Keywords
mucormycosis - aspergillosis - fungal sinusitis - invasive sinusitis - COVID-19
Introduction
Invasive fungal sinusitis is a rare infection of the nose and paranasal sinuses. It is classified into three groups—acute fulminant invasive sinusitis (AFIS), chronic granulomatous invasive fungal sinusitis, and chronic nongranulomatous invasive fungal sinusitis (CIFS).[1] Since the sinonasal cavity is closely related to the skull base and orbit, there is disease extension in these regions.[2] Over the years, it was evident that the most common pathogen causing AFIS was Mucorales species (rhino-oribitocerebral mucormycosis [ROCM]). AFIS has a poor prognosis due to the underlying immunocompromised state.[3] Chronic invasive sinusitis, on the other hand, has a long course and is encountered in immunocompetent individuals.
The Indian subcontinent saw an unprecedented rise in invasive fungal rhinosinusitis owing to the coronavirus disease 2019 (COVID-19) pandemic.[4] Poor glycemic control, steroid therapy, and virus-induced immunological changes were some factors speculated to influence the pathogenesis.[5] The most common pathogen encountered was the Mucorales species, followed by Aspergillus. Aspergillus species causes chronic invasive fungal sinusitis more commonly than acute disease.[6] It is frequently seen in the Indian subcontinent and African countries where a hot climate and fungal spores are ubiquitous. The incidence is relatively low, and diagnosis requires a high suspicion, especially in the early stage due to nonspecific symptoms. Diagnosis is often made when a patient presents with complications. In our experience, tissue diagnosis is difficult, particularly in cases limited to the orbital apex, pterygopalatine fossa (PPF), or the infratemporal fossa. Sometimes, even if tissue diagnosis is obtained, it is only occasionally diagnostic of fungal elements, putting the surgeon in a dilemma. Radiological characteristics and biochemical markers such as galactomannan can be used in these cases. Galactomannan is a polysaccharide antigen that exists primarily in the cell walls of Aspergillus species and can be detected using the ELISA test in the serum and body fluids.[7]
Treatment of invasive fungal rhinosinusitis depends mainly on the pathogen and disease course, and the treatment goal is different in acute versus chronic disease. This study evaluates the changing nature of disease course observed with COVID-19-related ROCM and elaborates on the clinical characteristics, prognosis, response to treatment, and management strategies for chronic invasive fungal disease.
Materials and Methods
This was a retrospective study. Medical records were acquired for all patients diagnosed with invasive fungal rhinosinusitis from 2015 to 2022. The institute's ethics committee approval was obtained for this study (IEC code: 2022-150-IP-EXP-50). Informed consent was obtained. The clinical, radiological, and operative notes were reviewed. We included all cases of invasive fungal rhinosinusitis with clinicoradiological and/or intraoperative evidence of anterior and central skull base, orbit, and orbital apex involvement with or without intracranial disease. Patients with a sinonasal-palatal disease without the involvement of the skull base or orbit and patients with incomplete data were excluded from the study.
The skull base was divided into: frontal, anterior ethmoidal, posterior ethmoidal, planum, sella, clival recess, PPF, infratemporal fossa, greater wing of the sphenoid, and temporal bone. Neurovascular components in each of these areas were separately evaluated.
The patients were divided into two groups depending on the fungal species causing the infection (ROCM and Aspergillus). Various risk factors predisposing to invasive fungal rhinosinusitis were analyzed. These were COVID-19 viral infection, oxygen therapy required for COVID-19 viral pneumonia, steroid therapy required for viral pneumonia, and association with diabetes mellitus (DM). Histopathological reports were reviewed to see for the presence of granuloma and chronic inflammatory infiltrate. The galactomannan assay was performed in patients with Aspergillus before initiating the antifungal regimen and every 12 weeks to assess the response to the treatment.
