Introduction
Newly evolved coronavirus poses a high threat to global public health. The current coronavirus disease 2019 (Covid-19) is the third coronavirus outbreak in humans over the past two decades. As this disease has unfolded over time, myriad manifestations and complications have been documented around the world. Each passing day in this pandemic teaches us new theories about this novel coronavirus disease.
There are several worldwide reports describing Covid-19 patients as being co-infected with fungal infection. In addition, when India was dealing with a second wave of Covid-19 in April 2021, there was an emergence of mucormycosis in several Indian states, resulting in an outbreak, and on 20 May 2021, the Government of India declared mucormycosis a ‘notifiable disease’ under the Epidemic Diseases Act 1897. In view of the rising number of mucormycosis cases, separate out-patient departments and wards were created in several hospitals including ours for early identification and treatment of the disease.
Rhino-orbito-cerebral mucormycosis is an acute invasive fungal infection that is rare, opportunistic and potentially fatal, and mostly occurs in immunocompromised patients. Uncontrolled diabetes mellitus (pre-existing and new-onset diabetes mellitus), diabetic ketoacidosis, haematological malignancies, hypertension, kidney disease and use of systemic corticosteroids have been recognised as predisposing factors associated with mucormycosis, with diabetes mellitus being the most common. Immunosuppression in Covid-19 patients, along with the humid climate in India with high fungal spore counts, provide a favourable environment for the development of invasive mould diseases.
In sinonasal mucormycosis, infection commonly originates from the nasal cavity or paranasal sinuses; it then extends to the palate, orbit, infratemporal fossa and brain, producing facial and orbital pain, blurry vision, swelling, fever, malaise, generalised pain and headache related to the spread of disease. At our centre, atypical presenting symptoms in post-coronavirus patients included facial abscess, facial palsy, gingival abscess, and maggots in the nose along with common symptoms of rhino-orbito-cerebral mucormycosis. This paper examines these unusual symptoms, rarely seen in rhino-orbito-cerebral mucormycosis patients.
Materials and methods
We retrospectively collected data of 400 rhino-orbito-cerebral mucormycosis patients admitted to Sawai Man Singh Medical College and affiliated hospitals in Jaipur, a tertiary care centre, from May 2021 to June 2021. Our study aimed to report unusual presentations in Covid-19 associated mucormycosis cases. All patients with atypical symptoms other than common presentations of rhino-orbito-cerebral mucormycosis were included in the study. Patients with only common manifestations of rhino-orbito-cerebral mucormycosis, namely facial and orbital pain, blurry vision, swelling, fever, malaise, generalised pain, and headache, were excluded from the study.
All patients with a history of Covid-19 infection were asked about the severity of the infection. History of any associated disease or relevant medication was taken. Those patients who reported no history of Covid-19 infection underwent a coronavirus antibody titre test. Epidemiological, clinical, biological, radiological and therapeutic data were collected. Only those patients with histological findings of mucormycosis in their nasal biopsy samples were included in the study.
This study was conducted after ethical and scientific committee clearance from the institutional review board of our institute. All patients included in the study signed a consent form approving their willingness to participate in the study, after ethical committee approval.
Results
A retrospective study of 62 patients was conducted based on the collected data of 400 patients admitted to the Department of Otorhinolaryngology at Sawai Man Singh Medical College and affiliated hospitals, in Jaipur. The ages of the 62 patients ranged from 16 to 72 years, with a mean age of 50.03 years. The female to male ratio was 2.4:1.
All patients were asked about their coronavirus infection history and hospitalisation for the same; 40 per cent of patients reported a history of hospitalisation for Covid-19. Patients were categorised according to Covid-19 severity in terms of mild, moderate and severe disease, based on guidelines issued by the Indian Council of Medical Research (Table 1). Twenty patients with moderate to severe Covid-19 infection required oxygen support for 5–7 days (Table 2). Use of systemic corticosteroids and anticoagulant was reported in 53 per cent and 38 per cent of patients, respectively. The time interval between the diagnosis of Covid-19 and the appearance of symptoms suggestive of mucormycosis ranged from 2 months to 7 days prior. It was noted that 38 per cent of patients had recent-onset type II diabetes mellitus and 42 per cent of patients had a past history of type II diabetes mellitus, while 20 per cent had no history of diabetes (Figure 1). Eleven patients (17.7 per cent) reported no history of Covid-19 infection; antibody titre was performed in these cases and it was found to be positive in over 95 per cent of cases. These results suggest a direct temporal and spatial association between mucormycosis and the second wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Delta variant) during April and May 2021 in India. A similar association was reported by Sharma et al.Reference Sharma, Grover, Bhargava, Samdani and Kataria1
Distribution of diabetes mellitus in patients. (Note that summed values equal less than 100 following the rounding of numbers.)
