Filariasis pathophysiology: Difference between revisions

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Latest revision as of 21:46, 29 July 2020

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

The pathogenesis of lymphedema and its progression to elephantiasis is controversial. Factors involved in the clinical manifestations of filariasis include:^[1]^[2]^[3]^[4]^[5]^[6]

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	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. 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

A mutation in the vascular endothelial growth factor receptor 3 (VEGFR-3) is associated with development of primary lymphedema secondary to dysfunction of the endothelial cells and impaired lymphangiogenesis.^[3]^[7]
Mutation in the forkhead transcription factor (FOXC2) also leads to hereditary lymphedema.

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.^[8]^[9]^[10]^[11]

Type of filariasis	Causative nematode	Vectors	Life Cycle
Lymphatic filariasis	Wuchereria bancrofti	Culex as C. pipiens Aedes as A. aegypti Anopheles as A. arabinensis Coquillettidia.as C. juxtamansonia	Source: https://www.cdc.gov/
Lymphatic filariasis	Brugia timori and Brugia malayi	Mansonia Aedes	Source: https://www.cdc.gov/
Subcutaneous filariasis	Loa loa filaria	Chrysops C. silacea C. dimidiata	Source: https://www.cdc.gov/
	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)	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

↑ Chandy A, Thakur AS, Singh MP, Manigauha A (2011). "A review of neglected tropical diseases: filariasis". Asian Pac J Trop Med. 4 (7): 581–6. doi:10.1016/S1995-7645(11)60150-8. PMID 21803313.
↑ Taylor MJ (2002). "A new insight into the pathogenesis of filarial disease". Curr Mol Med. 2 (3): 299–302. PMID 12041732.
↑ ^3.0 ^3.1 Lammie PJ, Cuenco KT, Punkosdy GA (2002). "The pathogenesis of filarial lymphedema: is it the worm or is it the host?". Ann N Y Acad Sci. 979: 131–42, discussion 188-96. PMID 12543723.
↑ Babu S, Nutman TB (2012). "Immunopathogenesis of lymphatic filarial disease". Semin Immunopathol. 34 (6): 847–61. doi:10.1007/s00281-012-0346-4. PMC 3498535. PMID 23053393.
↑ Cross HF, Haarbrink M, Egerton G, Yazdanbakhsh M, Taylor MJ (2001). "Severe reactions to filarial chemotherapy and release of Wolbachia endosymbionts into blood". Lancet. 358 (9296): 1873–5. doi:10.1016/S0140-6736(01)06899-4. PMID 11741630.
↑ Kar SK, Mania J, Kar PK (1993). "Humoral immune response during filarial fever in Bancroftian filariasis". Trans R Soc Trop Med Hyg. 87 (2): 230–3. PMID 8337737.
↑ Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA; et al. (2000). "Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema". Nat Genet. 25 (2): 153–9. doi:10.1038/75997. PMID 10835628.
↑ CDC https://www.cdc.gov/dpdx/mansonellosis/index.html Accessed on June 27, 2017
↑ CDC https://www.cdc.gov/parasites/lymphaticfilariasis/biology_w_bancrofti.html Accessed on June 27, 2017
↑ CDC https://www.cdc.gov/parasites/loiasis/biology.html Accessed on June 27, 2017
↑ CDC https://www.cdc.gov/parasites/loiasis/biology.htmlhttps://www.cdc.gov/parasites/onchocerciasis/biology.html Accessed on June 27, 2017

Template:WikiDoc Sources

[pmid21803313-1] Chandy A, Thakur AS, Singh MP, Manigauha A (2011). "A review of neglected tropical diseases: filariasis". Asian Pac J Trop Med. 4 (7): 581–6. doi:10.1016/S1995-7645(11)60150-8. PMID 21803313.

[pmid12041732-2] Taylor MJ (2002). "A new insight into the pathogenesis of filarial disease". Curr Mol Med. 2 (3): 299–302. PMID 12041732.

[pmid12543723-3] 3.0 ^3.1 Lammie PJ, Cuenco KT, Punkosdy GA (2002). "The pathogenesis of filarial lymphedema: is it the worm or is it the host?". Ann N Y Acad Sci. 979: 131–42, discussion 188-96. PMID 12543723.

[pmid23053393-4] Babu S, Nutman TB (2012). "Immunopathogenesis of lymphatic filarial disease". Semin Immunopathol. 34 (6): 847–61. doi:10.1007/s00281-012-0346-4. PMC 3498535. PMID 23053393.

[pmid11741630-5] Cross HF, Haarbrink M, Egerton G, Yazdanbakhsh M, Taylor MJ (2001). "Severe reactions to filarial chemotherapy and release of Wolbachia endosymbionts into blood". Lancet. 358 (9296): 1873–5. doi:10.1016/S0140-6736(01)06899-4. PMID 11741630.

[pmid8337737-6] Kar SK, Mania J, Kar PK (1993). "Humoral immune response during filarial fever in Bancroftian filariasis". Trans R Soc Trop Med Hyg. 87 (2): 230–3. PMID 8337737.

[pmid10835628-7] Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA; et al. (2000). "Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema". Nat Genet. 25 (2): 153–9. doi:10.1038/75997. PMID 10835628.

