COVID-19 vaccination-related small vessel vasculitis with multiorgan involvement.

Since its first outbreak in 2019, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, has been ongoing, and the pandemic is not over yet. Vaccines developed against COVID-19 have been approved and widely used since 2020; however, vaccine safety concerns need to be addressed. Autoimmune symptoms have been reported as a side effect of many COVID-19 vaccines. In particular, several cases of COVID-19 vaccine-induced vasculitis have recently been reported. Herein, we report the case of a 77-year-old woman who developed small-vessel vasculitis with multiorgan involvement after receiving the BNT162b2 COVID-19 vaccine (Pfizer and BioNTech, New York City, NY, USA).

Introduction

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in 2019 eventually led to a global pandemic situation. Vaccines developed against COVID-19 became available for use in late 2020, playing an important role in preventing the spread of COVID-19.

Among the several available COVID-19 vaccines, those approved by the United States Food and Drug Administration include the BNT162b2 vaccine (Pfizer and BioNTech, New York City, NY, USA), mRNA-1273 vaccine (Moderna Therapeutics, Cambridge, MA, USA), and AZD1222 vaccine (AstraZeneca and Oxford University, UK). Although the safety of these vaccines has been established in several trials, various side effects have been reported. These include symptoms related to autoimmune diseases such as inflammatory arthritis and alopecia, as well as other autoimmune symptoms such as a skin rash [9, 13]. Vasculitis is a rare autoimmune disease that affects blood vessels, leading to tissue damage [15]. Its clinical features vary depending on the type of affected vessel. The possible causes of vasculitis include drugs, infection, and vaccination [15]. Herein, we report the case of a patient who developed small-vessel vasculitis with multiorgan involvement after receiving a COVID-19 vaccine.

Case

A 77-year-old woman visited the emergency room because of weakness and weight loss persisting for 1 month. She had received the second dose of the Pfizer-BioNTech COVID-19 vaccine 1 month previously, following which she experienced fever and myalgia. The symptoms persisted and were accompanied by anorexia, sweating, and weight loss. Furthermore, she presented with dyspnea, dizziness, and an ear fullness sensation. She had no specific medical history except for hypertension, and no other new drug history. Her vital signs were stable: blood pressure 120/80 mm Hg; pulse rate 71 beats/min; respiratory rate 21 breaths/min; and temperature 36.5 °C. Physical examination revealed hyperemia in both eyes and livedo reticularis of the upper and lower extremities; however, joint swelling or tenderness was not observed. Blood test results revealed a white blood cell count of 15,000/µL and markedly elevated high-sensitivity C‑reactive protein levels at 38 mg/dL. Furthermore, she had azotemia accompanied by high creatinine levels (6 mg/dL); urinalysis showed 200 erythrocytes/µL (3+) and 15 leukocytes/µL. The spot urine protein-to-creatinine ratio was 4700 mg/g Cr, showing nephrotic-range proteinuria.

Regarding hyperemia in both eyes, slit-lamp examination was performed, showing conjunctivitis. Tympanometry was performed for the ear fullness sensation, and bilateral otitis media with effusion was confirmed (Fig. 1a).

Fig. 1

a tympanogram of the left ear with effusion of tympanic membranes; b computed tomography (CT) image of the chest showing variable sized enhancing nodules in both lungs, with lower lung zone predominance; c positron-emission tomography/CT image

Chest computed tomography (CT) imaging revealed enhancing nodules of variable sizes in bilateral lungs; the nodules were predominantly observed in the lower lung zone, suggesting atypical pneumonia or pulmonary metastasis (Fig. 1b). Empirical antibiotic therapy was initiated for managing pneumonia. Positron-emission tomography/CT was performed for the differential diagnosis of the pulmonary lesions; the findings showed inflammatory changes suggestive of vasculitis rather than metastasis (Fig. 1c).

