A retrospective analysis for the management of oromaxillofacial invasive mucormycosis and systematic literature review

Abstract

Purpose

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.

Methodology

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.

Results

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.

Conclusions

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.

Introduction

Mucormycosis is a saprophytic opportunistic, but a highly aggressive fungal infection caused by the class Zygomycetes, belonging to members of Mucorales order, subphylum Mucoromycotina [1]. 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 [2]. 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).

Methods

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.

Results

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).

Table 1 Clinical information of the patients

Fig. 1

Extraoral appearance of invasive mucormycosis seen in A and B; intraoral appearance of invasive mucormycosis seen in C and D

Fig. 2

Computerized tomography scanning (A axial image; B sagittal image; C coronal image) showed swelling of soft tissue in right maxillofacial region, heterogeneous opacification of subcutaneous fat space, in-sinus low density in ethmoid, frontal, sphenoid, maxillary with partial destruction of sinuses’ wall. Scope of infection was indicated by the arrows

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%).

Literature review

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.

Table 2 Characteristics of studies recruited in the systematic review

Fig. 3

Flow diagram of the study selection process

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 (M_n = 54, F_n = 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).

Fig. 4

Characteristics of the age distribution reviewing of all extant literature of mucormycosis in cranio-maxillo-facial region. A grouping by the frequency; B general trend; C male trend; D female trend

Fig. 5

Distribution of all the cases of cranio-maxillo-facial mucormycosis that was reported from all over the world

Discussion

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 [60]. 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 [67]. Maxilla, particularly the four pairs of sinuses (i.e. frontal, sphenoid, ethmoid, maxillary) [68], 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 [70]. 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 [71].

Fig. 6

The computerized tomography angiography and three-dimensional reconstruction showed that left facial artery and ophthalmic artery were not developed indicating thromboembolisms existence. A Frontal view; B Left 45-degree-angled view; C Left side view; D Left posterior view

(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. [72] 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 [73] (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 [74]. 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).

Fig. 7

Histopathological examination of mucormycosis (microscopic view). A Bone and sinus tissue (100× magnification, H&E*): Area of acute inflammation and fungal forms infiltration arteries (arrow); B Sinus specimen (400× magnification, H&E*): Colonies of fungal spores and non-septate hyphae invaded the lumen of a blood vessel, causing thrombosis (arrow); C Sinus tissue (400× magnification, PAS**): Multinucleated giant cells with a numerous PAS-positive fragments in the cytoplasm (arrow); D Sinus section (100× magnification, GMS***): Intravascular invasion by fungal hyphae (arrow); E Sinus tissue (400× magnification, PAS**): Non septate wide branched hyphae (arrow); F Sinus tissue (400× magnification, PAS**): Numerous fungal hyphae which were aseptate, broad with obtuse angle branching, and without spore formation (arrow). *H&E = Hematoxylin and Eosin stain. **PAS = Periodic acid-Schiff stain. ***GMS = Gomori methenamine-silver stain

Fig. 8

Sizes and branching angles for Mucorales and aspergillus were stained by fluorescence. A and B corresponded to Aspergillus fumigatus; C and D corresponded to Rhizopus arrhizus. Hyphae can artefactually seem to have septae because tissue can fold over itself during processing, which can create artificial lines that can be confused with septations. Similarly, the historically described 90° branching angle of Mucorales in tissue, versus 45° branching angle of septate moulds, can be difficult to identify in tissue due to interstitial pressures exerted on the fungi by the tissue and alterations in tissue architecture during processing. Thus the wider and irregular (ribbon-like) nature of the hyphae are more reliable distinguishing characteristics than septations and angle of branching [4]

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 [77].

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 [41]. 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 [83]. It is imperative to perform a biopsy of affecting area and initiate intravenous antifungal treatment, once the clinical suspicion has increased [84]. 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 [82]. 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 [87]. 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 [50]. Thus, a pedicled forearm flap was designed and performed [88] (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).

Fig. 9

Typical case in our patients suffering from maxillofacial mucormycosis. Due to the disease’s high affinity to the arteries and its internal elastic lamina causing embolism and infarctions. Previous imaging results revealed opacification of the left maxillary sinus, ethmoid sinus, and frontal sinus, erosion of the anterolateral wall of left maxillary antrum with thickening of the sinus lining, embolus formation in left facial artery and ophthalmic artery. A Preoperative physical sign showed orbital and facial cellulitis with areas of necrotic skin; B Massive necrotic infected tissue removed; C The first surgical debridement; D Clinical aspect 2 weeks after operation; E Follow-up photo documentation (wound covered by Vaseline gauze) after 5 months; F The second surgical debridement along with reconstruction for disfiguring maxillofacial deformity; G The pedicled forearm flap was harvested; H. The skin island reconstructed the defect cavity; I Postoperative view in the follow-up of 45 days

Early initiation of antimycotic intervention at the very first likelihood of acute invasive maxillofacial mycotic pathology can reduce mortality rate to a certain extent [89]. Amphoterecin B (AmB), either conventional or liposomal, is probably the mainstay of treatment that has been successfully applied in zygomycosis [90]. 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 [93]. 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 [94]. 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) [95]. 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 [4].

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].

Conclusion

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.