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 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 »  References
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 Table of Contents    
SYSTEMATIC REVIEW
Year : 2021  |  Volume : 53  |  Issue : 4  |  Page : 317-327
 

Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review


1 Department of Ophthalmology, Government Medical College and Hospital, Bathinda, Punjab, India
2 Department of Pharmacology, PGIMER, Bathinda, Punjab, India
3 Department of Internal Medicine, Silchar Medical College and Hospital, Assam, India
4 Department of Anaesthesia, Assam Medical College and Hospital, Assam, India
5 Biophysics, PGIMER, Bathinda, Punjab, India
6 Scientific Officer, Department of Pharmacology, Indian Pharmacopoeia Commission, Ghaziabad, Uttar Pradesh, India
7 Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
8 Department of Microbiology, Assam Medical College and Hospital, Assam, India

Date of Submission27-May-2021
Date of Decision31-Jul-2021
Date of Acceptance02-Aug-2021
Date of Web Publication18-Aug-2021

Correspondence Address:
Prof. Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.ijp_419_21

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 » Abstract 


Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment.


Keywords: Corticosteroid, COVID-19, diabetes, fungal co infection, mucormycosis, rhino-orbito-cerebral mucormycosis, supplemental oxygen


How to cite this article:
Bhattacharyya A, Sarma P, Sharma DJ, Das KK, Kaur H, Prajapat M, Kumar S, Bansal S, Prakash A, Avti P, Thota P, Reddy DH, Gautam BS, Medhi B. Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review. Indian J Pharmacol 2021;53:317-27

How to cite this URL:
Bhattacharyya A, Sarma P, Sharma DJ, Das KK, Kaur H, Prajapat M, Kumar S, Bansal S, Prakash A, Avti P, Thota P, Reddy DH, Gautam BS, Medhi B. Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review. Indian J Pharmacol [serial online] 2021 [cited 2021 Sep 17];53:317-27. Available from: https://www.ijp-online.com/text.asp?2021/53/4/317/324044





 » Introduction Top


Mucormycosis refers to a spectrum of diseases caused by order of mucorales[1] with worldwide annual incidence rate is 0.4–1.7 cases/10 lakh population.[2] It is an acute opportunistic infection caused by a group of fungi phylum Glomeromycota (saprophytic fungi, found in soil and air). The disease entity was first described by Meyer 1815.[3] Previously, they were treated as nonpathogenic fungi and treated as fungal contaminant in microbiology lab, but the trend changes nowadays and now treated as pathogenic fungi which leads to devastating outcome, especially in immunocompromised host or person with preexisting comorbidities in specific clinical setting, leading to immunocompromised state.[1] Cases of mucormycosis have also being reported in the healthy individuals.[4],[5] Although previously reported as rare occurrence (incidence rate: 0.005–1.7/million[6] with the surge of the COVID-19 pandemic incidence has been rapidly raising (Up to 26.7%),[7] especially in India in post-COVID-19 patient population and forming a major point of concern.[8],[9] The association of rhino-orbital-cerebral–mucormycosis (ROCM) is the most common form of mucormycosis found in with common risk factor associated to be with diabetes mellitus (DM) (especially uncontrolled DM) followed by other immunosuppressive conditions, e.g. hematological malignancy (commonly patients with blood transfusion), chronic kidney disease, organ transplant, HIV population also hospitalized people under prolong broad-spectrum antibiotics, and immunosuppressive treatment especially steroids,[10] which is more commonly related to the injudicious use of corticosteroid related to COVID-19 treatment reported in various recent literature.[11] While mucormycosis without predisposition medical immune condition is also reported in literature.[11]

