Rhino-orbito-cerebral mucormycosis (ROCM) is a fulminant fungal infection associated with high morbidity and mortality rates [1–3]. Diabetes is the most common predisposing factor for ROCM [4, 5]. Other predisposing factors include malignant hematological disorders, metabolic acidosis, deferoxamine and glucocorticoid therapy, and chronic renal failure [6, 7]. Opportunistic fungi, belonging to the order Mucorales, are responsible for this rapidly progressing fatal infection [8–11]. Among the several Mucorales genera, species from the genus Rhizopus are the most common causes of ROCM and are detected in the majority of cases, followed by Lichtheimia, Mucor, Rhizomucor, Saksenaea, Apophysomyces, and Cunninghamella [12, 13]. Following the inhalation of fungal spores that are present in the environment , the fungi colonize the nasal/sinus mucosa and cause infection in neighboring areas including the orbit, cavernous sinus, and brain .
The Mucoralean fungi have angio-invasive ability and cause thrombosis of blood vessel leading to tissue necrosis . It is believed that acidosis facilitates the invasion of blood vessel walls by these fungi because these fungi have keto-reductase system, which activate in acidic pH caused by uncontrolled diabetes .
Although the combination of host factors, clinical manifestations, and radiological findings may help with early diagnosis of mucormycosis, definitive diagnosis relies on direct microscopy, histopathology, and culture of tissue samples. Deep tissue biopsy of the involved site is commonly cumbersome because the patients are often too unstable to undergo invasive procedures [18, 19]. Due to delicacy, fragility, and low viability of fungal elements, culture results are often negative. Although advanced molecular and other non-culture based approaches are promising and may improve and complement the conventional methods, diagnosis of mucormycosis remains a challenge . Early diagnosis of sino-nasal mucormycosis, management of the underlying condition, and prompt therapeutic interventions are critical for the prevention of invasion to the orbital and cerebral tissues. In the current study, we reviewed the confirmed cases of ROCM (2007–2013) referred to Bu-Ali Sina Hospital, a university-affiliated tertiary referral hospital in northern Iran, during a period of seven years. We evaluated the patients’ demographic characteristics, underlying diseases, clinical manife-stations, management, and disease outcomes.
Materials and Methods
A retrospective study was conducted on ROCM cases (2007-2013) that were recorded at the Ear, Nose and Throat (ENT) Department of Bu-Ali Sina Hospital in Sari, Iran, during a period of seven years. The study protocol was approved by the Ethics Committee of Mazandaran University of Medical Sciences (IR.MAZUMS.REC.95.1560). As this was a retrospective analysis of medical records, no written informed consent was obtained from the patients.
According to the criteria put forth by the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) for invasive fungal disease (IFD) , patients with mycological and histo-pathological evidence of mucormycosis in tissue biopsy (including observation of aseptate hyphae branching at wide angle and ribbon-like hyphae associated with tissue damage) taken by functional endoscopy sinus surgery (FESS) or needle aspiration were considered in the study as a proven case. Direct examination of biopsy or aspirated material was performed using 10% potassium hydroxide (KOH) or calcofluor white (CFW) staining solution (Polysciences, Inc., Warrington, PA, USA) . The specimens were inoculated on Sabouraud dextrose agar (SDA, Difco) with antibiotics (50 µg/ ml chloramphenicol) and incubated at 30°C up to one week. Rapid growth of grey fluffy colonies resembling cotton candy was identified at genus level based on the conventional morphological method. The growth of pure and similar colonies of Mucorales onmore than one culture media was considered significant .
All the demographic and clinical characteristics comprising of ophthalmic and neurologic manife-stations, underlying conditions, as well as medical and surgical interventions were recorded in specific data sheets and analyzed. Data obtained from computed tomography (CT) scanning of paranasal sinuses, such as the evidence of mucosal thickening, turbidity, fluid levels, bone destruction, and osteomyelitis, were recorded in data sheets, as well. To analyze the data, descriptive statistics were used in SPSS, version 14.
Over the seven-year period, 15 patients diagnosed with ROCM met the inclusion criteria. The demographic characteristics, underlying conditions, clinical manifestations, medical and surgical interventions, and diagnoses were outlined in Table 1.
The mean age of the patients was 54±11 years (age range: 28–70 years); 4 out of 15 patients (26.7%) were male and 11 (73.3%) patients were female (male: female ratio of 1: 2.7). Twelve (86.7%) patients had uncontrolled diabetes and two (13.3%) had hematological disorders; among the latter, one patient (case no. 4) had acute myeloid leukemia (AML), one patient (case no. 3) T-cell lymphoma, and one patient (case no. 2) suffered from beta-thalassemia major and secondary diabetes mellitus.
