10.14639/0392-100X-N0848
Objectives. The purpose of this study was to correlate acute invasive fungal rhinosinusitis (AIFRS) and chronic invasive fungal rhinosinusitis with underlying diseases, aetiological microorganisms, clinical symptoms, radiological findings, and surgical and medical treatment to determine the subset of patients who require more accurate diagnostic investigation and to prevent irreversible complications. Methods. This retrospective monocentric study included 17 patients who underwent endoscopic sinus surgery evaluated by paranasal computed tomography and magnetic resonance imaging. Age, sex and symptoms, and location of the invasive fungal infection and the causative fungus were analysed. Results. In total, 4 patients were affected by the AIFRS form, and 13 by the chronic form. Diabetes mellitus was reported in 41.17% of cases, and haematological diseases in 23.52%. The maxillary sinuses were involved in 47.05% of cases and sphenoidal sinuses in 52.94%; Aspergillus fumigatus was the fungus in 76.47% of cases, and Zygomycetes in 23.53%. Conclusions. An understanding of the different types of fungal sinusitis and knowledge of their features play a crucial role in reaching prompt diagnosis and initiation of appropriate therapy, which is essential to avoid a protracted or fatal outcome.
application/xml
1827-675X
848
en
Giovanni Cavallo
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
liposomal amphotericin B
Definition and management of invasive fungal rhinosinusitis: a single-centre retrospective study
Text.Serial.Journal
https://www.actaitalica.it/
41
Rhinology
2021-03-19
2020-05-12
2021-03-19
2021-03-24
43-50
1
Giovanni Cavallo
2021/03/19
10.14639/0392-100X-N0848
43
Department of Otolaryngology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy
1827-675X
liposomal amphotericin B
50
Definition and management of invasive fungal rhinosinusitis: a single-centre retrospective study
https://www.actaitalica.it/article/download/848/523
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:43-50; doi: 10.14639/0392-100X-N0848




Rhinology


Definition and management of invasive fungal
rhinosinusitis: a single-centre retrospective study
Definizione e gestione della rinosinusite fungina invasiva: uno studio retrospettivo
monocentrico
Gian Luca Fadda1, Federica Martino1,2, Giacomo Andreani3, Giovanni Succo4,5, Maurizio Catalani6,
Stefano Di Girolamo2, Giovanni Cavallo1
1
 Department of Otolaryngology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy; 2 Otorhinolaryngology
Unit, Department of Clinical Sciences and Translational Medicine, Tor Vergata University, Rome, Italy; 3 Department of Clinical and
Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy; 4 FPO IRCCS, Head & Neck Oncology
Unit, Candiolo Cancer Institute, Turin, Italy; 5 Oncology Dept. University of Turin, Italy; 6 Department of Otolaryngology, Humanitas
Cellini, Turin, Italy


