Human leukocyte antigen-associated severe cutaneous adverse drug reactions: from bedside to bench and beyond

Despite their being uncommon, severe cutaneous adverse drug reactions (SCARs) result in a very great burden of disease. These reactions not only carry with them a high mortality (10%–50%) and high morbidity (60%) with severe ocular complications, alopecia, oral and dental complications and development of autoimmune diseases, but also create a substantial economic burden for patients' families and society. SCARs are, therefore, an important medical problem needing a solution in many countries, especially in Asia. The clinical spectrum of SCARs comprises Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS (drug rash with eosinophilia and systemic symptoms) (also known as drug hypersensitivity syndrome or drug-induced hypersensitivity syndrome) and acute generalised exanthematous pustulosis. Recent crucial advances in determining genetic susceptibility and understanding how T cells recognise certain medications or their metabolites via the major histocompatibility complex and the effects of cofactors, have led to the implementation of cost-effective screening programs enabling prevention in a number of countries, and to further understanding of the patho-mechanisms involved in SCARs and their significance. In this review, we document comprehensively the journey of SCARs from bedside to bench and outline future perspectives in SCARs research.

Tick killing in situ before removal to prevent allergic and anaphylactic reactions in humans: a cross-sectional study

BACKGROUND: Tick anaphylaxis is a potentially fatal outcome of improper tick removal and management. OBJECTIVE: To investigate whether killing ticks in-situ with ether-containing sprays or permethrin cream, before careful removal by the mouthparts could reduce this risk. METHODS: This was a prospective study at Mona Vale Hospital Emergency Department (ED) in Sydney, New South Wales, over a 6-month period during the peak tick season of 2016. Tick removal methods, allergic/anaphylactic reactions were recorded for patients presenting with ticks in situ or having already removed the ticks themselves. Primary endpoint was allergic/anaphylactic reaction after tick killing/removal. RESULTS: One hundred twenty-one patients met study inclusion criteria. Sixty-one patients (28 known tick-hypersensitive) had ticks killed with Wart-Off Freeze or Lyclear Scabies Cream (5% w/w permethrin) before removal with fine-tipped forceps or Tick Twister. Three patients (2 known tick-hypersensitive) had allergic reactions (5%), none anaphylactic. The 2 known hypersensitive patients suffered reactions during the killing process and the third patient had a particularly embedded tick meaning it could not be removed solely by mouthparts. Fifty patients presented to the ED posttick removal by various methods, none using either fine-tipped forceps or Tick Twister, of which 43 (86%) experienced allergic reactions – 2 anaphylactic. Five patients suffered allergic reactions before presentation despite no attempt at kill or removal, but ticks had likely been disturbed by some other method. Five patients had live ticks removed in ED – 3 refused killing and had no reaction despite 1 having known hypersensitivity; 2 had ticks on eyelids contraindicating killing, 1 with known hypersensitivity but both had allergic reactions post removal. CONCLUSION: Results support killing ticks in-situ before careful removal by mouthparts to reduce allergic/anaphylactic reactions although further research is still required.

A novel Australian tick Ixodes (Endopalpiger) australiensis 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

HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in Vietnamese

BACKGROUND: In Vietnam, we observed a high incidence of carbamazepine (CBZ)-induced severe cutaneous adverse drug reactions (SCARs)-Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity rash with eosinophilia and systemic symptoms (DRESS). In other Asian countries, HLA-B*1502 is an established risk factor for SCARs. OBJECTIVE: The aim of our study was to determine the frequency of HLA-B*1502 in SCARs patients at a large University Medical Center in Hanoi, Vietnam. METHODS: Thirty-eight cases of SCARs caused by CBZ and 25 patients with epilepsy tolerating CBZ were enrolled in a case-controlled study. Clinical manifestations and laboratory findings were recorded for each subject. Genomic DNA was isolated using the QIAamp DNA purification system. The combination of polymerase chain reaction and sequence specific oligonucleotide probes with the Luminex 100×MAP flow cytometry dual laser system was then used to quantitate fluorescently labelled oligonucleotides attached to colour-coded microbeads. RESULTS: Cases comprised 20 SJS (52.6%), 7 TEN (18.4%), 8 overlap syndrome (21.1%), and 3 DRESS patients (7.9%). A strong association between HLA B*1502 and bullous skin reactions such as SJS/TEN and overlap was confirmed with an odds ratio (OR) of 33.78 (95% confidence interval [CI], 7.55-151.03), p < 0.0001, Sensitivity 91.4%, Specificity 76.0%, positive predictive value 84.2%, and negative predictive value 86.4%. We did not, however, observe any correlation between the presence of this allele and CBZ-induced nonbullous skin reactions (DRESS) (OR, 6.33; 95% CI, 0.48-82.74; p = 0.1592). CONCLUSION: Our results indicate the presence of HLA-B*1502 in Vietnamese is a pharmacogenetic risk factor for developing CBZ-induced SJS/TEN.

Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance

Serious tick-induced allergies comprise mammalian meat allergy following tick bites and tick anaphylaxis. Mammalian meat allergy is an emergent allergy, increasingly prevalent in tick-endemic areas of Australia and the United States, occurring worldwide where ticks are endemic. Sensitisation to galactose-α-1,3-galactose (α-Gal) has been shown to be the mechanism of allergic reaction in mammalian meat allergy following tick bite. Whilst other carbohydrate allergens have been identified, this allergen is unique amongst carbohydrate food allergens in provoking anaphylaxis. Treatment of mammalian meat anaphylaxis involves avoidance of mammalian meat and mammalian derived products in those who also react to gelatine and mammalian milks. Before initiating treatment with certain therapeutic agents (e.g., cetuximab, gelatine-containing substances), a careful assessment of the risk of anaphylaxis, including serological analysis for α-Gal specific-IgE, should be undertaken in any individual who works, lives, volunteers or recreates in a tick endemic area. Prevention of tick bites may ameliorate mammalian meat allergy. Tick anaphylaxis is rare in countries other than Australia. Tick anaphylaxis is secondarily preventable by prevention and appropriate management of tick bites. Analysis of tick removal techniques in tick anaphylaxis sufferers offers insights into primary prevention of both tick and mammalian meat anaphylaxis. Recognition of the association between mammalian meat allergy and tick bites has established a novel cause and effect relationship between an environmental exposure and subsequent development of a food allergy, directing us towards examining environmental exposures as provoking factors pivotal to the development of other food allergies and refocusing our attention upon causation of allergy in general.