Abstract
Introduction
Angioedema is a heterogeneous clinical condition characterized by transient swelling of the deeper dermal and submucosal tissues and may occur either in isolation or in association with urticaria. Despite its clinical importance, data regarding clinical phenotypes, triggering factors, and inflammatory laboratory markers in paediatric angioedema remain limited.
Aim
This study aimed to retrospectively evaluate the clinical characteristics and laboratory parameters of paediatric patients with angioedema.
Material and methods
In this single-centre retrospective study, medical records of paediatric patients aged 0–18 years diagnosed with angioedema between January 2024 and January 2025 were reviewed. Demographic characteristics, angioedema phenotype (isolated angioedema vs. angioedema with urticaria), triggering factors, drug-triggered angioedema, and atopic comorbidities were analysed. Laboratory parameters included hemogram indices, C-reactive protein (CRP), total immunoglobulin E (IgE), complement levels (C3 and C4), and neutrophil-to-lymphocyte ratio (NLR). Appropriate parametric and non-parametric statistical tests were applied.
Results
A total of 103 paediatric patients were included. Angioedema accompanied by urticaria was more frequent in females, whereas isolated angioedema predominated in males (p = 0.004). Upper airway involvement, multiple site involvement, and atopic comorbidities were significantly more common in patients with urticaria-associated angioedema (p < 0.05). Idiopathic angioedema showed higher neutrophil counts (p = 0.033), while CRP (p = 0.018) and total IgE levels (p = 0.026) were elevated in trigger-associated angioedema. Drug-triggered angioedema occurred less frequently in patients with atopic comorbidities (p < 0.001) and was associated with higher NLR values (p < 0.001) and lower basophil counts (p = 0.038).
Conclusions
Paediatric angioedema shows distinct clinical phenotypes and laboratory patterns depending on urticaria and triggering factors. Inflammatory markers such as neutrophil counts, CRP, NLR, and basophil levels may help characterize the inflammatory profile of angioedema. Larger multicentre studies are needed to confirm these findings.
Keywords: paediatric angioedema, clinical phenotypes, inflammatory markers, neutrophil-to-lymphocyte ratio, immunoglobulin E, angioedema triggers
Introduction
Angioedema (AE) is a clinical condition characterized by oedema formation in the deep dermis of the skin and the submucosa of the respiratory and gastrointestinal tracts. It most commonly involves the tongue, eyelids, face, and larynx, although less frequently it may also affect the extremities, genital mucosa, and the submucosal layers of visceral organs [1, 2].
The concept of angioedema is not recent; its origins date back to the late 19th century. Notably, William Osler described in 1888 that recurrent angioedema attacks could be transmitted across generations, thereby establishing the familial nature of the disease. The diagnosis of hereditary angioedema is confirmed by the presence of low serum C4 levels together with reduced levels or functional deficiency of C1 inhibitor [3].
According to the classification proposed by the European Academy of Allergy and Clinical Immunology (EAACI), angioedema can be broadly categorized based on the underlying mechanism into bradykinin-mediated angioedema (BK-AE), histamine- or mast cell–mediated angioedema, and angioedema of unknown origin. Certain forms of angioedema develop due to hereditary alterations affecting C1 inhibitor (C1-INH) levels, whereas others arise from acquired causes. Bradykinin-mediated angioedema includes genetic forms associated with C1-INH deficiency, such as hereditary angioedema types I and II, as well as other genetic abnormalities, including factor XII mutations [4].
The oedema observed in angioedema typically involves deeper tissue layers, particularly the subcutaneous or submucosal compartments, distinguishing it from the more superficial lesions observed in classical urticaria [5].
Clinically, angioedema presents as localized swelling with poorly defined borders, often accompanied by pain or a burning sensation rather than pruritus. The lesions are usually skin-coloured or mildly erythematous and may persist for several hours or even days [6].
Following exposure to a triggering factor, angioedema generally develops rapidly, often within minutes to a few hours, manifesting as sudden tissue swelling [7].