Proposed mechanism of pathogenesis of ROCM is through colonization of nasal mucosa; sinuses than spreading to adjacent structures, e.g. orbit (extra ocular muscles and orbital apex), bone erosion, and rarely to intracranial spread. The diagnosis is based on early clinical suspicion, computational tomography of paranasal sinus, orbit and brain, and preliminary microbiological investigation (potassium hydroxide [KOH] mount/calcofluor white stain) (first investigation) which is followed by definitive investigation such as contrast-enhanced computed tomography (CT)/gadolinium-enhanced magnetic resonance imaging (MRI) reserved for suspected intracranial spread and microbiological culture or biopsy.[12] In the era of COVID-19 related mucormycosis, empirical start of intravenous (IV) liposomal Amphotericin B with surgical debridement of nose and paranasal sinus to reduce infective tissue and better penetration of antifungal is commonly practiced as treatment modality (once mucormycosis is confirmed) with the aim of increasing survival. In refractory cases or patient intolerant to amphotericin B, posaconazole is considered as alternative or add-on therapy and to increase bioavailability of the drug intraorbital amphotericin B is also have been tried with varied result. However, inspite of all available modalities of treatment, prognosis is poor, especially in Indian population (33.3%–80% mortality in COVID-19 era) causing panic situation of “Black Fungus epidemic.”[13]

Although various studies, case report, and review articles are published, there is not a single systematic review is available till date evaluating various risk factors, clinical profile, especially in ROCM cases associated with COVID-19. Therefore, we performed the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis.


 » Materials and Methods Top


We conducted the systematic review in accordance with the “Preferred Reporting Items for Systematic Review and Meta-analysis” guidelines. The study population was COVID-19 associated rhino-orbito-cerebral-mucormycosis population of all age group. The aim of the study was to describe the clinical presentation, radiological finding, and outcome of treatment in our studied population and to give an overall view of the disease scenario in the current COVID-19 pandemic and also to find out probable risk factor associated with the said disease in an evidence based approach.

Eligibility criteria

We included all the published studies including/describing clinically diagnosed or microbiologically proved ROCM patients as defined by recent guideline set by “Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer, and the Mycoses Study Group Education and Research Consortium”[14] of all age group which is associated with COVID-19 disease. Our outcome parameters were clinical presentation, co-morbidity and risk factors, radiological involvement, treatment modalities, and the final outcome following treatment. Only published studies of any study design (prospective, retrospective, cohort study, and case series with more than and equal to 5 ROCM cases) were included in our study. We excluded single case report, case series of <5 cases, survey, review articles, consensus, or nonpeer-reviewed articles.

Literature search

A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, “rhino orbital cerebral mucormycosis,” “ROCM,” COVID-19, SARS-CoV-2 (from November 01, 2019 to June 30, 2021). First the abstract were screened and full text was further screened for the relevant articles.

Data extraction

Two authors namely PS and AB extracted the data from the full text article and entered in tabular form which contains all descriptive variables namely author, country of origin and area, type of study, co-morbidity/risk factors, study population, diagnosis, clinical manifestation, radiological manifestation, treatment (all modality), and outcome of therapy [Table 1].
Table 1: Details of included studies

Click here to view



 » Results Top


A total of 15 studies were included in the final analysis. Except four studies[15],[16],[17],[18] all the other studies[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] studies were from Indian population from different zone of India. Among all 4[17],[22],[25],[27] are case series and all other are observational study. Except Sharma et al.[24] and Bayram et al.[16] (prospective study) all are retrospective study. Among all these studies, study by Pakdel et al.[15] and Patel et al.[28] were multicentered study [details of included studies in [Table 1] and PRISMA flow diagram of included studies in [Figure 1].
Figure 1: Preferred reporting items for systematic review and meta-analysis flow diagram of included studies

