Title:Granulomatosis with Polyangiitis Following COVID-19 Infection and Pfizer-BioNTech Vaccination Authors:Alyssa Kang, DO. Jefferson Einstein Montgomery Hospital Alyssa.kang@jeffereson.eduShivani Modi, MD. Jefferson Einstein Montgomery Hospital Shivani.modi@jefferson.edu   Kibo Yoon, MD. Cleveland Clinic yoonk2@ccf.orgKey Clinical Message: COVID-19 infection and the administration of the COVID-19 vaccine both have the potential to trigger an immunogenic response that can uncover a pre-existing vasculitis. This is a case of granulomatosis with polyangiitis that manifested with progressive episodes of hemoptysis after receiving the Pfizer-BioNTech vaccine and contracting COVID-19 3 months later.Introduction:In August 2021, the U.S. Food and Drug Administration approved the first COVID-19 vaccine known as Pfizer-BioNTech. Over the subsequent months, the global rollout of the vaccine was associated with significant decreases in COVID-19 morbidity and mortality. However, recent research has reported cases of immunologic complications following both vaccination and COVID-19 infection.Granulomatosis with polyangiitis (GPA) is a systemic small- and medium-vessel vasculitis typically characterized by necrotizing granulomas in the respiratory tract, necrotizing glomerulonephritis, and the presence of antineutrophil cytoplasmic antibodies (ANCA). Recent studies have identified neutrophil extracellular traps (NETs)—web-like structures released by activated neutrophils—as playing a key role in the pathogenesis of vasculitis, including GPA. Furthermore, both COVID-19 and the Pfizer-BioNTech vaccine have been shown to increase NET formation, potentially linking the two as contributing factors in the development or unmasking of GPA. This case report discusses a unique case of a 41-year-old male who developed GPA following COVID-19 infection shortly after receiving the second dose of the Pfizer-BioNTech vaccine.Case History/examination:A 41-year-old Caucasian male with a history of recurrent sinus infections, obesity, and alcohol abuse presented with a 3-week history of hemoptysis, arthralgias, and a petechial rash over the bilateral lower extremities. He reported no personal or family history of autoimmune diseases. His vaccination history included receiving the second dose of the Pfizer-BioNTech vaccine approximately 15 months prior. Three months after vaccination, he contracted COVID-19, after which he developed persistent sinusitis symptoms which he managed with over-the-counter medications. During the two weeks preceding hospitalization, he developed progressive arthralgias that began in his feet and ankles and later involved his wrists and hands, as well as a petechial rash over the anterior shins and oral aphthous ulcers.Differential diagnosis, investigations and treatment:Upon presentation, the patient was hypoxic with an oxygen saturation of 84% and was placed on 3L oxygen via nasal cannula. A computed tomography pulmonary embolism study revealed multifocal ground-glass opacities and a reverse halo sign, suggesting alveolar hemorrhage (Figure 1). Initial lab results showed an elevated creatinine of 1.73 mg/dL (baseline 1.26 mg/dL), a positive rheumatoid factor (RF) of 41 U/mL, negative antinuclear antibody (ANA), and positive c-ANCA and proteinase 3 (PR3) antibodies. The respiratory viral panel was negative. A renal biopsy demonstrated necrotizing glomerulonephritis, confirming the diagnosis of GPA.The patient was treated with rituximab and pulse steroid therapy. He later received a second dose of rituximab and transitioned from steroids to avacopan, a C5a receptor inhibitor that has been shown to be as effective as prednisone therapy according to the ADVOCATE trial.5Discussion:COVID-19 has been associated with increased formation of neutrophil extracellular traps (NETs), which are comprised of inflammatory proteins with the potential to precipitate vasculitis. They have also been reported to contain enzymes from all types of neutrophil granules including proteinase 3 (PR3).3 ANCA in GPA reacts with PR3 which leads to de-granulation and damage of endothelial cells.1 Thus, there may be an association between an increased concentration of NETs and a predisposition to the development or diagnosis of GPA. SARS-CoV2 spike proteins in vaccines have been shown to evoke the release of NETs4, and this suggests that contracting COVID-19 within a certain timeframe after receiving the vaccine may lead to a synergistic increase in the formation of NETs. The immune response triggered by the combination of the vaccine and subsequent COVID-19 infection may create a “double hit”, resulting in a surge of NETs that could predispose an individual to the development or the unmasking of a pre-existing inflammatory condition like GPA.The “double-hit” hypothesis implies that the combined effects of the vaccine and the viral infection might tip the balance in individuals with a subclinical predisposition to autoimmunity or incite the onset of an inflammatory disease like GPA. Indeed, emerging case reports have detailed instances of ANCA-associated vasculitis following COVID-19 or even post-vaccination, although such events remain rare. More broadly, the interplay between NETosis and autoimmune activation is supported by both in vitro studies and investigations in patients with severe COVID-19, where NET-derived components are elevated and correlate with markers of vascular injury and inflammation.6This hypothesis is further underpinned by observations that heightened NET formation has been associated with various autoimmune disorders. NETs expose and modify self-antigens, such as PR3, thereby facilitating a break in immune tolerance and potentially triggering a pathogenic autoimmune response. In GPA, the exposure to a high burden of NETs may lead not only to enhanced autoantigen presentation but also to an amplification of the inflammatory cascade that damages blood vessels.7,8 Consequently, in individuals who have been recently vaccinated with SARS-CoV-2 spike protein–based vaccines, contracting COVID-19 may represent a precarious “perfect storm” that results in a marked increase in NETosis—potentially predisposing them to the de novo development of GPA or unmasking a previously latent condition.This case highlights a possible connection between the Pfizer-BioNTech COVID-19 vaccine, COVID-19 infection, and the development of GPA. While further research is needed to understand the exact mechanisms by which COVID-19 and vaccination may trigger or unmask autoimmune diseases, this case underscores the importance of screening for vasculitis in patients who experience prolonged sinus infections and symptoms following COVID-19 infection. Understanding the interplay between COVID-19, the vaccine, and immune system dysregulation may guide clinicians in early diagnosis and treatment of such conditions.Author Contributions:Alyssa Kang: conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation, visualization, writing – original draft, writing – review and editing.   Shivani Modi: writing – original draft, writing – review and editing.Kibo Yoon: writing – review and editing.Acknowledgements: NoneFunding: No funding was used for this case report.Ethics Statement:As a case report with the patient’s signed consent, no other ethical review was required.Consent:Written informed consent was obtained from the patient for the publication of this case report.Conflicts of Interest:The authors declare no conflicts of interest.