Acute invasive fungal rhinosinusitis (AIFRS) - A histopathological analysis of expanding spectrum of fungal infections in backdrop of COVID-19 pandemic.

Context: Acute invasive fungal rhinosinusitis (AIFRS) is an aggressive infection affecting immunocompromised patients and carries a high morbidity and mortality. It is commonly seen in immunocompromised patients, mainly in uncontrolled diabetes, malignancy, acquired immunodeficiency syndrome, and so on. However, there has been an exponential increase in the incidence of AIFRS in relation to recent coronavirus disease 2019 (COVID-19) infection. Aims: We present this study to assess histomorphological features of fungal infections in the background of COVID-19 era. Materials and Methods: The study includes interpretation of 34 biopsies of suspected AIFRS in post COVID-19 patients. The demographic details like patients age, sex, diabetic status, COVID-19 status, and history of steroid intake were collected. All specimens were stained with hematoxylin and eosin and PAS stain. Detailed microscopic examination including the presence of fungal hyphae in the tissue, characterization of inflammatory response, presence of tissue invasion, angioinvasion, and necrosis was noted for each case. Results: Thirty-four biopsy specimens from various sites - nasal cavity, maxillary sinus, ethmoid sinus, and so on - were studied. The mean age of the patients with AIFRS was 52.68 years. The dominant fungi were Mucorales in 31 (91.3%), Aspergillus and Mucorales in 1 (2.9%), a combination of Mucorales and Candida identified in 1 (2.9%) case, and Candida alone in 1 case (2.9%). Bony invasion and perineural invasion were observed in 5 cases (14.7%) and 1 (2.9%) case, respectively. Conclusion: Histopathological examination plays an essential role in the diagnosis and appropriate management of the patients. Histopathological features including characterization of fungi, angioinvasion, and bone invasion may provide information on rare dreaded infections in post-COVID-19 patients for possible prognostic characteristics on histology.

Neurosarcoidosis - A diagnostic challenge?

Background: Sarcoidosis is an inflammatory granulomatous multisystem disease with an unknown etiology. Neurosarcoidosis is a cryptogenic neuroinflammatory manifestation of sarcoidosis. Objective: This article aims at better understanding of one of the rarer diseases whose diagnosis may be difficult leading to delay in definitive management of the patient. Method: We describe a case of neurosarcoidosis with initial presentation similar to acute invasive fungal rhinosinusitis, whose diagnosis was challenging and delayed owing to the presenting symptoms. Conclusion: The diagnosis of neurosarcoidosis becomes challenging when it presents as isolated clinical neurological symptoms. We want to highlight the variable nature of neurosarcoidosis and its consideration as diagnosis after excluding other common infectious and inflammatory conditions.

Orbital Complications of Acute Invasive Fungal Rhinosinusitis: A New Challenge in the COVID-19 Convalescent Patients.

Purpose: Increased incidence of acute invasive fungal rhinosinusitis (AIFR) in the setting of COVID-19 is undeniable. This can be attributed to its effect on innate immunity and extensive use of corticosteroids. The goal of our study was to assess the orbital complications of AIFR and its management in the COVID-19 convalescent patients. Methods: Our longitudinal prospective study included 45 patients with orbital complications of AIFR in recently recovered COVID-19 patients. We performed otorhinolaryngological, ophthalmological, and neurological examinations to monitor the manifestations of the disease. Computed tomography and contrast enhanced magnetic resonance imaging were performed to detect the extent of infection. Antifungal medications, surgical intervention, and general condition management were all provided to all the patients. Results: We reported pre-septal cellulitis, orbital cellulitis, and orbital apex syndrome in 18, 13, and 10 patients, respectively. Four patients had cavernous sinus thrombosis. Mucormycosis and Aspergillus species were detected in 80% and 11.11% of our patients, respectively, while the mixed infection was found in 8.88% of our patients. Diabetes mellitus was the most common cause of immunocompromise (95.55% of our patients). Orbital pain and ophthalmoplegia were the most common ocular manifestations, followed by proptosis and relative afferent pupillary defect. All patients underwent surgical intervention, except for one patient who was unfit for surgery. One patient had orbital exenteration. The ophthalmological manifestations were reversible in cases of orbital and pre-septal cellulitis. The overall survival rate was 66.67%. Conclusion: Early diagnosis and treatment of AIFR can decrease the morbidity and mortality rate of affected patients.

Magnetic Resonance Imaging Prognostic Findings for Visual and Mortality Outcomes in Acute Invasive Fungal Rhinosinusitis.

