Rhino-orbito-cerebral mucormycosis and its resurgence during COVID-19 pandemic: A review

Abstract

This study aimed to review the current literature for epidemiology, pathogenesis, clinical spectrum and management of rhino-orbito-cerebral-mucormycosis (ROCM), especially highlighting the association between ROCM and COVID-19 disease and factors resulting in its resurgence during the pandemic. Mucormycosis is a rare, but an important emerging opportunistic fungal infection, often associated with high morbidity and mortality. ROCM is the commonest and also the most aggressive clinical form occurring in debilitated patients in conjunction with sinus or para-sinus involvement due to the propensity for contiguous spread. Recently ROCM has shown an unprecedented resurgence during the current pandemic. Reports from different parts of the world indicated an increased risk and incidence of ROCM in patients who had required hospital admission and have recovered from moderate-to-severe COVID-19 disease. A majority of mucormycosis cases have been reported from India. The presence of diabetes mellitus (DM) and use of corticosteroids for COVID-19 pneumonia were found to be the key risk factors, resulting in higher mortality. Amidst the ongoing pandemic, with the third wave already having affected most of the world, it becomes imperative to adopt a risk-based approach toward COVID-19 patients predisposed to developing ROCM. This could be based on the most recently published literature and emerging data from centers across the world. The present review intended to elucidate the causes that brought about the current spike in ROCM and the importance of its early detection and management to reduce mortality, loss of eye, and the need for mutilating debridement.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), commonly known as coronavirus, is responsible for the coronavirus disease 2019 (COVID-19) pandemic and belongs to the family Coronaviridae.[1] There is an ever-increasing pool of data with respect to its pathophysiology, disease presentation, transmission, organs affected, and treatment. Various ocular manifestations ranging from conjunctivitis and retinal vasculitis to compartment syndrome have been reported.[2,3]

However, currently there is no clear consensus on the ocular manifestations of COVID-19, owing to paucity of comparative studies with large sample size. While the world was grappling with this pandemic, a new challenge emerged in the form of mucormycosis.[4] The surge in COVID-19 cases in India during the second wave of the pandemic has been linked to an increase in rhino-orbito-cerebral-mucormycosis (ROCM) cases following COVID-19 infection.[5] ROCM is an uncommon opportunistic infection with invasion of the blood vessels by fungal hyphae, infarction, and necrosis of host tissue. This review discusses epidemiology, risk factors, clinical presentation, diagnosis, and management of ROCM. The article emphasizes on shifting clinical trends and treatment challenges in SARS-CoV-2-infected patients and attempts to investigate the factors leading to the resurgence in this fungal infection.

Method of literature search

A literature review was performed within PubMed, Medline Plus, and Google Scholar using the following keywords: “mucormycosis”, “rhino-orbital cerebral mucormycosis”, “orbital mucormycosis”, “antifungal therapy”, “amphotericin B”, “orbital exenteration”, “SARS-CoV-2”, “COVID-19”, “diabetes and corticosteroids”. One keyword/phrase from each cluster was used unless repeated. All case reports, case series, reviews, and original articles published till December 2021 were screened and evaluated with relevant studies and then included. Reference lists of these articles were also searched and articles were included, if clinically relevant and falling within the scope of this review.

Epidemiology and Risk Factors

Opportunistic fungi, belonging to the order Mucorales, are responsible for this rapidly progressing fatal infection.[6] Mucor infections have become more common worldwide and is found with increasing prevalence among large populations with uncontrolled diabetes, especially in developing countries like India and China.[7,8] Nevertheless, according to a recent systematic review, Europe accounted for a majority of cases (34%), followed by Asia (31%) and North or South America (28%). This discrepancy may be attributable to Asian countries’ having underreported the prevalence during this time period. India, however, has been reporting an increasing number of instances.[9]

ROCM may either be caused directly by fungal invasion or could occur in the presence of other risk factors, namely chronic debilitating illnesses, typically in immunocompromised individuals.[10] A majority of the cases (approximately 60%–80%) are found in poorly controlled diabetics especially those with ketoacidosis.[11] Hematological malignancies constitute a second major predisposing cause of ROCM.[11] Other risk factors include neutropenia, solid-organ and bone-marrow transplantation, graft-versus-host disease, chemotherapy, indiscriminate use of corticosteroids or immunosuppressive therapy, intravenous drug abuse, trauma, AIDS, neonatal prematurity, malnourishment, and conditions causing iron overload such as hemodialysis, hemochromatosis and desferrioxamine therapy.[11,12]

Medical procedures and devices, such as contaminated air filters, oxygen tubing, humidifiers, infected wound dressings, tongue depressors, intravenous catheters, transdermal nitrate patches, and even allopurinol pills, have all been linked to nosocomial mucormycosis.[13] Voriconazole and caspofungin are two antifungal agents that are ineffective against zygomycetes and have also been linked to zygomycosis outbreaks.[11,12]

Clinical Presentation

ROCM can occur in humans of any age, gender, or race and can rarely affect otherwise healthy individuals.[14] The involvement is usually unilateral and remains so in most cases.[14] A majority of cases present as acute infection with a rapid and aggressive course (progressing over days); however, chronic infections (occurring over weeks to months) are uncommon.

The classical stages[15,16] of progression of ROCM are.

Stage I: Infection of the nasal mucosa and paranasal sinuses;

Stage II: Orbital involvement;

Stage III: Cerebral involvement.

The infection spreads from the nasal mucosa to the paranasal sinuses, palate, and pharynx. Invasion of the retro-orbital area occurs via the paranasal sinuses, specifically the ethmoid and maxillary sinuses.[17] Sadr-Hosseini et al.[17] reported that the pterygopalatine space is the main portal for propagation of infection from the nasal mucosa to other sites. Infection from the pterygopalatine space progresses into the orbit and facial soft tissue, and then via inferior orbital fissure, extends into the retro-bulbar area and further into the orbital apex, eventuating in ocular manifestations.[17] Intracranial spread occurs via one of the following routes:

1. Superior orbital fissure: Infection through this route could result in cavernous sinus thrombosis and thrombotic occlusion of the internal carotid artery (ICA).

2. Ophthalmic artery: Direct invasion of this vessel could result in intracranial spread via the ICA.

3. Cribriform plate: Infection could spread to the anterior cranial fossa and cavernous sinus through the cribriform plate and the orbital apex, respectively, via the perivascular and perineural channels.

Sino-nasal involvement

The initial clinical features are variable, encompassing unilateral nasal obstruction, serous nasal discharge, sneezing, frontal headaches, or tearing with a burning sensation in the eyes. Later, there is development of anosmia and purulent nasopharyngeal discharge.[17,18] At this stage, examination reveals black lesions representing the necrotic and hemorrhagic aspect of the pituitary mucosa, close to the septum or the turbinates.[18] The black eschar-like lesion is highly indicative of mucormycosis; however it remains absent in about half the cases.[19,20]

Sinusitis was seen in all 34 cases reported by Nithyanandam et al.[21] and in yet another series of 35 cases reported by Bhansali et al.[22] The paranasal sinuses may be involved before or after nasal involvement. The maxillary sinus is the most frequently involved, followed by ethmoidal sinus. The frontal and sphenoidal sinuses are less commonly involved. Infection from the sinuses can sometimes extend to the mouth, exhibiting painful, necrotic ulcers on the hard palate.