SUMMARY
Objectives. The purpose of this study was to correlate acute invasive fungal rhinosinusitis
(AIFRS) and chronic invasive fungal rhinosinusitis with underlying diseases, aetiological
microorganisms, clinical symptoms, radiological findings, and surgical and medical treat-
ment to determine the subset of patients who require more accurate diagnostic investigation
and to prevent irreversible complications.
Methods. This retrospective monocentric study included 17 patients who underwent endo-
scopic sinus surgery evaluated by paranasal computed tomography and magnetic resonance            Received: May 12, 2020
imaging. Age, sex and symptoms, and location of the invasive fungal infection and the             Accepted: September 14, 2020
causative fungus were analysed.
Results. In total, 4 patients were affected by the AIFRS form, and 13 by the chronic form.        Correspondence
Diabetes mellitus was reported in 41.17% of cases, and haematological diseases in 23.52%.         Gian Luca Fadda
                                                                                                  Department of Otolaryngology, San Luigi Gonzaga
The maxillary sinuses were involved in 47.05% of cases and sphenoidal sinuses in 52.94%;
                                                                                                  Hospital, Regione Gonzole 10, 10043 Orbassano,
Aspergillus fumigatus was the fungus in 76.47% of cases, and Zygomycetes in 23.53%.               Turin, Italy
Conclusions. An understanding of the different types of fungal sinusitis and knowledge of         Tel. +39 011 9026463
their features play a crucial role in reaching prompt diagnosis and initiation of appropriate     E-mail: dott.fadda@gmail.com
therapy, which is essential to avoid a protracted or fatal outcome.
KEY WORDS: Aspergillus, Mucormycosis, invasive fungal rhinosinusitis, isavuconazole,              Funding
                                                                                                  None.
liposomal amphotericin B
                                                                                                  Conflict of interest
RIASSUNTO                                                                                         The Authors declare no conflict of interest.
Obiettivi. Nonostante i progressi in termini di trattamento, la mortalità nei casi di rinosinu-
site fungina invasiva rimane elevata, pertanto, scopo dello studio è stato correlare le forme       How to cite this article: Fadda GL, Martino
acute invasive e quelle croniche con patologie concomitanti, agenti eziologici, i sintomi           F, Andreani G, et al. Definition and manage-
clinici, radiologia e trattamento, al fine di identificare e trattare i pazienti con prognosi       ment of invasive fungal rhinosinusitis: a sin-
peggiore.                                                                                           gle-centre retrospective study. Acta Otorhi-
Metodi. Il seguente studio retrospettivo monocentrico ha incluso 17 pazienti sottoposti a           nolaryngol Ital 2021;41:43-50. https://doi.
chirurgia endoscopica sinusale, valutati mediante TC e RM e analizzati per età, sesso, sin-         org/10.14639/0392-100X-N0848
tomi, sede dell’infezione fungina invasiva e microrganismi eziologici.
Risultati. 4 pazienti sono risultati affetti dalla forma invasiva acuta,13 pazienti dalla forma   © Società Italiana di Otorinolaringoiatria
                                                                                                  e Chirurgia Cervico-Facciale
cronica. Il diabete mellito è stato riscontrato nel 41,17% dei casi, malattie ematologiche
nel 23,52%. I seni mascellari sono risultati coinvolti nel 47,05% dei pazienti e seni sfenoi-
                                                                                                                 OPEN ACCESS
dali nel 52,94%; Aspergillus ha provocato il 76,47% dei casi, Zigomiceti il 23,53%.
Conclusioni. Un’adeguata comprensione dei diversi tipi di sinusite fungina e la conoscen-         This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
za delle loro caratteristiche svolgono un ruolo cruciale ai fini di una diagnosi precoce e        Commercial-NoDerivatives 4.0 International) license. The
l’avvio di una terapia appropriata con lo scopo di ridurne la mortalità.                          article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: Aspergillus, Mucormycosis,                  rinosinusite   fungina    invasiva,    only in the original version. For further information: https://
Isavuconazolo, amfotericina B liposomiale                                                         creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                            43
G.L Fadda et al.




