Scedosporiosis

Scedosporiosis
SpecialtyInfectious diseases
Typeslocalized, disseminated
CausesScedosporium prolificans, Scedosporium apiospermum
Risk factorsimmunodeficiency, neutropenia, cancer
TreatmentAntifungal drugs, surgery

Scedosporiosis is a fungal infection caused by Scedosporium, generally in people with less ability to fight infection.[1][2]

Current population-based studies suggest Scedosporium prolificans (also known and recently more commonly referred to as Lomentospora prolificans) and Scedosporium apiospermum to be among the most common infecting agents from the genus,[3] although infections caused by other members thereof are not unheard of.[4] The latter is an asexual form (anamorph) of another fungus, Pseudallescheria boydii. The former is a “black yeast” (aka dematiaceous fungus),[5] currently not characterized as well, although both of them have been described as saprophytes.[6]

The fungi of this genus are more and more recognized as significant human pathogens. S. apiospermum is described as an emerging and even an “underrated” opportunistic pathogen.[4] It was reported[7] in a 2003 US study that Scedosporiosis had been associated with 25% of all non-Aspergillus fungal infections for organ transplant patients. In a similar 2005 study[6] scedosporal infections caused a 58% mortality rate for transplant recipients affected with it. Among the patients with cystic fibrosis, it is the second most common fungal infection.[8][9] Moreover, a certain difficulty has been reported with correctly identifying the pathogen as, for example, scedosporal infections are in some cases almost indistinguishable[10] from infections with other filamentous fungi, like the already-mentioned Aspergillus – this difficulty could have potentially contributed to the “underrating” of the pathogen. All of this, along with the wide resistance possessed by the pathogens to the antifungal therapies currently in medical use, presents the increased interest for researchers to further study the scedoporal infections and develop treatments.

Background

First detectable description of a scedosporal disease arises in 1911[6] where S. apiospermum was identified as a cause of human mycetoma – a deep fungal subcutaneous infection. S. apiospermum is, indeed, not a recently discovered human pathogen and data about it have been aggregated over a period of more than 120 years.[10] S. prolificans, on the other hand, was discovered more recently, in 1974, under the name L. prolificans.[11]

There has been a series of name changes for both S. apiospermum and its teleomorph P. boydii. It has also been reported that at different timepoints, both, at some point, have been referred to as Petriellidium boydii, Allescheria boydii, Pseudallescheria sheari and Monosporium apiospermum[12]. S. prolificans, likewise, went through a name change, and in the most recent literature, the original name L. prolificans is generally preferred as proposed[13] by Lackner et al. in 2014.

The risk of misidentification of the fungi for other infecting agents is, as previously mentioned, extant and significant as a given treatment will be differently applicable to different fungal infections, especially considering resistance patterns. In 2002, a corneal disease case was reported wherein Acrophialophora fusispora was mistaken for S. prolifcans. The identification[14] performed by the researchers based on the specifics of the pathogen’s morphology was shown to be erroneous. In the correction to that particular case,[15] a distinction was suggested based on the arrangement of cells and shape and color of conidia, however, in practice, difficulties therein still can persist.

S. apiospermum was found[16] to be resistant to a wide range of the known antifungal drugs, displaying high minimal inhibitory concentration values to amphotericin B, isavuconazole and posaconazole, and is, to different extents, susceptible to voriconazole, micafungin and anidulafungin. S. prolificans was found to be consistently resistant to all of these drugs and the effectiveness of voriconazole against it in vitro is limited.

Interestingly, it was recently established[17] that the growth S. prolificans can be inhibited by non-mucoid strains of Pseudomonas aeruginosa.

Infection

Both S. apiospermum and S. prolificans are capable of causing a wide range of infections, both in immunocompromised and immunocompetent individuals. Infections arising therefrom can be both localized and disseminated.

It was reported[4] that solid organ transplant and hematopoietic stem cell transplant patients are a significant proportion of those at risk of Scedosporium mycoses.

Localized mycosis

Localized scedosporiosis can occur in a vast range of internal organs and in joints and limbs. It can commonly be found on the surface of the skin in a form of white and yellow papules. Among the other most common manifestations would be mycetoma, specifically, eumycetoma (a mycetoma caused by a fungus), affecting subcutaneous tissue, joints and even muscles and bones, although foot or leg is a common location of such an infection.[4] A typical cause could be an open wound or surgery and both immunocompetent and immunocompromised patients can develop the infection. Eumycetoma grows in a granular fashion, is usually painless at first and grows steadily, causing complications and even disability if left untreated.[4] Osteomyelitis, particularly, sternal and lower rib bone infection, caused by S. apiospermum was reported[8] in a successfully cured lung transplant patient in 2016.

