Reconstruction in Rhino-Orbito-Cerebral Mucormycosis Survivors: A Systematic Review

The COVID-19 pandemic has affected the entire world tremendously. In India, the impact of the second wave was huge, with 19.29 million confirmed cases and 242,211 confirmed deaths reported between March 1 and June 30, 2021.¹ Particularly during the second wave, a dangerous complication followed in the form of COVID-19–associated mucormycosis (CoAM).² Widely reported in the popular media as the “black fungus,” CoAM had been declared by many states in India as an epidemic and a disease notifiable to the national health authorities.³ A systematic review of CoAM identified 101 cases, of which 82 were from India and 19 from the rest of the world, with a 31% mortality rate among the patients. It was also found that approximately 59.4% of these cases occurred during an active COVID-19 infection and 40.6% occurred in the survivors of COVID-19.⁴ On June 7, 2021, the Indian Union Health Minister stated that 28,252 cases of mucormycosis were reported from 28 states/union territories in the country, of which 86% cases had a history of COVID-19 and 62.3% had a history of diabetes.⁵

John et al found out that the clinical presentation of CoAM was similar to the clinical picture of mucormycosis in diabetic individuals where rhino-orbital or rhino-cerebral disease predominates.⁶ Rhino-orbito-cerebral mucormycosis (ROCM) refers to the entire spectrum ranging from limited sinonasal disease, limited rhino-orbital disease, to rhino-orbital-cerebral disease with central nervous system involvement.⁴ Patients with ROCM usually require multiple radical debridements for controlling the infection along with antifungal agents. A recent review of 41 cases of CoAM by John et al found that 33 (80%) of these patients underwent adjunct surgery (sinus and thoracic cavity debridement, orbital exenteration, decortication, and lung resection).⁶ In ROCM, this results in a variety of composite tissue defects of the facial region. In India, it is expected that over the course of next few months, many survivors of CoAM will present for reconstructive needs. The purpose of this review is to summarize the evidence regarding reconstruction in ROCM from the available literature to provide directions for the reconstructive efforts in CoAM survivors.

A PubMed search was conducted for English-language studies published from 1988 through May 22, 2021, using the terms “mucormycosis AND reconstruction.” Studies that dealt with reconstruction in rhino-orbito-cerebral mucormycosis were included. Studies that dealt with reconstruction in non-ROC mucormycosis and those that did not describe reconstruction were excluded. A manual search was also performed of the references of the selected articles. The final list of the selected articles was mutually agreed upon by the authors.

The search yielded 102 results. After excluding the articles not describing reconstruction in mucormycosis, 53 abstracts were screened. Then 34 articles dealing with reconstruction in non-ROC regions were excluded. The full text of 16 articles was reviewed. Additionally, 3 articles were identified from the reference search. The selection process of the articles included is shown in Figure 1. There is a paucity of literature regarding reconstruction in ROCM, as it was a relatively uncommon disease before the COVID-19 pandemic. The available literature is in the form of isolated case reports or as a part of case series describing orbital exenteration. The available literature is summarized here. Some of the pertinent etiopathological, clinical, and therapeutic issues to be considered during reconstruction are also discussed.

Etiology

Mucormycosis is a clinical syndrome caused by some genera of fungi belonging to the order Mucorales, which is a member of the class Zygomycetes.⁷ These are ubiquitous saprophytic fungi but become pathogenic in an immunocompromised host.^7–9 They grow rapidly and release large numbers of spores that become airborne and are inhaled by humans, hence they are frequently found in the upper airway mucosa. Mucormycosis is classified into 6 categories (Table 1).

ROCM is the most common form of presentation, seen in nearly 40% of cases.^9,10Rhizopus oryzae is responsible for nearly 60% of mucormycosis cases in humans and accounts for 90% of the cases of ROCM.⁴ Once considered a fatal disease, the prognosis of ROCM remains poor with mortality rates of 15 to 34%.^7,11 Intracranial extension is very dangerous and must be prevented with early treatment.¹²

Pathophysiology

There are several possible factors that could be responsible for the germination of Mucorale spores in COVID-19 patients (Table 1).

