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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 349-354

Infection of mucormycosis inpatients in Covid-19: an experience at the tertiary medical center in Maharashtra, India


Department of Radiology, MGM Medical College and Hospital, N-6, CIDCO, Aurangabad 431003, Maharashtra, India

Date of Submission23-Aug-2021
Date of Acceptance05-Oct-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Dr. Harshul Sharma
Department of Radiology, MGM Medical College and Hospital, N-6, CIDCO, Aurangabad 431003, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_64_21

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  Abstract 

Introduction: Mucormycosis is a rare infection known to be one of the most rapidly progressing and lethal forms of fungal infection in humans, with a high mortality rate of 70–100%. Covid-19 cases were reported from all states of the country, but cases of mucormycosis in the setting of COVID-19 pneumonia were very low and that too reasoned that this was most likely due to the patient’s immune-compromised condition. Aims and Objectives: The aim of this article is to assess mucormycosis in Covid-19 patients and its association with the immune status of patients. Materials and Methods: Over 5 months, from February 2021 to June 2021, a retrospective observational study was conducted at MGM Medical College, Aurangabad, Maharashtra, India. The study included all patients who came for imaging to the Radiology Department with mucormycosis who were either coronavirus-positive or had recovered from coronavirus infection. All patients with a molecular diagnosis of SARS-CoV-2 infection admitted to our hospital and having a clinical diagnosis of invasive fungal infections were included. Results: All 30 (100%) patients were diabetic; 17 of these had uncontrolled blood sugar levels with HbA1C levels >6.5%, and the remaining 13 patients had controlled diabetes. The majority of uncontrolled diabetics (17 out of 30) had invasive mucormycosis, rhino-orbital mucormycosis and rhino-orbital cerebral stage, whereas only 3 subjects with control diabetes had invasive mucormycosis. Five uncontrolled diabetic patients had rhino-orbital cerebral stage, whereas only two controlled had rhino-orbital cerebral stage. There is a significant difference between controlled and uncontrolled diabetes with P-value of 0. Conclusion: Covid-19 connection to invasive mucormycosis infection is extremely dangerous and should be taken seriously. Uncontrolled diabetes and inappropriate use of steroids during the management of Covid-19 are two of the most common causes of disease aggravation, and both must be addressed.

Keywords: Covid-19, diabetes, fungal infection, mucormycosis, steroid


How to cite this article:
Sharma H, Pole S, Sabatina G, Saraf R, Joshi S, Dahipale DB, Mishrikotkar PS. Infection of mucormycosis inpatients in Covid-19: an experience at the tertiary medical center in Maharashtra, India. MGM J Med Sci 2021;8:349-54

How to cite this URL:
Sharma H, Pole S, Sabatina G, Saraf R, Joshi S, Dahipale DB, Mishrikotkar PS. Infection of mucormycosis inpatients in Covid-19: an experience at the tertiary medical center in Maharashtra, India. MGM J Med Sci [serial online] 2021 [cited 2022 Jan 18];8:349-54. Available from: http://www.mgmjms.com/text.asp?2021/8/4/349/333325




  Introduction Top


The pandemic coronavirus disease 2019 (COVID-19) is still a major issue around the world, currently at its peak in India. Although several treatment strategies have been proposed, no objective guideline on the use of steroids is reached, this may lead to inappropriate use of the steroid.

The widespread use of glucocorticoids, unfortunately, may result in secondary bacterial or fungal infections. Patients with pre-existing conditions such as asthma, diabetes, or coronary artery disease are particularly vulnerable to COVID-19 pneumonia-related complications.[1]

Fungal infection is more likely to occur in patients with poorly regulated diabetes and immunodeficiency. Mucormycosis is a fatal yet rare fungal infection found in Covid-19 cases. Very few confirmed cases of mucormycosis in the setting of Covid-19 pneumonia were there and that too were mainly due to the patient’s immunocompromised condition.[2]

Mucormycosis (phycomycosis, zygomycosis) is a rare opportunistic infection caused by Mucorales order and Mucoraceae family fungi. Paultauf first described mucormycosis in 1885.[3] It is known to be one of the most rapidly progressing and lethal forms of fungal infection in humans, with a high mortality rate of 70–100%.[4],[5]

Mucormycosis is characterized by the presence of hyphal invasion of sinus tissue and a time course of fewer than 4 weeks.[6],[7] Clinically, rhinocerebral mucormycosis can mimic the signs and symptoms of complicated sinusitis, such as nasal obstruction. If the intracranial extension is present, crusting, proptosis, facial pain and edema, ptosis, chemosis, and even ophthalmoplegia may occur, along with headache, fever, and various neurological signs and symptoms. A black eschar can be found in the nasal cavity or on the hard palate, but it is not typical. Mycotic invasion of blood vessels, vasculitis with thrombosis, tissue infarction, hemorrhage, and acute neutrophilic infiltrate are histological characteristics.[8]

