Much More Mucor

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The Pre-brief

  • Mucormycosis is an acute and often deadly fungal infection caused by the Mucorales order of molds
  • Patients traditionally at risk for mucormycosis are diabetics or immunocompromised 
  • Morbidity is immense as surgical debridements often require ocular enucleation, and mortality rate is high at ~38%  
  • There has been a recent surge in global mucormycosis cases in post COVID-19 patients which have been deemed COVID-19 Associated Mucormycosis (CAM) 
  • Early recognition, surgical debridement, and antifungal therapy are the mainstays of treatment with hyperbaric oxygen therapy (HBOT) being an adjunctive therapy to consider where available

Mucormycosis

Inhalation of spores in a susceptible host is required for Mucorales infection.  Rhizopus and Mucor are the most common genera of molds leading to mucormycosis cases with predominant species varying by region.  Susceptible hosts are typically diabetics, are neutropenic, or are otherwise immunocompromised.  Interestingly, mucormycosis affecting diabetics tends to affect the rhinocerebral anatomy, whereas, patients with an immunocompromised state due to hematologic malignancy or organ transplant tend to be affected with pulmonary mucormycosis. Derangement in a diabetic’s baseline cell-mediated immunity (i.e. cytokine secretion, chemotaxis, phagocytosis) is thought to contribute to susceptibility.  Additionally, local conditions such as hyperglycemia and ketoacidosis offer an environment favorable to fungal inoculation in which angioinvasive hyphae cause endothelial injury and subsequent septic arteritis and thrombophlebitis. Local tissue necrosis ensues and contiguous spread leads to rhinocerebral involvement with orbital and cerebral extension being responsible for most of the morbidity and mortality.   

Symptoms of early mucormycosis include facial swelling, headache, and fever.  Perhaps the most suggestive early finding is a black eschar or discoloration affecting the nose, upper lip, or orbit.  Ophthalmoplegia is a later but common exam finding.  Diagnosis can be made with biopsy but treatment should not be delayed for laboratory confirmation in the appropriately susceptible patient with a history and exam concerning for mucormycosis.  Early recognition is imperative in treating rhinocerebral mucormycosis for the patient to have any chance at survival with minimized morbidity.  The mainstays of treating mucormycosis are listed below.  Isavuconazole can be considered as an alternative to amphotericin B in patients with poor renal function.  Retrobulbar amphotericin B has also been considered but data is limited.

Mucor in the New

In several Asian and Middle Eastern countries, mucormycosis cases in post COVID-19 patients are surging.  India has been one of the most affected countries. Likely due to a high prevalence of diabetes mellitus but for ultimately unclear reasons, India had one of the highest pre-pandemic rates of mucormycosis at 80 times the global prevalence.   It is unclear if or how this high prevalence of mucormycosis may be contributing to the surge in CAM cases now. The increased rate in cases of mucormycosis is reported at roughly twofold from a baseline case rate of 14 per 100,000 people.  There are reports of amphotericin B shortages in regions of Asia.  Case series and observational reports from large tertiary centers in India continue to emerge regarding CAM.  Most reports describe the mucormycosis diagnosis occurring in 12-18 days following SARS-CoV-2 diagnosis.  

The pathophysiologic association between COVID-19 and mucormycosis remains unclear though there are several proposed theories.  The foremost and the elephant in the room is inappropriate steroid usage in poorly controlled diabetic patients.  There is some concern that steroids have not been judiciously reserved for the hypoxemic COVID-19 patients, which could accentuate mucor susceptibility in the population of uncontrolled diabetics.  Additionally, COVID-19 associated inflammatory response itself likely leads to glycemic imbalance.  According to available data, more severe COVID-19 cases have a greater association with CAM, and COVID-19 related hypoxemia was an independent predictor of risk for CAM in one reported series.  A theory here is that hypoxemia contributes to end-organ acidosis.  In both cases of glycemic imbalance and local tissue acidosis, a favorable environment for Mucorales molds is created.  Endovascular injury from COVID-19 could also possibly contribute to a more favorable scenario for the angioinvasive hyphae of the mold. Lastly, some authors have theorized as to whether COVID-19 leads to an imbalance of nasal microbiota, promoting Mucorales inoculation.

 

It is unclear whether infection with SARS-CoV-2 in and of itself has immunomodulatory effects which could predispose a patient to mucormycosis and other secondary infections.  Both Aspergillus and Candida infections have also been reported in association with COVID-19 but typically with much less devastating outcomes. While most reported CAM cases are occurring in uncontrolled diabetic patients and in patients treated with steroids, one epidemiological study regarding CAM cases in India reports 32% of patients having no comorbid conditions other than COVID-19.  

