key: cord-0913367-yxvggrlk authors: Koutalos, Antonios A.; Stefanou, Nikolaos; Malizos, Konstantinos N. title: Post-acute sequelae of SARS-CoV-2 infection. Osteonecrosis must not be overlooked. date: 2022-04-21 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2022.04.026 sha: 2c6a9b3cdcefe662602bd2bdb4712ddcad0dab6d doc_id: 913367 cord_uid: yxvggrlk Recovery from COVID-19 is not always uneventful, especially in critically ill hospitalized patients. Persistent symptoms including fatigue/ weakness, short of breath, anxiety and depression has 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 up to one year. Infection with SARS-CoV-2 itself has been associated with endothelial damage, and together with high dose corticosteroid treatment, predispose to the dissemination of micro-thrombi and the development of femoral head osteonecrosis (FHOn), as it has been shown during the previous (2003-4) 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. COVID-19 patients treated with corticosteroids should be screened for avascular necrosis early after discharge from the hospital. Every health care worker involved in the management of these patients should maintain a high level of suspicion and be alert when patients report symptoms such as vague ache at the buttocks, the hip area, the 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. Faculty of Medicine, University of Thessaly, 3 University str. 41500 Biopolis, Larissa, Greece. • SARS-CoV-2 infection is associated with symptoms and signs from coagulopathy • Treatment with steroids can cause osteonecrosis, so patients should be monitored • Post COVID-19 sequelae from the musculoskeletal system is frequent • Physicians should maintain a high level of suspicion for early diagnosis of FHOn Recovery from COVID-19 is not always uneventful, especially in critically ill hospitalized patients. Persistent symptoms including fatigue/ weakness, short of breath, anxiety and depression has 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 up to one year. Infection with SARS-CoV-2 itself has been associated with endothelial damage, and together with high dose corticosteroid treatment, predispose to the dissemination of micro-thrombi and the development of femoral head osteonecrosis (FHOn), as it has been shown during the previous (2003-4) 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. COVID-19 patients treated with corticosteroids should be screened for avascular necrosis early after discharge from the hospital. Every health care worker 3 involved in the management of these patients should maintain a high level of suspicion and be alert when patients report symptoms such as vague ache at the buttocks, the hip area, the 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. Keywords: COVID-19; corticosteroids; femoral head osteonecrosis; symptoms; musculoskeletal system The immense burden of the COVID-19 pandemic has globally challenged the healthcare delivery and the healthcare system reserves. The post-acute sequelae of SARS-CoV-2 infection (PASC) and complications of the disease, as well as of the therapeutic interventions, in millions of patients worldwide are intensively studied and monitored as a matter of great importance. Few studies have reported PASC after infection with SARS-CoV-2. Darcis et al., (2021) reported improvement in radiographic imaging and pulmonary functional tests but persistence of symptoms after six months. The most prevalent symptoms were shortness of breath and fatigue. Fatigue and memory impairment was unexpectedly increased over time. There was a trend for association between diffusion capacity of carbon monoxide (DLCO) and persistent symptoms. In another study, Huang et al. reported a wide range of less well-known PASC in COVID-19 survivors one year after discharge from hospital (Huang et al., 2021) . Again, dyspnea, anxiety and depression increased in prevalence at one year. Female sex and corticosteroid therapy at the acute phase were risk factors for fatigue or muscle weakness, with more prevalent mobility or discomfort problems, than did matched controls (Huang et al., 2021) . Reporting PASC, regarding the musculoskeletal system, however, is inconsistent and variable. Fatigue and muscle weakness are one of the most common persistent long-term symptoms and is probably associated with lung diffusion capacity injury, viral myositis or steroids myopathy (Huang et al., 2021; Tsai et al., 2004) . Other symptoms like "mobility and discomfort problems", joint pain and stiffness are not systematically investigated and reported. Huang et al reported 12% incidence of joint pain and 4% of myalgia. In addition, 9% of the patients had "mobility problems" (Huang et al., 2021) . Generally, the impact of SARS-CoV-2 infection and the combined therapeutic interventions on the bone are not thoroughly investigated, as part of the follow-up protocol in most long-term studies. More specifically, there is no report of the incidence of femoral head osteonecrosis (FHOn) or other necrotic lesions of the skeleton. In hundreds of thousands of patients globally, the systemic corticosteroids have been extensively utilized at the early stages of the disease in variable dosages and treatment durations (Agarwala et al., 2021; Mont et al., 2015; Zhao et al., 2021) . Compared with usual care or placebo, they have been associated with lower 28-day all-cause mortality of critically ill patients (Huang et al., 2021) . In the study by Huang anticipate that there will be a resurgence of cases in the femoral head and/or other joints of the skeleton (Mont et al., 2015) (Figures 1, 2 and 3) . It is estimated that a cumulative dose of 2000 mgr of prednisolone or equivalent is associated with increased risk of FHOn (Jones, 2001) . This varies with daily administered dose, type of steroid, maximum dose and underlying disease (Powell et al., 2010) . The minimum dose for FHOn development is approximately 700 mgr of prednisolone or equivalent (Anderton and Helm, 1982) . At least six months to one year are needed after corticosteroid treatment, before FHOn develop symptoms (McKee et al., 2001) . Corticosteroids may induce osteonecrosis (ON) mainly through altering the lipid metabolism resulting in fat accumulation in