Spanish Society of Allergology and Clinical Immunology (SEAIC) Vision of Drug Provocation Tests.

The controlled drug provocation test (DPT) is currently considered the gold standard for the diagnosis of drug allergy. Adverse drug reactions (ADRs) are an increasingly common presenting complaint in both primary and specialized care. In Spain, ADRs are usually assessed via the allergology department, which rules out immunological mechanisms in up to 90% of cases. An adequate approach to ADRs clearly impacts the costs and efficacy of the treatments prescribed by other specialists. Consequently, if we did not use DPTs, patients would require more expensive, more toxic, and less effective treatments in many cases. In recent years, many new drugs have been developed. This document is intended to be a practical guideline for the management of DPTs according to the vision of the Spanish Allergology Society. The diagnostic work-up begins with a detailed clinical history. Skin tests are only useful for some medications, and in most cases the diagnosis can only be confirmed by DPT. Although cross-reactivity is common, DPTs can confirm the diagnosis and help to find an alternative drug. Programmed individualized patient management based on the type of drug to be studied and the patient´s comorbidities usually enables a solution to be found in most cases.

Practical guidelines for diagnosing hypersensitivity reactions to nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity reactions. These reactions include various clinical entities with different mechanisms leading to the release of inflammatory mediators. Characterization of patients based on clinical manifestations and suspected underlying mechanisms is critical for implementation of adequate diagnostic procedures and patient management. Our objectives were to prepare a systematic review of available scientific evidence and to provide general guidelines for the diagnosis and management of patients with hypersensitivity reactions to NSAIDs. We also propose a practical algorithm for the diagnosis of specific types of hypersensitivity to NSAIDs and provide recommendations for the management of hypersensitive patients.

Adverse Reactions to Anti-Infective Vaccines: an Emerging Problem in the COVID-19 Era.

Purpose of review: Vaccines are an essential tool for preventing infectious diseases and reducing associated morbidity and mortality. Vaccination has a significant impact at both individual and community levels, and COVID-19 vaccination programs are a new example of the great value of this public health strategy. However, adverse reactions, especially severe reactions such as anaphylaxis, prevent these programs from progressing properly, thus limiting vaccination uptake in the population. Recent findings: The frequency of reactions and types of vaccine components, with special attention to COVID-19 vaccines studies, provides information on the magnitude and causes of adverse events. The understanding of mechanisms involved has made it possible to adequately guide diagnosis, especially to COVID-19 vaccine components, such as polyethylene glycol, trometamol, and polysorbate-80. Summary: This review focuses on adverse reactions to vaccines, with emphasis on allergic reactions. A diagnostic pathway is suggested that, on the one hand, enables to take the necessary precautions in persons with a history of allergy to vaccine components or allergic reactions to vaccines and, on the other, supports administration of subsequent doses. The overall objective is to ensure that people with allergy can be vaccinated in the same way as the rest of the population, and that they are offered alternatives where necessary.

Allergy to quinolones: low cross-reactivity to levofloxacin.

BACKGROUND: Immediate-type hypersensitivity reactions to quinolones are rare. Some reports describe the presence of cross-reactivity among different members of the group, although no predictive pattern has been established. No previous studies confirm or rule out cross-reactivity between levofloxacin and other quinolones.Therefore, a joint study was designed between 2 allergy departments to assess cross-reactivity between levofloxacin and other quinolones. MATERIAL AND METHODS: We studied 12 patients who had experienced an immediate-type reaction (4 anaphylaxis and 8 urticaria/angioedema) after oral administration of quinolones. The culprit drugs were as follows: ciprofloxacin (5), levofloxacin (4), levofloxacin plus moxifloxacin (1), moxifloxacin (1), and norfloxacin (1). Allergy was confirmed by skin tests and controlled oral challenge tests with different quinolones. The basophil activation test (BAT) was applied in 6 patients. RESULTS: The skin tests were positive in 5 patients with levofloxacin (2), moxifloxacin (2), and ofloxacin (2). BAT was negative in all patients (6/6). Most of the ciprofloxacin-reactive patients (4/5) tolerated levofloxacin. Similarly, 3 of 4 levofloxacin-reactive patients tolerated ciprofloxacin. Patients who reacted to moxifloxacin and norfloxacin tolerated ciprofloxacin and levofloxacin. CONCLUSIONS: Our results suggest that skin testing and BAT do not help to identify the culprit drug or predict cross-reactivity. Oral challenge testing is the only way to confirm tolerance to a quinolone before prescribing it as a safe alternative. Levofloxacin could be a safer alternative in cases of reaction to first-, second-, or fourth-generation quinolones.

