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This week at Infection Landscapes I will cover another of the soil-transmitted helminths, and another of the important neglected tropical diseases: hookworm. Hookworm is a major contributor to morbidity in the developing world, particularly with respect to growth and development in children.
The Worm. Human hookworm infections can be caused by two different species, both of which are nematodes. Necator americanus and Ancylostoma duodenale are the two main hookworm species that cause human infection. N. americanus has the greatest global distribution, and is responsible for the greatest prevalence of infection, whereas the prevalence of A. duodenale infection is more focally clustered across Africa, South Asia, China and a few foci in the Americas.
Both species employ complex life cycles, as we saw with A. lumbricoides, however the pathway is somewhat different for the life cycle of hookworms and, subsequently, so is the resulting disease ecology. Let's describe the life cycle. The eggs of both species are deposited in the feces of an infected host and, following deposition, embryonate. The eggs require warm and moist soil that is sandy or loamy in composition. If these immediate ecologic needs are met, in about 2 days the eggs will develop into the first stage (L1), rhabditoform larvae, which are not infective and subsist on the microbial contents of the soil. These larvae will molt twice, the first time (L2) resulting in a second soil-stage rhabditoform, and the second time (L3) resulting in the infective filariform larvae. This stage of development no longer feeds, but its mobility increases dramatically so that it can remove itself from within the soil and relocate to high points above the soil horizon, such as rocks or grass. By moving above the soil horizon, the larvae are able to increase the likelihood that they will successfully engage the skin of their host. Once the larvae make contact with the skin, they penetrate by way of hair follicles or through open wounds or lesions on the skin's surface. Having achieved cutaneous and subcutaneous penetration, the filariform larvae must reach the lung to continue the next stage of the their life cycle. They do this by passive transfer through the venous circulation, which the larvae access by way of the capillary beds under the skin. The vasculature ultimately deposits these L3 larvae in the capillary beds of the lung from which they penetrate into the alveoli and migrate up the bronchii and trachea until they reach the throat. From here the larvae are swallowed and, thus, finally gain access to the alimentary tract of the host. In the small intestine the larvae molt for the third and final time forming the adult worm, which is the parasitic feeding stage of this worm. In this stage the adult worm targets the intestinal mucosa where it attaches and feeds on both the villi of the epithelium and the blood which it sucks from the blood vessels of the submucosa. The total infective process (skin penetration to intestinal feeding adult) typically requires 1 to 2 months to complete. Adult females and males mate in the host intestine and produce several thousand fertilized eggs per day. N. americanus females will produce up to 10,000 eggs each day, while A. duodenale females can produce three times as many eggs per day. These eggs are passed into the environment with the host's stool and the cycle continues. Below is a nice graph by the Centers for Disease Control and Prevention that depicts the complex life cycle of both hookworm species:
It is important to note that the life cycle stages above describe the strategies employed by both N. americanus and A. duodenale. Transmission by skin penetration is the only mode of transmission for N. americanus, and it is the most common mode of transmission for A. duodenale. However, A. duodenale can also transmit by ingestion of the larvae. When the latter strategy is employed the life cycle is shortened since the lung stage is bypassed and the larvae develop directly into the adult stage in the small intestine of the host.
The Disease. Most hookworm infections are asymptomatic. When symptoms do occur, they typically involve 1) the subcutaneous migration of the larvae, 2) the larval development within the lungs, and/or 3) the attachment of the adult worms in the small intestine. Subcutaneous larvae migration can cause a hypersensitivity reaction in the course of the migrating worms that produces very itchy lesions on the skin:
Hypersensitivity reactions involving pruritic lesions are more common in hyperendemic areas following repeated infections over time. Larval infection in the lungs can produce cough and hypereosinophilia, and even mimic pneumonia with radiographically apparent chest infiltrates and fever. However, these more severe pulmonary symptoms are also usually only associated with high volume infections. Abdominal pain is the most common intestinal symptom, but irregular stool, with either diarrhea or constipation, and vomiting are also possible presentations. But again, symptomatic gut infection is more common in high volume infections.
The most important clinical consequence of hookworm infection at the population level is anemia. An iron-deficiency anemia results from the blood lost into the lumen of the gut, and which is ultimately passaged in stool, as the adult worms feed in the small intestine. Protein deficiency is also an important consequence of long-term or high volume infection. Because of the iron-deficiency anemia and protein deficiency, chronic hookworm infection is particularly damaging to children, often leading to arrested musculoskeletal growth and cognitive development. As such, children account for a large preponderance of the overall morbidity experienced by a population and so are typically the age group targeted in de-worming campaigns. This is the typical practice even though adults can often acquire higher volume infections under some circumstances. For example, due to the widespread use of human feces as fertilizer in farming among poor agricultural communities, adults working the fields contaminated by hookworm may have much more extensive exposures and subsequent infections.
