- Open Access
A retrospective analysis for the management of oromaxillofacial invasive mucormycosis and systematic literature review
BMC Oral Health volume 23, Article number: 115 (2023)
Mucormycosis is a type of fatal infectious disease, rarely involved in the oromaxillofacial region. This study aimed to describe a series of 7 cases with oromaxillofacial mucormycosis and to discuss the epidemiology, clinical features, and treatment algorithm thereof.
Seven patients in the author’s affiliation have been treated. They were assessed and presented as per their diagnostic criteria, surgical approach, and mortality rates. Reported cases of mucormycosis originally happened in craniomaxillofacial region were synthesized through a systematic review so as to better discuss its pathogenesis, epidemiology, and management.
Six patients had a primary metabolic disorder, and one immunocompromised patient had a history of aplastic anemia. The criteria for a positive diagnosis of invasive mucormycosis were based on clinical presentation of signs and symptoms, and a biopsy for microbiological culture and histopathologic analysis. Each patient used antifungal drugs and five of them also underwent surgical resection at the same time. Four patients died due to the unregulated spread of mucormycosis, and one patient died owing to her main disease.
Although uncommon in clinical practice setting, mucormycosis should be of great concern in oral and maxillofacial surgery, due to the life-threatening possibility of this disease. The knowledge of early diagnosis and prompt treatment is of utmost importance for saving lives.
Mucormycosis is a saprophytic opportunistic, but a highly aggressive fungal infection caused by the class Zygomycetes, belonging to members of Mucorales order, subphylum Mucoromycotina . Mainly, the genera of Absidia, Mucor, Rhizomucor, and Rhizopus are responsible for its aetiology, although Apophysomyces, Cunninghamella, and Saksenaea can also be associated pathogenic species [2, 3]. It is an uncommon, rapidly emerging infection of fungi, with high morbidity and mortality that can produce widespread oral-maxillofacial tissue necrosis [4, 5]. Due to the rarity of this disease (especially occurred in craniofacial units), it is almost impossible to conduct multicentric and randomized clinical trials with large sample size; hence, most of the existent data in respect of epidemiological characteristics, diagnostic strategy, and therapeutic decision-making originate from case series and case reports.
According to the published literature, the prevalence of mucormycosis is the highest in India that stands approximately at 14 per 100,000 populations, whereas it varies between 0.01 and 0.2 for each 100,000 population in European countries and the United States . However, the information on the incidence of oromaxillofacial mucormycosis manifestations is limited. Reported cases presented mucoraceous lesions in the rhino-orbito-cerebral (34%), pulmonary (20%), cutaneous (22%), disseminated (13%), gastrointestinal (8%), and other unusual rare sites (3%) including renal, middle ear, parotid gland, mediastinum, heart and valves, uterus, urinary bladder, cervical lymph nodes, and even oral cavity [6, 7]. Following the initial infection, mucormycosis typically progresses quickly, with rapid invasion of blood vessels resulting in tissue necrosis and thrombosis [8, 9].
The diagnosis and treatment of oromaxillofacial mucormycosis is difficult because of its scarcity. Grasping the magnitude of this formidable challenge would help advance our understanding of oromaxillofacial mucormycosis. Our study, therefore, sought to investigate the diagnostic criteria and treatment approach in the Department of Oromaxillofacial Oncology and Surgery, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China between 2013 and 2021, through 7 rare cases that demonstrate oromaxillofacial mucormycosis; as well as update and collate the review of literature regarding mucormycosis, exploring the epidemiological characteristics, course of infection, treatment regimens, and clinical outcomes.
The present study was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (approval No. 52966-05/08/2022).
On the whole, 7 cases admitted to our department from 2013 to 2021 were enrolled in this study. For the objective of guiding internal medication, all patients were assigned to consult a clinical pharmacist group as well. Clinical presentation of signs and symptoms, blood routine examination, blood biochemistry indexes, liver/kidney function tests, radiographic imaging, treatment procedure, post-operative histopathological findings, pathogenic microbes’ culture and antimicrobial susceptibility test, and survival and prognosis were retrospectively analyzed and reported. The study protocol was approved by the Ethics Committee, the First Affiliated Hospital of Xinjiang Medical University and followed the principles outlined in the Declaration of Helsinki. Written informed consent to participate in this study was provided by the participants or legal guardian/next of kin. All data generated or analyzed during this study are included in this published article.
In this case series, female patients were affected less frequently than the males with a ratio of 2:5. The median age of patients was 45.0 year-old, ranging from 27 to 63. All seven patients were moderately built and moderately nourished, of which six were known as a history of poorly controlled diabetes mellitus without regular treatment (insulin injection/oral hypoglycemic medication); and one patient was diagnosed with severe aplastic anemia (Table 1). Three of these patients had undergone tooth extraction under local anesthesia but without any complications. The lesion of all patients were characterized by extensive ulceration involved orbital part, nasal cavity, maxilla, maxillary sinus, hard palate and alveolar process, resulting in exposed bone and teeth exfoliation (Fig. 1). Possible orbital cellulitis, osteomyelitis as well as maxillary sinusitis mimicking pain or toothache presented in all 7 cases (100%) and fever in 3 cases (42.86%) (Table 1). Total features of craniomaxillofacial computerized tomography (CT) scanning our patients revealed clouding haziness in the maxilla; maxillary sinus thickening/fullness; extensive soft tissue swelling (Fig. 2).