Mucormycosis must be diagnosed correctly because its management necessitates the use of toxic antifungal drugs. Mucormycosis is difficult to diagnose clinically due to clinical characteristics that contrast with those of other infections and the absence of blood markers such as galactomannan and D-glucan. Definitive diagnosis often necessitates invasive sampling, which may cause care to be delayed and is not always effective. As a result, imaging results that indicate a diagnosis are crucial in the treatment of these patients.[9] Here, we present our recent and still ongoing continuing experience with 30 cases of mucormycosis seen over 5 months, with these patients being, or having been, Covid-19-positive.

Aims and objectives

  1. To assess mucormycosis in Covid-19 patients and its association to the presence of diabetes.


  2. To study the treatment strategies and their outcomes.



  Materials and methods Top


Over 5 months, from February 2021 to June 2021, a retrospective observational study was conducted at MGM Medical College, Aurangabad, Maharashtra, India.

Inclusion criteria

The study included all patients with mucormycosis who came to the hospital as were either coronavirus-positive or had recovered from coronavirus infection for their imaging.

All patients with a confirmed molecular diagnosis of SARS-CoV-2 infection admitted to our hospital and who were tested for invasive fungal infections were included.

Exclusion criteria

The study subjects with other fungal infections were excluded. Those study subjects who were Covid-19-positive or history of Covid-19 positivity on RT–PCR testing and having clinical symptoms of fungal infections were included. A brief history of the complaint, its length, and related factors was obtained. With the help of leading questions and past reports, a detailed history of risk factors such as immunocompromised status like diabetes (control/diabetic ketoacidosis), human immunodeficiency virus (HIV), medication consumption, and previous antibiotic therapy was elicited. Other important histories were also elicited and recorded. History of diabetes and management of steroids, type, and duration of steroids were elicited by the history from study subjects.

Total hemogram, renal function test, liver function test, urine routine, HIV and hepatitis B surface antigen, X-ray chest, and ECG were all performed on all patients. Fasting and post-prandial blood glucose levels, as well as urine ketone, were measured in diabetic patients. Histopathological examination was done for confirmation of diagnosis. A mandatory computed tomography (CT) and magnetic resonance imaging (MRI) of the brain and paranasal sinuses was performed. Other tests were carried out based on patients’ needs.

The patients were classified into stages based on the extent of their disease’s clinical manifestations. The maxilla, oral cavity-palate, retromaxillary space, pterygopalatine fossa, and infratemporal fossa are all affected by rhino-maxillary mucormycosis. Patients with rhino-orbital mucormycosis (ROM) had disease affecting the orbital mucosa (intraconal, extraconal).

Patients with cavernous sinus and intracranial mucormycosis, with or without the involvement of the orbit and maxilla, are classified as rhino-orbito-cerebral mucormycosis (ROCM).

Each patient’s care was customized. Glycemic regulation, metabolic factor correction, control/reversal of immunocompromised factors such as neutropenia, correction of renal parameters, correction of anemia as required, and antifungal agents are all parts of medical management.

The key drug used was amphotericin B iv. After hydrating the patient with 500 mL normal saline, the patient was given 1 mg/kg body weight/day up to a cumulative dose of 50 mg/day with 5% dextrose over 4–6 h. About 2 g iv or higher was considered completion of the treatment course. However, depending on the patient’s needs, it was raised to 3 g iv. If there was renal dysfunction, then Inj. Liposomal Amphotericin was given up to 3 g iv or it was given after receiving a nephrology opinion.

Statistical analysis

Statistical analyses were performed using Microsoft Excel and Epi Info 7.2.1 software. The data were presented as mean ± standard deviation. P-value <0.05 was considered statistically significant. Number and percentage were used to describe frequency and prevalence.


  Results Top


A total of 30 patients were presented: 19 of these were male and 11 were female. Six of the patients were coronavirus-positive at the time of presentation but had been infected for more than 14 days; the remaining 24 had been infected earlier and had recovered. The mean age of the study subjects was 51.03±11.47 years. The distribution of study of subjects as per symptoms has been presented in [Figure 1].
Figure 1: Distribution of study subjects as per symptoms

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The majority of study subjects, i.e., 28 out of 30, had nasal obstruction, 80% had headache, 66.67% had nasal discharge, 60% had loss of vision, and 56.67% had proptosis. Two of these patients are currently receiving intra-orbital amphotericin treatment. Intracranial involvement has seen seven cases. The classical black eschar on the hard palate was observed in 14 patients. All 30 (100%) patients were diabetic: 17 of these had uncontrolled blood sugar levels with hemoglobin A1c levels higher than 6.5%, and the remaining 13 patients had controlled diabetes.