Scedosporal eye infection, specifically, keratitis, arises usually after an injury of the cornea, both S. apiospermum and S. prolificans are known to be able to cause it. It presents itself in a form of painful lesions within the retina accompanied by symptoms like photophobia and blurred vision.[4]

Disseminated mycosis

Severely immunocompromised patients, patients on immunosuppressive therapy, as well as those suffering from cancers including leukemia, have a risk of developing an infection that would constitute a spread of the extant localized infection throughout the organism.[4] Additional and highly significant risk factor is neutropenia, found especially in leukemia patients.[18]

Disseminated infections present a significant challenge to manage and result in consistently high mortality. Some studies suggest overall mortality rates for disseminated infections to be within 58-75%.[19] A review of 25 cases published in 2006 reported mortality rates of disseminated infections with S. apiospermum and S. prolificans to be 70 and 100%, respectively. A 2002 review[5] of 72 cases of disseminated phaeohyphomycosis reported poor outcomes for the antifungal treatment using amphotericin B with the overall mortality being 79% among all patients, with a likewise 100% mortality for infections by S. prolificans.

The culmination of disseminated scedosporiosis would be a highly fatal infection (>90% mortality rate[19]) of the central nervous system. This development is possible in both immunocompromised and immunodeficient individuals. Studies report the former group develops the condition after a near-drowning experience in water contaminated with the pathogen's conidia.[4][20] An extreme manifestation of this highly lethal case of scedosporiosis would be a brain abscess.[21]

Reported as "most catastrophic", a systematic disseminated scedosporal infection happens after its infiltration of blood vessel and subsequent growth in tissues. In neutropenic patients and patients with HIV, this produces most severe case of the infection and fatality.[4]

Treatment

Effective treatment against Scedosporiosis continues to present a challenge to modern medicine - as do many other fungal infections. It is still being researched and can vary depending on the localization and type of infection. Factors like immunodeficiency can significantly hinder the chances of a successful outcome. Studies suggest[22] Voriconazole to be effective as clinical treatment for infections caused by S. apiospermum. A study of 107 patients with saw the treatment successfully working in 57% in patients infected with scedosporiosis with best effects in localized S. apiospermum skin and bone infections.[23] A 2003 review[24] confirms its effectiveness for treating invasive mycosis of S. apiospermum while also citing evidence for efficacy of ravuconazole. A 2007 case report likewise shows[25] the effectiveness of voriconazole in a renal transplant patient with disseminated scedosporiosis.

In cases of S. apiospermum-caused mycetoma, a treatment constituting a combination of surgery and terbinafine was reported[26] to be effective in 2017. An immunocompromised patient suffering from an intense subcutaneous infection in his right leg was successfully treated using this method.

S. prolificans treatment presents a more significant challenge due to its wider array of antifungal resistance. Localized limb infections might require extensive surgery or even amputation. A review[27] of 162 cases of S. prolificans infection found no association with antifungal treatment (using then-currently available medications) and reduced risk of death. One study,[28] however, argued for the efficiency of combination therapy using voriconazole and terbinafine to cure an orthopedic infection in a non-immunocompromised host without the need for a radical surgery.

More resent medical advances show[29] hope for more efficient antifungal therapies, however, as novel drugs like Ibrexafungerp - a glucan synthase inhibitor - is somewhat effective in treating S. prolificans infections. Another drug, Fosmanogepix, another fungal enzyme inhibitor, showed in vitro efficacy as treatment for scedosporiosis (including S. prolificans). Olorofim, a new dihydroorotate dehydrogenase inhibitor - which disrupts pyrimidine biosynthesis, - is also deserving of the reader's attention as it showed efficacy against both S. prolificans and S. apiospermum as well as other fungi known to be universally resistant to known antifungal medications.

