Complications of COVID-19 in the maxillo-facial region: Clinical case and review of the literature

COVID-19 is currently causing a pandemic around the world. With the increase in the number of patients, there was a slight increase in the incidence of various complications. In particular, infectious and inflammatory diseases of the face and jaw are observed in patients with COVID-19 in the early infectious stages of the disease, as well as in the late stages. In the previous literature, as a sign or complication of COVID-19 were mentioned cases of changes in the oral cavity - ulcers, rashes, and inflammation of salivary glands. The conditions presented in this article are a serious complication of COVID-19, radically different from the usual course of osteomyelitis, in which the patient has a course with a predominance of long-term, chronic-progressive, atrophic processes. Treatment was somewhat ineffective due to local chronic inflammation (pansinusitis), metabolic, microcirculatory, immune, and coagulation disorders in patients.


Introduction
In December 2019, the first cases of pneumonia of unknown etiology were registered in the city of Wuhan (PRC) [1]. Subsequently, a new type of coronavirus called SARS-CoV-2 (COVID- 19) was isolated from the lower respiratory tract of several patients with pneumonia. In March 2020, the World Health Organization (WHO) announced a pandemic of the new coronavirus, which indicates its global spread throughout the world. Since then, as of February 2021, there have been more than 107.8 million cases of infection worldwide and 2.37 million deaths [2].
The most common symptoms of the disease caused by the COVID-19 coronavirus are fever, weakness, cough, and diarrhea. In severe cases, acute respiratory distress syndrome (ARDS) develops, which can be fatal. [3,4]. There was a slight increase in the number of complications with the increase in the number of patients, in particular, infectious-inflammatory diseases of the face and jaw are more common in patients with COVID-19 in the early infectious stages of the disease, as well as in the late stages [5][6][7]. Such patients also have serious complications such as deformities of the facial bones, osteomyelitis, thrombosis of the cavernous sinuses.
Let us overview some of such cases Case 1. Patient M.R. 65 years old. He was admitted to the Adults' ENT Department of the Multidisciplinary Clinic of the Tashkent Medical Academy with a diagnosis of upper jaw osteomyelitis, phlegmon of the infraorbital regions. According to the patient's words, 2 months before, he was treated at the Infectious Diseases Hospital with the diagnosis of COVID-19. Concomitant diseases: diabetes, pneumonia, arterial hypertension, IHD. 10 days after the Covid-19 infectious period, the patient complained of swelling around and under the left eye, redness of the skin, pain on palpation, long and diffuse pain in the left half of the head, loss of vision in the left eyeball. On clinical examination observed disorders of the left side function of the II, III, V, VII pairs of nerves (paresis, paralysis, paresthesia). Volumetric edema covered almost half of the face, the opening of the mouth was normal, the left corner of the mouth was lagging in movement due to paresis n. facialis. Ptosis was observed in the left upper eyelid. In the oral cavity -in the region of the alveolar process of the left upper jaw was observed loss of sensitivity in the teeth, the beginning of atrophy of the mucous membrane of the jaw, with redness and necrosis on the edges. Despite intensive antibacterial, antiinflammatory, anticoagulant, angioprotective vitamin therapy, insulin therapy, hormone therapy, and symptomatic treatment was observed deepening and continuation of the process. The wound in local regions and the oral cavity was treated continuously and systematically with antiseptic solutionsiodine-containing betadine, chlorhexidine solution, potassium permanganate, 3% hydrogen peroxide solution, also, with dental adhesive paste, solcoseryl, parodium gel, metrogil dental ointment was applied dressings in the teeth. A protective plate was placed on the surface of the defect of the altered part of the bone so that the effect of the ointment would be permanent.
Within 6 months, the mucous layer on the affected jawbone is almost completely absorbed, the surrounding mucous layer is often light pink, without inflammation, the jawbone is bare, there is almost no granulation tissue on the surface (Fig. 1). Maxillofacial osteomyelitis in these patients was coursed for a very long time, with a predominance of chronic progressive, atrophic processes. During this period, no sequestration process was observed in the upper jaw bone.