Involvement of the larynx may lead to airway obstruction and represent a life-threatening condition requiring urgent airway management, including possible endotracheal intubation. Similarly, intestinal angioedema can present with severe abdominal pain and, in rare cases, may lead to complications such as intussusception requiring surgical intervention [8].
Angioedema may occur either in association with urticaria or as isolated angioedema without accompanying wheals [9, 10].
Histamine-mediated angioedema is commonly associated with urticaria and other manifestations of anaphylaxis, including bronchospasm, wheezing, and hypotension. It typically has a rapid onset and a relatively short duration of attacks. In contrast, bradykinin-mediated angioedema is characterized by a slower onset, longer duration, and frequently involves abdominal symptoms.
While histamine-mediated angioedema generally responds well to antihistamine therapy, patients who remain symptomatic despite high-dose antihistamines may benefit from treatment with omalizumab [11–14].
Acute angioedema attacks occurring without urticaria often suggest a bradykinin-mediated mechanism and typically do not respond to conventional treatments such as systemic H1 antihistamines, corticosteroids, or epinephrine [15].
Acute attacks of bradykinin-mediated angioedema can be effectively treated with icatibant, a bradykinin B2 receptor antagonist, or with C1 inhibitor (C1-INH) concentrates, which are among the approved advanced therapies for hereditary angioedema [16].
Aim
In this study, we evaluated the clinical and laboratory characteristics of paediatric angioedema, with particular emphasis on clinical phenotypes, potential triggering factors, and their associations with laboratory findings.
Material and methods
Study design and setting
This single-centre retrospective observational study was conducted at a tertiary paediatric allergy and immunology outpatient clinic. Medical records of paediatric patients diagnosed with angioedema between 1 January 2024 and 1 January 2025 were retrospectively reviewed. The study aimed to evaluate the clinical characteristics, potential triggering factors, and laboratory findings of paediatric angioedema and to investigate possible associations between clinical features and laboratory parameters.
Participants and inclusion/exclusion criteria
The study population consisted of paediatric patients aged 0–18 years who were diagnosed with angioedema during the study period. The inclusion criteria were age between 0 and 18 years, a clinical diagnosis of angioedema by paediatric allergy specialists, presentation to the paediatric allergy and immunology outpatient clinic between January 2024 and January 2025, and availability of sufficient clinical data for study inclusion. Laboratory parameters were analysed when available.
The exclusion criteria were incomplete or insufficient medical records, chronic systemic diseases such as autoimmune diseases or malignancies, known congenital or acquired immunodeficiency disorders, oedema due to causes other than angioedema such as trauma or localized infections, and dermatological conditions mimicking angioedema. All eligible patients meeting the inclusion criteria during the study period were included in the study.
Data collection and study variables
Clinical and laboratory data were obtained retrospectively from the hospital electronic medical record system and patient files. Demographic variables included age, sex, and date of admission. Clinical characteristics included angioedema phenotype (isolated angioedema or angioedema associated with urticaria), presence of upper airway involvement, number of involved anatomical sites (single versus multiple site involvement), presence of potential triggering factors such as drugs, foods, or infections, idiopathic versus trigger-associated angioedema, drug-triggered angioedema, and the presence of atopic comorbidities including asthma, allergic rhinitis, and atopic dermatitis.
Patients were categorized according to clinical phenotype (isolated angioedema versus angioedema associated with urticaria), presence of identifiable triggers (trigger-associated versus idiopathic angioedema), drug-triggered angioedema, and presence or absence of atopic comorbidities.
Triggering factors were identified based on patient history and clinical assessment recorded in medical files.
Laboratory parameters
Laboratory parameters obtained during clinical evaluation were recorded. These included white blood cell count (WBC), neutrophil count (NEU), lymphocyte count (LYM), monocyte count (MONO), basophil count (BASO), eosinophil count and percentage (EOS and EOS%), platelet count (PLT), C-reactive protein (CRP), total immunoglobulin E (total IgE), C3 level, and C4 level.
