Orbital-Zygomatic-Maxillary Mucormycosis: Does the Aesthetic Influence on Treatment Guidelines?

Abstract

Study Design

This is a two-part study, involving a cross-sectional retrospective analysis based on data collection, and a broad literature review.

Objective

To provide a statement and guideline for treating orbitozygomatic-maxillary mucormycosis focusing on the patient's facial aesthetic and function.

Methods

The cross-sectional stage enrolled patients with confirmed mucormycosis on the face, recorded through written medical records. The literature review employed a comprehensive search strategy to identify relevant articles.

Results

Immediate reconstruction was found to positively influence the patient's aesthetics and function.

Conclusion

This study highlights the importance of immediate reconstruction for patients with orbitozygomatic-maxillary mucormycosis, as it positively impacts the patient's facial aesthetics and function. Surgical planning was based on the size and complexity of the defect and the patient's facial aesthetics. The treatment should be carried out following each patient's clinical course, focusing on the control of the adjacent immunosuppression.

Introduction

Mucormycosis is an aggressive and disfiguring infection that is most commonly observed in patients with immunosuppressive conditions such as diabetes, malignancies, neutropenia, organ transplantation, and recently the coronavirus disease 2019 (COVID-19). These infections are usually caused by abnormal populations of Rhizopus spp, Mucor spp, Rhizomucor spp, Cunninghamella spp, and Lichtheimia spp [1]. However, usually, an extensive diversity of fungi is involved. Facial involvement is not rare, and rhino-orbital-cerebral mucormycosis (ROCM) still has excessively high mortality rates, ranging up to 50% of the patients [2].

Maxillofacial disease's most prevalent clinical characteristics include facial swelling, discolored and damaged skin, usually followed by mucosal lesions, headache, fever, nasal congestion, globe proptosis, palpebral ptosis, chemosis, and ophthalmoplegia as a result of retro-orbital extension. Paranasal sinus opacity with scalloped bone can be visualized at computed tomography [3].

The treatment may vary according to the patient's general health condition and the compromised tissues, usually a combination of systemic antifungal therapy and surgical intervention, with extensive resection and tissue debridement [3]. This therapy is associated with an 80% plus success rate, contrary to the 30% good prognosis for the noninvasive option alone [3].

After these resections, cranio-orbital reconstruction can prove challenging from technical and esthetic standpoints, and usually in esthetically important regions, such as maxillofacial and orbits, the absence of reconstruction could impact the patient's quality of life [4].

Those procedures could be performed on single-stage or delayed reconstruction, with alloplastic and donor tissue grafts. The size and complexity of the defect are the factors that play a role in the surgical planning; however, the patient's facial aesthetic could be a standpoint for both techniques.

This study aims to provide a statement among the treatment options for orbitozygomatic-maxillary mucormycosis, focusing on the facial aesthetic and function as the standpoint for developing a treatment guideline.

Methods

This is a two-part study, the first a cross-sectional, retrospective analysis based on data collection, associated with a broad review of the literature. The study aimed to answer the question of whether immediate reconstruction would influence the patient's aesthetics and function. There was no distinction regarding the date or language of publication. This study has been submitted and approved by the ethics committee under protocol 65,293,922.6.0000.5419/5.914.252.

First Part: Cross-Sectional Analysis

The patients of the cross-sectional stage were enrolled by the Oral and Maxillofacial Surgery Service of the University of São Paulo, Ribeirão Preto School. All patients with confirmed data of mucormycosis on the face, recorded through written medical records, were considered for this study. Records had been included regardless of sex, race, and age.

