired for use in agriculture). The objective is to increase the range of insecticide classes which are available for public health use and therefore allow greater choice for rotation in resistance management. The full development of a new active ingredient can take more than 10 years however, even after a molecule is first identified. While there are candidates which show promise, it is unlikely that these will reach the market prior to 2022. Developing smarter formulations of existing products: Improving the effectiveness of existing insecticides may provide added benefits, such as greater flexibility in application or, in some cases, greater cost ® effectiveness. K-Othrine Polyzone (also borne out of a collaboration project with the IVCC) is a new formulation of the pyrethroid deltamethrin which utilises a Bayer polymer to extend the residuality on IRS relevant surfaces. K-Othrine® Polyzone achieved a WHOPES recommendation in 2013 and has a unique position in terms of residual activity compared to other pyrethroid products. This new formulation is expected to be available widely in 2015 (after country registrations are achieved) and is expected to improve the cost-effectiveness of IRS in areas where pyrethroid susceptibility remains. What about the practical elements of IRS application? Having a longer term plan to make new insecticide classes available is one thing but it is also necessary to preserve the compounds and formulations which we have today. The implementation strategy is therefore highly important; the “state of the art” today (as it has been for many years) is rotational use of non-cross-resistant insecticides, ensuring the selection pressure varies within the rotation scheme. Ideally such rotational use should be pre-emptive but this is not always possible. Given the current cost differential between pyrethroids and non-pyrethroids currently used for IRS, the ultimate goal is to rotate as long as necessary until pyrethroids can be included in the program again. However, since pyrethroids remain the only class of insecticide used on nets, the long-term outlook seems to be continued selection pressure from PUBLIC HEALTH JOURNAL 25/2014

Editor’s note

LNs; necessitating ongoing rotation within IRS programs (involving non-pyrethroids). Rotation intervals need to be defined based on monitoring and evaluating the resistance / susceptibility levels of the vector population involved. The WHO Global Plan for Insecticide Resistance Management in malaria vectors (GPIRM) describes a rotation interval “… from one year to the next”. This may prove practically challenging if there are significant differences between the insecticide formulation types (e.g. spraymen getting used to using liquids versus dry formulations) and, under situations of established resistance, it could also take longer for susceptibility levels to reach a point where rotation could occur (especially given the current limited range of options available). This publication indicates that Ficam® has been used successfully across a range of country IRS programs in situations where pyrethroid resistance has been widespread. Some countries have been using bendiocarb consecutively for several years, without carbamate resistance emerging (there are experiences from programs across Africa, the Middle East and Latin America). We would, of course, advocate caution under such circumstances; ensuring that usage and monitoring takes into account the potential for resistance to develop, but results have shown that after a number of applications (to be determined by monitoring and evaluation) susceptibility to pyrethroids is increasing again, so that a switch back could be considered. The design of any resistance management strategy needs to be established in discussion with relevant experts and local product registrations and the potential increased costs need to also be taken into account. As more experience is gained with different resistance mechanisms in different strains of resistant vectors, this will inevitably lead to more effective strategies to both achieve effective control and limit the development of resistance in other areas. There is still great discussion about the most effective ways to manage resistance under various settings and the benefits of ‘basic’ strategies such as complete rotation, versus implementation of (more complex) mosaic spraying are still under debate. Fundamentally though it is better to do something PUBLIC HEALTH JOURNAL 25/2014

than to simply stay on the same path - and the best path will certainly be found through good and regular resistance monitoring. All of this adds costs to a program but it is generally recognised (and certainly referred to within the GPIRM document) that the short-term additional costs of IRM should be balanced against the positive public health impacts and potential long-term costs of insecticide resistance. In Summary Effective IRM in vector control is complicated by a range of factors which include the single insecticide class which is available for use on nets; the limited range of insecticide classes available for IRS and the higher short-term costs associated with using current non-pyrethroids. The carbamate bendiocarb has been shown to be highly effective for IRS and is a suitable rotation option in situations where pyrethroid resistance is present and, with good monitoring and evaluation, it can be used to good effect over a number of years. The approach of rotating between modes of action should be standard practice but there are always challenges under every situation and this therefore reinforces the importance of good monitoring and evaluation and a good understanding the resistance status of the vector population. WHO’s GPIRM document rightly highlights that “insecticide resistance management is a shared responsibility for all relevant stakeholders”. It lists the roles for the private sector as evaluating IRM strategy, R&D, resource mobilization and advocacy. Inevitably there is also a strong focus or expectation towards the private sector on cost reduction and strategies surrounding affordability. In order to make this expectation a viable one, that yields certain returns for all parties, the principle for Bayer (and I would argue for industry as a whole) is not to focus on the off-the-shelf cost of a product used within a given intervention category but to look at the overall impact in terms of cost-effectiveness. From our own development pipeline we certainly see the potential for new resistance management tools to be available in the future which could save overall costs for malaria programs through improved performance and therefore greater cost-effectiveness. 7

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Insecticide resistance in African malaria mosquitoes

LOOKING TO THE FUTURE Resistance to pyrethroid insecticides, the only class of insecticide available to treat bednets, is now widespread in African malaria mosquitoes. The number of long-lasting insecticide-treated nets in use in Africa is increasing each year, and pyrethroids, as well as other insecticide classes, are also being used in indoor residual spraying programs in a growing number of settings. With little prospects of new public health insecticides being available for at least another five years, what, if anything, can control programs do to tackle this growing resistance problem? This article presents evidence that insecticide resistance is increasing in African malaria vectors, describes the options available for insecticide resistance management, and considers the success and limitations of these strategies.

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Photo: Michelle Cornu

A DECADE AGO one child died from malaria every 30 seconds. More recently this has changed to one child every 60 seconds. Halving malaria mortality in Africa can be attributed to scaling up personal protection methods particularly sleeping under long-lasting insecticideÂtreated nets. How can we continue to save lives?

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ide-scale implementation of tools to prevent malaria transmission by mosquito vectors has achieved dramatic results across Africa. An estimated 36% of the population at risk of malaria in Africa is now protected by long-lasting insecticide-treated nets (LNs), and approximately 8% live in houses that have received indoor residual spraying (IRS). The scale up in coverage with these preventative measures has contributed to approximately halving malaria mortality in Africa between 2000 and 2012.

percentage mortality, and a threshold of less than 90% mortality is used to define resistance. This standardized methodology is useful for tracking the spread of resistance, but does not provide information on the strength of this resistance or its impact. For example, it is not uncommon to find close to zero mortality after exposing the main African malaria vectors, Anopheles gambiae or Anopheles funestus, to diagnostic doses of pyrethroids. But does this mean that pyrethroids are no longer effective in these settings?

With resistance now being detected However these fragile gains are in malaria vectors from the majority threatened by both economic and of African countries, a new set of biological factors that could either standardized methods for quantifying reduce access to the tools or reduce the strength of the resistance (and their efficacy. One of the major biolinking this to the efficacy of LNs and logical threats is the emergence of The author: IRS) is urgently needed. These assays resistance to the limited number of need to be simple enough to perform insecticides in use for public health. HILARy ranson in the field, in resource poor settings. Only pyrethroid insecticides are Department of Cone bioÂ assays, where resistant approved for bednet treatment. The Vector Biology, mosquitoes are exposed to insectiÂ majority of IRS programs also rely Liverpool School of Tropical Medicine, UK cide-treated surfaces are a useful on this insecticide class, although an additional tool for assessing whether increasing number of countries are switching to carbamates (bendiocarb), organo- the resistance is likely to have an operational phosphates (principally pirimiphos-methyl) or the impact, provided the necessary controls with laboorganochlorine DDT, in response to emerging ratory susceptible mosquitoes are included (to exclude inadequate bioavailability of insecticides pyrethroid resistance. as a contributing factor to reduced mortality of field mosquitoes). How to monitor insecticide resistance Before reviewing the evidence that insecticide resistance is increasing, and the impact of this resistance, it is important to reflect on the methodologies being used to detect resistance and be aware of their limitations. The vast majority of insecticide resistance monitoring in malaria control programs rely entirely on the use of diagnostic dose bioassays, using World Health Organization tube assays (or, in a small number of cases, CDC bottle bioassays). Data are reported as

Detecting resistance mechanisms Molecular assays can complement bioassays. They can provide an early warning of the presence of resistance genes in the population, prior to control failure, which is important for proactive resistance management (see below). In addition, they can aid in the selection of alternative insecticides. For example, both DDT and pyrethroids share the same target site, so if resistance is caused by a target site mutation, substituting between these insecticide classes would not be appropriate.

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Alternatively, if resistance is caused by elevated activity of an enzyme that is only able to degrade one insecticide class, a wider range of options is available. Unfortunately, cross-resistance between insecticide classes seems to be a common phenomenon in malaria mosquitoes. In addition to kdr (knock-down resistance) or ace-1 (acetylcholinesterase target site mutation), which confer crossresistance between DDT and pyrethroids, or between carbamates and organophosphates respectively, recent studies have detected a number of cytochrome P450 enzymes that are elevated in resistant mosquitoes; these enzymes are able to metabolize at least three out of the four insecticide classes. More reports of resistance to all insecticide classes Pyrethroid resistance was first detected in An. gambiae s.l. in West Africa in 1993 and remained relatively rare until the end of the twentieth century. In recent years reports of pyrethroid resis-

tance in the major African malaria vectors have escalated (Fig. 1) and it is now difficult to find a population of An. gambiae that is fully susceptible to this insecticide class. Pyrethroid resistance is also widespread in An. funestus in southern Africa and has been detected in West and East African populations of this vector species. Few studies have quantified the strength of this resistance, but comparisons of the length of time required to obtain 50% mortality after exposure to a diagnostic dose of insecticide (LT50 measurements) have repeatedly detected resistance ratios in excess of 100–fold in West African An. gambiae. Pyrethroid resistance ratios of >50–fold have also been detected using CDC bottle bioassays to measure LD50 in field and lab populations of An. gambiae. Resistance to carbamates and organophosphates is also on the increase. In some populations this is associated with the ace-1 target site mutation. But a growing number of reports also describe metabolic resistance to carbamates. Of particular concern are populations of both An. gambiae and An.

Pyrethroid resistance in malaria vectors Data from 2000-2005

Dots indicate mortality in WHO bioassays Fig. 1

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Data from 2005-2010

< 90% mortality

90 - 97% mortality

> 97% mortality

Source: IR Mapper (www.irmapper.com) Nov 2013

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funestus that show cross resistance between carbamates and pyrethroids, thought to be mediated by the same cytochrome P450-based mechanism. At least one population of An. gambiae has now developed resistance to all four classes of insecticide available for public health. Assessing the impact of resistance While general consensus is that insecticide resistance is rapidly spreading in African malaria mosquitoes, opinions differ on the impact of this resistance on current control activities. With current monitoring and evaluation practices, it is very difficult to attribute control failures at the programmatic level directly to insecticide resistance. Probably the best evidence that resistance is impacting control comes from retrospective analysis in countries that have changed the insecticide class in IRS programs (in response to either reports of resistance or increases in malaria cases) and seen an improvement in control. Under more controlled environments, it is possible to assess the impact of resistance by assessing mosquito mortality and/or blood feeding rates in experimental huts containing LNs or after IRS, and replicating these experiments in sites differing in their level of resistance. Some of these studies have shown a clear reduction in LN and/or IRS efficacy in areas where the vectors are resistant. In general however, the data generated by resistance monitoring is disconnected from the data needed to assess the impact of this resistance on malaria control activities. Improving resistance monitoring, including establishing thresholds at which operational failure occurs, would help interpret the threat posed by resistance. But the epidemiological impact of resistance will depend on a

large number of factors (e.g. behavior of major vectors, efficacy of case management approaches, drug resistance, etc.). Nevertheless, there can be no doubt that if the selection pressure on malaria mosquitoes is allowed to continue unchecked, resistance will eventually result in the failure of existing tools. In 2012 the WHO published the â&#x20AC;&#x153;Global Plan for Insecticide Resistance Managementâ&#x20AC;? (GPIRM) and this document included a number of short, medium, and long-term strategies designed to prevent this scenario becoming a reality. The theory of insecticide resistance management (IRM) For malaria control programs using IRS, theoretically it should be possible to manage insecticide resistance by careful pre-planned rotation of insecticide classes with different modes of action (MoA). In practice this means alternating between DDT or pyrethroids and carbamates or organophosphates. IRM is most effective if an insecticide class is replaced before resistance to any available insecticides is detected. This is because the chances of a mosquito simultaneously developing resistance to two different MoA are predicted to be rare (although metabolic resistance mechanisms may be an exception). In reality, rotation of insecticide classes is usually triggered by reports of resistance or perceived failures of the current product (e.g. increases in malaria cases, more reports of mosquitoes inside homes). If resistance to one or more classes of insecticide to be used in rotation has already developed, effective IRM will only be achieved if resistance has a fitness cost. In this scenario, when selection pressure is removed or reduced, resistant individuals are at a disadvantage and compete less effectively for resources, so the frequency of the resistant genes decreases in the population. As a result, after a given time period, and before resisnd tance to the 2 compound becomes established, st the 1 compound can be re-introduced.

