Lymphatic Filariasis

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This week at Infections Landscapes, I will cover the last of the nematode infections in this extended helminth series. Lymphatic filariasis, which includes the advanced form, elephantiasis (often incorrectly referred to as elephantitis), causes extensive disability in several tropical and sub-tropical regions of the world. Like onchocerciasis, lymphatic filariasis is caused by filarial worms and is vector-borne.

The Worm. Lymphatic filariasis is caused primarily by three main helminth species in the Onchocercidae family of nematodes: Wuchereria bancrofti, Brugia malayi, and Brugia timori. Approximately 90% of infections are caused by W. bancrofti, while most of the remaining infections are caused by B. malayi (~9%) and B. timori (~1%). Humans are the reservoir for W. bancrofti, while non-human hosts serve as reservoirs for Brugia species, and thus infections with the latter result from zoonotic transmission.

Wuchereria bancrofti

In the human host, the adult worms concentrate in the vessels and nodes of the lymphatic system. Gravid females release motile sheathed microfilariae, which migrate to the peripheral circulation. It takes approximately 6 to 12 months from initial infection to the time when the microfilariae begin to appear in the periphery. These peripheral microfilariae exhibit a fascinating circadian rhythm, wherein they migrate at night into the peripheral blood via the circulation, returning to the arterioles in the lungs during the day. This migration to the periphery aids in the transmission of the microfilariae to the vectors, which are primarily, though not exclusively, night-biting mosquito species. After the microfilariae are ingested by the mosquito, the sheath is lost and they migrate out of the mosquito stomach and into the flight muscle tissues of the thorax. At this loaction, the microfilariae will molt three times, developing into the infectious 3rd stage larvae (L3) after approximately 10 to 20 days. The exact time required is dependent on the density of infection in the mosquito and the local climate conditions at the time of development. Infectious L3 larvae migrate to the proboscis of the mosquito. The larvae are not directly injected into the human host by the mosquito, but rather are deposited on the skin and migrate into the bite wound. The L3 larvae then migrate through subcutaneous tissues to gain the lymphatic system, where they will develop into adults over the course of approximately 1 year. Male and female adults will mate soon after reaching maturity and gravid females subsequently release their motile microfilariae. The following graphic developed by the Centers for Disease Control and Prevention (CDC) nicely depicts the life cycle of the nematodes that cause lymphatic filariasis:

The symbiotic relationship between this helminth and a bacterium constitutes another critical, and fascinating, component to the worm's life cycle. Wolbachia is a genus of bacteria that commonly infects many species of insects, and a few species of nematodes. These ubiquitous bacteria can engage either parasitic or symbiotic relationships with their hosts. In the case of W. bancrofti, L3 larvae cannot complete their adult development without this bacterial infection, and, as such, the helminth's life cycle is arrested in the human host.

Because the vast majority of infections are caused by W. bancrofti, this discussion will focus primarily on bancroftian lymphatic filariasis. However, certain aspects of infections caused the Brugia spp. (i.e. brugian lymphatic filariasis) will be discussed where noted.

The Vector. Mosquitoes are the vectors for the helminths that cause lymphatic filariasis. The species capable of transmitting these filarial nematodes are many and varied, making the medical ecology of lymphatic filariasis extraordinarly complex, and the landscape epidemiology hyperlocal. W. bancrofti is vectored by Culex mosquitoes (primarily Culex quinquefasciatus) in most urban and semiurban areas of the world where this helminth is endemic. However, anopheline mosquitoes are important vectors in rural areas, especially in rural areas of sub-Saharan Africa, and Aedes mosquitoes are important vectors in southeast Asia and the endemic islands of the Pacific. The primary vectors for Brugia nematodes, however, are Mansonia mosquitoes. We'll briefly examine the ecology of each genus of mosquito below, although it is important to keep in mind that the behavior of species within genera can also vary widely, especially for anopheline mosquitoes. 

