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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 18  |  Issue : 3  |  Page : 192-195

COVID-19–associated central nervous system mucormycosis


1 Department of Critical Care Medicine, Holy Family, Indraprastha Apollo Hospital, New Delhi, India
2 Department of Neurosciences, Indraprastha Apollo Hospital, New Delhi, India

Date of Submission23-Jul-2021
Date of Decision18-Aug-2021
Date of Acceptance20-Aug-2021
Date of Web Publication18-Sep-2021

Correspondence Address:
Pushpendra Nath Renjen
Department of Neurosciences, Indraprastha Apollo Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_84_21

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  Abstract 


Mucormycosis is a life-threatening infection caused by fungi of the order Mucorales. Central nervous system (CNS) mucormycosis is usually an extension of the infection from the sinuses to the eyes and brain. CNS mucormycosis arises from an adjacent paranasal sinus infection (rhinocerebral) by direct extension or hematogenous dissemination from the lungs, but isolated CNS mucormycosis is a rare presentation. During an episode of fungemia, seeding may occur in brain tissue, leading to this infection. The most common clinical presentation of mucormycosis is rhino-orbital-cerebral infection, which is presumed to start with inhalation of spores into the paranasal sinuses of a susceptible host. In this article, we emphasize on the COVID-19–associated mucormycosis, particularly the involvement of CNS.

Keywords: COVID-19–associated mucormycosis, central nervous system, coronavirus disease 2019, fungal infection, mucormycosis, rhino-orbital-cerebral mucormycosis


How to cite this article:
Mishra A, Chaudhari DM, Renjen PN. COVID-19–associated central nervous system mucormycosis. Apollo Med 2021;18:192-5

How to cite this URL:
Mishra A, Chaudhari DM, Renjen PN. COVID-19–associated central nervous system mucormycosis. Apollo Med [serial online] 2021 [cited 2021 Dec 6];18:192-5. Available from: https://www.apollomedicine.org/text.asp?2021/18/3/192/326242




  Introduction Top


The pandemic coronavirus disease 2019 (COVID-19) continues to be a significant problem, worldwide. While several treatment options have been evaluated, none except systemic glucocorticoids have been shown to improve survival in COVID-19. Unfortunately, the widespread use of glucocorticoids can lead to secondary bacterial or fungal infections. Invasive pulmonary aspergillosis complicating the course of COVID-19 is widely recognized;[1] however, mucormycosis is uncommonly suspected or diagnosed. Besides the diffuse alveolar damage with severe inflammatory exudation, COVID-19 patients always have immunosuppression with a decrease in CD4+T and CD8+T cells.[2] Critically ill patients, especially the patients who were admitted to the intensive care unit (ICU) and required mechanical ventilation, or had a longer duration of hospital stays, even as long as 50 days, were more likely to develop fungal coinfections.[3]

Initially, it was debated whether a person taking immunosuppressants, such as corticosteroids, and monoclonal antibodies will be at higher risk for COVID-19 or whether the immunosuppressive state would cause a more severe COVID-19 disease. However, immunosuppressants are currently continued unless the patients are at greater risk of severe COVID-19 infection or are on high-dose corticosteroids therapy. As understood so far, COVID-19 infection may induce significant and persistent lymphopenia, which in turn increases the risk of opportunistic infections. It is also noted that 85% of the COVID-19 patients' laboratory findings showed lymphopenia. This means that patients with severe COVID-19 have markedly lower absolute number of T-lymphocytes, CD4+ T cells, and CD8+ T cells, and since the lymphocytes play a major role in maintaining the immune homeostasis, the patients with COVID-19 are highly susceptible to fungal coinfections.[4]


  Mucormycosis Top


Mucormycosis is a life-threatening infection caused by fungi of the order Mucorales. Recent re-classification has abolished the class Zygomycetes and placed the order Mucorales in the subphylum Mucormycotina.[5] Therefore, we refer to infection caused by Mucorales as mucormycosis rather than zygomycosis.[6]

The genera in the order Mucorales cause most human infection. The genera most commonly found in human infections are Rhizopus, Mucor, and Rhizomucor; Cunninghamella, Absidia (now reclassified as Lichtheimia), Saksenaea, and Apophysomyces are genera that are less commonly implicated in infection.[7]


