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.