Click here to view


Clinical features

Commonest clinical feature at presentation were nasal block, ocular pain, or swelling of lid in all the included studies.[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] Apart from these, rare presentations like sudden loss of vision was also seen as presenting feature.[21] Bilateral eye involvement reported in small number of patients (single study[18] 2 out of 12 patients, i.e., 16.7% bilateral involvement of eye) and maximum study reported unilateral involvement. Nearly 53.7% of ROCM cases were associated with a significant loss of vision.[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] Similarly percentage of occurrence of ophthalmoplegia among COVID-19 associated ROCM were 61.68%, lid oedema 60.6%. Proptosis were seen in 60.6%, facial oedema 34.7%, ptosis 72.7%, pupil involvement was seen in 58.1% ROCM patients. Among the rare but vision threatening presentation panophthalmitis (Ashour et al.,[17] unilateral 4 out of 7 and bilateral 1 out of 7) and endophthalmitis[16] (63.3%), orbital compartment syndrome[17] (1 out of 7) have been reported as rare occurrence. Classic black Escher has been seen in very small number of patients[24] (9 out of 23). Regarding rhino-nasal involvement, 2 studies reported nasal blockage as presenting symptom in their study population (11.8%),[15],[25] 6 studies reported palatal involvement as presenting feature in their study population (35.6%).[17],[21],[24],[25],[27] Very few studies reported palatal Escher,[20],[25] black discharge,[25] epistaxis 18.5%,[20],[25] bleeding gum[20] as infrequent presentation. Sarkar et al.[22] reported incidence of 6 in 10 cases of central retinal artery occlusion in their study and all were unilateral.[22]

Radiological presentation

CT (paranasal sinuses [PNS], orbit) was the primary modality of diagnosis in all the included study after clinical suspicion. Among all the included studies, the most common presentation is involvement of paranasal sinus among which the most common involved sinus is the ethmoid sinus, followed by maxillary sinus. Involvement of orbit is also seen among all the studies primarily involving the extraocular muscle. Occurrence of boney erosion and involvement of apex of the orbit is reported by only few studies. Rarest radiological feature is the involvement of brain commonly radiological presentation is infarction, cavernous sinus involvement, and very rarely internal cranial artery involvement. The most common modality of radiological method is the CT scan followed by MRI. Sharma et al. reported the involvement of the ethmoid sinus is the most common involved paranasal sinus (100%) among the included patients.[24] Orbital involvement was seen in 43.47% (10 out of 23, ocular involvement at the time of presentation) followed by intracranial extension (8.69%). Mishra et al. reported that all the patients had imaging evidence in the form of CT PNS and MRI brain revealing mucosal thickening of sinuses and adjacent bony erosions.[20] Satish et al. in their retrospective study of 25 patients (COVID-19 associated in 11) predominant presentation was rhino-orbital mucormycosis followed by rhino-orbito-cerebral (n = 6) presentation.[19] Only nasal involvement was also seen in their study (n = 7) [detail in [Table 1].

