World Malaria Day 2014 – How Best to Invest in Malaria Prevention and Control

by

Each year, April 25 provides an opportunity to reflect on the current status of the fight against malaria. We are in the middle year of the World Malaria Day theme of “Invest in the Future. Defeat Malaria,” which is set to last until 2015.

Funding for malaria control and prevention, as with all international public health endeavors, has always been perceived as a critical issue, but there is a refreshing diversity to the ways in which it is being discussed this World Malaria Day.  The U.S. Centers for Disease Control and Prevention (CDC), who spear-headed the successful eradication of malaria in the U.S. back in the 1950s, specifically mention their efforts to maximize effectiveness, and their strategies for using and evaluating new tools such that they can get the most impact per precious dollar spent.  The WHO has highlighted the importance of sustained political commitment, as a crucial factor related to ensuring continued financial support for malaria initiatives. The Global Fund to Fight AIDS, TB, and Malaria recently announced a new funding model, designed to enable “strategic investment for maximum impact.” [Read more…]

The Future of Subsidized Malaria Drugs (ACTs)

by

In November 2012, the Board of the Global Fund meets to determine the future of the Affordable Medicines Facility – malaria. Should it be cut, to make better use of limited funds? Or does it still have a role to play in the fight against malaria?

In late 2009, the Global Fund to Fight AIDS, Tuberculosis and Malaria (hereafter, the Global Fund) launched an initiative called the Affordable Medicines Facility – malaria (AFMm), designed to improve access to artemisinin-based combination therapies (ACTs) to malaria endemic countries. The motivation for the facility was two-fold: first of all, there was a realization that the current prices of ACTs were prohibitive for most inhabitants of malaria-endemic countries, particularly if they sought health care via for-profit private clinics. Secondly, in contrast to the high price of ACTs, artemisinin monotherapies were widely available and much more affordable, leading to fears about the emergence of resistance. ACTs are thought to be more robust against resistance, and so by lowering the price, the AMFm hoped to improve market share against monotherapies, and also make ACTs more widely available to developing country populations.

The mechanism decided on by the Global Fund was relatively straightforward. The AMFm would negotiate with the manufacturers of ACTs and pay them directly a proportion of the cost of the drug. The remainder, roughly 20% of the total in most cases, would then be paid for by whole-sale drug distributors in target malaria-endemic countries, many of which are in sub-Saharan Africa. As they were able to purchase the drug at low cost, these whole-sale distributors, many of which were in the private sector, could still make a profit without passing on prohibitive costs to their customers. As mentioned above, the hope was that this would increase local people’s ability to purchase ACTs, and move them away from the less effective monotherapies that were also available. The first trials of the scheme were started in early 2010; now, less than three years later, the Board of the Global Fund is poised to decide whether the AMFm should continue in a modified form, or, due to wide-scale funding shortfalls, it should be abandoned entirely.

pharmacy liberia erik hersman flickr

A small-scale, for-profit private sector pharmacy in Liberia. Such pharmacies supple a large proportion of anti-malarial drugs in some countries in sub-Saharan Africa (Photo courtesy of Erik Hersman, via Flickr).

Of course, the overall aim of the Global Fund is to reduce malaria morbidity and mortality, and the mandate of the AMFm is along the same lines; however, such an outcome was never going to be a plausible metric in the few short years since the facility’s inception. So how should the success of the AMFm be judged? Two papers [1,2] were published in this week’s issue of Science magazine, one of the world’s leading scientific journals, shed light on the achievements of the AMFm, though without shying away from some ways in which it has perhaps fallen short. Overall, both recommend the future continuation of the AMFm, albeit with changes to its remit.

One way in which the effects of the AMFm can be judged is through studying ACT availability in different markets in the countries which received subsidized medication. Overall, most research seems to have demonstrated that ACT availability has increased, and particularly in rural areas and in the private sector. However, in many countries surveyed, monotherapies were also still available, maintaining fears that artemisinin resistance could arise in Africa, as it appears to have in parts of Asia. However, just because medications are available does not mean they are being taken appropriately, and this is a key point made by both sets of authors.

Indeed, the analysis by Cohen et al. suggests that in many settings, the market for purchase of ACTs is much larger than the actual need, based on the number of people seeking treatment for malaria in the private sector versus the actual numbers of malaria cases. While this is good news for the private sector, in terms of making profits from sale of malaria treatment, it also implies that overtreatment remains a large issue, and thus the subsidy provided by the AMFm is not being put to the best use. Of course, the scale of this issue varies from country to country; those with high malaria endemicity probably have lower rates of overtreatment since more people are likely to require treatment; likewise, younger children (particularly those under the age of five) are more likely to have malaria than adults, and so overtreatment is less of an issue in this age group. I have mentioned overtreatment in previous blogs as a potentially enormous problem in many parts of Africa; both authors make it clear that addressing the issue of overtreatment is crucial is determining a future direction for the AMFm.

A promising avenue of engagement for reduced overtreatment is through improving diagnosis. Therefore, the authors suggest, the AMFm could seek to reduce its involvement in providing subsidies for countries with high levels of overdiagnosis. Instead, in these settings, the money could be redirected into providing affordable malaria rapid diagnostic tests (mRDTs), which are extremely effective, easy to use, and provide an accurate indication of whether malaria treatment is actually required. For countries with lower rates of overdiagnosis, subsidies could continue, though one way of making them more effective could be to pass the price negotiations into the hands of the whole-sale drug distributors, rather than being handled exclusively by the Global Fund. The AMFm could still step in to fill pricing shortfalls, but letting individual companies lead the negotiations will improve outcomes, and also improve long-term sustainability of the program: as countries become more developing, AMFm can slowly reduce funding, allowing the market, and the populace, to step up their investment.

mRDT Gates Flickr

A typical lateral flow malaria rapid diagnostic test. These tests may fill a crucial role in improving diagnosis of malaria, particularly in areas where overtreatment is rife (Photo courtesy of Prashant Panjiar at the Gates Foundation, via Flickr).

