Thursday, April 7, 2011

Malaria Part 4: The Landscape

In this final post of the malaria series, I will describe the epidemiology of malaria, with a particular emphasis on the role of the geography and landscape of infection. Let's start with some descriptives and move on from there.

One of the most important aspects to identifying the malaria burden in different parts of the world is the great variation in disease endemicity and transmission that occurs across the micro- and macro-geography of diverse regions. Let's begin with the concept of incidence. This is a universal and useful measure of disease occurrence employed by epidemiologists for many diseases. Incidence measures the number of new cases of disease that develop among all those who are susceptible for that disease during a specific period of time, or during the time period at which each individual is susceptible. Forty cases of cervical cancer per 100,000 women per year is an an example of incidence. There are several ways of measuring incidence and, subsequently, of quantifying risk based on this measure. But for the current discussion, the above generalized definition will suffice. However, taken in the context of the great variation in malaria transmission, the use of incidence for malaria can be rendered virtually useless. In areas of the highest transmission, for example, the incidence of disease offers little information because virtually everyone is infected to some degree all of the time. Incidence can be useful, however, in areas of low to moderate transmission. In 2004, the World Health Organization (WHO) completed its latest effort at a global quantification of the burden of disease, but this is a cross-sectional survey of all those with evidence of infection and thus more accurately depicts the prevalence of disease, rather than the incidence:

It should be immediately clear that sub-Saharan African countries suffer a disproportionate caseload compared to other tropical countries, although malaria is still a serious problem in Central and South America, and South and Southeast Asia.. We will explore sources of the heterogeneity of this distribution as we proceed. The map below provides further nuance to the global distribution of malaria by depicting the variation in the level of endemicity:

Notice here how endemic disease is highly concentrated in tropical Africa, and also in Southeast Asia, albeit to a lesser extent. Keep in mind that endemicity refers to the extent to which a disease is always present in a location. As such, the level of endemicity gives one account of the level of transmission of disease. The larger the extent to which a disease is present, in other words the greater the prevalence of that disease, the larger will be the potential for infected people to pass on the infection to non-infected susceptible people. Of course, given that this infection is vector-borne there are other important ecologic parameters that must be met in order for transmission to occur. But typically, in the tropical setting, these parameters are met. So a map detailing the level of endemicity provides important information regarding the potential for new or repeated infections.

Before describing the specifics of endemicity and it's consequences, there is an important epidemiologic concept related to the mosquito vector that I would like to highlight. There are two measures that provide a quantification of the vector's efficiency at transmitting the pathogen. These are quite useful in infectious disease epidemiology and medical ecology and are especially relevant to the transmission of malaria. The first measure is the entomological inoculation rate (EIR), which, in the case of anopheline mosquitoes, is the number of infected mosquito bites received per person per unit of time (usually per night). The EIR can be obtained in the field by direct mosquito collection. The EIR is the product of the number of human landings per night (an ethical proxy for the number of bites) and the proportion of infected mosquitoes out of all mosquitoes captured over the same period of time. The EIR provides a direct measure of malaria transmission and the risk of human exposure to infected mosquito bites. The second measure is the vectorial capacity (VC). The VC is the number of potentially infective contacts a person could have with the vector population per unit time. This is a more indirect measure of malaria transmission as it measures the rate of potentially infective contact. In other words, it measures the potential for malaria transmission. The VC can be expressed as follows:

In this equation: 

m is the density of vectors in relation to humans, i.e. the density of the vector where the vector and humans occupy the same landscape. 

a is the human biting habit, which simply refers to the number of blood meals taken from humans as a proportion of all blood meals taken from all hosts. Therefore, a person occupying the same landscape as the mosquito will potentially be bitten by ma vectors per unit time (usually per night). 

p is the daily survival probability of the vector. In other words,  the probability that any given vector will be alive to take a blood meal during each instance of the unit of time under study. 

n is the length of time of the sporogonic cycle of the parasite, which, you will remember from Part 1, is the stage of the parasite life cycle that occurs in the mosquito. 
pn represents the number of vectors that survive the sporogonic cyle of the parasite, and so gives an estimate of the number of viable mosquitoes that are potentially infectious. 

