Alpha-Gal Syndrome Subcommittee Report to the Tick-Borne Disease Working Group

Disclaimer

Information and opinions in this report do not necessarily reflect the opinions of the Working Group, the U.S. Department of Health and Human Services, or any other component of the Federal Government. Readers should not consider the report or any part of it to be guidance or instruction regarding the diagnosis, care, or treatment of tick-borne diseases or to supersede in any way existing guidance. All subcommittee members actively participated in the development of this report. Members voted to approve submission of the report to the Working Group and on the wording of each of the possible actions contained in the report. The vote to submit the report indicates general agreement with the content of the document, but it does not necessarily indicate complete agreement with each and every statement in the full report.

Definitions

Alpha-gal is a carbohydrate found in all mammals but not in humans or Great Apes. Mammals are warm- blooded animals that give live birth, have hair (or fur), and nurse their young. Examples of commonly consumed mammalian meats that contain alpha-gal include beef, pork, lamb, venison, rabbit, goat, squirrel, buffalo, etc. Alpha-gal is present in the milk from these animal sources as well as their organ meats. Chicken, turkey (that is, poultry), fish and shellfish (that is, seafood) do not have alpha-gal and are safe for patients with Alpha-gal Syndrome (AGS) allergy to consume. For the purposes of this report, the term “mammalian meat” and “mammalian-derived” will be used to refer to non-primate mammalian meat (beef, pork, lamb, etc.) and its animal sources as these are alpha-gal containing foods or products. Equally, note that references may state “mammalian meat” or “red meat” yet these also refer to non-primate mammalian meat, which is the primary source of alpha-gal.

Background

Alpha-gal Syndrome (AGS) is an allergy to the carbohydrate galactose-alpha-1,3-galactose (“alpha-gal”) that is present in lower mammals such as cows, sheep, pigs, cats, and dogs (Levin et al., 2019). People who develop AGS most commonly report allergic reactions after eating beef, pork, or lamb (Commins et al., 2014). Unlike more traditional food allergies, reactions to alpha-gal occur 3-6 hours (or more) after consuming mammalian meat, and this prolonged delay frequently creates a challenge in diagnosis (Commins et al., 2014; Flaherty, Kaplan, & Jerath, 2017; Levin et al., 2019). Moreover, alpha-gal allergy is currently best understood as a “syndrome” because of the ubiquitous presence of mammalian-derived products and sources in seemingly innocuous exposures such as gummy bears and capsules (gelatin), medications (for example, heparin and thyroid hormone), bioprosthetics (for example, porcine heart valves), surgical mesh, select vaccines, and unlabeled “natural flavorings” in countless foods (Commins, 2016).

Although it is not fully established how AGS develops, accumulating evidence suggests that tick bites play a causal role (Commins et al., 2011). In the United States, the primary tick associated with AGS is Amblyomma americanum (the lone star tick) (Commins et al., 2011). However, in other areas of the world different species of ticks have been associated with the allergy (Chinuki, Ishiwata, Yamaji, Takahashi, & Morita, 2016; Levin et al., 2019; Van Nunen, O'Connor, Clarke, Boyle, & Fernando, 2009). There is no current evidence of an infectious or pathogenic etiology associated with the development of AGS (Commins, 2016). Studies related to the etiology of AGS implicate tick bites but have not demonstrated the specific factor(s) within ticks (or humans) that triggers the allergic immune response (Chinuki et al., 2016; Commins et al., 2011; Crispell et al., 2019; Khoury, Khoury, Schaefer, Chitnis, & Hassen, 2018). Furthermore, studies using murine models also implicate tick bites as triggering an Immunoglobulin E (IgE) response (Chandrasekhar et al., 2019), which is an allergic reaction resulting from the production of IgE antibodies in response to a foreign substance. Despite the association with tick bites, at this time AGS is not reportable as a tick-borne disease per the guidelines of the National Institutes of Health or the Centers for Disease Control and Prevention (CDC).

It is also not known how to identify individuals pre-disposed to AGS. For example, why do some people bitten by the lone star tick develop the allergy but others do not? For individual pediatric and adult patients with AGS, symptoms vary and may include hives, itching, redness, anaphylaxis, gastrointestinal distress, cramping, diarrhea, nausea, and vomiting (Commins et al., 2014; Levin et al., 2019).Co-factors, such asphysical activity, alcohol consumption, and stress, may also affect individual allergic reactions (Commins, 2016; Levin et al., 2019). Because additional tick bites may affect the immune response to alpha-gal, it has been suggested that without additional tick bites, the allergic response to alpha-gal may wane 4-5 years later for some patients (Commins et al., 2011). However, it has been suggested that this might be a state of “remission” because additional tick bites have been reported to cause the allergy to recur (Commins, 2016; Khoury et al., 2018). For many patients, AGS appears to be a permanent condition. Additional resources are needed to establish the natural history of alpha-gal allergy.

Accumulating data suggest that the incidence of AGS is on the rise, with thehighest number of incidences reported in the southeast region of the United States, which correlates with the expanding geographic distribution of lone star ticks (Commins, 2016; Commins et al., 2011; Levin et al., 2019; Pattanaik, Lieberman, Lieberman, Pongdee, & Keene, 2018). In 2009, there were 24 reported cases of alpha-gal syndrome; however, most recent estimates exceeded 5,000 cases and AGS was identified as the leading cause of anaphylaxis in a southeastern registry of patients (Pattanaik et al., 2018). AGS has been diagnosed throughout the world and in each population ectoparasitic ticks (or other parasitizing exposures) have been implicated, which demonstrates a scope beyond the lone star tick and beyond the United States (Chinuki et al., 2016; Commins et al., 2011; Levin et al., 2019; Van Nunen et al., 2009).

However, more accurate diagnostic data on the scope and true incidence of the allergy are needed to fully appreciate and validate the rates. Including human-biting tick data in epidemiological investigations and linking them with clinical data would overcome limitations in alpha-gal surveillance and allow for more accurate risk assessment. To overcome diagnostic challenges, advances in diagnostic tools are needed to further evaluate the prevalence of alpha-gal-specific antibodies in humans. In addition, the assignment of a diagnosis code for alpha-gal would help accumulate more accurate prevalence data (Z91.018, allergy to other foods, is the currently used ICD 10 code). The identification of marker(s) that can correlate tick bite with clinical symptoms of AGS and associated conditions is also needed. Currently, symptom presentation complicates diagnosis as patients may show different symptoms, which are delayed from ingestion of alpha-gal-containing foods. Studies have suggested that CD63 might be a possible diagnostic biomarker for allergic activation (Commins et al., 2014), and the tick sialome may offer clues into the development of the allergy (Crispell et al., 2019).

Clinicians manage AGS differently from other tick-borne conditions (Commins, 2016; Levin et al., 2019). However, there is currently no Food and Drug Administration (FDA)-approved treatment for food allergy in general or alpha-gal allergy specifically. Treatment plans are either “off-label”, which may affect payer coverage, or part of a clinical protocol. Research to expand treatment options for AGS is warranted, along with provider access and reimbursement coverage. There is also a need for evidence-based treatment guidelines, which will benefit both healthcare providers (for example, clinicians, emergency medical services) and payers, and for integrated validated resources for identifying mammalian products to support patients with coordinated nutritional care.

AGS may have a significant impact on patients’ lifestyles, resulting in illness and life-long changes to eating habits (Flaherty et al., 2017). These changes affect not only patients, but also their caregivers and families physically, psychosocially, emotionally, and financially (Flaherty et al., 2017). Prevention strategies for AGS should be focused on awareness and education. Currently, knowledge of the general public is limited around lone star ticks, allergic reactions to alpha-gal, and the implications of the syndrome (Commins, 2016; Flaherty et al., 2017).

As deer (versus white footed mouse) are the principal host for lone star ticks, population control strategies for deer (for example, hunting) are needed to aid tick management.

Methods

Characteristics of the Subcommittee

During the June 4, 2019 meeting of the Tick-Borne Disease Working Group (TBDWG), members volunteered to co-chair subcommittees, with at least one federal and one public representative leading each group. One federal employee (Angel Davey, PhD) and two members of the public (Scott Commins, MD, PhD and Leigh Ann Soltysiak, MS) volunteered to co-chair the Alpha-Gal Syndrome Subcommittee.

In line with the guidance from the 21st Century Cures Act to seek expert opinion and cross-functional stakeholder guidance, the co-chairs invited individuals to participate as subcommittee members based on their knowledge and expertise relevant to the subcommittee’s focus area, while ensuring well-rounded, diverse representation. Invitees included academic researchers who are experts in lone star ticks (alpha-gal allergy in the United States is associated primarily with bites from the lone star tick), as well as tick surveillance in general, scientist clinicians with expertise in AGS and immunology, and importantly alpha-gal patients and patient advocates. The total composition of the Alpha-Gal Syndrome Subcommittee, as well as key characteristics of the subcommittee co-chairs and members (for example, professional expertise, past experience addressing these issues, personal experience as a patient, etc.) are outlined in Table 1.

Subcommittee Meetings

Alpha-Gal Syndrome Subcommittee conducted weekly conference calls on every Tuesday, beginning July 16, 2019. As of December 12, 2019, the subcommittee has conducted a total of 18 meetings. Member attendance, presenters, and topics discussed during the conference calls are explained in Table 2.

The first two meetings included discussion around development of the subcommittee report to TBDWG, as well as discussion of the key issues/topic areas and gaps in knowledge to be included in the Background section (Table 2). In addition, subcommittee members via email submitted high-level content for framing the preliminary report and exchanged meeting agendas and timelines, as well as draft presentation slides. During those initial subcommittee meetings, members identified the following key issues in the fields of AGS research and patient care.

Awareness and education
Treatment and support
Etiology, pathogenesis, and symptoms
Diagnosis and diagnostics
Tick surveillance and tick-species correlation
Prevention and tick-targeted interventions
Transmission and the tick sialome.

Experts in the identified priority areas were identified and were invited to present at subcommittee meetings (Table 3). These presentations provided the subcommittee with further information and knowledge related to AGS and helped the subcommittee foster discussion between subcommittee members and external speakers. These presentations along with peer-reviewed literature identified by subcommittee members helped clarify and refine key issues and concerns to be addressed in the Alpha-Gal Syndrome Subcommittee Report.

Public Comment and Inventory

In addition, the subcommittee co-chairs reviewed all public comments submitted to TBDWG to obtain information on specific concerns of patients with AGS and on general concerns of patients with tick-borne diseases because some of these concerns could be relevant to AGS as well. This public information was incorporated into all topic areas of the report. Because AGS is not reportable as a tick-borne disease, information from the federal inventory may not be directly applicable or informative to this subcommittee. Resources, including meeting summaries and presentations were made available via SharePoint for reference by subcommittee members.

