Hymenoptera venom allergy among children in Italy: time for pediatricians to take action.

Hymenoptera venom allergy (HVA) is one of the most frequent causes of anaphylaxis following a bee, vespid or ant sting. Real-life data regarding the management of HVA in children are lacking. To address this unmet need, we carried out a survey defining the current management of HVA in children among pediatric allergists in Italy. Educational investments on the improvement of the management of pediatric patients with HVA are urgently needed, and our analysis represents a relevant instrument in targeting a roadmap with this aim. The time for pediatric allergists to take action has come, and a task force from the Rare Allergic Diseases Commission of the Italian Society of Pediatric Allergy and Immunology is working on the topic to improve pediatricians' knowledge and optimize the care of these patients.

Epidemiology and drug allergy results in children investigated in allergy unit of a tertiary-care paediatric hospital setting.

BACKGROUND AND OBJECTIVE: Drug Hypersensitivity Reactions (DHRs) are considered adverse effects of medications that resemble allergy symptoms. The reported positive clinical history of pediatric drug reactions is about 10%, however, after allergy investigations, only a small percent is confirmed as hypersensitivity. The aim of this study was to analyze the clinical history, allergy work-up results and sensitization profile of children and adolescents referred to our Allergy Unit for suspected DHRs. METHODS: The study evaluated data related to a group of children with a positive history of drug reactions during a two-year period. The allergy work-up consisted of in vivo and in vitro tests, in accordance with the recommendations of the ENDA/EAACI guidelines. RESULTS: Data from a group of 637 patients [348 M (54.6%); 289 F (45.4%)] were retrospectively analyzed. Beta lactams (BLs) were the most common drugs involved in the reported clinical history, followed by non-steroidal anti-inflammatory drugs (NSAIDs). Severe cutaneous adverse reactions (SCARs) were most frequently observed during BL treatment. The confirmation of BL hypersensitivity was higher for immediate reactions (IRs) [9.4%; 5.1% through positive skin tests (STs) and 5.5% through drug provocation test (DPT)] compared to non-immediate reactions (non-IRs) (8.1%; 2.2% through STs and 6.2% through DPT). A higher number of positive results was obtained for BLs and macrolides when the tests were performed within 12 months after the index reaction (p < 0.05). During DPTs with amoxicillin-clavulanic acid, four hypersensitivity reactions (including one anaphylaxis) occurred despite negative STs. CONCLUSION: Our data demonstrated that only 9.1% of patients resulted in being positive to allergy tests which is in line with the data in literature. An allergy work-up is mandatory for excluding suspected hypersensitivity.

Hymenoptera Venom Allergy: Management of Children and Adults in Clinical Practice.

Hymenoptera venom allergy is an epidemiologically underestimated condition and a major cause of morbidity worldwide. Preventing future allergic reactions in patients who experience a systemic reaction is based on the correct management of the emergency followed by an accurate diagnosis, prescription of adrenaline autoinjectors, and, where indicated, specific venom immunotherapy. Some epidemiological studies highlight our poor knowledge of this disease and the frequent inadequacy of its management. Moreover, they emphasize the importance of such a life-saving treatment as specific immunotherapy. The availability of high-quality hymenoptera venom extracts for diagnostic and therapeutic use has dramatically improved the prognosis and quality of life of allergic patients. Subcutaneous venom immunotherapy is currently the most effective form of allergen-based immunotherapy, with a carry-over effect lasting up to several years after its interruption. This report on the management of hymenoptera venom-allergic children and adults was prepared by a panel of Italian experts. The main objective of this consensus document is to review the scientific evidence related to diagnosis, therapy, and management of patients allergic to hymenoptera venom. Thus, we can improve our knowledge of the disease and promote good clinical practices. The present document provides practical suggestions for correct diagnosis, prescription of emergency therapy and immunotherapy, and strategies for patient care.

Increase of natural killer cells in children with liver transplantation-acquired food allergy.

