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{{Filariasis}}
{{Filariasis}}
{{CMG}} {{AE}} {{KD}}
{{CMG}}; {{AE}} {{KD}}, {{AEL}}
 
==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 [[Wound|skin wound]] and spread to the different sites such as [[lymphatic vessels]], [[Subcutaneous tissue|subcutaneous tissues]] or the [[Serous cavity|serous cavities]]. At these sites, the larvae matures in a six to twelve months period into the adult [[Filaria|filariae]] which can live up to fifteen years. [[Reproduction]] takes place between the [[male]] and [[female]] adult [[Worm|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 [[Mosquitoes|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 [[Antigen|worm antigens]], release of [[Wolbachia]] [[bacteria]] from the [[worm]] and the [[genetic predisposition]].
 
==Pathophysiology==
==Pathophysiology==
Infective larvae are transmitted by infected biting arthropods during a blood meal.  The larvae migrate to the appropriate site of the host's body, where they develop into microfilariae-producing adults. The adults dwell in various human tissues where they can live for several years.  The agents of lymphatic filariasis reside in lymphatic vessels and lymph nodes; Onchocerca volvulus in nodules in subcutaneous tissues; Loa loa in subcutaneous tissues, where it migrates actively; Brugia malayi in lymphatics, as with Wuchereria bancrofti; Mansonella streptocerca in the dermis and subcutaneous tissue; Mansonella ozzardi apparently in the subcutaneous tissues; and M. perstans in body cavities and the surrounding tissues.  The female worms produce microfilariae which circulate in the blood, except for those of Onchocerca volvulus and Mansonella streptocerca, which are found in the skin, and O. volvulus which invade the eye. The microfilariae infect biting arthropods (mosquitoes for the agents of lymphatic filariasis; blackflies [Simulium] for Onchocerca volvulus; midges for Mansonella perstans and M. streptocerca; and both midges and blackflies for Mansonella ozzardi; and deerflies [Chrysops] for Loa loa).  Inside the arthropod, the microfilariae develop in 1 to 2 weeks into infective filariform (third-stage) larvae. During a subsequent blood meal by the insect, the larvae infect the vertebrate host.  They migrate to the appropriate site of the host's body, where they develop into adults, a slow process than can require up to 18 months in the case of Onchocerca.
===Pathogenesis===
===Life Cycle of Wuchereria Bancrofti===
The pathogenesis of [[lymphedema]] and its progression to [[elephantiasis]] is controversial. Factors involved in the clinical manifestations of filariasis include:<ref name="pmid21803313">{{cite journal| author=Chandy A, Thakur AS, Singh MP, Manigauha A| title=A review of neglected tropical diseases: filariasis. | journal=Asian Pac J Trop Med | year= 2011 | volume= 4 | issue= 7 | pages= 581-6 | pmid=21803313 | doi=10.1016/S1995-7645(11)60150-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21803313  }} </ref><ref name="pmid12041732">{{cite journal| author=Taylor MJ| title=A new insight into the pathogenesis of filarial disease. | journal=Curr Mol Med | year= 2002 | volume= 2 | issue= 3 | pages= 299-302 | pmid=12041732 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12041732 }} </ref><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="pmid23053393">{{cite journal| author=Babu S, Nutman TB| title=Immunopathogenesis of lymphatic filarial disease. | journal=Semin Immunopathol | year= 2012 | volume= 34 | issue= 6 | pages= 847-61 | pmid=23053393 | doi=10.1007/s00281-012-0346-4 | pmc=3498535 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23053393 }} </ref><ref name="pmid11741630">{{cite journal| author=Cross HF, Haarbrink M, Egerton G, Yazdanbakhsh M, Taylor MJ| title=Severe reactions to filarial chemotherapy and release of Wolbachia endosymbionts into blood. | journal=Lancet | year= 2001 | volume= 358 | issue= 9296 | pages= 1873-5 | pmid=11741630 | doi=10.1016/S0140-6736(01)06899-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11741630 }} </ref><ref name="pmid8337737">{{cite journal| author=Kar SK, Mania J, Kar PK| title=Humoral immune response during filarial fever in Bancroftian filariasis. | journal=Trans R Soc Trop Med Hyg | year= 1993 | volume= 87 | issue= 2 | pages= 230-3 | pmid=8337737 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8337737  }}</ref>
[[Image:W bancrofti LifeCycle.gif|500 px|center]]
*[[Immune response]] of the [[patient]]
*The number of [[filarial]] and [[bacterial infection]]
*The accumulation of the [[Antigen|worm antigen]] in the [[lymphatic vessels]]
*The release of [[Wolbachia]] [[bacteria]] following death of the [[worm]]