The issue of diagnosis also brings forth a broader point, which is that of integrated management of disease, another topic I have discussed before, though previously in the context of neglected tropical diseases. In these papers, both authors make a point to mention that fevers in malarial countries are not always caused by malaria; the use of mRDTs can help elucidate when malaria is not the cause, but it does help when it comes to finding out the actual cause of illness. Instead, countries, and, by association, development donors, should look ahead to promoting integrated management of febrile illnesses. This way, as efforts to combat malaria continue, and continue to be successful, health systems will be ready to deal with the changes in proportion and prevalence of other diseases, as malaria becomes less of a leading cause of morbidity and mortality.

References

  1. JM Cohen, AM Woolsey, OJ Sabot, PW Gething, AJ Tatem & B Moonen  (2012). Optimizing Investments in Malaria Treatment and Diagnosis, vol. 338, no. 6107, pp 612-614.
  2. R Laxminarayan, K Arrow, D Jamison & BR Bloom (2010). From Financing to Fevers: Lessons of an Antimalarial Subsidy Program, vol. 338, no. 6107, pp 615-616.

Malaria meeting

by

QUESTION

FACT meeting for malaria control programme directors in Asia are proposing to host a meeting in Penang, Malaysia probably in September 2012 for the all the Head of Malaria Department.

Can you kindly update us the details of Head of Malaria Department (name, job position, company address & contacts) so that we can contact him/her regarding the details of the meeting.

Looking forward for your help.

ANSWER

At Malaria.com, while we are committed to malaria control, we do not directly manage any control programs ourselves. Instead, we provide a resource of malaria information and networking opportunities for the various stakeholder groups interesting in malaria, such as clinicians, researchers, travelers and the general public living in malarial areas.

Please feel free to contact us, if you would be interested in more information about our site, or how we might be able to help you spread the message about your upcoming conference. Thank you for your message.

– Dr Claire Standley, Managing Editor

As American as…Plasmodium vivax?

by

While its evolutionary history is disputed, there’s no doubt malaria was a key factor in the history of the Americas

I am in the midst of a fascinating book about the way the world changed after Columbus “discovered” America in 14921. Called, appropriately, 1493: Uncovering the World Columbus Created, it is author Charles C. Mann’s follow-up to an earlier, equally engaging book on pre-Colombian America (no prizes for guessing the title, which is 1491: New Revelations of the Americas Before Columbus2).

In both works, Mann devotes significant attention to the role that disease played in re-shaping the Americas in the immediate aftermath of European arrival. However, it is only in 1493 that he turns to malaria, and here he presents several startling examples of how malaria may have influenced key events in the history of the Americas, with subsequent knock-on effects on Europe as well. It is worth noting early on that Mann is very open about the uncertainty in his theories – not only were many other factors clearly involved, but malaria never acted alone, and was commonly accompanied by other introduced diseases, such as yellow fever. Yet even with these disclaimers, Mann’s stories are thought-provoking and illuminating.

For example, he describes how malaria contributed to the establishment of the enormously successful and unarguably brutal slave plantations of the American South. In its early years, the colony of Carolina was a net exporter of slaves, as captured Indians (Mann’s terminology) were sent elsewhere in colonies as forced labour. Additional work in the fields was provided by indentured servants, who were contracted for set periods of time; at first, slaves from Africa were relatively rare.

Anopheles quadrimaculatus Florida

Mosquitoes which were capable of transmitting malaria, such as this Anopheles quadrimaculatus, were already present in the Americas when Europeans and Africans arrived, carrying different forms of malaria. Photo courtesy of smccann on Flickr (http://www.flickr.com/photos/deadmike/)

This all changed as European and African diseases intermingled and became established in the New World; new agricultural practices, also imported by the Europeans, created habitats favourable for a native mosquito species which was able to transmit both Plasmodium vivax and Plasmodium falciparum malaria. Mann attributes the introduction of the former to Europeans, as P. vivax tolerates relatively low temperatures and was rife throughout southern England during the 1600s; P. falciparum was likely brought by African slaves.

Since, according to Mann, no human malaria had been present in the Americas prior to Columbus’ arrival, native Indian people were highly susceptible to these diseases, and either died or were incapacitated and unable to work while infected. Similarly, while some of the contracted servants brought from Europe may have been exposed to P. vivax in their home regions, and thus had some measure of acquired immunity, they fell like flies before the highly pathogenic P. falciparum species.

Africans, conversely, were exposed to P. falciparum as children in Africa and if they survived, were awarded a level of protection. Moreover, a high proportion of people from West and Central Africa possess one or more of a group of genetic mutations, the best-known of which is the Duffy negative phenotype, which makes the carrier almost completely resistant to P. vivax malaria.

As a result, in the newly-malarial fields and marshlands of what is now the American south, plantation owners rapidly ran out of native Indian slaves and indentured European labourers became financially unviable. The solution? Bring in a group of people resistant to the diseases decimating your other workers. And thus, in part, was borne the horrifying trans-Atlantic slave trade, bringing malaria-resistant West and Central Africans to live and die on the plantations in the American South, in a divided society that would persist for over three centuries.

Another quick example: Mann describes how malaria, in part, was responsible for the formation of Great Britain as a nation in the early 18th century. It turns out that in the late 1600s, Scotland, not wanting to miss out on the spoils of colonization, decided to establish a trading post in Panama. As with the plantations of the north, Mann explains that malaria (along with yellow fever) was brought to the isthmus of Central America by Europeans and Africans post-Colombus. Ravaged by disease, and unable to trade with any local tribes (presumably they too had been decimated by imported infections), the first Scottish colony was an abject failure. So, too, was a relief expedition a few years later. Both had been “joint-stakes” ventures, whereby thousands of merchants had contributed a small investment, with a hope of rich returns. Unfortunately, all of these investors lost everything. England had for a century shared a monarch with her neighbour to the north but was consistently denied full union by Scots understandably wary of domination by the larger country. Now, her leaders saw an opening. The English offered to repay the lost funds of all those who had invested in the ill-fated Panama scheme; in return, all they asked for was unification. In the end, England got her wish, and the Union Act of 1707 combined the two countries into the modern nation of Great Britain, a move, perhaps, that was partially defined by malaria.

While these are without doubt beautifully written and captivating tales of dramatic changes occurring throughout the first few centuries post-Columbus, particularly the idea of African slaves being brought in to replace Indian workers relies heavily on the supposition that Plasmodium vivax was introduced to the Americas by Europeans in the late 16th and early 17th centuries. Unfortunately, this is not strictly true.

