A Comprehensive Review of COVID-19 Infection and Steroid-Associated Treatment Bone Avascular Necrosis: A Multi-Study Analysis (preprint)

Background: The COVID-19 pandemic has presented numerous challenges to global healthcare system and emerging evidence suggests a potential link between COVID-19 treatment, specifically steroid therapy, and the development of avascular necrosis (AVN) of the hip. This review aims to provide a comprehensive overview of recent studies and case reports investigating the relationship between COVID-19, corticosteroid therapy, and the development of AVN. Understanding the nuances of AVN in the context of COVID-19 is crucial for healthcare professionals to navigate treatment decisions and mitigate potential complications. Materials and Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) was used in the systematic review until September 1st, 2023. The full-texts of the remaining twenty-three (n=23) articles were independently reviewed by the authors of this review.  Conclusions: The association between steroid therapy for COVID-19 and the development of hip AVN is a noteworthy concern even though, no relationship is evident between the duration of treatment, cumulative dosage of medication, maximum daily dosage received, and the presence of AVN. Further research with larger cohorts and long-term follow-up is needed to better understand the causative relationship and optimal management strategies for hip AVN in the context of COVID-19 and steroid therapy

OUTCOME OF COVID-19 PATIENTS ON STEROID THERAPY: A LONGITUDINAL STUDY (preprint)

ABSTRACT: Introduction: SARS-CoV-2 is responsible for global pandemic that originates from Wuhan, China (1). Patients presentation van be varied from asymptomatic to severe ARDS and multiorgan dysfunction likely due the dysregulated systemic inflammation (2). Glucocorticoids inhibits the inflammation by down streaming of cytokine receptor and promote resolution (3). The role of corticosteroid in COVID-19 still remains controversial. Corticosteroids associated with many long terms side effects. Previous MARS outbreak had experienced avascular necrosis with corticosteroid use (4). Objectives: The aim of the study was to evaluate the outcome of covid-19 patients on the corticosteroid therapy and estimate mortality rate with corticosteroid therapy and investigate potential long-term adverse events associated with its use. Methods: We did a longitudinal follow up study at the AIIMS Rishikesh to assess the side effects of corticosteroids in COVID-19 patients. Patients with moderate to severe COVID-19 pneumonia requiring the oxygen support were included in the study. According to the institutional protocol patients received conventional dose steroids versus pulse dose steroids. (Based on CT/ X-ray findings). Patients were followed up in the hospital till discharge/death for assessment of adverse events due to corticosteroids and all other biochemical parameters (Inflammatory markers) and SOFA score were obtained during hospitalisation till discharge. And at the 6 month follow up patient was assessed for infection and avascular necrosis of the femur. Results: A total of 600 patients were screened out of which 541 patients who received corticosteroids were included in this study. 71.3% were male and 26.6 % were females. Most prevalent comorbidity was systemic hypertension (38.8%) followed by diabetes mellitus (38%). Most common presenting symptoms was dyspnoea followed by fever and cough. Majority patients received dexamethasone (95%). 65.8 % patients received conventional dose while 34.2% of patients received pulse dose. Mortality was more associated with pulse dose (44%) then a conventional dose (30%) (p-value 0.0015). the median duration of the corticosteroids was 10 days with an IQR of 7-13 days. During the hospitalisation 142 patients (26.2%) develops hyperglycaemia. Hyperglycaemia was more prevalent in the pulse dose steroid group (16.8% versus 9.4%). One patient develops pancreatitis. There was a significant reduction in the levels of inflammatory markers (p<0.005) after steroid initiation. At the 6th month of follow patients were assessed for AVN and suspected infection. 25 patients (8.25%) had infection out of which 19 received pulse dose. Out of 25 patients cultures was available for 7 patients and 2 patients grows pathogenic organism in the urine (pseudomonas and E. coli). 02 patients develop non-specific joint pain at 6 months. No patient had AVN during the follow up.