BACKGROUND: Transplantation-acquired food allergies (TAFA) are frequently reported and considered to be caused by immunosuppressive therapy. The aim of this study was to investigate the allergic and immunologic responses in children who had liver or kidney transplantations. METHODS: Twelve children receiving liver transplantations and 10 children receiving kidney transplantations were investigated. All children underwent the allergy work-up and in most of them, lymphocyte screening and serum cytokine measurements were also performed. RESULTS: TAFA were found in 7/12 (58%) children with liver transplantations and in none of the 10 children with kidney transplantations. The mean age at transplantation was significantly lower in children who underwent liver transplantations (p<0.001). The immunosuppressive therapy administered to children with liver transplantation was tacrolimus in 11 patients and cyclosporine in one patient, while all 10 children with kidney transplantation received tacrolimus plus mycophenolate. The most common antigenic food was egg. The natural killer (NK) cell numbers were significantly higher in liver-transplant children than in kidney-transplant children. No significant differences were found in the serum cytokine levels. CONCLUSIONS: This study confirms that liver-transplant children treated with tacrolimus alone have a higher risk of developing TAFA than kidney-transplant children treated with tacrolimus plus mycophenolate. NK cells might be involved in this difference.

Skin prick test results to artesunate in children sensitized to Artemisia vulgaris L.

Artemisia vulgaris L and Artemisia annua L (Chinese: qinghao) are similar plants of the Asterbaceae family. Artesunate, a semi-synthetic derivate of artemisin which is the active principle extract of the plant qinghao, has antimalarial properties. Some cases of severe allergic reactions to artesunate have been described. The purpose of this study was to evaluate the association between positive skin tests to Artemisia vulgaris L allergen and a preparation of injectable artesunate. A total of 531 children were skin prick tested with inhalants (including Artemisia vulgaris L), foods, and artesunate. Among the 59 patients positive to Artemisia vulgaris L only one child was also positive to artesunate. No child was positive to artesunate in those negative to Artemisia vulgaris L. We conclude that Artemisia vulgaris L sensitization is not associated with sensitization to artesunate; consequently, skin test to artesunate should not be carried out before using the drug considering the rare allergic reactions.

Azithromycin is more allergenic than clarithromycin in children with suspected hypersensitivity reaction to macrolides.

BACKGROUND: Macrolides are considered safe antibiotics with reduced allergenic activity. However, studies on the safety of macrolides are scarce, particularly in children. OBJECTIVE: The aim of this study was to assess the frequency of hypersensitivity reactions to clarithromycin and azithromycin in a group of children referred to our allergy unit for suspected macrolide allergy. METHODS: We retrospectively reviewed the charts of 90 children aged 1-17 years with symptoms suggestive of hypersensitivity reaction to clarithromycin or azithromycin between December 31, 2008 and December 31, 2013. The allergy workup included skin tests (ie, skin prick tests and/or intradermal tests), determination of serum specific IgE (sIgE) to clarithromycin and azithromycin, and, if necessary to reach a diagnosis, oral provocation tests. RESULTS: Seventy-seven children completed the allergy workup. A reaction to clarithromycin was recorded in 58 children (75.3%): 21 (36.2%) had a history of immediate reactions, and 37 (63.8%) had a history of nonimmediate reactions. A reaction to azithromycin was recorded in 19 children (24.6%): 6 (31.5%) had a history of immediate reaction, and 13 (68.42%) had a history of nonimmediate reaction. Positive results in skin tests and oral provocation tests with the suspect drug confirmed the diagnosis in 15.5% of reactions to clarithromycin (9 of 58) and in 47.3% of reactions to azithromycin (9 of 19) (P = .004). CONCLUSION: A complete allergy workup enabled us to confirm a diagnosis of clarithromycin and azithromycin allergy in 15.5% and 47.3% of cases, respectively. Azithromycin was more allergenic than clarithromycin in children.

Azithromycin anaphylaxis in children.

