Abstract
Pythiosis is an emerging infectious disease caused by the aquatic oomycete Pythium insidiosum, a fungal-like organism. It is believed that P. insidiosum’s zoospores, its infected form, play major role in pathogenesis. Vascular and ocular infections are the most common clinical manifestation in humans. It is difficult to establish the diagnosis given its relatively rarity and difficulty to distinguish P. insidiosum from other molds. Delay in diagnosis and treatment has been associated with poor outcomes. High index of suspicion is the key, particularly in thalassemia patients with arterial insufficiency and patients with fungal keratitis/endophthalmitis without improvement on antifungal therapy. Tissue culture and zoospore induction remain gold standard for diagnosis; however, DNA-based method should be performed simultaneously. The combination of radical surgery, antifungal agents, and immunotherapy has been recommended. It was previously believed that surgery with negative surgical margins was the essential to survive in vascular pythiosis; however, it was recently found that patients could have residual disease despite documented negative surgical margins as infected clot may be dislodged to proximal arterial sites prior to surgery. Serum β-d-glucan (BG) has been used to monitor disease response after treatment initiation in vascular pythiosis. A significant decrease in BG levels within 2 weeks after surgery is indicative of the absence of residual infection. Unfortunately, monitoring tools for ocular pythiosis are not yet available. Itraconazole plus terbinafine have generally been used in P. insidiosum-infected patients; however, antibacterial agents, including azithromycin and linezolid, have also been used with favorable outcomes in ocular disease. Recently, azithromycin or clarithromycin plus doxycyclin were used in two relapsed vascular pythiosis patients with good outcomes.
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References
Gaastra W, Lipman LJ, De Cock AW, Exel TK, Pegge RB, Scheurwater J, et al. Pythium insidiosum: an overview. Vet Microbiol. 2010;146(1–2):1–16.
Bridges CH, Emmons CW. A phycomycosis of horses caused by Hyphomyces destruens. J Am Vet Med Assoc. 1961;138:579–89.
Austwick PK, Copland JW. Swamp cancer. Nature. 1974;250(461):84.
Chandler FWW, Kaplan W, Ajello LA. Color atlas and textbook of the histopathology of mycotic diseases. Chicago: Year Book Medical Publishers; 1980.
De Cock AW, Mendoza L, Padhye AA, Ajello L, Kaufman L. Pythium insidiosum sp. nov., the etiologic agent of pythiosis. J Clin Microbiol. 1987;25(2):344–9.
Shipton WA. Pythium destruens sp. nov., an agent of equine pythiosis. J Med Vet Mycol. 1987;25(3):137–51.
Kwon-Chung KJ. Phylogenetic spectrum of fungi that are pathogenic to humans. Clin Infect Dis. 1994;19(Suppl 1):S1–7.
Hudspeth DSS, Nadler SA, Hudspeth MES. A COX2 molecular phylogeny of the peronosporomycetes. Mycologia. 2000;92:674–84.
Martin FN. Phylogenetic relationships among some Pythium species inferred from sequence analysis of the mitochondrially encoded cytochrome oxidase II gene. Mycologia. 2000;92:711–27.
Dick MW. Straminipilous fungi: systematics of the Peronosporomycetes including accounts of the marine straminipilous protist, the plasmodiophorids and similar organisms. London: Kluwer Academic Publishers; 2001.
Kammarnjesadakul P, Palaga T, Sritunyalucksana K, Mendoza L, Krajaejun T, Vanittanakom N, et al. Phylogenetic analysis of Pythium insidiosum Thai strains using cytochrome oxidase II (COX2) DNA coding sequences and internal transcribed spacer regions (ITS). Med Mycol. 2011;49(3):289–95.
Worasilchai N, Permpalung N, Chindamporn A. High-resolution melting analysis: a novel approach for clade differentiation in Pythium insidiosum and pythiosis. Med Mycol. 2018;56(7):868–76.
Thianprasit M, editor. Cutaneous pythiosis in human-being. In: Siriraj 100th academic meeting. Mahidol University: Bangkok, Thailand; 1988. pp. 18–22 April.