  Pathogenesis Top


  • Hyperglycemia – Rhizopus organisms have an enzyme, ketone reductase, which allows them to thrive in high glucose, acidic conditions. Serum from healthy individuals inhibits growth of Rhizopus, whereas serum from individuals in diabetic ketoacidosis stimulates growth.[8] Rhino-orbital-cerebral mucormycosis (ROCM) and pulmonary mucormycosis are acquired by the inhalation of spores
  • Deferoxamine and iron overload – Deferoxamine, which chelates both iron and aluminum, increases the risk of mucormycosis by enhancing growth and pathogenicity.[9]



  Central Nervous System Mucormycosis Top


CNS mucormycosis is usually an extension of the infection from the sinuses to the eyes and brain. Isolated cerebral mucormycosis is extremely rare. In a meta-analysis of 929 cases, CNS disease was described in 30% of the cases, and out of these cases, only 16% were confined to the CNS.[7] In most of these cases, cerebral mucormycosis resulted from the spread of a rhinocerebral infection, while isolated CNS cases tended to be a result of disseminated fungal infection and were particularly common among intravenous (IV) drug users. In such cases, the basal ganglia were the most common site involved. This predilection to the basal ganglia is interesting; the sporangiospore size is thought to facilitate the distribution of the fungus to the basal ganglia through the striatal arteries. In addition, high levels of iron in the basal ganglia stimulate further fungal growth.[10]


  Rhino-Orbital-Cerebral Mucormycosis Top


The most common clinical presentation of mucormycosis is rhino-orbital-cerebral infection, which is presumed to start with inhalation of spores into the paranasal sinuses of a susceptible host. Hyperglycemia, usually with an associated metabolic acidosis, is the most common underlying condition. Rhinocerebral mucormycosis most commonly presents in an acute setting, reminiscent of sinusitis, or periorbital cellulitis. Facial pain and unilateral facial swelling are also important parts of the clinical picture of the patient, with variable grade fever being present although not in all cases.[11]

Progression of the infection to CNS is heralded by the development of confusion and disorientation, with bloody nasal discharge also reported as a potentially early sign of disease extension to the brain.[11] CNS damage may also result from cavernous sinus thrombosis and internal carotid artery encasement, leading to cerebral infractions and hematogenous dissemination of the disease to other organ sites.[12]


  COVID-19–Associated Mucormycosis Top


COVID-19 has already claimed more than one million lives, worldwide. In the absence of an effective vaccine or antiviral therapy, supportive care plays a vital role in the management of COVID-19. Glucocorticoids and probably remdesivir are the only drugs proven to be beneficial in COVID-19. Glucocorticoids are inexpensive, widely available, and have been shown to reduce mortality in hypoxemic patients with COVID-19.[13] However, diabetes/steroid-induced hyperglycemia appears to be more likely than other conditions to predispose to rhinocerebral infection, but the reason for this is unknown.[14] Glucocorticoids can increase the risk of secondary infections. Moreover, the immune dysregulation caused by the virus and the use of concurrent immunomodulatory drugs such as tocilizumab could further increase the risk of infections in COVID-19 patients. The presence of multiple risk factors or comorbid illnesses in severe COVID-19 patients, along with the additional immunosuppression caused by glucocorticoids, increases the net state of immune suppression, thereby predisposing them to invasive mold infections.[15]


  Diagnosis Top


There are currently no clinically available circulating biomarkers of mucormycosis. Therefore, definitive diagnosis relies on microbiological analyses of tissue obtained by biopsy or surgical debridement.[16] Presumptive diagnosis can be made by direct microscopic examination of fresh tissue. The sensitivity of direct microscopy is greatly enhanced with the use of optical brighteners, such as Calcofluor white, and fluorescence microscopy. Direct microscopy eaxmination showing of nonseptate (or pauciseptate) and broad (6–16 μm) hyphae with branching at right angles suggest Mucormycosis.

Sinus mucormycosis is seen on computed tomography and magnetic resonance imaging (MRI) as nonspecific nodular mucosal thickening. Inflammatory soft tissue infiltration frequently extends to subcutaneous facial tissue and to the infratemporal and temporal fossae.[17] Nonenhancing mucosal tissue within the involved sinuses and turbinates on contrast MRI (the “black turbinate” sign) may be helpful in differentiating mucormycosis from bacterial sinusitis, where mucosal contrast enhancement is usually detected.[17] This phenomenon is believed to be due to small-vessel occlusion and mucosal ischemia. Radiological evidence of bony destruction in the turbinate, sinus walls, orbital wall, skull base, or hard palate is observed in 40% of ROCM cases;[18] hence, the absence of bone destruction is not sufficient to exclude mucormycosis.[17] Extension to the orbit results in thickening and lateral displacement of the medial rectus muscle, preseptal edema, proptosis, and orbital fat infiltration, particularly at the orbital apex.