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Photo: Wikimedia/Johns Hopkins Malaria Research Institute

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Unfortunately very little is known about the fitness costs of different resistance mechanisms in mosquitoes, and this raises questions about the longterm efficacy of current IRM strategies. Hence, with just two MoA available, preserving insecticide susceptibility long-term via IRS rotations will be a major challenge. Furthermore simply changing the insecticide class may not be sufficient to relieve the selection pressure on the mosquito. Three out of the four insecticide classes used in public health are also widely used in agriculture. Hence mosquitoes may be continually exposed to low doses of these chemicals even if their use in vector control is suspended. Even more critical, with current and projected coverage with LNs, pyrethroid exposure is likely to continue, even in programs that have stopped using this class of insecticide for IRS. Severe IRM challenge with LNs The challenges for IRM in control programs relying on LNs are even more severe. There are currently no LNs with alternative MoAs that can be used in rotation, and even if these are developed, the LN paradigm relies on nets being effective for three years in the field, a timescale incompatible with a proactive rotational IRM strategy. With

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rotations not being possible, the two remaining options are mixtures or mosaics. LNs that contain both a synergist and a pyrethroid are now available: Permanet 3.0, a mosaic with PBO (piperonyl butoxide) on the roof of the net and deltamethrin on the sides, and Olyset Plus with PBO and permethrin combined throughout the net. While these may prove more effective than conventional LNs in reducing malaria transmission in some areas with high levels of resistance, there is no data to suggest that the use of synergists can reduce the selection for pyrethroid resistance. Additional bitreated nets containing two MoAs are under development, but are likely several years from deployment. If pyrethroid resistance is detected in areas where LNs are the main form of control, the GPIRM document recommends that countries introduce IRS with a non-pyrethroid insecticide. The only exception is in cases where it is clear that the pyrethroid resistance is solely caused by the target site kdr resistance mechanism and where there is no evidence that malaria cases are increasing. In reality, our knowledge of resistance mechanisms is

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Photo: Elissa Jensen/USAID

IRM robust enough to persuade those funding malaria control to adopt IRM strategies recommended by GPIRM?

SWITCHING OR ROTATING insecticide classes used for IRS should be performed before resistance is detected in order to stay ahead of mosquitoes developing resistance.

insufficient to be able to rule out additional mechanisms, but this recommendation is based on the premise that kdr alone does not compromise control, whereas metabolic resistance can result in operational failure in isolation. So in essence, in areas currently dependent on LNs alone, GPIRM recommends the use of combinations of insecticides by combining IRS and LNs, in order to maintain malaria control against resistant mosquitoes. Lack of funds Almost all malaria control programs have a shortfall of funds. All IRM strategies are more costly than the alternative of taking no action. In theory, short-term expenditure is rewarded by long-term gains, since the effectiveness of available tools is maintained and the expense (both economic and in terms of disease burden) of control failure is averted. Is the current evidence for the success of

Undoubtedly, the threat of insecticide resistance is now being taken more seriously by national malaria control programs and by financers of malaria control. There are a number of good examples of a change in insecticide use in IRS as a direct response to the emergence, or risk of emergence of resistance. But for how long can we stay ahead of the game, and prevent resistance from derailing further gains in reducing the malaria burden, using the current approaches to resistance management? IRM in practice in malaria control: Is it working? As described in other articles in this issue, there are now several good examples of malaria control being sustained, or restored, by switching insecticide classes for IRS. In most cases the switch has been from sodium channel modulators (DDT or pyrethroids) to acetylchoine esterase inhibitors (carbamates and organophosphates). The latter insecticide classes incur a higher expense per unit sprayed than pyrethroids, and additional safety measures are needed to protect the spray teams. But these negative aspects are typically outweighed by the reduction in malaria cases attributed to the change in insecticide class. However, although these are good examples of sustaining, or even improving, malaria control despite the presence of resistance, are these actual examples of effective IRM? Put another way, does a switch from pyrethroids for IRS reduce selection pressure sufficiently to result in restoring susceptibility to pyrethroids in the mosquito population? If the answer is no, because pyrethroid resistance is stable (or â&#x20AC;&#x153;fixedâ&#x20AC;?) in the mosquito population, then what options remain for these control programs once resistance to carbamates and/or organophosphates inevitably emerges? Of course, if an unlimited number of insecticides with different MoAs were available, there would

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be no need to reintroduce insecticides in a rotational manner; instead a succession of insecticides with alternative MoAs could be used. But with just two MoAs it is essential that the dynamics of the resistance genes are tracked. For reasons described above it is very difficult to remove pyrethroid selection pressure entirely. So by introducing the only other MoA into malaria control “too early” (i.e. prior to confirmed control failure) are we simply accelerating the pace at which resistance to both available MoAs becomes fixed in the mosquito population? We simply do not know the answer to these questions, but with the increasing availability of molecular tools to track resistance genes, it should be possible to work with control programs to start addressing these key operational research questions. The benefits of combining LNs and IRS are also unclear. Several recent studies have sought to address this question in areas with varying vector composition, malaria endemicity, and insecticide resistance levels, but the initial results appear to be very context specific. The importance of regular monitoring for insecticide resistance is finally becoming more widely accepted by the malaria community. But it is time to switch the emphasis from simply describing the problem to providing effective, practical solutions. These should be based on the best available evidence, and of course the information should be presented in a format that is accessible to decision makers and implementers of malaria control.

Two key challenges face malaria vector control in Africa: • How can we maintain or enhance malaria control activities with current tools while we wait for new products? • What can be done to ensure the maximal effective lifespan of any new insecticides in the public health market?

conclusion The use of other non-insecticidal based control methods will become increasingly important as resistance increases. Targeting both interventions and IRM strategies is also likely to assume more importance as the costs of alternative insecticides or products exceed available budgets. Looking to the future there is optimism that new insecticides will be available for LNs and/or IRS before the end of the decade. But these must be used judiciously from the start to delay the onset of resistance. It may be too late to preserve pyrethroids for future generations, but now is the time to start planning effective IRM for new public health insecticides. Article on the enclosed Public Health CD-ROM.

Lessons for the future Malaria vector control is at a critical point. New insecticides with novel MoAs are urgently needed. Several promising products are in the pipeline, but it will be at least five years before these reach the market. Moreover, many of these may fail before they reach this endpoint.

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History of Ficam®

Bendiocarb revived as prime insecticide Global efforts over the last decade to increase availability and access to longlasting insecticidal nets have dramatically reduced the incidence of malaria, particularly in sub-Saharan Africa. Unfortunately the only insecticide class approved for nets is pyrethroids. This has led to steadily increasing pyrethroid resistance in malaria vectors, severely compromising the use of this and similaracting classes of insecticide in indoor residual spraying (IRS) programs. Reintroduction of the almost forgotten carbamate, bendiocarb, for use in IRS has moved it back to the top of the list of recommended insecticides for managing pyrethroid insecticide resistance in mosquitoes.

n this day and age, with rapid advances in technology being almost a daily expectation, it is perhaps odd to consider that 43 years after the birth of a particular product, we would still be talking about its continued importance (particularly for a product which is an insecticide). Such is the remarkable position ® of Ficam (bendiocarb) today. New insecticides for agriculture Bendiocarb was invented in 1971 by a chemist working for the UK-based company Fisons Ltd. It was introduced in Europe during the 1970s and first launched in the USA in 1980.

reasonably large number of new insecticide families that have been developed for agricultural uses, but have not yet necessarily found uses as insecticides for public health. Few insecticides for public health The author: Justin McBeath Market Segment Manager Vector Control, Bayer S.A.S. Environmental Science, Lyon, France

The insecticide industry has undergone such major changes since then that not only does Fisons no longer exist as an insecticides supplier, but even the company that acquired it in 1995 no longer exists. During that time we have also seen a

Currently there are only four classes of insecticides represented within the WHO recommended list of insecticides for indoor residual spraying (organochlorines, organophosphates, carbamates, and pyrethroids) and only one class of insecticide recommended for use on long-lasting insecticide-treated nets (the pyrethroids). With the scale up in distribution of long-lasting

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nets the selection pressure for pyrethroid resistance has increased steadily over the last 10 years, contributing to a position today where pyrethroid resistance in malaria-transmitting mosquitoes is widespread.

sional pest control market evolving away from residual surface sprays towards baits and more targeted applications, the market demand for bendiocarb declined

update the registration dossier) a decision had to be made – invest to retain bendiocarb, or consider retaining propoxur instead? When the relative merits of the two insecticides were assessed, the decision was made to ensure the ongoing availability of bendiocarb. Bayer therefore divested propoxur in 2007. In so doing the specification that now applies to the active ingredient is no longer linked to Bayer’s manufacturing source.

“WHO Specifications now only apply to products for which the technical materials have been evaluated.”

However, the continued availability of Ficam® and retaining its use for malaria vector control has not been a simple path. With no uses in crop protection, the volumes needed to service the public health insecticide market have been a tiny fraction of the production volumes needed for other insecticides used in agriculture. In 1999, with the profes-

to a position where its registration in the USA was voluntarily withdrawn (reducing global production demand even further). Choosing between carbamates By the early 2000s the only remaining needs for bendiocarb were for professional pest control in Europe, Australia, and South America, as well as some uses for scorpion control in Mexico; however it was during these same few years that the potential for bendiocarb as a resistance management tool in malaria vector control was recognized. At the same time Bayer was also selling another carbamate (propoxur) for similar use patterns, and it recognized that space to retain both compounds from the same family of insecticides in the same markets was limited. So when both i nsecticide molecules and their associated products came up for re-registration in Europe (requiring a multi-million Euro investment to

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Photo: Roger Griffith / Wikipedia

So it is that, 40 years on, bendiocarb currently represents arguably one of the most important of the 12 insecticidal active ingredients on the WHO recommended list for malaria vector control. Perhaps this is because at this point in ® time, Ficam represents the only carbamate insecticide still manufactured and supplied according to the WHO Specifications applicable to it. Also until 2013 bendiocarb WP80 was the only WHO recommended non-pyrethroid and non-DDT based product that had residual activity exceeding three months on most surfaces.

SPANGLE GALL on an oak leaf (underside), caused by a small wasp.

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Manufacturing bendiocarb What may not be widely known about bendiocarb is that the primary raw material used to manufacture it, ironically, comes from the interaction between an insect and a tree. In response to attack from a small wasp, oak trees produce growths called galls (these are part of the tree’s defense mechanism). The image on page 17 illustrates what these galls look like. They contain high levels of tannic acid, a component that is essential for manufacturing the primary precursor of bendiocarb. The galls cannot be “farmed” and so must be harvested from wild trees and then processed to generate the necessary material. About 60% (by mass) of bendiocarb is derived from material originating from these oak galls, and seasonal variations in the availability of galls obviously have a dramatic impact on the pricing of the raw material derived from them. Increased use of bendiocarb for IRS As already mentioned, demand for Ficam® has grown in recent years in parallel to increasing pyrethroid resistance, and the greater emphasis placed on resistance management within malaria vector control programs. The WHO’s 2012 launch of their

global call-to-action for managing insecticide resistance in malaria vectors (GPIRM)1 has also prompted some countries to take pre-emptive measures and implement pro-active rotation of products used. This meant that between 2008 and 2010 the global demand for bendiocarb increased by a factor of five, and between 2010 and 2012 demand tripled again. Bayer estimates that, based on the volumes procured for indoor residual spraying programs over the last four ® years alone, Ficam has protected more than 100 million people against vector borne diseases (malaria, leishmaniasis and Chagas disease). We have seen usage for IRS across more than 15 countries and a range of different organizations involved in procuring it (e.g. USAID,2 PMI3 supported programs in Sub-Saharan Africa; UNDP4 supported programs in the Middle East and Africa, and local vector-control programs across South America and Africa). In 2011 a study published in the October edition of “The American Journal of Tropical Medicine and Hygiene” highlighted the “dramatic reduction

GPIRM: Global Plan for Insecticide Resistance Management 2 USAID: United States Agency for International Development 3 PMI: President’s Malaria Initiative 4 UNDP: United Nations Development Programme

in malaria transmission” following several years of Ficam® use in areas of pyrethroid resistance in Benin. Similar anecdotal reports have been provided from Uganda and other countries where it has been used (some of which are described in more detail in this publication). Looking to the future However, as we reach a stage where some countries have now been using bendiocarb for some years, it is clearly in the best interest to ensure that monitoring and evaluation is embedded into the decision making for insecticide choice in indoor residual spraying programs and that insecticide rotation is implemented where necessary. We are aware that carbamate resistance has been reported in some mosquito populations in some countries (some of which is attributed to agricultural usage of carbamates) and that this necessitates a move to alternatives. The recent availability of a longer lasting organophosphate formulation presents a potential option, which could therefore help in those situations where resistance to organophosphates does not already exist; but any such switch should clearly be based on sound operational evidence to do so (especially given the additional expense associated with this new formulation). It is quite evident from some of the published PMI 2014 opera-

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Cost/household/month of activity

these trials then we expect to be able to have this product going through the WHOPES evaluation process within the next few years. This could mean a new option for IRS within the next five years.

2.5 2.0 1.5 1.0

conclusion

0.5

In response to pyrethroid resistance, many countries have already introduced bendiocarb as the insecticide to use in IRS programs, and seen dramatic reductions in many vector borne diseases such as malaria, leishmaniasis and Chagas disease. However, while Ficam® remains an important tool in the IRS armory, like other insecticides it should be used judiciously in an integrated management program in order to maximize the impact against malaria and other diseases, and preserve its usefulness for as long as possible.

0 Pirimiphosmethyl CS

Bendiocarb WP80

Pyrethroids

DDT

The figures are calculated based on the median point of the residual range of the WHOPES recommendation, the current market pricing, and an assumption that one filled sprayer is enough on average to spray two households. Fig. 1

tional plans and the recent Africa IRS comparative cost analysis that the additional costs of implementing IRS with nonpyrethroids in some situations is hard to sustain under conditions of limited funding. Carbamates are certainly more expensive than pyrethroids; and the longer-lasting pirimiphosmethyl formulation that has recently been made available seems to be even more expensive. The challenge we have decided to take up within Bayer is to develop additional insecticides that could provide more costeffective solutions than these current standards. The metric Bayer uses to measure cost effectiveness is based

on the cost of the insecticide per household sprayed per month of residual activity. Bayer’s target is to have a low-dose product with a low unit cost, offering improved residual activity. If this metric is applied to the principal insecticides currently available then the relative costeffectiveness can be clearly seen in Fig. 1 above.

