Abstract
Background:
Mucormycosis, an opportunistic fungal infection, has surged during the COVID-19 pandemic, especially with the delta variant, due to factors like steroid use and diabetes. This study examines radiological features through computed tomography (CT) and magnetic resonance imaging (MRI) findings in COVID-19-associated mucormycosis (CAM) patients.
Materials and Methods:
This single-center cross-sectional study conducted between March 2021 and March 2022 at a tertiary care center involved COVID-19 patients over 18 diagnosed with mucormycosis through pathological and endoscopic findings. Paranasal CT scans and brain, sinus, and orbit MRIs were performed to assess various involvements, including sinus, retroantral fat, intraorbital, and bone status, as well as cavernous sinus, internal carotid artery, superior ophthalmic vein, superior ophthalmic fissure, and intraparenchymal brain involvement. Demographic and clinical data, including medical history and laboratory findings, were collected. Statistical analysis using independent t-tests, Chi-squared tests, Fisher’s exact test, and logistic regression was conducted with a significance threshold of P < 0.05.
Results:
This study of 54 CAM patients in Isfahan, Iran, found a high prevalence of diabetes (68.5%) and a 24.1% mortality rate. Imaging revealed significant sinonasal (87%), brain (35.2%), and intraorbital (60%) involvement. Chest CT scans showed predominant ground glass opacity (96.3%) and lower-zone lung involvement.
Conclusion:
This cross-sectional study underscores the critical role of imaging in diagnosing and managing CAM. Paranasal CT and MRI scans revealed extensive sinonasal, brain, and intraorbital involvement, essential for guiding surgical interventions.
Keywords: Brain MRI, COVID-19, CT scan, imaging, mucormycosis
INTRODUCTION
Mucormycosis is a fungal opportunistic infection that leads to infarction and necrosis of tissues in various organs, including the central nervous system (CNS), orbit, paranasal sinuses, lungs, kidneys, gastrointestinal system, and skin.[1] During the COVID-19 pandemic, there has been a significant increase in cases of mucormycosis, leading to defining a new term named COVID-19-associated mucormycosis (CAM), particularly during the emergence of the delta variant. This virus variant is more infectious and virulent, compromising the immune system.[2] The use of systemic steroids in severe cases, broad-spectrum antibiotics, combined with underlying conditions like diabetes, has contributed to the rise of mucormycosis cases, highlighting immunosuppression as a key factor in its prevalence.[3] With CAM mortality rates reaching 29%,[4] precise diagnosis and treatment are necessary. Imaging is a crucial part of our workups not only for the diagnosis of suspected cases but also for delineating the location, size, and extension of involvement, which could help the following surgical interventions. Several studies have shown some radiological features of CAM.[5,6] Our cross-sectional study aims to provide more data about CAM radiological features by reporting the computed tomography (CT) scan and magnetic resonance imaging (MRI) findings.
MATERIALS AND METHODS
Study design and subjects
This single-center cross-sectional study was conducted between March 2021 and March 2022 at the largest tertiary care center in Isfahan, Iran, for COVID-19 patients. The study included patients with COVID-19 who were diagnosed with mucormycosis infection and met the following criteria: (i) age over 18, (ii) confirmed mucormycosis infection diagnosis through pathological and endoscopic findings, (iii) confirmed COVID-19 diagnosis via polymerase chain reaction (PCR) test, and (iv) provided informed consent to participate in the study. Demographic and clinical data of patients, including COVID-19 to the mucormycosis infection interval, hospitalization duration, past medical history of diabetes mellitus, diabetic ketoacidosis, hypertension, cerebrovascular accident, hyperlipidemia, heart failure, ischemic heart disease, and laboratory findings of blood sugar, were reported.
Imaging protocols and variables
A paranasal CT scan without contrast was performed using the paranasal sinus (PNS) protocol (125 KV, 80–160 mAs, field of view 140 mm, and slice thickness 0.625 mm with scan extension from the hard palate to above the end of frontal sinuses) on Philips Computed Tomography machines. The following items were evaluated and interpreted: (i) sinus cavity, (ii) retroantral fat, (iii) intraorbital involvement, and (iv) bone status.