Anisakis simplex: from obscure infectious worm to inducer of immune hypersensitivity.

Infection of humans with the nematode worm parasite Anisakis simplex was first described in the 1960s in association with the consumption of raw or undercooked fish. During the 1990s it was realized that even the ingestion of dead worms in food fish can cause severe hypersensitivity reactions, that these may be more prevalent than infection itself, and that this outcome could be associated with food preparations previously considered safe. Not only may allergic symptoms arise from infection by the parasites ("gastroallergic anisakiasis"), but true anaphylactic reactions can also occur following exposure to allergens from dead worms by food-borne, airborne, or skin contact routes. This review discusses A. simplex pathogenesis in humans, covering immune hypersensitivity reactions both in the context of a living infection and in terms of exposure to its allergens by other routes. Over the last 20 years, several studies have concentrated on A. simplex antigen characterization and innate as well as adaptive immune response to this parasite. Molecular characterization of Anisakis allergens and isolation of their encoding cDNAs is now an active field of research that should provide improved diagnostic tools in addition to tools with which to enhance our understanding of pathogenesis and controversial aspects of A. simplex allergy. We also discuss the potential relevance of parasite products such as allergens, proteinases, and proteinase inhibitors and the activation of basophils, eosinophils, and mast cells in the induction of A. simplex-related immune hypersensitivity states induced by exposure to the parasite, dead or alive.

Allergenicity and cross-reactivity of pine pollen.

BACKGROUND: Pine pollen has long been considered a non-allergenic pollen. The large size of the grain and its low levels of proteins are the main reasons invoked to explain this low allergenicity. The aim of this study was to describe the main allergenic bands of Pinus radiata (PR) and its cross-reactivity with other pine species, other conifers and grass pollen. METHODS: Sixty-five pine-pollen-allergic patients (51% also sensitized to grass pollen) were studied. Skin prick tests (SPT) to a battery of allergens including PR, Pinus pinea, Pinus sylvestris, Pinus nigra and Cupressus sempervirens pollens and specific IgE determination to PR and Pinus strobus were performed. IgE-immunoblotting to a PR extract and other pine pollens was also carried out. UniCAP inhibition and immunoblotting inhibition studies were performed to assess the cross-reactivity between different pollens. RESULTS: The SPTs were positive with all the pine pollen extracts tested in 69% of the patients. Specific IgE was positive to PR or P. strobus in 77% of the patients, and to Lolium perenne in 51%. Nine different allergenic bands were detected. The two main allergens were a 42 kDa band recognized by 85% of the patients and a band of approximately 6-8 kDa recognized by 40%. A high degree of cross-reactivity was observed between different pine pollen species, but not between pines and C. sempervirens pollen. A partial cross-reactivity could be seen between pine and grass pollens only in patients also sensitized to L. perenne. CONCLUSIONS: Pine pollen should be considered as a potential allergenic pollen especially where this pollen is abundant. The detection of a high number of patients that were monosensitized to pine pollen suggests the possibility of treating these patients with specific immunotherapy.

Diagnosis of clavulanic acid allergy using basophil activation and leukotriene release by basophils.

