A rare post-coronavirus disease 2019 complication of maxillary mucormycotic osteomyelitis in a Southeast Asian patient

Bhoowit Lerttiendmrong ,Pvinee Annoppornchi ,Pemik Lerttiendmrong ,Pornthep Pungrsmi

a Division of Plastic and Reconstructive Surgery,Department of Surgery,Faculty of Medicine,Chulalongkorn University,Bangkok 10330,Thailand

b Faculty of Dentistry,Chulalongkorn University,Bangkok 10330,Thailand

Keywords:Osteomyelitis Mucormycosis Coronavirus disease 2019 Plastic surgery

ABSTRACT Mucormycosis,a rapidly invasive form of fungal infection caused by Mucorales fungi,has high morbidity and mortality rates.Rhino-orbital-cerebral mucormycosis is the most common form of mucormycosis.With the coronavirus disease 2019 (COVID-19) outbreak,a causal correlation between mucormycosis and COVID-19 has been suspected,contributing to the abrupt increase in opportunistic fungal infection cases.We present a case of a Southeast Asian woman in her 60s with complaints of pus discharge in the palatal region with maxillary teeth mobility for 3 months.Physical examination revealed multiple nonvital upper teeth with severe mobility.Incisional biopsy of the maxilla and multidetector computed tomography of the head and neck confirmed the diagnosis of osteomyelitis of the maxilla secondary to mucormycosis.Surgical treatment was performed,and amphotericin B and posaconazole were administered.No operative complications or further bone destruction were observed at 8 months postoperatively.

1.Introduction

Mucormycosis is the most rapidly invasive and lethal form of fungal infection in humans caused byRhizopus,Mucor,orAbsidiafungi.1The incidence of mucormycosis,ranging from 1.2 cases per million in France to 0.14 cases per 1 000 people in India,has been increasing.2,3Mucormycosis can be classified into rhino-orbital-cerebral,pulmonary,gastrointestinal,cutaneous,disseminated,and miscellaneous mucormycosis.Rhino-orbital-cerebral mucormycosis is the most common form of mucormycosis.Mucormycosis is commonly caused by inhalation of fungal spores dispersed into the air from decaying material.4The risk factors for mucormycosis include diabetes mellitus,hematologic malignancies,corticosteroids,trauma,and iron overload.3

With the coronavirus disease 2019 (COVID-19) outbreak,an abrupt increase in opportunistic fungal infections has been reported.A causal correlation between mucormycosis and COVID-19 has been suspected.5Here,we present a case of a Southeast Asian woman in her 60s with invasive fungal osteomyelitis of the maxilla secondary to mucormycosis.The patient was diagnosed with COVID-19 pneumonia and had received steroid treatment for 2 weeks prior to symptom onset.

2.Case presentation

A woman in her 60s presented with complaints of pus discharge in the palatal region with maxillary tooth mobility for 3 months prior to presentation.Initially,the patient reported small ulcers with swelling in the palatal region,which were painful on contact.No pus discharge was initially reported.Two months prior to admission,the patient experienced ulcer progression,with active bleeding,swelling,and increased pain on local contact.The patient visited a local dental clinic,and maxillary tooth mobility was detected on physical examination.The dentist suggested further evaluation at a dental hospital and prescribed conservative treatment with antibiotics and topical medication.The patient complained of progressive symptoms with pus discharge from the palatal region and multiple maxillary tooth mobilities.At the tertiary dental hospital,incisional biopsy of the maxilla and multidetector computed tomography (MDCT) of the head and neck with contrast administration were performed.Subsequently,the patient was transferred to the plastic surgery unit of our tertiary care center for definite management.