Modern analysis of the origins of malaria usually relies on genetic evidence – that is, comparison between sequences of DNA between malaria from different regions and even different species, which can give clues as to how the parasite has changed and evolved over time. However, genetic traces of the path of malaria can also be uncovered from looking at malaria’s hosts, including human populations. For example, the Duffy negative group of mutations, mentioned earlier, provides almost or even complete protection against P. vivax. Given the high prevalence of these mutations in West and Central African populations (95-99% in some places!), some scientists have considered this evidence that P. vivax has co-evolved with humans in these regions for thousands of years, and that therefore the parasite might have evolved here3.

However, more recently, this suggestion has been refuted by looking at genetic patterns present within different strains of the Plasmodium vivax parasite itself, and comparing it to other species of malaria throughout the world. It turns out that genetically, P. vivax is actually very closely related to a group of malaria species that infect macaque monkeys in south-east Asia4,5. Estimates of the age of different strains of P. vivax also places the most ancient lineages in Asia, consistent with an “out of Asia” hypothesis. While this view has now approached consensus in the literature, the scientific jury is still out to explain the high occurrence of Duffy negative populations in Africa.

howler monkey

South American monkeys, such as this howler, are infected with forms of malaria which are closely related to that which infects humans. This has been used as evidence to show that Plasmodium vivax arrived in the Americas prior to Europeans in the 15th century. Photo courtesy of Rainbirder on Flickr (http://www.flickr.com/photos/rainbirder/)

Similar molecular tools have also been used to try to figure out when Plasmodium vivax first reached the Americas. In this, scientists have been assisted by the discovery of a species of malaria that infects monkeys, called P. simium. Genetically very similar to P. vivax, scientists have dated its evolutionary origins to show that P. vivax probably first entered the Americas via Melanesia and the Pacific several thousand years ago5. After this time, it managed to switch hosts into monkeys, producing modern variants of P. simium over time. As such, some native Indian populations may have encountered P. vivax long before Europeans ever arrived. However, what is also clear from analysis of modern P. vivax strains that are present in the Americas is that they are largely of European origins. It may even have been that native populations of pre-Columbian America found ways to manage P. vivax, perhaps through controlling its mosquito vector, thus reducing the parasite’s impact. Once Europeans arrived, however, not only were Indians unable to continue managing the land as they had done for generations, but they were suddenly faced with a huge new influx of P. vivax, and of strains they had not yet encountered3.

As such, having thus dashed a drop of water on Charles C. Mann’s parade, I concede that Europeans probably were responsible for the bulk of P. vivax in the early years of the Columbian Exchange, and particularly in the south-eastern United States where he argues it had such a big impact on the nascent trade in African slaves. Moreover, P. falciparum, by far the more deadly of malaria species, was also clearly introduced by these forced labourers from Africa, leading to greater mortality and perhaps, ironically, an even greater dependence on more African slaves. While perhaps hardly a game-changing disease like malaria, Mann might also be interested to learn that another wide-spread parasitic disease, intestinal schistosomiasis, was also likely transported to the Americas by the slave trade, and still remains a public health threat in parts of Latin America today.

In our highly globalized world, we are well aware of the risks of transporting diseases between continents and societies. However, as the theories regarding the origin of malaria in the Americas show, humans (and other animals) have in fact been disseminating disease-causing organisms to new places since the very dawn of our evolutionary history. In fact, Mann argues, very successfully, that while we attribute globalization to 20th century, transport and communications technology, we should instead look half a millennium back, and appreciate how the conquest of the Americas created the first global trade network spanning the Pacific, Atlantic and Indian Oceans, and therefore sowed the seeds of our own modern inter-connected age. And, within those early origins of globalization, even diseases themselves, such as malaria, may have played a role in shaping history.

 

Cited literature

1. Mann, CC (2005) 1491: New Revelations of the Americas Before Columbus. Knopf: New York, 480 pp.

2. Mann, CC (2011) 1493: Uncovering the New World Columbus Created. Knopf: New York, 560 pp.

3. Carter, R (2003) Speculations on the origins of Plasmodium vivax malaria, TRENDS in Parasitology, 19 (5): 214-219.

4. Escalante AA et al. (2005) A monkey’s tale: The origin of Plasmodium vivax as a human malaria parasite, PNAS, 102 (6): 1980-1985.

5. Cornejo OE & Escalante AA (2006) The origin and age of Plasmodium vivax, TRENDS in Parasitology, 22 (12): 558-563.

Looking Ahead to 2012 and Beyond – What is the Future of the Global Fund?

by

At the beginning of December I went to the 60th annual meeting of the American Society of Tropical Medicine and Hygiene. Attended by over 3500 scientists, practitioners, clinicians and students from around the world, the meeting is one of the pre-eminent global events for discussing and disseminating information related to all tropical diseases and health issues. Malaria, as you might expect, has a strong presence among the symposia, posters and presentations, with research on all aspects of its transmission, biology, molecular structure, epidemiology, control and more. [Read more…]

Where There is No Medicine, Let Alone a Doctor

by

Remote or poorly accessible communities create special challenges for delivery of health care.

There were goats in my classroom this morning. Quite adorable kids, but unfortunately not the right species for my health survey. The school is located in Bunda District, sandwiched between Lake Victoria and the long western arm of Serengeti National Park, which stops only a few kilometers from the lake’s shoreline.

This zone of the Serengeti, the so-called Western Corridor, is a crucial stop-over point in the famous circular migration of wildebeest, zebra and other animals, following the rains around the vast grasslands. However, its relative remoteness means it doesn’t see quite the same surge of visitors as other parts of the park; still, every day fancy 4x4s and shiny tourist vans pull up to the Ndabaka Gate, full of foreigners paying $50 a day in park fees alone, for the unique experience of seeing Africa’s magnificent wildlife in one of the world’s most awe-inspiring natural landscapes.

goat tanzania

A kid goat sitting under a desk in a primary school in Tanzania. Photo: CJ Standley

There is little indication here in the village of the vast turnover of foreign currency occurring just a few kilometers to the east. The proximity to Lake Victoria, with its bounty of fish and permanent water supply, allowing year-round irrigation of crops, ensures that few children in this area are severely undernourished.