The maxillary sinus was the most frequently affected sinus (10 patients; 66.7%) followed by the ethmoid sinus (8 patients; 53.3%) and sphenoid sinus (three patients; 20%). Orbital involvement was apparent in six (40%) cases. Necrosis of the hard palate was observed in patients no. 3 and 10; both patients expired. The clinical signs and symptoms of infection in RCOM cases were presented in Table 1. Ophthalmic and facial involvements were the most common evidence of ROCM. Periorbital swelling, ocular pain, ocular ptosis and proptosis, and loss of vision were observed in 13 (86.7%) patients; facial pain, swelling, and dysesthesia at the affected site were evident in 12 (80%) patients. Nasal discharge, crust, and necrosis of the turbinate were present in nine (60%) patients. Eight (53.3%) patients had a headache 3–10 days prior to hospital admission. Fever was present in three (20%) cases and was accompanied with chills and dizziness in two (13.3%) cases. Ear pain and itching were evident in two (13.3%) cases.
|Case no.||Sex/age||Underlying disease*||Area involved (CT scan)||Clinical signs and symptoms||Histopathological findings||Mycological findings||Treatment||Outcome|
|1||M/64||UDM*||Ethmoid, maxilla,orbit,sphenoid||-Facial swelling, dysesthesia, pain-Ptosis, proptosis, loss of vision-Nasal crust, discharge, necrosis of the turbinate, cranial nerve palsy-Headache 3-10 d before hospitalization-Fever and chills||H&E(aseptate hyphae)||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement+ medical treatment with cAMB||Expired|
|2||F/28||BT, D, UDM||Ethmoid, maxilla, sphenoid||-Nasal crust, discharge, necrosis of the turbinate-Cranial nerve palsy-Headache 3-10 d before hospitalization-Fever||H&E and PAS(aseptate hyphae)||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement+ medical treatment with cAMB||Expired|
|3||F/54||MT, C||Nose, maxilla, hard palate, orbit||Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain-Nasal crust, discharge, necrosis of the turbinate-Palate necrosis-Cranial nerve palsy-Headache 3-10 d before hospitalization||H&E(aseptate hyphae)||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement+ medical treatment with cAMB||Expired|
|4||F/60||AML, C||Nose, maxilla,medial concha, orbit||Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain-Nasal crust, discharge, necrosis of the turbinate-Cranial nerve palsy||H&E(aseptate hyphae)||Direct smear (aseptate hyphae)Culture (Mucor spp.)||Sino-nasal debridement+ medical treatment with cAMB||Cured|
|5||F/59||UDM||Ethmoid, medial, inferior concha, orbit||Nasal crust, discharge, necrosis of the turbinate-Ptosis, proptosis, loss of vision, pain-Cranial nerve palsy-Headache 3-10 d before hospitalization-Ear itching, pain||Not performed||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement+ medical treatment with cAMB||Cured|
|6||F/61||UDM||Nose, orbit||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain-Nasal crust, discharge, necrosis of the turbinate-Cranial nerve palsy||H&E and PAS(aseptate hyphae)||Direct smear (aseptate hyphae)Culture (Mucor spp.)||Sino-nasal debridement+orbital exenteration + medical treatment with cAMB||Cured|
|7||M/47||UDM||Maxilla, posterior turbinate, orbit||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain||H&E(aseptate hyphae)||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement||Cured|
|8||F/69||UDM||Ethmoid, orbit, medial concha||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain-Headache 3-10 d before hospitalization--Ear itching, pain||H&E (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement||Cured|
|9||F/47||UDM||Ethmoid, orbit||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain||H&E and PAS (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (not performed)||Sino-nasal debridement||Cured|
|10||F/61||UDM||Maxilla, nose, hard palate, orbit||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, and pain-Nasal crust, discharge, necrosis of the turbinate-Palate necrosis-Cranial nerve palsy-Headache 3-10 d before hospitalization||H&E (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (Mucor spp.)||Sino-nasal debridement+ Medical treatment with cAMB||Expired|
|11||M/70||UDM||Ethmoid, sphenoid||-Facial swelling, dysesthesia, and pain||H&E (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (Rhizopus spp.)||Sino-nasal debridement+ medical treatment with cAMB||Cured|
|12||F/56||UDM||Ethmoid, maxilla, orbit||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain-Nasal crust, discharge, necrosis of the turbinate-Fever and chills||H&E and PAS (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement+ medical treatment with cAMB||Cured|
