Filariasis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2], Ahmed Elsaiey, MBBCH [3]

Overview

Filariasis infection occurs when a larva carrying mosquito bites an individual, introducing these larvae into the skin. The larvae then enters the patient's blood through the skin wound and spread to the different sites such as lymphatic vessels, subcutaneous tissues or the serous cavities. At these sites, the larvae matures in a six to twelve months period into the adult filariae which can live up to fifteen years. Reproduction takes place between the male and female adult worms producing microfilariae which are premature organisms with sheath that circulate the blood in case they are settled in the lymphatic vessels. During another blood meal, the mosquito takes up the microfilariae, then these microfilariae lose their sheath within two weeks to be larvae that enter the human body. When a human is bitten by a mosquito, the cycle restarts again. Pathogenesis of the disease depends on number of factors including immune response of the patient, the number of secondary bacterial infections, the accumulation of the worm antigens, release of Wolbachia bacteria from the worm and the genetic predisposition.

Pathophysiology

Pathogenesis

• Pathogenesis of developing lymphedema and its progression to elephantiasis is controversial. A study conducted to completely understand the pathogenesis of the disease showed that some factors have an obvious impact in development of the filariasis clinical manifestations. These factors include:
  • Immune response of the patient
  • The number of filarial and bacterial infection
  • The accumulation of the worm antigen in the lymphatic vessels
  • The release of Wolbachia bacteria following death of the worm

Factor	Role in pathogenesis
Immune response of the host	Several studies show that there is a strong correlation between the host immune response and lymphedema development. Patients with lymphedema mount a higher immune response when compared to those with microfilariae just circulating in the blood. It is believed that the role of the immune response in the development of the lymphedema leads to inflammation and obstruction of the lymphatic vessels. Infection by filariasis induces cell mediated immunity in response to the filarial antigens. This leads to the production of cytokines and interleukins. High levels of immunoglobulins (IgG1,2,3) have been detected in patients with lymphedema which increases the evidence of the role of the immune response in pathogenesis of the disease.
Secondary bacterial infections	Adenolymphangitis is a result of the inflammation induced by the filarial infection and the immune response. It is believed that it worsens the disease and leads to morbidity. It affects the lower limbs resulting in cord like lesion of the lymphatic vessels and worsening of the filariasis.
Wolbachia bacteria	The round worms causing filariasis are carriers of a kind of bacteria called Wolbachia that is released after the death of the worms. It has been found that there is a correlation between Wolbachia bacteria and the inflammatory reactions in cases of filariasis especially in the phase of treatment by chemotherapy that ends with lymphedema. Immunologically, serum antibodies released against Wolbachia surface protein may also play a role in the development of the lymphedema.

Genetics

• Studies have been held to detect the genetic predisposition probability in patients developing lymphedema.
• It is found that patients who develop primary lymphedema have a mutation in gene of the vascular endothelial growth factor receptor 3 (VEGFR-3). This will lead to dysfunction of the endothelial cells and impaired lymphangiogenesis.
• Mutation in the forkhead transcription factor (FOXC2) also leads to hereditary lymphedema and forms impaired protein.
• The last two genetic mutations increase the possibility of filarial lymphedema to be genetically related and increase the risk of disease occurrence among the same family members.

Life cycle of filariasis nematodes

In order to understand how filariasis could occur, it is important to know the life cycles of different nematodes causing filariasis. Through this table the important steps in the worms life cycle is discussed as well as the vectors responsible for disease transmission.

Type of filariasis	Causative nematode	Vectors	Life cycle	Illustrative image	Distinctive features
Lymphatic filariasis	Wuchereria bancrofti	Culex as C. pipiens Aedes as A. aegypti Anopheles as A. arabinensis Coquillettidia.as C. juxtamansonia	Infected mosquito bite introduces the third stage larva onto the skin and then enters to the blood through the wound. The larvae develop to adult which reside in the lymphatic vessels. Adult worm produce sheathed microfilariae that migrate to lymph and blood. They have nocturnal periodicity. Another mosquito ingests the microfilariae. The microfilariae lose their sheaths and work their way through the wall of the proventriculus and cardiac portion of the midgut to reach the thoracic muscles. Microfilariae mature inside the mosquito till third stage larvae. In another bite to a host skin the mosquito introduces the larvae onto the skin.	Source: https://www.cdc.gov/	The difference between the nematodes causing lymphatic filariasis is in the shape and size of the worm. The Brugia worms are similar to the W. bancrofti but smaller.
	Brugia timori and Brugia malayi	Mansonia Aedes
Subcutaneous filariasis	Loa loa filaria	Chrysops C. silacea C. dimidiata	Infected fly bite introduces the third stage larva onto the skin and then enters to the blood through the wound. The larvae develop to adult which reside in the subcutaneous tissue. Loa loa adult worm produce sheathed microfilariae that are found in the blood during day and in the lungs during the non circulating phase. They have diurnal periodicity. Another fly ingests the microfilariae. After ingestion, the microfilariae lose their sheaths and migrate from the fly's midgut through the hemocoel to the thoracic muscles of the arthropod. Microfilariae mature inside the fly till third stage larvae. The third-stage infective larvae migrate to the fly's proboscis and in another bite the cycle restarts.	Source: https://www.cdc.gov/	Unlike Loa loa filaria, Mansonella streptocerca , Mansonella ozzardi and Onchocerca volvolus produce unsheathed non-periodic microfilariae. Mansonela streptocerca adults residue in the dermis. Onchocerca volvulus adults residue mainly in the subcutaneous nodules. Their microfilariae can be found in the peripheral blood, urine, and sputum but are typically found in the skin and in the lymphatics of connective tissue.
	Mansonella streptocerca	Midge (genus Culicoides)
	Mansonella ozzardi	Midge (genus Culicoides)
	Onchocerca volvulus	Blackfly (genus Simulium)
Serous cavity filariasis	Mansonella perstans	Midge (genus Culicoides) Blackfly (genus Simulium)	Infected midget bite introduces the third stage larva onto the skin and then enters to the blood through the wound. The larvae develop to adult which reside in the different body cavities like peritoneal cavity, pleural cavity, and less frequently in the pericardium. Adult worm produce unsheathed subperiodic microfilariae that reaches the blood stream. Another midge ingests microfilariae during a blood meal. After ingestion, the microfilariae migrate from the midge's midgut through the hemocoel to the thoracic muscles of the arthropod. Microfilariae mature inside the midge till third stage larvae. The third-stage infective larvae migrate to the midge's proboscis and in another bite the cycle restarts.	Source: https://www.cdc.gov/

Microscopic pathology

This video gives a brief explanation on the possible histopathological findings of soft tissue sample of case of filariasis: {{#ev:youtube|67zC7mXigpY}}

References

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