However, the lake is also a source of disease. The reedy fringes are the perfect habitat for certain species of freshwater snail, which transmit intestinal schistosomiasis; stagnant pools are also ideal nursery grounds for mosquito larvae.

Sanitation infrastructure is basic at best, with some houses possessing a pit latrine in a corner of the compound but many families simply doing their business in the tall papyrus groves right on the lakeshore. Most water for cooking, drinking and washing is collected directly from the lake, usually by children, and once their chores are done they play barefoot in the muddy alleys between huts: shoes are only worn for special occasions, sometimes not even for school. As a result, prevalence of schistosomiasis is high, malaria is an everyday burden and transmission of hookworm is rife.

What health care options exist for this community? The closest doctors are probably at the district hospital in Bunda, about a 20 minute drive north along the fast, tarmac road running between Mwanza and Musoma. However, to get to the main road, the villagers have to negotiate several kilometers of dirt track, rough and pitted, its ruts filled deep with water and mud during the rains. Closer by, there are shops which may stock basic medical items, such a few tablets of paracetemol or other generic painkillers, but sourcing malaria treatment requires again a trip to Bunda, or Lamadi, a town almost equidistant to the south.

The village does have a community health worker, but without funds or drugs, or indeed robust training, the help he can offer is limited. Tanzania has been trying to implement a national programme for the control of basic intestinal worms, and so about once a year, a team may sail through and distribute albendazole to all the children who happen to be attending school that day. Given that absenteeism rates run high, this is hardly providing blanket coverage. Moreover, the source of infection is not addressed; with high rates of transmission, re-infection is almost inevitable. What solutions can there be for remote, rural villages like this?

Kimi Island aerial Stothard

An aerial picture of Kimi Island in Lake Victoria, Uganda. Itinerant fishing communities can be seen at both ends of the island. Photo: JR Stothard

Perhaps some lessons can be learnt from Uganda. The Lake Victoria shoreline there consists of thousands of islands, each with one or more fishing shanty-towns, solely accessible by boat. Access difficulties here are even greater than in Tanzania, yet progress is being made. The Ugandan National Control Programme for Neglected Tropical Diseases has combined interventions for soil-transmitted helminthes (like hookworm) and schistosomiasis, training community medicine distributors in every possible village in the methods for administering treatment for both conditions. At the same time, educational workshops have been held to educate communities as to how to reduce transmission.

Over the last 8 years the programme has successfully reduced the burden of infection in many places, and the programme has expanded to include treatment for other neglected tropical diseases, such as lymphatic filariasis.

Yet, challenges remain. For example, as we see in Tanzania, rates of malaria prevalence are also high in Uganda, yet are not directly tackled by the neglected tropical disease teams; other branches of the Ministry of Health are responsible for the distribution of bednets and Coartem. However, the basic health infrastructure required is the same: mobilization of drugs/equipment, training of health personnel at the village level and education for the community themselves in order to change behaviours that may result in greater infection risk.

Last year I was lucky enough to participate in surveys of island communities in the Sesse Islands, as part of a much wider monitoring effort (funded by the Global Network of Neglected Tropical Diseases). Across the board, we observed villages where increased efficiency of health service delivery could make a huge difference.

Nyatwali children

The children who participated in our health survey, at their primary school in Tanzania. Photo: CJ Standley

It’s not hard for me to see parallels with my study village near the Serengeti. There are existing initiatives to de-worm school-age children; there is a community health worker; there is a basic need for prevention alongside treatment. All that is needed is for efforts to be more coordinated and packaged alongside education about the diseases.

Recognizing this need, the Bunda District Education Office has been incredibly supportive of our inquiries into designing a curriculum to teach the primary school children and their parents in the village about parasites and disease prevention. If all goes to plan, once we hold the workshop, the kids in attendance will be people, not goats!


The “E” word and the “V” word: Two Holy Grails of Malaria Control

by

The Roll Back Malaria Partnership talks confidently of elimination—many others question if this is possible without new interventions. The recent publication of the first Phase 3 clinical trial for a malaria vaccine shows promise, but is it actually good enough?

REVIEW OF:

  • Roll Back Malaria Partnership, “Eliminating Malaria: Learning from the Past, Looking Ahead”, Progress & Impact Series, vol 8, October 17th, 2011
  • RTS,S Clinical Trials Partnership, “First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children”, New England Journal of Medicine, October 18th, 2011

This past week has been a busy one in the world of malaria research and control. On Monday, the Roll Back Malaria Partnership (a joint enterprise between the World Health Organisation, UNICEF, UNDP and the World Bank) released the 8th volume in its Progress & Impact Series, entitled, “Eliminating Malaria: Learning from the Past, Looking Ahead”. The report summarizes RBM’s malaria eradication and elimination efforts to date, and outlines action plans and on-going progress in all malaria-endemic countries around the world. The overall tone of the document is highly positive, emphasizing the various success stories of countries achieving or nearing elimination of malaria in different parts of the world.

This is nowhere more obvious than in Chapter V’s regional summary of the WHO African Region, where no mention is made of the countries that are struggling the most with malaria control, but instead the focus is entirely on congratulating the 4 countries that have already achieved elimination, and praising those 12 countries with existing or imminent plans to move towards elimination. The document as a whole is a comprehensive overview of the status of malaria control, although somewhat light on epidemiological specifics. I was also dismayed to see at least two large photographs of fingerprick blood samples being taken without protective gloves being worn, against all standard diagnostic protocol!

But that’s an aside. In their conclusion, the authors primarily support “existing interventions”, and caution against waiting for “better options” to become available, given the measurable successes already being achieved in many settings using already-available control strategies such as bednet distribution, improved access to diagnosis and treatment and vector control.

It is not perhaps without a touch of irony then that on Tuesday, the first comprehensive analysis of an on-going Phase 3 clinical trial for one of the most promising malaria vaccine candidates was published, in the New England Journal of Medicine. The quest for a malaria vaccine has been protracted, expensive and, thus far, basically unsuccessful, yet to many, global elimination of malaria will not succeed without an intervention that gives lasting protection against re-infection, given the extraordinarily high rates of transmission of malaria in some parts of the world.