|13||M/53||UDM||Ethmoid, maxilla, orbit||-Ptosis, proptosis, loss of vision, chemosis, pain-Cranial nerve palsy-Headache 3–10 d before hospitalization||H&E (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (negative)||Sino-nasal debridement+ medical treatment with cAMB||Cured|
|14||F/52||UDM||Maxilla, orbit||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain||H&E (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (not performed)||Sino-nasal debridement+ medical treatment with cAMB||Cured|
|15||F/33||UDM||Maxilla, orbit, nose||-Facial swelling, dysesthesia, and pain-Ptosis, proptosis, loss of vision, pain-Nasal crust, discharge, necrosis of the turbinate-Cranial nerve palsy-Headache 3-10 d before hospitalization||H&E and PAS (aseptate hyphae)||Direct smear (aseptate hyphae)Culture (Mucor spp.)||sino-nasal debridement+Orbital exenteration+ Medical treatment with cAMB||Cured|
|* UDM: uncontrolled diabetes mellitus; BT: beta-thalassemia; AML: acute myeloid leukemia; MT: malignant T-cell lymphoma; D: deferoxamine therapy; C: chemotherapy; cAMB conventional amphotericin B|
Four (26.7%) patients had history of tooth extraction before the onset of disease manifest-tations (case no. 3: three weeks before; and cases no. 2, 7, and 13: one week before the onset of manifestations). Two (13.3%) patients had history of surgery (case no. 9: two sinus surgeries; and case no. 13: a cataract surgery eight months before the onset of manifestations). FESS was conducted in all the patients and biopsies of the mucosa were obtained from the involved areas under endoscopic visualization. Diagnosis in 5/15 (33.3%) of the cases was confirmed by culture and in 8/15 (53.3%) cases, no growth in culture was noted (Table 1). Amphotericin B in combination with surgical debridement was used in the treatment of 80% of the cases.
Furthermore, 11 out of 15 (73.3%) patients who were diagnosed early and underwent medical and extensive surgical debridement of the infected tissues survived. Conventional amphotericin B (cAMB) treatment (average total dose of 50 mg/day) was administered for 5-31 days. Patients at an advanced stage of the disease at the time of diagnosis received the shortest periods of treatment. Despite the initiation of the treatment, these patients deteriorated rapidly and died shortly. Curative surgical interventions, such as ethmoidectomy, sphenoiddectomy, septectomy, and maxillary antrostomy, were applied in nine patients (60%; cases no. 1–5 and 10–13). Debridement of tissue and polypotomy were performed in two (13.3%) patients (cases no. 7 and 8); ethmoid suction was performed in cases no. 9 and 14 (Table 1).
Three out of 15 (20%) patients (cases no.7–9) were diagnosed at an early stage and cured only with surgical debridement of the affected tissues through FESS; in case no. 7, the ethmoid sinus was not affected and the right maxillary sinus was turbid and polypoid. In case no. 8, turbidity was observed in the medial concha; patient no. 9 had extensive bloody nasal discharge with ethmoid involvement and underwent right ethmoidectomy and antrostomy. Despite medical and surgical treatment, 4 out of 15 (26.6%) patients died (cases no. 1–3, and 10).
Fungal infections caused by the members of the order Mucorales (i.e., mucormycosis) are characterized by severe morbidity and high mortality . These life-threatening infections develop expediently and spread by a rapid angioinvasion, causing thrombosis of the blood vessels and tissue necrosis in immunocompromised hosts . The annual incidence of mucormycosis is 1.7 per 1,000,000 individuals . The disease rarely affects healthy individuals . In patients suffering from mucormycosis, the involvement is most commonly rhino orbital cerebral (33-49%), cutaneous (10-16%), pulmonary (10-11%), disse-minated (6-12%), or gastrointestinal (2-11%) (23). ROCM refers to infection of the nose and sinuses, with a critical involvement of the eye and cranial structures .
Predisposing factors and pathogenesis
The majority (86.7%) of our cases had uncontrolled diabetes; one of these patients had beta-thalassemia major and suffered from secondary diabetes mellitus because of iron overload and was receiving iron chelation therapy for years. Moreover, 13.3% of the cases had a hematological malignancy and were receiving chemotherapy for 18 months, which resulted in functional and/or quantitative deficiencies in neutrophils and macrophages, as well as susceptibility to mucormycosis.
