Title: Pythiosis

{{Short description|Tropical disease caused by the oomycete Pythium insidiosum}}
[[Image:Pythiosis 2.jpg|thumb|Destructive skin lesion on a dog caused by ''P. insidiosum'']]
[[Image:Pythiosis hyphae.jpg|thumb|''Pythium'' hyphae]]
'''Pythiosis''' is a rare and deadly [[tropical disease]] caused by the [[oomycete]] ''[[Pythium insidiosum]]''. Long regarded as being caused by a fungus, the causative agent was not discovered until 1987. It occurs most commonly in horses, dogs, and humans, with isolated cases in other large mammals.&lt;ref name=&quot;pmid19494087&quot;&gt;{{cite journal |vauthors=Jindayok T, Piromsontikorn S, Srimuang S, Khupulsup K, Krajaejun T |title=Hemagglutination Test for Rapid Serodiagnosis of Human Pythiosis |journal=Clin. Vaccine Immunol. |volume=16 |issue=7 |pages=1047–51 |date=July 2009 |pmid=19494087 |pmc=2708401 |doi=10.1128/CVI.00113-09 }}&lt;/ref&gt;  The disease is contracted after exposure to stagnant fresh water such as swamps, ponds, lakes, and rice paddies. ''P. insidiosum'' is different from other members of the genus in that human and horse hair, skin, and decaying animal and plant tissue are [[chemoattractant]]s for its [[zoospore]]s.&lt;ref name=&quot;Liljebjelke&quot;/&gt; Additionally, it is the only member in the genus known to infect mammals, while other members are pathogenic to plants and are responsible for some well-known plant diseases.

==Epidemiology==
Pythiosis occurs in areas with mild winters because the organism survives in standing water that does not reach freezing temperatures.&lt;ref name=&quot;Helman&quot;&gt;{{cite journal |vauthors=Helman R, Oliver J |title=Pythiosis of the digestive tract in dogs from Oklahoma |journal=J Am Anim Hosp Assoc |volume=35 |issue=2 |pages=111–4 |year=1999 |pmid=10102178 |doi=10.5326/15473317-35-2-111}}&lt;/ref&gt; In the United States, it is most commonly found in the Southern Gulf states, especially [[Louisiana]], [[Florida]], and [[Texas]], but has also been reported as far away as [[California]] and [[Wisconsin]].&lt;ref&gt;Gastrointestinal pythiosis in 10 dogs from California. J Vet Intern Med. 2008 Jul-Aug; 22(4):1065-9. Berryessa NA, Marks SL, Pesavento PA, Krasnansky T, Yoshimoto SK, Johnson EG, Grooters AM. Department of Medicine and Epidemiology, University of California, School of Veterinary Medicine, Davis, CA, USA. 
&lt;/ref&gt; It is also found in [[southeast Asia]], eastern [[Australia]], [[New Zealand]], and [[South America]].

==Pathophysiology==
Pythiosis is suspected to be caused by invasion of the organism into wounds, either in the skin or in the gastrointestinal tract.&lt;ref name=&quot;Helman&quot;/&gt; The disease grows slowly in the [[stomach]] and [[small intestine]], eventually forming large lumps of [[granulation tissue]]. It can also invade surrounding [[lymph node]]s.&lt;ref&gt;{{Cite journal |last=Grooters |first=Amy M. |last2=Leise |first2=Britta S. |last3=Lopez |first3=Mae K. |last4=Gee |first4=Melaney K. |last5=O'Reilly |first5=Kathy L. |date=2002 |title=Development and Evaluation of an Enzyme-Linked Immunosorbent Assay for the Serodiagnosis of Pythiosis in Dogs |url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1939-1676.2002.tb02345.x |journal=Journal of Veterinary Internal Medicine |language=en |volume=16 |issue=2 |pages=142–146 |doi=10.1111/j.1939-1676.2002.tb02345.x |issn=1939-1676|doi-access=free }}&lt;/ref&gt;

==In different animals==
The species are listed in decreasing frequency of infection.

