Archives of Academic Emergency Medicine. 2022; 10(1): e56 OR I G I N A L RE S E A RC H Comparing the Characteristics of Mucormycosis Between Cases with and without COVID-19; a Cross-sectional Study Mohammad Sistanizad1,2, Mohammad Haji Aghajani1, Mehrdad Haghighi3, Hossein Amini2, Asma Pourhoseingholi1, Niloufar Taherpour1, Shadi Ziaie2, Sara Salarian4, Omid Moradi5∗ 1. Prevention of Cardiovascular Disease Research Center, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Department of Pulmonary and Critical Care Medicine, Imam Hossein Teaching and Educational Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Department of Clinical Pharmacy, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Hormozgan, Iran. Received: April 2022; Accepted: May 2022; Published online: 12 July 2022 Abstract: Introduction: Mucormycosis as a rare but life-threatening disease with 46-96% mortality, which challenged the healthcare system during the COVID-19 pandemic. This study aimed to compare the characteristics of mu- cormycosis between cases with and without COVID-19. Methods: This cross-sectional study was done in two referral hospitals, Imam Hossein and Labbafinezhad Hospitals, Tehran, Iran, between 21 March to 21 December 2021. Data related to all hospitalized adults subject with the diagnosis of mucormycosis during the study period was collected from patients’ profiles and they were divided into two groups of with and without COVID-19 based on the results of real time PCR. Then demographic, clinical, and laboratory findings as well as outcomes were compared between the two groups. Results: 64 patients with the mean age of 53.40±10.32 (range: 33-74) years were studied (53.1% male). Forty-three (67.2%) out of the 64 subjects had a positive COVID-19 PCR test. The two groups had significant differences regarding some symptoms (cough (p < 0.001), shortness of breath (p = 0.006)), acute presentation (p = 0.027), using immunosuppressive (p = 0.013), using corticosteroid (p < 0.001), and outcomes (mortality (p = 0.018), need for intubation (p < 0.001)). 22 (34.3%) patients expired during hospi- tal admission. Univariate analysis showed the association of in-hospital mortality with need for ventilation (p < 0.001), sinus involvement (p = 0.040), recent use of dexamethasone (p = 0.011), confirmed COVID-19 disease (p = 0.025), mean body mass index (BMI) (p =0.035), hemoglobin A1c (HbA1c) (p = 0.022), and median of blood urea nitrogen (BUN) (p =0.034). Based on the multivariate model, confirmed COVID-19 disease (OR = 5.01; 95% CI: 1.14-22.00; p = 0.033) and recent use of dexamethasone (OR= 4.08, 95% CI: 1.05-15.84, p = 0.042) were indepen- dent predictors of mortality in this series. Conclusion: The mucormycosis cases with concomitant COVID-19 disease had higher frequency of cough and shortness of breath, higher frequency of acute presentation, higher need for immunosuppressive, corticosteroid, and ventilator support, and higher mortality rate. The two groups were the same regarding age, gender, BMI, risk factors, underlying diseases, symptoms, and sites of involvement. Keywords: COVID-19; Mucormycosis; Mortality; Cross-sectional studies; Risk factors; Diabetes mellitus Cite this article as: Sistanizad M, Haji Aghajani M, Haghighi M, Amini H, Pourhoseingholi A, Taherpour N, Ziaie S, Salarian S, Moradi O. Comparing the Characteristics of Mucormycosis Between Cases with and without COVID-19; a Cross-sectional Study. Arch Acad Emerg Med. 2022; 10(1): e56. https://doi.org/10.22037/aaem.v10i1.1608. ∗Corresponding Author: Omid Moradi; Department of Clinical Pharmacy, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Ab- bas, Iran. Zip code: 7919691982 Phone number: +987633710406, Email: O_moradi@outlook.com, ORCID: http://orcid.org/0000-0001-5754-535X. