Natural History and Prognostic Factors of Chronic Urticaria in Children Aged < 2 Years: A Single‐Centered, Real‐World, and Retrospective Study

Abstract

Background: To date, a limited number of studies have reported on the natural course and prognostic factors of chronic urticaria (CU) among children aged < 2 years.

Objective: In this study, we delineated the characteristics and natural history of CU in children aged < 2 years, with an additional aim of identifying prognostic factors closely associated with CU.

Methods: This study included children aged < 2 years who had CU between May 2019 and June 2023. The clinical data and laboratory results of these children were retrieved from their medical records or through telephone interviews.

Results: The study population comprised 111 children with a median age of 16.30 (0.3–24) months at onset. Remission rates at 6, 12, and 36 months after the onset of CU were 36.08%, 51.55%, and 77.32%, respectively. After the sex and age at onset were adjusted, multivariate regression analysis revealed that allergic conjunctivitis was a risk factor for CU (OR_adjusted = 5.14 [95% CI, 1.03–28.52]).

Conclusion: The course of CU in children aged < 2 years is relatively short, with most children having a favorable outcome. Allergic conjunctivitis serves as a risk factor for CU in this age group.

1. Introduction

Chronic urticaria (CU) is characterized by the presence of wheals, angioedema, or both for more than 6 weeks. The symptoms may occur daily or nearly daily or exhibit an intermittent or recurring pattern [1]. With an estimated prevalence of 0.5%–5% in the general population, CU affects 0.1%–1.0% of children [2–4]. Although epidemiological data on CU in children are limited, the condition tends to be less prevalent among them owing to their immature immune system [5, 6].

CU is classified as chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). CIndU encompasses a wide range of conditions such as symptomatic dermographism, delayed-pressure urticaria, cold urticaria, solar and heat urticaria, vibratory angioedema, contact urticaria, cholinergic urticaria, and aquagenic urticaria. The etiological factors of CSU remain unknown; however, certain triggers have been reported in previous studies [1].

Urticaria in infants may lead to considerable anxiety in parents, particularly when the trigger remains unidentified. Persistence of symptoms may raise concerns regarding an underlying systemic illness, which may pose a risk to the health of infants. Additionally, parents may be worried regarding the safety of medication use, especially if the condition of infants does not improve despite treatment [7, 8].

Most guidelines for CU in children are primarily based on limited evidence pertaining to the pediatric population. Moreover, existing recommendations for the treatment of first CU in infancy present as a distinct and complex condition compared to adults. To date, only a few studies have reported on urticaria in children aged < 2 years. Therefore, this retrospective study aimed to investigate the natural history of CU in children aged < 2 years and identify prognostic factors for predicting the time to remission.

2. Methods

2.1. Patients and Study Design

This study was conducted in the urticaria specialty outpatient clinic in the Department of Dermatology, Shanghai Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine. Children aged < 2 years who developed CU between May 2019 and June 2023 were enrolled. The follow-up duration was at least 6 months for each patient. The study protocol was approved by the institutional review board of Shanghai Xinhua Hospital (approval #XHEC-D-2024-103), and informed consent was duly obtained from parents.

CU was defined as the persistence of wheals, angioedema, or both for more than 6 weeks. Notably, children who exhibited recurrent angioedema without wheals were excluded. At the beginning of the study, a trained member of our team recorded demographic characteristics, including sex, age at admission and onset of symptoms, comorbid allergic and chronic diseases diagnosed by doctor, family history of atopy and urticaria, precipitating factors, and duration of symptom onset at the time of admission, and clinical follow-up data of all children. All the infants with CU included in our study were diagnosed with CSU.

A treatment regimen was designed based on the guidelines established by the European Academy of Allergy and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization [1]. Initially, all children were prescribed a second-generation, nonsedating antihistamine, such as desloratadine or cetirizine, to be taken once daily (based on age-specific recommendations) for approximately 2–4 weeks. If symptoms persisted after the initial treatment, the dosage was increased to up to four times the recommended starting dose.