===Horses===

In horses, [[subcutis|subcutaneous]] pythiosis is the most common form and infection occurs through a wound while standing in water containing the pathogen.&lt;ref name=&quot;Liljebjelke&quot;&gt;{{cite journal |vauthors=Liljebjelke K, Abramson C, Brockus C, Greene C |title=Duodenal obstruction caused by infection with Pythium insidiosum in a 12-week-old puppy |journal=J Am Vet Med Assoc |volume=220 |issue=8 |pages=1188–91, 1162 |year=2002 |pmid=11990966 |doi=10.2460/javma.2002.220.1188|doi-access=free }}&lt;/ref&gt;  The disease is also known as '''leeches''', '''swamp cancer''', and '''bursatti'''. Lesions are most commonly found on the lower limbs, abdomen, chest, and [[Horse anatomy#Reproductive system|genitals]].  They are [[granuloma]]tous and itchy, and may be ulcerated or [[fistula]]ted.  The lesions often contain yellow, firm masses of dead tissue known as 'kunkers'.&lt;ref name=&quot;Merck_oo&quot;&gt;{{cite web | title=Oomycosis | work=The Merck Veterinary Manual | year=2006 | url=http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/51112.htm | access-date=2007-02-03 }}&lt;/ref&gt; It is possible with chronic infection for the disease to spread to underlying bone.&lt;ref&gt;{{cite journal |vauthors=Worster A, Lillich J, Cox J, Rush B |title=Pythiosis with bone lesions in a pregnant mare |journal=J Am Vet Med Assoc |volume=216 |issue=11 |pages=1795–8, 1760 |year=2000 |pmid=10844973 |doi=10.2460/javma.2000.216.1795|doi-access=free }}&lt;/ref&gt;

===Dogs===

Pythiosis of the skin in dogs is rare, and appears as [[Skin ulcer|ulcerated]] lumps. Primary infection can also occur in the bones and lungs. Dogs with the gastrointestinal form of pythiosis have severe thickening of one or more portions of the gastrointestinal tract that may include the stomach, small intestine, colon, rectum, or in rare cases, even the esophagus. The resulting pathology results in anorexia, vomiting, diarrhea (sometimes bloody), and abdominal straining. Extensive weight loss may be evident.&lt;ref&gt;Dr. Susan Muller, DVM. http://www.critterology.com/articles/pythiosis-dog {{Webarchive|url=https://web.archive.org/web/20100417235003/http://www.critterology.com/articles/pythiosis-dog |date=2010-04-17 }}&lt;/ref&gt;

