Pediatric allergy and immunology:

• ACUTE CHOREA IN A CHILD RECEIVING SECOND DOSE OF HUMAN PAPILLOMA VIRUS VACCINE (Decio A, Balottin U, De Giorgis V, Veggiotti P. Pediatr Allergy Immunol 2014; 25: 295–296):

• Human papilloma virus (HPV) infection: pathogenic factor for cervix cancer.

• Vaccination against HPV (e.g. quadrivalent vaccine Gardasil): (i) main objective: reduce incidence of cervix cancer; (ii) severe neurologic adverse effects have been reported (e.g. Guillain–Barré syndrome, demyelinizating diseases, acute disseminated encephalomyelitis).

• Authors report the case of a previously healthy 11-yr-old girl with rapid-onset persistent neurologic symptoms (generalized choreic movements, facial grimaces, ataxic gait, dysarthria) 1 month after receiving the 2^nd dose of Gardasil (1^st dose=February 25^th 2013; 2^nd dose=April 8^th 2013) → laboratory analysis: normal CBC, liver enzymes, renal testing, cardiac testing, autoimmune panel, brain MRI and CSF analysis → common causes of chorea in children were excluded (e.g. rheumatic chorea, SLE, Wilson disease) → suggestive diagnosis: autoimmune chorea after Gardasil vaccine → successful treatment (complete resolution of symptoms within 1 wk): oral methylprednisolone (2 mg/kg/day for 4 wks, then gradual tapering).

• Author’s commentaries: (i) Gardasil vaccine may trigger immune-mediated neurologic disease (proposed mechanism: molecular mimicry); (ii) the target population for the wide HPV immunization program (girls in pubertal age) is per se predisposed to autoimmune reactions.

• EGG YOLK: AN UNUSUAL TRIGGER OF FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME (Yilmaz EA, Cavkaytar O, Uysal Soyer O, Sackesen C. Pediatr Allergy Immunol 2014; 25: 296–297):

• Food allergy: (i) IgE-mediated: urticaria, angioedema, bronchospasm, GI symptoms, anaphylaxis; (ii) non-IgE-mediated: enterocolitis, proctocolitis, celiac disease, contact dermatitis, Heiner syndrome; (iii) IgE- and cell-mediated: atopic dermatitis, eosinophilic GI diseases.

• Food protein-induced enterocolitis syndrome (FPIES): (i) non-IgE-mediated allergy to food proteins; (ii) usually starts in the 1^st yr of life; (iii) clinical history: vomiting, diarrhea, dehydration, hypotension, shock, acidemia, methemoglobinemia (2-6 hrs after eating the culprit food); (iv) frequent culprits: cow’s milk, soy, grains; (v) diagnosis: clinical history, OFC; (vi) differential diagnosis: sepsis, metabolic diseases; (vii) treatment: allergen avoidance; (viii) prognosis: typically resolves by 3-5 yrs of age (OFCs are usually performed to confirm resolution); (ix) breast-fed infants with FPIES can usually continue lactating without maternal diet (FPIES is very rare in exclusively breast-fed infants); (x) egg white-induced FPIES has been reported.

• Authors report the case of a 9-month-old boy with 3 episodes of FPIES (vomiting, diarrhea, pallor, weakness, irritability, hypotension, loss of consciousness) 2-3 hrs after ingesting egg yolk (boiled egg yolk; cake containing whole egg) → laboratory analysis: normal CBC, liver function tests, renal function tests, serum albumin and aminoacid levels in serum and urine; total IgE=4.33 kU/l; negative SPT and specific IgE to egg white and yolk → diagnosis: positive OFC with boiled hen’s egg yolk at 12 months of age (vomiting, diarrhea, pallor, irritability, weakness) → successful management: avoidance of egg yolk.

• Author’s commentary: 1^st reported case of FPIES triggered by hen’s egg yolk.