The paper reports a reduction of clinical malaria and severe malaria by 56% and 47% respectively, although protection seemed to decay over time; further evaluations will be analysed in 2012 and at the conclusion of the trial in 2014. The authors of the paper are careful to note that the trial was conducted in a cohort with generally good access to medical care, well-supplied health facilities and widespread usage of bednets and other control interventions. As such, mortality from malaria was low even in the control group, and so conclusions about the impact of the vaccine on malaria-related deaths may be difficult to draw.

Moreover, the paper did not directly analyse the relationship between the antibody titers (levels of immune protection to malaria in the blood) conferred by the vaccine and if the patient got malaria or not. In previous studies (for example, Bejon et al.’s 2008 paper also in the NEJM), this relationship was weak, suggesting that the vaccine itself was not contributing strongly to levels of protection against infection, and that other factors were at play. One suggestion is that the adjuvant, a non-specific immune-response enhancer included in the vaccine, may itself play a role, and given that the control groups received vaccines with a different adjuvant, this may partially account for the variations in malaria prevalence seen between the children studied. However, these early data still show potential at least for reducing clinical cases of malaria in a highly-endemic African setting.

It should be noted that these findings do not come entirely as a surprise; there were early signs of potential, at least partial, protection from this vaccine (the results of the Phase 2b trials were published in The Lancet back in 2004). Despite this, the word “vaccine” is mentioned but twice in the latest RBM report. I have a deep admiration for the RBM and all that the partnership has achieved thus far in the struggle to control malaria throughout the world. Without a doubt, the scale of the problem is immense, and they are right to emphasise the enormous achievements many countries have realized, and particularly in reducing malaria mortality in the last 10 years. Nor would I advocate for countries to latch onto the promise of a vaccine too quickly; clearly more research is needed to evaluate the long-term efficacy of the vaccine, as well as its impacts specifically on mortality as opposed to morbidity; hopefully we will have some of these answers in a year, at the conclusion of the Phase 3 trial.

However, in the meantime, there is clearly a huge opportunity for using these preliminary findings to determine what role there might be, if any, for the vaccine in its existing form as part of new and improved control strategies. For example, if the vaccine is not fully protective, might it, perhaps counter-intuitively, actually be more effective in areas which are already well on their way to successful control, by reducing transmission below that which is viable for the persistence of malaria? Or will its role in reducing incidence of severe disease be equally well utilized in extremely high prevalence and low health infrastructure areas, where access to diagnosis and treatment is the limiting step in effecting control? To its credit, RBM has acknowledged this since the publication of the vaccine trial results, with the following statement from the CDC: “These promising vaccine trial results add to the hope that adding an effective vaccine to current malaria interventions will move us closer to that goal.” Perhaps the “better option” wasn’t so long in coming after all.

 

Breaking the Promise of Bednets? Let’s Not Jump to Conclusions…

by

Review of Trape et al., (2011), Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study, The Lancet Infectious Diseases, published online August 18th.

Jean-François Trape and colleagues have been causing quite a media stir with the article they recently published in The Lancet Infectious Diseases, an offshoot of the eminent medical journal. The research consisted of a longitudinal study, following the inhabitants of a village in Senegal for almost four years, recording all instances of malaria and treating cases with artemisinin-based combination therapies (ACTs), the WHO-recommended front-line medication for uncomplicated malaria cases. In addition, 18 months into the study, the villagers were provided with long-lasting insecticide treated bednets (LLINs); concurrently, throughout the study period Anopheles mosquitoes, the vectors of malaria, were collected from the village area and tested for resistance to the insecticides used in these LLINs.

The scientists noted an immediate decrease in the monthly incidence of malaria in the initial period following the introduction of LLINs, but then recorded a substantial, and statistically significant, increase in re-infections in the final three months of the study. Moreover, when broken down into age groups, this rebound of malaria cases was most notable in children aged 10-14 years, which is unusual given that normally younger children are considered most susceptible to malaria infection. Perhaps most concerning of all, more than a third of mosquitoes tested at the end of the study were resistant to the insecticide in the LLINs, and the prevalence of a gene known to correlate with resistance had increased from 8% to 48% over the four-year period.

This research is clearly highly important, timely, and worthy of deeper consideration. While LLINs have been shown to be highly effective in earlier studies to prevent malaria infection, fewer studies have focused on the long-term consequences of these interventions, which are being rolled out at great speed throughout malaria endemic areas. Clearly, insight into the effects on mosquitoes, as well as re-infection rates, is warranted. However, a few gentle caveats should also be made.

For one, although the observation of reduced immunity being responsible for higher rebound rates is of great interest, and a sound conclusion from the evidence, it requires much further testing before a causal relationship can be proven. Secondly, the authors compare a rebound period of three months, at the end of the study, with the preceding two years of LLIN use as well as the initial LLIN-free 18 months, in order to draw their conclusions about re-infection rates.

Malaria is highly seasonal; while this is acknowledged by the authors (one of the figures includes rainfall in the graph of Anopheles biting rates), it is unclear whether this was included as a covariate in the statistical analysis, and therefore controlled for as a variable. As it happens, that final three month period occurred during a season of high rainfall, usually associated with high numbers of mosquitoes and subsequently high biting rates. Similarly, the authors do not account for the possibility of other environmental factors influencing the rate of malaria during this final, and very short, time period. Had they compared time periods of equal length, and incorporating all seasons, it might be easier to ascertain whether the increase they observe is a true trend or a statistical artifact of sampling bias.

However, I am getting slightly off the point with technical grievances. The methods the authors use are sound; their conclusions valid, if perhaps in need of further justification. My main concern with the impact of this paper lies in its misinterpretation by the media. Already, I have seen one newspaper report (The Independent on Sunday August 21st, 2011 “Twenty Holiday Myths Exposed”) which erroneously stated “Research published last week suggested mosquito nets were not as effective as previously believed.”

I can only assume they are referring to the Trape paper; this is patently not the conclusion the scientists come to. Rather, they state that in one area of high malaria endemicity, bednets may reduce immunity, leaving people more vulnerable later, and secondly, that LLINs may result in increased resistance to insecticides in mosquitoes.