Orbital involvement

Orbital involvement ranges from 66% to 100% in ROCM.[23] The most common presenting signs and symptoms are decreased vision, external ophthalmoplegia (total or partial), proptosis, and periorbital edema or pain [Table 1][15,18,20,24,25] Yohai et al.[20] reviewed 145 case reports of ROCM and found ophthalmoplegia (67%), decreased vision (65%), and proptosis (64%) as predominant ocular manifestations [Table 2].[20,22,25,26] The impaired vision indicates invasion of the optic nerve or vascular channels.

Table 1.

Frequency of presenting ocular signs/symptoms as reported in various studies [n (%)]

Signs/Symptoms	Ferry et al.[24] 1983 (n=16)	Yohai et al.[20] 1994 (n=114)	Talmi et al.[18] 2002 (n=19)	Jiang et al.[15] 2016 (n=11)	Vaughan et al.[25] 2018 (n=152)
Decreased vision	4 (25)	34 (30)	4 (21) 9 (47) [Total loss of vision]	11 (100)	30 (20)
Ophthalmoplegia	-	33 (29)	10 (53) [Complete] 4 (21) [Partial]	-	23 (15)
Proptosis	2 (13)	18 (16)	13 (68)	9 (82)	16 (11)
Periorbital edema	-	39 (34)	-	9 (82)	42 (27)
Periorbital pain	6 (38)	13 (11)	-	-	22 (14)
Chemosis	-	10 (9)	15 (79)	-	7 (4.5)
Blepharoptosis	-	4 (3.5)		11 (100)	27 (18)
Periorbital cellulitis	-	-	14 (74)	-	-
Orbital cellulitis	-	18 (16)	-	-	3 (2)
Diplopia	-	6 (5)	-	9 (82)	5 (3)
Orbital apex syndrome (OAS)	-	-	-	11 (100)	-
Cranial nerve palsy	-	-	-	11 (100)	-
Trigeminal anesthesia	-	8 (7) [V1]	9 (47) [V2]	-	5 (3)
Afferent pupillary defect (APD)	-	15 (13)	-	-	1 (0.5)
Corneal anesthesia	-	19 (17)	-	-	-

Table 2.

Frequency of all ophthalmic manifestations as reported in various studies [n (%)]

Signs/Symptoms	Yohai et al.[20] 1994 (n=80)	Bhansali et al.[22] 2004 (n=35)	Kursun et al.[26] 2015 (n=28)	Vaughan et al.[25] 2018 (n=152)
Ophthalmoplegia	49 (61) [External Complete] 5 (6) [External Partial] 32 (46) [Internal]	31 (89)	16 (57)	86 (57)
Decreased vision	52 (65)	28 (80)	13 (46)	68 (45)
Proptosis	51 (64)	29 (83)	-	81 (53)
Periorbital edema	34 (43)	23 (66)	20 (70)	64 (42)
Periorbital pain	9 (11)	15 (43)	-	19 (12.5)
Chemosis	19 (24)	26 (74)	-	28 (18)
Blepharoptosis	2 (3)	1 (3)	18 (64)	35 (23)
Periorbital cellulitis	-	-	21 (75)	-
Orbital cellulitis	16 (20)	-	-	24 (16)
Diplopia	3 (4)	-	7 (25)	13 (9)
Orbital apex syndrome (OAS)	-	-	16 (57)	-
Cranial nerve palsy	-	-	16 (57) [Mydriasis]	-
Trigeminal anesthesia	21 (26) [V1]	-	-	8 (5)
Afferent pupillary defect (APD)	30 (38)	-	-	16 (10.5)
Corneal anesthesia	11 (14)	-	-	6 (4)
Central retinal artery occlusion (CRAO)	13 (16)	7 (20)	-	2 (1.3)
Cavernous sinus thrombosis	10 (13)	-	-	14 (9)
Eyelid necrosis	9 (11)	5 (14)	-	11 (7)
Endophthalmitis	1 (1)	2 (6)	-	-
Eye pain	6 (8)	-	-	12 (8)
Corneal edema	5 (6)	-	-	3 (2)
Orbital abscess	5 (6)	-	-	1 (0.6)
Optic disc edema	4 (5)	-	-	7 (4.6)
Periorbital discoloration	3 (4)	-	-	22 (14.5)
Optic disc pallor	2 (3)	-	-	8 (5)
Eyelid abscess	1 (1)	-	-	-

The external ocular signs may be eyelid abscess or necrosis, infra-orbital anesthesia, ptosis, and periorbital cellulitis. Other established ocular manifestations include chemosis, orbital cellulitis, orbital abscesses, corneal anesthesia, corneal edema, fungal vitritis/endophthalmitis, afferent pupillary defects, optic disc edema, central retinal artery occlusion (CRAO), superior orbital fissure syndrome (SOFS), orbital apex syndrome (OAS), internal ophthalmoplegia, involvement of multiple cranial nerves, diplopia, and cavernous sinus thrombosis (CST) [Tables 1 and 2].

In contrast to the edema associated with pyogenic periorbital cellulitis that appears warm, firm, tense, and tender, the periorbital edema associated with mucormycosis remains cool, soft, lax, and non-tender. Mucormycosis results in paralytic ptosis, wherein the eyelid can be easily lifted by the clinician. Jiang et al.[15] investigated 11 cases of invasive ROCM presenting with OAS as an initial sign. The observed ocular findings were progressive reduction in vision, involvement of cranial nerves, ptosis (100%), exophthalmia, periorbital edema, and diplopia (81.8%) [Table 1]. Although rare, the OAS may be the primary presentation of this disease, marked by vision loss, retro-orbital pain, sensory deficit, ptosis, and complete ophthalmoplegia.[17] Early intervention improves the prognosis; however, once intracranial spread ensues—in case when the disease process has not been timely controlled—it invariably results in a poorer outcome.

Few cases of mucormycosis isolated to the orbits and brain have been documented with unilateral or bilateral orbital involvement.[27] Fundus examination is very important for the diagnosis of ROCM. It may reveal optic disc edema or atrophy, venous congestion or thrombosis of the central retinal vein or artery of the retina, or panophthalmitis. Kim et al. reported a case of ROCM complicated by serous retinal detachment and retinal necrotic lesions in a middle-aged man with diabetic ketoacidosis. Scleral inflammation in close contact with necrotic “mucorale material” was proposed as the probable cause for serous retinal detachment.[28]

Mucormycosis is known to cause occlusion of the central retinal and ciliary arteries. Bullock et al.[29] and Brown et al.[30] reported one of two cases and one of eight cases, respectively, with obstruction of the retinal and choroidal circulations in orbital mucormycosis. Song et al.[31] documented bilateral ophthalmic artery occlusion in an 89-year-old male with ROCM. The presence of isolated “black eschar-like lesions” at bilateral canthi due to the occlusion of bilateral ophthalmic arteries with involvement of dorsal nasal arteries is rare, but a diagnostic marker of ROCM. The onset of signs and symptoms in the fellow eye, such as bilateral proptosis, chemosis, vision loss, and painful ophthalmoplegia is highly indicative of CST and signals a grave prognosis.