PURPOSE: To identify initial, preintervention magnetic resonance imaging (MRI) findings that are predictive of visual and mortality outcomes in acute invasive fungal rhinosinusitis (AIFRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with histopathologically or microbiologically confirmed AIFRS cared for at a single, tertiary academic institution between January 2000 and February 2020. METHODS: A retrospective review of MRI scans and clinical records of patients with confirmed diagnosis of AIFRS was performed. For each radiologic characteristic, a modified Poisson regression with robust standard errors was used to estimate the risk ratio for blindness. A multivariate Cox proportional hazards model was used to study AIFRS-specific risk factors associated with mortality. MAIN OUTCOME MEASURE: Identification of initial, preintervention MRI findings associated with visual and mortality outcomes. RESULTS: The study comprised 78 patients (93 orbits, 63 with unilateral disease and 15 with bilateral disease) with AIFRS. The leading causes of immunosuppression were hematologic malignancy (38%) and diabetes mellitus (36%). Mucormycota constituted 56% of infections, and Ascomycota constituted 37%. The overall death rate resulting from infection was 38%. Risk factors for poor visual acuity outcomes on initial MRI included involvement of the orbital apex (relative risk [RR], 2.0; 95% confidence interval [CI], 1.1-3.8; P = 0.026) and cerebral arteries (RR, 1.8; 95% CI, 1.3-2.5; P < 0.001). Increased mortality was associated with involvement of the facial soft tissues (hazard ratio [HR], 4.9; 95% CI, 1.3-18.2; P = 0.017), nasolacrimal drainage apparatus (HR, 5.0; 95% CI, 1.5-16.1; P = 0.008), and intracranial space (HR, 3.5; 95% CI, 1.4-8.6; P = 0.006). Orbital soft tissue involvement was associated with decreased mortality (HR, 0.3; 95% CI, 0.1-0.6; P = 0.001). CONCLUSIONS: Extrasinonasal involvement in AIFRS typically signals advanced infection with the facial soft tissues most commonly affected. The initial, preintervention MRI is prognostic for a poor visual acuity outcome when orbital apex or cerebral arterial involvement, or both, are present. Facial soft tissues, nasolacrimal drainage apparatus, intracranial involvement, or a combination thereof is associated with increased mortality risk, whereas orbital soft tissue involvement is correlated with a reduced risk of mortality.

Rinosinusitis fúngica invasiva aguda: actualización en pacientes adultos y pediátricos / Acute invasive fungal rhinosinusitis: update in adults and pediatric patients

RESUMEN La rinosinusitis fúngica invasiva aguda (RSFIA) es una enfermedad poco frecuente caracterizada por una infiltración fúngica de la submucosa y vasos sanguíneos de las cavidades nasal y paranasal. Afecta a pacientes con grados variables de inmunosupresión, destacando entre estas patologías subyacentes la diabetes mellitus y las neoplasias malignas hematológicas. Presenta una alta tasa de mortalidad, pudiendo reducirse significativamente si el diagnóstico y el tratamiento se realizan precozmente. Este artículo tiene por objetivo presentar una revisión actualizada de la literatura respecto a la presentación clínica, microbiología, factores de riesgos, métodos diagnósticos, tratamiento y pronóstico de la RSFIA, tanto en adultos como en niños.

ABSTRACT Acute invasive fungal rhinosinusitis (AIFS) is a rare disease characterized by fungal infiltration of the submucosa and blood vessels of the nasal y paranasal cavities. It affects almost exclusively patients with different degrees of immunosuppression, with underlying pathologies such as diabetes mellitus and hematological malignancies. AIFS has a high mortality rate, but it can be significantly reduced if the diagnosis and treatment are carried out early in the course of disease. This article aims to present an updated literature review regarding clinical presentation, microbiology, risk factors, diagnostic methods, treatment and prognosis of AIFS, both in adults and children.

Impact of early detection of acute invasive fungal rhinosinusitis in immunocompromised patients.