Inflammatory indices were also calculated from hemogram parameters. In particular, the neutrophil-to-lymphocyte ratio (NLR) was calculated and analysed as a marker of systemic inflammation.
Laboratory samples had been obtained under routine clinical conditions.
Sample selection
Because this study was retrospective and exploratory in nature, no formal sample size calculation was performed. All patients meeting the eligibility criteria during the study period were included in the analysis.
Statistical analysis
Statistical analyses were performed using IBM SPSS Statistics version 22.0. Continuous variables were expressed as mean ± standard deviation or median (minimum–maximum), as appropriate, and categorical variables were presented as frequencies and percentages. Normality of distribution was evaluated using histograms, probability plots, and the Kolmogorov–Smirnov or Shapiro–Wilk tests.
For comparisons between two independent groups, the independent-samples t-test was used for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. A p-value of < 0.05 was considered statistically significant.
Results
The distribution of angioedema phenotypes according to sex and age groups was evaluated. A significant association was identified between sex and angioedema type, whereas no significant difference was observed across age groups. Angioedema accompanied by urticaria was significantly more frequent among females, while isolated angioedema was more common in males (χ2(1) = 8.11, p = 0.004). Upper airway involvement occurred exclusively in patients with angioedema accompanied by urticaria (χ2(1) = 14.04, p < 0.001). Similarly, multiple site involvement (χ2(1) = 4.33, p = 0.038) and the presence of atopic comorbidity (χ2(1) = 17.38, p < 0.001) were significantly more frequent in patients with angioedema accompanied by urticaria. No statistically significant association was detected between age group and angioedema type (χ2(2) = 1.48, p = 0.477) (Table 1).
Table 1.
Comparison of demographic and clinical characteristics according to angioedema type
| Variable | Category | Isolated angioedema, n (%) | Angioedema + urticaria, n (%) | χ2 | P-value |
|---|---|---|---|---|---|
| Sex | Female | 19 (35.2) | 35 (64.8) | 8.109 | 0.004* |
| Male | 31 (63.3) | 18 (36.7) | |||
| Upper airway involvement | No | 50 (55.6) | 40 (44.4) | 14.036 | < 0.001* |
| Yes | 0 (0.0) | 13 (100.0) | |||
| Multiple site involvement | No | 31 (58.5) | 22 (41.5) | 4.325 | 0.038* |
| Yes | 19 (38.0) | 31 (62.0) | |||
| Atopic comorbidity | Yes | 27 (36.0) | 48 (64.0) | 17.379 | < 0.001* |
| No | 23 (82.1) | 5 (17.9) | |||
| Age group | ≤ 6 | 6 (37.5) | 10 (62.5) | 1.481 | 0.477 |
| 7–13 | 25 (54.3) | 21 (45.7) | |||
| ≥ 14 | 19 (46.3) | 22 (53.7) | |||
p < 0.05.
The relationship between clinical characteristics and trigger status (trigger-associated versus idiopathic angioedema) was analysed using the χ2 test. Trigger status was not significantly associated with the presence of atopic comorbidity (χ2(1) = 2.34, p = 0.126). Likewise, upper airway involvement showed no significant relationship with trigger status (χ2(1) = 0.24, p = 0.624). Multiple site involvement was also similarly distributed between trigger-associated and idiopathic angioedema groups (χ2(1) = 0.03, p = 0.855) (Table 2).
Table 2.
Association between clinical characteristics and trigger status (trigger present vs. idiopathic angioedema)
| Variable | Category | Trigger present, n (%) | Idiopathic, n (%) | χ2 | P-value |
|---|---|---|---|---|---|
| Atopic comorbidity | Yes | 44 (58.7) | 31 (41.3) | 2.336 | 0.126 |
| No | 21 (75.0) | 7 (25.0) | |||
| Upper airway involvement | No | 56 (62.2) | 34 (37.8) | 0.240 | 0.624 |
| Yes | 9 (69.2) | 4 (30.8) | |||
| Multiple site involvement | No | 33 (62.3) | 20 (37.7) | 0.033 | 0.855 |
| Yes | 32 (64.0) | 18 (36.0) | |||
Laboratory parameters were then compared according to trigger status. Neutrophil counts were significantly higher in patients with idiopathic angioedema than in those with trigger-associated angioedema (p = 0.033). In contrast, CRP levels (p = 0.018) and total IgE levels (p = 0.026) were significantly elevated in patients with trigger-associated angioedema. No statistically significant differences were observed between the two groups regarding WBC, basophil count, eosinophil count, eosinophil percentage, lymphocyte count, monocyte count, platelet count, NLR, or complement levels (C3 and C4) (p > 0.05) (Table 3).