Common risk factors and co-morbidities

High blood sugar level at presentation

Rabagliati et al. in their retrospective study of 16 nonimmunocompromised CAIMI adults (all admitted in intensive care unit [ICU]) reported 1 ROCM case (causative agent being R. microspore) and the risk factor was uncontrolled DM (glycated hemoglobin [HBA1c] 8%) with brain involvement (MRI diagnosed).[30] Among all the 16 CAIMI cases, highest incidence of mould infection were seen (11% incidence rate) in severe COVID-19 populations and only 0.7% mucormycosis case were seen. The author concluded that critically ill patients with COVID-19 have certain characteristics that could predispose them to fungal colonization and further invasive infection although immunocompetent such as severe hypoxia, injudicious use of broad-spectrum antibiotic drugs plus high corticosteroid doses, prolonged ICU length of stay, long intubation period, and airway/lung damage and infarction areas. Moorthy et al. in their retrospective observational multi-centric study while explored the relationship between SARS-CoV-2 and probable risk factors.[23] Out of total 18 COVID-19 positive patients, mucormycosis were confirmed in 16 patients and 1 was mixed fungal infection (Mucor + aspergillosis). Total 4 out of 16 were COVID positive on admission including 1 mixed infection and 13 out of 16 were previously COVID positive. While exploring risk factors, it was seen that, out of 18 patients, 16 were diabetic (15 patients received corticosteroid during management of COVID-19. However, among 16 mucormycosis patients, 1 were nondiabetic and not received steroid therapy and mixed fungal infection patient were none diabetic and not received steroid therapy. There was a significantly higher incidence of diabetes (P = 0.03) amongst these cohort of patients who were COVID-19 positive with mucormycosis. Sarkar et al. in their case series of 10 cases of clinically diagnosed orbital mucormycosis with concurrent COVID-19 illness (all reverse transcription-polymerase chain reaction positive at the time of presentation) and all the patients were diabetic (100%).[22] Diabetic ketoacidosis (DKA) was evident in four patients during admission, while five more patients developed DKA after the initiation of corticosteroid therapy for COVID-19 disease. Sharma et al. in their prospective observational study of COVID-19-associated ROCM, the most common risk factor was diabetes (91% cases) among which uncontrolled diabetes was seen in 57% of cases and HBA1c level was above 6.5 mg/dl in all those uncontrolled patients.[24] Hypertension was another risk factor present (60%) and all of them were diabetic. Similar finding was reported by Satish et al.[19] Out of COVID-19-associated ROCM patients (n = 11), maximum had a HbA1c level ranging from 7 to 15 with majority having HbA1c of above 10, while COVID-19-negative Mucor patients in their study population had HbA1c ranging from 6 to 13, with majority values below 10. Mishra et al. in their study including ROCM population, reported that only one out of 10 patients had COVID-19 infection at the time of presentation (severe COVID-19 disease) while rest of the patients was presented after COVID-19 infection (mild and moderate COVID-19).[20] All the patients were treated similarly with adequate local debridement of the infected and necrotic tissue along with IV amphotericin B in addition to treatment of COVID-19 disease and the overall mortality was 44.4% (4 out of 9).

Steroid use

Moorthy et al. in their study including 18 cases of mucormycosis reports that 16 out of all cases received corticosteroid treatment related to COVID-19 management at some points of time which is significantly higher (P = 0.0013).[23] They observed that there is an increased trend of occurrence of “Angio-invasive maxillofacial fungal infections” specially in the patient with DM who were treated for COVID-19 and there was a strong association of occurrence of mucormycosis with steroid treatment. Similarly in the case series by Sarkar et al. strong association of steroid treatment were seen with occurrence of ROCM as all the patients were under corticosteroid treatment at some point of time.[22] The author concludes that corticosteroid use and injudicious use of broad spectrum antibiotic related to COVID-19 may be the probable predisposing factor to increase incidence of new-onset fungal infection or cause of exacerbation. Sharma et al.[24] (23 out of 23 i.e., 100% were steroid user) and Mishra et al.[20] (6 of the 10 patients i.e., 60% were steroid user) reported similar observation in their respective study.

Renal failure

In the study by Sharma et al. there were one patient of renal failure at the time of presentation of mucormycosis out of 23, another association/risk factor of occurrence of mucormycosis.[24]

Microbiological profile of COVID-19 associated rhino-orbital-cerebral–mucormycosis

KOH positivity were seen in 62% patients.[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] Among the fungal culture mucorale were isolated in 59.3% of fungal culture mucorale were isolated in 59.3% of fungal culture and Rhizopus species were the commonest species identified consisted of 44.8% of total fungal culture[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] while mixed fungal growth was seen in 3.9% growth and bacterial co infection has been reported in 36.3% culture [Table 1].

Treatment

The mainstay of antifungal therapy was amphotericin B. Pooled result showed that total amphotericin B has been given in 93% COVID-19-associated ROCM patients among which liposomal amphotericin B has been given in 90% patients.[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] Intraorbital amphotericin B was given by few studies with orbital involvement;[16],[24] however extra advantage has not been established yet.[24] Intravitreal amphotericin B was given in Mucor-associated panophthalmitis patients in 54.5% of patients in a single study.[16] Other antifungals used in the management of ROCM patients were voriconazole. Other therapeutic treatments were broad-spectrum antibiotics,[31] tocilizumab,[20] vessopressor,[31] ionotropic agent, and IV dexamethasone.[16],[22] Mechanical debridement was done in 70.9% ROCM patients[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] and orbital decompression was done in 10% cases in a single study[20] while exenteration was required in 21.2% patients (10 studies, proportion 0.212, 95% confidence interval: 0.092–0.333.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15]