Knee osteonecrosis after SARS-CoV-2 infection: a systematic case-based review (preprint)

Background: SARS-CoV-2 is the virus responsible for COVID-19. Patients with Covid-19 manifested symptoms mainly related to the respiratory system, but also the musculoskeletal system can be involved. Covid-19 has been described as a possible cause of knee osteonecrosis (ON). We performed a systematic review to investigate the hypothetical correlation between Covid-19 and knee ON.  Methods: Inclusion criteria were all articles reporting cases of knee ON after a diagnosis of SARS-CoV-2 infection. Considering that Covid-19 is an emerging disease, we included all levels of evidence studies.  Results: We finally included 2 case series and 2 case reports. We extracted data regarding demographic and clinical characteristics, details of magnetic resonance imaging (MRI), use of corticosteroids (CCS), temporal correlation between ON and Covid-19, treatment of the lesion and its outcomes. A total of 6 cases of post-Covid knee ON have been described. Knee pain arose on average 8 weeks after the diagnosis of Covid-19. All patients had knee MRI showing osteonecrosis. CCS were used to treat COVID-19-related symptoms in 3 cases. The medial femoral condyle was always involved by ON. Conservative treatment was successful in 4 patients.  Conclusions: It is unclear the correlation between COVID-19 and ON. Probably post Covid-19 osteonecrosis has a multifactorial origin in which factors related to the patient, consequences of Covid-19 and CCS therapy add up to cause a reduction of blood supply and bone vitality until ON is triggered. A greater number of patients is needed to clarify the role of Covid-19 in the etiopathogenesis of knee ON.

Incidental osteonecrosis in the distal left femur in a case of beta-thalassemia with COVID-19: Role of [99mTc]Tc-MDP whole-body bone scan.

Secondary anemia in hemoglobinopathies like thalassemia can cause expansion of the bone marrow cavities because of compensatory marrow hyperplasia. This case demonstrates spontaneous osteonecrosis of the distal left femur in a patient with ß-thalassemia that may be secondary to ischemic infarction secondary to occlusion of the microvasculature within the expanded cancellous bone. This subject was referred to Hazrat Rasool Akram Hospital because of fever, cough, and bone pain. In the CT scan she had scattered peripheral CGO in both lungs due to COVID-19 with two paravertebral masses due to extramedullary hematopoiesis. The patient had also generalized bone pain so the physician asked for a whole-body bone scan and incidentally, we found a cold lesion with a rim of increased uptake in the distal left femur that with bone biopsy it was consistent with osteonecrosis. This case illustrates the importance of performing a whole-body bone scan in ß-thalassemia for the management of patients and diagnosis of occult osteonecrosis.

[COVID-induced facial bones necrosis]. / COVID-indutsirovannyi nekroz chelyustnykh kostei.

The article focuses on the clinical manifestation of inflammatory and destructive lesions of the bones of the midface, nose and paranasal sinuses as a long-term complication of COVID-19 with clinical examples provided.

Post Mucormycosis Frontal Bone Osteonecrosis: "A Road Less Traveled During the Pandemic".

BACKGROUND: Osteonecrosis in mucormycosis is a rare phenomenon and has been reported usually following trauma or in immunocompromised individuals. Osteonecrosis of skull as a complication of mucormycosis is a rare presentation, which makes the study ever so rare and interesting. METHODS: Within 6 months, a total of 114 patients presented with mucormycosis as COVID-19 sequel, 60 of whom underwent form of endoscopic sinus debridement. Six of these 60 patients presented with frontal bone osteonecrosis and were included in the study. All 6 patients presented within a time period of 2-4 months' post FESS. RESULTS: One of the 6 patients succumbed to her illness. Another patient presented with local recurrence after 3 months, for which she underwent resurgery and debridement. The other 4 patients showed gradual recovery and are without symptoms or radiologic progression at 6-month follow-up. CONCLUSIONS: Osteonecrosis in mucormycosis is a rare phenomenon, and the 2 entities have rarely been reported together. The disease usually limits itself to the frontal bone only, and pathogenesis for spread is due to a vicious cycle of infection and ischemia. Prompt diagnosis via imaging, aggressive surgical debridement with a good antifungal cover, good patient compliance, and regular follow-up form the mainstay of treatment.

The painful joint after COVID-19 treatment: A study on joint osteonecrosis following COVID-19-related corticosteroid use.