In line with our study, other studies also showed that diabetes mellitus is the main underlying condition of ROCM followed by hematological disorders and transplantation due to chemotherapy causing immune defects [1, 3, 5, 9, 26–29]. In a study of 98 cases of mucormycosis in Iran, Vaezi et al.  reported that uncontrolled diabetes was the most common underlying condition. Pak et al.  stated that in 40% of all cases of mucormycosis, diabetes mellitus was the most common underlying disease present in 70% of rhino cerebral mucormycosis cases. In review of 929 mucor-mycosis cases, Roden et al.  also ascribed that diabetes was the main predisposing factor. Mane et al.  reported 13 cases of ROCM with diabetes as the underlying disease in all of them. Sachdeva et al.  described six cases of ROCM all of whom had diabetes.
The Mucoralean fungi are highly common in nature. Their spores are widespread and found in decaying foods, plants, and soil. The most common route of entry of sporangiospores is via respiration. After sporangiospore inhalation, the spores enter the nose, settle on the nasal turbinate, and may germinate to form hyphae and invade the tissues in immunocompromised hosts and patients with uncontrolled diabetes . In uncontrolled diabetes patients with ketoacidosis, neutrophil functions including chemotaxis, adherence, and oxidative burst are impaired [33–36], thereby failing to damage the hyphae. Uncontrolled diabetes generates favorable conditions facilitating the growth of Rhizopus oryzae, a common agent of mucormycosis; this organism produces keto-reductase as a virulence factor that enables them to grow in the acidic and glucose-rich environment generated in ketoacidosis states .
Mucoralean fungi have a remarkable affinity for small- and medium-sized arteries and penetrate the internal elastic lamina, causing endothelial damage, thrombosis, and tissue infarction . In a healthy host, tissue macrophages and functional neutrophils effectively respond to the sporangiospores and hyphal elements of the Mucoralean fungi. Macrophages digest and kill the spores by non-oxidative mechanisms [32, 39] and neutrophils damage the hyphae by releasing the contents of their granules, thereby preventing fungal invasion of the surrounding tissues .
In the current study, 20% of the patients with ROCM were associated with hematological disorders such as AML and T-cell lymphoma. Chemotherapy-induced neutropenia has led to an increase in the incidence of ROCM in patients with hematologic malignancy. Quantitative and qualitative abnor-malities in neutrophils and macrophages result in elevated risk of mucormycosis . In addition, one patient in the current study had beta-thalassemia major and secondary diabetes mellitus. Iron overload associated with blood transfusion enhanced the risk of mucormycosis.
Members of the order Mucorales are ferrophilic. High glycosylation of proteins, such as transferrin and ferritin, results in a decreased affinity of these proteins for iron, making free iron available to the microorganisms [41–45]. The importance of iron in the pathogenesis of mucormycosis was described in several studies on chronic deferoxamine therapy and iron overload states. Deferoxamine acts as a siderophore for the Mucorales fungi and increases their iron uptake, and in turn, enhances hyphal growth [46–50].
Common mucormycosis agents
In the present study, only 33.3% of the cases were confirmed by culture. As a caveat, the report of the causative agents may be unreliable because more than half of the cases were culture-negative and were unconfirmed by molecular methods. Recovery rate of zygomycetes in culture is considerably low . Low recovery might be as a result of few viable fungal elements, delay in culturing, long storage in refrigerator, and high manipulation (grinding) of tissue samples . According to several reports, the most common cause of mucormycosis is R. oryzae, followed by Mucor, Cunninghamella, Apophysomyces, and Lichtheimia species [8–11, 12, 28, 52].
The extent and typical clinical presentations
In this study, ptosis and ophthalmoplegia (13/15 or 86.7%) as well as facial involvement symptoms (12/15 or 80.0%) were the typical manifestations. Cutaneous or mucosal necrosis, facial palsy, and diplopia are noted in late stages of the disease . These were apparent in four of our cases, all with paranasal sinus involvement; prognosis was poor and these patients died of infection.
In agreement with our findings, there are several reports on the most common manifestations of mucormycosis in ROCM patients indicating ptosis, proptosis, periorbital swelling, facial swelling, and dysesthesia on the involved side and black necrotic area in the turbinate, palate, and other involved sites [1–4, 6, 7, 9, 12, 30, 32,].
The disease usually starts in the nasal mucosa, turbinate, or palate and spreads to the paranasal sinuses; it spreads to the retro-orbital region via the ethmoid sinus. Kulkarni et al.  proposed that the fungi enter the anterior ethmoidal sinus, which could not have any presentations until they spread to the orbit. Additionally, the cribriform plate and the roof of the orbit are very thin and could be portal of entry to the intracerebral area. The disease may also progress through the retro-orbital region or cause sphenoid sinus involvement. Sadr-Hosseini et al.  reported that although the intracranial spread of fungi can occur via several routes, the pterygopalatine space is the main portal of entry in the majority of cases. The authors determined that the disease spread to the orbit and soft facial tissue from pterygopalatine space, and then through the inferior orbital fissure, extend to the retro-global area of the orbit, resulting in ophthalmic manifestations. Pterygopalatine involvement was also reported in other studies [55–57].
