Mucormycosis: Pathogenesis, Diagnosis, and Management

  • Pratibha Rauthan Department of Pharmacy Practice, Shri Guru Ram Rai Institute of Technology and Sciences, Dehradun
  • Deepak Chand Sharma SR Research fellow R&D Emcure pharmaceutical.ltd

Abstract

Mucormycosis (black fungus) is caused by Mucor and Rhizopus. After getting affected such warning signs; pain and redness around the eyes and nose, fever, headache, coughing, shortness of brain, bloody vomit can see. It can suspect in COVID-19 patients, diabetics, or immunosuppressed individuals. Mucormycosis, if not cared it may be turned fatal. Mucormycosis can cause different types of infections: rhino-cerebral, pulmonary, cutaneous, gastrointestinal, and dissemination mucormycosis. In a study β- hydroxybutyrate (a representative of ketone bodies) and elevated serum iron levels were the major factors that enhanced expression of both CotH and GRP78, whereas lactic acidosis did not affect their expression. In addition, sodium bicarbonate reversed the effect of acidosis and protected β- hydroxybutyrate –treated mice from mucormycosis, implying the significance of correction acidosis as a treatment measure in patients with DKA and mucormycosis. The objective of this paper is screening, different pathogenesis, diagnosis, and management of Mucormycosis. An additional factor that significantly contributes to the poor prognosis of these infections is the inherent resistance of Mucorales to the most available antifungals, with amphotericin-B, posaconazole, and isavuconazole considered the most potent antifungals in vitro. According to the studies Rhizopus arrhizus is present in 85% of rhino-cerebral forms, compared with only 17% of non-rhino cerebral forms. However, recent data enlarge the antifungal armamentarium with the US Food and Drug Administration and European Medicines Agency’s approval of the new triazole isavuconazole, however, comparative clinical data are lacking, and the respective places of polyenes and different azoles need to be discussed.


 

Keywords: Mucormycosis, DKA, Antifungal, rhino-cerebral, Amphotericin B.

Downloads

Download data is not yet available.

Author Biographies

Pratibha Rauthan, Department of Pharmacy Practice, Shri Guru Ram Rai Institute of Technology and Sciences, Dehradun

Department of Pharmacy Practice, Shri Guru Ram Rai Institute of Technology and Sciences, Dehradun

