EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Coronavirus 2019, Immunosuppression, Kidney transplant, Opportunistic infection, Proptosis

The immune dysregulation caused by COVID-19 and use of concurrent immunomodulatory drugs such as tocilizumab could further increase the risk of secondary infections in patients with COVID-19.¹ Secondary bacterial and fungal infections or coinfections are important challenges that increase patients’ risk of morbidity and mortality, due to COVID-19 itself and/or due to the concurrent immunomodulatory treatments.¹

Mucormycosis is a rare, life-threatening oppor-tunistic fungal infection characterized by vascular invasion of the hyphae.² Herein, we describe a case of rhino-orbital-cerebral mucormycosis (ROCM) in a 50-year-old woman with a previous renal transplant and with a recently acquired COVID-19 infection.

A 50-year-old woman who received a deceased donor kidney transplant 10 years previously was admitted to our hospital and presented with shortness of breath and mild respiratory failure 3 days after she had received a positive test result for a COVID-19 infection. She was on immunosup-pressive treatment with tacrolimus, mycophenolate sodium, and prednisone, with a baseline creatinine of 1.3 to 1.6 mg/dL. The patient was started on a treatment regimen of favipiravir, lopinavir-ritonavir, acetylsalicylic acid, prophylactic low-molecular-weight heparin, and methylprednisolone (40 mg/d).

The patient was admitted to the inpatient service. After her hospitalization, mycophenolate sodium was discontinued but tacrolimus was continued. The patient was followed up with nasal oxygen therapy to satisfy oxygen demand. The patient received 40 mg daily of methylprednisolone for 10 days. On day 10 of her follow-up, the patient was switched from nasal oxygen to high-flow oxygen therapy to mitigate acute respiratory distress.

During follow-up at inpatient service, the patient developed pain, edema, and proptosis in the right eye. On day 11 of follow-up, she was transferred to intensive care in response to the deterioration in her clinical condition. The patient’s physical examination on admission showed that she was conscious, oriented, and cooperative, but with weak light reflex, chemosis, edema, and proptosis in the right eye. We also observed an ecchymotic necrotic area medial to the right eyelid and ophthalmoplegia (Figure 1). The otolaryngologist evaluated the patient and observed a necrotic area on the uvula and a black crusty area in the nasal cavity; subsequent biopsy and culture sampling were performed with prediagnoses of mucor and vasculitis.

The patient underwent a complete systemic and laboratory evaluation. Relevant baseline investigations revealed a hemoglobin value of 9.9 g/dL, lymp-hopenia of 1.5%, and serum creatinine of 1.34 mg/dL. C-reactive protein was 48 mg/L, procalcitonin was 0.34 ng/mL, D-dimer assay was 1547 ng/mL, level of interleukin 6 was 3439 mg/mL, and hemoglobin A1C was 7.1%. A reverse-transcriptase polymerase chain reaction test from a nasopharyngeal swab was positive for the SARS-CoV-2 virus. Widespread consolidated patchy areas of ground-glass and cobblestone appearance in both lungs were detected on a thorax computed tomography (CT) image of the patient, and CT imaging also revealed a right-side orbital abscess. Paranasal CT imaging showed inflammatory mucosal thickenings in both frontal sinuses, the right-side sphenoid sinus, ethmoid cells, and both maxillary sinuses. Magnetic resonance imaging with cranial contrast revealed a right-side frontal corticosubcortical area of acute ischemia that extended from the gyrus rectus to a superior parasagittal position. In addition, magnetic resonance imaging detected acute ischemia in the form of focal millimetric foci in (1) the right-side frontal and parietal cortex, centrum semiovale; (2) the right-side temporobasal, deep white matter posterior to the right-side lateral ventricle trunk; (3) the right-side occipital cortex; and (4) the right-side optic tract (Figure 2).

With the preliminary diagnosis of mucormycosis, the patient was started on a regimen of intravenous meropenem (2 g twice daily) and vancomycin (1 g twice daily) with the addition of both local and intravenous amphotericin B (0.5 mg/kg/d). Methylprednisolone was reduced (10 mg/d), and tacrolimus was discontinued. The patient received 10 mg/d of methylprednisolone for 10 days from day 11, which was the day of admission to the intensive care unit, until her death. She also received subcutaneous enoxaparin (40 mg/0.6 mL) twice daily. She was intubated and connected to a mechanical ventilator to treat the deterioration of respiratory function.

No growth was observed in the tissue culture of the patient. The histopathological evaluation showed suppurative inflammation and broad nonseptate hyphae branching at right angles, consistent with mucormycosis. Results of Grocott-Gomori methe namine silver (GMS) stain and hematoxylin-eosin stain were also consistent with mucormycosis (Figure 3). For this reason, the diagnosis of mucormycosis was confirmed on day 13, ie, 2 days after the patient had been admitted to the intensive care unit.

The patient underwent debridement of the involved sinuses, but mucormycosis spread to the orbit. Norepinephrine therapy was initiated to maintain mean arterial pressure when it was observed that the blood pressure of the patient remained low despite adequate fluid therapy. The patient was evaluated by an ophthalmologist, and exenteration was performed. Exitus was observed on the 10 days after transfer to the intensive care unit (day 21 after hospital admission).