Results
There were 79 patients, of which 65.8% had skull base ROCM, and 34.2% had invasive aspergillosis. In the skull base ROCM group, there were 52 patients, with 33 men and 19 women. Out of this, 88.7% of patients had a history of COVID-19 infection, and 96% had DM. The average duration between the COVID-19 infection and the first symptom of mucormycosis was 25.57 days with 61.53% of patients presenting within a month after turning up COVID-19 positive. The median duration from the onset of symptoms to presentation was 31 (27, 40) days, and 66% of them presented 30 days after the onset of symptoms. Mortality was seen in six (11.53%) patients, of which two died from causes unrelated to ROCM, while the rest had extensive intracranial disease at presentation. The most common symptom at presentation was facial swelling, numbness, and vision loss. Surgery via the endoscopic nasal approach was performed in 76.9% of patients, whereas 21.15% underwent open approach to access the intracranial disease or undergo orbital exenteration or to address the malar skin. Two patients underwent a combined endoscopic endonasal approach with an open approach to the anterior wall of maxilla to address the disease affecting the malar skin. The part of skull base involved in descending order of frequency was the PPF (88.5%), followed by the infratemporal fossa (73.1%), anterior and posterior ethmoidal skull base (fovea) (61.5 and 59.6%, respectively). In comparison, the most common vascular structure was the sphenopalatine artery (75%), and the neural structure was the infraorbital nerve (65.4%) and maxillary division of the trigeminal nerve (53.8%) ([Table 1]). All patients have received antifungal treatment in addition to their surgical debridement. The imaging parameters assessed preoperatively were contrast-enhancement patterns in T1 contrast magnetic resonance imaging (MRI)sequences and sequestral changes of skull base bones on computed tomography (CT). Of all patients, seven had the intracranial extension of disease with intraparenchymal abscess, and four succumbed secondary to the disease. Histopathology reports were reviewed, which revealed that 71% of patients had granuloma with chronic inflammatory infiltrate (p < 0.003). The fungal cultures were positive for Mucorales species in only 32.69% patients.
Table 1
Different neurovascular structures involved in ROCM and aspergillosis
|
Subsites
|
ROCM (%)
|
Aspergillosis (%)
|
|
AEA
|
47.16
|
3.8
|
|
PEA
|
45.28
|
7.69
|
|
SPA
|
75.47
|
11.53
|
|
IMA
|
22.64
|
11.53
|
|
ION
|
64.15
|
53.84
|
|
V3
|
16.98
|
11.53
|
|
V2
|
52.83
|
57.69
|
|
Vidian
|
50.94
|
23.07
|
|
Optic
|
30.18
|
30.76
|
Abbreviation: ROCM, rhino-orbitocerebral mucormycosis; AEA, anterior ethmoidal artery; PEA, posterior ethmoidal artery; SPA, sphenopalatine artery; IMA, internal maxillary artery; ION, infraorbital nerve; V3, mandibular division of trigeminal nerve; V2, maxillary division of trigeminal nerve.
In the invasive aspergillosis group, there was a total of 27 patients, with 12 men and 15 women with a mean age of 41.7 ± 11.8 years. One patient was pregnant (29 weeks' gestation at presentation) and had a history of the holo cranial headache of 3 months duration with imaging suggestive of invasive fungal sphenoid sinusitis. The median time after the onset of symptoms to presentation was 21 weeks (13, 38.4); 25.9% of patients had DM, and only one patient had COVID-19-associated aspergillosis who presented within 28 days after the onset of symptoms. Tissue diagnosis for confirmation of aspergillosis was obtained in 59.25% of patients, and in the rest of the patients, clinicoradiological findings and galactomannan assay were used to support the diagnosis. A similar trend as seen in ROCM was observed, and the most common area involved was the PPF (62.9%) and infratemporal fossa (55.5%), superior orbital fissure (37%), inferior orbital fissure (29.6%), and sella (29.6%) ([Fig. 1]). In 33.3% of the patients, the optic nerve was involved. Orbital involvement was seen in 62.9% of the patients. The intracranial extension was seen in five (18.7%) patients of which one succumbed due to extensive intracranial disease at presentation. All patients were treated with oral voriconazole and responded well to the treatment. Of those patients whose tissue diagnosis was available (16 of 27), 13 showed granuloma and chronic inflammatory infiltrates in tissue analysis.
