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Article Summaries - August 2014

ANAPHYLAXIS: GUIDELINES FROM THE EUROPEAN ACADEMY OF ALLERGY AND CLINICAL IMMUNOLOGY

(Muraro A, Roberts G, Worm M, Bilo MB, Brockow K, Fern andez Rivas M, Santos AF, Zolkipli ZQ, Bellou A, Beyer K, Bindslev-Jensen C, Cardona V, Clark AT, Demoly P, Dubois AEJ, DunnGalvin A, Eigenmann P, Halken S, Harada L, Lack G, Jutel M, Niggemann B, RuŃ‘ff F, Timmermans F, Vlieg–Boerstra BJ, Werfel T, Dhami S, Panesar S, Akdis CA, Sheikh A on behalf of the EAACI Food Allergy and Anaphylaxis Guidelines Group. Allergy 2014; 69: 1026–1045):

  • Anaphylaxis: (i) definition: acute, severe, life-threatening systemic hypersensitivity reaction; (ii) lifetime prevalence: 0.05-2%; (iii) mechanisms: release of mediators from mast cells and basophils (IgE-mediated, IgG-mediated, complement-mediated, idiopathic); (iv) most common culprits: foods, drugs, hymenoptera venom, latex (in up to 20% of cases the elicitor is not identified); (v) factors that influence severity: patient’s age, pathogenic mechanism, allergen properties, allergen dose, route of exposure, degree of sensitization, affinity of specific IgE, presence of cofactors, basal tryptase level, comorbidities (uncontrolled asthma, mast cell disorders, cardiovascular disease), concomitant use of drugs (β-blockers, ACE inhibitors); (vi) augmentation factors: exercise, alcohol, infections, NSAIDs, drugs, menses, stress; (vii) diagnosis: clinical history (NIAID/FAAN criteria: sensitivity=96.7%, specificity=82.4%; anaphylaxis can present without cutaneous signs in ~15% of patients), measurement of allergy mediators (e.g. serum tryptase, serum/urinary histamine or metabolites, serum PAF), allergy testing (e.g. sIgE detection by skin and in vitro tests); (viii) biphasic anaphylactic reactions (recurrent anaphylactic symptoms after resolution of the primary event) may occur in up to 20% of reactions; (ix) treatment in the acute setting: intramuscular epinephrine (1st line therapy; no absolute contraindications), trigger removal, correct positioning of the patient (hypotension → lying on back with lower extremities elevated; pregnant → semirecumbent on the left side with lower extremities elevated; respiratory distress without hypotension → sitting up), intravenous fluids (crystalloids are the 1st choice, given in boluses of 20 ml/kg), inhaled β2-agonists, oxygen, systemic H1- and H2- antihistamines (intravenous antihistamines may cause hypotension), systemic corticosteroids (may prevent biphasic reactions), nebulized adrenaline (for laryngeal edema), nebulized budesonide (for airway edema), adrenaline infusion (in refractory cases), glucagon (in cases of resistance to epinephrine), cardiopulmonary resuscitation; (x) long-term management: allergen avoidance, epinephrine autoinjectors, immunotherapy, anaphylaxis management plan, medical identification, psychological evaluation, group support.
  • Adrenaline acts on: (i) α-1 receptors → peripheral vasoconstriction, ↑ blood pressure, ↓ mucosal edema; (ii) β-1 receptors → ↑ rate and force of cardiac contractions, ↑ blood pressure; (iii) β-2 receptors → bronchodilation, ↓ release of inflammatory mediators.
  • Augmentation factors (cofactors) for anaphylaxis (↓ anaphylaxis threshold; appear in up to 30% of anaphylactic episodes; >1 cofactor may be needed to elicit anaphylaxis): (i) Physical exercise: most frequent cofactor (e.g. ‘food-dependent exercise-induced anaphylaxis’, which only occur in the presence of exercise; described for wheat, shrimps, meat, pistachio, spinach, etc.; most frequent with hard exercise and high degree of food sensitization; may also occur with minimal exercise [e.g. ironing]); differential diagnosis: cholinergic urticaria, exercise-induced asthma, physical urticaria. (ii) Alcohol: relevant factor in up to 15% of anaphylactic episodes. (iii) Infections (mild or severe): relevant factor in up to 11% of episodes; may complicate venom or pollen immunotherapy (SIT must be paused or ↓ during infections. (iv) NSAIDs: relevant factor in up to 9% of episodes. (v) Other drugs: mast cell-activating drugs (iodinated RCM [most frequently iomeprol and iopromide], muscle relaxants [most frequently suxamethonium], quinolones, opioids), drugs that ↑ bradikinin levels (e.g. ACE inhibitors), drugs that ↓ gastric acid (proton pump inhibitors, H2-receptor blockers [↑ risk of anaphylaxis in patients with oral allergy syndrome due to acid-sensitive allergens]), drugs that block counteracting mechanisms during anaphylaxis (β-adrenergic antagonists, ACE inhibitors, angiotensin receptor blockers, MAO inhibitors). (vi) Menstruation. (vii) Stress. (viii) Fever.
