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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 5  |  Page : 1501-1504
Coronavirus Disease 2019-associated mucormycosis and cytomegalovirus coinfection in a kidney transplant recipient

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

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Date of Web Publication4-May-2022

How to cite this article:
Etta PK, Madhavi T, Avula NR. Coronavirus Disease 2019-associated mucormycosis and cytomegalovirus coinfection in a kidney transplant recipient. Saudi J Kidney Dis Transpl 2021;32:1501-4

How to cite this URL:
Etta PK, Madhavi T, Avula NR. Coronavirus Disease 2019-associated mucormycosis and cytomegalovirus coinfection in a kidney transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 May 25];32:1501-4. Available from: https://www.sjkdt.org/text.asp?2021/32/5/1501/344779

To the Editors,

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 leads primarily to lower respiratory tract infection but can cause cytokine storm and immune dysregulation with resultant multiorgan dysfunction, hypercoagulable state and can predispose to a variety of secondary infections. Emergence of invasive fungal infections associated with COVID-19 has 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 associated with COVID-19 have been previously reported, that to in non-transplant setting alone.[2],[3],[4] Mucormycosis and cytomegalovirus (CMV) coinfection in a kidney transplant recipient (KTR) was first reported by Ju et al in 2001.[5] Thereafter, similar reports were published across the world including from India.[6] However, to the best of our knowledge, the combination of mucormycosis and CMV co-infection was never reported in the post- COVID-19 setting in KTRs. We herein report a case of KTR affected with COVID-19-associated rhino-orbital mucormycosis and CMV coinfection which progressed to septic shock and death of the patient.

A 44-year-old male KTR was admitted with COVID-19 disease of moderate severity and treated elsewhere. He was having hypertension and posttransplant diabetes mellitus (PTDM). He underwent transplantation in January 2019 with mother-in-law as donor, with anti-thymocyte globulin (rATG) induction. He was on 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 in 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 non-invasive ventilation to maintain his oxygen saturation. Computed tomography (CT) severity index was moderate (10/25). Inflammatory markers and D-dimer were elevated moderately. MMF dose was reduced by 50%, but TAC was continued at same dose. Mild graft dysfunction was noted. He made a gradual recovery from COVID-19 at the end of two weeks. After about another week, he developed intermittent fever, facial pain, nasal stuffiness, which progressed to reduced vision in both eyes over a period of five days. He rapidly worsened and developed pancytopenia with 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 admission again. He was reinitiated on broadspectrum antibiotics and parenteral steroids. Chest and neuroimaging were performed. CT scan of the chest showed extensive tiny centrilobular nodules in both lungs, confluent ground-glass opacities in the right lower lobe and multiple larger nodules in the left lower lobe [Figure 1]a. In the presence of pancytopenia and with suspicion of CMV pneumonia, quantitative polymerase chain reaction was done, which confirmed CMV DNAemia. Both CT and magnetic resonance imaging (MRI) of the 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 orbital spread of infection from the ethmoid sinuses and roof of the maxillary sinuses [Figure 1]b. Few lacunar infarcts were also noted in cerebral hemispheres on MRI. Although clinically suspected, 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. Bronchoscopy could not be done in this case. Both MMF and TAC were stopped. Strict glycemic control was achieved. He was started on liposomal amphotericin B (5 mg/kg) and IV ganciclovir. 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 1]c. Later, IV posaconazole was also added as there was no improvement. Blood culture revealed growth of multidrug resistant Acinetobacter baumani. 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 from septic shock on day 13 of his admission.
Figure 1: (a) HRCT axial section of the lungs reveals multiple tiny nodules in both lungs and small patchy consolidations in the superior segment of right lower lobe. (b) Non-contrast CT axial section at the level of the orbits reveals soft tissue opacification of the visualised right maxillary, bilateral ethmoid and sphenoid sinuses (air fluid level in the left sphenoid sinus) with erosion of lateral walls of bilateral ethmoid sinuses with soft tissue density in medial aspects of both orbits suggesting orbital spread of infection from the ethmoid sinuses. (c) CT coronal image of paranasal sinuses, bone window showing post-maxillectomy changes and dehiscence of the lamina papyracea.

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Mucormycosis (zygomycosis or phycomycosis) is a rare, life-threatening, rapidly progressive, devastating, 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 the diabetes and the mucormycosis. There are several reports of MM even in relatively immunocompetent patients from India.[7] Both rhino-orbital-cerebral and pulmonary mucormycosis have been described post-COVID-19. However, there are no published reports of mucormycosis triggered by COVID-19 in transplant recipients. To our knowledge this is the first reported case of COVID-19 associated mucormycosis in the posttransplant setting; and another peculiarity of our case is associated CMV coinfection.

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 - use of glucocorticoids and monoclonal antibodies (such as tocilizumab) for the 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 mucormycosis. 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 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. CMV infection can also exhibit a direct immunomodulatory effect and is known to precipitate secondary infections (including mucormycosis) in KTRs.[8] Many of the above-mentioned risk factors including CMV coinfection were existing in our patient which led to a lethal outcome. Though 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 mucormycosis 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 management of invasive fungal infections associated with COVID-19.[9] There is no biomarker for mucormycosis and hence a negative galactomannan and (1,3)-β-D-glucan are not useful to rule out the diagnosis. Biopsy remains the mainstay of diagnosis in majority of the cases. Gomori’s methenamine silver (GMS) stain shows characteristic broad, aseptate, irregular non-dichotomous 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 mucormycosis was proposed.[10] The drugs effective against mucormycosis 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 the multiple fatal infections. This case highlights the need for high index of suspicion for invasive fungal infections associated with COVID-19, and CMV by its immunomodulatory effect, might also precipitate or worsen secondary infections.

Conflict of interest: None declared.

   References Top

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
Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med 2021;42: 264.e5-8.  Back to cited text no. 2
Mekonnen ZK, Ashraf DC, Jankowski T, 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
Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus 2020;12:e10726.  Back to cited text no. 4
Ju JH, Park HS, Shin MJ, et al. Successful treatment of massive lower gastrointestinal bleeding caused by mixed infection of cytomegalovirus and mucormycosis in a renal transplant recipient. Am J Nephrol 2001;21: 232-6.  Back to cited text no. 5
Nandwani A, Jha PK, Duggal R, Kher V. Invasive gastric mucormycosis and cytomegalovirus infection in an ABO incompatible renal transplant recipient. Indian J Nephrol 2015;25:373-6.  Back to cited text no. 6
[PUBMED]  [Full text]  
Bhadauria D, Etta P, Chelappan A, 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. 7
Freeman RB Jr. The ‘indirect’ effects of cytomegalovirus infection. Am J Transplant 2009;9:2453-8.  Back to cited text no. 8
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. 9
Cornely OA, Alastruey-Izquierdo A, Arenz D, 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. 10

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

DOI: 10.4103/1319-2442.344779

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