Culex Mosquitoes

Culex mosquito taking a blood meal

Culex mosquitoes seek out dirty water, rich in decayed nutrients, for oviposition, and lay their eggs on the water's surface in the form of an egg raft. Culex mosquitoes bite primarily at night, and also during the dusky times of dawn and sunset. Different Culex species have very different preferences with respect to their hosts.

Culex life cycle

Culex quiquefasciatus is the most important Culex mosquito vector for lymphatic filariasis. This Culex species is highly anthropophilic, and so prefers to take its blood meals from humans, unlike other Culex vectors that are ornithophilic (e.g. Culex pipiens pipiens). This preference for humans, and stagnant water around human habitation for larval development, make this mosquito's ecology very similar to Aedes aegypti, which is another prominent disease vector for humans. C. quiquefasciatus is responsible for a substantive burden of lymphatic filariasis in South Asia.

Anopheles Mosquitoes

Anopheles gambiae

Anopheline mosquitoes are quite heterogeneous and so exhibit tremendous differences across species in their preference of vertebrate hosts, biting and resting behavior, and selection of sites for oviposition.

Of course, the anopheline mosquitoes require the same transition through four stages of development to complete the life cycle. Here is a comparison between three mosquito genera, with Anopheles on the far left. All four stages of the life cycle are depicted for each genus:

Notice the adult mosquitoes in the picture above. One of the distinguishing features of anopheline mosquitoes is the roughly 45 degree angle their abdomen forms with respect to the surface on which they land. This is unique to Anopheles and can be used to identify the mosquito. Keep in mind however that after taking a blood meal the abdomen will be heavy and weighed down form the extra mass, and so will likely no longer form this distinguishing 45 degree angle.

Most anophelines feed during the night, but some will also feed during the dusky hours of morning and evening. As with with C. quinquefasciatus, the night biting preference of anophelines means that humans are at greatest risk of infection during sleep, when we are at our most vulnerable. Some anopheline species are zoophilic, while other species are anthropophilic. Some anopheline mosquitoes are endophagic, prefering to take their blood meal indoors. Others are exophagic, meaning they prefer to take the blood meal outside. Another important distinction among species is determined by what they do after they take their blood meal. Adding further heterogeneity to this genus, some anopheline species are endophilic rest-ers, meaning they prefer to rest inside, while others are exophilic, which means they prefer to rest outside. This aspect of mosquito behavior is very important for mosquito control efforts, which may include residual spraying and thus would need to target inside or outside the home depending on the resting preference.

Most species of Anopheles mosquitoes prefer to lay their eggs in clean water, which is quite different to the Culex and Aedes species. While this helps to characterize anopheline ecology somewhat, there can still be great differences between individual Anopheles species with respect to their water preferences for oviposition. Here is a depiction of some different potential breeding sites published in: Keating J, Macintyre K, Mbogo CM, Githure JI, Beier JC. Characterization of potential larval habitats for Anopheles mosquitoes in relation to urban land-use in Malindi, Kenya. Int J Health Geogr. 2004 May 4;3(1):9. (PMID: 15125778)

Pictures illustrating the types of habitat identified by strata during this study: (A) Swimming pool in well drained tourist area; (B) Broken water pipe in well drained residential area; (C) Open water tank in poorly drained area; (D) Pond in poorly drained area; (E) Drainage channel in well drained area; and (F) Ditch and tire tracks in poorly drained area.

Let's talk a little more specifically about water preference. For example, Anopheles gambiae one of the most important vectors for transmitting lymphatic filariasis in sub-Saharan Africa. It prefers small sunlit pools, and it's natural habitat is tropical forest. In natural, undisturbed habitat, this mosquito is limited in abundance by the distribution of breaks in the tree canopy that allow the sun to reach the forest floor. However, when habitat is disturbed, due to deforestation or agriculture, for example, much larger areas of land cover become exposed. In this situation any pools of collected rainwater can receive direct sunlight and provide ideal and abundant breeding for A. gambiae. Such habitat disturbances often also coincide with increased human proximity, and so more and more people come into greater contact with more and more of this efficient vector of W. bancrofti. Here are a few CDC pictures of some diverse land cover that A. gambiae can make use of:

