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Table of Contents
LETTER TO EDITOR
Year : 2021  |  Volume : 15  |  Issue : 4  |  Page : 385-387

Emergence of invasive fungal infections in the COVID-19 pandemic


1 Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad, Telangana, India
2 Department of Radiodiagnosis, Niloufer Hospital, Hyderabad, Telangana, India

Date of Submission03-Feb-2021
Date of Decision04-Aug-2021
Date of Acceptance01-Sep-2021
Date of Web Publication30-Dec-2021

Correspondence Address:
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_6_21

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How to cite this article:
Etta PK, Madhavi T. Emergence of invasive fungal infections in the COVID-19 pandemic. Indian J Transplant 2021;15:385-7

How to cite this URL:
Etta PK, Madhavi T. Emergence of invasive fungal infections in the COVID-19 pandemic. Indian J Transplant [serial online] 2021 [cited 2022 Jan 26];15:385-7. Available from: https://www.ijtonline.in/text.asp?2021/15/4/385/334435



Sir,

Coronavirus disease-2019 (COVID-19) leads primarily to a lower respiratory tract pathology but can cause systemic immune dysregulation and cytokine storm with resultant multiorgan dysfunction, hypercoagulable state and can predispose to a variety of secondary infections. The emergence of invasive fungal infections associated with COVID-19 have been reported recently, especially in critically ill patients who required admission to the intensive care unit (ICU) or mechanical ventilation or had a longer duration of hospital stay.[1] The common secondary fungal pathogens are Aspergillus (COVID-19-associated pulmonary aspergillosis) and Candida. Only a limited number of cases of mucormycosis (MM) triggered by COVID-19 have been previously reported that to in nontransplant setting.[2],[3],[4] To the best of our knowledge, COVID-19-associated MM was never reported in transplant recipients. Recently, we have encountered a case of a kidney transplant recipient (KTR) affected with life-threatening COVID-19-associated rhino-orbital MM.

A 44-year-old male KTR was treated elsewhere for COVID-19 disease of moderate severity. He was having hypertension and posttransplant diabetes mellitus (PTDM). He underwent transplantation in January 2019 with his mother-in-law as a donor, with rabbit antithymocyte globulin (rATG) induction. He was on the standard triple-drug immunosuppression, i.e., steroids, tacrolimus (TAC), and mycophenolate mofetil (MMF). TAC trough level was optimal. Except for PTDM, his posttransplant course was uneventful until he was affected with COVID-19. He was admitted to ICU and received parenteral steroids, remdesivir, broad-spectrum antibiotics, and anticoagulants for COVID-19. He was changed to insulin therapy due to poor glycemic control. He required oxygen supplementation and intermittent noninvasive ventilation to maintain his oxygen saturation. Computed tomography (CT) severity index was moderate (13/25). Inflammatory markers and D-dimer were elevated moderately. MMF dose was reduced by 50%, but TAC was continued at the same dose. Mild graft dysfunction was noted. He made a gradual recovery from COVID-19 at the end of 2 weeks. After about another week, he developed intermittent fever, facial pain, and nasal stuffiness, which progressed to reduced vision in both eyes over a period of 5 days. He rapidly worsened and developed persisting fever. Blood and urine cultures were sent. The patient was transferred to our center due to the deterioration in the clinical condition of the patient. He was breathless and required ICU readmission. He was reinitiated on broad-spectrum antibiotics and parenteral steroids. Chest and neuroimaging were performed. Both CT and magnetic resonance imaging (MRI) brain revealed significant mucosal thickening in the right frontal, bilateral maxillary, ethmoid, and sphenoid sinuses. The nasal turbinates were enlarged and associated with soft-tissue opacification of bilateral nasal cavities, with extension into surrounding tissues including bilateral infratemporal fossa. There was soft-tissue swelling in medial aspects of both orbits with bulky extraocular muscles, suggesting the orbital spread of infection from the ethmoid sinuses and roof of the maxillary sinuses [Figure 1]. Few lacunar infarcts were also noted in cerebral hemispheres on MRI. Although clinically suspected, the extension of infection to cavernous sinuses was not documented on imaging. Nasal endoscopy and tissue biopsy revealed broad aseptate filamentous fungal hyphae. Serum galactomannan assay was negative. Awaiting culture reports, treatment was started for suspected MM. Both MMF and TAC were stopped. Strict glycemic control was achieved. He was started on liposomal amphotericin B (5 mg/kg/day). Local debridement with partial maxillectomy was performed. Hard palate, floor, and medial walls of bilateral maxillary sinuses and inferior portion of the bony nasal septum were resected [Figure 2]. Later, IV Posaconazole was also added as there was no improvement. Blood culture revealed the growth of multidrug-resistant Acinetobacter baumannii. Parenteral nutrition was also given along with Ryle's tube feeds. The patient continued to deteriorate was ventilated and eventually required inotropic support. Despite all measures, he succumbed fromseptic shock on day 13 of his admission.
Figure 1: Noncontrast computed tomography axial section at the level of the orbits reveals soft-tissue opacification of the visualized portion of right maxillary, bilateral ethmoid, and sphenoid sinuses (with air fluid level) with erosion of lateral walls of ethmoid sinuses with soft-tissue density in medial aspects of both orbits suggesting orbital spread of infection from the ethmoid sinuses