Prior to surgical operation, 6 of our patients underwent endocrine therapy to treat their primary illness; for the remaining aplastic anemia case, we planned to transfuse platelets during surgery, in cases where platelet count did not reach the minimum level (greater than 50,000). Antifungal pharmacologic (taking amphotericin B as the principal administration) and comprehensive surgical (partial or total maxillectomy, or inferior conchotomy and ostectomy of maxillary sinus) treatment were given to five patients (Table 1). And the surgeries were performed as soon as possible. The overall number of deaths was 5 (71.43%); nevertheless, only 1 patient (20%) was resulted from her primary disease and the other 4 patients’ deaths were caused by the disseminated fungal infections (80%).
The review section was registered on PROSPERO (International Prospective Register of Systematic Reviews) (CRD42022382257). We searched for relevant articles within several databanks (Pubmed, Embase, Web of Science, Ovid MEDLINE, and Scopus) published from database inception until June 2022. Search strings used were “mucormycosis”, “Zygomycetes”, “Mucorales”, “Mucoromycotina”, “fungal infections”, “head and neck region”, “maxillofacial” and “oral cavity”, in combination with Boolean Operators ‘OR’ and ‘AND’. We excluded studies lacking the necessary data and cases with other concomitant suppurative infection lesions resulted from bacteria, such as Staphylococcus aureus, Streptococcus, and Escherichia coli. The resulting publications were searched, and the references of all articles were verified to decrease the possibility of omitting relevant publications. The initial search and review of references retrieved 329 related articles, 183 of which were rejected because of information deficit after screening the titles and abstracts. Two experienced investigators (C. Li and Z. Gong) independently extracted the following characteristics from each eligible study: name of the first author, year of publication, geographical location, demographic information, scope of involvement, clinical manifestation, care given, follow-up period, and outcome (Table 2). The results of the systematic literature retrieval have been depicted in Fig. 3.
We included 48 articles [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57] with available and suitable data, contributing to the craniomaxillofacial mucormycosis. A total of 88 patients suffered from mucormycosis, of whom 28 (31.82%) were secondary to tooth extraction. The majority of patients were aged 45 to 65 years (55.68%, n = 49), and males were a little more than females with a sex ratio of 1.59:1 (Mn = 54, Fn = 34) (Fig. 4). These cases have been reported from across the world, among them, 39 cases (44.32%) from India; 14 (15.91%) from the United States; 11(12.50%) from Israel; 4 (4.55%) from Turkey; 3 (3.41%) from Italy; 2 (2.27%) from Thailand, Singapore, Iran and Oman; 1 case each (1.14%) from Canada, Saudi Arabia, Bahrain, United Arab Emirates, South Africa, Indonesia, Egypt, Greece and France (Fig. 5). The fundamental conditions predisposing mucormycosis involved in cranio-maxillo-facial region were as follows: a. diabetes mellitus with or without ketoacidosis (25 cases, 28.41 percent); b. acute/chronic myeloid leukemia (12 cases, 13.64 percent); c. acute lymphoblastic leukemia (4 cases, 4.55 percent); d. diabetes along with renal failure/hypertension (5 cases, 5.68 percentage); e. diabetics along with leukemia/neutropenia (3 cases, 3.41 percentage); f. diabetes along with asthma/hypertension (3 cases, 3.41 percentage); g. lymphoma (2 cases, 2.27 percentage); h. leukemia along with renal failure, i. generalized Castleman disease, j. chronic obstructive pulmonary disease treated with corticosteroids, k. cardiovascular stroke, l. tetralogy of fallot, m. neuroblastoma, n. long-term of intermittent systemic antibiotics, o. Burkitt leukemia (1 case, 1.14 percentage); notably, as well as p. diabetes mellitus along with COVID-19 (20 cases, 22.73 percentage). But, there also exited non-immunocompromised patients (6 cases, 6.82 percentage) suffering with this fungal infection (Table 2).
Mucormycosis, as a rare and fatal deep fungal infection, is given rise to the family Mucoraceae (Mucorales order, in detail, the Absidia, Mucor, Rhizomucor, Rhizopus genera can be the most frequently isolated strain from infecting patients) [58, 59]. These fungi are recognized as filamentous, ferrophillic, saprophytic, and ubiquitous in the nature, collectively known as phycomycetes . Changes in molecular taxonomy and nomenclature support and decide the use of the appropriate name mucormycosis instead of the broader name zygomycosis, which describes any invasive fungal infection caused by the former Zygomycota phylum species [61, 62].
Due to its scarcity, this is always being a formidable challenge for maxillofacial clinicians to work on the diagnosis of mucormycosis, which is also the key crux to the entire therapeutic schedule. Based on the microbiological characteristics of mucormycosis, the experience of our clinical practice as well as the information of our critical review, we reckon that some points deserve attention as the following sections.
(1) Disease site. Generally, mucormycosis can be seen in pulmonary, cutaneous, rhino-orbito-cerebral, and even gastrointestinal infections [63,64,65,66]. Among them, rhino-orbito-cerebral fungus is the most prevalent form of mucormycosis, representing around 1/3–1/2 of all cases, of which approximately 90% occurring in head and neck region is affected by Rhizopus . Maxilla, particularly the four pairs of sinuses (i.e. frontal, sphenoid, ethmoid, maxillary) , makes an ideal niche, wherein the stable habitat of constant temperature and humidity provided for the growth of these fungi which are also usual commensalism of nasal mucosa. Hence, the early stage of maxillofacial mucormycosis can be masqueraded as osteomyelitis and maxillary sinusitis that mimicking pain or toothache (seen in all our patients). In this stage, presentation include a potential onset of sinus drainage, sinus pressure, and soft tissue swelling, while it may be increasingly progressive and diffuse to adjacent tissues.
