What is Lymphatic Filariasis (LF)?

Lymphatic filariasis (LF) is caused by a group of parasitic worms that are transmitted through the bites of infected mosquitoes. Although the majority of people infected with these parasites are asymptomatic, slow damage to the lymphatic system and other organs from chronic infection leads to a variety of pathologies ranging from sub-clinical damage through severe disfigurement. The most well recognized manifestation of LF is elephantiasis, the swelling of the limbs or genitals with lymph fluid that results from total blockage of the lymphatic system by adult worms.

Global Burden

Lymphatic Filariasis (LF)

LF is estimated to affect more than 120 million people worldwide, 98% of whom live in the tropical and subtropical regions of Africa and Asia.1 There are 72 countries with endemic LF and a total population of more than 1.3 billion at risk for infection.2 Approximately one third of infected individuals have physical manifestations of elephantiasis.

Physical disabilities due to elephantiasis and other chronic organ damage result in the loss of nearly 6 million DALYs per year as summarized in the table below. The greatest impact is in Asia followed by Africa.

WHO Region DALY (in thousands)3
Africa 2,263
Americas 10
Eastern Mediterranean 75
Southeast Asia 3,525
Western Pacific 65
Total: 5,938

In 1997, the World Health Assembly called for a resolution to eliminate LF as a global health problem within 20 years. As a result, the World Health Organization (WHO) launched the Global Program to Eliminate Lymphatic Filariasis (GPELF) in 2000 with the goal of eliminating LF by the year 2020.

LF is estimated to result in the loss of almost US$1.3 billion per year in productivity.2

Causative Agent

pathogen

LF is caused by three species of filarial worms (a subset of roundworms and other helminths):Wuchereria bancroftiBrugia malayi, and Brugia timori. Nearly 90% of all infections are caused by W. bancroftiBrugia spp. are far less common and are more restricted to Asia, especially India, Malaysia, Indonesia, and the Philippines. Larvae of all three species are transmitted to humans through the bite of an infected mosquito.

Upon taking a blood meal, an infected mosquito introduces larvae of the parasite into the skin. The larvae migrate through the skin to the lymphatic system where they mature into adult male and female worms over the course of 6-12 months. The term macrofilariae describes the adult worms. The term "filariae" means "thread-like," an appropriate description for a parasite where female adult worms can grow up to 10 cm in length. The adult male and female worms continue to reside in the lymphatics where they mate and produce large numbers of larvae, called microfilariae. The microfilariae circulate in the blood stream where they can be picked up by a biting mosquito. Adult worms can live for many years, continuously producing microfilariae and contributing to ongoing transmission of the disease.

life cycleUnlike many other vector-borne parasitic diseases, where parasites are only transmitted by a very narrow range of vector species, LF parasites are transmitted by many species of mosquitoes across the genera of CulexAedes,Anopheles, and Mansonia. Mosquitoes become infected when taking a blood meal from a person with circulating microfilariae. Within the mosquito, the microfilariae egg hatches and the parasite begins larval development. Larvae are then injected into the skin of another human when the infected mosquito takes a blood meal. There is no animal reservoir for the parasites that cause human LF, so mosquitoes transmit parasites from humans to humans.

 

Pathogenesis

Adult worms, or macrofilariae, cause long-term damage to the vessels of the lymphatic system. The strong inflammatory response to the presence of adult worms causes dilation, thickening, and eventually incompetence of lymph vessels. This damage results in lymphedema or swellings of the limbs due to accumulation of lymphatic fluids, thus producing the classic presentation of elephantiasis. Of those infected with LF parasites, approximately 20% (predominantly men) have genital manifestations of disease and an additional 13% (predominantly women) have elephantiasis or lymphedema of the leg, although any part of the leg can be affected.4

Beyond classic elephantiasis, imbalances in the lymphatic system due to LF can cause damage to multiple organs. Nearly 40% of those affected by LF have measurable kidney damage.4

Current Control Strategy

The current control strategy for LF is guided by the GPELF and includes:

  1. Extensive mapping to understand the full extent of the burden of LF
  2. Mass drug administration (MDA)
  3. Integration of LF control programs with other neglected tropical disease control programs
  4. Vector control

Mapping is being used to help guide control programs and determine optimal interventions for different countries or regions. The global status of LF has been mapped for 68 of the 81 endemic countries and mapping is ongoing to 10 additional countries, and 9 countries have been declared free of LF. Mapping remains challenging in several countries. Areas with extreme government instability, limited infrastructure, and the potential for violence against surveyors are difficult to access to conduct surveys and analysis.