Two weeks before the onset of palatal ulcers,the patient tested positive for severe acute respiratory syndrome coronavirus 2 and was diagnosed with COVID-19 pneumonia.The patient was anosmic after COVID-19 onset.She received inpatient treatment for 16 days;oral dexamethasone was prescribed for the first 13 days,while oral prednisolone was prescribed for the last 3 days.Favipiravir was administered during hospitalization.The presenting symptoms were detected on the last day of hospitalization for COVID-19.However,the patient was not concerned about the symptoms,and no immediate treatment was administered.No fever,significant weight loss,weight gain,or systemic symptoms were observed.The patient reported having a 5-year history of hypertension,which was well-controlled.However,she denied having any previous history of surgery,herbal drug use,smoking,or alcohol consumption.The patient had no family history of malignancy or immunocompromised status.The patient had good oral hygiene without any previous episodes of pus discharge or tooth mobility in the maxillary region.Physical examination at our center revealed multiple nonvital upper teeth with severe mobility and anosmia.A friable alveolar process and bimanual palpation of the maxilla were detected.A fistula measuring 0.5 cm with discharge at the upper labial gingiva and mild fluctuating swelling of the palatal fistula were observed(Fig.1).The patient had no facial swelling and sensory deficits of the cranial nerves V1,V2,and V3 bilaterally.Destruction of the nasal septum at the posterior bony part and darkening of the nasal mucosa extending from the right nasal floor to the septum were observed on nasal endoscopy.

Vertical bite wing,full mouth,panoramic,and periapical radiographs were obtained at the tertiary dental hospital.Disruption of the floor of the maxillary sinus and apical periodontitis were noted.Cone-beam computed tomography (CT) of the maxilla demonstrated abnormal bone trabeculation from the anterior part of the maxilla to the second maxillary molar,mucosal thickening of the right maxillary sinus,and antrolith of tooth 16.Cortical loss and bone thinning in the right maxillary sinus area of teeth 14-15,palatal area of teeth 14-17,left maxillary sinus area of teeth 24-28,and palatal area of posterior maxillary teeth were noted.MDCT of the head and neck confirmed heterogeneous density of the maxilla with cortical disruption and bony destruction,mucoperiosteal thickening of both maxillary sinuses,retention cyst in the left maxillary sinus,and right otomastoiditis (Fig.2).Subsequently,incisional biopsy of the maxilla revealed positive largesized and non-septate hyphae,which was concluded to be mucormycosis from the periodic acid-Schiff stain and negative beta glucan assay.Acid-fast staining yielded negative results.The bacterial culture of the specimen was positive forSerratia marcescensandKlebsiella pneumoniae.The patient was initially prescribed intravenous ceftriaxone and was referred to our tertiary care center for definite management.

Fig. 1.Physical examination of the maxilla demonstrating a friable alveolar process and discharge at the upper labial gingiva.

Fig. 2.Computed tomography of the head and neck revealing heterogeneous density of the maxilla with cortical disruption and bony destruction.

On presentation at our tertiary care center,the patient was admitted to the inpatient department.The patient was referred to the ophthalmology department for additional preoperative status and had bilateral myopia (visual acuity,20/100;left eye,20/70).No other abnormal ophthalmic history or physical examination findings were noted.Intravenous ceftriaxone was continued and amphotericin B was prescribed.Urgent surgery for removal of the destructive bone was planned.Gingival pus culture was negative for KOH,Wright stain,Grocott-Gomori’s methenamine silver (GMS) stain,and presence of fungi.Subsequently,debridement with partial maxillectomy,right endoscopic sinus surgery(ESS) uncinectomy,anterior ethmoidectomy,and frontal sinusotomy were performed.A palatal obturator fixed to the bone with a wire was applied to the defect.Gum recess with teeth 15-25 luxation and an infected and fragile maxilla in the underlying area was noted surgically.A blackish mucosa was observed on both the maxillary sinus and infected palatal mucosa.Mucopurulent discharge at the right frontal sinus was also observed.Gross examination of the soft palate revealed a tan-brown soft tissue mass measuring 4.5 × 3.6 × 1.5 cm3.The maxilla was divided into three surgical specimens measuring 3.5 × 2.5 × 0.5 cm3,4.5 × 2.5 × 2 cm3,and 6 × 5 × 3 cm3(Fig.3).Multiple broad pauci-septate hyphae infiltrating the bone cavity and inside multinucleated giant cells were observed on microscopic examination.Mucormycosis and chronic inflammation with focal granuloma were evident in both soft palate and maxilla specimens (Fig.4).Pseudomonas aeruginosaandEnterococcus faecaliswere found on postoperative tissue culture,prompting the discontinuation of ceftriaxone.Subsequently,ampicillin and ceftazidime were administered.Inpatient admission was complicated by acute kidney injury,with a peak creatinine level of 3.39 mg/dL 1 day after surgical intervention.Posaconazole was used to replace liposomal amphotericin B on postoperative day 19.Sixteen days after surgery,the palatal obturator and wiring were removed in a bedside setting.Three-dimensional MDCT of the facial bones and biopsy of the bilateral maxillary sinuses were performed before discharge.Postoperative CT demonstrated evidence of maxillectomy,right frontal sinusotomy,right uncinectomy,and right lower part of the nasal septum with a maxillary obturator prosthesis.Increased bony destruction and erosion of the right posterior wall of the right maxillary sinus and right ethmoid septation were evident.CT also demonstrated an increased degree of sinusitis in all paranasal sinuses,increased soft tissue thickening in the left retroantral region,and bilateral chronic oromastoiditis.Granulation and tissue necrosis were found on repeat biopsy of the bilateral maxillary sinuses.The patient was discharged with a prescription of oral posaconazole once daily.

