Are Specific Immunoglobulin (IgE and IgG) and Tryptase Levels Correlated with the Severity of Allergic Reactions in Patients with Bee Venom Hypersensitivity?

Abstract

Objectives

This review aims to evaluate the clinical utility of specific immunoglobulins (IgE and IgG) and serum tryptase levels as biomarkers for predicting allergic reaction severity in patients with bee venom hypersensitivity.

Methods

A systematic review of nine original cross-sectional and prospective observational studies was conducted. Sample sizes ranged from 30 to over 1,100 participants. The analysis focused on correlations between baseline immunological markers—whole-venom IgE, component-resolved IgE (e.g., Api m 1), IgG/IgG4, and baseline serum tryptase (BST)—and sting reaction severity.

Results

Five studies identified elevated BST as the strongest predictor of severe systemic sting reactions and anaphylaxis. In contrast, specific IgE showed limited predictive value whole-venom IgE titers did not correlate with reaction severity, whereas component-resolved IgE (Api m 1) showed potential associations in subgroups such as beekeepers. Baseline IgG and IgG4 levels did not predict clinical severity, although increased IgG4 during venom immunotherapy was associated with protection. Age was identified as a potential risk modifier, but its influence varied across cohorts.

Conclusion

BST is the most reliable biomarker for risk stratification in bee venom hypersensitivity. Baseline-specific IgE and IgG provide limited prognostic value. Given the heterogeneity of current studies, further standardized prospective research is needed to refine risk assessment protocols for patients with bee venom allergy.

INTRODUCTION

Bee venom is widely used in traditional Korean medicine and incorporated into pharmacopuncture for clinical use. It has been administered to manage musculoskeletal disorders, cancer, Parkinson’s disease, and other chronic conditions. Despite its diverse applications, clinical use is limited due to the risk of adverse reactions ranging from mild local symptoms (erythema and pruritus) to severe anaphylaxis and, rarely, fatal outcomes. Current clinical risk assessment often relies on intradermal skin testing with bee venom to evaluate the wheal-and-flare response. However, this method limits predictive value for systemic reactions, hindering the identification of patients at high risk of severe adverse events.

In recent years, attention has shifted to immunological biomarkers that may improve risk stratification. Among these, baseline serum tryptase (BST) is the most consistent predictor of severe systemic sting reactions. Five independent studies show that elevated tryptase significantly correlates with more severe clinical outcomes [1-5]. Age is a potential risk modifier; although not an independent predictor in multivariate analysis, older patients in some studies exhibit higher tryptase levels and more severe reactions [3, 5]. Conversely, venom-specific IgE shows inconsistent predictive value. Whole-venom IgE titers do not correlate with clinical severity in most studies [6], whereas component-resolved IgE, including Api m 1/phospholipase A2 (PLA2), shows potential associations with severity in selected populations such as beekeepers [7]. Similarly, baseline IgG and IgG4 levels do not correlate with reaction severity [8, 9], but one study reports that IgG4 increases during venom immunotherapy (VIT) reflect treatment-induced protection [8].

Overall, these findings suggest that baseline tryptase, rather than IgE or IgG titers, may be a practical biomarker for identifying patients at higher risk of severe systemic reactions to bee venom. However, heterogeneity in study design, patient populations, and severity classification limits direct comparability. Therefore, this review aims to synthesize the available evidence on immunoglobulin and tryptase levels in bee venom hypersensitivity. The findings of this review could provide a basis for developing more reliable diagnostic tools to predict adverse events and prevent severe complications.

METHODS

1. Search strategy

An extensive literature search was conducted to determine whether specific immunoglobulin (IgE and IgG) and tryptase levels correlate with allergic reaction severity in patients with bee venom hypersensitivity. Electronic databases, including PubMed, were searched for all articles published up to January 2025.

The PubMed search strategy was: (honeybee OR “Apis mellifera” OR Hymenoptera OR bee) AND venom AND (tryptase OR “basal tryptase” OR “baseline tryptase” OR “specific IgE” OR sIgE OR IgG OR IgG4) AND (severity OR “Mueller grade” OR “systemic reaction” OR anaphylaxis) (Fig. 1).

Figure 1.

PRISMA flow diagram of the study selection process. *Records identified from: PubMed etc.

2. Eligibility criteria

Studies were eligible if they met the following criteria:

RESULTS

1. Characteristics of included studies

nine original studies involving approximately 2,000 participants with bee venom hypersensitivity were included (Table 1) [1-9]. The study designs comprised cross-sectional analyses, prospective observational cohorts, retrospective cohorts, and one single-challenge study, with sample sizes ranging from 30 to over 1,100 participants (Table 1).