Article on the enclosed Public Health CD-ROM

New insecticide mode of action Of course, Bayer is already involved in the IVCC1 Partnership to search for completely new modes of action for vector control. Also during the MIM2 Conference in Durban, October 2013, Bayer announced that it is taking a new insecticide mode of action to field trials across Africa in 2014. If the results are good enough from

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IVCC: Innovative Vector Control Consortium 2 MIM: Multilateral Initiative on Malaria

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Malaria vector control and insecticide resistance in Sudan

Keeping check on susceptibility

Photos: Hmooda Toto Kafy

Intervention measures to restrict the transmission of malaria by controlling the vector population comprises the main part of vector control. Effective vector control strategies are based on four elements: identifying the vector species; knowledge and understanding of the biology and ecology of the vector; monitoring and surveillance, and implementing effective control measures. This Âreport describes these different aspects of malaria vector control and strategies to deal with insecticide resistance in Sudan.

Rearing a field-collection of An. arabiensis.

uring the years 1980 to 2000, malaria posed a significant health problem in all parts of the Sudan; however considerable progress has been achieved since the country became a recipient of GFATM aid (Global Fund to Fight AIDS, Tuberculosis and Malaria). The World Malaria Report (2011) showed that the estimated Âmalaria incidence in Sudan was around 1,000 cases per 100,000 people annually, with a case fatality rate of about six deaths per 100,000. 20

Transferring mosquitoes during insecticide susceptibility assessments.

Malaria parasites and vectors Among the four human malaria parasites, Plasmodium falciparum is responsible for more than 95% of malaria cases in the whole country. However, other species such as P. vivax and P. ovale have been increasingly reported.1 In Sudan, so far more than 30 species of Anopheline mosquitoes have been reported2, but only three species are malaria

vectors. Anopheles arabiensis is known to be the principal malaria vector in parts of the country, while the two species An. gambiae s.s. and An. funestus have been suggested to contribute to limited focal (southern part) malaria transmission.3 Vector control measures In Sudan vector control programs, as is the case with many anti-malaria programs elsewhere in the world, mostly rely on using chemical insecticides that

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can kill the target insects. Historically, different formulations of synthetic chemical insecticides have been used for vector control. During the years 1900 to 1950, most of the control efforts were confined to the use of diesel oil, paris green (copper (II) acetoarsenite), and larvivorous fish in breeding habitats, as well as providing proper water management.4 In the 1950s, indoor residual spraying (IRS) with BHC (gam-

for IRS for more than five years, until 1980 when it was replaced with fenitrothion 50% EC.5,6 For larvicidal control temephos 50% EC, has been in use since 1975. During the 1990s, insecticides belonging to the synthetic pyrethroid group were introduced into the public health program. Deltamethrin (2.5% WP), is still being used for indoor residual spraying in many parts of the country, while permethrin (25% EC) is also in use for ultralow

The author: Hmooda Toto Kafy Head of Integrated Vector Management (IVM) Unit, Federal Ministry of Health, Khartoum, Sudan.

ENTOMOLOGISTS are trained in the field of phenotyping and genotyping to analyze mosquitoes.

Bioassay test on surfaces sprayed with Ficam® 80% to monitor the quality and bioefficay of IRS.

maxine) became the main control measure in all malarious areas of the Gezira and Khashm Elgirba irrigation schemes until 1960. In 1961, DDT 50% WP (wettable powder) was introduced for IRS in the Sennar and Gezira areas as part of the malarial eradication pilot project. But it was not sustained for many reasons, including insecticide resistance issues. In response to that, malathion 50% EC (emulsion concentrate) was introduced in 1975, and it was successfully used as the insecticide of choice

volume (ULV) and thermal fog space spraying. The synthetic pyrethroid, deltamethrin, is also used in long-lasting insecticidetreated nets (LNs). In the last four years more than 12 million LNs have been distributed to targeted areas all over the country. Recently, as a way to face problems concerning An. arabiensis resistance to deltamethrin, bendiocarb (Ficam® 80% WP) was introduced for IRS application in 2007 (at a dose of 200 mg/m2) in Gezira irrigated schemes.

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Malaria risk map The Republic of Sudan has historically been classified as covering a wide range of malaria endemicities.7 Recently, a national malaria risk map was developed where the whole country was classified into five strata: desert fringe, riverine, irrigated schemes, urban areas, and refugee camps for internally displaced persons (IDPs).7 This map was further improved by using the parasite survey data 21

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Malaria stratification map of Sudan THE ENDEMICITY CLASSES are estimated from age-corrected Plasmodium falciparum parasite rates (PfPR2-10). The geographical features map the Nile rivers, aridity defined from thresholds of enhanced vegetation index, irrigation schemes, refugee camps 7 (IDPs), and urban areas.

Malaria strata Urban areas Refugee camps Irrigation schemes Desert fringe PfPR2-10 < 1% (Hypoendemic) 1 - 10% (Hypoendemic) > 10 - 50% (Mesoendemic) > 50 - 75% (Hyperendemic)

Fig. 1

from the 2005 and 2009 Malaria Indicator Survey of Roll Back Malaria within a Bayesian geostatistical framework to produce an empirical map of malaria risk, which also shows the distribution of refugee camps, irrigation schemes, the desert, and urban areas (Fig. 1).7 Insecticide resistance profile Insecticide resistance was first reported in the country in 1972.8 In recent decades, many studies have been conducted in the country investigating insecticide resistance in An. arabiensis, the main malaria vector. All the results indicated that there is a 22

wide distribution and intensive knock-down resistance (kdr) to pyrothroids in An. arabiensis.9 (See table 1 on next page). Threat to LNs Insecticide resistance is a threat to the success of malaria vector control interventions relying on insecticides. The rational use of insecticides depends on the knowledge of the status of insecticide susceptibility levels in malaria vectors. Thus a study was designed to discover the status of insecticide susceptibility levels in malaria vectors and monitor insecticide resistance/ susceptibility levels of An. arabiensis Patton.

Co-resistance to permethrin was observed to be coupled with the occurrence of high resistance to DDT, and high kdr frequencies in populations of An. arabiensis could greatly affect malaria vector control in Sudan especially in Gezira, Sennar, White Nile and Kassala states.10 This would have serious implications for the LNs used as the malaria control strategy largely adopted in the country. Monitoring insecticide resistance The Sudan began addressing the insecticide resistance problem in 2006, when an international workshop was held and an oper-

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Number of sites reporting resistance to different insecticides Insecticide

No. target sentinel sites

No. sites with test results

No. sites reporting resistance

Deltamethrin

Permethrin

DDT

Bendiocarb

Fenitrothion

Malathion

ational plan was put in place for insecticide resistance management.11 Mosaic and rotation strategies were initiated and applied in the field for indoor residual spraying.

The second two columns list the sentinel sites where resistance monitoring was carried out, and where test results have been obtained. The last column clearly shows no detected resistance to bendiocarb and fentirothion. Table 1

In 2005, the national integrated vector management (IVM) unit identified 64 sentinel sites for vector surveillance and routine monitoring of insecticide resistance. Nowadays, the IVM unit routinely uses WHO susceptibility procedures in malaria vectors, which is considered the first step towards detecting insecticide resistance. Data from most of these sites are considered as the base line data for mapping insecticide resistance in the Sudan.

Photo: James Gathany, CDC

conclusion

BENDIOCARB FOR IRS IN SUDAN The use of bendiocarb as a suitable insecticide to use in IRS in Sudan was initiated because resistance to DDT (organochlorine), malathion (organophosphate), and recently pyrethroids, had emerged in these areas. Moreover, bendiocarb represents the sole insecticide tested against An. arabiensis and it showed 98 â&#x20AC;&#x201C; 100% mortality rates in the regions tested and all over the country. The use of bendiocarb began in the state of Gezira in 2008 and was scaled up to include the state of Sennar as a tactic to manage insecticide resistance problems there. Initially the use of bendiocarb in IRS to control mosquito vectors contributed to suppressing malaria episodes in ÂGezira PUBLICâ&#x20AC;&#x2C6;HEALTH and Sennar by JOURNAL 50% in general. 25/2014

In the Sudan malaria vector control puts a strong emphasis on insecticide resistance management. This is vital to maintain the protection effect of over 12 million distributed LNs and continue effective IRS. In the face of widespread resistance to DDT, malathion and more recently pyrethroids, IRS switched to using fenitrothion and bendiocarb. The national IVM unit uses a risk map with parasite survey data, close surveillance, and routine monitoring to keep a close check on insecticide susceptibility. Article with references on the enclosed Public Health CD-ROM 23

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Introducing bendiocarb for IRS in Senegal

Restoring sensitivity Indoor residual spraying with insecticide (IRS) was implemented in Senegal in 2007. Since 2008, the sensitivity/resistance of Anopheles gambiae s.l. to the main classes of insecticide commonly used in vector control has been monitored annually. After bendiocarb was introduced for IRS in 2011, a significant reduction in the number of mosquitoes surviving exposure to DDT and pyrethroids was confirmed, suggesting this is a possible alternative strategy for managing resistance to pyrethroids on all IRS sites. The authors: Konaté Lanssana, Diop Abdoulaye, Dia Ibrahima, SY Mamadou Demba, Diagne Moussa, Gadiaga Lebasse, Julie Thwing, Elleen Dotson, Faye Ousmane

urrently, the fight against malaria relies on five major components, which are: early detection of cases by means of rapid diagnostic tests (RDTs), quick access to early treatment

using artemisinin-based combi nation therapy (ACT); inter mittent preventive treatment (IPT) giving doses of sulfadoxine-pyrimethamine to pregnant women; seasonal malaria che-

moprevention (SMC); and vector control. This last component includes promotion of the use of insecticide-treated nets (ITNs) including long-lasting insecticidal nets (LNs), indoor residual

Photo: Jean-Luc Benoist / Fotolia.com

SAVING THE LIVES OF CHILDREN in Senegal, one of the African countries where dramatic progress has been made in malaria control. Since 2005, nationwide surveys have shown a 40 percent reduction in deaths of children under the age of five.

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spraying with insecticide (IRS), the use of larvicides, and changing the environment so as to produce conditions unfavorable for vector breeding.

Richard-Toll

S E N E G A L Malem Hoddar

A substantial reduction in the burden imposed by malaria has been noted in sub-Saharan Africa over the last ten years. A significant reduction in the transmission and morbidity/ mortality rates associated with the disease, resulting from intensifying the fight against anopheles vectors, partially explains this decrease in the disease’s prevalence. In Senegal, promotion of the use of insecticide-treated nets since the end of the 1990s, and the limited introduction of indoor residual spraying towards the end of the 2000s are the main vector control approaches implemented by the National Malaria Control Program (NMCP). Promoting IRS and LNs Since 2007 Senegal has benefited from the support of the United States President’s Malaria Initiative (PMI). This is the background against which indoor residual spraying with insecticide was implemented in three selected districts (RichardToll, Nioro du Rip and Vélingara). Other districts were then subsequently enrolled, three (Guinguinéo, Malem Hoddar and Koumpentoum) in 2010, and Koungheul in 2012.

Dakar

Koungheul

Guinguinéo Koumpentoum

Nioro du Rip Vélingara

Fig. 1

MAP OF SENEGAL showing the districts with sentinel sites, three of which have been abandoned (green) and four kept up (red).

But following a significant decrease and even interruption in transmission rates, the districts of Richard-Toll (in 2010), and Nioro and Guinguinéo (in 2013), withdrew from the IRS program. During this same period, the NMCP boosted promotion of the use of long-lasting insecticidal nets by increasing their availability and access to gradual universal coverage, between 2010 and 2013. Insecticides used in IRS An. gambiae s.l. (sensu lato) is the main vector of malaria in Senegal. First identified in the 1960s, its resistance to DDT was verified in various bio-geographical regions in 19871. Since then, further work confirmed this resistance to DDT and other insecticides, especially pyrethroids2,3,4. However, from 2007 to 2010,

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only pyrethroids were used for IRS. These included lambda- cyhalothrin (10% WP in 2007, and 10% CS in 2008 to 2009) and deltamethrin (K-Othrine WG 250 in 2010). Since 2008, evaluation and monitoring has taken place every year between July and October. On each site, An. gambiae s.l. larvae are collected and raised to obtain adults for sensitivity tests conducted according to the WHO’s standard method (WHO, 5 1998) . The insecticides tested are those in the various classes chosen by the WHO (WHOPES)5 for intra-domiciliary spraying. These mainly include pyrethroids (0.75% permethrin, 0.05% deltamethrin; and 0.05%

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lambda-cyhalothrin), carbamates (0.1% bendiocarb), organo phosphates (1% fenitrothion) and organochlorines (4% DDT). After four years of using pyrethroids, a carbamate (bendio carb: Ficam® 80% WP) was introduced in 2011 (Table 1). The sensitivity of vectors to insecticide was monitored in around twenty sentinel sites (villages) spread around various bio-geographical regions in the country (Figure 1). Rising insecticide resistance The intense pressure from insecticides exerted between 2007 and 2010 by IRS and promotion of the use of LNs were pivotal in the selection and expansion of

Photo: wikimedia (Antoinette Sullivan/USAID)

SENEGALESE CHILDREN at an event to promote universal c overage of long-lasting insecticidetreated bednets.

resistance in An. gambiae s.l. populations to pyrethroids. By 2010, their post-exposure mortality was considerably less than 80% in IRS districts (except in Vélingara) for lambda-cyha lothrin (Figure 2). In contrast, the fall in sensitivity seen on IRS sites after the four years of using pyrethroids (2010) was not recorded on sentinel sites in

non-IRS districts, even though resistant samples had been recorded in these districts, with the exception of Oussouye in the south of the country (Figure 3). Reversing the trend From the first year (2011) when pyrethroids were replaced with a carbamate (bendiocarb) for IRS,

IRS districts and insecticides used by year Pyrethroids

Carbamates

Districts

ICON 10% WP

ICON 10% CS

K-Othrine WG 250

Ficam ® 80% WP

Vélingara

2007

2008 - 2009

2010

2011 - 2013

Nioro

2007

2008 - 2009

2010

2011 - 2012

Richard-Toll

2007 - 2010

2008 - 2009 - 2010

Guinguinéo

2010 - 2011

2011 - 2012

Koumpentoum

2010

2011 - 2013

Malem Hoddar

2010

2011 - 2013

Koungheul

2013

Table 1

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Average mortality rate trends in An. gambiae s.l. females

The red lines indicate the threshold for resistance (<80% mortality). Samples where mortality is above the red line are still sensitive to the insecticide tested.