The authors make no statement about the efficacy of bednets in preventing infection. Moreover, the use of bednets in a highly endemic area, where people have no other option for malaria prevention, is a very different situation than what travelers face, visiting a malarial area for a matter of days or weeks, armed in conjunction with prophylactic medication and insect repellant sprays. The Independent‘s ignorant throw-away statement may encourage travelers to forsake bednets, which still are a key way of preventing malaria infection, thus leaving themselves at greater risk. I am sure Trape and his colleagues did not intend for this to be a consequence of their research.

Can of Worms: Travel Parasites to Know About

by

Malaria isn’t the only parasite you need to think about when you travel

In my last post, I shared some of the misguided myths about malaria that I had heard while hanging out with the tourists on Zanzibar. Then, in the in-flight magazine on the internal flight between Dar and Mwanza (my flight was over an hour late…hence how the airline, Precision Air, earned its local nickname: “Imprecision Air”), I saw an article about a little fly which I hadn’t heard about for quite some time. I flicked through my East Africa Lonely Planet: nope, no mention of it there either. That got me thinking about some of the various other parasites, bugs and worms that can sometimes take travelers by surprise when they visit Africa or other tropical destinations; everyone’s heard of the Big Three (HIV/AIDS, tuberculosis and malaria), and plenty of people know what diseases like dysentery, cholera, typhoid and polio are.

After all, apart from malaria, all are also or have historically been scourges of northern latitudes as well; even today the number of TB cases in the US remains alarmingly high. But maybe it would be worth writing about a few of these less well-known infections, not necessarily confined to the tropics but more common in those latitudes, some of which have indeed officially been branded as “neglected tropical diseases” by the World Health Organisation, having long been relegated to the bottom of the global health priority list. Yet far more people are infected with neglected tropical diseases, and particularly worms, than any of the Big Three; it has been estimated that up to 2 BILLION people could be at risk from exposure to certain types of intestinal worms alone. That’s getting close to a third of the world’s population!

Intestinal Worms Part I: Soil-transmitted Helminthes

The catch-all phrase “intestinal worms” is deceivingly simple, containing instead an array of different parasites, from vastly different zoological backgrounds and with a bewildering assortment of life history strategies. The group can be broken down further; schistosomiasis, a parasite which can infect the intestines or the bladder, is usually put in a category of its own. This leaves the “soil-transmitted helminthes”, or “geohelminthes”, in itself an amalgam of three types of worm, and belonging to four different species. The three types are hookworms (two different types cause disease in humans, depending on where you are, though their range does overlap: Necator americanus and Anclyostoma duodenale), whipworms (Trichuris trichiura is the Latin name) and another type of roundworm, called Ascaris lumbricoides. None of them is particularly pleasant; most hookworms infect you by latching on to the soles of people walking barefoot and entering directly into the bloodstream. Whipworms and roundworms pass their eggs in stool and if these are ingested, can infect a person this way; therefore their transmission usually relies on poor sanitation and bad hygiene.
Ascaris Life Cycle
All have fascinatingly complex lifecycles in the human body, sometimes involving some pretty gory details: hookworms and Ascaris, for example, have a maturation stage in the lungs, irritating the bronchioles so much that their host is racked with discomfort (see above for a schematic of the life cycle of Ascaris). Their coughing dislodges the worms and passes them up the windpipe into the person’s mouth, whereupon they are usually immediately swallowed. This is how they get into the gastrointestinal tract, their final destination! In any case, all three finally end up in the intestines, where they cause discomfort, diarrhea, malnutrition and lethargy, among other symptoms. I’ve seen a kid pass roundworms in his stool, having received treatment: the bucket looked like it was full of writhing spaghetti, since these worms can grow bigger than 40cm (over 15 inches) long! Chronic worm infections have even been associated with poor work attendance in adults and reduced concentration in schools, thus demonstrating some of the indirect costs of these infections.

Intestinal Worms Part II: Schistosomiasis

Another intestinal worm which is known for its global distribution and high indirect economic burden is schistosomiasis, caused by flatworms (also known as “flukes”) of the genus Schistosoma. Three species cause the vast majority of infections in humans: S. japonicum is distributed through south-east Asia, with endemic foci in southern China and the Philippines. S. mansoni was originally confined to Africa and the Middle East, but is believed to have crossed the Atlantic inside captured West African slaves, and now the parasite is widespread throughout Latin America and the Caribbean as well. S. haematobium is only found in Africa and the Middle East; the vast bulk of the burden of infection from these latter two parasites is in sub-Saharan Africa.

Rutale Tanzania

Typical transmission site in Kigoma, western Tanzania.

The unusual thing about flukes is that they require one or more intermediate hosts in order to complete their life cycle; in the case of schistosomiasis, this intermediate host is a freshwater snail. The larvae emerge from the snail into the water, and can penetrate directly through the skin of people bathing, swimming, collecting water or washing clothes nearby. Once in the blood stream, the larvae undergo several stages of maturation as they pass through various parts of the body, before finally ending up in the veins surrounding the intestines, in the case of S. japonicum and S. mansoni, or around the bladder, in the case of S. haematobium.

The worms then churn out eggs, some of which make it through the wall of the intestine or bladder and are voided either in the stool or urine, respectively. The eggs must make contact with freshwater again in a matter of a day or so if they are to hatch successfully and find a suitable snail host; therefore schistosomiasis transmission only occurs in areas with poor sanitation, and where people regularly defecate and urinate outdoors, near streams, ponds and lakes. The picture above shows a typical transmission site, in western Tanzania; a still pond, full of snails, that is used by the local villagers as their source of drinking water, for washing clothes and for bathing. My research revolves partially around understanding what factors cause a particular water body to be a good habitat for the snail hosts, and therefore high risk for establishment of schistosomiasis transmission; in this case, the pond appeared to be highly suitable, since the muddy fringes of the pond were full of them!

Snails at a nearby marsh site. These snails are intermediate hosts for intestinal schistosomiasis.