Sathapatayavongs B, Leelachaikul P, Prachaktam R, Atichartakarn V, Sriphojanart S, Trairatvorakul P, et al. Human pythiosis associated with thalassemia hemoglobinopathy syndrome. J Infect Dis. 1989;159(2):274–80.
Krajaejun T, Sathapatayavongs B, Pracharktam R, Nitiyanant P, Leelachaikul P, Wanachiwanawin W, et al. Clinical and epidemiological analyses of human pythiosis in Thailand. Clin Infect Dis. 2006;43(5):569–76.
Permpalung N, Worasilchai N, Manothummetha K, Torvorapanit P, Ratanawongphaibul K, Chuleerarux N, et al. Clinical outcomes in ocular pythiosis patients treated with a combination therapy protocol in Thailand: a prospective study. Med Mycol. 2019;57(8):923–28.
Chitasombat MN, Petchkum P, Horsirimanont S, Sornmayura P, Chindamporn A, Krajaejun T. Vascular pythiosis of carotid artery with meningitis and cerebral septic emboli: a case report and literature review. Med Mycol Case Rep. 2018;21:57–62.
Laohapensang K, Rerkasem K, Chotirosniramit N. Mini-laparotomy for repair of infrarenal abdominal aortic aneurysm. Int Angiol. 2005;24(3):238–44.
Permpalung N, Worasilchai N, Plongla R, Upala S, Sanguankeo A, Paitoonpong L, et al. Treatment outcomes of surgery, antifungal therapy and immunotherapy in ocular and vascular human pythiosis: a retrospective study of 18 patients. J Antimicrob Chemother. 2015;70(6):1885–92.
Reanpang T, Orrapin S, Orrapin S, Arworn S, Kattipatanapong T, Srisuwan T, et al. Vascular pythiosis of the lower extremity in northern Thailand: 10 years’ experience. Int J Low Extrem Wounds. 2015;14(3):245–50.
Sermsathanasawadi N, Praditsuktavorn B, Hongku K, Wongwanit C, Chinsakchai K, Ruangsetakit C, et al. Outcomes and factors influencing prognosis in patients with vascular pythiosis. J Vasc Surg. 2016;64(2):411–7.
Worasilchai N, Permpalung N, Chongsathidkiet P, Leelahavanichkul A, Mendoza AL, Palaga T, et al. Monitoring anti-Pythium insidiosum IgG antibodies and (1→3)-beta-d-glucan in vascular pythiosis. J Clin Microbiol. 2018;56(8):e00610–8.
Agarwal S, Iyer G, Srinivasan B, Agarwal M, Kumar SP, Therese LK. Clinical profile of pythium keratitis: perioperative measures to reduce risk of recurrence. Br J Ophthalmol. 2018;102(2):153–7.
Agarwal SIG, Srinivasan B, Benurwar S, Agarwal M, Narayanan N, Lakshmipathy M, Radhika N, Rajagopal R, Krishnakumar S. Clinical profile, risk factors and outcome of medical, surgical and adjunct interventions in patients with Pythium insidiosum keratitis. Br J Ophthalmol. 2019;103(3):296–300.
Bagga B, Sharma S, Madhuri Guda SJ, Nagpal R, Joseph J, Manjulatha K, et al. Leap forward in the treatment of Pythium insidiosum keratitis. Br J Ophthalmol. 2018;102(12):1629–33.
Hasika R, Lalitha P, Radhakrishnan N, Rameshkumar G, Prajna NV, Srinivasan M. Pythium keratitis in South India: incidence, clinical profile, management, and treatment recommendation. Indian J Ophthalmol. 2019;67(1):42–7.
Kunavisarut S, Nimvorapan T, Methasiri S. Pythium corneal ulcer in Ramathibodi Hospital. J Med Assoc Thail. 2003;86(4):338–42.
Mittal R, Jena SK, Desai A, Agarwal S. Pythium insidiosum keratitis: histopathology and rapid novel diagnostic staining technique. Cornea. 2017;36(9):1124–32.
Sharma S, Balne PK, Motukupally SR, Das S, Garg P, Sahu SK, et al. Pythium insidiosum keratitis: clinical profile and role of DNA sequencing and zoospore formation in diagnosis. Cornea. 2015;34(4):438–42.
