ABSTRACT
Objective
Allergy is a hypersensitivity reaction triggered by various factors through immunological mechanisms. Elevated serum total immunoglobulin E (IgE) and peripheral blood eosinophil levels are commonly observed in allergic diseases; however, these biomarkers are not specific to allergy. This study aimed to evaluate the diagnostic value of serum total IgE, eosinophil, and basophil levels in predicting atopy.
Method
Atopic and non-atopic patients under 18 years of age diagnosed with atopic dermatitis, food allergy, allergic rhinitis, or asthma were compared in terms of serum total IgE levels, eosinophil, and basophil counts.
Results
A total of 673 patients including 406 (60.3%) atopic and 267 (39.7%) non-atopic cases constituted the study population. Most frequently sensitization developed to egg in atopic dermatitis, and food allergy, to tree pollens in allergic rhinitis, and to house dust mite in asthma. Elevated total IgE levels were significantly associated with atopy in patients with allergic rhinitis and asthma, with odds ratios of 3.33 and 16.37, respectively (p<0.001). The optimal predictive cut-off value of serum total IgE for atopic asthma was calculated as 108.5 kU/L, with a sensitivity of 85.6% and specificity of 76.6%. Similarly, a significant association was observed between eosinophilia and atopy in allergic rhinitis and asthma, but not in atopic dermatitis.
Conclusions
Our findings suggest that serum total IgE is a sensitive and specific biomarker for predicting atopy in patients with asthma.
INTRODUCTION
Allergy is a hypersensitivity reaction that develops through immunological mechanisms induced by various triggers. Atopic dermatitis, food allergy, allergic rhinitis, and asthma constitute the allergic march(1). Recently, an increase in the prevalence of allergic diseases has been observed worldwide(2, 3).
Although elevated total serum immunoglobulin E (IgE) levels and increased eosinophil counts in blood are frequently seen in allergic diseases, this increase is not specific to allergic conditions alone. High serum IgE levels can also be encountered in a variety of clinical entities such as parasitic infestations, infections, malignancies, and immunodeficiencies(4). On the other hand, some allergic diseases may present without elevated eosinophil or IgE levels. Unlike the Basophil Activation Test, which is highly sensitive in detecting atopic allergy, the clinical significance of absolute peripheral basophil count remains unclear(5). Therefore, studies continue to search for more definitive clues and specific diagnostic methods helpful in the diagnosis and monitoring of allergic diseases.
The objectives of this study are to determine whether serum total IgE, eosinophil, and basophil levels are elevated in patients with allergic diseases followed in a tertiary care hospital in Turkey, and also to investigate whether these laboratory parameters have diagnostic value in identifying atopy. In addition, as a secondary objective, the distribution of common allergen sensitization patterns among different allergic disease groups will also be analyzed to provide contextual information for interpreting these laboratory findings.
MATERIALS and METHODS
This retrospective, single-center, cross-sectional study was conducted at a tertiary care hospital that serves as a referral center for pediatric patients. Patients under the age of 18 with allergic symptoms who had been clinically diagnosed with atopic dermatitis, food allergy, allergic rhinitis, or asthma between January 2018 and January 2021 were included in the study if they had undergone both skin prick and allergen-specific IgE tests. The diagnoses were established according to the following guidelines: Hanifin and Rajka(6) criteria for atopic dermatitis, European Academy of Allergy and Clinical Immunology guidelines for food allergy, Allergic Rhinitis and its Impact on Asthma guidelines for alleric rhinitis and the Global Initiative For Asthma guidelines for asthma(7-9).
The medical records of the patients were reviewed retrospectively after obtaining approval from the University of Health Sciences Turkey, Dr. Behçet Uz Pediatric Diseases and Surgery Training and Research Hospital, Local Research Ethics Committee (approval number: 2021/17-02, dated: 04.11.2021). Patients with known chronic diseases (such as immunodeficiency), parasitic infections, or chronic drug users, as well as those with missing either complete blood count or serum total IgE test results, were excluded from the study to minimize factors that could affect total IgE, eosinophil, or basophil levels. Data including age, sex, allergic disease diagnosis, serum total IgE levels, eosinophil and basophil counts/percentages, skin prick test, and allergen-specific IgE test results were recorded in case report forms.
In the study, ALK-Abello prick test solutions were used for the skin prick tests. Inhalant allergens included house dust mites, mold, grass pollens, tree pollens, cat dander, dog dander, and cockroach. Food allergens included egg white, egg yolk, cow’s milk, wheat flour, peanut, and soy flour. An induration of ≥3 mm compared to the negative control was considered a positive result.
