Filariasis: A Neglected Tropical Disease

The human race is fighting against a lot of diseases, starting from AIDS and cancer to the latest addition of COVID. Recognition and increased scientific research has shown a biased and somewhat inclined awareness towards the same. The number of people aware of a disease like cancer or AIDS is far more exceeding than those having knowledge of a disease like filariasis. Although, this bubble is not only filled with filariasis, but rather consists of several neglected diseases like rabies, onchocerciasis, leishmaniasis, mycetoma and many more. But what’s common in all these apart from them being neglected diseases? They are all common in tropical areas where people do not have access to clean water or safe ways to dispose off human waste and access to healthcare are substandard. And hence, they are all bracketed under Neglected Tropical Diseases.

Introduction

Filariasis is a neglected tropical disease caused by parasitic roundworms belonging to the phyla Aschelminthes and of Filarioidea type. It is a vector borne disease transmitted by the bite of blood feeding insects such as black flies and different species of female mosquitoes. Being a vector borne tropical disease, it apparently connects the link between its abundance in the areas to the favourable climatic conditions of tropic regions where insect diversity and abundance is high. Developing countries like Africa and India lack in case of sanitation, thus providing the poor income civilians with improper medical care and also keeping them unaware in terms of hygiene.

Why filariasis?

Of all the diseases mentioned under NTD, we will be specifically focussing on filariasis, more precisely on lymphatic filariasis, as will be differentiated in further text. The most probable and logical explanation to our selection of filariasis can be its significant abundance in our own country India, and also the negligence which is generally shown for its transmission. It is one of those diseases in which vector and its breeding cycle largely control the transmission rate.

Neglected tropical diseases such as filariasis, dengue, malaria, leishmaniasis, etc. are considered neglected because they severely affect the poor population which are already suffering from a lot of social, medical and physical negligence.

Geographical Distribution:

Lymphatic filariasis(LF) is a neglected tropical disease that can cause permanent disability by infecting the lymphatic system. The most recent estimated population, which is at risk for contraction by LF includes 1.2 billion people. Over 120 million people in 72 countries throughout the tropics and sub-tropics of Asia, Africa, the Western Pacific, and parts of the Caribbean and South America are being diagnosed with LF, which includes 25 million men who suffer from the genital swellings (as in hydrocele; a type of swelling in the scrotum) and 15 million people who suffer from severe lymphodema or elephantiasis of the leg.

The economic burden of lymphatic filariasis is tremendous. Patients who are heavily infected with LF have a high risk of developing chronic symptoms, including lymphodema and elephantiasis. Such symptoms can result in a decrease in productivity, as they can lead to life-threatening infections if not properly cared for. In India alone, it has been estimated that the annual economic loss due to sufferance by LF is $1 billion USD. In nations that are endemic, the economic losses are often not calculated, but likely significant.

Types of filariasis:

Filariasis can be divided into several types based on their site of infection. The three most described types of filariasis are:

• Lymphatic filariasis: As is evident by the name, lymphatic filariasis is the condition when the site of infection for the filarial worms is the lymphatic vessels and the lymph nodes. It is caused by the worms Wuchereria bancrofti, Brugia malayi, and Brugia timori. In chronic cases, these worms lead to the syndrome of elephantiasis.
• Subcutaneous filariasis: These worms occupy the layer just under the skin. It is caused by Loa loa (the eye worm), and Onchocerca volvulus. L. loa causes loiasis, while O. volvulus causes river blindness.
• Serous cavity filariasis: It is caused by the worms Mansonella perstans and Mansonella ozzardi, which occupy the serous cavity of the abdomen.

Life cycle of the vector:

We already mentioned that lymphatic filariasis is a vector borne disease and hence requires mobile carriers like mosquitoes or black flies to transmit the filarial worm through its blood meal. Therefore, it is very important to evaluate and understand the life cycle of the vector (for any vector borne disease) and thereby the infective stages responsible for the infection load in order to eradicate or at least minimise its effect.

Wuchereria bancrofti is the filarial nematode that causes Wuchereriasis or Lymphatic filariasis (commonly called elephantiasis) in human beings. The name of this worm is given Wuchereria bancrofti in honor of the two scientists Wucherer and Bancroft who made a considerable contribution in studying the disease caused by these worms.