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Sistanizad et al. 2 1. Introduction From late 2019 to date, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected many people, and more than 400 million cases of coronavirus disease 2019 (COVID-19) have been reported (1). Increasing cases of co- infections with bacterial and fungal pathogens have been re- ported in COVID-19 patients (2). Opportunistic infections, including aspergillosis, and mucormycosis, have been re- ported in patients with COVID-19 (3). Most of the reported cases are from India during the Delta variant (B.1.617.2) out- break. Mucormycosis is an opportunistic lethal fungal infection. This fungus could infect patients with altered immune sys- tem (4). Inhalation of the fungal spores in an immunocom- promised patient results in angioinvasion (4, 5). Many mechanisms have been proposed for the increased chance of infection by opportunistic fungi (Mucorales) in hospitalized patients due to COVID-19. Hypoxia, diabetes mellitus, metabolic acidosis, and lymphocytopenia increase the probability of mucormycosis in COVID-19 patients. Also, using immunomodulating medications such as corticos- teroids and biological agents could increase the risk of infec- tion in some COVID-19 patients (6, 7). The mortality rate due to mucormycosis could be as high as 90 percent (7). Diagnosis and treatment of this opportunistic infection in hospitalized patients could be lifesaving, and the therapy consists of surgical and pharmacologic approaches (8). Twelve hours of delay in diagnosis of the disease could be associated with a significantly increased mortality risk (9, 10). Based on the above-mentioned points, this study aimed to compare the characteristics of mucormycosis between cases with and without COVID-19. 2. Methods 2.1. Study design and setting This cross-sectional study was done in two referral hospitals, Imam Hossein and Labbafinezhad Hospitals, Tehran, Iran, between 21 March to 21 December 2021. Data related to all hospitalized adult subjects with the diagnosis of mucormy- cosis (black fungus) during the study period was collected from patients’ profiles and they were divided into two groups of with and without COVID-19, based on the results of real time PCR. Then demographic, clinical, and laboratory find- ings as well as outcomes were compared between the two groups. The study was in accordance with the principles of the Helsinki declaration and the ethics committee of Shahid Beheshti University of Medical Sciences approved the study protocol (IR.SBMU.RETECH.REC.1400.660). 2.2. Participants In this study, all adults referred to the two hospitals, who were diagnosed with mucormycosis or hospitalized patients with mucormycosis complications during hospital stay were included using the census method. Diagnosis of mucormy- cosis as a fungal disease was made by an infectious dis- ease specialists, based on the clinical presentation and by considering specific signs and symptoms. Acute mucormy- cosis was defined as the duration of clinical presentation of the disease being seven days or less, and the sub-acute form was defined as presence of symptoms for 7-21 days (12). In addition, all subjects were screened for the possibil- ity of COVID-19 co-infection using the standard Real-Time reverse-transcriptase–Polymerase-Chain-Reaction (rt- PCR) test. Patients with incomplete information were excluded from the study. 2.3. Data gathering Data were extracted from patients’ medical records using the researcher-made checklist. The checklist contained informa- tion about demographic characteristics, history of underly- ing diseases, smoking status, drug history, clinical presenta- tion, clinical signs and symptoms, baseline laboratory data, site of mucormycosis involvement, prescribed medications in the hospital, SARS-CoV-2 RT-PCR test result, length of hos- pital stay, history of SARS-CoV-2 infection, the time interval between initial mucormycosis clinical symptoms to diagno- sis, and in-hospital mortality. Data gathering and extraction were performed by trained medical staff. 