MRI of 30 patients is analyzed retrospectively; maxillary sinus was found to be most commonly involved in 28 patients (93%), whereas ethmoid, sphenoid, and frontal (84%) are 83%, 83%, and 84%, respectively. The nasal cavity is involved in 22 patients (73%) [Table 1].
Table 1: Distribution of study subjects as per sinus involvement on MRI

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The medial maxillary sinus wall is eroded in 14 patients (46%), most common to involve. Nasal septum/turbinate was in 9 patients (30%), orbital wall (medial) in 10 patients (33%), and orbital wall (lateral) in 3 patients (10%) [Table 2].
Table 2: Distribution of study subjects as per bone erosion on MRI

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Involvement of fat pad in the retro-maxillary region is noted in 14 patients (63%), which is considered to be a highly sensitive sign for invasive fungal sinusitis. Four patients (13%) have infratemporal fossa involved and 12 patients (40%) have pterygomaxillary fissure involvement.

Orbital involvement is noted in 50% of the cases, out of which extracranial involvement is noted in all the cases and intracranial involvement in 10 patients (66%) leading to orbital cellulitis, 8 patients (53%) have optic neuritis, and 9 (60%) patients have proptosis. Ten (66%) patients had involvement of superior orbital fissure. Extraocular muscle involvement is noted in 10 patients (66%) and the medial rectus is the most common muscle involved. Preseptaledema is noted in six patients (40%). Intracranial involvement is noted in seven patients (23%), the most common intracranial complication is an abscess in the temporal lobe accounting in four patients, intracranial infarct in three patients, and intracranial hemorrhage in two patients. Contrast studies were done in nine patients; contrast is better for detecting involvement of optic nerve, osteomyelitis, intracranial involvement like an abscess.

Eighteen patients had hypertension, of which two were uncontrolled. One patient was in renal failure at the time of presentation. All 30 patients had used steroids during the management of their coronavirus-associated illness [Table 3].
Table 3: Distribution of study subjects as per associated co-morbid conditions

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One subject with control diabetes had ROM. Five uncontrolled diabetic patients had ROCM, whereas only two controlled patients had ROCM. There is a significant difference between controlled and uncontrolled diabetic patients with a P-value of <0.01 [Table 4].
Table 4: Association of stages of mucormycosis with the uncontrolled diabetes

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Out of 17 uncontrolled diabetic patients, 3 died whereas 14 survived; however all 13 subjects with controlled diabetics survived. One death is due to cardiac arrest whereas the other two deaths were due to respiratory failure, but all three had fulminant fungal infections and their complications. On applying the χ2 test, there was a non-significant difference with a P-value of 0.11 [Table 5].
Table 5: Association of the outcome of mucormycosis with the uncontrolled diabetes

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  Discussion Top


Covid-19 infection, which is caused by the novel SARS-CoV-2, has been linked to a wide range of symptoms, from a mild cough to life-threatening pneumonia. As we learn more about this novel Covid-19 pandemic, a plethora of symptoms and complications have been documented, and new ones are arising and being reported every day. Paltaufalso elaborates its effect on the immunological system.[10] It is a fatal fungal infection, with rhinocerebral manifestations being the most common.[11] Despite its low incidence rate (ranging from 0.005 to 1.7 per million population), several cases have been recorded recently, indicating a substantial rise in its incidence in the wake of the current coronavirus pandemic.[12] SARS-CoV-2, like SARS-CoV and Middle East respiratory syndrome, causes inflammation in the lower respiratory tract and can lead to acute respiratory distress syndrome.[13] Covid-19 patients still have immunosuppression, with a decline in CD4+ T and CD8+ T cells, in addition to diffuse alveolar damage with extreme inflammatory exudation.[14] During the spread of the SARS-CoV infection in 2003, the rate of fungal infection was 14.8–27%, and it was the leading cause of death in SARS patients, accounting for 25–73.7% of all deaths. Based on several findings, physicians should pay close attention to the high likelihood of increased occurrence of fungal infections in Covid-19-infected or recovered patients, similar to what we saw in mucormycosis cases. Few such incidental case reports had previously been released, but now there is a strong link between Covid-19 and increased fungal infections. In September 2020, Mehta and Pandey recorded a single case of ROM linked to Covid-19 in a 60-year-old man. In the same month, Werthman-Ehrenreich[12] released another case study. In a study of 135 adults with Covid-19 infection, White et al.[15] found a 26.7% prevalence of invasive fungal infections. In April 2020, Song et al.[16] investigated the connection between Covid-19 and invasive fungal sinusitis, concluding that a substantial number of patients who have been exposed to or recovered from Covid-19 are at an elevated risk of developing invasive fungal diseases and providing a management algorithm for these patients. According to a recent study, 8% of coronavirus-positive or -recovered patients developed secondary bacterial or fungal infections while in the hospital, despite extensive use of broad-spectrum antibiotics and steroids.[17] The immunosuppression induced by the Covid-19 infection and disease process, as well as the extensive use of steroids and broad-spectrum antibiotics in the management of Covid-19, could all contribute to the development or exacerbation of a pre-existing fungal disease.