The Epidemiology and the Landscape. There are likely close to one billion prevalent infections with hookworm in the world today. The vast majority of these occur in sub-Saharan Africa, Southeast, South and East Asia, and parts of South America:
As mentioned above, the morbidity associated with such a high burden of infection is predominantly manifested as impaired physical and cognitive development in children. When this morbidity is translated into disability-adjusted life years we can see below that sub-Saharan Africa and Southeast Asia are saddled with a disproportionate burden of disease, and we can also see that this burden is quite substantive:
The morbidity that attends hookworm infection in areas of high endemicity makes this one of the most significant infections currently affecting humans. This is further highlighted by the fact that this infection is one of the primary neglected tropical diseases, meaning it typically draws little consideration and/or resources in the overall global fight against infectious disease.
The range of hookworm species is determined by important aspects of the physical landscape and because of this, as well as critical overlapping characteristics of the human social landscape, the occurrence of hookworm in humans is distinctly delineated by geographic features. Soil and climate are two critical landscape features that determine the distribution of hookworm species. During the first two larval stages of development in the life cycle of both A. duodenale and N. americanus, the larvae require sandy, loamy soils in order to undergo the first two molts to the L3 stage, which can then infect humans. If the hookworm eggs hatch and find themselves in hard clay soils then the larvae will not reach the L3 developmental stage and thus they cannot infect humans and they cannot complete their life cycle. In addition, the soils must be moist and the temperature must be warm. As such, the specific climatic conditions limit the range of the worms to the tropical and subtropical regions of the world that receive significant amounts of precipitation on an annual basis, while the pedological and edaphological constraints further define the microgeography of these worms. Notice below the global distribution of soil morphology in the map produced by the Natural Resources Conservation Service (NRCS) of the United States Department of Agriculture:
And this NRCS map below depicting the global distribution of soil moisture:
Wearing good shoes without holes while outside in endemic areas is another critical step in the prevention of new hookworm infections. Unfortunately, footwear is often simply not available for those people who need it most, and as such this very simple transmission block cannot be utilized.
Finally, changing agricultural practices that rely on human feces for fertilization of crops could dramatically help reduce the widespread distribution of hookworm in soils in many agricultural subsistence communities.
Unfortunately this, too, can be a difficult practice to disengage since human feces serves as a very rich fertilizer and, thus, can form a critical component to subsistence farming in many parts of the world where other fertilizers or farming technologies are cost prohibitive. And, of course, without an affordable substitute refraining from human feces fertilization could very well lead to starvation. The massive scope of the problem presented by soil-transmitted helminths in general, and hookworm in particular, should now be coming into focus.
De-worming campaigns do offer some hope, since there are safe, effective, and fairly cheap anti-helminthic drugs available. However, as one might expect, there are obstacles to overcome in de-worming. First, these drugs are not free and, while cheap they may be, without adequate funding poor communities will not be able to prioritize the cost, especially since most infections are generally asymptomatic. Second, effective ways to deliver the de-worming medications to communities need to be implemented, which can be logistically challenging particularly in remote communities or during times of the year when travel may be restricted (i.e. during the rainy season). Third, the extensive use, or misuse, of these drugs will likely lead to antihelminthic-resistance in the worms, thus making the drugs ineffective. Nevertheless, if adequate resources can be put behind de-worming campaigns, and if delivery systems can be adapted to actively engage community members in the delivery and monitoring of these de-worming medications to simultaneously circumvent logistical obstacles and reduce the development of resistance, then substantial reductions in hookworm infections may still be possible.
This week at Infection Landscapes I will cover another of the soil-transmitted helminths, and another of the important neglected tropical diseases: hookworm. Hookworm is a major contributor to morbidity in the developing world, particularly with respect to growth and development in children.
The Worm. Human hookworm infections can be caused by two different species, both of which are nematodes. Necator americanus and Ancylostoma duodenale are the two main hookworm species that cause human infection. N. americanus has the greatest global distribution, and is responsible for the greatest prevalence of infection, whereas the prevalence of A. duodenale infection is more focally clustered across Africa, South Asia, China and a few foci in the Americas.