HBOT and Mechanisms

Similar to necrotizing fasciitis and brain abscess where surgery and antimicrobial therapy are first and foremost, the same is true for mucormycosis.  In each of these devastating diagnoses though, HBOT can be considered as an adjunctive therapy where alternative therapies are quite limited.  Mechanisms by which HBOT can benefit fungal CNS infection are as follows:

  • Reduction in local hypoxia and acidosis: both are conditions that favor and promote fungal growth.  
  • Reduction in local brain edema.  This results from hyperoxic vasoconstriction, reduction in cerebral blood flow, and concurrent tissue oxygenation leading to the cessation of cyclical progression of tissue injury and edema.  
  • HBOT has also previously been shown in vitro to enhance neutrophil phagocytosis.
  • HBOT can inhibit the growth of anaerobic organisms though most Mucorales sp. can grow and survive in a variety of conditions.

The Debrief

  • Mucormycosis is a rare and devastating fungal infection that is currently spiking in association with COVID-19 in India and many parts of the world  
  • Mechanistic linkage is unclear but likely related to increased steroid use and altered immune state in diabetic patients
  • Judicious use of steroids and immunomodulators for COVID-19 is important to avoid further immunocompromising select populations for secondary infections
  • The primary treatment for Mucormycosis is early and aggressive surgical debridement with concurrent liposomal amphotericin B
  • HBOT can be considered as adjunctive therapy for mucormycosis if available  

 

References

  1. Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, Lanternier F, Pagano L, Skiada A, Akova M, Arendrup MC, Boekhout T, Chowdhary A, Cuenca-Estrella M, Freiberger T, Guinea J, Guarro J, de Hoog S, Hope W, Johnson E, Kathuria S, Lackner M, Lass-Flörl C, Lortholary O, Meis JF, Meletiadis J, Muñoz P, Richardson M, Roilides E, Tortorano AM, Ullmann AJ, van Diepeningen A, Verweij P, Petrikkos G; European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; European Confederation of Medical Mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014 Apr;20 Suppl 3:5-26. doi: 10.1111/1469-0691.12371. PMID: 24479848.
  2. García-Covarrubias L, Barratt DM, Bartlett R, Van Meter K. Tratamiento adjunto con oxigenación hiperbárica en mucormicosis. Presentación de cinco casos tratados en la misma institución y revisión de la literatura [Treatment of mucormycosis with adjunctive hyperbaric oxygen: five cases treated at the same institution and review of the literature]. Rev Invest Clin. 2004 Jan-Feb;56(1):51-5. Spanish. PMID: 15144043
  3. Gupta G, S R, Singh Y, Thangavelu L, Singh SK, Dureja H, Chellappan DK, Dua K. Emerging cases of mucormycosis under COVID-19 pandemic in India: Misuse of antibiotics. Drug Dev Res. 2021 Jul 29. doi: 10.1002/ddr.21862. Epub ahead of print. PMID: 34323298.
  4. Hooli SA, Gadre VN, Bage S, Gilvarkar MD. The aftermath of COVID-19 pandemic: Rhino-orbital mucormycosis. Indian J Anaesth. 2021 Jul;65(7):548-553. doi: 10.4103/ija.ija_371_21. Epub 2021 Jul 23. PMID: 34321687; PMCID: PMC8312397.
  5. Kumari A, Rao NP, Patnaik U, Malik V, Tevatia MS, Thakur S, Jaydevan J, Saxena P. Management outcomes of mucormycosis in COVID-19 patients: A preliminary report from a tertiary care hospital. Med J Armed Forces India. 2021 Jul;77:S289-S295. doi: 10.1016/j.mjafi.2021.06.009. Epub 2021 Jul 26. PMID: 34334896; PMCID: PMC8313063.
  6. Nair AG, Adulkar NG, D’Cunha L, Rao PR, Bradoo RA, Bapaye MM, Kothari A, Dave TV, Shinde CA. Rhino-orbital mucormycosis following COVID-19 in previously non-diabetic, immunocompetent patients. Orbit. 2021 Aug 1:1-6. doi: 10.1080/01676830.2021.1960382. Epub ahead of print. PMID: 34338124.
  7. Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, et al.; MucoCovi Network. Multicenter epidemiologic study of coronavirus disease–associated mucormycosis, India. Emerg Infect Dis. 2021 Sep [date cited]. https://doi.org/10.3201/eid2709.210934
  8. Singh R, Kumari A. Nasal Microbiota Imbalance as a Contributory Link in the Emergence of COVID-19 Associated Mucormycosis. ACS Infect Dis. 2021 Jul 30. doi: 10.1021/acsinfecdis.1c00371. Epub ahead of print. PMID: 34328718.

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