Tropical Health Matters

Charles Darwin’s 200th birthday is this Thursday, 12 February 2009, and Darwin published his masterwork, On the Origin of Species, 150 years ago and died in 1882. This was just two years after Alphonse Laveran identified the parasite that caused malaria.  Since then it has been possible to learn how the wheels of evolution roll along for humans, mosquitoes and the plasmodia species that cause malaria. These lessons aid in the continuing battle to save human life.

Within humans, evolution of “the protective effects of sickle cell trait (HbAS) against severe malaria and the resulting survival advantage are well known.” Malaria Journal reports that “protection against mild malaria episodes” among those with the trait may also result in improved child nutrition and reduced stunting. A reduced survival rate of SS fetal genotype may be associated with placental malaria. The LA Times also describes the human side of the malaria evolution triangle:

Among the genes whose purpose is understood, the biggest category is devoted to fighting infectious diseases. For instance, the researchers found more than a dozen new genetic variants involved in fighting malaria to be spreading rapidly among Africans.  Scientists had previously identified several mutations that offered protection against the disease. Most were shared by people of African descent, because the scourge is most widespread on that continent. But malaria afflicts people throughout the tropics and subtropics, and additional mutations to combat the disease arose in Thailand and New Guinea, Hawks said. One of the newly discovered mutations helps defend against a form of the disease in which malaria parasites congregate in blood cells in the placenta, causing a high rate of miscarriage.

Issues like drug resistance by malaria parasites provide focus to the discussion on continuing evolution of the malaria parasites.  Durand and colleagues explain that, “Drug development programs exhibit a high attrition rate and parasite resistance to hemotherapeutic drugs exacerbates the problem. Strategies that limit the development of resistance and minimize host side-effects are therefore of major importance.” They report on efforts to use an understanding of evolution to design better malaria drugs.

The mosquitoes themselves evolve to adapt to changing environments, human behavior and pesticides. Muller and co-researchers encourage continued study on how “Insects exposed to pesticides undergo strong natural selection and have developed various adaptive mechanisms to survive.”

Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is receiving increasing attention because it threatens the sustainability of malaria vector control programs in sub-Saharan Africa. An understanding of the molecular mechanisms conferring pyrethroid resistance gives insight into the processes of evolution of adaptive traits and facilitates the development of simple monitoring tools and novel strategies to restore the efficacy of insecticides.

With continued changes in human behavior such as in agriculture and urbanization, as well as human impact on the environment, malaria will continue to evolve. Darwin has given a guide to understanding the complex evolution of malaria. Two hundred years on, we must continue to fund research that advances this understanding and uses it to keep ahead of the disease.

Kenya is facing at least two major and seemingly opposing changes in its malaria epidemiological profile.  SciDev.net reports on an article from The Lancet that confirms, “An analysis of data collected over 18 years from malaria-infected children at Kilifi District Hospital, on Kenya’s Indian Ocean coast, found that paediatric admissions for malaria had fallen by 75 per cent over a period of just five years.”

At the same time, “In recent years malaria has also appeared in the highland areas where it was previously unheard of,” according to Inter Press Service (Johannesburg).  Keeping pace with these changes is essential if the national malaria control services and its malaria donor partners are to provide appropriate interventions for each part of the country.

In the highlands where people are less used to malaria, Sumba and colleagues found that. “A significant proportion of this highland population chooses local shops for initial malaria treatment and receives inappropriate medication at these local shops, resulting in delay of effective treatment.”

Because highland residents, for example those in Kibera, Nairobi, travel back to their home villages in malaria endemic areas, they bring the parasites back. With the potential of global warming making the highlands more favorable to malaria transmitting mosquitoes, the highlands will face increasing risk, according to an IRIN news release. Furthermore, “As 20 percent of Kenya’s population — eight million people — living in the highland areas are now exposed to malaria, new plans for preparing and responding to an epidemic are needed” (Inter Press Service News).

In The Lancet article O’Meara and colleagues believe that the reduction in transmission in coastal Kilifi is multi-factorial and could be related to bednet use and changes in malaria drug policy among others. They conclude that, “Our results are consistent with comparisons between multiple sites and provide further evidence that reduction of trans mission leads to a change in pattern of severe disease but might not lead to immediate reductions in disease burden.” This means that …

Emphasis on use of insecticide-treated bednets, early treatment, and other control measures must be increased to maintain reductions in disease burden and prevent a potential resurgence of malaria in a population with far less immunity than before.

