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Chronic spontaneous urticaria following COVID-19 vaccination

CASE SERIES The median age of the patients was 56.5 years (range, 27-78 years) and 75% (n = 6) were women. Wheals and/or angioedema occurred a median of 8.6 days (range, 1-18 days) after vaccination. All patients presented with wheals, and 5 also presented with angioedema (Fig 1). None of the patients presented with anaphylactic symptoms, and inducible urticaria was excluded. Acute urticaria following vaccination was initially suspected. However, as wheals and/or angioedema lasted for [6 weeks in all patients, a diagnosis of CSU was made according to international EAACI/GA2LEN/EuroGuiDerm/ APAAACI guidelines. Wheals and/or angioedema appeared for the first time after the administration of the first vaccine dose for 6 patients and after the second dose of vaccine for 2 patients. Three patients received the BNT162b2 vaccine (Pfizer/BioNTech), 1 received the messenger RNA-1273 vaccine (Moderna), and 4 received the ChAdOx1 nCoV-19 vaccine (AstraZeneca). Three patients reported an exacerbation of urticaria after the second dose, and 1 patient after the third dose. Two patients discontinued their vaccination protocol due to concern for further urticaria exacerbation. The mean duration of follow-up was 9.9 months (range, 8-11 months). All patients received H1antihistamines; 2 received short-course systemic corticosteroids, 1 received cyclosporine, and 2


INTRODUCTION
We report a case series of 8 patients who developed chronic spontaneous urticaria (CSU) following vaccination against SARS-CoV-2 infection (Table I).

CASE SERIES
The median age of the patients was 56.5 years (range, 27-78 years) and 75% (n = 6) were women. Wheals and/or angioedema occurred a median of 8.6 days (range, 1-18 days) after vaccination. All patients presented with wheals, and 5 also presented with angioedema (Fig 1). None of the patients presented with anaphylactic symptoms, and inducible urticaria was excluded. Acute urticaria following vaccination was initially suspected. However, as wheals and/or angioedema lasted for [6 weeks in all patients, a diagnosis of CSU was made according to international EAACI/GA2LEN/EuroGuiDerm/ APAAACI guidelines. 1 Wheals and/or angioedema appeared for the first time after the administration of the first vaccine dose for 6 patients and after the second dose of vaccine for 2 patients. Three patients received the BNT162b2 vaccine (Pfizer/BioNTech), 1 received the messenger RNA-1273 vaccine (Moderna), and 4 received the ChAdOx1 nCoV-19 vaccine (AstraZeneca). Three patients reported an exacerbation of urticaria after the second dose, and 1 patient after the third dose. Two patients discontinued their vaccination protocol due to concern for further urticaria exacerbation.
The mean duration of follow-up was 9.9 months (range, 8-11 months). All patients received H 1antihistamines; 2 received short-course systemic corticosteroids, 1 received cyclosporine, and 2 received omalizumab. Four patients were asymptomatic at the end of the follow-up period (5-11 months) and were able to discontinue the treatment. The mean duration of CSU for these 4 patients was 6.8 months (range, 5-9 months). In contrast, 4 other patients were still symptomatic at follow-up, with a CSU duration of 8 months (n = 1), 9 months (n = 1), and 11 months (n = 2).
One patient, who developed severe arthritis 2 months after vaccination, was subsequently diagnosed with systemic lupus erythematosus. None of the patients had a history of CSU before COVID-19 vaccination, but 1 patient reported a history of transient cholinergic urticaria 30 years earlier.

DISCUSSION
Disease onset following vaccine may be coincidental or related to the vaccination. However, since the incidence of CSU in the general population at the same time is not known, it is not possible to define whether the prevalence was higher during this vaccination period. However, the short delay between vaccinations and the first symptoms of urticaria in our patients (median, 8.6 days) with no previous history of CSU and the exacerbation in 4 patients after the second or third vaccine dose, raise the possibility that the vaccines served as a trigger. Clinical experience suggests that vaccinations, as well as infections, are exacerbating factors of CSU. However, data in this area are sparse. Acute urticaria and anaphylaxis have been described after COVID-19 vaccines. 2,3 Exacerbations of CSU after COVID-19 vaccines have also been described. 4 A few cases of new-onset CSU after COVID-19 vaccination have been published and are summarized in Table II. [5][6][7][8] For instance, Magen et al 8 reported 27 patients with relapse of CSU and 32 patients with new-onset CSU within 3 months after receiving the BNT162b2 vaccine. The latter authors have previously described a case series of new-onset CSU occurring 4 to 16 days after vaccination with adjuvanted vaccines. 9 In our series, CSU followed adenoviral vector or messenger RNA vaccines, neither of which are adjuvanted vaccines.
Although a coincidence cannot be ruled out, these observations of CSU following COVID-19 vaccination raise questions about their etiopathogenic mechanism. During SARS-CoV-2 infections and vaccination, mast cells could be activated through different mechanisms. They can be triggered by pathogen-associated molecular patterns via the activation of Toll-like receptors. Furthermore, viral infections may stimulate mast cell degranulation via complement activation. Mast cells also express angiotensin-converting enzyme 2, now known as a receptor for SARS-CoV-2. 10 Moreover, in the specific case of CSU, an autoimmune pathway is implicated. For instance, several  patients with CSU also have a concomitant autoimmune disease or family history of autoimmune disease, and/or the presence of some autoantibodies. Therefore, molecular mimicry in patients with genetic predispositions to autoimmune diseases could be one hypothesized mechanism for the development of CSU. The immune response induced by SARS-CoV-2 infection or vaccination, although primarily against viral antigens, could target host molecules that share sequence homology or structural similarities with viral epitopes. Indeed, studies have shown similarity and homology between SARS-CoV-2 proteins and human tissue antigens. 11 Moreover, antibodies to SARS-CoV-2 could bind some human tissue antigens. 11,12 This crossreactivity in patients with preexisting self-tolerance deregulations may lead to development of autoimmune disease. Concomitant occurrence of systemic lupus erythematosus in 1 of our patients possibly supports this hypothesis. However, a delay of the onset of urticaria of 1 to 4 days after vaccination (observed in 3 of our patients) appears too short to involve an autoimmune reaction, unless these patients had previously been infected by SARS-CoV-2. These patients had no history of symptomatic SARS-CoV-2 infection; however, anti-nucleocapsid antibody testing was not performed. If this crossreactivity could occur after vaccination, it should also occur after SARS-CoV-2 infection. However, our literature search revealed no reported onset of CSU after SARS-CoV-2 infection. This may possibly be due to the delay or avoidance of medical care during the pandemic and/or to newly diagnosed CSU not being associated with the virus or being attributed to other triggering factors, such as lockdown and pandemic stress or medications (anti-inflammatory drugs) or because many patients have asymptomatic SARS-CoV-2 infection, and so the link could not be made. Despite the absence of anaphylaxis or contraindications to the continuation of the vaccination protocol, because CSU is potentially disabling, its occurrence could lead to vaccination interruption, as was observed in 2 of our patients. It is important to inform patients not to interrupt vaccination after the onset of urticaria (acute or chronic) and to encourage them to complete the full protocol as recommended by international health organizations. Dermatologists can lend their expertise to help control/treat/minimize cutaneous reactions that may be triggered by the vaccines, including CSU. For instance, the administration or increase of H 1 -antihistamines around the time of vaccination could reduce or avoid urticaria flares and allow patients to continue vaccination protocols.
We thank Dr Mariana Andrade who provided editorial assistance. Dr Andrade received payment for her service but no commercial funding was received for this purpose.