Similarly, Pillsbury and Fischer  proposed that the infection begins in the nose and spreads to the paranasal sinuses and orbit, and after invading the orbit, it can reach the central nervous system (CNS) tissue. Diplopia and ophthalmoplegia are the initial findings of the cavernous sinus involvement, which are observed before any alterations are apparent by diagnostic imaging. When entering posteriorly to the optic foramen, these fungi cause edema, inflammation, necrosis, and damage to the ophthalmic artery and optic nerves. The orbital apex syndrome may therefore manifest by chemosis, ptosis, proptosis, loss of vision, and blindness [59, 60]. Bhadada et al.  reported six patients with ROCM and type I diabetes mellitus. They indicated proptosis and ptosis as the most common symptoms. Yohai et al.  and Ferry et al.  reported proptosis and ophthalmoplegia in the majority of their patients.
Definitive diagnosis is based on histopa-thological examination of biopsy specimens from the involved area. In the present study, a similar approach was used successfully in all the patients. The Mucoralean fungi appear as broad aseptate hyphae, 10–50 µm in size, with right angle branching . Histological evaluation is consi-dered more sensitive than culturing [62, 63].
Imaging is very important and useful for assessing the extent of disease. CT scanning provides evidence for the thickening of the mucosa and turbidity in the sinuses. Infection spread to the orbit and cranial area can be evaluated by magnetic resonance imaging (MRI) . Opacification of the paranasal sinuses is the principal radiographic finding concerning the sinuses during mucor-mycosis. CT scanning may also reveal fluid levels, bone destruction, and osteomyelitis [65–67].
To prevent spread of infection to the orbit compartment, early diagnosis of sinusitis in mucormycosis is of great significance. It was shown that even 12 hours delay in diagnosis could be fatal and studies on autopsy reported that 50% of diagnoses were postmortem [68, 69].
All of our cases were confirmed by histological examination of biopsy specimens from sinus endoscopy and broad, coenocytic hyphae were detected. Diagnostic nasal endoscopy was performed on all the patients, and turbidity accompanied by thickening of the involved area was observed.
Treatment and prognosis
In the current study, 80% of the patients received medical treatment in addition to surgical debridement of the affected area and survived. The patients were diagnosed at late stages of the disease with an extensive involvement of the sinuses and the treatment was not effective. Ericson et al.  reported survival of 80% of the patients receiving medical and surgical treatment. Straus et al.  reported 40% survival of patients. Mortality rate is high in patients with CNS involvement in initial examination . In ROCM, delayed diagnosis and treatment leads to facial necrosis, bilateral sinus involvement, and hemiparesis .
Endoscopic sinus surgery may help patients with focal and localized disease and is associated with low morbidity . The main approaches to the treatment of ROCM include management of hyperglycemia and acidosis, systemic anti-fungal therapy with amphotericin B, and immediate aggressive surgical resection of the involved area. The granulocyte colony-stimulating factor (G-CSF) may help reconstitute host defense; hyperbaric oxygen can inhibit the growth of microorganisms by reducing tissue hypoxia [65, 68].
Curative surgical procedures, both endoscopic and open techniques, are utilized to debride the whole necrotic tissues. These modalities include Caldewell-Luc, medial or radical ethmoidectomy, maxillectomy, sphenoidectomy, and even orbital exenteration, depending on the involved area. Medical management alone is not effective since vascular thrombosis results in poor drug delivery to the site of infection. Prognosis is directly associated with time interval before diagnosis and treatment. Early diagnosis and initiation of proper treatment are extremely important for successful eradication of the infection and patient survival. Teamwork, with the involvement of highly skilled ENT surgeons, neurologists, ophthalmologists, and dental specialists is critical in the management of ROCM patients [69, 73].
The prevalence of diabetes in developing countries, as a common risk factor for ROCM, has led to an increase in the incidence of ROCM. Health care surveillance programs, awareness of the clinicians, and cooperation of mycologists and pathologists can lead to early and accurate diagnosis and facilitate management of this devastating infection. Patients with hematological malignancies presenting with periorbital pain and swelling or blood-stained nasal discharge poorly respond to prolonged antibiotic therapy and multiple cranial nerve palsy and should raise the suspicion of ROCM.
