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Mucormycosis; Mucorales; Covid- 19 ROCM; Rhinoorbito- cerebral

Mucormycosis, also known as black fungus, is a serious fungal infection, usually in people with reduced ability to fight infections. It is formerly called Zygomycosis. This type of Fungi belongs to the class Zygomycetes and order Mucorales [1]. It most commonly infects the nose, sinuses, eye and brain resulting in a runny nose, one sided facial swelling and pain, headache, fever, blurred vision, swollen and bulging eye, and tissue death. Other forms of disease may infect the lungs, stomach and intestines, and skin. First case description was reported by Paultiff A in 1885 in a paper tittle “Mycosis Mucorina” [2]. Mucormycotina are the common saprobes originating from the rotten matter or soil. Mucormycosis was increasingly seen among immune compromised patient. Worldwide occurrence along with the possibility of seasonal variation of Mucorales infection has been reported [3]. The principal risk factors involved in Mucormycosis cases are uncontrolled diabetes and diabetic ketoacidosis, prolonged steroid therapy, neutropenia, haematological malignancies. There are many types of Mucormycosis present in humans as Rhino-orbital- cerebral, Pulmonary, Gastrointestinal, Renal, Disseminated, and Cutaneous. Among all, Rhino-orbital-cerebral (ROCM) is the most common type and has a characteristic method of spread. It is highly invasive and high rates of morbidity and mortality [4]. In ROCM infection begins from Paranasal sinuses affect orbit, nose and extension to brain also due to subsequent inhalation of spores. Medical Imaging of Mucormycosis involved water’s view of Para Nasal Sinuses, Contrast Enhanced MRI and Computed Tomography scan. Treatment of Mucormycosis involves a combination of surgical debridement of the affected tissues and antifungal therapy after histopathological confirmation.

Epidemiology

Causative fungi are highly dependent on geo-graphical location. Apophysomyces variabilis has its highest prevalence in Asia and Lichtheimia spp. in Europe [5]. It is the third most common serious fungal infection to infect people, after aspergillosis and candidiasis.

Diabetes is the main underlying disease in low and middle-income countries, whereas, leukaemia’s and organ transplantation are the more common underlying problems in developed countries. As new immunomodulation drugs and diagnostic tests are developed, the statistics for mucormycosis have been changing [6]. In addition, the figures change as new genera and species are identified, and new risk factors are reported such as tuberculosis and kidney diseases.

Most of the data regarding the epidemiology of mucormycosis originate from case reports and case series. The first extensive review of the literature was made by Rodent et al. in 2005 [7]. The analysis comprised 929 cases published from 1940 to 2003, providing useful information about the disease, but it also included cases of entomophthoramycosis. More recently, Jeong et al. analysed 851 cases published from 2000 to 2017. In this study, the review was undertaken and reported using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines and it included only cases caused by Mucorales [8]. Other relatively large case series were collected either on a national level or in patients with selected underlying diseases, for example, hematopoietic stem cell transplantation [9]. Registries are another source of valuable information, despite their inherent limitations.

Aims and Objectives

• To observe the patient characteristics and Covid-19 status and Imaging features.

• To find out MRI imaging Profile of ROCM.

The present study was a retrospective observational study performed in a rural Medical Institute of western U.P. and done with 30 cases of suspected Covid-19 Mucormycosis (ROCM) over a period of two months attending the Department of Radiology of Uttar Pradesh University of Medical Sciences for MR Imaging. Among these 22 were males and 08 females. The demographic data regarding the patient’s characteristics and Covid-19 status was obtained from the requisition form and medical records. The study population was selected on the basis of Inclusion and Exclusion criteria given below. Final diagnosis of Mucormycosis was confirmed by histopathological examination. Informed written consent was obtained and the study was cleared by Ethical committee of the Institute. All these clinically suspected patients of ROCM were imaged by MRI Philips Achieva Nova 1.5T for MR imaging.

MR-Imaging Parameters

Routine MRI Sequence T1- and T2-weighted, FLAIR sequence and also using spin echo sequences, and T1 ,T2 and STIR images in multiple planes followed by contrast enhanced 3 planes T1 weighted FAT saturated images and Multiplanar imaging were performed in all the patients. For all cases, contrast gadolinium study was performed on 1.5 Tesla scanner Philips Achieva Nova using 8 channel head coil with TR 1000-2000 ms TE 90-130 ms for T2W and for T1W TR 300-800ms TE 10-15ms with flip angle 90°C. Post contrast fat saturated sequences also performed in all cases. MR examination of PNS and Nasal cavity was done in supine position with dedicated head coil and Brain should be included when extension suspected or when orbital/skull base involvement was present

Inclusion Criteria

• Only patients with positive findings of Mucormycosis were included.

