Facebook: World Allergy Organization
Twitter: World Allergy Organization
LinkedIn: World Allergy Organization
Instagram: World Allergy Organization
Back to Top

Article Summaries - June 2014


(Hill DA, Siracusa MC, Ruymann KR, Tait Wojno ED, Artis D, Spergel JM. Allergy 2014; 69: 674–677):

  • Asthma: (i) most common chronic respiratory disease; (ii) affects 300 million people worldwide;  (iii) incidence is rising; (iv) multifactorial etiology: genetic susceptibility, environmental burden, epigenetics; (v) impact: significant morbidity, ↓ QoL, mortality risk, high costs; (vi) features: airway inflammation, bronchial hyperreactivity, reversible airway obstruction, airway remodeling; (vii) typical symptoms: cough, wheezing, breathlessness, chest tightness; (viii) TH2-mediated inflammation occurs in ~80% of asthma cases (allergic asthma: ↑ production of IL-4, IL-5, IL-9 and IL-13; ↑ IgE synthesis; attraction of innate effector cell populations including eosinophils, mast cells and basophils).
  • Basophils: (i) represent <1% of blood leukocytes; (ii) participate in TH2 responses and IgE-mediated allergies; (iii) other potential functions: allergy initiation, antigen presentation, defence against ectoparasites.
  • Omalizumab: (i) recombinant humanized anti-IgE mAb → binds to free IgE → ↓ IgE binding to its receptors, ↓ expression of IgE receptors → ↓ IgE-mediated inflammation; (ii) FDA-approved for [uncontrolled asthma + serum IgE levels between 30 and 700 IU/mL + sensitization to perennial allergens] and antihistamine-refractory CU; (iii) dose (for asthma) is calculated in a chart, based on body weight and pretreatment IgE levels (between 30 and 700 IU/mL); (iv) alternative formula when the chart is not suitable: ≥0.016 mg/kg per IgE unit every 4-wk period; (v) suggested maximum dose: 750 mg every 4 wks; (vi) protocols recommend patient observation of 2 hrs for the first 3 doses and 30 min for subsequent doses (due to anaphylaxis risk in patients with severe asthma); (vii) efficacy has also been documented in mastocytosis, anaphylaxis (idiopathic; exercise-induced), eosinophilic chronic rhinosinusitis, atopic dermatitis.
  • Authors show that omalizumab therapy reduced circulating basophil numbers in children with severe asthma.


(Tedeschi A, Kolkhir P, Asero R, Pogorelov D, Olisova O, Kochergin N, Cugno M. Allergy 2014; 69: 683–691):

  • Chronic urticaria (CU):
  • (i) Definition: recurrent wheals for >6 wks due to liberation of vasoactive mediators (e.g histamine, serotonin, C3a, C5a, platelet-activating factor, neuropeptides, arachidonic acid metabolites [PGD2, LTC4, LTD4, LTE4]).
  • (ii) Lifetime prevalence: 1-20% of the population.
  • (iii) Impact: significant morbidity, ↓ QoL (similar to angina pectoris), high costs.
  • (iv) Classified in 2 types (both can co-occur in the same patient): spontaneous (CSU; no clear triggers; 50% of cases have ‘autoimmune’ features [IgG1/IgG3 to FcεRIα or IgE; ↑ frequency of HLA DRB1*04]; coagulation, fibrinolysis and complement systems may have a role in pathogenesis; wheals usually last between 4 and 24 hrs; concomitant angioedema may occur in ~50% of cases); inducible (triggered by stimuli such as cold, heat, touch, pressure, vibration, sunlight, water or exercise; wheals usually last <2 hrs after stimuli ceases, except for delayed pressure urticaria [similar to CSU wheals]).
  • (v) 1st-line treatment: nonsedating anti-H1 at usual dosing (50% of patients may not respond).
  • (vii) 2nd-line treatment: up to quadruple dose of anti-H1, such as desloratadine or levocetirizine (50% of patients may not respond → antihistamine-refractory CU).
  • (viii) Other therapies: mast cell-stabilizing drugs (e.g. ketotifen), antileukotrienes, topical corticosteroids, systemic corticosteroids (3-10 days to control severe exacerbations; risk: side effects; key to success: limit the dose to a maximum of 20 mg every other day or 10-15 mg daily with subsequent dose tapering), biologic therapies (e.g. omalizumab, anti-TNF-α, IVIG), epinephrine, desensitization, moisturizers, UV phototherapy, cyclosporin A (only FDA-approved immunosuppressant drug for CU; side effects: ↑ blood pressure, renal damage; renal function reverts to normal within 4 to 6 wks after drug stopping), sulfasalazine, dapsone, colchicine (colchicine, dapsone or sulfasalazine are reasonable choices for neutrophilic CSU), chloroquine, hydroxychloroquine (may have particular efficacy for the hypocomplementemic urticarial vasculitis syndrome), calcineurin inhibitors, mycophenolate, pseudoallergen-free diet, anticholinergics, androgens, selective serotonin reuptake inhibitors, tranexamic acid, psoralens, plasmapheresis, anticoagulants.
  • (ix) Prognosis: 50% of cases may resolve spontaneously within 1 yr; 75% of cases within 5 yrs.
  • CU and coagulation: (i) coagulation and inflammation activate each other; (ii) coagulation factors, mainly tissue factor and thrombin, may participate in CU pathophysiology (whether activation of coagulation is a primary phenomenon or a secondary process enhancing or maintaining inflammation is controversial); (iii) mechanisms: activation of eosinophils (e.g. by IL-5, eotaxin, TNF-α, PAF, GM-CSF or autoantibodies to FcεRII) → eosinophils produce tissue factor and VEGF → blood coagulation extrinsic pathway is activated → thrombin is generated → thrombin acts on protease-activated receptors and activates C5 directly → endothelial cells and mast cells are activated, mast cells amplify the loop by producing tryptase (↑ thrombin generation) → ↑ vascular permeability; (iv) it is unclear if patients with CU and ↑ coagulation are at higher risk of thrombosis or CV disease; (v)  D-dimer: a fibrin degradation product, can ↑ during urticaria crisis and normalize during remission, can be a biomarker of antihistamine-refractory CU; (vi) anticoagulant therapy: may benefit CU patients, especially those with increased levels of coagulation/vascular biomarkers (e.g. D-dimer, prothrombin fragment F1 + 2, FVIIa, fibrinogen, VEGF); successful reports with oral anticoagulants, heparin, protease inhibitors (nafamostat mesylate, camostat mesylate) and nandroparin + tranexamic acid.
  • Other conditions with ↑ levels of coagulation biomarkers: urticarial vasculitis, bullous pemphigoid, atopic dermatitis, multiple drug allergy syndrome, nonallergic asthma.