Mortality

Higher parentage of treatment failure/mortality was seen in spite of giving antifungal therapy and debridement in 37.3% of study population. Moorthy et al. reported 11 out of 18 of the patients survived while 6 died.[23] Sarkar et al. reported that four patients out of 10 in their series expired within 1 month of the diagnosis, five patients had satisfactory systemic outcomes, but with irreversible vision loss, while only one patient had both ocular and systemic favorable outcomes.[22] Satish et al. reported that during follow up 2/25 mortalities were seen, one patient with leukemia and the other who presented as severe COVID-19[19] [Table 1].


 » Discussion Top


Occurrence of ROCM is rare in the pre-COVID-19 era with maximum occurrence was seen among immunocompromised patients. This is a rare form of opportunistic infection with rapid progression with lethal outcome if not treated at the earliest. The etiological fungi belong to the family Mucoraceae (class Phygomycetes or Zygomycetes). The fungi usually found as commensel of nasal mucosa and become pathogenic in cases of immunosuppression such as diabetes, organ transplant patients under immunosuppression, malignancy, long-term immunosuppression due to any cause etc., as the organism multiplies in nasal cavity and paranasal sinus and invades palate and orbit and may reach up to brain leading to death. Following COVID-19 pandemic no of mucormycosis cases are rising rapidly especially in Indian population. In India till 25 May 2020, approximately 66.8% of COVID-19 cases were identified with predominantly involving males and the commonest type seen is rhino-cerebro-orbital mucormycosis (44%–49%). The overall prognosis is poor with mortality ranging from 33.3% to 80%.

This acute increase in incidence of ROCM related to COVID-19 infection is hypothesized to be due to interplay between various factors: [23] first due to dysregulation of immune status owing to decreasing T lymphocyte count and altered CD4 and CD8 ratio. This may alter the natural immune system of the host, thus predisposing COVID-19-infected patients for secondary fungal infection. Second, the pathogenesis of COVID-19 also mimics the angioinvasive process seen in Mucor infection related angioinvasion due to thrombotic microangiopathy related to COVID-19 disease spectrum which adds on the pathogenesis of mucormycosis. Last but not the least, injudicious use of corticosteroid in COVID-19 patient management (dexamethasone and methylprednisolone both been incorporated in hospital guideline above the recommended dose) adds on the immune suppressive status for these population although many of not known diabetic as seen in our study. In our systematic review, occurrence of diabetes and COVID-19-related steroid therapy is found to be the most common risk factor in the COVID-19 ROCM population.

In the current scenario of COVID-19 pandemic, associated ROCM high mortality (80% of patients die within 3 months of diagnosis) has been seen in spite of using liposomal amphotericin B which become the point of concern and needs exploration of newer drug or drug target which is the need of the day to cope up the present situation.


 » Conclusion Top


Since the onset of the COVID-19 pandemic, incidence of secondary infection (both bacterial and fungal) is rising owing to disease or treatment-related immune suppression with the distribution of organisms varies in different part of the world. Especially, excessive use of corticosteroid or broad-spectrum antibiotic as a part of COVID-19 management protocol is leading to aggravation of preexisting fungal disease or occurrence of newer infection. Strong clinical suspicion of possible secondary fungal infections in COVID-19 infection or post-COVID-19 infection population with preexisting risk factors is necessary to cope up with this “black fungal epidemic” parallel to COVID pandemic. Early diagnosis and treatment can reduce the mortality as well as morbidity associated with ROCM associated with COVID 19. Lowest dose and shortest dose of steroid is recommended in COVID-19 population and use of broad spectrum antibiotic should be under specialist guidance and should be tailored to patient to patient, not be a general protocol. While corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price hence prescription of steroid should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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