J.M. Zubeldia

Intranasal Immunotherapy Is More Effective Than Intradermal Immunotherapy for the Induction of Airway Allergen Tolerance in Th2-Sensitized Mice

Immunotherapy (IT) by injection more readily induces clinical tolerance to stinging insects than to respiratory allergens. However, while systemic immunization induces adaptive responses systemically, the induction of mucosal immunity generally requires local Ag exposure. Taken together, these observations suggest that the poor success rate of systemic IT for asthma could be a consequence of inadequate immune modulation in the airways. In support of this position, investigations presented in this report demonstrate that allergen IT more effectively induces airway allergen tolerance in Th2-sensitized mice, when delivered by the intranasal (i.n.) vs the intradermal (i.d.) route. Moreover, compared with native allergen, allergen immunostimulatory sequence oligodeoxynucleotide conjugate proved to be a more effective i.n. IT reagent for protecting allergic mice from airway hypersensitivity responses. Furthermore, for both native allergen and allergen immunostimulatory sequence oligodeoxynucleotide conjugate, i.n. and i.d. IT delivery were similarly effective in modulating systemic immune profiles in Th2-sensitized mice, while only i.n. IT had significant immunomodulatory activity on B and T cell responses in the airways. The present investigations may be the first to suggest that i.n. IT is more effective than i.d. IT for the treatment of asthma. Furthermore, our results suggest that modulating airway rather than systemic immunity may be the more important therapeutic target for the induction of clinical tolerance to respiratory allergens.

Inhibition of Chronic Airway Inflammation and Remodeling by Galectin-3 Gene Therapy in a Murine Model

We previously demonstrated that treatment of acute asthmatic rats with gene therapy using plasmid-encoding Galectin-3 (Gal-3) resulted in an improvement of cellular and functional respiratory parameters. The next question that we wanted to clarify was if in a chronic situation where the treated animal continues to inhale the Ag, does this procedure prevent the chronicity and the remodeling? Chronic inflammation was induced by intranasal administration of OVA over a period of 12 wk. In the treated group, the Gal-3 gene was introduced by intranasal instillation in 50 μl of plasmid-encoding Gal-3. Noninvasive airway responsiveness to methacholine was tested at different times. Cells were obtained by bronchoalveolar lavage and used for RNA extraction and cytometric studies. Eosinophils were counted in blood and bronchoalveolar lavage fluid. Real-time PCR was used to measure Gal-3 and cytokine mRNA expression in lung. Lungs were paraffined and histologic analyses were performed (H&E, periodic acid-Schiff, and Masson Trichrome stain). Our results showed that 12 wk after the first intranasal Ag instillation in chronically asthmatic mice, treatment with the Gal-3 gene led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion and subepithelial fibrosis in the chronically asthmatic mice, with a quantitatively measured reduction in lung collagen, a prominent feature of airway remodeling. Plasmid-encoding Gal-3 acts as a novel treatment for chronic asthma in mice producing nearly complete blockade of Ag responses with respect to eosinophil airway accumulation, airway hyperresponsiveness, and remodeling.

Anisakis simplex-sensitized patients: should fish be excluded from their diet?

BACKGROUND Anisakis simplex (A.s.) allergy is an emerging disease. The third-stage larvae of this nematode are a source of hidden allergens in fish. There are no clear guidelines concerning dietary restrictions for patients with serum-specific IgE to this parasite. OBJECTIVE To follow up the clinical data and immunological parameters of patients sensitized to A.s. during 6 to 23 months. METHODS The clinical symptoms and serologic status of 17 patients with specific IgE and positive skin prick test results to A.s. were studied prospectively. Six of these had anaphylaxis (ANA) attributed to A.s. and 11 patients experienced concomitant chronic urticaria (CU). All patients were advised not to eat fish for 6 months. RESULTS Four patients from the ANA group excluded fish, and ANA did not recur. Two other patients with ANA refused to exclude fish; one remained free of symptoms and the other experienced several urticarial episodes. During this 6-month period total IgE levels decreased in all six ANA patients; specific IgE for A.s. decreased in four patients and increased in two. Two patients from the CU group did not exclude fish, and symptoms persisted in these two patients. Clinical improvement was observed in 78% of the patients with CU who excluded fish. Total and specific IgE levels decreased in all the patients with CU. CONCLUSIONS Because ANA symptoms are very severe, patients should always be advised to exclude fish until specific food allergens are identified. However, in patients with CU and specific IgE to A.s., only the clinical response to fish ingestion will determine the need for strict fish avoidance.