Nioro

Vélingara

Maleme

100

Perm. 75% Lambd. 05%

Delt. 05%

DDT 4%

Perm. 75% Lambd. 05%

Delt. 05%

DDT 4%

AVERAGE MORTALITY RATE TRENDS IN IRS DISTRICTS DURING THE PYRETHROID PHASE (lambda-cyhalothrin in 2008 - 2009 and K-Othrine in 2010) and after introduction of a carbamate (bendiocarb in 2011 - 2013).

Fig. 2

Fenitrothion 1%

Bendiocarb 0.1% 100

100

ouy

Oss

Pod

i ba édj ane Tam ioukh Berk Nd

Dak

ffio

Dio

ouy

Oss

Permethrin 0.75%

Pod

i ba édj ane Tam ioukh Berk Nd

Dak

ffio

Dio

Fig. 3

Pod

i ba édj ane Tam ioukh Berk Nd

Dak

ffio

Dio

ouy

Oss

i ba édj ane Tam ioukh Berk Nd

Dak

ffio

Dio

ouy

Oss

Pod

i ba édj ane Tam ioukh Berk Nd

AVERAGE MORTALITY RATE TRENDS IN RESPONSE TO THE VARIOUS INSECTICIDES tested in non-IRS districts between 2008 - 2010 (pyrethroid phase in IRS districts) and 2011 - 2013 (carbamate phase in IRS districts). Fenitrothion

Bendiocarb

100

Pod

Nioro

Vélingara

Maleme

Nioro

Vélingara

2008 - 2009 2010 2011 - 2013

Dak

ffio

Dio

DDT 4% 100

ouy

Pod

Lambda-cyhalothrin 0.05% 100

Oss

ouy

Oss

100

DDT 4%

Deltamethrin 0.05%

100

Perm. 75% Lambd. 05%

Delt. 05%

Dak

ffio

Dio

2008 - 2010 2011 - 2013

2008 - 2009 2010 2011 - 2013

Maleme

AVERAGE MORTALITY RATE TRENDS IN RESPONSE TO FENITROTHION (1%) AND BENDIOCARB (0.1%) in IRS districts during the pyrethroid phase (lambda-cyhalothrin in 2008 - 2009 and K-Othrine in 2010) and after introduction of a carbamate (bendiocarb in 2011 - 2013).

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PREPARING FOR INDOOR SPRAYING with Ficam®. This insecticide was introduced for IRS vector control in 2011 in response to growing resistance to pyrethroids.

standing acquired from molecular biology should provide us with more opportunities for insecticide resistance management (IRM). conclusion

a dramatic increase in the mortality of An.gambiae s.l. after exposure to pyrethroids and DDT was recorded over the next two years (2012 and 2013) in all IRS districts, especially in Vélingara (Figure 2). However for non-IRS sites this restored sensitivity, indicated by increased mortality after exposure to DDT or pyrethroids, was not observed (Figure 3). The mosquitoes were always sensitive to organophosphates (1% fenitrothion), since the mortality of samples tested remained 100% in all three IRS districts (Figure 4). However a relative tolerance was recorded in some non-IRS sites, especially in the cotton-growing district of Tambacounda, the marketgardening region of Thiès and the conurbation of Dakar. Resistance to carbamates (0.1% bendiocarb), which varies considerably from one year to another, was restricted to a few sites. These included both IRS sites (Vélingara and Nioro districts, Fig. 4) and non-IRS sites in the Tambacounda, Thiès and Dakar districts.

Insecticide resistance management Specific identification of the collected vectors and research into the knock-down resistance gene as well as other mechanisms involved in the development of resistance to pyrethroids (use of synergists), including the level of resistance (increased diagnostic doses), are ongoing. These studies are in progress to check whether a possible replacement of the species could explain this return of sensitivity in Senegal. However, our knowledge is still limited about how resistance evolves in space and time. The same is true of the mechanisms of resistance, which have not yet been studied in depth. Both existing and new knowledge of mechanisms and better under-

This last decade has seen unprecedented progress in the fight against malaria, which has led to a considerable reduction in the global mortality rate due to this disease. Increased resistance to insecticides is a setback to achieving the targets set for malaria control. The phenomenon of insecticide resistance is increasing at an alarming rate. In Senegal, evaluation and monitoring of vector resistance to insecticides recorded a significant fall in sensitivity to pyrethroids on sites using IRS. When pyrethroids were replaced with bendiocarb for IRS, the restoration of mosquito populations’ sensitivity to pyrethroids was seen for the first time. Strategic IRS may constitute an important strategy in managing resistance to pyrethroids and maintaining the efficacy of ITNs. Article with references on the enclosed Public Health CD-ROM

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Photo: © africa / Fotolia.com

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Indoor residual spraying in Zambia

Prioritizing resistance monitoring Scale-up of vector control interventions has significantly reduced the burden of malaria in Zambia. However, high levels of insecticide resistance were detected in 2009. This prompted national efforts to improve entomological monitoring and evaluation to strengthen evidence-based implementation of interventions, such as switching insecticides used according to the regional vector species. Recent data suggest such strategies can re-establish vector susceptibility.

ambia is continuing to make significant progress in malaria prevention and control. According to the malaria indicator survey (MIS) conducted in 2012, malaria parasite prevalence was found to be 14.9%, and severe anemia prevalence was found to be 6.8% among children under five years of age. This represents a slight decrease in both these parameters since 2010, and a general trend in decreasing malaria burden nationally since 2006. These

decreases can be attributed to vector control and improved case management. Despite these successes, the disease is still a very challenging problem throughout the country. Malaria control as public health priority Vector control using insecticidetreated nets (ITNs) and indoor residual spraying (IRS) remain the primary control strategies for preventing malaria transmission in Zambia. Since 2006, there has been rapid scale-up of malaria

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vector control by the Government of the Republic of Zambia in collaboration with many partners. These efforts coupled with improved case management translated into a 53% drop in malaria parasite prevalence among children between 2002 and 2008* . The observed reduction in the burden of malaria prompted the Zambian Govern ment to maintain malaria control as one of its main public health priorities in subsequent national

* Chizema-Kawesha et al, 2010

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health strategic plans. The current national malaria strategic plan (NMSP) 2011–2015, is aimed at significantly sustaining the gains achieved during initial scale-up efforts of malaria control interventions toward achieving the national vision of “a malaria-free Zambia.” Emerging insecticide resistance Zambia is on the verge of accomplishing its ambitious target of universal coverage of vector control to reduce malaria incidence by 75% by 2015. Zambia’s MIS 2012 report indicated that 73% of households either had at least one ITN or had been covered by IRS. However, insecticide resistance monitoring data collected since 2010 by NMCC and other partners in Zambia has

confirmed the selection of resistance in both An. funestus and An. gambiae to DDT, pyrethroids and carbamates. Mandate to interpret resistance data The problem of insecticide resistance is a threat to malaria control efforts and can severely undermine the drive towards elimination. Responding to insecticide resistance is not easy or cheap largely because the approved compounds used to control adult mosquitoes are so limited. Only four insecticide classes acting on two different target sites are currently registered for use in IRS. In an effort to improve the entomological monitoring and evaluation, and re-emphasizing the ideals of integrated vector management

Vector distribution (2013) An. funestus and An. gambiae An. funestus An. gambiae An. funestus and An. arabiensis Insufficient data

B M

Fig. 1

Mulenga Musapa Entomologist, Integrated Systems Strengthening Program (ZISSP), Zambia

(IVM) to strengthen the evidence-based implementation of interventions, an insecticide resistance technical working group (IRTWG) was established in 2010. The IRTWG includes a network of entomological partners and resources in Zambia, and a technical advisory committee comprising technical experts whose mandate is to interpret data collected by the network and make recommendations to the NMCP. Vector control based on entomological criteria

DD 20 T re 03 g - 2 ion 01 0

The author:

Before 2010, in Zambia, the choice between IRS and/or longlasting insecticide-treated net (LN) interventions was made on the basis of program capacity and malaria endemicity, rather than on entomological criteria. However, since the establishment of IRTWG, vector control

Map of Zambia depicting mosquito species prevalent in different regions.

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Percentage mortality in field sample of An. gambiae s.l 24 hours after a 1-hour exposure to insecticide-impregnated papers in WHO test tubes

4% DDT

0.75% Permethrin

Kamatipa (Kitwe) Chipata (Kitwe) Ndeke (Kitwe) Chipulukusu (Ndola) Mushili (Ndola) Masaiti (Ndola) Twashuka Luanshya Kawama (Chililabobwe) Kawama (Mufulira) St. Dorothy (Solwezi) Kyabankaka (Solwezi)

Classes of insecticides 0.05% Deltamethrin

0.05% Lambdacyhalothrin

Mosquito mortality rates (%)

100

0.1% Bendiocarb

90 80 70 60 50 40 30 20 10 Kamatipa (Kitwe) Chipata (Kitwe) Ndeke (Kitwe) Chipulukusu (Ndola) Mushili (Ndola) Masaiti (Ndola) Twashuka Luanshya Kawama (Chililabobwe) Kawama (Mufulira) St. Dorothy (Solwezi) Kyabankaka (Solwezi)

Kamatipa (Kitwe) Chipata (Kitwe) Ndeke (Kitwe) Chipulukusu (Ndola) Mushili (Ndola) Masaiti (Ndola) Twashuka Luanshya Kawama (Chililabobwe) Kawama (Mufulira) St. Dorothy (Solwezi) Kyabankaka (Solwezi)

Bendiocarb showed between 90% to 100% mosquito mortality rates on the Copperbelt Province and parts of North Western Province. Based on these results, the carbamate, Ficam®, was used in the two provinces where susceptibility was noted in the 2011/12 and 2012/13 spray seasons. Fig. 2

has become more diverse, and more contingent on local entomological data. The main malaria vectors in the country are An. gambiae sensi strictu (s.s) s-form, An. arabiensis and An. funestus s.s. A marked difference in vector distribution was noted (Fig. 1): An. gambiae dominates northwest and north central, while An. funestus is abundant in southeast and southwest of Zambia. Prior to re-introduction of IRS in 2000, baseline surveys were conducted and no resistance was detected in malaria vectors to all

four classes of insecticides. A paucity of entomological data existed from 2000 to 2009, although vector control interventions were scaling-up during this period. Between 2009 and 2010, high levels of resistance to pyrethroids, DDT and carbamates were detected. Some populations of An. gambiae s.s. were resistant to pyrethroids, DDT and carbamates. The resistant phenotype was conferred by both target-site and metabolic mechanisms. An. funestus s.s. was largely resistant to pyrethroids and carbamates. The resistant phenotype was conferred by elevated levels of cytochrome p450s.

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Decision to use Ficam® Based on these findings, an informed decision was made by IRTWG to ban the use of DDT and deltamethrin in Zambia, and switch to lambda-cyhalothrin and alpha-cypermethrin. In 2011, more resistance data was generated and further decisions were made to use carbamates (specifically Ficam®) a more efficacious insecticide against An. gambiae s.s. and An. arabiensis. Actellic® CS was chosen against An. funestus s.s. due to carbamate resistance in this group (Fig. 2).

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Insecticide rotation for IRS 2011/2012 Carbamate Pyrethroids Organophosphate (OP) Etofenprox

2012/2013 Carbamate Pyrethroids Organophosphate (OP) Carbamate and/or OP

In spray years 2011/2012 and 2012/2013 different insecticides were used in some regions. For spray season 2013/2014 a switch to organophosphate was discussed to remove selection pressure for resistance development. Fig. 3

The insecticide resistance profile of Zambia is complex and requires a matrix of insecticides to be deployed. This will result in cheaper IRS activities in certain districts and more expensive activities in others due to the difference in logistical costs for the different insecticides. The decision about which insecticide to be used is based on efficacy, residual effect, cost, and safety of the product in this order of preference (Fig. 3). Switching classes relieves resistance To maximize efficacy and limit evolution of resistance, an organophosphate insecticide

was preferred for 2013 IRS spraying. However, DDT can be used for IRS in An. funestus areas while bendiocarb is the viable option in An. gambiae regions. The 2013 data suggests the resistance frequencies have been declining after switching classes of insecticides. This could well mean the shift may be leading to reversal of vector susceptibility. Mortality to deltamethrin in An. gambiae ranged from 15-70% in 2011-2012 and 65-96% in 2012-2013 while mortality to deltamethrin An. funestus ranged from 11-65% in 2011-2012 and 17-91% in 20122013.

conclusion After insecticide rotations using Ficam® or Actellic® CS in IRS, recent resistance monitoring points towards vector populations reverting back to pyrethroid (An. gambiae and An. arabiensis) and carbamate (An. funestus) susceptibility. It is imperative that resistance monitoring continues to be prioritized to guide decision-making about the insecticides to use in IRS programs. Choice of insecticides should be based first on efficacy, then residual effect, cost, and safety of the product.

Article on the enclosed Public Health CD-ROM

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Malaria in mid-Northern Uganda

Promoting socioeconomic stability While malaria is most commonly associated with mortality of children under five, and high risk to pregnant women, it also exerts a crippling effect on socioeconomic stability and productivity. The use of carbamate (bendiocarb) in IRS since October 2010 in mid-Northern Uganda has not only reduced the malaria burden and saved lives, but has had a positive impact on the socioeconomic life of the community.