• ETIOLOGY, CLINICAL OUTCOME, AND LABORATORY FEATURES IN CHILDREN WITH NEUTROPENIA: ANALYSIS OF 104 CASES (Angelino G, Caruso R, D’Argenio P, Calo Carducci FI, Pascone R, Lanciotti M, Cancrini C, Palma P, Aiuti A, Rossi P, Finocchi A. Pediatr Allergy Immunol 2014; 25: 283–289):

• Neutropenia: (i) absolute neutrophil count <1,000/μL in infants (≤1 yr of age) and <1,500/μL thereafter (lower cutoff values should be used in black populations due to shorter neutrophil life); (ii) acute: ≤3-6 months, chronic: >3-6 months; (iii) usually benign (e.g. infection-induced or autoimmune); (iv) occasionally life-threatening (e.g. severe congenital neutropenia [SCN]).

• Author’s studied retrospectively 104 children with recently detected neutropenia (patients with neutropenia due to chemotherapy, proliferative disorders and myelodysplastic syndromes were excluded) → (i) 66 patients (63.5%) had chronic neutropenia (most frequent forms: chronic idiopathic neutropenia [CIN], autoimmune neutropenia [AIN]); (ii) congenital neutropenia was identified in 6 patients (3 cases of SCN; 1 case of CD40L deficiency; 1 case of methylmalonic aciduria); (iii) acute neutropenia was mainly post-infectious; (iv) among patients with AIN and CIN, ~50% recovered within 7-46 months and ~25% had significant infections during follow-up.

• PARASITIC WORMS AND ALLERGIES IN CHILDHOOD: INSIGHTS FROM POPULATION STUDIES 2008–2013 (Amoah AS, Boakye DA, van Ree R, Yazdanbakhsh M. Pediatr Allergy Immunol 2014; 25: 208–217):

• Allergic diseases have dramatically increased (probably due to environmental and lifestyle factors; unlikely due to genetic causes). Risk factor: ↓ exposure to pathogens during childhood → insufficient maturation of regulatory immunity.

• Helminths: (i) metazoan parasites that can ↓ host’s immunity to prevent their elimination and ↓ severe pathology in the host; (ii) infect ~1 billion people worldwide; (iii) risk factors for infection: living in tropical regions, poverty, poor sanitation; (iv) immune response to helminths depends on the infected tissue and the type of helminth (e.g. TH2 vs T regulatory responses).

• Relationship between helminth infections and allergic diseases: (i) helminth infections may protect, promote or have no effect on allergic sensitization/disease (recombinant allergen technology may help to clarify this relationship); (ii) contributing factors: type of helminth, site of infection, host’s characteristics; (iii) antihelmintic therapy may either worsen or relieve allergic sensitization and disease; (iv) helminth infections can induce IgE cross-reactivity (often clinically irrelevant) against allergen proteins (e.g. tropomyosin, paramyosin, glutathione S-transferase) or glycans (e.g. xylose, core-3-linked fucose); (v) a prominent feature of helminth infection consists in high levels of IgE against allergens without SPT reactivity; (vi) helminth products have been used as therapies to promote immune tolerance and treat inflammatory conditions (e.g. Trichuris suis eggs to treat allergies and IBD); (vii) further research is necessary.

• POTENTIAL NON-T CELLS SOURCE OF INTERLEUKIN-4 IN FOOD ALLERGY (Amoah AS, Boakye DA, van Ree R, Yazdanbakhsh M. Pediatr Allergy Immunol 2014; 25: 208–217):

• IL-4: (i) essential cytokine for TH2 immune responses; (ii) actions: TH2-cell differentiation, B-cell switching to IgE production, ↑ MHC-II expression on mast cells (also basophils?); (iii) therapeutic target for allergic diseases.

• Sources of IL-4: (i) TH2 lymphocytes; (ii) innate lymphoid cells type 2; (iii) basophils.

• IL-4-expressing non-T cells, particularly basophils, might play an essential role in the early development of food allergy.

• THE EDITOR RECOMMENDS THIS ISSUE’S ARTICLES TO THE READER (Lau G-Y, Janse JJ, Angelino G. Pediatr Allergy Immunol 2014; 25: 205):

• Mothers of food-allergic children, but not children themselves, had increased levels of anxiety and stress, especially when there was a history of poorly controlled asthma and anaphylaxis.

