Alpha-gal Immunoglobulin E Seroprevalence Among Blood Donors — 10 States, 2024–2025

Abstract

Alpha-gal syndrome (AGS) is an emerging, noninfectious tickborne disease characterized by an allergic reaction to galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in red (mammalian) meat and other mammalian products such as dairy and gelatin. As of 2022, AGS was estimated to affect up to 450,000 persons in the United States (1). Anaphylactic AGS reactions can be fatal, and AGS allergic reactions encompass a range of symptoms including urticaria, angioedema, wheezing, and gastrointestinal distress. AGS is primarily managed through an avoidance diet. The U.S. geographic distribution of AGS is closely associated with the range of the lone star tick (Amblyomma americanum); bites from this tick introduce alpha-gal through its saliva, which can trigger the allergy. Diagnosis of AGS requires both the presence of clinically compatible symptoms and the detection of serologic immunoglobulin E (IgE) antibodies against alpha-gal. Persons can have alpha-gal–specific IgE antibodies without clinical symptoms. The proportion of persons in the United States who are seropositive for alpha-gal IgE is unknown. To better understand the distribution and seroprevalence of alpha-gal IgE among U.S. adults, 3,000 serum samples collected during November 2024–April 2025 from blood donors living in 10 states were tested for the presence of alpha-gal IgE antibodies. States previously reported to have high numbers of suspected AGS cases were found to have correspondingly high seroprevalences. Among the 10 states, the highest estimated seroprevalences among persons aged ≥16 years were detected in Arkansas (31.2%) and Missouri (26.0%). These findings can guide the development of surveillance systems for AGS and help identify regions at increased risk.

Introduction

Alpha-gal syndrome (AGS) is an emerging, noninfectious tickborne disease. Persons with AGS experience allergic symptoms after exposure to the oligosaccharide galactose-α-1,3-galactose (alpha-gal). Alpha-gal is found in red (mammalian) meat, dairy products, and mammalian-derived byproducts such as gelatin. Alpha-gal is found naturally in the saliva of many tick species (2). In the United States, AGS is most commonly understood to develop after the bite of a lone star tick (Amblyomma americanum). Lone star and certain other tick bites induce production of alpha-gal–specific immunoglobulin E (IgE) by injecting salivary alpha-gal (the allergen) along with other tick salivary molecules such as prostaglandins that provoke the human immune response. Physical disruption of the skin barrier (e.g., through a tick bite) plays an important role in the development of this allergy (2,3).

Persons with IgE antibodies against alpha-gal either have AGS (symptomatically seropositive) or are sensitized (asymptomatically seropositive). The Council of State and Territorial Epidemiologists 2022 alpha-gal syndrome confirmed case definition requires clinical criteria and confirmatory laboratory evidence of serum or plasma alpha-gal–specific IgE of ≥0.1 kU/L. A case with no clinical information available but with confirmatory laboratory evidence is considered a suspect case. Tick bites increase the risk for both AGS and sensitization to alpha-gal (4,5). Only a small minority of persons who are seropositive have AGS, although the precise percentage is unknown. A 2019–2020 case-control study identified 63 control participants who were alpha-gal IgE seropositive in North Carolina, none of whom had AGS (4). However, as with other allergies, being sensitized to a specific allergen might be a risk factor for future development of the corresponding allergy (6).

Studies have examined alpha-gal IgE seroprevalence in certain populations at risk for tick exposure or within specific geographic regions (3,5). Among adults in the southeastern United States, seroprevalences between 16% in a Virginia study (3) and 60% among North Carolina state park and forestry employees (5) have been reported. To further understand the geographic distribution of alpha-gal IgE seropositivity, seroprevalence was estimated at a state population level using data from blood donor samples in 10 states.

Methods

Data Source

During November 14, 2024–April 9, 2025, samples of residual donor serum and corresponding demographic variables (age, sex, race and ethnicity, zip code, and county of residence) were obtained from specimens collected from 3,000 unique blood donors* (300 per state from 10 selected states: Arkansas, Kentucky, Maine, Minnesota, Missouri, New Mexico, South Carolina, Tennessee, Virginia, and Washington).^† County of residence included U.S. Census Bureau county–equivalent entities, including the city of St. Louis, Missouri, and multiple independent cities in Virginia. Samples were acquired by Creative Testing Solutions via quota sampling of sequential residual donor sera. Consent for the use of specimens for research purposes was obtained by the American Red Cross and Vitalant from blood donors at the time of blood donation, per routine protocol.

