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03-09-12

ALLERGY:

• CO-FACTOR-ENHANCED FOOD ALLERGY (CEFA):

• CEFA: exercise, alcohol or NSAID intake G Thr309Arg; c.971_1018+24del72*.

• There is no established treatment for type III HAE. Successful experience with C1-INH concentrate (64 attacks), tranexamic acid (1 attack), icatibant (3 abdominal attacks), ecallantide (1 facial attack). C1-INH concentrate was not effective in 12 attacks. In our patients, we obtained success in 2 of 3 patients treated with icatibant, 1 of 2 patients treated with C1-INH concentrate, and 1 of 6 patients treated with IV tranexamic acid.

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• IS NERVE GROWTH FACTOR (NGF) INVOLVED IN THE SYMPTOMS OF RHINITIS?

• NGF ↑ growth and survival of sensory neurons that express tyrosine kinase receptor A (TRKA). NGF can regulate immune and inflammatory responses.

• Compared to controls, patients with allergic or idiopathic rhinitis had a 30-fold increased number of mast cells in nasal biopsies; 60% of these mast cells expressed NGF. No difference between allergic and idiopathic rhinitis.

• Hypothesis: mast cells release NGF → NGF promote nerve growth and neuropeptide production in nasal mucosa → hyperinnervation with substance P and CGRP (calcitonin gene related peptide) containing sensory nerve fibers (“hypersensitive” state) → histamine and leukotriene D4 produced by mast cells stimulate the nearby nasal trigeminal sensory nerves → inflammation.

• Drugs that interfere with the NGF-TRKA axis can relieve inflammatory pain. This kind of drugs can help in allergic and nonallergic rhinitis.

• LATEX IMMUNOTHERAPY: STATE OF THE ART:

• Latex juice comes from Hevea brasiliensis plants. It contains rubber particles and lutoids suspended in an aqueous liquid called C-serum, whereas the lutoids contain another fluid called B serum. Those suspensions contain the allergenic proteins that are responsible for IgE sensitization, which include genuine sensitizers (Hev b 1, Hev b 5, Hev b 6) and cross-reacting proteins (Hev b 8/profilin or Hev b 12/lipid transfer protein). Those pan-allergens are usually responsible for the latex-fruit syndromes (banana, kiwi, apple, etc.).

• Latex can cause type I (urticaria/angioedema, respiratory symptoms, anaphylaxis) and type IV hypersensitivity (allergic contact dermatitis, usually associated with chemical additives used during latex processing).

• Diagnosis of latex allergy: clinical history; SPT with latex extract; latex-specific IgE; provocation tests (whole glove or glove finger wearing, rubbing test).

• Prevalence of latex positivity in health care workers: 12.1%.

• Health care workers with latex allergy can use synthetic latex-free gloves (vinyl, neoprene, nitrile, or polysoprene gloves), but the characteristics of those materials are often unacceptable to surgeons or they are very expensive. Pathernium argentatum, which produces guayule latex (a rubber with low allergenicity, no cross-reactivity with Hevea brasiliensis latex, and an effective barrier action against viral infections) may be an alternative.

• 2 of the 3 SCIT trials with latex reported some benefit in adults but a remarkable occurrence of side effects. 7 of the 8 SLIT trials (included 1 in children) reported positive results, and the safety profile was superior to SCIT.

• Although guidelines do not consider allergy to latex as an accepted indication to desensitization, SLIT can be offered, in addition to symptomatic treatment, to patients with severe symptoms or and who cannot avoid latex.

• Optimal maintenance dose (balancing reasonably side effects and efficacy) should be between 300 and 500 μg extract per week. Efficacy has been documented with 9- to 12-month courses, although no data are available on the optimal duration of the treatment to achieve long-term effects. Also in those cases, strict medical supervision is recommended.

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• OMALIZUMAB TREATMENT IN A CHILD WITH SEVERE ASTHMA AND MULTIPLE STEROID-INDUCED MORBIDITIES:

• Omalizumab in asthma: ↓ exacerbations, ↓ symptoms, ↑ QoL, ↓ steroid use.