The author: John Bosco Rwakimari

n the past, mid-Northern Uganda was referred to as the “malaria epicenter of the world” and the “most malarial region on earth”. In 2006, a study revealed that on average each person received about six malariainfected mosquito bites per night. Moreover, the north of Uganda has undergone a historical catastrophe, where more

than a million people have been displaced by two decades of civil war. Despite the ceasefire, the region still lacks many services and infrastructure. Hardly surprising that northern Uganda had one of the highest rates of malaria in the world. A poor family can spend as much as 25% of its annual income on malaria treatment and prevention, which even then is not enough. The rainy season, which is a critical time for agriculture, is also the main malaria season, so farmers lose valuable time working in the field when they are recovering from the disease. Children miss school either due high fevers or when looking after parents and relatives. The health ministry esti-

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OLIVIA ACAYO, a small scale farmer of Omeer village in the Amuru district harvesting rice says: “Spraying Ficam® has led to savings for the family. My children don’t suffer from malaria episodes since our houses got sprayed”.

mates that malaria causes 60% of miscarriages in pregnant women in Uganda, and the disease frequently causes low birth weights and stillbirths. Remarkable effects of IRS Since 2010, the impact of introducing indoor residual spraying (IRS) using Ficam® (bendiocarb) has been dramatic. Not only has this resulted in reducing

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Epidemiological impact of IRS 100 IRS rounds implemented

90 80

Percentage of SPR

70 60 50 40 30 DDT

Pyrethroid 10

Bendiocarb

Slide positivity rate (SPR)

0 01 04 07 10 01 04 07 10 01 04 07 10 01 04 07 10 01 04 07 10 01 04 07 10 01 04 07 10 01 04 07 2006 2007 2008 2009 2010 2011 2012 2013 Month/Year

mortality due to malaria, but farmers are also now engaged in growing various food and cash crops – cassava, coffee, and peanuts – and earning money from farming. It is evident that in mid-Northern Uganda that while saving many lives, IRS is also enabling the people to live more stable and productive lives. Food security “There is food security among beneficiaries, increased volume of trade in agricultural products, and a steady transition from grass thatched houses to permanent structures”, says Walter Komakech, NAADS,* district program coordinator. * National Agricultural Advisory Services

MALARIA SLIDE POSITIVITY RATES and IRS rounds from January 2006 to August 2013 in the Oyam District. The slide positivity rate (SPR) is defined as the number of confirmed malaria cases per 100 suspected cases, and is plotted as a red line over time. The bars represent rounds of IRS (R1 to R8), indicating the time of application, and are color-coded to display the insecticides used.

conclusion For a region plagued by civil war, population displacement, severe poverty, and debilitating disease, regaining community life is essential. Combating malaria through IRS is proving an essential component in the path to re-establishing socioeconomic stability in midNorthern Uganda.

Article on the enclosed Public Health CD-ROM

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Malaria and insecticide resistance in Mali

Photo: Mamadou B. Coulibaly

Using FicamÂŽ to control pyrethroid-resistant mosquitoes The entire population of Mali is at risk from malaria. Distribution of traditional insecticide-treated nets since the mid1990s and long-lasting insecticidal nets since 2006 has been complemented by indoor residual spraying since 2008. All these control measures use pyrethroids, which has led to wide-spread resistance to this insecticidal class. This is a major problem facing the National Malaria Control Program in Mali.

alaria is endemic in Mali and the entire population of more than 14 million inhabitants is at risk. National statistics indicate that malaria is the major cause of morbidity and mortality, with 2,171,542 cases and 3,006 deaths occurring in 2010.1 Most of the cases are pregnant women and children under five years old. Transmission of the disease is seasonal, with the most cases observed during the rainy season when vector densities are the highest.2 Disease prevalence declines from south

to north (see Fig. 1). However malaria-specific transmission patterns occur in irrigation and urban areas. For example, transmission can have two peaks in irrigated rice cultivation areas. Malaria cases are distributed in the country in relation to ecoclimatic zones. As recommended by the WHO, in addition to case management, involving intermittent preventive treatment and seasonal malaria chemoprevention, the National Malaria Control Program (NMCP) started implementing the distribution of traditional

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MALARIA IN MALI is most prevalent in areas with perennial or seasonal water supplies.

insecticide-treated nets in the mid-1990s. Distribution of longlasting insecticidal nets (LNs) has been implemented since 2006 and indoor residual spraying (IRS) since 2008 in selected districts. In 2010, a survey showed that 85% of households possessed at least one long-lasting insecticidal bednet, with a usage rate of about 80% among children under five years old, and 75% among women.3

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Insecticide resistance in malaria vectors Pyrethroids are the insecticides used in both traditional insecticide-treated nets and LNs. From 2008 to 2010 pyrethroids were also used for IRS in Mali. This, in addition to pressure from the agricultural use of pesticide, has certainly led to the development of resistance among malaria vectors. Several studies (published and unpublished) have shown evidence of resistance to pyrethroids among malaria vectors in Mali.4, 5 Recently, studies conducted by the Malaria Research and Training Center (MRTC) and sponsored by the President’s Malaria Initiative (PMI) and the

Bill & Melinda Gates Foundation (BMGF) showed wide-spread pyrethroid resistance in Mali. In fact, in 2010, evidence from a number of IRS districts showed very low vector mortality rates when pyrethroids or DDT were tested (Fig. 2). In contrast, at all the sites where WHO susceptibility bioassays have been conducted so far, malaria vectors were susceptible to bendiocarb, with mortality rates ranging between 94%, 98% and 100% (Fig 2). National policy against resistance No official insecticide resistance management plan exists at the national level. However projects

PREDICTED MALARIA PREVALENCE IN MALI (MARA/ARMA 1998)*. L ocated in sub-Saharan West Africa, Mali is a landlocked country with a land surface of 1,241,238 km2. It shares borders with Algeria in the north, Niger and Burkina Faso in the east, Senegal and Mauritania in the west, and Guinea Conakry and the Ivory Coast in the south.

Mamadou B. Coulibaly Malaria Research and Training Center (MRTC), Bamako, Mali

or programs using large insecticide-based malaria vector control strategies are advised by the MRTC to apply insecticide rotation. These projects or programs include, among others, the NMCP and gold mining companies. Discussions are underway to complete the national policy for insecticide resistance management. In the face of the observed wide spread of pyrethroid resistance, the NMCP switched from pyrethroids to bendiocarb (Ficam®) in 2011 for IRS operations. Bendiocarb alternative for pyrethroids

Desert Predicted prevalence category: < 10% * MARA/ARMA: Mapping Malaria Risk in Africa / Atlas du Risque de la Malaria en Afrique: http://www.mara.org.za/

10 - 30%

Fig. 1

Perennial water

The author:

Bendiocarb showed high mosquito mortality rates in the two first months (>95% on average) with residual efficacy decreasing 3-4 months after treatment. Therefore bendiocarb remains one of the best alternatives for pyrethroids for the time being.

30 - 70% > 70%

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Mean mortality rates in six Mali villages 90

Mortality (%)

100

50 40

MEAN MORTALITY RATES in six villages after WHO susceptibility a ssays using deltamethrin 0.05%, lambda-cyhalothrin 0.05%, bendiocarb 0.1%, and DDT 4%, performed in 2010. Note that not all insecticides were tested in each village (Report MRTC/PMI/USAID 2011)**.

20 0

Kouala

Sirakorola

Karadie

Tia

Niala

Bagadaji

Villages Deltamethrin

Lambda-cyhalothrin

Fig. 2

Moreover there is evidence that its use reduces entomological parameters (see box). conclusion Due to wide-spread pyrethroid resistance among Anopheles gambiae mosquitoes in Mali, the Malaria Research and Training Center advises using insecticide rotation in all projects or programs employing insecticidebased malaria vector control strategies. Based on bioassay studies showing high efficacy of IRS with a carbamate (bendiocarb) over several months, with a drop-off rate indicating good biodegradability, the National Malaria Control Program in Mali modified IRS operations in 2011 to use bendiocarb (Ficam®).

Article with references on the enclosed Public Health CD-ROM

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Bendiocarb

DDT

** This study was made possible by the generous support of the American people through the United States Agency for International Development (USAID). The contents are the responsibility of MRTC and do not necessarily reflect the views of USAID or the United States Government.

BENDIOCARB AS A POTENTIAL ALTERNATIVE TO PYRETHROIDS A study published by Akogbeto et al. in 20106 compared the deterrency, exophily, blood feeding rate, and mortality, either immediate or within 24 hours, of wild populations and laboratory colonies of Anopheles gambiae mosquitoes entering or released into experimental huts sprayed with different insecticides. Volunteers slept in the huts under untreated mosquito nets, and mosquitoes were collected for counting and analysis every morning. Spraying with two pyrethroids, deltamethrin and alphacypermethrin, as well as bendiocarb significantly reduced mosquito entry into the treated huts. In the second month, blood feeding rates of mosquitoes in the bendiocarb-treated hut were significantly less than in the untreated hut, and the sleepers reported that the biting nuisance of mosquitoes was less. Immediate mortality was clearly higher in the bendiocarb-treated hut than the two pyrethroid-treated huts, as was overall mortality 24 hours after capture. Overall mortality remained high until the third month post IRS treatment for all insecticide classes tested, except with the two pyrethroids, where mortality rates declined rapidly. Bendiocarb decayed within four months, but still seemed a promising insecticide for use in IRS operations to control pyrethroid-resistant vectors. A new study recently published showed that LifeNet® is superior to Olyset® and PermaNet 2.0® in areas with host seeking resistant An. gambiae and where repeated washings is a common practice. LifeNet® lasted 40 successive washings with a mortality rate of over 80%, whereby the other nets beyond 10 washes decreased dramatically. (Malaria Journal 2014; Agossa et al. / www.malariajournal.com/content/13/1/193/abstract)

Neglected Tropical DiseaseS

Tungiasis

Tungiasis (sand flea disease) is caused by female sand fleas (Tunga penetrans) penetrating the skin of the feet. This results in acute and chronic inflammation, eventually leading to painful and debilitating foot mutilation, accompanied by impaired physical fitness and mobility. Sand flea disease is a zoonosis, with dogs, cats, pigs, goats, and rodents being animal reservoirs. It is common in resource-poor communities in South America and sub-Saharan Africa with up to 80% prevalence in the general population. Recently, it has re-emerged in epidemic dimensions in East Africa. As of now, no effective drug treatment is available, and systematic control has never been attempted.

Fig. 1 OVERLAP of the human, domestic and sylvatic cycle in rural East Africa.

riginally, the parasite causing the skin disease tungiasis existed only in the Americas. According to anecdotal evidence, the sand flea parasite T. penetrans was introduced into Africa around 1870. Within two decades tungiasis had spread along trading routes to many colonies in Central and East Africa and reached Madagascar in 1899. Reports in colonial documents indicate that tungiasis caused extremely severe morbidity in the African population. It is also known that military operations had to be stopped, because the feet of the indigenous soldiers, who did not wear

Photo: Hermann Feldmeier

A debilitating but neglected parasitic skin disease

shoes, were so sore and mutilated that they could not walk. Overlapping life cycles T. penetrans belongs to the genus Tunga of the order Siphonaptera and is unique in that the female flea permanently penetrates underneath the skin of its hosts and remains there until it dies four weeks later.1 Within two weeks of penetration, the burrowed flea increases its volume by a factor of 2000, eventually reaching a diameter of up to 12 mm. The flea’s abdominal cone – through which it breathes, defecates, and expels its eggs – remains in contact with the air, PUBLIC HEALTH JOURNAL 25/2014

Neglected Tropical DiseaseS

Fig. 2

leaving an opening of 250 to 500 µm in the skin, which provides an entry point for microorganisms. About 99% of all lesions occur on the feet. The off-host life cycle is similar to that of other Siphonaptera species and involves larvae, pupae and adults. The development requires dry and warm soil with an optimal temperature range between 22°C and 31°C in the upper level of the soil. In a tropical environment, three life cycles coexist: the human cycle, the domestic animal cycle, and the sylvatic cycle. According to the setting, the cycles partially

or totally overlap (Figure 1). In rural South America, for instance, dogs and cats lie around and come in and out of the house constantly during the day, whereas small rodents enter during the night. In Uganda, pigs, sheep, and goats inhabit the house with their owners during the night to prevent them from being stolen. Local patterns of co-habitation between humans and animals explain why different animal species act as key reservoirs in different settings. In dwellings without a solid floor – common in resourcepoor settings in South America

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DWELLING WITHOUT A SOLID FLOOR in rural northeast Brazil, where the whole transmission cycle is completely indoors.

and sub-Saharan Africa – the whole life-cycle may be completed indoors2 (Figure 2). Actually, T. penetrans is probably the only parasite that can maintain its life cycle in a person’s sleeping quarter: Eggs expelled when a person sleeps will fall directly onto the floor or indirectly when the bed is made the next morning. The eggs are transferred to crevices and holes, etc. when the floor is swept. The larva then feed on the ever-pres39

Neglected Tropical DiseaseS

ent organic material. Eventually, adults emerging from pupae adhere to and penetrate into the skin when a person places their feet on the ground. Lesions, inflammation and bacterial infections The preferred localization of T. penetrans is the peri-ungual region of the toes. Lesions may also develop on the sole and heel of the foot. The inflammatory response around burrowed, viable, or dead and decaying sand fleas causes the pathological manifestations, with different inflammatory mechanisms acting simultaneously or consecutively.3 Acute inflammation – characterized by erythema, edema, itching, and pain – is caused by the constant growth of a biologically active foreign body exerting pressure on the surrounding tissue.

legs of adult sand fleas and are carried into the epidermis, and eventually the dermis, when the parasite penetrates the stratum corneum and inserts its proboscis into dermal capillaries. In addition, pathogens present on the human skin can be actively introduced through scratching. Obviously, bacterial superinfection of a lesion will increase the inflammatory response in the surrounding tissue. Tungiasis, as a cause of tetanus, has long been known. A study in Haiti reported a high incidence of tetanus in areas where tungiasis was common. In 2011, in Kenya 260 deaths were attributed to tungiasis-associated tetanus in one year.4

Debilitating mutilation of the feet The pathogenesis of other chronic manifestations of tungiasis, such as hyperkeratosis, formation of fissures, hypertrophy of nail rims, deformation of toes, and loss of nails is not understood. Frequently, lesions occur in clusters at certain preferred sites with up to 30 embedded sand fleas aggregated in a small area, accompanied by necrosis of the surrounding tissues (Figure 4). Cluster formation seems to be an important factor for severe inflammation. Studies in Brazil indicated that individuals with a high parasite load are prone to develop severe clinical pathology.3 The persistent inflammation of the feet is debilitating and disabling, and causes mutilation of the feet (Figure 5). This results in difficulty in walking and restricted mobility, and is likely to have a negative impact on household economics.