Mucormycosis is an angioinvasive disease. Vascular invasion by the fungal hyphae produces a fibrin reaction and the development of mucor thrombi or dissecting aneurysms, which can lead to tissue ischemia and infarction.⁷ The infarction produces the black necrotic eschars in the nasal and oral cavities and face that are characteristic of ROCM. Vascular occlusion also impairs the penetration of the antifungal agents. The infection can spread rapidly to the sinuses and orbit and then into the cranium by direct extension through the ethmoid bone or orbital vessels. Mucorales can also cause cavernous sinus or carotid artery thrombosis.¹³ This results in a high risk of lethal outcomes or hematological spread and dissemination into other organs, such as the brain or lung.¹⁴

Clinical Presentation

Patients usually present when the infection extends to the orbital region. Clinical features may include fever, palpebral edema, ptosis, proptosis, decreased visual acuity, acute sinusitis, erythema over the sinuses, headache, and dark nasal and/or palatine mucosal eschar.^9,10,15 In patients with altered consciousness, imaging can be used to confirm clinical suspicion.⁸

Assessment and Diagnosis

Imaging should be used for initial evaluation. Computed tomography findings include mucosal thickening and occupation of paranasal sinuses, with the ethmoid and maxillary sinuses being most frequently involved; cavernous sinus thrombosis and cranial base involvement may be found in some cases. Magnetic resonance imaging may show hypointense areas in both T1- and T2-weighted images. The gold standard for diagnosis is biopsy and histopathology.⁸ Tissue biopsies can be obtained from endoscopy or during surgical debridement.⁹ These fungi are characterized by nonseptate, wide ribbon-shaped hyphae, branching at angles ranging from 45 to 90°.⁸ The laboratory culture of Mucorales is very difficult and often unsuccessful.¹⁴    

Management

Overview of the Management of ROCM

Early diagnosis and treatment are vital for a successful outcome in ROCM.¹⁰ Treatment consists of the correction of the underlying predisposing factor(s) wherever possible, antifungal medications, improvement of the general health status, and radical surgical debridement of the necrotic and infected tissues.

The vascular invasion by the fungi may prevent adequate delivery and penetration of the antifungal agents into the affected areas; hence, adjunct surgical intervention may be needed. Surgical debridement reduces the microbial load and aids in diagnosis by enabling identification of the organisms. It also changes the anaerobic and microaerophilic tissue environment, which favors fungal growth. Debridement should continue to well-perfused bleeding tissues, taking into consideration the vaso-occlusive effects of mucormycosis. Sometimes a multidisciplinary approach involving various surgical specialties may be needed during the debridement.⁸ Very often multiple debridements may be required.¹⁶ It should be remembered that the cosmesis and possible loss of function should not take precedence over satisfactory surgical excision.¹⁵ According to a study published by Tedder et al, debridement of all infected tissues reduces the mortality by 49%.¹⁷

Where possible correction of the underlying predisposing factor, such as reversal of immunosuppression, leads to improved outcomes.¹⁰ Other adjunctive measures include aggressive management of acidosis and hyperbaric oxygen therapy.⁷

Aims of Reconstruction in ROCM

Owing to the aggressive debridements needed for clearance of the infection, ROCM survivors may be left with complex tissue defects, which may be associated with significant functional and aesthetic impairment. It is fundamental to offer reconstructive solutions that improve their quality of life once the infection has been brought under control.¹⁰ The aims of reconstruction may differ in individual cases according to the tissue and functional deficits present. These may include providing wound coverage, obliteration of the dead spaces, closure of fistulae, and restoration of the skeletal structure. It is important to try to restore as much function as possible and try to get a socially acceptable appearance for the patient. Functional goals include restoration of nasal breathing, oral nutrition, and comprehensible speech. Aesthetic goals are to restore cover, form, and volume, and in cases where orbital exenteration has been performed, to enable usage of an eye prosthesis that will look as natural as possible.¹⁶