The specific IgE test was performed using the IMMULITE® 1000 immunoassay analyzer and the enzyme-linked immunosorbent assay (ELISA) method, with values of 0.35 kU/L or higher considered positive. Specific IgE testing for egg, milk, grass pollens, and house dust mite was performed individually. In addition, standardized allergen panels were used. The inhalant panel consisted of Dermatophagoides pteronyssinus, cat dander, dog dander, horse dander, cockroach, and Cladosporium herbarum, while egg, milk, codfish, wheat, peanut, and soybean included in the food panel. The serum total IgE test was also conducted using the IMMULITE® immunoassay analyzer and the ELISA method, and values of 100 kU/L or higher were defined as elevated IgE levels. Eosinophil and basophil counts were determined using the Sysmex XN-1000™ Automated Hematology Analyzer and the flow cytometry method. Eosinophilia was defined as an eosinophil count greater than 450/mm³ or its percentage above 4%, while basophilia was defined as a basophil count greater than 100/mm³ or a percentage above 1%.
The patients with allergic symptoms and a clinical diagnosis of allergic diseases (atopic dermatitis, food allergy, allergic rhinitis, or asthma) were classified into two groups: the atopic group (case group), with at least one positive skin prick test or allergen-specific IgE test result, and the non-atopic group (control group), with negative results in both tests despite the presence of allergic symptoms.
Statistical Analysis
Statistical analyses were performed using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). All numerical and categorical data were evaluated using descriptive statistical methods. Non-parametric continuous numerical variables were described using the median and interquartile range (IQR), while categorical variables were presented as numbers and percentages.
A multivariate logistic regression analysis was conducted to evaluate the relationship between atopy and peripheral blood parameters (elevated serum total IgE levels, eosinophilia, and basophilia) in different allergic diseases. Results were reported as odds ratios (OR), 95% confidence intervals (CIs), and p-values. Receiver operating characteristic (ROC) analysis and the Youden index were used to determine the cut-off values of serum total IgE levels, eosinophil counts, and percentages that best predicted atopic disease. Results with a p-value <0.05 were considered statistically significant.
RESULTS
A total of 673 participants including 423 (62.9%) male and 250 (37.1% ) female patients were included in the study. The patients received the diagnosis of asthma (n=299; 44.4%), allergic rhinitis. (n=206; 30.6%), atopic dermatitis (n=89; 13.2%), and food allergy (n=79; 11.7%). The median age of the patients was 60 months (IQR: 36-96). A majority of patients with atopic dermatitis (80.9%, n=72) and food allergy (78.5%, n=62) were aged 12 months or younger. Atopy was detected in 60.3% (n=406) of the patients. Table 1 presents the demographic and clinical characteristics of the patients.
According to serum-specific IgE test results, the rates of sensitization to any allergen were 80.9% (n=72) in atopic dermatitis, 94.9% (n=75) in food allergy, 53.4% (n=110) in allergic rhinitis, and 30.1% (n=90) in asthma. Based on skin prick test results, the rates of sensitization to any allergen were 62.9% (n=56) in atopic dermatitis, 86.1% (n=68) in food allergy, 63.6% (n=131) in allergic rhinitis, and 33.1% (n=99) in asthma. When both tests were evaluated together, the overall rates of atopy were 85.4% (n=76) in atopic dermatitis, 100% (n=79) in food allergy, 68.0% (n=140) in allergic rhinitis, and 37.1% (n=111) in asthma.
According to serum-specific IgE test results, the most common sensitizing allergen in patients with atopic dermatitis and food allergy was egg, with sensitization rates of 75.3% and 74.7%, respectively. In patients with allergic rhinitis and asthma, the most common sensitization was to grass pollens, with sensitization rates of 30.1% and 9.4%, respectively. Table 2 shows the specific IgE test results of the patients.
According to the skin prick test results, food allergens were the most frequently identified sensitizers in patients with atopic dermatitis (62.9%) and food allergy (84.8%). The most common food allergen was egg with indicated sensitization rates in atopic dermatitis (58.4%) and in food allergy, (64.6%) followed by milk (20.2% vs 39.2%) and cereals (16.9% vs 8.9%).
Sensitizations to tree nuts, legumes, and seeds were less frequent. Sensitization to multiple food allergens was observed in 31.6% of the patients with food allergy. In patients with allergic rhinitis the most common sensitization was to tree pollens (32.0%), while in patients with asthma, it was to house dust mites (18.1%). Table 3 presents the skin prick test results.
Elevated serum total IgE levels was detected in 47.8% (n=143), eosinophilia in 47.2% (n=141), and basophilia in 5.4% (n=16) of the patients of the patients diagnosed with asthma. In patients with asthma, a significant association was found between elevated serum total IgE levels and atopy (OR: 16.37; 95% CI: 8.531-31.412; p<0.001). The presence of eosinophilia was also significantly associated with atopy (OR: 1.99; 95% CI: 1.086-3.631; p=0.026). However, no significant relationship was observed between the presence of basophilia and atopy in patients with asthma (OR: 3.15; 95% CI: 0.754-13.121; p=0.116).