The good news? While there’s no sure-fire way of preventing yourself from getting soil-transmitted helminthes or schistosomiasis, there are some pretty simple steps you can take to greatly reduce your chance of infection. For example, don’t walk around barefoot, do make sure you wash your hands before eating, try to peel fruit and vegetables before eating them (or cook them thoroughly), and avoid swimming or bathing in still or slowly flowing streams, ponds and lakes, unless you have reliable local evidence that the area is schisto-free. Moreover, all of these infections are easily treated with a single dose of medication; another big aspect of my research, in conjunction with National Institute of Medical Research in Tanzania and the Vector Control Division of the Ministry of Health in Uganda, has been to monitor the on-going efforts to give these much-needed drugs to school-age kids in high risk areas around Lake Victoria, and evaluating how effective the programme has been, in order to refine future efforts.

Guinea worm (Dracunculiasis)

Speaking of contaminated water, here’s another really gross and entirely preventable worm for you. Guinea worm, Latin name Dracunculus medinensis, used to be endemic throughout many countries in both Africa and Asia, though concerted control attempts and educational campaigns have reduced its distribution significantly; it is now only found in Ghana, Mali, Ethiopia, Sudan and maybe Chad. Like schistosomiasis, the worm requires an intermediate host; in this case, a tiny water bug called a copepod, which lives in stagnant water. When people drink the water without boiling, filtering or treating it, they also swallow the copepods, which are dissolved by the stomach’s acid. The larval worms inside it, however, are unharmed, and pass into the body. After male and female worms mate, the male dies, and the female burrows deeper into the host’s tissues, usually down towards the legs. Eventually, a blister forms on the skin, causing the host a huge amount of pain and a burning sensation; the female worm sticks her end out of the hole, and when the suffering patient tries to soothe his burning skin by immersing it in water, the female releases thousands of eggs, infecting more copepods and continuing the life cycle.

Now for the gross bit; as you can see from the picture above, this worm is HUGE. Females can grow to almost a meter long (3 feet!), and once infected, there is no way of curing the disease. The only option is to catch the tip of the worm as it emerges from the blister, wrap it around a stick and slowly, slowly wind it out, a process that can take weeks or even months. This process was first described over 3500 years ago, in an ancient Egyptian medical text known as the Ebers papyrus; nice to know that some things haven’t advanced since then!

Tumbo flies

In any case, the little fly that caught my eye in the in-flight magazine is not considered a neglected tropical disease, since rather than causing illness, it’s just a nuisance, and one travelers should DEFINITELY know about, since it’s easy to avoid if you know what to do. Scientifically known as Cordylobia anthropophagus (literally “eater of men” in Greek), it is more commonly called the tumbo fly, the mango fly or, descriptively, the skin maggot fly. Looking like a normal buzzing blow-fly, the females lay eggs in moist ground contaminated with faeces or otherwise smelling of people. Unfortunately, wet clothes hung out to dry work just as well; the larvae penetrate the host’s skin when they put the clothes back on, and create a boil as they mature through three further larval stages. When ready (8-12 days usually), they squeeze themselves out of the boil and drop to the ground to pupate and continue the life cycle. The boils they cause can be uncomfortable, but rarely serious; most people just get a bit freaked out when they see the maggot wiggling around under their skin! The bold can apply petroleum jelly to the larva’s breathing hole, causing it to suffocate and die; then it can be easily squeezed out. Otherwise, just make sure to iron all your clothing, including underwear and bra straps, if you’ve laid them out to dry in East and Central Africa!

I was going to write about filariasis as well, but I’ve actually started to gross myself out, and I deal with this kind of stuff every day! So maybe I’ll save elephantiasis, river blindness and loa loa for another post…

Myths About Malaria

by

I infiltrated the tourist circles of Zanzibar to find out what travellers really know about the most deadly parasite on the planet

Travellers these days are pretty savvy; the ease of international travel and the ubiquity of the internet have encouraged more people to explore the world than ever before, and to be well-informed about the locations they are planning to visit. A key milestone in this travel revolution has been in health; specialized travel clinics tend to the lines of expectant voyageurs, awaiting their roster of immunizations and patiently listening to the lists of do’s and don’ts. The vast, fortunate majority come back with no more than war stories about their first case of “Delhi belly”, or peeling skin, a testimony to the tropical sun. They have dutifully followed the advice about drinking water, haven’t touched raw vegetables and didn’t play with stray cats and dogs. They meticulously applied insect-repellant, slept under bednets and took anti-malarial medication. However, there are exceptions.  As a researcher in tropical diseases, I am always amazed when I come across one of the minority; the cowboys who consider malaria a badge of honour, a symbol of truly “experiencing” the tropics, who think yellow fever sounds romantic and amoebas are good company. More to the point, they are often woefully ignorant of some of the basic facts and principles guiding good health while travelling, and so rather than proving their fortitude, are usually the ones ending up in hospital.

A Ministry of Health worker asks a woman questions during a health survey in Dole, Zanzibar. (Photo © Claire Standley)

Having spent four weeks in the far west of Tanzania studying the distribution of schistosomiasis (one of the so-called neglected tropical diseases, since they tend to take the back-burner in the parade of tropical disease priorities; more on that in the next blog!), I decided to take some R&R in Zanzibar, and first met up with some friends in the backpacker haven of Nungwi, on the northern tip of Unguja island. My friends were all journeying overland through Africa, and, like the conscientious travellers described above, were sensibly concerned about getting sick and ruining their trip, so were taking every possible precaution. Their combined first aid kits would probably have kept an African hospital stocked for weeks! However, as befits the rule, there was an exception. Lovely chap, had travelled extensively over the world, and confidently told me that he wasn’t bothering to take any anti-malarials this trip. When I asked him, disappointed (although not altogether surprised), why this was, he replied that he didn’t need to: after all, he had already got malaria once, and since it was also in Tanzania (just across the strait, in the capital Dar es Salaam), he’s immune to that “strain” and so can’t get re-infected.

Myth number 1 about malaria: Being infected once makes you immune.

BUSTED! You cannot be immune. The species, strain or whatever does not make a difference. Yes, people who have grown up in malaria-endemic areas, and particularly if they were exposed as children, can gain some level of protection, but they can still get the disease. More to the point, if they are removed from the source of infection for a significant period of time (for example they move to a malaria-free zone), they lose that protection, and so become susceptible again.