Serologic Analysis

Serum was tested at the University of North Carolina at Chapel Hill using ImmunoCAP o215 (Thermo Fisher Scientific; Waltham, Massachusetts), a highly sensitive blood test component that measures alpha-gal–specific IgE antibodies, using the Phadia 250 instrument (Phadia; Uppsala, Sweden). An alpha-gal IgE titer of ≥0.1 kU/L was defined as a positive result.

Statistical Analysis

For population inference, poststratification based on 2020 U.S. Census Bureau data was used to account for differences between the sampled blood donors and each donor’s state population, aligning the sample data with the age group (16–34, 35–44, 45–54, 55–64, 65–74, and ≥75 years) and sex distributions of each donor’s state population. Univariate logistic regression was used to calculate the estimated odds of seropositivity by age, sex, race, ethnicity, and urban-rural county designation adapted from the 2023 National Center for Health Statistics (NCHS) Urban-Rural Classification Scheme. The six NCHS categories were subgrouped into three categories: urban (large central metropolitan), suburban (large fringe metropolitan, medium metropolitan, and small metropolitan), and rural (micropolitan and noncore). Bonferroni adjustments for multiple comparisons were applied to comparisons of interest. A logistic quasibinomial regression model was used to quantify the relationship between seropositivity and county population density from the 2020 U.S. Census Bureau. Statistical analyses were performed using R (version 4.5.0; R Foundation). Statistical significance was defined as a 95% CI that excluded the null value. This activity was reviewed by CDC, deemed research not involving human subjects, and conducted consistent with applicable federal law and CDC policy.^§

Results

Demographics of Blood Donors

The median age of blood donors included in the study was 62 years (range = 16–95 years). A total of 56.2% were male, 92.9% were White, and 93.4% were not Hispanic or Latino (non-Hispanic) (Table 1).

Estimated Alpha-gal IgE Seroprevalence, by State

Estimated (poststratified) alpha-gal IgE seroprevalence ranged from 1.1% in Washington to 31.2% in Arkansas (Table 2). Among positive test results in each state, estimated geometric mean alpha-gal IgE titers were highest in Kentucky and lowest in Washington (Supplementary Figure 1). Seroprevalence was not uniform within states, as evidenced by substantial variations by county (Figure). The combined estimated seroprevalence in the five states with the highest seroprevalence was 24.0%.

Population Characteristics by Alpha-gal IgE Serostatus

The estimated alpha-gal IgE seroprevalence among persons aged 16–34 years was lower than that among persons aged 55–64 years (odds ratio [OR] = 0.40). Estimated seroprevalence was higher among males than among females (OR = 1.61). The estimated seroprevalence among Hispanic persons (who accounted for 4.8% of blood donor samples) was lower than that of non-Hispanic persons (OR = 0.43). For every tenfold increase in county population density, the probability that a county resident aged ≥16 years was alpha-gal IgE seropositive decreased by 29.5%. Counties with at least one seropositive donor were predominantly suburban or rural. However, in states with high seroprevalences, urban counties also had seropositive donors (Supplementary Figure 2). Blood donors with positive alpha-gal IgE antibody titers were identified in urban counties in Kentucky, Missouri, Tennessee, and Virginia. Among all counties in Arkansas, none of them are classified as urban.

Discussion

The U.S. geographic distribution of alpha-gal IgE seroprevalence identified in this serosurvey is similar to the distribution of suspected cases of AGS (1). In this analysis, estimated alpha-gal IgE seroprevalence was higher in states with established populations of lone star ticks (Arkansas, Kentucky, Missouri, South Carolina, Tennessee, and Virginia) than in the four analyzed states outside the lone star tick range. New Mexico and Washington are outside the established range of this tick species, whereas southernmost Minnesota and southeastern coastal Maine are within the estimated range but do not have documented established populations of lone star ticks. Despite the documented presence of lone star ticks in South Carolina, estimated seroprevalence in this state was low. The reason South Carolina has fewer reported cases of both AGS and ehrlichiosis, a serious bacterial infection primarily transmitted by the lone star tick, compared with reported cases from neighboring states, is unknown (1). Although coastal Maine is on the northern edge of the lone star tick range, recent evidence indicates that bites from blacklegged ticks (Ixodes scapularis), a species found in Maine, can also cause AGS. This finding might account for the relatively high seroprevalence observed in Maine (2,7). Understanding the geographic distribution of seroprevalence in selected U.S. states can strengthen public health surveillance and guide clinicians about local risk.