A similar clinical presentation is observed in the pediatric age group. Bhadada et al.[32] described proptosis and ptosis (100%) as the most common symptoms and ophthalmoplegia and vision loss (85%) as the most common signs of ROCM in children (mean age 16.1 ± 3.0 years) with type I DM. Although rare, isolated orbital mucormycosis in immunocompetent children has been reported with orbital cellulitis as a presenting sign.

Cerebral involvement

The infection can reach the brain either from the orbit or paranasal sinuses, or cerebral involvement may rarely occur as an isolated event. Cerebral infection is characterized by mental status changes and cranial nerve palsies. The frontal lobe involvement results in behavioral changes like euphoria, aphasia, agitation, confusion, or altered consciousness. The examination may reveal meningeal signs, hemiparesis/hemiplegia contralateral to the lesion with ipsilateral facial nerve palsy, auditory hallucinations, or involvement of cranial nerves (VI to XII). CST may impair the function of ocular motor nerves III, IV, and VI and trigeminal nerve branches V1 and V2 passing through it. Extensive intracranial involvement is potentially lethal due to thrombosis of the cavernous sinus or the ICA.

Investigations

The clinical signs of early ROCM are nonspecific and are limited to sinus involvement. It usually starts in the inferior and middle meatus then spreads to the paranasal sinuses, the orbit, and eventually involves brain. Hence, formulating a suitable treatment strategy requires the aid of radiological and microbiological evidences to make an early and timely diagnosis.

Non-contrast computed tomography (NCCT) scan of the paranasal sinuses reveals hypo-attenuating mucosal thickening or intrasinus and/or intranasal soft-tissue attenuation, associated with bony erosion. Delineating the extent of infection could therefore help in guiding the surgical debridement. Computed tomography (CT) scan reveals orbital soft tissue involvement, bone involvement (rarefaction, erosion, and necrosis—a late finding and a poor prognostic sign), and intracranial involvement. It also helps to detect involvement of the cavernous sinus and ICA, seen as thickening and non-enhancement on post-contrast scans, with the presence of abnormal surrounding soft-tissue. CT findings with non-enhancing opacification of sinuses, presence of retro-antral and orbital fat stranding, and hypodense orbital soft-tissue extension indicates the aggressive nature of the infection [Fig. 1].[33]

Figure 1.

Non-contrast computed tomography (NCCT) and magnetic resonance imaging (MRI) scans: (a) NCCT axial scan showing involvement of the left orbital apex (arrow) with orbital fat stranding; (b) contrast-enhanced MRI (CE-MRI) coronal section showing non-enhancement of the bilateral middle and inferior turbinate, indicating a characteristic black turbinate sign (arrow) along with orbital fat stranding; (c) axial scan showing T2-hyperintense fluid collection in right post-septal region (arrowhead) just anterior to the eyeball along with orbital fat stranding (yellow arrow) and mucosal thickening in bilateral ethmoidal sinus (red arrow); (d) sagittal scan showing extension of the soft tissue in left middle ethmoidal air-cells into the left frontal lobe of the brain through the cribriform plate (arrow)

Contrast-enhanced magnetic resonance imaging (CE-MRI) provides a better visualization of the invasion or involvement of the orbital soft tissue, infra-temporal fossa, intracranial structures, perineural invasion, and vascular occlusion. Diego A Herrera et al. observed that MRI signal intensity of mucormycosis lesions tends to be iso-intense or hypo-intense in all sequences, with a post-contrast variable enhancement patterns ranging from homogeneous to heterogenous.[34] Ischemia causing non-enhancing turbinates in the mucosa in post-contrast sequences is an early sign of mucormycosis on MRI—the black turbinate sign [Fig. 1]. However, invasive fungal sinusitis is not the only condition that causes focal nonenhancement of sinonasal soft tissues. It could be seen as a physiological variance in healthy people. This finding should be interpreted with caution.[35]

Aribandi et al.[36] in their study showed inflammatory changes in the orbital fat and extra-ocular muscles to be an early sign of orbital involvement. The medial aspect of the orbital compartment including lateral displacement of the medial rectus muscle needs specific consideration to detect early subtle changes, as orbital invasion usually occurs through the medial orbital wall.[35] Medial rectus thickening, patchy enhancement of the orbital fat involving the superior orbital fissure, inferior orbital fissure and the orbital apex, with associated bony destruction of the paranasal sinuses—relative to orbit—signify severe disease. Reddy et al.[37] in a case series have beautifully described the posterior globe tenting as a “guitar pick sign”: an important radiological surrogate marker of tense orbit and profound vision loss in ROCM. Magnetic resonance angiography is an important tool to determine involvement of the cavernous sinus and the ischemic damage to the cerebral tissues, as demonstrated by Parsi et al.[38] Kaushik et al.[39] reported a unique case with concomitant anterior and posterior ischemic optic neuropathy where posterior ischemic optic neuropathy was diagnosed on diffusion-weighted MRI scans even when clinical signs were absent, thereby being advantageous as posterior ischemic optic neuropathy was otherwise a diagnosis of exclusion.

Microscopy (direct and histopathological) and culture remain the cornerstone of diagnosis. The ideal media for growing Mucorales is Sabouraud dextrose agar (SDA) or potato dextrose agar (PDA) with gentamicin and polymyxin B, but without cyclohexamide. Mucorales species grow within 3–5 days and fill the culture with a grayish-white, aerial mycelium with a wooly texture. The fungal isolates are identified by lactophenol-blue mount. Blood cultures are rarely positive [Fig. 2]. The recent advances in the development of quantitative polymerase chain reaction (qPCR) systems seem a promising area of ongoing research that may enable more rapid diagnoses, especially during critical and clinically ambiguous scenarios.[40] Newer techniques like enzyme-linked immunosorbent spot (ELISpot) detect Mucorales-specific T cells in the blood samples of patients via an enzyme-linked immunospot assay.

Figure 2.

10% potassium hydroxide (KOH) mount showing characteristic broad, pauci-septate hyphae (a); lactophenol cotton blue mount showing broad aseptate hyphae with extension of columella into sporangium (b); Sabouraud dextrose agar (SDA) showing characteristic cottony growth with black spores (c)

Treatment

The principles of ROCM management include risk stratification depending on the severity of the disease and formulate an optimal plan of management. This requires a multidisciplinary approach that further depends on four basic prerequisites: early diagnosis utilizing a high index of suspicion, reversal of underlying host impairments, expedited use of antifungal therapy, and aggressive surgical debridement when indicated.

