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BRIEF RESEARCH ARTICLE
Year : 2022  |  Volume : 66  |  Issue : 4  |  Page : 494-497  

Risk factors for severe rhino-orbital mucormycosis during its epidemic post-COVID-19 pandemic


1 Director Professor, Department of Ophthalmology, University College of Medical Sciences and GTB Hospital, Delhi, India
2 Assistant Professor, Department of Ophthalmology, University College of Medical Sciences and GTB Hospital, Delhi, India
3 Senior Resident, Department of Ophthalmology, University College of Medical Sciences and GTB Hospital, Delhi, India
4 Resident, Department of Ophthalmology, University College of Medical Sciences and GTB Hospital, Delhi, India

Date of Submission29-May-2022
Date of Decision01-Aug-2022
Date of Acceptance11-Aug-2022
Date of Web Publication31-Dec-2022

Correspondence Address:
Nitika Beri
E-417, Aastha Kunj, Rohini Sector-18, Delhi-110 089
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijph.ijph_714_22

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   Abstract 


Postsecond wave of COVID-19 pandemic in the year 2021, rhino-orbital mucormycosis (ROM) was seen as an epidemic in the Indian community. Severe ROM disease has poor prognosis and requires a multidisciplinary approach for treatment. Hence, its prevention is better than cure. Studies done during the epidemic assessed predisposing factors, but this was a novel study which focused on assessing risk factors for severe disease of ROM. Ninety-four consecutive patients of ROM admitted at our designated nodal tertiary hospital of North India were enrolled, and data were collected and analyzed. Facial edema was the most common presenting complaint. Subclinical and mild COVID-19 infection was associated with severe ROM. Uncontrolled diabetes mellitus and prophylactic zinc supplementation were other significant risk factors for severe ROM. Public awareness among the general population for the above risk factors can prevent a debilitating disease like severe ROM.

Keywords: COVID-19 pandemic, epidemic, rhino-orbital mucormycosis, risk factors


How to cite this article:
Das GK, Singh A, Beri N, Sahu PK, Bisht T, Sharma I. Risk factors for severe rhino-orbital mucormycosis during its epidemic post-COVID-19 pandemic. Indian J Public Health 2022;66:494-7

How to cite this URL:
Das GK, Singh A, Beri N, Sahu PK, Bisht T, Sharma I. Risk factors for severe rhino-orbital mucormycosis during its epidemic post-COVID-19 pandemic. Indian J Public Health [serial online] 2022 [cited 2023 Feb 1];66:494-7. Available from: https://www.ijph.in/text.asp?2022/66/4/494/366591



During the second wave of COVID-19 infection, an exponential increase in cases of rhino-orbital mucormycosis (ROM) was seen worldwide, and based on the literature, it is estimated that India contributed to around 71% of global cases during that period.[1] The Government of India made it a notifiable disease in May 2021. Our tertiary care hospital was declared as a nodal center in North India for treatment of this disease and have treated over 250 cases and counting till date.

Mild ROM disease (involvement of sinuses only) is less debilitating and requires mainly intervention by ear, nose, and throat (ENT) specialists. Severe ROM disease (involvement of sinuses, eyes, and/or brain) requires a multidisciplinary team approach of ENT, eye, and neurosurgery specialist and is highly debilitating disease with a higher mortality.

This study was designed to assess the risk factors for severe form of ROM for a better understanding of this public health problem to better manage and form preventive guidelines for severe ROM disease. Previous studies done during the epidemic have postulated predisposing factors, but none have concentrated on severe disease which our study intended to do.[2],[3]

This was an observational cross-sectional study and was approved by the institution's Ethics Committee and registered under Clinical Trials Registry of India (CTRI/2021/10/037466).

A total of 94 consecutive patients with confirmed microbiological evidence of ROM admitted to the hospital were included in the study after informed consent during July 2021–November 2021. Data were collected by standard questionnaire formulated for the study [Supplementary Annexure 1].

All patients were staged according to the staging of rhino-orbital-cerebral mucormycosis[4] [Supplementary Annexure 2]. We divided the patients into mild disease of ROM (≤3a stage [sinuses with or without medial orbit involvement]) and severe disease of ROM (≥3b stage [sinuses with diffuse orbital with or without brain involvement]). The rationale behind this division was that in patients with ≥3b stage (diffuse orbital involvement and more), ophthalmic surgical intervention was undertaken as appropriate for the patients along with sinus debridement to prevent the progression of the disease.

Severity of COVID-19 infection was defined as mild for those patients not requiring oxygen and severe for those requiring oxygen.[5]

COVID-19-positive patients were defined as patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA by reverse transcriptase-polymerase chain reaction, positive by rapid antigen test, and those who were unable to get tested, but had a history and symptoms strongly suggestive of COVID-19 infection.

Cases of ROM with a positive history of COVID-19 were labeled as COVID-associated mucormycosis (CAM), and rest were labeled as non-CAM.