(2) Typical clinical appearance. Grey-black discoloration is observed when the involved tissues undergo necrosis resulting from thrombosed blood vessels. In particular, when the embolization of maxillary, facial or ophthalmic artery forms, massive necrotic area that donated by them can be seen through physical examination. Accordingly, CT angiography may be considered as a necessary imaging examination for maxillofacial mucormycosis (Fig. 6). Proptosis and ophthalmoplegia (restricted motion of eyeball) and loss of vision are often resulted from extension into the periorbital region and eventually into the orbit/globe [44, 69]. Mucosa-lined, air-filled sinuses promote the invasion into oral cavity giving rise to painful, necrotizing ulcerations usually with a blackish slough . Through intraoral examination, it can be shown the exposure of black bare bone with the deprivation of mucoperiosteum over the entire maxillary alveolar process and hard palate up to the soft palate, sometimes occurring palatal fistula in the soft palate area .
(3) Predisposing illness or risk factors. Organ systems as well as microorganisms involved in the location of contamination associate closely with the clinical manifestations of mucormycosis. Maxillofacial mucormycosis is typically caused by direct infection of non-healing/incurable wound or inhalation/swallow of fungal spores. By reviewing the literature, we found mucormycosis affecting maxillofacial region predominantly appeared in immunocompromised patients (n = 84, 95.45%), embracing diabetes mellitus, hematological disorders, malignant tumor, etc. In our case series presenting maxillofacial mucormycosis, primarily diabetics (n = 6, 85.71%) had been identified likewise. On the other side, mucormycosis is capable to afflict healthy individuals owing to the role of local factors in the pathogenesis of this disease as described by Mignogna et al.  Local risk factors for example surgical trauma of a tooth extraction could damnify the local vascularity, thereupon then it would provide the microbes with a portal of entry. As per the reviewed literature, nonetheless, merely 5.68% (5/88) mucormycosis patients who had no significant medical or family history were secondary to the exodontia. Additionally, even though 31.82% (28/88) individuals demonstrated their mucormycosis suffering was next to a history of dental extraction, these patients were totally on the basis of dysimmunity of body condition. Furthermore, it is well-known that hyperglycemic hyperosmolar status, low pH value, and iron-rich environment in abnormal immune metabolism favors fungous growths  (Additional file 2: Fig. S1). These findings are consistent with the fact that oromaxillofacial invasive mucormycosis attacks mostly patients with compromised immunity (e.g. in our cases, 100%, presented in Table 1).
Various diagnostic methods extant constitute of biopsy for microbiological culture, conventional microscopic examination, specific histopathologic staining, antigen–antibody reaction, molecular testing, and antifungal susceptibility assay (Additional file 1: Table S1). Notwithstanding, not all fungi can be recognized via any one given method; and proper diagnostic aids depend on the epidemiology of prevalent fungal infection in the locality as well as the available laboratory tests. In ambiguous cases, fungal culture, microscopy of hematoxylin and eosin staining, and polymerase chain reaction test are often useful adjuncts highlighting the role of multiple diagnostic methods . The diagnosis of oromaxillofacial invasive mucormycosis though sometimes difficult can be simplified by a team approach having specialists of different fields. For our cases, the conclusive diagnosis of invasive mucormycosis is ultimately received through histopathological analysis after taking tissue biopsy that identifies extensive tissue necrosis and the presence of broad (5–20 μm or more in width), thinned-wall fungal hyphae, which irregularly branched and occasionally have a ribbon-like appearance. These numerous nonseptate hyphae invaded the lumen of a large blood vessel, causing thrombosis, typical for invasive mucormycosis (Fig. 7). In addition, high power photomicrograph of the fungal hyphae stained by fluorescence can be more depictive of the characteristic microscopic appearance (Fig. 8).
The clinical progression of mucormycosis usually precedes its radiological appearances. Displaying on non-contrast CT scans of coronal with axial reformats has the best visualization [75, 76]. Maxillofacial mucormycosis commonly shows with pansinusitis or multiple sinuses involvement, which is oftentimes unilateral but can be quickly aggressive to bilateral components. Its CT images present with air-fluid levels, enlargement in mucosal thickness, and bone erosion; however that is s not sufficiently precise to help distinguish mucormycosis from maxillary malignancies .
Contemporary treatment strategy for mucormycosis is principally surgical management, which should be performed whenever feasible in parallel to antifungal drugs. Various authors have reported higher cure and survival rates through surgical interventions [73, 78,79,80,81,82]. Successful regime counts on timing, but it also should be noted that many patients may be too sick to undergo surgery. Oromaxillofacial invasive mucormycosis should be treated by radical surgical debridement with margins clear of infection, although it is currently unclear how to define such margins. Identifying margins of infected borders during the surgical procedure may be achieved in real time using fluorescent brightener on the resected tissue . This approach limits unnecessary resection of non-infected tissue in craniofacial areas. Complete debridement, including endoscopic debridement or excision of infected tissues, increased survival rates in a cohort of solid organ transplant recipients . It is imperative to perform a biopsy of affecting area and initiate intravenous antifungal treatment, once the clinical suspicion has increased . Surgical operation should be conducted with a sense of urgency so as to limit the fulminant spread of infection to contiguous structures. Adapting the extent of surgery to the distribution of mucormycosis improves outcome and reduces unnecessary loss of healthy tissue . Thorough cut out of the infected sinuses as well as sufficient debridement of the retro-orbital space (fatty tissue) can effectively prevent necrotic infection from disseminating into the eye, thereby improving the cure rate. Currently, debridement extends until clean tissue is seen, but no intraoperative microscopic evaluation is done. Patients need to be closely followed after surgery to identify new necrosis, which must be managed by repeated debridement. Radical resection or repeated debridement of lesion is regularly recommended with subsequent reconstructive surgery [85, 86] (Fig. 9). Few scientific literatures proposed treatment about the surgical technique of reconstruction for this disease. There are a multitude of considerations and perioperative measures that aim to maximize the success of tissue transfer, including acknowledgment of psychological and psychiatric factors, tight glycemic control, nutritional support, intraoperative surgical technique, and close postoperative monitoring of the patients' hemodynamic physiology . The defect resulted from radical surgical debridement is extensive, requiring reconstructive surgery with a pedicled than free flap. Additionally, given that the fungal affinity to blood vessels as well as poor blood circulation of free flaps, were not considered for reconstruction due to be short of a continuous arterial inflow and venous outflow . Thus, a pedicled forearm flap was designed and performed  (Fig. 9). This harvested flap was elevated and turned over the disfigurement site. The skin island filled the defect cavity, and a skin graft covered the muscle deep surface to restore maxillofacial continuity (Fig. 9).