Finally, - logp is the daily expectation of life of the vector

Since this equation for VC estimates the potential for infective contacts between persons and mosquitoes per day, it provides a guideline for predicting the number by which the mosquito vector must be reduced in order to reduce malaria transmission. Importantly, this estimate is fundamentally a hyperlocal estimate of the interaction between humans and mosquitoes. It is specific to the micro-geography and local landscape defined by a limited area. It is micro-geographic because all of the parameters in the equation are highly dependent on local conditions. For example, the biting habits of mosquitoes will depend on the specific species of Anopheles in the area, as well as the availability of other vertebrate host species in the area. The density of the mosquitoes will also depend on the species, but it will also depend on land cover generally, and the natural habitat of the mosquito more specifically. Furthermore, there will be important interactions between these factors and the extent to which mosquito habitat has been disrupted by human encroachment. Additionally, the length of the sporogonic cycle, the survival probability of the mosquito, and the 4-stage life cycle development of the mosquito, are all highly dependent on very localized weather conditions. Temperature, humidity and precipitation all play critical ecologic roles in the life cycles of both the parasite and mosquito. These weather patterns and habitat qualities can and do vary drastically by landscape even over small areas and, thus, so too does the vectorial capacity of the mosquito. Ultimately, so too does the transmission of malaria. 

Let's return now to the specific geographic classification of malaria endemicity.

Hypoendemic areas are those areas with only limited malaria transmission. People in these areas typically have little or no immunity to Plasmodium parasites. As with all endemic levels, the classification is based on children under the age of 10 years. When splenomegaly and parasitemia prevalence is less than 10% in these children, the area is considered hypoendemic. While malaria is less problematic in hypoendemic areas, these areas can still experience large epidemics that involve all age groups.

Mesoendemic areas experience regular transmission of malaria, but at moderate levels. The areas can be dangerous epidemiologically because of regular epidemics that can involve individuals with low immunity and produce high morbidity and mortality. Those areas in which splenomegaly and parasitemia prevalence range between 10% and 50% in children under 10 years are considered mesoendemic for malaria.

Hyperendemic areas experience more regular, often seasonal, transmission. The EIRs and VC are typically seasonal, in concert with the occurrence of disease. In this setting immunity in some of the population does not confer protection at all times, which reinforces the seasonal nature of this kind of transmission. Those areas whose children under 10 years experience splenomegaly and parasitemia prevalence ranging from 50% to 75% are hyperendemic.

Holoendemic areas undergo the most intense transmission of malaria, with continuously high EIRs and VC. In these areas, virtually everyone in the population is infected with the malaria parasites at all times (even though most will be asymptomatic most of the time). In older children and adults substantive immunity develops across the whole population, which prevents malaria complications in adulthood even though regular episodes of more minor malarial symptoms will often continue throughout the lifecourse. Nevertheless, the burden of morbidity and mortality experienced by young children in these areas is extreme, with 50% of child mortality in children under 5 years directly attributable to malaria. Areas with splenomegaly and parasitemia prevalence greater than 75% in children under 10 years are holoendemic.

To summarize, here again is the global map depicting the different levels of endemicity:

The ways in which malaria, and especially severe malaria, manifest are also determined largely by endemicity, and thus are also spatially defined by the landscape. For example, as endemicity increases, and consequently as the intensity of transmission increases, the population that is affected by severe malaria is shifted to the younger age groups. A such, in holoendemic areas, severe malaria and death are typically experienced by children less than 5 years of age, and most clinical disease is experienced by children less than 10 years. However, as transmission intensity varies across micro-geography, the age distribution of children with severe malaria, as well as the relative importance of the attendant syndromes, can vary dramatically. For example, in areas where the entomological inoculation rate (EIR) averages 100 infectious bites per year, severe malaria will most commonly manifest as severe anemia and it will do so at younger ages (15 to 24 months). In areas of lesser transmission, where the EIR averages 10 infectious bites per year, for example, severe malaria will commonly manifest as cerebral malaria and at an older age (36 to 48 months).

Constancy of transmission is also important, with perennial transmission more commonly associated with severe anemia in complicated malaria, while seasonal transmission is more often associated with the presentation of cerebral malaria when complicated.

So, we have outlined how malaria transmission varies in geographical space, given some ecologic and epidemiologic causes for this variation, and described how this variation translates into different manifestations of malarial disease. Let's now shift the discussion to human action within the landscape.

Human activities occur on living surfaces. This means that they occur within the landscape and thus affect important aspects of the environment that are coincident with the landscape. Agricultural industry, large scale population movement, and rapid urbanization are all important mechanisms by which human activities can alter landscape and subsequently change the patterns of malaria transmission. Let us examine each of these more closely.