A good control of diabetes mellitus was defined as glycated hemoglobin (HbA1c) value <7% and poor control if HbA1c value ≥7%.[6]

Quantitative data were analyzed using Mann–Whitney test and independent t-test. Qualitative data were analyzed using Chi-square test and Fisher's exact test. Univariate analysis was done for all predisposing factors, and those which came statistically significant, multivariate logistic regression analysis was done to ascertain severity of ROM disease with any particular predisposing factor. P < 0.05 was considered statistically significant. Data analysis was done using Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, ver 21.0.

A total of 94 patients with a mean age of 51.04 ± 12.1 years (range 20–77 years) were included in the study [Table 1]. Males were more affected with ROM (60 [63.83%] males and 34 [36.14%] females), which is in agreement with previous literature.[2],[3] The severity of ROM disease was also more severe in males [Table 1].
Table 1: Association of parameters with severity of rhino-orbital mucormycosis disease

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The average presentation of ROM after COVID-19 infection was 20 ± 17 days. The most common presenting complaint was facial edema, 50/94 (53.19%), and others were nasal eschar (28.72%), dental pain (10.64%), and eye problems such as ptosis and diplopia (7.45%).

Diabetes mellitus (78/94 [82.98%]) was noted to be the most common comorbidity among the patients. Uncontrolled diabetes (HbA1c ≥7 g%) was statistically significant in patients with severe disease [Table 1], and odds ratio was calculated to be 1.213 (95% confidence interval [CI] = 0.867–1.697) indicating that higher the value of HbA1c more is the chance of severe disease from ROM [Table 2].
Table 2: Multivariate logistic regression to predict independent risk factors for severe rhino-orbital mucormycosis disease

Click here to view


Diabetes mellitus is a known risk factor for immunosuppression and impairment of phagocytic function in innate immunity which causes an increased susceptibility to fungal infections.[7]

Of 94 patients, 77 (81.91%) were CAM and 17 (18.09%) patients were non-CAM. Of 77 CAM patients in the study, 33 had severe COVID-19 infection and 44 had mild COVID-19 infection [Table 1]. The odds ratio for association of severe COVID-19 disease with severe ROM was 0.351 (95% CI = 0.106–1.161), indicating a weak association [Table 2]. One possible explanation is that patients with severe COVID-19 disease also had a higher mortality rate, hence could not survive long enough to present with severe ROM disease.

In non-CAM patients, severe ROM was seen in 14/17 (77.78%) compared to CAM 28/77 (36.84%) (P = 0.003). None of the non-CAM patients were on systemic steroids or supplemental oxygen. All patients of non-CAM with severe ROM (14/17) had uncontrolled diabetes.

We hypothesize that non-CAM patients might have had some exposure to the virus and had subclinical COVID-19 infection. This is because in the nonepidemic era, patients with such poor glycemic control would not have ROM disease, but during the epidemic of ROM, it was noted to be the most common risk factor across multiple studies.[2],[3],[8] Muthu et al.[8] discussed that endotheliitis and vasculitis occur due to release of cytokines in response to COVID-19 virus, which causes inflammation and damage to the vessel wall. This makes it more prone to invasion by infective organisms like fungus. The above highlights the possibility of exposure to SARS CoV2 virus and the importance of keeping blood sugars under control.

Systemic steroids were taken by 13/42 patients (30.95%) with severe ROM disease and 28/52 patients (53.84%) with mild ROM disease. A negative correlation between severe ROM disease and systemic steroid intake was noted ([P = 0.026] [Table 1]).

Supplemental oxygen exposure was seen in 10/42 patients (23.81%) with severe ROM disease and 25/52 patients (48.08%) with mild ROM disease. A negative correlation between severe ROM disease and supplemental oxygen exposure was noted ([P = 0.031] [Table 1]).

One possible explanation can be that since both of these are an integral part in the management of severe COVID-19 disease, which itself was seen to be weakly associated with severe ROM disease. Severe ROM disease was also seen in non-CAM patients, and none of these had exposure to supplemental oxygen or systemic steroids. Hence, we would like to suggest that both systemic steroids and supplemental oxygen should be continued in the management of severe COVID-19 disease, but with a strict glycemic control.

Patients who had taken zinc as a preventive medication for COVID-19 infection had more severe disease with ROM versus who did not take zinc as supplements (P = 0.024). The odds ratio for zinc intake was 2.745 (95% CI = 0.879–8.570), which indicates predilection for severe disease of ROM with zinc intake [Table 2].

Studies have shown that our body conceals zinc intracellularly and creates a state of nutritional immunity by limiting the availability of zinc in the local environment. This is a protective measure of the body against fungal infection.[9] Zinc supplementation as a prophylactic measure to prevent COVID-19 infection may promote fungal infections by increasing availability of zinc in the blood. The acidotic environment in the host's body (like ketoacidosis due to uncontrolled diabetes) along with the availability of zinc becomes a fertile ground for the fungus to invade the host (some fungal transporters work optimally at acidic pH in the presence of zinc).[10] This explains the result seen in the study that increased zinc intake and uncontrolled diabetes associate to increased severity of ROM disease.