Introduction                                                     < 18 years, those who had previously received nasal sur-
                                                                 gery or who had been diagnosed with non-invasive fungal
The concept of invasiveness for a fungal infection refers to
                                                                 rhinosinusitis were excluded.
the potential for fungal hyphae to invade epithelial tissue
                                                                 Patients’ records were analysed retrospectively for pre-
with potential neural and vascular involvement 1,2. We can
                                                                 senting symptoms, underlying diseases, causative micro-
categorise invasive fungal rhinosinusitis (IFRS) into three
                                                                 organisms, radiological findings, and medical and surgical
subgroups: acute invasive fungal rhinosinusitis (AIFRS),
                                                                 treatment. All enrolled patients were evaluated preop-
chronic invasive fungal rhinosinusitis and chronic granu-
                                                                 eratively with paranasal computed tomography (CT) and
lomatous invasive fungal rhinosinusitis 3.
                                                                 magnetic resonance imaging (MRI). In addition, age, sex
Invasive fungal rhinosinusitis (IFRS) generally occurs in
                                                                 and symptoms as well as the location of the invasive fun-
immunocompromised patients, i.e. those with haemato-
                                                                 gal infection and the causative fungus were analysed for
logical malignancies or undergoing chemotherapy or allo-
                                                                 each patient.
geneic haematopoietic transplantation, patients with AIDS,
                                                                 Tissue samples were collected for both microbiological
and in poorly controlled diabetic patients undergoing im-
                                                                 and histopathological examination to provide a definitive
munosuppressive therapy 4.
                                                                 diagnosis. A mucosal biopsy sample was also collected
Acute invasive fungal rhinosinusitis (AIFRS) is defined by
                                                                 from the sinus wall and evaluated histologically. A swab
a time course of less than 4 weeks’ duration, with predomi-
                                                                 sample was taken from purulent sinus secretions and sent
nant vascular invasion. The infection results from rapid
                                                                 to the microbiology laboratory for bacterial culture under
spread of fungi from the paranasal sinuses to the adjacent
                                                                 both aerobic and anaerobic conditions. When feasible,
orbits and central nervous system with hyphal invasion of
                                                                 galactomannan and beta-D-glucan were tested in blood
blood vessels, vasculitis with thrombosis, haemorrhage,
                                                                 samples. Galactomannan (GM) is a molecule that is pre-
tissue infarction and acute neutrophilic infiltrates with a
                                                                 sent in the cellular walls of Aspergillus species and can
necrotising pathological reaction 5.
                                                                 be secreted extracellularly. Several studies have shown
Chronic IFRS is an indolent infection with a slow destruc-
                                                                 that the determination of GM is beneficial for diagnosis
tive process that most commonly affects the ethmoid and
sphenoid sinuses, but may involve any paranasal sinus 6,7.       and, together with 1,3-beta-D-glucan (BDG) antigens,
Despite improvements in both medical and surgical thera-         can improve the sensitivity of invasive aspergillosis di-
pies, the mortality of patients with IFRS remains high (50-      agnosis 11.
80%) mostly due to invasion of the orbit and intracranial        All patients underwent debridement through endoscopic
cavity 8,9; in fact, early and accurate diagnosis is essential   sinus surgery (ESS) under general anaesthesia as the first
because prognosis is often governed by the rapid initiation      choice to remove the entire lesion in the sinus using rigid
of antifungal therapy and/or surgical debridement 10.            endoscopes (Karl Storz Endoskope, Germany) with a di-
Therefore, the purpose of this article was to correlate AI-      ameter of 4 mm and viewing angles of 0°, 45° and 70°. Af-
FRS and chronic indolent IFRS with underlying diseases,          ter surgery, specific medical antifungal treatment was initi-
aetiological microorganisms, clinical symptoms, radiologi-       ated as prescribed by an infectious disease specialist, and
cal findings, and surgical and medical treatment.                in the case of positive cultures indicating bacterial coinfec-
The study aimed to aid clinicians in the decision-making         tion, the type of antibiotic therapy was determined by an-
process by systematically assembling previously published        tibiogram results. All patients were prospectively followed
evidence and new updates on medical treatment, and to            through endoscopic monitoring performed at intervals of
consider the possibility of identifying a subset of patients     15, 30, 60, 90 days, 6 months and 1 year after surgery. Us-
who require more accurate diagnostic investigation to pre-       ing a rigid endoscope, secretions and crusts were removed
vent irreversible complications.                                 at the outpatient department and postoperative home treat-
                                                                 ment included nasal saline irrigation twice a day for at least
                                                                 3 months. Therapeutic success was clinically and endo-
Materials and methods                                            scopically defined as patients who were asymptomatic at 6
This single-centre retrospective study included 17 patients      months after completing the antifungal therapy. Follow-up
affected by IFRS who underwent endoscopic sinus surgery          with MRI was only performed when recurrence was sus-
(ESS) at the ENT Department in San Luigi Gonzaga Hos-            pected. No patient was lost during the follow-up period.
pital, Turin, Italy between January 2016 and January 2020.       This study was in line with the guidelines of the Helsinki
For inclusion, patients were required to have histopatholog-     Declaration for ethical consideration. Accordingly, written
ically confirmed IFRS, defined by the evidence of fungal         informed consent was obtained from all patients. Categori-
hyphae in the mucosa of the affected sinus. Patients aged        cal data are presented as frequencies.