Fig. 3.Gross examination of the excised maxilla.

Fig. 4.Multiple broad pauci-septate hyphae infiltrating the maxilla (400×).

At the 4 months postoperative outpatient department follow-up visit,the patient was prescribed oral posaconazole once daily with routine posaconazole level monitoring.The patient was diagnosed with stage 3 chronic kidney disease,with a creatinine level of 2.01 mg/dL and an estimated glomeruli filtration rate of 33.12 mL/min/1.73 m2.Threedimensional MDCT of the facial bones showed no significant changes in bony destruction,erosion,and soft tissue thickening.Chronic otomastoiditis was observed on the right side.Eight months after surgical treatment,physical examination showed a bilateral dark mucosa at the inferior turbinate.Nasal endoscopy revealed less debris and crust and absence of necrotic tissue.Repeat three-dimensional MDCT of the facial bones showed bone defects,soft tissue thickening,and chronic otomastoiditis,compatible with previous findings.

3.Discussion

Osteomyelitis is an infection of the bone that can be characterized into hematogenous osteomyelitis,vertebral osteomyelitis,and posttrauma osteomyelitis.The most common infectious pathogens areStaphylococcus aureusand coagulase-negative staphylococci.6Fungal and mycobacterial osteomyelitis are usually found in immunocompromised patients.7The clinical manifestations of osteomyelitis are dependent on the etiology of the infection.Hematogenous osteomyelitis usually presents with subacute or chronic pain at the site of bone infection,but soft tissue swelling and sinus-draining tract may also occur.Chronic infections may be secondary to open fractures,bacteremia,or vascular insufficiency,presenting as ulceration,erythema,swelling,and drainage.6,7

Mucormycosis,a rapidly invasive form of fungal infection due to Mucorales fungi,is associated with high morbidity and mortality.8The incidence of mucormycosis has been increasing.3,8Fungal osteomyelitis is more common in men than in women.9Mucormycosis usually occurs from inhalation of fungal spores,resulting in the invasion of paranasal sinuses and necrosis of the nasal mucosa and palates.Osteomyelitis involvement of the maxilla is rare,which is attributed to its rich blood supply.8,9The common predisposing factors for osteomyelitis are immunocompromised status,diabetes,lymphomas,long-term steroid therapy,organ transplantation,and acquired immunodeficiency syndrome.The clinical presentation of osteomyelitis in the orofacial region includes rhinorrhea,turbinate necrosis,facial cellulitis,and nasal discharge.10Ophthalmic involvement of painful eyes,blurred vision,and chemosis can occur in later stages.11

Here,we present a case of a woman in her 60s with invasive fungal osteomyelitis of the maxilla secondary to mucormycosis who presented with complaints of pus discharge in the maxillary region and maxillary teeth mobility.The patient had a contributing factor of steroid treatment for the treatment of COVID-19 pneumonia for 2 weeks.No other precipitating factors were identified.Apart from existing myopia,the patient did not exhibit any ophthalmic symptoms and abnormal physical examinations findings.

