Risk factors and clinical presentation of rhino-orbital mucormycosis: Lesson learnt during Covid pandemic

ABSTRACT

Aim:

To analyze the potential predisposing factors and clinical presentation of mucormycosis in patients with COVID-19.

Material and Methods:

Medical records of 141 patients with COVID-19-associated mucormycosis (CAM) treated at a tertiary care center in Bihar were reviewed. The predisposing factors, clinical features, and imaging findings of mucormycosis were analyzed.

Results:

The median age was 48 years (IQR, 43-60). A total of 58 patients developed concurrent CAM and 83 post-CAM. The median interval between COVID-19 and onset of CAM symptoms was 15 days (IQR, 9–16). A total of 80 patients received at-home treatment for COVID-19, and 73 had mild-to-moderate disease. While 61 patients received in-hospital treatment, 57 had severe disease. At presentation, 131 patients had hyperglycemia: 64 type 2 diabetes mellitus (DM) and 67 new-onset DM. The history of glucocorticoid use for COVID-19 was present in 125 patients; 47% were administered at home without monitoring plasma glucose. The common presenting features were toothache, periocular or facial pain, and edema. Rhino-orbital mucormycosis was the most common. Imaging revealed rhinosinusitis in all patients, including pansinusitis (68%), pterygopalatine fossa involvement (21%), cavernous sinus thrombosis (38%), brain abscess (8%), and infarct (4%). All patients received intravenous liposomal amphotericin B, and surgical debridement was performed in 113.

Conclusion:

COVID-19 patients with hyperglycemia are at risk of developing CAM, irrespective of the severity. Timely recognition of symptoms and prompt initiation of therapy by primary healthcare physicians are imperative for enhancing outcomes. Additionally, glucocorticoid overuse should be avoided, and close monitoring for hyperglycemia development is warranted.

Introduction

Commonly known as “black fungus,” mucormycosis is a deadly infection caused by fungi of the order Mucorales. It is a most common and most aggressive form referred to as rhino-orbito-cerebral mucormycosis (ROCM), in which the infection begins in the nasal cavity, spreads to the paranasal sinuses, and then invades the orbit or cranium, eventually causing rapid, widespread destruction and death. Overall, the mortality rate varies from 46% to 96%. 9.[1,2,3] Diabetes, organ transplantation, immunosuppressive therapy, prolonged neutropenia, or malignancy are well-known risk factors for this disease.[1,2,3]

ROCM has been increasingly reported in patients with COVID-19 in many countries, and the term “COVID-19-associated mucormycosis (CAM)” has now been used to describe this condition.[4,5] The surge of CAM in India during the second wave of COVID-19 was unprecedented. Over 28,000 cases and over 2,000 deaths had been reported till June 13, 2021.[6,7] Several states of India, including our state (Bihar), declared mucormycosis as an epidemic. Approximately half of the patients were admitted to our Institute at Patna. What led to this CAM epidemic in India during the second wave is a matter of serious concern and the subject of investigation.

Recent studies from India, mainly case reports or multicenter studies, have addressed this question.[4,8,9] Almost all studies have consistently found that two factors, uncontrolled diabetes, and glucocorticoid use, are associated with over 70% of CAM cases in India.[5,10,11,12] However, there might be other factors or issues of considerable interest that have not yet received appropriate attention. We investigated the factors predisposing to CAM in 141 patients who received treatment at our institute. Additionally, we describe the presenting signs and symptoms in these patients.

Material and Methods

Study design and patient population

We reviewed the medical records of 192 patients with mucormycosis admitted at Indira Gandhi Institute of Medical Sciences, Patna, Bihar, between May 15 and July 15, 2021. The diagnosis of mucormycosis was established by demonstrating the characteristic broad, nonseptate-branched hyphae in the tissue obtained from surgical debridement or tissue biopsy on microscopic examination. All but five had recent (within three months) COVID-19, diagnosed by RT-PCR. Fifty-one patients were excluded: 46 because of incomplete data and five because of negative recent RT-PCR results for COVID-19. Finally, 141 patients with confirmed mucormycosis constituted the core study group. Written consent from patients and approval from the Institutional Ethics Committee (159/IEC/IGIMS/2021) were obtained. The study adheres to the tenets of the Declaration of Helsinki.