Second Part: Literature Review

For the articles collected in the literature review, the following search strategy was used “("maxillofacial"[All Fields] AND ("mucormycosis"[MeSH Terms] OR "mucormycosis"[All Fields] OR "mucormycoses"[All Fields] OR "phycomicosis"[All Fields] OR "zygomicosis"[All Fields])) OR (("mucormycosis"[MeSH Terms] OR "mucormycosis"[All Fields] OR "mucormycoses"[All Fields] OR "phycomicosis"[All Fields] OR "zygomicosis"[All Fields]) AND ("face"[MeSH Terms] OR "face"[All Fields] OR "facial"[All Fields] OR "facials"[All Fields])) OR (("mouth"[MeSH Terms] OR "mouth"[All Fields] OR "oral"[All Fields]) AND ("mucormycosis"[MeSH Terms] OR "mucormycosis"[All Fields] OR "mucormycoses"[All Fields] OR "phycomicosis"[All Fields] OR "zygomicosis"[All Fields])) OR (("orbit"[MeSH Terms] OR "orbit"[All Fields] OR "orbits"[All Fields] OR "orbit s"[All Fields] OR "orbital"[All Fields] OR "orbital s"[All Fields] OR "orbitals"[All Fields] OR "orbited"[All Fields] OR "orbiter"[All Fields] OR "orbiters"[All Fields] OR "orbiting"[All Fields] OR ("orbit"[MeSH Terms] OR "orbit"[All Fields] OR "orbits"[All Fields] OR "orbit s"[All Fields] OR "orbital"[All Fields] OR "orbital s"[All Fields] OR "orbitals"[All Fields] OR "orbited"[All Fields] OR "orbiter"[All Fields] OR "orbiters"[All Fields] OR "orbiting"[All Fields])) AND ("mucormycosis"[MeSH Terms] OR "mucormycosis"[All Fields] OR "mucormycoses"[All Fields] OR "phycomicosis"[All Fields] OR "zygomicosis"[All Fields])) OR (("nose"[MeSH Terms] OR "nose"[All Fields] OR "rhino"[All Fields] OR "rhinos"[All Fields] OR ("nasalance"[All Fields] OR "nasality"[All Fields] OR "nasalization"[All Fields] OR "nasalized"[All Fields] OR "nasally"[All Fields] OR "nose"[MeSH Terms] OR "nose"[All Fields] OR "nasal"[All Fields] OR "nasals"[All Fields]) OR ("nose"[MeSH Terms] OR "nose"[All Fields] OR "naso"[All Fields])) AND ("mucormycosis"[MeSH Terms] OR "mucormycosis"[All Fields] OR "mucormycoses"[All Fields] OR "phycomicosis"[All Fields] OR "zygomicosis"[All Fields])) OR (("zygomatic"[All Fields] OR "zygomatics"[All Fields]) AND ("mucormycosis"[MeSH Terms] OR "mucormycosis"[All Fields] OR "mucormycoses"[All Fields] OR "phycomicosis"[All Fields] OR "zygomicosis"[All Fields])).”

The patient's age, sex, previous underlying diseases, medications used in the treatment, the indication for surgical debridement or reconstruction, type of material used for reconstruction, and treatment complications were the variables collected.

Statistical Analysis

Statistical analysis of the results was performed using SPSS software (Statistical Package for Social Sciences) version 24 (IBM, Armonk, New York, USA). Descriptive analyses were performed to determine the mean, median, standard deviation, and minimum and maximum extremes, especially for the age variable. For the other variables, a descriptive analysis was performed in addition to an intervariable correction, focused on demarcating the statistical power of the variable reconstruction of the defect in changing the outcome of complications.

Results

In the present study, a total of 27 articles were included. Among those, a total of 84 patients with orbital-zygomatic-maxillary mucormycosis were enrolled, three of them gathered from the retrospective analysis obtained in this study. There was a higher prevalence of male patients, 54.77%, followed by females with 45.23%, in a ratio of 1.2:1. The mean age was 46.1 years, ranging from 6 to 87 years old (Table 1).

Table 1.