Toxic epidermal necrolysis induced by levofloxacin.

TOXIC EPIDERMAL NECROLYSIS INDUCED BY LEVOFLOXACIN Toxic epidermal necrolysis (TEN) is a severe bullous dermatitis with a mortality rate of 30% to 35%.1 Fluoroquinolones, especially ciprofloxacin, have been implicated in cases of TEN.2–7 However, there is little published information on levofloxacininduced TEN.4,6,7 We report a fatal case of TEN induced by levofloxacin. A 59-year-old woman with a history of endometrial carcinoma (stage III), type 2 diabetes mellitus, and allergy to streptomycin and penicillins was admitted to the oncology department with pyelonephritis. Treatment with levofloxacin, 500 mg/d, was started. On the ninth day of treatment, the patient developed generalized purpuric exanthema. Levofloxacin use was discontinued, and the exanthema improved spontaneously. Four days later, the patient was discharged from the hospital, in good health. Forty-eight hours after discharge, the patient visited the emergency department with urinary syndrome and fever (temperature, 39°C). During the interview with the patient, a possible allergy to quinolones was not acknowledged and treatment with levofloxacin was restarted. Six hours after the administration of the first dose, the purpuric exanthema reappeared; after 24 hours, it had extended to 40% of the total body surface and became painful. Progression to desquamation and formation of conjunctival and epidermal erosions were observed in the next 24 hours. A characteristically lateral displacement of the necrotic epidermis in response to slight pressure was confirmed (Nikolsky sign) (Fig 1). The skin and mucous lesions involved the chest, back, face, neck, hands, legs, mouth, eyes, ears, and vagina. The laboratory results revealed normal red and white blood cell counts with a slightly increased erythrocyte sedimentation rate of 18 mm/h. The level of total serum proteins was 5.5 g/L; glucose, 221 mg/dL; creatinine, 1.5 mg/dL; and urea, 69 mg/dL. Levels of total bilirubin, aspartate aminotransferase, alanine aminotransferase, -glutamyltransferase, potassium, and sodium were within normal limits. The patient was transferred to the intensive care unit and treated as a severe burnt patient. Protection of the skin and denuded areas and replacement of fluids and electrolytes were begun immediately. The patient also received methylprednisolone, 1 mg/kg intravenously, for 2 days, with no improvement. Laboratory test results showed abnormal liver and kidney function, hyperglycemia, hypoalbuminuria, and hypopotassemia. Her fever continued, and Pseudomonas aeruginosa was isolated from the blood and urine cultures. Five days later, the patient died. TEN and Stevens-Johnson syndrome are 2 forms of the same life-threatening process.1 Characteristically, severe mucosal erosions with widespread erythematous cutaneous maculae are the main features of the disease. The cutaneous lesions often become confluent, with a positive Nikolsky sign and epidermal detachment. TEN is defined as an epidermal detachment of more than 30% of the skin, and it has the highest mortality rate (range, 30%–35%). Stevens-Johnson syndrome–TEN is essentially a drug-induced disease. A few cases are related to infections, such as herpes simplex and mycoplasma; also, genetic susceptibility has been suggested. Fluoroquinolones have seldom been implicated in TEN.2–7 Levofloxacin is effective against a number of gram-positive and gramnegative bacteria. Because of its broad spectrum of action, levofloxacin is empirically prescribed for a wide range of infections but there is little published information on levofloxacin-induced TEN.4,6 To our knowledge, there is only 1 report of a fatal outcome.7 The risk of death in patients with TEN can be accurately predicted by the TEN-specific severity-of-illness score.8 According to this scale, our patient had a final score of 6 and a mortality risk higher than 90%. Patients with TEN must be quickly referred to burn or intensive care units for supportive management and nutritional support (correction of electrolyte disturbances, administration of high-caloric enteral nutrition, and prevention of sepsis). There are no randomized controlled trials of pharmacologic agents in the treatment of this disorder. Consequently, although case reports of a variety of therapeutic approaches have emerged, more research is needed to determine the real efficacy of any new treatment. These new agents include intravenous immunoglobulin, systemic corticosteroids, tumor necrosis factor inhibitors, cyclosporine, cyclophosphamide, plasmapheresis, and hemodialysis.9

Anaphylaxis in the Pediatric Emergency Department: Analysis of 133 Cases After an Allergy Workup

