Safety of COVID-19 mRNA vaccination in children with chronic urticaria.

Clinical ImplicationsData on the safety of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine in children with chronic urticaria are sparse. Our findings suggest a low risk of allergic reaction and flare-ups of urticaria that attests to the safety of the COVID-19 vaccine in this population. Data on the safety of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine in children with chronic urticaria are sparse. Our findings suggest a low risk of allergic reaction and flare-ups of urticaria that attests to the safety of the COVID-19 vaccine in this population. Chronic urticaria (CU) is a mast cell–driven disease with a global point prevalence of approximately 1%, which can be subcategorized into spontaneous (CSU) and inducible (CIndU) forms.1Zuberbier T. Abdul Latiff A.H. Abuzakouk M. Aquilina S. Asero R. Baker D. et al.The international EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.Allergy. 2022; 77: 734-766Crossref PubMed Scopus (190) Google Scholar Children with CU may be more at risk of adverse reactions to the Pfizer-BioNTech BNT162b2 COVID-19 vaccine (hereafter referred to as BNT162b2) because atopy is a risk factor for postvaccination hypersensitivities (urticaria, angioedema, and anaphylaxis).2Alhumaid S. Al Mutair A. Al Alawi Z. Rabaan A.A. Tirupathi R. Alomari M.A. et al.Anaphylactic and nonanaphylactic reactions to SARS-CoV-2 vaccines: a systematic review and meta-analysis.Allergy Asthma Clin Immunol. 2021; 17: 109Crossref PubMed Scopus (26) Google Scholar Case series of adults have reported relapsed CSU following long-term remission after BNT162b2.3de Montjoye L. Herman A. Baeck M. Chronic spontaneous urticaria following COVID-19 vaccination.JAAD Case Rep. 2022; 25: 35-38Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar However, there is a paucity of safety data in children, which may contribute to vaccine hesitancy. Therefore, we assessed the safety of BNT162b2 among children with CU. From December 2021 to March 2022, we contacted families with children aged 5 to 18 years from a previously established registry4Netchiporouk E. Sasseville D. Moreau L. Habel Y. Rahme E. Ben-Shoshan M. Evaluating comorbidities, natural history, and predictors of early resolution in a cohort of children with chronic urticaria.JAMA Dermatol. 2017; 153: 1236-1242Crossref PubMed Scopus (48) Google Scholar of children with CU recruited from 3 allergy clinics in Montreal, Canada, and from the Sheba Medical Center in Israel. CU was defined as wheals, angioedema, or both lasting ≥6 weeks.1Zuberbier T. Abdul Latiff A.H. Abuzakouk M. Aquilina S. Asero R. Baker D. et al.The international EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.Allergy. 2022; 77: 734-766Crossref PubMed Scopus (190) Google Scholar All children with CU (vaccinated or not) who were reachable by phone and consented to participate in the study were included in the analysis. Institutional review board approval was received from the respective institutions. Data were collected at study entry with a questionnaire on demographics, comorbidities, and CU management. In addition, urticaria control test and weekly urticaria activity score (UAS7)5Gabrielli S. Mule P. Prosty C. Gooding G. Le M. Zhang L. et al.Validation of UAS7 among children with chronic spontaneous urticaria.J Allergy Clin Immunol Pract. 