Description of literature review articles and statistical analysis

Patient	Author & Year of Publication	Sex	Age	Comorbidities	Medication	Debridement	Reconstruction	Material	Complications
1	Econnomopoulou et al. (1995)	Female	55	DM, Immunosuppression	Amphotericin B	Yes	No	No	No
4	Fortún et al. (1995)	Male	32	No	Amphotericin B + Antibiotics	Yes	No	No	Amaurosis
8	Damante et al. (1998)	Female	25	DM	Amphotericin B	Yes	Delayed	Maxillofacial Prosthesis	Amaurosis
9	Feeley et al. (1999)	Female	41	Leukemia	Amphotericin B	Yes	No	No	No
10	Hong et al. (2000)	Male	69	DM, CRF	Amphotericin B + Antibiotics	Yes	No	No	Amaurosis
32	Rapidis et al. (2005)	Female	32	No	Amphotericin B	Yes	Immediate	Polyethylene Implant and Temporalis Myofascial Flap	Disease Progression
34	Kasapoglu et al. (2010)	Female	38	Leukemia	Amphotericin B	Yes	No	No	No
35		Female	49	Immunosuppression	Amphotericin B	Yes	No	No	No
36		Female	26	CRF	Amphotericin B	Yes	No	No	No
37		Female	44	DM	Amphotericin B	Yes	No	No	Revision Surgery
38		Male	63	Immunosuppression	Amphotericin B	Yes	No	No	None
39		Female	50	Leukemia	Amphotericin B	Yes	No	No	None
40		Male	51	Leukemia	Amphotericin B	Yes	No	No	None
41		Female	53	Leukemia	Amphotericin B	Yes	No	No	None
42		Male	32	Leukemia	Amphotericin B	Yes	No	No	None
47	Singh et al. (2011)	Male	48	No	Amphotericin B + Antibiotics	Yes	Delayed	Temporalis Muscle Flap	No
50	Singh et al. (2012)	Male	48	No	Amphotericin B	Yes	Immediate	Titanium mesh	No
51		Female	40	No	Amphotericin B	Yes	No	No	Amaurosis
52		Female	35	No	Amphotericin B	Yes	No	No	No
55	Cohen et al. (2019)	Female	21	Leukemia	Amphotericin B	Yes	Delayed	No	No
56		Male	14	Leukemia	Amphotericin B	Yes	Delayed	No	No
57		Male	41	Leukemia	Amphotericin B	Yes	Delayed	No	No
60	Parvati et al. (2021)	Female	21	DM	Amphotericin B	Yes	Immediate	Free Myocutaneous Flap	Flap Loss
61		Male	27	DM	Amphotericin B	Yes	Immediate	Free Myocutaneous Flap	No
62		Male	38	DM, Hypertension	Amphotericin B	Yes	Immediate	Free Myocutaneous Flap	No
63		Male	32	DM	Amphotericin B	Yes	Immediate	Fibula Osteocutaneous Flap	No
64		Male	16	DM	Amphotericin B	Yes	Immediate	Free Myocutaneous Flap	No
65		Male	50	DM, Hypertension	Amphotericin B	No	No	No	No
68	Emodi et al. (2021)	Male	24	Leukemia	Amphotericin B	Yes	No	No	No
73		Female	23	Leukemia	Amphotericin B	Yes	No	No	No
74		Female	30	Leukemia	Amphotericin B	Yes	No	No	No
77	Kaufman et al. (2022)	Male	42	DM, CRF, Immunosuppression	Amphotericin B + Antibiotics	Yes	No	No	No
78	Munhoz et al. (2022)	Male	67	DM	Amphotericin B	Yes	Delayed	Aesthetic Reconstructive Surgery	Amaurosis
79	Deek et al. (2022)	Male	75	DM, Cardiopathy	Amphotericin B + Antibiotics	Yes	Delayed	Free Myocutaneous Flap	No
81	Ribeiro et al. (2023)	Female	64	DM, Cardiopathy, COVID-19	Amphotericin B + Antibiotics	Yes	No	No	No
82		Male	60	DM, COVID-19	Amphotericin B + Antibiotics	Yes	No	No	Amaurosis
83		Male	57	DM, Cardiopathy	Amphotericin B + Antibiotics	Yes	Immediate	Titanium mesh	No
84		Male	45	DM, Hypertension	Amphotericin B + Antibiotics	Yes	Delayed	Temporalis muscle flap + Titanium mesh	Amaurosis
Total		Male-54,77% Female-45,23%	Mean 46,15 years (6–87)	Combined Comorbidities-36,92% Leukemia-36,90% DM-14,28% Malignancy-8,33% Immunosupresion-3,57%	Amphotericin B-78,57% Combination of Amphotericin B—20,24% None-1,19%	Yes-97,62% No-2,38%	No-76,20% Immediate-13,09% Delayed-10,71%	Free Myocutaneous Flap-8,33% Maxillofacial Prosthesis-1,19% Titanium mesh-1,19% Polyethylene Implant and Temporalis Myofascial Flap—1,19% Temporalis muscle flap + Titanium mesh-1,19% Fibula Osteocutaneous Flap-1,19%	No-33,34% Death-54,76% Amaurosis-8,33% Disease Progression-1,19% Flap loss-1,19% Revision surgery-1,19%