Early initiation of antimycotic intervention at the very first likelihood of acute invasive maxillofacial mycotic pathology can reduce mortality rate to a certain extent . Amphoterecin B (AmB), either conventional or liposomal, is probably the mainstay of treatment that has been successfully applied in zygomycosis . Intravenous high-dose (1.0–1.5 mg/kg/day) AmB deoxycholate was widely administrated; however, lately liposomal AmB (5–10 mg/kg, daily) with lower nephrotoxicity has become the empirical drug of choice in Mucor species management [91, 92]. Even so, some trials have raised concerns over its evidence of dose-dependent hepatotoxicity . Moreover, high drug costs of liposomal AmB also remains the biggest obstacle in its prolonged use, despite it proves stable activity against Mucorales. Apart from that, medical management alone is not effective because of poor drug delivery to the infection site due to extensive vascular thrombosis . Posaconazole is the secondary drug of choice (recommended dosage: 800 mg/day in 4 divided doses) in treating mucormycosis as a promising newer azole approved by the US FDA (Food and Drug Administration) . A few articles reviewed have taken posaconazole as a combined medicine for curing maxillofacial invasive mucormycosis [18, 20, 23, 39, 42]. Considering it can be taken orally with low incidence of side effects and is hence excellent for prolonged outpatient regimes. First-line treatment with high-dose liposomal AmB is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. AmB deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings .
Use of adjuvant hyperbaric oxygen therapy has a direct fungicidal effect and has been reported as an effective adjunct in some comprehensive regimes especially in patients with diabetic ketoacidosis-induced mucormycoses [96, 97].
In conclusion, the uncommon phenomenon of cranio-maxillo-facial invasive mucormycosis may be associated with fatal disease. Better recognition this condition, by avoiding both unnecessary investigations and possible misdiagnosis could result in more timely treatment. Mucormycosis should be known to the dental practitioner and maxillofacial surgeon, especially in any underlying predisposing disorder (e.g. diabetic individuals and other immunosuppressed patients). For this life-threatening infection that is considered to be a medical emergency, prompt and aggressive intervention with a combination of ablative surgery, intravenous antifungal treatment as well as hyperbaric oxygen therapy, along with simultaneous appropriate elimination of underlying causes of immunosuppression and risk factors should be recommended.
Availability of data and materials
The analyzed data sets generated during the study are available from the corresponding author on reasonable request.
Hibbett DS, Binder M, Bischoff JF, Blackwell M, Cannon PF, Eriksson OE, et al. A higher-level phylogenetic classification of the Fungi. Mycol Res. 2007;111(Pt 5):509–47. https://doi.org/10.1016/j.mycres.2007.03.004.
Skiada A, Lass-Floerl C, Klimko N, Ibrahim A, Roilides E, Petrikkos G. Challenges in the diagnosis and treatment of mucormycosis. Med Mycol. 2018;56(suppl_1):93–101. https://doi.org/10.1093/mmy/myx101.
Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20(Suppl 3):5–26. https://doi.org/10.1111/1469-0691.12371.
Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405–21. https://doi.org/10.1016/S1473-3099(19)30312-3.
Baranova IB, Popova MO, Yaremenko AI, Zubkova NV, Pinegina ON, Nikolaev IY. Invasive mucormycosis affecting maxillofacial region in oncohematological patients undergoing chemotherapeutic treatment and transplantation of hematopoietic stem cells. Stomatologiia (Mosk). 2022;101(2):80–6. https://doi.org/10.17116/stomat202210102180. (Russian).
Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Chen SC, et al. Contemporary management and clinical outcomes of mucormycosis: a systematic review and meta-analysis of case reports. Int J Antimicrob Agents. 2019;53(5):589–97. https://doi.org/10.1016/j.ijantimicag.2019.01.002.
Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Kong DCM, et al. The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports. Clin Microbiol Infect. 2019;25(1):26–34. https://doi.org/10.1016/j.cmi.2018.07.011.
Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012;54(Suppl 1):S23-34. https://doi.org/10.1093/cid/cir866.
Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev. 2005;18(3):556–69. https://doi.org/10.1128/CMR.18.3.556-569.2005.
Moorthy A, Gaikwad R, Krishna S, Hegde R, Tripathi KK, Kale PG, et al. SARS-CoV-2, uncontrolled diabetes and corticosteroids-an unholy trinity in invasive fungal infections of the maxillofacial region? A retrospective, multi-centric analysis. J Maxillofac Oral Surg. 2021;20(3):418–25. https://doi.org/10.1007/s12663-021-01532-1.