OBJECTIVES: This study aims to evaluate the incidence of osteonecrosis (ONC), with a special focus on ONC of the femoral head (ONFH), in novel coronavirus disease 2019 (COVID-19) patients two years after the pandemic. PATIENTS AND METHODS: This prospective study included COVID-19 patients who were admitted to our center between March 2020 and June 2020. A total of 472 patients (289 males, 183 females; mean age: 42.3±12.0 years; range, 18 to 60 years) were arranged in a list according to their date and time of admission and, then, divided into two groups: those not receiving corticosteroid (CS) treatment (Group 1, n=236) and those receiving CS treatment (Group 2, n=236). The patients were evaluated for joint pain based on X-rays and magnetic resonance imaging scans, and the patients were routinely followed. For each patient in Group 2, additional data regarding CS use were recorded. The possible relationship between ONC and risk factors was analyzed. RESULTS: Both groups were similar in terms of age and sex. Group 2 had a significantly longer hospitalization period. A significant increase in the number of painful joints was observed in Group 2. At two years, 5.1% of the patients in Group 1 complained of at least one painful joint compared to 11.9% of patients in Group 2. Eight patients from Group 2 developed ONC. CONCLUSION: The incidence of ONC after CS therapy in COVID-19 patients is on the rise. At two years, 5% of patients receiving various doses of CSs may develop ONC. Residual joint pain is common even after recovering from the virus. No relationship is evident between the duration of treatment, cumulative dosage of medication, maximum one-day dosage received, and the presence of ONC.

Osteonecrosis and Osteomyelitis of the Proximal Third of Tibia as a Late Sequela of COVID-19: A Case Report.

Coronavirus disease was first described as an identified syndrome in December 2019 (COVID-19). Since then, a global pandemic has taken place and the disease has repeatedly been associated with thromboembolic complications, most of which are venous, but may also occur at the arterial level, even in patients receiving thromboprophylaxis. To date, only medium- and large-caliber vessels have been affected by arterial thrombosis secondary to COVID-19. This article describes the case of a 60-year-old woman with a prior severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection who developed multiple bone infarcts, complicated by secondary osteomyelitis. The patient underwent multiple surgical debridements and received a variety of antibiotics before the correct diagnosis was made and a multidisciplinary surgery was planned that provided coverage with a medial gastrocnemius flap. At 5-months follow-up, the patient had recovered well without any clinical evidence of infection or other complications. To the best of our knowledge, this is the first known case of a bone infarct complicated with a secondary osteomyelitis occurring in a patient having suffered a previous SARS-CoV-2 infection. We postulate as our main hypothesis that the prothrombogenic state secondary to SARS-CoV-2 infection may have contributed to thrombosis of small-caliber vessels, in our patient the arteria nutricia tibialis, triggering bone infarcts and a secondary infection with Staphylococcus aureus .

An unusual case of metaphyseal osteonecrosis of humerus in a post covid patient: a case report.

Osteonecrosis of the metaphysis is often rare as it is a highly vascular region. Here we report an unusual case of non-traumatic osteonecrosis of the humerus predominantly involving the metaphysis in a post covid elderly female. The patient had a pathological fracture of humerus during the post-operative period of intertrochanteric femur fracture surgery. She was evaluated for the causes of pathological fracture and the fracture was managed with hemi replacement of the shoulder because of the extensive bone loss. The pathology here could only be explained as some sequelae of hyper inflammatory state associated with COVID-19 infection. The possible differentials are also discussed here. This case report will help clinicians to consider COVID-19 infection as a cause for non-traumatic osteonecrosis among other reported causes of osteonecrosis.

Transient spontaneous osteonecrosis of the knee (SONK) shortly after SARS-CoV-2 infection: A report of 2 cases.

BACKGROUND: This article describes 2 cases of post-coronavirus disease 2019 (COVID-19) transient spontaneous osteonecrosis of the knee (PCT-SONK) observed in patients who had previously recovered from COVID-19 without corticosteroid administration. OBJECTIVES: The possible pathomechanisms by which a recent SARS-CoV-2 infection may contribute as a causative factor for osteonecrosis are reviewed, and the differential diagnosis and treatment are discussed. MATERIAL AND METHODS: Two patients (males, 45- and 47-year-old) presented with sudden onset knee pain with no trauma history. The pain persisted during rest and at night. On magnetic resonance imaging (MRI), no subchondral bone thickening was observed; bone edema was diffusely distributed in the whole femoral condyle, in contrast to the more focal edema that is typically concentrated mainly around the subchondral region in classic SONK. Both patients were treated nonoperatively with no weight bearing and pharmacological agents, and complete resolution of symptoms was achieved. RESULTS: A follow-up MRI 10 weeks after presentation revealed a near-complete loss of signal in the medial femoral condyle in both patients. CONCLUSION: Orthopedic surgeons should be cautious when sudden knee pain without concurrent trauma or a history of injury occurs shortly after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, even with mild COVID-19 illness. While some studies report the development of post-COVID-19 osteonecrosis after lower doses of corticosteroids and sooner after their administration than in comparable non-COVID-19 cases, our study is the first to report 2 cases with no corticosteroid administration at all. Therefore, the authors believe it adds to the body of knowledge on the potential connections between COVID-19 and PCT-SONK. The transient nature of symptoms and radiological findings suggest that aggressive surgical treatment of non-injury local bone edema occurring shortly after SARS-CoV-2 infection should be avoided.

