An analysis of proposed etiological factors for sudden spike in mucormycosis infection during COVID-19 pandemic at a tertiary hospital of North India

Akhil Pratap Singh; Prabhat Agrawal; Vikas Kumar

doi:10.4103/injms.injms_15_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 13 | Issue : 3 | Page : 150-153

An analysis of proposed etiological factors for sudden spike in mucormycosis infection during COVID-19 pandemic at a tertiary hospital of North India

Akhil Pratap Singh¹, Prabhat Agrawal², Vikas Kumar³
¹ Department of Ent, S N Medical College, Agra, Uttar Pradesh, India
² Department of Medicine, S N Medical College, Agra, Uttar Pradesh, India
³ Department of Microbiology, S N Medical College, Agra, Uttar Pradesh, India

Date of Submission	01-Feb-2022
Date of Decision	18-Feb-2022
Date of Acceptance	19-Feb-2022
Date of Web Publication	13-Jul-2022

Correspondence Address:
Dr. Akhil Pratap Singh
Department of Ent, S N Medical College, Agra, Uttar Pradesh
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injms.injms_15_22

Abstract

Aim: The aim is to analyze various possible etiological factors for the sudden outbreak of mucormycosis. Methods: A prospective observational study involving consecutive individuals with proven mucormycosis was undertaken at a tertiary care teaching hospital in North India from May 2021 to July 2021. A total of 88 patients with mucormycosis were studied for the demographic profile, COVID-19 status, various risk factors, COVID-19 immunization status, clinical staging of disease, and outcome of patients. Results: Out of 88 patients, 54 (61%) were males and 34 (39%) were females. The mean age of male patients was 50.5 ± 13.8 and female patients was 52.1 ± 14.1. Most of the patients were in stage two, i.e., 45 (51.1%) and 26 (29.5%) in stage three of the disease. Past history of diabetes was present in 49 (55%) patients. Forty-one (46.6%) patients had documented Reverse Transcription Polymerase Chain Reaction (RTPCR) reports in favor of COVID-19 and others had clinical features consistent with COVID-19. Only 1% of patient took COVID-vaccination. Of the total 88 patients, 42 (47%) were on oxygen therapy, 72 (81%) had history of blood transfusion, and 48 (54%) were given steroids. Conclusions: No conclusive etiological factor was identified although few recommendations are suggested for prevention, early diagnosis, and prompt management of mucormycosis in hospitalized COVID-19 patients.

Keywords: COVID-19 immunization, mucormycosis, risk factors

How to cite this article:
Singh AP, Agrawal P, Kumar V. An analysis of proposed etiological factors for sudden spike in mucormycosis infection during COVID-19 pandemic at a tertiary hospital of North India. Indian J Med Spec 2022;13:150-3

How to cite this URL:
Singh AP, Agrawal P, Kumar V. An analysis of proposed etiological factors for sudden spike in mucormycosis infection during COVID-19 pandemic at a tertiary hospital of North India. Indian J Med Spec [serial online] 2022 [cited 2023 Jun 9];13:150-3. Available from: http://www.ijms.in/text.asp?2022/13/3/150/350771

Introduction

Systemic invasive fungal infections, usually are not a matter of concern for public health authorities, but left them perplexed with a sudden spike in once so rare mucormycosis, especially following the second wave of COVID-19 in India and other middle-and low-income countries. In India, during the first wave of the COVID-19 pandemic, sporadic reporting of mucormycosis cases were made, following the subsidence of the first wave, in the final month of 2020 but the actual number was very low to raise any concern.^[1],[2] COVID-19 infections can get complicated by secondary infections, most common being bacterial infections but the systemic fungal infection cases are on rise, making them a matter of concern for public health authorities.^[3] In this ongoing global pandemic, COVID-associated mucormycosis has reached epidemic proportions, particularly in low-to middle-income countries and among various reasons purported are improper management, late diagnosis, and misleading unsupervised treatment.^[4] The most common type of mucormycosis is Rhizopus Oryzae, responsible for 60% of cases in humans and 90% of rhino-orbital-cerebral mucormycosis (ROCM).^[5]

As high mortality is associated with mucormycosis, an effective treatment requires early detection of condition followed by surgical debridement with metabolic corrections and systemic antifungal therapy.^[3]

The presence of several risk factors such as hematological disorders, neutropenia, organ transplant, steroidal use, metabolic acidosis, intravenous drug abusers, renal insufficiency, broad-spectrum antibiotic usage, increased iron in serum, malnutrition, and steroid use in COVID-19 treatment makes patients more vulnerable to mucormycosis.^[6] Steroids increase the blood sugar level, which makes its usage challenging in uncontrolled diabetes and makes the body environment acidic that favors the growth of mucor (fungus).