Early Diagnosis

In the absence of a major breakthrough in therapeutic intervention, only an early diagnosis can likely have the greatest impact in improving the survival and clinical outcome in patients with mucormycosis. Diagnosing ROCM early in the course of the disease, however, remains a challenge. The definitive diagnosis needs a combination of positive Mucorales culture, along with microscopic evidence, which is often unachievable in a majority of the cases. Hence, the diagnosis in remaining cases is often based on a combination of clinical features, presence of risk factors, and identification of non-septate, right-angled, branching hyphae.[14]

Chamilos et al.,[41] in their study on a group of mucormycosis patients, observed that delaying antifungal therapy by ≥ 6 days after diagnosis resulted in a two-fold increase in mortality rate at 12 weeks following diagnosis, when compared to an early initiation of antifungal therapy. The authors concluded that early initiation of therapy improved survival by nearly 70%. In another study by Guevara et al.,[42] out of nine patients with mucormycosis the early diagnosis was made by endoscopic evaluation, biopsy, and subsequent frozen-section examination in five patients. This resulted in overall survival of these five patients among all the cases.

The role of conventional imaging modalities, both CT and MRI, remains orthodox in the context of early diagnosis of ROCM. However, multimodal imaging and role of molecular diagnostic assay appears to play a promising role in early diagnosis. qPCR assay of Mucorales, could help establish a very early diagnosis and should therefore be used as a screening tool in patients falling in significantly high-risk profiles.[43]

Reversal of host impairment factors

In addition to early diagnosis, it is imperative that simultaneous correction of a patient’s underlying host impairments is critical to the successful management of mucormycosis.

A majority of these patients may already be on multiple pharmacological drugs like immunosuppressive therapy, systemic corticosteroids, chemotherapeutic and hypoglycemic agents, all of which bring about immune compromise. Reducing or modulating the dose and frequency of such drugs, or altogether withdrawal or switching over to an alternative therapy are crucial steps that must be undertaken in conjunction with appropriate antifungal therapy in the management of ROCM. A majority of these patients being neutropenic, the role of recombinant cytokines, namely, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-g (IFN-g) become significant.[44]

Antifungal therapy

Antifungal therapy remains the mainstay of treatment for ROCM in the early stages as well as in combination with other modalities in advanced stages of the disease. There is substantial evidence, however, only in favour of the polyene class of antifungal agents supporting their significant activity against mucormycosis.[45] Amphotericin B deoxycholate (AMB-DOC) is considered as the drug of choice for primary treatment of mucormycosis.[46] The therapeutic efficacy of amphotericin B (AMB) has been demonstrated in both laboratory (in vitro and in vivo) and clinical studies.[47] Lipid formulations of AMB in the form of colloidal dispersion (AB-CD), liposomal AMB (L-AMB); and AMB lipid complex (ABLC) have a better therapeutic index, than the conventional AMB-DOC and therefore are the preferred first-line therapy for the treatment of mucormycosis.[48] As per a large review of the therapeutic role of AMB in the treatment of mucormycosis, multivariate analysis showed that antifungal therapy was found to be significantly associated with better survival in patients treated with AMB, whereas mortality was nearly uniform for those who received no treatment at all.[49]

Despite its significant efficacy, AMB-DOC has a narrow therapeutic window due to dose-dependent adverse effects and severe nephrotoxicity in particular. Formulation of alternative parenteral agents employing lipid vehicles for AMB delivery was developed with a view toward improving drug tolerability and to optimize clinical efficacy. These lipid formulations have demonstrated a better safety profile compared to conventional AMB-DOC and improved therapeutic efficacy (although at larger doses) in preclinical and clinical studies.[48,50] It is noteworthy that the high cost of these preparations remains a concern in resource-limited settings where AMB-DOC still may be the only feasible approach. There are no standard recommendations on the duration of therapy for mucormycosis. The standard daily dose of intravenous L-AMB and ABLC suggested by current guidelines is 5 mg/kg of bodyweight per day.[48] Newer triazoles, including posaconazole and isavuconazole, have been observed to demonstrate better in vitro activity against ROCM, although there is evidence both in support and against the use of posaconazole therapy, which demonstrates variable activity against the Mucorales.[51]

Only sparse literature is available on the role of posaconazole in orbital mucormycosis, where orally administered posaconazole was utilized late in the course of the disease with beneficial results at the time, that is, when the patient had already received a maximum recommended dosage of AMB and/or had extensive surgical debridement. In a report by Zhang et al.,[52] authors used posaconazole early in the course of the disease (following diagnosis) in conjunction with AMB and other antifungal agents and observed better outcomes in terms of disease progression and the need for exenteration. Overall, in the absence of definitive clinical data, orally administered posaconazole may be useful as salvage therapy but cannot be recommended as a primary therapy for orbital mucormycosis.[46,47]

With a better therapeutic and pharmacokinetic profile, a newer broad-spectrum triazole isavuconazole has been observed to act as salvage therapy for mucormycosis in heavily immunosuppressed patients, including cases of posaconazole failure.[53] However, its role in cases with ROCM is not well tested.

Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis and there occurs enhanced predisposition to mucormycosis in patients with diabetic ketoacidosis because of acidemia-induced higher concentration of free-iron.[54] In an animal study on mice, Ibrahim et al.[54] demonstrated that deferasirox, an iron chelator, synergistically improved survival and reduced tissue-mucor burden when combined with liposomal amphotericin B. Reed et al.,[55] in a case report, highlighted treatment with iron-chelation as salvage therapy in advanced ROCM. However, outcomes of the Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study does not recommend deferasirox as part of an initial combination regimen for the treatment of mucormycosis.[56]

Local/regional therapy: Intraconal or retrobulbar AMB

The idea behind locally delivering AMB in and around the orbital tissues is predicated on the angio-invasive nature of the mucormycosis that limits tissue penetration of systemic antifungal agents. Additionally, AMB possesses a very slow diffusion capacity into tissues due to its high protein-binding capacity and large molecular weight. Regional therapy in the form of intraconal or retrobulbar injection and catheter-assisted local irrigation of AMB helps build up a target therapeutic concentration necessary to have orbital tissue-specific activity.