• Case report: 9-year-old boy with severe asthma; many ICU admissions; SPT (+) to HDM, trees, grass, cats, dogs; basal IgE=1,337 IU/mL; FEV1=80% of best predicted; therapy: ICS since 3 years old, LTRA, oral prednisone (maintenance dose of 2.5 mg/day, max dose given was of 40 mg/day for 8 months); adrenal insufficiency, vertebral compression deformities, ↓ bone mass 2ary to steroids.

• Approval to use omalizumab was obtained from Health Canada (FDA approves its use for >12 years old; EMEA for >6 y-o). Given dose: 375 mg every 2 weeks.

• Results after 11 months: no exacerbations during treatment; prednisone was stopped and was not required again; total ICS dose ↓ from 800 μg/day to 200 μg/day; FEV1 ↑ to 106% of predicted; serum cortisol level normalized (from 12 nmol/L to 215 nmol/L), bone mass density ↑; QoL normalized (Pediatric Asthma Quality of Life Questionnaire); no adverse reactions to omalizumab.

• Omalizumab therapy can ↓ steroid dependency and use. We do not promote off-label use of omalizumab in general, but in selected children with serious steroid-induced complications the risk-benefit ratio may fall in favor of its use.

• TYPE III HEREDITARY ANGIOEDEMA (HAE): DEFINED, BUT NOT UNDERSTOOD:

• Type III HAE: no urticaria, no response to anti-H1 or steroids; C4 and C1 INH protein and function are usually normal; most patients are women; attacks are associated with ↑ estrogen (contraception, postmenopausal replacement).

• Mutations in factor XII (FXII) are found in only 25-30% of suspected patients.

• Proposed mechanism: gain of function mutation in FXII → excessive conversion of prekallikrein to kallikrein. Controversies: in vitro studies show normal activity of FXIIa, with no resistance to C1 INH. Thus, if the FXII mutation causes ↑ production of bradykinin, we do not know how that occurs.

• Estrogen increase FXII and decrease activity of C1 INH and bradykinin-degrading enzymes (aminopeptidase P and angiotensin-converting enzyme).

• Should we screen for FXII mutations in patients with suspected type III HAE, considering that: (1) mutations are found in a minority of patients even when there is a family history and; (2) idiopathic angioedema is far more common?

• Who might be screened for FXII mutations? (1) Patients with nonhistaminergic idiopathic angioedema (ie, those refractory to high-dose antihistamines), family history, and normal C4 and C1 INH protein and function.

CURRENT OPINION IN IMMUNOLOGY:

• INBORN ERRORS OF HUMAN STAT1: ALLELIC HETEROGENEITY GOVERNS THE DIVERSITY OF IMMUNOLOGICAL AND INFECTIOUS PHENOTYPES:

• 4 types of inborn errors of human STAT1: (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity.

• Both types of AR STAT1 defect → susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines.

• AD STAT1 deficiency → selective predisposition to mycobacterial disease, owing to impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained.

• AD gain of STAT1 activity → autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity, and chronic mucocutaneous candidiasis, through undetermined mechanisms involving inhibition of Th17 cells.

• STAT1 is not the only host defense gene to harbor LOF or GOF mutations. X-linked WASP gene → LOF mutations underlie XR Wiskott–Aldrich syndrome; GOF mutations underlie XR severe congenital neutropenia.

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• SUSCEPTIBILITY AND IMMUNITY TO HELMINTH PARASITES:

• Helminth infection → epithelium secretes ‘alarmin’ cytokines (IL-25, IL-33, TSLP) → innate lymphoid cells (ILCs, e.g. nuocytes) produce IL-4, IL-5, IL-13 → potent adaptive Th2 cell response → type 2 anti-parasite mechanisms (IgE, inflammatory innate cells, mucus secretion) → worm destruction or expulsion.

• Helminth infection → Treg responses (to reduce pathology or as parasite immune evasion strategies) → increase of IL-10 and TGF-β → downregulation of Th2 response → worm tolerance.

• Nuocytes: type 2 ILCs; RORα-dependent; produce IL-4, IL-5, IL-13.

• Type 1 ILCs: RORγt-dependent; produce IL-17A and IL-22; IBD pathogenesis?

• N. brasiliensis infection → IL-13-producing CD4+ T cells and ILCs localize in the tissue and regulate worm expulsion and eosinophilia; IL-4 producing CD4+ TFH cells concentrate in draining lymph nodes and drive humoral response.

• Aside from immunity to helminths, Th2 response promotes wound healing.

