Tuesday, June 18, 2013

Why less malaria can be more of a problem

Most people who are interested in malaria are concerned with regions with really high transmission.  These are areas, such as sub-Saharan Africa, where malaria prevalence is high year round and where malaria related mortality is highest.  Sadly, that mortality generally seems to disproportionately affect children.  It’s no wonder then, that these are the areas that most people think about.  

Huge amounts of research money goes toward potential vaccines, toward genome sequencing of parasites, laboratory and field based science, and much of it is focused on the malaria situation in sub-Saharan Africa.  I’ve already questioned whether this is a wise use for a limited amount of money and that by changing socio-economic factors we would probably get more bang for our buck.   

Here I am also going to argue that for what most of us in tropical medicine, epidemiology, and disease ecology do, areas of low transmission are more important.  And while I can make this argument from a few different vantage points, today I’m going to base it off the fact that drug resistant malaria (see Note 1) seems to recurrently arise in areas of low transmission, only to spread to places like Africa where the implications of treatment failure at the population level are most severe (White, 2004).   

First, what do I mean by low or high transmission?  

In the malaria system there are always at least two hosts, humans and mosquitoes.  Humans get infected by infectious mosquitoes that have in turn been infected by infectious humans.  In areas of high transmission, people are bitten by infected and infectious mosquitoes more frequently in comparison to people in low transmission areas.  For example, in parts of sub-Saharan Africa people may be bitten by infectious mosquitoes more than 100 times in a single year.  In areas of low transmission people might only be bitten by an infectious mosquito once a year (Bousema & Drakeley, 2011)

There are several ways to break the transmission cycle between humans and mosquitoes.  Some efforts are based on preventing mosquitoes from feeding on human blood (e.g. mosquito nets).  Others are based on treating infected humans with antimalarials; which should both cure the infected persons and halt the spread of parasites within the infected to others.  Suffice it to say that at least a huge component of modern malaria control efforts depends on the use of antimalarials.  Drug resistance is therefore a very large problem, and it is a problem with a relatively long history.  

For example, chloroquine was a wonder drug for malaria treatment, it was easy to manufacture, cheap, and compared to previous antimalarials it seemed to have fewer negative side effects.  However, it wasn’t long after it had been rolled out into the global scene that people in the field began to notice decreased sensitivity in parasites to chloroquine, almost simultaneously in parts of Southeast Asia and South America in the late 1950s and early 1960s (Payne, 1987).  The move was slow for chloroquine resistant parasites, but they eventually did make the passage to Africa.  Perhaps especially in Southeast Asia this story has been repeated over and over again (Parker et al., 2012), with each new antimalarial losing its efficacy shortly after its widespread use and subsequently parasites with the drug resistant mutation (or mutations) spread throughout the world (Anderson & Roper, 2005).  

I believe that I’m relatively safe in stating that there is a growing consensus among malariologists that drug resistant strains continue to emerge in certain areas and not in others because of the level of transmission intensity in those areas (Klein, 2013).  Take Thailand, for example: This is a nation that has very little malaria in the central plains regions and highly seasonal malaria along its international borders with Cambodia and Myanmar.  Those border sites appear to consistently be centers for the emergence of drug resistant parasites strains, most recently with decreased sensitivity to artemisinin (Noedl et al., 2008; Phyo et al., 2012).  

But what is it about low transmission areas that make them primed for drug resistant strains to pop up?  

Here there is certainly room for debate.  Several things must happen in order for drug resistant parasites to become prevalent enough to be a public health problem.  First there must be mutations that arise which confer some sort of resistance to antimalarial drugs.  However, some mutations are likely to be harmful for the parasite, even if offering some protection against antimalarials.  Therefore the mutation must not be so harmful as to provide an overall disadvantage in comparison to its advantage in the presence of drugs.  Then, that mutation (or mutations) must spread and be retained throughout the population.  

One potential explanation is that in low transmission areas people are unlikely to have developed immunity to malaria (White, 2004).  When they are infected they have high parasite densities in their blood and they are more likely to take antimalarials; meaning that more parasites are exposed to more antimalarials, therefore leading to more chances for resistance to emerge.  Then, parasites with resistant strains don’t have to survive their host’s immune responses, and are likely to have higher parasite densities, meaning that they are also more likely to be passed on to mosquitoes and ultimately other human hosts.  