  • Mechanisms underlying cofactor-induced anaphylaxis: (i) ↑ gut permeability (exercise-induced, alcohol-induced, infection-induced, NSAID-induced [e.g. NSAIDs ↓ expression of the tight junction protein claudin-7]) → ↑ allergen bioavailability; (ii) ↓ activation threshold of mast cells and basophils (exercise-induced, NSAID-induced, infection-induced, drug-induced); (iii) ↑ synthesis of leukotrienes (NSAID-induced); (iv) ↓ gastric acid (drug-induced) → ↑ allergen bioavailability; (v) immune system stimulation (infection-induced): formation of IgG/IgM immune complexes, release of complement anaphylotoxins (C5a is more potent than C3a for mast cell degranulation; mucosal mast cells do not express anaphylotoxin receptors), cell activation through innate immune receptors (e.g. peptidoglycan can induce mast cell degranulation).
  • Median times to cardiovascular and/or respiratory collapse during anaphylaxis: (i) 5-10 min for IV drugs, (ii) 15 min for field insect stings and IM drugs, (iii) 30 min for food and oral drugs.
  • Allergists must know: (i) how to treat acute anaphylaxis (it may occur after immunotherapy application, skin testing [especially with food or drugs], or food/drug challenges); (ii) how to evaluate and manage a patient with a suspected history of anaphylaxis (confirm diagnosis, determine the etiology, give a treatment plan to prevent and treat further episodes).
  • Approach to a patient with a history of anaphylaxis: (i) evaluate all potential triggers (e.g. food, drugs, insect stings, latex, exercise [or food + exercise], temperature changes, menstruation) within 6 hrs before symptom onset (idiopathic anaphylaxis can account for 60% of adult cases); (ii) assess severity by taking a thorough history of all signs and symptoms (place and time of onset, duration, recurrence, response to treatment); (iii) exclude differential diagnosis (e.g. mastocytosis, mast cell activation disorder [risk factor for anaphylaxis], carcinoid syndrome, neuroendocrine tumors, drug-induced flush [niacin, nicotine, ACE inhibitors, corticosteroids, cathecolamines], alcohol-related flush [alone or in combination with drugs such as disulfiram, griseofulvin or cephalosporins], acute coronary syndrome, pulmonary embolism, postprandial syndromes [ingestion of monosodium glutamate or sulfites, scombroidosis], hereditary angioedema, vocal cord dysfunction syndrome, panic attack, somatoform disorder); (iv) perform proper laboratory tests (serum tryptase, plasma histamine, urinary histamine metabolites, serum PAF, serum PGD2, in vivo and in vitro allergy tests, allergen challenges, tests to exclude differential diagnosis [e.g. imaging studies if suspicion of neuroendocrine tumors, neuropeptide levels if suspicion of carcinoid syndrome, bone marrow biopsy if suspicion of mastocytosis]); (v) give detailed written indications to prevent and quickly-treat further anaphylaxis episodes (e.g. trigger avoidance, use of medical identification, use of autoinjectable epinephrine [>1 dose is needed in up to 30% of episodes], correct positioning, avoidance of some drugs [β-blockers and MAO inhibitors can ↓ epinephrine action; ACE inhibitors can ↓ angiotensin action and ↑ bradykinin levels]); (vi) consider use of immunotherapy (e.g. for hymenoptera sting or food allergy).
  • Absolute indications for an adrenaline auto-injector: (i) previous anaphylaxis with food, latex, aeroallergens and other unavoidable triggers; (ii) previous exercise-induced anaphylaxis; (iii) previous idiopathic anaphylaxis; (iv) co-existent unstable or moderate to severe, persistent asthma with food allergy; (v) venom allergy in adults with previous systemic reactions (unless on maintenance venom immunotherapy) or children with more than systemic cutaneous reactions; (vi) underlying mast cell disorder and any previous systemic reaction.