44
                                                                                                               Management of chronic and acute invasive fungal rhinosinusitis




Results                                                                                        days for the chronic indolent form. No patient had received
                                                                                               medical treatment at other healthcare facilities.
The study included 17 patients (8 women and 9 men) affect-                                     CT and MRI were used preoperatively to determine the
ed by IFRS, diagnosed between January 2016 and January                                         extent of fungal invasion: 14 (82.35%) patients had uni-
2020. Their median age was 57 years, range: 31-82 years,                                       lateral involvement of the paranasal sinuses and one of
and the interquartile range (IQR) was 27 ± 14.77 years. In                                     them (5.88%) also showed the simultaneous involvement
total, 4 patients were affected by the AIFRS form (Tab. I)                                     of two different sinuses, the maxillary and sphenoid sinus
and 13 patients had the chronic indolent form (Tab. II).                                       (#4 Tab. II) on the right side. Three patients (17.64%) had
The most common underlying disease was diabetes mellitus                                       bilateral fungal invasion.
reported in 7 cases (41.17%) followed by haematological                                        Our data also showed involvement of the maxillary sinus-
diseases in 4 cases (23.52%): myelodysplastic syndrome                                         es in 8 patients (47.05%) and of the sphenoid sinuses in 9
(n = 1), non-Hodgkin lymphoma (n = 1) and acute myeloid                                        patients (52.94%); there was simultaneous involvement of
leukaemia (n = 2). Furthermore, 5 patients (29.41%) had                                        both paranasal sinuses in 1 patient (5.88%). The principal
neutropenia. An autoimmune condition, rheumatoid arthri-                                       radiologic findings with CT and MRI are summarised in
tis, was recognised in 1 case. Another cause of immunode-                                      Tables III and IV, respectively.
ficiency was steroid therapy, found in 1 patient. Alveolar                                     Five patients showed extra-sinus involvement of the fun-
rhabdomyosarcoma together with chemoradiotherapy and                                           gal disease (29.41%): the cavernous sinus was the site of
neutropenia were observed in 1 patient. As reported in Ta-                                     the most frequent dissemination being present in 5 patients
bles I and II, several patients showed different associations                                  (29.41%), followed by 2 cases (11.76%) with intracranial
of these underlying diseases, with different symptoms oc-                                      involvement and 2 cases (11.76%) with thrombosis of the
curring simultaneously in the same patient.                                                    internal carotid artery (ICA) (11.76%). Ocular manifesta-
Facial pain and headache were the most commonly re-                                            tions were also detected: orbital and optic nerve involve-
ported presenting signs and symptoms in 12 (70.58%)                                            ment (n = 2, 11.76%) and VI cranial nerve palsy (n = 4,
and 8 (47.05%) patients, respectively; 6 patients had ocu-                                     23.52%).
lar diseases (35.29%): diplopia was observed in 4 patients                                     All patients underwent endoscopic debridement with endo-
(23.52%), proptosis in 3 (17.64%) and bilateral amaurosis                                      scopic sinus surgery (ESS) under general anaesthesia, with
in 1 case (5.88%). Cranial nerve palsy (VI) was present in                                     complete removal of all necrotic tissue. No other surgical
2 patients (11.76%) and trigeminal neuralgia in 1 patient                                      procedures were performed. The time from the patient’s ar-
(5.88%). The average time between the onset of symptoms                                        rival at the hospital to ESS varied from less than 1 day to
to presentation in the emergency room and the beginning of                                     70 days (median: 35 days, IQR: 57.5 days): all AIFRS pa-
the diagnostic process was about 2 days for AIFRS and 10                                       tients underwent emergency ESS immediately. In the group