Relatively higher serum total IgE levels were observed in 60.7% (n=125), eosinophilia in 50.5% (n=104), and basophilia in 6.8% (n=14) of the patients diagnosed with allergic rhinitis. Among patients with allergic rhinitis, atopy was significantly associated with elevated serum total IgE levels (OR: 3.33; 95% CI: 1.737-6.379; p<0.001) and eosinophilia (OR: 2.81; 95% CI: 1.441-5.493; p=0.002). There was no statistically significant association between basophilia and atopy (OR: 5.02; 95% CI: 0.626-40.218; p=0.129).
Age-stratified analysis revealed differences in serum total IgE levels of the patients with atopic dermatitis. Relatively higher serum total IgE levels were observed in 23.6% of those aged ≤12 months and 41.2% of those older than 12 months. Overall, 27.0% (n=24) of patients presented with elevated serum total IgE values, while indicated number (%) of patients had eosinophilia (n=66; 74.2%) or basophilia (n=3; 3.4%). In patients with atopic dermatitis, any significant correlations were not found between atopy and elevated serum total IgE values, eosinophilia, or basophilia (p>0.05). Among those diagnosed with food allergy, elevated serum total IgE values were detected in 50.0% of those aged ≤12 months and 76.5% of those older than 12 months. Overall, indicated number (%) of patients had elevated serum total IgE values (n=44; 55.7%), eosinophilia (n=48; 60.8%) and basophilia (n=3; 8%). Since all patients diagnosed with food allergy were in the atopic group, predictive analyses for atopy could not be performed for this group. Table 4 displays the relationships between peripheral blood parameters and atopy across different types of allergic diseases.
According to the Youden Index, the optimal cut-off value of serum total IgE for predicting atopic asthma was calculated as 108.5 kU/L [area under the curve: 0.854 [95% CI: 0.811-0.897], p<0.001], with a sensitivity of 85.6% and specificity of 76.6%. Furthermore, in patients with asthma, a significant correlation was found between the number of sensitizations identified by the skin prick test and serum total IgE levels (r=0.532, p<0.001).
DISCUSSION
This study focused on evaluating whether elevated serum total IgE, eosinophil, and basophil levels at the time of diagnosis can serve as predictive markers for atopy in various allergic diseases observed in a pediatric hospital setting. Additionally, skin prick and serum-specific IgE test results of the patients were assessed to determine atopy profiles of these patients. Egg was found to be the most common sensitizing allergen in patients with atopic dermatitis and food allergy, while tree pollens were the most common allergens in allergic rhinitis, and house dust mites in asthma. In asthmatic patients, elevated total IgE levels increased the likelihood of atopy by 16.4 times, and the cut-off value of total IgE for predicting atopy in asthma was calculated as 108.5 kU/L.
There is a strong association between atopic dermatitis and food sensitization, and early detection of these entities is essential to prevent disruption of the skin barrier(1). Previous studies have shown that egg and milk are the most frequently observed allergens in food allergies in patients with atopic dermatitis, while rates of sensitivities to peanuts, soy, wheat, and fish vary across populations(10–14). Consistent with the literature, our study found that egg was the most common sensitizing allergen based on serum-specific IgE results in patients diagnosed with atopic dermatitis. Wahn et al.(15) observed that sensitization to food allergens generally develops within the first year of life, while severity of sensitization to aeroallergens increases with age. In our study, 80.9% of patients with atopic dermatitis were infants, which explains their low sensitization rates to aeroallergens.
Avoiding trigger allergens plays a crucial role in the management of allergic rhinitis. Therefore, understanding the distribution of aeroallergens in the region where patients reside is necessary. According to our skin prick test results, the most common allergens inducing epicutaneous sensitization among children with allergic rhinitis were tree pollens (32.0%), followed by grass pollens (23.8%) and house dust mites (21.8%). In studies conducted in South Korea, USA, and China, house dust mites were reported as the most common allergens in children with allergic rhinitis(16-18). According to relevant studies performed in various regions of Turkey the most common allergens were house dust mites in İstanbul, and grass pollens in Sakarya(19, 20). The regional distribution of aeroallergen sensitization in our study is likely to be influenced by regional climatic features, vegetation, and allergen diversity. Additionally, the finding that sensitization was detected in only 68% of patients diagnosed with allergic rhinitis can be explained by the preexisting local allergic rhinitis in some patients.
