key: cord-1037842-0bci6osb authors: Meyer, C.; Haustrate, M-A; Nisolle, JF; Deltombe, Th title: Heterotopic ossification in COVID-19: a series of 4 cases date: 2020-10-26 journal: Ann Phys Rehabil Med DOI: 10.1016/j.rehab.2020.09.010 sha: efda3343039f69860b4156aeda1622dd20fb618b doc_id: 1037842 cord_uid: 0bci6osb nan Dear Editor. Heterotopic ossification (HO) refers to abnormal formation of mature lamellar bone in soft tissues without connection to the periosteum, around proximal articulations, knees and elbows. The hip joint is affected in 77% of cases and the shoulder in 18%, and HO results in muscular and articular pain, joint ankylosis and loss of independence. [1] HO is usually found in patients with central and peripheral nervous system lesions. We present 4 cases of patients with severe SARS-CoV-2 infection (COVID-19) who required mechanical ventilation and exhibited HO in hips and shoulders. Men aged 64 years old (patient 1), 73 years old (patient 2) and 74 years old (patient 3) presented severe COVID-19 requiring mechanical ventilation and prone positioning for 26, 27 and 30 days, respectively, in an intensive care unit. Comorbidities for patient 1 were high blood pressure, atrial fibrillation and cervical myelopathy. Patients 2 and 3 had a history of high blood pressure and chronic obstructive pulmonary disease. During the intensive care period, patient To our knowledge, these are the first reported cases of COVID-19 complicated by HO. HO usually affects patients with central neurologic system lesions such as traumatic brain injury, stroke, and spinal cord injury [2] . The incidence of HO ranges from 11% to 73.3% in traumatic brain injury and from 10% to 78% in spinal cord injury and is most likely to occur in the presence of spasticity, extended unconsciousness and bone fractures [3] . Guillain-Barré Page 3 of 6 J o u r n a l P r e -p r o o f syndrome, joint replacement surgeries, fractures, muscular contusions, and severe burns are less frequent possible causes [1, 4] . HO can cause joint and muscular pain, decreased range of motion, soft tissue swelling, erythema and heat in the involved region as well as low-grade fever appearing 4 to 12 weeks post-onset [2] . HO exacerbates functional disabilities by increasing difficulty in sitting, eating and dressing [5] . Bone maturation usually occurs after 6 months with histology and radiology findings identical to normal bone [1, 5] . In the early stage (2-6 weeks), nuclear bone scans are more sensitive than plain radiography to detect HO, whereas CT allows for better visualization of the heterotopic bone [2] . Laboratory investigation may reveal elevated alkaline phosphatase and creatine phosphokinase levels. The etiopathogenesis of HO and the association with COVID-19 is unclear [5] . HO is thought to be associated with local inflammation affecting soft-tissue mesenchymal stem cells releasing prostaglandins (particularly prostaglandin E2), which leads to lamellar heterotopic bone formation. Altered acid base homeostasis and tissue hypoxia during the mechanical ventilatory period may play a role in the pathophysiology [6] . In COVID-19, the haematogenous spread seems responsible for the central and peripheral "neuroinvasion" of SARS-CoV-2 [7] . Consequences of this process are neurological diseases such as encephalitis, stroke, critical illness myopathy and neuropathy (CRIMYNE) or Guillain-Barré syndrome. Zeilig et al. reported 6% of patients with Guillain-Barré syndrome affected by HO; blocking the neuromuscular junction enhanced the HO size [8, 9] . HO highly depends on inflammation and phagocytic macrophages in soft tissues, but also SARS-CoV-2 infection modulates macrophage-mediated events [5, 10] . COVID-19 global inflammation may play a role in HO genesis. That most of our patients had a severe form of COVID-19 reinforces this hypothesis. Another common factor among COVID-19, traumatic brain injury and spinal cord injury (known to cause HO) is prolonged immobilization. control and HO is sufficiently constituted for excision [11, 12] . Early rehabilitation is essential in managing HO and COVID-19 [7] . In the acute phase, COVID-19 patients may present respiratory deficit, cognitive disorders, central and peripheral nervous system disorders, deconditioning, critical illness-related myopathy and neuropathy, joint stiffness and pain [13] . An estimated 53% of SARS-CoV-2 infection survivors have reported joint pain [13] . HO could be underdiagnosed in patients with COVID-19 requiring intensive care. 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