The experience in Kenya shows that changing climatic conditions and increasing effectiveness of malaria control interventions may in the short run put more people at risk of severe malaria due to reduced immunity levels.  The need for sustaining efforts in some parts of the country and focusing new interventions on others makes the elimination of malaria a challenging and ever shifting target.

The field of malaria research is dynamic. We are always learning new aspects about the disease and its interaction with the biological, social and economic environments.  News stories today highlight two such interactions that have implications for public health beyond malaria control.

Reuters reports on Canadian researchers whose “surprising findings suggest that treating malaria with the cheap, widely used drug chloroquine — a close cousin of fluoroquinolones — may boost the risk of resistance to these antibiotics,” in South America. This resistance has even been found in remote villages where people have never even taken the antibiotics, fluoroquinolones.

As Davidson and colleagues note in PLoS One, It is not only a matter of chloroquine, but the some of replacement first line treatments, artimisinin-based combination therapies (ACTs) that contain a related drug like amodiaquine. We may be preventing death from malaria while boosting the chances of people not being able to control other diseases with cheap, available antibiotics.

Another interesting dynamic reported by the BBC is that, “A gene which apparently evolved to protect people from malaria increases their vulnerability to HIV infection by 40%.”The story points out an irony: “People of African descent have a variation of the “DARC” (Duffy antigen receptor for chemokines) gene which may interfere with their ability to fight HIV in its early stages. The Cell Host and Microbe study says the gene accounts for millions of extra HIV cases in sub-Saharan Africa.However, people with the gene appear to live longer with HIV than other.”

The scientific article on this dynamic, appearing in Cell Host and Microbe, and observed that, “The sum of the in vitro and genetic epidemiologic findings demonstrates that HIV might exploit DARC to its advantage: binding of HIV to DARC, a molecule that is expressed on one of the most abundant cell types (RBCs), might afford a unique biological niche that favors viral survival and persistence.”

The Weijing He and colleagues point out the need for further understanding of the dynamic among malaria, immune defenses, HIV and genetics: “Of broad interest, our studies underscore that DARC impacts on chemokines, malaria, and HIV, a ménage à trois. However, given the importance of the chemokine system in host defense, immune responses, and inflammation, it will be important to determine the contribution of DARC to the pathogenesis of other infectious disease and inflammatory disease states.” Ultimately we cannot address the problem of malaria without looking at the broader dynamics of infectious diseases and genetics in a given setting.

To date the Roll Back Malaria Partnership has focused its attention of tackling the scourge of malaria in Africa, but the call has been growing for the Roll Back Malaria Partnership to give more attention to malaria in Asia and Latin America. About 40% of the malaria grants awarded to date from the Global Fund have been outside Africa, so attention is being paid to the need in some quarters. The US President’s Malaria Initiative has focused on 15 countries Africa, in part to achieve impact within focused population and financial limits, but USAID is also active in malaria control in the Mekong Region.

Three articles focusing on Indonesia and Papua New Guinea bring into focus the malaria control needs in parts of Asia. Poespoprodjo and colleagues explain that while, “Plasmodium falciparum infection exerts a considerable burden on pregnant women, but less is known about the adverse consequences of Plasmodium vivax infection.”

After studying over 3000 pregnant women with either falciparum, vivax or co-infection, they suggested that, “Malaria increases the risk of preterm delivery and stillbirth through fever and contribution to severe anemia rather than through parasitemia per se,” regardless of type of infection. They also debunked the myth that vivax infections are benign.

Drug resistance is increasing in both forms of malaria parasites, but as Tjitra and colleagues point out the myth of vivax being benign has led to some complacency. They found severe forms of the disease in both forms, and stressed that, P. vivax “is associated with severe and fatal malaria particularly in young children.”

Genton et al., with research support from both the US and Australian aid agencies, found the P. vivax and mixed infections resulted in severe malaria. They concluded that, “Interventions targeted toward P. falciparum only might be insufficient to eliminate the overall malaria burden, and especially severe disease, in areas where P. falciparum and P. vivax coexist.

In a commentary on the two PLoS articles Rogerson and Carter state that, “With calls for increased efforts to control malaria internationally, it will be important to ensure that P. vivax receives appropriate attention. We still lack reliable estimates of its global burden, and are only now starting to appreciate certain aspects of disease presentation of P. vivax malarial infection. The burden and severity of vivax in different settings requires further study.” They expressed hope in vaccine development but also highlighted the need for “more effective curative treatment and and better relapse prevention” because of the unique lifecycle of vivax.