(Hsieh FH. Ann Allergy Asthma Immunol 2014; 112: 484-488):

  • Hypereosinophilic syndrome (HES): (i) heterogeneous disease characterized by persistent blood eosinophilia and eosinophil-induced organ damage; (ii) several phenotypes have been identified; (iii) in most cases the molecular pathogenesis is unknown (idiopathic).
  • Original definition (Chusid et al, 1975): (i) peripheral blood eosinophilia (>1,500 cells/μL) for >6 months; (ii) evidence of eosinophil-related organ damage; (iii) exclusion of other diseases causing eosinophilia.
  • Proposed definition: (i) peripheral blood hypereosinophilia (>1,500 cells/μL) for ≥1 month checked on ≥2 occasions, and/or tissue hypereosinophilia (eosinophils comprising >20% of nucleated cells in the bone marrow; extensive organ infiltration determined by histology; histologic evidence of eosinophil degranulation in a target organ [e.g. major basic protein] in the absence of tissue eosinophils); (ii) evidence of eosinophil-mediated organ damage (generally multiorgan system involvement as opposed to single system disease [e.g. GI eosinophilic diseases, eosinophilic myocarditis]); (iii) exclusion of other causes of hypereosinophilia.
  • Classification: (i) primary HES: clonal expansion of an eosinophil lineage cell due to a primary eosinophil defect (e.g. myeloproliferative variant HES associated with PDGFRA fusion kinase [~15% of HES cases]; other mutations in PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ASCSL6, MYH11, ABDL and KIT [beyond PDGFRA, the other defects likely comprise <1% of HES cases]); (ii) secondary HES: polyclonal eosinophil expansion due to cytokines released by another disease (e.g. malignancy, lymphoproliferative disease, clonal nonmalignant T cells [e.g. lymphocytic variant HES]); (iii) familial HES: hypereosinophilia inherited in an autosomal dominant pattern (rare, typically asymptomatic, linkage to chromosome 5q31-33); (iv) overlap HES: hypereosinophilia with single-organ system involvement (e.g. eosinophilic GI disease, pulmonary eosinophilia syndromes, eosinophilic fasciitis, eosinophilic myocarditis); (v) HES with undetermined significance: hypereosinophilia with no target organ damage (progression to organ damage is not well defined); (vi) idiopathic HES (up to 50% of cases): undetermined molecular defect and mechanism despite thorough evaluation.
  • Clinical presentation: (i) HES can affect nearly every organ system (CV system, nervous system, skin, lungs, GI tract, eye, blood/coagulation, etc.); (ii) symptoms can appear insidiously or acutely; (iii) lymphocytic variant HES has more tendency to cause skin symptoms (e.g. urticarial plaques, angioedema, erythroderma); (iv) myeloproliferative variant HES has more tendency to cause mucosal ulcerations, anemia, splenomegaly, hepatomegaly and fibrotic disease (especially in the heart).
  • Treatment: (i) PDGFRA-associated myeloproliferative variant HES → tyrosine-kinase inhibitor imatinib mesylate; (ii) all other forms of HES → corticosteroids (generally 1st-line therapy), steroid-sparing agents (hydroxyurea, interferon α-2b, methotrexate, vincristine, cladribine, cytarabine, cyclophosphamide, etoposide, chlorambucil); (iii) refractory patients → HSCT, investigational agents (mepolizumab [anti-IL-5 mAb], alemtuzumab [anti-CD52 mAb]).
  • Future challenges: (i) evidence-based refinements in nomenclature and diagnostic criteria; (ii) recognition of biomarkers to identify HES phenotypes and predict disease evolution; (iii) development of mechanism-based therapeutics for general clinical use.