Subcommittee Report Development

Alpha-Gal Syndrome Subcommittee Report content was developed during meeting discussions and email conversations between meetings. The subcommittee co-chairs wrote the Background and Methods sections, and subcommittee members wrote sections related to their expertise and assigned topic areas. The co-chairs finalized each subcommittee member’s writing and distributed to the group for them to review, discuss, and obtain consensus. Disagreements and differences in opinions were addressed by allowing everyone to express their opinion and capturing all views in the subcommittee report. The subcommittee members discussed and voted on the ranking of the priorities/topic areas and the wording of each of the possible actions. Votes were recorded for/against each of the possible actions within the various topic areas comprising the Results and Potential Actions section and for/against the prioritization of the various topic areas themselves. The subcommittee also subsequently voted on the top three possible actions for the Working Group to consider. Being a diverse group, a wide variety of interests were identified and discussions continued until a consensus was reached for the primary recommendations. There were no minority responses for this subcommittee.

Brief for the Working Group

The Alpha-Gal Syndrome Subcommittee developed its PowerPoint briefings for the Working Group based on the gaps, identified needs, and possible actions addressed within each of the key issues/topic areas of the subcommittee report (Surveillance, Epidemiology, and the Role of Tick Bites in Alpha-gal Syndrome; Diagnosis and Management of Alpha-gal Syndrome; Education, Awareness, and Support from Patients’ Perspective; and Tick Bite Prevention and Tick Control.

Table 1: Members of the Alpha-Gal Syndrome Subcommittee

Subcommittee Members	Type	Stakeholder Group	Expertise
(Co-chair) Scott P. Commins, MD, PhD,University of North Carolina, Chapel Hill, NC	Public	Scientist and Health Care Provider	Expert in AGS, among the first researchers to link the allergy to bites from ticks; maintains an active research program and clinical practice
(Co-chair) Angel M. Davey, PhD, Congressionally Directed Medical Research Programs, Fort Detrick, MD	Federal	DoD: Scientist	Program Manager for the Tick-Borne Disease Research Program
(Co-chair) Leigh Ann Soltysiak, MS, Integrated Marketing Communications; Founder, Silverleaf Consulting, LLC, Summit, NJ; Adjunct Professor, Entrepreneur Thinking, Stevens Institute of Technology, Hoboken, NJ	Public	Recovered TBD Patient; Industry Stakeholder	Lyme and tick-borne disease advocate
Charles Apperson, PhD, Public Health Entomology and Vector Biology, North Carolina State University	Public	Scientist	Entomologist and vector biologist, studies lone star ticks
Beth Carrison, INHC, Tick-Borne Conditions United, Chelmsford, MA	Public	Patient	Advocate for patients with AGS and Lyme disease; co-founder of an advocacy organization
Shahid Karim, PhD, Biological Sciences, University of Southern Mississippi	Public	Scientist	Vector biologist, studies tick sialome, lone star ticks
Stephen Rich, PhD, Laboratory of Medical Zoology, Department of Microbiology, University of Massachusetts	Public	Scientist	Vector biologist, tick pathogen surveillance expert
Sarah Stuart	Public	Patient	Advocate for AGS patients

Table 2: Overview of Alpha-Gal Syndrome Subcommittee Meetings, 2019

Meeting No.	Date	Nicole Green (DHHS),Present	Topics Addressed
1	July 16, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Leigh Ann Soltysiak (co-chair), Sarah Stuart Jennifer Gillissen (contract support), Katie Terra (contract support)	Introduction of members; review of subcommittee purpose and processes, including milestones and responsibilities, topics suggested for subcommittee report, and discussion of potential expert speakers.
2	July 30, 2019	Charles Apperson, Beth Carrison, Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair) Nicole Greene (TBDWG support), Jennifer Gillissen (contract support.), Katie Terra (contract support)	Discussion of topic area assignments for developing subcommittee report, including evaluation of public comments and submission of high-level summaries; development of meeting agendas including scheduling expert speakers; discussion of gaps in knowledge to be included in Subcommittee Report Background section.
3	Aug 6, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support)	PowerPoint overview presentation by Dr. William Nicholson (Division of Vector Borne Diseases, CDC), “Alpha-gal Allergy Following Tick Bite: What Do We Really Know?”; presentation discussion included distribution in nature, allergic reactions to alpha-gal, clinical and epidemiological features, management of the allergy, role of ticks in the allergy, and localization of alpha-gal in ticks; discussion of progress on Background and Methods sections of the subcommittee report; review of milestones and deliverables for Results and Potential Actions sections.
4	Aug 13, 2019	Beth Carrison, Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair) Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	PowerPoint presentation by Dr. Stephen Rich (member), “Tick-Borne Disease Surveillance and Exposure” framed around the TickReport effort at UMASS; subsequent group discussion included metagenomics of ticks, role of mass spectroscopy in testing pathogens, value of tick testing, testing for AGS, tick-species correlation, biomarkers, and linking surveillance data to clinical data; discussion of progress on Background and Methods sections of the Subcommittee Report; reminder of high-level summaries.
5	Aug 20, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support	PowerPoint presentation by Dr. Thomas Mather (Tick Encounter Center, University of Rhode Island [URI]), “How TickSmart Are YOU? 5 Things to Do Now to Prevent Tick-borne Disease” framed around the TickSpotters program at URI; presentation discussion included public education needs, ticks and the pathogens they may carry, pathogenesis and disease transmission, reservoir host and tick management strategies, and testing and identifying tick risk factors; reminder of high-level summaries.
6	Aug 27, 2019	Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Cat Thomson (contract support)	PowerPoint presentation by Dr. Scott Commins (co-chair), “Alpha-gal Diagnosis and Management”; presentation discussion included allergy etiology, pathogenesis, and symptoms, the role of the individual microbiome in gastrointestinal reactivity, alpha-gal immune response and organ transplants, safety of nursing with alpha-gall allergy, patient’s perspective of management, importance of public and clinical education; discussion of preparation for briefing the TBDWG during the September 12, 2019 public meeting.
7	Sept 3, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Stephen Rich, Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	PowerPoint presentation by Beth Carrison (member), “Alpha-gal Syndrome Patient Perspectives and Experiences” covering treatment, support, education, and awareness issues; presentation discussion included causes of allergic reactions, carrageenan, and prevalence of AGS; discussion of preparation for briefing the TBDWG during the September 12, 2019 public meeting.
8	Sept 10, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Nicole Green (TBDWG support),Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review of slides for briefing the TBDWG during the September 12, 2019 public meeting; discussion of revisions to slides pertaining to effective presentation methods, appropriate use of graphs, risk/hazards/exposure, etiology of AGS, and maternal transfer; further discussion included lack of education and awareness, differences in symptoms and reactions, uniqueness of AGS as an allergy not an infection, and increasing incidence; review of Subcommittee Report timelines.
9	Sept 17, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review of Subcommittee Report timeline and discussion of report guidelines; PowerPoint presentation by Dr. Shahid Karim (member), “Sialome switches to alpha-gal syndrome” covering tick hematophagy (feeding on blood), and efforts in investigating tick salivary glands and understanding their roles in the pathogenesis of Tick-borne diseases (TBDs), including AGS; presentation discussion included proteins (sialome), alpha-gal and the allergic response, antibodies and cross-reactivities, tools and pathogenesis, and tick species and sources of alpha-gal.
10	Oct 1, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Discussion of draft Background and Methods sections of the Alpha-Gal Syndrome Subcommittee Report, including the increasing incidence, syndrome versus allergy, potential causes, surveillance, the role of the human microbiome, and lone star ticks, in preparation for submission to the Working Group on Oct 1, 2019. Subcommittee members provided brief updates regarding the areas of the Results and Potential Actions section of the Subcommittee Report that they had been working on.
11	Oct 15, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review and discussion of the draft section of the Results and Potential Actions section of the Subcommittee Report focused on Tick Bite Prevention and Tick Control. Discussion included tick repellants, habitat modification, host-targeted methods, and acaricides. A range of other related topics were discussed and recommendations were made for revising the content. Other subcommittee members provided brief updates regarding the areas of the Results and Potential Actions section of the Subcommittee Report that they had been working on.
12	Oct 22, 2019	Charles Apperson, Scott Commins (co-chair), Angel Davey (co-chair), Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review of timeline for completing the Subcommittee Report to the Working Group and discussion of an actionable plan for completing the first draft of the Results and Potential Actions section before the due date.
13	Oct 29, 2019	Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review and discussion of three of the four topic areas comprising the draft Results and Potential Actions section of the Subcommittee Report and planned next steps. For the section ‘Surveillance, Epidemiology, and the Role of Tick Bites in AGS’, suggestions were made regarding additional details to include such as tools for identifying tick species and the pathogens associated with human-biting ticks. For the ‘Diagnosis and Management of AGS’ section, several topics were discussed including mammalian meat versus red meat, diagnosis thresholds/guidelines and diagnostic codes, medication, terminology, mammalian-free versus alpha-gal free, and organ meat. Comments and suggestions were also provided for the section ‘Education, Awareness, and Support from Patients’ Perspectives’, including the discussion of case numbers and sources of data/information.
14	Nov 5, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review and discussion of the draft Results and Potential Actions section of the Subcommittee Report that was submitted to the Working Group on Nov 1, 2019 for further revision. For the Diagnosis and Management of Alpha-gal Syndrome section, discussion included how to further clarify red meat/mammalian meat, dairy products, and at-risk populations, as well as potential actions. Potential actions were also suggested for the Tick Bite Prevention and Tick Control section, and it was discussed whether information on Pathogenesis and Physiology should be folded into the other topic areas rather than being a stand-alone section.
15	Nov 12, 2019	Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Stephen Rich, Leigh Ann Soltysiak (co-chair) Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review of and further revisions/clarifications to the draft Results and Potential Actions section of the Subcommittee Report. Discussion of some of the Possible Actions for the Working Group to consider. Preference for the ordering of topic areas/sections within the Results and Potential Actions was also discussed.
16	Nov 19, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Further review of and revision to the draft Results and Potential Actions section of the Subcommittee Report. Discussion and voting on Possible Actions for the Working Group to consider completed. Discussion and voting on the ordering of topic areas/sections within the Results and Potential Actions completed.
17	Dec 3, 2019	Charles Apperson, Beth Carrison, Scott Commins (co-chair), Angel Davey (co-chair), Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review and update of the Results and Potential Actions section of the Subcommittee Report, discussion of how to prioritize key proposed possible actions for the Working Group to consider, and planning for the next steps.
18	Dec 10, 2019	Beth Carrison, Angel Davey (co-chair), Shahid Karim, Stephen Rich, Leigh Ann Soltysiak (co-chair), Sarah Stuart Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review and update of the three prioritized possible actions for the Working Group to consider, review and discussion of the big-picture summary, and planning for the next steps.
19	Dec 17, 2019	Beth Carrison, Angel Davey (co-chair), Stephen Rich, Leigh Ann Soltysiak (co-chair), Scott Commins (co-chair) Debbie Seem (TBDWG support), Jennifer Gillissen (contract support), Yanni Wang (contract support)	Review of and vote on the Subcommittee Report to the Working Group, review and discussion of the prioritized possible actions for the Working Group, and planning for the next steps.