On pathohistological examination, inflammation and necrosis of the vascular wall, thrombosis, soft tissue homogenization, lymphocytic, and leukocyte infiltration were observed (Fig. 2).
In the MSCT image -in the overtime monitoring, cavernous sinus thrombosis, partial destruction of the skeletal bones of the middle and upper part of the left face was observed (Fig. 3).
In the blood analysis, during follow-up, leukocytosis decreased from 16 * 10 9 to 07 *10 9 . ESR ranged from 43 mm/h to 24mm/h. Hemoglobin was 112 g/l, erythrocyte count was below the norm of 3.8*10 12 , the color index was 0.8. During the observation, C-reactive protein (CRP), rheumatoid factor (RF) fibrinogen, the amount of which remained above normal. PTT, INR, D-Dimer prothrombin time normalized. The blood calcium was 1.71 μmol/l in the initial examination and increased to 2.21 μmol/l during treatment.
Case 2 -A 62-year-old woman. From 07/27/2020 to 09/26/2020, she was treated as an inpatient at Zangiota Medical Association, specializing in Covid-19, for 2 months for severe bilateral multisegmental lung damage. During this period, the patient underwent operative treatment on the right side with a diagnosis of "phlegmon of the ear, buccal, temporal and maxillar regions." Once the patient's general condition stabilized, she was treated at home. Over the last 10 days, the patient's condition worsened (SpO2-40%), for which she was admitted to the intensive care unit of the multidisciplinary clinic of the Tashkent Medical Academy. Complaints on the admission of purulent wounds on the right face, right side of the maxilla, partial discharge of liquid food from the mouth and nose, purulent discharge from the wound, loss of sensation on the right side of the face, and lasting of this process for several months, acute respiratory failure, general weakness, fever. On examination of the local condition, a fistulous wound was visible on the right cheek and the front of the ear. There is a drip pus discharge, with pus excreted in a liquid consistency of whitish color, foul-smelling. There is partial, limited reddening of the skin around the wound. When the wound is probed, the bottom is a bone and connects with the maxillary sinus. The opening of the mouth is unrestricted, but the corner of the mouth is immobile and is based on facial nerve palsy. On the inside of the mouth, on the right palatal side in the area of the alveolar bone, the gum mucosa is atrophied, baring the bone and molar teeth falling out, the root part is connected to the bottom of the upper jaw cavity (Fig. 3). Drops of pus are secreted from these regions too.
Examination of the nasal cavity by anterior rhinoscopy revealed perforation of the medial septum of the lower nasal passage on the right with necrotic lesions and defects in the soft and bony tissue of the lateral wall. The general condition of the patient was severe, conscious, but in a stupor. Arterial blood pressure was 120/80mm mercury column. The pulse was 98 beats per minute and the respiration rate was 25 beats per minute. Bacteriological examination of the patient's pus revealed several types of staphylococcus, streptococcus, Escherichia coli. Antibiotics were selected based on sensitivity to the microflora.
During the treatment, the patient underwent surgery to open the local purulent process, evacuate the pus, and treatment of a wound regularly with antiseptic solutions. In the general part of the treatment, after the examination, additional investigations and consultation of a neuropathologist, ENT, vascular surgeon, endocrinologist, ophthalmologist, therapist, rheumatologist, maxillofacial surgeon, and dentist were prescribed antibacterial, detoxification, drugs that improve blood aggregation and rheology and antianemic drugs. However, the general condition of the patient and the process of recovery in the local area were very slow. There was an enlargement of the zone of osteomyelitis in the upper jaw, the subsequent loss of teeth, continuous discharge of pus in the mouth and oral cavity. The mean values of changes in the patient's blood analysis are given in the table below. According to several general blood analyzes, the patient had grade 1 anemia, hemoglobin levels and erythrocyte counts were normalized during treatment. Initially, leukocytosis (12.9 *10 6 /l) was detected, during treatment it decreased to 6.0 * 10 6 /l, ESR -decreased from 22 to 3 mm/h. Indicators associated with the coagulation system were normalized, but the concentration of fibrinogen and D-dimer was slightly higher than normal, the hematocrit amount was 42%, and the upper limit was maintained. In addition, high levels of C-reactive protein, rheumatoid factor, antistreptolysin indicate a general inflammation in the organism.