Ancylostoma duodenale (photo by Jay Reimer)
Necator americanus (photo by David Scharf)
Both species employ complex life cycles, as we saw with A. lumbricoides, however the pathway is somewhat different for the life cycle of hookworms and, subsequently, so is the resulting disease ecology. Let's describe the life cycle. The eggs of both species are deposited in the feces of an infected host and, following deposition, embryonate. The eggs require warm and moist soil that is sandy or loamy in composition. If these immediate ecologic needs are met, in about 2 days the eggs will develop into the first stage (L1), rhabditoform larvae, which are not infective and subsist on the microbial contents of the soil. These larvae will molt twice, the first time (L2) resulting in a second soil-stage rhabditoform, and the second time (L3) resulting in the infective filariform larvae. This stage of development no longer feeds, but its mobility increases dramatically so that it can remove itself from within the soil and relocate to high points above the soil horizon, such as rocks or grass. By moving above the soil horizon, the larvae are able to increase the likelihood that they will successfully engage the skin of their host. Once the larvae make contact with the skin, they penetrate by way of hair follicles or through open wounds or lesions on the skin's surface. Having achieved cutaneous and subcutaneous penetration, the filariform larvae must reach the lung to continue the next stage of the their life cycle. They do this by passive transfer through the venous circulation, which the larvae access by way of the capillary beds under the skin. The vasculature ultimately deposits these L3 larvae in the capillary beds of the lung from which they penetrate into the alveoli and migrate up the bronchii and trachea until they reach the throat. From here the larvae are swallowed and, thus, finally gain access to the alimentary tract of the host. In the small intestine the larvae molt for the third and final time forming the adult worm, which is the parasitic feeding stage of this worm. In this stage the adult worm targets the intestinal mucosa where it attaches and feeds on both the villi of the epithelium and the blood which it sucks from the blood vessels of the submucosa. The total infective process (skin penetration to intestinal feeding adult) typically requires 1 to 2 months to complete. Adult females and males mate in the host intestine and produce several thousand fertilized eggs per day. N. americanus females will produce up to 10,000 eggs each day, while A. duodenale females can produce three times as many eggs per day. These eggs are passed into the environment with the host's stool and the cycle continues. Below is a nice graph by the Centers for Disease Control and Prevention that depicts the complex life cycle of both hookworm species:
And here is another nice graph by MetaPathogen.com that nicely contextualizes the life cycle within transmission:
The Disease. Most hookworm infections are asymptomatic. When symptoms do occur, they typically involve 1) the subcutaneous migration of the larvae, 2) the larval development within the lungs, and/or 3) the attachment of the adult worms in the small intestine. Subcutaneous larvae migration can cause a hypersensitivity reaction in the course of the migrating worms that produces very itchy lesions on the skin:
Hypersensitivity reactions involving pruritic lesions are more common in hyperendemic areas following repeated infections over time. Larval infection in the lungs can produce cough and hypereosinophilia, and even mimic pneumonia with radiographically apparent chest infiltrates and fever. However, these more severe pulmonary symptoms are also usually only associated with high volume infections. Abdominal pain is the most common intestinal symptom, but irregular stool, with either diarrhea or constipation, and vomiting are also possible presentations. But again, symptomatic gut infection is more common in high volume infections.
The most important clinical consequence of hookworm infection at the population level is anemia. An iron-deficiency anemia results from the blood lost into the lumen of the gut, and which is ultimately passaged in stool, as the adult worms feed in the small intestine. Protein deficiency is also an important consequence of long-term or high volume infection. Because of the iron-deficiency anemia and protein deficiency, chronic hookworm infection is particularly damaging to children, often leading to arrested musculoskeletal growth and cognitive development. As such, children account for a large preponderance of the overall morbidity experienced by a population and so are typically the age group targeted in de-worming campaigns. This is the typical practice even though adults can often acquire higher volume infections under some circumstances. For example, due to the widespread use of human feces as fertilizer in farming among poor agricultural communities, adults working the fields contaminated by hookworm may have much more extensive exposures and subsequent infections.
The Epidemiology and the Landscape. There are likely close to one billion prevalent infections with hookworm in the world today. The vast majority of these occur in sub-Saharan Africa, Southeast, South and East Asia, and parts of South America:
As mentioned above, the morbidity associated with such a high burden of infection is predominantly manifested as impaired physical and cognitive development in children. When this morbidity is translated into disability-adjusted life years we can see below that sub-Saharan Africa and Southeast Asia are saddled with a disproportionate burden of disease, and we can also see that this burden is quite substantive:
Age-standardised disability-adjusted life year (DALY) rates from Hookworm disease by country (per 100,000 inhabitants).
no data
less than 10
10-15
15-20
20-25
25-30
30-35
35-40
40-45
45-50
50-55
55-60
more than 60
The morbidity that attends hookworm infection in areas of high endemicity makes this one of the most significant infections currently affecting humans. This is further highlighted by the fact that this infection is one of the primary neglected tropical diseases, meaning it typically draws little consideration and/or resources in the overall global fight against infectious disease.