A follow-up questionnaire was administered to all patients either via telephone interviews with their parents, allowing for a more convenient and timely collection of data, or during consultation sessions to assess the resolution and management of CU. The questionnaire was designed to be concise yet comprehensive, encompassing important information such as the date of the last urticarial symptoms, medications administered to the children, and concomitant symptoms experienced by the children. These symptoms included gastrointestinal symptoms such as abdominal pain or cramps, diarrhea, mucus or blood in stools, anal pruritus, and vomiting and general symptoms such as lethargy, loss of appetite, fatigue, and fever. Remission was defined as the absence of urticaria for a minimum of 6 months after discontinuation of second-generation antihistamines (SG-AHs) [9].

Consenting patients underwent measurements for complete blood counts, eosinophil and basophil percentages, baseline levels of C-reactive protein (CRP), total immunoglobulin E (IgE) levels, 25-hydroxyvitamin D (25[OH]D) levels, antinuclear antibodies (ANA), complement C3 and C4 levels, thyroid function and antibody test results, and D-dimer assay.

2.2. Statistical Analysis

All collected data were comprehensively analyzed using the SPSS Statistics for Windows 22.0 software (SPSS Inc., Chicago, IL). Continuous variables were expressed as median values accompanied by their respective interquartile ranges. The prevalence rates were expressed as percentages. The Kaplan–Meier analysis was used to estimate cumulative survival rates, whereas the log-rank test was used to assess the relationship between the cumulative probability of achieving complete remission and various prognostic factors. The impact of prognostic factors on remission was initially evaluated through the univariate Cox regression analysis. Subsequently, the relative significance of multiple prognostic factors on remission was analyzed through a multivariate analysis incorporating the Cox regression model. A p value of < 0.05 was considered statistically significant.

3. Results

3.1. Characteristics of Patients

A total of 111 children who developed CU before the age of 2 years were enrolled in this study. Among these children, 97 children successfully completed the follow-up process. The demographic characteristics of the 111 patients are summarized in Table 1. A total of 62 (55.86%) patients were boys. The median age at the time of inclusion was 19.83 months (range: 3–35 months), whereas the median age at the onset of CU was 16.30 months (range: 0.3–24 months). The median duration of urticaria from onset was 14.66 months (range: 1.9–70 months), and that of urticaria before inclusion was 3.57 months (range: 1.4–18 months).

Table 1 Demographic data of patients with chronic urticaria.

Variable
Characteristics
Male (% [n/N])	55.86% (62/111)
Median age (range) (m)	19.83 (3.00∼35.00)
Median age at onset (range) (m)	16.30 (0.3∼24)
Median course at first visit (range) (m)	3.57 (1.4∼18)
Median duration of urticaria (range) (m)	14.66 (1.9–70)
Personal history of atopy (% [n/N])	57.66% (64/111)
Atopic dermatitis	41.44% (46/111)
Allergic rhinitis	24.32% (27/111)
Asthma	17.12% (19/111)
Allergic conjunctivitis	6.31% (7/111)
Developmental abnormalities (% [n/N])	22.52% (25/111)
Family history of atopy (% [n/N])	56.70% (55/97)
Family history of CU (% [n/N])	14.43% (14/97)
Family history of AU (% [n/N])	13.40% (13/97)
Autoimmune diseases (% [n/N])	1.80% (2/111)
Influencing factors during the course (% [n/N])	35.05% (34/97)
Infections	9.28% (9/97)
Vaccines	7.22% (7/97)
Season	7.22% (7/97)
Food	7.22% (7/97)
Heat	6.19% (6/97)
Inhalation	1.03% (1/97)
Exercise	2.06% (2/97)
Insect bites	1.03% (1/97)

During the follow-up, parents of some patients reported certain factors that triggered or exacerbated urticaria, including infection (9.28%, 9/97), vaccination (7.22%, 7/97), seasons (7.22%, 7/97), food (7.22%, 7/97), heat (6.19%, 6/97), inhalation (1.03%, 1/97), exercise (2.06%, 2/97), and insect bites (1.03%, 1/97) (Table 1).

