COVID-19-Associated Mucormycosis (CAM): An Updated Evidence Mapping

Mucormycosis, a serious and rare fungal infection, has recently been reported in COVID-19 patients worldwide. This study aims to map all the emerging evidence on the COVID-19-associated mucormycosis (CAM) with a special focus on clinical presentation, treatment modalities, and patient outcomes. An extensive literature search was performed in MEDLINE (Ovid), Embase (Ovid), Cochrane COVID-19 Study Register, and WHO COVID-19 database till 9 June 2021. The primary outcome was to summarize the clinical presentation, treatment modalities, and patient outcomes of CAM. Data were summarized using descriptive statistics and presented in tabular form. This evidence mapping was based on a total of 167 CAM patients with a mean age of 51 ± 14.62 years, and 56.28% of them were male. Diabetes mellitus (73.65% (n = 123)), hypertension (22.75% (n = 38)), and renal failure (10.77% (n = 18)) were the most common co-morbidities among CAM patients. The most common symptoms observed in CAM patients were facial pain, ptosis, proptosis, visual acuity, and vision loss. Survival was higher in patients who underwent both medical and surgical management (64.96%). Overall mortality among CAM patients was found to be 38.32%. In conclusion, this study found a high incidence of CAM with a high mortality rate. Optimal glycemic control and early identification of mucormycosis should be the priority to reduce the morbidity and mortality related to CAM.


Introduction
The coronavirus disease (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 228 million people globally, with about 4.7 million deaths as of 21 September 2021 [1]. The novel COVID-19 strains that have emerged this year are more severe variants of the disease and have resulted in higher intensive care unit (ICU) admissions, need for mechanical ventilation, and mortality [2,3]. This, consequently, has increased the burden on healthcare systems globally [4].
COVID-19 patients often have several comorbidities, including diabetes [5]. Ample evidence has found patients with comorbidities to be at higher risk of ICU admissions and mortality [5][6][7]. Study findings by Liu et al. from Wuhan Union Hospital found a more

Materials and Methods
The proposed study was developed by adhering to the JBI methodology for evidence mapping and is reported as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Scoping Reviews (PRISMA-ScR) [26,27]. Compliance with the PRISMA-ScR is presented in Supplementary Table S1.
Furthermore, this review was conducted by adhering to our protocol registered prospectively at OSF with an identification number (osf.io/438sm) and published as a preprint at the Preprint Server for Health Sciences (medRxiv) [28]. There were slight deviations from the protocol; firstly, the critical appraisal was skipped as it is not mandatory as per the JBI guidelines. The second deviation was the inclusion of suspected COVID-19 cases with confirmed mucormycosis, as patients developed mucormycosis after recovery from COVID-19.

PCC Elements
According to the JBI reviewer's manual, the following PCC (Population, Concept, and Context) elements were used for this review.
(a) Participants: patients with confirmed COVID-19 (RT-PCR) and mucormycosis (either histologically or microbiologically confirmed) based on the definition of Centers for Disease Control and Prevention were included in the study. We also included studies with suspected COVID-19 patients (based on the included studies assessment) who had confirmed mucormycosis. (b) Concept and context: this review included all studies that described the clinical presentation, treatment modalities, and patient outcomes of CAM.

Types of Sources
We included analytical observational studies (cohort, case-control) and descriptive observational studies (case report, case series, cross-sectional).

Exclusion Criteria
(a) Non-English language studies; (b) studies with no confirmed mucormycosis; and (c) systematic reviews, narrative reviews, editorials, opinions, and study protocols were excluded.

Information Sources and Search Strategy
A three-step search strategy was utilized to identify published, unpublished, or ongoing studies with no language restrictions. An initial limited search was undertaken in MEDLINE (Ovid), followed by analyzing the text words in the title and abstract and the index terms assigned to the articles. Slightly modified Ovid Expert Searches for COVID-19 were combined with keywords and index terms related to mucormycosis to perform the searches in MEDLINE (Ovid) [29] and Embase (Ovid) [30] (Appendix A).
Complete search strategies are presented in Supplementary Table S2 for each database with their respective hits. Third, the manual search of reference lists of all included studies and relevant systematic reviews was screened for any potentially eligible studies. Citation tracking was also performed for all the included articles.