Brain, sinuses, and orbit MRI with contrast were performed using the Philips Ingenia 1.5 T MRI. DWI (diffusion-weighted imaging) at a b-value of 0 and 1000 was conducted for the MRI of the brain, sinus, and orbit, and short tau inversion recovery (STIR) sequences were acquired for evaluation of the cavernous sinus and orbit. The following items were checked and recorded for each patient:
(i) Description of involved sinuses, nasal cavity, retroantral fat, and associated enhancement patterns. (ii) Evaluation of cavernous sinus involvement and associated features, including the side of involvement, presence of lateral bulging of the sinus wall, signal intensity on spin echo sequence, post-contrast filling defects, and dural enhancement of the lateral wall. (iii) Evaluation of internal carotid artery (ICA) involvement and associated features, including the side of involvement, the diameter of ICA on the affected side, and signal intensity on spin echo sequence. (iv) Evaluation of superior ophthalmic vein involvement on the affected and unaffected sides and associated features, including diameter and signal intensity on spin echo sequence. (v) Evaluation of the status of the superior ophthalmic fissure. (vi) Description of intraparenchymal brain involvement for the following features: the presence of infarction, the pattern of infarction (internal watershed, external watershed, or nonwatershed), unilateral or bilateral involvement, and the presence of intraparenchymal abscess or cerebritis and their associated locations [Figures 1 and 2].
Figure 1.
62 years old male. (a) Axial CT scan of paranasal sinus soft tissue window reveals mucosal thickening of left maxillary sinus along with increased density of retroantral fat (red arrow). compare with the contralateral side. (b) Axial fat-saturated T2 W sequence at the level of maxillary sinus shows increased signal intensity in retro antral fat and parapharyngeal space. (c) Axial fat-saturated T2 W sequence shows opacification of left side mastoid air cells with intraorbital fat involvement. notice to normal intraorbital fat at the right side (green arrow). There is also vasogenic edema in the anterior aspect of the left temporal lobe. (d) Coronal contrast-enhanced image shows asymmetric enhancement and lateral bulging of the left cavernous sinus indicative of cavernous sinus thrombosis. Also ring enhancing lesion compatible with abscess formation in the anterior aspect of the left temporal lobe is discerned
Figure 2.
A 52-year-old male, known case of mucormycosis debriding paranasal sinuses, presented with right-side hemiparesis and cavernous sinus thrombosis. (a) Axial fat-suppressed T2w image; there is increased signal intensity of the petrosal portion of the left ICA (red arrow). (b) Axial fat-suppressed T2w image at the level of cavernous sinus notice to diameter of left ICA (green circle), which is decreased compared to contralateral size. (c, d) In DWI and ADC map images, there are multifocal areas of diffusion restriction in the left centrum semiovale indicative of acute internal watershed infarction
The chest CT scan of patients during COVID-19 were evaluated regarding the pattern (ground glass opacity or consolidation), distribution of lung involvement, and severity score.
Statistical analysis
Data analysis included the independent t-test, Chi-squared test, and, when necessary, Fisher’s exact test. Logistic regression analysis was also conducted. A P value of < 0.05 was considered as significant. All statistical analyses were performed using SPSS version 20 (IBM Corp., IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp).
RESULTS
In this study, we included 54 CAM patients with a male predominance of 68.5%. Sinonasal and brain MRI scans were performed for 48 patients, and chest CT scans were conducted for 30 patients. The mean age of the patients was 56.25 ± 13.22 years. The mean COVID-19 to mucormycosis infection interval was 18.61 ± 15.22 days, following a mean hospitalization duration of 33.48 ± 11.85 days with a death rate of 24.1%. In terms of past medical history, diabetes mellitus, diabetic ketoacidosis, hypertension, cerebrovascular accident, hyperlipidemia, heart failure, and ischemic heart disease were observed in 68.5%, 1.9%, 56.6%, 7.5%, 11.3%, 1.9%, and 18.5%, respectively. Mean blood sugar and CRP were 242.85 mg/dl (SD = 122.30) and 47.97 mg/dl (SD = 37.48), respectively [Table 1].
Table 1.
Basic demographic and clinical data
| Variable | Value (Mean ± SD or n, %) |
|---|---|
| Age (yrs) | 56.25±13.22 (min:17, max:90) |
| Sex | |
| Male | 37 (68.5%) |
| Female | 17 (31.5%) |
| COVID-19 to mucormycosis interval (day) | 18.61±15.22 (min:0, max:80) |
| Sinonasal and brain MRI | 48 (88.9%) |
| Death in hospital | 13 (24.1%) |
| Hospitalization duration (day) | 33.48±11.85 (min:17, max:66) |
| Diabetes mellitus | 37 (68.5%) |
| Diabetic ketoacidosis | 1 (1.9%) |
| Hypertension | 23 (43.4%) |
| Previous cerebral vascular accident | 4 (7.5%) |
| Hyperlipidemia | 6 (11.3%) |
| Blood sugar | 242.85±122.30 (min:50, max:576) |
| C-reactive protein | 47.97±37.48 (min:1.00, max:95.00) |
As mentioned in Table 2, maxillary sinus involvement was observed in 47 cases (87%), while ethmoid sinus involvement was seen in 43 patients (81%). The prevalence of retroantral fat involvement was 76.6%. Cavernous sinus involvement was detected in 10 patients (20.8%), while 38 patients (79.2%) showed no involvement. The mean (SD) size of the cavernous sinus was 7.99 (2.26) mm and 5.33 (0.85) mm on the affected and unaffected sides, respectively. In patients with cavernous sinus involvement, the size difference between affected and unaffected sides was not statistically significant (P value > 0.05) [Table 3].