With a more extensive orbital tissue burden in cases with sino-orbital fungal infections, catheter placement has been observed to potentially allow more diffuse drug delivery.[57] Joos et al.[58] demonstrated that the use of local AMB irrigation directly into the orbit resulted in local control of the infection without orbital exenteration—a good cosmetic outcome and excellent postoperative visual acuity. Murthy et al.[59] described an alternative technique of retrobulbar injections using an intravenous cannula to stop the orbital disease progression in ROCM. Retrobulbar injection of AMB is an off-label procedure and has an associated risk of significant complications. Multiple reports have documented successful outcomes without visual loss; the local administration has a potential for orbital tissue toxicity and neurotoxicity. as demonstrated in various in vitro studies.[58,60,61] Ramamurthy et al.[62] observed transcutaneous retrobulbar injection of amphotericin B (TRAMB) as a very effective, economical, and time-saving procedure in patients with orbital mucormycosis of mild-to-moderate severity. Murthy et al.[63] in a series of ten cases with ROCM showed that superior outcomes with localized surgical orbital debridement and application of amphotericin B gel to the site of debridement can help in salvaging the vision and avoiding exenteration in most cases. However, AMB has the potential to incite inflammation and could result in transient orbital soft-tissue edema when locally injected.[61] Furthermore, there is a real procedure-related risk of increased intraocular-intraorbital pressure and subsequent orbital compartment syndrome, especially with multiple repeated injections.[64]

Surgical treatment

By virtue of blood vessel thrombosis and resultant tissue necrosis, mucormycosis results in poorer penetration and delivery of systemic antifungal agents to the site of infection. Therefore, surgical debridement of necrotic tissues may be fundamental for successful management in most cases of ROCM. The Mycoses Study Group Education and Research Consortium (MSGERC) and European Confederation of Medical Mycology (ECMM) global guidelines for diagnosis and management of mucormycosis strongly recommend that an immediate and complete surgical intervention should be undertaken in the first place, whenever possible, in addition to first-line systemic antifungal therapy.[65] According to a comprehensive review analysis, patients who underwent surgery had a survival rate of 78% compared to 22% for those who did not.[66]

Orbital exenteration

Orbital exenteration is a radical removal of the orbital contents including the globe, periorbital, and retrobulbar structures. This radical surgical procedure has long been the surgical standard for ROCM with orbital invasion. The most arduous task in the management of ROCM is the decision to exenterate the patient. Exenteration could be a life-saving step but at the cost of a permanent facial mutilation and life-long disfigurement. However, indications and timing for doing so remain unclear in the absence of well-established guidelines, and evidence from literature appears inadequate to provide a sufficient body of information in order for the physicians to determine the appropriate timing for exenteration.[67]

In a majority of cases, the decision for exenteration and evaluation of its indication rests entirely on the clinical judgment of the treating physician. An actively infiltrated orbit with a blind, painful, frozen globe is frequently one of the most common indications, wherein exenteration of the involved orbit reduces the overall fungal-load, thereby possibly making the treatment of mucormycosis easier even after an intracranial spread. A large review of invasive fungal sinusitis revealed that orbital exenteration may be required chiefly in the cases of central retinal artery thrombosis, orbital apex syndrome, or intraocular invasion.[68]

Overall, though ontologically secure and life-saving, the procedure is gravely disfiguring and possesses deep, life-altering, psychological ramifications. It is noteworthy here that, the early diagnosis plays a major role in reducing the effective number of patients requiring exenteration.

ROCM and COVID-19 Disease: Perspectives and Changing Trends

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was found to be associated with a variety of secondary bacterial and fungal co-infections. There has been a huge resurgence seen in the number of mucormycosis cases in association with the second wave of COVID-19 disease, especially in India.[69] Such outbreaks of mucormycosis, even in immunocompetent adults, have been observed in the past, associated with major natural disasters.

Epidemiology, incidence and microbiological spectrum of COVID-19 patients

Scant literature is available including case reports, small data-based case series, and reviews describing an association between COVID-19 and ROCM [Table 3].[70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98] However, the swiftness and ferocity with which this pandemic has engulfed the world and the unprecedented investment of healthcare professionals and resources has made it necessary to evaluate any level of evidence available in the literature not only to guide management strategy but also to plan current and future research. With varied clinical forms of mucormycosis, pulmonary mucormycosis was the predominant clinical form (87.5%) observed, while ROCM was the most common presentation (28.6%) that was noted in developing countries like India.[99] Rhizopus species was observed to be the most common pathogen causing COVID-19-associated mucormycosis (26.7%).[99] In comparison with the pre-COVID-19 ROCM, a significant rise in both incidence and mortality was observed among COVID-19-associated ROCM.[41] A significantly greater number of cases had been reported in the pre-COVID-19 era from developing countries like India in comparison with the developed world. This could be owing to a large section of the population with undiagnosed diabetes and extensive, indiscriminate use of steroid therapy, especially outside the formal health care system. In a large cohort epidemiological study from a tertiary care referral center in western India, authors noted that mucormycosis involving the nose and sinuses (≈95%) was most common presentation followed by rhino-orbital (45%) form where higher incidence observed in active as well as recovered patients, especially those with co-morbid medical conditions.[100]

Table 3.

Rhino-orbito-cerebral mucormycosis (ROCM) in COVID-19 disease: Summary of clinical presentation, treatment received, and clinical outcomes of cases reported worldwide till March 2022