Vector control for LF, focusing on indoor residual spraying and the use of long lasting insecticide treated nets (LLITNs), overlaps with vector control strategies for other diseases such as malaria. In countries with both malaria and LF, particularly in Africa, integrated strategies for vector management are poised to benefit control programs for both diseases.

MDA is the cornerstone of the LF elimination program. The goal is to target all individuals, including children, in endemic areas to take a once yearly dose of a combination of two medications for 4-6 years or to use drug-fortified table salt for 1-2 years (see next section on Existing Products: Drugs for details of these medications). The rationale is that by decreasing the number of microfilariae circulating in the human population, transmission of parasites to mosquitoes will be interrupted followed by interruption of transmission to humans. MDA programs began in 2000 with the help from drug donations from GlaxoSmithKline (GSK) and Merck. Cumulatively since 2000, over 2.8 billion MDA doses have been given in 53 endemic countries.5

Both vector control and MDA overlap with strategies being employed for other neglected tropical disease control programs. Better integration of activities across programs with different disease focuses will help ensure that resource use is optimized to provide the greatest health benefit.

Existing Products

Drugs

There are three drugs currently in use for the treatment of LF: albendazole (GSK), ivermectin (Merck), and diethylcarbamazine (DEC) (Eisai and others). Albendazole is administered in combination with either ivermectin or DEC through MDA programs. DEC is also used in fortified salt for use in cooking as an alternative MDA strategy. Both albendazole and ivermectin are donated by GSK and Merck for MDA programs, and Sanofi, Eisai, and the Bill & Melinda Gates Foundation recently committed to donating DEC tablets from 2012-2020.7 The estimated cost for one MDA dose per person is US$0.05-0.10.2

Although these drugs are highly effective in removing microfilariae from the blood, there are several limitations:

  1. None of these three drugs kills the adult worms requiring retreatment each year until the adult worm dies
  2. DEC cannot be used in regions with co-endemic onchocerciasis (a related filarial worm) due to the risk of serious side effects
  3. Ivermectin cannot be used in regions with co-endemic Loa loa disease (a related filarial worm) due to the risk of serious side effects

Vaccines

There is currently no vaccine for the prevention of LF.

Diagnostics

Diagnosis of LF is primarily done through immunochromatographic cards test kits. These kits rapidly detect antigen in blood samples collected during MDA treatment programs. When parasite antigen is no longer detectable in the blood of a sampling of patients in a village, decisions regarding stopping MDA in that village can be made. There are three disadvantages to this test: 1) the test only detects W. bancrofti, 2) the test costs US$2-4 per person which is too expensive to support programs actively treating more than 380 million people per year5, and 3) people may still test positive after worm death. Since people can still test positive even after worm death, many programs rely on testing the children of treated individuals to verify that transmission was blocked .

Traditional diagnosis of LF is conducted by microscopy to detect circulating microfilariae. As the microfilariae primarily circulate at night (~10pm-2am), it is not easy to obtain appropriate blood samples to evaluate by microscopy. Furthermore, microscopy requires equipment and a trained technician which are not practical for accompanying MDA programs to rural areas. Finally, the test may give a false negative result of infection status because even though microfilariae are killed by treatment, this does not mean that the adult worm is dead.