Oxygen therapy is often given in the patient of COVID-19, any contamination in delivery devices may serve as the source of mucormycosis infection.^[7] These are the common possible factors for the occurrence of mucormycosis in COVID-19 infected or recovered cases.^[3] This study is to analyze various possible etiological factors for the sudden outbreak of mucormycosis.

Materials and Methods

This prospective observational study was conducted at a tertiary care teaching hospital in North India from May 20, 2021 to July 31, 2021. The present study describes the demographic profile of patients with mucormycosis, COVID-19 status, various risk factors [Table 1], COVID-19 immunization status, clinical staging of disease, mycological profile of fungi, and outcome of patients with mucormycosis at 90 days from initiation of treatment. The diagnosis of COVID-19 in patients admitted for mucormycosis treatment was based on any one of the following parameters; RT-PCR test positive on nasopharyngeal or oropharyngeal swabs, rapid antigen test positive, or computed tomography chest findings in the absence of a positive RT-PCR test in a clinically symptomatic case. We defined proven mucormycosis as those patients who had clinically compatible disease and simultaneous demonstration of fungi with broad ribbon-like aseptate hyphae in the tissue by direct microscopy [Figure 1]. Diabetes mellitus was diagnosed as per the latest American Diabetes Association guidelines.

Table 1: Distribution of patients' data

Click here to view

Figure 1: Fungus on microscopy. (a) LPCB mount of R homothallicus showing golden brown globose zygospores with stellate spines (b) LPCB mount: Rhizopus spp (c) KOH mount: broad aseptate fungal filament (d) LPCB mount: Apophysomyces spp.

Click here to view

All the patients included in the study were managed in the department of otorhinolaryngology in association with ophthalmic and neurosurgeons. Internal medicine consultations were done for deranged blood sugars and electrolytes. Nephrology consults were done for patients with deranged renal parameters. Systemic antifungal therapy, injection amphotericin, was used for all the patients.

Statistical analysis

Analysis was done using the IBM SPSS Statistics for Windows, Version 23.0. (Armonk, NY: IBM Corp.) after compiling the data in Microsoft Excel sheet. The mean and standard deviation were computed for quantitative data. Chi-square test was used for qualitative data. ANOVA was used to compare three or more groups in normally distributed data.

Results

Out of 88 patients, 54 (61%) were males and 34 (39%) were females. The mean age of male patients was 50.5 ± 13.8 and female patients was 52.1 ± 14.1. Most of the patients were in stage two, i.e., 45 (51.1%) and 26 (29.5%) in stage three of the disease, whereas 2 (2.2%) patients were in stage one and 14 (15.1%) in stage four, and only one patient had cutaneous symptoms [Figure 2]. Past history of diabetes was present in 49 (55%) patients but all patients had deranged blood sugar at the time of hospitalization for mucormycosis. History of hospitalization was present in 41 (46.6%) patients and among those who were never hospitalized, 41 (46.6%) took ayurvedic treatment and steam inhalation 62 (70%). Forty-one (46.6%) patients with mucormycosis had positive RT-PCR reports and the rest had clinical features consistent with COVID-19 infection. Only one patient was vaccinated for COVID-19. Of total 88 patients, 42 (47%) were on oxygen therapy, 72 (81%) had history of blood transfusion, 48 (54%) were given steroids, only 7 (8%) had history of remdesivir treatment, and 58 (65%) had history of zinc intake. Forty-eight (54%) patients were discharged, 15 (17%) expired, whereas 25 (28%) left the treatment against medical advice and thus were lost to follow-up at the end of 90 days. Among the cases of mucormycosis, there was no statistically significant association of survival and deceased with history of diabetes (P = 0.965), COVID infection (P = 0.602), steroid use (P = 0.896), oxygen therapy (P = 0.71), and steam inhalation (P = 0.302). COVID-associated mucormycosis and non-COVID-associated mucormycosis were found to be statistically insignificant with history of diabetes (P = 0.341) and stages of mucormycosis (P = 0.971) [Table 2].