Definitions

Concurrent CAM was considered when the symptoms of mucormycosis developed within two weeks of the onset of COVID-19 symptoms, and post-COVID-19 CAM when it developed after two weeks. Mild or moderate COVID-19 was defined as an asymptomatic or symptomatic disease with no signs of severe pneumonia or requirement for supplemental oxygen. Severe COVID-19 was defined as a disease with signs of severe pneumonia requiring supplemental oxygen. At-home treatment was defined as the treatment of COVID-19 received at home and in-hospital treatment when received at the hospital. Hyperglycemia was defined as blood glucose ≥200 mg/dl. New-onset diabetes mellitus (DM) was defined as the diagnosis of DM during the initial workup of CAM without prior history of DM or use of hypoglycemic medications. Uncontrolled DM was defined as hyperglycemia at presentation despite the use of hypoglycemic drugs. Overweight was defined as body mass index (BMI) ≥25 kg/m2. The interval between COVID-19 and CAM was considered from the onset of the symptoms of mucormycosis or COVID-19.

Data collection

The medical records of 141 patients were analyzed. The following data were extracted for each patient: age, gender, BMI, past medical history, presenting signs and symptoms, site and extension of disease at presentation, interval between onset of symptoms of COVID-19 and CAM, interval between onset of CAM symptoms to admission to the hospital, underlying risk factors, and details of ophthalmologic and otolaryngologic examination. The ophthalmologic examination included visual acuity, extraocular movements, pupil, and fundus examination. The otolaryngologic examination included anterior rhinoscopy and nasal endoscopy. The place of care for COVID-19 (at-home or in-hospital) was recorded for each patient. Details of drugs, particularly glucocorticoid therapy, used during COVID-19 disease were obtained with respect to dose and duration of therapy. Daily glucocorticoid dose was recorded. For the patients who received methylprednisolone and prednisolone, the dexamethasone-equivalent dose was calculated at 0.75 mg dexamethasone per 4 mg methylprednisolone and per 5 mg prednisolone. A specific inquiry was made as to whether or not blood glucose monitoring was performed during the treatment with steroids.

Staging of CAM was based on disease extension as determined by imaging studies: stage I (nasal) involving the nasal cavity, stage II (sino-nasal) involving both nasal cavity and sinuses, stage III (rhino-orbital) extending to one or both orbits, and stage IV (rhino-orbito-cerebral) extending into skull base or cranium. The imaging studies included 67 computed tomography (CT) and 74 magnetic resonance imaging (MRI); all imaging studies were performed within one week of admission. Only four patients having suspicion of pulmonary involvement had high-resolution CT (HRCT) chest at presentation. Laboratory data at the presentation included the following: hemogram, fasting blood glucose, glycosylated hemoglobin (HbA1c), serum ferritin, and renal function test.

Standard protocol for managing mucormycosis was followed.[4] The details of treatment (duration and type of antifungal medications, sinus debridement/orbital exenteration) were recorded. All cases were followed-up till the hospital stay. The outcome measures were stable or progressive disease, mortality, or recovery.

Statistics analysis

Descriptive data were expressed as mean (standard deviation, SD) or median (interquartile range, IQR) for continuous variables and number (%) for categorical variables. Categorical data were analyzed using the Chi-square test and continuous data by t-test. P < .05 was considered statistically significant.

Results

The median age of 141 patients was 48 years (IQR, 43–60; range, 19–82); 72% were men, and 28% were women. All patients were residents of Bihar, India, and had preceding COVID-19. The median interval between COVID-19 and the onset of CAM symptoms was 15 days (IQR, 9–16 days; range, 3–31 days), and the median lag time from the onset of mucormycosis symptoms to the initiation of treatment was five days (IQR, 2–15 days). Fifty-eight (41%) patients developed concurrent CAM, and 83 (59%) post-COVID-19 CAM.

Eighty (57%) patients had received at-home treatment for COVID-19 and did not require supplemental oxygen [Table 1]. Sixty-one (43%) had received in-hospital treatment, and most received supplemental oxygen for a median period of 5 days (range, 2–30 days). Forty-five (74%) patients receiving in-hospital treatment had wholly recovered and were discharged after recovery from COVID-19, but 16 (26%) patients developed CAM during the same admission (concurrent CAM). Of 16 patients with concurrent CAM, 12 were in the intensive care unit (ICU), and four were in the hospital ward when they developed symptoms of CAM.

