Exacerbations follow COVID-19 vaccination in minority of patients with chronic urticaria
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Key takeaways:
- 9% of patients experienced an exacerbation after vaccination.
- Exacerbations most often started within 48 hours of vaccination.
- Most exacerbations were treated with antihistamines.
A minority of patients with chronic urticaria experienced exacerbations after COVID-19 vaccination, with rare systemic reactions, according to a study published in The Journal of Allergy and Clinical Immunology.
Also, the frequency of these common patient-reported adverse events did not exceed frequencies seen in clinical trials, Emek Kocatürk, MD, associate professor, Urticaria Center of Reference and Excellence (UCARE), department of dermatology, Koç University School of Medicine, and colleagues wrote.
The international, multicenter, observational COVID-CU study comprised 2,769 adults (median age, 43.7 years; 71.7% women) with chronic urticaria (CU) treated at 50 member centers of the UCARE network in 26 countries between August 2021 and March 2022.
These patients included 70.9% with chronic spontaneous urticaria (CSU), 12.2% with chronic inducible urticaria (CIndU) and 16.9% with both. Also, 90% had received at least two doses of a COVID-19 vaccine, most commonly Pfizer-BioNTech (BNT162b2) or Oxford/AstraZeneca.
Complete control of CU ranged from 54.8% before the first vaccination to 61.5% before the fourth vaccination. Also, 84.2% to 100% of patients were receiving treatment for urticaria before all vaccine doses.
Treatments while receiving the first dose of the vaccine included second-generation antihistamines (n = 1,707; 61.7%), omalizumab (Xolair; Genentech, Novartis; n = 924; 33.4%), cyclosporine A (n = 40; 1.4%) and glucocorticosteroids (n = 78; 2.8%).
With 5,877 administered vaccine doses overall, 456 patients had 527 exacerbations (9%), with 8% experiencing exacerbations after the first dose, 9.6% after the second dose and 11% after the third dose. No patients had any exacerbations after the fourth dose.
Also, 312 of the patients with exacerbations (68.4%) only had wheals, 104 (22.8%) had wheals and angioedema, and 25 (5.5%) only had angioedema, with 261 exacerbations (59.2%) happening within 48 hours and 79 (17.9%) within 6 hours of vaccination.
Exacerbation rates also included 9.6% for patients who did not use any premedication and who are not on omalizumab or glucocorticosteroids and 13.6% for all other patients (P < .001).
Before the first dose, 56.4% expressed slight to extreme concerns about vaccination, with 47% concerned before the second dose, 35.5% before the third dose and 20% before the fourth dose. Also, 79.5% of those who were concerned before the first dose got two or more doses, compared with 93.2% of those who were not concerned (P < .001).
Patients who received adenovirus viral vector (AVV) vaccines had a 13.7% exacerbation rate after the first dose, whereas those who received inactivated viral vaccines (IVV) had an 8% exacerbation rate (P = .003). Additionally, patients who received mRNA vaccines had a 7% exacerbation rate (P < .001 compared with AVV vaccines).
The onset of exacerbations occurred within a week or less of vaccination for 21.2% of the patients who received an AVV vaccine, 20.4% of those who got an IVV vaccine and 29.5% of patients with an mRNA vaccine, which the researchers called similar.
Exacerbation durations included a maximum of a few days for 46% of the patients, 24.3% who experienced exacerbations for a few weeks and 22.9% who had exacerbations for a few months.
By type of vaccine, exacerbations lasted a few days or less for 62.5% of the patients with AVV vaccines, 55.3% for those with IVV vaccines and 48.6% of those with mRNA vaccines. Similarly, they lasted for a few months for 14.9% for those with AVV vaccines, 9.4% for those with IVV vaccines and 22.2% of those with mRNA vaccines.
Treatments for exacerbations included second-generation antihistamines (70.2%) and systemic glucocorticosteroids (13.4%), whereas 10% of patients did not get treatment for their exacerbations.
Among the 223 patients who had an exacerbation after a first vaccine dose, 73% (n = 163) got one or more following doses, with 53.4% of them (n = 87) experiencing an exacerbation after a second dose. Among the 2,282 patients who did not have an exacerbation with a first dose, 140 (5.5%) had one with a second dose.
There also were 55 patients (9.8%) who did not have an exacerbation with their first or second dose but who did have one with their third dose.
Further, 11.6% of patients who developed fever with vaccination and 7.2% of those who did not had exacerbations (P < .001). Exacerbations also occurred among 11.3% of those with fatigue and 7.3% of those who did not have fatigue (P = .002), 11.4% of those with muscle pain and 7.3% of those without it (P = .002), 15.3% of those with and 7.5% of those without joint pain (P < .001) and 13.6% of those with headache and 7.1% of those who did not have headache (P < .001).
Using multivariable logistic regression analyses, the researchers identified six risk factors for vaccine-induced exacerbations, including:
- female sex (adjusted OR = 1.9; 95% CI, 1.3-2.7);
- disease duration shorter than 24 months (aOR = 2.2; 95% CI, 1.4-3.2);
- having CSU instead of CIndU (aOR = 2.3; 95% CI, 1.3-4);
- receiving an AVV vaccine (aOR = 1.8; 95% CI, 1.3-2.7);
- NSAID/aspirin intolerance (aOR = 1.4; 95% CI, 1-2); and
- concern about vaccination (aOR = 1.7; 95% CI, 1.2-2.2).
