The University of Sydney

Quantifying the allergenic potency of mammalian meat sources, an important step in providing a framework for improved management of mammalian meat allergy after tick bite (alpha-gal syndrome/AGS).

A systematic review of tick removal techniques: Relationship to outcomes of tick-induced allergic reactions and tick-borne illnesses.

Australia has the highest prevalence worldwide of tick-induced allergies (mammalian meat and tick allergy/anaphylaxis). Inappropriate tick removal techniques are known to trigger tick anaphylaxis. This study aimed to ascertain the evidence for the effectiveness of tick removal methods and their relationship to the outcomes of tick-induced allergies and tick-borne illnesses. The design involved is a systematic literature review. Scopus, Embase, and Medline were searched (September 20, 2023) for studies of tick removal techniques and for outcomes of tick-induced allergic reactions and tick-borne illnesses. Two reviewers reviewed abstracts and full texts. Included studies were appraised (Joanna Briggs Institute critical appraisal tools), and data were extracted, tabulated, and evaluated. Six studies investigated a relevant outcome, all of low or moderate quality. Tick-killing in situ before removal resulted in allergic reactions in only 3/61 patients and no anaphylaxis. 23/28 who presented to the Emergency Department following removal with tweezers had allergic reactions (one anaphylaxis). When those with known tick anaphylaxis killed ticks in situ before removal there was no subsequent anaphylactic reaction. A significant decrease in disease transmission and/or seropositivity ( and/or ) was shown with crushing ticks or gentle pressure before removal with fine-tipped forceps, forceps alone, and surgical tweezers. Manipulation before removal with tweezers made no difference to seropositivity. Few studies worldwide have examined outcomes of tick removal techniques. Tick-killing in situ reduces recurrent tick anaphylaxis in Australians. Early removal with forceps may be effective where tick-borne disease is of greater concern. Further studies of tick-killing in situ focusing upon disease transmission should be prioritized.

A protocol for pre-treatment testing for antibodies to galactose-alpha-1,3-galactose to mitigate the risk of cetuximab hypersensitivity reactions - a retrospective cohort review.

Cetuximab improves survival in KRAS wildtype metastatic colorectal cancer. However, high rates of hypersensitivity reactions (HSRs) limit its use, with HSR rates up to 10-20 %. A major driver of cetuximab HSR is from pre-formed IgE antibody response to galactose-1,3-alpha-galactose (alpha-gal). Evidence from retrospective studies supports alpha-gal pre-screening in this setting. This study reports the impact of prospective alpha-gal antibody screening on cetuximab HSR. Records were reviewed across three medical oncology centres that have adopted alpha-gal antibody screening measures. Data for patients with metastatic colorectal cancer treated with cetuximab were retrieved. All centres assessed alpha-gal levels using the ImmunoCAP® immunoassay. Due to variability in alpha-gal screening practices across study sites, a standardised protocol was applied to all cases. This protocol allowed cetuximab administration if alpha-gal levels were ≤0.10 kUA/L, but prohibited it if alpha-gal levels were >0.10 kUA/L in favour of panitumumab administration. Patients were allocated to either the Alpha-gal Pre-screening Applied ('Pre-screening') or Alpha-gal Pre-screening Not Applied ('Reference') cohorts based on protocol requirements being met. The primary outcome between these patient groups was the incidence of cetuximab HSRs. Of 254 assessable patients, 39 underwent the pre-treatment screening protocol. Of the Pre-screening group, 3% (n=1/39) experienced a cetuximab HSR compared to 16% (n=35/215) in the Reference group (Odds ratio (OR) 0.14; 95% CI 0.0033-0.86, p= 0.02). Patients with alpha-gal antibody titres >0.10 kUA/L were more likely to experience a cetuximab HSR (OR 69.71; 95% CI 5.18-4296.81, p=0.0001). Pre-treatment screening for alpha-gal antibodies significantly reduces the incidence of cetuximab HSRs. A testing threshold of 0.10 kUA/L is effective in identifying patients at risk. Implementing this protocol can improve the safety of cetuximab therapy in high-risk populations. Hypersensitivity reactions (HSRs) limit cetuximab use in KRAS wildtype advanced colorectal cancer, with a significant driver being pre-formed IgE antibodies against galactose-1,3-alpha-galactose (alpha-gal). Our multicentric retrospective study assessed the impact of prospective alpha-gal antibody screening on HSR incidence following cetuximab administration. Of 254 assessable patients, pre-treatment alpha-gal antibody screening significantly reduced the incidence of cetuximab HSRs (3% vs 16%; OR 0.14, p=0.02). Our findings support pre-treatment alpha-gal screening to improve safety of cetuximab therapy in high-risk populations.

Newly Recognized α-Gal Syndrome in the Upper Midwestern United States.

Immunoglobulin E Sensitization to Mammalian Oligosaccharide Galactose-α-1,3 (α-Gal) Is Associated With Noncalcified Plaque, Obstructive Coronary Artery Disease, and ST-Segment-Elevated Myocardial Infarction.

