Features of Chronic Spontaneous Urticaria Induced by COVID-19

Dear Editor,

Chronic spontaneous urticaria (CSU) is a mast cell-mediated disease characterized by the recurrent appearance of wheals, angioedema, or both for longer than 6 weeks. The main pathophysiology that drives mast cell activation in CSU is held to involve autoimmune mechanisms, whereas viral infections are commonly accused as a triggering factor for urticaria onset [1]. COVID-19 is commonly reported in association with urticaria, given that urticaria occurs in 12.5–19.0% of patients with COVID-19 with a median symptom duration of 6.8 days [2]. Furthermore, urticaria exacerbation during COVID-19 infection has been reported in up to 44% of CSU patients, particularly more common when COVID-19 infection is severe 4‒6. As of now, all reported cases of urticaria linked to COVID-19 are acute spontaneous urticaria (ASU), defined by its spontaneous resolution within 6 weeks after onset. In contrast, no cases of CSU after COVID-19 have been reported as of now; only 1 cholinergic urticaria patient was reported recently [7]. Here, we present the first case series of patients who developed CSU after COVID-19, and we describe their clinical and laboratory features.

Fourteen cases of CSU after COVID-19 were identified across five Urticaria Centers of Reference and Excellence (UCARE) [8]. The mean age was 32.9 (17–49), and 64.3% of patients were females. The average time between COVID-19 infection and urticaria onset was 17.9 days (3–28 days), and all but 1 patient developed urticaria after 14 days or longer following COVID-19. The mean duration of CSU at the time of reporting was 15.9 months (7–36 months), when all patients still had ongoing CSU and were on follow-up for their urticaria. Ten (71.4%) patients had standalone CSU, and four had accompanying inducible urticaria (2 symptomatic dermographism, 1 cholinergic urticaria, and 1 delayed pressure urticaria plus symptomatic dermographism). All 14 patients had recurrent wheals, 4 (28.6%) patients had wheals and angioedema, and no patient had standalone angioedema. CSU, in eleven of the patients, was controlled with antihistamines, and 3 (21.4%) patients required omalizumab treatment (300 mg/month). Other information on COVID-19 infection, vaccination, and laboratory findings is presented in Table 1. Written informed consent was obtained from the patients for publication of this case report.

The described cases of CSU possibly triggered by COVID-19 here have an average time to urticaria onset of 2 weeks after infection. While the onset of urticaria has been reported to proceed COVID-19 symptoms in 16.1% of patients in ASU, it is most commonly concurrent with the symptoms of infection, in 79% of the cases. Late-onset ASU (i.e., 2–4 weeks after the onset of COVID-19 symptoms) like in our cases has only been reported in 3.9% of the patients [9]. Of note, only one of our patients developed urticaria simultaneously with the infection [3]. This indicates that the onset of ASU, after COVID-19, is earlier in those patients who do not progress to CSU as compared to those who do, suggesting that the former may differ from the latter in underlying pathogenic pathways. The drivers of progression from ASU to CSU are not well understood. In line with the hypothesis that patients with ASU who have mast cell-activating autoantibodies may have a higher risk of developing CSU as compared to those who do not, Magen et al. [10] reported that ASU patients who progressed to CSU more often have a positive autologous serum skin test, thyroid autoimmunity, and pronounced basopenia as compared to those who did not. In our patients, 4 (36.4%) had eosinopenia, 5 had basopenia (45.4%), 4 (36.4%) had antinuclear antibody positivity, and 3 (27.3%) had high anti-thyroid peroxidase, all of which are signs of autoimmunity and similar to the rates in Magen’s study.

ASU associated with COVID-19 has been reviewed by Algaadi et al. [3] among 30 articles and 202 patients. The age range was between 2 months and 84 years (mean ~45 y) with 64% female dominancy where angioedema was only reported in 2 of these patients and most of them responded well to antihistamines and in some cases to systemic steroids while 11% required intensive care unit treatment for COVID-19. Our patient population had a similar gender distribution and mean age whereas angioedema frequency was much higher (28.6%). Most of our patients responded to antihistamine treatment (78.6%) and COVID-19 manifested as severe disease in 21.4% of them which seems to be higher than the severe disease frequency reported for ASU cases. Referring to this, urticaria did not correlate with disease severity in most of the reports; however, Galvan et al. [11] reported that the presence of urticaria and maculopapular lesions was associated with more severe COVID-19 and a higher (2%) mortality.

At present, it is unknown how viral infections trigger the onset of urticaria; however, viral infections can activate mast cells via the innate immunity receptors and complement receptors [12] and also by triggering autoimmunity since similarities and homology between SARS-CoV-2 proteins and human tissue antigens have been reported which can lead to binding of antibodies against SARS-CoV-2 to some human tissue antigens and result in generation of autoimmune diseases [13, 14]. Unfortunately, it is not possible to prove that our patients developed CSU because of COVID-19. It is also possible that the stress linked to having COVID-19 or the medications used to treat it may have contributed to the onset of urticaria; furthermore, several CSU cases triggered by COVID-19 vaccination have been reported [15, 16]. In our patients, to avoid possible cases induced by vaccination, the vaccination status of the patients was carefully considered. Three patients were vaccinated before the start of CSU: two with Sinovac (CoronaVac) 6 months before urticaria onset and one with BNT162b2 mRNA (Pfizer-BioNTech) vaccine 2.5 months before urticaria onset. The patient who was vaccinated with BNT162b2 mRNA (Pfizer-BioNTech) re-administered the BNT162b2 mRNA (Pfizer-BioNTech) during follow-up period without exacerbation of urticaria. Considering the time between vaccination and urticaria onset, we did not think of an association with vaccination and urticaria. Six patients received favipiravir treatment for COVID-19, of whom the occurrence of urticarial symptoms ranged from 14 to 22 days after favipiravir. We did not consider favipiravir as a cause of urticaria since favipiravir-induced urticaria usually occurred within 1 week and regressed immediately after cessation of favipiravir treatment in the previous reports [17].

In conclusion, despite the increase in reports of COVID-19 vaccine-associated chronic urticaria cases, the cases that are possibly triggered by the infection itself remains to be underreported possibly due to the difficulty in making the possible causality link. However, CSU can develop after COVID-19. In contrast to ASU, it starts with a delay of 2 weeks, in most patients. This can help to better counsel patients who develop urticaria after COVID-19 on the expected course and duration of the disease.