Emodi O, Ohayon C, Bilder A, Capucha T, Wolff A, Rachmiel A. Postextraction mucormycosis in immunocompromised-patient management and review of literature. J Oral Maxillofac Surg. 2021;79(7):1482–91. https://doi.org/10.1016/j.joms.2021.01.019.
Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med. 2021;42:264.e5-264.e8. https://doi.org/10.1016/j.ajem.2020.09.032.
Mekonnen ZK, Ashraf DC, Jankowski T, Grob SR, Vagefi MR, Kersten RC, et al. Acute invasive rhino-orbital mucormycosis in a patient with COVID-19-associated acute respiratory distress syndrome. Ophthalmic Plast Reconstr Surg. 2021;37(2):e40-80. https://doi.org/10.1097/IOP.0000000000001889.
Dallalzadeh LO, Ozzello DJ, Liu CY, Kikkawa DO, Korn BS. Secondary infection with rhino-orbital cerebral mucormycosis associated with COVID-19. Orbit. 2021;23:1–4. https://doi.org/10.1080/01676830.2021.1903044.
Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus. 2020;12(9):e10726. https://doi.org/10.7759/cureus.10726.
Srivastava A, Mohpatra M, Mahapatra A. Maxillary fungal osteomyelitis: a review of literature and report of a rare case. Ann Maxillofac Surg. 2019;9(1):168–73. https://doi.org/10.4103/ams.ams_218_18.
Arani R, Shareef SNHA, Khanam HMK. Mucormycotic osteomyelitis involving the maxilla: a rare case report and review of the literature. Case Rep Infect Dis. 2019;2019:8459296. https://doi.org/10.1155/2019/8459296.
Gholinejad Ghadi N, Seifi Z, Shokohi T, Aghili SR, Nikkhah M, Vahedi Larijani L, et al. Fulminant mucormycosis of maxillary sinuses after dental extraction inpatients with uncontrolled diabetic: two case reports. J Mycol Med. 2018;28(2):399–402. https://doi.org/10.1016/j.mycmed.2018.01.003. (French).
Prabhu S, Alqahtani M, Al SM. A fatal case of rhinocerebral mucormycosis of the jaw after dental extractions and review of literature. J Infect Public Health. 2018;11(3):301–3. https://doi.org/10.1016/j.jiph.2017.09.026.
Nilesh K, Vande AV. Mucormycosis of maxilla following tooth extraction in immunocompetent patients: reports and review. J Clin Exp Dent. 2018;10(3):e300–5. https://doi.org/10.4317/jced.53655.
Afroze SN, Korlepara R, Rao GV, Madala J. Mucormycosis in a diabetic patient: a case report with an insight into its pathophysiology. Contemp Clin Dent. 2017;8(4):662–6. https://doi.org/10.4103/ccd.ccd_558_17.
Habroosh FA, Eatamadi H, Mohamed RM. Concomitant orbital aspergillosis and mucormycosis in a 17 months old immunocompetent child. Saudi J Ophthalmol. 2017;31(3):193–5. https://doi.org/10.1016/j.sjopt.2017.05.006.
Mahomed S, Basanth S, Mlisana K. The successful use of amphotericin B followed by oral posaconazole in a rare case of invasive fungal sinusitis caused by co-infection with mucormycosis and aspergillus. IDCases. 2015;2(4):116–7. https://doi.org/10.1016/j.idcr.2015.10.001.
Selvamani M, Donoghue M, Bharani S, Madhushankari GS. Mucormycosis causing maxillary osteomyelitis. J Nat Sci Biol Med. 2015;6(2):456–9. https://doi.org/10.4103/0976-9668.160039.
Kumar N, Singh AK, Pandey S, Singh S. Rhino-maxillary osteomyelitis due to mucormycosis in an immunocompromised geriatric patient: a case report with review of treatment options. Int J Health Allied Sci. 2015;4:160–4.
Nilesh K, Malik NA, Belgaumi U. Mucormycosis in a healthy elderly patient presenting as oro-antral fistula: report of a rare incidence. J Clin Exp Dent. 2015;7(2):e333–5. https://doi.org/10.4317/jced.52064.
Motaleb HY, Mohamed MS, Mobarak FA. A Fatal outcome of rhino-orbito-cerebral mucormycosis following tooth extraction: a case report. J Int Oral Health. 2015;7(Suppl 1):68–71.
Laihad FM, Ketut Sudiana I, Guritno Suryokusumo M. Case report: the diagnosis, treatment and outcome of a rare case suspected as mucormycosis. Pinnacle Med Med Sci. 2015;2(2):502–5.
Arya S, Sharanamma B, Patil N, Anitha B, Bhateja S. Basavaraj. Rhino-maxillary form of mucormycosis causing sinusitis: a rare case report with review of literature. J Oral Med Oral Surg Oral Pathol Oral Radiol. 2015;1:39–44.
Garlapati K, Chavva S, Vaddeswarupu RM, Surampudi J. Fulminant mucormycosis involving paranasal sinuses: a rare case report. Case Rep Dent. 2014;2014:465919. https://doi.org/10.1155/2014/465919.
Choudhary P, Bhargava D, Chandavarkar V, Sharma R. Mucormycosis of maxilla. Indian J Dent Adv. 2014;6:1503–6.
Kumar JA, Babu P, Prabu K, Kumar P. Mucormycosis in maxilla: rehabilitation of facial defects using interim removable prostheses: a clinical case report. J Pharm Bioallied Sci. 2013;5(Suppl 2):S163–5. https://doi.org/10.4103/0975-7406.114322.