Irrigation in forest ecotones

Rice fields

Tire tracks

Aedes Mosquitoes

Aedes aegypti mosquito

A. aegypti mosquitoes have a very particular preference for the water environment it selects for laying its eggs. It likes SMALL containers that collect rainwater. And the mechanics work as follows. This mosquito does not lay its eggs either in the water or on the surface of the water, as most other species do. Instead, A. aegypti lays its eggs above the water on the interior wall of the vessel containing the water so that when the water vessel is refilled, from the water line at which the mosquito laid its eggs to the lip of the vessel, the eggs will have enough time to complete their developmental cycle to adulthood before evaporation depletes the water source. A truly incredible evolutionary adaptation.

This mosquito is originally adapted to a forest habitat wherein it would seek out holes in trees that would regularly collect rainwater. Tree holes are much more ubiquitous than you might think in a forest (think woodpeckers), and so this is quite an effective niche for this mosquito. As humans encroached more and more on forest habitat establishing agriculture, and building increasingly dense communities and living conditions, A. aegypti readily adapted to the new circumstances. The mosquitoes found an abundance of new and highly effective small containers strewn in and around households that can easily collect, or are intended to store, water. The mass production of plastics has been a major factor in the proliferation of potential water containers. Today A. aegypti is just as much an urban mosquito as it is a forest mosquito and probably more so. As such, A. aegypti is now adapted to the human environment. They will often live in the household with humans, and can complete their whole life cycle here. They also bite during the day, so they have unlimited access to humans for taking blood meals. And finally, this mosquito is anthropophilic so its preferred host is humans.

While, A. aegypti is a vector of lesser importance for W. bancrofti across southeast Asia, Aedes polynesiensis is a very important vector of W. bancrofti in the South Pacific Islands of Polynesia, and shares similar characteristics with A. aegypti.

Mansonia Mosquitoes

Adult Mansonia Mosquito

Mansonia mosquitoes are the primary vectors of brugian filariasis, and they are partial to stagnant water, typically in swamp, marsh, or rice field habitats. Mansonia mosquitoes have adopted a unique exploitation of these specific aquatic environments during larval development. The larvae and pupae attach and fix to the aquatic plant stems or roots below the surface of the water, acquiring oxygen directly from these plants:

The Disease. Lymphatic filariasis is comprised of a very wide spectrum of clinical disease. Most endemic infections occur in children and young adults who are asymptomatic. This level of infection is referred to as asymptomatic microfilaremia.

Acute clinical disease can present in several forms. The most common acute presentation (~97%) is acute dermatolymphangioadenitis (ADLA). Fever is a common symptom, often accompanied by some lymphedema at a site (or sites) that is typically associated with lymph centers in the extremities. The draining lymph nodes swell and can become quite sore, possibly with redness and warm skin at the affected area. Depending on the volume of infection and the degree of lymphedema associated with the acute episode, lymphangitis, lymphadenitis and cellulitis are possible sequelae in ADLA. Interestingly, ADLA attacks are largely due to secondary bacterial infections. With high grades of lymphedema, affected limbs are more susceptible to breaches in the skin due cuts, drying cracks, or fungal infections, especially between the toes. Invading bacterial pathogens take advantage of the comprised skin integrity and cause additional infection secondary to the filariasis, ultimately leading to persistent cycles of ADLA. 

Acute filarial lymphangitis occurs when the adult worms die in the host, either naturally or by pharmacological treatment. Nodules form at the lymph centers where the worms die. Lymph nodes can become swollen and painful, and large tracts of the lymphatic system can actually stand out under the skin due to the inflammatory response that follows the death of the worms. These acute episodes are rare, and typically do not present with fever as does ADLA, and neither are they associated with secondary bacterial infection.