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Figure 2: Noncontrast computed tomography coronal section of the paranasal sinuses, bone window showing postoperative changes (such as maxillectomy), and dehiscence of the right lamina papyracea

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MM (zygomycosis or phycomycoses) is a rare, life-threatening, rapidly progressive, devastating, and angioinvasive fungal infection caused by a group of filamentous fungi of the class zygomycetes. Most cases are caused by Rhizopus. India is considered to be the “capital” of the world for both diabetes and MM. There are several reports of MM even in relatively immunocompetent patients from India.[5] Both rhino-orbital-cerebral and pulmonary MM have been described postCOVID-19. However, there are no published reports of MM triggered by COVID-19 in transplant recipients. To our knowledge, this is the first reported case of COVID-19-associated MM in the posttransplant setting.

Physicians should be aware of the possibility of secondary invasive fungal infections in patients with COVID-19, especially in patients with predisposing factors such as the use of glucocorticoids and monoclonal antibodies (such as tocilizumab) for treatment of COVID-19, uncontrolled diabetes mellitus (especially ketoacidosis), prolonged neutropenia/lymphopenia, treatment with broad-spectrum antibiotics, hematopoietic stem cell or solid organ transplantation, chronic obstructive pulmonary disease, malignancy, cystic fibrosis, and parenteral nutrition. Hyperglycemia leads to increased expression of the endothelial receptor GRP78, resulting in polymorphonuclear dysfunction, impaired chemotaxis, and defective intracellular killing. Iron is an essential element for the growth of Mucorales. In conditions of ketoacidosis, free iron becomes readily available in the serum. This excess endogenous iron is efficiently taken up by the Mucorales, further enhancing their virulence. Hemochromatosis and treatment with iron chelators such as deferoxamine increase the risk of MM. High serum ferritin level may also predispose to it. Corticosteroids cause impairment in the neutrophil migration, ingestion, and phagolysosome fusion. In addition, steroid-induced hyperglycemia further worsens the vulnerability to the development of MM. In addition to the local erosion of the epithelial barrier of the respiratory tract, systemic immune dysregulation, and cytokine storm of COVID-19 may predispose to secondary infections. COVID-19-associated microvascular coagulation can cause ischemic tissue injury, which may also play a role in pathogenesis. Many of the abovementioned risk factors were existing in our patient which led to a lethal outcome. Although remote, exposure to rATG which is a T-cell depleting agent, and others such as prolonged ICU stay, parenteral nutrition, and renal (graft) dysfunction might have also played a role.

Early diagnosis and treatment of MM may significantly reduce morbidity and mortality, as it is associated with very high mortality rate despite active management. Song et al. have suggested an algorithm for the early diagnosis and the management of invasive fungal infections associated with COVID-19.[6] There is no biomarker for MM, and hence a negative galactomannan and (1,3)-β-D-glucan arenot useful to rule out the diagnosis. Biopsy remains the mainstay of diagnosis in the majority of the cases. Gomori's methenamine silver stain shows characteristic broad, aseptate, irregular nondichotomous right-angled branching fungal hyphae. Microscopy with the use of 10% potassium hydroxide and Calcofluor stain may help in few cases. Mucor is difficult to routinely culture. Treatment principles include early aggressive complete surgical debridement, systemic antifungal therapy, and reversal of underlying predisposing factors. Recently, a global guideline for the diagnosis and management of MM was proposed.[7] The drugs effective against MM include amphotericin B, posaconazole, and isavuconazole. The conventional amphotericin B deoxycholate is associated with a high incidence of adverse events and is not recommended but may be the only option in resource-limited settings. Lipid formulations are especially useful in patients with renal failure and can be given at higher doses with fewer side effects. Despite best possible efforts, unfortunately, our patient succumbed to multiple fatal infections. This case highlights the need for a high index of suspicion for COVID-19-associated invasive fungal infections, especially in patients with predisposing factors including transplant recipients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Gangneux JP, Bougnoux ME, Dannaoui E, Cornet M, Zahar JR. Invasive fungal diseases during COVID-19: We should be prepared. J Mycol Med 2020;30:100971.  Back to cited text no. 1
    
2.
Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med 2021;42:264.e5-264.e8.  Back to cited text no. 2
    
3.
Mekonnen ZK, Ashraf DC, Jankowski T, Grob SR, Vagefi MR, Kersten RC, et al. Acute invasive rhino-orbital mucormycosis in a patient with COVID-19-associated acute respiratory distress syndrome. Ophthalmic Plast Reconstr Surg 2021;37:e40-80.  Back to cited text no. 3
    
4.
Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus 2020;12:e10726.  Back to cited text no. 4
    
5.
Bhadauria D, Etta P, Chelappan A, Gurjar M, Kaul A, Sharma RK, et al. Isolated bilateral renal mucormycosis in apparently immunocompetent patients - A case series from India and review of the literature. Clin Kidney J 2018;11:769-76.  Back to cited text no. 5
    
6.
Song G, Liang G, Liu W. Fungal co-infections associated with global COVID-19 pandemic: A clinical and diagnostic perspective from China. Mycopathologia 2020;185:599-606.  Back to cited text no. 6
    
7.
Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SC, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: An initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis 2019;19:e405-21.  Back to cited text no. 7
    


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