  Management Top


Successful treatment of mucormycosis requires surgical debridement of infected tissue, prompt institution of effective antifungal treatment, and correction of the underlying metabolic and immune derangement [Table 1].[18] IV amphotericin B (lipid formulation) (5–10 mg/kg/day IV for up to initial 28 days) is the drug of choice for initial therapy.[19] Posaconazole (300 mg twice a day orally for 1 days followed by 300 mg QD up to 6 months) or isavuconazole (200 mg TID orally for 2 days followed by 200 mg QD up to 6 months) is used as step-down therapy for patients who have responded to amphotericin B. Posaconazole or isavuconazole can also be used as salvage therapy for patients who do not respond to or cannot tolerate amphotericin B; for salvage therapy, the decision to use oral or IV posaconazole or isavuconazole depends on how ill the patient is, whether an initial course of amphotericin B was able to be administered, and whether the patient has a functioning gastrointestinal tract.[19] Isavuconazole is strongly supported as salvage treatment. Posaconazole delayed release tablets or infusions are strongly supported for salvage treatment, and when available should be preferred over posaconazole oral suspension. In cases of primary treatment failure with isavuconazole or posaconazole, the guideline group supports recommendations for all three lipid-based amphotericin B formulations with strong to moderate strength.[20]
Table 1: Recommendations for treatment of central nervous system mucormycosis[18]

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Amphotericin B is the drug of choice for initial therapy; most clinicians use a lipid formulation of amphotericin B (rather than amphotericin B deoxycholate) to deliver a high dose with less nephrotoxicity. The usual starting dose is 5 mg/kg daily of liposomal amphotericin B or amphotericin B lipid complex, and many clinicians will increase the dose as high as 10 mg/kg daily in an attempt to control this infection.[21] There are anecdotal reports of using combination therapy with amphotericin B and either posaconazole or an echinocandin. However, there are no convincing data to support any form of combination therapy, and combination therapy is not recommended in the major treatment guidelines.[21]


  Conclusion Top


  • Progressive and rapid involvement of the cavernous sinus, vascular structures, and intracranial contents is the usual evolution of rhinocerebral mucormycosis
  • Rhinocerebral mucormycosis remains a difficult to treat disease with high mortality rate
  • Treatment of mucormycosis involves a combination of surgical debridement of involved tissues and antifungal therapy. Aggressive surgical debridement of involved tissues should be undertaken as soon as the diagnosis of ROCM is suspected.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Arastehfar A, Carvalho A, van de Veerdonk FL, Jenks JD, Koehler P, Krause R, et al. COVID-19 associated pulmonary aspergillosis (CAPA)-from immunology to treatment. J Fungi (Basel) 2020;6:91.  Back to cited text no. 1
    
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Sehgal A, Raghavendran M, Kumar D, Srivastava A, Dubey D, Kumar A. Rhinocerebral mucormycosis causing basilar artery aneurysm with concomitant fungal colonic perforation in renal allograft recipient: A case report. Transplantation 2004;78:949-50.  Back to cited text no. 12
    
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Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Kong DC, et al. The epidemiology and clinical manifestations of mucormycosis: A systematic review and meta-analysis of case reports. Clin Microbiol Infect 2019;25:26-34.  Back to cited text no. 14
    
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Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, et al. Coronavirus disease (COVID-19) associated mucormycosis (CAM): Case report and systematic review of literature. Mycopathologia 2021;186:289-98.  Back to cited text no. 15
    
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Schelenz S, Barnes RA, Barton RC, Cleverley JR, Lucas SB, Kibbler CC, et al. British Society for Medical Mycology best practice recommendations for the diagnosis of serious fungal diseases. Lancet Infect Dis 2015;15:461-74.  Back to cited text no. 16
    
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Introduction
Mucormycosis
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Central Nervous ...
Rhino-Orbital-Ce...
COVID-19–A...
Diagnosis
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Conclusion
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