2022; 10: 1927-1929.e1Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar were obtained during the initial visit and at follow-up. Our standardized COVID-19 questionnaire queried on BNT162b2 vaccination status and on the postvaccination development of urticaria/angioedema, respiratory or gastrointestinal symptoms, or anaphylaxis (defined as a reaction involving at least 2 systems and/or hypotension6Sampson H.A. Munoz-Furlong A. Campbell R.L. Adkinson Jr., N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.Ann Emerg Med. 2006; 47: 373-380Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar). An additional questionnaire was given to participants infected with COVID-19 to assess their symptoms. Analyses were performed using R. The association of common postvaccination symptoms with first and second BNT162b2 vaccination visits was analyzed via generalized estimating equation logistic regression using the R package geepack. Multivariate logistical regression was used to assess factors associated with vaccine hesitancy. Demographic data were compared by the Mann-Whitney U test for continuous variables and the χ2 test for categorical variables. A total of 101 children (90% from Canada and 10% from Israel) were included in the study, 50 (50%) were male, and their median age was 13.0 (interquartile range: 9.3-15.0). A total of 76 (75%) children had isolated CSU (defined CSU, without concomitant CIndU), 14 (14%) had isolated CIndU, and 11 (11%) had concurrent CSU and CIndU (Table I).Table IPatient demographics, comorbidities, type of CU, and management of CUFirst doseSecond doseUnvaccinated childrenCohort of all patients with CUPopulationCanada (N = 66)Israel (N = 8)Total (N = 74)Canada (N = 48)Israel (N = 8)Total (N = 56)Canada (N = 25)Israel (N = 2)Total (N = 27)Canada (N = 91)Israel (N = 10)Total (N = 101)Sex: male, n (%)33 (50)2 (25)35 (47)25 (52)2 (20)27 (48)15 (60)1 (50)16 (59)48 (53)2 (20)50 (50)Age at vaccination (y), median (IQR)14.0 (10.0-16.0)13.5 (11.3-14.8)14.0 (10.3-16.0)14.0 (13.0-16.0)13.5 (11.3-14.8)14.0 (13.0-16.0)10.0 (7.0-12.0)12 (9.5-14.5)10 (7.0--12.5)13 (9-15)13.5 (11.3-16.3)13 (9.3-15.0)Age at CU onset (y), median (IQR)7.0 (4.0-10.0)11.0 (10.8-13.0)8.0 (4.0-11.0)8.5 (5.3-12)11 (10.8-13)9 (6-12.8)4 (2.3-5.8)11 (8.5-13.5)4 (2.8-6.3)5.5 (3.4-9.3)11 (10.3-13.0)6 (3.5-10.8)Type of CU, n (%) Pure CSU51 (77)5 (62)56 (76)37 (77)5 (63)42 (75)19 (76)1 (50)20 (74)70 (77)6 (60)76 (75) Pure CIndU9 (14)2 (25)11 (15)8 (17)2 (25)10 (18)2 (8)1 (50)3 (11)11 (12)3 (30)14 (14) Cold urticaria10 (15)0 (0)10 (14)9 (19)0 (0)9 (16)2 (8)0 (0)2 (7)12 (13)0 (0)12 (12) Cholinergic urticaria3 (5)2 (25)5 (7)2 (4)2 (25)4 (7)1 (4)1 (50)2 (7)4 (4)3 (30)7 (7) Delayed pressure urticaria1 (2)0 (0)1 (1)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)1 (1)0 (0)1 (1) Solar urticaria0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)1 (4)0 (0)1 (4)1 (1)0 (0)1 (1) Uncategorized CIndU1 (2)0 (0)1 (1)0 (0)0 (0)0 (0)2 (8)0 (0)2 (7)3 (3)0 (0)3 (3) Concomitant CSU and CIndU6 (9)1 (12)7 (10)3 (6)1 (13)4 (7)4 (16)0 (0)4 (15)10 (11)1 (10)11 (11)Atopic comorbidities, n (%) Asthma∗Data were not collected for Israeli patients.8 (12)NCNA7 (15)NCNA3 (12)NCNA11 (12)NCNA Hay fever (allergic rhinitis)∗Data were not collected for Israeli patients.4 (6)NCNA3 (6)NCNA0 (0)NCNA5 (5)NCNA Atopic dermatitis∗Data were not collected for Israeli patients.11 (17)NCNA7 (15)NCNA4 (16)NCNA15 (17)NCNA Food allergy6 (9)0 (0)6 (8)4 (8)0 (0)4 (7)1 (4)0 (0)1 (4)7 (8)0 (0)7 (7) Venom allergy1 (2)0 (0)1 (1)1 (2)0 (0)1 (2)0 (0)0 (0)0 (0)1 (1)0 (0)1 (1) Environmental allergens2 (3)0 (0)2 (3)2 (4)0 (0)2 (4)0 (0)0 (0)0 (0)2 (2)0 (0)2 (2)Second-generation antihistamine∗Data were not collected for Israeli patients., n (%) Standard dose38 (58)NCNA27 (56)NCNA0 (0)NCNA1 (1)NCNA Two times21 (32)NCNA17 (35)NCNA11 (44)NCNA51 (56)NCNA Three times1 (2)NCNA1 (2)NCNA14 (56)NCNA30 (33)NCNA Four times2 (3)NCNA2 (4)NCNA0 (0)NCNA1 (1)NCNANonspecified or no treatment∗Data were not collected for Israeli patients.3 (5)NCNA1 (2)NCNA0 (0)NCNA2 (2)NCNAMost recent UAS7, median (IQR) for CSU patients∗Data were not collected for Israeli patients.4.3 (0.8-9.2)NCNA4.8 (1.7-9.1)NCNA5.0 (0.7-16.0)NCNA4.0 (0.6-9.4)NCNAMost recent UCT score, median (IQR) for CIndU patients∗Data were not collected for Israeli patients.13.0 (10.0-14.3)NCNA12.5 (8.0-14.8)NCNA12.0NCNA13.0 (9.0-14.5)NCNAEducation of caregiver, n (%) High school5 (8)0 (0)5 (7)3 (6)0 (0)3 (5)1 (4)1 (50)2 (7)6 (8)1 (10)7 (7) College15 (23)0 (0)15 (20)15 (31)0 (0)15 (27)4 (16)0 (0)4 (15)19 (21)0 (0)19 (19) University37 (56)4 (50)41 (55)25 (52)4 (50)29 (46)15 (60)0 (0)15 (56)53 (58)4 (40)57 (56) Nondisclosed9 (14)4 (50)13 (18)5 (10)4 (50)9 (16)5 (20)1 (50)6 (22)13 (14)5 (50)18 (18)CIndU, Chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; IQR, interquartile range; NA, not applicable; NC, not collected; UAS7, weekly urticaria activity score; UCT, urticaria control test.∗ Data were not collected for Israeli patients. Open table in a new tab CIndU, Chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; IQR, interquartile range; NA, not applicable; NC, not collected; UAS7, weekly urticaria activity score; UCT, urticaria control test. Seventy-four children (73%) received the first dose of BNT162b2. After vaccination, 47 patients (64%) did not experience any symptoms, 20 (27%) patients had an injection site reaction (hereafter abbreviated as ISR, that is, erythema, soreness, and swelling), 6 patients (8%) reported flu-like symptoms (chills, fatigue, arthralgia, headache, mild fever, and myalgia), and 1 patient (1%) reported high fever (>39°C) (Table II).Table IISide effects after first and second doses of BNT162b2 vaccineFirst dose (N = 74)Second dose (N = 56)Medication intake on vaccination day, n (%) Acetaminophen4 (5)4 (7) Ibuprofen1 (1)1 (2) Antihistamine Prophylactic5 (7)∗One patient took both montelukast and prophylactic antihistamine before vaccination.4 (7)∗One patient took both montelukast and prophylactic antihistamine before vaccination. Regular medication3 (4)4 (7) Montelukast1 (1)∗One patient took both montelukast and prophylactic antihistamine before vaccination.1 (2)∗One patient took both montelukast and prophylactic antihistamine before vaccination. Methylphenidate1 (1)0 (0) None60 (81)43 (77)N (%)Onset of symptoms (h), median (IQR)Duration of symptoms (d), median (IQR)N (%)Onset of symptoms (h), median (IQR)Duration of symptoms (d), median (IQR)Side effects, n (%) Allergic reaction Hives/urticaria0 (0)NANA0 (0)NANA Flare of current hives0 (0)NANA0 (0)NANA Swelling of face/tongue/throat0 (0)NANA0 (0)NANA Respiratory symptoms0 (0)NANA0 (0)NANA Chest discomfort or palpitations0 (0)NANA0 (0)NANA Flu-like symptoms (chills, fatigue, arthralgia, headache, mild fever, myalgia)6 (8)8.0 (10.3-16)1.5 (1.0-1.5)10 (18)8 (7.3-10.0)1.0 (1.0-1.5) Severe/high fever (>39°C)1 (1)10.01.51 (1.8)2.01.5 Injection site reaction (redness, soreness, swelling)20 (27)8.5 (4.1-12.8)1.3 (1.0-1.9)18 (32)6.25 (4.4-8.0)1 (1.0-1.5) No symptoms47 (64)NANA26 (46)NANAIQR, Interquartile range; NA, not applicable.∗ One patient took both montelukast and prophylactic antihistamine before vaccination. Open table in a new tab IQR, Interquartile range; NA, not applicable. Fifty-six children (55%) received a second dose of BNT162b2. Twenty-six (46%) patients did not report any postvaccination symptoms, 18 patients (32%) reported ISR, 10 patients (18%) reported flu-like symptoms, 1 patient (2%) reported high fever, and 1 patient (2%) reported nausea (Table II). At the time of the questionnaire, 18 children (17%) were waiting to schedule their second-dose appointment. For both the first and second BNT162b2 doses, no patients reported any allergic reaction, including exacerbations of CSU, and no patients experienced chest discomfort or palpitations. Furthermore, there was no statistically significant difference (P > .05) between the proportion of children having reported each type of side effect after the first- and second-dose vaccines (Table II). Twenty-seven children (27%) were not vaccinated (Table I). Parental education (adjusted odds ratio [aOR]: 1.03, 95% confidence interval [CI]: 0.83, 1.28), sex (aOR: 0.93, 95% CI: 0.77, 1.13), and UAS7 score (aOR: 0.99, 95% CI: 0.97, 1.00) were not associated with COVID-19 vaccination. However, vaccination was more likely among older children (aOR: 1.05, 95% CI: 1.02, 1.08). Further, children with CU were taking higher doses of second-generation antihistamine (sgAH) (>1×) in the unvaccinated/vaccine-hesitant group compared with the vaccinated group (P < .01) (Table E1, available in this article’s Online Repository at www.jaci-inpractice.org). A total of 17 patients (17%) had been infected with COVID-19, and 9 of them (53%) were unvaccinated at the time of infection. Most infected children (10, 59%) reported flu-like symptoms, and 5 (29%) children were asymptomatic. One 14-year-old patient with CSU (fully vaccinated) reported an eczema flare-up, which lasted for 12 hours and improved after the application of topical hydrocortisone (Table E2, available in this article’s Online Repository at www.jaci-inpractice.org). Our study is the first to assess the safety of BNT162b2 in pediatric patients with CU. Our findings demonstrate that children with CU are at minimal risk of suffering from an allergic reaction secondary to COVID-19 vaccination. Moreover, our results suggest that COVID-19 infection in children with CU does not precipitate a CU flare. These findings are consistent with a single-center Italian study of adults suggesting a low risk of a CU flare after vaccination.7Grieco T. Rossi A. Maddalena P. Sernicola A. Ambrosio L. Fino P. et al.COVID-19 infection and BNT162b2 vaccine triggering sarcoid-like lesions in the same patient. Response to: Sarcoid-like reaction in a patient recovering from COVID-19 pneumonia.JAAD Case Rep. 2022; 23: 162-163Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Similar to healthy pediatric populations, our CU cohort reported most adverse effects after BNT162b2 to be minor, the most common being ISR.8Walter E.B. Talaat K.R. Sabharwal C. Gurtman A. Lockart S. Paulsen G. et al.Evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age.N Engl J Med. 2022; 386: 35-46Crossref PubMed Scopus (300) Google Scholar Further, we found that children with CU taking a higher dose of sgAH were more likely to be unvaccinated, which suggests that children with a more treatment-resistant form of CU are more likely to be vaccine hesitant due to the fear of urticaria flare-up. One child who was known for a history of atopic dermatitis reported lesions speculated to be consistent with eczema after COVID-19 infection. A recent retrospective study also reported that COVID-19 is more likely to cause CU exacerbation in moderate-to-severe forms of infection.9Muntean I.A. Pintea I. Bocsan I.C. Dobrican C.T. Deleanu D. COVID-19 disease leading to chronic spontaneous urticaria exacerbation: a Romanian retrospective study.Healthcare (Basel). 2021; 9: 1144Crossref PubMed Scopus (12) Google Scholar Our study is subject to some limitations. Our study may have underestimated the risk of allergic reaction after vaccination, given that vaccinated patients in our cohort may have had less severe CU (ie, lower sgAH dose), which may be correlated negatively with reaction incidence. In addition, the low sample size reduces the likelihood of identifying anaphylaxis/adverse reactions, which are rare complications of COVID-19 vaccination in the general population but may still be more common among patients with CU. In conclusion, our study provides evidence supporting the safety of BNT162b2 vaccine in children with CU. In the future, it would be important to assess the safety of mRNA COVID-19 vaccines in children <5 years old with CU as vaccines have now been approved in that age group. Table E1Comparison of patient demographics, comorbidities, type of CU, and management of vaccinated and vaccine-hesitant childrenVaccinatedUnvaccinatedP value (95% CI)PopulationTotal (N = 74)Total (N = 27)Sex: male, n (%)35 (47.3)16 (59.3).29 (−9.6, 31.8)Age, median (IQR)14.0 (10.3–16.0)10 (7.0-12.5).0005∗Denotes statistical significance.Type of CU, n (%) Pure CSU56 (75.6)20 (74.0).86 (−15.2, 22.1) Pure CIndU11 (14.9)3 (11.1).63 (−14.3, 16.0) Cold urticaria10 (13.5)2 (7.4).40 (−10.9, 17.1) Cholinergic urticaria5 (6.8)2 (7.4).92 (−9.1, 17.0) Delayed pressure urticaria1 (1.35)0 (0.0).55 (−11.2, 7.2) Solar urticaria0 (0.0)1 (3.7).09 (−2.1, 18.3) Uncategorized CIndU1 (1.4)2 (7.4).12 (−2.0, 22.0) Concomitant CSU and CIndU7 (9.5)4 (14.8).45 (−7.2, 23.6)Atopic comorbidities, n (%) Asthma8 (12.1)†Total only includes Canadian patients because data were not collected for Israeli patients.3 (12.0)†Total only includes Canadian patients because data were not collected for Israeli patients..98 (−17.9, 12.2) Hay fever (allergic rhinitis)4 (6.1)†Total only includes Canadian patients because data were not collected for Israeli patients.0 (0.0)†Total only includes Canadian patients because data were not collected for Israeli patients..19 (−6.9, 14.0) Atopic dermatitis11 (16.7)†Total only includes Canadian patients because data were not collected for Israeli patients.4 (16.0)†Total only includes Canadian patients because data were not collected for Israeli patients..93 (−18.4, 14.5) Food allergy6 (8.12)1 (3.7).44 (−10.8, 13.4) Venom allergy1 (1.4)0 (0.0).53 (−11.1, 7.3) Environmental allergens2 (2.7)0 (0.0).39 (−9.9, 9.3)Second-generation antihistamine, n (%) Standard dose (1×)38 (57.6)†Total only includes Canadian patients because data were not collected for Israeli patients.0 (0.0)†Total only includes Canadian patients because data were not collected for Israeli patients.<.0001 (40.7, 68.2)∗Denotes statistical significance. >1× standard dose (X2, X3, X4)24 (32.4)25 (92.6)<.0001 (40.6, 71.2)∗Denotes statistical significance.Nonspecified or no treatment, n (%)3 (4.5)†Total only includes Canadian patients because data were not collected for Israeli patients.0 (0.0)†Total only includes Canadian patients because data were not collected for Israeli patients..26 (−8.2, 11.9)Education of caregiver, n (%) High school5 (6.8)2 (7.4).91 (−9.1, 17.0) College15 (20.3)4 (14.8).53 (−13.7, 19.3) University41 (55.4)15 (55.6).99 (−21.0, 20.5) Nondisclosed13 (17.6)6 (22.2).60 (−10.9, 24.4)UAS7, mean (±SD)5.3 (±7.2)8.3 (±9.9).72UCT, mean (±SD)11.5 (±4.0)12.5 (±0.81).89CIndU, Chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; IQR, interquartile range; SD, standard deviation; UAS7, weekly urticaria activity score; UCT, urticaria control test.∗ Denotes statistical significance.† Total only includes Canadian patients because data were not collected for Israeli patients. Open table in a new tab Table E2Characteristics of COVID-19 infection in CU children (N = 17/101)Variablesn (%)Sex: male9 (53)Age, median (IQR)–Type of urticaria Pure CSU11 (65) Pure chronic inducible urticaria4 (24) Cold urticaria2 (12) Cholinergic urticaria2 (12) Delayed pressure urticaria1 (6) Solar urticaria0 (0) Concomitant CSU and CIndU1 (6)Time of infection Before vaccination9 (53) Between first and second dose vaccines3 (18) After 2 doses of vaccine2 (12) Undocumented3 (18)SymptomsUnvaccinatedVaccinatedUnknownTotal Cutaneous reaction0 (0)1 (6)0 (0)1 (6) Flu-like symptoms (fever, fatigue, cough, nasal congestion, headache)5 (29)2 (12)3 (18)10 (59) Loss of taste and smell1 (6)0 (0)0 (0)1 (6) No symptoms3 (18)2 (12)0 (0)5 (29)CIndU, Chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; IQR, interquartile range; NA, not applicable. Open table in a new tab CIndU, Chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; IQR, interquartile range; SD, standard deviation; UAS7, weekly urticaria activity score; UCT, urticaria control test. CIndU, Chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; IQR, interquartile range; NA, not applicable.