the bone marrow, and enlargement of fat cells with subsequently increased intra-medullary pressure. Furthermore, by decreasing the blood supply at the femoral head through fat embolism and micro-thrombosis, and by corticosteroids induced apoptosis of the osteocytes through which corticosteroids may cause ON (Wang et al., 2018) . In case of COVID-19, the "thrombo-inflammatory cascade" causes endothelial injury and predisposes to microthrombosis. The hypercoagulability state of SARS-CoV-2 infection is also considered a risk factor for ON (Mehta et al., 2020) . In addition, other treatments studied during the early phase of the pandemic like the anti-virals ritonavir and lopinavir may trigger the FHOn (Patel et al., 2021) . Observational studies of patients treated with corticosteroids for SARS-1 epidemic in 2003, reported FHOn and/or major joints, as early as 4 months from the infection, ranging from 24% to 41%, when the patients were followed up to 3 and even to 7 years (Guo et al., 2014; Hong and Du, 2004; Hui et al., 2009; Zhao et al., 2010; Zhao et al., 2013) . FHOn was confirmed by MRI which is considered the method of choice for early-stage diagnosis. The mean total steroid dose varied from 4904 mg to 4117 mg of prednisone or equivalent and higher dose was associated with increased risk for ON (Guo et al., 2014) . In some cases, bilateral FHOn was noted. Besides femoral head other skeleton sites were also affected including the shoulder, knee and ankle (Guo et al., 2014; Hong and Du, 2004; Hui et al., 2009; Zhao et al., 2010; Zhao et al., 2013) . The natural history of these necrotic bone lesions at the weight bearing areas of the joints, is the progression to articular surface collapse, painful and restricted range of motion and non-reversible joint destruction (Zhao et al., 2010; Zhao et al., 2013) . In a recent review, it was reported that the time interval between corticosteroid treatment and FHon onset is shorted in COVID-19 compared to non-COVID-19 patients and in some cases FHon develops without corticosteroid treatment (Shetty, 2021 ). The precise cumulative corticosteroids dose and/or duration of therapy for developing FHon cannot be estimated in SARS-CoV-2 infection but higher dose, longer duration, severe COVID-19 pneumonia, ICU admission, elevated inflammatory serum markers and personal history of smoking or excessive alcohol consumption have been postulated as potential risk factors (Shetty, 2021) . However, no observational cohort study has been published regarding COVID-19 and FHon incidence. When assessing PASC, especially in patients treated with high dose of corticosteroids, it is crucial to maintain high index of suspicion for the development of the initially, and for several months asymptomatic but potentially evolving to collapse, infarcts at the femoral head, the knees, the shoulders and/or the talus (Krez et al., 2021; Zhang et al., 2021; Zhao et al., 2010) . Close follow-up with MRI screening of the hips and all major joints, should be conducted in the first 3-4 months after discharge, for early detection of the lesions, prior to collapse of the necrotic bone. Upon diagnosis, prompt intervention might save the native joint, and avoid a nondesirable total joint replacement in the young patients. All specialties involved in management of COVID-19 patients should be aware of this potential serious consequence of the disease and its treatment. Additionally, mobility problems caused by fatigue or muscle weakness should promptly managed to avoid any decline in quality of life of COVID-19 patients. Furthermore, future studies of long-term follow-up of patients with SARS-CoV-2 infection should include in their methodology the reporting of musculoskeletal symptoms and especially the incidence of FHOn. In addition, these studies could help determine the predisposing factors that are associated with FHOn development, including the cumulative dose of corticosteroids, the type and route of corticosteroid administration, the duration of therapy, the disease severity, the inflammatory biomarkers, and other yet unknown risk factors. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Multiple joint osteonecrosis following short-term steroid therapy. Case report Avascular necrosis as a part of "long COVID-19 Long-term clinical follow-up of patients suffering from moderate-to-severe COVID-19 infection: a monocentric prospective observational cohort study The influence of age, gender and treatment with steroids on the incidence of osteonecrosis of the femoral head during the management of severe acute respiratory syndrome: a retrospective study Avascular necrosis of bone in severe acute respiratory syndrome 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study Avascular osteonecrosis after treatment of SARS: a 3-year longitudinal study Arthritis and allied conditions: a textbook of rheumatology Risk factors for multi-joint disease in patients with glucocorticoid-induced osteonecrosis Osteonecrosis of the femoral head in men following short-course corticosteroid therapy: a report of 15 cases COVID-19: consider cytokine storm syndromes and immunosuppression High-dose corticosteroid use and risk of hip osteonecrosis: meta-analysis and systematic literature review Efficacy and safety of lopinavir-ritonavir in COVID-19: A systematic review of randomized controlled trials Steroid induced osteonecrosis: An analysis of steroid dosing risk Double trouble-COVID-19 and the widespread use of corticosteroids: are we staring at an osteonecrosis epidemic? Neuromuscular disorders in severe acute respiratory syndrome The pathogenesis of steroid-induced osteonecrosis of the femoral head: A systematic review of the literature Beware of steroid-induced avascular necrosis of the femoral head in the treatment of COVID-19-Experience and lessons from the SARS epidemic Lesion size changes in osteonecrosis of the femoral head: a long-term prospective study using MRI Osteonecrosis of the femoral head in SARS patients: seven years later Follow-up study on the COVID-19 survivors after one year discharged from hospital No funds were received for this perspective article The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the University General Hospital of Larissa.