Chronic urticaria (CU) is a common skin disease. Its manifestations include recurrent appearance of wheals, angioedema, or both. The episodes can last for more than 6 weeks [1].  It has a severe impact on the quality of life because of the constant itching, pain, and sleeping problems [2]. CU has been broadly divided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), of which CSU occurs in almost 70-80% of cases [3]. Although it is not a life-threatening condition, the unpredictability of its progression and the variable response to treatment in a significant number of patients poses a clinical challenge [44. The etiopathogenesis of chronic urticaria is still complicated due to the mechanisms of immune dysregulation, autoimmunity, infections, stress, and activation of the coagulation pathway [5]. Recent data indicate that CU is not only a cutaneous response but is defined as a systemic inflammatory disease characterized by the activation of mast cells, the presence of inflammatory mediators, and immune responses [6]. Mast cell degranulation results in the release of histamine, leukotrienes, prostaglandins, and cytokines, which cause edema, erythema, and pruritus [7]. Since a specific diagnostic biomarker does not exist, the assessment of the severity of the disease is frequently based on clinical scales, including the Urticaria Activity Score (UAS7) [8]. Nevertheless, lab parameters, which pertain to immune and inflammation activity, are being investigated in studies for a possible role as markers of disease severity. Serum Immunoglobulin E (IgE) has become a valued biomarker in CU because of its association with both autoimmune and atopic pathways [9]. Higher levels of total serum IgE have been observed in a considerable percentage of patients with CSU and were associated with the severity of the disease and the response to the treatment with omalizumab [10, 11]. There are studies that indicate that IgE may mediate via autoantibodies containing FcεRIα or IgE itself, which is a factor of autoimmune urticaria [12]. Therefore, serum IgE levels could be assessed to give an idea of the disease activity and prognosis. Another parameter that has been commonly studied in CU is absolute eosinophil count (AEC). Eosinophils are the effector cells of allergic and inflammatory responses and are usually increased in cases of atopic and autoimmune diseases [13]. Studies have revealed an increase in eosinophil count in more serious cases of CU, suggesting that they might be contributing to the persistence of symptoms and inflammation [14]. Additionally, the eosinophils also secrete mediators, such as eosinophil cationic protein and peroxidase, which could worsen the vascular permeability and wheal development [15]. Therefore, assessing AEC would be a cheap and valuable indicator of the severity of diseases. D-Dimer, which is a product of fibrin degradation, has proved to be a new biomarker that is associated with the severity of the disease in CU. However, recent studies have indicated the activation of the coagulation cascade by chronic urticaria patients, where the situation is difficult and unresponsive [16]. High levels of D-dimer have been linked to prolonged healing and severity of the disease in question, which indicates that coagulation and inflammation are interconnected [16, 17]. Moreover, patients who have an elevated D-dimer work poorly with antihistamine monotherapy and might need immunomodulators or biologics [18]. So, D-dimer has become a relevant prognostic tool in the treatment of CU. With this background, the current study was designed to assess the correlation between serum IgE, absolute eosinophil count, and D-dimer with clinical disease severity in chronic urticaria. The results of this study could provide valuable input data for laboratory indicators of the severity of the disease, and this can help in monitoring disease progression and prognosis.

The prospective observational study was conducted in the Department of Dermatology in coordination with the departments of Pathology/Biochemistry at Gandhi Medical College and Hospital, Secunderabad, Telangana. The study protocol was approved by the Institutional Ethical Committee after duly following the protocol for human research based on the Helsinki Declaration. Written consent was obtained from all the participants of the study after explaining the nature of the study in the vernacular language.

Inclusion criteria

1. Age group of 18–65 years.
2. Males and Females
3. Patients meeting diagnostic criteria for chronic urticaria (CU), such as recurrent wheals and/or angioedema for ≥6 weeks.
4. Voluntarily willing to participate in the study and able to be present for follow-up evaluations.

Exclusion criteria

1. History of acute urticaria (<6 weeks)
2. Other dermatologic conditions mimicking urticaria
3. History of trauma from surgery recently
4. Pregnant or lactating females
5. Malignancy
6. Liver or renal diseases
7. On anticoagulants
8. Use of immunosuppressive drugs within 4 weeks

Sample size calculation: The sample size was chosen to detect a moderate correlation (r ≈ 0.4) between laboratory parameters and clinical severity with approximately 80% power and α = 0.05 (required n ≈ 45–50); recruitment of 45 subjects was feasible within the study period based on the inclusion and exclusion criteria.

Clinical evaluation and severity assessment of chronic urticaria: after recruitment of the patient, a detailed history and clinical examination were performed for each participant, including demographic data, disease duration, possible triggers (food, drugs, infections, stress), personal/family atopy history, medication use, and prior treatments. All the data was stored in a pre-designed questionnaire. Disease severity was assessed using the Urticaria Activity Score over 7 days (UAS7 scores): patients were either instructed to complete a 7-day diary if feasible, or the UAS7 was estimated based on the history of the preceding week. UAS7 ranges from 0–42 (higher scores indicate greater activity). Based on UAS7, patients were categorized into standard severity groups (e.g., well-controlled 0, mild 1–6, moderate 7–15, severe 16–27, very severe 28–42) for subgroup analyses.