===Humans===

In humans, it can cause [[arteritis]], [[keratitis]], and periorbital cellulitis.&lt;ref name=&quot;Grooters_2003&quot;&gt;{{cite journal |author=Grooters A |title=Pythiosis, lagenidiosis, and zygomycosis in small animals |journal=Vet Clin North Am Small Anim Pract |volume=33 |issue=4 |pages=695–720, v |year=2003 |pmid=12910739 |doi=10.1016/S0195-5616(03)00034-2}}&lt;/ref&gt; This has previously been thought to be a rare disease with only 28 cases reported in the literature up to 1996.&lt;ref name=Thianprasit1996&gt;{{cite journal | author = Thianprasit M, Chaiprasert A, Imwidthaya P | year = 1996 | title = Human pythiosis | journal = Curr Top Med Mycol | volume = 7 | issue = 1| pages = 43–54 | pmid = 9504058 }}&lt;/ref&gt; However, keratitis due to Pythium may be more common than previously thought, accounting for a proportion of cases that were due to unidentified pathogens.&lt;ref&gt;{{cite journal|pmid=25738236 | doi=10.1097/ICO.0000000000000349 | volume=34 | issue=4 | title=Pythium insidiosum keratitis: clinical profile and role of DNA sequencing and zoospore formation in diagnosis | year=2015 | journal=Cornea | pages=438–42 |vauthors=Sharma S, Balne PK, Motukupally SR, Das S, Garg P, Sahu SK, Arunasri K, Manjulatha K, Mishra DK, Shivaji S | s2cid=35114121 }}&lt;/ref&gt; Although this disease was first reported in 1884&lt;ref name=Gaastra2010&gt;{{cite journal | author = Gaastra W, Lipman LJ, De Cock AW, Exel TK, Pegge RB, Scheurwater J, Vilela R, Mendoza L | year = 2010 | title = Pythium insidiosum: an overview | url = https://hal.archives-ouvertes.fr/hal-00636632/file/PEER_stage2_10.1016%252Fj.vetmic.2010.07.019.pdf| journal = Vet Microbiol | volume = 146 | issue = 1–2| pages = 1–16 | doi = 10.1016/j.vetmic.2010.07.019 | pmid = 20800978 }}&lt;/ref&gt; the species infecting humans - ''Pythium insidiosum'' - was only formally recognised in 1987.&lt;ref name=DeCock1987&gt;{{cite journal |vauthors=De Cock AW, Mendoza L, Padhye AA, Ajello L, Kaufman L | year = 1987 | title = ''Pythium insidiosum'' sp. nov., the etiologic agent of pythiosis | journal = J Clin Microbiol | volume = 25 | issue = 2| pages = 344–349 | doi = 10.1128/JCM.25.2.344-349.1987 | pmid = 3818928 | pmc = 265897 }}&lt;/ref&gt; Diagnosis can be difficult in part because of a lack of awareness of the disease.&lt;ref name=Botton2011&gt;{{cite journal | author = Botton SA, Pereira DI, Costa MM, Azevedo MI, Argenta JS, Jesus FP, Alves SH, Santurio JM | year = 2011 | title = Identification of ''Pythium insidiosum'' by nested PCR in cutaneous lesions of Brazilian horses and rabbits | journal = Curr Microbiol | volume = 62 | issue = 4| pages = 1225–1229 | doi = 10.1007/s00284-010-9781-4 | pmid = 21188592 | s2cid = 23439760 }}&lt;/ref&gt; It does not appear to be transmissible either animal to animal or animal to human. There appear to be three clades of this organism: one in the Americas, a second from Asia and Australia and a third with isolates from Thailand and the USA.&lt;ref name=Schurko2003&gt;{{cite journal | author = Schurko AM, Mendoza L, Lévesque CA, Désaulniers NL, de Cock AW, Klassen GR | year = 2003| title = A molecular phylogeny of ''Pythium insidiosum'' | journal = Mycol Res | volume = 107 | issue = 5| pages = 537–544 | doi = 10.1017/s0953756203007718 | pmid = 12884950}}&lt;/ref&gt; The most probable origin of the organism seems to be in Asia.

Most human cases have been reported in Thailand, although cases have been reported elsewhere. In humans, the four forms of the disease are: subcutaneous, disseminated, ocular, and vascular.&lt;ref name=&quot;Pan&quot;&gt;{{cite journal |author1=Pan J |author2=Kerkar S. |author3=Siegenthaler M |author4=Hughes M |author5=Pandalai P |title=A complicated case of vascular Pythium insidiosum infection treated with limb-sparing surgery |journal=International Journal of Surgery Case Reports |volume=5 |issue=10 |pages=677–680 |year=2014 |pmid=25194603 |doi=10.1016/j.ijscr.2014.05.018 |pmc=4189057}}&lt;/ref&gt; The ocular form of the disease is the only one known to infect otherwise healthy humans, and has been associated with contact lens use while swimming in infected water. Ocular pythiosis occurs more frequently in the Americas, while corporal infections tend to occur in Asia. This is also the rarest form with most cases requiring [[enucleation of the eye]].&lt;ref name=&quot;Permpalung&quot;&gt;{{cite journal |vauthors=Permpalung N, Worasilchai N, Plongla R, Upala S, Sanguankeo A, Paitoonpong L, Mendoza L, Chindamporn A |title=Treatment outcomes of surgery, antifungal therapy, and immunotherapy in ocular and vascular human pythiosis: a retrospective study of 18 patients |journal=Journal of Antimicrobial Chemotherapy |volume=70 |issue=6 |pages=1885–1892 |year=2015 |doi=10.1093/jac/dkv008|pmid=25630647 |doi-access=free }}&lt;/ref&gt; The other forms of the disease require a pre-existing medical condition, usually associated with [[Thalassemia|thalassemic hemoglobinopathy]].&lt;ref name=&quot;Pan&quot; /&gt; Prognosis is poor to guarded and treatments include aggressive surgical resection of infected tissue, with amputation suggested if the infection is limited to a distal limb followed by immunotherapy and chemotherapy.&lt;ref name=&quot;Permpalung&quot; /&gt; A recently published review lists nine cases of vascular pythiosis with five survivors receiving surgery with free margins and all except one requiring amputation. The same review lists nine cases of ocular pythiosis with five patients requiring enucnleation of the infected eye and four patients requiring a [[corneal transplant]].&lt;ref name=&quot;Permpalung&quot; /&gt;  