Different species of the following genera of mosquitoes are vectors of W. bancrofti filariasis depending on geographical distribution. Among them are: Culex (C. annulirostris, C. bitaeniorhynchus, C. quinquefasciatus, and C. pipiens); Anopheles (A. arabinensis, A. bancroftii, A. farauti, A. funestus, A. gambiae, A. koliensis, A. melas, A. merus, A. punctulatus and A. wellcomei); Aedes (A. aegypti, A. aquasalis, A. bellator, A. cooki, A. darlingi, A. kochi, A. polynesiensis, A. pseudoscutellaris, A. rotumae, A. scapularis, and A. vigilax); Mansonia (M. pseudotitillans, M. uniformis); Coquillettidia (C. juxtamansonia). During a blood meal, an infected mosquito introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound '''(1)'''. They develop in adults that commonly reside in the lymphatics '''(2)''' . The female worms measure 80 to 100 mm in length and 0.24 to 0.30 mm in diameter, while the males measure about 40 mm by .1 mm. Adults produce microfilariae measuring 244 to 296 μm by 7.5 to 10 μm, which are sheathed and have nocturnal periodicity, except the South Pacific microfilariae which have the absence of marked periodicity. The microfilariae migrate into lymph and blood channels moving actively through lymph and blood '''(3)''' . A mosquito ingests the microfilariae during a blood meal '''(4)''' . After ingestion, the microfilariae lose their sheaths and some of them work their way through the wall of the proventriculus and cardiac portion of the mosquito's midgut and reach the thoracic muscles '''(5)''' . There the microfilariae develop into first-stage larvae '''(6)'''  and subsequently into third-stage infective larvae '''(7)'''. The third-stage infective larvae migrate through the hemocoel to the mosquito's prosbocis '''(8)''' and can infect another human when the mosquito takes a blood meal '''(1)'''.
{| class="wikitable"
===Life Cycle of Brugia Malayi===
!Factor
[[Image:B malayi LifeCycle.gif|500 px|center]]
!Role in pathogenesis
|-
|[[Immune response]] of the host
|
* 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]].  
* [[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]] ([[Immunoglobulin G|IgG]]1,2,3) have been detected in [[patients]] with [[lymphedema]] which increases the evidence of the role of the immune response in pathogenesis of the disease.
|-
|[[Bacterial infections|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]]
|
* [[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]].  
* 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]].
|}


The typical vector for Brugia malayi filariasis are mosquito species from the genera Mansonia and Aedes. During a blood meal, an infected mosquito introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound '''(1)'''. They develop into adults that commonly reside in the lymphatics '''(2)'''. The adult worms resemble those of Wuchereria bancrofti but are smaller. Female worms measure 43 to 55 mm in length by 130 to 170 μm in width, and males measure 13 to 23 mm in length by 70 to 80 μm in width. Adults produce microfilariae, measuring 177 to 230 μm in length and 5 to 7 μm in width, which are sheathed and have nocturnal periodicity. The microfilariae migrate into lymph and enter the blood stream reaching the peripheral blood '''(3)''' . A mosquito ingests the microfilariae during a blood meal '''(4)''' . After ingestion, 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 '''(5)''' . There the microfilariae develop into first-stage larvae '''(6)'''  and subsequently into third-stage larvae '''(7)''' . The third-stage larvae migrate through the hemocoel to the mosquito's prosbocis '''(8)''' and can infect another human when the mosquito takes a blood meal '''(1)'''.
===Genetics===
===Life Cycle of Onchocerca volvulus===
*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>
*Mutation in the [[FOXC2|forkhead transcription factor (FOXC2)]] also leads to [[hereditary lymphedema]].