BACKGROUND Data on the incidence and characteristics of pediatric anaphylaxis are scarce. Reported causes of anaphylaxis are mostly those suspected by the physician in the emergency department (ED), which may not coincide with the real triggers. OBJECTIVES To investigate the incidence, management, and etiology of pediatric anaphylaxis in the ED of a Spanish tertiary hospital and to determine the concordance between the suspected etiology in the ED and diagnosis after the allergy workup. METHODS We performed an observational, descriptive study of all patients with anaphylaxis attended in the pediatric ED from 2012 to 2014. Cases were considered anaphylaxis based on National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria. We recorded data on clinical characteristics, management, etiology suspected by the ED physician and patient (or relatives), and the workup performed in the allergy department. RESULTS We recorded 133 cases of anaphylaxis (incidence, 0.12%), with 20 cases (15%) recorded in children younger than 12 months. Anaphylaxis was correctly diagnosed in the ED in 70 cases (53%). Food allergy was the cause of anaphylaxis in 106 out of 118 studied in the allergy department (AD) (90%). The final etiology differed from the etiology initially suspected in the ED in 42 cases (39%). After the study, the frequency of patients with unidentified triggers decreased by 75%. CONCLUSIONS The incidence of anaphylaxis is higher in children than previously reported in adults from the same center, and food is the trigger in most cases. To prevent erroneous diagnoses, the etiology of anaphylaxis should be established after an appropriate workup.

Allergy to lingonberry: A case report

Past few years cranberry/lingonberry products have been incorporated as healthy products to the US and European market as prophylaxis of recurrent urinary tract infections in young women as well as in chronic infections in elderly which because of there are many biological activities attributed to the that fruit is a very popular additive to the new diets. To the best of our knowledge, this is the first case of allergy to lingonberry. We speculate that previous exposure to lingonberry products could be sensitising. The symptoms, timing of the episode, positive skin test, IgE-ELISA and western-blot strongly support the role of lingonberry as the causative agent.

Trends in Twitter use during the Annual Meeting of the Spanish Society of Allergology and Clinical Immunology (2013-2016)

Twitter (Twitter Inc, San Francisco, Calif) is a platform that enables users to publish a 140-character message known as tweet. The use of social media at medical conferences has been documented. Studies have demonstrated that Twitter can increase the influence of conferences. In the case of Allergology, English-speaking allergists’ use of Twitter increased by 470% between 2011 and 2012, whereas the American Academy of Allergy, Asthma and Immunology annual meetings tweets increased by 790% from 2012 to 2015. There is no information available on Twitter activity during other Allergy conferences. The objective of this study was to describe whether this phenomenon is taking place in a European country such as Spain. We performed a prospective, observational study including all the tweets published under the official hashtags for the 2013 to 2016 Spanish Society of Allergology and Clinical Immunology (SEAIC) annual meetings (Table I). Advertisements inserted in the Web site, program, and screens encouraged attendees to use the hashtags. Total tweets during the congress dates, transcripts, number of participating users, and impressions (tweets number of followers) were recovered from the Symplur Healthcare Hashtag database. Data were collected by A.A.P. 7 days after each congress. Tweets, excluding retweets, were categorized by 1 investigator (A.A.P.) into (1) “Scientific” if they concerned a meeting topic; (2) “Social” if they contained informal comments; (3) “Administrative” if they involved practical information; (4) “Commercial” if published by industry representatives, or publicity; and (5) “Other” if they did not fit into any of the previous, including press publications. Users were identified as physicians, nurses, general public, industry, organizations (including scientific and patient associations), or other. Physicians and nurses were cross-referenced with SEAIC members listing. Their attendance to each congress, sex, and location were extracted from their Twitter profile. The number of congress delegates was provided by the organizers (Table I). Statistical analysis was performed with IBM SPSS Statistics 20 (IBM Corporation, Armonk, NY) and Microsoft Excel 2013 (Microsoft Corporation, Redmond, Wash). Twitter activity increased during the past 4 congresses, including the number of tweets, retweets, participants, impressions, tweets per day, and impressions per participant (Table I). Tweets, excluding retweets, were mostly administrative in 2013 and 2014, whereas scientific tweets were the most common in 2015 and 2016 (Figure 1). Personal accounts activity, as opposed to other entities, increased along the observation period. Most participants were located in Spain. Non-Spanish accounts represented 19% in 2016, accounting for 4.4% of the activity. Up to 37.5% of the participants were SEAIC members, with a number of tweets that peaked at 87.3%. Congress delegates never accounted over 37.5%, but their activity in 2015 reached 84.5% (Table I). The participants were mostly physicians, up to 48.1% in 2015. Their activity totaled almost 90% of all tweets in the last 2 congresses. Nurses’ activity was low. Involvement of public has been low until 2016, when they represented 12.3% of participants and 3.1% of activity (Table I). When looking at the number of congresses that each user tweeted at, most participants took part in 1 congress (n 1⁄4 401), while 47 participated in 2 congresses, 18 in 3, and 10 were active during all the 4 congresses. In this study, we have examined the use of social media during a European Allergy conference for the first time. The use of Twitter during the last 4 SEAIC annual meetings grew exponentially from 2013 to 2016. This growth cannot be explained by the length of the congress, the increase in Twitter users (36%), or congress delegates (70%) during the same period. Not only the number of participants but also the rate of tweets and impressions per participants grew every year. In our opinion, the perception of Twitter as a useful tool during previous congresses might be one of the reasons behind the growth. Two other studies have reported the Twitter activity of a congress for multiple years. Attai et al followed the American Society of Breast Surgeons Annual Meeting from 2013 to 2016. The growth rate was higher for the Spanish congresses, with a lower number of participants. In the field of Allergology, Stukus published a follow-up of the American Academy of Allergy, Asthma and Immunology Annual Meeting from 2012 to 2015. In this case, all the metrics were higher than SEAIC’s, probably due to a higher attendance, but the growth rate was again lower. The design of our study gives an insight into how the use of social media by Spanish allergists evolved along the years. It is worth noting that the role of physicians grew exponentially, in contrast to the experience of the American Society of Breast Surgeons, which showed a steadier number of physicians, probably due to an earlier adoption of Twitter by American doctors. Each tweet published during the SEAIC meetings reached around 1,000 additional users, many of them nonattendants, as