Table 3: Presenters to the Alpha-Gal Syndrome Subcommittee

Meeting No.	Date	Presenters	Topics Discussed
3	Aug 6, 2019	William Nicholson, PhD	Overview of AGS following tick bite
4	Aug 13, 2019	Stephen Rich, PhD	Tick-borne disease exposure and surveillance, including relevance to AGS surveillance and testing
5	Aug 20, 2019	Thomas Mather, PhD	Tick-targeted interventions and bite prevention, including relevance to lone star ticks and AGS
6	Aug 27, 2019	Scott Commins, MD, PhD	Diagnosis and management of AGS, including relevant alpha-gal exposures
7	Sept 3, 2019	Beth Carrison	Patient’s perspective on AGS treatment, support, education, and awareness
9	Sept 17, 2019	Shahid Karim, PhD	Tick salivary glands, including information on alpha-gal transmission and pathogenesis of AGS

Table 4: Votes Taken by the Alpha-Gal Syndrome Subcommittee

Meeting No.	Date	Motion	Result	Minority Response
16	Nov 19, 2019	Approve the possible actions in the Results section of the report for the Working group to consider.	Outcome: Passed with suggestion for minor revision to one possible action. All present in favor (7), none opposed. One member was absent.	No
16	Nov 19, 2019	Approve the order/ranking of the topic/priority areas	Outcome: Passed. All present in favor (7), none opposed. One member was absent.	No
19	Dec 17, 2019	Approve the Subcommittee Report to the Working Group	Outcome: Passed. All members (8) voted in favor (5 member voted verbally during the conference call; other 3 members voted in writing prior to the conference call)	No

Results and Potential Actions

Priority 1: Surveillance, Epidemiology, and the Role of Tick Bites in Alpha-gal Syndrome

Summary

AGS is an emergent allergy, increasingly widespread in tick endemic areas in the United States of America, and also worldwide where ticks are endemic. Since there is currently no known pathogen associated with AGS, careful consideration must be taken to properly surveil its risk to human health. It is known that human-biting ticks can cause AGS in bite victims (Commins et al., 2011; Commins et al., 2009) but it is also clear that not all tick bites result in AGS. While certain species (including the lone star tick, Amblyomma americanum, in North America) have been implicated, the range of species associated with risk remains unknown. In fact, the characterization of these entomological exposures remains largely enigmatic. The subcommittee discussed these shortcomings and proposes a course of action to surveil human-biting tick activity to determine fundamental exposure parameters leading to human disease.

Issue

Most diseases associated with human-biting ticks are linked to microbial causative agents (viruses, bacteria, or protozoa) and so epidemiological investigation to determine the cause of such disease begins and ends with determining the pathogen and its transmission among vertebrate hosts and biting ticks. A notable exception to this infection paradigm is the peculiar example of tick paralysis described nearly a century ago in Australia (Ross, 1926). While the nature of this paralysis was long understood to be associated with intoxication by compounds in saliva of the Australian paralysis tick (Ixodes holocyclus), many other species were implicated over the decades (Gothe, Kunze, & Hoogstraal, 1979). It was not until recently that the holocylotoxins associated with presynaptic inhibition were identified and in fact found to be present in some 73 of the 900+ known tick species (Chand et al., 2016; Durden & Mans, 2016). I. holocylous is just one of those tick species, albeit the species associated with the most severe clinical manifestations. Determining the breadth of tick paralysis clinical symptoms and the hazards associated with various tick species took decades of observation in human and companion animals bitten by ticks. There are lessons to be learned from this history as we confront the challenge of investigating AGS.

While the clinical signs and symptoms of AGS are coming into clearer view, the nature and extent of its tick-borne etiology remains obscured by a lack of epidemiological surveillance linking the set of undefined hazards with measurable risks. Our discussion on AGS surveillance focused on supporting an agenda to develop a sound epidemiological surveillance approach to elucidate the connections between human-biting ticks and AGS. AGS appears to be a non-infectious, tick-borne etiology but to properly surveil its occurrence we must borrow concepts from environmental epidemiology to outline the parameters in need of further elucidation. For environmental health concerns, the goal is to identify hazards to human health, measure the risk in terms of reported incidence of disease, and determine the mitigating exposure that conjoins hazard to risk. Quite simply, risk assessment and subsequent management of that risk is only possible with complete epidemiological understanding of the hazards and characterization of exposure to those risks.

The objective in AGS epidemiological investigation must be to determine causal relationships between characteristics of tick bite and those clinical signs and symptoms associated with disease. This necessitates identifying unambiguous tick-bite history. While there is a hope to identify biomarkers in humans of past tick-bite exposures, the existing methodologies (Alarcon-Chaidez et al., 2006) fall short of concise and objective determination of whether a tick bite occurred, which species of tick made the bite, how long the bite/feeding occurred, etc. In the absence of suitable biomarker, the most reliable means of determining these parameters is rigorous active surveillance of human-biting ticks. We know that AGS can be caused by a tick bite (Commins et al., 2009) but we also know that not every tick-bite results in AGS. The surveillance goal should be to determine those factors that mitigate tick-bite exposure and human disease risk. Focusing exclusively on incidence of human disease and correlating that risk geography or seasonal occurrence leads only to weak inferences about the exposures and identification of hazards.

In addition to establishing the link between human-biting ticks and AGS, the subcommittee discussed needing more understanding of the pathogenesis of why tick bites lead to the development of an allergic response in some humans. Thus, increased knowledge about the actual ticks associated with human disease is critical. Although recent work has confirmed the presence of alpha-gal in the saliva and salivary glands of Amblyomma americanum, it is not clear whether ticks have the innate capacity to form alpha-gal or this antigen is derived from prior blood meals or even synthesized using acquired enzymes (Crispell et al., 2019). Interestingly, this same work showed that the Ixodes scapularis also contain alpha-gal moieties in the salivary compartment – raising the possibility that this important vector may also contribute to AGS (Crispell et al., 2019). Beyond human-biting ticks, the subcommittee discussed that the available literature also includes references to “chigger bites” as a possible vector that may initiate alpha-gal specific IgE (Stoltz et al., 2019). Whether additional vectors beyond ticks can be associated with AGS is an important unanswered question with significant ramifications.

Tick adaptation to blood feeding resulted in the evolution of complex cocktail of salivary components that help the tick to overcome the host’s defense against blood loss (hemostasis) and inflammatory proteins at the feeding site that may disrupt blood flow or trigger host-defensive behavior by the sensation of pain or itch. Tick saliva composition, as revealed by sialotranscriptome (from the Greek, sialo means saliva), indicates the presence of over 5,000 putative secreted peptides, containing representatives of dozens of protein families (Karim & Ribeiro, 2015; Karim, Singh, & Ribeiro, 2011). The tick saliva can counteract host inflammation and immunity by injecting a plethora of pharmacologically active components into the host’s skin during the probing and ingestion phases of feeding. Very little is known about the functions of most of the salivary components injected during tick attachment, despite recent insight into the identification of tick-derived salivary factors and their role in blood feeding. Thus, significant gaps in knowledge exist and include:

How do A. americanum ticks induce an IgE response (that is, the production of IgE antibodies that results in an allergic reaction)?
Why is it directed against only alpha-gal?
What is the source of alpha-gal in the tick?
Are the only glycosylated peptides responsible for AGS?
What is the mechanism of alpha-gal secretion from the salivary glands?
What is the role of tick microbiome in alpha-gal synthesis?

Opportunities

Risk of tick-borne disease is not only associated with tick populations, but also with human behaviors. Preventative measures such as early tick detection and removal dramatically decreases the chance of contracting a tick-borne disease when a tick bite occurs. However, approximately 70% of people who contract Lyme borreliosis do not recall being bitten (Poland, 2001). Knowledge of tick attachment preferences (Felz & Durden, 1999), duration of attachment (Piesman, Mather, Sinsky, & Spielman, 1987), and age-specific prevalence of transmission events (Bacon, Kugeler, Mead, Centers for Disease, & Prevention, 2008) are likely to be critical to AGS risk as they are to infection. These factors can only be measured accurately by conducting surveillance of human-biting ticks by trained personnel using tools to identify tick species unambiguously, determine the feeding status of these ticks, and where appropriate to identify the pathogens associated with those ticks (Xu, Mather, Hollingsworth, & Rich, 2016).

Accurate determination of human-biting tick species is often challenging due to the cryptic nature of some species (Rich et al., 1995), and information about tick exposures can be compromised when the specimen is either not in hand, or the investigator lacks sufficient training or tools to make the ID. One recent study of human-biting ticks in California, Oregon, and Washington found that most of the Lyme infected human-biting ticks tested from that region were non-endemic Ixodes scapularis (blacklegged ticks) and not native Ixodes pacificus (Western blacklegged ticks), i.e. those ticks were acquired while the person travelled to the Northeastern U.S. (Xu, Pearson, Dykstra, Andrews, & Rich, 2019). That same study found that the endemic ticks were of a species (Ixodes spinipalpis) not commonly associated with transmission of Lyme in that region. These three Ixodes species (I. scapularis, I. spinipalpis, and I. pacificus) appear almost identical to an untrained eye, but can be readily distinguished unambiguously by molecular methods (Xu et al., 2019).

Passive surveillance of human-biting ticks and associated pathogens is already being conducted in several labs to provide customized individual risk assessment of pathogen exposure. The list of tick-borne pathogens is long and growing, with a tendency toward specific correspondences between pathogen and tick species. There are hundreds of tick species in the world, but only a small proportion of these are common human-biting ticks and hence associated with infectious disease transmission. The most common pathogens are found in the human-biting blacklegged tick (Ixodes scapularis), and include Borrelia burgdorferi (Lyme borreliosis), Anaplasma phagocytophilum (anaplasmosis), Babesia microti (babesiosis), Ehrlichia muris-like agent (ehrlichiosis), Borrelia miyamotoi (relapsing fever spirochetosis), and Deer tick virus (Powassan Type-2). Other human-biting ticks include the lone star tick (Amblyomma americanum) and the dog tick (Dermacentor). Dog and lone star ticks are not known vectors of Lyme disease, but are occasionally associated with Ehrlichia chaffeensis (Ehrlichiosis), Borrelia lonestari, Francisella tularensis (tularemia), and various rickettsial species. Labs that test for these pathogens in human-biting ticks could be enlisted to provide tractable information about human-biting ticks throughout the United States, including areas of AGS endemicity. Moreover, if a program of epidemiological investigation was initiated, it would be possible to investigate potential AGS clinical outcomes associated with various species of human-biting ticks (and their pathogens). Passive surveillance of unambiguously identified human-biting ticks has also proven effective at identifying novel tick/pathogen associations (Xu, Pearson, & Rich, 2018). And because tick testing provides insights on individual risk assessments (Krause et al., 2016), it is highly valued and can be crowd-sourced. A surveillance program of this kind would have the dual benefit of determining hazards and risks while at the same time providing victims of human-biting ticks with qualitative and quantitative information about their risk.