Because of its low virulence capacity, mucor can be found as a commensal in the nasal mucosa of healthy people,[18] which may be aggravated if the patient becomes immunocompromised. The non-invasive test of choice is non-contrast CT of the paranasal sinuses, followed by gadolinium-enhanced MRI if the intra-orbital or intracranial extension is suspected.

The importance of imaging in the diagnosis and prognosis of post-Covid mucormycosis cannot be underestimated. A common finding on a cranial CT in post-Covid patients is bone loss. A cranial MRI is recommended for added sensitivity as the findings will reveal any involvement of the brain, sinuses, or orbit. The staging will be noted on imaging in terms of sinus and cerebral involvement. The staging and involvement of neighboring structures are taken into account when deciding on management. Imaging has the added benefit of being non-invasive and providing a swift result in the management of post-Covid mucormycosis.

Once the diagnosis is confirmed, surgical debridement of the infected area should be done as soon as possible. While surgery alone is not curative, an aggressive surgical approach has been shown to improve survival rates.[19] Amphotericin-B deoxycholate is the antifungal treatment of choice, with liposomal formulations preferred due to lower nephrotoxicity. Posaconazole is a viable alternative to amphotericin treatment in situations in which it is refractory or intolerant (6.32%). Even with intensive treatment and intravenous antifungal therapy, the prognosis is low, with mortality rates ranging from 33.3% to 80%, with disseminated infections reaching 100%.

During the 5-month study period, we discovered 30 cases of mucormycosis; all of these patients were either coronavirus-positive at the time of diagnosis or had previously been infected. Surgical debridement was performed on all of the patients.


  Conclusion Top


We are learning more about the long-term manifestations of Covid-19 infections. Its connection to invasive mucormycosis infection is extremely dangerous and should be taken seriously. Uncontrolled diabetes and overuse of steroids are two of the most common causes of disease aggravation, and both must be addressed. In cases of post-coronavirus mucormycosis, early surgical intervention and intravenous anti-fungal therapy should be pursued as a positive prognosis and less fulminant disease course can be obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Ethical consideration

The Institutional Ethics Committee for Research on Human Subjects has approved the proposal to undertake the clinical study entitled “A rare but fatal infection of mucormycosis inpatient of Covid-19: A experience at the tertiary medical center at Maharashtra, India” vide their letter no. MGM-ECRHS/2021/75 dated September 15, 2021.



 
  References Top

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Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, et al. Coronavirus disease (Covid-19) associated mucormycosis (CAM): Case report and systematic review of literature. Mycopathologia 2021;2:1-5.  Back to cited text no. 1
    
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Alekseyev K, Didenko L, Chaudhry B. Rhinocerebral mucormycosis and COVID-19 pneumonia. J Med Cases 2021;12:85-9.  Back to cited text no. 2
    
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Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am 2000;33:227-35.  Back to cited text no. 6
    
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Chakrabarti A, Denning DW, Ferguson BJ, Ponikau J, Buzina W, Kita H, et al. Fungal rhinosinusitis: A categorization and definitional schema addressing current controversies. Laryngoscope 2009;119:1809-18.  Back to cited text no. 7
    
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Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med 2021;42:264.e5-8.  Back to cited text no. 12
    
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Wang YH, Liao J, Zhang DM, Wu DB, Tao YC, Wang ML, et al. Tenofovir monotherapy versus tenofovir plus entecavir combination therapy in HBeAg-positive chronic hepatitis patients with partial virological response to entecavir. J Med Virol 2020;92:302-8.  Back to cited text no. 13
    
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White L, Dhillon R, Cordey A, Hughes H, Faggian F, Soni S, et al. A national strategy to diagnose coronavirus disease 2019: Associated invasive fungal disease in the intensive care unit. Clin Infect Dis 2020;1298:1-5.  Back to cited text no. 15
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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