Selection Process
Two independent reviewers (S.H. and H.B.) screened all the retrieved articles against the eligibility criteria. We included all those articles describing the mucormycosis case (diagnosed either based on histopathology, culture, or stain) in COVID-19-positive patients.
In the initial screening phase, articles were selected based on the title and abstract scanning. In the second phase, full-text screening was performed for the final inclusion of articles. Any confusion regarding study inclusion was resolved by discussion with the third reviewer (M.K.). A detailed description of the study selection process is shown using the PRISMA flow diagram in Figure 1.

Data Extraction
Two reviewers (S.H. and H.B.) independently extracted the data in a pre-designed data extraction template. The following information was extracted from all the eligible studies qualified for inclusion: study author, year of publication, country, study design, demographic characteristics of the population (age and sex), sample size, comorbidities, treatment for COVID-19, symptoms of mucormycosis, diagnosis of mucormycosis, identification of fungal species, treatment for mucormycosis, and patient outcomes. The included studies are described using descriptive statistics and presented in a tabular form.

Data Extraction
Two reviewers (S.H. and H.B.) independently extracted the data in a pre-designed data extraction template. The following information was extracted from all the eligible studies qualified for inclusion: study author, year of publication, country, study design, demographic characteristics of the population (age and sex), sample size, comorbidities, treatment for COVID-19, symptoms of mucormycosis, diagnosis of mucormycosis, identification of fungal species, treatment for mucormycosis, and patient outcomes. The included studies are described using descriptive statistics and presented in a tabular form.

Results
A total of 209 articles were identified by searching the selected sources. After removing duplicates, only 92 articles were found to be unique. After the full-text screening, 37 studies  qualified for inclusion in this evidence mapping study. Four additional articles [68][69][70][71] were identified by hand search during bibliography screening and citation tracking. Finally, a total of 41 articles were included in this review . Refer to Supplementary Table S3 for the list of articles excluded during full-text screening with reason.

Results
A total of 209 articles were identified by searching the selected sources. After removing duplicates, only 92 articles were found to be unique. After the full-text screening, 37 studies  qualified for inclusion in this evidence mapping study. Four additional articles [68][69][70][71] were identified by hand search during bibliography screening and citation tracking. Finally, a total of 41 articles were included in this review . Refer to Supplementary Table S3 for the list of articles excluded during full-text screening with reason.

Studies Characteristics
Out of 41 studies, the majority of studies (n = 15) were from India with 82 mucormycosis cases, 9 studies with 9 cases of mucormycosis were from the USA, while only 3 studies were from Iran but with 17 mucormycosis cases. Most of the included studies were case reports (n = 27) followed by case series (n = 9), and the rest were of other study designs. Diabetes mellitus (73.65% (n = 123)), hypertension (22.75% (n = 38)), and renal failure (10.77% (n = 18)) were the most common co-morbidities among CAM patients. Diabetic ketoacidosis was observed in one-tenth of the diabetic patients.

Clinical Presentation
This evidence mapping was based on a total of 167 CAM patients with a mean age of 51 ± 14.62 years, of which 56.28% of them were male. COVID-19 was confirmed through the RT-PCR test in approximately three-fourth (74%) of the included studies.
The majority of the patients (76.04%) were treated using steroids, while only 11.64% of patients were treated with remdesivir to manage COVID-19. Most patients who developed mucormycosis had severe (based on included studies' categorization) or critical COVID-19 (defined based on ICU status/mechanical ventilation).
Twenty-nine (17.57%) patients had concurrent CAM, while the remaining patients were diagnosed with CAM after an average of 19.24 days. Mucormycosis was diagnosed using stain (24 studies), culture (26 studies), or histopathology (30 studies), and nine studies diagnosed mucormycosis using all three diagnostic techniques. The Rhizopus species were the most common fungal species infecting CAM patients (13.77%).
Facial pain, ptosis, proptosis, visual acuity, and vision loss were the most common symptoms observed in CAM patients. Rhino-orbital (16%) followed by rhino-orbitalcerebral (11.3%) mucormycosis was the most common form of mucormycosis found in CAM patients (Table 1).