ANAPHYLAXIS TREATMENT: CURRENT BARRIERS TO ADRENALINE AUTO-INJECTOR USE

(Song TT, Worm M, Lieberman P. Allergy 2014; 69: 983–991):

  • Anaphylaxis: (i) potentially fatal severe hypersensitivity reaction; (ii) 1st-line acute treatment: intramuscular adrenaline into the anterolateral portion of the midthigh (middle of vastus lateralis muscle); (iii) failure or delay in adrenaline administration can ↑ death risk; (iv) a high proportion of individuals with fatal anaphylaxis have had no previous anaphylactic episodes.
  • Adrenaline autoinjectors (AAIs): (i) indicated for patients at risk of anaphylaxis (potentially lifesaving); (ii) no absolute contraindications to use AAIs during an anaphylactic episode; (iii) 5 commercial AAIs currently available and licensed in Europe and/or US (Europe: Anapen, EpiPen, Jext; US: Adrenaclick, Auvi-Q, EpiPen); (iv) mean time to maximum adrenaline concentration (Tmax): EpiPen=8 min, subcutaneous adrenaline=34 min; (v) holding the EpiPen for 1 second was as effective as 10 seconds; (vi) EpiPenpropels adrenaline reaching a depth of ~2.78 cm (needle’s length=1.43 cm), enough to reach the muscle even in obese patients.
  • Barriers to AAI use: (i) patient´s factors: low rates of carrying, fear, insecurity, low knowledge; (ii) physician’s factors: low knowledge, low ability to educate, bad relation with the patient; (iii) social/economic factors: cost, local unavailability, unavailability in public places.

EAACI FOOD ALLERGY AND ANAPHYLAXIS GUIDELINES: DIAGNOSIS AND MANAGEMENT OF FOOD ALLERGY

(Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C, Cardona V, Dubois A, duToit G, Eigenmann P, Fernandez Rivas M, Halken S, Hickstein L, Høst A, Knol E, Lack G, Marchisotto MJ, Niggemann B, Nwaru BI, Papadopoulos NG, Poulsen LK, Santos AF, Skypala I, Schoepfer A, Van Ree R, Venter C, Worm M, Vlieg–Boerstra B, Panesar S, de Silva D, Soares-Weiser K, Sheikh A, Ballmer-Weber BK, Nilsson C, de Jong NW, Akdis CA on behalf of the EAACI Food Allergy and Anaphylaxis Guidelines Group. Allergy 2014; 69: 1008–1025):