Prerequisites for Reconstruction

The most important prerequisite is to achieve clearance of the infection. Metzen et al recommended delaying the reconstructive surgery until it is known that the patient is going to survive, infection has been cleared, and the remaining tissue is healthy.¹⁴ As and when required, serial imaging can be used to monitor the disease process and to guide further debridements. Biopsies play an important role in ensuring that the residual tissues are free from infection. Reinbold et al advocated controlling the infection with long-term antifungal therapy to ensure the success of free tissue transfers because the angioinvasive nature of the fungus can lead to thrombosis and vascular dissections.¹⁸ The vascular obstructions can also impede the penetration of antifungals into the tissues invaded by the fungus. To promote faster clearance of the infection, Navarro-Perea et al combined local treatment of the wound with liposomal amphotericin B along with the systemic treatment and achieved clearance of the infection within 1 month in 2 cases permitting subsequent reconstruction.¹⁰ Frozen section analysis of the margins can be performed to ensure clearance, especially when debridement and reconstruction are being performed simultaneously.

Timing of Reconstruction

The timing of reconstruction in the studies reviewed is given in Table 2. Based on the available literature, the consensus is in favor of delayed rather than immediate reconstruction after ensuring that the infection has been eliminated/controlled and that there are no recurrences. In the reports that described immediate reconstruction after debridement, patients had already been treated sufficiently with antifungals before the surgical intervention.

Tissue Defects in ROCM

A list of post-ROCM tissue defects that were encountered in the studies reviewed is given in Table 2. The most common defects were the ones that resulted from orbital exenteration and excision of a varying extent of the involved contiguous bony and soft tissue structures. Defects created by varying degrees of maxillectomy, defects of the palate, alveolus, nasal septum and side walls, skin and soft tissue defects over the cheek, and naso-orbital fistulae were the other defects reconstructed.^10,22 Honeybul et al reported an extensive calvarial defect following an unusual invasion and destruction of skull vault.¹¹ In some cases there were large composite defects, which were reconstructed with a combination of flaps or involved multiple stages of reconstruction. For instance, Rashid et al reconstructed a large composite defect of cheek, maxilla, palate, and nasal wall with a combination of 3 local flaps.²³ Augustine et al described a case wherein reconstruction involved multiple surgical interventions over more than 2 years.¹⁵

Technique of Reconstruction

The various reconstructions that were described are summarized in Table 2. The basic requirement in the majority of the cases was to obliterate the orbital cavity and achieve continuity of the epithelial lining. The consensus opinion favors reconstruction with pedicled flaps rather than free flaps in cases where the infection is not eliminated completely. The reason for this recommendation is the angioinvasive nature of mucormycosis, which can lead to vascular thrombosis and failure of the free flaps.¹³ Another very important consideration while contemplating reconstruction in ROCM, especially in postorbital exenteration cases, is to ensure that the reconstructive option chosen considers the planned ocular prosthetic rehabilitation.

Alfano et al performed a pedicled pectoralis major myocutaneous flap for reconstruction in their patient. A pedicled flap was preferred for reconstruction in this condition because of the patient’s excellent blood perfusion, which enables antifungal agents and self-defense molecules to be transported to the site of infection after debridement. It was also suggest that free flaps may play a role in delayed reconstruction.¹³ Navarro-Perea et al used a combination of a pedicled temporalis muscle flap, a pedicled skin island flap, and a titanium mesh implant for reconstruction in their case with successful results. They believe that temporalis muscle flap allows acceptable reconstruction in a single stage without the need of microvascular surgery and provides adequate vascularization in combination with a shorter healing time than other techniques.¹⁰ Alleyne Jr et al transposed the anterior two-thirds of the temporalis muscle across a defect in the orbit and anterior cranial fossa  and obliterated the communication between the intracranial and transfacial dissections.⁷ Lari et al reconstructed an exenterated orbital cavity with a concomitant naso-orbital fistula with an anteriorly based galea-frontalis pericranial flap; the flap filled the cavity completely and was folded to close the fistula.²¹