Laboratory investigations were done by drawing venous blood samples under aseptic conditions from each subject before any rescue medication was administered on the day of evaluation.

Complete blood count (for Absolute Eosinophil Count, AEC): 3 mL blood in an EDTA tube; analyzed on an automated hematology analyzer (Coulter-type or equivalent) within 2–4 hours. AEC was recorded as cells ×10^9/L (or cells/µL) and converted to absolute eosinophil count where required.

Total serum IgE: 3–5 mL blood collected into plain/serum separator tube; allowed to clot, centrifuged at 1500–2000 × g for 10 minutes; serum separated and assayed. Total IgE was measured using a validated chemiluminescent immunoassay (CLIA) or enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions. Results reported in IU/mL.

D-dimer: 3 mL blood collected into a citrate (3.2% sodium citrate) tube (9:1 blood: citrate); centrifuged to obtain platelet-poor plasma and assayed immediately or stored at −20°C for batch analysis. D-dimer was measured using a quantitative immunoturbidimetric assay or enzyme-linked immunofluorescence assay per kit protocol. Results reported in ng/mL or µg/mL FEU (state units used).

All assays were performed in the hospital diagnostic laboratory using standard quality control procedures and calibrated instruments. Laboratory personnel were blinded to clinical severity during testing.

Primary outcome: correlation between serum total IgE, absolute eosinophil count (AEC), and plasma D-dimer levels and UAS7 score (disease severity). Secondary outcomes: comparison of laboratory parameters across UAS7 severity categories, proportion of patients with elevated biomarkers, and utility of each marker to predict severe disease (exploratory ROC analysis).

Statistical analysis: all the available data were refined, segregated, and uploaded to an MS Excel spreadsheet and analyzed by SPSS version 25 in Windows format. The continuous variables were expressed as mean, standard deviation, percentages, and median (interquartile range) for non-normal distributions. Categorical variables were calculated by using Spearman’s rank correlation for non-normal data. Correlation coefficients (r or ρ) and p-values are reported. Comparison of biomarker levels across severity categories used ANOVA (with post hoc tests). Receiver operating characteristic (ROC) curve analysis was performed to explore the discriminative ability of biomarkers to predict severe disease (UAS7 threshold), with area under the curve (AUC), optimal cut-off, sensitivity, and specificity reported.

A total of n=45 cases of chronic urticaria were included in the study. The demographic characteristics of the cases are given in Table 1. The age range was 19 years to 57 years, and the mean age was 38.5 ± 12.1 years. The study shows that chronic urticaria is commonly diagnosed in young or middle-aged adults. Overall, there was a female preponderance, with 60% of cases showing gender dominance in the disease. The mean duration of the disease was 9 months, with a range (IQR 5-18) months. The mean Urticaria disease activity score was found to be 24 (IQR 16-32), indicating the existence of moderate to severe disease activity. The results of the study also showed that 66.6% experienced severe and very severe forms of urticaria. A history of atopy in 35.6% of cases plays an important role as a contributing factor. Angioedema was present in 44.4% of cases due to mast cell activation and aggressive disease type. 

The analysis of serum biomarkers is presented in Table 2. A critical analysis of the table showed that the mean IgE levels were 1858.5 IU/mL, with 62.2% of the cases having the values above the normal limits, showing the strong involvement of the allergic component in a large proportion of patients. The values of Absolute eosinophil count (AEC) were found to be elevated in 17.8% of cases, showing that eosinophilia was not a consistent marker in this cohort. The values of D-dimer were found to be elevated in 48.9% of the cohort, indicating the existence of systemic inflammation or subclinical thrombosis. The elevated D-dimer was due to activation of the coagulation pathway, which is evident from the literature, which linked chronic urticaria to systemic endothelial dysfunction.

The correlation of disease severity with biomarker levels is given in Table 3. The analysis showed that the urticaria disease activity score (UAS7) severity showed ρ = 0.65 (p < 0.001), making it a promising biomarker for assessment of disease activity. Similarly, the serum IgE showed moderate and significant correlation (ρ = 0.42, p = 0.005), which indicates its usefulness in evaluating allergic contributions. The absolute eosinophil count showed only a weak and statistically insignificant correlation (ρ = 0.28, p = 0.07) and was of limited value. These results show that among all the biomarkers, D-dimer and IgE had more sensitivity for active inflammation and severity of disease.