• Any model of helminth immunity must stress interdependence of innate and adaptive arms. Innate cells sound the alarm; T cells ↑ effective immunity.

• 3 effects against helminths: (1) Disabling effects: restriction of parasite growth, motility and reproduction; mechanisms: antibodies neutralising physiological functions, innate molecules such as RELM-b, amino acid deprivation through macrophage-expressed arginase. (2) Degrading effects: cumulative damage to parasite integrity; mechanisms: phagocyte attack, enhanced by opsonization, calcification of adult worms. (3) Dislodging effects: expulsion from the GI tract; mechanisms: ↑ in epithelial permeability, fluid transfer and mucus secretion, hypercontractibility of smooth muscle cells, rapid epithelial cell turnover (‘epithelial escalator’), switch in intestinal mucins from the dominant Muc2 to Muc5ac, not normally expressed in the intestine.

• Not all helminths can be subjected to the 3 described effects; e.g. established cysts of Echinococcus granulosus cannot be degraded by the immune system.

• Exceptions that show us the complexity of helminth-immune interactions: (1) Th1 cells appear to mediate immunity to microfilarial stage of B. malayi; (2) eosinophils promote infection with T. spiralis; (3) mast cell degranulation increases vascular permeability and may facilitate skin invasion by filarial larva.

• Th2 immunity to helminths can be rescued by ↓ Treg function (deletion of Foxp3+ cells; administration of antibodies to CD25, CTLA-4 and GITR; inhibition of TGF-b signalling). However, this measure may increase immunopathology.

• Filarial and schistosome patients have higher frequencies of Foxp3+ cells, which may be natural (thymic) Tregs or de novo induced Tregs. The reason of Treg expansion in helminthiases may be to protect the host against pathological outcomes of immunity.

• Regulatory B cells can contribute to worm tolerance.

• Helminth infections → high levels of IL-4 and IL-13 → differentiation of alternatively activated macrophages (AAM) → immunity to helminths, tissue repair. Counterbalancing these benevolent effects, it should be noted that the induction of type 2 phenotype of AAMs by N. brasiliensis results in compromised resistance to Mycobacterium tuberculosis in the lung.

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JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY:

• AUTOIMMUNE MECHANISMS IN CHRONIC IDIOPATHIC URTICARIA (CIU):

• Prevalence of CIU in the general population: 0.5%.

• IgG anti-FcεRIα is the main autoimmune mechanism of CIU (30-60% of cases).

• Our CIU population was mainly composed of women 40 ± 14 years old. The majority had markers of autoimmunity, including anti-FcεRI (9 of 14), positive ASST (9 of 14), and/or antithyroid (anti-TG or anti-TPO) antibodies.

• We used a unique connective tissue mast cell line to study the effect of CIU patient sera on activation, analyzing PgD2 secretion and Ca2+ influxes. Activation after incubation with IgE and inhibition after preincubation with a syk inhibitor or recombinant human FcεRI points to a role for FcεRI-dependent autoimmune mechanisms. Other mechanisms appear to be involved.

• Connective tissue mast cell activation tests may be more appropriate than basophil activation test to evaluate autoimmune mechanisms in CIU.

• INCREASING COST OF EPINEPHRINE AUTOINJECTORS:

• Average wholesale price of 1 epinephrine autoinjector has increased from $35.59 in 1986 to $87.92 in 2011 (147%).

• Increased access to epinephrine → decreased fatal anaphylaxis. In countries where autoinjectors are unavailable or unaffordable, prefilled syringes made in a clinic can be safely provided and used.

• Prefilled syringes are stable and sterile for 2 months in arid climates and 3 months in humid climates. Materials: (1) ampules with epinephrine 1 mg/mL plus a preservative; (2) plastic 1-mL syringe; (3) a 23-gauge, 2.5-cm needle.

• Other alternative: provide to the patient the materials without prefilling the syringe. Main risks: (1) time required to prepare the syringe: 142 ± 13 seconds; (2) psychological issues to prepare the syringe during anaphylaxis episode.

• Epinephrine ampule and prefilled syringes must be protected from light with an aluminum foil or a container (eyeglasses case). Syringes must be labeled.

• Physicians can make prefilled syringes with doses personalized to a patient’s weight (useful in children 3 dozen cytokines (including IL-4, IL-13, IFN-g, TGF-β).