Distribution of patients according to Covid-19 severity
Categorisation of severity based on guidelines issued by the Indian Council of Medical Research. Covid-19 = coronavirus disease 2019
Summary of 62 patients
Pt. no. = patient number; HbA1c = haemoglobin A1c; M = male; DM = diabetes mellitus; NA = not applicable; F = female
Out of 400 patients, these 62 patients had clinical manifestations other than common symptoms of rhino-orbito-cerebral mucormycosis. The unusual presentations included: facial palsy, in 34 patients; gum ulcers, in 19 patients; cheek abscess, in 6 patients; maggots in the nose along with rhino-orbito-cerebral mucormycosis symptoms, in 2 patients; and cerebellar infarct, in 1 patient.
Facial palsy
Among 34 patients with facial palsy, 76.4 per cent had lower motor neuron type facial palsy (Figure 2) and the rest had upper motor neuron type. Seventy-three per cent of patients developed facial palsy during the course of their treatment; the remaining patients presented with common symptoms of mucormycosis, such as facial numbness, headache, proptosis with an inability to close the eye, and deviation of the angle of the mouth.
A 71-year-old male who presented to our out-patient department with complaints of unilateral facial numbness, pain, nasal blockage and unilateral facial palsy. Published with patient's permission.
On otoscopy, 20 per cent of patients showed findings suggestive of serous otitis media; in the remaining patients, no abnormality was detected. High-resolution computed tomography of the temporal bone showed mastoiditis with erosion of the tympanic part of the facial canal in 15 patients. Nerve conduction velocity showed motor axonal degeneration in all cases. Topodiagnostic tests (Schirmer's test and the stapedial reflex test) revealed that the lesion site was beyond the geniculate ganglion in all patients.
Gum ulcers
Nineteen patients showed swelling and pain over gingival mucosa (Figure 3). Three patients had gum ulcers as their presenting complaint, for which they first visited a dentist; however, when there was no improvement after 3–5 days of treatment, these patients were referred to the mucormycosis out-patient department for evaluation, in view of their history of Covid-19 and diabetes.
A 36-year-old female who presented to our ENT out-patient department with complaints of gum ulcers. Published with patient's permission.
Magnetic resonance imaging (MRI) of the nose and paranasal sinuses of these patients revealed mucosal thickening in the maxillary sinus of the involved side, and diagnostic nasal endoscopy showed inflamed nasal mucosa. The biopsy and potassium hydroxide mount from the nasal and sinus mucosa were positive for mucormycosis. Eleven patients developed gum swelling and pain during the course of treatment.
Cheek abscess
Six patients developed a cheek abscess (Figure 4) during the course of treatment. These patients underwent incision and drainage, and pus was sent for culture sensitivity testing. Culture testing results predominantly revealed pseudomonas.
(a & b) Patients admitted to the mucormycosis ward who developed a cheek abscess on the side of involved sinus, which was treated with incision and drainage and systemic antibiotics. Published with patients’ permission.
Rhino-orbito-cerebral mucormycosis has long been reported on in the literature, but no studies have highlighted the development of abscess during the course of treatment. However, in coronavirus-associated mucormycosis patients, we have observed cheek abscess.
Nasal myiasis
Two patients presented with complaints of nasal blockage, nasal discharge, proptosis and loss of vision on the involved side. The MRI scans of the nose and paranasal sinuses of both patients showed disease in all sinuses, without intracranial and intra-orbital extension. Both patients complained of maggots from the involved side of the nose, along with rhino-orbito-cerebral mucormycosis symptoms. The two patients were admitted to the isolation ward and the maggots were managed with turpentine oil. Within a week, the patients were better and free of maggots. This management was followed by extensive surgical debridement.
Cerebellar ataxia
One patient presented with imbalance that developed with other symptoms of nasal blockage, headache, unilateral facial pain and eye pain. The brain and paranasal sinus MRI scans showed an acute cerebellar infarct. Results of the finger-to-nose test, heel-to-shin test and Romberg test were positive. The patient was also treated with anti-coagulants.
Treatment
All patients were treated with prompt surgical debridement along with medical management. Surgical management included debridement of all diseased nasal mucosa, ranging from ethmoidectomy, sphenoidotomy, medial maxillectomy to radical maxillectomy, with endoscopic orbital decompression or orbital exenteration depending on the extent of disease. The main stay of medical management was injectable liposomal amphotericin B (1 mg/kg/day), depending upon the patient's renal status and other underlying conditions.