References

  1. ↑ "ICD-11 - ICD-11 for Mortality and Morbidity Statistics". icd.who.int. Archived from the original on 1 August 2018. Retrieved 11 July 2021.
  2. ↑ Chen, Sharon C.-A.; Halliday, Catriona L.; Hoenigl, Martin; Cornely, Oliver A.; Meyer, Wieland (4 January 2021). "Scedosporium and Lomentospora Infections: Contemporary Microbiological Tools for the Diagnosis of Invasive Disease". Journal of Fungi. 7 (1). doi:10.3390/jof7010023. ISSN 2309-608X. Archived from the original on 29 August 2021. Retrieved 11 July 2021.
  3. ↑ Heath CH, Slavin MA, Sorrell TC, Handke R, Harun A, Phillips M, et al. (July 2009). "Population-based surveillance for scedosporiosis in Australia: epidemiology, disease manifestations and emergence of Scedosporium aurantiacum infection". Clinical Microbiology and Infection. 15 (7): 689–93. doi:10.1111/j.1469-0691.2009.02802.x. PMID 19549223.
  4. 1 2 3 4 5 6 7 8 9 Ramirez-Garcia A, Pellon A, Rementeria A, Buldain I, Barreto-Bergter E, Rollin-Pinheiro R, et al. (April 2018). "Scedosporium and Lomentospora: an updated overview of underrated opportunists". Medical Mycology. 56 (suppl_1): 102–125. doi:10.1093/mmy/myx113. PMID 29538735.
  5. 1 2 Revankar SG, Patterson JE, Sutton DA, Pullen R, Rinaldi MG (February 2002). "Disseminated phaeohyphomycosis: review of an emerging mycosis". Clinical Infectious Diseases. 34 (4): 467–76. doi:10.1086/338636. PMID 11797173.
  6. 1 2 3 Husain S, Muñoz P, Forrest G, Alexander BD, Somani J, Brennan K, et al. (January 2005). "Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome". Clinical Infectious Diseases. 40 (1): 89–99. doi:10.1086/426445. PMID 15614697.
  7. ↑ Husain S, Alexander BD, Munoz P, Avery RK, Houston S, Pruett T, et al. (July 2003). "Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi". Clinical Infectious Diseases. 37 (2): 221–9. doi:10.1086/375822. PMID 12856215.
  8. 1 2 Denton EJ, Smibert O, Gooi J, Morrissey CO, Snell G, McGiffin D, Paraskeva M (June 2016). "Invasive Scedosporium sternal osteomyelitis following lung transplant: Cured". Medical Mycology Case Reports. 12: 14–6. doi:10.1016/j.mmcr.2016.07.001. PMC 4995602. PMID 27595059.
  9. ↑ Nagano Y, Cherie MB, Goldsmith CE, Stuart EJ, Rendall J, Moore JE (2009-01-08). "Emergence of Scedosporium apiospermum in patients with cystic fibrosis". BMJ Case Reports. 2009 (jan08 1): bcr2007119503. doi:10.1136/bcr.2007.119503. PMC 3034750. PMID 21687279.
  10. 1 2 Guarro J, Kantarcioglu AS, Horré R, Rodriguez-Tudela JL, Cuenca Estrella M, Berenguer J, de Hoog GS (June 2006). "Scedosporium apiospermum: changing clinical spectrum of a therapy-refractory opportunist". Medical Mycology. 44 (4): 295–327. doi:10.1080/13693780600752507. PMID 16772225.
  11. ↑ "Immunoproteomics-Based Analysis of the Immunocompetent Serological Response to Lomentospora prolificans". doi:10.1021/acs.jproteome.5b00978.s001. {{cite journal}}: Cite journal requires |journal= (help)
  12. ↑ Antachopoulos C, Katragkou A, Roilides E (January 2012). "Immunotherapy against invasive mold infections". Immunotherapy. 4 (1): 107–20. doi:10.2217/imt.11.159. PMID 22150004.
  13. ↑ Lackner M, De Hoog GS, Yang L, Moreno LF, Ahmed SA, Andreas F, et al. (2014). "Proposed nomenclature for Pseudallescheria, Scedosporium and related genera". Fungal Diversity. 67 (1): 1–10. doi:10.1007/s13225-014-0295-4. ISSN 1560-2745. S2CID 14284012.
  14. ↑ Arthur S, Steed LL, Apple DJ, Peng Q, Howard G, Escobar-Gomez M (December 2001). "Scedosporium prolificans keratouveitis in association with a contact lens retained intraocularly over a long term". Journal of Clinical Microbiology. 39 (12): 4579–82. doi:10.1128/jcm.39.12.4579-4582.2001. PMC 88594. PMID 11724890.
  15. ↑ Guarro J, Gené J (September 2002). "Acrophialophora fusispora misidentified as Scedosporium prolificans". Journal of Clinical Microbiology. 40 (9): 3544–3545. doi:10.1128/JCM.40.9.3544-3545.2002. PMC 130777. PMID 12202618.