Deepak Chand Sharma, SR Research fellow R&D Emcure pharmaceutical.ltd

SR Research fellow R&D Emcure pharmaceutical.ltd

References

1. Guinea J, Escribano P, Vena A, et al.: Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: Epidemiology and microbiological characterization of the isolates. PLoS One. 2017; 12(6): e0179136.
2. Lanternier F, Dannaoui E, Morizot G, et al.: A global analysis of mucormycosis in France: the Retro Zygo Study (2005-2007). Clin Infect Dis. 2012; 54 Suppl 1: S35–43.
3. Roden MM, Zaoutis TE, Buchanan WL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005; 41: 634– 653.
4. Park BJ, Pappas PG, Wannemuehler KA et al. Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001–2006.EmergInfectDis. 2011; 17: 1855–1864.
5. Benoit Pilmis, Alexandre Alanio et. al.: Recent advances in the understanding and management of mucormycosis [version 1; referees: 2approved]: 07 Sep 2018, 7(F1000 Faculty Rev):1429 (DOI: 10.12688/f1000research.15081.1)
6. Liu J, Li S, Liu J, Liang B, Wang H, Li W, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBio Med. 2020; 55:102763.
7. Bitar D, Lortholary O, Le Strat Y, et al.: Population-based analysis of invasive fungal infections, France, 2001-2010. Emerg Infect Dis. 2014; 20(7): 1149–55.
8. Katragkou A, Walsh TJ, et al. Why is mucormycosis more difficult to cure than more common mycoses? Clin Microbiol Infect. 2014; 20 Suppl 6: 74–81.
9. Dannaoui E: Antifungal resistance in Mucorales. Int J Antimicrob Agents. 2017; 50(5): 617–21.
10. Skoda A, Lanternier F, Groll AH et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica. 2013; 98: 492–504.
11. Lewis RE, Kontoyiannis DP. Epidemiology and treatment of mucormycosis. Future Microbiol. 2013; 8: 1163–1175.
12. Ibrahim AS, Spellberg BJ, et al. Vaccination with recombinant N-terminal domain of Als1p improves survival during murine disseminated candidiasis by enhancing cell-mediated, not humoral, immunity. Infect Immun. 2005; 73: 999–1005.
13. Ribes JA, Vanover-Sams CL, Baker DJ, et al. Zygomycetes in human disease. Clin Microbiol Rev. 2000; 13(2):236–301.
14. Binder U,MaurerE,Lass-FlörlC.Mucormycosis:fromthe pathogensto the disease. Clin MicrobiolInfect. 2014; 20:60– 66.
15. Schmidt S, Tramsen L, Perkhofer S, et al. Rhizopus oryzae hyphae are damaged by human nature lkiller (NK) cells, but suppress NK cell-mediated immunity. Immunobiology. 2013; 218: 939–944.
16. MaL -J, Ibrahim AS, Skory C, et al.Genomic analysis of the baseline age fungus rhizopus oryzae reveals a whole-genome up location. Madhani HD, ed. PLoSGenet. 2009; 5: e1000549.
17. Brunke S, Mogavero S, Kasper L, Hube B, et al. Virulence factors in fungal pathogens of man. Curr Opin Microbiol. 2016; 32: 89–95.
18. Baldin C, Ibrahim AS, et al. Molecular mechanisms of mucormycosis-The bitter and the sweet. PLoS Pathog. 2017; 13(8): e1006408.
19. Spellberg B et al.: Mucormycosis pathogenesis: Beyond Rhizopus. Virulence. 2017; 8(8):1481–2
20. Pana ZD, Seidel D, Skiada A, et al.: Invasive mucormycosis in children: an epidemiologic study in European and non-European countries based on two registries. BMC Infect Dis. 2016; 16(1): 667.
21. Xhaard A, Lanternier F, Porcher R, et al.: Mucormycosis after allogeneic hematopoietic stem cell transplantation: a French Multicentre Cohort Study (2003-2008). Clin Microbiol Infect. 2012; 18(10): E396–400.
22. Gebremariam T, Liu M, Luo G, et al. CotH3 mediates fungal invasion of host cells during mucormycosis. J Clin Invest. 2014;124:237–250.
23. Aird WC, et al.: Endothelial cell heterogeneity. Cold Spring Harb Perspect Med. 2012. doi:10.1101/Csh Perspect.a006429.
24. Liu M, Spellberg B, Phan QT, et al. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J Clin Invest. 2010; 120: 1914–1924.
25. Roilides E, Antachopoulos C, SimitsopoulouM, et al. Pathogenesis and host defense against Mucorales: the role of cytokines and interaction with antifungal drugs. Mycoses. 2014; 57: 40–47.
26. Gebremariam T, Lin L, Liu M, et al. Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J ClinInvest. 2016;126: 2280–2294.
27. Chibucos MC, Soliman S, Gebremariam T, et al. An integrated genomic and transcriptomic survey of mucormycosis- causing fungi. Nat Commun. 2016;7: 12218.
28. Ibrahim AS, Voelz K, et al. The micromycetes –host interface. Curr Opin Microbiol. 2017;40:40–45.
29. Shirazi F, Kontoyiannis DP, Ibrahim AS, et al. Iron starvation induces apoptosis in Rhizopus oryzae in vitro. Virulence. 2015;6:121–126.
30. Cantinieaux B, Janssens A, Boelaert JR, et al. Ferritin-associated iron induces neutrophil dysfunction in hemosiderosis. J LabClin Med. 1999; 133:353–361.
31. Farmakiotis D, Kontoyiannis DP, et al. Mucormycosis. Infect Dis Clin North Am. 2016; 30:143–163.
32. MaL-J, Ibrahim AS, Skory C, et al. Genomic analysis of the baseline age fungus rhizopus oryzae reveal saw whole-genome duplication. Madhani HD, ed. PLoSGenet. 2009;5: e1000549.
33. Ibrahim AS, Gebermariam T, Fu Y, et al. Their on chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Invest. 2007;117:2649–2657.