Possible Actions for Working Group to Consider

This subcommittee identified the following potential actions that the federal government could take to surveil human-biting ticks associated with AGS and to use that surveillance information to clarify the epidemiological circumstances of this disease, including the risk factors associated with tick bites, specifically by:

Fund “Novel Surveillance” of human-biting ticks (that is, ticks captured actively feeding on human hosts) toidentify specific exposure factors such as the characteristics of the tick-bite pertaining to its species, duration of feeding, and/or potential pathogens. This “Novel Surveillance” is critical, as we already know that people are acquiring AGS through tick-bites. Interestingly, however, not all tick-bites result in disease (acute or chronic). Determining the factors that affect clinical outcomes is crucial to preventing and treating AGS. This “Novel Surveillance” will be accomplished by systematically characterizing human-biting ticks and conducting longitudinal follow up of tick-bite victims for signs and symptoms of AGS. The effort will further determine the specific factors of exposure risk and how to advise the public to best mitigate those risks.
Fund investigation of the cellular mechanisms that lead to AGS, including influence of the host, potential role of tick salivary factors, and tick-related diagnostic testing for AGS.
Establish guidelines for case reporting of human AGS and funding research on the incidence and prevalence of AGS.

Votes of Subcommittee Members

Possible actions were presented and discussed by subcommittee members. The wording of possible actions here were voted on by subcommittee members and results are presented here.

Vote:The subcommittee unanimously voted yes to accept the list of possible actions for this priority.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	1

Priority 2: Diagnosis and Management of Alpha-gal Syndrome

Summary

AGS has many novel features that are relevant to diagnosis and management. In most cases the diagnosis can be made based on a history of delayed allergic reactions that occur 3-8 hours after eating non-primate mammalian meat*(e.g., “red meat” such as beef, pork, or lamb) and a positive blood test (>0.1 IU/mL) for immunoglobulin E (IgE) to the oligosaccharide galactose-α-1,3-galactose (alpha-gal) (Commins, Jerath, Cox, Erickson, & Platts-Mills, 2016). The combination of both an appropriate clinical history and supporting blood test is necessary to establish an accurate AGS diagnosis (Commins et al., 2009). In general, the diagnosis also dictates the primary management strategy: avoiding mammalian meat and also dairy in some cases (Commins, 2016). Owing to the geographical range and analysis of tick salivary factors, the lone star tick appears to be the primary cause of this disease in the U.S. but different ticks are responsible in other countries (Commins et al., 2011; Crispell et al., 2019; Levin et al., 2019). Blood levels of alpha-gal IgE often decrease in patients who avoid recurrent tick bites, but the rate of decline varies from patient to patient (Commins et al., 2011). Similarly, the delay before reactions vary and the severity of the allergic reactions cannot be predicted by the delay or the titer of specific IgE (Commins et al., 2014). Some mammalian-derived products such as heart valves, gelatin-based plasma expanders, and pancreatic enzymes, are only relevant to select patient groups (Mozzicato, Tripathi, Posthumus, Platts-Mills, & Commins, 2014; Stone et al., 2019; Stone et al., 2017). A minority of patients may benefit from avoiding a wide range of products that are prepared with mammalian-derived constituents, such as gelatin (Mullins, James, Platts-Mills, & Commins, 2012).

* Non-primate mammalian meat refers to meat derived from any mammal that is not a human or Great Ape. Commonly consumed examples are beef, pork, lamb, venison, rabbit, goat, squirrel, buffalo, etc. and include organ meats. For the purposes of this report, the term ‘mammalian meat’ and ‘mammalian-derived’ will be used to refer to non-primate mammalian meat and its animal sources as these are alpha-gal containing foods or products. Equally, note that references may state ‘mammalian meat’ or ‘red meat’ yet these also refer to non-primate mammalian meat, which is the primary source of alpha-gal.

Issue

In 2009 the AGS was described in 24 patients who reported delayed allergic reactions to mammalian meat (Commins et al., 2009). Unlike more traditional food allergies where consumption of an allergen produces symptoms within minutes, AGS reactions typically occur 3-8 hours after eating (Commins et al., 2014). Thus, many patients fail to consider food as a possible trigger and many healthcare providers do not routinely recognize the characteristic delay – both issues can lead to prolonged time to reach a diagnosis. Following identification of AGS, patients with the same allergy in Australia, Europe, Scandinavia, Japan, and South Africa have been reported (Levin et al., 2019). Accumulating data support a strong association between bites from the lone star tick (Amblyomma americanum) and the development of AGS in the U.S. (Commins et al., 2011); however, no case-control study has confirmed this link. An association between AGS and tick bites has been reported throughout the world, despite the differences in tick species and populations (Levin et al., 2019).

There are currently no U.S. FDA-approved medications for food allergy in general, including AGS; therefore, allergen avoidance along with rescue medication(s) are the mainstays of management (Renz et al., 2018). Although AGS is no different from other food allergies in this regard, avoidance of mammalian-derived products is more challenging due to a lack of adequate labeling and the inclusion of common components, such as gelatin, in numerous foods. In addition, multiple medications are derived from mammals and specific mammalian tissues are used as medical devices. Owing to the ubiquitous inclusion of mammal-derived products within both food and healthcare settings, allergen avoidance for patients with AGS can present unique challenges for management (Commins et al., 2016).

Evidence and Findings

Diagnosis of AGS. The following characteristics have been observed and reported in most patients with AGS (Wilson et al., 2019):

Onset in adult life after eating mammalian meat without problems for many years
Reactions range from localized hives or angioedema to severe anaphylaxis, which requires emergency treatment and hospital observation/admission
Reactions start 3-8 hours after eating non-primate mammalian meat (or consumption of dairy, gelatin, or other mammalian-derived products containing alpha-gal for some patients)
Positive testing for alpha-gal IgE (>0.1 IU/mL)
Improvement of symptoms when adhering to an appropriate avoidance diet

However, it is important to realize that some patients with AGS may not present with these characteristics. For example, a recent study found that 16% of patients with AGS reported subjective symptom onset in less than two hours after consuming mammalian meat (Wilson et al., 2019). In addition, a significant number of pediatric cases of AGS has been reported, and the published data suggest that the condition in children has similar features to those of adult patients (Kennedy et al., 2013).

In terms of diagnosis, skin prick tests with extracts of mammalian meats (beef, pork, or lamb) were shown to be unreliable (Commins et al., 2009). Sensitization can be investigated using intradermal skin tests to the same diluted extracts (Commins et al., 2009). However, few clinics carry out intradermal testing for food antigens and the majority of providers rely on a commercially available blood test for alpha-gal IgE. There are no established criteria for the titer of alpha-gal IgE that confirms an AGS diagnosis and most clinical authorities report using the cut-off of >0.1 IU/mL as a positive test result (Levin et al., 2019; Wilson et al., 2019). Diagnosis is particularly challenging in two groups of patients: patients with an unclear history of allergic reactions to mammalian products who are found to have alpha-gal IgE, and patients who give a history of reacting to mammalian products but whose blood test for alpha-gal IgE is negative. Additional studies are needed in both groups to further characterize these patients and understand the limitations of current diagnostic testing for AGS.

Range of symptoms that can occur in relation to AGS. Published work suggests that the most important group of “non-classical” symptoms are those that involve the gastrointestinal (GI) tract (Levin et al., 2019). While GI complaints are not uncommon as part of an allergic reaction in conjunction with hives, some patients with AGS have reported abdominal pain without any skin involvement (Iweala, Choudhary, & Commins, 2018). These uncommon symptoms complicate the diagnosis as well as management of AGS because the possibility of food allergy is not obvious, but the symptoms can be severe (Iweala et al., 2018). Indeed, examples of patients with AGS who have had exploratory surgery, removal of gallbladder or appendix, and partial pancreatectomy have been reported (Commins, 2016). Notably, very few patients have reported isolated itching in the mouth or swelling of the tongue (Wilson et al., 2019). Other diagnoses that arise less commonly are arthritis and chronic pruritus (Wilson et al., 2019). Distinguishing AGS from chronic hives can be challenging, and in some cases the two entities may overlap.

Seronegative patients with allergic responses to one or more mammalian products. Longitudinal data of patients with AGS suggest that alpha-gal IgE declines over time; additional tick bites, however, appear to lead to rises in alpha-gal IgE (Commins et al., 2011; Wilson et al., 2019). Thus, one possible reason for seronegative testing despite a history of symptoms is that a patient’s alpha-gal IgE has declined below the limit of test detection yet remains clinically relevant. A second possibility is pork-cat syndrome, in which primary sensitization to cat serum albumin is associated with reactions to pork meat (Posthumus et al., 2013). Several experts suggest that seronegative patients may benefit from a diagnostic food challenge to resolve confusion (Commins et al., 2014; Iweala et al., 2018).

Management of AGS. Firstly, all patients should be informed that further tick bites can maintain or lead to increases in the titer of alpha-gal IgE (Commins et al., 2011; Levin et al., 2019). By contrast, most patients who successfully avoid tick bites will experience a decrease in their alpha-gal IgE level. Although the rate of decline varies and it is not clear what degree of decrease is required to successfully regain tolerance, a few studies have reported patients whose titers became negative (<0.1 IU/mL) and who successfully re-introduced mammalian meat in their diet (Commins, 2016). Published data provide strong evidence that eating mammalian meat alone is not sufficient to induce an IgE response to alpha-gal (Commins et al., 2012). Equally, similar data also argue against a role for other mammalian exposures in developing AGS (Commins et al., 2012). While no studies have isolated the transfer of maternal IgE in breast milk as the cause of a food allergy in infants, it is worth noting that IgE in human breast milk has been detected in cases of elevated maternal allergen specific IgE (Hochwallner et al., 2014). This finding may raise the possibility of maternal to infant sensitization via breast milk. Whether alpha-gal specific IgE shares similar properties has not been studied. There is also a lack of data regarding whether eating mammalian meat or consuming dairy can influence the levels of alpha-gal IgE in patients with AGS. An additional point is that some patients with the syndrome may tolerate mammalian meat on some occasions with few or no symptoms but have severe reactions on others. This intra-individual variability is often not explained by the amount of meat consumed and may reflect differences in the quantity or form of alpha-gal that is present in the meat or could reflect the importance of co-factors such as medications, exercise, or alcohol consumption (Iweala et al., 2018). Regarding patients who test positive for alpha-gal IgE but do not report symptoms after eating mammalian meat, there are currently no population-based follow-up studies and management options for these patients could be limited to avoidance of tick bites.