Fig. 1 Bar graph with standard error showing the involvement of invasive aspergillosis and ROCM at different anatomical locations. AE, anterior ethmoidal skull base; GW, greater wing of sphenoid; IOF, inferior orbital fissure; ITF, infratemporal fossa; PE, posterior ethmoidal skull base; PPF, pterygopalatine fossa; ROCM, rhino-orbitocerebral mucormycosis; SOF, superior orbital fissure.
A multivariate analysis of risk factors such as COVID-19 infection, DM, steroid use, and oxygen supplementation was done. However, only DM and COVID-19 infection were taken into consideration due to interdependent factors. This analysis revealed that the risk of developing ROCM in patients suffering from COVID-19 infection or DM is higher than that of developing Aspergillus invasive fungal rhinosinusitis.
Discussion
Fungal infections of the nose and paranasal sinuses have numerous clinical presentations and pathogenesis ranging from benign conditions such as the fungal ball to fulminant disease. It is considered invasive when there is evidence of infiltration of tissues and neurovascular structures.
ROCM is the most common cause of acute fulminant sinusitis[8] and is commonly seen in immunocompromised patients causing neurovascular complications. Chronic ROCM is a rare disease with prolonged course and less mortality, commonly seen in patients with DM and may be associated with cavernous sinus thrombosis.[9]
[10] Invasive fungal rhinosinusitis secondary to Aspergillus infection is similarly classified into acute and chronic invasive disease depending on disease duration. The incidence of invasive fungal sinusitis has significantly increased in the past two decades with incidence of ROCM rising more than 80 times in the Indian subcontinent.[11]
[12]
[13] With the second wave of COVID-19 infection, India witnessed a tremendous rise in invasive fungal rhinosinusitis particularly ROCM among those infected and recovering from COVID-19 infection.[14] The mean duration of onset of symptoms as described in the literature was 14 ± 7 days.[15]
[16]
[17] In our series, the mean duration of onset of illness was 36.75 ± 20.97 days, with the majority of patients (66%) presenting after 30 days of onset of symptoms making it a predominantly chronic ROCM.[17] Although Aspergillus is known to cause acute fungal rhinosinusitis, our series had only one case of acute disease due to aspergillosis, and the rest of the cases were chronic invasive rhinosinusitis with an indolent course over a period of months with longest duration from disease onset to presentation to hospital of 3 years in one patient. “RED FLAG” signs of invasive fungal rhinosinusitis in ROCM and Aspergillus were unilateral facial swelling, numbness, orbital complications such as proptosis, restricted global movements, and vision loss. It is reported in the literature that most chronic invasive rhinosinusitis patients present with rhinosinusitis features and ophthalmological signs.[18]
[19]
The most common predisposing factor was COVID-19 infection (either in the recent past or ongoing infection) in 90.4% of patients with ROCM (p < 0.005). It was also seen that those patients with active infection had a poorer prognosis than those who presented after recovering from COVID-19 infection.[5] Ninety-eight percent of patients with both the acute and chronic variants of ROCM had DM (p < 0.005) with similar findings encountered in the literature.[10]
[14]
[15]
[16]
[20] In patients with newly diagnosed DM, it was studied that insulin resistance develops secondary to cytokine storm due to the COVID-19 infection, which, combined with steroid therapy, pushes the patient into a severely immunocompromised state predisposing to opportunistic infections.[21] The rampant use of steroids to treat the inflammatory sequelae of COVID-19 infection was an added burden to the already compromised immunity.[22] In our study, 82.7% of the patients had received steroid therapy (oral or injectable) similar to what was observed in the literature.[23] In contrast to ROCM, CIFS due to Aspergillus infection is observed in immunocompetent individuals in both granulomatous and nongranulomatous disease variants.[24]
[25]
Since nasal endoscopy and a nasal swab from microscopy and culture are negative in invasive fungal disease, imaging the nose, orbit, paranasal sinuses, and brain is an integral part of diagnostic workup.[26] CT with contrast is nonspecific in early disease and often not very helpful in differentiating the infection from malignancy. However, it is essential for surgical planning and assessment of bony involvement, often seen in the late course of the disease.[27]
[28] MRI of the nose, paranasal sinuses, orbit, and brain with contrast is more sensitive and aids early diagnosis of invasive fungal rhinosinusitis.[29]
[30] Contrast MRI is iso- to hypointense in all sequences with heterogeneous or nonenhancing diseased tissue.[31]