A significant increase in mucormycosis cases has been reported worldwide since the start of the COVID-19 pandemic.12A mean duration of 19.5 days between the diagnosis of COVID-19 and diagnosis of mucormycosis has been reported.13Ahmed et al.reported a series of patients who were diagnosed with maxillary mucormycosis osteomyelitis after recent COVID-19 diagnosis.COVID-19 is a significant risk factor for maxillary mucormycosis,either directly or through the side effects of steroid treatment.COVID-19 may disrupt a patient’s immune system through hypoxia and inadequate nutritional status.Corticosteroid use predisposes patients to COVID-associated mucormycosis through immunosuppression and anti-inflammatory effects.8,14Diabetes is also a risk factor for severe COVID-19,while poorly controlled diabetes,with or without COVID-19,is the most common risk factor for mucormycosis.A characteristic feature of COVID-19 is hyperferritinemia,and patients with iron overload are prone to mucormycosis;therefore,patients with COVID-19 may have an increased risk of mucormycosis.13

We present the first post-COVID maxillary mucormycotic case in the Southeast Asia region,with an initial presentation 16 days after COVID-19 diagnosis.No diabetes or iron overload was detected in our patient.However,COVID-19 and dexamethasone and prednisolone use might have disrupted the immune system and predisposed the patient to mucormycotic osteomyelitis.

Mucormycosis is a life-threatening condition,with an overall mortality rate of 50%,correlating with the extent of the disease.Histopathology and culture are the cornerstones of mucormycosis diagnosis.Periodic acid-Schiff and GMS staining facilitate visualization of fungal hyphae,while hematoxylin and eosin staining facilitate visualization of fungal elements.15Mucormycosis diagnosis is based on galactomannan and beta-D-glucan negativity.16,17Multimodality treatment has been the mainstay treatment for mucormycosis;treatment of predisposing factors,administration of antifungal agents,and complete removal of all infected tissues are necessary.Rapid correction of hyperglycemia and acidemia in uncontrolled diabetes and suspected mucormycosis has also been suggested.Amphotericin B has been the primary drug of choice for mucormycosis treatment,whereas posaconazole has been suggested as an option for patients with severe invasive fungal infections.17,18In the present case,we performed urgent debridement with partial maxillectomy,right ESS uncinectomy,anterior ethmoidectomy,and frontal sinusotomy.Our patient was prescribed intravenous amphotericin B,which was continued along with oral posaconazole after discharge.At the 8-months postoperative visit,no operative complications or further bone destruction were observed.Secondary maxillofacial reconstruction using vascularized fibula free flaps has been planned at 12 months after the initial operation.19

4.Conclusion

We present the first case report of a post-COVID-19 maxillary mucormycotic patient,with complaint of pus discharge and maxillary teeth mobility,in the Southeast Asia region.The initial presentation of small ulcers in the palatal area was detected 16 days after COVID-19 diagnosis.A diagnosis of mucormycosis of the maxilla was established on the basis of incisional biopsy and CT findings.The patient underwent surgical resection of the maxilla,and amphotericin B and posaconazole were prescribed.No recurrence was detected 8 months postoperatively.We urge clinicians to actively evaluate osteomyelitis in post-COVID patients treated with steroids.A subtle history and physical examination of small ulcers may predispose patients to severe bone infections.

Ethics approval and consent to participate

The need for ethical approval and consent to participate was waived as this is a case report.

Consent for publication

The patient gave written informed consent to publish the data contained within this study.

Authors’ contributions

Lerttiendamrong B: Conceptualization,Data curation,Formal analysis,Investigation,Methodology,Project administration,Resources,Validation,Writing-Original draft,Writing-Review and editing.Annoppornchai P: Conceptualization,Data curation,Formal analysis,Investigation,Validation,Writing-Original draft,Writing-Review and editing.Lerttiendamrong P: Conceptualization,Data curation,Formal analysis,Investigation,Validation,Writing-Original draft,Writing-Review and editing.Pungrasmi P:Conceptualization,Data curation,Formal analysis,Investigation,Validation,Supervision,Writing-Original draft,Writing-Review and editing.

Competing interests

The authors declare that they have no competing interests.