Fig. 3

Fig. 4

Fig. 5

MULTIPLE ABSCESSES around the nail of the fourth and the fifth toe.

CLUSTER of penetrated sand fleas at the heel in different stages of development.

MUTILATED FOOT after repeated severe tungiasis.

Photos: Hermann Feldmeier

Bacterial superinfection of the lesion is almost constant (Figure 3). Presumably, bacteria present in the soil stick to the body and

Another mechanism of inflammation seems to be related to endosymbiotic Wolbachia bacteria, which are constantly found in sand fleas. When sand fleas die in situ and Wolbachia antigens are released in the surrounding tissue, an increased inflammatory response is expected.

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Neglected Tropical DiseaseS

No effective treatment To date, no drug treatment has been found to be effective against burrowed sand fleas. Therefore, in endemic areas, people with tungiasis try to remove embedded sand fleas surgically. This is done by using inappropriate instruments such as safety pins, needles, scissors, a knife or sharply pointed pieces of wood. The instruments are not disinfected and are subsequently used by several household members, and shared between neighbors. Since a burrowed sand flea cannot be extracted without causing bleeding, traditional treatment may transmit blood-borne pathogens such as hepatitis B and C viruses, and even HIV, from one person to another, which may explain the high prevalence of hepatitis B and C virus in children in many countries in subSaharan Africa. A disease of poverty Tungiasis is acquired when people walk barefoot or rest on soil where T. penetrans occur. Studies in urban and rural Brazil have shown that eggs develop into adult fleas both outdoors and indoors. This explains why in resource-poor communities infection is acquired peridomiciliary as well as intradomi ciliary. Sand flea disease is a zoonosis affecting a broad spectrum of domestic and sylvatic animals with dogs, cats, pigs, goats, and rats as typical reservoirs. These

animal reservoirs are a key element in the transmission dynamics. Poor housing, lack of health education, and the presence of animals on the compound have been identified as independent risk factors in Brazil and Nigeria. The age-specific prevalence shows an s-shaped distribution with a peak in school-age children and elderly people. Tungiasis also shows a characteristic seasonal pattern. The incidence rises with the beginning of the dry season, peaks at the end of the dry season and decreases with the first rains. T. penetrans is widespread in South America and sub-Saharan Africa, and it occurs on several Caribbean islands. In South America, tungiasis is known in all countries except Chile. In sub-Saharan Africa, all countries including Madagascar and the Comoro Islands seem to be affected. Tungiasis thrives when living conditions are precarious, such as in poor villages located near the beach, in rural communities in the hinterland, in the periphery of small towns, and in slums of big cities. Expanding geographical distribution During peak transmission, the prevalence of tungiasis in resource-poor rural and urban communities in Brazil, Nigeria, and Madagascar is up to 60%. Prevalence, intensity of infestation and morbidity are closely related. Reports indicate that in East Africa tungiasis has reemerged in recent years, with

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The author: HERMANN FELDMEIER Institute of Microbiology and Hygiene, Charité Medical School, Campus Benjamin Franklin, Berlin, Germany

several hundred thousand cases 4 in Uganda alone in 2011 . A survey carried out by the Ministry of Health in the Busoga sub-Region, north of Lake Victoria, showed prevalences between 8% and 100% in the general population. Reports from Kenya show similar figures.4 The question arises, why sand flea disease has re-emerged in sub-Saharan Africa in such a dramatic way. The explanation for this may lie in the complex interactions between the parasites and the impoverished segments of the population. After its introduction to the African continent, tungiasis had been confined to people in the rural hinterland. With the construction of roads and increasing mobility, the parasite could easily extend its spatial distribution: If an infested individual does not wear closed shoes (still the case in many rural communities in 41

Neglected Tropical DiseaseS

Africa) and boards a bus or pick-up, expelled eggs will fall on the floor of the vehicle and contaminate the soil when the vehicle is cleaned out at its destination. Hence, T. penetrans might easily travel hundreds of kilometers a day. Since the offhost life cycle can take place wherever an appropriate animal reservoir also exists, local propagation could start immediately. Neglected public health problem Tungiasis is a paradigmatical example of a neglected tropical disease that is unnoticed by health policy-makers and health professionals. Reliable data on disease occurrence are not at hand, the social implications of tungiasis-associated morbidity are ignored, and systematic control has never been attempted. Children with tungiasis have disproportionately high absenteeism at school. There is anecdotal evidence that pupils with tungiasis perform worse in school than unaffected pupils. This seems plausible, since children with constant itching and pain will have difficulties in concentrating in class. If penetrated sand fleas are removed under sterile conditions early during their development, acute and chronic clinical pathology can be kept at bay. However, in resource-poor urban settings, characterized by social neglect and deprivation, burrowed sand fleas are not removed – or are only taken out when the 42

parasite has fully developed – hence, inflammation accumulates over time. Severely inflamed toes and mutilated feet cannot be hidden. Individuals with sand flea disease feel ashamed in a similar way seen in other parasitic skin diseases with abhorrently inflamed skin. In rural Kenya, children with tungiasis are teased and ridiculed. In Brazil and Nigeria, patients with tungiasis suffer from social stigmati5 zation.

deltamethrin and the use of propoxur-flumethrin impregnated collars in dogs and cats reduced the prevalence in the general population from 43% to 10%. However, after one year, prevalence had reached the pre-intervention level, although the intensity of infection remained significantly reduced. The authors concluded that a long-lasting reduction of tungiasis requires regular treatment of infected humans and elimination of the 7 animal reservoir. conclusion

There is a general agreement that the occurrence of tungiasis is linked to poverty. Impaired morbidity and physical fitness negatively affect productivity, and thereby perpetuate poverty. Disease control and prevention It is a matter of debate whether wearing shoes protects against invading sand fleas. Even if shoes were protective in principle, in an endemic reality they would rapidly perish with cracks and holes through which freerunning sand fleas could easily penetrate. Prevention is feasible through regular application of a repellent based on coconut oil. Several randomized controlled trials have shown that the regular application of such a repellent reduces the attack rate by 92% to almost 100% and prevents the development of severe morbidity.6 In an intervention study in rural Brazil, premise-spraying with

A public health approach to control tungiasis needs transdisciplinary cooperation. For long-lasting reduction of prevalence and morbidity a “One Health Approach” provides a suitable framework, since it means aiming to improve human and animal health simultaneously. With regard to the protection of animals it seems probable that compounds with activity against other Siphonaptera species will also show insecticidal and repellent efficacy against Tunga penetrans. With its strong association with poverty, sand flea disease would be an excellent starting-point for a community-based fight against rural poverty in South America, the Caribbean, and sub-Saharan Africa. Article with references on the enclosed Public Health CD-ROM

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NGO

Catholic Relief Services

Photo: Karen Kasmauski

Compassion for the very poorest

THE CLINIC IN BAYAMAH, Sierra Leone, supported by CRS’ health programs, screens babies to see if they need medical intervention.

uring World War II the Roman Catholic Bishops of the United States established Catholic Relief Services (CRS) to provide aid to people in wartorn Europe and help with the resettlement of refugees. From the start the guiding principles were based on human dignity and values, and its aims were to promote and work towards justice, lasting peace, and the common good of all. Relief for the developing world

Catholic Relief Services (CRS) is the official international humanitarian agency of the Catholic community in the United States. It was established in 1943 to help World War II refugees in Europe. Since then, CRS has continued to help those most in need by providing expertise and compassion to the very poorest in 91 countries worldwide. In partnerships with local, national and international institutions and organizations, CRS strives to combat malaria by providing protective insecticide-treated nets in remote regions of Africa. in emergency situations. Over the next two decades CRS opened offices in Africa, Asia, and Latin America. During this time CRS extended its relief work to help people in the developing world break the cycle of poverty and set up community-based, sustainable development initiatives. These programs ensure that the efforts and resources of the local community and population are central components of any project. In the 1990s CRS strived to combine relief with a continuing commitment to the development of civil society following natural disasters such as Hurricane Mitch in Central America or human

In the 1950s CRS started to expand its horizons beyond Europe to other parts of the world where the Catholic communities in the USA could provide relief

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tragedies such as Kosovo. CRS understands that rebuilding societies requires more than bricks and mortar, and seeks to foster a sense of global solidarity and tradition of compassionate service to the world. Working with the world’s poorest CRS is now an organization of 5,000 people with 70 years of experience working with the world’s poorest, reaching more than 100 million people each year in 91 countries in Africa, Asia, Europe, Latin America, the Caribbean, Middle East and United States. Its main areas of involvement are public policy, agriculture, education, emergency response, food and hunger, health, HIV and AIDS, human trafficking, microfinance, peacebuilding, social safety nets, and water and sanitation. 43

A CRS-SUPPORTED SHELTER in India helps girls leave the red light district in Mumbai.

Supporting civil society Public policy complements CRS’ humanitarian and development work and CRS calls on its experience with policy analysis and advocacy to address causes of poverty, conflict, and marginalization. Social safety net programs for the extremely vulnerable, disabled, traumatized, elderly, or discriminated, help people acquire life skills to earn a living and become active members of society. In some cases these extremely vulnerable people may need assistance for the rest of their lives. Others who desperately need help, but are often overlooked, are the millions of people subjected to human trafficking and enslavement worldwide. Of the 12.3 million victims of trafficking, more than one million are children. Human trafficking is a US$ 32 billion industry that goes on in 161 countries worldwide, including the USA. CRS works together with other organizations to help liberate these people and give them a new life, as well as in the urgent fight to end slavery and human trafficking. 44

Emergency preparedness, mitigation and response

Peace-building and microfinance

To respond to emergencies wherever needed, CRS works together with a wide range of partners, including local communities, local governments, international 1 NGOs, UN agencies, USAID, 2 DFID, and Caritas International (CI). Adhering to international standards, its ultimate goal is moving from relief to reconstruction and implementing measures to prevent future disasters.

An important aspect of reconstruction in the context of complex emergencies is peace-building and preventing future violent conflict. CRS strives to ensure that emergency relief does not prolong the conflict, but rather helps conflicting parties address injustices and reconcile relationships. In areas recovering from conflict, CRS helps people rebuild their homes and reestablish a viable economy. Sometimes this involves technical assistance to farmers or providing micro finance. CRS’ microfinance programs have helped more than

In addition to natural disasters, complex emergencies often involving violent intra-state conflicts result in huge numbers of displaced people and refugees. In the world today 20.3 million people are displaced within their own country and 13.7 million people are refugees in other countries; every seven to eight years these numbers double around the world. During the acute stage of an emergency the first priority is addressing food and hunger, providing primary healthcare, and supplying temporary shelter. CRS also distributes essential household supplies such as cooking pots, water containers, blankets, soap, and hygiene items. Over the longer term CRS strives to ensure food security and promote activities to support sustainable livelihoods. It supports local health institutions with access to medicines, and provides materials for more permanent housing to encourage community-based reconstruction.

Photo: Jim Stipe

Photo: Jennifer Hardy

NGO

A HEALTH WORKER measures a girl’s upper arm to determine her nutritional health in a village in Senegal.

one million people in 35 countries save more than US$ 10.7 million to increase their financial security. Food and hunger Hunger kills about five million children each year. 98% of the 1

USAID: United States Agency for International Development 2 DFID: Department for International Development

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nearly 842 million people suffering from hunger live in developing countries, and about 17 million babies are born underweight due to inadequate maternal nutrition before and during pregnancy. CRS has various programs to help end hunger, such as teaching mothers new nutritious recipes to feed their children, and introducing simple farming innovations to produce crops and vegetables (for example no-till methods, see below). Food-Assisted Education CRS believes in access to quality education for all. Since 1958 CRS has supported school feeding programs known as FoodAssisted Education (FAE). School meals encourage parents to send their children to school because they can save on limited family funds, knowing their child will receive a good midday meal. School feeding not only helps address food and hunger issues, but also encourages children to attend school and provides them with essential nutrients, which improve their ability to learn. Over the long-term, investments in education, especially for girls, have been shown to improve family health and income, as well as future food security. CRS has also expanded its programs to combine school feeding with promoting increased access to education, especially for girls in Africa and Asia. This provides health and hygiene education, improving the quality of education and school infrastructures, increasing parental and commu-

Photo: Sara A. Fajardo

NGO

Preventing malaria

VALERINE, AGE 70, prepares a sack of freshly dried rice to have its hulls removed in the village of Tsinjorano, Madagascar.

nity involvement in schools, and supporting teachers. Agriculture and environment CRS works with local partners and farm communities in 34 countries worldwide to implement agriculture and environment programs to improve family well-being and help farmers develop long-term solutions. Its work focuses on farm families, laborers, and the landless, often in remote areas with hostile climates, degraded ecosystems, and limited natural resources (productive land, water). This includes helping communities struggling with the physical, economic, social, and emotional devastation of HIV and AIDS, natural and man-made disasters, and war. No-till agriculture methods introduced into the equatorial forest region of the Democratic Republic of the Congo have allowed farmers to improve the quality of their land and thus produce larger harvests on smaller areas. Importantly, this replaces centuries-old practices of slashand-burn that destroy the rainforest, deplete the soil and leave sterile savannah unsuitable even for livestock.