[Mansonellosis-8] CDC https://www.cdc.gov/dpdx/mansonellosis/index.html Accessed on June 27, 2017

[Lymphatic_filariasis-9] CDC https://www.cdc.gov/parasites/lymphaticfilariasis/biology_w_bancrofti.html Accessed on June 27, 2017

[Loiasis-10] CDC https://www.cdc.gov/parasites/loiasis/biology.html Accessed on June 27, 2017

[Onchocerciasis-11] CDC https://www.cdc.gov/parasites/loiasis/biology.htmlhttps://www.cdc.gov/parasites/onchocerciasis/biology.html Accessed on June 27, 2017

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@@ Line 20: / Line 20: @@
 |[[Immune response]] of the host
 |
-* Several studies show that there is a strong correlation between the host [[immune response]] and [[lymphoedema|lymphedema]] development.
+* There is a strong correlation between the host [[immune response]] and [[lymphoedema|lymphedema]] development.
 * Patients with [[lymphedema]] mount a higher immune response when compared to those with [[Microfilaria diurnal|microfilariae]] just circulating in the [[blood]].
 * It is believed that the role of the [[Immune system|immune response]] in the development of the lymphedema leads to [[inflammation]] and [[obstruction]] of the [[lymphatic vessels]].
@@ Line 36: / Line 36: @@
 |
 * [[Nematodes|The round worms]] causing filariasis are carriers of a kind of [[bacteria]] called [[Wolbachia]] that is released after the death of the [[Worm|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]].
+* 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 [[Protein|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]].<ref name="pmid12543723">{{cite journal| author=Lammie PJ, Cuenco KT, Punkosdy GA| title=The pathogenesis of filarial lymphedema: is it the worm or is it the host? | journal=Ann N Y Acad Sci | year= 2002 | volume= 979 | issue=  | pages= 131-42; discussion 188-96 | pmid=12543723 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12543723  }} </ref>
+*A mutation in the [[Vascular endothelial growth factor|vascular endothelial growth factor receptor 3 (VEGFR-3)]] is associated with development of [[primary lymphedema]] secondary to [[dysfunction]] of the [[endothelial cells]] and [[impairment|impaired]] [[lymphangiogenesis]].<ref name="pmid12543723">{{cite journal| author=Lammie PJ, Cuenco KT, Punkosdy GA| title=The pathogenesis of filarial lymphedema: is it the worm or is it the host? | journal=Ann N Y Acad Sci | year= 2002 | volume= 979 | issue=  | pages= 131-42; discussion 188-96 | pmid=12543723 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12543723  }} </ref><ref name="pmid10835628">{{cite journal| author=Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA et al.| title=Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. | journal=Nat Genet | year= 2000 | volume= 25 | issue= 2 | pages= 153-9 | pmid=10835628 | doi=10.1038/75997 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10835628  }} </ref>
-*It is found that patients who develop [[primary lymphedema]] have a mutation in [[gene]] of the [[Vascular endothelial growth factor|vascular endothelial growth factor receptor 3 (VEGFR-3)]]. This will lead to [[dysfunction]] of the [[endothelial cells]] and [[impairment|impaired]] [[lymphangiogenesis]].<ref name="pmid10835628">{{cite journal| author=Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA et al.| title=Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. | journal=Nat Genet | year= 2000 | volume= 25 | issue= 2 | pages= 153-9 | pmid=10835628 | doi=10.1038/75997 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10835628  }} </ref>
+*Mutation in the [[FOXC2|forkhead transcription factor (FOXC2)]] also leads to [[hereditary lymphedema]].
-*Mutation in the [[FOXC2|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====
@@ Line 53: / Line 51: @@
 !Causative nematode
 !Vectors
-!Life cycle
+!Life Cycle
-!Illustrative image
-!Distinctive features
 |-
 | rowspan="2" |Lymphatic filariasis
@@ Line 64: / Line 60: @@
 *  [[Anopheles]] as ''A. arabinensis''
 * Coquillettidia.as ''C. juxtamansonia''
-| rowspan="2" |
+| rowspan="2" |[[Image:W bancrofti LifeCycle.gif|500px|thumb|center|Source: https://www.cdc.gov/]]
-* [[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]].
-| rowspan="2" |[[Image:W bancrofti LifeCycle.gif|350 px|thumb|center|Source: https://www.cdc.gov/]]
-| rowspan="2" |
-* The difference between the [[nematodes]] causing lymphatic filariasis is in the shape and size of the [[worm]].
-* The [[Brugia malayi|Brugia worms]] are similar to the [[Wuchereria bancrofti|W. bancrofti]] but smaller.
 |-
 |[[Brugia timori]] and [[Brugia malayi]]
@@ Line 88: / Line 73: @@
 * ''C. silacea''
 * ''C. dimidiata''
-| rowspan="4" |
+| rowspan="4" |[[Image:L loa LifeCycle.gif|500px|center|thumb|Source: https://www.cdc.gov/]]
-* 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 [[Microfilaria diurnal|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.
-| rowspan="4" |[[Image:L loa LifeCycle.gif|350 px|center|thumb|Source: https://www.cdc.gov/]]
-| rowspan="4" |
-* 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 [[Lymphatic|lymphatics]] of [[connective tissue]].
 |-
 |[[Mansonella streptocerca|''Mansonella streptocerca'']]
@@ Line 119: / Line 92: @@
 * Midge (genus Culicoides)
 * Blackfly (genus Simulium)
-|
+|[[Image:M perstans LifeCycle.gif|500px|center|thumb|Source: https://www.cdc.gov/]]
-* 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 [[Microfilaria diurnal|microfilariae]] that reaches the [[blood stream]].
-* Another midge ingests microfilariae during a [[blood]] meal.
-* After [[ingestion]], the [[Loa loa filariasis|microfilariae]] migrate from the midge's [[midgut]] through the [[hemocoel]] to the thoracic muscles of the [[arthropod]].
-* [[Loa loa filariasis|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.
-|[[Image:M perstans LifeCycle.gif|350 px|center|thumb|Source: https://www.cdc.gov/]]
-|
 |}
@@ Line 137: / Line 101: @@
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