Clavulanic acid is a potent inhibitor of B-lactamase that is increasingly prescribed in association with amoxicillin. We report 2 cases of patients who experienced pruritus, wheals, and angioedema after oral intake of amoxicillin/clavulanic acid. Routine skin tests for B-lactam antibiotics and specific immunoglobulin (Ig) E were negative in both patients. Analysis of CD63 expression by the basophil activation test (BAT) using flow cytometry and of sulphidoleukotriene (sLT) release by basophils using the cellular allergen stimulation test (CAST) revealed significant positive responses with amoxicillin/clavulanic acid and with clavulanic acid, and negative responses with amoxicillin and other beta-lactam antibiotics. In addition, cultured CD3+CD4+ cells showed a significant increase in the expression of CD69, CD25, and HLA-DR in the presence of clavulanic acid. Both patients tolerated therapeutic doses of amoxicillin. BAT and CAST are useful ex vivo procedures for the detection of specific IgE-mediated allergy to clavulanic acid, especially for patients with negative skin test results.

Study of hypersensitivity reactions and anaphylaxis during anesthesia in Spain.

BACKGROUND: Several studies have identified neuromuscular blocking agents as the most common cause of anaphylaxis during general anesthesia. The reported frequencies vary considerably between countries. There are few reports from Spain, probably due to the low prevalence of reactions. METHODS: For 5 years (1998-2002), all the patients who presented perioperative anaphylactic-type reactions, were studied in 2 Spanish allergy departments (Santiago Apostol, Vitoria-Gasteiz and San Pedro, Logroño). The diagnostic protocol consisted of a case history (age, gender, number of previous interventions, characteristics of the reaction, reaction phase, previously administered drugs), serum tryptase measurements, skin tests, and specific immunoassays (immunoglobulin [Ig] E determination against latex, penicillin, and Echinococcus). RESULTS: Forty-eight patients were studied, with ages ranging from 7 to 86 years. The ratio of women to men was 3:2. An IgE-mediated mechanism was confirmed in 27/48 patients (56%). The etiological agents were antibiotics in 12 cases (44%) (10 betalactams, 1 vancomycin, and 1 ciprofloxacin), muscle relaxants in 10 cases (37%), pyrazolones in 2 cases, latex in 2 cases, and Echinococcus in 1 case. CONCLUSIONS: Fifty-six percent of the perianesthetic reactions studied were IgE-mediated. Antibiotics and neuromuscular blocking agents were the most frequent causal agents, as verified by skin tests, and specific IgE and/or challenge tests. It is important to keep appropriate documentation on any of the drugs used during surgery, since our results show that those drugs involved in the reaction as the etiological agent, such as antibiotics and nonsteroidal anti-inflammatory agents, can be used again outside the context of surgery.

Rheumatic manifestations in the course of anaphylaxis caused by Anisakis simplex.

Human anisakidosis is a parasitic infection caused by the larvae of Anisakis simplex. Classical clinical manifestations include epigastric pain, occlusion, diffuse abdominal pain, appendicitis, and anaphylactoid reactions. Arthralgias or arthritis have been infrequently reported. We present three patients with proven hypersensitivity to A. simplex together with rheumatologic complaints after ingestion of parasitized fishes. A. simplex must be considered in the differential diagnosis of arthralgias/ arthritis especially if associated with urticaria.

Hereditary angioedema and pneumomediastinum.

Gastrointestinal and respiratory involvement is common in hereditary angioedema, laryngeal edema being the main cause of mortality in these patients. We report the case of an 18 year-old woman with a history of hereditary angioedema, who presented an episode of coughing and vomiting the night before, and who was diagnosed with pneumomediastinum as a complication of an episode of angioedema. We review the causes and pathogenesis of the mediastinic emphysema.

Anisakis simplex induces not only anisakiasis: report on 28 cases of allergy caused by this nematode.