• Hepatitis A, Toxoplasma gondii and salmonella infections did not have significant association with allergic sensitization to food and aeroallergens.

• Childhood neutropenia has diverse etiologies (benign causes are more frequent [e.g. post-infectious, autoimmune or idiopathic neutropenia]; severe causes can occur [e.g. severe congenital neutropenia or metabolic disease]).

• USE OF IgE AND IgG4 EPITOPE BINDING TO PREDICT THE OUTCOME OF ORAL IMMUNOTHERAPY IN COW’S MILK ALLERGY (Savilahti EM, Kuitunen M, Valori M, Rantanen V, Bardina L, Gimenez G, Mäkelä MJ, Hautaniemi S, Savilahti E, Sampson HA. Pediatr Allergy Immunol 2014; 25: 227–235):

• IgE-mediated food allergy (FA): (i) rising prevalence worldwide (6% of children and 4% of adults in the westernized world); (ii) impact: significant morbidity, ↓ QoL, mortality risk, high costs; (iii) >170 foods have been reported to cause allergic reactions; (iv) main allergenic foods (comprise 90% of cases): milk, egg, peanut, tree nuts, wheat, soy, seafood; (v) diagnosis: specific IgE detection by SPT or in vitro testing (serum sIgE, component-resolved diagnosis), basophil activation test, food challenge (gold standard); (vi) 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); (vii) optimal treatment: restore tolerance by exposing patients to gradually increasing doses of allergen (immunotherapy).

• IgE-mediated cow’s milk (CM) allergy: (i) prevalence: 1-2% of children; (ii) impact: significant morbidity, ↓ QoL, mortality risk, high costs; (iii) ~70% of children outgrow CM allergy spontaneously by 8 yrs of age; (iv) up to 75% of children with CM allergy tolerate baked CM products (in this children consumption of baked CM accelerates tolerance to raw CM); (v) some children recover tolerance to CM ‘incompletely’ (e.g. some children tolerate minimal quantities of CM but react to ‘normal’ intake; others react to CM only when cofactors are present [e.g. infections, exercise]); (vi) CM oral immunotherapy (OIT) can restore tolerance to CM.

• 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 (RCTs with cow’s milk, egg and peanut OIT have reported successful desensitization in 33–90% of subjects; however, ability of OIT to induce long-lasting tolerance remains uncertain); (ii) allergic reactions during OIT, including reactions to previously tolerated doses (common triggers: concurrent infection, physical activity within 2 h, poorly controlled asthma, empty stomach, pollen season, menses); (iii) OIT should be performed by expert physicians in an appropriate environment; (iv) patient and family should collaborate actively.

• Mechanisms of OIT: (i) ↑ specific T regulatory cells; (ii) ↑ IL-10–secreting B regulatory cells (BR1 cells [CD25^high, CD71^high, CD73^low]); (iii) deletion, suppression and anergy of effector T cells (TH2, TH1, TH17); (iv) ↑ specific IgG4 and IgA; (v) ↓ specific IgE (poor correlation with clinical improvement); (vi) very early desensitization of mast cells and basophils (within hours; mediated by upregulation of histamine 2 receptors?); (vii) ↓ migration and activation of allergy effector cells (eosinophils, basophils, mast cells).

• Authors studied 32 children (6-17 yrs of age) with CM allergy (26 children who successfully completed OIT; 6 children who discontinued OIT due to adverse reactions) → (i) children who achieved desensitization after OIT: IgE binding to CM peptides decreased, IgG4 binding increased, IgE and IgG4 antibodies more often recognized the same epitopes; (ii) children who discontinued OIT due to adverse reactions: quantity and affinity of epitope-specific IgE antibodies increased, diversity of IgE and IgG4 binding increased, IgE and IgG4 antibodies less often recognized the same epitopes; (iii) IgE affinity to CM epitopes may discriminate children who will complete OIT successfully from those who will have to discontinue therapy.

• Author’s commentary: detailed analysis of IgE and IgG4 binding to CM peptides may help to predict whether CM OIT will be tolerated successfully.