FOP is recognized as one of the most debilitating diseases known to medicine. In addition to its severe and often unpredictable clinical course, there is, despite extensive research, no specific curative or preventive treatment. The exact mechanism and triggers for HO in FOP remain largely unclear. It is recognized that the ACVR1 mutation leads to enhanced Smad1/5/8 signaling and altered responsiveness to canonical (BMP) and non-canonical (Activin A) ligands [
14]. However, ACVR1 mutation and Activin A are not solely responsible (or sufficient) for HO to occur. Previous research shows that involvement of immune cells, such as macrophages and mast cells, as well as various cytokines are of great importance in the process of HO [
5]. In a previous study of plasma cytokine levels in FOP patients, it was hypothesized that RANTES (Regulated on activation, normal T-cell expressed and secreted/CCL5) might be a potential trigger and/or indicator of HO [
6]. Cytokine analysis of a sample obtained during a flare-up prior to COVID-19 infection from the same patient, showed a significantly lower amount of elevated pro-inflammatory cytokines compared to the post-COVID-19 panel. These laboratory findings were also reflected in better pre-COVID-19 reaction to radiotherapy, which was followed by symptom alleviation. In our patient’s post-COVID-19 cytokine panel, most notable elevations were found in MCP-1, RANTES and IL-13, which are cytokines with emerging roles in bone remodeling and cortical bone formation [
15‐
17]. We also found a significant elevation of plasma IL-5, which has been reported to cause ectopic bone formation in animal models [
18]. Of the 23 analyzed cytokines, a staggering number of 21 were above normal (healthy control) expression levels. Among them, IL-1, IL-6, IL-8, Interferon-γ, TNFα and GM-CSF were prominently increased. Limitations of the cytokine analysis we conducted include the lack of remission phase sample of our patient, inability to precisely quantify cytokine concentrations and possibility that crucial cytokines for understanding of the observed HO are not part of the cytokine panel kit we employed. In spite of these limitations, our findings suggest an upward trend from our patient’s “baseline” flare-up values. We suggest that such cytokine hyperproduction is the result of an imbalance in natural regulation mechanisms that are used to eliminate pathogens and avoid an exaggerated immune response. In this case, an overabundance of cytokines probably initiated marked worsening of the underlying disease. We observed no other systemic manifestations or damage to vital organs that are usually present in conditions with similar cytokine disturbances [
19]. We hypothesize that COVID-19 might have acted as a long-term trigger for disease exacerbation, i.e., as an inductor of flare-ups which progressed to sites of HO. The effects of influenza-like illness on FOP patients have been documented before, as patients reported flare-ups which occurred after influenza-like symptoms [
11]. Interestingly, in patients of the aforementioned study, the neck and trunk were commonly affected sites—which were also affected in our FOP patient after COVID-19 infection. However, these reported flare-ups occurred within days of viral illness onset, whereas our patient experienced disease worsening 4 weeks after COVID-19 infection convalescence with no improvement to this moment. This might be due to the specific nature of this disease, namely, its associated post-COVID-19 syndrome, which occurs beyond 4 weeks from the onset of symptoms. Tissue damage and innate immune response with inflammatory cytokine production may contribute to the various sequelae of this syndrome [
20]. We argue that tissue damage caused by post-COVID-19 syndrome might be the potential trigger of our patient’s notable disease progression, as well as the associated elevation of inflammatory cytokines. Notably, several instances of non-FOP-related HO after severe forms of COVID-19 have been reported, which further supports our hypothesis [
12,
13].