3.2. Comorbidities

Regarding comorbidities, 64 patients (57.66%) had a personal history of atopy (Table 1). The most common allergic disease was atopic dermatitis (AD) (41.44%), followed by allergic rhinitis (24.3%), asthma (17.12%), and allergic conjunctivitis (AC) (6.31%). Only two patients were diagnosed with comorbid autoimmune diseases, with one patient having juvenile rheumatoid arthritis and the other having thyroid dysfunction. A total of 25 children were found to have unrelated developmental abnormalities (Table 1). A total of 55 patients (56.70%) had a family history of allergic diseases, with 14 (14.43%) and 13 (13.40%) patients having a family history of CU and acute urticaria (AU) history, respectively (Table 1).

3.3. Laboratory Analysis

Of the 97 patients, 58 (59.79%) patients consented to provide blood samples. Blood cell count showed that 14 (24.14%) patients exhibited elevated white blood cell (WBC) counts, whereas none of the patients had elevated eosinophil counts. Moreover, basophil counts were undetectable in two (3.45%) patients. Of the 39 patients tested, 13 (33.33%) patients had elevated IgE levels (range: 100–401 IU/mL). Of the 34 patients tested, none exhibited a decrease in the concentration of 25-OH vitamin D. Thyroid antibodies were present in five patients, with four patients having elevated thyroid peroxidase antibody (TPO-Ab) levels and one patient having elevated thyroid-stimulating hormone receptor antibody (Tr-Ab) levels. In addition, one patient tested positive for ANA, and four patients had low levels of C3. Of the four patients tested, three patients had increased D-dimer levels (Table 2).

Table 2 Laboratory parameters of patients with chronic urticaria.

Laboratory parameters (% [n/N])
Elevated WBC	24.14 (14/58)
Elevated EOS	0.00 (0/58)
Basophiles absent	3.45 (2/58)
Elevated IgE	33.33 (13/39)
Low 25-OH vitamin D	0.00 (0/34)
Elevated TPO-Ab	13.33 (4/30)
Elevated Tg-Ab	0.00 (0/30)
Elevated Tr-Ab	4.17 (1/24)
ANA positive	4.35 (1/23)
Low C3	22.22 (4/18)
Elevated D-Dimer	75 (3/4)

3.4. Natural Course and Predictors of CU

A total of 97 patients successfully completed the follow-up and were consequently included in the prognostic analysis (Figure 1). The average duration of follow-up was 31.43 months (range: 6–51 months). Notably, the overall remission rate of patients with CU in this study was 77.32%. According to the Kaplan–Meier survival analysis, remission rates at 6, 12, 24, and 36 months after the onset of symptoms were 36.08%, 51.55%, 73.20%, and 77.32%, respectively. No significant sex differences were observed in the overall remission rate.

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Univariate and multivariate logistic regression analyses were performed to identify risk factors for CU. After the sex and age at onset were adjusted, the multivariate analysis showed that AC was a significant risk factor for CU (adjusted OR = 5.14 [95% CI, 1.03–28.52]).

3.5. Management

Before they visited the outpatient clinic, five patients had orally taken first-generation antihistamines (FG-AHs). Subsequently, upon consultation, all patients were prescribed SG-AHs. A standard dose of SG-AHs effectively controlled the symptoms of CU in 88.29% of the patients. A total of 9.91% of the patients required a double dose, whereas 1.80% of the patients required a four-time highest dose. A total of 10 patients (9.01%) were administered two SG-AHs or more, whereas only two patients (1.80%) were administered systemic corticosteroids for managing acute exacerbations. During the treatment, four patients showed symptoms of lethargy, while one patient exhibited excessive crying. All these symptoms improved after discontinuation of the medication. One patient developed transient proteinuria during the medication period. Among patients with complete remission, the average treatment duration was 6.2 (0.1–24) months and the average course of the disease was 10.3 (1.5–38) months. Of the patients, 44.0% gradually reduced their dosage of SG-AHs until they stopped using it, while the rest chose to stop using it suddenly. Patients who continued to experience urticaria had an average treatment duration of 25.9 (3–70) months and a mean disease duration of 29.9 (12–70) months. Among patients with persistent CU, a total of 63.6% regularly took SG-AHs, 31.8% took them as required, and 4.5% discontinued the medication despite their condition remaining uncontrolled (Table 3).