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CRS works together with partners such as the President’s Malaria Initiative (PMI), Malaria No More, and Nothing But Nets to promote malaria prevention measures such as indoor residual spraying (IRS) and insecticidetreated bednets. With a generous grant from the Global Fund to Fight AIDS, Tuberculosis and Malaria, CRS and partners delivered 3 million nets across Niger in 2009. In 2013, CRS’ program for massive distribution of 3.2 million nets reached half the population of Guinea. For the price of US$ 30 anyone can purchase a mosquito net on CRS’ website to help protect an entire family from malaria. conclusion Careful stewardship of all our resources is essential to ensure that we distribute them justly and equitably, not just today, but also for future generations. In an increasingly interconnected world, CRS strives to pay particular attention to the needs of the poorest and most vulnerable. CRS acts to promote human development by nurturing peaceful and just societies, responding to major emergencies, and fighting poverty and disease, particularly malaria. Source http://www.crs.org/

Article on the enclosed Public Health CD-ROM

Notes

Book review

All you ever wanted to know about Anopheles mosquitoes Knowledge is essential, knowledge is power – better understanding and upto-date information can help us develop superior strategies to control, and eventually eradicate our adversaries. So far we, the humans, still do not have the upper hand in this struggle with them, the Anopheles mosquitoes. Time to get to know the enemy better? This book should help.

ow can one keep up to date with a disease and continue to develop effective strategies to combat it without keeping close tracks on the vectors that transmit it? Especially when the vectors are malaria-spreading mosquitoes that have survived an evolutionary “arms race” over millions of years and specialized in sidestepping the “weapons” we throw at them. As Jean Mouchet writes in the preface to this book: “A current estimate of the impact of malaria worldwide … falls short of the expected results despite enormous financial expenditures of the WHO, charitable organizations, foundations and national initiatives.” Just as with any global threat or challenge, it is time to stand back, and look at what we know so far; in other words call in the experts. According to the editor, Sylvie Manguin, this book compiles contributions from 71 authors, all internationally recognized experts in the field, from 20 countries on five conti-

nents: Africa, Asia, Australia, America, and Europe. But first off, one really needs to praise the editor and give her due credit – this must have been a mammoth task, contacting, coordinating and cajoling so many scientists and reminding them to meet the deadlines. Goldmine of information The compilation of scientific and historical reviews, researchbased data (lots of data), modern molecular methods, recent experimental results, meta analyses and distribution maps (lots of maps), as well as extensive lists of recent scientific publications, is immense. The book compiles a body of knowledge that is invaluable to any scientist, medical entomologist, public health manager, or policy decision maker in the field today. Although quite specialized, the writing style is accessible; you don’t need a science degree to understand most of the key messages. Of course it is a reference

book, not something to read from start to finish, unless you are stranded on a deserted tropical island (where there are likely some species or other of Anopheles). This is something to keep on the shelf to dip into, or rather nowadays store in your virtual library. Particularly advantageous, the book is available as an open access download from InTech – so the pdf version is free. The book “Anopheles mosquitoes – New insights into malaria vectors” is divided into five sections: • Species identification and phylogeny of Anopheles • Genetic diversity and distribution of dominant vector species • Ecology and spatial surveillance • Pathogen transmission and influencing factors • Vector control: Current situation, new approaches and perspectives

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Notes

Species identification and phylogeny of Anopheles In Section 1 we learn that there are over 500 species of Anopheles, evolved to thrive in countless different environments; about 80 act as vectors for malaria, filarial nematodes, encephalitis viruses, and arboviruses. Hybrids and subspecies compound the problem of identifying which are disease vectors, as well as the risk of disease transmission abilities spreading to more species, as happened in the past. Primitive humans migrating out of Africa across the world took the disease with them, and local Anopheles presumably picked up the parasite. In fact Anopheles have affected, and still affect the lives of more humans than any other insect, even influencing human evolution; for example sickle cell anemia emerged as form of resistance to the malaria parasite. Despite being the best-studied genus of mosquitoes, reliable identification and classification of certain species and species complexes has been difficult. Modern molecular methods and rapidly accessible databases are now being applied to unravel these problems. More precise phylogeny should help us better understand specific characteristics, such as biting and resting behavior, susceptibility to malaria parasites, transmission efficiencies, and genetic relationships to determine genes for insecticide resistance and ecological and behavior traits. All

Edited by Sylvie Manguin, University Montpellier ISBN 978-953-51-1188-7 Open access publication for download (pdf format) from InTech under: http://www.intechopen.com/books/anopheles-mosquitoesnew-insights-into-malaria-vectors

these play important roles in transmitting malaria. Such information will be invaluable in a variety of ways to combat malaria. Genetic diversity and distribution of dominant vector species This section combines up-todate phylogeograpical and molecular genetic studies to gain information on genetic diversity, and the distribution of dominant vector species in the Americas, Africa, and Asia-Pacific regions. Particularly problematic is Southeast Asia with so many diverse habitats, and India deserves close attention since it accounts for nearly 80% of all malaria cases in this region. Such information must be considered when improving vector control strategies and deciding on the best method to apply – one must know which species is

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where and behavior.

understand

its

Considering future epidemiological consequences, we are warned that less studied malaria vectors in tropical Africa (A. funestus, A. nili and A. moucheti) represent a gap in current knowledge that must be addressed if malaria is to be eradicated from the African continent. Moreover, these mosquitoes bite humans as well as other animals, so could act as bridge vectors for wildlife pathogens, causing zoonosis in humans. Many malaria risk maps are supplied for focused interventions and monitoring insecticide resistance vectors and drug resistant parasites. Moreover, understanding pre-historical to present-day diversity and distribution provides clues about factors driving Anopheles speciation and disease transmission. Climate 47

Notes

change in the past clearly played a major role. Ecology and spatial surveillance The growing force of remote sensing (RS) and geographic information systems (GIS) is providing effective spatial (Anopheles and disease) surveillance. Monitoring and modeling environmental aspects that affect interactions between vectors, pathogens and humans can lead to more targeted measures. Larval and adult habitat ecology monitors how a species breeds and survives, and includes looking at human impacts of deforestation, building dams, draining or restoring wetlands, and eutrophication of freshwater through discharge of fertilizers. Changes in temperature and rainfall, and rising sea levels are all likely to affect not only larval stages of malaria vectors but also the predominant local Anopheles species. Pathogen transmission and influencing factors To deal with pathogen transmission one needs to understand the factors that affect vector infectivity. Apparently one emerging public health problem in Southeast Asia is the simian (monkey) parasite Plasmodium knowlesi, which highlights the potential problems of nonhuman parasites. Any elimination program must consider the risks of these spreading to humans, and acting as “invisible” reservoirs of disease. 48

Other factors discussed as influencing transmission are insect thermoregulation during blood feeding and the role of the mosquito midgut microbiota. Microbial gut flora are now being recognized as essential companions of all animals, even humans. These microbial passengers are closely linked to their host’s immune systems and play a vital role in their host’s development, survival, and (hologenome) evolution. Mani pulating the microbiota of Anopheles represents a possible means to control malaria by reducing vector fitness and transmission competence. Vector control: Current situation, new approaches and perspectives This section starts by reviewing the current status of insecticide resistance. Malaria vectors have developed resistance to the main classes used in public health insecticides (PHI): pyrethroids, DDT, carbamates, and organophosphates. Moreover crossresistance and multi-resistance are becoming a serious treat. It is important to understand the biological mechanisms of insect resistance and develop laboratory methods for early detection in order to implement resistance management strategies, integrated resistance management (IRM), and specifically integrated vector management (IVM). Other aspects to be considered are dealing with negative public views of PHIs (specifically DDT), and controlling residual

transmission by mosquitoes that rest (exophilic) or feed (exophagic) outdoors during the day. Evidence is growing that such transmission is increasing as a result of widespread use of indoor residual spraying (IRS), which only affects mosquitoes that rest indoors, and insecticide-treated nets (ITNs), which target night-biting mosquitoes. This calls for integrating as many approaches as possible into IVM. The book concludes with discussions of innovative approaches to vector control, such as a new larvicide, spinosad, or adultdebilitating fungal entomopathogens. New tools based on detecting antibodies to Anopheles saliva biomarkers can quickly detect whether someone has been bitten, important information for evaluating the efficacy of any control measure. Finally, the last chapter discusses perspectives for using transgenic (GM) mosquitoes in malaria control. This is a challenging field, not just for molecular biologists and ecologists, but also from ethical, sociological, and regulatory perspectives. However, this biotech approach, combined with all the information, insights, methods, suggestions, strategies, and tools presented in this book may help us finally gain the upper hand, and end the arms race by eradicating malaria. Author: Avril Arthur-Goettig

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NOTES

Malaria deaths: Numbers halved since 2000 progress is no cause for complacency: absolute numbers of malaria cases and deaths are not going down as fast as they could. The fact that so many people are infected and dying from mosquito bites is one of the greatest tragedies of the 21st century.” In 2012, there were around 135 to 287 million cases of malaria worldwide that led to 473,000 to 789,000 deaths.

Fifty-nine countries are on track to meet the Millennium Goal of

Photo: Michelle Cornu

Published by the WHO in December, the World Malaria Report 2013 estimates that global efforts to control malaria have saved 3.3 million lives between 2000 and 2012. The majority of these averted deaths were in the ten countries with the highest malaria burden and among children under five years old, whose mortality rates fell by an estimated 54% in Africa, and 51% globally.

Funding levels fell off between 2010 and 2012, reflected in only 70 million new ITNs being delivered in 2012. In 2013 this increased to 136 million delivered ITNs, but not yet reaching the minimum of 150 million ITNs needed each year to protect everyone at risk. However predictions for 2014 point to delivery of around 200 million ITNs, which is a positive step towards meeting the health-related Millennium Goals.

Despite higher populations now living in malaria endemic regions, the incidence of malaria fell by 29% globally and 31% in Africa, where 80% of malaria cases occur in just 17 countries. About 40% of malaria deaths and 32% of cases occur in Nigeria and the Democratic Republic of the Congo. Overall mortality rates between 2000 and 2012 declined by 45% globally and 49% in Africa.

Between 2000 and 2012 international funding for malaria control increased from under US$ 100 million to almost US$ 2 billion. However, at least US$ 5.1 billion is needed each year to ensure universal coverage of control measures. For example, in 2013 more that 50% of the population in sub-Saharan Africa still had no access to an insecticide- treated net (ITN).

Introducing the report, Margaret Chan, the WHO DirectorGeneral, said: “This remarkable PUBLIC HEALTH JOURNAL 25/2014

halting and reversing malaria cases between 2000 and 2015, and 52 countries look set to reach the World Health Assembly target of cutting malaria incidences by 75% by 2015. However, these countries only represent 4% of the 3.4 billion people at risk from malaria, most of whom live in the poorest countries. And a child in Africa still dies from malaria approximately every minute.

Source http://www.who.int/mediacentre/news/releases/2013/worldmalaria-report-20131211/en/

NOTES

Football World Cup in Brazil: Threat of dengue The World Cup is in Brazil this summer, with a predicted influx of over 500,000 international football fans eager to cheer on their teams. But many will be unaware of a potential and serious danger: the threat of catching dengue fever. In more southern locations the annual infection season will have passed, but in the northern host cities of Fortaleza, Natal, and Salvador, dengue will be at its highest in June, precisely during the first round matches.

Billions of people in tropical countries worldwide are continually at risk from dengue, an incurable disease that can be fatal when contracting a second infection with a different genotype. One or two of the four types of virus are usually found in different combinations in different

In an article published in Nature (see below), Simon Hay from Oxford University, UK, warns fans to take all possible precautions to avoid mosquito bites. The dengue vector is a city dwelling, daytime mosquito that bites in the morning and evening. Hay also particularly urges FIFA, Brazilian authorities, and the World Cup sponsors to implement extensive vector control programs. Targeting not only adult Aedes mosquitoes using fogging with insecticide aerosols, but also the immature s tages using larvicides will be essential, as is removing potential breeding sites, such as plastic rubbish and used tires where water can collect.

global regions. So an additional risk posed by so many visitors is that they introduce virus types to which the local community is not immune. Also in the event of an outbreak, large crowds of susceptible people could rapidly accelerate transmission of dengue, and fans may subsequently travel between destinations or home, before quarantine or other control efforts can be effectively implemented.

Host cities of the FIFA World Cup 2014 in Brazil.

Manaus

Fortaleza Natal

Recife

L Salvador

Cuiabá

Brasilia

Belo Horizonte Rio de Janeiro Curitiba

São Paolo

Porto Alegre

Probability of dengue occurence: The scale moves from green (zero probability of occurrence) to red (100% probability of occurrence).

Sources and more information http://www.nature.com/news/football-fever-could-be-a-dose-of-dengue-1.14248 http://simonhay.zoo.ox.ac.uk/uploads/publications/195/FIFA.pdf

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notes

Financial crisis in Greece: Return of tropical diseases data has also revealed the emergence and spread of West Nile virus and cases of nonimported malaria. Conditions throughout Greece are favorable for local malaria vectors as well as mosquitoes arriving from endemic countries.

Cut backs in health spending in Greece have resulted in outbreaks of several infectious diseases, including influenza and HIV/AIDS, during the last three years. Evaluation of surveillance

Climate change: Malaria moves to higher altitudes

Scientists at Michigan University, and the London School of Hygiene and Tropical Medicine analyzed the effects of temperature on the spatial distribution of malaria infections for over ten years. Temperature not only affects the population growth of mosquitoes that transmit m alaria, but also how fast the pathogen develops within the disease vector. For example, the parasite Plasmodium vivax can no longer grow or replicate below 15°C.