Agriculture. Malaria has been linked to farming practices for many hundreds of years. The manipulation of water and natural vegetation and the subsequent patterns of malaria emergence did not go unnoticed down through the centuries, although the infectious pathogen and the mode of transmission have only been known for about one hundred years. Sub-Saharan Africa has experienced some of the most dire effects of agricultural manipulation of the environment. The clearing of tropical forest for the production of crops has led to the proliferation of breeding sites for Anopheles gambiae, which is one of the most efficient malaria vectors. You'll recall from Part 2 that this species prefers open, sunlit pools of water. When forest integrity is maintained, the mosquitoes are naturally controlled by way of the intact canopy providing few open water breeding sites. As forest is cleared, appropriate water sources become more and more abundant for A. gambiae to breed. Small towns, dam projects and irrigation systems often arise in concert with the clearing of forest during agricultural development. This tenuous situation concentrates humans and vectors in relatively confined geographic spaces in close proximity to water. This, of course, promotes malaria transmission. And so, too, does the increased use of pesticides in modern agricultural practice as this has led to increased insecticide-resistant mosquito vectors.

Large-scale Population Movement. In many parts of Africa, South America, and South and Southeast Asia, seasonal migration has been a part of traditional life for millennia. Farming practices in these communities will often see people moving from settled villages to rural seasonal farms at the beginning of the rainy season. The intensity of transmission is often much higher in these farmlands where water control is greatly reduced and where mosquito breeding is enhanced due to the increased precipitation. Pastoral peoples are also often exposed to higher malaria transmission as they move their livestock from highland grazing to lowland pastures according to the seasons. While these types of population movement do contribute to baseline levels of endemicity that are inescapable if traditional subsistence practices are to be maintained, they do not come close to contributing to the high levels of malaria endemicity that occur in association with drought, famine, and conflict. These kinds of large-scale population-wide disasters create massive population displacements and refugee movements across large geographical spaces. These people are typically moving from settled communities to fringe areas and, therefore, are not able to access government health services, antimalarial drugs, and malaria control programs. As a result, malaria transmission explodes in these increasingly common settings.

Urbanization. Most migration in the developing world directs from relatively small rural communities to large urban areas. This kind of migration can happen for a variety of reasons, but most commonly it is driven by external economic pressure. An increasingly poor global rural population seeks work in urban centers. As a result, urban centers tend to develop rapidly, without the appropriate infrastructural development that can accommodate the influx of people. One result is the expanse of an urban sprawl that lacks basic conditions such as clean water and sanitation resources. People living in these conditions are often at much greater risk for many of the infectious diseases that are closely associated with poverty, such as tuberculosis and diarrheal infections. We can add to that, malaria. Malaria is primarily a rural disease, especially in sub-Saharan Africa where the malarial burden is greatest. Nevertheless, there are 2 important factors that still make urbanization a very relevant contributor to malaria transmission. First, some anopheline mosquitoes have become very well adapted to the urban environment, while remaining efficient vectors for Plasmodium. A. arabiensis is one such species and has become one of the most efficient vectors for malaria transmission. As an example, here and below is a map published by the American Journal of Tropical Medicine and Hygiene depicting a large distribution of Anopheles breeding sites in Dar es Salaam, Tanzania:

Notice how the breeding sites shown in this map are concentrated in the urban periphery, corresponding to the "urban sprawl" described above. There is less breeding concentrated in the city center. This is a common characteristic of urban anopheline mosquitoes.

The second important factor that makes urbanization a contributor to increased malaria transmission also has to do with urban sprawl. The larger the influx of migration into cities from rural surrounding areas, the greater the expansion of those cities, and the greater the sprawl. As urban areas take up more physical space in any particular geography, they encroach upon and disturb natural habitat. As a result, the periphery of the urban areas, which is where the most uncontrolled sprawl typically develops, brings many people into ecological transition zones (ecotones) characterized by the close proximity of vectors and hosts in increasingly favorable landscape conditions for the vectors.

This will conclude the extended series on malaria. This series was not intended to be exhaustive in content, but rather to serve as an introduction to a very serious disease of major global importance. We will return frequently to an ongoing discussion of malaria at Infection Landscapes. Indeed, before too much time has passed I would like to give a description of malaria drug resistance because this is a major problem in control efforts. But for now, we will conclude.

Next time at Infection Landscapes we will discuss trypanosomiasis, including both the African and American forms. Stay tuned.


  1. After reading the post I have a great understanding of the overarching landscape of malaria. The most interesting component is the ecotones, those transitional sites that change the entire ecology, which have historically been beneficial to the proliferation of the anopheles mosquito.
    Because farmland is so engrained into life in SSA, and there is qidespread deforestation the possibility of bringing mosquitoes back into the forest is unthinkable.
    what can be done to prevent urbanization as being an add on to the diseases growth is identification and control of possible breeding sites. if you see a puddle, get a broom and break it up or no cans of water without a cover...