This is the first study to associate risk factors for severe ROM disease during its epidemic postsecond wave of COVID-19 pandemic. Public awareness among patients of mild COVID-19 infection of signs and symptoms of ROM with an immediate need for medical opinion in case of facial edema in uncontrolled diabetics is required to catch this disease earlier and prevent severe form of ROM. Zinc supplementation should be used judiciously as a preventive measure for COVID-19 infection. Systemic steroid intake and oxygen supplementation may be continued in the management of COVID-19 disease, but with strict glycemic control. Regular monitoring of blood sugars as a part of routine health examination for achieving a good glycemic control by diabetic patients must be done.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Supplementary Annexure

Supplementary Annexure 1

Study Questionnaire

Name: Age: Sex: Serial Number:

Residential Address:

Phone Number:

Occupation:

Microbiological evidence of mucormycosis:

(KOH/Tissue Sample)

Details of Mucormycosis

Stage of rhino-orbital mucormycosis (ROM):

Presenting complaint of ROM:

History of COVID infection:

RT-PCR for COVID/Rapid antigen test (positive/negative):

COVID symptom (fever/cough/breathlessness):

Duration of COVID illness:

Requirement of oxygen at home (yes/no)

- Duration of oxygen requirement at home

Requirement of oxygen at hospital (yes/no):

- Number of days on oxygen at hospital

- Low flow (oxygen given through simple mask)

- high flow (oxygen given through mask with bag)

- NIV at hospital (oxygen given through machine)

Days of onset of mucormycosis symptoms from COVID infection:

Severity of COVID:

Mild: Patients not requiring oxygen:

Severe: Patients requiring oxygen:

Treatment of COVID taken:

Systemic steroid intake (yes/no)

-Duration of steroid intake

Nebulization with steroids (yes/no):

Remdesivir given (yes/no):

Tocilizumab given (yes/no):

Antibiotics taken:

- Doxycycline

- Azithromycin

- Azithromycin + Doxycycline

- None

Preventive measures taken to prevent COVID infection:

Steam inhalation taken (yes/no):

Kadha (ayurvedic concoction of herbs) (yes/no):

Zinc Intake:

History of comorbidities in patients:

Diabetes mellitus (yes/no):

HBA1C:

Control of diabetes

- Good (HBA1C <7%)

- Poor (HBA1C ≥7%)

Any other comorbidities-

Vaccination status:

-Complete:

-Incomplete:

-Not vaccinated:

Reference: 1. Honavar SG. Code mucor: guidelines for the diagnosis, staging and management of rhino-orbito-cerebral mucormycosis in the setting of COVID-19. Indian Journal of Ophthalmology 2021 Jun 1;69(6):1361-5.

Supplementary Annexure 2

Title of the article: Risk Factors for Severe Rhino-Orbital Mucormycosis during its Epidemic post COVID-19 Pandemic

Proposed Staging of Rhino-Orbito-Cerebral Mucormycosis (ROCM) by Honavar et al[1]



Reference: 1. Honavar SG. Code mucor: guidelines for the diagnosis, staging and management of rhino-orbito-cerebral mucormycosis in the setting of COVID-19. Indian Journal of Ophthalmology 2021 Jun 1;69(6):1361-5.



 
   References Top

1.
John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: The perfect storm for mucormycosis. J Fungi (Basel) 2021;7:298.  Back to cited text no. 1
    
2.
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.  Back to cited text no. 2
[PUBMED]  [Full text]  
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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.  Back to cited text no. 3
    
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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.  Back to cited text no. 4
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Mohfw.gov.in. Clinical Management Protocol for Covid-19 in Adults [Internet]. 2021 [updated May 24 2021; cited December 4 2021]. Available from: https://www.mohfw.gov.in/pdf/UpdatedDetailedClinicalManagementProtocolfor COVID19adultsdated24052021.pdf”  Back to cited text no. 5
    
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American Diabetes Association. 6. Glycemic targets: Standards of medical care in diabetes-2021. Diabetes Care 2021;44:S73-84.  Back to cited text no. 6
    
7.
Shodja MM, Knutsen R, Cao J, Oda K, Beeson LE, Fraser GE, et al. Effects of glycosylated hemoglobin levels on neutrophilic phagocytic functions. Jacobs J Diabetes Endocrinol 2017;8:9-16.  Back to cited text no. 7
    
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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.  Back to cited text no. 8
    
9.
Crawford A, Wilson D. Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens. FEMS Yeast Res. 2015 Nov;15(7).  Back to cited text no. 9
    
10.
Staats CC, Kmetzsch L, Schrank A, Vainstein MH. Fungal zinc metabolism and its connections to virulence. Front Cell Infect Microbiol 2013;3:65.  Back to cited text no. 10
    



 
 
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