Serologic test results revealed an elevated antinuclear antibody titer (1:320), moderate anticentromere antibody titer, and low rheumatoid factor titer; renal biopsy was performed to determine the cause of severe proteinuria. Crescentic glomerulonephritis was observed using light microscopy (Fig. 2a, b); no immune complexes were observed using immunofluorescence and electron microscopy (Fig. 2c).

Fig. 2

a Light microscopy of the glomerulus (periodic acid-Schiff, × 200); b Masson trichrome stain, × 200; c electron microscopy, × 2000

Small-vessel vasculitis was diagnosed on the basis of systemic symptoms (weight loss and fever), conjunctivitis, otitis media, livedo reticularis, lung nodules leading to the suspicion of vasculitis, and pauci-immune glomerulonephritis.

Methylprednisolone (1 mg/kg and day) was initiated for vasculitis management. Hemodialysis was performed to correct azotemia and acidosis. The patient exhibited gradual improvement in general and respiratory symptoms. One month after starting the treatment, follow-up chest CT imaging revealed markedly decreased nodules; furthermore, the inflammatory marker levels had recovered to normal. However, the patient had to undergo permanent dialysis owing to several irreversible glomerular sclerotic changes. During steroid dose tapering, she was started on azathioprine. She remains well without recurrence.

Discussion

Although the safety of COVID-19 vaccines has been recognized and their use approved, several cases of autoimmune-related side effects of these vaccines have been reported [2, 4, 7, 9, 11, 12, 16]. Arthralgia is a common adverse reaction observed as a side effect of COVID-19 vaccines; however, inflammatory arthritis has rarely been reported. An et al. reported a case of reactive arthritis in a young woman [2]; further, Chan et al. reported a case of severe but self-limiting inflammatory polyarthritis occurring after the first dose of ChAdOx1 nCoV-19 vaccination in an elderly patient [7]. Similarly, Manzo et al. reported the case of a patient who developed polymyalgia rheumatica (PMR) after receiving the Pfizer vaccine [10]. The pathophysiological mechanism of PMR is thought to be similar to that of giant cell arteritis (GCA), which is a large-vessel vasculitis [14].

Vasculitis has been reported as an autoimmune-related side effect following COVID-19 vaccination. Reportedly, vasculitis accounted for 2.9 and 0.7% of the cutaneous side effects in patients receiving the first doses of Pfizer-BioNTech and Moderna (mRNA-1273) vaccines, respectively [11]. The disease was limited to cutaneous vasculitis in most patients [5, 6, 8]; however, organ involvement was reported in some cases. Shakoor et al. reported renally limited ANCA-associated vasculitis after Pfizer-BioNTech COVID-19 vaccine administration [16], whereas Mucke et al. reported immunoglobulin A vasculitis with arthritis, abdominal pain, and purpura after BNT162b2 vaccine administration [12].

Although vasculitis can be caused by drugs or viral infection, vaccination is considered a triggering factor [3]. Typically, several cases of vasculitis following influenza vaccination have been reported [4]. Soriano et al. reported 10 cases of GCA/PMR after the administration of an influenza vaccine; most patients exhibited a genetic predisposition, such as harboring the HLA-DRB1 gene, showing that both environmental and genetic factors play an important role in the pathogenesis of vasculitis [17].

The underlying mechanism of vasculitis occurring after COVID-19 vaccination remains to be elucidated. It has been postulated that host antibody production against the SARS-CoV‑2 spike protein via molecular mimicry initiates immune complex formation [1]. Furthermore, it is speculated that the mRNA vaccine itself activates Toll-like receptors, thus increasing interleukin‑6 production, which is possibly linked to the development of diseases such as PMR and vasculitis [10]. Further investigation of these interactions is warranted to determine the underlying pathophysiological processes.

Conclusion

We report the development of small-vessel vasculitis with multiorgan involvement following Pfizer-BioNTech COVID-19 vaccination in a female patient. Interestingly, the patient exhibited involvement of the lungs and kidneys, which are commonly affected by vasculitis, but did not exhibit the symptoms of skin involvement such as purpura. We believe that this case, with its radiological and histological findings, will help in the management of vaccine-induced vasculitis in the future.