Lohnoo T, Yingyong W, Kumsang Y, Payattikul P, Jaturapaktrarak C, Chailurkit LO, et al. Seroprevalence of anti-Pythium insidiosum antibodies in the Thai population. Med Mycol. 2019;57(3):284–90.
Triscott JA, Weedon D, Cabana E. Human subcutaneous pythiosis. J Cutan Pathol. 1993;20(3):267–71.
He H, Liu H, Chen X, Wu J, He M, Zhong X. Diagnosis and treatment of Pythium Insidiosum corneal ulcer in a chinese child: a case report and literature review. Am J Case Rep. 2016;17:982–8.
Hilton RE, Tepedino K, Glenn CJ, Merkel KL. Swamp cancer: a case of human pythiosis and review of the literature. Br J Dermatol. 2016;175(2):394–7.
Hung C, Leddin D. Keratitis caused by Pythium insidiosum in an immunosuppressed patient with Crohn’s disease. Clin Gastroenterol Hepatol. 2014;12(10):A21–2.
Franco DM, Aronson JF, Hawkins HK, Gallagher JJ, Mendoza L, McGinnis MR, et al. Systemic Pythium insidiosum in a pediatric burn patient. Burns. 2010;36(5):e68–71.
Bosco Sde M, Bagagli E, Araujo JP Jr, Candeias JM, de Franco MF, Alencar Marques ME, et al. Human pythiosis, Brazil. Emerg Infect Dis. 2005;11(5):715–8.
Tanhehco TY, Stacy RC, Mendoza L, Durand ML, Jakobiec FA, Colby KA. Pythium insidiosum keratitis in Israel. Eye Contact Lens. 2011;37(2):96–8.
Bernheim D, Dupont D, Aptel F, Dard C, Chiquet C, Normand AC, et al. Pythiosis: case report leading to new features in clinical and diagnostic management of this fungal-like infection. Int J Infect Dis. 2019;86:40–3.
Calvano TP, Blatz PJ, Vento TJ, Wickes BL, Sutton DA, Thompson EH, et al. Pythium aphanidermatum infection following combat trauma. J Clin Microbiol. 2011;49(10):3710–3.
Farmer AR, Murray CK, Driscoll IR, Wickes BL, Wiederhold N, Sutton DA, et al. Combat-related Pythium aphanidermatum invasive wound infection: case report and discussion of utility of molecular diagnostics. J Clin Microbiol. 2015;53(6):1968–75.
Ri M. Investigations into the biology of three ‘phycomycotic’ agents pathogenic for horses in Australia. Mycopathologia. 1983;81(1):23–8.
Mendoza L, Ajello L, McGinnis MR. Infections caused by the Oomycetous pathogen Pythium insidiosum. J Mycol Med. 1996;6(4):151–64.
de Sousa M. Immune cell functions in iron overload. Clin Exp Immunol. 1989;75(1):1–6.
Gordeuk VR, Ballou S, Lozanski G, Brittenham GM. Decreased concentrations of tumor necrosis factor-alpha in supernatants of monocytes from homozygotes for hereditary hemochromatosis. Blood. 1992;79(7):1855–60.
Wanachiwanawin W, Mendoza L, Visuthisakchai S, Mutsikapan P, Sathapatayavongs B, Chaiprasert A, et al. Efficacy of immunotherapy using antigens of Pythium insidiosum in the treatment of vascular pythiosis in humans. Vaccine. 2004;22(27–28):3613–21.
Ud-Naen S, Tansit T, Kanistanon D, Chaiprasert A, Wanachiwanawin W, Srinoulprasert Y. Defective cytokine production from monocytes/macrophages of E-beta thalassemia patients in response to Pythium insidiosum infection. Immunobiology. 2019;224(3):427–32.
Krajaejun T, Khositnithikul R, Lerksuthirat T, Lowhnoo T, Rujirawat T, Petchthong T, et al. Expressed sequence tags reveal genetic diversity and putative virulence factors of the pathogenic oomycete Pythium insidiosum. Fungal Biol. 2011;115(7):683–96.