  • Food allergy (FA=immunologic reactions to food): (i) IgE-mediated: urticaria, angioedema, bronchospasm, anaphylaxis; (ii) cell-mediated: enterocolitis, proctocolitis, celiac disease, contact dermatitis; (iii) IgE- and cell-mediated: atopic dermatitis, eosinophilic GI diseases.
  • Important points about FA: (i) self-reported FA is ~5 times higher than challenge-proven FA; (ii) several genetic and environmental factors play a role in FA pathogenesis; (iii) diagnosis depends on clinical history and appropriate allergy testing; (iv) food allergen sensitization does not imply clinical reactivity and vice versa; (v) sensitization to food allergens can occur by nonoral routes (e.g. allergy to α-gal after tick bites, allergy to peanut after sensitization through skin); (vi) only trained healthcare professionals, able to interpret results and manage possible adverse reactions, should perform SPTs; (vii) component-resolved diagnosis (CRD) is a promising diagnostic tool that adds sensitivity and specificity to IgE-allergy testing; (viii) management of FA depends on the clinical syndrome; (ix) a “personalized medicine” approach to diagnose and treat FA is likely required but remains elusive.
  • Factors associated with FA: (i) genetic susceptibility; (ii) ↓ gut epithelial barrier; (iii) use of gastric acid suppressive drugs; (iv) ↑ intestinal inflammation; (v) ↑ ‘proinflammatory’ microbiota (e.g. Clostridium, Staphylococci); (vi) ↓ ‘tolerogenic’ microbiota (e.g. Lactobacillus, Bifidobacterium); (vii) ↑ TH2 responses (including IgE production); (viii) food sensitization through skin; (ix) vitamin D insufficiency; (x) unhealthful dietary fat; (xi) obesity; (xii) increased hygiene; (xiii) “inappropriate” timing of 1st exposure to foods.
  • IgE-mediated FA: (i) rising prevalence worldwide (6% of children and 4% of adults in the westernized world); (ii) etiology: genetic factors (currently not modifiable), environmental/exposure factors (targets for prevention); (iii) impact: significant morbidity, ↓ QoL, mortality risk, high costs; (iv) >170 foods have been reported to cause allergic reactions; (v) main allergenic foods (comprise 90% of cases): milk, egg, peanut, tree nuts, wheat, soy, seafood; (vi) diagnosis: clinical history, specific IgE detection by SPT or in vitro testing (serum sIgE, component-resolved diagnosis, basophil activation test), elimination diet, food challenge (gold standard); (vii) conventional treatment: allergen avoidance (does not prevent accidental exposure), epinephrine autoinjectors, nutritional counseling, follow up to confirm spontaneous development of tolerance (especially in egg, milk, wheat and soy allergy), ingestion of extensively heated egg or milk products in children who tolerate them (this may accelerate resolution of egg and milk allergy, respectively); (viii) optimal treatment: restore tolerance by exposing patients to gradually increasing doses of allergen (immunotherapy).
  • Importance of component-resolved diagnosis (CRD): (i) CRD can help to determine patient′s sensitization on a molecular basis (e.g. specific IgE to Ara h 2 [main peanut allergen]; specific IgE to prolamins or cupins [plant allergens with high anaphylactic potential]; specific IgE to PR-10 proteins or profilins [heat-labile plant allergens with low anaphylactic potential]; specific IgE to ovomucoid [Gal d 1, an egg-white allergen resistant to heat and digestion, associated with persistent and severe allergic reactions]; specific IgE to ovalbumin, ovotransferrin or lysozyme [heat-labile egg-white allergens, associated with mild and transient allergic reactions]); (ii) CRD can help to define clinical entities (e.g. specific IgE to omega-5-gliadin in patients with wheat-dependent exercise-induced anaphylaxis; specific IgE to galactose-alpha-1,3-galactose in patients with delayed-type immediate allergy to red meat); (iii) CRD can help to identify cross-reactive allergens (e.g. latex-fruit allergy syndrome; mite-cockroach-crustacean allergy syndrome; pork-cat allergy syndrome; allergy to cross-reactive carbohydrate determinants [CCDs] in plants, latex or Hymenoptera venoms; allergy to parvalbumin [a fish panallergen]).
  • Oral immunotherapy (OIT) for FA is under active investigation; potential benefits: long-lasting acquisition of tolerance, ↑ QoL, ↓ danger of accidental food exposure.
  • Main limitations of OIT: (i) lack of evidence of long-lasting efficacy (RCT with cow’s milk, egg and peanut OIT have reported desensitization in 33–90% of subjects; however, ability for OIT to induce long-lasting tolerance remains uncertain); (ii) allergic reactions during OIT, including reactions to previously tolerated doses (cofactors: concurrent infection, physical activity within 2 hrs, alcohol, NSAIDs, poorly controlled asthma, empty stomach, pollen season, menses); (iii) it should be performed by expert physicians in an appropriate environment; (iv) patient and family should collaborate actively.
  • How to ↑ efficacy and safety of OIT? (i) adding omalizumab (anti-IgE mAb); (ii) using modified allergens (baked food, recombinant allergens, peptides), (iii) adding immune response modifiers (monophosphoryl lipid A [TLR-4 agonist], CpG containing DNA [TLR-9 agonist],  probiotics); (iv) personalized OIT schemes.
  • Recommendations for primary prevention of FA: (i) exclusive breastfeeding for the first 4-6 months of life; (ii) no special dietary restrictions for pregnant or lactating mothers; (iii) use of hypoallergenic formula if breastfeeding is insufficient in high-risk infants up to 4 months of age (then a standard milk can be used); (iv) introduction of complementary foods after 4 months of age, irrespective of atopic heredity; (v) no special dietary restrictions after 4 months for age, irrespective of atopic heredity.
  • Eosinophilic esophagitis (EoE): (i) prevalence in the general population: ~1/2,000 subjects; (ii) incidence is rising; (iii) male to female ratio=3:1; (iv) impact: significant morbidity, ↓ QoL, high costs; (v) pathogenesis: genetic susceptibility, environmental insults to the esophageal epithelium (e.g. allergens, infections, irritants) → epithelial barrier dysfunction (e.g. ↓ expression of the cell adhesion protein DSG-1), ↑ secretion of TSLP and IL-33 → ↑ allergen entry through the epithelium → immune reaction to food or respiratory allergens → infiltration of eosinophils into esophageal mucosa → chronic inflammatory infiltrate (eosinophils, mast cells, a special basophil population, TH2 cells, iNKT cells) → esophageal fibrosis, remodelling (e.g. transdifferentiation of epithelial cells to a myofibroblast phenotype) and dysfunction; (vi) common causal foods in children: milk, egg, soy, wheat, beef, chicken; (vii) common causal foods in adults: legumes, nuts, fruits, wheat, milk, soy, egg; (viii) frequent association (40-90%) with other atopic diseases (asthma, allergic rhinitis, food allergy, atopic dermatitis).
  • Diagnosis of EoE: (i) clinical history: abdominal pain, vomiting, dysphagia, heartburn, cough, choking, food aversion; (ii) complications: food impaction, failure to thrive, esophageal perforation, mental affectation; (iii) esophageal endoscopy: edema, white exudative plaques, mucosal rings (‘trachealization’), strictures, linear furrows, mucosal tearing; (iv) esophageal biopsy (2-4 biopsies from the proximal and distal esophagus; positive result: ≥15 eosinophils per high-power field; other findings: superficial layering, microabscesses, extracellular eosinophil granules, basal cell hyperplasia, dilated intercellular spaces, lamina propria fibrosis); (v) allergy testing (skin prick test [SPT], serum specific IgE, atopy patch test [APT]) with food and respiratory allergens; (vi) food elimination-reintroduction trials (elimination diets can take up to 6 wks per food); (vii) detection of eosinophil-mediated inflammation (e.g. cationic eosinophil granule proteins) by SPECT imaging.
  • Treatment of EoE: (i) diet options: 6-food elimination diet (milk, egg, wheat, soy, fish/seafood, peanut/tree nuts), diet guided by allergy tests, aminoacid formula; (ii) topical corticosteroids: low bioavailability, low potential for systemic adverse effects, ↑ risk of local fungal infection; (iii) systemic corticosteroids: effective, severe side effects; (iv) biologic therapies targeting the eosinophil (e.g. anti-IL-5 mAb, anti-IL-5R mAb); (v) esophageal dilation: might provide short-term symptomatic relief, only used if dietary and medical therapy has failed.