Table 3 Treatments and prognosis of patients with CU.

Treatments (% [n/N])
First-generation antihistamine	4.50 (5/111)
Second-generation antihistamine at approved doses	1.00 (111/111)
Combination two kinds of sgAHs	9.01 (10/111)
Updosing of sgAH	11.71 (13/111)
Double doses of sgAH	9.91 (11/111)
Quadruple doses of sgAH	1.80 (2/111)
Oral steroids	2.06 (2/97)
Side effects during treatment with sgAH (% [n/N])	6.19 (6/97)
Lethargy	4.12 (4/97)
Crying	1.03 (1/97)
Proteinuria	1.03 (1/97)
Prognosis
Complete remission of CU (% [n/N])	77.32 (75/97)
Median course of treatment (range) (m)	6.2 (0.1∼24)
Median course of disease (range) (m)	10.3 (1.5∼38)
Gradually reduced dosage of SG-AH (% [n/N])	44.0 (33/75)
Persistence of CU (% [n/N])	22.7 (22/97)
Median course of treatment (range) (m)	25.9 (3∼70)
Median course of disease (range) (m)	29.9 (12∼70)
Regular oral SG-AH at present (% [n/N])	63.6 (14/22)
Irreguar oral SG-AH at present (% [n/N])	31.8 (7/22)
Discontinue medication (% [n/N])	4.5 (1/22)

4. Discussion

In this study, we investigated the characteristics and natural progression of CU in children aged < 2 years. A male preponderance was observed in CU cases. The prognostic analysis showed that the overall remission rate of patients with CU was 77.32%, with approximately half of the patients achieving remission within 1 year. In addition, AC was identified as a major factor influencing the prognosis of CU.

The correlation between CU and atopy remains unclear. A study suggested that children who were diagnosed with AD in their early life were at a higher risk of developing CSU later in life [10]. However, in this study, AC was positively associated with CU. Previous studies have showed that the prevalence of atopy, characterized by a positive skin test result or a history of allergic disorders, ranges from 16.7% to 33.7% among children aged 0–18 years who have CU [9, 11, 12]. In this study, the incidence of concomitant allergic diseases was significantly higher in patients with CU, accounting for 57.7% of the patient population. This discrepancy may be attributed to the varying characteristics of the study cohorts, particularly considering that the patients included in this study were younger. Furthermore, a study reported that 40.9% and 14.8% of the participants had a family history of allergic diseases and CU, respectively [13]. In this study, the proportion of patients with a family history of atopy (56.7%) was higher than that in a previous study (30.4%) [11], and the proportion of patients with a family history of CU (14.4%) was similar to that in another previous study (14.8%) [13]. In both adults and children, CU has been associated with autoimmune disorders, accompanied by an increase in the levels of autoimmune markers, including rheumatoid factor and ANA [14–16]. In this study, autoimmune diseases were diagnosed in two patients, and thyroid antibodies were present in five patients. Additionally, one patient tested positive for ANA and four patients had low C3 levels, indicating potential thyroid dysfunction or immune-related disorders. Infections are common in children and are widely acknowledged as pathogenic factors responsible for up to 80% of AU cases [17]. As reported in the studies focusing on adult CU, D-dimer emerges as one of the robust predictors for a poor or no response to SG-AHs [14, 18]. Of the four patients tested for D-dimer in our study, three showed elevated D-dimer levels, and two of the three patients used double doses of SG-AHs. This suggests that D-dimer may also need to be tested in the pediatric CU population and may be a factor in poor response to antihistamine treatment. The prevalence of infections related to CU has been reported by Yilmaz et al. and Netchiporouk et al. [9, 16]. In this study, the most common factor that triggered or aggravated urticaria was infection, followed by vaccines, seasons (mostly in summer), and food.