Treating known risk factors for coronary artery disease (CAD) has substantially reduced CAD morbidity and mortality. However, a significant burden of CAD remains unexplained. Immunoglobulin E sensitization to mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal) was recently associated with CAD in a small observational study. We sought to confirm that α-Gal sensitization is associated with CAD burden, in particular noncalcified plaque. Additionally, we sort to assess whether that α-Gal sensitization is associated with ST-segment-elevated myocardial infarction (STEMI) Methods: We performed a cross-sectional analysis of participants enrolled in the BioHEART cohort study. We measured α-Gal specific-immunoglobulin E antibodies in serum of 1056 patients referred for CT coronary angiography for suspected CAD and 100 selected patients presenting with STEMI, enriched for patients without standard modifiable risk factors. CT coronary angiograms were assessed using coronary artery calcium scores and segmental plaque scores. α-Gal sensitization was associated with presence of noncalcified plaque (odds ratio, 1.62 [95% CI, 1.04-2.53], =0.03) and obstructive CAD (odds ratio, 2.05 [95% CI, 1.29-3.25], =0.002), independent of age, sex, and traditional risk factors. The α-Gal sensitization rate was 12.8-fold higher in patients with STEMI compared with matched healthy controls and 2.2-fold higher in the patients with STEMI compared with matched stable CAD patients (17% versus 1.3%, =0.01 and 20% versus 9%, =0.03, respectively). α-Gal sensitization is independently associated with noncalcified plaque burden and obstructive CAD and occurs at higher frequency in patients with STEMI than those with stable or no CAD. These findings may have implications for individuals exposed to ticks, as well as public health policy. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12618001322224.

Genetic and structural basis of the human anti-α-galactosyl antibody response.

Humans lack the capacity to produce the Galα1-3Galβ1-4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development.

Review of topical gelatin-based haemostatic agents; an insidious culprit of intraoperative anaphylaxis?

An under-recognized complication of gelatin-based haemostatic agents is their potential to cause anaphylactic reactions. This review aims to collate and analyse case in the literature of intraoperative anaphylaxis secondary to locally applied haemostatic agents. An electronic search was performed on databases Medline, Embase, Pubmed and ProQuest. A total of 7671 articles were reviewed from title and abstract. After exclusion criteria and duplicates removed, 19 articles with 21 cases were included for analysis. Data extracted from each of the articles included patient demographics, haemostatic agent used, surgery type, known allergies and any objective evidence of hypersensitivity post anaphylactic episode, that is tryptase levels, IgE levels, skin prick testing. Fifty-seven percent of cases involved patients <18 years of age; 57% of cases involved spinal surgery; 100% of cases displayed objective evidence of hypersensitivity (tryptase levels, bovine or porcine IgE levels, or skin prick testing). Thirty-three percent of patients had exposure preoperatively to a known agent causing anaphylaxis or allergy which would preclude the use of a gelatin-based haemostat. These products included vaccines, spam meats, red meat, Jell-O and CollaPlug. Gelatin-based haemostat agents included Floseal, Gelfoam, Surgiflo, fibrin glue, Avitene, haemofibrine sponge, topical bovine thrombin and thrombin-soaked gelatin. Increased awareness of allergy to gelatin-based haemostats for surgical and anaesthetic is imperative, with 33% of cases having a known contraindication to gelatin-based haemostat. This review highlights important aspects in the pre-operative patient history and post-event patient investigation that could assist anaesthetists and surgeons in the prevention of future events.

Global Trends in Anaphylaxis Epidemiology and Clinical Implications.

The true global scale of anaphylaxis remains elusive, because many episodes occur in the community without presentation to health care facilities, and most regions have not yet developed reliable systems with which to monitor severe allergic events. The most robust data sets currently available are based largely on hospital admissions, which are limited by inherent issues of misdiagnosis, misclassification, and generalizability. Despite this, there is convincing evidence of a global increase in rates of all-cause anaphylaxis, driven largely by medication- and food-related anaphylaxis. There is no evidence of parallel increases in global all-cause anaphylaxis mortality, with surprisingly similar estimates for case-fatality rates at approximately 0.5% to 1% of fatal outcomes for hospitalizations due to anaphylaxis across several regions. Studying regional patterns of anaphylaxis to certain triggers have provided valuable insights into susceptibility and sensitizing events: for example, the link between the mAb cetuximab and allergy to mammalian meat. Likewise, data from published fatality registers can identify potentially modifiable risk factors that can be used to inform clinical practice, such as prevention of delayed epinephrine administration, correct posturing during anaphylaxis, special attention to populations at risk (such as the elderly on multiple medications), and use of venom immunotherapy in individuals at risk of insect-related anaphylaxis.

Specific-IgE to galactose-α-1,3-galactose (alpha-gal) has limited utility in diagnosing meat allergy in a tick-endemic population.

A novel Australian tick () inducing mammalian meat allergy after tick bite.

Tick-induced mammalian meat allergy has become an emergent allergy world-wide after van Nunen et al. first described the association between tick bites and the development of mammalian meat allergy in 2007. Cases of mammalian meat allergy have now been reported on all 6 continents where humans are bitten by ticks, in 17 countries - Australia, United States of America (USA), Europe (France, Spain, Germany, Belgium, Switzerland, Sweden, United Kingdom, Italy, and Norway), Asia (Korea and Japan), Central America (Panama), South America (Brazil), and Africa (South Africa and Ivory Coast). To date, in each of these countries, bites from only a single tick species have been linked to the development of mammalian meat allergy: (Australia), (USA), (Europe), and (Panama) are confirmed as culprits, and (Japan and Korea), (Brazil), (Ivory Coast), and (Japan) suspected of provoking mammalian meat allergy after tick bite. Other tick species remain to be formally identified (South Africa). Identification of tick species associated with development of mammalian meat allergy is crucial to the uptake of public health measures to prevent tick bites from culprit tick species, for both individuals living in these tick-endemic areas and those who choose to visit these regions. We report a tick associated with the enhancement of mammalian meat anaphylaxis after tick bite which is novel for both Australia and the world and establishes () as a second tick species associated with mammalian meat allergy in Australia.