Population genetics likely also plays an important role.  In areas with really high transmission, a single infected person is likely to be carrying multiple parasite strains at the same time.  Mosquitoes are also likely to be infected by multiple strains, as they have probably both fed off of individuals with more than one strain and potentially have fed on more than one infected individual.  Malaria parasites have quite complicated life cycles, undergoing several different life stages within human and mosquito hosts.  They reproduce asexually inside humans until some of them split off and become ready for sexual reproduction, basically developing into either males or females.  These sexual parasites are then picked up by the mosquito where they undergo sexual reproduction.  Therefore genetic recombination only occurs within the mosquito.  This has strong implications for drug resistance which is conferred through multiple genes.  Genetic recombination means that such mutant combinations can be lost through sexual recombination.  However, in areas of low transmission, such as in Southeast Asia, many parasites are actually reproducing with themselves; the mosquito isn’t picking up sexual parasites from multiple strains but instead from a single strain (Anderson et al., 2000).  Recombination still occurs, but it is occurring with a single parasite strain, meaning the gene combinations will not be lost.

Intrahost competition between parasites is probably also important.  There is evidence that, within individuals who are infected by multiple strains of parasites, not all parasite strains do equally as well.  Some appear to be more aggressive and to propagate themselves at higher levels than other strains.  In areas with high transmission, a parasite strain with a drug resistance mutation may still need to out-compete other parasite strains within the host (Klein, 2013).  Since a mutation isn’t likely to confer absolute resistance to antimalarials, and since it might actually be slightly harmful to the parasite strain, it is possible that aggressive parasite strains (even without drug resistance mutations) can out-compete those with such mutations.  Conversely, in low transmission areas this is less likely to be the case.   

What does all of this mean for the big picture though?   The obvious implication related to the drug resistant strains that keep emerging in Southeast Asia and then spreading throughout the world is only part of this story.  

Currently there are increased efforts for malaria control and, in some situations, even efforts directed toward malaria elimination.  But there are no easy fixes to the malaria problem.  That is, in some areas, malaria transmission will be greatly reduced but will continue to persist at very low levels of transmission.  Most likely, even in areas where complete eradication is achieved, there will be periods of time where malaria persists at low transmission levels.  The paradox, therefore, is that as the malaria situation improves, as transmission is reduced and less people become sick or even die, the situation with regard to effective antimalarials might simultaneously worsen.  

Previously I’ve argued that if we really want to fix the malaria problem we should look toward socio-economic factors.  Malaria remains a disease that mostly afflicts poor people in poor nations in the tropical world.  If we could increase economic wellbeing and improve sanitation, we would probably fix a large part of the problem, much like we did here in the U.S.A. over half a century ago.  Also, it might make more sense to dump the millions of dollars that are directed toward researching single diseases into funding primary health care for children in the industrializing world (which is the approach of groups such as Partners in Health).  That is, if children in poor nations received free health care regardless of the cause of their illness we will probably see huge improvements in global health.

But the situations that I describe above, where the conditions in low transmission areas lead to a type of perfect storm, are probably best addressed through epidemiological, ecological, and evolutionary approaches.  While I’m quite pessimistic about spending millions and millions of dollars on potential vaccines to save children in Africa from one (out of a lot) of pathogens, I do think there is a very important role for the life and biomedical sciences in malaria control.  Here are a few examples:

1.) Antimalarials will continue to be important, even if they are only used sparingly in areas of low transmission.  That means that evolutionary biologists will continue to have an important role in malaria control (Read, Day, & Huijben, 2011).  

2.) Another interesting factor that I completely avoided in this post has to do with areas with several different hosts (zoonosis and anthroponosis) – such as in Borneo where nonhuman primates carry malaria parasites that can also easily infect humans (Singh et al., 2004).  This type of situation can also lead to persistent low transmission and is perhaps best addressed by ecologists.  

3.) Finally, in areas with low, sporadic transmission the role of human migration in continued transmission is quite important; meaning that human demographers, geographers, and population ecologists are also important for addressing the malaria situation (Prothero, 1999; Tatem & Smith, 2010).  

