A case series of invasive mucormycosis in patients with COVID-19 infection

INTRODUCTION

Zygomycetes comprises of mucorales and entomothorales. The former order causes life threatening fungal infections, mucormycosis mainly in immunocompromised hosts while the latter order causes superficial and mucocutaneous infections in immunocompetent hosts. Among Mucoraceae, Rhizopus oryzae is the most common cause of infection.¹ Phagocytes are the major host defense mechanism against mucormycosis.^2,3 Additionally, corticosteroid treatment affects the ability of macrophages to prevent the germination of the spores of these fungi. A hallmark of mucormycosis infection is the presence of extensive angioinvasion with resultant vessel thrombosis and tissue necrosis.⁴

In the current times there is a pandemic due to COVID-19. It is a nonsegmented negative sense RNA virus which causes profound lymphopenia. In later stages of infection, when viral replication accelerates, epithelial-endothelial barrier integrity is compromised and the inflammatory response and triggering an influx of monocytes and neutrophils is accentuated. Collectively, endothelial barrier disruption, dysfunctional alveolar-capillary oxygen transmission and impaired oxygen diffusion capacity are characteristic features of COVID-19.⁵ Recently, we have noticed that there is an increase in the incidence of invasive mucormycosis infections in COVID-19 disease. We have come across 10 such cases and all the cases were found to have some similarities. Here we presented to you a case series of 10 cases.

CASE SERIES

We retrospectively reviewed patients with rhino-orbito-cerebral mucormycosis and COVID 19 infection admitted at our centre and managed by the departments of infectious diseases and otorhinolaryngology from August to December 2020. The medical records were retrieved and the demographic findings along with clinical, histopathological and radiological data were reviewed. 4 of the 10 patients were diagnosed and managed for COVID-19 at our hospital. Remaining (6 out of 10) were treated for COVID-19 at outside centers. Details of these patients are described in Table 1. Mucormycosis was diagnosed and treated for all the patients in our hospital. The mean age of our patients was 55.8 years (range 37 to 78 years), wherein 8 of the 10 patients were diabetic. Eye pain, facial pain and nasal block were the presenting complaints. All the patients had imaging evidence in the form of CT PNS and MRI brain revealing mucosal thickening of sinuses and adjacent bony erosions (Figure 1 and 2). Orbital involvement was also seen in few cases. 6 of the 10 patients (60%) received steroids and one patient received tocilizumab for the management of COVID-19. Except one patient, others had underlying comorbidities like diabetes mellitus, hypertension and/or chronic kidney disease. Only one patient at presentation had severe COVID-19 disease, rest of the patients had mild and moderate disease. All the patients were treated similarly with adequate local debridement of the infected and necrotic tissue along with IV amphotericin B in addition to treatment of COVID-19 disease. One patient was lost to follow up and the overall mortality was 44.4% (4 of the 9).

DISCUSSION

Our case series highlights the possibility of a correlation between COVID-19 and mucormycosis infections. We know from the pathogenesis of mucormycosis that mononuclear and polymorphonuclear phagocytes of normal hosts kill mucorales by generation of oxidative metabolites and defensins, hence neutropenic patients and those with dysfunctional phagocytes are susceptible to develop invasive mucormycosis.^2,3 In COVID-19 there is profound lymphopenia and in advanced infections viral replication accentuates the inflammatory response and neutrophil and monocyte influx in the blood stream.⁵ This leads to an imbalance between neutrophil and lymphocyte action making the patient more susceptible to systemic fungal infections.

The hallmark recovery trail emphasized the use of steroids in reducing the need of invasive ventilation in hypoxic patients and the hospital stay and ultimately decreasing the mortality. Administration of steroids results in a neutrophilic leukocytosis and the impaired ability of leukocytes to migrate to the site of inflammation due to its inhibitory effects on cytokines and chemokines. Steroids are also known to cause lymphopenia (T more than B cells). Prolonged use of glucocorticoids is known to increase the risk of the patient to infections especially many opportunistic ones.⁶ Recent published evidence say that COVID-19 is a pro-coagulable state and there is increased incidence of thrombotic events.⁵ This pro-coagulable state provides a perfect ground for the angioinvasion of mucor invasion due to vessel thrombosis and leading to disseminated infections. A study published by Song G et al in they have investigated a total of 99 patients of fungal infections post COVID-19 in China have found out that about 5% of these are due to Aspergillus and 7% Mucor species. They have concluded that the impairment of T cell immunity along with presence of underlying immunocompromised state is one of the most important pathogenesis.⁷ In a case report published by Mehta et al where they have reported a case of post COVID-19 rhino-orbital mucormycosis in which the patient received steroids according to the protocols after which he developed mucormycosis. According to their hypothesis it may be due to the alterations in the immunity especially T cells and innate immunity and the use of steroids may be the cause of invasive fungal infection post covid.⁸ Similar observations have been reported by Amanda et al from America and by Chaudhary et al from Delhi.^9,10

CONCLUSION

We propose that, patients with COVID-19 infection are susceptible to mucormycosis because of impairment of barrier defense, dysfunction of phagocytes and lymphocytes and the use of immunosuppressive medications such as steroids and tocilizumab. Treating clinicians need to be aware of the possibility of mucormycosis, in such patients particularly in those with underlying comorbidities. Early diagnosis and treatment of secondary fungal infections can substantially reduce morbidity and mortality.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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