Table I. Clinical and radiological features of the 4 patients with AIFRS.
 ID           Underlying              Presenting              Sinuses                        Extra                 Fungal           Microbiologic          Antifungal           F/U
 sex,          diseases         symptoms and signs           involved                   sinonasal sites            species                                  therapy
 age
 1             Acute myeloid                Diplopia                    SS             Cavernous sinus               Zygo             Rhizomucor             L-AmB             25 m
 M, 57          leukaemia,            cranial nerve palsy               (r)            thrombosis ICA,                                                        (74 d)
                Neutropenia             (VI), trigeminal                                cerebral fungal                                                        ISC
                                           neuralgia                                       infection                                                         (12 m)
 2            Myelodysplastic        Facial pain proptosis              MS                     −                     Asper          Asp. fumigatus           Vorico            23 m
 F, 56           syndrome                                               (r)                                                                                  (12 m)
               Neutropenia
 3             Non-Hodgkin            Diplopia, headache,               SS             Cavernous sinus,              Zygo                 Neg.               L-AmB             13 m
 F, 53          lymphoma               proptosis, cranial               (r)            VI cranial nerve,                                                     (15 d)
               Neutropenia              nerve palsy (VI)                                thrombosis ICA                                                          ISC
                                                                                                                                                              (9 m)
 4           Diabetes mellitus       Headache amaurosis                 SS             Cavernous sinus,              Zygo           Asp. fumigatus           L-AmB             2 d/D
 M, 76          Debilitated               bilateral                     (b)               intracranial                                                         (3 d)
                                                                                      involvement, Optic
                                                                                         nerve, Orbit
AIFRS: acute invasive fungal rhinosinusitis; CHT: chemotherapy; MS: maxillary sinus; SS: sphenoid sinus; b: bilateral; l: left; r: right; Asper: Aspergillus; Zygo: Zygomycetes; L-AmB:
Liposomal-Amphotericin B; ICA: internal carotid artery; ISC: Isavuconazole; Vorico: Voriconazole; Posa: Posaconazole; m: months; d:days; F/U: follow-up; D: dead; d: day.




                                                                                                                                                                                      45
G.L Fadda et al.




Table II. Clinical and radiological features of the 13 patients with chronic IFRS.
 ID              Underlying          Presenting symptoms          Sinuses             Extra                        Fungal          Microbiologic         Antifungal           F/U
 sex,              diseases                and signs              involved       sinonasal sites                   species                                therapy
 age
 1               Acute myeloid                  Facial pain                  MS                   −                  Zygo                Neg.               Vorico           52 m
 F, 52             leukaemia                                                 (b)                                                                            (1 m)
                  Neutropenia
 2              Diabetes mellitus                Headache                    SS                   −                 Asper            Penicillium            Vorico           49 m
 M, 65                                                                       (l)                                                                             (2 m)
 3                  Alveolar                    Facial pain                  MS                   −                 Asper                Neg.               Vorico           44 m
 F, 31         rhabdomyosarcoma                                               (l)                                                                            (2 m)
                   CHT+RT. N
 4              Diabetes mellitus               Headache                 SS + MS (r)              −                 Asper          Asp. fumigatus           Vorico           40 m
 F, 43                                          Facial pain                                                                                                  (2 m)
 5                       −                      Facial pain                  MS                   −                 Asper          Asp. fumigatus           Vorico           33 m
 M, 47                                                                       (r)                                                                             (1 m)
 6              Diabetes mellitus               Facial pain                  MS                   −                 Asper          Asp. fumigatus           Vorico           29 m
 M, 47                                                                       (l)                                                                             (3 m)
 7                Steroid therapy         Headache, facial pain,             SS          Cavernous sinus,           Asper                Neg.               Vorico         16 m/D
 M, 82                                          diplopia                     (r)            intracranial                                                    (12 m)
                                                                                         involvement V3,
                                                                                                Orbit
 8                       −                      Facial pain                  MS                  −                  Asper                Neg.               Vorico           14 m
 M, 77                                                                        (l)                                                                           (1 m)
 9              Diabetes mellitus               Facial pain                  MS                   −                 Asper                Neg.               Vorico           14 m
 F, 59                                                                         (l)                                                                          (20 d)
 10            Rheumatoid arthritis             Headache                     SS                   −                 Asper                Neg.               Vorico           13 m
 F, 53                                          facial pain                  (b)                                                                             (3 m)
 11             Diabetes mellitus               Facial pain                  MS                   −                 Asper                Neg.               Vorico           12 m
 M, 68                                                                        (r)                                                                            (3 m)
 12             Diabetes mellitus               Headache                     SS           Cavernous sinus           Asper          Asp. fumigatus          L-AmB              8m
 F, 79                                         Facial pain                    (l)                                                                        (1 m), Posa
                                            Proptosis, diplopia                                                                                             (2 m)
 13                      −                      Headache                         SS               −                 Asper          Asp. fumigatus        Vorico (3m)          4m
 M, 79                                                                           (l)
CHT: chemotherapy; RT: radiotherapy; MS: maxillary sinus; SS: sphenoid sinus; b: bilateral; l: left; r: right; Asper: Aspergillus; Zygo: Zygomycetes; L-AmB: Liposomal-Amphotericin B;
ISC: Isavuconazole; Vorico: Voriconazole; Posa: Posaconazole; m: months; d: days; F/U: follow-up; D: dead; d: day.



