 Abstract | | |
Background: The clinical effects of Pfizer-BioNTech coronavirus disease 2019 (COVID-19; BNT162b2) vaccine on the clinical course of chronic spontaneous urticaria (CSU) is unclear. Aims and Objectives: To evaluate the clinical effects of BNT162b2 vaccine on the clinical course of CSU. Methods: In this study, 90 CSU patients vaccinated with one or two repeated doses of BNT162b2 vaccine were included. Urticaria Activity Score over 28 days (UAS28), Urticaria Control Test (UCT), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), and Medication Scores (MSs) were obtained before the vaccination, 28 days after the first and, if available, after the second dose of BNT162b2 vaccine. The demographic, clinical, and laboratory features were compared between the subjects with exacerbated (group A) and non-exacerbated (group B) disease activity. Results: Among the 90 study participants, 14 (15.5%) experienced exacerbations in their urticarial activity after the first or repeated doses of BNT162b2 vaccinations. The demographic, clinical, and laboratory features were similar between the exacerbated and non-exacerbated CSU patients. However, the rate of adverse reactions within 48 hours, such as hives, injection site reactions and wheals lasting <1 hour, were significantly higher in group A than in group B (P = 0.004, P < 0.001, P = 0.001, P = 0.018). Conclusions: BNT162b2 vaccination caused an exacerbation in 15.5% of CSU patients during the short-term follow-up. The long-term evaluation can be informative about the lasting effects of BNT162b2 vaccine on the clinical course of CSU patients.
Keywords: Adverse reaction, BNT162b2 vaccine, chronic spontaneous urticaria, disease severity, quality of life
How to cite this article:
Tuzer C, Sezer S. Clinical effects of BNT162b2 vaccine on the short-term course of chronic spontaneous urticaria patients. Indian J Dermatol 2022;67:674-81 |
How to cite this URL:
Tuzer C, Sezer S. Clinical effects of BNT162b2 vaccine on the short-term course of chronic spontaneous urticaria patients. Indian J Dermatol [serial online] 2022 [cited 2023 Mar 23];67:674-81. Available from: https://www.e-ijd.org/text.asp?2022/67/6/674/370320 |
| Introduction | |  |
Chronic spontaneous urticaria (CSU) is defined as spontaneous wheals with or without angioedema, lasting for more than six weeks without definite physical triggers.[1] The pathophysiology of CSU involves activation of mast cells and basophils, which gives a rise to the release of proinflammatory mediators and causes the generation of wheals. Many studies have suggested that CSU may be an autoimmune disease in most cases, but it is still important to identify potential triggers.[2] Exacerbating factors include stress, environmental conditions, medications, physical stimuli, and infections.[1]
To prevent mortality and morbidity from the coronavirus disease 2019 (COVID-19), vaccines seem to be the only preferable option.[3] However, from the beginning of COVID-19 vaccinations, some rare adverse events have been described. Hypersensitivity reactions (HSRs) to the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine have been reported in five cases per million doses.[4] Also, a patient developed CSU with AstraZeneca/Oxford (ChAdOx1) adenovirus vector vaccine.[5] Nowadays, it is of great interest that the subjects with allergic comorbidities are at a risk of experiencing a HSR or clinically deteriorating after COVID-19 vaccinations.[6],[7] The Vaccine Adverse Event Reporting System (VAERS) dataset of the United States notes that vaccine recipients with allergic comorbidities are twice as likely to develop anaphylaxis after vaccination as those without these comorbidities.[8] However, no HSRs to COVID-19 vaccines were experienced in allergic rhinitis (AR) patients on subcutaneous immunotherapy.[9] There are a few case reports about the interaction between CSU and mRNA COVID-19 Vaccines.[10],[11] In a recent paper, Bermingham et al.[7] pointed out that a proportion of CSU/angioedema patients could be expected to experience worsened symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) vaccination. They suggested a proactive approach for CSU patients during the SARS-CoV-2 vaccination program.
The present study aimed to evaluate the clinical effects of BNT162b2 vaccine on the clinical course of CSU and investigate the risk factors for a possible exacerbation of the disease by this vaccine.
| Subjects and Methods | | |
Study population
CSU patients (aged ≥18 years) vaccinated with at least one dose of BNT162b2 vaccine (an mRNA-based vaccine) and those having had repeated doses with at least a 28-day interval were recruited for the study. CSU patients who had NSAID-exacerbated cutaneous disease (NECD) and also used non-steroidal anti-inflammatory drugs (NSAIDs) during the follow-up were excluded. Subjects who were not infected with SARS-CoV-2 over the preceding three-month and the two-month follow-up periods and whose disease severity remained the same during the preceding three-month period were included in the study. Those who had severe disease activity at initial evaluation and under omalizumab and/or cyclosporine treatment were excluded as well.