Rashid et al reconstructed a large composite defect with a combination of local flaps; a forehead flap was used to reconstruct the lateral wall of the nose, a cheek rotation advancement flap was used to cover the cheek defect, and the temporalis muscle flap was used to reconstruct the palate and obliterate the dead space. The flaps healed well with a good mucosalization of the temporalis flap seen by the fourth week. This patient underwent a second procedure consisting of flap division, advancement, and scar revision at around 6 months with good healing.²³

Herford et al performed a combination of Le Fort I advancement and a tongue flap with an anterior maxillectomy defect.²⁰

Bhatnagar and Agarwal used a free radial artery forearm flap for the reconstruction of an orbital exenteration defect with a concomitant naso-orbital fistula. The pedicle was anastomosed to the facial artery and vein in the neck. The adipo-fascial component was placed into the defect; the central skin paddle was sutured to the skin margins. Radial forearm flap was preferred because it offers a thin, soft, and easily foldable tissue in comparison to other free flaps. Also, the flexible pedicle length and pliable tissue offer a suitable contour restoration of the exenterated orbit.²² Sham et al described a case of a post-maxillectomy defect in which reconstruction of the mid-face was performed with a free serratus anterior flap including the seventh rib.²⁶

Augustine et al reported 2 cases of ROCM. In one case with a defect spanning from root of the nose to palate and entire alveolus, they performed a free fibula osteo-cutaneous flap and reconstructed the dorsal nasal strut with a bone graft. In another case, an initial temporary reconstruction was performed to cover the exposed orbital apex in the form of a cheek rotation flap and a skin graft was used for nasal defect. Definitive reconstruction was performed after 8 months with an osteo-musculo-cutaneous iliac crest flap after ensuring clearance of the infection. Skin paddles were fashioned for both the reconstruction of the enucleation defect and for the palate. Bone was used for alveolus and zygoma reconstruction and was osteotomized and hinged for the reconstruction of the nasal dorsum. Further, a forehead flap was also performed for the nasal reconstruction 2 years later, with the lining provided by a turndown flap from the skin paddle of the iliac crest flap.¹⁵ Davies et al performed a free anterolateral thigh flap for facial reconstruction.¹⁹ Metzen et al performed a free osteocutaneous scapula flap after hemi maxillectomy. Bone gaps in the flap were supplemented with autologous iliac crest bone graft after 9 months, and ultimately the patient could undergo oral rehabilitation with dental implants.¹⁴

Murphy et al reconstructed an extensive hemifacial defect with a free anterolateral thigh flap that incorporated a segment of vastus lateralis to obliterate the dead space left by debridement of the sinuses. The flap was anastomosed with the facial vessels.²⁵

Shand et al performed a free radial artery forearm flap for the reconstruction of a midfacial orbital defect due to an invasive infection of the midfacial-orbital complex with Scedosporium apiospermum and Mucormycosis. The flap settled well enough to permit prosthetic reconstruction of the orbit.²⁷

Odessey et al performed a tarsal strip procedure for paralytic ectropion of the lower eyelid, gold weight placement in the upper eyelid, endoscopic brow lift, and scar revision in the upper lip in their patient in the first stage. In the second stage they performed a free vertical rectus abdominis myocutaneous flap to improve the cheek contour and obliterate an orophrayngeal fistula, and the skin paddle was used to reconstruct the hard palate. Further debulking and cheek and oral commissure suspension were also performed at a later stage in this case.⁹

Silberstein et al used a free rectus abdominis myocutaneous flap for reconstruction of a large complex defect including orbit, maxillary sinus, nose, and oral cavity. The vascular anastomosis was performed on the branches of facial artery and vein. After 4 months further secondary reconstructive procedures were performed. These included closure of the oronasal fistula and creation of an ophthalmic socket in the muscle flap using split-thickness skin graft (STSG). Tissue expansion of the remaining cheek skin was performed for reconstruction of lower eyelid, medial canthus, and nasal skin. The remaining exposed surfaces of palate, nasal cavity, and external surface of orbit were skin grafted. An acrylic, nonintegrated oval ocular prosthesis could be used satisfactorily.¹⁶

Honeybul et al used a 3D-printed titanium implant for reconstructing a calvarial defect.¹¹