===Cats and other animals===

In cats, pythioisis is almost always confined to the skin as hairless and edematous lesions. It is usually found on the limbs, [[perineum]], and at the base of the tail.&lt;ref name=&quot;Wolf_2005&quot;&gt;{{cite book|editor=August, John R.|chapter=Opportunistic fungal infections|author=Wolf, Alice|title=Consultations in Feline Internal Medicine Vol. 5|publisher=Elsevier Saunders|year=2005|isbn=978-0-7216-0423-7}}&lt;/ref&gt;  Lesions may also develop in the [[nasopharynx]].&lt;ref name=&quot;Merck_oo&quot;/&gt; Rabbits are susceptible to pythiosis and are used for ''in vivo'' studies of the disease.{{Citation needed|date=December 2018}}
Other animals reported to have contracted pythiosis are bears, jaguars, camels, and birds, although these have only been singular events.{{Citation needed|date=December 2018}}

==Diagnosis and treatment==

Pythiosis is suspected to be heavily underdiagnosed due to unfamiliarity with the disease, the rapid progression and morbidity, and the difficulty in making a diagnosis. Symptoms often appear once the disease has progressed to the point where treatments are less effective. 
As the organism is neither a bacterium, virus, nor fungus, routine tests often fail to diagnose it. In cytology and histology, the organism does not stain using [[Giemsa stain|Giemsa]], H&amp;E, or Diff-Quick, but the hyphae are outlined by surrounding tissue. [[Grocott's methenamine silver stain|GMS staining]] is required to identify the hyphae in slides, and highlights the lack of septation which helps distinguish the organism from fungal hyphae. Granulomatous inflammation with numerous eosinophils is suggestive that the hyphae are oomycetes rather than fungi, which are less likely to attract eosinophils.  The symptoms are usually nonspecific and the disease may not be included in a differential diagnosis in human medicine, though it is familiar to veterinarians.

Biopsies of infected tissues are known to be difficult to culture, but can help narrow the diagnosis to several different organisms. A definite diagnosis is confirmed using [[ELISA]] testing of serum for pythiosis antibodies, or by [[Polymerase chain reaction|PCR]] testing of infected tissues or cultures.

Due to the poor efficacy of single treatments, pythiosis infections are often treated using a variety of different treatments, all with varying success.  Most successful treatments include surgery, immunotherapy, and various prescription drugs.&lt;ref name=&quot;Permpalung&quot; /&gt;

Aggressive surgical resection is the treatment of choice for pythiosis.&lt;ref&gt;{{cite journal |vauthors=Thieman KM, Kirkby KA, Flynn-Lurie A, etal | year = 2011 | title = Diagnosis and treatment of truncal cutaneous pythiosis in a dog | journal = J Am Vet Med Assoc | volume = 239 | issue = 9| pages = 1232–1235 | doi=10.2460/javma.239.9.1232| pmid = 21999797 | doi-access = free }}&lt;/ref&gt; Because it provides the best opportunity for cure, complete excision of infected tissue should be pursued whenever possible. When cutaneous lesions are limited to a single distal extremity, amputation is often recommended. In animals with gastrointestinal pythiosis, segmental lesions should be resected with 5-cm margins whenever possible. Unfortunately, surgical excision of tissue and amputation do not guarantee complete success and lesions can reappear. So, surgery is often followed by other treatments.&lt;ref name=&quot;Permpalung&quot; /&gt;