- Chakrabarti A, Das A, Sharma A, Panda N, Das S, Gupta KL. Ten years’ experience in zygomycosis at a tertiary care centre in India. J Infect. 2001; 42(4):261-6.
- Gamaletsou MN, Sipsas NV, Roilides E. Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Rep. 2012; 14(4):423-34.
- Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005; 41(5):634-53.
- Prabhu RM, Patel R. Mucormycosis and entomoph-thoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect. 2004; 10(Suppl 1):31-47.
- Lanternier F, Lortholary O. Zygomycosis and diabetes mellitus. Clin Microbiol Infect. 2009; 15(5):21-5.
- Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycete in human disease. Clin Microbiol Rev. 2000; 13(2):236-301.
- Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis Pathophysiology presentation and management. Clin Microbiol Rev. 2005; 18(3):556-69.
- Antoniadou A. Outbreaks of zygomycosis in hospitals. Clin Microbiol Infect. 2009; 15(Suppl 5):55-9.
- Cunha MA, Nery AF, Lima FP, Diniz Junior J, Maciel Neto J, Calado NB. Rhinocerebral zygomycosis in a diabetic patient. Rev Soc Bras Med Trop. 2011; 44(2):257-9.
- Mohebbi A, Jahandideh H, Harandi AA. Rare presentation of rhino-orbital-cerebral zygomycosis: bilateral facial nerve palsy. Case Rep Med.. 2011; 2011:216404.
- Richardson M. The ecology of the Zygomycetes and its impact on environmental exposure. Clin Microbiol Infect. 2009; 15(Suppl 5):2-9.
- Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M. A global analysis of mucormycosis in France: the Retro Zygo Study (2005–2007). Clin Infect Dis. 2012; 54(Suppl 1):S35-43.
- Gomes MZ, Lewis RE, Kontoyiannis DP. Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species. Clin Microbiol Rev. 2011; 24(2):411-45.
- Yohai RA, Bullock JD, Aziz AA, Market RJ. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol. 1994; 39(1):3-22.
- Parfy AN. Improved diagnosis and prognosis of mucormycosis: a clinicopathological study of 33 cases. Medicine. 1986; 65(2):113-23.
- Ferry AP, Abedi S. Diagnosis and management of rhino-orbitalcerebral mucormycosis (phycomycosis) A report of 16 personally observed cases. Ophthalmology. 1983; 90(9):1096-104.
- West BC, Oberie AD, Know-Chung KJ. Mucormycosis caused by Rhizopus microspores var microspores: cellulitis in the keg of a diabetic patient cured by amputation. J Clin Microbiol. 1995; 33(12):3341-4.
- De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008; 46(12):1813-21.
- Walsh TJ, Gamaletsou MN, McGinnis MR, Hayden RT, Kontoyiannis DP. Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (zygomycosis). Clin Infect Dis. 2012; 54(Suppl 1):S55-60.
- Dannaoui E. Molecular tools for identification of Zygomycetes and the diagnosis of zygomycosis. Clin Microbiol Infect. 2009; 15(Suppl 5):66-70.
- Haghani I, Amirinia F, Nowroozpoor Dailami K, Shokohi T. Detection of fungi by conventional methods and semi-nested PCR in patients with presumed fungal keratitis. Curr Med Mycol. 2015; 1(2):31-8.
- Greenberg RN, Scott LJ, Vaughn HH, Ribes JA. Mucormycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis. 2004; 17(6):517-25.
- Bouza E, Munoz P, Guinea J. Mucormycosis: an emerging disease. Clin Microbiol Infect. 2006; 12(7):7-23.
- Singh J, Prasdnna NM. Phycomycosis in an apparently normal host. J Otolaryngol. 1977; 6(1):37-42.
- Smith HW, Kirchner JA. Cerebral mucormycosis: a report of three cases. AMA Arch Otolaryngol. 1958; 68(6):715-26.
- Petraitis V, Petraitiene R, Antachopoulos C, Hughes JE, Cotton MP, Kasai M. Increased virulenceof Cunninghamella bertholletiae in experimental pulmonary mucormycosis: correlation with circulating molecular biomarkers, sporangiospore germination and hyphal metabolism. Med Mycol. 2013; 51(1):72-82.
- O'Connell MA, Pluss JL, Schkade P, Henry AR, Goodman DL. Rhizopus-induced hypersensitivity pneumonitis in a tractor driver. J Allergy Clin Immunol. 1995; 95(3):779-80.