Post-COVID-19 related osteonecrosis of the jaw (PC-RONJ): an alarming morbidity in COVID-19 surviving patients.

PURPOSE: The recent coronavirus disease (COVID-19) pandemic mainly affects the respiratory system; however, several oral and maxillofacial post-COVID-19 complications have also been observed. This series reports the growing number of osteonecrosis cases associated with post-COVID-19 patients. MATERIALS AND METHODS: This is a retrospective, multi-center case series that reports cases with maxillary osteonecrosis after various periods of SARS-CoV-2 infection in the period between January and August 2021 based on the PROCESS guidelines. RESULTS: Twelve cases were reported with post-COVID-19 manifestation of spontaneous osteonecrosis of the maxillary jaw. Five patients were hospitalized during COVID-19 management and all of the twelve cases had at least one systematic Co-morbidity, and undertake corticosteroids prescription based on the COVID-19 disease treatment protocol. The mean onset of osteonecrosis symptoms appearance was 5.5 ± 2.43 weeks calculated from the day of the negative PCR test. The management was successfully done through surgical debridement and pre and post-operative antibiotics. No anti-fungal medications were prescribed as the fungal culture and the histopathological report were negative. CONCLUSION: Post-COVID-related osteonecrosis of the jaw (PC-RONJ) could be now considered as one of the potential post-COVID-19 oral and maxillofacial complications that occurs unprovokedly and mainly in the maxilla.

Postacute sequelae of SARS-CoV-2 infection. Osteonecrosis must not be overlooked.

Recovery from COVID-19 is not always uneventful, especially in critically ill hospitalized patients. Persistent symptoms including fatigue/ weakness, shortness of breath, anxiety, and depression have been described at one-year follow-up. Furthermore, symptoms from the musculoskeletal system like joint pain or stiffness are underreported in studies with long-term follow-up of up to one year. Infection with SARS-CoV-2 itself has been associated with endothelial damage, and together with high-dose corticosteroid treatment, it is predisposed to the dissemination of microthrombi and the development of femoral head osteonecrosis (FHOn), as it has been shown during the previous (2003-2004) coronavirus outbreaks. A resurgence of FHOn cases is anticipated but this is not reflected in the existing studies with long-term follow-up. Prompt diagnosis is critical for early treatment and possibly for the hip joint preservation. Patients with COVID-19 treated with corticosteroids should be screened for avascular necrosis early after discharge from the hospital. Every healthcare worker involved in the management of these patients should maintain a high level of suspicion and should be alert when patients report symptoms such as vague aches at the buttocks, hip area, adductors, and/or above the knee. Studies are needed to identify risk factors for FHOn including disease severity, type of steroid, cumulative dose, and duration of treatment.

COVID-Associated Avascular Necrosis of the Maxilla-A Rare, New Side Effect of COVID-19.

PURPOSE: The purpose of this article is to present an interesting, rare case of a patient who experienced avascular necrosis of the maxilla associated with COVID-19 infection. METHODS AND RESULTS: Our team retrospectively evaluated this patient's chart after completion of surgical management. The patient is a 72-year-old male who presented to the University of Texas Health Science Center at Houston for surgical management of his infarcted maxilla, which developed as a sequela of infection with COVID-19. A literature review was completed using PubMed. Twenty-five articles are reviewed and discussed. CONCLUSIONS: Infection with COVID-19 confers a hypercoagulable state in patients, leading to various complications in the head and neck region. In our case report, we present a patient who developed avascular necrosis of the maxilla secondary to infection with COVID-19. Thromboembolic prophylaxis is imperative in COVID-19 patients due to the high rate of potential systemic complications.

Secondary osteonecrosis of the knee as a part of long COVID-19 syndrome: a case series.

COVID-19 infection affects different organ systems with long-term sequelae, which has been termed as long COVID-19 syndrome. To the best of our knowledge, osteonecrosis of the knee as a part of long COVID-19 syndrome has not been documented. Corticosteroids are being used extensively in moderate and severe cases of COVID-19. We report two cases who developed osteonecrosis of the knee after being treated for COVID-19 infection. In our case series, the mean cumulative dose of prednisolone was 1156.5 mg (900-1413 mg), which is less than the cumulative dose reported in literature for osteonecrosis of the knee. In our case series, the patients developed symptomatic osteonecrosis at a mean interval of 73 days after initiation of steroid therapy, with the earliest presenting at 25 days. Early diagnosis of osteonecrosis of the knee on high clinical suspicion by MRI would help in early intervention with bisphosphonate therapy.