Anisakis simplex R., parasitizes several sea-fish and cephalopods. This parasite induces not only anisakiasis but also anaphylactic reactions, as has recently been confirmed. We present 28 patients with immediate hypersensitivity to Anisakis simplex, developed after parasitized fish ingestion. Each case was diagnosed by suggestive anamnesis, skin prick tests with an A. simplex extract, specific IgE detection in serum (CAP System), and histamine release test. The clinical manifestations were urticaria/angioedema in all 28 patients and respiratory arrest in one. Paradoxically, the patients reported tolerance to ingestion of the same kind of fish between and after the allergic episodes. Type 1 hypersensitivity to A. simplex was demonstrated by a positive skin-prick test reaction, specific IgE detection in all cases and positive histamine release in a representative case. Sensitization to the proteins of the fish themselves was ruled out by negative reactions of the same tests in all cases. It was also proven that the allergen/s involved may be resistant to cooking and deep freezing. Hence, anaphylactic reactions may result either from infection or, more frequently, from mere exposure to the allergen. The results confirm that A. simplex can develop IgE-mediated anaphylactic reactions, the clinical severity of which was pronounced in the patients examined. Physicians must take into account that the consumption of parasitized fish may cause severe reactions, even if fish of the same kind is subsequently tolerated. A higher frequency of reactions of this type can be expected in countries where fish is a staple diet.

Seasonal versus perennial immunotherapy: evaluation after three years of treatment.

We have performed a comparative study to evaluate seasonal and perennial schedules after 3 years of immunotherapy. Sixty patients suffering from rhinitis and/or asthma due to grass pollen sensitization were randomly allocated to receive a semi-depot extract of Phleum pratense according to a perennial or seasonal schedule. The last year of the study, 14 patients were recruited as a control group without immunotherapy. The cumulative dose was 602 BU in the perennial group and 372 BU in the seasonal group. The frequency and severity of side-effects were similar and very low in both treated groups. The IgE level was significantly lower after perennial immunotherapy at the end of the first 2 years. A seasonal decrease in specific IgG levels was observed in patients who interrupted immunotherapy, while this was not observed in patients under the perennial schedule. Symptoms and medication scores did not show differences between groups. Nevertheless, we found a significant difference between treated patients and the control group.

Systemic reactions to immunotherapy: influence of composition and manufacturer.

BACKGROUND: Although immunotherapy clearly demonstrated the benefit of reducing allergic symptoms, it has the drawback of adverse events, mainly systemic reactions that could be very inconvenient for patients and even life-threatening. OBJECTIVE: The aim of the present study was to assess the incidence of systemic reactions to immunotherapy in a large number of patients, and its potential relationship with the characteristics of therapy, such as allergen composition or manufacturing laboratory. METHODS: This study analysed the administration of specific immunotherapy during a period of 5 years, involving 1212 patients affected by respiratory hypersensitivity or hymenoptera venom anaphylaxis. Commercial extracts were supplied by five different laboratories. All the patients were attended at an out-clinic immunotherapy unit by the same experienced staff. Immunotherapy was given following a conventional schedule, modified according the usual recommendations. RESULTS: A total of 250 adverse reactions have been recorded, resulting in a frequency of 0.84% over the total number of injections. Seventy-nine of them (32%) were systemic reactions (0.27% SR/injection). The 79 systemic reactions were observed in 60 patients (5% of the patients). The frequency of systemic reactions was significantly lower (P < 0.01) on the group of mites than on the other groups. The frequency of systemic reactions varies according to the manufacturing laboratory. In the case of mite extracts, although one of the laboratories had a lower frequency of adverse systemic reactions, it did not reach the level of statistical significance. However, in relation to pollen extracts, preparations of one of the manufacturers had a significantly lower frequency of systemic reactions. Concerning the time of occurrence, 27% of systemic reactions were delayed, thus they appeared at least 30 min after the vaccine injection, most of them due to pollen extracts. CONCLUSION: This is a preliminary study to evaluate the factors that could facilitate the appearance of systemic reactions demonstrating that not only the composition but also the manufacturer is connected to systemic reactions. Although further studies are needed to clearly establish the influence of manufacturer on frequency and time of appearance of systemic reactions, it seems necessary to reach a wide consensus on allergen extract standardization methods.