Discussion
The Covid-19 infection caused by the novel SARS-CoV-2 has been associated with a wide range of disease patterns, ranging from a mild cough to life-threatening pneumonia. The symptoms of this disease can be diverse, as the virus can affect any organ in the body of an infected person. Severe acute respiratory syndrome coronavirus-2 usually affects the respiratory system, although nervous system involvement has also been reported in some recent studies among patients with Covid-19. Coronaviruses can attack the neural tissue including microglia and astrocytes. They also cause nerve injury through direct nerve invasion. The nervous system injuries could manifest as headache, dizziness, seizure, impaired consciousness, acute cerebrovascular disease and ataxia. Peripheral nervous system involvement can cause olfactory dysfunction, dysgeusia, vision impairment and neuropathic pain.Reference SeyedAlinaghi, Afsahi, MohsseniPour, Behnezhad, Salehi and Barzegary2
During the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak in 2002–2004, the incidence of fungal infection was 14.8–27 per cent, and it was the main cause of death for severe acute respiratory syndrome patients.Reference Werthman-Ehrenreich3 Studies have shown that SARS-CoV and SARS-CoV-2 share a somewhat similar genomic profile, with the latter also attacking the lower respiratory tract.Reference Yin, Wang, Tang, Zhang and Wang4 The host–pathogen interaction is crucial in disease development. As well as acute respiratory distress syndrome, SARS-CoV-2 also causes immunosuppression, leading to decreases in cluster of differentiation 4+ and 8+ T cells.Reference Peeri, Shrestha, Rahman, Zaki, Tan and Bibi5 During the outbreak of 2003, a high incidence of fungal infection was found in patients affected by or recovered from novel coronavirus disease.
Mucormycosis is considered to be the most invasive and rapidly progressive fungal infection. This fungal infection can be fatal in humans if not diagnosed in a timely manner or treated aggressively. In 1885, Paltauf named the infection Mycosis mucorina,Reference Paltauf6 which eventually became mucormycosis. It is caused by saprophytic and opportunistic fungi of class Phycomycetes, order Mucorales, family Mucoraceae, and belonging to genera Mucor and Rhizopus.
Despite its low incidence rate, which ranges from 0.005 to 1.7 per million population, there has been a sudden rise in the number of mucormycosis cases recently, associated with the ongoing coronavirus pandemic.Reference Yin, Wang, Tang, Zhang and Wang4
Rhino-orbito-cerebral mucormycosis usually presents with facial pain, headache, eye swelling, facial numbness, palatal ulcer, blurry vision, fever, malaise and generalised pain. The clinical hallmark of mucormycosis is vascular invasion, resulting in thrombosis and tissue infarction or necrosis. An inflammatory reaction is caused by fungal hyphae infestation on endothelia tissues. This leads to the formation of a thrombus, which enlarges in size and eventually compromises blood supply of the tissues, ultimately causing ischaemic necrosis. The organism tends to spread intracranially along the nerves, cribriform plate and ophthalmic artery, resulting in softening, necrosis and infarction of the brain as a result of vascular invasion.
In typical rhino-orbito-cerebral mucormycosis cases, direct invasion or haematogenous spread of infection is usual, and perineural spread of disease is quite unusual, as reported by Sravani et al.; these authors found perineural invasion in 15 out of 30 tissue biopsies.Reference Sravani, Uppin, Uppin and Sundaram7 The first description of perineural invasion identified using contrast-enhanced MRI appeared in radiology literature in 2001.Reference Yang, Cao, Qin, Wang, Cheng and Pan8 In our study, MRI scans of the brain and temporal bone of 6 patients with a cheek abscess showed perineural spread along the maxillary nerve, and hyperintensities in the Meckel's cave area. In a retrospective review of 20 patients with zygomycosis infection, Frater et al. found prominent perineural invasion in 9 of the 10 biopsies in which peripheral nerves were present.Reference Frater, Hall and Procop9
In cases of cheek abscess, we are of the opinion that perineural invasion is the main route of viral spread. From the pterygopalatine fossa, the virus invades the infra-orbital nerve, and reaches the cheek via the infra-orbital canal where it causes thrombosis, tissue infarction and necrosis. This is followed by secondary infection mainly by pseudomonas owing to poor immunity in these patients, leading to the formation of abscess. This is in line with the intra-operative findings of involvement of the infra-orbital nerve and vessels at the infra-orbital foramen on the anterior wall of the maxilla (Figure 5).