  16. ↑ Lackner M, de Hoog GS, Verweij PE, Najafzadeh MJ, Curfs-Breuker I, Klaassen CH, Meis JF (May 2012). "Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species". Antimicrobial Agents and Chemotherapy. 56 (5): 2635–42. doi:10.1128/AAC.05910-11. PMC 3346635. PMID 22290955.
  17. ↑ Chen SC, Patel S, Meyer W, Chapman B, Yu H, Byth K, et al. (February 2018). "Pseudomonas aeruginosa Inhibits the Growth of Scedosporium and Lomentospora In Vitro". Mycopathologia. 183 (1): 251–261. doi:10.1007/s11046-017-0140-x. PMID 28512704. S2CID 26000119.
  18. ↑ Walsh TJ, Gamaletsou MN (2013-12-06). "Treatment of fungal disease in the setting of neutropenia". Hematology. American Society of Hematology. Education Program. 2013 (1): 423–7. doi:10.1182/asheducation-2013.1.423. PMID 24319214.
  19. 1 2 Martin-Vicente A, Guarro J, González GM, Lass-Flörl C, Lackner M, Capilla J (April 2017). "Voriconazole MICs are predictive for the outcome of experimental disseminated scedosporiosis". The Journal of Antimicrobial Chemotherapy. 72 (4): 1118–1122. doi:10.1093/jac/dkw532. PMID 28031271.
  20. ↑ Katragkou A, Dotis J, Kotsiou M, Tamiolaki M, Roilides E (September 2007). "Scedosporium apiospermum infection after near-drowning". Mycoses. 50 (5): 412–21. doi:10.1111/j.1439-0507.2007.01388.x. PMID 17714363. S2CID 42935146.
  21. ↑ Gelabert-González M, Arcos-Algaba A, Serramito-García R, García-Allut A, Llovo-Taboada J, Peñalver-Barral MD, Reyes-Santías R (2010). "Absceso cerebral por Scedosporium apiospermum. Presentación de un caso con revisión de la literatura". Neurocirugía. 21 (2): 125–131. doi:10.1016/s1130-1473(10)70068-3. ISSN 1130-1473.
  22. ↑ Box H, Negri C, Livermore J, Whalley S, Johnson A, McEntee L, et al. (May 2018). "Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis". Antimicrobial Agents and Chemotherapy. 62 (5): e02516–17. doi:10.1128/AAC.02516-17. PMC 5923149. PMID 29439967.
  23. ↑ Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, et al. (May 2008). "Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients". Antimicrobial Agents and Chemotherapy. 52 (5): 1743–50. doi:10.1128/aac.01388-07. PMC 2346616. PMID 18212110.
  24. ↑ Klimko, N.N; Veselov, A.V. (2003) New Antifungals for the treatment of Invasive Mycoses. Clinical Microbiology and Antimicrobial Chemotherapy 5 (4) https://cmac-journal.ru/publication/2003/4/cmac-2003-t05-n4-p342/cmac-2003-t05-n4-p342.pdf Archived 2021-05-07 at the Wayback Machine
  25. ↑ Rogasi PG, Zanazzi M, Nocentini J, Fantoni E, Trotta M, Faggi E, et al. (2007). "Disseminated Scedosporium apiospermum infection in renal transplant recipient: long-term successful treatment with voriconazole: a case report". Transplantation Proceedings. 39 (6): 2033–5. doi:10.1016/j.transproceed.2007.05.044. PMID 17692684.
  26. ↑ Tóth EJ, Nagy GR, Homa M, Ábrók M, Kiss IÉ, Nagy G, et al. (April 2017). "Recurrent Scedosporium apiospermum mycetoma successfully treated by surgical excision and terbinafine treatment: a case report and review of the literature". Annals of Clinical Microbiology and Antimicrobials. 16 (1): 31. doi:10.1186/s12941-017-0195-z. PMC 5391591. PMID 28410611.
  27. ↑ Rodriguez-Tudela JL, Berenguer J, Guarro J, Kantarcioglu AS, Horre R, de Hoog GS, Cuenca-Estrella M (June 2009). "Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases". Medical Mycology. 47 (4): 359–70. doi:10.1080/13693780802524506. PMID 19031336.
  28. ↑ Gosbell IB, Toumasatos V, Yong J, Kuo RS, Ellis DH, Perrie RC (June 2003). "Cure of orthopaedic infection with Scedosporium prolificans, using voriconazole plus terbinafine, without the need for radical surgery". Mycoses. 46 (5–6): 233–6. doi:10.1046/j.1439-0507.2003.00878.x. PMID 12801370. S2CID 30626011.
  29. ↑ Rauseo AM, Coler-Reilly A, Larson L, Spec A (February 2020). "Hope on the Horizon: Novel Fungal Treatments in Development". Open Forum Infectious Diseases. 7 (2): ofaa016. doi:10.1093/ofid/ofaa016. PMC 7031074. PMID 32099843.
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