Author	Place	No. of Cases	Age	Comorbidities		Mean Duration between COVID-19 Infection and ROCM Onset	Steroid Use	Prominent Ocular Manifestations Presentation
Werthman-Ehrenreich et al.[70]	USA	1	33	HTN, COPD		Concurrent	N	Unilateral ptosis, proptosis, fixed dilated pupil with complete ophthalmoplegia
Mehta et al.[71]	India	1	60	Known DM		10th Day	Y	Bilateral lid edema with right eye proptosis
Dallalzadeh et al.[72]	USA	2	36, 48	Known DM			Y
Mekonnen et al.[73]	USA	1	60	Known DM		7th Day	N	Unilateral proptosis, chemosis, and fixed mid-dilated pupil
Maini et al.[74]	India	1	38	Nil		18th Day	Y	Unilateral proptosis, chemosis, periorbital cellulitis, and restricted medial gaze movement
Saldanha et al.[75]	India	1		Known DM		Concurrent	N	Unilateral ptosis, fixed dilated pupil with ophthalmoplegia
Revannavar et al.[76]	India	1	Middle-aged	Recently diagnosed DM		Concurrent	N	Unilateral ptosis, fixed dilatedpupil with total ophthalmoplegia
Sen et al.[77]	India	5	46, 60, 74, 73, 62, 47	All known DM 3 HTN		Concurrent in one case Rest Cases: 17 days, 30 days, 14 days, 42 days, 3 days	Y- 1/5 N- 4/5	Most Common: Unilateral ptosis, impaired pupillary reflex, external ophthalmoplegia
Sarkar et al.[78]	India	10	23-67	All known DM		Concurrent in all cases	Y 10/10	-
Mishra et al.[79]	India	10	37-78	Known DM - 8/10 HTN - 3/10 CKD - 2/10		-	Y - 6/10 N - 4/10	Most common: Unilateral chemosis
Moorthy et al.[80]	India	18	37-73	Known DM - 16/18		-	Y - 16/18	Loss of vision - 12/18
Veisi et al.[81]	Iran	2	40, 54	Y 1/2		2 weeks 1 week	Y	Bilateral in 1 case, unilateral in another Ptosis, ophthalmoplegia, proptosis and fixed dilated pupils
Sargin et al.[82]	Turkey	1	56	N		1 week	Y	Unilateral ophthalmoplegia and proptosis
Ashour et al.[83]	Egypt	8	41-67	Known DM - 6/8 HTN - 2/8 End-stage renal disease - 2/8		Concurrent in one case 2 weeks in other cases	NA	Most Common: Unilateral ophthalmoplegia and chemosis
Nehara et al.[84]	India	5	52-70	Known DM - 5/5, HTN - 2/5		Concurrent in one case 1 week to 1 month in other cases	3/5	Most common: Chemosis, mild proptosis, loss of vision, and ophthalmoplegia
Ostovan et al.[85]	Iran	1	61	Known DM		2 weeks	-	Proptosis, chemosis, and ophthalmoplegia
Palou et al.[86]	Honduras	1	56	HTN		4 weeks	Y	Diplopia, unilateral decreased visual acuity, and signs of periorbital cellulitis
Shakir et al.[87]	Pakistan	1	67	Known DM, HTN, Ischemic heart disease		1 week	N	Unilateral chemosis, ophthalmoplegia
Tabarsi et al.[88]	Iran	1	50	Known DM, HTN		1 week	Y	Signs of unilateral periorbital cellulitis
Dilek et al.[89]	Turkey	100	22-86	DM, HTN, CKD, obesity		Concurrent - 53%, Post-COVID-19 - 47%	86/100	-
Dubey et al.[90]	India	55	53±10.28	DM (100%)		Post-COVID-19 - 46	33/55	Headache (45) Ptosis/Proptosis (43) Retro-orbital pain (34) Facial numbness (31) Diminution of vision (27) Tooth ache/loosening (17) Diplopia (13) Facial deviation (11) Disorientation (9) Focal weakness (6) Nasal regurgitation/Nasal intonation (5) >Dysarthria (4) Seizure (1)
Patel et al.[69]	India	187	56.9	DM (113) Renal transplant (3) Hematological malignancy (2)		Concurrently-16, Post COVID-19 - 171	48	Hypoxemia (74), toothache
Pradhan et al.[91]	India	46	48.80±10.83	DM (44),		Post-COVID-19 - 46	41	Facial pain, swelling
Yadav et al.[92]	India	50	49.5	DM (48), Renal transplant (2)			22	Proptosis (27)
Pal et al.[93]	India	99	52.6±13.9	DM (84), HTN (28), Heart disease (6), CKD/ESRD (8), Asthma (2), Hypothyroidism (3), Hematological malignancy (2), Chronic liver disease (1)		15 days	82	-
Jindal et al.[94]	India	15	38-62	DM (15), HTN (5)		-	12	Pain and heaviness over the cheek; facial pain; numbness, and swelling; nasal congestion and itching; and headache
Chouhan et al.[95]	India	41	48.2	DM (40), CKD (1)		-	36	Ptosis, proptosis, peri-orbital edema, ophthalmoplegia, necrosis, blurred or reduced vision
Singh et al.[96]	India	3	47, 36, 46, 70	DM (3), HTN (1), Heart disease (1)		7 days, 14 days, 60 days	3	Eye pain, toothache, ptosis, ophthalmoplegia, headache, vomiting, altered mental status
Singh et al.[97]	India	6	51, 42, 52, 32, 45, 22	DM (6)		9 days, 8 days, concurrent (2), 16 days, 11 days	4	Headache, ptosis, proptosis, ophthalmoplegia, nasal stuffiness
Dallalzadeh et al.[72]	USA	2	36, 48	DM (2)		Concurrent (1), 6 days (1)	2	Proptosis, Periorbital edema and Conjunctival chemosis
Author	Prominent Ocular Manifestations Complications		Treatment (ROCM)			Outcomes
			Medical	Surgical	Others	Life Salvage	Vision Salvage	Eye Salvage
Werthman-Ehrenreich et al.[70]	Orbital compartment syndrome		Amphotericin B	Emergent lateral canthotomy	ED	Deceased	-	-
Salil et al.[71]	? Cavernous Sinus Thrombosis		Amphotericin B	-	-	Deceased	-	-
Dallalzadeh et al.[72]
Mekonnen et al.[73]	-		Amphotericin B Posaconazole	-	FESS	Deceased	-	-
Maini et al.[74]	-		Amphotericin B	Debridement with lateral canthotomy and inferior cantholysis	FESS	Y	Y	Y
Saldanha et al.[75]	Orbital apex syndrome		Amphotericin B	-	ED	Y	N	Y
Revannavar et al.[76]	Orbital apex syndrome		Amphotericin B	-	FESS	Y	Y	Y
Sen et al.[77]	Cavernous sinus thrombosis 4/6 Orbital apex syndrome 1/6		Amphotericin B - All	Orbital Exenteration 2/6	FESS - All	6/6	0/6	4/6
Sarkar et al.[78]	Orbital apex syndrome 5/10		Amphotericin B - All	Orbital exenteration 1/6	FESS - 2/10	6/10	1/6	5/6
	Cavernous sinus thrombosis 1/10			*3 Cases: Not fit for surgical intervention	Maxillectomy - 4/10
Mishra et al.[79]	-		Amphotericin B - 9/10	Orbital exenteration - 1/10	FESS - 8/10	6/10	2/6	5/6
				Orbital decompression - 1/10
Moorthy et al.[80]	-		Amphotericin B - All	Orbital Exenteration - 7/18	FESS - 17/18 Maxillectomy - 11/18	11/18	NA	7/11
Veisi et al.[81]	-		Amphotericin B	-	FESS	1/2	0/2	1/2
Sargin et al.[82]	-		Amphotericin B	-	ED	Deceased	-	-
Ashour et al.[83]	Cavernous sinus thrombosis - 3/10		Amphotericin B - All	Orbital exenteration - 2/8	ED 7/8	3/8	3/5	4/5
Nehara et al.[84]	Cavernous sinus thrombosis 3/5		Amphotericin B - All	-	ED - 2/5	2/5	2/3	3/3
Ostovan et al.[85]	Cavernous sinus thrombosis, partial ICA thrombosis		Amphotericin B	-	ED	Deceased	-	-
Palou et al.[86]	-		Amphotericin B	Orbital floor debridement	ED	Y	Y	Y
Shakir et al.[87]	-		Amphotericin B	Orbital exenteration	FESS	Y	N	N
Tabarsi et al.[88]	-		Amphotericin B	-	FESS	Y	Y	Y
Dilek et al.[89]	-		Amphotericin B - 94/100 Posaconazole - 4/100 Voriconazole - 2/100 Isavuconazole - 2/100	Orbital exenteration - 1/100 Surgical debridement - 53/100	FESS - 6/100 ED - 2/100	33/99	-	-
Dubey et al.[90]	-		Amphotericin B, followed by posaconazole	Orbital exenteration, surgical debridement	ED	Y
Patel et al.[69]	-		Amphotericin B (167), posaconazole (73),Isavuconazole (19)	Major resection and debridement (131/187)	-	75
Pradhan et al.[91]	Frontal lobe abscess (5), extradural abscess (1)		Amphotericin B (46)	Orbital exenteration (8), surgical debridement (46)	ED (3)	9	38
Yadav et al.[92]	Cavernous sinus involvement (16), orbital apex syndrome (23)
Pal et al.[93]	-		Amphotericin B (87)	Debridement (80)	-	33	-	-
Jindal et al.[94]	Cavernous sinus (9), brain abscess (1)			Orbital exenteration (8), maxillectomy (3)	FESS and endoscopic surgery (12)	-	-	-
Chouhan et al.[95]	Cavernous sinus thrombosis (8),Orbital apex syndrome.(10)		Amphotericin B (37)	Orbital exenteration (4), maxillectomy (6)	ED (21)	4	-	-
Singh et al.[96]	-		Amphotericin B (3)	Anterior frontal lobectomy, with excision of abscess,Excision of pus cavity	FESS (3)	0	-	-
Singh et al.[97]	-		Amphotericin B (6)	Maxillectomy (2)	FESS (4)	1	-	-
Dallalzadeh et al.[72]	Scattered intracranial infarcts		Amphotericin B (2)	-	-	1/2	0/2	1/2