Allergic reactions associated to the use of macrolides are uncommon; in particular only two cases of anaphylaxis with erithromycin and clarithromycin have been reported to date. The aim of this study was to investigate macrolide-induced anaphylaxis. Between December 2007 and December 2011, 136 consecutive children were referred to the Allergy Unit of A. Meyer Children's Hospital because of a past history of reactions to macrolides. Allergy work-ups were carried out according to the European Network for Drug Allergy protocol. Anaphylaxis was diagnosed according to the clinical criteria proposed by Sampson et al. and graded according to Brown SGA et al. Sixty-six out of 136 patients completed the allergologic work-up and among them we investigated three cases of anaphylaxis due to azithromycin which included one child with anaphylaxis to both clarithromycin and azithromycin. In two of the children with anaphylaxis, the diagnosis was only confirmed with the skin prick test, the third was positive to the Intradermal Test. The azithromycin allergy shows a surprisingly high sensitivity to the in-vivo tests. Moreover, this study shows that cross-reactivity may occur between different macrolidic molecules; it has even been suggested that macrolide allergies are unlikely to be class allergies.

A multicentre retrospective study of 66 Italian children with food protein-induced enterocolitis syndrome: different management for different phenotypes.

BACKGROUND: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE-mediated paediatric disorder triggered by the ingestion of specific food proteins. Many features of this syndrome are not yet well defined. OBJECTIVE: The aim of our study was to describe demographic features, causative agents, clinical features, treatments and outcomes of children suffering from acute FPIES at three Italian of Pediatric Allergology Centers. METHODS: A retrospective study was performed over a 7-year period (2004-2010). Hospital medical record databases and hospital outpatient electronic charts were screened for the diagnosis of FPIES. Information on the first and subsequent FPIES' episodes was collected. RESULTS: We diagnosed 66 children with FPIES. The number of diagnoses significantly increased between 2008 and 2010 (P < 0.001). We collected a total of 165 FPIES episodes (median per child 2, range 1-10). Cow's milk was the most common trigger food (65%), followed by fish, egg, rice, soy, corn, poultry and goat's milk. Fifty-six (85%) children reacted to a single food. Mean documented time from ingestion to symptom onset was 2.4 h (SD 0.7 h). Vomiting was the most common symptom (98%). Among patients diagnosed with OFC, 78% reacted after eating a whole serving size of the trigger food per age. Skin prick tests (SPT) for trigger foods were negative in 97% of cases. Thirty-two/66 children (48%) achieved tolerance at a mean age of 29 months (SD 17 months). Age of achieved tolerance for cow's milk was significantly lower compared to that of other foods (24 ± 8 vs. 53 ± 17 months, P < 0.0006). CONCLUSION AND CLINICAL RELEVANCE: This article provides new insights on FPIES in Italy by describing its largest series, and shows how a significant increase in the FPIES diagnosis has been observed in the last few years. We also discussed selected management aspects of this syndrome where different phenotypes can be found.

Long-term safety and efficacy of topical cyclosporine in 156 children with vernal keratoconjunctivitis.

Vernal keratoconjunctivitis (VKC) is a chronic and potentially sight-threatening disease. Topical corticosteroids (Cs) seem to be the only effective treatment for this condition, although severe side effects may occur owing to their prolonged use. More recently, cyclosporine (Cyc) eye drops have been reported as a valid alternative, but so far such treatment has only been successfully experimented for a short time and in small numbers of patients. The aim of our study is to evaluate the long term safety and efficacy of topical cyclosporine eye drops in children suffering from VKC. Over a period of 7 years we followed a large group of children suffering from severe VKC. They were selected to start cyclosporine eye drop treatment, because of the prompt relapse of their disease as soon as they stopped topical corticosteroids administration. All patients were followed-up in an ambulatory care assessment. A total of 156 children with VKC were treated with topical cyclosporine eye drops over a period ranging from two to seven years [mean time 3.8 +/- 1.09 years] during the seasonal relapse [range 9-66 months; mean time 24.7+/-10.4 months]. Two formulations, at 1% and 2% (82% and 18%, respectively) concentrations, of cyclosporine eye drops were made. The dosage administered was one drop in each eye from two to four times a day, depending on the severity of the disease and the season. The ocular objective scores were determined and compared every year, at the beginning and at the end of each treatment period. Blood samples were collected once a year in order to check both kidney and liver functions, as well as cyclosporine serum levels. We enrolled 156 patients (mean age 8.31+/-2.79 years; 116 males and 40 females) who were followed-up over a period of 7 years [156 (100%) children during the first and the second year; 138 (88.5%) patients until the third year; 90 (57.7%) until the fourth year; 32 (20.5%) until the fifth year; 10 (6.4%) until the sixth year and 2 (1.3%) until the seventh year]. The ocular objective scores significantly improved (p less than 0.001) over the years when comparing them at the beginning and the end of each seasonal treatment period, except for the last year. Over the treatment period, non-significant changes were recorded in terms of kidney and liver enzymatic activities and also in terms of cyclosporine serum levels. Cyclosporine eye drops, either at 1% or 2% concentrations, resulted safe and effective for long-term treatment of VKC in 156 children. The lack of significance of the score results during the seventh year can be explained by the small number of subjects treated for such a long period. A systematic ocular examination and both liver and kidney functional investigations allowed us to exclude the possibility of local or systemic side effects due to cyclosporine. If either transient or long-lasting, the occurrence of burning was referred by some of the patients treated, but none of them required to discontinue the drug. In conclusion, this is the first study showing that topical cyclosporine is easily handled even by children, with safe and effective results even when it is used over a long period of time. Our findings, though encouraging, need to be confirmed by further studies.