Elephantiasis is the primary chronic manifestation of lymphatic filariasis and is strongly associated with ongoing lymphedema and the cycles of ADLA described above. This clinical manifestation is responsible for extraordinary disfigurement and disability in the host. The progression of lymphedema is graded as follows:

Grade 1: Pitting edema, reversible on elevation of the affected limb

Grade 2: Pitting or non-pitting edema that does not reverse on elevation of the affected limb; no skin changes

Grade 3: Non-pitting edema that is not reversible; thickening of the skin

Grade 4: Non-pitting edema that is not reversible; thickening of the skin, with nodular or warty excrescences:

With progressive chronic infection and advanced lymphedema, thickening of the skin also advances until extensive folding occurs in concert with increasing nodular development, and ulceration, ultimately leading to severe disability and immobility:

Hydrocele is another common clinical manifestation of chronic infection with W. bancrofti. This condition results from the accumulation of fluid in the serous membrane surrounding the testes. Swelling increases over the period of the chronic infection and, when left untreated, leads to very large growth of the scrotum. This can be very painful and another severe impediment to mobility:

The pathogenesis of these filarial helminths in the lymphatic system begins with dilation of the lymph vessels where the adult worms are located. This early, often asymptomatic, damage seems to be present among individuals with adult worms as well as those with only microfilariae present. With extended exposure to the worms, the vessel damage proliferates throughout the lymphatics of the affected limb(s). In high volume chronic infection, occlusion of the lymphatic vessels plays a role in the progression to the more profound clinical manifestation of elephantiasis. However, secondary bacterial infection, as described above, likely plays the most important role in the progression of lymphatic filariasis.

The Epidemiology and the Landscape. There are approximately 120 million prevalent infections with the filarial worms that cause lymphatic filariasis, most of which are W. bancrofti. These infections occur in at least 83 countries, where it is estimated that over 1 billion people are at risk for infection. There are approximately 40 million people who experience severe disability due to their lymphatic filariasis. Approximately 1/3 of the cases occur in Africa, 1/3 occur in India, and the remaining 1/3 occur throughout Southeast Asia, the Pacific Islands, and in the Americas. Just four countries alone, India, Bangladesh, Nigeria, and Indonesia, account for 70% of the world's total infections. The map below by the World Health Organization shows the countries that are endemic for lymphatic filarisis:

However the map below, produced by the CDC, depicts a more specific distribution of lymphatic filariasis as it occurs in endemic countries:

The disability-adjusted life years associated with lymphatic filariasis are quite significant:

Age-standardised disability-adjusted life year (DALY) rates from Lymphatic filariasis by country (per 100,000 inhabitants).

   no data

   less than 10

   10-50

   50-70

   70-80

   80-90

   90-100

   100-150

   150-200

   200-300

   300-400

   400-500

   more than 500

Control and Prevention. Unfortunately, the transmission of lymphatic filariasis is not limited to one vector. Rather, there are several genera of mosquitoes capable of transmitting infectious larvae to humans, and these mosquitoes demonstrate extraordinarily different behaviors in the widely varied landscapes they inhabit and ecologies they exploit. As such, while vector control should never be ruled out as a means of blocking transmission, there can also never be a universal approach to vector control that can be expected to be effective. Instead, any such vector control strategies must be hyperlocal, considering the specific mosquito species that transmit infection in the endemic local landscape.

The primary Aedes (A. polynesiensis and A. aegypti) and Culex (C. quiquefasciatus) mosquito vectors can be controlled with vigilant maintenance of open water containers in the home and its surroundings. The emphasis must be placed on "vigilant control" because it takes everyone in a community to be dedicated to eliminating this water source to reduce transmission in most places in the world where lymphatic filariasis is endemic. Pesticides can be used, and they are effective as well, but their application is cost prohibitive to control efforts in most places in the world. Instead, by changing the landscape of the mosquito where that landscape intersects with the human landscape, we can expect some results in transmission reduction where these species are important vectors.

The logistics of Anopheles vector control are not as straightforward. 

Control of anopheline mosquitoes typically is comprised of several domains. The first entails control of breeding sites, i.e. water sources. The second entails control of the larval stage of the mosquito as it lives and develops in the water. The third entails control of the adult mosquitoes, either prior to taking a blood meal or following the blood meal.