Avoidance of mammalian meat. The primary advice for newly diagnosed patients with AGS is to completely avoid meat of mammals (Commins, 2016). In most areas of the U.S. this means beef, pork, and lamb. However internal organs are equally or more able to induce reactions. These organs include kidneys, liver, heart, and intestines (tripe), and the evidence is strongest for pork kidneys (Fischer, Hebsaker, Caponetto, Platts-Mills, & Biedermann, 2014). Other animals such as rabbits, horses, and goats, which are often eaten in Europe and other parts of the world, should equally be avoided (Fischer & Biedermann, 2016).
Avoidance of dairy products. Several general reviews of AGS do not include avoidance of dairy products as part of primary avoidance, stating that most of the patients do not react to milk or cheese (Commins, 2016; Levin et al., 2019). However, published evidence and expert opinion articles indicate that full avoidance of dairy products perhaps should be recommended in patients avoiding mammalian meat but have inadequate control of symptoms (Commins, 2016). Many of these patients have subsequently responded to a diet that also includes avoidance of other commonly consumed foods from cows, pigs, and sheep—mostly dairy avoidance (Commins, 2016; Wilson et al., 2019).
Additional considerations for managing AGS. Mammal products can be introduced into food and other products that are not obviously mammalian during preparation or manufacturing processes (Caponetto, Fischer, & Biedermann, 2013). Evidence for the presence of alpha-gal in these different food and medical products varies markedly, with some items clearly expressing the oligosaccharide (e.g., cetuximab) and other products being labeled by some authorities as “risky” seemingly only because there is some constituent that is derived from mammals (e.g., magnesium stearate, glycerin). In many cases, it is challenging to make informed assessment based on the available data. Here is a general framework for consideration of relative risk and for management of the syndrome.

Non-meat, non-dairy food products:

Pork gut casings for sausages: Many varieties of sausages use casings derived from the pork gut. As a result, chicken and turkey sausages, which would otherwise be safe, can induce anaphylactic or other reactions.
Mammalian fat in foods: Lard (rendered pork fat) is an important element of cooking. It is found in gravies and sauces, and may also be added to mashed potatoes, vegetables, confectionary, or fry oil to add flavor. Suet (un-rendered fat from sheep or cattle) is also used in cooking, for instance as part of mince-meat.
Gelatin: Gelatin is a glycoprotein that is normally derived from collagen in the skin or hooves of cows or other large mammals. In regard to food, gelatin is a main ingredient of jelly beans, marshmallows, and puddings.

It is worth noting that many stocks and bouillon cubes also are derived from mammalian sources and additional research is needed to understand the risks from these and other “hidden” exposures. A potential non-mammalian source of alpha-gal exposure that requires further investigation is carrageenan—a family of linear sulfated polysaccharides extracted from red edible seaweeds that may contain the alpha-gal epitope. Carrageenan is widely used for thickening and stabilization properties but no controlled food challenge studies have been reported among patients with AGS (further discussed in Education & Awareness section).

Other medical uses of mammalian proteins or parts:

Monoclonal antibodies: Despite the fact that many monoclonal antibodies (mAbs) that are in clinical use are generated in non-primate mammalian cell systems, the evidence for alpha-gal expression on most monoclonal antibodies other than cetuximab is minimal. One exception is infliximab, which has been shown to express low amounts of the glycan and has been linked to reactions in a small number of patients with AGS.
Gelatin-containing medications: Gelatin is present in some vaccines, including Zostavax and MMR. Cases of reactions to these vaccines in patients with alpha-gal IgE have been reported (Stone et al., 2019; Stone et al., 2017). Gelatin is also used as a plasma expander in some countries, particularly Australia and the U.K. (Mullins et al., 2012). Gelatin-based capsules are used for many medicines and may give rise to symptoms in a small proportion of patients. This exposure could add confusion in patients for whom a mammal-free diet has not successfully controlled symptoms (Commins, 2016).
Enzyme replacement: The pancreatic enzymes that are used for replacement in some cases of cystic fibrosis or other causes of pancreatic failure are purified from the pancreas of large mammals. These proteins, and other mammalian-derived enzymes, have been shown to express alpha-gal and have a functional activity in basophil activation tests.
Bovine or porcine heart valves: Published reports have described patients who experienced hives or even a mild episode of anaphylaxis after transplantation of mammalian heart valves (Mozzicato et al., 2014). More recently, mammalian valve degeneration in patients with alpha-gal IgE have been reported (Hawkins, Frischtak, Kron, & Ghanta, 2016). This problem may be solved by using alpha-gal deficient pigs as a source of heart valves.
Anti-venom: The presence of alpha-gal epitopes in anti-venom formulations, which are purified fragments from venom-immunized non-primate mammals, was convincingly shown by Fischer et al. There has been at least one case report of an acute reaction to CroFab in a patient with AGS (Fischer et al., 2017).
Heparin: Heparin is derived from pig intestines. A small number of case reports have raised the possibility of heparin-induced allergic reactions in patients with AGS (Commins, 2016; Mozzicato et al., 2014).

Opportunities

Increasing awareness of AGS among healthcare providers is a critical first step in addressing the unmet needs in the diagnosis and management of AGS. Considerations could include making AGS a reportable diagnosis, and this could be accomplished in conjunction with the Centers for Disease Control and Prevention. Development of a repository of AGS-related information for patients and families, as well as providers is also an opportunity. In addition, published data related to the characteristics of alpha-gal IgE testing is lacking, including more basic parameters as sensitivity, specificity, as well as positive and negative predictive values. Larger population studies represent an important opportunity to define these diagnostic issues. As with management for any food allergy, AGS management is based on allergen avoidance. For patients with AGS, however, this tenet of self-protection is made difficult by the lack of adequate labeling for mammalian-derived sources in foods, medications, and vaccines. Approval of alpha-gal free porcine products would represent an effective way to develop “AGS-safe” foods, medications, and implantable devices.

Threats or Challenges

The prevalence of AGS cases is unknown, and it remains a challenge for widespread integration of AGS into healthcare training and awareness. In addition, the lack of a confirmed association between AGS and ticks as a vector for disease poses challenges for funding and for identification of at-risk individuals. We also need to better understand the risk of reactions to the wide variety of products that may include small amounts of material derived from mammals.

Possible Actions for Working Group to Consider

This subcommittee identified the following potential actions that the federal government could take related to the diagnosis and management of AGS:

Fund/support an AGS "Health Alert" to all relevant professional medical societies/associations, for timely distribution nationwide to generate awareness and provide the groundwork for provider education/training, especially within endemic areas.
Support the development of consensus guidelines or expert opinion on AGS diagnosis, management, natural history, and risk assessment.
Fund studies that evaluate health risks from exposure to alpha-gal that include threshold testing, airborne (fume) risk and effect of continued dairy exposure.

Votes of Subcommittee Members

Possible actions were presented and discussed by subcommittee members. The wording of possible actions here were voted on by subcommittee members and results are presented here.

Vote: The subcommittee unanimously voted yes to accept the list of possible actions for this priority.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	1

Priority 3: Education, Awareness, and Support from Patients’ Perspectives

Summary

This section provides an overview of AGS patients’ perspectives on the need for education, awareness, and support. These perspectives will provide insight into the daily lived experience of patients with AGS.

Insights presented here include the need for education—not only education for patients with AGS and their families, but in particular education for healthcare providers across the healthcare system, including but not limited to emergency medical transportation staff members who are called in for emergencies and unwittingly administer IV fluid with gelatin, general practitioners taking care of patients who present with unexplained hives, and dentists whose patients react badly to topical numbing gels. Closely intertwined with the need for education is the need for increased awareness. Awareness of the existence of AGS as a tick-borne condition is needed to help the increasing number of people (likely in the thousands in the U.S. alone) who suffer from the disease yet whose condition remains undiagnosed. Finally, ongoing support through mechanisms such as product labeling and individualized patient care is needed to help everyone who is involved with AGS management to navigate the constantly changing state of knowledge around AGS.

Sources of Patient Perspectives

Several different sources were used to obtain patient perspectives for this report, including public commentary, surveys, and comments made in online posts and published articles. To the best of the subcommittee’s knowledge, no peer-reviewed publications exist at this time that address the perspectives of patients with AGS.

First, more than a hundred people have submitted written or provided in-person commentaries about AGS to the Department of Health and Human Services (HHS) TBDWG. Public comments have been solicited online since the inception of the TBDWG in 2017 and all commentaries are published online at the HHS website.

Second, the Alpha-gal Syndrome Subcommittee Patient Advocate Representative Beth Carrison conducted a survey through the nonprofit Tick-borne Conditions United (TBC United). The survey was distributed electronically through emails to the TBC United community and attendees of the Virginia Tech “New Research New Hope” conference in Martinsville, VA; and posted online in the AGS Facebook Support Groups. The survey was available for three days, and a total of 131 participants submitted feedback.

Last, personal perspectives have been collected from online posts in various support groups (with permission) and from published articles.

The perspectives not presented here include people who haven’t reached out for support by attending educational seminars or participating in online support groups via resources such as Facebook. Indeed, some physicians advise against seeking support via Facebook due to inaccurate information distributed in these online platforms. It is worth noting that 85 percent of survey respondents in published articles such as the publication by Flaherty et. al (Flaherty et al., 2017) have college degrees. This may indicate underdiagnosis in people with less than college-level education. A final observation is the near absence of participation of people of color across the surveys, webinars, symposiums, and online support groups. Thus, it was not possible to include their perspectives on a representative scale.

“The allergist I have here in town thinks I am *overreacting*. You mean, overreacting when my neighbors next door are cooking their meat on the grill and when I walk outdoors and the fumes hit me, it feels like I have been snatched up by the throat and I start having trouble breathing. …There are days I am afraid to even leave my house. But I have to earn a living, otherwise I will not have a house…. I already had to quit one job because of Alpha Gal. My job was right next door to a restaurant and their pot roast night and burger nights made it impossible for me to keep that job, as the fumes wafted over into my store… I live in a constant state of apprehension and fear, because I like to breathe. This allergy threatens to take that and my life away from me, every time I walk out my front door.”

-- Anonymous 2, 9/12/19 written public comment submitted to TBDWG (Anonymous, 2019)

Issues

Patients with AGS face significant challenges on a daily basis. Many issues hinder these patients’ as well as their healthcare providers’ ability to management the condition. Key issues around AGS include the following.

Unknown Prevalence.While the number of people affected by AGS is on the rise, the exact number of confirmed cases is yet unknown.

Lack of awareness and knowledge. Patients’, healthcare providers’, and the general public’s knowledge of AGS currently is alarmingly limited, which can lead to delayed or wrong diagnosis and treatment.

Lack of educational materials and ongoing support.Patients with AGS are often left to their own devices for education and ongoing management. However, educational materials and proper guidance are lacking to ensure patient safety and self-management.

Evidence and Findings

Unknown Prevalence of AGS

The exact number of people affected by AGS is currently unknown. A comprehensive 2019 survey of food allergies in the U.S. failed to mention the existence of AGS (Gupta et al., 2019). However, Wilson et. al (2019) reported AGS as “a regionally common form of food allergy that has a characteristic but not universal delay in symptom onset, includes gastrointestinal symptoms, can develop at any time in life, and is equally common in otherwise nonatopic individuals.”

A study by Pattanaik et. al (Pattanaik et al., 2018) found that AGS was the most common etiology of anaphylaxis. Further, the percentage of cases attributed to idiopathic anaphylaxis decreased from 59% to 35% in successive reports, likely explained by the increase in cases identified as AGS.