[32] Extrasinus disease extension into the retroantral fat pad, orbital apex involvement, and meningeal enhancement are some of the findings seen on MRI in both ROCM and Aspergillus infection. Another vital imaging sign seen in ROCM is the “lack of contrast enhancement” of the infected tissues, which suggests ischemic changes in the mucosa and invasion of vessels by the fungi ([Fig. 2]).[33]
Fig. 2 A 58-year-old man with a history of COVID-19 infection presented with headache, nasal discharge, and left-sided facial numbness. Coronal T2W (A) Image showing bilateral ethmoid and left maxillary sinusitis (yellow arrow) with the hypodense area at the level of left anterior cribriform suggestive of necrosis (red arrow). (B) Image showing sphenoid sinusitis with a hypointense left base of the sphenoid, pterygoid, and part of the greater wing of sphenoid suggestive of sequestrum which is surrounded by the heterointense area suggestive of inflammation (yellow arrow). Coronal postcontrast T1W (C) image showing nonenhancing lesion at the level of anterior cribriform plate (red arrow) and (D) sphenoid bone sequestrum with surrounding inflammation (yellow arrow). COVID-19, coronavirus disease 2019; T1W, T1-weighted; T2W, T2-weighted.
In ROCM, the most common anatomical site in descending order of involvement was the PPF, infratemporal fossa, and the anterior and posterior ethmoidal skull base.[33]
[34] In contrast, in Aspergillus infection, ethmoidal fovea is most commonly involved.[19]
[35] This involvement of the anterior and posterior ethmoidal fovea and cribriform often leads to cerebrospinal fluid leak during disease debridement, and preoperative preparation for this complication is necessary. Even if the disease course in acute and chronic infection differs, the spread mechanism remains the same. Both acute and chronic invasive fungal sinusitis due to ROCM and Aspergillus were spread by neurovascular involvement. Thus, one of the early features is vessel thrombosis, with sphenopalatine vessel most commonly involved. Early involvement of the infraorbital nerve and pterygopalatine ganglion is classically seen in ROCM and Aspergillus infection. As seen in our study, the first complaint the patient often presented was facial numbness. The temporal lobe abscess results due to the spread of disease intracranially via the infratemporal fossa into the superior orbital fissure and foramen rotundum.
Histopathological analysis of the tissues helps identify the fungus and assess the physiological response to the disease process. In ROCM, aseptate right-angle branching fungi are seen interspersed with inflammatory cells and necrotic tissue. Angioinvasion is one of the classical features of invasive fungal disease. Factors favoring good survival outcomes in ROCM are fungal load, granuloma, chronic inflammatory infiltrate, and the degree of tissue necrosis.[36] In our series of cases, we had 71% of patients with noncaseating granuloma and chronic infiltrates (p < 0.001) and only one of the seven patients who succumbed showed granuloma. This is consistent with the results from Goel et al and Castillo et al.[36]
[37] In the Aspergillus infection group, tissue samples of 59% were available. Among these, 81.25% of patients had evidence of granuloma and chronic inflammatory infiltrate and were classified as granulomatous invasive sinusitis, and the remaining were classified as chronic invasive nongranulomatous sinusitis.
Another tool for diagnosing Aspergillus infection was using the serum galactomannan assay. The galactomannan assay is an additional marker for the “probable” diagnosis of invasive aspergillosis in patients with malignancies.[38] Its use in the routine diagnosis of invasive aspergillosis is avoided owing to its low sensitivity and high specificity. Still, when there is a high clinical suspicion with radiological features of fungal disease, the galactomannan assay has been proven to be helpful.[39] Galactomannan assay levels can also be tested on tissue samples from the nasal biopsy. It is seen that the combination of histology and galactomannan levels had higher sensitivity than microscopy and culture of the tissues in the diagnosis of CIFS.[40] In our series, we used serum galactomannan assay levels in two ways. First, in cases where it was difficult to obtain tissue samples, but clinicoradiological signs pointed toward invasive aspergillosis, we decided to do a galactomannan assay to support our diagnosis and initiate antifungal treatment ([Fig. 3]). Similarly, if pretreatment values of galactomannan were available, we used them to compare them with the posttreatment values to ascertain their utility in determining treatment duration. This is an ongoing project, and results will be obtained when the number of patients is significantly higher, as there are many dropouts in the current patient series.