Ultimately, malaria can never be eradicated without attention to its global spread.

Two news items require greater world-wide attention if current malaria control tools are to remain effective.

News-Medical.net asks the question, is “Monkey malaria the next bird flu?” The article reports that Dr. McCutchen, “An expert at the NIH, has highlighted the threat of an emergent highly virulent form of malaria, questioning whether the disease has made the jump from animal to man.”

The news story further states that, “Although at least ten species of Plasmodium can infect humans, only four forms of specifically human malaria are believed to exist. In the case of these four established human malaria types, the parasite is transmissible from one human to another, and a stable transmission cycle is established in the absence of any other vertebrate host. Now Dr McCutchan has raised the question – has a monkey malaria made that switch and become the fifth human malaria?” The full article appears in Future Microbiology and focuses on Borneo.

Dr McCutchan explained that interest was generated because of the severity of the infections and that, “The study of P. knowlesi is extremely significant regardless of whether it has entered humans permanently or represents a zoonosis. In either case, we face a health problem of potentially widespread significance and one that will present new problems for malaria control.”

Two other recent studies have documented the transmission of Plasmodium knowlesi to humans in the Philippines and Singapore. Research by Luchavez et al. (2008) extends the geographic range of known human P. knowlesi infections from Thailand, Myanmar, peninsular Malaysia, and Malaysian Borneo to Palawan Island in the Philippines. Their “report documents autochthonous human cases in the country. Major progress in malaria control has been achieved in many malarious areas in the Philippines. However, P. knowlesi forms a previously unrecognized pool of infections that may be maintained in forested areas through its presence in a simian reservoir, despite control efforts in the human population.”

Ng et al. (2008) in the Singapore example note that the case was originally misdiagnosed as Dengue, which is endemic in the region. They were fortunate that the infection responded to chloroquine.

Finally, another malaria control challenge was reported by Wongsrichanalai and Meshnick (2008) in the form of growing resistance to artesunate-mefloquine on the Cambodia-Thailand border. They suggest that, “These ACT failures might be caused by high-level mefl oquine resistance because mefloquine was used for monotherapy long before the introduction of ACT. This observation raises 2 questions. First, how can existing P. falciparum–resistant strains be controlled? Second, how can the evolution of new ACT- resistant strains be avoided elsewhere, e.g., in Africa?”

Not only does malaria not respect political borders, but now it seems, not even the ‘borders’ between species.

The Cape Times has issues a warning that greatr than normal malaria transmission is expected during the current rainy season in southern Africa. They quote a WHO official as syaing, “Malaria transmission from November 2007 to May 2008 is expected to be above normal in most parts of southern Africa. In East Africa, October to May is an important part of the rainy season, when malaria transmission and epidemics can occur. In southern Africa, the heavy rains and likelihood of flooding in certain areas from December may lead to an increase in malaria transmission.” This prediction links with US Weather Service reports for early December that state, “In southern Africa, consistent with the current moderate La Nina episode, rainfall was overall above average across much of southern Africa.”

Jones et al., (2007) tested a model for understanding forecasting malaria in the highlands of Tanzania, Such highland areas, like much of southern Africa are subject to epidemics as opposed to the year round transmission found in the lowlands of much of Africa. They addressed the issue of Malaria Early Warning Systems (MEWS) based on climate variations that have been proposed to warn ministries of health of the potential of increased risk of malaria epidemics and drew attention to the The El Niño Southern Oscillation cycle. this builds on suggestions for creating such a system by Thomson and Connor (2001).

Jones et al., found that “malaria incidence is positively correlated with rainfall during the first season (Oct-Mar). For the second season (Apr-Sep), high malaria incidence was associated with increased rainfall, but also with high maximum temperature during the first rainy season.” Chaves and Pascual (2007) built on the malaria early warning experience to propose and discuss early warning systems for other neglected tropical diseases. They concluded that, “EWS are a feasible ecological application for neglected tropical diseases,” and recommended that “Forecasts can be useful in planning services for the populations affected, allowing estimates of approximate number of hospital beds, vaccine shots, drug doses and vector control measures.”

The increasing ability to understand weather and climate and their effects on malaria, especially in epidemic regions of the world is extremely helpful for planning timely deployment of malaria treatment and prevention interventions. This presents a big challenge to countries dependent on large scale donor project funds, which are not always dispersed in a timely manner or on a regular schedule and are thus, not always in tune with general national health and development planning cycles.