An immunotherapy product derived from antigens of ''P. insidiosum'' has been used successfully to treat pythiosis.&lt;ref&gt;Grooters AM, Foil CS.  Miscellaneous fungal infections.  In:  Greene CE, ed. Infectious Diseases of the Dog and Cat, 4th ed.  Elsevier Saunders, St. Louis, MO, 2012; 675-688.&lt;/ref&gt;

Case reports indicate the use of the following prescription drugs with varying levels of success: [[potassium iodide]],&lt;ref name=&quot;Laohapensang&quot;&gt;{{cite journal |vauthors=Laohapensang K, Rutherford RB, Supabandhu J, Vanittanakom N |title=Vascular pythiosis in a thalassemic patient |journal=Vascular |volume=17 |issue=4 |pages=234–8 |year=2009 |pmid=19698307 |doi= 10.2310/6670.2008.00073|s2cid=46238054 |url=http://www.bcdecker.com/pubMedLinkOut.aspx?pub=VASO&amp;vol=17&amp;iss=4&amp;page=234|url-access=subscription }}&lt;/ref&gt; [[amphotericin B]],&lt;ref name=&quot;Laohapensang&quot; /&gt; [[terbinafine]],&lt;ref name=&quot;Laohapensang&quot; /&gt;&lt;ref name=&quot;Grooters 2008&quot;&gt;Grooters AM.  Pythiosis and Lagenidiosis.  In:  Bonagura, ed.  Kirk’s Current Veterinary Therapy XIV.  Saunders Elsevier,  St. Louis, MO,  2008; 1268-1271.&lt;/ref&gt; [[itraconazole]],&lt;ref name=&quot;Permpalung&quot; /&gt;&lt;ref name=&quot;Grooters 2008&quot; /&gt; [[fluconazole]],&lt;ref name=&quot;Permpalung&quot; /&gt; [[ketoconazole]],&lt;ref name=&quot;Permpalung&quot; /&gt; [[natamycin]],&lt;ref name=&quot;Permpalung&quot; /&gt; [[posaconazole]],&lt;ref name=&quot;Permpalung&quot; /&gt; [[voriconazole]],&lt;ref name=&quot;Permpalung&quot; /&gt; [[prednisone]],&lt;ref name=&quot;Pereira&quot;&gt;{{cite journal |vauthors=Pereira D, Botton S, Azevedo M, Motta M, Lobo R, Soares M, Fonseca A, Jesus F, Alves S, Santurio J |title=Canine gastrointestinal pythiosis treatment by combined antifungal and immunotherapy and review of published studies |journal=Mycopathologia |volume=176 |issue=3–4 |pages=309–315 |date=2013 |doi=10.1007/s11046-013-9683-7|pmid=23918089 |s2cid=14558278 }}&lt;/ref&gt; [[flucytosine]],&lt;ref name=&quot;Pereira&quot; /&gt;  liposomal [[nystatin]]&lt;ref name=&quot;Pereira&quot; /&gt; and [[azithromycin]] + [[doxycycline]].&lt;ref&gt;{{cite journal|pmid=32015039 |date=2020 |last1=Worasilchai |first1=N. |last2=Chindamporn |first2=A. |last3=Plongla |first3=R. |last4=Torvorapanit |first4=P. |last5=Manothummetha |first5=K. |last6=Chuleerarux |first6=N. |last7=Permpalung |first7=N. |title=In Vitro Susceptibility of Thai Pythium insidiosum Isolates to Antibacterial Agents |journal=Antimicrobial Agents and Chemotherapy |volume=64 |issue=4 |doi=10.1128/AAC.02099-19 |pmc=7179303 }}&lt;/ref&gt;

==References==
{{reflist|2}}

[[Category:Dog diseases]]
[[Category:Horse diseases]]
[[Category:Pythium]]
[[Category:Rare infectious diseases]]
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