In any case, I gently told him he was wrong, and probably getting confused with dengue fever (which, incidentally, has the opposite effect; many initial infections are asymptomatic or only result in mild illness. However, a second infection, with a different strain, can leave the patient at greater risk from dengue hemorrhagic fever or dengue shock syndrome, both of which are pretty nasty and can be fatal). They were heading on back to Dar and from there, down to Malawi, so I hoped that he would soon be in the highlands and out of the worst of the malaria transmission area.

I had a few more days of vacation, so made my way down to Paje for a change of scenery. Paje is the kite-surfing capital of Zanzibar, and boasts a stunning stretch of sugar-white sand. While there, unable to stay away from conversations about tropical diseases, I started chatting to a British doctor who was spending the year in one of the two main district hospitals on the island. He informed me of a myth I hadn’t yet heard; apparently, the touts promoting Zanzibar as a paradise destination are prone to telling potential tourists that there isn’t any malaria on the island, in order to encourage them to visit. I had to laugh; there very definitely is malaria on Zanzibar. I had done a bit of work on intestinal worms, in collaboration with the Ministry of Health, and knew that there were on-going diagnosis and treatment programmes as part of the Ministry’s activities. The doctor I was speaking to concurred; he reckoned he saw at least ten cases a week in the district hospital.

Myth number 2 about malaria: There is no malaria on Zanzibar

BUSTED! There most certainly is; while transmission might well be lower than on the mainland, due to a lower population size and fewer mosquitoes, cases do occur and so visitors should remain vigilant about sleeping under bednets, taking preventative medicine and using insect repellant, particularly in the evenings and when going out at night.

In any case, I managed to pass the rest of the night without boring too many other people with details about parasitic infections. The next morning, I sacrificed a few minutes of beach time to check how many dozens of emails had built up over the week I was incommunicado. One of the few interesting ones was from my senior thesis student, Kelly, who is working on a malaria diagnosis study in Mang’ula, several hours south-west of Dar. Her project aims to compare incidences of malaria as determined by two different diagnostic methods: the first, the traditional blood slide, which has to be read under a microscope by a trained technician, and the second, a rapid diagnostic test (RDT) which uses a tiny droplet of blood to test for the presence of antibodies against malaria, indicating an infection. Now, the plenty of trials have been conducted on several of the different formulations of malaria RDT; by and large, all are more sensitive than looking at blood slides, which are known to have low reliability especially when someone has few malaria parasites in their blood. So, usually, the prevalence of malaria infection as detected by RDT is higher than by blood film, though the cases that make the difference are people who have light infections and so not usually feeling that sick anyway. What had surprised Kelly was that in the clinic where she was working, the records showed much higher levels of malaria when people were diagnosed with blood films than with RDTs! In any case, I am hoping she can write her experiences up as a post for malaria.com once all the data is analysed, so you can find the conclusion to the story then.

However, her email had reminded me of a discussion I’d had over breakfast with an ex-pat friend of mine, who is European but has been living in Dar for the last couple of years. Malaria prophylaxis cannot be taken for very long periods at a time – they would get prohibitively expensive, for one, plus the effects of taking the medicine long-term are not well known. So people who live permanently in malarial areas have to rely on other preventative measures; the most effective is sleeping under a long-lasting insecticide treated bednet, which can be purchased for only a few dollars (they are given out for free to many communities in Africa…see the press release about NetGuarantee, a programme run by Malaria No More). Proper bednet usage can reduce malaria transmission by an overwhelming percentage, preventing many cases of the disease; this is particularly important for pregnant women and children, who are most at risk from contracting malaria and suffering severe cases. My friend also mooted another possibility; since malaria drugs can be bought pretty easily over the counter in many places in Tanzania, how about just keeping a few doses around the house and taking them if he gets malaria symptoms?

Myth number 3 about malaria: If I get sick in Africa, it’s probably malaria, so I can treat myself without getting diagnosed.

BUSTED! There is so much wrong with this. First of all, not all malaria is alike. There are different forms of the disease, each caused by different species of the parasite. The major types that infect humans can have subtle variations in their clinical presentations, and, more importantly, are sometimes treated with different drugs. While the go-to cure for most kinds of malaria is chloroquine sulphate, several species of malaria, and most notably Plasmodium falciparum, has become resistant to this form of treatment in some areas of the world. Improper administration of medication, for example not finishing the course of pills, taking the wrong dose or using out-of-date drugs, can assist in the emergence of resistance. Similarly, if you take malaria medication when you don’t really need to (for example, like my friend who might just have a cold), it can contribute to the parasites being able to withstand the drugs in future.

Other types of treatment, such as quinine sulphate, doxycycline and atovaquone-proguanil (sold under the brand name Malarone) may be suitable in some instances as a chloroquine replacement; it is worth noting that if you use Malarone as a prophylaxis, then you can’t also use it to treat malaria if you should happen to become infected. Based on World Health Organisations established in 2006, most chloroquine-resistant malaria is now being treated with artemisinin-based combination therapies, or ACTs. But there’s one more catch; even once you’ve been treated for the initial infection, you may need more medication, depending on the type of malaria you have. Some species, namely P. vivax and P. ovale, have forms that reproduce in the liver; these can lay dormant there for many months and even years, before re-emerging into the bloodstream and causing a relapse of symptoms. The liver stages can be effectively killed with a course of a drug called primequine; however, knowing to take it requires accurate diagnosis, another argument for thinking twice before just taking some drugs at the drop of a fever.

This image shows a traditional "dhow," the sailing ships introduced to Zanzibar and the East African coast by Arab traders over a thousand years ago. They are still used today for fishing and transport. (Photo © Claire Standley)

After my week in paradise, it was time to head back into the dusty interior; to Mwanza this time, to continue my research on schistosomiasis. Spending time with the tourists on Zanzibar reminded me how important it is to continue educating people about the dangers of tropical diseases; it also impressed on me how much at the forefront of people’s minds is malaria, when it comes to thinking about traveller’s health in the tropics. It certainly is one of the most deadly infections, if left undiagnosed and untreated, but it’s also not the only parasite that you can come home with or which can cause significant discomfort during a trip. Given some of these other bugs and worms are favourite research subjects of mine, I’ll use the excuse of my on-going fieldwork in the area around Mwanza to talk about the underdogs of tropical medicine next time!