Quality of life and disease activity assessment
The Turkish version of the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) was used to determine the impairment in the quality of life (QoL) of the patients. The CU-Q2oL is a 23-item questionnaire that uses a five-point Likert-type scale. The minimum score is 0 and maximum score is 100 for the total scores of assessment for CU-Q2oL.[12]
The Urticaria Control Test (UCT) and Urticaria Activity Score over 28 days (UAS28) were used to assess disease activity in all the subjects. The UCT consists of four questions evaluating QoL impairment, control of signs and symptoms of the disease, efficacy of treatment and disease control and covers the prior four weeks. Each question is scored from 0 to 4 and the total score is calculated by summing the scores related to the four questions.[1],[13] The Urticaria Activity Score (UAS) values were calculated daily according to the number of wheals and intensity of pruritus using a three-point Likert-type scale. The total score of the 28 consecutive days was used to determine the categorical severity of the disease. The patients who had <6, 7–24, 25–64, ≥65 UAS28 scores were designated as ones having none, mild, moderate, and severe disease activity, respectively.[13],[14] Medication scores (MSs) were modified from Sussman et al.[15] and calculated as follows: 2 points (antihistamine, once a day), 4 points (antihistamine, twice a day), 6 points (antihistamine, three times a day), 8 points (antihistamine, four times a day), 2 points (montelukast, once a day), 10 points (anti -IgE, 300 mg monthly) and 8 points (cyclosporine, 3.5-5 mg/kg once a day).
Study design
The registered CSU patients being followed by the Adult Allergy and Dermatology Units in our hospital were phoned and asked to participate in the survey. The patients whose disease severity remained the same (according to UAS28 scores from the routine control visits in their follow-up files) during the preceding three-month period and who accepted to participate in the study were invited 28 days before the BNT162b2 vaccination. The patients were asked to note their scores daily for 28 consecutive days to calculate the UAS28 scores. The UAS28 (over the preceding four weeks), UCT (over the preceding four weeks), CU-Q2oL (over the preceding 15 days), and MSs were calculated on the first day of vaccination. The same scores were re-evaluated 28 days after the first vaccination and, if available, after the second dose of BNT162b2 vaccine.
Group A consisted of the patients who progressed to a higher categorical assessment (mild, moderate, and severe) following vaccination and were designated as having an increased disease activity. The remaining subjects were included into group B.
The demographic and clinical features such as age, sex, body mass index (BMI), duration of CSU, non-allergic comorbidities, and personal and family histories of allergic comorbidities were recorded. The non-allergic (fever, fatigue, vomit, dizziness, diarrhoea, headache, dyspnoea, injection-site reaction), and allergic (urticarial attack, angioedema, anaphylaxis) adverse reactions within 48 hours following the vaccination were also noted. Additionally, the wheal durations were noted and those less than an hour were defined as short attacks while the ones between 1 and 24 hours were describes as long attacks. Besides, laboratory parameters comprising total leukocytes, absolute peripheral neutrophil counts, absolute peripheral eosinophil counts, absolute peripheral basophil counts, serum levels of basal tryptase, total IgE, high-sensitivity C-reactive protein (hs-CRP), thyroid-stimulating hormone (TSH), the positivity of anti-thyroid peroxisomal antibody (anti-TPO), anti-thyroglobulin antibody (anti-TG), and antinuclear antibodies (ANA) were retrospectively assessed from their follow-up files.
All the demographic, clinical, and laboratory features were compared between groups A and B. Additionally, the risk factors were searched for the exacerbation of CSU in the study participants.
Statistics statement
Categorical variables were summarized as frequencies and percentages, and continuous variables were defined as median with interquartile range (IQR) values or mean with standard deviation (SD) when appropriate. To compare the continuous variables for the data of two groups, two-tailed t and Mann–Whitney U tests were used where appropriate. The frequencies of categorical variables were compared using the Chi-squared test and Fisher's exact test where appropriate. Dependent group analyses of the variables were performed using the Wilcoxon signed–rank test and paired sample t-test where appropriate. The risk factors for the exacerbation of CSU were determined by binary logistic regression with both univariate and multivariate analyses. The risk factors with P value < 0.25 in the univariate analysis were subsequently analysed with multivariate analysis. P values <0.05 were considered significant. All statistical analyses were done using IBM SPSS Statistics for Windows, Version 24.0. (IBM Corp., Armonk, NY: USA).
