key: cord-1047649-5p9og4d8
authors: Singh, Awadhesh Kumar; Singh, Ritu; Joshi, Shashank R.; Misra, Anoop
title: Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India
date: 2021-05-21
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2021.05.019
sha: 569f53f740cb64842cf349e77ee8f6cf7e6a921d
doc_id: 1047649
cord_uid: 5p9og4d8

BACKGROUND AND AIMS: There are increasing case reports of rhino-orbital mucormycosis in people with coronavirus disease 2019 (COVID-19), especially in India. Diabetes mellitus (DM) is an independent risk factor for both severe COVID-19 and mucormycosis. We aim to conduct a systematic review of literature to find out the patient's characteristics having mucormycosis and COVID-19. METHODS: We searched the electronic database of PubMed and Google Scholar from inception until May 13, 2021 using keywords. We retrieved all the granular details of case reports/series of patients with mucormycosis, and COVID-19 reported world-wide. Subsequently we analyzed the patient characteristics, associated comorbidities, location of mucormycosis, use of steroids and its outcome in people with COVID-19. RESULTS: Overall, 101 cases of mucormycosis in people with COVID-19 have been reported, of which 82 cases were from India and 19 from the rest of the world. Mucormycosis was predominantly seen in males (78.9%), both in people who were active (59.4%) or recovered (40.6%) from COVID-19. Pre-existing diabetes mellitus (DM) was present in 80% of cases, while concomitant diabetic ketoacidosis (DKA) was present in 14.9%. Corticosteroid intake for the treatment of COVID-19 was recorded in 76.3% of cases. Mucormycosis involving nose and sinuses (88.9%) was most common followed by rhino-orbital (56.7%). Mortality was noted in 30.7% of the cases. CONCLUSION: An unholy trinity of diabetes, rampant use of corticosteroid in a background of COVID-19 appears to increase mucormycosis. All efforts should be made to maintain optimal glucose and only judicious use of corticosteroids in patients with COVID-19.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with a wide range of opportunistic bacterial and fungal infections [1] . Both Aspergillosis and Candida have been reported as the main fungal pathogens for co-infection in people with COVID-19 [2] . Recently, several cases of mucormycosis in people with COVID- 19 have been increasingly reported world-wide, in particular from India. The primary reason that appears to be facilitating Mucorales spores to germinate in people with COVID-19 is an ideal environment of low oxygen (hypoxia), high glucose (diabetes, new-onset hyperglycemia, steroid-induced hyperglycemia), acidic medium (metabolic acidosis, diabetic ketoacidosis [DKA]), high iron levels (increased ferritins) and decreased phagocytic activity of white blood cells (WBC) due to immunosuppression (SARS-CoV-2 mediated, steroid-mediated or background comorbidities) coupled with several other shared risk factors including prolonged hospitalization with or without mechanical ventilators.

Phycomycosis or zygomycosis was first described in 1885 by Paltauf [3] and later coined as Mucormycosis in 1957 by Baker [4] an American pathologist for an aggressive infection caused by Rhizopus. Mucormycosis is an uncommon but a fatal fungal infection that usually affects patients with altered immunity.

Mucormycosis is an angioinvasive disease caused by mold fungi of the genus Rhizopus, Mucor, Rhizomucor, Cunninghamella and Absidia of Order-Mucorales, Class-Zygomycetes [5] . The Rhizopus Oryzae is most common type and responsible for nearly 60% of mucormycosis cases in humans and also accounts J o u r n a l P r e -p r o o f for 90% of the Rhino-orbital-cerebral (ROCM) form [6] . Mode of contamination occurs through the inhalation of fungal spores.

Globally, the prevalence of mucormycosis varied from 0.005 to 1.7 per million population, while its prevalence is nearly 80 times higher (0.14 per 1000) in India compared to developed countries, in a recent estimate of year 2019-2020 [7] [8] [9] . In other words, India has highest cases of the mucormycosis in the world.

Notwithstanding, India is already having second largest population with diabetes mellitus (DM) and was the diabetes capital of the world, until recently [10].

Importantly, DM has been the most common risk factor linked with mucormycosis in India, although hematological malignancies and organ transplant takes the lead in Europe and the USA [9] . Nevertheless, DM remains the leading risk factor associated with mucormycosis globally, with an overall mortality of 46% [11] .