County population density was found to be inversely associated with seroprevalence. Although residents of less populated areas are at higher risk for tick bites, and bites of the lone star tick are the primary known risk factor for alpha-gal IgE seropositivity (4), seroprevalence was not statistically different in rural, suburban, and urban areas. This might be attributable in part to the details of rural, suburban, and urban definitions; the narrow definition of urban in this study (comprising large central metropolitan counties only, accounting for 8.0% of blood donors); travel and relocation; and opportunities for tick encounters in all county types.

Alpha-gal IgE testing has low specificity for AGS; results from this study indicate that nearly one fourth (24%) of the population aged ≥16 years in states with the highest numbers of suspected AGS cases per population would receive a positive alpha-gal IgE test result. In one 10-year chart review of patients seeking care at an allergy clinic in Suffolk County, New York, 7.5% of referred patients were determined by the allergist to be seropositive only (i.e., sensitized), without clinically compatible AGS symptoms (8). Reliance on positive alpha-gal IgE test results without considering whether patients also have clinical signs and symptoms of AGS might result in overdiagnosis and unnecessary dietary restrictions. In addition, although cardiovascular implications of sensitization have been studied (9), the evidence is insufficient to recommend dietary modifications for sensitized but nonallergic persons. Overdiagnosis poses challenges for public health surveillance, the goal of which is to identify clinical disease. Indiscriminate clinical testing might increase the time and effort needed by public health officials to verify that clinical criteria are met for case identification.

Limitations

The findings in this report are subject to at least three limitations. First, the voluntary blood donor population differs from the general population because it typically comprises persons who have higher socioeconomic and health statuses, are predominantly White, and were born in the United States (10). Poststratification by age and sex was used to reduce potential biases in inference that might have resulted from using blood donor samples; however, these characteristics are not expected to be completely aligned with relevant donor and population differences. The number of donors in this study who were not White was too low to enable making reliable inferences by race. Second, opportunistic sampling methods and the location of blood donation centers resulted in uneven geographic coverage within states, decreasing statewide representativeness. Finally, blood donors disproportionately have type O blood, which might have affected the findings; increasing evidence indicates that alpha-gal IgE seroprevalence might be lower in persons with type B blood (3). Type B blood has been found to be protective against both alpha-gal seropositivity and AGS. This might have resulted in seroprevalence overestimates in this report because the general U.S. population includes more persons with type B blood than does the blood donor sample population.

Implications for Public Health Practice

The estimated state-level alpha-gal IgE seroprevalences in this study far exceed the 2022 estimate of up to 450,000 persons nationwide affected by AGS (0.14% of the U.S. population, based on the 2022 U.S. Census Bureau estimated population). As AGS becomes a reportable condition in an increasing number of states and disease surveillance efforts increase, more data will become available to ascertain the proportion of seropositive persons who also are allergic (i.e., have AGS).

In areas of the United States where lone star tick populations are established, 5.5%–31.2% of the human population aged ≥16 years might receive a positive alpha-gal IgE test result and therefore possibly be at increased risk for future development of AGS. Because of this level of population seroprevalence using the current diagnostic test and threshold for positivity, IgE testing should only be performed for patients with a clinical history and symptoms consistent with AGS. A more specific diagnostic method, and possibly an increase in the threshold for alpha-gal IgE positivity, are needed to improve AGS surveillance (4). Public health case investigations will be required to evaluate clinical symptoms in addition to IgE testing data, which could strain the resources in the most affected states. Blood donor seroprevalence data align well geographically with areas where persons are impacted by AGS. This adds further support for a geographic focus for AGS surveillance, tick bite prevention, and health care provider education. Elevated alpha-gal IgE seroprevalence might also serve as sentinel surveillance for areas and populations where cases might be underdiagnosed and underreported to improve estimates of AGS incidence.