The natural course of CU in the pediatric population has been examined in several studies. A prospective study conducted by Chansakulporn showed that remission rates at 1, 3, and 5 years after the onset of CU were 18.5%, 54%, and 67.7%, respectively, in 92 children (range: 4–15 years) with CU [11]. Du Toit et al. reported that 25% of children (range: 1.25–19 years) with CU achieved remission within 3 years [19]. Sahiner et al. conducted a retrospective study involving 100 children (range: 0.7–17.2 years) with CSU for a follow-up period of 8 years and revealed that remission rates at 1, 3, and 5 years after the onset of CSU were 16.5%, 38.8%, and 50.0%, respectively [20]. In this study, remission rates were significantly higher in children with CSU, with 51.55% and 77.32% of the children achieving remission after 1 and 3 years of symptom onset. These rates are considerably higher than those reported in several other previous studies but are comparable to those reported in a study by Park et al. (33.4%, 53.0%, and 71.2% at 6, 12, and 24 months, respectively, among children aged 2.5–9.1 years) [21]. Inconsistencies in the natural history of CU among studies may be attributed to differences in the age ranges of the children involved, the definitions used to categorize the disease and remission criteria, and the duration of follow-up. Notably, younger children tend to have a more favorable prognosis [20–22]. Our results indicate that a single dose of SG-AHs is adequate to manage the condition in the majority of childhood (< 2 years) CU cases, with little need for additional treatments such as omalizumab or immunosuppressive agents. This finding differs significantly from observations in adult patients, as the research by Curto-Barredo et al. reveals that while 31.8% of CSU patients achieved complete control with standard dosages of SG-AHs, a notable 33.7% still required an increased dose to effectively manage their symptoms [23].

Altogether, this study revealed a significant higher remission rate of CU in children aged < 2 years. In addition, AC was identified as a major risk factor for CU. In-depth studies determining the mechanisms responsible for these associations should be conducted to improve the understanding of the pathogenesis of CU and develop effective management strategies accordingly.

Despite important findings, this study has several limitations that should be acknowledged. First, as the study was conducted in a single tertiary center, there may exist selection bias. Second, owing to the retrospective nature of the study, the remission status and triggering factors of some patients were determined through telephone interviews, which might have introduced a degree of uncertainty. Additionally, recall bias could also be present. Although we used structured questionnaires to minimize this bias, future studies should incorporate clinical follow-ups or objective measures to further enhance data reliability. Third, another limitation was the lack of adjustment for multiple comparisons, particularly in the analysis of comorbidities and laboratory markers. However, it is important to note that this study was primarily exploratory in nature. As such, our main objective was to identify potential associations and patterns, rather than to confirm prespecified hypotheses. Lastly, owing to the young age of the patients, the sample size for laboratory examination was small, and provocation tests were not performed.

Data Availability Statement

The data that support the findings of this study are openly available in Mendeley data ().

Ethics Statement

This study was reviewed and approved by the institutional review board of Shanghai Xinhua Hospital; approval #XHEC-D-2024-103.

Consent

Consent for the publication of recognizable patient photographs or other identifiable material was obtained by the authors and included at the time of article submission to the journal stating that all patients gave consent with the understanding that this information may be publicly available.

Conflicts of Interest

The authors declare no conflicts of interest.

Author Contributions

Chun-Xiao Li, Hua-Guo Li, and Bei-Bei Zhang contributed equally to this work.

Funding

This work was supported by the following grants: Chun-Xiao Li discloses support for the research of this work from the National Nature Science Foundation of China (grant number 81903190) and Hospital Funded Clinical Research, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (grant number 24XHCR09C). Yi-Feng Guo discloses support for publication of this work from the National Nature Science Foundation of China (grant number 82373490). Hui Zhang discloses support for publication of this work from the National Nature Science Foundation of China (grant number 82173413). This work was supported by The Clinical Research Plan of SHDC (grant number SHDC22022302).

Acknowledgments

We thank Yun Huang (Ministry of Education—Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine) for statistical analysis.

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