Control of breeding sites requires the elimination of viable water sources for Anopheles oviposition. This can be quite a daunting task because of the immense diversity in preferred water habitat across the different species of Anopheles mosquito. Nevertheless, limiting human impact on natural resources, particularly forest transformation, can go a long way. This is, however, a long-term approach that must overcome societal, governmental, and economic constraints that simply may not be amenable to change for the sake of lymphatic filariasis reduction. Nevertheless, more localized efforts may focus on minimizing the number of potential rainwater collection areas in and around areas close to human habitation. The task is still incredibly daunting, especially given the sheer amount of rainfall in tropical climates.

While elimination of water sources suitable to mosquito breeding may not be possible in most circumstances for Anopheles, targeting the water source can still be a viable means to control the mosquito larvae. Instead of eliminating the water source, such interventions take advantage of the larval water environment by introducing agents that can kill the larvae. These may include chemical agents, such as pesticides, but often they may include options that do not pollute potentially important water sources with chemical substances. For example, predatory animals, such as certain kinds of fish or other insects, can be introduced to feed on the larvae and thus reduce the numbers of mosquitoes reaching adulthood.

Here is one researcher who is exploring pathogens and predators as viable non-chemical means of mosquito control:

Notice the emphasis on "natural enemies" for mosquito control. The use of natural enemies is very important as the introduction of an alien, potentially invasive, species may control mosquito populations, but may also have damaging effects on the larger ecosystem.

Control of adult mosquitoes can take various forms depending on when they are targeted with respect to taking the blood meal.

Intercepting the mosquito with insecticide treated bed nets (ITNs) before it can take a blood meal from sleeping humans has become a major staple of malaria intervention, and is also relevant to the control of lymphatic filariasis. ITNs can be quite effective, but they need to be used correctly and they need to be widely distributed, adopted, and correctly maintained in order to translate to reduced transmission. For example, some barriers to ITN effectiveness can be comfort and cleanliness. In many tropical areas, the temperatures are often quite high and the tight mesh of the ITNs typically does not allow much breeze to pass through in the night. As a consequence, sleeping under an ITN can be quite uncomfortable in endemic areas where they are most needed. People may opt for comfort over protection if it improves their sleep. Similarly, the ITNs easily collect dust and become dirty, which means people want to wash the nets regularly. However, if the ITNs are washed without being impregnated again with the insecticide, they will not effectively kill landing mosquitoes and some will be able to access the sleeping person beneath the net.

The resting mosquito offers another point of intervention. You will recall that immediately after taking a blood meal, the mosquito must rest. Some rest indoors and some rest outdoors. Targeted insecticide spraying will aim to cover the resting surfaces of the mosquitoes so that they are killed after taking the blood meal. This will not prevent infection in the person from whom the blood meal was taken, but it will stop transmission by killing the mosquito before it can infect someone else. Residual spraying on walls in the home is a particularly common control measure, though this is of course limited to endophilic Anopheles species. However, residual spraying can be quite effective against A. aegypti and C. quinquefasciatus, which are more likely to reside in or close to the human residence. Targeting of exophilic anopheline mosquitoes is more difficult because potential resting surfaces are much more dispersed in the outside environment.

Chemotherapy/chemoprophylaxis is another major component of control and prevention of lymphatic filariasis. Indeed, while vector control by itself, or in concert with de-worming drugs, is implemented in some settings, prophylaxis has become the foundation for most elimination efforts. This is largely due to the problems described above with widely varied vector control initiatives requiring hyperlocalized implementation to interrupt transmission in distinct ecologic niches. The Global Programme for the Elimination of Lymphatic Filariasis (PELF) was launched following the resolution of the World Health Assembly to eradicate this disease. Treatment and chemoprophylaxis with one of two drug regimens comprise the primary approach to this initiative. The first regimen is albendazole plus diethylcarbamazine, and the second is albendazole plus ivermectin. The implementation of these regimens, without specific universal vector control (although vector control in specific geographic locations can often supplement the de-worming campaigns), constitute the current major global eradication initiative under PELF.