Significant correlation and alterations in etiopathogenesis: Highlights

COVID-19 infection and its associated predisposing comorbidities, systemic diseases, and drug-induced immunosuppression have all rendered patients more susceptible to developing secondary infections, like mucormycosis. Enhanced disease severity among known diabetics and the ability of the SARS-CoV-2 infection, to induce hyperglycemia in persons without a previous diagnosis of diabetes has contributed significantly to the rising cases of mucormycosis during this pandemic.[101]

Diabetes mellitus, per se, is well established and a major risk factor for development of mucormycosis.[102] Additionally, corticosteroid therapy almost always precipitates blood glucose levels to manifest persistent hyperglycemia even in healthy individuals, frequently leading to corticosteroid-induced diabetes. Additionally, the combination of corticosteroid therapy and DM—a significant association that stands out in almost all severe cases of COVID-19 patients—further augments immunosuppression and hyperglycemia, thereby increasing the risk of infection.[103] This association has been found to have contributed maximally to the rising cases of mucormycosis during the pandemic.[101] Persistent hyperglycemia secondary to diabetes is believed to be responsible for impaired chemotaxis and phagocytosis of neutrophils. Besides this, diabetes-induced ketoacidosis causes impaired binding of iron to transferrin, thereby elevating the free serum iron concentration. Subsequently, an increased iron uptake by the Mucorales allows rapid fungal growth.

A severe COVID-19 disease, per se, is associated with a storm of pro-inflammatory markers and hence an altered immune activity. There is an increase in pro-inflammatory cytokines, namely, interleukins (IL-1 and IL-6), tumor necrosis factor alpha (TNF-α), and decreased CD-4 interferon-gamma expression. Severe COVID-19 disease causes an increase in neutrophil count as well as a decrease in lymphocyte count, specifically CD4+ and CD8+ T cells. These cells (CD4+ and CD8+ T cells) play a major role in maintaining immune homeostasis and impart protection against secondary fungal infections, like mucormycosis, via recruitment of cytokines, such as IL-4, IL-10, and IL-17.[104] Consequently, this “cytokine-storm” along with significant and persistent lymphopenia renders the patient highly susceptible to secondary bacterial and fungal infections.[105]

The SARS-CoV-2 virus has a propensity to cause extensive lung parenchymal involvement and subsequent alveolo-interstitial disease. A resultant decompensated pulmonary function predisposes the COVID-19-infected person to invasive fungal infections of the airways, including the sinuses and the lungs.[71] In addition to this, the frequent need for intensive care unit admissions, intubation, and mechanical ventilation in severe COVID-19 disease has been well established and these function as independent risk factors that enhance fungal multiplication.[106] In the absence of definitive evidence on dosing and frequency of systemic corticosteroids combined with the extensive use of monoclonal antibodies and broad-spectrum antibiotics in the management of COVID-19 illness, has increased the likelihood of newer fungal infections in predisposed patients [Fig. 3].[104] Furthermore, to assess histopathological correlation of COVID-19-associated ROCM, authors noted angio-invasion and minimal neutrophilic inflammation as poor prognostic histopathological features.[107]

Figure 3.

Presumed role of various predisposing factors and their interactions that are responsible for emerging cases of ROCM in COVID-19 disease

Clinical spectrum of COVID-19: Evidence from recent literature

The clinical spectrum of ROCM was observed to be more aggressive in patients with COVID-19 infection [Table 3]. During the second wave of COVID-19, a case series from India reported six cases of ROCM following COVID-19 diagnosis.[77] All six patients suffered from type 2 DM and two were diagnosed with COVID-19. The mean duration between the diagnosis of COVID-19 and the development of symptoms of ROCM was 15.6 ± 9.6 days. Out of six, only one patient presented with ROCM concurrently with COVID-19 infection and had not received systemic corticosteroids. The progression was rapid among all the patients, with five patients reporting severe visual impairment in the form of no light perception at presentation. All patients underwent endoscopic sinus debridement, whereas two patients eventually required orbital exenteration.[77] Interesting observations from this rather limited case series highlights the relatively rapid progression of this diseases and that the symptoms of ROCM could develop nearly a month (30–42 days) after the diagnosis of COVID-19. Similarly, in other case series from the north-western part of India, in five cases—all known diabetics—the symptoms of ROCM progressed very rapidly with a 40% mortality. Authors also observed a trend toward rapid progression into devastating vision and life-threatening complications such as endophthalmitis and CST in three out of five patients.[84]

In the largest multicentric collaborative study, COSMIC, of patients with COVID-19-associated ROCM managed or co-managed by ophthalmologists in India, corticosteroids and DM were the most important predisposing factors observed in the development of COVID-19-associated ROCM.[98] The study highlighted that awareness of red flag symptoms and signs, high index of clinical suspicion, prompt diagnosis, and early initiation of treatment with AMB, aggressive surgical debridement of the PNS, and orbital exenteration, where indicated, were essential for a successful outcome.[98] Another large retrospective multicentric interventional case series of 58 eyes concluded that over a third of patients with ROCM following COVID-19 have an unfavorable clinical outcome with uncontrolled diabetes mellitus at presentation, involvement of the orbital apex, CNS, and the use of steroids were associated with poor prognosis.[108] In another study from western India, the most severely affected part of Asia, the use of systemic steroids and need for supplemental oxygen were observed as the strongest predisposing factors for mucormycosis with predominantly affecting patients recovering from COVID-19.[109]

Ocular manifestations of COVID-19-associated ROCM can be varied from conjunctival chemosis, proptosis, relative afferent pupillary defect, and exposure keratitis to CRAO. A few case reports also observed rare and unique presentations in the form of exudative retinal detachment,[110] complete and incomplete lower motor neuron (LMN)-type facial palsy,[111] and orbital infarction syndrome.[112] The available clinical data clearly indicates a variable onset of ROCM, secondary to COVID-19 infection, that culminates into a rapidly progressing clinical picture, vision-threatening complications, and a high mortality rate [Table 3].[113,114,115] A lower efficacy of conservative medical treatment and a majority of cases requiring surgical intervention has also been observed. Furthermore, medical management demands superior antifungals such as intravenous L-AMB and other oral posaconazole. However, this remained the biggest limited resource in view of demand and supply mismatch with all the developing countries including India.[116] Despite the fact that there is limited evidence generated during the COVID-19 pandemic, it is still substantial to demonstrate considerable diversity in clinical presentation and outcomes of ROCM [Table 3]. Based on the evidence drawn from tabulated clinical data, previous guidelines on the management of ROCM and clinically observed effectiveness of various treatment options,[115,117] we have laid out an algorithm to guide decision-making in the management of ROCM and relevance of available ocular therapeutic modalities [Fig. 4].