[[Image:O volvulus LifeCycle.gif|500 px|center]]
====Life cycle of filariasis nematodes====
In order to understand how filariasis could occur, it is important to know the [[Life cycle|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.<ref name="Mansonellosis">CDC https://www.cdc.gov/dpdx/mansonellosis/index.html Accessed on June 27, 2017 </ref><ref name="Lymphatic filariasis">CDC https://www.cdc.gov/parasites/lymphaticfilariasis/biology_w_bancrofti.html Accessed on June 27, 2017 </ref><ref name="Loiasis">CDC https://www.cdc.gov/parasites/loiasis/biology.html Accessed on June 27, 2017 </ref><ref name="Onchocerciasis">CDC https://www.cdc.gov/parasites/loiasis/biology.htmlhttps://www.cdc.gov/parasites/onchocerciasis/biology.html Accessed on June 27, 2017 </ref>


During a [[blood]] meal, an infected blackfly (genus Simulium) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound '''(1)'''.  In [[subcutaneous tissue]]s the larvae '''(2)''' develop into adult filariae, which commonly reside in nodules in subcutaneous connective tissues '''(3)'''. Adults can live in the nodules for approximately 15 years. Some nodules may contain numerous male and female [[worm]]s. Females measure 33 to 50 cm in length and 270 to 400 μm in diameter, while males measure 19 to 42 mm by 130 to 210 μm. In the subcutaneous [[nodule]]s, the female worms are capable of producing microfilariae for approximately 9 years. The microfilariae, measuring 220 to 360 µm by 5 to 9 µm and unsheathed, have a life span that may reach 2 years. They are occasionally found in peripheral [[blood]], [[urine]], and [[sputum]] but are typically found in the [[skin]] and in the [[lymphatic]]s of connective tissues '''(4)'''. A blackfly ingests the microfilariae during a blood meal '''(5)'''. After [[ingestion]], the microfilariae migrate from the blackfly's midgut through the hemocoel to the [[thoracic muscle]]s '''(6)'''. There the microfilariae develop into first-stage larvae '''(7)''' and subsequently into third-stage infective larvae '''(8)''' . The third-stage infective larvae migrate to the blackfly's proboscis '''(9)''' and can infect another human when the fly takes a blood meal '''(1)'''.
{| class="wikitable"
===Life Cycle of Mansonella Perstans===
!Type of filariasis
[[Image:M perstans LifeCycle.gif|500 px|center]]
!Causative nematode
During a blood meal, an infected midge (genus Culicoides) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound '''(1)''' .  They develop into adults that reside in body cavities, most commonly the peritoneal cavity or pleural cavity, but less frequently in the pericardium '''(2)''' .  The size range for female worms is 70 to 80 mm in length and 120 μm in diameter, and the males measure approximately 45 mm by 60 μm.  Adults produce unsheathed and subperiodic microfilariae, measuring 200 by 4.5 μm that reach the blood stream '''(3)''' .  A midge ingests microfilariae during a blood meal '''(4)''' .  After ingestion, the microfilariae migrate from the midge's midgut through the hemocoel to the thoracic muscles of the arthropod '''(5)''' .  There the microfilariae develop into first-stage larvae '''(6)'''  and subsequently into third-stage infective larvae '''(7)''' .  The third-stage infective larvae migrate to the midge's proboscis '''(8)'''  and can infect another human when the midge takes a blood meal '''(1)'''  .
!Vectors
!Life Cycle
|-
| rowspan="2" |Lymphatic filariasis
|[[Wuchereria bancrofti]] 
|
* Culex as ''C. pipiens''
* [[Aedes]] as ''A. aegypti''
*  [[Anopheles]] as ''A. arabinensis''
* Coquillettidia.as ''C. juxtamansonia''
| rowspan="2" |[[Image:W bancrofti LifeCycle.gif|500px|thumb|center|Source: https://www.cdc.gov/]]
|-
|[[Brugia timori]] and [[Brugia malayi]]
|
* Mansonia
* Aedes
|-
| rowspan="4" |Subcutaneous filariasis
|[[Loa loa filaria]]
|
* Chrysops
* ''C. silacea''
* ''C. dimidiata''
| rowspan="4" |[[Image:L loa LifeCycle.gif|500px|center|thumb|Source: https://www.cdc.gov/]]
|-
|[[Mansonella streptocerca|''Mansonella streptocerca'']]
|
* Midge (genus Culicoides)
|-
|[[Mansonella ozzardi|''Mansonella ozzardi'']]
|
* Midge (genus Culicoides)
|-
|[[Onchocerca volvulus]]
|
* Blackfly (genus Simulium)
|-
|[[Serous cavity|Serous cavity filariasis]]
|[[Mansonella perstans]]
|
* Midge (genus Culicoides)
* Blackfly (genus Simulium)  
|[[Image:M perstans LifeCycle.gif|500px|center|thumb|Source: https://www.cdc.gov/]]
|}