Table 2: Statistical analysis of proposed etiological factors

Click here to view

Discussion

The second wave of COVID-19 pandemic was associated with severe complications and high fatality rate in post-COVID patients, along with a rise in patients of a rare disease, mucormycosis, a black fungus infection which is now a notifiable disease in India.^[8] The peak number and graph of cases reported for COVID-19 and mucormycosis in India were parallelly placed [Graph 1] with a time gap of about 30 days, which strongly suggests association between the two.^[9] In the present study, the mean age of male patients was 50.5 ± 13.8 and female patients was 52.1 ± 14.1 and there were 61% of male patients which was consistent with studies done by Sen et al.^[10] and Kamleshun et al.^[6] Male gender has been found to be more associated with infection due to more outdoor activity leading to fungal spores exposures.^[10] Most of the patients were in stages two and three of the disease, very few in stages one and four.^[11] Mucormycosis typically infects diabetic patients, the risk of mucormycosis is 7.5 times higher in diabetics than the general population.^[12],[13] In a case series by John et al.,^[14] ninety-three percent were diabetic, whereas an existing global data by Singh et al.^[15] diabetics account for 80% of cases, whereas in this study, the past history of diabetes was present in only 55% of patients. Mucormycosis is a rare opportunistic infection, and COVID-19 patients are at risk of developing mucormycosis because of precompromised immune systems.^[16] COVID was an underlying disease as 46.6% of patients were having COVID-associated mucormycosis in our study is similar to 32.6% in Patel et al.^[17] and 50% was found in Salman Hussain et al.^[16] Steroid therapy is used as a line of treatment for COVID but if not used judiciously, predisposes secondary bacterial infections or invasive fungal infections, acting as double-edge sword to impact the outcome of the disease. In this study, 54% of patients had history of steroid use, whereas 76.3% of cases were found in study done by Mona G Alshahawey et al.^[4] The recommended patterns for the management involve proper glycemic control, wise use of glucocorticoids, and prompt antifungal treatment with proper surgical debridement. The presence of free iron in blood was found in some of patients presented with hyperglycemia and COVID-19-induced inflammation leading to mucormycosis.^[18] Eighty-one percent of patients in our study had history of blood transfusion as well. In the present study, history of oxygen therapy was present in 47% and remdesivir in 8% of patients similar finding seen in study by Sen et al.^[10]

Figure 2: Distribution of staging of study participants

Click here to view

It is difficult to conclude if greater oxygen support required in hospitalized patients led to ROCM; there is no large and published study done to prove it.^[10] No clinical correlation was identified between the mucormycosis and mode of delivery for oxygen therapy as usage of nonsterile oxygen prong or industrial oxygen use had been suggested as a predisposing factor.

Patients with COVID-associated mucormycosis had better survival rate if both surgical and medical management were done rather than just medical management. Despite the best management of these patients, the outcome was poor, suggesting the need for early identification of cases and taking preventive steps.

During surgeries, it was observed that well-demarcated areas of infarction/necrosis were present in many patients involving the areas supplied by sphenopalatine, greater palatine, ethmoid, and maxillary arteries corresponding to areas of necrosis/infarction of hard palate, nasal turbinate, or septal mucosa, particularly of bony septum which gets predisposed to saprophytic fungal infections. The similar observation is made by Ahmed et al.^[19] and Abou-Ismail et al. proposed multiple mechanisms for inflammatory thrombosis which are among the widely accepted pathophysiological mechanisms of COVID-19 in the occurrence of a generalized prothrombotic state. Underlying uncontrolled diabetes results in hyperactivation of the coagulation cascade in susceptible patients.^[20]

Several challenges were also identified in managing mucormycosis in our study including a delay in seeking health care, the lack of knowledge among physicians, and financial constraints. As a result of sudden spike in cases of mucormycosis, the availability of liposomal amphotericin was also constrained at many places.

Limitations

Our study is not without limitations. Although ours was an epidemiological study, the true incidence or prevalence of mucormycosis in different risk groups could not be ascertained. Despite proposing predisposing factors, we were not able to assess the strength of association and no conclusive evidence about any etiological factor could be identified. The reported treatment outcome of mucormycosis from a heterogeneous population in our study could not be used to draw conclusions for individual clinical presentations and outcomes.

