Robert J. Heddle

Ant venom immunotherapy: a double-blind, placebo-controlled, crossover trial

BACKGROUND The jack jumper ant Myrmecia pilosula is responsible for about 90% of ant venom anaphylaxis in southeastern Australia. We aimed to establish whether M pilosula venom immunotherapy (VIT) prevents lifethreatening sting anaphylaxis in otherwise healthy adults. METHODS We did a double-blind, placebo-controlled crossover trial of M pilosula VIT. Participants were randomly allocated either immunotherapy, in accordance with the semirush hyposensitisation regimen, or placebo. The primary endpoint was systemic reaction after a deliberate sting challenge. Analysis was per protocol. FINDINGS We randomly allocated 68 healthy volunteers (aged 20-63 years) who were allergic to M pilosula venom to placebo (33) and VIT (35). Four on placebo were stopped early and 12 on VIT had their treatment allocations revealed before the sting challenge, thus 29 on placebo and 23 on VIT were included in the primary analysis. Objectively defined systemic reactions to sting challenges arose in 21 of 29 participants (72%) on placebo (8 reactions were associated with hypotension) and none of 23 on VIT (p<0.0001). Of the remaining 12 on VIT who underwent sting challenges after treatment allocations were revealed, only one reacted to sting challenge with transient urticaria that did not require treatment. After crossover of the placebo group to VIT, one of 26 had a reaction to sting challenge (transient urticaria). In all patients who had VIT, we recorded objective systemic reactions in 22 of 64 (34%) during VIT; two of which were hypotensive. INTERPRETATION In well motivated, highly allergic, but otherwise healthy adults, VIT is highly effective in prevention of M pilosula sting anaphylaxis. The risk of systemic reactions during VIT means that treatment should be given where there is immediate access to resuscitation facilities.

Myrmecia pilosula (Jack Jumper) ant venom: identification of allergens and revised nomenclature

Background:  The ‘Jack Jumper Ant’ (JJA; Myrmecia pilosula species complex) is the major cause of ant sting anaphylaxis in Australia. Our aims were to determine the allergenicity of previously described venom peptides in their native forms, identify additional allergens and if necessary, update nomenclature used to describe the allergens according to International Union of Immunological Societies criteria.

Ultrarush versus semirush initiation of insect venom immunotherapy: A randomized controlled trial

BACKGROUND Venom immunotherapy can be initiated by different schedules, but randomized comparisons have not been performed. OBJECTIVE We aimed to compare the safety of 2 initiation schedules. METHODS Patients of any age with prior immediate generalized reactions to jack jumper ant (Myrmecia pilosula) stings were randomized to venom immunotherapy initiation by a semirush schedule over 10 visits (9 weeks) or an ultrarush schedule over 3 visits (2 weeks). In a concurrent treatment efficacy study, the target maintenance dose was randomized to either 50 μg or 100 μg. The primary outcome was the occurrence of 1 or more objective systemic reactions during venom immunotherapy initiation. Analyses were by intention to treat. We also assessed outcomes in patients who declined randomization. RESULTS Of 213 eligible patients, 93 were randomized to semirush (44 patients) or ultrarush (49 patients) initiation. Objective systemic reactions were more likely during ultrarush initiation (65% vs 29%; P < .001), as were severe reactions (12% vs 0%; P= .029). Times to maximal increases in venom-specific IgG(4) were no different between treatments, whereas the maximal increase in venom-specific IgE occurred earlier with ultrarush treatment. Similar differences between methods were observed in patients who declined randomization. One hundred seventy-eight patients were randomized to maintenance doses of either 50 μg (90 patients) or 100 μg (88 patients). The target maintenance dose had no effect on the primary outcome, but multiple-failure-per-subject analysis found that the 50 μg dose reduced the likelihood of reactions. CONCLUSION Ultrarush initiation increases the risk of systemic reactions. A lower maintenance dose reduces the risk of repeated reactions, but the effect on treatment efficacy is unknown.

Immediate-type hypersensitivity drug reactions.

Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. The incidence of drug‐induced anaphylaxis deaths appears to be increasing and our understanding of the multiple and complex reasons for the unpredictable nature of anaphylaxis to drugs is also expanding. This review highlights the importance of enhancing our understanding of the biology of the patient (i.e. immune response, genetics) as well as the pharmacology and chemistry of the drug when investigating, diagnosing and treating drug hypersensitivity. Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive.

Oral drug challenges in non‐steroidal anti‐inflammatory drug‐induced urticaria, angioedema and anaphylaxis

Background:  Urticaria, angioedema and anaphylaxis are common adverse reactions to non‐steroidal anti‐inflammatory drugs (NSAIDs).

IgE+ cells in the peripheral blood of atopic, nonatopic, and bee venom–hypersensitive individuals exhibit the phenotype of highly differentiated B cells☆☆☆★★★

We have analyzed IgE+ cells in peripheral blood of atopic donors, donors hypersensitive to bee venom, and nonatopic control donors with two- and three-color flow cytometry. Although the percentage of IgE+ cells varied among these groups, the overall phenotypic patterns were similar. Most IgE+ cells do not display typical B-cell markers, such as CD19, CD20, and CD21. A significant proportion of these cells stain for CD38, indicating that they are more differentiated. IgE+ cells express Fc gamma RII and CD45RO, an isoform associated with an advanced level of differentiation. The majority of IgE+ cells do not coexpress other surface immunoglobulin isotypes. In the case of bee venom-hypersensitive donors, we have been able to identify a small population of IgE+ cells with a specificity for phospholipase A2, a major immunogenic component of bee venom. The phospholipase A2+ cells display a phenotype similar to that of the IgE+ cells.

Prevention of anaphylaxis with ant venom immunotherapy.

Purpose of reviewWorldwide, eight genera of ants have been associated with sting allergy. Until recently only whole ant body extracts have been used for immunotherapy. The purpose of this review is to examine recent advances in the understanding of ant venom allergy and treatment using venom immunotherapy. Recent findingsPublic health problems due to severe ant sting anaphylaxis are not confined to the imported fire ant of North America. Pachycondyla sennaarensis (samsum ant), Pachycondyla chinensis, and Myrmecia pilosula (jack jumper ant) also appear to pose notable threats. The risk to humans from a particular species probably depends on complex interactions between likelihood of human contact, insect aggression, efficiency of the venom delivery apparatus, and venom allergenicity. The highest population prevalence of clinical ant sting allergy so far (3.0%) was reported from south-eastern Australia, due mainly to M. pilosula. Prospective follow-up of untreated people suggests that those older than 30 years with a history of severe reactions (respiratory compromise or hypotension) will benefit most from venom immunotherapy. Whereas the efficacy of ant whole body extract immunotherapy remains to be proven, ant venom immunotherapy has been demonstrated to reduce the risk of systemic reactions to M. pilosula from 72% to 3%. Although a simple method of venom extraction has been developed, small market size means that the treatment may never become widely available. SummaryAnt venom immunotherapy is feasible and highly efficacious. However, the limited geographical distribution of each species presents a major challenge to making venom extracts available for clinical use.

Wheat flour immunotherapy in baker's asthma.