34. Spellberg B, Andes D, Perez M, et al. Safety and outcomes of open-label deferasirox iron chelation therapy for Mucormycosis. Antimicrob Agents Chemother. 2009; 53:3122–3125.
35. Spellberg B, Ibrahim AS,Chin-Hong PV,etal. TheDeferasirox–AmBisome TherapyforMucormycosis (DEFEAT Mucor) study:arandomized,dou- ble-blinded,placebo-controlledtrial. J AntimicrobChemother. 2012; 67: 715–722.
36. GebremariamT,LiuM,LuoG,etal. CotH3mediatesfungalinvasionof hostcellsduringmucormycosis. J Clin Invest. 2014;124:237–250.
37. Ibrahim AS, Voelz K, et al. Themucormycete–host interface. Curr Opin Microbiol. 2017; 40:40–45.
38. Speth C, Rambach G,Lass-FlörlC. Platelet immunology in fungal infections. Thromb Haemost. 2014; 112:632–639.
39. Semple JW, Italiano JE, Freedman J, et al. Platelets and the immune continuum. Nat RevImmunol. 2011;11:264–274. 35. BruserudØ. Bidirectionalcrosstalk between platelets and monocytes initiated by Toll-like receptor: an important step in the early defense against fungal infections? Platelets. 2013; 24:85–97.
40. Schulze B, Rambach G, Schwartze VU, et al. Ketoacidosis alone does not predispose to mucormycosis by Lichtheimia in a murine pulmonary infection model. Virulence. 2017; 8:1657–1667.
41. Vivier E, Tomasello E, Baratin M, Walzer T, et al. Functions of natural killer cells. Nat Immunol. 2008. doi:10.1038/ni1582
42. Gill S,Olson JA,NegrinRS.Natural killercellsinallogeneictransplanta- tion:effectonengraftment,graft- versus-tumor,andgraft-versus-host responses. BiolBloodMarrowTrans- plant. 2009; 15:765–776. 38. Schmidt S,TramsenL,Lehrn- becher T .Naturalkillercellsin antifungal immunity. Front Immu- nol. 2017;8.
43. SchmidtS, Schneider A,DemirA, et al.Naturalkillercell-mediated damageofclinicalisolatesofmucor- mycetes. Mycoses. 2016;59:34–38.
44. Potenza L, Ballerini D, Barozzi P, et al. Mucorales-specific T cells emerge in the course of invasive mucormycosis and may be used as a surrogate diagnostic marker in high-risk patients. Blood. 2011; 118:5416–5419.
45. Castillo P, Wright KE, Kontoyiannis DP, et al. A new method for reactivating and expanding T cells specific for Rhizopus oryzae. Mol Ther Methods Clin Dev. 2018; 9:305–312.
46. Monheit JE, Cowan DF, Moore DG. Rapid detection of fungi in tissues using calcofluor white and fluorescence microscopy. Arch Pathol Lab Med. 1984; 108:616–618
47. Chakrabarti A, Das A, Mandal J, et al. The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus. Med Mycol. 2006; 44:335–342.
48. Nagao K, Ota T, Tanikawa A, et al. Genetic identification and detection of human pathogenic Rhizopus species, a major mucormycosis agent, by multiplex PCR based on internal transcribed spacer region of rRNA gene. J Dermatol Sci. 2005; 39:23–31.
49. Machouart M, Larche J, Burton K, et al. Genetic identification of the ´ main opportunistic Mucorales by PCR-restriction fragment length polymorphism. J Clin Microbiol. 2006; 44: 805–810.
50. Springer J, Lackner M, Ensinger C et al. Clinical evaluation of a Mucorales-specific real-time PCR assay in tissue and serum samples. J Med Microbiol. 2016; 65: 1414–1421.
51. Lackner M, Caramalho R, et al. Laboratory diagnosis of mucormycosis: current status and future perspectives. Future Microbiol. 2014; 9: 683–695.
52. Gebremariam T, Liu M, Luo G, et al. CotH3 mediates fungal invasion of host cells during mucormycosis. J Clin Invest. 2014; 124: 237–250.
53. Ben-Ami R, Luna M, Lewis RE, et al. A clinicopathological study of pulmonary mucormycosis in cancer patients: extensive angioinvasion but a limited inflammatory response. J Infect. 2009; 59:134–138.
54. Ibrahim, A. S., B. Spellberg, V. Avanessian, Y. Fu, and J. E. Edwards. Rhizopus oryzae adheres to, is phagocytosed by, and damages endothelial cells in vitro. Infect. Immun. 2005; 73:778–783
55. Tissot F, Agrawal S, Pagano L, et al.: ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis, and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017; 102(3):433–44.
56. Chretien ML, Legouge C, Pagès PB, et al.: Emergency and elective pulmonary surgical resection in hematological patients with invasive fungal infections: a report of 50 cases in a single center. Clin Microbiol Infect. 2016; 22(9):782–7.
57. Chretien ML, Legouge C, Pagès PB, et al.: Emergency and elective pulmonary surgical resection in hematological patients with invasive fungal infections: a report of 50 cases in a single center. Clin Microbiol Infect. 2016; 22(9):782–7.
58. Sabatelli F, Patel R, Mann PA, et al.: In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother. 2006; 50(6):2009–15.
59. Almyroudis NG, Sutton DA, Fothergill AW, et al.: In vitro susceptibilities of 217 clinical isolates of zygomycetes to conventional and new antifungal agents. Antimicrob Agents Chemother. 2007; 51(7):2587–90.
Statistics
76 Views | 88 Downloads
How to Cite
Rauthan, P., & Sharma, D. (2021). Mucormycosis: Pathogenesis, Diagnosis, and Management. Asian Journal of Pharmaceutical Research and Development, 9(3), 144-153. https://doi.org/https://doi.org/10.22270/ajprd.v9i3.975