2.4. Statistical analysis Data analysis was carried out using SPSS (IBM Corp, released 2017. IBM SPSS statistics for windows, version 25.0. Ar- monk, NY: IBM Corp.). The normality of data was assessed using Shapiro-Wilk test and Q-Q plot. Complete Case (“CC”) analysis was used in the presence of missing data. Contin- uous variables are described using mean ± standard devi- ation or median and interquartile range (IQR). Categorical variables are reported as frequency and percentage. To com- pare continuous variables between groups, appropriate tests, including Student’s t-test or Mann-Whitney U test, were used for normally and non-normally distributed variables, respec- tively. The distribution of categorical variables was evalu- ated between the groups using Chi-squared or Fisher’s exact test (if more than 25% of the variables had a frequency be- low 5). Logistic regression was used to assess the association between in-hospital mortality and selected variables at uni- variate and multivariate levels. To select the potential factors for entering the multivariate model, we used a backward se- lection approach with p-value < 0.05. All calculations were performed at a significant level of less than 0.05 with a 95% This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e56 Table 1: Comparing the baseline characteristics of mucormycosis between COVID-19 and non-COVID-19 patients Variables Total (n=64) COVID-19 p-value Yes (n=43) No (n=21) Gender Female 30 (100) 20 (66.7) 10 (33.3) 0.934 Male 34 (100) 23 (37.6) 11 (23.4) Age (years) 53.40±10.32 52.16±10.63 55.95 ±9.38 0.170 Body mass index (kg/m2) 25.47±3.66 26.16 ±3.32 23.96 ±4.04 0.062 Length of stay Median (IQR) 16 (23.5) 20 (24) 15 (18) 0.710 Symptoms Sore eyes 41 (100) 27 (65.9) 14 (34.1) 0.760 Swelling of eyes and face 38 (100) 25 (65.8) 13 (34.2) 0.773 Blurred vision 23 (100) 16 (69.6) 7 (30.4) 0.762 Cough 19 (100) 19 (100) 0 (0) <0.001 Weakness 15 (100) 11 (73.3) 4 (26.7) 0.403 Headache 13 (100) 9 (69.2) 4 (30.8) 0.507 Fever 12 (100) 7 (56.3) 5 (41.7) 0.570 Shortness of breath 12 (100) 12 (100) 0 (0) 0.006 Symptoms to diagnosis Median (IQR) 5 (4) 6 (6) 5 (3) 0.824 Presentation Acute 59 (100) 40 (67.8) 19 (32.2) 0.027 Subacute 5 (100) 3 (60) 2 (40) 0.534 Risk factors/ Underlying Smoking 31 (100) 23 (74.2) 8 (25.8) 0.247 Opium 4 (100) 1 (25) 3 (75) 0.099 Alcohol 2 (100) 1 (50) 1 (50) 1.000 Coronary artery disease 11 (100) 10 (90.9) 1 (9.1) 0.085 Diabetes mellitus 45 (100) 32 (71.1) 13 (28.9) 0.304 Dyslipidemia 18 (100) 14 (77.8) 4 (22.2) 0.259 Hypertension 26 (100) 17 (65.4) 9 (34.6) 0.799 Drug History Immunosuppressive 10 (100) 4 (40) 6 (60) 0.068 Anticoagulant 4 (100) 3 (75) 1 (25) 1.000 Antiplatelet aggregation 22 (100) 16 (72.7) 6 (27.3) 0.495 Antidiabetic 43 (100) 30 (69.8) 13 (30.2) 0.529 Antihypertensive 28 (100) 19 (67.9) 9 (32.1) 0.920 Laboratory tests ESR (sec) 56.34±33.50 60.32±31.74 47.94 ±36.38 0.187 Albumin (g/dL) 3.19±0.58 3.18±0.64 3.22 ±0.44 0.822 HbA1C (g/dL) 9.54 ±2.99 9.90±2.91 8.63 ±3.07 0.166 Blood urea nitrogen (mg/dL) 38.2 (31.8) 39 (36.7) 34.6 (27.45) 0.139 Blood sugar (mg/dL) 189 (211) 180 (210.75) 192 (310) 0.974 Data are presented as mean ± standard deviation (SD), frequency (%), and median (IQR). ESR: erythrocyte sedimentation rate; HbA1C: hemoglobin A1c. Confidence Interval (CI). 3. Results 3.1. Baseline characteristics of studied cases 64 patients with the mean age of 53.40±10.32 (range: 33-74) years were studied (53.1% male). The most common under- lying diseases were diabetes mellitus with 45 (70.3%), hyper- tension with 26 (40.6%), dyslipidemia with 18 (28.1%), and coronary artery disease with 11 (17.2%) cases. Nine (13.8%) patients were hospitalized due to malignancy. The most common chief complaints were sore eyes with 41 (64.1%), swelling of the eyes and face with 38 (59.4%), blurred vi- sion with 23 (35.9%), and cough with 19 (29.7%) cases. Fifty- nine (92.2%) patients had the acute presentation of mu- cormycosis, and 5 (7.7%) had a sub-acute presentation. The most prevalent sites of fungal involvement were orbit with 60 (93.8%) and sinus with 38 (59.4%) subjects. The median duration of hospitalization was 16 days with an IQR of 23.5, the median time from onset of COVID-19 to the diagnosis This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Sistanizad et al. 4 Table 2: Comparing the management and outcome of mucormycosis between COVID-19 and non-COVID-19 patients Variables Total (n=64) COVID-19 p-value Yes (n=43) No (n=21) Involvements Sinus 38 (100) 26 (68.4) 12 (31.6) 0.799 Orbit 60 (100) 39 (65) 21 (35) 0.294 Pulmonary 9 (100) 7 (77.8) 2 (22.2) 0.706 CNS 4 (100) 3 (75) 1 (25) 1.000 Managements Immunosuppressive 41 (100) 32 (78) 9 (22) 0.013* Corticosteroid 33 (100) 32 (97) 1 (3) <0.001 Outcomes Ventilation 21 (100) 18 (85.7) 3 (14.3) <0.001 In-hospital mortality 22 (100) 19 (86.4) 3 (13.9) 0.018 CNS: central nervous system. of COVID-19-associated mucormycosis (CAM) was 11 days with an IQR of 19.3, and the median time from onset of symp- toms to diagnosis of CAM was six days with an IQR of 7.8. 