| Results | | |
Demographic and clinical characteristics of patients
A total number of 90 patients were recruited into the study. More than half of the patients (n = 54, 60%) were women and mean age was 38.13 ± 13.85 years. Fourteen (15.5%) of them had a progression in the disease activity. Out of the 90 subjects, 27 (30%) were vaccinated with only one dose and 63 (70%) with two doses of BNT162b2 vaccine. Ten (11.1%) out of 90 patients had an urticarial reactivation after the first dose (P = 0.004) while 5 (7.9%) of 63 patients experienced such a reactivation after the second dose (P > 0.05) [Table 1]. In one subject, the disease progressed from mild to moderate following the first dose and from moderate to severe after the second dose. One subject had an urticarial attack 30 minutes after the first dose of BNT162b2 vaccine. That patient refused to undergo allergy diagnostic work-up and took the second dose without any preventive measures which resulted in anaphylaxis (bronchospasm and generalized urticaria with angioedema).
Demographic, clinical, and laboratory data in group A and group B
The demographic, clinical. and laboratory features of groups A and B are given in [Table 2]. There was a higher frequency of the subjects having short wheal duration (<1 h) in group A than in B (P = 0.018). The rate of adverse reactions within 48 hours such as hives and local injection site reactions were significantly higher in group A than in B (P = 0.004, P < 0.001, P = 0.001, respectively). | Table 2: Demographic, clinical, and laboratory features of the patients vaccinated with BNT162b2 vaccine
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Risk factors for exacerbation of CSU
In the univariate analysis, the short wheal duration (<1 h), the presence of an adverse reaction, and the local injection site reactions were detected as significant risk factors for urticarial reactivation after BNT162b2 vaccine (P = 0.012, P = 0.003, P = 0.001, respectively) [Table 3]. In the multivariate analysis, the short wheal duration (<1 h) was detected as a significant risk factor for the CSU exacerbation (P = 0.033) [Table 3]. | Table 3: Risk factors for the exacerbation of chronic spontaneous urticaria by BNT162b2 vaccine
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Quality of life and disease severity assessment during the follow-up
Half (50%) of the subjects in group A were under control with no disease severity at the initial evaluation whereas their urticarial activity rose to severe level with a rate of 42.9% and 66.7% after the first and second dose, respectively [Figure 1]. However, the urticarial activity in group B remained stable during the follow-up (34.2%, 34.2%, 35.3% with no disease severity; 32.9%, 32.9%, 37.3% with mild disease severity, 32.9%, 32.9%, 27.5% with moderate disease severity, respectively) [Figure 1]. There were significant differences in the disease severities between groups A and B at the second and third evaluations (both P < 0.001) whereas it was similar at the initial evaluation (P > 0.05) [Figure 1]. | Figure 1: Evaluation of the categorical disease severity during follow-up
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In all the patients, the second and third measurements of CU-Q2oL, UAS28, and MS were significantly higher (P = 0.012, P = 0.025, P = 0.005, P = 0.005, P = 0.016, P = 0.003, respectively) and UCT values were lower (P = 0.006, P = 0.012) when compared to the initial ones [Figure 2]. In group A, there was an increase in the second and third assessment scores of CU-Q2oL, UAS28, and MS (P = 0.005, P < 0.001, P = 0.001, P < 0.001, P = 0.003, P < 0.001, respectively) and a decrease was found in UCT scores (P = 0.001, P < 0.001) when compared to the initial scores [Figure 2]. However, the second and third values of CU-Q2oL, UAS28, UCT, and MS were similar to the initial scores in group B (all P > 0.05) [Figure 2]. | Figure 2: Evaluation of (a) Chronic Urticaria Quality of Life Questionnaire (b) Urticaria Activity Score over 28 days (c) Urticaria Control Test (d) Medication Scores during follow-up
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| Discussion | | |
This is a pivotal study that prospectively evaluated the effects of the BNT162b2 vaccine on the short-term clinical course of CSU, and about 15.5% of CSU patients in this study were clinically affected by this vaccine in terms of disease activity. These effects may be self-limited in the long-term period, as previously shown in adverse cutaneous reactions related to COVID-19 vaccines, but the long-term follow-up can be informative on how long these effects of BNT162b2 vaccine persist in CSU patients.
In Turkey, the vaccinations against SARS-CoV-2 started with an inactivated virus vaccine (CoronaVac, developed by Sinovac Life Sciences in China). Due to the limited numbers of the first imported vaccine, priority was given to healthcare workers and the elderly, which was followed by other professions and age groups. A few months later, with the approval of BNT162b2 vaccine, the vaccinations continued with the same or a different type of vaccine. Consequently, COVID-19 vaccinations continued with a predominance of BNT162b2 vaccine.