Occupational asthma and rhinoconjunctivitis from inhalation of dried cow's milk caused by sensitization to alpha-lactalbumin.

A chocolate candy worker was diagnosed as having occupational asthma and rhinoconjunctivitis on the basis of clinical record and methacholine challenge. Positive conjunctival and bronchial challenge tests with lactalbumin showed that this protein was the pathogenetic agent. Type I hypersensitivity mechanism is demonstrated by means of skin prick test and RAST.

O-glycans as a source of cross-reactivity in determinations of human serum antibodies to Anisakis simplex antigens.

BACKGROUND: Anisakis simplex is a seafood-borne parasite that may both infect humans and cause allergy. Serodiagnosis of anisakiasis and allergy caused by this nematode is difficult since most Anisakis antigens show cross-reactivity problems. OBJECTIVE: To analyse the possible role of sugar epitopes contained in Anisakis simplex antigens as causes of false-positive results in serodiagnostic assays. METHODS: The antigens UA2R and UA3R recognized by two anti-Anisakis monoclonal antibodies were used in this study. Capture ELISA techniques were used to compare the reactivities with native or O-deglycosylated antigens of sera from Anisakis-free children (most of them infected by several other parasites) and from Anisakis allergy patients. O-deglycosylation was done by mild alkali treatment with NaOH. SDS-PAGE and immunoblotting were used to characterize the effects of NaOH or N-glycanase F treatment on UA3R. RESULTS: Native UA2R was recognized by IgG1 and IgM antibodies in the sera of both Anisakis-free subjects and allergy patients. Native UA3R was recognized by most sera from allergy patients (92% considering immunoglobulin (Ig) G1, 100% considering IgE), but also by a significant proportion of sera from Anisakis-free subjects (36% considering IgG1, 14% considering IgE). O-deglycosylation of UA3R greatly improved specificity: none of the sera from Anisakis-free patients showed either IgG1 or IgE reactivity with O-deglycosylated UA3R, while the proportion of sera from allergy patients showing IgE reactivity with this antigen was practically unaffected. O-deglycosylation of UA2R did not improve the specificity of assays using this antigen. Our results also show that the protein core of glycoproteins may be altered by even very mild alkali treatment, depending on the nature of the protein. CONCLUSION: Native glycoproteins of A. simplex should not be used for diagnostic purposes. O-deglycosylated UA3R seems to be an excellent candidate for use as target antigen in the serodiagnosis of anisakiasis and A. simplex allergy.

Periodate treatment of Anisakis simplex allergens.

Anaphylactic reactions after parasitized fish consumption are mediated by an IgE response. However, positive skin tests and specific IgE can also be found in many asymptomatic subjects who recognize a single medium-mol.-wt. antigen by IgE immunoblot. The study aimed to find out whether this unspecificity was due to the carbohydrate moieties of parasite antigens. Sixty-two patients with suspected parasite allergy, 51 blood donors, 18 bakers, and 38 atopic patients were studied by blotting. Parasite proteins were treated with periodate. Several selected sera were inhibited with a crude wheat extract and fungal amylase. Twelve patients (19%), eight donors (16%), six bakers (33%), and one atopic patient (3%) recognized a single medium-mol.-wt. band in blotting and should be considered false-positive. This band was periodate-sensitive, but specific IgE to this allergen could not be inhibited by a wheat extract nor by fungal amylase and was clinically irrelevant. Diagnosis of Anisakis simplex hypersensitivity by skin tests and/ or specific IgE values should always be confirmed by specific IgE immunoblotting in order to detect the presence of clinically unrelated antibodies directed to periodate-sensitive allergens. These allergens are probably not a carbohydrate moiety of a parasite glycoprotein.