In our study, the most common allergen sensitization detected by skin prick test in asthmatic children was to house dust mites (18.1%). Similarly, the literature supports that house dust mites are major aeroallergens involved in the development of asthma and also the most commonly detected sensitizers in skin prick testing(21). A 16-year longitudinal study conducted in İstanbul on allergen sensitization in children with asthma reported a decline in sensitization rates to house dust mite since 2001, possibly attributed to periodic education on preventive measures against this allergen(22).
Marsh et al.(23) identified 100 kU/L as the optimal serum total IgE level to distinguish allergic conditions in adults, and this cut-off value is widely used. However, due to the dynamic nature of serum total IgE levels in children, its association with the risk of allergen sensitization and atopic disease remains unclear. Wong et al.(24) reported that in infants younger than 6 months, total IgE levels rarely exceeded 100 kU/L due to immature IgE production, making it unsuitable for predicting disease in this age group. In our study, serum total IgE levels did not predict atopy in patients with atopic dermatitis which may be explained by the fact that most of these patients were under 12 months old, resulting in an uneven age distribution and age-dependent increase in total IgE levels. Although a higher rate of elevated serum total IgE values was observed in patients older than 12 months with atopic dermatitis, the relatively small number of patients in this age group limits the interpretation of this finding.
In contrast to atopic dermatitis, our study found a significant association between atopy and elevated serum total IgE levels in patients with allergic rhinitis and asthma. This finding supports the presence of a strong relationship between serum total IgE levels and atopy, especially in respiratory allergies. Gergen et al.(25) also reported significantly elevated total IgE levels in individuals aged 6 and above with asthma who were sensitized to at least one specific allergen. Similarly, Sherrill et al.(26) demonstrated a significant relationship between skin prick test positivity and high serum total IgE levels in asthmatic children.
In our study, elevated serum total IgE emerged as a strong predictor of atopy in patients with asthma, with an OR of 16.37. Based on this significant value, a ROC analysis was conducted to assess the predictive power of total IgE for atopic asthma. With a threshold of 108.5 kU/L, this biomarker had 85.6% sensitivity and 76.6% specificity in predicting atopy in patients with asthma. These findings suggest that serum total IgE could be a meaningful biomarker for predicting atopy in asthmatic children. However, we believe that this cut-off value should be validated in multicenter studies with larger sample sizes.
Eosinophilia has been identified as a risk factor for severe atopic dermatitis. Infants with eosinophilia and a family history of atopy have an increased risk of developing allergic diseases within the first 6 years of life(27-30). Although eosinophilia was detected in 74.2% of patients with atopic dermatitis in our study, no significant association was found between eosinophilia and atopy. In a study examining the clinical significance of eosinophilia in food allergy, Noh et al.(31) reported a correlation between eosinophilia and food allergy in patients with atopic dermatitis. They observed a decrease in eosinophil counts following elimination diets and an increase after intake of oral food challenges. They also found eosinophilia in 63.0% (85/135) of patients with atopic dermatitis and food allergy. Similarly, 60.8% of patients with food allergy in our study had eosinophilia.
In our study, a significant association was found between eosinophilia and atopy in patients with allergic rhinitis and asthma. Similar findings have been reported in the literature. For example, Winther et al.(32) showed that eosinophil counts in patients with allergic rhinitis increased during the pollen season and returned to baseline after the season. Özçeker et al.(19) also reported a significant association between eosinophilia and allergen sensitization in allergic rhinitis. These results are consistent with our findings. On the other hand, the relationship between eosinophil counts and clinical severity of allergic rhinitis remains controversial in the literature, and there is no consensus on this issue(33, 34).
Hu et al.(28) reported a significantly higher prevalence of basophilia in patients with atopic dermatitis compared to healthy controls, and that patients with severe atopic dermatitis had significantly higher basophil counts compared to those with mild disease. However, our study did not find basophilia to be a significant predictor of atopy.
Study Limitations
This study has several limitations. Firstly, the inclusion of different allergic diseases resulted in a heterogeneous study population. This issue was solved by conducting separate analyses based on initial diagnoses. The lack of a homogeneous age distribution due to differing age ranges at the time of diagnosis represents another limitation. Furthermore, as the classification of atopic and non-atopic groups relied solely on skin prick test and allergen-specific IgE results, potential false-negative results might have led to misclassification of some patients. Additionally, our study was single-center and retrospective in design. The findings need to be supported by larger scale multicenter studies.
CONCLUSION
In conclusion, our findings suggest that serum total IgE may serve as a valuable biomarker for predicting atopy, particularly in children with asthma, and could support the diagnostic process in clinical practice. It is important to ensure the absence of comorbid conditions when interpreting these laboratory values. Furthermore, given the age-dependent increase in total IgE levels, its use may be limited in children under the age of one year.