Treatment Modalities and Outcomes
Liposomal amphotericin B in various doses (5 mg/kg/day) was the most commonly used drug for managing mucormycosis infection in 158 patients (35 studies). Adjunct surgery was performed on 142 patients, and surgical debridement was the most common surgical procedure performed. Only 23 CAM patients were managed without surgery, and most of them (18 CAM patients) died between 7 to 62 days after the diagnosis of mucormycosis.
Survival was higher in patients who underwent both medical and surgical management (64.96%) than in CAM patients who underwent medical management only (21.73%). Overall mortality among CAM patients in the included studies was 38.32% (n = 64). The patients died between 6 to 90 days after mucormycosis diagnosis ( Table 2).

Discussion
To the best of our knowledge, this is the most comprehensive and up-to-date evidence mapping aimed to explore the published and unpublished evidence on the clinical presentation, treatment modalities, and patient outcomes of CAM. The current body of evidence was based on the 41 studies that met our inclusion criteria and discussed the association of COVID-19 with mucormycosis.
Mucormycosis is a rare opportunistic infection, and COVID-19 patients are at risk of developing mucormycosis because of pre-compromised immune systems. A growing body of evidence supports that comorbidities (diabetes, transplantation, malignancies) and medications (steroids) make the patients more vulnerable to CAM [5][6][7]. A recent case report found an invasive pulmonary mucormycosis case in a patient after a short course of steroids [72]. Likewise, Pan et al. found mucormycosis in a patient with AIDS receiving short-term systemic steroids [73]. In our study, we found that COVID-19 patients with comorbidities had a higher occurrence of mucormycosis.
Around 50% of CAM cases in our study were reported from India. A possible reason for this could be the deadly COVID-19 delta variant wave infecting around half a million people every day in recent months and a high prevalence of diabetes mellitus in CAM patients [74]. Diabetes mellitus is a predisposing factor for the development of mucormycosis [75,76]. The potential mechanism behind this could be the aggravation of the inflammatory state due to hyperglycemia and activation of antiviral immunity [77]. The risk of developing CAM increases significantly in patients with diabetic ketoacidosis, where Mucorales use free iron levels in the serum for pathogenesis [78].
In our study, the number of male mucormycosis patients was twice the number of female patients. These findings are aligned with a previously published study by Roden et al. [79] that found mucormycosis in 65% of male patients.
Rhino-orbital and rhino-orbital-cerebral were the most common forms of mucormycosis observed in this study. In both forms of infection, the fungus invades the nasal mucosa and orbital wall and leads to the occurrence of symptoms such as facial pain, vision loss, proptosis, apoptosis, and ophthalmoplegia [80,81]. CAM patients who underwent both surgical and medical management had a better survival rate than those with medical management alone. Published studies from different parts of the world have also found better outcomes in mucormycosis patients who underwent combined surgical and medical management [82,83]. However, despite the best management of CAM patients, the overall mortality was high, suggesting the need for the early identification of cases.
Our study findings suggest that clinical practitioners (intensivists and their teams) should be alerted about the increased possibility of CAM in critically ill COVID-19 patients; therefore, they should act proactively and monitor for potential fungal and bacterial co-infections and secondary infections among the COVID-19 cohorts, especially the immunocompromised and diabetic patients [84]. Moreover, these findings call drug regulators and health systems, especially in low-and lower-middle-income countries, to implement strict policies for steroid stewardship.

Limitations
Like every study, this evidence mapping has few limitations. Firstly, we could not differentiate the outcome based on glycemic-controlled status due to the lack of information on the glycosylated hemoglobin value of the CAM patients with diabetes in the included studies. Secondly, there was variability in the definition of severity of COVID-19 in the included studies. Lastly, limited information (fungal species identified, RT-PCR result) in a few included studies was also a drawback.

Strengths
The major strength of this review was a large number of exhaustive literature searches in major databases, a protocol-oriented approach, most up-to-date evidence with sound methodology, and the capture of each minute detail of 167 CAM patients to make this review a one-stop source of information for CAM.

Conclusions
This evidence mapping found a high incidence of CAM with a high mortality rate. Therefore, clinicians should cautiously use the steroids using the risk-benefit analysis approach. Optimal glycemic control and early identification of mucormycosis should be the priority to reduce the morbidity and mortality related to CAM.

Institutional Review Board Statement:
The study was exempted from ethical approval due to its observational nature and the use of publicly accessible data.

Data Availability Statement:
The data that support the findings of this study are available from the corresponding author (S.H. or M.K.) upon reasonable request.