(Mahdavinia M, Carter RG, Ocampo CJ, Stevens W, Kato A, Tan BK, Kern RC, Conley DB, Chandra R, Hulse KE, Suh LA, Norton JE, Peters AT, Grammer III LC, Schwartz LB, Schleimer RP. J Allergy Clin Immunol 2014; 133: 1759-1762):

  • Chronic rhinosinusitis (CRS): (i) definition: inflammation of nasal and paranasal mucosa lasting ≥12 wks; (ii) impact: significant morbidity, ↓ QoL, high costs.
  • CRS phenotypes: (i) CRS with nasal polyps (CRSwNP): TH2 environment (eosinophilic inflammation), better response to intranasal corticosteroids; (ii) CRS without nasal polyps (CRSsNP): ↑ remodeling (TGF-β, MMP, TIMP, collagen), predominance of neutrophils.
  • Aspirin-exacerbated respiratory disease (AERD): subgroup of CRSwNP characterized by the triad of CRSwNP, asthma and hypersensitivity to NSAIDs.
  • Basophils: (i) physiologic role in defense against helminths and ectoparasites; (ii) pathologic role in allergic diseases; (iii) numbers are increased in asthma (bronchial mucosa and submucosa), allergic rhinitis (nasal submucosa) and inflammatory skin diseases (e.g. eczema).
  • Authors evaluated the presence of basophils in nasal polyps (NP) from 10 patients with AERD and 17 patients without AERD, and in uncinate tissue (UT) from 16 patients with CRSwNP, 15 patients with CRSsNP and 15 control cases → (i) UT from CRS patients had a trend toward higher basophil numbers than UT from controls; (ii) NP from patients without AERD had significantly higher basophil numbers than UT from patients and controls; (iii) NP from patients without AERD had significantly higher basophil numbers than NP from patients with AERD.
  • Author’s commentary: basophils may play a pathogenic role in patients with CRS, especially in those with CRSwNP without AERD.


(Allam J-P, Wuestenberg E, Wolf H, Klimek L, Decot E, Horn A, Schnitker J, Bieber T, Novak N. J Allergy Clin Immunol 2014; 133: 1757-1759):

  • Immune tolerance: nonresponsiveness of the adaptive immune system or active regulatory cell response to antigens.
  • Immune tolerance is essential to prevent: (i) self-destruction; (ii) inflammatory response to beneficial or harmless exogenous molecules (e.g. food, commensal bacteria, allergens).
  • Loss of immune tolerance → allergic or autoimmune disorders (e.g. exposure to aeroallergens via the nasopharyngeal mucosa in genetically susceptible subjects → specific TH2 responses to aeroallergens → IgE-mediated allergic respiratory diseases).
  • Allergen immunotherapy: (i) only therapy that can alter the natural history of IgE-mediated allergy; (ii) conventional routes of administration: subcutaneous, sublingual; (iii) new potential routes of administration: intralymphatic, epicutaneous, intranasal, oral vestibular.
  • Sublingual immunotherapy (SLIT): (i) mechanisms: antigen presentation by tolerogenic mucosal dendritic cells (it is important to keep the allergen 2-3 min under the tongue; passive resorption is considered as the major mucosal crossing factor for peptides) → ↑ T regulatory responses, ↓ TH2 responses → ↑ production of IgG4, IgG1 and IgA, ↓ production of IgE; (ii) advantages: self-administration, convenience, safety; (iii) limitations: very low adherence (56% of patients discontinue SLIT during the 1st year; only 15% of patients complete 3 years of SLIT); (iv) reasons for SLIT discontinuation: cost, side-effects, no perception of efficacy.
  • Oral vestibule (OV) immunotherapy: (i) allergen administration in the pouch formed by lip and gingival mucosa; (ii) potential greater efficacy than SLIT (reasons: the OV region has more tolerogenic DCs and fewer mast cells compared to the sublingual region; allergens in the OV region are less likely to be swallowed too early; no major salivary ducts drain into the OV region → dilution of allergen is reduced).
  • Authors performed a multicenter, parallel-group, 1:1 randomized noninferiority phase II trial in 72 adults with allergic rhinoconjunctivitis induced by birch pollen → OV immunotherapy was noninferior than SLIT regarding immunologic responses (e.g. levels of specific IgE-blocking factor, specific IgE and specific IgG4) and adverse effects up to 36 wks of therapy.
  • Author’s commentaries: (i) the OV region might be a useful administration route for IT; (ii) further studies are necessary to evaluate safety and efficacy of OV immunotherapy before widespread clinical use.