Figure 4.

Recommendations on various ocular treatment modalities with substantial evidence for their role in ROCM as per the different stages of the disease

Prevention of ROCM: Special Emphasis on ROCM Associated with COVID-19

Patients with pre-existing risk factors and a higher pre-disposition should be treated with caution since they may develop opportunistic secondary mucormycosis. Therefore, preventive measures should particularly be targeted toward the population at risk.

Systemic factors

Patients with DM, hematological malignancies, and other chronic debilitating illnesses frequently constitute a high-risk group.[118,119] A strict control of blood glucose in diabetics, regular monitoring of glucose levels for those on corticosteroids, limiting the duration of neutropenia and lymphopenia, and rapidly addressing ketoacidosis are few important measures which often prove helpful.[118,120,121] While treating COVID-19 patients, falling in this high-risk category, a judicious use of corticosteroids and broad-spectrum antibiotics must be taken into consideration.

Dysfunctional immune system and immunosuppressive states

Patients on immunosuppressive therapy, transplant recipients, and those undergoing dialysis on iron-chelators constitute another high-risk group. Judicious titration of dose and duration of immunosuppressive therapy and iron-chelators are small interventions that could prove as effective and important preventive measures.[122] Moreover, limiting the duration of neutropenia and lymphopenia plays a vital role. Dental procedures including tooth extraction should be performed with utmost care and under complete aseptic conditions, specifically in predisposed patients.

Considering a low prevalence of infection in the population at risk, the routine use of prophylactic antifungals is unwarranted. Drugs such as posaconazole have been used for prophylaxis against ROCM infections in predisposed patients.[48] However, there is no standardization in this aspect and is currently not a recommendation in the Indian practice guidelines even for COVID-19 disease.

Environmental factors

Interventional measures such as modification and control of the environment within healthcare facilities, use of high-efficiency particulate air (HEPA) filters, and proper maintenance of air conditioning and ventilation systems inside intensive care units should be undertaken.[123] Use of non-sterile or tap water could be a probable cause of acquiring mucormycosis as observed during second wave of COVID-19, although clear evidence is currently lacking in this aspect. Multiple guidelines, however, have recommended frequent cleaning and use of sterile water for humidifiers.[123] Few preventive steps which need special attention while dealing with COVID-19 patients are enumerated [Table 4].

Table 4.

Strategies for prevention of ROCM in COVID-19 disease patients

Protocols to be Followed for the Prevention of ROCM In COVID-19 Infected Patients
Prevention modalities can be of very high significance
Stratification of high-risk patients and their segregation
An aggressive and strict control of blood sugar
Immediate address of hyperglycemia, diabetic ketoacidosis, and metabolic acidosis
Judicious use of steroids and other immunosuppressive therapy
Total aseptic oxygen support system (use of only distilled water in the humidifier and to remain strictly adhered with sterilization guidelines)
Prevention modalities of reasonable significance
Proper maintenance of air conditioning and ventilation systems
Personal hygiene including betadine mouth wash
Immediate shifting of the patient from intensive care unit (ICU) or high dependency unit to the general ward once they are stable
Prudent use of broad-spectrum antibiotics, biological agents, and monoclonal antibodies like tocilizumab
Consideration of prophylactic antifungal therapy such as posaconazole in high-risk cases (high-risk cases include uncontrolled diabetics, patients on immunosuppressive therapy, longer duration of hospitalization, ICU patients)
Frequent systemic and local examination of the patient to detect warning signs
Daily assessment of blood counts in high-risk cases to detect early lymphopenia

Rehabilitation

Orbital exenteration results in permanent facial disfigurement and life-altering psychosocial issues in the patient besides significant functional handicap. A multidisciplinary approach remains the basis for an effective and lasting rehabilitation which involves cosmetic, psychosocial, social, and vocational rehabilitation.

Cosmetic rehabilitation includes surgical reconstruction methods or the use of prostheses. Surgical reconstruction procedures including galeal-frontalis-pericranial flap for orbital, periorbital, and anterior cranial-base defects or free anterolateral thigh flap incorporating a segment of vastus lateralis for extensive hemifacial defect have been described.[124] Prosthetic rehabilitation requires minimum surgical intervention in addition to an increase in the patient’s facial esthetics. Recommended methods to retain a prosthesis are adhesives, conformers, osseo-integrated implants, and the use of mechanical undercuts.[125] Kaur et al.[126] designed a two-component prosthesis (conformer substructure of heat-polymerized polymethyl methacrylate and silicone superstructure) for rehabilitation of resected orbit in a case of mucormycosis. The unique design ensured the health of the underlying tissue and durability of the prosthesis by minimizing the tissue contact of silicone (prone to surface deterioration in hot climates).

The profound impact of losing a vital sense organ, like the eye, in addition to surrounding structures such as the maxilla, palate, or even brain tissue in life-saving surgical debridement/resection procedures could result in psychosocial manifestations. Hence, mental health professionals should constitute an essential part of the multidisciplinary team involved in patient management and rehabilitation. Adequate measures must be taken toward improvement of the patients’ quality of life.[127] Occupational rehabilitation measures such as workplace modifications, alternative work programs, or career counselling are needed so that ROCM survivors remain functioning and productive members of the society.

Conclusion

We have recently only just emerged from the thick of the second wave of pandemic in India and amidst the third wave—a country that has witnessed a unique challenge in the form of an unprecedented surge in the number of mucormycosis cases following COVID-19 infection. The requirement of antifungal agents spiked overnight, surpassing the availability and manufacturing capacity, as well as overwhelming the supply chain. The availability of L-AMB became increasingly scarce and a large number of patients underwent extensive debridement and orbital exenteration and still succumbed to the invasive fungus. While the real numbers remain elusive, the official statistics are undoubtedly staggering.

Immune dysregulation caused by SARS-CoV-2, and extensive, indiscriminate, and unregulated use of corticosteroids and broad-spectrum antibiotics combined with poorly controlled or undiagnosed diabetes with ketoacidosis are some of the factors that could have contributed to this unprecedented phenomenon. Early diagnosis, correction of systemic immune suppression, control of diabetes and ketoacidosis, extensive and timely debridement as well as effective antifungal therapy are the key factors for the successful management of ROCM.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.