BACKGROUND: Early diagnosis of acute invasive fungal rhinosinusitis (AIFRS) is vital to improving outcomes in immunocompromised patients. This study evaluated the impact of a systematic protocol with nasal endoscopy and biopsies to early detect AIFRS in immunocompromised patients. Additionally, we compared the accuracy of frozen-section biopsy and culture with formalin-fixed paraffin-embedded (FFPE) biopsy. METHODS: Retrospective cohort in a Tertiary Referral Hospital. Patients with the suspected diagnosis of AIFRS were evaluated following a standardized protocol, including serial nasal endoscopies and biopsies when necessary. The sensitivity and specificity of frozen-section biopsy and culture were also compared with FFPE. RESULTS: The mortality rate related to AIFRS of this standardized cohort (13/43) was 30.2%. Better outcomes were observed in patients with disease limited to the turbinates and in those with higher peripheral neutrophils count. Frozen-section biopsy positivity correlated with FFPE findings for fungi detection (p-value < 0.0001), with a sensitivity of 90.6%, specificity of 72.7%, and accuracy of 86.0%. CONCLUSION: Implementation of this standardized protocol was related to a considerably low mortality rate among patients with suspected AIFRS at our Institution. Frozen-section biopsy revealed high accuracy to diagnose AIFRS. The current protocol including frozen-tissue biopsy improved the evaluation and survival rates of immunocompromised patients with presumed AIFRS.

Acute Invasive Fungal Rhinosinusitis: Frozen Section Histomorphology and Diagnosis with PAS Stain.

Acute invasive fungal rhinosinusitis (AIFRS) is a fulminant infection in immunocompromised patients requiring rapid diagnosis (DX), frequently made on frozen section (FS) of sinonasal biopsies, followed by prompt surgical debridement. However, FS interpretation is often difficult and DX sometimes not possible. In this study we sought to characterize reasons for misinterpretation and methods to improve diagnostic accuracy. The FS slides from 271 biopsies of suspected AIFRS in a 16-year period were reviewed and the morphologic features evaluated for their utility in DX. Recurring specific patterns of necrosis were identified, which to our knowledge have not been described in the literature. Although they provide strong evidence for AIFRS, identifying fungus consistently in necrotic tissue is essential for DX. Clues to identifying fungus and pitfalls in misidentification were identified, but even with expert knowledge of these, a gap in accurate DX remained. The key to FS DX of AIFRS is to improve fungus identification in necrotic tissues. Methods had been sought in the past to stain fungus at FS without consistent success. The Periodic Acid Schiff's Reaction for Fungi was modified by our histopathology department for use on frozen tissue (PASF-fs) resulting in effective staining of the fungus. It stained fungus on all 62 positive slides when applied retrospectively over hematoxylin and eosin (H&E) stained FSs and used prospectively at FS for DX. Although knowledge of histologic morphology on FS is important, the crucial value of this study is the novel use of PASF-fs to identify fungus in the DX of AIFRS.

Frozen Section as a Rapid and Accurate Method for Diagnosing Acute Invasive Fungal Rhinosinusitis.

Objective Identify methods to improve the frozen-section diagnosis of acute invasive fungal rhinosinusitis. Study Design Biopsies with frozen section for suspected acute invasive fungal rhinosinusitis were reviewed to identify causes for missed diagnoses and evaluate methods for potential improvement. Setting All aspects of the study were performed at the Penn State Milton S. Hershey Medical Center. Subjects and Methods All frozen sections performed for suspected acute invasive fungal rhinosinusitis between 2006 through 2017 were reviewed with their diagnoses compared to the final diagnoses. Sensitivity and specificity were determined for each biopsy specimen to evaluate the diagnostic method and for each patient for its effectiveness on outcome. Causes for frozen-section failures in diagnosis were identified. A periodic acid-Schiff stain for fungus (PASF) was modified for use on frozen tissue (PASF-fs) and applied both retrospectively and prospectively to frozen sections to determine its ability to identify undetected fungus and improve diagnostic sensitivity. Results Of 63 biopsies positive for acute invasive fungal rhinosinusitis, 51 were diagnosed on frozen section, while 61 were identified by including the novel PASF-fs stain, reducing the failure rate from 19% to 3%. Of 41 cases that were positive, 34 were diagnosed on frozen section. Of the 7 that were not, 5 were identified by including the PASF-fs, reducing the failure rate from 17% to 5%. Conclusions Frozen section interpretation of biopsies for suspected acute invasive fungal rhinosinusitis using a PASF-fs stain should enable a rapid and accurate diagnosis with improved outcomes by shortening the time to surgery.

Acute invasive fungal rhinosinusitis: MR imaging features and their impact on prognosis.