- Pak J, Tucci VT, Vincent AL, Sandin RL, Greene JN. Mucormycosis in immunochallenged patients. J Emerg Trauma Shock. 2008; 1(2):106-13.
- Vaezi A, Moazeni M, Rahimi MT, de Hoog S, Badali H. Mucormycosis in Iran: a systematic review. Mycoses. 2016; 59(7):402-15.
- Mane RS, Watve JK, Mohite AA, Patil BC. Rhinocerebral mucormycosis: a deadly disease on the rise. Indian J Otolaryngol Head Neck Surg. 2007; 59(2):112-5.
- Sachdeva K. Rhino-oculo cerebral mucormycosis with multiple cranial nerve palsy in diabetic patient: review of six cases. Indian J Otolaryngol Head Neck Surg. 2013; 65(4):375-9.
- Sugar AM. Mucormycosis. Clin Infect Dis. 1992; 14(Suppl 1):S126-9.
- Diamond RD, Clark RA. Damage to Aspergillus fumigatus and Rhizopus oryzae hyphae by oxidative and nonoxidative microbicidal products of human neutrophils in vitro. Infect Immun. 1982; 38(2):487-95.
- Waldorf AR, Levitz SM, Diamond RD. In vivo bronchoalveolar macrophage defense against Rhizopus oryzae and Aspergillus fumigatus. J Infect Dis. 1984; 150(5):752-60.
- Waldorf AR, Ruderman N, Diamond RD. Specific susceptibility to mucormycosis in murine diabetes and bronchoalveolar macrophage defense against Rhizopus. J Clin Invest. 1984; 74(1):150-60.
- Mowat A, Baum J. Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N Engl J Med. 1971; 284(12):621-7.
- Marx RE, Stern D. Oral and maxillofacial pathology: a rationale for diagnosis and treatment. Quintessence Publishing: Chicago; 2006.
- Kulkarni NS, Bhide AR, Wadia RS. Rhinocerebral mucormycosis: an analysis of probable mode of spread and its implication in an early diagnosis and treatment. Indian J Otolaryngol Head Neck Surg. 2005; 57(2):121-4.
- Levitz SM, Selsted ME, Ganz T, Lehrer RI, Diamond RD. In vitro killing of spores and hyphae of Aspergillus fumigatus and Rhizopus oryzae by rabbit neutrophil cationic peptides and bronchoalveolar macrophages. J Infect Dis. 1986; 154(3):483-9.
- Roilides E, Kontoyiannis DP, Walsh TJ. Host defenses against Zygomycetes. Clin Infect Dis. 2012; 54(Suppl 1):S61-6.
- Bybee JD, Rogers DE. The phagocytic activity of polymorphonuclear leukocytes obtained from patients with diabetes mellitus. J Lab Clin Med. 1964; 64:1-13.
- Ibrahim A, Spellberg B, Walsh TJ, Kontoyiannis DP. Pathogenesis of mucormycosis. Clin Infect Dis. 2012; 54(Suppl 1):S16-22.
- Baldwin DA, De Sousa DM, Von Wandruszka RM. The effect of pH on the kinetics of iron release from human transferrin. Biochim Biophys Acta. 1982; 719(1):140-6.
- Artis WM, Fountain JA, Delcher HK, Jones HE. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes. 1982; 31(12):1109-14.
- Espinoza CG, Halkias DG. Pulmonary mucormycosis as a complication of chronic salicylate poisoning. Am J Clin Pathol. 1983; 80(4):508-11.
- de Locht M, Boelaert JR, Schneider YJ. Iron uptake from ferrioxamine and from ferrirhizoferrin by germinating spores of Rhizopus microsporus. Biochem Pharmacol. 1994; 47(10):1843-50.
- Boelaert JR, Fenves AZ, Coburn JW. Deferoxamine therapy and mucormycosis in dialysis patients: report of an international registry. Am J Kidney Dis. 1991; 18(6):660-7.
- Boelaert JR, van Roost GF, Vergauwe PL, Verbanck JJ, de Vroey C, Segaert MF. The role of desferrioxamine in dialysis-associated mucormycosis: report of three cases and review of the literature. Clin Nephrol. 1988; 29(5):261-6.
- Maertens J, Demuynck H, Verbeken EK, Zachée P, Verhoef GE, Vandenberghe P. Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant. 1999; 24(3):307-12.
- Boelaert JR, de LochtM, Van Cutsem J, Kerrels V, Cantinieaux B, Verdonck A. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection: in vitro and in vivo animal studies. J Clin Invest. 1993; 91(5):1979-86.