Table 1.

Characteristics of included studies

Study	Reference no.	Study design	Population size	Immunological parameters measured	Severity classification system
Haeberli et al. (2003)	[1]	Retrospective clinical study	72 HV-allergic patients	Baseline serum tryptase	Clinical severity of sting reactions (graded)
Ruëff et al. (2009)	[2]	Multicenter registry cohort	> 1,100 HV-allergic patients	Baseline serum tryptase	Mueller grading of systemic sting reactions
Kucharewicz et al. (2007)	[3]	Prospective observational	109 HV-allergic patients	Basal tryptase	Mueller grading (I-IV)
Kopač et al. (2021)	[4]	Prospective cohort	332 HV-allergic patients	Baseline tryptase, Venom-specific IgE, component-resolved IgE, basophil activation	Ring and messmer classification, systemic adverse events (SAEs) during VIT
Soyyigit et al. (2019)	[5]	Prospective cohort	82 honeybee venom allergic patients	Baseline serum tryptase, venom-specific IgE, total IgE	Ring and Messmer classification
Sturm et al. (2007)	[6]	Cross-sectional study	220 HV-allergic patients	Venom-specific IgE, total IgE	Ring and Messmer classification
Matysiak et al. (2016)	[7]	Cross-sectional (beekeepers)	54 beekeepers with BV allergy	PLA2-specific IgE, whole venom IgE	Clinical grading based on systemic symptoms
Wilson et al. (1994)	[8]	Prospective study (before and after VIT)	30 untreated + VIT patients	Venom-specific IgG, IgG subclasses, IgE	Severity of last systemic sting reaction
Ewan et al. (1993)	[9]	Retrospective analysis	38 untreated + 16 HV-allergic patients	Venom-specific IgE, IgG	Severity classification system (I-VIII)

“HV” = Hymenoptera venom (bee and/or wasp).

Severity systems were most commonly Mueller grading (I-IV) or equivalent clinical grading of systemic anaphylaxis.

Population sizes are from the original reports.

Among the immune parameters assessed, venom-specific IgE is most frequently measured (8/9 studies), followed by BST (5/9 studies). Total IgE and IgG or IgG4 are each reported in three studies (Table 1).

2. Immune parameters and reaction severity

1) Baseline tryptase

Five studies consistently show that elevated baseline tryptase is associated with more severe systemic reactions [1-5], and none reports a protective or inverse relationship. Baseline tryptase is therefore identified as the most reliable biomarker across cohorts (Table 2).

Table 2.

Studies on baseline tryptase in bee venom allergy

Study	Reference no.	Correlation with severity	Age-related effects	Clinical significance
Haeberli et al. (2003)	[1]	Higher basal tryptase strongly associated with more severe systemic sting reactions; mastocytosis patients at particular risk	Not emphasized	Elevated tryptase identifies patients at high risk of severe or fatal anaphylaxis
Ruëff et al. (2009)	[2]	Strong positive correlation: higher basal tryptase → higher risk of severe systemic reactions	Not specified	Baseline tryptase recommended as a predictor of systemic reaction severity; useful for risk stratification
Kucharewicz et al. (2007)	[3]	Significant positive correlation between basal tryptase and sting reaction severity (r ≈ 0.28)	Older patients showed higher tryptase and greater severity	Supports inclusion of tryptase and age in risk assessment
Kopač et al. (2021)	[4]	Baseline serum tryptase (BST): Significantly higher in patients with severe field sting reactions (grades III-IV) compared to those with mild/moderate reactions (grades I-II). Basophil activation test (BAT): Stronger basophil reactivity correlated with more severe systemic reactions to honeybee stings. Venom-specific IgE and component IgE (Api m 1, Api m 10): No consistent correlation with sting reaction severity.	Severity of sting reactions increased with age: older patients were more likely to experience grade III-IV systemic reactions. Logistic regression confirmed that both higher age and higher Basal serum tryptase were independent predictors of severe reactions.	BST and BAT are valuable prognostic tools: baseline tryptase identifies patients at risk for severe systemic sting reactions and systemic events during VIT, while BAT provides functional evidence of effector cell activation. Venom-specific IgE alone is not predictive. Age should be considered as a risk modifie
Soyyigit et al. (2019)	[5]	Higher tryptase associated with more severe systemic reactions. Logistic regression confirmed elevated tryptase as an independent risk factor for severe anaphylaxis (p = 0.047)	Age itself was not an independent predictor in logistic regression, but advanced age was associated with higher tryptase levels and increased risk.	Baseline tryptase is confirmed as a clinically relevant biomarker for identifying patients at risk of life-threatening anaphylaxis.