As of this writing, the number of patients diagnosed with AGS in the U.S. is unknown. Neither an International Classification of Disease diagnosis code nor a healthcare provider reporting requirement exists to provide at least a baseline. Viracor Eurofins Clinical Diagnostics, the only company that tests for the presence of the alpha-gal IgE, reported in mid-2018 they had a total of 58,000 positive results (threshold >.1) for alpha-gal IgE (as presented in International AGS Webcast on May 2018)(Merritt, 2019). However, the number of results from repeated tests is unknown. The CDC is currently working with Viracor Eurofins to update the number of AGS cases and develop a consistent threshold for reporting.

While published data on the prevalence of AGS are lacking, the following data points provide some insight on the potential scale of the number of people affected.

In rural Chatham County, NC, the triennial 2018 Chatham County Health Assessment ("Chatham County Community Assessment," 2018) found that 14.2% of the adults surveyed were diagnosed with a tick-borne illness and 8.3% of the adults with a tick-borne illness had AGS. This equals 862 people with AGS when extrapolated to the county’s total population of 73,139 ("The U.S. Census Bureau QuickFacts," 2018).
Dr. Aneysa Sane of the Carilion Clinic in Roanoke, VA, reported about AGS, “I’m seeing at least two new cases a week, which to me is an epidemic of food allergy.” (Zibton, 2019).
Dr. Erin McGintee of Ear, Nose and Throat and Allergy Associates in Southampton NY stated that “Alpha-gal Allergy is an epidemic on the East End” and reported having “one of the largest patient clusters in the country” with 530 AGS patients as of August 2019 and “is diagnosing more every day”("Local allergist has over 500 patients with alpha-gal meat allergy from tick bites," 2019).
In Arkansas, 270 patients were diagnosed with AGS between January 2013 and September 2015 ("Draft Citizen Petition to the U.S. Food and Drug Administration from Arkansas Legislative Task Force on Alpha-Gal," 2016).
An allergist in 2018 said his medical practice group currently diagnoses twenty AGS cases per week on the Eastern Shore of Maryland (Meyer, 2019).
As of October 28, 2019 the two primary Facebook AGS support groups have between 5,100 (c. 2016) and 6,000 (c. 2011) members, respectively (the number of people that are members of both groups is unknown). The top ten locations represented by members the groups (starting in 2011) are:
1. Lynchburg, VA
2. Sydney, NSW, Australia
3. Raleigh, NC
4. Nashville, TN
5. Tulsa, OK
6. Richmond, VA
7. Fayetteville, AR
8. St. Louis, MO
9. Louisville, KY
10. Bentonville, AR

As of October 28, 2019, local/regional AGS Facebook Support Groups exist in at least sixteen different states, including Arkansas, Delaware, Georgia, Illinois, Kansas, Kentucky, Missouri, New Mexico, North Carolina, Oklahoma, Tennessee, and Wisconsin.
The “Where in the world is Alpha Gal?” patient-driven Zee map shows 3,836 pins worldwide ("Where in the world is Alpha Gal?," 2019). Admittedly there are some discrepancies such as patients marked where they were bitten and some marked where they reside.

Lack of Awareness and Knowledge

Knowledge gaps about AGS

In a recent survey of 131 patients with AGS, the top two overwhelming concerns were the lack of healthcare provider knowledge about AGS (89%) and the need for ingredient labeling on food and pharmaceuticals (79%). Many patients with AGS learn about their condition through Google, friends, news, or social media rather than through their healthcare providers. As a result, a rampant distrust of healthcare providers exists (Platt & Carrison, 2019). In addition to patient concerns about the lack of healthcare provider knowledge, Platt and Carrison (2019) also reported a lack of knowledge about AGS across pharmacists, public health practitioners, product manufacturers (household products, cosmetics, medical and dental devices, and pharmaceuticals both OTC and prescription), schools, employers, policymakers, legal counsel, and the general public.

Flaherty et. al (2017) found that in more than 100 medical visits (including 28 emergency department and two urgent care visits) the correct diagnosis or appropriate referral for patients with AGS occurred “less than 10% of the time.” Crow et al reported the significant costs of misdiagnosis, relaying a case where during an anaphylaxis episode a patient suffered non-ST segment elevation myocardial infarction (NSTEMI) and was given (porcine-derived) heparin (Crow, Samples, & Purser, 2019). The authors commented that“...if the diagnosis had been made during one of his prior episodes, avoidance of red meat would have prevented this hospitalization.” Further,“Additionally, avoidance of porcine-derived heparin could have prevented a small bowel resection,” the authors added. They suggested that “Patients diagnosed with mammalian meat allergy should be advised to avoid all red meat, bovine or porcine-derived medications, and always carry an epinephrine auto- injector,” and they noted that “in clinical practice, the diagnosis can be confirmed with serum IgE specific to alpha-gal.”

The average time to receive a correct AGS diagnosis was 7.1 years for nearly eighty percent of the respondents (Flaherty et al., 2017). In addition, Kennedy et. al (Kennedy et al., 2013) found that children in particular with recurrent symptoms consistent with allergic reactions seem to elude a diagnosis (note that this study did not refer specifically to AGS but to allergies in general). As media coverage and the number of patients diagnosed increases, however, the time to obtain a correct medical diagnosis should decrease.

Even after diagnosis, patients with AGS are mostly given vague directions or just told “to avoid red meat, or hooved animals.” The frequent recommendation to avoid hooved animals can mislead patients because many mammals (such as rabbits, squirrels, and beavers) that can cause AGS are not hooved. Numerous patients surveyed reported arguing with their healthcare providers about what animals qualify as mammals (Platt & Carrison, 2019). In addition, some patients react to even the slightest trace of mammalian ingredients. More research is needed to figure out the causes of the reactions and why the reactions vary from patient to patient. A comprehensive overview of the myriad sources of mammalian ingredients is rarely offered by the healthcare provider (see “Lack of Education and Support” below).

Knowledge Gaps about Ticks

Understanding which ticks, or possibly other sources, cause the allergy will help improve prevention and diagnosis. Patients surveyed reported that their healthcare providers often rely on 1) outdated recommendations found online, including CDC’s website, and 2) materials that do not mention the presence of alpha-gal in ticks other than the lone star tick (Amblyomma americanum) (Platt & Carrison, 2019). As a result, testing for AGS may not take place unless the patient can specify a bite from a lone star tick (assuming the patient is aware that he or she was bitten by a tick, and can properly identify the species). In addition, patients may report “chigger” bites; however, whether the bites are truly from chiggers or actually larval ticks is often unclear (Stoltz et al., 2019).

Better understanding of the associated ticks’ geographical locations, behaviors, and pest control options is desperately needed. Some patients reported being told “that tick doesn’t exist in our area,” (Platt & Carrison, 2019) despite published evidence confirms the presence of the lone star tick in the area (Monzon, Atkinson, Henn, & Benach, 2016; Nieto et al., 2018).

Patient Support Through Education

Patients with AGS are often left to their own devices for education and ongoing support. However, providing proper education and guidance after diagnosis is crucial to patients’ safety and successful management of AGS. Few professionals who may have contact with AGS patients seem to be aware of the management implications associated with AGS.

To better support patients with AGS, their families, and others who provide services to patients with AGS, accurate and current educational materials on AGS are needed. Materials should address prevention, diagnosis, treatment, and ongoing supportive care. Increased education and awareness will reduce harm from unnecessary exposure and unnecessary medical costs (for example, emergency room visits) caused by misdiagnosis, inappropriate prescriptions, and unnecessary hospitalizations (Crow et al., 2019; Florin-Dan Popescu, Cristea, Floriana-elvira Ionica, & Vieru, 2019). Supporting healthcare professionals and patients with alpha-gal-free ingredient labeling will reduce exposure and costs, including direct costs related to emergency room visits and treatments, and indirect costs from lost work and school productivity.

Patient Support

According to the Food Allergy Research and Education, a non-profit organization dedicated to food allergy awareness, education, research, and advocacy, each year about 200,000 people require emergency medical care for allergic reactions to food ("FARE Facts and Statistics," 2019).

Ongoing treatment and support impact many areas of the AGS patient's life. Patients with AGS would benefit from a wide range of support provide by healthcare professionals and other trained practitioners who can help them navigate the myriad aspects of AGS management, including medical support from physicians and other healthcare providers such as compounding pharmacists, surgeons, or other medical specialists; nutritional guidance from dietitians or nutritionists; emotional support from experienced healthcare professionals; and student support from educational professional for a safe learning environment. Without a comprehensive support network, opportunistic medical conditions can creep in, which could have otherwise been avoided, saving unnecessary pain, suffering and medical costs for both the patient and insurance companies.

Allergens and Labeling

In the survey conducted by Platt and Carrison, many patients reported difficulties in obtaining reasonable accommodations to continue gainful employment or to attend school (Platt & Carrison, 2019). AGS patients need thorough documentation of AGS and its impacts to support medical and/or disability claims. AGS currently is protected under the Americans with Disabilities Act (ADA) and Section 504.** Under the ADA, students with a food allergy are considered to have a disability. A Task Force/ Committee Report titled "The Allergist's Role in Anaphylaxis and Food Allergy Management in the School and Childcare Setting” provides a comprehensive overview of how federal civil rights legislation addresses food allergies in the school setting (Wang, Bingemann, Russell, Young, & Sicherer, 2018).

** A person with a disability is someone who has an impairment (either physical or mental) that substantially limits major life activities (such as eating and breathing and going to school), or who is regarded as having such impairments. In 2008, the ADA was amended to include conditions that only show symptoms at certain times.

The list of top eight allergens as identified in the Food Allergen Labeling and Consumer Protection Act of 2004 ("FDA Food Allergen Labeling and Consumer Protection Act," 2014) does not currently include alpha-gal. As a result, AGS patients find that it is extremely difficult and often not possible to determine if a product contains mammalian-derived ingredients when trying to verify with manufacturers or service providers, such as restaurants. Manufacturers often hide under the veil of “proprietary ingredients.” In addition, the FDA does not require manufacturers of medical products to report or describe food allergens in labeling. The consequences of the lack of alpha-gal labeling can be life-threatening and even fatal.

The lack of labeling of medications, foods, beverages (including alcohol), cosmetics, and other products has been a concern of patients with AGS for years. In 2016 the Arkansas Legislative Task Force on Alpha Gal submitted a citizen’s petition to request the U.S. FDA “support Congressional action requiring the labeling of all products intended for human ingestion or injection if they contain mammal meat or mammalian meat products, such as gelatin or glycerin.” (Arkansas Legislative Task Force on Alpha Gal, 2016).

Healthcare providers, manufacturers, and patients are left at risk without awareness and proper labeling of mammalian-derived ingredients. Mammalian-derived ingredients can be found in common household products such as soaps and cosmetics, and in many medical and dental devices and pharmaceuticals. Vaccines also pose a risk to AGS patients that is often underestimated as reported by Stone et al (2019): “Clinicians who manage [AGS] should be made aware of a risk of anaphylaxis to vaccines containing higher gelatin content, such as MMR and zoster vaccine, especially because of their parenteral delivery.”