Table 3.
Comparison of laboratory parameters according to trigger status (trigger present vs. idiopathic angioedema)
| Variable | Trigger present, n (mean ± SD) | Idiopathic, n (mean ± SD) | t(df) | P-value |
|---|---|---|---|---|
| WBC | 65 (8035.08 ±2180.16) | 38 (8997.89 ±2844.57) | –1.93 (101) | 0.057 |
| NEU | 65 (4336.31 ±1525.68) | 38 (5081.32 ±1942.82) | –2.16 (101) | 0.033* |
| BASO | 65 (36.31 ±20.88) | 38 (33.16 ±12.76) | 0.95 (100.77) | 0.344 |
| EOS | 65 (314.00 ±295.43) | 38 (250.79 ±147.75) | 1.23 (101) | 0.221 |
| EOS % | 65 (3.73 ±2.92) | 38 (2.85 ±1.63) | 1.70 (101) | 0.091 |
| LYM | 65 (2832.46 ±1005.49) | 38 (3005.32 ±1207.39) | –0.78 (101) | 0.437 |
| MONO | 65 (496.15 ±187.83) | 38 (563.29 ±220.94) | –1.64 (101) | 0.104 |
| PLT | 65 (312646.15 ±81677.23) | 38 (312710.53 ±73267.71) | –0.00 (101) | 0.997 |
| NLR | 65 (1.72 ±0.88) | 37 (1.76 ±0.72) | –0.26 (100) | 0.797 |
| CRP | 34 (4.91 ±8.11) | 23 (1.35 ±1.90) | 2.46 (38.20) | 0.018* |
| Total IgE | 63 (298.57 ±306.75) | 36 (166.22 ±228.41) | 2.25 (97) | 0.026* |
| C3 | 58 (1.32 ±0.23) | 34 (1.35 ±0.27) | –0.63 (90) | 0.529 |
| C4 | 58 (0.22 ±0.08) | 35 (0.23 ±0.09) | –0.67 (91) | 0.504 |
The number of patients varies across variables due to missing laboratory data inherent to the retrospective study design.
p < 0.05
A significant association was also found between atopic comorbidity and drug-triggered angioedema (χ2(1) = 12.90, p < 0.001). Drug-triggered angioedema was more common in patients without atopic comorbidity (28.6%) compared with those with atopic comorbidity (4.0%). However, upper airway involvement (χ2(1) = 1.78, p = 0.182) and multiple site involvement (χ2(1) = 0.73, p = 0.392) were not significantly associated with drug-triggered angioedema (Table 4).
Table 4.
Association between clinical characteristics and drug-triggered angioedema
| Variable | Category | Drug trigger present, n (%) | No drug trigger, n (%) | χ2 | P-value |
|---|---|---|---|---|---|
| Atopic comorbidity | Yes | 3 (4.0) | 72 (96.0) | 12.904 | < 0.001* |
| No | 8 (28.6) | 20 (71.4) | |||
| Upper airway involvement | No | 11 (12.2) | 79 (87.8) | 1.779 | 0.182 |
| Yes | 0 (0.0) | 13 (100.0) | |||
| Multiple site involvement | No | 7 (13.2) | 46 (86.8) | 0.731 | 0.392 |
| Yes | 4 (8.0) | 46 (92.0) | |||
p < 0.05.