Schmidt et al performed reconstruction with a combination of 4 zygomaticus implants and 2 standard endosseous implants in their patient, who had undergone near total maxillectomy for maxillary mucormycosis; the patient was later able to use an obturator and denture. With the obturator and the denture in place, the patient had an adequate lip support, normal speech, and normal swallowing.²⁴

Croce et al performed eye socket reconstruction with a full-thickness skin graft (FTSG). They observed that for the reconstruction following orbital exenteration, a FTSG or a pedicled myocutaneous flap are the simplest options for the elderly population with significant comorbidities. In their experience the final outcome is comparable with that of more complex flap reconstructions, with less donor site morbidity and shorter operation times. Though with FTSG they note that some time is needed for it to take completely in the eye-socket, during which scabs and granulations need to be removed repeatedly.²⁸

A treatment algorithm for reconstruction of tissue defects in ROCM is proposed based on this literature review in Figure 2.

Adjunctive Antifungal Treatment

The adjunctive antifungal treatments used in the studies reviewed are summarized in Table 2. Amphotericin B was the agent used most frequently.^{7,15,16,19,21,25} The use of liposomal amphotericin B was recommended in some studies because it was found to be more effective in ROCM than conventional amphotericin B; it could also be used when conventional amphotericin B failed.^{10,13–15,27,28} It was also found to be less nephrotoxic and hence was used in cases where the renal function started to deteriorate on conventional amphotericin B treatment.^9,11,12 Amphotericin B was given intravenously; it was also given intrathecally in some cases.^7,19 The use of amphotericin B for intraoperative irrigation and for daily dressings of the wound was also associated with favorable results.^10,21

Oral posaconazole (800 mg per day, in 2 or 4 doses) was used as an alternative in patients who could not tolerate amphotericin B; it is particularly useful for treatment in an outpatient setting.^14,25 Voriconazole was also used successfully in some cases.^13,27

Complications

The complications related to the reconstruction in the studies reviewed are summarized in Table 2. Complications were usually minor. Alfano et al had a relapse of fungal infection and partial necrosis of the pedicled pectoralis major myocutaneous flap in the immediate postoperative period.¹³ Augustine et al had to perform reexploration of vascular anastomosis for suspected arterial compromise in their free fibula osteocutaneous flap. Because the anastomosis was found to be patent, all the tension on the skin paddle was released and reinsetting was done without any tension. The flap survived but required minimal revision for partial dehiscence.¹⁵ Total loss of flaps was not reported in any of the cases.

Follow-up

Survivors of mucormycosis are high-risk patients. They are susceptible to recurrences and are also at a higher risk for other conventional bacterial infections and sepsis, which may be further aggravated in the setting of tissue ischemia. A close follow-up is required to detect and treat any possible recurrence of infection.¹⁶ The length of the follow-up in the studies reviewed is summarized in Table 2.

Patients and survivors of ROCM with tissue defects in the maxillofacial region can be satisfactorily reconstructed using a multitude of options. These include skin grafts, pedicled flaps, free flaps, and in some cases implants and prosthetics. Some patients with large complex defects may require a combination of techniques or multi-staged reconstruction. Ensuring eradication/control of mucormycosis infection with appropriate antifungal therapy prior to reconstruction is an essential prerequisite. Sometimes antifungals need to be continued after reconstruction to prevent recurrence of the infection. The ultimate aim of reconstruction should be to achieve as much functional restoration as possible and a socially acceptable appearance. In orbital exenteration defects, reconstruction should consider the possibility of prosthetic rehabilitation. More experiences with reconstruction of this condition are anticipated over the coming few months, which will lead to the publication of larger case series describing further treatment options.

Affiliations: All India Institute of Medical Sciences, Bhopal, India

Correspondence: Ved Prakash Rao Cheruvu; vedprakash.plasticsurg@aiimsbhopal.edu.in

Ethics: This study conforms to the Declaration of Helsinki ethical principles for medical research. The study is based on de-identified information and is exempt from IRB.

Disclosures: The authors have no relevant financial or nonfinancial interests to disclose.