2) Specific IgE

The predictive value of venom-specific IgE is inconsistent. Absolute whole-venom IgE titers do not correlate with severity in several studies [6, 9], whereas component-resolved diagnostics—such as Api m 1 (PLA2), and, in some reports, Api m 10—show potential associations with severity in selected populations such as beekeepers [7]. Overall, IgE titers alone are poor predictors of severity, although component-resolved IgE may hold promise in selected populations (Table 3).

Table 3.

Studies on IgE in bee venom allergy

Study	Reference no.	Correlation with severity	Age-related effects	Clinical significance
Soyyigit et al. (2019)	[5]	Venom-specific IgE: Vespula vulgaris–specific IgE levels and the V. vulgaris–specific IgE/total IgE ratio were higher in grade IV patients, suggesting an association with severity. Total IgE: No significant difference in total IgE between patients with mild/moderate vs. severe systemic reactions	This older subgroup also showed higher Vespula vulgaris-specific IgE. A direct correlation between age and IgE was limited	Vespula-specific IgE levels and the sIgE/total IgE ratio were higher in patients with severe (grade IV) reactions. Total IgE did not differ significantly between mild/moderate and severe groups, limiting its predictive value.
Sturm et al. (2007)	[6]	Venom-specific IgE levels showed no significant positive correlation with severity; an inverse trend was observed (higher sIgE associated with lower grades, borderline significance). Total IgE tended to be higher in less severe reactions.	Not specifically reported	Absolute sIgE levels are poor predictors of sting reaction severity; do not rely on sIgE titers alone for risk stratification.
Matysiak et al. (2016)	[7]	PLA2 (Api m 1)-specific IgE positively correlated with clinical severity among beekeepers, whereas whole-venom sIgE correlated less consistently.	Not emphasized	Component-resolved diagnostics (e.g., Api m 1) may better reflect severity risk than whole-venom IgE alone.

3) IgG and IgG4

Two studies report no association between baseline IgG or IgG4 levels and sting reaction severity [8, 9]. In contrast, increases in IgG4 during VIT correlate with clinical protection, indicating its role as a treatment-response marker rather than a predictor of baseline risk (Table 4).

Table 4.

Studies on IgG in bee venom allergy

Study	Reference no.	Correlation with severity	Age-related effects	Clinical significance
Wilson et al. (1994)	[8]	In untreated patients, venom-specific IgG/IgG subclasses did not correlate directly with the severity of prior sting reactions; during/after VIT, IgG4 increased and was associated with protection rather than baseline severity.	Not reported	IgG/IgG4 serve as markers of immunotherapy-induced protection but are not reliable baseline predictors of natural sting severity.
Ewan et al. (1993)	[9]	Venom-specific IgG antibody levels did not correlate with the severity of previous systemic sting reactions. Venom-specific IgE levels also did not show a consistent correlation with reaction grade (1-8 scale).	Not reported	Findings indicate that neither IgG nor IgE titers reliably predict the severity of systemic sting reactions in bee or wasp venom allergy.

3. Age-related effects

Three studies show that older age is associated with higher tryptase levels and greater reaction severity [1, 3, 5], while others did not confirm this association [8]. Evidence regarding IgE is limited and inconsistent: some cohorts report an age-related increase in severity [2], whereas others do not [8]. Overall, age may act as a risk modifier, but its effect remains inconclusive (Tables 2-4).

4. Clinical evidence

1) Risk factor stratification

Baseline tryptase is the most consistent predictor of severe systemic reactions. Venom-specific IgE has limited predictive value, except for Api m 1 in specialized subgroups. Baseline IgG/IgG4 levels are not predictive, though IgG4 increases during immunotherapy reflect treatment response. Age may increase risk, but the evidence remains inconsistent (Table 5).

Table 5.