===Life Cycle of Mansonella Ozzardi===
===Microscopic pathology===  
[[Image:M ozzardi LifeCycle.gif|500 px|center]]
This video gives a brief explanation on the possible histopathological findings of soft tissue sample of case of filariasis:
During a blood meal, an infected arthropod (midges, genus Culicoides, or blackflies, genus Simulium) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound '''(1)'''  .  They develop into adults that commonly reside in subcutaneous tissues '''(2)''' .  Adult worms are rarely found in humans.  The size range for females worms is 65 to 81 mm in length and 0.21 to 0.25 mm in diameter but unknown for males.  Adults worms recovered from experimentally infected Patas monkeys measured 24 to 28 mm in length and 70 to 80 μm in diameter (males) and 32 to 62 mm in length and .130 to .160 mm in diameter (females).  Adults produce unsheathed and non-periodic microfilariae that reach the blood stream '''(3)''' .  The arthropod ingests microfilariae during a blood meal '''(4)''' .  After ingestion, the microfilariae migrate from the arthropod's midgut through the hemocoel to the thoracic muscles '''(5)''' .  There the microfilariae develop into first-stage larvae '''(6)'''  and subsequently into third-stage infective larvae '''(7)''' .  The third-stage infective larvae migrate to arthropod's proboscis '''(8)'''  and can infect another human when the arthropod takes a blood meal '''(1)'''
{{#ev:youtube|67zC7mXigpY}}


===Life Cycle of Mansonella Streptocerca===
[[Image:M streptocerca LifeCycle.gif|500 px|center]]
During a blood meal, an infected midge (genus Culicoides) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound '''(1)''' .  They develop into adults that reside in the dermis, most commonly less than 1 mm from the skin surface '''(2)''' .  The females measure approximately 27 mm in length.  Their diameter is 50 μm at the level of the vulva (anteriorly) and ovaries (near the posterior end), and up to 85 μm at the mid-body.  Males measure 50 μm in diameter.  Adults produce unsheathed and non-periodic microfilariae, measuring 180 to 240 μm by 3 to 5 μm, which reside in the skin but can also reach the peripheral blood '''(3)''' .  A midge ingests the microfilariae during a blood meal '''(4)''' .  After ingestion, the microfilariae migrate from the midge's midgut through the hemocoel to the thoracic muscles '''(5)''' .  There the microfilariae develop into first-stage larvae '''(6)'''  and subsequently into third-stage larvae '''(7)''' .  The third-stage larvae migrate to the midge's proboscis '''(8)'''  and can infect another human when the midge takes another blood meal'''(1)'''  .
==References==
==References==
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Latest revision as of 21:46, 29 July 2020

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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

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]

Factor Role in pathogenesis
Immune response of the host
Secondary bacterial infections
Wolbachia bacteria

Genetics

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/
Brugia timori and Brugia malayi
  • Mansonia
  • Aedes
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

  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.
  2. ↑ Taylor MJ (2002). "A new insight into the pathogenesis of filarial disease". Curr Mol Med. 2 (3): 299–302. PMID 12041732.
  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.
  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.
  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.
  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.
  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.
  8. ↑ CDC https://www.cdc.gov/dpdx/mansonellosis/index.html Accessed on June 27, 2017
  9. ↑ CDC https://www.cdc.gov/parasites/lymphaticfilariasis/biology_w_bancrofti.html Accessed on June 27, 2017
  10. ↑ CDC https://www.cdc.gov/parasites/loiasis/biology.html Accessed on June 27, 2017
  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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