PURPOSE: Acute invasive fungal rhinosinusitis (AIFRS) is a life-threatening disease that is difficult to diagnose. Its overall imaging features have not been evaluated and the prognostic impact is unclear. The purpose of our study was to present MR imaging features and their impact on prognosis of AIFRS. METHODS: MR images and clinical records of 23 patients with AIFRS were retrospectively evaluated to identify the imaging features and to determine the factors affecting patients' survival. A multivariable Cox proportional hazard model was used to estimate the hazard ratio of the prognostic factors, and Kaplan-Meier survival curves were compared by using a log-rank test. RESULTS: All cases showed extra-sinonasal involvement and the orbit was the most common (65.2%, 15/23) location. The lesion enhancement pattern was classified into lack of contrast enhancement (LoCE) (47.8%, 11/23) and homogeneous (34.8%, 8/23) and heterogeneous (17.4%, 4/23) enhancement. Although LoCE showed variable signal intensity (SI), homogeneously or heterogeneously enhancing lesions showed exclusively low SI (100%, 12/12) on T2WI. Among various clinical and imaging factors, LoCE was correlated with coagulation necrosis, probably provoked by numerous fungal hyphae, and was found to be a sole independent prognostic factor for disease-specific mortality (hazard ratio = 16.819; 95% CI, 1.646-171.841, p = 0.017). In addition, patients with LoCE showed worse survival than patients without LoCE (p = 0.008). CONCLUSION: AIFRS showed frequent extra-sinonasal involvement and variable MR enhancement patterns. An enhancement pattern of LoCE was seen in about half of the cases and was a unique prognostic factor among the various clinico-radiologic factors.

Pathology of Fungal Rhinosinusitis: A Review.

Fungal rhinosinusitis (FRS) comprises a spectrum of disease processes that vary in clinical presentation, histologic appearances, and biological significance. FRS can be acute or chronic and is most commonly classified as non-invasive or invasive based on whether fungi have invaded into tissue. This manuscript will review the pathologic classification of FRS.

Acute Invasive Fungal Rhinosinusitis in Children With Hematologic Malignancies: Outcome of Surgical Treatment.

The incidence of acute invasive fungal rhinosinusitis (AIFR) is rising due to more aggressive chemotherapy and longer survival of immunosuppressed patients. Early diagnosis and appropriate but nonmutilating surgical treatment are particularly problematic in the pediatric population. This study aimed to evaluate the outcome of surgery for pediatric AIFR. Medical records of children surgically treated for AIFR between 1998 and 2014 were reviewed. Diagnosis was based on both histopathological and microbiological confirmation. Surgery was performed with curative intent and repeated for any resectable extension. The children underwent endoscopy and magnetic resonance imaging every 2 and 6 months, respectively, during the first postoperative year. Thirteen patients (2-18 years old) met the EORTC/MSG criteria for proven invasive fungal sinusitis; fungal invasion was diagnosed by preoperative biopsy and confirmed in the surgical specimen. All patients underwent an average of two endoscopic procedures (range 1-3), and four of them also underwent an open surgery. The local control rate was at least 79%. There was no facial disfiguration during follow-up (average 41 months). Although AIFR is still associated with high mortality, aggressive medical and surgical treatment provides local control in most cases. Fair outcome should encourage a maximal joint effort of pediatric hemato-oncologists and otorhinolaryngologists in the management of AIFR.

The prognostic value of gadolinium-enhanced magnetic resonance imaging in acute invasive fungal rhinosinusitis.

OBJECTIVES: This study aimed to assess the prognostic value of gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) in acute invasive fungal rhinosinusitis (AIFRS) and offer recommendations for determining surgical extent based on loss of contrast enhancement (LoCE), which reveals tissue ischemia from fungal invasion. METHODS: Preoperative and postoperative Gd-enhanced MRI was evaluated in 21 patients with confirmed AIFRS who underwent wide debridement and antifungal therapy. Patients were subdivided by AIFRS-specific survival. LoCE and contrast enhancement (CE) of intrasinonasal and extrasinonasal sites in preoperative and postoperative MRI were compared between the two groups. RESULTS: All patients had preoperative intrasinonasal LoCE and CE lesions, which did not differ between survivors and non-survivors. Bone destruction on CT was detected in 8 of 16 survivors (50%) and 4 of 5 non-survivors (80%). Intrasinonasal LoCE lesions were completely removed by surgery in all cases. Postoperative extrasinonasal LoCE lesions were found in all non-survivors but no survivors (p < 0.001). However, postoperative intrasinonasal and extrasinonasal CE lesions were detected in both survivors and non-survivors (p = 0.119 and p = 0.111, respectively). In addition, remission of hematologic diseases at the time of diagnosis of AIFRS and blood sugar control in diabetic patients were significantly associated with AIFRS-specific survival (p = 0.028 and p = 0.023, respectively). CONCLUSIONS: LoCE lesions, which have to be surgically removed, should be screened using Gd-enhanced MRI for an earlier diagnosis of AIFRS, determination of surgical extent, and management of follow-up. Remnant LoCE lesions after surgery, active hematologic diseases, and poorly controlled blood sugar adversely affect the AIFRS-survival.