Tick bites linked to alpha-gal syndrome
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Tick bite history was a risk factor for alpha-gal syndrome and elevated alpha-gal-specific IgE levels, according to a case-control study published in Annals of Allergy, Asthma & Immunology.
These data, which confirm findings suggested by case reports and series, make tick bite prevention critical in preventing long-term health effects, according to the researchers.
Although the lone star tick (Amblyomma americanum) is the primary suspect, other species may be responsible as well, Gilbert J. Kersh, PhD, chief of the rickettsial zoonoses branch in the division of vector-borne diseases at the CDC, and colleagues wrote in the study.
“As one of the branches at CDC that is responsible for tickborne diseases, our attention was drawn to the increasing reports of alpha-gal syndrome (AGS) in the United States,” Kersh told Healio.
However, the researchers noted that the relationship between tick bites and AGS was largely based on case reports, case studies and anecdotal evidence.
“There were very few controlled studies that addressed the relationship between tick bites and AGS. We set up a case-control study to see if the suspected relationship between tick bites and AGS would hold up,” Kersh said.
Study design, results
The study involved 82 patients (median age, 58.5 years; 55% women; 2% Black) presenting for diagnosis and treatment of AGS at a university-based allergy clinic as well as 191 controls (median age, 54 years; 62% women; 14% Black) from an internal medicine clinic in 2019 and 2020.
All the control individuals were residents of North Carolina, whereas patients included 10 from Virginia, four from Alabama, three each from Tennessee and Maryland, and one each from the District of Columbia, Kentucky, New Jersey, Pennsylvania and Rhode Island.
Results of a questionnaire showed patients were more likely to report that they had found a tick on their body in the year before symptom onset than controls did in the previous year (OR = 11.2; 95% CI, 4.97-25.15).
“This study found that there is clearly a strong association between patients reporting tick bites and being diagnosed with AGS,” Kersh said.
Also, patients found ticks more often on their bodies and were more likely to have found embedded ticks than the controls, with 39% of patients and 17% of controls finding ticks 10 or more times (OR = 4.2; 95% CI, 1.91-9.24).
Similarly, a greater proportion of patients than controls found four or more embedded ticks (48% vs. 9%: OR = 33.05; 95% CI, 9.92-155.12) and experienced a reaction (76% vs. 29%; OR = 7.93; 95% CI, 3.74-16.8).
Blood serum results showed more patients than controls tested positive for antibodies to the Rickettsia rickettsii and/or Ehrlichia chaffeensis tickborne pathogens (17% vs. 9%; OR = 2; 95% CI, 0.9-4.2), suggesting greater exposure to ticks among patients.
Compared with controls, patients also were more likely to have five or more acres of land (OR = 2.9; 95% CI, 1.33-6.29), shrubs and brush (OR = 2.32; 95% CI, 1.19-4.48), farmland (OR = 2.05; 95% CI, 1.17-3.6) and woods (OR = 2.27; 95% CI, 0.92-5.55) around their home, as well as to have spent 25 hours or more outside per week (OR = 2.62; 95% CI, 1.16-5.91) and 17 hours or more per week in wooded areas (OR = 5.58; 95% CI, 2.56-12.19).
Overall, 98% of patients and 33% of controls had a positive test for alpha-gal sIgE at enrollment using a 0.1 kU/L cutoff, although these controls did not report any AGS symptoms and presumably were not aware that they were positive for alpha-gal sIgE.
Still, finding a tick in the previous year increased odds of alpha-gal sIgE positivity among controls (OR = 4.25; 95% CI, 2.21-8.18), but this risk did not increase with the number of times that ticks were found or with the number of embedded ticks.
Patients with AGS had higher total IgE levels (geometric mean [GM], 145.2 kU/L; 95% CI, 110.4-191) than the controls (GM = 44.3 kU/L; 95% CI, 36.2-54.2) as well, in addition to higher percentage of total IgE attributable to alpha-gal sIgE (6.7% vs. 2.4%).
“The levels of alpha-gal IgE were lower in the control group compared with people diagnosed with AGS, but people in the control group with antibodies also reported having been bitten by ticks, although they reported fewer ticks and bites,” Kersh said.
Conclusions, next steps
The lone star tick is most likely to bite human beings in the Southeast, leading the researchers to believe it was the source of most of the bites in this study. However, the researchers cautioned that AGS occurs in other areas, indicating that other ticks may be involved.
“This study emphasizes the point that avoiding further tick bites is critical for patient management and reducing alpha-gal sIgE levels, as repeated tick bites can induce higher levels of IgE antibodies,” Kersh said.
The researchers recommended the use of personal protective measures such as EPA-registered insect repellents, checking for ticks after time outdoors and prompt removal of any ticks that are found.
“These personal protective measures can not only help prevent tickborne infections but also reduce the risk for a potential lifelong sensitivity to mammalian meat,” Kersh said.
Patients with AGS manage their illness primarily by avoiding mammalian meat and other products that may include alpha-gal such as milk in their diet, Kersh said, adding that if their alpha-gal sIgE levels decline over time, some patients can slowly reintroduce these items.
“Lastly, given the high percentage of people without AGS in the control group who tested positive for antibodies to alpha-gal, clinicians need to be aware that AGS is diagnosed with both a thorough patient history and clinical exam along with positive IgE results,” Kersh said.
The researchers now are using this data to examine intrinsic risk factors, such as the health or genetic factors that make patients more likely to respond to tick bites by developing an allergic response to alpha-gal.
“We are also working to improve reporting and surveillance of AGS in the United States to get a better understanding of the distribution and burden of this emerging condition,” he said.
For more information:
Gilbert J. Kersh, PhD, can be reached at hws7@cdc.gov.
Perspective
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I am thrilled that this study by Kersh et al has been published. For years, researchers worldwide have reported an association between tick bites and the development of AGS, or alpha-gal sensitivity. This work enables us to now move beyond an association to recognize exposure to ticks as a proven risk factor for AGS.
Physicians in areas with a prevalence of ticks, especially the lone star tick, should immediately consider AGS a possibility for patients who manifest common AGS symptoms, such as gastrointestinal distress and hives. Additionally, because AGS has delayed-onset signs, if people experience abnormal symptoms in the middle of the night, that should also raise a red flag for AGS.
Doctors must listen to their patients if they describe ongoing issues that are not resolving. For example, I know a little girl who experienced severe stomach aches for months while living in a tick-endemic area. Doctors ran thousands of dollars of tests on her to no avail. With proper knowledge of the signs, symptoms and prevalence of AGS, her doctors could have conducted a $38 AGS test and gained an accurate diagnosis from the beginning.
The results of this study match very closely with what we have been finding at Tick-Borne Conditions United. Most patients we have surveyed recall having a tick bite. We also know from research that the more “edge” in our environment — the interface between humans and the woods (natural areas) — that people are more likely to get tick bites.
We need significantly more education and research about the lone star tick. Most people do not understand the aggressive behavior of this species. It responds to carbon dioxide from as far as 100 feet away and comes running. We also need to better understand the role of the black-legged tick (Ixodes scapularis), which transmits Lyme disease, in the development of AGS. Researchers have isolated the alpha-gal carbohydrate in its saliva as well. If Lyme disease patients also have undiagnosed alpha-gal sensitivity, they could experience ongoing health challenges due to treatment with medications that contain mammalian ingredients.
We look forward to continued research and education about alpha-gal sensitivity and AGS.
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