• New drugs: (1) tyrosine kinase inhibitors: imatinib; (2) anti-IL-5: mepolizumab, reslizumab; (3) anti-IL5-R: benralizumab; (4) anti-CD52: alemtuzumab; (5) CD2-binding fusion protein: alefacept; (6) anti-IgE: omalizumab; (7) competitive antagonist of IL-4α: pitrakinra, blocks both IL-4 and IL-13; (8) TPI ASM8, which contains 2 antisense oligonucleotides directed against the mRNA for human CCR3 and of the common β chain of IL-3, IL-5, and GM-CSF receptor.

• Promising agents: (1) affecting eosinophil survival: anti–Siglec-8, anti-CD172a, CD300a; (2) blocking eosinophil migration: anti-CCR3, anti-VLA4, anti-CRTH2.

• Anti–IL-5 → neutralization of an important growth factor → eosinophil starvation. Anti–IL-5R (benralizumab) → direct target of eosinophils for ADCC.

• Biomarkers that predict responsiveness to therapy need to be identified.

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• PATCHY EOSINOPHIL DISTRIBUTIONS IN AN ESOPHAGECTOMY SPECIMEN FROM A PATIENT WITH EOSINOPHILIC ESOPHAGITIS (EoE): IMPLICATIONS FOR BIOPSY:

• EoE: patchy infiltration into the esophagus by eosinophils (normally not found in healthy esophagus) → pathologic diagnosis can be difficult because of insufficient sampling.

• Guidelines recommend sampling at 4 to 5 sites throughout the esophagus. However, five 2 mm biopsy specimens represent less than 0.7% of the 20- to 25-cm-long esophageal mucosa and might result in underdiagnosis of EoE.

• We mapped eosinophil density across the entire esophageal epithelium of a specimen from a patient with known EoE who underwent esophagectomy for a concomitant esophageal adenocarcinoma.

• We used a statistical simulation to predict the number of biopsy specimens required for EoE diagnosis. Taking 4 to 5 biopsies per endoscopy, there is a 62 to approximately 100% probability of detecting EoE (≥1 biopsy specimen with ≥15 eosinophils/hpf), which may result in underdiagnosis of EoE in areas of low eosinophil density. Patients with EoE would require ≥31, ≥12, or ≥4 random biopsy specimens to detect the disease with 95% confidence from regions of low, average, and high eosinophil density, respectively.

• PREVENTING DISEASE IN THE 21ST CENTURY: THE IMPORTANCE OF MATERNAL AND EARLY INFANT DIET AND NUTRITION:

• Early nutrition has implications to growth trajectory, neurodevelopment and microbiome profile.

• Controversies exist about optimal diet for infants, pregnants and lactating women. In the last 10 years we have moved from concepts of avoidance for preventing sensitization to exposure for promoting immune tolerance.

• Concerns over the risk of obesity are often raised in response to the concept that earlier feeding in infants might be important to prevent allergic disease.

• Modern dietary patterns → obesity, altered microbiome → low-grade systemic inflammation, metabolic dysregulation → allergies, chronic diseases.

• Restoring traditional dietary patterns → protection against allergic and other chronic diseases.

• SERUM IL-9 AND LUNG FUNCTION:

• IL-9 stimulates tissue infiltration by mast cells; cell sources: T cells, eosinophils, neutrophils and mast cells. TH9 cells produce IL-9, lack suppressive function and promote tissue inflammation and mucus production.

• A recent study shows that allergic patients had ↑ TH9 cell numbers compared to nonatopic subjects, TH9 cell numbers correlated with total IgE levels. Observation: patient ages or the type of allergic disorder were not presented.

• A personal report shows a strong inverse relation between serum IL-9 and FEV1 values; IL-9 may be involved in airway inflammation and flow limitation.

• Serum IL-9 could be a promising surrogate marker for allergy severity.

• SERUM PERIOSTIN AS A MARKER OF TH2-DEPENDENT EOSINOPHILIC AIRWAY INFLAMMATION:

• 5- 10% of asthmatic patients need excessive use of corticosteroids for control. Possible reasons: pharmacogenomics, pharmacokinetics, neutrophilic asthma.