- Lass-Flörl C. Zygomycosis: conventional laboratory diagnosis. Clin Microbiol Infect. 2009; 15(Suppl 5):60-5.
- Salehi E, Hedayati MT, Zoll J, Rafati H, Ghasemi M, Doroudinia A. Discrimination of Aspergillosis, Mucormycosis, Fusariosis, and Scedosporiosis in formalin-fixed paraffin-embedded tissue specimens by use of multiple Real-Time Quantitative PCR Assays. J Clin Microbiol. 2016; 54(11):2798-803.
- Bhadada S, Bhansali A, Reddy KS, Bhat RV, Khandelwal N, Gupta AK. Rhino-orbito-cerebral mucormycosis in type 1 diabetes mellitus. Indian J Pediatr. 2005; 72(8):671-4.
- Hosseini SM, Borghei P. Rhinocerebral mucormycosis: pathways of spread. Eur Arch Otorhinolaryngol. 2005; 262(11):932-8.
- Alleyne CH Jr, Vishteh AG, Spetzler RF, Detwiler PW. Long term survival of a patient with invasive cranial base rhinocerebral mucormycosis with combined endovascular, surgical and medical therapies: case report. Neurosurgery. 1999; 45(6):1461-3.
- Pelton RW, Peterson EA, Patel BC, Davis K. Successful treatment of rhino-orbital mucormycosis without exentration: the use of multiple treatment modalities. Ophthal plast Rconstr Surg. 2001; 17(1):62-6.
- Harrill WC, Sewart MG, Lee AG, Cernomg P. Chronic rhinocerebral mucormycosis. Laringoscope. 1996; 106(10):1292-7.
- Pillsubry HC, Fischer ND. Rhinocerebral mucor-mycosis. Arch Otolaryngol. 1977; 103(10):600-4.
- Gamaletsou MN, Sipsas NV, Roilides E, Walsh TJ. Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Rep. 2012; 14(4):423-34.
- Kwon-Chung KJ. Taxonomy of fungi causing mucormycosis and entomophthoramycosis (zygo-mycosis) and nomenclature of the disease: molecular mycologic perspectives. Clin Infect Dis. 2012; 54(Suppl 1):S8-15.
- Spelberg B, Walsh TJ, Kontoyiannis DP, Edwards J Jr, Ibrahim AS. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis. 2009; 48(12):1743-51.
- Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last 30 years. Arch Intern Med. 1999; 159(12):1301-9.
- Kantarcioglu AS, Yücel A, Nagao K, Sato T, Inci E, Ogreden S. A Rhizopus oryzae strain isolated from resected bone and soft tissue specimens from a sinonasal and palatal mucormycosis case Report of a case and in vitro experiments of yeast like cell development. Med Mycol. 2006; 44(6):515-21.
- Grant P, Skilbeck CJ. Rhinocerebral mucormycosis: a devastating rhinological condition. Practical Diabetes. 2014; 31(1):37-9.
- Maartens G, Wood MJ. The clinical presentation and diagnosis of invasive fungal infections. J Antimicrob Chemother. 1991; 28(Suppl A):13-22.
- Thahim K, Jawaid MA, Marfani MS. Presentation and management of allergic fungal sinusitis. J Coll Physicians Surg Pak. 2007; 17(1):23-7.
- Lazo A, Wilner HI, Metes JJ. Craniofacial mucormycosis: computed tomographic and angio-graphic findings in two cases. Radiology. 1981; 139(3):623-6.
- Couch L, Theilen F, Mader JT. Rhinocerebral mucormycosis with cerebral extension successfully treated with adjunctive hyperbaric oxygen therapy. Arch Otolaryngol Head Neck Surg. 1988; 114(7):791-4.
- Munir N, Jones NS. Rhinocerebral mucormycosis with orbital and intracranial extension: a case report and review of optimum management. J Laryngol Otol. 2007; 121(2):192-5.
- Ericsson M, Anniko M, Gustafsson H, Hjalt CA, Stenling R, Tärnvik A. A case of chronic progressive rhinocerebral mucormycosis treated with liposomal amphotericin B and surgery. Clin Infect Dis. 1993; 16(585):586-6.
- Strauss MD, Kennedy RJ, Adam RD. Therapy with amphothericin B lipid complex. Arch Intern Med. 1996; 156:337-40.
- Choi HY, Jew JN, Jackson IT. Rhinocerebral mucormycosis combined with brain abscess. Eur J Plast Surg. 1992; 15(3):146-50.
- Jiang Rs, Hsucy CY. Endoscopic sinus surgery for rhinocerebral mucormycosis. Am J Rhinol. 1999; 13(2):105-9.