Intaramat A, Sornprachum T, Chantrathonkul B, Chaisuriya P, Lohnoo T, Yingyong W, et al. Protein A/G-based immunochromatographic test for serodiagnosis of pythiosis in human and animal subjects from Asia and Americas. Med Mycol. 2016;54(6):641–7.
Krajaejun T, Chongtrakool P, Angkananukul K, Brandhorst TT. Effect of temperature on growth of the pathogenic oomycete Pythium insidiosum. Southeast Asian J Trop Med Public Health. 2010;41(6):1462–6.
Reinprayoon U, Permpalung N, Kasetsuwan N, Plongla R, Mendoza L, Chindamporn A. Lagenidium sp. ocular infection mimicking ocular pythiosis. J Clin Microbiol. 2013;51(8):2778–80.
Mendoza L, Newton JC. Immunology and immunotherapy of the infections caused by Pythium insidiosum. Med Mycol. 2005;43(6):477–86.
Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev. 2000;13(2):236–301.
Rees CA. Disorders of the skin. Equine internal medicine. 2nd ed. Philadelphia: Saunders; 2004.
Grooters AM. Pythiosis and zygomycosis. Equine infectious diseases. Amsterdam: Elsevier; 2007.
Pracharktam R, Changtrakool P, Sathapatayavongs B, Jayanetra P, Ajello L. Immunodiffusion test for diagnosis and monitoring of human pythiosis insidiosi. J Clin Microbiol. 1991;29(11):2661–2.
**dayok T, Piromsontikorn S, Srimuang S, Khupulsup K, Krajaejun T. Hemagglutination test for rapid serodiagnosis of human pythiosis. Clin Vaccine Immunol. 2009;16(7):1047–51.
Krajaejun T, Kunakorn M, Niemhom S, Chongtrakool P, Pracharktam R. Development and evaluation of an in-house enzyme-linked immunosorbent assay for early diagnosis and monitoring of human pythiosis. Clin Diagn Lab Immunol. 2002;9(2):378–82.
Chareonsirisuthigul T, Khositnithikul R, Intaramat A, Inkomlue R, Sriwanichrak K, Piromsontikorn S, et al. Performance comparison of immunodiffusion, enzyme-linked immunosorbent assay, immunochromatography and hemagglutination for serodiagnosis of human pythiosis. Diagn Microbiol Infect Dis. 2013;76(1):42–5.
Worasilchai N, Leelahavanichkul A, Permpalung N, Kuityo C, Phaisanchatchawan T, Palaga T, et al. Antigen host response differences between the animal-type strain and human-clinical Pythium insidiosum isolates used for serological diagnosis in Thailand. Med Mycol. 2019;57(4):519–22.
Chindamporn A, Vilela R, Hoag KA, Mendoza L. Antibodies in the sera of host species with pythiosis recognize a variety of unique immunogens in geographically divergent Pythium insidiosum strains. Clin Vaccine Immunol. 2009;16(3):330–6.
Grooters AM, Gee MK. Development of a nested polymerase chain reaction assay for the detection and identification of Pythium insidiosum. J Vet Intern Med. 2002;16(2):147–52.
Schurko AM, Mendoza L, de Cock AW, Bedard JE, Klassen GR. Development of a species-specific probe for Pythium insidiosum and the diagnosis of pythiosis. J Clin Microbiol. 2004;42(6):2411–8.
Worasilchai N, Chaumpluk P, Chakrabarti A, Chindamporn A. Differential diagnosis for pythiosis using thermophilic helicase DNA amplification and restriction fragment length polymorphism (tHDA-RFLP). Med Mycol. 2018;56(2):216–24.
Thitithanyanont A, Mendoza L, Chuansumrit A, Prachartam R, Laothamatas J, Sathapatayayongs B, Lolekha S, Ajello L. Use of an immunogenic therapeutic vaccine to treat a life-threatening human arteritic infection caused by Pythium insidiosum. Clin Infect Dis. 1998;27:1394–400.
Narkwiboonwong TTK, Watanakijthavonkul K, Paocharern P, Singsakul A, Wongsa A, Woracharoensri N, Worasilchai N, Chindamporn A, Panoi A, Methipisit T, Sithinamsuwan P. Cerebral pythiosis: a case report of Pythium insidiosum infection presented with brain abscess. J Infect Dis Antimicrob Agents. 2011;28:129–32.