Conclusions

Based on the surgical findings of the surgeons, it is postulated that due to microthrombi in the maxillary artery system, it led to ischemia and gangrene of the rhino-orbital regions which further led to fungal population of the decaying tissue, thus starting the vicious circle of RCOM. This theory is in consonance with the pathophysiology of COVID-19 infection where thrombosis of small and medium-sized vessels is well documented. To reduce the mortality and morbidity due to mucormycosis, it is important to form a multidisciplinary medical team for early diagnosis and treatment of the patients suffering from mucormycosis. Spreading the awareness among the health-care workers and common people is recommended. Physicians have to be vigilant with the use of steroids; it should be done according to risk‒benefit ratio. Glycemic control is important along with early detection and prompt treatment of disease for favorable outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus 2020;12:e10726.
2.	Sen M, Lahane S, Lahane TP, Parekh R, Honavar SG. Mucor in a viral land: A tale of two pathogens. Indian J Ophthalmol 2021;69:244-52. [PUBMED] [Full text]
3.	Sahu RK, Salem-Bekhit MM, Bhattacharjee B, Almoshari Y, Ikbal AM, Alshamrani M, et al. Mucormycosis in Indian COVID-19 patients: Insight into its patho-genesis, clinical manifestation, and management strategies. Antibiotics (Basel) 2021;10:1079.
4.	Alshahawey MG, El-Housseiny GS, Elsayed NS, Alshahrani MY, Wakeel LM, Aboshanab KM. New insights on mucormycosis and its association with the COVID-19 pandemic. Future Sci OA 2022;8:FSO772.
5.	Yasmin F, Najeeb H, Naeem A, Dapke K, Phadke R, Asghar MS, et al. COVID-19 associated mucormycosis: A systematic review from diagnostic challenges to management. Diseases 2021;9:65.
6.	Kamleshun R, Renuka V, Nomesh K, Yogeshwaree R, Stephenie M, Petras L. Rising concerns of mucormycosis (Zygomycosis) among COVID-19 patients; an analysis and review based on case reports in literature. Acta Biomed 2021;92:e2021271.
7.	Mahalaxmi I, Jayaramayya K, Venkatesan D, Subramaniam MD, Renu K, Vijayakumar P, et al. Mucormycosis: An opportunistic pathogen during COVID-19. Environ Res 2021;201:111643.
8.	Al-Tawfiq JA, Alhumaid S, Alshukairi AN, Temsah MH, Barry M, Al Mutair A, et al. COVID-19 and mucormycosis superinfection: The perfect storm. Infection 2021;49:833-53.
9.	Muthu V, Rudramurthy SM, Chakrabarti A, Agarwal R. Epidemiology and pathophysiology of COVID-19-associated mucormycosis: India versus the rest of the world. Mycopathologia 2021;186:739-54.
10.	Sen M, Honavar SG, Bansal R, Sengupta S, Rao R, Kim U, et al. Epidemiology, clinical profile, management, and outcome of COVID-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India – Collaborative OPAI-IJO study on mucormycosis in COVID-19 (COSMIC), Report 1. Indian J Ophthalmol 2021;69:1670-92. [PUBMED] [Full text]
11.	Honavar SG. Code mucor: Guidelines for the diagnosis, staging and management of rhino-orbito-cerebral mucormycosis in the setting of COVID-19. Indian J Ophthalmol 2021;69:1361-5. [Full text]
12.	Bala K, Chander J, Handa U, Punia RS, Attri AK. A prospective study of mucormycosis in north India: Experience from a tertiary care hospital. Med Mycol 2015;53:248-57.
13.	Ibrahim AS, Spellberg B, Walsh TJ, Kontoyiannis DP. Pathogenesis of mucormycosis. Clin Infect Dis 2012;54 Suppl 1:S16-22.
14.	John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: The perfect storm for mucormycosis. J Fungi 2021;7:298.
15.	Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes Metab Syndr 2021;15:102146.
16.	Hussain S, Baxi H, Riad A, Klugarová J, Pokorná A, Slezáková S, et al. COVID-19-associated mucormycosis (CAM): An updated evidence mapping. Int J Environ Res Public Health 2021;18:10340.
17.	Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, et al. Multicenter epidemiologic study of coronavirus disease-associated mucormycosis, India. Emerg Infect Dis 2021;27:2349-59.
18.	Prakash H, Skiada A, Paul RA, Chakrabarti A, Rudramurthy SM. Connecting the dots: Interplay of pathogenic mechanisms between COVID-19 disease and mucormycosis. J Fungi (Basel) 2021;7:616.
19.	Ahmed O, Aladham Y, Mahmood S, Abdelnaby MM. Complicated sinusitis with sphenopalatine artery thrombosis in a COVID-19 patient: A case report. J Surg Case Rep 2021;2021:rjab010.
20.	Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management. Thromb Res 2020;194:101-15.