• Taking complete history of all suspected patients.

• MRI of Brain/PNS/Orbit/Nose using 1.5T MR scanner, with using Gadolinium based contrast media.

Exclusion Criteria

• Patients having history of Claustrophobia were excluded in this study.

• Patients having cardiac pacemaker, aneurysm clip, prosthesis and any metallic foreign body in situ were excluded.

• Cases where MRI scanning not possible due to other conditions.

The present study included total 30 patients in which 22 males and 8 females with age ranging from 35 to 62 years. All patients have history of Covid-19 infection and underwent treatment in designated Covid hospital as per standard protocol. After turning Covid negative on RTPCR and discharged from Covid hospital. These patients were admitted in post Covid ward of our hospital. All patients had history of Diabetes mellitus, taken steroid during Covid treatment and of oxygen therapy (Table 1).

Table 1: Patients Demographics (N =30, 100%).

The patients presented with Proptosis, periorbital swelling, nasal stiffness with blackish discharge from the nostril and other associated features. The clinical features included rhino-orbito-cerebral mucormycosis in all patients.

All Patients with rhino-orbital-cerebral Mucormycosis, 19 patients presented with fever, headache, acute sinusitis and periorbital swelling. 08 patients presented with nasal necrosis in addition and 03 patients presented in addition with decreased vision (Table 2).

Table 2: Clinical Features of Patients.

All patients with rhino-orbital-cerebral form of Mucormycosis go for Gadolinium based contrast MRI at 1.5.Tesla Philips Achieve Nova machine. Imaging showed anatomical involvement of maxillary sinus, orbit, ethmoid cells and nasal cavity in 22 patients. 08 patients in addition to cavernous sinus and sphenoid sinus and extension to frontal lobe also (Figure 1).

Figure 1: Turbinate Sign.

Soft tissue infiltration of peri-antral fat planes premaxillary and retro maxillary fat planes seen best on Fat Suppressed Sequences like T2FS, STIR or T1 Post Gadolinium Fat Suppressed. The lesions are intermediate to hypo intense on T2 weighted sequences. However Hyper intense signal may also be seen. Lack of contrast enhancement is highly suggestive of tissue necrosis and is a sign of angioinvasive fungal sinusitis “Black Turbinate Sign”. Homogenous and heterogeneous contrast enhancement may also be seen. In case of orbital extension MRI finding suggestive of Preseptal and eyelid thickening seen as high signal on T2FS/STIR Sequences and edema, thickening of extra ocular muscles seen on post GD enhancement (Figure 2).

Figure 2: Guitar pick sign.

Involvement of Optic nerve. DWI restriction also occurs due to nerve infarction. The thickening of the extra ocular muscles, fat infiltration and edema raise the intra orbital pressure, compression and distortion of globe called “guitar pick sign”. In case of cerebral extension multifocal hyper intense areas indicating diffuse parenchymal involvement and also seen temporal lobe abscess were also seen.

Amongst the diabetic patients, poorly controlled type II diabetes is the most common risk factor for mucormycosis, being involved in nearly 44-88% of the cases mainly from the north and south India, with nearly half of them exhibiting ketoacidosis [10,11]. In our study all the patients were of also type II Diabetes mellitus diagnosed and being treated at least more than one year. Hence it correlates with ROCM observed in other studies.

Several factors relate the unique predisposition of diabetic patients to mucormycosis. Firstly, diabetes and ketoacidosis render the phagocytic cells dysfunctional. Both the neutrophils and macrophages exhibit an impaired chemo taxis and defective killing by both oxidative and Non-oxidative pathways under such conditions, although the precise mechanisms mediating these remain to be elucidated [12].