Table III. Radiologic characteristics of IFRS in non-contrast CT scan.
 Sinus involved                                                  Calcification                                  Bony sclerosis                            Bone erosion
 MS                                                                         10 (58.8)                                3 (17.6)                                3 (17.6)
 SS                                                                         5 (29.4)                                 6 (35.3)                                4 (23.5)
 Total                                                                        15/17                                    9/17                                    7/17
 n (%)                                                                       (88.2%)                                 (52.9%)                                 (41.1%)
IFRS: invasive fungal rhinosinusitis; MS: maxillary sinus; SS: sphenoid sinus.


with the chronic indolent form, the delay to surgery in 1 pa-                                 Histological examination confirmed the invasive fungal
tient (#13) was linked to the onset of concomitant diseases                                   disease in all cases: Aspergillus was detected in 13 patients
which required further investigations by other specialists                                    (76.47%) (1 patient in the AIFRS group and 12 patients in
and, consequently, postponed the anaesthesiologic eligibil-                                   the group with the chronic form), and Zygomycetes was
ity for surgery.                                                                              detected in 4 patients (23.52%): the intraoperative view
Bilateral nasal packing was performed in each patient and                                     showed typical friable cheesy-like yellow to brown mate-
was removed 48 hours after surgery. No intraoperative                                         rial in sinus cavities, confirming the fungal aetiology of the
complications occurred (Figs. 1-3).                                                           disease already diagnosed macroscopically.



46
                                                                                                                 Management of chronic and acute invasive fungal rhinosinusitis




Table IV. Radiologic findings of IFRS in MRI.
                           Signal intensity                                                                    Extra-sinonasal involvement
 Sinus                    T1WI                T2 WI markedly            Peripheral              Cavernous         Intracranial   Perineural      Orbital     Thrombosis ICA
 involved                  iso/                hypointense             enhancement                sinus                           spread
                       hypointense
 MS                       7 (41.1)                7 (41.1)                 2 (11.7)                  -                  -             -             -                -
 SS                       9 (52.9)                9 (52.9)                 3 (17.7)              5 (29.4)           2 (11.7)          4         2 (11.7)         2 (11.7)
 Total                     16/17                16/17 (94%)                  5/17              5/17 (29.4%)           2/17          4/17          2/17             2/17
 n (%)                     (94%)                                           (29.4%)                                  (11.7%)       (23.5%)       (11.7%)          (11.7%)
IFRS: invasive fungal rhinosinusitis; MS: maxillary sinus; SS: sphenoid sinus; ICA: internal carotid artery.