Independent-samples t-test analysis demonstrated that basophil count (BASO) was significantly lower in patients with drug-triggered angioedema compared with those without a drug trigger (p = 0.038). In addition, the NLR was significantly higher in the drug-triggered group (p < 0.001). No statistically significant differences were found between groups in terms of WBC, neutrophil count, eosinophil count, eosinophil percentage, lymphocyte count, monocyte count, platelet count, CRP, total IgE, C3, or C4 levels (p > 0.05) (Table 5).
Table 5.
Comparison of laboratory parameters according to drug-triggered angioedema
| Variable | Drug trigger present, n (mean ± SD) | No drug trigger, n (mean ± SD) | t(df) | P-value |
|---|---|---|---|---|
| WBC | 11 (8847.27 ±2653.85) | 92 (8335.65 ±2464.73) | 0.65 (101) | 0.520 |
| NEU | 11 (5448.18 ±1827.41) | 92 (4511.09 ±1690.05) | 1.72 (101) | 0.088 |
| BASO | 11 (25.45 ±14.40) | 92 (36.30 ±18.44) | –2.29 (14.25) | 0.038* |
| EOS | 11 (306.36 ±271.41) | 92 (288.80 ±251.37) | 0.22 (101) | 0.828 |
| EOS % | 11 (3.03 ±2.59) | 92 (3.45 ±2.56) | –0.51 (101) | 0.611 |
| LYM | 11 (2532.73 ±1253.53) | 92 (2939.70 ±1058.81) | –1.18 (101) | 0.240 |
| MONO | 11 (490.00 ±241.37) | 92 (524.62 ±198.29) | –0.54 (101) | 0.594 |
| PLT | 11 (308272.73 ±52630.96) | 92 (313195.65 ±81039.84) | –0.20 (101) | 0.845 |
| NLR | 11 (2.58 ±1.48) | 91 (1.63 ±0.64) | 3.86 (100) | < 0.001* |
| CRP | 4 (5.13 ±7.79) | 53 (3.35 ±6.55) | 0.52 (55) | 0.606 |
| Total IgE | 11 (205.64 ±225.69) | 88 (256.05 ±294.14) | –0.55 (97) | 0.585 |
| C3 | 10 (1.25 ±0.13) | 82 (1.34 ±0.25) | –1.09 (90) | 0.279 |
| C4 | 10 (0.20 ±0.07) | 83 (0.23 ±0.08) | –1.06 (91) | 0.291 |
CRP data were available for a limited number of patients. The number of patients varies across variables due to missing laboratory data inherent to the retrospective study design.
p < 0.05.
Discussion
IgE-mediated reactions typically occur shortly after exposure and may involve cutaneous, respiratory, and systemic manifestations, including urticaria, angioedema, and, in severe cases, anaphylaxis [17, 18].
Previous studies investigating paediatric angioedema have generally involved relatively small cohorts. For example, one study evaluating children with idiopathic histaminergic acquired angioedema analysed 36 patients aged 0–18 years [19]. In contrast, the present study included 103 paediatric patients, allowing the evaluation of both isolated angioedema and angioedema associated with urticaria within a larger patient population.
Angioedema in children is frequently reported in association with urticaria, and approximately 40% of paediatric patients with urticaria may develop angioedema [20]. In the present cohort, the distribution of isolated angioedema and urticaria-associated angioedema did not differ significantly across age groups (p = 0.477), suggesting that age alone may not play a decisive role in determining angioedema phenotype.
A significant association was identified between sex and angioedema phenotype. Angioedema accompanied by urticaria was more frequent in females, whereas isolated angioedema predominated in males. Similar findings have been reported in studies comparing isolated histaminergic angioedema with urticaria-associated angioedema, where a higher proportion of males was observed in isolated angioedema and a marked female predominance in chronic spontaneous urticaria [21]. These findings suggest that sex-related factors may contribute to differences in disease expression.
Upper airway involvement was observed exclusively in patients with angioedema accompanied by urticaria in our cohort. Although histaminergic angioedema has been reported to involve mucosal and upper airway structures [21], comparative data examining airway involvement across different angioedema phenotypes remain limited.