    1. Even with that being said, leaving vector control to the responsibility of the individual, I feel, will not significant impact the spread of malaria. From my understanding, malaria is hyperlocal which is the point I think you are dwelling on. However, the actual impact of malaria is so wide across SSA and other endemic areas of the world, that watching for cans or containers of stagnant water in urban areas simply would not do much for the disease as a whole. I know that for the tsetse fly, they used the sterile insect technique to reduce the burden of disease and that fly population affecting humans and animals. Since this is probably costly, I know this can't be advocated for the anopheles mosquito given the widespread distribution of malaria. I do wonder though, could this be implemented in areas that have endemicity and are urbanized? I would assume that cities could more realistically push for this than rural areas and poor villages. The best question would be if this technique could be applied to anopheles and could there be some public health campaign reducing the cost that would be tied into this kind of eradication?

    2. Although most malaria vector control has been centered on taking advantage of the plasmodium falciparum life cycle, the responsibility of vector control should take a multifaceted approach and involve individuals and community interventions. With regions where malaria is highly prevalent, there has been deforestation, urbanization and exponential population growth, which has provided the appropriate environmental factors for disease transmission as well as consistent maintenance of the parasite lifecycle and host reservoir. Malaria is extremely difficult to control due to the complex life cycle and interactions by the parasite.

  2. In response to the previous post:
    Based on malaria prevention and control program, infrastructure projects are an essential element of development and can contribute to the long-term health and well being of beneficiaries.Most infrastructure projects undertaken in malaria endemic areas can be expected to adversely affect malaria transmission and disease but in most cases, that effect can be reduced by careful analysis and design. Infrastructure projects can exacerbate malaria risk if they have components that include construction of roads, dams, irrigation schemes, pipelines, water supplies and new or upgraded residential sites. It is in the government, corporations and local people's interest to expand existing environmental assessment tools to include an assessment of malaria consequences, and to develop a process by which personnel can access environmental health professionals to assist in developing mitigation plans.
    About maIaria vaccine, recent Phase III clinical trials, the RTS,S malaria vaccine had lower-than-desired efficacy, but the data demonstrated that it is possible to vaccinate against a parasite.
    Indoor residual spraying and long-lasting insecticide-treated bed nets are currently the two most effective interventions for reducing and interrupting malaria transmission. Unfortunately, their effectiveness is threatened by increasing mosquito resistance to the pesticides used. Moreover, indoor sprays and bed nets are not effective against mosquito species that are active outside homes or that bite during the daylight hours.

    1. thanks blue moon for pointing out that infrastructural projects are essential element of fighting malaria. Since India is one of the most stricken areas of the world with diseases that is caused by mosquitos, including malaria, dengue, ..etc
      I wonder what will be the effect of the indian government's new commitment and campaign to improve health and sanitation on all these diseases, since improving sanitation will remove a lot of the habitat of the mosquitos and what that will lead india to, and also if successful can it be copied in other areas of the world.

    2. Yet another hope and breakthrough in public health, global health and infectious diseases, as the fear of emerging resistance to the most potent anti-malarial medication artemisinin spread in Burma and India, a new drug that tackles all the stages of malaria parasite life cycle and can probably decrease transmission as well is in its final stages of clinical trials.

      #Please see link for article June/17/2015

  3. I thought it was interesting that, despite malaria not being endemic to the US, that an estimated 1500 cases are diagnosed here each year. That led me to dig a bit deeper into how malaria was eradicated here. I was surprised to find out that it was considered to be eliminated over 65 years ago. Eradication efforts began in 1947, headed by the National Malaria Eradication Program (participants were state and local health agencies and the CDC). At that time over 15,000 cases of malaria were reported each year. By 1950, that number had dropped over 80% to 2,000 cases, and by 1951 it was considered completely eradicated. Pretty impressive results in just 4 year time span.


      I don't know if eradicating the disease in the US (and most of developed countries) decades ago caused the lack of urgency to develop a malaria vaccine.
      The article above is about the mixed reviews for the newly developed vaccine and the worry about who is going to pay for a pilot program which would take another 5 years.

  4. i found it interesting that although the vector for Malaria does not move very far in its lifetime, it is able to adapt very well to the changing lifestyles of humans. The urbanization of the population made it even easier for the vector to breed all the while making it more difficult for the human population to control it. while human movement and man made water systems, such as canals for agriculture has made great breeding grounds for the vector, with urbanization, there are so many small and efficient breeding grounds for continued transmission. avoiding open pools of water seems like a simple initiative, yet it doesn't seems simple enough to avoid the enormous spread of malaria

    1. Shmuel, you make an interesting point that though it seems intuitive for people to avoid open pools of water. I think this would be very difficult to achieve, particularly in developing countries where malaria is endemic. Without the proper infrastructure it would be unlikely that people would be able to avoid all mosquito breeding grounds. The best prevention efforts would still likely be distribution of malaria drugs.


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