Figure 1. Patient #2 in the AIFRS group – (A, B) Coronal CT scan shows
an opacity of the right maxillary sinus (MS) with associated multiple foci of
microcalcifications (white arrowhead) and sclerosis of the MS walls by reac-
tive osteitis. Focal interruption (white arrow) of the lateral wall is also present.
(C) Coronal T2-MRI shows marked hypointense signal with areas of hyperin-
tense signal in the lateral and inferior recess of the MS. (D) Intraoperative view
showing typical friable cheesy-like yellow to brown material on the floor of the                 Figura 2. Patient #4 in the AIFRS group – Axial (A) and coronal (B) CT scans
maxillary sinus.                                                                                 display heterogeneous opacity of the sphenoid sinuses (SS) with associated
                                                                                                 microcalcification (white arrowhead), thickening and sclerosis of the bone sur-
                                                                                                 rounding the SS, and multiple interruptions of its bony wall (black arrow). (C)
                                                                                                 Axial gadolinium-enhanced T1-weighted MRI demonstrates a marked hypoin-
Microbiological analysis was also performed: Aspergillus                                         tense signal (asterisk) in the left SS with inflamed mucosa at the periphery.
fumigatus was isolated in 7 patients (41.17%), Rhizomucor                                        (D) Endoscopic removal of fungal concretion after opening the anterior wall
                                                                                                 of the left SS.
in 1 (5.88%), and Penicillium in 1 case (5.88%). The causa-
tive microorganism could not be determined in 8 patients
(47.05%).
Bacterial co-infections occurred in 6 patients (35.29%) and                                      lation when possible, on average after a period of 3.41
were most frequently caused by Staphylococcus species                                            months (range = 20 days-12 months, median = 2 months,
and Pseudomonas aeruginosa (11.76%), followed by one                                             IQR = 2); 4 patients (23.52%) were treated with liposo-
case of Streptococcus pyogenes (5.88%), one case of Actin-                                       mal amphotericin B (L-AmB) (range = 3 days-12 months,
omyces (5.88%) and one of Haemofilus influenzae (5.88%).                                         median = 0.74 months, IQR = 1.88) with dosages from 3
All patients promptly started systemic antimycotic treat-                                        to 10 mg/kg/day; in 3 selected cases, isavuconazole with a
ment. Voriconazole was administered to 13 patients                                               dosage of 200 mg/day in intravenous or oral formulation or
(76.47%); the 200 mg bid intravenous formulation was                                             posaconazole at 300 mg/day were also used in association.
preferred initially and was switched to an oral formu-                                           In total, 15 patients are still in follow-up with a mean



                                                                                                                                                                            47
G.L Fadda et al.




                                                                                        cases of intracranial mycotic dissemination: Zygomycetes
                                                                                        (Rhizopus, Mucor, Rhizomucor) and species of Aspergillus
                                                                                        are the most common aetiologic agents in the sinonasal cav-
                                                                                        ity, with more frequent neurovascular and orbital invasion 13.
                                                                                        CT scans show homogeneous opacification of the sinus
                                                                                        with calcification, adjacent bone erosion, dehiscence of
                                                                                        the lateral sphenoid’s recess with signs of remodeling in
                                                                                        the wall of the sphenoid sinus, especially in immunocom-
                                                                                        promised patients 14. Signal intensity was evaluated using
                                                                                        MRI, and was grouped into three categories: slightly T1-
                                                                                        weighted iso- or hypointense, markedly T2-weighted hy-
                                                                                        pointense (near signal void), and peripheral enhancement
                                                                                        of the surrounding mucosa. On MRI, orbital and intracrani-
                                                                                        al involvement were present as suggested findings, together
                                                                                        with perineural spread and expansion outside the confines
                                                                                        of the sinonasal cavity with cavernous sinus involvement
                                                                                        or thrombosis of the ICA, and have been reported previ-
                                                                                        ously 15.
                                                                                        Clinical suspicion of AIFRS should be raised in the immu-
                                                                                        nocompromised patient presenting with new-onset, rapidly
                                                                                        progressive sinusitis or facial discomfort 16.
                                                                                        In our experience, symptomatology in AIFRS patients was
                                                                                        very evident when a sphenoidal localisation was present
                                                                                        (proptosis, diplopia, cranial nerve palsy (VI), trigeminal
                                                                                        neuralgia, or visual abnormalities) because of a connec-
Figura 3. Patient #1 in the AIFRS group – (A) Coronal CT scan showing com-              tion between the sphenoidal sinus and anatomic structures
plete opacification of the right sphenoid sinus with optical right nerve canal wall     such as the ICA, cavernous sinus, optic nerve, eyehole, or
erosion (black arrows). (B) Axial MRI with contrast shows a hypointense signal in
a large space-occupying lesion in the right SS extending into the right cavernous       brain 17. Therefore, thanks to the rapidity of onset, patients
sinus (asterisk). The cavernous carotid artery appears unobstructed. (C) Endocra-       with AIFRS came immediately to our clinic, and we per-
nial mycotic abscess (white arrow) with inflamed mucosa within Meckel’s cave            formed an emergency surgical intervention thereby pre-
on the right at periphery at day 41. (D) Intraoperative view during endoscopic si-      venting serious cerebral and ocular complications. On the
nus surgery in the right SS. (E) Absence of motility of the right eye in lateral gaze
related to the deficit of the right lateral rectus muscle for abducens nerve palsy.     other hand, patients with the chronic indolent form showed
                                                                                        nonspecific and slowly progressive signs and symptoms
                                                                                        that did not arouse suspicion in the patient, delaying access
duration of 20.12 months (range = 0.06-58 months; me-                                   to the emergency room and consequently, to the diagnostic
dian = 16 months, IQR = 24), 2 patients died (11.76%), 1                                and therapeutic process.
patient from cerebral ischaemia and the other from uncon-                               As reported in a review of over 800 patients by Turner et
trolled rhinocerebral infection.                                                        al., Aspergillus spp. and Mucor spp. can both be found in
Only one relapse was observed with persistence of fungal                                neutropenic patients and in those with chronic systemic
pathology in the sphenoidal sinus, requiring revision sur-                              steroid treatment, whereas Mucor spp. has a propensity for
gery at 6 months and with a histological diagnosis of As-                               diabetic and iron-overloaded patients 18.
pergillus.                                                                              Neutropenia plays a key role as a factor contributing to the
                                                                                        development of infection in patients with haematological
                                                                                        disease. In the present study, 29.41% of patients were af-
Discussion                                                                              fected by a severe neutropenic state, defined as a neutro-
A diagnosis of IFRS requires histopathologic evidence of                                phil count < 500/mmc 19, and 23.52% of patients had an
fungi invading nasal tissue, characterised by a dense ac-                               underlying haematological disease, such as non-Hodgkin
cumulation of hyphae, the occasional presence of vascular                               lymphoma, myelodysplastic syndrome or acute myeloid
invasion and a diffuse inflammatory reaction 12.                                        leukemia. Other underlying conditions included poorly
Acute IFRS is characterised by a rapid evolution and is as-                             controlled DM, immunosuppressive treatment and corti-
sociated with a high mortality rate that can reach 100% in                              costeroid exposure 20.