Table 2.
Imaging findings of patients
| Variable | Value (Mean ± SD or n, %) |
|---|---|
| Stroke manifestation | 19 (35.2%) |
| Cavernous sinus involvement | 10 (20.8) |
| ICA involvement | 11 (22.9%) |
| SOV involvement | 8 (16.7%) |
| Intraparenchymal brain abscess | 5 (9.4%) |
| Intraparenchymal brain abscess location | Temporal 2 (40%) |
| Frontal 1 (20%) | |
| Cerebellum 2 (40%) | |
| Intraorbital involvement | 27 (60%) |
| Propotosis | 16 (34%) |
| Ethmoid sinus involvement | 43 (81.1%) |
| Sphenoid sinus involvement | 38 (70.4%) |
| Maxillary sinus involvement | 47 (87%) |
| Frontal sinus involvement | 24 (44.4%) |
| Nasal cavity involvement | 35 (74.5%) |
| Sinus enhancement | 17 (38.6%) |
| Retroantral fat involvement | 36 (76.6%) |
| Superior ophthalmic fissure involvement | 9 (25%) |
| Lung ground glass opacity | 26 (96.3%) |
| Lung consolidation | 15 (55.6%) |
| Lung reticulation | 11 (40.7%) |
| Craniocaudal distribution | Upper 3 (11.1%) |
| Lower 15 (55.6%) | |
| None 9 (33.3%) | |
| Axial distribution | Central 0 |
| Peripheral 22 (81.5%) | |
| None 5 (18.5%) | |
| Unilateral or bilateral | Unilateral 2 (7.4%) |
| Bilateral 25 (92.6%) | |
| Diffusion of pulmonary lesions | Focal 2 (7.4%) |
| Multifocal 24 (88.9%) | |
| Diffuse 1 (3.7%) | |
| Chest CT severity score | 9.00±5.98 (min:0,max=25) |
| RUL score | 1.40±1.24 (min:0,max:5) |
| RML score | 1.40±1.24 (min:0,max:5) |
| RLL score | 2.23±1.47 (min:0,max:5) |
| LUL score | 1.66 ±1.39 (min:0,max:5) |
| LLL score | 2.30±1.51 (min:0,max:5) |
ICA=internal carotid artery, SOV=superior ophthalmic vein, RUL=right upper lobe, RML=right middle lobe, RLL=right lower lobe, LUL=left upper lobe, LLL=left lower lobe
Table 3.
Comparing the size difference between affected and unaffected sides
| Involvement size | Noninvolvement size | P | |
|---|---|---|---|
| Sinus cavernous (n=10) | 7.99±2.26 | 5.33±0.85 | 0.057 |
| Internal carotid artery (n=11) | 1.77±0.93 | 3.65±0.48 | <0.001 |
| Superior ophthalmic vein (n=8) | 1.92±0.69 | 1.22±0.32 | 0.049 |
Intraorbital involvement was observed in 27 patients (60%). Proptosis was evident in 16 patients (34%), while it was not revealed in 31 (66%). Superior ophthalmic fissure involvement was observed in 9 patients, while 27 showed no such involvement. Among the nine patients with superior ophthalmic fissure involvement, seven also had cavernous sinus involvement (77.8%), whereas among the 27 patients without superior ophthalmic fissure involvement, only one patient (3.7%) had cavernous sinus involvement [Table 2]. Patients with superior ophthalmic fissure involvement had a 91-fold higher chance of having cavernous sinus involvement than those without (odds ratio: 91, P value < 0.001). Superior ophthalmic vein involvement was revealed in 8 patients (16.7%) [Table 2]. The mean (SD) size of the superior ophthalmic vein was 1.92 (0.69) mm and 1.22 (0.32) mm in the affected and unaffected sides, respectively. In patients with superior ophthalmic vein involvement, the difference in size between the two sides (affected and unaffected) was statistically significant (P value < 0.05) [Table 3].
