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Post-COVID steroid induced avascular necrosis of the jaw: Emerging challenge in India

The COVID-19 pandemic continues to evolve and spread with new variants of SARS-CoV-2 across the globe, as well as bring to clinical attention several post-COVID conditions. We report a post-COVID condition observed at our tertiary care center: spontaneous de novo development of steroid induced avascular necrosis in patients who have recently recovered from COVID-19 following high dose steroid usage in a short span of time. Pre-COVID published literature indicates that these lesions were seen very rarely in the jaws and were related to long-term usage of steroids and recent tooth extraction. They were considered under the broad spectrum of medication-related osteonecrosis of the jaws. Present authors believe that the post–COVID-19 steroid-induced avascular necrosis of the jaws is a distinct new entity. It is analogous to the avascular necrosis noticed in the femoral head of individuals recuperating from COVID-19, a condition conventionally known to be strongly associated with steroid therapy. Rapid progression, associated morbidity and mortality, and its possible differential diagnosis require pathologists to be vigilant regarding the chance encounter of such cases in jaws. Further reporting of such cases is required to gain additional insight into its features.

The COVID-19 pandemic continues to evolve and spread with new variants of SARS-CoV-2 across the globe, as well as bring to clinical attention several post-COVID conditions. We report a post-COVID condition observed at our tertiary care center: spontaneous de novo development of steroid induced avascular necrosis in patients who have recently recovered from COVID-19 following high dose steroid usage in a short span of time. Pre-COVID published literature indicates that these lesions were seen very rarely in the jaws and were related to long-term usage of steroids and recent tooth extraction. They were considered under the broad spectrum of medication-related osteonecrosis of the jaws. Present authors believe that the postÀCOVID-19 steroid-induced avascular necrosis of the jaws is a distinct new entity. It is analogous to the avascular necrosis noticed in the femoral head of individuals recuperating from COVID-19, a condition conventionally known to be strongly associated with steroid therapy. Rapid progression, associated morbidity and mortality, and its possible differential diagnosis require pathologists to be vigilant regarding the chance encounter of such cases in jaws. Further reporting of such cases is required to gain additional insight into its features. The COVID-19 pandemic continues to evolve and spread with the episodic appearance of new variants, creating panic and alarm around the globe. The associated morbidity and mortality with the infection is continuously challenging the understanding of this disease among health care workers. In addition, several novel post-COVID conditions have been reported in the literature due to the multiorgan damage induced by SARS-CoV-2. Such damage further impedes the recovery and affects the quality of life of the patients for a prolonged period following recovery from COVID. 1 Herein, we report a post-COVID condition increasingly observed at our tertiary care center: spontaneous de novo development of osteonecrosis (avascular necrosis) in the jaws in patients who have recently recuperated from COVID-19 and have received intensive steroid therapy in a short span of time.
Avascular bone necrosis is a degenerative bone disorder in which reduction or obstructed subchondral blood supply results in cellular bone necrosis. 2 It is also known as osteonecrosis, aseptic necrosis, and ischemic bone necrosis and has primarily been reported in the long bones. Several theories have been proposed to explain its etiology including use of glucocorticoids, chemical toxicity, radiation, thermal injury, smoking, bone fractures or recurrent traumas, blood vessel abnormalities, intraosseus vascular compression or occlusion, and so on. 2,3 Steroid (glucocorticoid)-induced osteonecrosis has been commonly reported within the femoral head. It is hypothesized to be caused by abnormal lipid metabolism; decreased osteogenic potential of bone marrow mesenchymal stem cells; intravascular thrombosis; increased osteocytic and osteoblastic apoptosis; and polymorphisms of the CYP3A4, MMP8, tumor necrosis factor alpha (TNFa), and MDR1 genes. Osteonecrosis of the jaws (ONJ) induced by steroid use is rare. We could find only 3 cases in the published literature despite extensive search. 4,5,6 All of the published case reports had 2 common features: history of long-term usage of steroids and a recent tooth extraction.

MATERIALS AND METHODS
The second wave of COVID-19 pandemic in India has seen an indiscriminate use of short-term, high dose steroid therapy in infected patients. In the aftermath, we have observed an unusual increase in the number of cases of ONJ invariably associated with a history of short-term usage of a high dose of corticosteroids. Four such cases were identified within a span of 4 months following the subsidence of second wave of the pandemic. All the patients were men within an age range of 28-65 years (median: 48.5 years). They all admitted to being treated with oral/intravenous steroids for a period of approximately 2 weeks. Before the COVID illness, these patients had been healthy and denied receiving steroids for any other condition previously.
Within a few days of recovery from COVID-19 infection, these patients presented with pain, facial swelling, and sudden mobility in the teeth (Table I). Radiographs of 3 of the patients depicted ill-defined osteolytic lesion in the maxilla with maxillary sinus involvement ( Figure 1A, B). In the fourth patient (case  4), moth-eaten appearance was found in the mandibular ramus and angle region ( Figure 1C, D). All the lesions were unilateral. Incisional biopsies were done for all the cases to rule out any invasive fungal or other microbial disease and exclude other entities that can present in a similar manner like metastasis, plasmacytoma of bone, and Langerhans cell histiocytosis (Table II). During gross examination, the specimens showed necrotic fragments of bone. Histopathologic examination revealed fragments of irregular bony trabeculae with empty lacunae accompanied by surrounding necrotic bone marrow  Necrotic bone is a finding common to these entities.
( Figure 2A, B). Special stains like Periodic acid Schiff and Grocott-Gomori's methenamine silver revealed no fungal organisms. Ziehl Neelsen staining showed no mycobacterium, ruling out any microbial involvement. In 3 of the patients, further surgical interventions (curettage with extraction of involved teeth) were undertaken (Supplementary Figure S1), following which they received broad spectrum antibiotics. Satisfactory healing was seen in these cases. In 1 patient (case 1), endoscopic debridement of maxillary sinus was attempted, and KOH (potassium hydroxide) mount showed presence of hyaline aseptate hyphae. However, histopathology, special staining, and culture were negative for fungal organisms. Thus, possibilities of steroid induced ONJ and/or mucormycosis were considered. Due to the suspicion of mucor in the KOH mount, an antifungal therapy with amphotericin B was promptly initiated. However, the patient succumbed to the disease because of the treatment associated intractable nephrotoxicity and subsequent complications.