Fig. 3 Diagnostic and treatment algorithm for chronic invasive fungal sinusitis secondary to invasive aspergillosis.
Treatment goal of invasive fungal rhinosinusitis is reversing of the immunocompromised state, surgical debridement, and antifungal therapy. In acute ROCM, the surgical debridement is radical and surgery aims to remove all possible necrotic debris and fungal tissue. However, as noticed in our series of patients where most of the cases were chronic, we followed a maximal “safe” surgical debridement preferably using endoscopic endonasal Denker's approach, and all the vital structures such as orbit, meninges, skin, and subcutaneous tissue were not subjected to radical treatment ([Fig. 4]). Depending on the extent of orbital involvement, the treatment strategy differed. This included transcutaneous retrobulbar amphotericin B injection or limited debridement of necrotic tissue or complete orbital exenteration.[41] Depending on the patients hemodynamic condition, an open approach to address the intracranial abscess was done simultaneously with the endoscopic nasal debridement, or it was staged. Open approach to extensive disease involving the skin and subcutaneous tissue is necessary, for complete disease removal and appropriate plastic reconstruction of the affected region. Antifungal therapy with systemic liposomal amphotericin B (LAMB) is effective in both ROCM and Aspergillus infection.[42] Other preparations which were considered in patients not tolerating LAMB due to associated comorbidities or adverse events were posaconazole and isavuconazole.[43] As per our hospital policy, we started the treatment with systemic LAMB till a cumulative dose of 4 to 5 g was achieved. Then, the patients were switched to oral preparation of posaconazole for 16 to 20 weeks with periodic disease monitoring with contrast MRI and nasal endoscopy. In patients with chronic Aspergillus infection, oral preparation such as voriconazole or itraconazole is preferred to reduce the adverse effects and the cost of treatment.[44]
[45] In Aspergillus infection causing CIFS, the main goal of surgical debridement was to obtain a tissue sample and reduce the fungal load. The disease eradication was not required due to the excellent response obtained with oral voriconazole. In our series, 59.25% of patients underwent debridement to obtain tissue diagnosis and reduce the disease load ([Fig. 5]). Periodic monitoring using galactomannan assay was used to assess the need for antifungals and the progress of the disease.
Fig. 4 Intraoperative pictures after a left endoscopic Denker's approach to left pterygopalatine fossa and infratemporal fossa. (A) Sequestrum involving ascending palatine bone, pterygoid, and greater wing of the sphenoid (black arrows), (B) granulations over middle fossa dura (arrow), (C) necrotic tissue over the anterior part of cribriform (arrow), and (D) granulations over the dura after necrotic tissue clearance (arrow).
Fig. 5 A 45-year-old man diagnosed with invasive aspergillosis. His CT shows disease involving right orbital contents and left ethmoidal sinus (yellow arrow) (A, B). After completion of 4 months of Voriconazole therapy, his MRI T1 contrast shows complete resolution of disease (yellow arrows) (C, D). CT, computed tomography; MRI, magnetic resonance imaging.
Conclusion
Early diagnosis of invasive fungal disease can be achieved with contrast MRI in patients with high suspicion of the disease, even if obvious clinical signs are negative. With changing pathophysiology of the disease as seen in our study, it is important to decide the surgical approach and antifungal therapy case-to-case basis, looking at all the factors affecting the disease course. With the increasing incidence of invasive fungal infections worldwide, particularly after COVID-19 pandemic and immunocompromised conditions such as DM, it is essential to understand the evolving nature of this disease. ROCM, documented in the literature to cause fulminant disease, evolved into a chronic disease, possibly due to the improvement of the patient's immunity during the disease course. Immunological study of this changing phenomenon should be the next research frontier as this would help the surgeons anticipate the disease course and thus significantly change the treatment outcome.