Respiratory impedance and bronchodilator response in healthy Italian preschool children.

OBJECTIVE: To define normal values for respiratory resistance (R(rs)) and reactance (X(rs)) and bronchodilator response (BDR) in a population of healthy Italian preschool children using a commercially available forced oscillation device. METHODS: R(rs) and X(rs) were measured in kindergartens in Viterbo, Italy. Regression analysis was performed taking into account height, weight, age, gender, and reference equations calculated. The coefficient of repeatability (CR) between two tests performed 15 min apart was calculated in a subset of children. BDR was assessed by repeating the measurements 15 min after the administration of 200 µg of inhaled salbutamol and calculated as an absolute change in R(rs) and X(rs) at 8 Hz, as a percent change in baseline, and as a change in Z-score calculated from the reference equations. RESULTS: Lung function was attempted in 175 healthy children and successful in 163 (81 male, median age 4.8, range 2.9-6.1 years). R(rs) and X(rs) at 6, 8, and 10 Hz were related to height but not other variables. The CR was 1.53 hPa s L(-1) for R(rs8) and 0.91 hPa s L(-1) for X(rs8). The 5th percentile for absolute R(rs8) BDR was -3.16 hPa s L(-1), whereas the 95th percentile for absolute X(rs8) BDR was 2.25 hPa s L(-1). These cut-off values corresponded to a change in the Z-score of -1.88 and 2.48, respectively. CONCLUSIONS: We have established reference equations for R(rs) and X(rs) in healthy Italian preschool children using forced oscillations. We recommend a change in Z-score of -1.88 for R(rs8) and 2.48 for X(rs8) as cut-off values for a positive BDR.

CD4+CD25+Foxp3+ T regulatory cells are not involved in oral desensitization.

Oral tolerance has been related to generation of T regulatory cells (Treg) or clonal anergy/deletion, respectively by administering low and high doses of fed antigens. CD4+CD25+ regulatory T cell clones can be induced by the antigen in Peyers patches of animal models. We selected ten subjects (mean age: 89.4 +/- 36.21 months; group A) with severe cows milk allergy. They underwent oral desensitization (OD) according to the current protocols. In six months they reached a tolerance of 50 ml of cows milk. CD4+CD25+Foxp3+ T(reg) blood levels were measured at the beginning of OD (A) and after 6 months (A), but almost the same values were obtained: A = 0.36 +/- 0.11 percent; A prime= 0.59 +/- 0.15 percent. These results were compared with a control group (C) of non-atopic children. Naturally outgrowing cows milk allergy can be related to high blood levels of CD4+CD25+Foxp3+ T(reg), as previously reported in children. On the other hand, a forced oral desensitization through a progressive intake of the antigenic food seems not to be related to an enhancement of CD4+CD25+Foxp3+ T(reg) levels in peripheral blood, making the role of long-lasting systemic immunologic changes unlikely.

Upper airways disease: role of corticosteroids.