Table 1.

Severity and place of treatment for COVID-19

Variables	At-home treatment (n=80, 57%)	In-hospital treatment (n=61, 43%)	P
Glucocorticoid use	66 (47%)	60 (43%)	0.001
New-onset DM	55 (39%)	12 (09%)	0.001
Pre-existing DM	16 (11%)	48 (34%)	0.001
Median blood glucose (mg/dl)	260	307	0.522
Severity of COVID-19
Mild/Moderate	73 (52%)	4 (03%)	0.001
Severe	07 (05%)	57 (40%)	0.001
CT score (median)	6	17	0.001

Glucocorticoids were used by most (89%), irrespective of the COVID-19 severity and place of treatment. Sixty-six (47%) of patients having at-home treatment received glucocorticoids (39, intravenous and 27, oral), whereas, for those having in-hospital treatment, 60 (42%) received glucocorticoids (all intravenous). All patients received dexamethasone in various doses, except one who received methylprednisolone; the median dexamethasone dose per day was 8 mg (IQR, 8–16 mg/day; range, 6–24 mg/day), and the median period of glucocorticoid use was 8.5 days (IQR, 6–14; range, 3–26 days). Sixteen (11%) patients had not received glucocorticoids during COVID-19. Less than 10% of patients received treatment at home and were given insulin or other oral hypoglycemics, while the rest remained unmonitored for blood glucose during glucocorticoid therapy.

One patient with post renal transplant had been taking other immunosuppressive drugs for 14 months. One patient had received remdesivir. All patients in this study had received empirical broad-spectrum antibiotic therapy during COVID-19 treatment.

Predisposing factors with CAM

A total of 131 (93%) of the patients had hyperglycemia at presentation. 45% had a history of DM for 1–15 years (median, five years), but 48% of patients were diagnosed with DM for the first time (new-onset DM) [Table 2]. No significant difference was observed between the mean blood glucose level of new-onset DM and pre-existing DM (391 vs 373 mg/dl, P = 0.522). Interestingly, most patients with new-onset DM had received at-home treatment for COVID-19. None of the patients were identified with diabetic ketoacidosis. All hyperglycemic patients received glucocorticoids during COVID-19 except 10 (7.6%) patients; however, five were diagnosed as diabetics. Other predisposing factors recognized were hypertension in 52 patients, chronic renal disease in 16 patients, and a history of renal transplantation with immunosuppression in one patient. Ten patients had no identifiable predisposing factors except COVID-19 illness; they had no history of DM or glucocorticoid therapy.

Table 2.

Risk factors of 141 patients with COVID-19 associated mucormycosis (CAM)

Variables	Number of patients, 141 (%)
Underlying diseases/risk factors
Hyperglycemia at presentation	131 (93%)
Pre-existing type 2 DM	64 (45%)
Uncontrolled DM	61 (43%)
Controlled DM	02 (02%)
New-onset DM (NODM)	67 (48%)
Pharmacological immunosuppression	126 (89%)
Corticosteroid therapy	125 (88.6%)
Other immunosuppression therapy	01 (0.7%)
Obesity	78 (55%)
Hypertension	52 (37%)
Organ transplantation (kidney)	01 (0.7%)
Chronic renal diseases	16 (11%)
HIV	01 (0.7%)
Laboratory parameters
Hemoglobin (mg/dl)	10.4
Total white cell count (per mm3)	10493
Absolute neutrophil count	76.5
Fasting blood sugar (mg/dl)	263.13
HbA1C (%)	9.7
Serum ferritin	774.12
Serum creatinine	1.03

Clinical findings and outcomes of CAM:

Presenting symptoms and signs are listed in Table 3. The most common presenting clinical features were periocular or facial pain, edema, and toothache, followed by one-sided facial numbness, nasal blockage, and nasal bleed/discharge. Otolaryngologic examination revealed sinusitis and rhinitis in all patients. Other common findings were nasal eschar in 72% and infra-orbital anesthesia in 21% of patients. Ophthalmic examination showed partial or complete ophthalmoplegia with ptosis and restriction of ocular movements in 45% of patients [Figure 1]. Diminution or loss of vision (n = 49, 35%, PL negative to 6/12) was mainly attributed to optic nerve involvement, central retinal artery occlusion, and complete ophthalmoplegia. Interestingly, diabetic retinopathy features were seen in only 7 (5%) patients with pre-existing type 2 DM. No sign of diabetic retinopathy was seen in the new-onset DM.

