CORONAVIRUS DISEASE 2019 AND MUCORMYCOSIS A GLOBAL THREAT: A SYSTEMIC REVIEW

Objectives: According to the recent studies, it is seen that coronavirus disease 2019 (COVID-19) infection is associated with many bacterial and fungal infections. In case of COVID-19 patients, diabetes mellitus (DM) and hypertension (HTN) are the prime risk factors and during the course of treatment, patients develop secondary fungal infections like mucormycosis. We conducted a systemic review of the present scenario and tried to evaluate the association of mucormycosis with COVID-19. Methods: We searched articles related to the COVID-19 associated mucormycosis, in PubMed, IndMed, and Cochrane Library. We conducted a meta-analysis on the basis of systemically reviewed all articles which reported COVID-19 associated with mucormycosis. We analyzed comorbidity, treatment, and outcome of patients in association with COVID-19 and mucormycosis. Results: We found a total of 196 articles based on mucormycosis, out of which only 25 were selected on the basis of our inclusion and exclusion criteria. 71 cases were found and most of the cases were from India and USA. We also found that it was more prevalent among male patients and patients with DM, and in association with HTN. Conclusion: It is seen from the studies that patients already suffering from DM and HTN when infected with coronavirus are most likely to develop mucormycosis. Treatment of latent DM, prediabetic patients, conversely, that efforts to diagnose, detect, and treat DM may have a beneficial influence in the treatment of secondary fungal infections like mucormycosis. Finding out all the cases of DM and treatment of DM can carry out an advantageous effect in all patients suffering from COVID-19. mucormycosis associated COVID-19 region of the study. The reveal with people do not have also mucormycosis. HTN pre disposing (n=8) (11.26%) no all cases associated DM (n=10) other People an risk of active mucormycosis associated with COVID-19. in risk in mucormycosis associated with COVID-19, in


INTRODUCTION
The pandemic coronavirus disease 2019 (COVID-19) has spread vastly on a global scale [1,2]. There is no definitive treatment of the disease till now. However, prevention and symptomatic management is the prime choice. COVID-19 patients suffer from various secondary infections such as pneumonia, severe respiratory disease, and heart complication but super-infections and co-infections in COVID-19 pneumonia are still under exploration [3]. Secondary infections are more common in severely ill COVID-19 patients, fungal infections being 10 times more common [3]. Severe complication of coronavirus disease with secondary infection with fungus is very dangerous and life threatening to patients. This is the black fungus disease that is known as mucormycosis. Steroids and other immunosuppressive drugs are being used in the treatment of COVID-19 which is resulting into further complications. The side effects include increased secondary infections, immune modulation, manifestation of latent diabetes mellitus (DM), dizziness, weight gain, mood changes, insomnia, and muscle weakness [4]. The incidence rate of mucormycosis globally is 0.005-1.7 per million [5]. In Indian population, its prevalence is 0.14 per 1000, which is about 80% higher than other developed countries [6]. The fatality rate of mucormycosis is 46% worldwide [7]. Mucormycosis is also known as Zygomycosis and now it's called black fungus disease [8]. It's a serious fungal infection disease which is a secondary complication of coronavirus disease. It mostly infects sinuses, brain causing headache, epistaxis, fever, etc. [9]. Patient who is already suffering from diabetes, blood disorders, AIDS, or has history long-term use of steroids are prone to be affected with secondary infection of mucormycosis [10].
The objective of systemic review and meta-analysis on mucormycosis associated with COVID-19 disease this study to provide better understanding and evaluation of mucormycosis or zygomycosis. It will help in the better treatment of such fungal infections.

METHODS
This systemic review has been done to know the possible total cases of mucormycosis associated with novel coronavirus disease all around the world and specially India. The search of literature was done by the electronic database of PubMed, Cochrane library, IndMed from the 2019 to 2021, using the search word-COVID-19 and mucormycosis. We conducted the meta-analysis on the basis of screening and recuperate all the papers for tittle and abstract, after that primary selection then full texts of the conversant studies was perused for the study. The eligibility criteria were: • Studies on COVID-19 associated with mucormycosis • Studies that were published all over the world in related to study keyword • Studies dealing with patients of mucormycosis • Studies were published after 2019 (after attack of COVID-19).
We exclude the: • Review articles on mucormycosis • Narrative article • Literature review • Study with less data.
These were the criteria for selection the studies which were included in the meta-analysis for better quality. All the data were extracted for   Tables 3 and 4, country wise data are presented in Table 3. Outcomes have been showed in four categories in Table 5. Sex ration is shown in Table 6. All data were thoroughly checked by four reviewers (Figs. 1 and 2).