48
                                                                               Management of chronic and acute invasive fungal rhinosinusitis




Our data show a significant proportion of patients infect-       Due to the relative rarity of AIFRS, our data was limited to
ed by Aspergillus fumigatus in the chronic indolent group        acute and chronic indolent IFRS, and unfortunately did not
(92.30%) and only one patient was affected (pt#1) by Zy-         include granulomatous forms, thus precluding larger cohort
gomycetes (7.70%). Conversely, in AIFRS patients, Zygo-          studies. The results are dependent on the quality of the lim-
mycetes were the fungi mainly responsible for the infec-         ited data available, but are in line with the current literature.
tion and only in one patient (#2) was Aspergillus fumigatus      Moreover, our study focused on differentiating acute and
isolated.                                                        chronic indolent forms, which was not always easy to rec-
In line with the results obtained in our previous study 21, it   ognise with certainty in previous studies, so as to guide the
is still unclear why the microbiological evidence for fungal     most appropriate diagnostic and therapeutic process.
disease was negative in 8 cases, although the radiologic and
endoscopic intraoperative findings were strongly indicative      Conclusions
of IFRS.
Treatment for both groups was based on a combination of          Invasive fungal rhinosinusitis is a difficult infection to diag-
antifungal therapy, reversal of immunocompromising fac-          nose and treat. Early diagnosis is the key to managing IFRS
tors, surgical debridement through ESS when possible and         successfully, and with a systematic approach, it is possible
obtaining material for histopathological and cultural ex-        to improve survival, taking into account the context of the
aminations 22.                                                   temporal course of the diagnostic work-up and treatment.
Vaughan et al. analysed 37 mucormycosis cases and found          The goal is diagnosis of the disease at an earlier stage while
no significant difference in survival between patients hav-      it is confined to the sinonasal cavities before mucosal dis-
ing surgery 1-30 days after diagnosis 23. These data agree       semination. A multidisciplinary approach consisting of
with our study, with an onset of treatment on average 32.41      antifungal therapy, surgical debridement, and reversal of
days after diagnosis, highlighting why the start of treatment    predisposing conditions is the best therapy to improve sur-
should be initiated as soon as IFRS is diagnosed.                vival.
For an early surgical approach, the correct medical therapy
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