Previously, two clinically well-controlled CSU patients were reported to have experienced a triggered urticarial activation after another mRNA COVID-19 vaccine (Moderna).[10] In another case report, a 20-year-old male patient who developed CSU after receiving the second dose of BNT162b2 vaccine was presented.[11] Also, 27 relapsed and 32 new-onset CSU patients within three months after BNT162b2 vaccination were retrospectively assessed.[16] As the mechanism of CSU, autoimmune processes are generally accepted. Autoantibodies directed against the mast cells high affinity receptor Fc-epsilon-RI and/or IgE have been found in up to 40% of patients with CSU.[17] However, at the moment, we can only speculate about the possible mechanisms of exacerbations of urticaria in CSU patients after COVID-19 vaccines. The immunological effects of the vaccination itself may have triggered an underlying autoimmune mechanism. Another issue is that inactive ingredients (e.g., polyethylene glycol [PEG)]) may have induced such an exacerbation. Segal and Shoenfeld[18] suggested that vaccines may cause autoimmune diseases through immune cross-reactivity caused by molecular mimicry in susceptible patients. Based on this approach, Magen et al.[19] demonstrated a temporal association between different vaccines and CSU in their 14 patients. In accordance with Segal and Shoenfeld's theory, potential antigenic cross-reactivity between SARS-CoV-2 and human tissue was proposed by Vojdani and Kharrazian.[20] Sharing similar concerns, Talotta postulated that besides the mechanism of molecular mimicry, mRNA vaccines may give rise to a cascade of immunological events eventually leading to the aberrant activation of the innate and acquired immune system.[21] Furthermore, the author suggested that young and female patients who are already affected or predisposed to autoimmune or autoinflammatory disorders should be carefully evaluated for the benefits and risks of mRNA vaccinations.[21] Similarly, a recent study showed that the vaccination with BNT162b2 was seen as a triggering factor for CSU in subjects with allergic diseases and/or predisposed autoimmunity.[16] In light of these observations, the exacerbation of CSU in the present study participants may be caused by an immune cross-reactivity between the vaccine and human proteins.
The most common cutaneous reactions were reported as injection site reactions and urticaria after mRNA-based COVID-19 vaccines.[22] In another study, delayed local reactions, injection-site reactions, and urticarial eruptions were detected as the most common adverse cutaneous symptoms after mRNA-based vaccines.[23] Cutaneous manifestations due to COVID-19 vaccines seem very heterogeneous (local injection site reactions, urticarial rashes, angioedema, herpes zoster, morbilliform/maculopapular/erythematous macular eruption, pityriasis rosea, and pityriasis rosea-like eruptions). However, they are rather self-limited and not life-threatening.[24] In the present study, the most common adverse reactions were as follows: local injection site reactions (n = 11, 12.2%), fatigue (n = 10, 11.1%), muscle-joint pain (n = 9, 10%), fever (n = 5, 5.5%), and hives (n = 4, 4.4%). In accordance with the previous studies, almost all the adverse reactions were mild. Only one case experienced anaphylaxis within a minute after the second injection of BNT162b2. That case had a history of incompatibility with cosmetic products and an HSR to tomato and chili pepper. An IgE-mediated allergic reaction to PEG may have elicited the anaphylaxis. An allergy diagnostic workup for those having a rapid HSR history with various drugs (antibiotics, analgesics, laxatives, and cough medicines) and cosmetics is recommended before the administration of COVID-19 vaccines containing PEG.[25]
Some limitations exist in this study. First, the numbers of CSU patients unvaccinated and vaccinated with CoronaVac were relatively small to create control groups to compare with the subjects vaccinated with BNT162b2 vaccine. Thus, the subjects whose urticarial disease severity remained the same during the preceding three months were recruited in the study. Second, the symptoms of some patients may have been triggered by the fear of vaccine side effects and a placebo group would have been helpful to differentiate those subjects. However, it was not possible to create a placebo group due to the vital necessity of COVID-19 vaccines.
In conclusion, the present study demonstrated that BNT162b2 vaccine triggered CSU disease activity in about 15.5% of CSU patients in the short-term period following the vaccination. The long-term effects of this vaccine on the clinical course of CSU warrant further follow-up studies.
Acknowledgements
We would like to thank Prof. Dr. Suna Büyüköztürk for reviewing the manuscript and the patients for participating in this study.
Ethics statement
This study received permission from the Turkish Ministry of Health, and the ethical approval was obtained from the Ethics Committee of Batman Training and Research Hospital (Approval no: 279, date: 08. October. 2021). All patients gave written and informed consent.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3] |