Comparison across UAS7 severity categories demonstrated a significant rise in all biomarkers as severity increased, as given in Table 4. Total serum IgE and D-dimer showed strong and consistent elevation from mild to very severe cases (p < 0.001). AEC also increased with severity but with borderline statistical significance (p = 0.03), supporting its secondary prognostic value. Notably, very severe cases showed markedly higher D-dimer levels (median 1.10 µg/mL), reinforcing its utility as a measurable indicator of systemic inflammation in chronic urticaria.

On ROC analysis presented in Table 5, D-dimer demonstrated the highest diagnostic accuracy with AUC = 0.92, and sensitivity and specificity of 86.7%, making it the most reliable biomarker for identifying severe disease. Serum IgE also performed well with AUC = 0.78, while AEC showed the lowest predictive ability (AUC = 0.66). These findings suggest that D-dimer can be used not only for evaluation but also for risk stratification and monitoring treatment response (Figure 1).

Figure 1: ROC curve of different biomarkers in this study

In summary, these results indicate that chronic urticaria was more towards the severe category in this cohort and was commonly associated with elevated IgE levels and accompanied by systemic inflammatory activity with increased D-dimer levels. Therefore, among all the biomarkers, D-dimer emerged as the strongest correlate of disease severity, and it could be used in clinical decision-making and prognosis.

Chronic urticaria (CU) is a complex, multifactorial inflammatory disease that involves complicated immunological and vascular pathways. The objectives of the current study were to assess the severity of the disease by measuring serum IgE, absolute eosinophil count (AEC), and D-dimer, which is used as a disease marker, and to determine the correlation of these markers with clinical scores. The overall findings of our study indicate that D-dimer and total serum IgE had moderate positive correlations with UAS7, which indicated their relevance as diagnostic and prognostic, whereas AEC had less association. Most of the patients in our study had severe to very severe urticaria, and almost 44% of the patients reported having angioedema, which shows greater inflammatory involvement. Studies done previously have reported similar trends of diseases with persistent mast cell activation and vascular leakage as the main causes of chronicity of symptoms [16]. More than 60% of our cohort had elevated levels of IgE, which is consistent with the literature that atopic tendency and the involvement of IgE-mediated pathways are significant contributors to CU pathogenesis [17]. Nevertheless, high IgE is not the complete explanation of the severity of the disease because there are also non-atopic patients with severe symptoms, which indicates involvement of other immunological pathways [18].

The most notable observation was the positive correlation between D-dimer levels and UAS7 score, and it was found to be strong, which confirms the involvement of the coagulation cascade activation in CU. Previous research in this field has revealed that mast cell products like tryptase and histamine facilitate the expression of tissue factor, which results in fibrin degradation and D-dimer generation [19]. This process suggests that chronic urticaria is not a mere skin response, but it can be characterized by endothelial dysfunction and subclinical vasculopathy in the body [20]. This is also supported by our ROC analysis, where D-dimer showed great diagnostic accuracy (AUC = 0.92) to predict severe/very severe disease. These results indicate that D-dimer can be an efficient biomarker to inform the increase of treatment or early immunomodulatory therapy. In this study, we found AEC was weakly associated with severity, and eosinophilia occurred in only about 18% of the patients, which is less than in other allergic diseases like asthma or atopic dermatitis. Nevertheless, the AEC values were higher in patients with very severe disease, which suggests the presence of eosinophil-mediated inflammation in the latter as a contributing factor to angioedema-prone ones [20]. This partial relevance still makes it worthy of inclusion as a secondary predictor of severity, and not a primary predictor of severity.

We found our results in line with the theory of endotype-driven urticaria, in which the severity of a disease is defined by its mechanisms but not only by its appearance [21]. Depending on the changes in biomarkers, CU can be categorized into mast cell-driven, IgE-mediated, and coagulation-mediated types that can potentially be used to personalize treatment, therefore, antihistamines in mild cases, omalizumab in IgE-mediated, and anticoagulant trial therapy in hypercoagulable phenotypes [22]. The limitations of the current study were due to its single-center patient selection and medium size, which can limit its external validity. A longitudinal follow-up and evaluation of biomarker therapy response would yield better information. Nonetheless, the given research confirms the assumption that D-dimer is a better inflammatory biomarker to assess the severity and potentially be applied in routine care. In the end, the research indicates that D-dimer and serum IgE are effective biomarkers of chronic urticaria severity, and D-dimer is a powerful prognostic biomarker. A combination of biomarker assessment and clinical scoring could enhance the diagnosis, stratification, and management of CU patients.

The current research, within its own limitations, indicates that serum IgE, absolute eosinophil count, and D-dimer are useful biochemical markers for the assessment of the severity of chronic urticaria. We found D-dimer had the best correlation with UAS7 scores and had a high diagnostic accuracy in measuring severe and very severe disease, making it an effective prognostic marker. Serum IgE level was also significantly correlated with the intensity of symptoms, but weakly with AEC. The results of this study showed that biomarkers are invaluable for decision-making and prognosis in cases of chronic urticaria.

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