MSCT diagnosed discirculatory encephalopathy, inflammation of the left sinuses (sinusitis, ethmoiditis, sphenoiditis, frontitis), cavernous sinus thrombosis.  The general condition of the patient upon admission was of medium severity, consciousness was clear, the position was semi-active, SPO2 -97. Body temperature was 37.60C. Respiratory rate -20 times a minute, dyspnea appeared during physical activity. BP 120/60 mmHg. Ps -88 beats per minute  On external examination, swelling and ptosis of the upper left eyelid were visualized in the left periorbital region and the left suborbital, buccal region. On objective examination, the patient showed retardation in the contraction of the corner of the oral cavity on the left side.. Impaired skin sensitivity of the upper and middle regions of the left side of the face was noted. Oropharyngoscopy: an examination of the oral cavity reveals complete adentia, necrotized wound in the left half of the hard palate in its entirety, covered with necrotic film with partial bone defect transition to the right half, bottom of the necrotized wound -hard palate bone, the color of necrotized hard palate bone pale yellowish, bone consistency partially softened. Around the necrosis the mucosa is hyperemic. The color of the oral mucosa in the rest of the oral cavity was pale pink (Fig. 5). Rhinoscopy: the mucosa was pink, there were areas of necrotic tissue in the left side of the nasal cavity, the nasal septum was curved to the right.
MSCT study of the chest on October 24, 2020, in axial, coronary, and sagittal projections revealed marked pathological areas of "frosted glass" thickening with indistinct contours, with reticular changes of the interstitium, merging in places, the degree of involvement on the right 40-45%, on the left 20-25%. On October 24, 2020, the patient underwent an MRI of the brain with angiography (arteries and veins). The examination showed signs of marked soft tissue edema of the face mainly on the left buccal region and left orbit with multiple dilated vessels extending deep into the pterygoid fossa on the left side. Diffuse  atrophy of the cerebral hemispheres. On MR angiography, there were posterior communicant arteries of cerebral vessels that were hypoplastic. On MR venography due to hypoplasia of transverse and hypoplasia of sigmoid sinus on the right venous sinuses were asymmetrical. There was noted signal enhancement in the projection of the cavernous sinus on the left. Blood flow in the other sinuses remained (Fig. 6).
Case 4. Akbarova M. 67-year-old female with a history of type 2 diabetes, arterial hypertension, and obesity who developed cavernous sinus thrombosis two weeks after the onset of the first symptoms of COVID-19 disease confirmed by RT-PCR, being 3 days after discharge from the COVID-19 hospital due to significant improvement of general status. The patient presented at the department of Adult ENT and Maxillofacial Surgery with necrosis of hard palate and glabella region of the face. (Fig. 7). Brain and facial CT scan revealed right cavernous sinus enlargement and thrombosis, old pontine infarcts, right eye ptosis, and orbital and periorbital swelling, pansinusitis. MRI Angiography confirmed findings of right cavernous sinus thrombosis, occlusion of the intracranial right internal carotid artery.
All patients showed increased inflammation in the bone during 8 months of treatment and follow-up. Although, in osteomyelitis, the    process of sequestration was observed after 5-6 months and the necrotic tissue had removed, as well as reparative processes had to be noted.

Discussion
Initially, COVID-19-related olfactory and gustatory dysfunction was described as a possible surrogate marker of SARS-CoV-2 infection, sometimes presented as a single symptom of the disease [8]. Then, a few isolated cases or short series of oral manifestations of COVID-19 such as oral ulcers, petechiae, and reddish spots, mostly on the palate, in addition to desquamative gingivitis and blisters on the lower lip and cheek mucosa were reported [9][10][11][12][13][14]. The authors point out that, such oral lesions have a special character in the early diagnosis and management of the disease [15]. Soares et al. (2020) on oral examination found aphthous lesions, multiple reddened macules on the tongue, palate, and cheek mucosa which healed within 3 weeks [16]. According to Bianca et al. severe acute respiratory syndrome coronavirus, 2 (SARS-CoV-2) can infect and multiply in the oral mucosa, resulting in painful oral ulcers. They reported 8 cases of COVID-19 infection with necrotic oral ulcers and aphthous ulcers that developed early after dysgeusia occurred and affected the tongue, lips, palate, and oropharynx. SARS-CoV-2 infect and multiply in oral keratinocytes and fibroblasts, causing oral ulcers and superficial necrosis [17]. The virus can primarily infect oral cells using ACE2 receptors leading to COVID-19-associated oral manifestations, SARS-CoV-2 binds to angiotensin-converting enzyme receptor 2 (ACE2), which is expressed by ACE2 receptors on the oral mucosa and salivary glands, in the gum and periodontal tissues [18].