3.2. COVID-19 vs. Non-COVID-19 cases Forty-three (67.2%) out of 64 subjects had a positive COVID- 19 PCR test. Table 1 and 2 compare the demographic, clini- cal, managements, and outcomes of mucormycosis between patients with and without COVID-19. Two groups had signifi- cant difference regarding symptom (cough (p < 0.001), short- ness of breath (p = 0.006)), acute presentation (p = 0.027), us- ing immunosuppressive (p = 0.013), using corticosteroid (p < 0.001) and outcome (in-hospital mortality (p = 0.018), and need for intubation (p < 0.001)). 3.3. Predictors of mortality 22 (34.3%) patients expired during hospital admission. Uni- variate analysis showed the association of in-hospital mortal- ity with need for ventilation (p < 0.001), sinus involvement (p = 0.040), recent use of dexamethasone (p = 0.011), confirmed COVID-19 disease (p = 0.025), mean body mass index (BMI) (p =0.035), hemoglobin A1c (HbA1c) (p = 0.022), and median of blood urea nitrogen (BUN) (p =0.034). Based on the multi- variate model, confirmed COVID-19 disease (OR = 5.01; 95% CI: 1.14-22.00; p = 0.033) and recent use of dexamethasone (OR= 4.08, 95% CI: 1.05-15.84, p = 0.042) were independent predictors of in-hospital mortality in this series. 4. Discussion The mucormycosis cases with concomitant COVID-19 dis- ease had higher frequency of cough and shortness of breath, higher frequency of acute presentation, higher need for immunosuppressive, corticosteroid, and ventilator support, and higher mortality rate. The two groups were similar re- garding age, gender, BMI, risk factors, underlying diseases, symptoms, and sites of involvement. COVID-19 was an inde- pendent predictor of mucormycosis in-hospital mortality. The condition of mucormycosis, a rare invasive fungal in- fection, was previously a matter of concern in immunocom- promised patients (13). These patients included those with hematologic malignancy, diabetes mellitus, transplant recip- ients, the receivers of immunosuppressive therapy and corti- costeroid, and those with other immunodeficient conditions such as acquired immunodeficiency syndrome (14). With in- crease in the prevalence of COVID-19, and using corticos- teroid and other immunosuppressive utilization to treat this disease, the number of cases has raised, significantly. In this article, the most prevalent site of involvement was si- nus and orbit. As previously reported, the site of involve- ment in mucormycosis patients is related to the predispos- ing condition. In patients with COVID-19, rhino-orbital in- volvement is the most prevalent (6). This is also the most common site of involvement in patients with mucormyco- sis due to uncontrolled diabetes (7). Involvement of other areas, such as pulmonary involvement are more commonly reported in patients with malignancy (7, 15, 16). Physicians should consider this phenomenon when they examine sus- pected mucormycosis patients. Diabetes mellitus was recognized as an important risk fac- tor for invasive mucormycosis. In 2019, Parakash H et al. reported 388 cases of mucormycosis, and diabetes was re- ported in 57% of these patients (17). It should be noted that the reported cases in the research had not been infected with SARS-CoV-2. As it was previously reported, diabetes melli- tus and uncontrolled hyperglycemia are risk factors for more severe COVID-19 (17). In the present study, diabetes melli- tus was the most prevalent underlying condition. We should consider that patients with severe COVID-19 will more often need to receive corticosteroid therapy and other immuno- suppressive agents such as tocilizumab. All these factors to- gether increase the rate of mucormycosis and a higher rate of This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e56 mortality is expected. Our study showed that corticosteroid therapy in these patients is linked to a higher mortality rate. Based on the recommendations of the latest guidelines, cor- ticosteroids are the cornerstone of pharmacotherapy for the patients in severe stages of COVID-19 and hypoxia (18). The results of our study indicate that we should be careful about the administration of corticosteroids in high-risk patients for mucormycosis. The triad of COVID-19, corticosteroid, and diabetes put these patients at increased risk for opportunis- tic infections such as mucormycosis. 