Susaengrat N, Torvorapanit P, Plongla R, Chuleerarux N, Manothummetha K, Tuangsirisup J, et al. Adjunctive antibacterial agents as a salvage therapy in relapsed vascular pythiosis patients. Int J Infect Dis. 2019;88:27–30.
Krajaejun T, Pracharktam R, Wongwaisayawan S, Rochanawutinon M, Kunakorn M, Kunavisarut S. Ocular pythiosis: is it under-diagnosed? Am J Ophthalmol. 2004;137(2):370–2.
Anutarapongpan O, Thanathanee O, Worrawitchawong J, Suwan-Apichon O. Role of confocal microscopy in the diagnosis of Pythium insidiosum keratitis. Cornea. 2018;37(2):156–61.
Shenep JL, English BK, Kaufman L, Pearson TA, Thompson JW, Kaufman RA, et al. Successful medical therapy for deeply invasive facial infection due to Pythium insidiosum in a child. Clin Infect Dis. 1998;27(6):1388–93.
Argenta JS, Santurio JM, Alves SH, Pereira DI, Cavalheiro AS, Spanamberg A, et al. In vitro activities of voriconazole, itraconazole, and terbinafine alone or in combination against Pythium insidiosum isolates from Brazil. Antimicrob Agents Chemother. 2008;52(2):767–9.
Cavalheiro AS, Maboni G, de Azevedo MI, Argenta JS, Pereira DI, Spader TB, et al. In Vitro activity of terbinafine combined with caspofungin and azoles against Pythium insidiosum. Antimicrob Agents Chemother. 2009;53(5):2136–8.
Loreto ES, Mario DA, Denardi LB, Alves SH, Santurio JM. In vitro susceptibility of Pythium insidiosum to macrolides and tetracycline antibiotics. Antimicrob Agents Chemother. 2011;55(7):3588–90.
Rawn CDSM. Protecion of Pythium Speccies Against Antibacterial Antibiotics by Cholesterol. Physiology and Biochemistry. 1987;77:319–23.
Rawn CDVJL. Mechanism of antibacterial antibiotic sensitivity in Pythium ultimum. J Gen Microbiol. 1978;108:133–9.
Mahl DL, de Jesus FP, Loreto E, Zanette RA, Ferreiro L, Pilotto MB, et al. In vitro susceptibility of Pythium insidiosum isolates to aminoglycoside antibiotics and tigecycline. Antimicrob Agents Chemother. 2012;56(7):4021–3.
Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother. 2005;49(1):220–9.
Loreto ES, Tondolo JS, Pilotto MB, Alves SH, Santurio JM. New insights into the in vitro susceptibility of Pythium insidiosum. Antimicrob Agents Chemother. 2014;58(12):7534–7.
Jesus FP, Ferreiro L, Loreto ES, Pilotto MB, Ludwig A, Bizzi K, et al. In vitro synergism observed with azithromycin, clarithromycin, minocycline, or tigecycline in association with antifungal agents against Pythium insidiosum. Antimicrob Agents Chemother. 2014;58(9):5621–5.
Jesus FP, Loreto ES, Ferreiro L, Alves SH, Driemeier D, Souza SO, et al. In vitro and in vivo antimicrobial activities of minocycline in combination with azithromycin, clarithromycin, or tigecycline against Pythium insidiosum. Antimicrob Agents Chemother. 2016;60(1):87–91.
Mendoza L, Mandy W, Glass R. An improved Pythium insidiosum-vaccine formulation with enhanced immunotherapeutic properties in horses and dogs with pythiosis. Vaccine. 2003;21(21–22):2797–804.
Hensel P, Greene CE, Medleau L, Latimer KS, Mendoza L. Immunotherapy for treatment of multicentric cutaneous pythiosis in a dog. J Am Vet Med Assoc. 2003;223(2):215–8.
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Permpalung, N., Worasilchai, N. & Chindamporn, A. Human Pythiosis: Emergence of Fungal-Like Organism. Mycopathologia 185, 801–812 (2020). https://doi.org/10.1007/s11046-019-00412-0
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DOI: https://doi.org/10.1007/s11046-019-00412-0