Table 3.

Clinical features and staging of 141 patients with COVID-19-associated mucormycosis (CAM) at presentation

Parameters	Number of patients (percentage)
Symptoms
Unilateral headache and facial pain	114 (81%)
Unilateral facial and periocular swelling	111 (79%)
Toothache	104 (74%)
Nasal blockage	89 (63%)
Facial numbness	54 (38%)
Diminution of vision	49 (35%)
Nasal bleed/discharge	36 (26%)
Bulging of eyeball	36 (26%)
Drooping of lids	35 (25%)
Fever	30 (21%)
Double vision	27 (19%)
Facial discoloration	25 (18%)
Palate ulcer	24 (17%)
Conjunctival congestion	17 (12%)
Clinical signs
Sinusitis and rhinitis	141 (100%)
Facial edema	125 (87%)
Nasal ulcer/eschar	101 (72%)
Ophthalmoplegia (partial/complete)	64 (45%)
Infra-orbital hypoesthesia	31 (22%)
Corneal anesthesia	25 (18%)
Central retinal vein/artery occlusion	14 (10%)
Tooth fall/loss	08 (6%)
Diabetic retinopathy	07 (5%)
Altered sensorium/seizures	06 (4%)
Keratitis	04 (3%)
Facial palsy	01 (0.7%)
Site of involvement:
Stage I (nasal)	0
Stage II (sino-nasal)	33 (23%)
Stage III (rhino-orbital)	81 (57%)
Stage IV (rhino-orbito-cerebral)	27 (19%)

Figure 1.

Clinical presentation of rhino-orbital mucormycosis: (a) unilateral periocular and facial edema; (b) right eye ptosis, proptosis and periocular edema; (c) necrotic facial eschar involving lateral wall of nose; (d) and (e) palate ulcer and loss of tooth; (f) orbital cellulitis, proptosis, and exposure keratopathy; (g) ptosis with subconjunctival hemorrhage, chemosis, and exposure keratopathy; (h), purulo-sanguineous discharge from right nostril

On radiological imaging on MRI (n = 74), CT (n = 67), or both (n = 19), 100% had paranasal sinus involvement: 68% of patients had pansinusitis, and none had single sinus involvement. In orbit, diffuse involvement predominated in 59 (42%), followed by involvement of the medial and inferior orbit in 49 (35%) and 21 (15%) patients, respectively. Staging of ROCM was based on disease extent radiologically. ROCM (stage 3) was the most common site of involvement (n = 81, 57%) at presentation. Intracranial complications were found as pterygopalatine fossa involvement (n = 47, 33%), cavernous sinus thrombosis (n = 39, 28%), frontal lobe and temporal lobe abscess (n = 7, 5%), internal carotid artery thrombosis (n = 7, 5%), and cerebral infarct in two patient (1%) [Table 4]. The most common route of intracranial spread was via the pterygopalatine fossa [Figure 2].

Table 4.

Extension of COVID-19-associated ROCM as demonstrated by contrast-enhanced MRI in 74 patients

Variables	Number of patients (n=93)
Orbital apex involvement	47 (33%)
Cavernous sinus thrombosis	39 (28%)
Vascular occlusion (ICA)	07 (05%)
Brain abscess	07 (08%)
Meninges	04 (03%)
Cerebral infarction	02 (01%)
Pterygopalatine fossa	47 (33%)
Infratemporal fossa	09 (06%)
Hard palate, alveolar arch	10 (07%)

Figure 2.

MRI T1-weighted post-contrast coronal image showing the presence of pansinusitis with nonenhancing necrotic mucosa in maxillary sinuses (a); and pansinusitis with intracranial extension with abscess formation in the left frontal lobe (black arrowhead) (b); T1-weighted post-contrast axial image showing extensive inflammatory changes in left maxillary sinus (c); and left ethmoid sinus with extensive intraorbital extension and proptosis of the left globe (d)

Direct microscopy and histopathology examination showed broad, nonseptate, wide-angle branched hyphae, and Rhizopus arrhizus was isolated in the majority. None of the culture growth was suggestive of Mucor.