5. Limitations In assessing the results of the present study, we should con- sider all the possible limitations. First of all, multicentric studies with a larger sample size evaluating different popula- tions are needed. Risk factor evaluation in a population with various predisposing factors is of value. Second, although we evaluated the effect of pre-hospitalization glycemic control based on HbA1c, the role of glycemic control during hospi- talization should be evaluated as it was shown that using in- sulin to control blood sugar during the hospital stay is impor- tant in COVID-19 patients (19). Third, we observed a higher rate of mortality in CAM patients. Both, severe COVID-19 and mucormycosis, could be lethal, and it is not possible to evaluate the net effect of each parameter on the outcome of the patients, separately, but a higher mortality rate is seen in mucormycosis patients with COVID-19. Fourth, we did not examine the association of the newer immunomodulators, such as baricitinib, anakinra, or tofacitinib, and CAM in high- risk patients or the effect of these agents on the outcome of CAM patients. These valuable agents are used in clinics for patients with severe COVID-19, but data about their associa- tion with increased risk of opportunistic infections is lacking. In this study, the diagnosis of mucormycosis was done based on clinical evaluation, and it could be proposed to confirm the diagnosis using organism identification via histopathol- ogy for further studies. 6. Conclusion The mucormycosis cases with concomitant COVID-19 dis- ease had higher frequency of cough and shortness of breath, higher frequency of acute presentation, higher need for immunosuppressive, corticosteroid, and ventilator support, and higher mortality rate. The two groups were similar re- garding age, gender, BMI, risk factors, underlying diseases, symptoms, and sites of involvement. COVID-19 was an inde- pendent predictor of mucormycosis in-hospital mortality. 7. Declarations 7.1. Acknowledgments We are thankful to Imam Hossein and Shahid Labafine- jad hospitals’ staff for their effort to help people and save lives during the COVID-19 pandemic as the most visited university-affiliated medical centers in Tehran, Iran. 7.2. Data availability The data is at the disposal of the corresponding author of the article and it it can be made available to the researchers upon request. 7.3. Authors’ contributions MS and OM designed, reviewed the study, and revised subse- quent drafts. MHA, MH, SHZ and SS were the medical con- sultants and participated in data acquisition. HA and NT pre- pared the first English draft of manuscript. AP analyzed data. All authors read and approved the final manuscript. 7.4. Funding and supports This study was supported by the vice-chancellor of research and technology, Shahid Beheshti University of medical sci- ences, Tehran, Iran, and did not receive any funding support from secondary institutions, organizations, or companies re- garding supplying medications types of equipment, techni- cal support or any other. 7.5. Conflict of interest There is none to declare. References 1. (WHO) WHO. WHO Coronavirus (COVID-19) Dashboard 2022 [Available from: https://covid19.who.int/. 2. Kubin CJ, McConville TH, Dietz D, Zucker J, May M, Nelson B, et al., editors. Characterization of bacte- rial and fungal infections in hospitalized patients with coronavirus disease 2019 and factors associated with health care-associated infections. Open Forum Infect Dis. 2021;8(6):ofab201. 3. Song G, Liang G, Liu W. Fungal co-infections associ- ated with global COVID-19 pandemic: a clinical and diagnostic perspective from China. Mycopathologia. 2020;185(4):599-606. 4. 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Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References