DISCUSSION
In view of the rapid progression, associated morbidity and mortality, the clinical overlap with conditions forming the differential diagnoses, and commonality of the susceptible patient group, it is advisable for head and neck/oral and maxillofacial pathologists to be vigilant about encountering ONJ and to initiate dialogue with the clinician in this regard. Few authors have already raised red flags regarding the potential emergence of avascular necrosis in the femoral head of patients recovering from COVID-19. Agarwala et al. reported it as a part of "long COVID-19." 7,8 Daltro et al. 9 reported a possible association between osteonecrosis and the use of glucocorticoids to treat COVID-19 infection.
Clinically, steroid-induced ONJ may be confused with medication-related ONJ, osteoradionecrosis, and bacterial/fungal osteomyelitis (Table II). It is crucial to differentiate it from mucormycosis and other fungal lesions, so that antifungal therapy can be initiated promptly in indicated cases. This was also essential because a wave of sinonasal mucormycosis was sweeping the country in the aftermath of the second pandemic. Histopathologic features and special stains can be helpful in distinguishing these entities. 10 Previously, Nisi et al. 5 reported jaw osteonecrosis after extraction of left mandibular premolar in a 50year-old male patient with history of 2-year intake of prednisone (7.5 mg/d) for psoriatic arthropathy. Surgical debridement was done with a 30-day follow-up showing recovery. Wong et al. 4 has also reported mandibular osteonecrosis at the site of non-healing extraction socket (left premolar) in a 30-year-old female with a history of 9-year steroidal intake for systemic lupus erythematosus. Conservative management with antibiotics and chairside chlorhexidine mouthrinse was initially attempted followed by sequestrectomy and ultrasound therapy. Interestingly, the patient developed bilateral femoral head osteonecrosis within the twoyear follow-up period and was managed with oral bisphosphonates. Silva et al. 6 has reported mandibular osteonecrosis caused by 18-month use of corticosteroids for mycosis fungoides in a 78-year-old woman at the extraction site of left second molar. The patient passed away before the treatment could be instituted.
There are significant differences in the current cases and the cases reported previously primarily in terms of gender, affected jaw, involved side, history of extraction, duration of steroid intake, and medical history. All our cases developed in men, whereas majority of the previous case reports are in women. Only 1 (n = 4) current case had a history of extraction, whereas all the previously reported cases had history of recent extraction. Curiously, all the previous cases of jaw osteonecrosis developed on the left side, whereas our cases predominantly affected the right side. Most importantly, prolonged steroidal intake has been reported in the previous case reports for varied autoimmune disorders, though only 1 of them mentions the drug and the dosage. All the current cases had a short history of intensive steroid therapy following diagnosis of COVID-19.
Osteonecrosis of the femoral head (ONFH) as a post-COVID-19 sequelae has been reported by several authors. Agarwala et al. reported a mean dose of 758 mg of prednisone used in such cases following which they presented with avascular osteonecrosis after a mean of 58 days. In a recent case series, Dhanasekararaja et al. 11 reported an average cumulative dose of methylprednisolone of 811 mg, an average duration of steroid intake of 2.8 weeks, and mean time of 39.3 days for the onset of symptoms. This is in agreement with the results of a meta-analysis conducted on high-dose corticosteroid use and risk of hip osteonecrosis. This analysis reported that patients on >20 mg/d had a higher risk of developing osteonecrosis. 12 Our cases received an average cumulative dose of 561.7 mg (average daily dose of approximately 44 mg) over a mean period of 12.7 days. A mean interval of 12 days was observed between conclusion of steroid therapy and oral symptoms. We believe that steroid therapy, along with COVID-19-induced impairment in microcirculation, may have complementary role in producing these complications of avascular necrosis in susceptible regions of the body. 13 Published literature has included steroid as a risk factor for MRONJ. 14 However, the present authors believe that the steroid induced osteonecrosis (avascular necrosis) of the jaws in the post-COVID period is a distinct entity. In view of the rarity of its occurrence, unequivocal recognition of its pathognomonic features and additional insights would require further reports of such lesions.