Similarly, the higher frequency of involvement of multiple anatomical sites in patients with angioedema accompanied by urticaria may indicate a more extensive distribution pattern, whereas isolated angioedema tended to present with more localized involvement. Atopic comorbidities were also more frequent in patients with angioedema accompanied by urticaria. Previous studies comparing isolated histaminergic angioedema with urticaria-associated angioedema did not demonstrate statistically significant differences in atopy; however, a tendency toward higher atopy rates in urticaria-associated cases has been reported [21].
When laboratory parameters were evaluated according to trigger status, CRP levels were significantly higher in patients with identifiable triggers compared with idiopathic cases. This finding suggests that trigger-associated angioedema may involve a more pronounced inflammatory response. Consistent with this observation, increased CRP levels have also been reported during acute episodes of ACE inhibitor–associated angioedema [22].
Total IgE levels were also significantly higher in patients with trigger-associated angioedema. This finding supports the possibility that allergic mechanisms may play a more prominent role in angioedema cases related to identifiable triggers such as foods, medications, or infections.
In addition, elevated IgE levels have been observed in some patients with hereditary angioedema, and previous studies suggest that allergic diseases may occur more frequently in this population than in the general population [23]. Although hereditary angioedema is primarily mediated by bradykinin, these findings indicate that allergic predisposition may coexist in certain patients. Overall, these observations suggest that allergic mechanisms and non-allergic pathways may overlap in the clinical presentation of angioedema.
In contrast, neutrophil counts were significantly higher in patients with idiopathic angioedema, whereas NLR values did not differ between groups. This pattern may reflect a more prominent nonspecific inflammatory response in idiopathic cases, while similar NLR values indicate that the overall systemic inflammatory balance between neutrophils and lymphocytes remains comparable. Most previous angioedema studies have primarily focused on complement pathways or allergic markers, and hematologic inflammatory parameters have been evaluated less frequently. Therefore, these findings may contribute to a better understanding of the inflammatory profile of idiopathic angioedema.
Another notable observation was that drug-triggered angioedema occurred less frequently in patients with atopic comorbidities. This finding may suggest that atopic disease may not be a major determinant in the development of drug-triggered angioedema. Such an observation supports the concept that drug-triggered angioedema cannot always be explained solely by classical IgE-mediated mechanisms and may involve alternative pathophysiological pathways.
Furthermore, patients with drug-triggered angioedema demonstrated significantly higher NLR values and lower basophil counts compared with patients without drug triggers. While previous angioedema studies have largely focused on clinical characteristics, triggers, or complement mechanisms, hematologic inflammatory markers have received relatively limited attention. In this context, these findings may provide additional insight into the inflammatory profile associated with drug-triggered angioedema.
Taken together, these results contribute to the existing literature by simultaneously evaluating demographic characteristics, clinical involvement patterns, and atopic comorbidities in relation to angioedema phenotypes. Comparative data examining airway involvement, cutaneous distribution, and atopic background across angioedema phenotypes remain limited, particularly in paediatric populations. Further studies focusing on phenotype-specific characteristics are therefore warranted to better understand the clinical heterogeneity of angioedema in children. Another limitation of this study is the lack of differentiation between histaminergic and bradykinin-mediated angioedema, which may influence the interpretation of the findings. The retrospective design resulted in missing laboratory data for some variables, and the relatively small number of patients with drug-triggered angioedema may have limited the statistical power of subgroup analyses. Additionally, potential confounding factors were not controlled for due to the retrospective design of the study. These findings may help improve clinical phenotyping and risk assessment in paediatric patients with angioedema.
Funding Statement
Funding No external funding.
Ethical approval
The study protocol was approved by the Ümraniye Training and Research Hospital Clinical Research Ethics Committee (approval no. 92; 10 April 2025). The study was conducted in accordance with the principles of the Declaration of Helsinki. Because of the retrospective design, patient data were analysed anonymously.
Conflict of interest
The authors declare no conflict of interest.
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