To the date of analysis, all patients have received intravenous liposomal amphotericin B (5–10 mg/kg BW) for a median period of 23 days (range, 12–31 days) along with vigorous control of underlying diseases. Some patients received amphotericin B deoxycholate or amphotericin B lipid complex due to intermittent unavailability of liposomal amphotericin B.

Blood glucose and renal functions were monitored during treatment. In patients with ophthalmoplegia, transcutaneous retrobulbar amphotericin B (liposomal) (TRAMB), 3.5 mg in 1 ml, was given at an area of concern as adjuvant therapy in 12 patients prior to sinus debridement. The median number of injections was 3 (range, 3–6); four patients with focal involvement of orbit (3, medial rectus and 1, inferior rectus) showed one-line improvement in visual acuity and improvement in ocular movements. The rest of the patients remained clinically stable with no further evidence of progression. No adverse reaction was seen. Sinus debridement was performed on 113 patients (80%): functional endoscopic sinus surgery (49, 43%) and open surgery (28, 25%). Along with sinus surgery, 16 patients underwent orbital exenteration, and seven underwent craniotomy. No adverse reaction to intravenous amphotericin was seen except for two patients, first with chronic renal disease who underwent hemodialysis before the scheduled dose of intravenous amphotericin and another patient who developed rashes all over the body that subsided with anti-allergic medications.

Till the preparation of the manuscript, at the end of 6 weeks, 124 showed regression or stabilization of disease, and 51 patients were discharged from the hospital (mean hospital stay, 25 days) with step-down therapy of oral posaconazole 300 mg every 24 hours for six weeks). A total of 17 patients succumbed to their disease, with most of the deaths within 6.88 ± 2.37 days (range, 2–22 days). The majority of them were admitted to the ICU.

Discussion

The emergence of mucormycosis during the COVID-19 pandemic in India in 2021 was unexpected and raised serious concerns among primary healthcare professionals. In this study, our primary aim was to identify the predisposing factors and clinical features of CAM. We found that uncontrolled diabetes and unsupervised use of corticosteroids were significant predisposing factors for CAM, and the most common presentation was unilateral facial pain and swelling.

COVID-19 causes extensive pulmonary disease and subsequent alveolo-interstitial pathology, which can predispose to invasive fungal infections of the airways, including the sinuses and the lungs.[13,14] This is further worsened by alteration of the innate immunity due to COVID-19-associated immune dysregulation characterized by decreased T cells, including CD4 and CD8 cells.

The predisposing factors for CAM appear to be multifactorial, with hyperglycemia induced by steroids playing a pivotal role. Several studies have demonstrated that hyperglycemia contributes to development of CAM in 62%–93% of patients, particularly those with uncontrolled pre-existing diabetes mellitus.[15] Our findings revealed that 93% of patients presented with hyperglycemia, and interestingly, nearly half of them (48%) were not previously diagnosed with diabetes, considerably higher than reported rates ranging from 16%–44%. This emphasizes the importance of identifying new-onset diabetes mellitus (NODM) during COVID-19 treatment and administering appropriate hypoglycemic medications. Surprisingly, our study did not find any cases of ketoacidosis, which is known to be associated with ROCM, suggesting a different disease pattern during the COVID-19 pandemic 15. Additionally, contrary to data of pre-COVID-19, emphasizing the association between ROCM and diabetic ketoacidosis, our study did not find any cases of ketoacidosis.[16,17] This observation finds corroboration in recent studies from India, wherein a low incidence of diabetic ketoacidosis in cases of CAM was reported.[18] Hypertension was identified as an additional risk factor (37%) in the patients who had diabetes.