DM diabetes mellitus, CRF chronic renal failure

Regarding the patient’s clinical conditions and comorbidities, 36.92% of those presented with more than one clinical condition; that is, they exhibited a combination of diseases.

Leukemia was the most prevalent clinical condition among the sample, affecting 36.90% of the patients. Diabetes mellitus was observed in 33.33% of the patients; however, the majority of the patients presented another clinical condition that could also influence the outcome. A total of 14.28% of the sample presented only the endocrinological disease.

The diagnosis of malignancy is a serious clinical condition and was related to ROCM in 8.33% of the patients; in addition, 3.57% presented with other autoimmune diseases. Other comorbidities were also present, but not noteworthy [Table 1].

Regarding the medications used in the treatment, all patients who accepted medication used Amphotericin B, with 78.57% using only this medication, and 20.24% using a combination with an antibiotic. A single patient refused to be treated with medicines for ROCM [Table 1].

The surgical procedure of choice was debridement, performed on 97.62% of the patients. In 76.20% of the patients, bone reconstructions were not performed, immediate reconstruction was perpetrated in 13.09% of the patients, and 10.7% of the patients underwent delayed reconstruction in a second surgical procedure [Table 1].

The free myocutaneous flap was the preferred material for reconstruction, delayed or immediate, ranging up to 8.33%. On the other hand, maxillofacial prosthesis, titanium meshes, polyethylene implant and temporalis myofascial flap, temporalis muscle flap together with titanium mesh, and fibula osteocutaneous flap were also used each in one patient.

The hard outcome, death, was most commonly observed among the patients (54.76%), followed by amaurosis (8.33%), disease progression (1.19%), flap loss (1.19%), revision surgery (1.19%). 33,34% of the patients did not present any complications over the follow-up period.

From the patients in which the immediate reconstruction was performed, it was possible to achieve a 75% satisfactory aesthetic result, and this result was not a success due to one patient with disease progression and the other one with flap loss.

The statistical analysis of the clinical conditions and the correlation with the outcome of death revealed a high impact of immunodeficiency on the clinical course of the ROCM. Leukemia, which is a severe cancer that directly impacts the cells of the immune system, was more correlated with the patient's death than DM (p = 0,041), the combination of other clinical comorbidities (p = 0,033), and also when compared with patients without a medical record (p = 0,04).

The age group presented a statistical impact on the clinical course, being the patients above the fifty-years-old more related to death (p = 0,035). All the data obtained by the correlations are presented in Table 2.

Table 2.

Descriptive data and correlations of comorbidities of patients diagnosed with mucormycosis

Correlation	Significancy (p value)
Age Group (Age < 50 Years vs Age > 50 Years)	0.035* (Favors Age > 50 Years)
Sex	0.699
Leukemia × DM	0.041* (Favors Leukemia)
Leukemia × Combination of clinical diseases	0.033* (Favors Leukemia)
Leukemia × Other	0.057
DM × Combination of clinical diseases	0.700
Leukemia ×None	0.04* (Favors Leukemia)
DM × None	0.918

DM diabetes mellitus

^*Present statistical significance in a confidence interval of 95%, in the Pearson’s chi-square test

Discussion

Mucormycosis is a highly aggressive and neglected fungal infection that is often associated with immunosuppression and has a high mortality rate among patients. The rhino-orbital-maxillary disease is a potentially aggressive lesion that often requires extensive osseous resections, leading to secondary surgeries for reconstructions of both soft and bony tissues, and causing significant suffering for patients.