Intra-operative picture of a patient showing involvement of the infra-orbital nerve and vessels at infra-orbital foramen on the anterior wall of the maxilla, causing avascular necrosis of the cheek soft tissue and therefore secondary bacterial infection.
The frequency of facial nerve paralysis in conjunction with rhino-orbito-cerebral mucormycosis is 11 per cent. Few case studies have reported facial nerve palsy as a presentation of rhino-orbito-cerebral mucormycosis.Reference Rajeshwari and Gangadhara10,Reference Bakshi11 Mehta et al. conducted a study on 196 patients with coronavirus-associated mucormycosis and found that 17 had facial palsy.Reference Mehta, Nagarkar, Ksbs, Ty, Arora and Aggarwal12 In our study, 34 patients had facial palsy. Although the pathophysiology for facial nerve paralysis is not known, some reports of rhino-orbito-cerebral mucormycosis indicate that the infection can reach from the pterygopalatine fossa to the inferior orbital fissure, orbital apex and infratemporal fossa.Reference Ferguson13 One hypothesis for facial nerve palsy in coronavirus-associated mucormycosis cases is that the pathology of resistance arteries in diabetics with SARS-CoV-2 infection flares up and these diseased small vessels, with decreased lumens, thicker walls and increased oxidative stress, lead to events that alter blood flow supply to nerves, causing facial nerve ischaemia and therefore palsy.Reference Pecket and Schattner14,Reference Galán and Jiménez-Altayó15 Another theory concerns the spread of mucormycosis to the middle ear via the Eustachian tube that therefore involves the facial nerve.Reference Mohebbi, Jahandideh and Harandi16 This latter theory is not supported by our study, as none of the patients had an abnormality around the Eustachian tube on diagnostic nasal endoscopy.
• During the second coronavirus wave in India, many patients attended ENT with rhino-orbital-cerebral mucormycosis symptoms
• This retrospective study of 400 patients reports on those with coronavirus-associated mucormycosis
• Unusual rhino-orbital-cerebral mucormycosis presentations included facial palsy, cheek abscess, gum ulcers and nasal myiasis
• Most mucormycosis patients had a history of coronavirus; the unusual presentations raise concerns amid the ongoing pandemic
• All patients with such symptoms following coronavirus infection should be evaluated for rhino-orbito-cerebral mucormycosis
Myiasis, an infection of tissues or organs caused by fly larvae, was found in two patients with extensively disseminated rhino-orbito-cerebral mucormycosis. These patients had a history of self-neglect, along with uncontrolled diabetes, who were secondarily infested by maggots. These mucormycosis patients, due to uncontrolled diabetes, developed secondary bacterial infection and foul-smelling nasal discharge that attracted the flies. The female flies deposit their eggs in the wound and these hatch into larvae within 8–24 hours. The nasal cavity provides a favourable environment for the development of larvae, which subsequently cause extensive destruction of the surrounding tissues, resulting in pain.Reference Manjunath and Pinto17 Atypical presentation with maggots is rare; to the best of our knowledge, concomitant involvement of mucormycosis and nasal myiasis in patients with uncontrolled diabetes has been documented in just a few case reports.Reference Pathak, Saxena, Awasthi, Gaur and Singh18
Intracranial involvement of mucormycosis involves the growth of hyphae in arterial lumen with direct endothelial injury.Reference Thajeb, Thajeb and Dai19 This mucormycosis-associated vasculopathy in combination with pre-existing diabetic vasculopathy increases the risk of intracerebral infarction and acute ischaemic stroke. Cerebral mucormycosis is often difficult to diagnose. It usually involves the internal carotid artery and/or large intracranial arteries, following a massive cerebral infarct, quickly impairing the clinical picture. However, involvement of the cerebellar arteries secondary to the basilar artery is rare. In our study, one patient developed cerebellar symptoms along with rhino-orbito-cerebral mucormycosis.
Conclusion
Mucormycosis is a severe, emergent and fatal infection requiring multidisciplinary management. It is a disease with various presentations. Coronavirus-associated mucormycosis has added unusual presentations to the existing list of manifestations. In these cases of rhino-orbito-cerebral mucormycosis, the main factor for patient survival is early diagnosis, followed by immediate surgical debridement and antifungal therapy. Thus, it is extremely pertinent that patients who develop unusual presentations after contracting SARS-CoV-2, in the form of facial palsy, cheek abscess, nasal myiasis, cerebral or cerebellar infarct, are evaluated for rhino-orbito-cerebral mucormycosis.
Competing interests
None declared