Indeed, presence of DM was an independent risk factor (Odds ratio [OR] 2.69; 95% Confidence Interval 1.77-3.54; P <0.001) in a large 2018 meta-analysis of 851 cases of rarely occurring mucormycosis, and the most common species isolated was Rhizopus (48%) [11] . While long term use of corticosteroids has often been associated with several opportunistic fungal infection including aspergillosis and mucormycosis, even a short course of corticosteroids has recently been reported to link with mucormycosis especially in people with DM. A cumulative prednisone dose of greater than 600 mg or a total methyl prednisone dose of 2-7 g given during the month before, predisposes immunocompromised people to mucormycosis [12] . There are few case reports of mucormycosis resulting from even a short course (5-14 days) of steroid therapy, especially in people with DM [13] . Surprisingly, 46% of the patients had received corticosteroids within the month before the diagnosis of mucormycosis in the European Confederation of Medical Mycology study [14] . Similarly, several case reports are being reported from other parts of globe. Several anecdotal cases are being reported in grey literature such as the print and electronic media. These finding are unprecedented and carry an immense public health importance especially because fatality rate with mucormycosis is pretty high.

Especially the intracranial involvement of mucormycosis increases the fatality rate to as high as 90% [15] . Moreover, rapidity of dissemination of mucormycosis is an extraordinary phenomenon and even a delay of 12 hours in the diagnosis could be fatal, the reason 50% of cases of mucormycosis have been historically diagnosed only in the post-mortem autopsy series [16] . This prompted us to conduct a systematic review of published case reports/series of mucormycosis in people with COVID-19, to know its temporal associations in relation to comorbidities, association with drugs being used in COVID-19 and overall characteristics of patients with its outcome. We additionally postulated a mechanistic explanation as to why mucormycosis could be increasingly linked to COVID-19 and is being reported increasingly from India.

A systematic literature search was conducted in the electronic database of PubMed and Google Scholar from inception until May 13, 2021 using keyword "COVID-19", "SARS CoV-2", AND "Mucormycosis", "Zygomycosis", "Phycomycosis, "Mucorales", "Mucor", "Rhizopus", "Rhizomucor", "Cunninghamella", and "Absidia". Details of all the cases that reported mucormycosis (both confirmed and suspected) in people with COVID-19 so far, were retrieved. Characteristics of J o u r n a l P r e -p r o o f each patient was collected on excel sheet and analyzed on various endpoints and outcomes. Two authors independently checked the veracity of data.

Overall, 28 articles were found to report the original case(s) from the database of PubMed (24/28) and Google Scholar (4/28) Table 2 summarizes the findings from 101 cases of mucormycosis in people with COVID-19.

Although mucormycosis is an extremely rare in healthy individuals but several immunocompromised conditions predispose it. This includes uncontrolled DM with or without DKA, hematological and other malignancies, organ transplantation, prolonged neutropenia, immunosuppressive and corticosteroid therapy, iron overload or hemochromatosis, deferoxamine therapy, severe burns, acquired immunodeficiency syndrome (AIDS), intravenous drug abusers, malnutrition and open wound following trauma [45] . Mucormycosis can involve nose, sinuses, orbit, central nervous system (CNS), lung (pulmonary), gastrointestinal tract (GIT), skin, jaw bones, joints, heart, kidney, and mediastinum (invasive type), but ROCM is the commonest variety seen in clinical practice world-wide [45] . It should be noted that term ROCM refers to the entire spectrum ranging from limited sino-nasal disease (sino-nasal tissue invasion), limited rhinoorbital disease (progression to orbits) to rhino-orbital-cerebral disease (CNS involvement) [46] . The area of involvement may differ due to underlying Nonetheless, there appears to be a number of triggers that may precipitate mucormycosis in people with COVID-19 in relation to corticosteroids: Table 2 .

Increase in mucormycosis in Indian context appears to be an unholy intersection of trinity of diabetes (high prevalence genetically), rampant use of corticosteroid (increases blood glucose and opportunistic fungal infection) and COVID-19

(cytokine storm, lymphopenia, endothelial damage). All efforts should be made to J o u r n a l P r e -p r o o f maintain optimal hyperglycemia and only judicious evidence-based use of corticosteroids in patients with COVID-19 is recommended in order to reduce the burden of fatal mucormycosis.

Nothing to declare for all authors.

No funding.

AKS J o u r n a l P r e -p r o o f 

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