Occupational asthma (OA) is the most reported occupational respiratory disorder in industrialized countries. It is defined as the new onset of asthma caused by workplace exposure. By identifying the suspected workplace trigger to the asthma, symptoms can be minimized by avoiding exposure to that allergen. Bakers have been long recognized as being at high risk of becoming sensitized to workplace allergens and subsequently developing asthma. We report the case of a male baker currently receiving wheat immunotherapy thathas significantly lessenedhis asthma. A 30-year-old smoker presented to clinic for further assessment of his allergic rhinitis and asthma. He was previously doing well and had no history of childhood asthma. Hehad startedworkingasabakerwhenhewas21andwhen he was 24, he was diagnosed with asthma. His symptoms comprised dry cough, dyspnoea and wheeze, all of which promptly resolved with inhaled salbutamol. His symptoms predominantly occurred in the workplace and at times he required hourly use of his salbutamol puffer. When away from work, the patient rarely, if ever, used his salbutamol puffers. His treatment regimen for his asthma comprised fluticasone/salmeterol 500 mcg/100 mcg and inhaled salbutamol (200 mcg) in themorning with PRN salbutamol at work. His baseline forced expiratory volume in 1 s (FEV1) was 3.3 L with a forced vital capacity (FVC) of 5.15 L (ratio of FEV1/FVC 0.64). There was no suggestion in history that the patient had non-specific airway hyperresponsiveness. Peak flow readings at the workplace were consistently 425 L/min whereas at home they averaged 500 L/min (15% higher at home compared with those at work). Given the history of worsening of asthma at the workplace, possibleallergenswereexaminedbyskinprick testing. This showed strongwheal andflare reactions towheat flour, soybean and rye grain with much lesser reactions to baker’s yeast and oat grain. The patient also had lesser reactions noted to various aeroallergens, including several grass pollens, house dust mite and Alternaria tenuis. Subsequent in vitro testing for a-amylase and storage mite were negative. On reviewing his workplace exposure to the suspected allergens, it was determined that wheat was the predominant allergen with exposures to rye grain and soybean beingminimal at hisworkplace. Avoidancemeasureswere difficult to implement asheowned thisbusiness andhewas compelled to work at the bakery. The patient consented to wheat flour immunotherapy after having the benefits and risks of immunotherapy fully explained to him. Following 12 months of immunotherapy (with appropriate dose escalation according to protocol in a supervised setting) with the wheat flour extract (Stallergenes SA, Antony, France), his workplace asthma symptoms have significantly decreased to the pointwhere he only rarely requires salbutamol for asthma and he has subsequently discontinued his inhaled fluticasone. Follow-up spirometry has shown a FEV1 of 4.29 L with an FVC of 6.02 L (a 30% improvement in FEV1 alone compared with the baseline spirometry results). The patient continues to smoke. There are several potential sensitizers in the baker’s environment, including wheat, rye, barley, baking enzymes, moulds, yeasts, eggs, sesame seeds and nuts. Wheat flour appears to be the dominant sensitizer inmost bakeries. Very few studies have considered using immunotherapy in OA. The largest study to date showed that wheat immunotherapy compared toplacebowas very effective in reducing both in vitro and in vivo measures of immunoglobulin E (IgE) directed against wheat as well as in reducing methacholine hyperresponsiveness.Nospecificworkhas beencarriedout considering the mechanism of action of wheat allergen immunotherapy in baker’s asthma. There is increasing evidence, however, that allergen-specific immunotherapy works by increasing allergen-specific IgG isotypes (especially IgG1 and IgG4), modification of responses by antigen presenting cells, T cells and B cells and decreasing the IgEmediated release of histamine by basophils. According to the wheat allergen manufacturer, this patient is the only one in Australia who is receiving 100% wheat immunotherapy for this indication and is probably one of very few around the world. This case emphasizes a potentially useful therapeutic intervention for some patients with OA.

Immunotherapy – 2076. A controlled study of delta inulin-adjuvanted honey bee venom immunotherapy

peak .gp A .0.822 (0.155), gp B 0.326 ((0.106), 52 weeks gp A 0.453 (0.223) gp B 0.170 (0.059)]. sIgE responses showed a wide scatter with a rise from baseline of similar magnitude but occurring earlier in group A, followed by a progressive fall, [baseline gp A 0.960 ((0.171), gp B 0.624 (0.138), peak gp A. 1.242 (0.154), gp B 0.888 (0.163), 52 weeks gp A 0.862 (0.243), gp B 0.541 (0.117)]. sIgG1 responses showed a similar pattern. Conclusions

Pharmacokinetics and safety of Intragam 10 NF, the next generation 10% liquid intravenous immunoglobulin, in patients with primary antibody deficiencies

Background and aims:  Intragam® 10 NF is the next generation 10% intravenous immunoglobulin with three pathogen reduction steps and a noncarbohydrate stabiliser. This open label, cross‐over study in patients with primary immunodeficiency was designed to evaluate whether Intragam 10 NF differed in its pharmacokinetics (PK) compared with Intragam P and to assess Intragam 10 NF safety and tolerability.