Needs and Opportunities

While issues and challenges around AGS abound, many opportunities for improvement exist, especially with the federal government’s support. The following is a list of areas where urgent needs and opportunities co-exist.

Research

More research is needed to better understand the baseline quantity of alpha-gal that triggers reactions, and why symptoms vary from person to person. For example, studies have indicated that carrageenan, an ingredient commonly used in food preparation and often included in many organic and vegan foods, may trigger allergic reactions in people with AGS. However, current and past research efforts have not reached conclusions. More research is needed to investigate the range and degree of sensitivity to alpha-gal in different patients.

Education and Awareness

Education and awareness for the following vocations should be considered as a top priority to support patients for healthcare, food, and other products and services.

First responders, including EMS, police, firefighters
Healthcare providers, including emergency departments physicians, primary care physicians, pediatricians, allergists, gastroenterologist, surgeons, and pharmacists
Dieticians, nutritionists, and case managers
Centers for Disease Control and Prevention
Public health departments
Department of Education; student awareness, nurse training, and property management
Emergency preparedness agencies; local, state and federal
United States Department of Food and Drug Administration
United States Department of Agriculture
Department of Defense
Department of Veterans Affairs

Education and awareness of the current status of AGS throughout other tick-borne support organizations and food allergy networks should be considered to further educate the public and support patients who may have a “co-infection” of AGS. Otherwise, they may be left mis/undiagnosed, which could leave them in daily risk for anaphylaxis and without epinephrine, which can be lifesaving. Lastly, as the science and understanding of the nature, causes, and treatment of AGS rapidly evolves, recommending a regularly designated frequency to update Alpha-gal Syndrome on the CDC website, and throughout the healthcare network is a wise practice to support the patients.

Diagnosis and Treatment Guidelines

Evidence-based diagnosis and treatment guidelines supported by providers and professional societies will help raise awareness of AGS, broad training and education, screening of at-risk populations, and standardized treatment in support of quality/clinical outcomes as well as improved clinical economic outcomes.

Possible Actions for Working Group to Consider

This subcommittee identified the following potential actions that the federal government could take to help raise awareness and better support patients with AGS.

Require labeling of foods, products, beverages (including alcohol), cosmetics, and pharmaceuticals that contain non-primate mammalian ingredients (active or inactive).
Update the FDA’s Food Safety Modernization Act to incorporate Alpha-gal Syndrome awareness training into the FDA’s “Retail Food Industry/Regulatory Assistance and Training” Program.
Support a "Call-to-Action" for Standard-of-Care/Evidence-based Guidelines. Professional societies/associations will collaborate to form an "AGS Task Force" that will set in motion clinical research to generate evidence in support of the best treatment practices for AGS.

Votes of Subcommittee Members

Possible actions were presented and discussed by subcommittee members. The wording of possible actions here were voted on by subcommittee members and results are presented here.

Vote: The subcommittee unanimously voted yes to accept the list of possible actions for this priority.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	1

Priority 4: Tick Bite Prevention and Tick Control

Summary

A major dilemma in public health is that despite the availability of effective tools for preventing tick bites, protective behaviors are often not adopted (Mowbray, Amlot, & Rubin, 2012). There is no question that tick bites deleteriously affect outdoor activities and may lead to the transmission of pathogens that cause illness in people, domestic animals, and wildlife. Notably, most of the available strategies for managing ticks and avoiding tick bites were developed to manage Ixodes scapularis and Lyme disease (LD) in the Northeastern U.S. These methods for ticks of public health importance in the southern U.S., specifically Amblyomma americanum and Dermacentor variabilis, and their associated diseases may be appropriate but some have not been well evaluated. AGS has been principally associated with bites of A. americanum. Although it is distributed across the southern U.S., the present geographic range of this tick species is expansive, involving 26 states. Collections of this tick have been made along the entire eastern seaboard and into the Midwestern U.S. (https://www.cdc.gov/ticks/maps/lone_star_tick.pdf). Currently, A. americanum is distributed from Florida to Maine and from the middle of Texas up through Oklahoma, Kansas, Nebraska, and Iowa. The states bordering the Great Lakes comprise the top end of the distribution of this tick. Further northward and westward expansion of this tick species is expected because of climate change (Raghavan, Peterson, Cobos, Ganta, & Foley, 2019). It is worthwhile noting that the geographical area of high prevalence of lone star ticks is the same as the geographical area where numerous major U.S. Army installations are located, thus increasing exposure to lone star tick bite during training exercises/physical training, and increasing possible AGS susceptibility. In fact, cases of AGS within military service personnel have already been reported (Wuerdeman & Harrison, 2014).

Effective prevention of tick bites requires knowledge of the efficacies of various techniques for local tick species and maximal use of these techniques by people at risk of tick exposure. As stated above, some of the protective techniques currently recommended for controlling ticks or prevention of bites from blacklegged ticks in the northern U.S. are likely to be effective in preventing tick bites in southern environments. These methods are discussed below. General information on ticks and tick-borne diseases and AGS is available on the website maintained by the Centers for Disease Control and Prevention at:https://www.cdc.gov/ticks/avoid/on_people.html.

Evidence and Findings

Prevention of tick bites and tick control. Avoidance of ticks or reduction of tick populations in woodland habitats to a point where it is unlikely that people will encounter ticks requires judicious use of a combination of methods. Some methods are best applied on an area-wide basis in public lands, such as parks, recreation areas, etc. Tick control in these areas would necessarily be carried out by governmental agencies. Other methods are available for use in peridomestic landscapes. Certainly, additional research is needed on all standard protective methods for the blacklegged tick to determine the effectiveness of these procedures in controlling and avoiding lone star and American dog ticks. Some of the methods briefly described below are discussed in more detail in a recent review (White & Gaff, 2018). Additional information on personal protective measures against blacklegged ticks can be found in the review by Eisen and Dolan (Eisen & Dolan, 2016).

Public knowledge, attitudes, and practices. Conscientious and proper application of tick bite prevention methods and tick management techniques are necessary to effectively avoid tick-borne diseases and AGS associated with tick bites. Studies in LD endemic regions suggest that public education can lead to varying degrees of compliance in the use of recommended methods. Niesobecki et al. (Niesobecki et al., 2019) determined that self-reported knowledge of the epidemiology of LD was significantly (p < 0.05) associated with performing a tick check. Some protective practices are, however, often applied with limited efficacy in preventing tick bites (Malouin et al., 2003; Poland, 2001). For example, failure to recall a tick bite, by LD patients is a common occurrence. In six Northeastern emergency rooms, a minority (18.5%) of 325 pediatric patients diagnosed with LD recalled being bitten by a tick (Nigrovic et al., 2019). Similar evaluations of educational or behavioral interventions in the southern U.S. where A. americanum is the predominant human-biting tick species need to be carried out to define public knowledge and attitudes that are impeding the adoption of protective practices against tick bites. It should be emphasized that such investigations need to be constructed using a robust sampling design that involves actively evaluating and measuring behaviors. Sole reliance on self-reported responses to questionnaires can yield misleading results because the responses may be based on beliefs not supported by factual information (Mowbray et al., 2012).

To make informed decisions about risk, the public needs access to accurate and timely information about local tick species, tick biology, the likelihood of contracting a tick-borne illness or AGS following a tick bite and, recommended practical methods of tick control and prevention of tick bites. Websites that provide tick-related information for southern populations are needed and should include links to other informative network web resources. On these websites, it should be easy for users to access information specifically relevant to their local area. The Tick Encounter Resource Center in the University of Rhode Island has a website (https://tickencounter.org/) on ticks and tick-borne diseases that is a model for what could and should be developed regarding southern tick species. Retail outlets, including chain and local drugstores and outfitters, should be encouraged to provide tick-bite prevention materials (e.g., forceps appropriate for tick removal, repellents, and informational material) that are available just before and during times of peak tick activity and, these materials should be affordable and easy to use.

The importance of promptly removing attached ticks. Tick-borne diseases can be avoided if attached ticks are removed before disease agents are transmitted. Accordingly, the importance of carrying out a “tick check” after visiting woodland areas cannot be understated. Tick attachment times required for pathogen transmission vary for different tick-pathogen systems (Richards, Langley, Apperson, & Watson, 2017). Notably, the attachment time required to illicit AGS is presently unknown. Instructions for safe removal of ticks can be obtained from the following CDC website: https://www.cdc.gov/ticks/removing_a_tick.html

Repellents. Personal protection from ticks can be obtained through the application of repellent chemicals to skin and clothing. Repellents that contain a variety of active ingredients, such as DEET, picaridin, and permethrin, are commercially available, and other products are available for protection against ticks when applied to exposed skin and clothing (see (B.W. Bissinger & Roe, 2010) for a review). Information on repellents registered for use can be found on the EPA website: https://www.epa.gov/insect-repellents; and information on botanical repellents can be obtained from the CDC website: https://www.cdc.gov/lyme/prev/natural-repellents.html. Various repellents have been found to be effective against southern tick species when applied to exposed skin and clothing (B. W. Bissinger, Apperson, Sonenshine, Watson, & Roe, 2009; B. W. Bissinger et al., 2011; Carroll et al., 2008; Carroll, Klun, & Debboun, 2005; Solberg et al., 1995). The length of protection would be expected to vary with the repellent and the formulation (aerosol, cream, lotion, wipes, etc.). The insecticide permethrin is the only long-lasting repellent for use against ticks, but the repellent can only be applied to clothing. People wearing summer clothing (sock, shorts and T-shirts) treated with permethrin received significantly fewer tick bites from blacklegged ticks compared to people wearing comparable clothing that was not treated (N. J. Miller, Rainone, Dyer, Gonzalez, & Mather, 2011). Permethrin-treated uniforms provided significant protection against lone star tick bites for forestry workers in North Carolina for one year (Vaughn et al., 2014). Aerosol formulations of permethrin can be obtained over-the-counter. Instructions for treating clothing are on the product label and can also be obtained from the CDC website on prevention of tick bites: https://www.cdc.gov/lyme/prev/on_people.html. Permethrin-treated clothing can be purchased by the public from the company Insect Shield (http://www.insectshield.com). There is no question that more field research with at-risk populations is needed to develop the information required to make reliable and informative recommendations about repellent use in the south.

Habitat modification. The habitats of A. americanum and D. variabilis have been characterized previously (Biology of Ticks, 1993; Hair & Bowman, 1986; Kessler, Ganser, & Glass, 2019) and effects of landscape modifications on populations of these ticks have been investigated. Environmental manipulations include controlled burns, removing canopy vegetation to promote desiccation by opening up ground-level plants and leaf litter to sunlight, raking of leaf litter, low mowing of lawns and meadows, and lowering vertebrate host populations or excluding hosts (especially deer) by fencing. Environmental management can influence habitat suitability for ticks directly or can influence tick abundance by altering the behavior of tick hosts (Presley & Hair, 1988). Applicability of these techniques varies and is likely to be suitable along the gradient from urban to suburban to rural to natural areas. For example, controlled burns for land management purposes has been found to significantly lower numbers of D. variabilis and A. americanum populations in Georgia and Florida (Gleim et al., 2014; Gleim et al., 2019), but this method would not suitable for tick control in residential areas in most peridomestic landscapes.