Risk factor stratification for severity in bee venom hypersensitivity

Risk factor	Predictive value	Clinical application	Evidence quality
Baseline serum tryptase [1-5]	Strong positive association with severe systemic reactions; higher levels predict higher risk.	Use baseline tryptase to stratify risk; counsel high-risk patients; consider closer follow-up and readiness for epinephrine; inform decisions around VIT and sting challenge planning.	High (multicenter/registry and prospective data: Ruëff et al. (2009) [2], Kopač et al. (2021) [4]; consistent replication across studies [1-5]).
Confirmed or suspected mastocytosis [1]	Very strong risk factor for severe/fatal anaphylaxis to stings.	Screen for mast cell disorders when tryptase is elevated or clinical suspicion exists; manage as very high risk.	Moderate–High (observational clinical data: Haeberli et al. (2003) [1]).
Age [3, 5]	Older age associated with higher tryptase and increased reaction severity in some cohorts.	Incorporate age as a modifier in risk assessment alongside tryptase and clinical history.	Moderate (observational cohorts with consistent direction: Kucharewicz et al. (2007) [3], Soyyigit et al. (2019) [5]).
Whole-venom specific IgE absolute titer [6, 9]	Inconsistent/poor predictor; no positive correlation with severity; inverse trend in one study.	Do not rely on absolute sIgE titer to estimate severity risk; use for diagnosis, not risk stratification.	Moderate (cross-sectional/observational: Sturm et al. (2007) [6], Ewan et al. (1993) [9]).
Component-resolved sIgE (e.g., Api m 1/ PLA2) [7]	Possible positive correlation with severity in beekeepers; not consistently shown across general populations.	Consider component testing when refining risk in specific groups (e.g., beekeepers), recognizing limited generalizability.	Low–Moderate (single cohort in occupational group: Matysiak et al. (2016) [7]).
IgG/IgG4 antibodies (baseline, untreated) [8, 9]	No clear correlation with baseline severity of prior sting reactions.	Not useful for predicting natural sting severity at baseline.	Moderate (prospective/observational evidence: Wilson et al. (1994) [8], Ewan et al. (1993) [9]).
IgG4 during/after venom immunotherapy (VIT) [8]	Increases with VIT and associates with clinical protection (treatment response marker), not baseline severity predictor.	Use as a pharmacodynamic marker of VIT response rather than a pre-treatment risk predictor.	Moderate (prospective VIT data: Wilson et al. (1994) [8]).
Total IgE [6]	Trend toward lower severity with higher total IgE in one study; overall poor predictive value.	Do not use total IgE to estimate severity; interpret in diagnostic context only.	Low–Moderate (single cross-sectional signal: Sturm et al. (2007) [6]).
Basophil activation test (BAT) [4]	Measured in a prospective cohort; limited evidence for direct severity prediction.	May complement assessment in specialized centers; evidence insufficient for routine severity risk prediction.	Low–Moderate (single prospective cohort including BAT: Kopač et al. (2021) [4]).

2) Combined parameters

Evidence suggests that combining biomarkers may improve prediction. For example, one cohort study reports that integrating age, baseline tryptase, and basophil activation testing enhances prognostic accuracy [4]. Other studies report that ratios such as IgE/IgG4 or the combination of Api m 5–specific IgE with tryptase levels show stronger associations with severity than any single marker alone [5, 8].

DISCUSSION

These findings suggest that a multiparameter approach to risk assessment is more effective than reliance on a single biomarker. Combining baseline tryptase with parameters such as component-resolved IgE or basophil activation may particularly enhance predictive accuracy. However, further prospective studies are needed to validate these approaches and determine the optimal set of biomarkers for clinical use.

Overall, this review shows that several immune parameters may predict the severity of allergic reactions in patients with bee venom hypersensitivity, with BST emerging as the most consistent and clinically relevant predictor across studies. In contrast, venom-specific IgE shows inconsistent predictive value: whole-venom IgE has limited prognostic significance, while component-resolved IgE (e.g., Api m 1) may be useful in selected populations. IgG and IgG4 levels do not reliably reflect baseline severity, although IgG4 increases during immunotherapy indicate treatment-related protection. Age may also be a risk modifier, but findings are heterogeneous and inconclusive.

In Korea, bee venom pharmacopuncture is widely used for musculoskeletal disorders, neurological diseases, and cancer, making safety a critical concern. This review partly addresses this need by evaluating biomarkers that may predict adverse reactions and improve patient safety.

In conclusion, baseline tryptase offers the strongest evidence for predicting severe systemic reactions to bee venom. Nevertheless, variability in IgE- and IgG-related findings, age effects, and molecular-level components underscore the need for further well-designed studies. Therefore, future research should focus on validating multiparameter diagnostic strategies and developing risk assessment tools suitable for clinical practice, particularly in settings such as bee venom pharmacopuncture, where patient safety is critical.

CONCLUSION

This review demonstrates that BST is the most consistent biomarker for predicting severe bee venom allergic reactions. In contrast, specific IgE and IgG have inconsistent predictive values, though component-resolved diagnostics may provide additional insights in selected populations. Age may influence risk, but it shows variable effects across studies. Overall, these findings suggest that integrating tryptase with other immunological markers is preferable to relying on a single biomarker.

In Korea, where bee venom pharmacopuncture is widely used in clinical practice, ensuring patient safety is particularly important. Reliable biomarkers could enhance risk stratification, prevent severe adverse events, and improve bee venom therapy safety. Further prospective studies are needed to validate these markers and develop standardized clinical guidelines.