Nasal topical steroids (INCSs) are well established effective therapy in allergic rhinitis both in children and adults. There is clear benefit in using INCSs over antihistamines in allergic rhinitis while short courses of oral corticosteroids (CSs) may be indicated in severe cases. The addition of INCSs to oral antibiotics has been proven to be more effective than antibiotics alone for achieving symptomatic improvement in patients with acute rhino sinusitis. INCSs as monotherapy are also effective in the treatment of allergic rhinosinusitis (ARS). Several randomized controlled trials have evaluated the role of INCSs in chronic RS with the majority demonstrating a beneficial effect. In adults, the clinical efficacy of oral corticosteroids in the management of chronic RS with nasal polyposis is well established. There are no randomized controlled trials evaluating the efficacy of systemic CSs in chronic RS without nasal polyposis.

Cytokine expression in CD3+ cells in an infant with food protein-induced enterocolitis syndrome (FPIES): case report.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by severe vomiting, diarrhea, and often failure to thrive in infants. Symptoms typically resolve after the triggering food-derived protein is removed from the diet and recur within few hours after the re-exposure to the causal protein. The diagnosis is based on clinical symptoms and a positive food challenge. In this study, we report a case of FPIES to rice in an 8-month-old boy. We performed a double-blind placebo-controlled food challenge (DBPCFC) to rice and we measured the intracellular T cell expression of interleukin-4 (IL-4); IL-10, and interferon gamma (IFN-gamma) pre-and post-challenge during an acute FPIES reaction and when tolerance to rice had been achieved. For the first time we describe an increase in T cell IL-4 and decrease in IFN-gamma expression after a positive challenge with rice (i.e. rice triggered a FPIES attack) and an increase in T cell IL-10 expression after rice challenge 6 months later after a negative challenge (i.e., the child had acquired tolerance to rice) in an 8 month old with documented FPIES to rice. A Th2 activation associated with high IL-4 levels may contribute to the pathophysiology of the disease. On the other hand, T cell-derived IL-10 may play a role in the acquisition of immunotolerance by regulating the Th1 and Th2 responses.

Urticaria and urticaria related skin condition/disease in children.

Urticaria is a rash, that typically involves skin and mucosa, and is characterized by lesions known as hives or wheals. In some cases there is an involvement of deep dermis and subcutaneous tissue that causes a skin/mucosa manifestation called angioedema. Urticaria and angioedema are very often associated: urticaria-angioedema syndrome. The acute episodic form is the most prevalent in the pediatric population, and it is often a recurrent phenomenon (recurrent urticaria). Acute episodic urticaria it is usually triggered by viruses, allergic reactions to foods and drugs, contact with chemicals and irritants, or physical stimuli. In many instances it is not possible to identify a specific cause (idiopathic urticaria). Chronic urticaria is a condition that can be very disambling when severe. In children is caused by physical factors in 5-10% of cases. Other trigger factors are infections, foods, additives, aeroallergens and drugs. The causative factor for chronic urticaria is identified in about 20% of cases. About one-third of children with chronic urticaria have circulating functional autoantibodies against the high affinity IgE receptor or against IgE. (chronic urticaria with autoantibodies or "autoimmune" urticaria). It is not known why such antibodies are produced, or if the presence of these antibodies alter the course of the disease or influence the response to treatment. Urticaria and angioedema can be symptoms of systemic diseases (collagenopathies, endocrinopathies, tumors, hemolytic diseases, celiachia) or can be congenital (cold induced familiar urticaria, hereditary angioedema). The diagnosis is based on patient personal history and it is very important to spend time documenting this in detail. Different urticaria clinical features must guide the diagnostic work-up and there is no need to use the same blood tests for all cases of urticaria. The urticaria treatment includes identification of the triggering agent and its removal, reduction of aspecific factors that may contribute to the urticaria or can increase the itch, and use of anti-H1 antihistamines (and/or steroids for short periods if antihistamines are not effective). In some instances an anti-H2 antihistamine can be added to the anti-H1 antihistamines, even if the benefits of such practice are not clear. The antileucotriens can be beneficial in a small subgroup of patients with chronic urticaria. In case of chronic urticaria resistant to all the aforementioned treatments, cyclosporine and tacrolimus have been used with good success. When urticaria is associated to anaphylaxis, i.m epinephrine needs to be used, together with antihistamines and steroids (in addition to fluids and bronchodilatators if required).