At the same time, questions have been raised to discuss whether these lesions result from direct infection by SARS-CoV-2 or are secondary manifestations of COVID-19. In addition to medications that can cause oral side effects, prolonged hospital stays with the possible need for orotracheal intubation can also cause oral mucosal changes [19].
As mentioned above, previously published articles described changes in the oral cavity, such as sores, rashes, candidiasis, and no profound and serious changes such as jaw osteomyelitis were noted. Since there is no standard treatment for COVID-19, the patient, especially those with respiratory complications, is administered many different medications. Continuous use of antibacterial drugs in huge doses leads to the development of dysbacteriosis and candidiasis processes [20,21]. The literature mention that some microbes and fungi are also the cause of osteomyelitis. In particular, fungal infection, mainly caused by Aspergillosis fungus, has been reported to cause upper jaw osteomyelitis [22][23][24]. In addition, the development of jaw osteonecrosis due to certain drugs or their interaction has been observed. Mainly, the drugs used in the treatment of rheumatoid arthritis -immunosuppressants, also, bisphosphonates and the use of other antiresorptive and antiangiogenic drugs, a wide range of drugs classified as tyrosine kinase inhibitors, monoclonal antibodies, radiopharmaceuticals, selective estrogen receptor modulators are involved in the development of osteonecrosis of the jaw. Bennardo et al. Studied Tocilizumab, which is a humanized receptor for interleukin-6 (IL-6R), a monoclonal antibody that inhibits interleukin-6 (IL-6) signaling, used as a treatment for rheumatoid arthritis causing osteomyelitis of the jaw [25,26]. Considering the rheumatic treatment of patients with severe COVID-19 due to high CRP, we can see that this is close to the truth because there are cases of osteomyelitis, necrosis of other bones in the literature [27,28].
Thus, the development of the process was observed due to the interaction of a wide range of drugs used in the treatment of Covid-19, secondary infections of the oral cavity, and ENT organs. Although the main characteristics of COVID-19 disease are respiratory symptoms, coagulopathy with the increased incidence of thrombotic and thromboembolic complications is a common finding [29]. Cavernous sinus thrombosis is a very rare, life-threatening condition. Typically, it is caused by an infection that has spread beyond the face, sinuses, teeth, pharynx, ears, or eyes, or have post-traumatic origin [30][31][32]. The course of the disease, blood rheology, and prevention of microcirculatory disorders is important in such patients because the continuation of the process in many cases, delays the sequestration and ineffectiveness of conservative treatment depend on general and local circulatory disorders, thrombosis, and other metabolic changes in patients.

Conclusion
Facial osteomyelitis in Covid 19 patients has a very long-term course, with predominant chronic progressive and atrophic processes. In almost all cases due to systemic changes in the vascular and coagulation system in patients the ineffectiveness of complex treatment has been identified. At a time when COVID-19 disease is widespread and new strains are emerging, measures must be taken to prevent such serious complications in patients, correct metabolic changes in the body, and improve treatment methods. It is necessary to treat patients with osteomyelitis and cavernous sinus thrombosis with the participation of specialists of various profiles (neurologist, ENT, ophthalmologist, therapist, rheumatologist, resuscitation specialist, maxillofacial surgeon, dentist, etc.) and develop protocols and guidelines for the rehabilitation of such patients.

Ethics statement
Informed consent was obtained from the patient for publication of this case description and any accompanying images. The study has been conducted following the ethical principles of the Declaration of Helsinki.

Financial support
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest
The authors declare that they have no conflict of interest.