The scientific literature describes several treatment options for ROCM, often focusing on lesion resection and, if necessary, reconstruction. This study aims to provide a statement regarding the focus of treatment on facial aesthetics as well as the clinical standpoint.

Based on the collected results observed in this study, it is evident that the disease correlates with immunosuppression, as leukemia was the most frequently observed clinical comorbidity among the patients. This association is not novel for other fungal infections, as previously described in the literature [5, 6]. Furthermore, leukemia patients typically face a more severe and fatal disease than non-leukemia patients.

One-third of the patients in this study presented with diabetes mellitus (DM), either associated or not with another disease. The association between DM and ROCM is considered a three-part problem. Firstly, DM patients tend to have lower blood and tissue pH, providing a fertile medium for Mucorales spores to germinate. Secondly, hyperglycemia, glycosylation of transferring, ferritin, and reduced iron binding capacity increase the free iron level, which is an excellent resource for mucormycosis. Lastly, when associated with COVID-19, it often causes endothelialitis, endothelial damage, thrombosis, lymphopenia, and reduction in CD4 + and CD8 + levels, thereby predisposing to mucormycosis [7].

Elderly patients are directly associated with death and poor outcomes caused by mucormycosis infection. This can be attributed to a combination of factors, including natural age-related immunosuppression, association with other comorbidities, and particularly the alteration of the fungal community that naturally occurs over the lifespan [8].

These patients are more vulnerable to non-indigenous zygomycosis due to the characteristics of the fungal communities, which are less virulent and less protected against other infections. Furthermore, immunosuppression further contributes to the inability to avoid ROCM.

As such, it is important to focus on immunosuppression as a key factor in the management and treatment of mucormycosis, as well as identifying and treating any underlying comorbidities.

The treatment for ROCM is highly variable, especially concerning the disease's clinical course. The liposomal antifungal Amphotericin B was the medication of choice for all the patients, being associated with antibiotics when necessary.

The surgical removal of debris and non-viable bone and tissues was the preferred invasive treatment among the samples. Also, unlike hypothesized prior, the reconstructions were not commonly performed, especially in a single-time surgery.

Only 13,09% of the patients received reconstruction at the same surgical time as the bone resections. This could be explained due to the disease's clinical course, which is a severe and often uncontrolled disease [9].

The treatment should be carried out following each patient's clinical course, focusing on the control of the adjacent immunosuppression. The ROCM is usually a progressive lesion, and immediate reconstruction should be an option for small lesions that are more welcoming for a treatment, with a good prognosis. Also, the good aesthetic response (75%) is an encouraging point for the reconstruction, reducing the social impairments of facial disfiguration.

Larger lesions should be reconstructed with caution, especially if the patient presents uncontrolled comorbidities, such as diabetes and leukemia.

Immediate reconstruction should be an option for patients with some clinical criteria, such as (1) small lesions, (2) good prognosis, (3) good/controlled systemic condition, and (4) severe aesthetic impairment, with psychosocial concerns.

Regarding the small/large lesion topic, there is not a reference in the literature describing a classification for the measure of ROCM lesions, so these criteria for small/large should be carried by the professional, in accordance with the location of the lesion and related structures.

This study has some limitations, as a complete description of the patient's visual impairments that may have arose during and after the treatment was not closely followed by the maxillofacial team but done by the ophthalmology team. Also, the complete functional recovery data were challenging due to the difficulty of assessing this information without the patient's opinion.

Conclusion

Mucormycosis is a highly aggressive infection that often results in significant morbidity and mortality among patients. Immediate reconstruction should be an option for patients with specific clinical criteria and severe aesthetic impairment, with psychosocial concerns. Treatment should be carried out following each patient's clinical course, focusing on controlling the adjacent immunosuppression.

Funding

This study does not receive funding.

Data Availability

Not applicable.

Declarations

Ethical Approval

This study has been submitted and approved by the ethics committee under protocol 65293922.6.0000.5419/5.914.252.