Wuchereria bancrofti is a digenetic parasite, meaning it completes its life cycle in 2 different hosts. The primary host is man, which is responsible for harbouring the adult worms; whereas the intermediate host is played by blood-sucking insects such as the female mosquitoes of the genus Culex, Aedes, or Anopheles. When a mosquito bites an infected individual, it sucks the filarial parasite microfilariae from the host along with its blood. The parasite then migrates to the mosquito’s mid gut and further to the thoracic muscles. Thereafter, followed by several moulting processes, the microfilarae advances for the salivary gland of the vector, where it is stored temporarily until the mosquito bites another healthy individual. By biting a healthy individual, the infective parasite (i.e. larval stage 3 microfilarae) reinitiates the chain of sequence and leads to filarial transmission.

The adult filarial worms live coiled up in the lymph glands and lymph passage of humans, where they usually block the flow of lymph and thus result into edema. The larval stage (i.e. microfilariae) on the other hand are found in the peripheral blood and show rhythmicity (which will be explained later in the text). Microfilariae occasionally are also found in chylous urine or in hydrocele fluid but are not the prime source of transmission or spread of infection.

Rhythmicity in filarial worm:

In India, China, and many other Asian countries, the microfilariae are observed to show a nocturnal periodicity in peripheral circulation, which means they are found in large numbers in peripheral blood only at night (between 10 pm and 4 am), but they disappear and hide underneath the blood vessels during the rest of the day. This makes it favourable for their transmission via the night biting vectors like Culex mosquitoes.

While in the Pacific islands and some parts of the Malaysian archipelago, the microfilariae are nonperiodic or diurnal subperiodic, such that they occur in peripheral circulation at all times, with a slight peak during the late afternoon or evening. This makes it favourable for their transmission via the day-biting vector mosquitoes like aedes mosquitoes.

The immunoglobulin crosstalk:

Any infection that involves a host and spends substantial time in its body must be advanced enough to fight against the immune responses of the same. For LF, microfilariae must be efficient and resistant enough to fight off against the immune responses created by humans. Immunoglobulins crosstalk is the term which will validate the parasites survival in the hosts body by explaining the phenomenon of resistance against the generated immune responses.

A normal individual, who is infected by microfilariae larvae, produces IL10 (interleukin 10) via T-regulatory cells. These cytokines (IL10) play a critical role in secretion of IgG4 subtype from the B-cells. The IgG4 subtype is believed to be a non cytolytic antibody and is less able to activate the complement system as compared to its other subtypes like IgG1, IgG2 and IgG3.
The increased IgG4 in case of LF, further competes with IgE, which happens to be a cytolytic antibody and thus, inhibits protective immune response of IgE in case of helminth infection.

However, in certain areas endemic for W. bancrofti, B. malayi, or B. timori, it has been observed that some individuals even after being repeatedly bitten by infective vectors do not develop any significant clinical evidence of infection and thus show immunity against microfilarae. Such individuals are called Endemic Normals. These individual’s immune response develops a resistance against filarial infection. The immunological pathway for the same has been shown via the illustration above.

It is increasingly evident that filarial parasites elicit a wide variety of immune responses, and that the relationship between the natural history of filariasis and the immune responses developed against it requires detailed examination. Ideally, such studies should be longitudinal and should take account of all parameters of immunity. Particular emphasis should be placed on responses to infective third-stage larvae (infective stage in human), the prime target for immunological intervention. Furthermore, we will discuss the effects of treatment with antifilarial drugs on the immunological component of host-parasite interactions and the challenges in vaccine development.

Challenges in Vaccine development:

As of now, there is no definitive cure or vaccine available for filariasis. Of all the possible reasons, the following aspects are considered to be the major hurdle in the way:

• Nature of helminth infection: Parasites migrate through different tissues, maturing from infective larval stages to adult worms, presenting a ‘moving target’ for the immune cells.
• Helminths are generally large: These are large, resilient organisms that may require a sustained and prolonged immune assault, rather than the one-off lethal hit that the immune system can deliver to virus infected cells.
• The complex life cycle of the parasite: The complex life cycle makes it difficult to target a specific antigen. The various moulting processes that lead to change in larval stages, also render changes in the antigen expression. This dynamic nature of antigen makes it difficult to be targeted by a single subunit vaccine.
• Lack of suitable Animals models: Nearly 90% of infections in humans are due to W. bancrofti. However, nearly all the vaccines development studies used the Brugia malayi or Brugia pahangi model to evaluate vaccine efficacy. This is mainly because of the difficulty in maintaining the W. bancrofti life cycle under laboratory conditions in rodents.