Glucocorticoids have been implicated in inducing hyperglycemia, leading to uncontrolled diabetes mellitus and NODM. Although prolonged and high-dose systemic corticosteroid usage (over more than three weeks) has been identified as a risk factor for mucormycosis in non-COVID-19 patients primarily due to immunosuppression, few case reports and our study have shown the occurrence of mucormycosis even after a short course of steroids.[19] This could be attributed to glucocorticoid-induced hyperglycemia, along with immunosuppression and lymphopenia. Cumulative doses exceeding 600 mg of prednisone and 2–7 g of methylprednisolone have been found to predispose immunocompromised patients to mucormycosis.[20] In our study, the median dose and duration of glucocorticoid use were 8 mg/day and 8.5 days, respectively. During the COVID-19 pandemic, management guidelines in India recommended the use of intravenous methylprednisolone (0.5–1 mg/kg/day) or dexamethasone (0.1–0.2 mg/kg) for 5–10 days in moderately severe cases, especially for patients with escalating oxygen requirements or elevated biomarkers. In our study cohort of 141 patients, 57% received at-home treatment for COVID-19, including broad-spectrum antibiotics and glucocorticoids, while 43% were managed in hospitals. Mishra et al.[21] in their study reported in their study that only one out of 10 patients had COVID-19 infection at the time of presentation (severe COVID-19 disease), while the rest of the patients presented after COVID-19 infection (mild and moderate COVID-19). Multicentric studies from India have also highlighted the inappropriate use of glucocorticoids, with 66% and 73% of patients receiving glucocorticoids at levels beyond the recommended dose (dexamethasone-equivalent dose ≥ 6 mg for ≥ 10 days), even in cases of mild COVID-19 severity.[1,9] This emphasizes the importance of judicious use and close monitoring of glucocorticoids to mitigate the risk of hyperglycemia development.

In accordance with earlier studies, unilateral headache, facial pain, and facial or periocular swelling constituted the most prevalent presenting symptoms, while rhinitis and sinusitis were evident in all patients.[4,5,18,21,22,23,24] Remarkably, our study revealed that 74% of patients presented with toothache, and 6% exhibited tooth loss. Patel et al.,[11] in their work, also documented that toothache, tooth loosening, and radiological involvement of the jaw were common manifestations in CAM patients, a pattern not observed among non-CAM patients.

Although literature on ROCM has consistently indicated that the ethmoid sinus is the most frequently affected sinus, followed by the maxillary sinus, all patients in our study had involvement of multiple paranasal sinuses, with 68% presenting with pansinusitis, and none with single sinus involvement. Because of its superior ability to provide enhanced visualization of soft tissue involvement compared to a CT scan, contrast-enhanced MRI is preferred imaging modality compared to a CT scan. However, in cases where MRI may not be feasible, contrast-enhanced CT scan offers the advantage of quicker acquisition. In our series, MRI was the modality of choice for 52% of patients, while 47% underwent a CT scan.

Prompt diagnosis of mucormycosis can be achieved with direct microscopy using KOH wet mounts of nasal-endoscopy-guided specimens. Although excluded from the analysis, several nonmucormycetes agents such as Aspergillus, Fusarium, Curvularia, and Penicillium were also detected in our study. In their study, Ambasta A et al.[25] have shown that, in contrast to mucormycetes, the cases with nonmucormycetes etiology show less severe orbital and intracranial involvement.

The management of mucormycosis involves controlling predisposing factors, performing optimal surgical debridement, and administering antifungal agents. Amphotericin B was the drug of choice for all our patients. For stage 3 ROCM, transcutaneous retrobulbar injection of amphotericin B (TRAMB) was added, limiting the disease to the orbit and preventing intracranial extension.[26] Surgical intervention was found to be beneficial, especially for patients without CNS involvement.

This study has some limitations. Firstly, it is a retrospective and single-center study, which may limit the generalizability of the findings. Secondly, the lack of a control group prevents us from making definitive conclusions about the identified risk factors. Further studies are needed to assess the long-term outcomes of CAM patients.

In conclusion, COVID-19 patients with hyperglycemia are at risk of developing CAM, irrespective of the severity of their COVID-19 infection. Timely recognition of symptoms and prompt initiation of therapy by primary healthcare physicians are imperative for enhancing outcomes. Additionally, glucocorticoid overuse in mild or moderate COVID-19 should be avoided, and close monitoring for hyperglycemia development is warranted.

Ethics approval

Ethical approval was received from the Indira Gandhi Institute of Medical Sciences, Patna (Bihar), India (159/IEC/IGIMS/2021), on June 25, 2021.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.