Granulomatous reaction at PRP/Fat injection sites after recovering from SARS‐Co‐V2: A case report

To the Editor Currently, combination protocols including injection of insulin, stromal vascular fraction, or platelet-rich plasma (PRP) with autologous fat transfer have gained popularity.1 Reports on using PRP in pro-survival strategy of fat graft have suggested positive effect on grafts with low rate of complications.2 Here, we present a woman with subcutaneous nodules which have developed 2 months after PRP and fat co-transplantation and discuss possible relationship with coronavirus infection. 39-year old woman with a past medical history of buccal fat removal and PRP-fat injection admitted with 2-month history of asymptomatic nodules on her neck (Figure 1a) and face (Figure 1c). She had received PRP therapy for a few times in recent years without any complication. The lesions developed at injection sites, 2 months after PRP fat transplantation for wrinkle treatment. In this period, approximately 3 weeks before the occurrence of the lesions, the patient had low-grade fever and asthenia. Nasopharyngeal swab RT-PCR–based SARS-CoV-2 detection was positive. On first examination, which corresponded to 3 months after the diagnosis of coronavirus disease 2019 (COVID-19), there were multiple non-tender subcutaneous nodules throughout the injected regions. A comprehensive work-up including complete blood count, serum angiotensin-converting enzyme (ACE), complete metabolic panel, serum and urine calcium, chest radiograph, and electrocardiogram was performed. Laboratory and imaging studies were unremarkable. Excisional biopsy of a nodule revealed granulomatous lymphohistiocytic infiltration surrounded by a sparse multinucleated giant cells in the upper and lower dermis (Figure 2). Central zone of altered collagen was noted. Systemic sarcoidosis was ruled out. Oral corticosteroid therapy was started at 0.5 mg/kg/day. At one-week follow-up, significant improvement of lesions in size was observed (Figure 1b-d). After the control of disease, the dosage of corticosteroid was tapered slowly. She is still under close follow-up. PRP is an autologous plasma containing concentrated platelets, growth factors, and cytokines. It has been used widely in many dermatological applications in particular for skin rejuvenation procedures.3 Despite the fact that PRP does not contain foreign bodies, it has been proposed that growth factors such as platelet-derived growth factor and vascular endothelial growth factor (VEGF) may result in granuloma formation by modulating chemotactic effects on mononuclear cells. Sarcoidal granulomas were associated with PRP injection for the first time by Serizawa et al.4 A very recent report by Izhakoff et al. reported formation of cutaneous sarcoid lesions after PRP treatment in a patient with subclinical sarcoidosis.5 Both PRP and fat transplantation seem to be effective in regenerative medicine, independently. Growing evidence indicates synergistic beneficial effects of co-transfer.2 Studies have proposed that complication rate is minimal, with majority of them are skin irregularities and asymmetry.6 Dystrophical calcification was also associated with fat transfer.7 Recently, according to the expert panel, delayed inflammatory reactions (DIR) to hyaluronic acid (HA) fillers are defined as reactions occurring 2–4 weeks or longer after cosmetic injections. DIR are mainly associated with infectious triggers.8 It is worth noting that DIR associated with HA dermal fillers in patients with exposure COVID-19 spike protein have been increasingly described in the literature.9-11 In addition, there is growing evidence that not only native acquired COVID infection, but also the COVID-19 vaccines may induce such HA-associated DIR.12, 13 Due to the rapid production of spike proteins, time of onset of DIR is shorter in vaccinated patients than the others with native COVID-19 infection.9 For today, the exact pathogenesis of such a delayed reaction is unclear. However, literature review highlights that spike protein and angiotensin 2–converting enzyme receptors (ACE2) interaction leading to pro-inflammatory, Th1 response, and CD8+ T cell reaction is likely to be responsible. With respect to this pathway, treatment of HA-associated DIR following COVID vaccination with oral angiotensin-converting enzyme inhibitors (ACE-I) has been recommended. Notably, low-dose oral lisinopril (10 mg/daily, 3–5 days) was found to be beneficial with favorable safety profile.14, 15 On the contrary, COVID infection-associated DIR are likely to be prolonged and may require systemic corticosteroid use.9 In line with the reports of DIR associated with HA filler treatment in patients with SARS-CoV-2 infection, the reaction of our patient was noted approximately 3 weeks after the infection. In fact, the necrobiotic granulomatous reaction in our patient was mostly similar to granuloma annulare (GA). The occurrence of sarcoidal lesions at injection points may be indicative of koebnerization reaction on the background of a granulomatous disorder. It is also worth considering that our patient was treated with PRP several times in previous years. There was no prior history of filler injection. However, at last session, she was treated with PRP and fat injection for skin rejuvenation. Considering the association of SARS-CoV-2 and granulomatous reaction, we found two reports very recently described.16, 17 Thus, given the patient history of COVID-19, we believe that, interferon γ (IFN-γ), the common key player in the cytokine storm of the disorder may give rise to delayed-type hypersensitivity reaction, in particular previously traumatized skin such as injection sites. Hence, ACE2 is a ligand for the COVID spike protein, one possible explanation for COVID-related granulomatous reaction with PRP/Fat injection in our patient could also be explained by the fact that higher ACE2 gene expression in the adipose tissue than the lungs.18 Even though there is still little evidence regarding possible causative relationship, our report should caution physicians about the combined use of PRP and autologous fat, particularly during the pandemic. The patients in this manuscript have given written informed consent to the publication of their case details. There is no conflict of interest of any of the authors. Authors declare human ethics approval was not needed for this study. The data presented here have not been published elsewhere.