Coronaviruses (CoVs) are a class of enveloped, single-stranded RNA viruses found globally in humans [1]. While coronavirus infections in humans are typically mild, several previous coronavirus outbreaks have been associated with significant morbidity and mortality. The first cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported in December 2019 [2]. The ensuing coronavirus (COVID-19) pandemic has spread worldwide, with over 177 million reported cases as of June 2021 [3]. Declared a Public Health Emergency of International Concern by WHO (World Health Organization) on January 30th, 2020, the COVID-19 outbreak has resulted in significantly worse outcomes for patients suffering from pre-existing conditions including diabetes, hypertension, and cardiovascular disease [4]. In addition, the COVID-19 outbreak has led to increased isolation and loss of in-person social interactions, which can have particularly negative impacts on patients with debilitating health conditions [5].
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive heterotopic ossification (HO) of tendons, ligaments, and other soft tissues within the body [6]. This ectopic formation of bone tissue is debilitating, causing chronic pain, restricted range of motion, pulmonary dysfunction, and impaired mobility. Although HO can occur spontaneously, incidents have been correlated to inflammation arising from trauma, tissue damage, viral infections [7], intramuscular diphtheria-tetanus-pertussis immunizations [8], and other traumatic stimuli [9]. In about half of cases of HO formation, individuals report episodic flare-ups, which are characterized by symptoms such as swelling, warmth, and stiffness [10].
FOP is caused by heterozygous activating mutations to the ACVR1 gene, which encodes ACVR1 (also known as ALK2), a bone morphogenic protein (BMP) type 1 receptor [11]. The most common of these mutations is c.617G > A, p.R206H [11], which causes the receptor to misinterpret the Activin A ligand as a BMP-like molecule, leading to activation of HO formation [12]. Barruet et al. showed that individuals with FOP have a pro-inflammatory state at baseline, even in the absence of ectopic bone formation or flare-ups [13]. Specifically, elevated levels of pro-inflammatory and myeloid cytokines were observed, which may suggest a role for the ACVR1 R206H mutation in causing this heightened immune response [14]. In FOP mouse models, abundant macrophages and mast cells were observed in developing heterotopic lesions [15], and depletion of mast cells and macrophages decreased trauma-induced HO by 50% individually and 75% combined [16]. Furthermore, Activin A is a major cytokine produced by macrophages, including FOP macrophages [14], and is a key regulator of macrophage polarization [17].
Clinically, FOP progression appears to be promoted by viral-like illnesses. A prior study assessed if FOP patients who had symptoms of influenza during the 2000–2001 influenza season experienced an increase in the incidence of HO-related flare-ups [7]. The FOP subjects exhibited a minimum of a three-fold increased risk of flare-ups when exposed to viral illness compared with before viral exposure, indicating that influenza-like viral illnesses are associated with flare-ups in FOP patients [7].
The severe respiratory compromise from thoracic insufficiency induced by HO formation in the chest wall, as well as the high risk of complications from intubation, put patients with FOP at particularly high risk of adverse outcomes in the event of severe COVID-19 complications [18]. The thoracic insufficiency syndrome is a result of multiple factors including costovertebral malformations, ankylosis of the costovertebral joints, and ossification of the intercoastal and paravertebral muscles [19]. This can lead to impaired pulmonary function and can also cause pneumonia and right-sided congestive heart failure [19]. In patients requiring respiratory care, surgical intubation procedures can give rise to complications, notably triggering of HO at the intervention site [20]. Additionally, due to the prevalence of jaw mobility limitations, flare-ups, and neck malformations, patients with FOP incur significant risk for advanced respiratory management such as with intubation [18].
A study looking at serum samples of patients with severe, active COVID-19 infections found that Activin A, Activin B, and follistatin were all upregulated during the time when COVID-19 patients tended to deteriorate [21]. In a COVID-19 study defining Acute Respiratory Distress Syndrome (ARDS), cytokine storms were observed in patients with severe COVID-19 symptoms [22]. The described pathway underlying ARDS, activated by cytokines, induces the production of Activin A in skeletal muscle, resulting in skeletal muscle atrophy.
Surprisingly, a small number of patients with severe COVID-19 appear at higher risk for developing HO [23], suggesting that the pro-inflammatory state found in COVID-19 could be detrimental in patients with FOP. Aziz et al. highlighted the prevalence of shoulder HO in two female subjects (with a history of hypertension and type 2 diabetes, and hypertension, respectively) after their COVID-19 infection [23]. A few months following hospitalization, the subjects reported shoulder pain/discomfort, which was identified as ossification. The study team indicated chronic hospitalization and hypoxia as the determinant factors.
A recent case report implicated the COVID-19 vaccine as a potential trigger for myositis ossificans-related intramuscular nodule formation and internal calcifications in a 51-year-old male patient [24]. Three months following the administration of the second COVID-19 vaccine dose, the patient reported right upper arm pain and a palpable mass, without any erythema or systemic symptoms. In addition to the trauma at the injection site, the subject’s immune response to the vaccine antigen was also thought to be a causal factor for the reported pain.
In this study, we set out to answer three main questions. First, how has the COVID-19 pandemic impacted the care and mental health of patients with FOP? Second, do patients with FOP who were exposed to SARS-CoV-2 have increased FOP disease activity? And third, does vaccination against SARS-CoV-2 impact FOP flare activity?