RESULTS
We have conducted the meta-analysis on 25 articles which were found to related studies from PubMed (n=23), IndMed (n=1), and Cochrane library (n=1   Maini et al. [11] yes (MRI brain) FESS was done followed by surgical debridement Patient was discharged after 38 days with satisfied improvement Johnson et al. [12] yes (BAL) Antifungal treatment, undergone tracheostomy and percutaneous endoscopic gastrostomy Patient was discharged after 36 th day Pasero et al. [13] yes (BAL) Symptomatic antifungal treatment, surgical intervention was not done Patient died after 62 th day after hospitalization Mehta and Pandey [14] yes (computed tomography (CT) scan) Symptomatic treatment, surgical intervention was not done Patient died on 6 th day after hospitalization Garg et al. [15] yes (MALDI-TOF) Symptomatic treatment, surgical intervention was not done Patient was discharged after 54 th day Monte Junior et al. [16] yes (EGD) There was no chance to treat the patient Patient died 7 days following hospitalization Sharma et al. [17] yes (tomography scan of paranasal sinuses Observational study (use steroids during the course of the treatment All patient were observed and managed Alekseyev et al. [18] yes (chest CT) A wide maxillary antrostomy, sphenoidotomy, and Patient was discharged after therapy Revannavar et al. [19] yes (histopathology followed by FESS) FESS was done on emergency basis. Her sugars were well controlled after the initiation of insulin therapy. However, there was no resolution of ophthalmoplegia or ptosis until she was discharged Patient was discharged after 17 days Saldanha et al. [20] yes (MRI brain) Endoscopic sinus surgery without debridement Her COVID test was positive after 14 days. She was discharged as per her request, follow-up taken on phone, and she reported that she was improving her facial pain and but no improvement of vision Werthman-Ehrenreich [7] yes (CT scan of face) Symptomatic treatment, surgical intervention was not done

Patient passed away after 27 days
Aljehani et al. [21] yes (MRI brain) Extensive surgical debridement Monthly follow-ups showed improvement Veisi et al. [22] yes (orbital CT scan) for both patients Endoscopic debridement was done for case 1. endoscopic sinus surgery and removal of necrotic tissue from paranasal sinus for case 2 For case 1 patient died after 3 months in spite of regular followup. For case 2, 7 months follow-up was done with no active infections Mekonnen et al. [23] yes (histopathological) Endoscopic surgical debridement was done Patient was died on 31 th day on hospital Ahmadikia et al. [24] yes (CT scan of paranasal sinuses) Symptomatic treatment After 8 months follow-up the patient showed no evidence of mucormycosis Sen et al. [25] Yes (culture and histopathology)

Endoscopic sinuses surgery was done in all patients
All patients were stable after 0-1.9 months of treatment Placik et al. [26] Yes (CT scan of chest) Cardiothoracic surgery was done, followed by right middle thoracotomy for repairing fistula After 33 days in hospital patient get worse and had respiratory failure and septic shock. Rhizopus was still positive Sebastian et al. [27] Yes (KOH and CT of paranasal sinus) both cases Case 1. symptomatic treatment Case 2. Antifungal treatment and symptomatic Case1. Died due to cardiac arrythmia and myocarditis. Case 2. 10 th day patient died due to massive peptic ulcer disease and developed shock Bellanger et al. [28] Yes (BAL) Symptomatic treatment Patient died at day 40 th day of hospitalization Karimi-Galougahi et al. [29] Yes (noncontract CT of paranasal sinuses) Extensive endonasal endoscopic debridement was done Right eye exenteration. stable Zurl et al. [30] Yes (BAL-GM) Autopsy After 24 th day Sargin et al. [31] Yes (culture study) Tracheostomy done on 3 rd day, followed by symptomatic antifungal treatment was done Patient died on 10 th day of hospitalization Hatri et al. [32] Yes (culture, biopsy) Symptomatic treatment 8 patients were died Mishra et al. [33] Yes (FESS) FESS followed local debridement -

CONCLUSION
In summary, we found consistent evidence for an increased risk of mucormycosis associated with COVID-19 among people with diabetes despite heterogeneity in study design, geographic area, underlying burden of mucormycosis, assessment of exposure and outcome, and control of potential confounders. Data from these human studies are consistent with emerging information on the biological mechanisms by which hyperglycemia may affect the host immune response to mucormycosis associated with COVID-19. Our findings suggest that fugal controls programs should consider targeting patients with diabetes with COVID-19 for interventions such as active case finding and the treatment of latent DM and, conversely, that efforts to diagnose, detect, and treat DM may have a beneficial impact on fungal control. We also recommend further studies investigating how comorbidity risk varies by type, duration, and severity of mucormycosis associated with COVID-19, for a more thorough understanding of the association that could be translated to a clear public health message.

AUTHOR'S CONTRIBUTION
Dr. Bikash Biswas: Concept, Study design, collection of data, Statistical analysis, original manuscript writing, writing-review and editing.