• Periostin: protein secreted by airway epithelium after IL-13 stimulation; not specific to asthma or the airway epithelium; also upregulated in injured and stressed tissues or in conditions with high cell proliferation and turnover; effect in asthma is not well understood.

• Serum levels of periostin might be a simple alternative to identify airway eosinophilia and monitor response to treatment (potential biomarker).

• Favourable effects of an anti–IL-13 mAb in patients with high periostin levels were modest and not sustained over a 23-week treatment period.

PEDIATRIC ALLERGY AND IMMUNOLOGY:

• ADRENALINE AUTOINJECTORS IN FOOD ALLERGY: IN FOR A CENT, IN FOR A EURO?

• There are still no agreed indication criteria for prescribing an adrenaline autoinjector for patients at risk of food anaphylaxis. Table 1 lists proposals.

• Adolescents have ↑ risk for anaphylaxis because: (1) food allergy is often more severe; (2) higher risk behavior; (3) poor communication about their food allergy; (4) not strictly enough avoidance; (5) they treat their asthma badly; (6) they forget to carry the autoinjector; (7) alcohol can lower risk threshold.

• Indications for prescribing >1 device may be: (1) high body weight; (2) fear of miss-firing or not sufficiency of 1st shot; (3) not promptly available medical help; (4) protracted or recurrent reactions in the past; (6) persistent asthma.

• A proposal is to prescribe one device for each regular location (e.g. at home and kindergarten) and other for transit. Disadvantage: higher costs.

• Consensus is to administer adrenaline ‘sooner rather than later’ (as soon as the initial signs and symptoms of anaphylaxis are observed, regardless of severity).

• Autoinjector should be immediately used in a patient with unconsciousness and/or dyspnea and/or involvement of 2 organ systems. If there are few hives or the patient is only vomiting, we should consider: (i) time interval between ingestion and symptoms; (ii) certainty of exposure and general condition.

• Who should be trained to use autoinjectors? Older patients and parents; possibly grandparents, older siblings, and staff at nurseries and schools. Regular training is necessary.

• Why adrenaline is not always administered when needed? (1) No anaphylaxis suspicion; (2) not sure about indication and technique; (3) fear of side effects.

• Mistakes in autoinjector use: administration in a finger (rare risk of ischemia and loss of the finger); needle overpenetration causing bones and joints injury.

• What to do after administration in a finger? Rub the digit in warm water; adequate hydration may help; vasodilatative treatment is not usually needed.

• Autoinjectors have a total shelf life of 18-24 months.

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• OXIDATIVE STRESS IN THE AIRWAYS OF CHILDREN WITH ASTHMA AND ALLERGIC RHINITIS:

• Children aged 6–18 years with asthma (n = 28), allergic rhinitis (n = 17), asthma and allergic rhinitis (n = 100), and healthy controls (n = 74) were enrolled. Levels of malondialdehyde as a marker of oxidative stress and glutathione as an antioxidant were measured in nasal and oral exhaled breath condensates.

• Asthma and allergic rhinitis are associated with ↑ oxidative stress in children’s airways. Co-existence of the 2 diseases does not ↑ oxidant stress further.

• PSYCHOGENIC AND FUNCTIONAL DISORDERS OF THE RESPIRATORY TRACT IN CHILDREN AND ADOLESCENTS – A PILOT STUDY:

• Psychogenic and functional breathing disorders can be included in ICD-10 as ‘Somatoform autonomic dysfunction of the respiratory tract’ (F45.33). These underdiagnosed diseases represent differential diagnoses to asthma. Both organic and functional diseases can coincide in a patient.

• Our study describes 132 children and adolescents diagnosed with F45.33.

• Habit cough seems to be more common in younger boys and pure psychogenic breathing disorders more common in older girls.

• Most patients with F45.33 do not show typical trigger factors. Physical exercise is the most common reported trigger, but it is unspecific (it can be also seen in bronchial hyperresponsiveness, bronchial asthma, etc.).

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• RELATIONSHIP BETWEEN RHINITIS AND NOCTURNAL COUGH IN SCHOOL CHILDREN:

• Nocturnal cough was defined as dry cough at night in the past 12 months in children without a cold. Data from 136,506 children were analyzed.

• There was a close association between rhinitis and nocturnal cough in children and adolescents; this effect was independent of asthma. Asthma, rhinitis, sinusitis and GER should be considered in children with nocturnal cough.

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