Ananthaneni AR, Undavalli SB, Velagapudi RP, Guduru VS. Mucormycosis: an atrocious mate of patients with diabetes. BMJ Case Rep. 2013;2013:bcr2013009600. https://doi.org/10.1136/bcr-2013-009600.
Aras MH, Kara MI, Erkiliç S, Ay S. Mandibular mucormycosis in immunocompromised patients: report of 2 cases and review of the literature. J Oral Maxillofac Surg. 2012;70(6):1362–8. https://doi.org/10.1016/j.joms.2011.05.012.
Suwan Y, Punyawattanaporn A, Preechawai P. Rhino-orbital fungal infection: two cases report. J Med Assoc Thai. 2012;95(5):739–42.
Vaidya D, Shah P. Coinfection by Aspergillus and Zygomycetes species in a case of acute rhinosinusitis. Case Rep Otolaryngol. 2011;2011:382473. https://doi.org/10.1155/2011/382473.
Doni BR, Peerapur BV, Thotappa LH, Hippargi SB. Sequence of oral manifestations in rhino-maxillary mucormycosis. Indian J Dent Res. 2011;22(2):331–5. https://doi.org/10.4103/0970-9290.84313.
Pandey A, Bansal V, Asthana AK, Trivedi V, Madan M, Das A. Maxillary osteomyelitis by mucormycosis: report of four cases. Int J Infect Dis. 2011;15(1):e66–9. https://doi.org/10.1016/j.ijid.2010.09.003.
Papadogeorgakis N, Parara E, Petsinis V, Vourlakou C. A case of successfully treated rhinocerebral mucormycosis: dental implications. Int J Dent. 2010;2010:273127. https://doi.org/10.1155/2010/273127.
Ojeda-Uribe M, Herbrecht R, Kiefer MH, Schultz P, Chain J, Chenard MP, et al. Lessons from a case of oromandibular mucormycosis treated with surgery and a combination of amphotericin B lipid formulation plus caspofungin. Acta Haematol. 2010;124(2):98–102. https://doi.org/10.1159/000315675.
McDermott NE, Barrett J, Hipp J, Merino MJ, Richard Lee CC, Waterman P, et al. Successful treatment of periodontal mucormycosis: report of a case and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(3):e64–9. https://doi.org/10.1016/j.tripleo.2009.11.012.
Kishel JJ, Sivik J. Breakthrough invasive fungal infection in an immunocompromised host while on posaconazole prophylaxis: an omission in patient counseling and follow-up. J Oncol Pharm Pract. 2008;14(4):189–93. https://doi.org/10.1177/1078155208094123.
Chua JL, Cullen JF. Fungal pan-sinusitis with severe visual loss in uncontrolled diabetes. Ann Acad Med Singap. 2008;37(11):964–7.
Auluck A. Maxillary necrosis by mucormycosis. A case report and literature review. Med Oral Patol Oral Cir Bucal. 2007;12(5):E360–4.
Dogan MC, Leblebisatan G, Haytac MC, Antmen B, Surmegozler O. Oral mucormycosis in children with leukemia: report of 2 cases. Quintessence Int. 2007;38(6):515–20.
Bakathir AA. Mucormycosis of the jaw after dental extractions: two case reports. Sultan Qaboos Univ Med J. 2006;6(2):77–82.
Jayachandran S, Krithika C. Mucormycosis presenting as palatal perforation. Indian J Dent Res. 2006;17(3):139–42. https://doi.org/10.4103/0970-9290.29873.
Pellacchia V, Terenzi V, Moricca LM, Buonaccorsi S, Indrizzi E, Fini G. Brain abscess by mycotic and bacterial infection in a diabetic patient: clinical report and review of literature. J Craniofac Surg. 2006;17(3):578–84. https://doi.org/10.1097/00001665-200605000-00034.
Lador N, Polacheck I, Gural A, Sanatski E, Garfunkel A. A trifungal infection of the mandible: case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(4):451–6. https://doi.org/10.1016/j.tripleo.2005.07.022.
Alfano C, Chiummariello S, Dessy LA, Bistoni G, Scuderi N. Combined mucormycosis and Aspergillosis of the rhinocerebral region. In Vivo. 2006;20(2):311–5.
Fogarty C, Regennitter F, Viozzi CF. Invasive fungal infection of the maxilla following dental extractions in a patient with chronic obstructive pulmonary disease. J Can Dent Assoc. 2006;72(2):149–52.
Maiorano E, Favia G, Capodiferro S, Montagna MT, Lo ML. Combined mucormycosis and aspergillosis of the oro-sinonasal region in a patient affected by Castleman disease. Virchows Arch. 2005;446(1):28–33. https://doi.org/10.1007/s00428-004-1126-x.
Kim J, Fortson JK, Cook HE. A fatal outcome from rhinocerebral mucormycosis after dental extractions: a case report. J Oral Maxillofac Surg. 2001;59(6):693–7. https://doi.org/10.1053/joms.2001.23407.
Salisbury PL 3rd, Caloss R Jr, Cruz JM, Powell BL, Cole R, Kohut RI. Mucormycosis of the mandible after dental extractions in a patient with acute myelogenous leukemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83(3):340–4. https://doi.org/10.1016/s1079-2104(97)90240-7.
Jones AC, Bentsen TY, Freedman PD. Mucormycosis of the oral cavity. Oral Surg Oral Med Oral Pathol. 1993;75(4):455–60. https://doi.org/10.1016/0030-4220(93)90170-9.