A CASE OF ANAPHYLAXIS TO PALIVIZUMAB

(Savitz J, Geaney C, Banks TA. Ann Allergy Asthma Immunol 2014; 113: 236-237):

  • Anaphylaxis: (i) definition: acute life-threatening systemic hypersensitivity reaction; (ii) lifetime prevalence: 0.05-2%; (iii) mechanisms: release of mediators from mast cells and basophils (IgE-mediated, IgG-mediated, complement mediated, idiopathic); (iv) most common culprits: foods, drugs, hymenoptera venom, latex; (v) diagnosis: clinical history, measurement of allergy mediators (e.g. serum tryptase, serum/urinary histamine or metabolites, serum PAF), allergy testing (e.g. sIgE detection by skin and in vitro tests); (vi) treatment in the acute setting: epinephrine (1st-line therapy), antihistamines, corticosteroids, β2-agonists, oxygen, fluids; (vii) long-term management: allergen avoidance, epinephrine autoinjectors, immunotherapy.
  • Respiratory syncytial virus (RSV): (i) enveloped RNA virus; (ii) common cause of upper respiratory infections in early childhood; (iii) probable causal role in asthma initiation; (iv) risk factors for severe RSV infection: prematurity, chronic lung disease, congenital heart disease.
  • Palivizumab: (i) licensed chimeric monoclonal antibody to prevent RSV infection in high-risk patients; (ii) conformation: human IgG1 framework + murine complementarity determining regions directed to the A antigenic site of the RSV F fusion protein; (iii) form of administration: intramuscularly, once every 30 days for 5 doses; (iv) excellent safety profile.
  • Authors report the case of a 2-yr-old girl with DiGeorge syndrome, tetralogy of Fallot and ventilator-dependent chronic lung disease of prematurity who developed an anaphylactic reaction (emesis, dyspnea, cough, urticaria, angioedema, hypoxia, hypotension, tachycardia; good response to epinephrine) minutes after Palivizumab administration (the 2nd dose of the 2nd-year course).
  • Author’s commentary: 1st report of anaphylaxis after Pavilizumab administration.