Omalizumab treatment (aOR = 0.5; 95% CI, 0.3-0.7) and Latino or Hispanic ethnicity (aOR = 0.5; 95% CI, 0.3-0.9) reduced risks for exacerbations.
Percentages of patients reporting vaccine-related side effects included 43.5% (n = 1,124) after the first dose of a vaccine, 44.7% (n = 1,043) after the second dose, 45.4% (n = 283) after the third and 33.3% (n = 9) after dose four.
The most common reactions included local reactions in 839 patients (30.3%), fever in 527 (19%), fatigue in 532 (19.2%), muscle pain in 511 (18.5%), joint pain in 203 (7.3%) and headache in 412 (14.9%).
Seven patients with CSU reported severe allergic reactions, and four of these reactions occurred within an hour of vaccination. None of them received any adrenaline treatment. Also, four of these seven reported exacerbations.
These severe reactions were associated with a history of allergy, previous episodes of anaphylaxis and NSAID intolerance, although the researchers said these findings had limited value due to the low number of patients involved.
Noting that they did not find any links between exacerbations and makers of autoimmune CSU or atopy, the researchers said that they likely were due to immune and inflammatory responses to the vaccines.
Based on these findings, the researchers said that it was important to have CU under control before COVID-19 vaccination, since CU treatment may provide a protective effect from exacerbations and common adverse events.
Also, considering the role of vaccination concerns in exacerbation risks, the researchers recommended communication between physicians and patients about the potential for adverse events among patients with CU receiving vaccination.
Perspective
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Kimberly G. Blumenthal, MD, MSC
This is an important global study about CU and exacerbation after COVID-19 vaccines. It contains unique data and important findings.
I was surprised that just 9% had an exacerbation overall. I suspect this is because treatment for CU is effective, and most of these patients were treated for their CU at the time they received their vaccine. Exacerbation risk was close to 14% without premedication of omalizumab or steroids, but this is still pretty low.
It is important to note that while the research team included U.S. physicians, I do not believe any cases came from the U.S., and Moderna was underused as a vaccine here compared with the U.S. experience. Our experience in the U.S. with CU after COVID-19 vaccination has been different, somewhat, as the mRNA vaccines have led to the most urticaria. (This study saw an increased risk with the adenoviral vector vaccines.)
We found that most patients after mRNA vaccines did not have a history of CU, like this group that was followed, but instead got incident CU after Moderna or, to a lesser extent, Pfizer COVID-19 vaccinations. So, we think most of the COVID-19 vaccine urticaria is among those without this prior history or CU.
Current data support the risk for urticaria after mRNA vaccination at 1% to 2% per dose and that most U.S. patients with urticaria after COVID-19 vaccination do not have a history of CU. This study referenced some of our group’s papers on cutaneous reaction and urticaria after vaccination.
However, today, we can use these data immediately in patient counseling. Our patients with CIU or CSU may ask about the risk for exacerbation, and we can better communicate their risk from these findings.
For example, we can ensure our patients, especially those more newly diagnosed given the finding that less than 2 years of disease was a significant risk for exacerbation, have good disease control when they get their vaccines. We can also use these data to alleviate concerns in those who had exacerbations in the past. This study and others support that just because an exacerbation happens once does not mean there will always be one.
Patients need to be able to have accessible and interpretable information that is relevant to them. This study could help with vaccine hesitancy in individuals with CU. However, many of our patients with reactions after COVID-19 vaccination were not initially hesitant but became secondarily vaccine hesitant because of their experience with incident hives.
While communication between doctors and patients is important to combat vaccine hesitancy, in this case, it is also important to prioritize scientific discovery to fully understand who gets hives and why so we can optimally communicate with our patients.
I hope there is more research into the etiology.
Perspective
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CU is a common condition addressed by both dermatologists and allergists, and the triggers that lead to exacerbations are often unknown. Of particular clinical relevance given the COVID-19 pandemic is how often vaccinations lead to CU flares.
This study brings together an impressively diverse worldwide population to study the rate of CU exacerbation following COVID-19 vaccinations. Despite more than half of CU patients in the study expressing concerns about being vaccinated, only 9% experienced a CU flare after COVID-19 vaccination. Notably, this is a much lower rate than has been shown to occur following COVID-19 infection in a different study referenced in this paper (40%).
As a dermatologist, I have seen many chronic skin conditions worsen following both COVID-19 infection and COVID-19 vaccination. This is thought to be due to general, nonspecific immune system activation that comes along with either infection or vaccination. Supporting this hypothesis, in this study, the patients who experienced CU exacerbations following COVID-19 vaccination were more likely to also experience whole-body symptoms such as fever, fatigue and muscle/joint pain.
Overall, my experience reflects that of the authors, but it is extremely helpful for clinicians to be able to provide their patients with real-world numbers when asked how likely their CU is to flare up following COVID-19 vaccination. Future work on the relationship between COVID-19 vaccination and new-onset urticaria, as well as exacerbations of other chronic conditions, will be useful to provide further information to patients who may be hesitant to get vaccinated.
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