The range of hookworm species is determined by important aspects of the physical landscape and because of this, as well as critical overlapping characteristics of the human social landscape, the occurrence of hookworm in humans is distinctly delineated by geographic features. Soil and climate are two critical landscape features that determine the distribution of hookworm species. During the first two larval stages of development in the life cycle of both A. duodenale and N. americanus, the larvae require sandy, loamy soils in order to undergo the first two molts to the L3 stage, which can then infect humans. If the hookworm eggs hatch and find themselves in hard clay soils then the larvae will not reach the L3 developmental stage and thus they cannot infect humans and they cannot complete their life cycle. In addition, the soils must be moist and the temperature must be warm. As such, the specific climatic conditions limit the range of the worms to the tropical and subtropical regions of the world that receive significant amounts of precipitation on an annual basis, while the pedological and edaphological constraints further define the microgeography of these worms. Notice below the global distribution of soil morphology in the map produced by the Natural Resources Conservation Service (NRCS) of the United States Department of Agriculture:
And this NRCS map below depicting the global distribution of soil moisture:
And, finally, the map below by the United Nations Food and Agriculture Organization depicts the global distribution of the annual mean temperature:
It is worth noting how closely the global distribution of hookworm coincides with the global distributions of soil regimes, moisture, and temperature, with one exception: the southeastern Untied States. Indeed, this geographic region was, at one time, highly endemic for hookworm infection. Why no longer? The answer to this question lies within the context of the social landscape of this infection.
There are three important factors from the hookworm life cycle that are critical to the landscape epidemiology of human transmission. First, the eggs pass out into the environment in the feces of the human host. Second, the larvae live in the soil during the first two larval stages of the life cycle. Third, the larvae must make contact with the skin of a new human host. These three factors determine how the social landscape intersects with the physical landscape to enable transmission to humans.
Lack of sanitation infrastructure, and especially a means by which human waste can be removed from sites of human occupation, results in feces being distributed directly in the human environment or in proximal spaces. Conditions of poverty that are associated with the lack of municipal resources for infrastructural development often coincide with a lack of personal resources for adequate clothing. As such, a barefoot lifestyle may be ubiquitous in the same human environments (both the home and places of work) in which hookworm egg-laden human feces are deposited on a daily basis. This leads to an abundance of points of contact for transmission between hookworm larvae and human hosts in those intersecting landscapes of warm, moist, structurally rich soils and conditions of poverty. This intersection currently defines a geography that encompasses, almost exclusively, the developing world. However, this geography did include the southeastern United States where the same intersection of the key physical and social landscapes was present until the early 20th century. When adequate sanitation became widespread in this region of the US, human hookworm largely disappeared.
In many poor subsistence agricultural communities, farmers use human feces as a fertilizer to enhance the growth of their crops. This readily available fertilizer provides a cheap, yet very rich, source of critical nutrients to the soil, which can mean the difference between a crop yield that provides the farmer with a livelihood and a yield that does not. Unfortunately, in areas where hookworm is endemic, the use of human feces as fertilizer means a constant and widespread distribution of hookworm eggs throughout the farming community, and thus a steady source of new infections.
Control and Prevention. Control and prevention of hookworm begins by following the usual guidelines: improving sanitation in resource poor areas. In most settings in the world where hookworm is a significant contributor to morbidity, improved infrastructure that can adequately remove human feces from the spaces of human occupation is a first priority in its prevention.
Where large-scale municipally-resourced sanitation infrastructure is not available, individual pit privies can be constructed for single homes, or clusters of homes. Here is a graphic that depicts the dimensions and structural components of such a privy:
Photo by Peter Byrne
Finally, changing agricultural practices that rely on human feces for fertilization of crops could dramatically help reduce the widespread distribution of hookworm in soils in many agricultural subsistence communities.
Unfortunately this, too, can be a difficult practice to disengage since human feces serves as a very rich fertilizer and, thus, can form a critical component to subsistence farming in many parts of the world where other fertilizers or farming technologies are cost prohibitive. And, of course, without an affordable substitute refraining from human feces fertilization could very well lead to starvation. The massive scope of the problem presented by soil-transmitted helminths in general, and hookworm in particular, should now be coming into focus.
De-worming campaigns do offer some hope, since there are safe, effective, and fairly cheap anti-helminthic drugs available. However, as one might expect, there are obstacles to overcome in de-worming. First, these drugs are not free and, while cheap they may be, without adequate funding poor communities will not be able to prioritize the cost, especially since most infections are generally asymptomatic. Second, effective ways to deliver the de-worming medications to communities need to be implemented, which can be logistically challenging particularly in remote communities or during times of the year when travel may be restricted (i.e. during the rainy season). Third, the extensive use, or misuse, of these drugs will likely lead to antihelminthic-resistance in the worms, thus making the drugs ineffective. Nevertheless, if adequate resources can be put behind de-worming campaigns, and if delivery systems can be adapted to actively engage community members in the delivery and monitoring of these de-worming medications to simultaneously circumvent logistical obstacles and reduce the development of resistance, then substantial reductions in hookworm infections may still be possible.