Brown OE, Finn R. Mucormycosis of the mandible. J Oral Maxillofac Surg. 1986;44(2):132–6. https://doi.org/10.1016/0278-2391(86)90196-5.
Eisenberg L, Wood T, Boles R. Mucormycosis. Laryngoscope. 1977;87(3):347–56. https://doi.org/10.1288/00005537-197703000-00007.
Eucker J, Sezer O, Graf B, Possinger K. Mucormycoses. Mycoses. 2001;44(7–8):253–60.
Ferguson BJ. Mucormycosis of the nose and paranasal sinuses. Otolaryngol Clin N Am. 2000;33(2):349–65. https://doi.org/10.1016/s0030-6665(00)80010-9.
Mohanty N, Misra SR, Sahoo SR, Mishra S, Kailasam S. Rhinomaxillary mucormycosis masquerading as chronic osteomyelitis: a series of four rare cases with review of literature. J Indian Acad Oral Med Radiol. 2012;24(4):315–23. https://doi.org/10.5005/jp-journals-10011-1321.
Binder U, Maurer E, Lass-Flörl C. Mucormycosis–from the pathogens to the disease. Clin Microbiol Infect. 2014;20(Suppl 6):60–6. https://doi.org/10.1111/1469-0691.12566.
Dai Y, Walker JW, Halloush RA, Khasawneh FA. Mucormycosis in two community hospitals and the role of infectious disease consultation: a case series. Int J Gen Med. 2013;6:833–8. https://doi.org/10.2147/IJGM.S52718.
Mejia Buritica L, Karduss Urueta AJ. Pulmonary mucormycosis. N Engl J Med. 2021;384(18):e69. https://doi.org/10.1056/NEJMicm2030205.
Ghuman SS, Sindhu P, Buxi TBS, Sheth S, Yadav A, Rawat KS, et al. CT appearance of gastrointestinal tract mucormycosis. Abdom Radiol (NY). 2021;46(5):1837–45. https://doi.org/10.1007/s00261-020-02854-3.
Prakash H, Chakrabarti A. Global epidemiology of mucormycosis. J Fungi (Basel). 2019;5(1):26. https://doi.org/10.3390/jof5010026.
Castrejón-Pérez AD, Welsh EC, Miranda I, Ocampo-Candiani J, Welsh O. Cutaneous mucormycosis. An Bras Dermatol. 2017;92(3):304–11. https://doi.org/10.1590/abd1806-4841.20176614.
Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev. 2000;13(2):236–301. https://doi.org/10.1128/CMR.13.2.236.
Whyte A, Boeddinghaus R. The maxillary sinus: physiology, development and imaging anatomy. Dentomaxillofac Radiol. 2019;48(8):20190205. https://doi.org/10.1259/dmfr.20190205.
Chikley A, Ben-Ami R, Kontoyiannis DP. Mucormycosis of the central nervous system. J Fungi (Basel). 2019;5(3):59. https://doi.org/10.3390/jof5030059.
Francis JR, Villanueva P, Bryant P, Blyth CC. Mucormycosis in children: review and recommendations for management. J Pediatric Infect Dis Soc. 2018;7(2):159–64. https://doi.org/10.1093/jpids/pix107.
Deepa A, Nair BJ, Sivakumar T, Joseph AP. Uncommon opportunistic fungal infections of oral cavity: a review. J Oral Maxillofac Pathol. 2014;18(2):235–43. https://doi.org/10.4103/0973-029X.140765.
Mignogna MD, Fortuna G, Leuci S, Adamo D, Ruoppo E, Siano M, et al. Mucormycosis in immunocompetent patients: a case-series of patients with maxillary sinus involvement and a critical review of the literature. Int J Infect Dis. 2011;15(8):e533–40. https://doi.org/10.1016/j.ijid.2011.02.005.
Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17(12):1859–67. https://doi.org/10.1111/j.1469-0691.2010.03456.x.
Lass-Flörl C. Current challenges in the diagnosis of fungal infections. Methods Mol Biol. 2017;1508:3–15. https://doi.org/10.1007/978-1-4939-6515-1_1.
Slonimsky G, Slonimsky E, Yakirevitch A, Sagiv D, Duvdevani S, Talmi YP, et al. The significance of computed tomography in invasive paranasal mucormycosis. Rhinology. 2018;56(1):54–8. https://doi.org/10.4193/Rhin17.153.
Groppo ER, El-Sayed IH, Aiken AH, Glastonbury CM. Computed tomography and magnetic resonance imaging characteristics of acute invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg. 2011;137(10):1005–10. https://doi.org/10.1001/archoto.2011.170.
Ni Mhurchu E, Ospina J, Janjua AS, Shewchuk JR, Vertinsky AT. Fungal rhinosinusitis: a radiological review with intraoperative correlation. Can Assoc Radiol J. 2017;68(2):178–86. https://doi.org/10.1016/j.carj.2016.12.009.
Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41(5):634–53. https://doi.org/10.1086/432579.
Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M, et al. A global analysis of mucormycosis in France: the RetroZygo Study (2005–2007). Clin Infect Dis. 2012;54(Suppl 1):S35-43. https://doi.org/10.1093/cid/cir880.
Vironneau P, Kania R, Morizot G, Elie C, Garcia-Hermoso D, Herman P, et al. Local control of rhino-orbito-cerebral mucormycosis dramatically impacts survival. Clin Microbiol Infect. 2014;20(5):O336–9. https://doi.org/10.1111/1469-0691.12408.