Treatment:

The WHO recommended mass drug administration (MDA) for elimination of lymphatic filariasis. However, the drugs used are actually aimed at the bacterial endosymbiont Wolbachia, which is also responsible for generating immune responses in host. The medicines used have a limited effect on adult parasites but effectively reduce the density of microfilariae in the bloodstream by destroying the Wolbachia, thus breaking the mutualistic relationship and prevent the spread of parasites to mosquitoes. WHO recommends the following MDA regimens: 

• Albendazole (400 mg) alone twice per year for areas co-endemic with loiasis. It inhibits the polymerization of worm β-tubulin and microtubule formation.
• Diethylcarbamazine citrate (DEC) (6 mg/kg) and albendazole (400 mg) in countries without onchocerciasis. The probable action of DEC has not yet been discovered.
• Ivermectin (200 mcg/kg) with albendazole (400 mg) in countries with onchocerciasis. Ivermectin acts by hyperpolarization of glutamate-sensitive channels, and was recently shown to block the contractile activity of the excretory/secretory vesicle. As a result, molecules that may modulate the immune response are not released, leaving the microfilariae undefended in the lymph nodes.

Current approaches in Vaccine development:

Nearly all attempts to develop a vaccine against LF with a single antigen (monovalent) gave unsatisfactory results. LF is a multicellular organism that uses multiple approaches to evade host immune responses and survive in the host. Therefore, targeting a single critical antigen will not have the desired effect. 

Subsequent approaches to combine potential vaccine antigens as cocktail vaccines, and multi epitope vaccines or multivalent vaccines, gave excellent results when tested in experimental rodent models. 

Among these, the combination of ALT-2 (alanine transferase), small heat shock protein 12.6 (HSP), thioredoxin peroxidase 2 and tetraspanin large extracellular loop (TSP) as a recombinant multivalent vaccine gave close to 88-94% protection against challenge infections in rodents and about 57% protection against challenge infections in rhesus macaques. To date, this is probably one of the leading prophylactic vaccine formulations for LF.

Conclusion:

The major issue with LF is that it goes undetected for a long period of time, resulting into a great deal of infection load. LF can be asymptomatic, acute and chronic. People who are asymptomatic for the parasitic infection with no external signs and symptoms contribute to high risk of transmission of the disease. This asymptomatic state in an individual causes damage to their lymphatic system, kidneys and finally alters the immune system.

Besides these systemic ups and downs, they also face a major challenge throughout their life of having a disfigured body part which further leads to psychological stress, lack of self confidence and less source of income due to social stigma.

It has been rightly said- “Prevention is better than cure”. This disease apparently requires more of prevention than an after treatment once it enters our body. Therefore, adequate preventive measures should be taken to curtail the reproductive growth of vector (i.e. mosquitoes). A proper well designed pipeline for vaccine development should be proposed and more precise survey should be made in tropical countries to alleviate the cases of filariasis.

References:

• A. Kwarteng & S. T. Ahuno (2017) Immunity in Filarial Infections: Lessons from Animal Models and Human Studies. Scandinavian Journal of Immunology, 2017, 85, 251–257. doi: 10.1111/sji.12533
• Babu S, Nutman TB. Immunology of lymphatic filariasis. Parasite Immunol. 2014 Aug;36(8):338-46. doi: 10.1111/pim.12081. PMID: 24134686; PMCID: PMC3990654.
• Davis, E.L. et al. (2019) Evaluating the evidence for lymphatic filariasis elimination. Trends Parasitol. 35, 860–869
• Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet 2007;369:2021–9.
• Pastor, A.F., Silva, M.R., dos Santos, W.J.T. et al. Recombinant antigens used as diagnostic tools for lymphatic filariasis. Parasites Vectors 14, 474 (2021). https://doi.org/10.1186/s13071-021-04980-3
• Ramaswamy Kalyanasundaram, Vishal Khatri and Nikhil Chauhan (2020) Advances in Vaccine Development for Human Lymphatic Filariasis; Trends Parasitol 36(2): 195-205. doi: 10.1016/j.pt.2019.11.005
• World Health Organization. Progress Report 2000-2009 and Strategic Plan 2010-2020 of the Global Programme to Eliminate Lymphatic Filariasis: Halfway Towards Eliminating Lymphatic Filariasis. (2010).
• Lymphatic filariasis: WHO