The study monitored temperature and disease in 124 villages in the Antioquia region of west Colombia, and 159 villages around Debre Zeyit in Ethiopia. The people who live in these regions are normally not at risk, so they are particularly vulnerable to malaria infection and disease. An average temperature rise of 1°C in these highland regions on both continents could increase the incidence of malaria by some

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100,000 cases per year, and overall in Ethiopia it could mean three million more malaria infections in children under 15 years of age. The implications of these analyses go further: When temperatures rise, the incidence of malaria will likely spread north and south of current endemic latitudes on a global scale. Source Science Vol. 343, pp. 1154-1158, 2014

The first concrete evidence that malaria moves to higher grounds in warmer years was recently published by researchers in the international journal Science. Evidence from highlands in Ethiopia and Colombia points to cases of malaria increasing in higher altitudes as a result of global warming.

The message from Greece is the importance of continuing to support public health funding in economically stressed countries to avoid the impacts of infectious diseases. It also emphasizes the need for Europe to prepare integrated responses to emerging tropical diseases and consider plans for malaria prevention.

Notes

Resistance management: Recurring theme The problem of emerging insecticide resistance in malaria control is a recurring theme, not just in WHO reports and data from the field. Already in 2006, Bayer dedicated its Public Health Journal (Vol. 18, November 2006) to insecticide resistance in vectors of important tropical diseases. Subsequently in 2011, Bayer introduced a new tool to communicate and educate stakeholders in finding solutions to insecticide resistance in vector-borne disease management with its publication “Resistance Matters”.

The publication not only provides operational solutions to implementing integrated resistance management (IRM), such as rotational use of a carbamate ® (Ficam ) with recommended pyrethroids, but also scientific information on resistance mechanisms and selection processes. Through cooperation with the IR Mapper is an interactive map for visualizing data from insecticide susceptibility and resistance mechanisms tests: www.ir-mapper.com

Innovative Vector Control Consortium (IVCC), Bayer is also dedicated to developing insecticides with new modes of action (see column page 6). This reflects Bayer’s commitment to making IRM an essential part of its toolkit for combating malaria and other vector-borne diseases.

Publication “Resistance Matters” on the enclosed Public Health CD-ROM. Here you can also find a pdf of the Public Health Journal Vol. 18 (2006).

UNITAID: Malaria Vector Control Report UNITAID was established as an “International Drug Purchasing Facility” in 2006 with the aim of developing sources of sustainable funding to create marketbased approaches that improve access to medicines, diagnostics and preventative tools. Such funding should also provide cost-effective incentives for producers. UNITAID now collects almost half of its funding from a levy on air tickets. UNITAID is hosted by the WHO, and originally supported by governments in Brazil, Chile, France, Norway and the UK, now joined by Cyprus, Korea, Luxembourg, Spain, Cameroon, Congo, Guinea, Madagascar, Mali, Mauritius and Niger, as 52

well as the Bill & Melinda Gates Foundation. Just before publication of the World Malaria Report at the end of 2013, UNITAID published its first market intelligence report on vector control products for the prevention of malaria. This report provides an overview of vector control approaches and global trends in coverage and use of malaria prevention tools, with a particular focus on longlasting insecticide-treated nets (LNs) and indoor residual spraying (IRS).

The main task of the report is setting priorities for UNITAID grants to optimize market-based approaches to improving vector control. The report is also designed to help stakeholders and organizations decide on how best to tackle the challenges ahead, such as maintaining current LN coverage rates, including replacing LNs that have reached the end of their effective life-span, strategies to combat insecticide resistance, and promoting research and development of new insecticide modes of action.

UNITAID Malaria Vector Control Commodities Landscape 2013: http://www.unitaid.eu/images/projects/malaria/UNITAID_Malariavector-control-landscape_1st-edition.pdf

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R Y

NOTES

West Nile virus West Nile virus is named after the region in Uganda where the virus was first identified in 1937. The arbovirus’ life cycle usually involves mosquitoes and birds, but infected mosquitoes will also bite other animals and humans. Although human infections had been recorded in many countries for over 50 years, the virus was considered relatively low risk until the mid1990s. But perhaps cycles of morbidity and mortality have occurred before – Alexander the Great is thought to have died from West Nile fever over two thousand years ago.

est Nile virus (WNV) is an arbovirus of the family Flaviviridae, genus Flavivirus, a family of viruses that cause encephalitis. WNV is spread by various mosquito species, including Aedes caspius, but the predominant vector is Culex spp. The mosquitoes pick up the virus when they feed on infected birds, and in turn transmit the virus to other birds or animals. The mosquito-bird-mosquito life cycle is a productive viral infection cycle, although the degree of severity and infectivity depends on the mosquito vector and bird species. Infected mosquitoes can spread the virus to humans, causing disease symptoms in around 20% of cases, but not enough viral load to continue the mosquito-borne infectious cycle. In a small number of cases WNV can be transmitted directly from an infected person through blood transfusions, organ transplants, breastfeeding, or during pregnancy. Mosquito vectors WNV was first isolated from a febrile woman in the West Nile district of Uganda during an epidemiological study of yellow fever in 1937. The isolated virus proved similar to the St. Louis encephalitis virus and Japanese B encephalitis virus, with a pathology that primarily involves the

central nervous system. Several outbreaks in Egypt between 1951 and 1954, and the first recognized epidemic in Israel in 1951 led to a better understanding of the epidemiology, ecology, and clinical manifestations of infection. The virus could be isolated from mosquitoes, but no other

Photo: Wikipedia

WEST NILE VIRUS is spread by ifferent mosquito species primarily d to birds (particularly crows) but also to other animals as well as humans.

arthropod vectors (e.g. ticks) seemed to serve as vectors. Analysis of sera showed that a wide range of host species, including birds (particularly crows), reptiles, non-human mammals (particularly horses), and humans, could be infected by the bite of a mosquito. Around 80% of people infected with WNV show no symptoms, while the rest develop West Nile fever. Symptoms include fever, headache, tiredness, body aches, nausea, vomiting, occasionally a skin rash, and swollen lymph

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glands, and often take months or even years to fully disappear. About one in 150 people infected with WNV develop a more severe, sometimes lethal form of disease, such as West Nile encephalitis or meningitis or West Nile poliomyelitis, with symptoms of headache, high fever, neck stiffness, stupor, disorientation, coma, tremors, convulsions, muscle weakness, and paralysis. People over the age of 50 and some immunocompromised patients are at the highest risk of developing severe WNV disease. There is no specific treatment for WNV other than supportive care, often involving hospitalization, intravenous fluids, respiratory support, and prevention of secondary infections. Although a vaccine is available for horses, no vaccine is available for humans. Imported into the USA Before 1998 WNV was not considered pathogenic for birds; but then a more virulent strain arising in Israel caused disease and death of different avian species. This was accompanied by more severe human disease, with an epidemic in Israel in 2000 causing encephalitis in 59% of 417 cases, and 33 deaths. This strain 53

NOTES

R Y

The historical message is that when vector-borne pathogens are imported into “new worlds” outside their usual habitat, whether due to migrating birds, climate change, or globalization, they can become a serious endemic threat to animal and human health.

A bad omen

is thought to have caused the first ever outbreak in the USA, imported by either a mosquito or migratory bird. Arriving in Queens, New York, in 1999, the virus spread rapidly throughout the USA into Canada and South America over the next few years. Birds of the New World, particularly crows, seemed much more susceptible to disease and death, suggesting Old World birds may have innate immunity after coevolving with the virus over many centuries. Avian outbreaks and deaths in the USA were geographically followed some weeks later by human infections. In 2002 the largest outbreak of West Nile meningoencephalitis ever recorded listed 4,156 laboratory-confirmed human cases and 284 neurological-linked deaths, mostly of elderly people, from the Mississippi river to the Pacific coast. Death of Alexander the Great Over the ages many scholars have suggested numerous causes for the death of one the world’s greatest military geniuses, including poisoning, malaria, typhoid fever, schistosomasis, leptospirosis, influenza, poliomyelitis, or pathogenic amoe54

bae. Alexander the Great’s symptoms were carefully chronicled at the time, and describe a 2-week illness with sustained fever and signs of encephalitis. Although Aristotle, Alexander’s tutor, is said to have procured arsenic to poison Alexander, this is not a likely cause of death since arsenic does not cause high fever. Historians described no dark urine or intermittent fevers compatible with malaria, nor symptoms of bubonic plague, hemorrhagic fevers or leishmaniasis endemic to this region. When Alexander’s symptoms were listed on GIDEON (Global Infec– tious Diseases and Epidemiology Network), influenza was given the highest probability (41.2%). However none of his troops and nobody else was recorded as showing any symptoms of influenza or any other disease at all.

When Alexander the Great returned triumphantly to Babylon in 323 BC, the historian Plutarch recounted how “before the walls of the city he saw a large number of ravens flying about and pecking one another, and some of them fell dead in front of him.” Probably this was not taken as a good omen, especially since several weeks later at the age of 32, Alexander the Great died. Before 1999 these events carefully recorded by Plutarch would have been considered irrelevant. However, the strange behavior of the ravens (Corvus corax), closely related to crows (Corvus corone sardonius), is reminiscent of the unusual behavior and deaths of both exotic and domestic birds (particularly crows) at the Bronx Zoo in 1999. This preceded the outbreak of West Nile virus infections in humans in the USA. This was the first time that the virus was seen outside the Eastern Hemisphere, signaling the arrival of WNV in the New World. Perhaps the virus was also a new arrival in Babylon over two thousand years ago, causing a sudden high fatality in local bird populations – and a few humans, including Alexander the Great.

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Public Health JOURNAL: No. 25 on CD-ROM

We wish you a pleasant and informative read.

If the CD-Rom is missing, please contact your regional Environmental Science manager at Bayer CropScience for a complimentary replacement (see green box on the right).

PUBLICâ&#x20AC;&#x2C6;HEALTH JOURNAL 25/2014

Link List With reference to the topics in this issue of Public Health Journal we include a summary of the main Internet links, where you can find further information, the latest reports and statements. Asia Pacific Network for Vector Resistance (APNVR) http://apmen.org/storage/apmen-iv/vcwg/Insecticide%20resistance%20 monitoring.pdf Bayer Vector Control www.vectorcontrol.bayer.com Catholic Relief Services (CRS) www.crs.org/ DFID (Department for International Development) www.dfid.gov.uk ECDC (European Centre for Disease Prevention and Control) www.ecdc.europa.eu Global Plan for Insecticide Resistance Management in Malaria Vectors (GPIRM) www.who.int/malaria/publications/atoz/gpirm/en/ IR Mapper www.ir-mapper.com Liverpool School of Tropical Medicine www.liv.ac.uk/lstm London School of Hygiene and Tropical Medicine www.lshtm.ac.uk Roll Back Malaria (RBM): Multisectoral Action Framework for Malaria www.rbm.who.int/malaria-multisectotral-approach.html Roll Back Malaria (RBM): Progress & Impact series www.rollbackmalaria.org/ProgressImpactSeries/ WHO (Neglected tropical diseases) www.who.int/neglected_diseases WHO: Reducing health risks through sound management of pesticides (WHO report) http://apps.who.int/iris/bitstream/10665/90546/1/9789241506106_ eng.pdf WHO: Sustaining the drive to overcome the global impact of neglected tropical diseases (WHO report) http://apps.who.int/iris/bitstream/10665/80245/1/WHO_HTM_ NTD_2013.2_eng.pdf WHOPES working group meeting (16th; report) http://apps.who.int/iris/bitstream/10665/90976/1/9789241506304_ eng.pdf World Malaria Report www.who.int/malaria/publications/world_malaria_report_2013/en/

You can find all links on the enclosed Public Health CD-ROM

Events RSTMH Royal Society of Tropical Medicine and Hygiene Challenges in Malaria Research September 22-24, 2014, Oxford, UK https://rstmh.org/challenges-malariaresearch ASTMH 63rd Annual Meeting The American Society of Tropical Medicine and Hygiene November 2-6, 2014, New Orleans, USA www.astmh.org/Home.htm JITMM Joint International Tropical Medicine Meeting December 2-4, 2014, Bangkok, Thailand www.jitmm.com ECTMIH 9th European Congress on Tropical Medicine and International Health September 6-10, 2015, Basel Switzerland www.festmih.eu/ectmihbasel2015

FOR INFORMATION Â PLEASE CONTACT Bayer CropScience Environmental Science Division Head of Global Partnering / Vector Control Gerhard Hesse email: gerhard.hesse@bayer.com Head of Market / Vector Control Frederic Baur email: frederic.baur@bayer.com Market Segment Manager / Vector Control (malaria) Justin McBeath email: justin.mcbeath@bayer.com Latin America Claudio Teixeira email: claudio.teixeira@bayer.com Eastern Asia Pacific Jason Nash email: jason.nash@bayer.com Sub-Saharan Africa Melanie Stradi email: melanie.stradi@bayer.com South Asia TR Prakash email: tr.prakash@bayer.com Middle East Khalil Awad email: khalil.awad@bayer.com

PUBLICâ&#x20AC;&#x2C6;HEALTH JOURNAL 25/2014

Public Health JOURNAL: No. 25 on CD-ROM As a special service for readers of Public Health Journal we include a CD-Rom (see inside back cover). Not only does it contain every page of the complete issue in pdf format, but also the individual articles. Some feature additional information.

Imprint Public Health Journal No. 25, June 2014 Publisher: Bayer SAS, Bayer CropScience, Environmental Science Division, 16 rue Jean-Marie Leclair CP 90106, F-69266 Lyon Cedex 09, France Editor-in-charge: Gerhard Hesse (Bayer S.A.S., Environmental Science) email: gerhard.hesse@bayer.com

Editors: Anne Müller (Bayer S.A.S., Environmental Science), Michael Böckler (SMP Munich), Avril Arthur-Goettig Realization: SMP Munich Layout: Artwork (Munich) Printing: Mayr Miesbach GmbH (Germany)

Comments expressed in this Journal are the views of the authors, not necessarily those of the publisher. Copying of any text and graphics is only allowed with permission of the publisher and/or specific author(s) of the relevant article(s). PUBLIC HEALTH JOURNAL 25/2014