References

  1. WHO Lymphatic Filariasis.
  2. WHO (2010) First WHO report on neglected tropical diseases 2010: working to overcome the global impact of neglected tropical diseases.
  3. WHO (2004) Global Burden of Disease.
  4. WHO Lymphatic Filariasis.
  5. WHO (2010) Progress report 2000-2009 and strategic plan 2010-2020 of the global programme to eliminate lymphatic filariasis: halfway towards eliminating lymphatic filariasis.
  6. WHO Fact Sheet (Jan 2012)
  7. Uniting to Combat Neglected Tropical Diseases (Jan 2012). Table of Commitments.

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Drugs

Analysis

There are no new drugs in clinical development for LF. Instead, efforts are focused on increasing access and distribution of existing drugs through MDA programs. There are some ongoing clinical trials to evaluate alternative uses of existing drugs — albendazole, ivermectin, and DEC — alone and different combinations with each other. Many of these are managed by the Death to Onchocerciasis and Lymphatic Filariasis (DOLF) consortium.

There are two discovery stage drug development programs for LF focusing on identification of new drugs that can kill the adult form of the worm, i.e., macrofilaricides. Killing the adult worm would prevent production of new microfilariae rather than just killing currently circulating microfiliariae. This process would speed the progress toward elimination by reducing the number of rounds of MDA required to stop transmission of the parasite. This strategy may be particularly beneficial in countries with government instability, conflict, or other factors limiting the implementation of multi-year MDA programs with existing drugs. However, rapid death of the adult worm may be associated with adverse events due to inflammation, especially in untreated populations. A balance will need to be maintained between the added benefits of killing the adult and the potential safety concerns of increased adverse reactions.

Vaccines

Analysis

Although there are discovery programs underway to assess antigens for potential vaccine development, the extremely low cost of current medications and the huge at risk population that would need to be vaccinated would suggest development and rollout of a vaccine  — which face long development timelines — would be far less cost effective than continuing to scale up MDA. Furthermore, LF is currently targeted for elimination by 2020 without the use of a vaccine.

As with new drug development, a vaccine that could block the production of new microfilariae would have value beyond existing tools to fight LF. It might also be easier to produce than a fully preventive vaccine. Again, the high cost of new vaccine development relative to the cost of scaling up of existing MDA programs is likely to be prohibitive.

Diagnostics

Future generations of LF diagnostics should be less expensive, detect both W. bancrofti and Brugia spp. parasites, and would preferably work with urine or saliva samples in place of blood to simplify use. Antibody-based diagnostics may be a better tool to detect exposure and potential re-emergence of disease while the elimination efforts move forward.

References

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The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for lymphatic filariasis. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The tools for lymphatic filariasis are extremely limited.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome: Draft genome, Brugia malayionly Genome sequences for symbiotic wolbachia bacteria (potential alternative drug target)

Key databases:GenBank:AAQA00000000 (B. malayi) and AE017321(wolbachia) 

In vitro culture: Yes,B. malayi

Gene knock-outs: No

Conditional gene knock-outs: No 

Transposon mutagenesis: No 

RNAi: No

Other antisense technology:  No 

Viability assays:  Yes,B. malayi 

Transcription microarrays: Yes, B. malayi 

Proteomics: Yes, B. malayi 

Crystal structures:  Yes, limited

Whole-cell screening assays: No 

Enzymatic screening assays:  Minimal

Animal models:  Limited, B. malayi in Mongolian jird, ferret, or immune deficient mouse

Monitoring treatment efficacy: Yes

Availability of endpoints: Partial, clearance of microfilariae, clearance of antigen via ICT

Availability of surrogate endpoints: No 

Access to clinical trial patients/sites: Yes

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: No 

Detection of endogenous antigen specific response in clinical samples: Yes 

Natural immunity well characterized: Minimal understanding

Surrogate markers of protection: No

Challenge studies possible: No

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes, microfilariae

Access to clinical samples: Yes, possible from MDA program monitoring 

Possible sample types: Blood, urine, or saliva would be preferred but not well explored

Access to clinical trial patients/sites: Yes

Treatment available if diagnosed: Yes

References

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