Note 1: Drug resistance isn't really a binary trait.  It is probably more accurate to talk about levels of reduced sensitivity to drugs, but this is quite a mouthful.  Typically when I use the term drug resistance, I am talking about parasites that no longer respond well to antimalarials at the doses that are safe to give to humans.    


Anderson, T. J. C., & Roper, C. (2005). The Origins and Spread of Antimalarial Drug Resistance: Lessons for Policy Makers. Acta Tropica, 94, 269–280.

Anderson, T. J., Haubold, B., Williams, J. T., Estrada-Franco, J. G., Richardson, L., Mollinedo, R., Bockarie, M., et al. (2000). Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Molecular biology and evolution, 17(10), 1467–82. 

Bousema, T., & Drakeley, C. (2011). Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clinical microbiology reviews, 24(2), 377–410. doi:10.1128/CMR.00051-10

Klein, E. Y. (2013). Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread. International journal of antimicrobial agents, 41(4), 311–317. 

Noedl, H., Se, Y., Schaecher, K., Smith, B., Socheat, D., & Fukuda, M. (2008). Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med, 359(24), 2619–2620.

Parker, D., Lerdprom, R., Srisatjarak, W., Yan, G., Sattabongkot, J., Wood, J., Sirichaisinthop, J., et al. (2012). Longitudinal in vitro surveillance of Plasmodium falciparum sensitivity to common anti-malarials in Thailand between 1994 and 2010. Malaria journal, 11(1), 290. 

Payne, D. (1987). Spread of chloroquine resistance in Plasmodium falciparum. Parasitology today (Personal ed.), 3(8), 241–6. 

Phyo, A. P., Nkhoma, S., Stepniewska, K., Ashley, E. A., Nair, S., McGready, R., ler Moo, C., et al. (2012). Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. The Lancet, 12.

Prothero, R. M. (1999). Malaria, forests and people in Southeast Asia. Singapore Journal of Tropical Geography, 20(1), 76–85.

Read, A. F., Day, T., & Huijben, S. (2011). The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy. Proceedings of the National Academy of Sciences of the United States of America, 108 Suppl , 10871–7. 

Singh, B., Kim Sung, L., Matusop, A., Radhakrishnan, A., Shamsul, S. S. G., Cox-Singh, J., Thomas, A., et al. (2004). A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet, 363(9414), 1017–24. 

Tatem, A. J., & Smith, D. L. (2010). International population movements and regional Plasmodium falciparum malaria elimination strategies. Proceedings of the National Academy of Sciences, 107(27), 12222.

White, N. J. (2004). Antimalarial Drug Resistance. The Journal of Clinical Investigation, 113(8), 1084–1092.


Anne Buchanan said...

This is a thought-provoking post, Daniel. The population dynamics of drug resistance are one issue, and clearly need to be understood, but will that understanding lead to better malaria control?

Unknown said...

Thanks Anne!
I think an understanding of the population genetics, and a few other things, could actually lead to better malaria control in some settings. Probably especially in low transmission settings, where the danger of drug resistance emerging or persisting in a population might be greater.
One thing to consider, from the Read and colleagues paper above, is how we treat malaria. They discuss a more slow and steady type of treatment that doesn't provide such a strong selective pressure on the parasites. In my mind, that would be easier and more important to implement in a low transmission area. Currently the treatment scheme is to hit the parasite as hard as possible with a dose that should hopefully kill everything in the host. When treatment means life or death for the individuals, as it more commonly does in parts of Africa, I think it might be hard to move away from this approach. On the other hand, in places like Thailand, where people are mostly otherwise healthy, and where we think drug resistance keeps emerging, it might make sense to begin an alternate strategy that makes more sense evolutionarily.
Also, I wonder if chopping geographical zones up, using malaria check points, wouldn't lead to smaller effective population sizes and an increase in the importance of genetic drift... perhaps randomly losing some resistance genes. Of course, resistance genes might reach fixation in some small populations, but if we're smart about how we are using antimalarials, we have quite a few others that could be used in those specific populations. All just preliminary thoughts, but yes, I think that in some settings there is a lot of room for population genetics and evolutionary biology to inform malaria control strategies.