In Brain MRI, stroke manifestations were revealed in 19 patients (35.2%). Five patients (9.4%) exhibited intraparenchymal abscesses located in the cerebellum (2 patients), temporal lobe (2 patients), and frontal lobe (1 patient). Internal carotid artery involvement was observed in 11 patients (22.9%), while 37 patients (77.1%) did not reveal any internal carotid artery involvement [Table 2]. The mean (SD) size of the internal carotid artery was 1.77 (0.93) mm and 3.65 (0.48) mm in the affected and unaffected sides, respectively. In patients with internal carotid artery involvement, the size difference between the affected and unaffected sides was statistically significant (P value < 0.001) [Table 3].
In the chest CT scan, four patients (10%) did not reveal any involvements, including ground glass opacity, consolidation, or reticulation. Ground glass opacity was seen in 26 patients (96.3%), 15 patients (55.6%) revealed consolidation, and reticulation was evident in 11 patients (40.7%). 15 patients (55.66%) had lower-zone dominant involvement, 3 (11.11%) patients had upper-zone dominant involvement, and nine patients (33.3%) were without any zone-dominant involvement [Table 2]. 22 (81.5%) patients showed peripheral involvement of the lung. Furthermore, 25 patients (92.6%) had bilateral lung involvement, while only two patients (7.4%) had unilateral lung involvement. Multifocal, focal, and diffuse involvement was evident in 24 (88.9%), 2 (7.4%), and 1 (3.7%) patients, respectively. In severity score evaluation in chest CT scan, the mean (SD) lung involvement score was 9 (5.98), and the two highest values of involvement score in lung lobes were 2.3 (1.51) and 2.23 (1.47) in the left lower lobe and right lower lobe, respectively [Table 2].
DISCUSSION
The mean age of the patients was 56.25 years (SD = 13.22), which was in line with the current idea that patients older than 50 years are more at risk of CAM.[3,7] The male predominance of patients in our study may be due to a higher risk of achieving severe COVID-19 in men and also more risk of mucormycosis spores exposure.[8,9] Diabetes mellitus was the most prevalent comorbidity in our study, observed in 68.5% of patients, and hypertension, as the second most prevalent, was seen in 56.5% of patients. The hypertension rate in our study was higher in comparison with a similar study conducted by Omranzadeh et al.,[5] but the prevalence of diabetes mellitus was in the range that they reported in their literature review. Hypertension could be associated with more severe COVID-19,[10] leading to high-dose treatment and subsequent immunosuppression. The mortality rate of CAM patients in our study was 24.1%, which was slightly lower than the expected rate of 29%, as reported by Watanabe et al.[4] in a systematic review and meta-analysis.
The gold standard for diagnosing mucormycosis is the pathology assessment, but the radiological evaluation is crucial for showing involvement extension, surgical planning, and reducing unnecessary interventions for diagnosis.[11,12] While a CT scan with PNS protocol is highly efficient for detecting hard tissue involvement, an MRI with contrast provides highly valued information about soft tissue status.
In our study, maxillary and ethmoid sinus involvement was seen in 87% and 81% of CAM patients, respectively. Frontal and sphenoid sinus involvement was less common in cases in line with previous studies.[5] While the prevalence of proptosis (35%) was less than in the previous studies, intraorbital (60%) and retroantral fat (76.6%) involvement prevalence was in the range of previous reports.[5] Notably, superior ophthalmic fissure involvement, seen in 16.6%, had a great correlation with cavernous sinus involvement, with a 91-fold higher chance of having cavernous sinus involvement than those without. In the Nair et al. study published in 2024, all CAM cases with cavernous sinus thrombosis had orbital apex involvement.[13] These findings align with the intracranial spread of mucormycosis following orbit apex and cavernous sinus involvement.[14] Stroke manifestation was evident in 35.2% of patients. Also, sinus cavernous and ICA involvement were evident in 20.8% and 22.9% of patients. Septic thrombophlebitis due to cavernous sinus involvement and subsequent ICA narrowing may cause stroke manifestation in CAM patients.[5,15,16]
CONCLUSION
This cross-sectional study underscores the critical role of imaging in diagnosing and managing CAM. Paranasal CT and MRI scans revealed extensive sinonasal, brain, and intraorbital involvement, essential for guiding surgical interventions. The study emphasizes the need for early detection and comprehensive imaging to diagnose CAM patients better.
Ethics approval and consent to participate
This study adhered to the tenets of the Declaration of Helsinki. The ethics committee of Isfahan University of Medical Sciences approved the study. Written informed consent to participate was obtained from all patients.
Publication consent
The authors express their gratitude to the patients for allowing the publication.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
None.
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