Rhino-Orbito-Cerebral Mucormycosis (ROCM) is the most common form, and it is usually seen in diabetic ketoacidosis or poorly controlled diabetes mellitus. A study from India has estimated that 88% of the patients with ROCM had diabetes mellitus. In susceptible hosts, standard defense mechanisms slow down. For example, in diabetic ketoacidosis, the serum pH is acidic and leads to the dissociation of free iron from sequestering proteins. This release of free iron results in rapid fungal growth. Altered mechanisms of phagocytic defense like neutropenia or functional defects due to corticosteroids or hyperglycaemia and acidosis due to diabetic ketoacidosis

Allow proliferation of the fungus. Eventually, adherence to and damage of the endothelial cells caused by the fungus allows fungal angioinvasion and vessel thrombosis leading to subsequent tissue necrosis and dissemination of the fungal infection.

Angioinvasion with infarction is the hallmark of invasive mucormycosis [13]. The critical vessels in the vicinity of the disease, such as ophthalmic artery, sphenopalatine artery were often found to be completely thrombosis with scanty bleeding intra-operatively .The resultant infarction contributes to the typical clinical findings of vision loss, pre-maxillary, peri-orbital soft tissue involvement, sinonasal mucosal discolouration and necrosis of the underlying

Bone. Early diagnosis is the key. High degree of clinical suspicion coupled with appropriate investigations should be done at the earliest in high-risk patients. Nasal endoscopy with biopsy and swabs for KOH mount and fungal culture are the most economical and easily available tools for diagnosis. In addition, MRI of Paranasal sinus with orbit and brain aid in surgical planning and extent of resection.

Rhino-orbito-cerebral mucormycosis (ROCM) is considered as a rare invasive infection caused by class phycomycetes fungi involving immunocompromised patients, arising from nasal and sinus mucosa, spreads rapidly to orbit and brain. Extensive angio-invasion is considered as the main cause leading to vascular thrombosis and tissue necrosis [14]. Vascular involvement is more common cause of high morbidity and mortality, infiltrating cavernous sinus and orbital apex leading to cellulitis of face, loss of vision. Intracranial involvement can cause narrowing of internal carotid artery leading to ischemic infarcts. Meningeal involvement can be seen.

Imaging helps in diagnosis of ROCM to evaluate the extent of disease plays a crucial role in early diagnosis and timely intervention. CT scan demonstrates nodular mucosal thickening with absence of fluid levels and Hyper dense content leading to erosions of bony sinus walls.

MRI provides better evaluation of intracranial and soft tissue involvement, skull base invasion, perineural spread and vascular obstruction. MRI demonstrates variable signal intensity depending on the sinus contents, due to iron and manganese in the fungal elements. MRI contrast study shows invasion of orbital soft tissues, skull base infiltration, per neural spread, intracranial complications and vascular obstruction involving internal carotid artery.T2 slow flow can suggest internal carotid artery invasion by the fungus [15]. Perineural spread is most commonly seen in head and neck malignancies more often seen in adenoid cystic carcinoma. Fungal hyphae tend to involve nerves and vessel wall leading to perineural spread and cavernous sinus invasion. In our case, perineural spread is seen along infraorbital nerve extending from floor of orbit into cavernous sinus and foramen rotundum noted. The patient developed symptoms after 20 days of admission for COVID-19, during which he was on broad-spectrum antibiotics and steroids and this is considered as an aggravating factor in our case, COVID-19 may lead to secondary infection primarily causing immune dysregulation. Clinicians should be aware of secondary invasive fungal infections as a complication in COVID-19 patients.

ROCM is considered as an emerging rapidly disseminating fungal infection when associated with immunocompromised conditions and carry fatal prognosis with cavernous sinus involvement. Hence, radiologists should evaluate the extension and involvement of invasive fungal sinusitis which can lead to early diagnosis and timely management with antifungal agents and surgical debridement further helps to reduce morbidity and mortality.

COVID-19 patients with high-risk features should be kept under surveillance. A slightest degree of suspicion must prompt early diagnosis and initiation of treatment. Mucormycosis has been long recognized as a rare, fulminant, life-threatening disease of fungal Etiology, belonging to Mucorales. It may present in many forms which include rhino-orbito-cerebral, pulmonary, cutaneous, gastrointestinal or disseminated disease. In India, the estimated number of cases diagnosed with mucormycosis is 0.14 cases per 1000 population. With the onset of COVID-19 pandemic, clinicians have seen an alarming rise in the number of cases of ROCM in post-infectious or active COVID-19 affected patients, which is manifold than the usual reported incidence of the disease in the pre-COVID setting. Research is needed for better prevention and management of infections related to COVID-19 Patients.