Zaoutis TE, Roilides E, Chiou CC, Buchanan WL, Knudsen TA, Sarkisova TA, et al. Zygomycosis in children: a systematic review and analysis of reported cases. Pediatr Infect Dis J. 2007;26(8):723–7. https://doi.org/10.1097/INF.0b013e318062115c.
Nithyanandam S, Jacob MS, Battu RR, Thomas RK, Correa MA, D’Souza O. Rhino-orbito-cerebral mucormycosis. A retrospective analysis of clinical features and treatment outcomes. Indian J Ophthalmol. 2003;51(3):231–6.
Sun HY, Forrest G, Gupta KL, Aguado JM, Lortholary O, Julia MB, et al. Rhino-orbital-cerebral zygomycosis in solid organ transplant recipients. Transplantation. 2010;90(1):85–92. https://doi.org/10.1097/tp.0b013e3181dde8fc.
Brunet K, Rammaert B. Mucormycosis treatment: recommendations, latest advances, and perspectives. J Mycol Med. 2020;30(3):101007. https://doi.org/10.1016/j.mycmed.2020.101007.
Cheema SA, Amin F. Five cases of rhinocerebral mucormycosis. Br J Oral Maxillofac Surg. 2007;45(2):161–2. https://doi.org/10.1016/j.bjoms.2005.06.021.
Talmi YP, Goldschmied-Reouven A, Bakon M, Barshack I, Wolf M, Horowitz Z, et al. Rhino-orbital and rhino-orbito-cerebral mucormycosis. Otolaryngol Head Neck Surg. 2002;127(1):22–31. https://doi.org/10.1067/mhn.2002.126587.
Walia A, Lee JJ, Jackson RS, Hardi AC, Bollig CA, Graboyes EM, et al. Management of flap failure after head and neck reconstruction: a systematic review and meta-analysis. Otolaryngol Head Neck Surg. 2022;167(2):224–35. https://doi.org/10.1177/01945998211044683.
Zhao X, Zhang Y, Fu S, Zhang C, Li M, Wu Y. Clinical application of a pedicled forearm flap in the reconstruction after oral cancer resection. J Craniofac Surg. 2017;28(3):e222–5. https://doi.org/10.1097/SCS.0000000000003406.
Malani PN, Kauffman CA. Invasive and allergic fungal sinusitis. Curr Infect Dis Rep. 2002;4(3):225–32. https://doi.org/10.1007/s11908-002-0083-2.
Ruhnke M, Maschmeyer G. Management of mycoses in patients with hematologic disease and cancer—review of the literature. Eur J Med Res. 2002;7(5):227–35.
Subirà M, Martino R, Gómez L, Martí JM, Estany C, Sierra J. Low-dose amphotericin B lipid complex vs. conventional amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies—a randomized, controlled trial. Eur J Haematol. 2004;72(5):342–7. https://doi.org/10.1111/j.1600-0609.2004.00239.x.
Walsh TJ, Goodman JL, Pappas P, Bekersky I, Buell DN, Roden M, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother. 2001;45(12):3487–96. https://doi.org/10.1128/AAC.45.12.3487-3496.2001.
Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther. 2007;29(9):1980–6. https://doi.org/10.1016/j.clinthera.2007.09.016.
Smith JL, Stevens DA. Survival in cerebro-rhino-orbital zygomycosis and cavernous sinus thrombosis with combined therapy. South Med J. 1986;79(4):501–4. https://doi.org/10.1097/00007611-198604000-00028.
Riley TT, Muzny CA, Swiatlo E, Legendre DP. Breaking the mold: a review of mucormycosis and current pharmacological treatment options. Ann Pharmacother. 2016;50(9):747–57. https://doi.org/10.1177/1060028016655425.
Steve AK, Hurdle VA, Brown JY. Orbitomaxillofacial mucormycosis requiring complex multifactorial management. Plast Reconstr Surg Glob Open. 2018;6(10):e1927. https://doi.org/10.1097/GOX.0000000000001927.
Segal E, Menhusen MJ, Shawn S. Hyperbaric oxygen in the treatment of invasive fungal infections: a single-center experience. Isr Med Assoc J. 2007;9(5):355–7.
We would like to express our cordial appreciation to the experts panel composed of maxillofacial surgeon, dentist, specialist in medical laboratory science, head and neck radiologist, pathologist, pharmacist, endocrinologist, mycologist, and immunologist in hematology, for their professional assistance to our work.
This study was funded by National Natural Science Foundation of China (Grant No.: 82160189); Tianshan Innovation Team of Xinjiang Uygur Autonomous Region (Grant No.: 2021D14001); Open Project of Shaanxi Clinical Medical Research Center for Dental and Maxillofacial Diseases—School of Stomatology, Xi’an Jiaotong University (Grant No.: 2020YHJB01); Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration (Grant No.: 2022kqhm008).
Ethics approval and consent to participate
The present study was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University. Procedures operated in this research were completed in keeping with the standards set out in the Announcement of Helsinki and laboratory guidelines of research in China. Written informed consent to participate in this study was provided by the participants or legal guardian/next of kin.
Consent for publication
Written informed consent was obtained by all patients, and they were willing to join our study and publication.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Additional file 1: Table S1.
Overview of laboratory methods available for the diagnosis of oromaxillofacial invasive mucormycosis.
Additional file 2: Fig. S1.
Risk factors for invasive oromaxillofacial mucormycosis.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Li, Cx., Gong, Zc., Pataer, P. et al. A retrospective analysis for the management of oromaxillofacial invasive mucormycosis and systematic literature review. BMC Oral Health 23, 115 (2023). https://doi.org/10.1186/s12903-023-02823-4
- Therapeutic regimen
- Maxillofacial area
- Systematic review