Comparative study of adjuvants for allergen-specific immunotherapy in a murine model

AIM To compare the immunological and clinical changes induced by allergen-specific immunotherapy (AIT) using different adjuvants. MATERIALS & METHODS Olea europaea pollen-sensitized mice were treated with olea plus aluminum hydroxide, calcium phosphate, monophosphoryl lipid A (MPL) or immunostimulatory sequences (ISS). RESULTS Aluminum hydroxide seems to drive initially to a Th2-type response. Bacteria-derived adjuvants (MPL and ISS) skew the immune response toward Th1 and Treg pathways. Specific-IgE production was lower after AIT with MPL and ISS. Moreover, IgG2a production significantly increased in ISS-treated mice. Bacteria-derived adjuvants also improved the Th1 cytokine response due to IFN-γ higher secretion. In addition, they improved bronchial hyper-reactivity and lung inflammation. CONCLUSION Bacteria-derived adjuvants may enhance the efficacy of AIT.

Differences in the Anaphylactic Response between C3H/HeOuJ and BALB/c Mice

Background: Anaphylaxis is a severe and potentially lethal allergic reaction whose incidence is increasing. Murine models can elucidate the underlying mechanisms and pave the way for appropriate therapeutic options. However, differences in strains and protocols hamper comparisons of data between researchers. We performed a parallel study of clinical and immune responses with 2 strains of mice, BALB/c and C3H/HeOuJ, in an allergen-induced systemic anaphylaxis protocol. Both strains have been widely used in allergy models, although they have not been compared in an intraperitoneal systemic model. Methods: Groups of 5-week-old female BALB/c and C3H/HeOuJ mice were intraperitoneally sensitized with peanut in the presence of adjuvants. Specific immunoglobulin (sIg) G1, sIgG2a, sIgE, total IgE, histamine release, and specific stimulated splenocyte cytokines, interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, and interferon (IFN)-γ, were assessed. At week 6, mice were intraperitoneally challenged with peanut. Anaphylaxis was evaluated by recognition of clinical symptoms and changes in body temperature. Results: All peanut-sensitized mice induced sIg and developed anaphylactic symptoms upon challenge. Nonetheless, the C3H/HeOuJ strain demonstrated earlier and persistently higher sIgG1 and sIgG2a production, elevated sIgE, and more severe clinical symptoms and histamine release than the BALB/c strain. In contrast, BALB/c exhibited higher release of IL-4, IL-5, IL-10, IL-13, and IFN-γ. Conclusions: Both models are suitable for studying anaphylaxis. Consequently, they could be used in research on the pathogenesis and therapy of anaphylaxis. However, according to the type of study performed, differences in the specific clinical, humoral, and cellular responses to antigens have to be considered.