Osteonecrosis with Concomitant Bacterial Osteomyelitis of Both Hips and a Knee in a Post-COVID-19 Patient: A Case Report.

CASE: We report the case of a coronavirus disease 2019 (COVID-19)-recovered, 42-year-old man with osteonecrosis and concomitant acute bacterial osteomyelitis of both hips and his left knee. The patient underwent total hip replacement for both hips and arthroscopic decompression and synovectomy of the knee joint. On follow-up, he has complete and painless range of motion with resolving osteomyelitis and no signs of active infection. CONCLUSION: Corticosteroid therapy and COVID-19-associated thrombotic microangiopathy might have caused osteonecrosis in our patient. However, concomitant osteomyelitis is extremely rare and might be overlooked because of elevated inflammatory markers after recovery from COVID-19 infection.

Avascular Necrosis Bone Complication after Active COVID-19 Infection: Preliminary Results.

Background and objectives: The course of SARS-CoV-2 (COVID-19) is still under analysis. The majority of complications arising from the infection are related to the respiratory system. The adverse effect of the viral infection on bone and joint tissue has also been observed. Materials and Methods: We present a group of 10 patients with degeneration of large joints and adjacent epiphyses of long bones and the spine, with a background of bone infarctions and avascular necrosis (AVN) immediately after infection with the COVID-19 virus. In MR imaging, changes in the characteristics of AVN were documented. Results: Observation of this group showed a clear correlation among the history of COVID-19 disease in the patients, moderately severe symptoms, high levels of IgG antibodies, and the time of occurrence of joint changes. No other clinically significant complications were observed following COVID-19 infection in the study group. No other risk factors for AVN or autoimmune or degenerative diseases were found in the study group. The group of patients responded well to empirical treatment with steroids, which normalized acute inflammatory symptoms and pain in the joints. Conclusions: During coronavirus (COVID-19) infection, there are complications in the locomotor system, such as microembolism and the formation of AVN; hence, more research is needed.

A Case Report on Steroid-Induced Avascular Necrosis Treated with Autologous Adult Live-Cultured Osteoblasts (AALCO) in COVID-19 Patients (preprint)

In the absence of a targeted antiviral agent effective against COVID-19, corticosteroids show improvements in hyperinflammation and acute respiratory distress syndrome (ARDS) associated with COVID-19. However, various adverse effects of corticosteroids have been reported, like delayed viral clearance, secondary infections, avascular necrosis and suppression of the hypothalamic-pituitary-adrenal axis. In this case report, we report clinical outcomes in two patients with symptomatic avascular necrosis (AVN) of the femoral head after being treated with corticosteroids for COVID-19. We implanted autologous adult live-cultured osteoblasts (AALCO), sourced from mesenchymal stem cells via bone marrow aspiration, for treating AVN in both patients. The MRI examination suggested steroid-induced AVN of the hip with Ficat-Arlet stage IIB in these patients. A prednisone (corticosteroid) was used during COVID-19 treatment for a mean treatment duration of 14.5 days. The AALCO implantation showed good clinical outcomes in treating steroid-induced AVN of the hip with Ficat-Arlet stage IIB in both patients with COVID-19.

Knee osteonecrosis after COVID-19.

BACKGROUND: COVID-19 is an emergent infection, the long-term complications of which are still under study. While hypercoagulability is a common feature in severe cases, the incidence of ischemic complications such as osteonecrosis remains unknown. Previous studies on SARS-CoV1 found an increase in osteonecrosis 3-36 months after infection, and it is still unclear if this was related to the use of corticosteroids or to the virus itself. METHODS: We introduce a 78-year-old woman who complained of right knee pain and swelling a month after COVID-19 infection onset. Her knee radiography showed no significant changes compared to previous ones. MRI, on the other hand, found osteonecrosis in the internal femoral condyle. No coagulation abnormalities were found in blood tests. RESULTS: While knee replacement should be her main treatment, it will be long delayed due to the pandemic. In the meantime, we increased her tapentadol and salicylic acid doses and gave her home exercises to improve functionality. CONCLUSION: In the follow-up after COVID-19, any muscular or joint pain with unusual characteristics should be carefully examined.