Knowledge of environmental factors that regulate tick abundance can be utilized to develop landscaping practices that decrease the survival or discourage the presence of ticks. Ticks can be avoided by separating areas where people are active from tick habitat. Combined use of mowing, fencing, wood chip or crushed rock lawn borders, construction of elevated decks and boardwalks, and placement of furniture and play areas away from woodlands can reduce the exposure of people to ticks (Stafford, 2007). These techniques have been evaluated for I. scapularis in the north so that recommendations are available for practical implementation (Stafford, 2007). The effectiveness of these techniques, however, is likely to differ for southern tick species and in southern environments, so research is needed to adapt these methods for implementation in the south. A manual similar to the one produced by the Connecticut Agricultural Experiment Station (Stafford, 2007) adapted for southern ticks and environments would be a valuable resource of information for prevention of tick-borne disease and potentially AGS.

Host-targeted methods. White-tailed deer, Odocoileus virginianus, are important hosts for all blood-feeding life stages of A. americanum (Childs & Paddock, 2003), and as such, management of deer populations can potentially influence tick abundance (Telford, 2017). Exclusion of deer by fencing can be utilized in suburban environments, but efficacy at lowering A. americanum populations has been reported to be modest (Bloemer et al., 1990; Bloemer, Snoddy, Cooney, & Fairbanks, 1986; Ginsberg, Butler, & Zhioua, 2002), and effectiveness of this method apparently depends on the size of the exclosure (Perkins, Cattadori, Tagliapietra, Rizzoli, & Hudson, 2006). Large exclosures have resulted in greater reductions in tick abundance compared to small exclosures (Perkins et al. 2006). Deer exclusion can, however, be integrated with other techniques (e.g. acaricide applications) to manage A. americanum (Bloemer et al., 1990).

Reductions in deer populations through hunting has produced mixed results in lowering tick populations in LD endemic areas. Deer removal from isolated habitats, such as islands, has had a dramatic impact on tick populations. The habitats, however, are not representative of the areas where LD is endemic. Reductions short of complete elimination of deer have given mixed results in significantly reducing cases of LD (Kugeler, Jordan, Schulze, Griffith, & Mead, 2016). Elimination of deer for the purposes of reducing tick populations in peridomestic landscapes is controversial and generally not practical for most homeowners.

Acaricides. Area-wide and barrier applications. Wide-scale acaricide applications for tick control are effective, but only when carefully targeted, because of the widespread but locally clustered nature of tick distributions (Goddard, 1997). Acaricides can be applied to heavy-use areas, such as in treatment of animal pastures for A. americanum control (Barnard, Mount, Haile, & Daniels, 1994), or acaricides can be targeted at the ecotone of woodlands and peridomestic landscapes as barrier applications to discourage tick movement into lawns (Jordan, Schulze, Eisen, & Dolan, 2017; Schulze et al., 2001; Stafford, 2007). Some acaricide formulations are registered for general-use by homeowners, but there are professional pest control services available in most suburban areas. Research is needed to evaluate the efficacy of area-wide and barrier applications in reducing tick populations in peridomestic and public-use areas in the southern U.S.

Targeted acaricidal applications.Acaricides can be targeted for application to domestic animals by direct applications, such as via tick collars or spot applications to dogs and cats. Application to deer for area-wide tick management is dependent on treatment of enough of the local host animals to attain successful control. Several devices have been developed to apply pesticides to small mammals, including bait boxes to control D. variabilis (Sonenshine & Haines, 1985) and I. scapularis (Dolan et al., 2004) on rodents, and cardboard tubes containing acaricide-treated cotton balls to control I. scapularis on mice (Mather, Ribeiro, & Spielman, 1987). As A. americanum does not utilize small rodents as hosts, bait boxes or cardboard tubes are not efficacious against this tick species. Techniques to target acaricides at large mammals include the use of systemics (such as ivermectin) applied to deer via treated bait (J. A. Miller, Garris, George, & Oehler, 1989; Pound, Miller, George, Oehler, & Harmel, 1996), and topical application of devices to deer using devices such as the 4-poster (Carroll et al., 2002; Pound, Miller, & George, 2000). In a recent study, Schulze et al. (Schulze, Jordan, Hung, & Schulze, 2009) reported 90%+ control of all blood feeding stages of A. americanum in areas where 4-posters were deployed. Additional information on the use of acaricides for control of ticks on deer can be found in Stafford and Williams’ publication (Stafford III & Williams, 2017). These methods are promising especially for control of A. americanum and I. scapularis on public lands (e.g. parks), but efficacy in preventing tick bites in southern states must be validated by research. Additionally, treatment of deer with acaricides is not practical for homeowners.

Opportunities

AGS has been associated with the bites of the lone star tick, Amblyomma americanum. The geographic distribution of this tick is expanding and has been collected in 26 states from the Midwest to the East Coast. Additionally, the lone star tick is a vector for rickettsial pathogens. Despite its public health importance, there are opportunities for research and public education that could reduce the burden of disease from this tick. Discovery of an attached tick can cause extreme anxiety. People need access to accurate and timely information on tick species that occur in their geographic locations and the risks associated with tick bites. The responsibility for developing educational resources for the public is best fulfilled by county and state health departments working in collaboration with the Agricultural Extension Service at land grant universities. Sustainment of behaviors for prevention of tick bites is a major dilemma in public health. Accordingly, educational resources are needed that are engaging, easily comprehended, and tailored to meet local needs. Internet-based educational resources have the potential to reach a large number of people and to provide accurate information in real-time on tick identification, biology, methods of personal protection and tick control, and most importantly, the health risks posed by tick bites from locally abundant species. Smart phone applications and citizen science programs on ticks are examples of programs that could be developed by university and state health department vector biologists in coordination with educational/media specialists. Studies of the attitudes and knowledge that motivate people to engage in tick bite prevention should be carried out by behavioral scientists. This information would help to guide development of educational programs.

Educational efforts would benefit greatly from applied research on the efficacy of commercially available tick repellents, habitat modification to minimize contact between people and ticks, and acaricides for tick control in peridomestic landscapes. Lone star ticks are inexorably linked to white-tailed deer that serve as tick blood meal hosts. Accordingly, research on the interaction of ticks and deer should be coordinated and carried out with wildlife biologists. Practical methods of habitat modification and exclusion techniques for deer should be developed and demonstrated.

Possible Actions for Working Group to Consider

This subcommittee identified the following potential actions that the federal government could take to improve preventing bites from and controlling the population of the lone star and American dog ticks:

Fund research on chemical repellents for personal protection against the lone star and other ticks associated with AGS.
Fund research to understand how the public's knowledge, attitudes, and practices related to ticks may or may not inhibit the adoption of tick bite prevention behaviors; and to specifically understand how prevention practices for the lone star tick may affect (increase/decrease) the risk of AGS.
Fund research to develop economical and practical methods that homeowners can use to eliminate ticks in peridomestic landscapes as well as methods that can be used by municipalities for towns, commercial properties, and common spaces.

Votes of Subcommittee Members

Possible actions were presented and discussed by subcommittee members. The wording of possible actions here were voted on by subcommittee members and results are presented here.

Vote: The subcommittee unanimously voted yes to accept the list of possible actions for this priority.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	1

Discussion

The implications of AGS are profound, as experienced by many patients; however, the general public’s as well as many medical professionals’ awareness and understanding of the condition are alarmingly limited. For many patients, AGS is a lifelong condition. As a results, patients with AGS must manage their food sources, how they eat, the types of medicines they take, the cosmetics they use, etc., on a daily basis. AGS may be considered a greater threat than a typical food allergy, given that alpha-gal can appear in many products (food and non-food) that may not be considered as hazards. As the public becomes more aware of AGS and its manifestations, the possibility of developing this life-altering condition may help increase compliance with tick prevention measures and prevent tick-borne diseases in general.

The emergence of AGS as a non-infectious tick-borne disease that can be induced by a bite from the lone star tick calls for efforts to better understand the mechanisms behind the allergic reaction to alpha-gal as well as the tick and human factors involved in AGS. Two aspects are necessary to elucidate the pathogenic mechanisms of AGS: 1) surveillance of human-biting ticks to determine the exposure parameters that lead to the disease and, 2) epidemiological surveillance to determine the link between the ticks that have bitten individuals and the development of AGS in some of those individuals. For many tick-borne diseases, case reporting and research on disease incidence and prevalence have been implemented; however, this is currently a significant gap for AGS. Additional under-explored areas in the pathogenesis of AGS are the potential role of tick salivary factors and influence of the human host’s defense.

For those with symptoms of AGS, skin tests can confirm sensitivity to the alpha-gal antigen, and blood tests that measure the level of antibodies to alpha-gal are largely used for diagnosis. Tick-related diagnostic testing for AGS has not been well investigated. Importantly, these diagnostic methods are of no benefit to patients if healthcare providers and emergency medical personnel are not aware of the prevalence of AGS and educated about its causes and symptoms. This is especially important in endemic areas where evidence-based guidelines for diagnosis/testing and management/treatment are most needed.

Management of AGS is focused on avoidance of mammalian meat and, in some cases, dairy and various mammalian-derived products. Avoidance is complicated by a lack of much needed labeling of foods, pharmaceuticals, and other commonly used non-dietary products. Effective therapies beyond dietary restriction would be beneficial in controlling allergic reactions to alpha-gal for those who have already been diagnosed. In addition, more research is needed to assess the range and degree of alpha-gal sensitivity among patients to better guide treatment and management.

Important to the patient community, making educational materials on AGS available and offering ongoing support for AGS patients should be a priority for tick-borne disease support organizations, food allergy networks, public health departments, as well as federal organizations involved in tick-borne disease research, management/surveillance, and policy/guideline development. Improved awareness and education will reduce misdiagnoses and identify patients with ongoing risk for anaphylaxis and other allergic reactions.

It is also important for the public to have access to accurate and timely educational materials about the tick species that occur in their geographical areas and the risks associated with the bites of those ticks. After all, while there may not be a way to prevent AGS in those with prior reactions other than by dietary avoidance and avoidance of mammalian-derived products, prevention for developing AGS or any tick-borne illness in the first place is achieved by avoidance of tick bites. Of benefit to all tick-borne conditions, further research is needed on improved methods of personal protection against the lone star tick and other ticks and methods of tick elimination on properties, as well as on the adoption of tick bite prevention strategies and understanding how these practices may affect disease risk.

Limitations

The primary challenges faced by the subcommittee in preparation of this report included the lack of an accurate estimate of the number of patients diagnosed with AGS and an incomplete understanding of the role of human-biting ticks in the development of AGS.

In summary, there is an overall lack of awareness, training, and education surrounding AGS causes, symptoms, diagnosis, and treatment/management, which negatively impacts appropriate implementation of tick-bite prevention measures.

References

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Content last reviewed on January 22, 2020