Mucormycosis, an asexual spore-forming fungus, can infect the oral and nasal cavities via inhalation. Spores are typically removed by phagocytic leukocytes in a normal, healthy immune system.³ Mucormycosis has an affinity to invade blood vessels, with resultant thrombosis and tissue necrosis.^2,3 Interaction of the fungal spores with endothelial cells facilitates angioinvasion and progression to the intracranial region, involves the cavernous sinuses and intracranial arteries (primarily the internal carotid artery), and may cause arterial thrombi that can result in cerebellar and cerebral infarction.² The global incidence rate of mucormycosis varies from 0.005 to 1.7 cases per million population.⁴ The global case-fatality rate of mucormycosis is 46%.⁵ However, factors such as intracranial or orbital involvement or irreversible immunosuppression increase the case-fatality rate to as high as 50% to 80%.⁶

The main risk factors for mucormycosis are diabetes mellitus, leukemia, antibiotic treatment, treatment with antineoplastic agents, immunosup-pressive therapy, corticosteroid treatment, protein-calorie nutrition, solid-organ and bone marrow transplant, drug addiction, and AIDS.⁷

Patients with COVID-19 have an increased risk of bacterial and fungal infections. Mucormycosis is an opportunistic fungal infection, which ranks third for all opportunistic infections among COVID-19 patients. The cause of mucormycosis infection in patients with COVID-19 is complex, and the important factors are comorbid diseases; use of glucocorticoids and immunosuppressive agents such as tocilizumab; preexisting lung conditions; and the interaction of factors such as the immune system changes caused by the COVID-19 virus itself, such as a decrease in the number of T lymphocytes, CD4⁺ T cells, and CD8+ T cells.⁸ Corticosteroid treatment impairs macrophage functions such as migration, engulfment, and phagolysosome formation. Long-term (>3 weeks) use of high-dose systemic corti-costeroids is a known risk factor for mucormycosis; however, cases of mucormycosis associated with short-term corticosteroid treatments have also been reported.⁹ Our patient had a renal transplant 10 years previously and a long-term history of treatment with tacrolimus and prednisolone (4 mg). In addition, she had impaired immune response and widespread lung involvement due to COVID-19.

The rates of posttransplant fungal infections were approximately 2% to 14%.10 Mucormycosis is associated with the longest duration of hospita-lization and the lowest rate of 2-year survival in renal transplant patients, although it comprises only 2% to 6% of invasive fungal infection.11 Mucormycosis is a rare complication in solid-organ transplants. Song and colleagues have published a review of 123 studies published from 1970 to 2015 and extracted 174 cases of mucormycosis.¹²

Our patient developed ROCM, which occurs in approximately 40% of mucormycosis cases.² Other forms of mucormycosis are seen in pulmonary, cutaneous, gastrointestinal, and central nervous systems, but it is rarely in disseminated form.² In the literature, Arana and colleagues have reported 2 diagnosed cases of rhinosinusal and musculoskeletal mucormycosis in 2 renal transplant patients who were followed up for COVID-19 pneumonia.¹³ Additionally, Meshram and colleagues have reported a case of rhino-orbital and pulmonary mucormycosis that developed after COVID-19 infection in 2 renal transplant patients.¹⁴ To the best of our knowledge, our patient is the first case of ROCM in the co-occurrence of renal transplant and COVID-19.

Radiological findings include inflammatory changes, thickening, and tissue loss due to the develop-ment of necrosis in the surrounding maxil-lofacial skin and subcutaneous tissues, and bone destruction in the sinus walls as revealed on CT images. In the involvement of cavernous sinus and intracranial arteries, areas of cerebellar/cerebral hypodensity due to the development of infarction were detected on CT.^1,2 In addition, cranial magnetic resonance imaging, which is indicated for cerebral involvement, revealed presence of foci of acute ischemia.¹

Histopathological staining is required for defi-nitive diagnosis of mucormycosis.⁴ The histological stains that identify the mucor structures include hematoxylin-eosin stain, periodic acid-Schiff stain, and GMS stain.² In our histopathological evaluation of the patient, we observed suppurative inflam-mation and broad nonseptate hyphae branching at right angles, consistent with mucor-mycosis. Results of hematoxylin-eosin stain and GMS stain were also positive.

Rhino-orbito-cerebral mucormycosis is a deadly infection, and mortality increases to 50% to 85% as a result of brain involvement.² The most important indicator of mortality is early diagnosis and treatment. Treatment of mucormycosis includes a multimodal approach that includes systemic antifungal therapy, surgical debridement, and reduction/discontinuation of immunosuppression to the extent possible.³ A combination of systemic liposomal amphotericin B and local irrigation with diluted amphotericin B is recommended as antifungal therapy. Many studies have suggested orbital exenteration in the presence of focal mass or extensive necrotic tissue.^2,3

In our case, intravenous amphotericin B was started and paranasal sinuses were debrided, and then we performed orbital exenteration irrigated with dilute amphotericin B. Immunosuppressive treatments were arranged according to the recom-mendations of a nephrologist. The patient died despite medical treatment and surgery.

This is the first reported case of ROCM in a renal transplant recipient with COVID-19. Mucormycosis may develop as the result of the COVID-19 disease itself and/or the treatment associated with COVID-19 pneumonia. Awareness should be maintained that this risk may be further increased in immunosup-pressed patients who have received a solid-organ transplant, such as a kidney.

Volume: 20 Issue: 2 February 2022

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