Cryoglobulinemic vasculitis (CryoVas) is an immune complex-mediated small-vessel vasculitis, caused by the presence in the serum of abnormal immunoglobulins (cryoglobulins). These cryoglobulins precipitate at temperatures below 37°C, forming circulating immune-complexes, which can cause severe tissue damage, mainly skin, joints, kidneys and peripheral nervous system. CryoVas is a rare auto-immune disease. Its prevalence is approximately estimated to be 1:100,000 worldwide. ¹ It is most commonly due to hepatitis C infection, but it can also be caused by a variety of conditions including other infections, hematologic malignancies, and autoimmune diseases. ² Cases of vaccine-induced Cryovas have also been described, for instance, with hepatitis B vaccine, ³ pneumococcal vaccine ⁴ and influenza vaccine. ^{4 , 5} Therapy is based on treating the underlying disease and, depending on the severity of the vasculitis, immunosuppressive therapies (mainly corticosteroids) and in some cases plasmapheresis.

Coronavirus disease 2019 (COVID-19) vaccine has been incriminated in the occurrence of several autoimmune diseases such as Guillain-Barré syndrome, Graves’ disease, systemic lupus erythematosus, ANCA-associated vasculitis. ^{6 – 9} Three cases of CryoVas following a COVID-19 vaccination have been previously reported. ^{10 – 12}

A 57 year-old woman, with no medical history, presented to our department of internal medicine with purpura of the lower limbs which appeared two days before her admission. There was no history of a similar previous clinical picture. She denied symptoms of fever, arthralgia and paresthesia. The patient received her first dose of Janssen ^® COVID-19 vaccine on 11/14/21, 5 days prior to the onset of the purpuric rash.

On physical examination, she had a symmetric polymorphic palpable purpuric rash on her lower limbs ( Figure 1). There was no mucosal involvement. Her blood pressure was 130/70 mmHg and her pulse rate was 72/minute. She had no fever and no arthritis. The cardio-pulmonary and neurological examinations were normal. Urinary dipstick was negative for protein and blood.

Histopathological examination of the skin biopsy revealed marked extravasation of red blood cells with focal perivascular fibrinoid necrosis consistent with leukocytoclastic vasculitis. Direct immunofluorescence showed vascular deposits of C3 and C1q and IgM.

Laboratory tests found normal serum creatinine (58 μmol/l), urea (5 mmol/l), alanine aminotransferase (27 U/L), aspartate aminotransferase (17 U/L), lactate dehydrogenase (182 U/L), and alkaline phosphatase (137 IU/L). CRP was 0.3 mg/L. Complete Blood Count showed normal leukocyte count (5800/mm ³), hemoglobin (12.7 g/dl) and platelets (242000/mm ³).

Immunological assessment revealed positive mixed cryoglobulinemia (IgG, IgA and IgM). ANA, anti-ENA, ANCA, rheumatoid factor and anti-CCP were negative.

Infectious workup including polymerase chain reaction (PCR) test for SARS-CoV-2, viral serologies for hepatitis C, hepatitis B, Cytomegalovirus, Ebstein Barr virus, Parvovirus B19 and Human Immunodeficiency virus (HIV) was negative.

Chest and abdominal CT scans were normal except for a vertebral dysraphism and a right-sided aortic arch variant.

The pharmacovigilance survey incriminated the vaccine in the occurrence of vascutitis after ruling out all other causes.

The patient was prescribed rest and leg raise. As there was no severe organ damage, immunosuppressive therapies were deemed unnecessary.

The purpura completely subsided after 3 weeks. There was no recurrence of the rash and no appearance of new symptoms. The current follow-up is of 18 months.

The present report described a case of a cutaneous vasculitis occurring 5 days after a COVID-19 vector vaccine in a female patient with no medical history. She had mixed cryoglobulinemia and skin biopsy was consistent with leukocytoclastic vasculitis, hence she was diagnosed with CryoVas.

Although we cannot assert its accountability, based on temporal association and by ruling out other etiologies of Cryovas, we can speculate that the COVID-19 vaccine is most likely the cause of our patient’s symptoms.

A literature review, by Abdelmaksoud and al, analyzed 38 cases of cutaneous vasculitis following a COVID-19 vaccination. It was noted that vasculitis developed more frequently after the first vaccine dose (63.2%). Leukocytoclastic vasculitis was the most prevalent histopathologic type (55.3%). The mean occurrence time was 6.2 days after vaccination and the average time for lesions to subside was 2.5 weeks. ¹³

Upon literature review, we found three additional cases of CryoVas post-COVID-19 vaccine ( Table 1). ^{10 – 12} These cases included two women and one man. One patient had a prior history of autoimmune condition. The skin lesions appeared 9 to 17 days after vaccination. Vascular purpura was observed in all three patients, and one of them also had digital necrosis. Skin Biopsy revealed leukocytoclastic vasculitis in all cases. In addition to rest, which was prescribed in all patients, plasma exchange was required in one case due to a worsening of the digital necrosis. Overall, the course of the disease was favorable. Similar to our case, Cryoglobulin control was negative in 2 patients, testifying to the transient nature of the CryoVas.

Furthermore, cases of relapsing cryoglobulinemic vasculitis following COVID-19 vaccination were also reported. ¹³ An Italian study, conducted by Visentini and al. on the safety and immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients with mixed cryoglobulinemia (MC) found that among the 63 patients with stable MC, 6 (9.5%) presented vaccination-related flares, which were more frequent in patient with essential MC. The flares were mainly cutaneous (purpura) and, in 2 cases, peripheral neuropathy and subsided spontaneously. ¹⁴

Our report suggests the possibility of a COVID-19 vaccine-induced CryoVas. COVID-19 vaccine has been incriminated in both the exacerbation of pre-existing autoimmune diseases as well as the new onset of such diseases. Thus, we must be aware of the possible association in order to initiate suitable diagnostic procedures and appropriate treatment.

Finally, our aim is not to undermine the undeniable role of the COVID-19 vaccine in reducing the overwhelming level of morbidity and mortality caused by the SARS-Cov-2 virus but to raise awareness of the possible side effects related to the COVID-19 vaccine.

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.