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.

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.

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 (AU)

La prueba de exposición controlada a fármacos (DPT) se considera actualmente el estándar de oro para el diagnóstico de alergia amedicamentos. Las reacciones adversas inducidas por medicamentos (RAM) son un motivo creciente de consulta tanto en atención primariacomo especializada. Las consultas de Alergología en España son las que habitualmente estudian estas RAM y descartan mecanismosinmunológicos implicados hasta en el 90% de los casos consultados. Un abordaje adecuado de estos casos repercute de una maneraevidente en los costes y la eficacia de los tratamientos requeridos por otros especialistas, de modo que, si no empleáramos los DPT, lospacientes requerirían tratamientos más costosos, más tóxicos y menos eficaces en la mayoría de los casos.En los últimos años se han desarrollado un gran número de nuevos fármacos y este documento pretende ser una guía práctica en lagestión de las DPT con la visión de la Sociedad Española de Alergología. El trabajo de diagnóstico comienza con un historial detalladodel paciente. Las pruebas cutáneas solo son útiles en algunos medicamentos y, en la mayoría de los casos, el diagnóstico solo puedeconfirmarse mediante el DPT. Aunque suele haber reactividad cruzada, las DPT pueden confirmar el diagnóstico y también contribuir aencontrar un fármaco alternativo tolerable. El manejo individual de los pacientes de forma programada, teniendo en cuenta tanto eltipo de fármaco a estudiar como las comorbilidades del paciente, suele permitir encontrar una solución para la mayoría de los pacientes (AU)

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.

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.

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.

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.

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.

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.

Alergia al polen de las oleáceas en un lugar donde no hay olivos / Oleaceae pollen allergy in a place where there’s no olive trees

Antecedentes y objetivos: El polen del fresno (Fraxinus excelsior), árbol perteneciente a la familia Oleaceae, se ha descrito recientemente como un alérgeno relevante en algunos países centroeuropeos. El objetivo de este trabajo es estudiar la importancia que este polen tiene como factor desencadenante de los síntomas alérgicos que sufren, al final del invierno y principio de la primavera, algunos pacientes que viven en País Vasco, donde no existen olivos pero el fresno es un árbol abundante. Métodos: Se seleccionaron 48 pacientes que se clasificaron en tres grupos en función de la sensibilización predominante: pacientes alérgicos a oleáceas (O), alérgicos a gramíneas (G) y alérgicos a ambos pólenes (M). Los pacientes se dividieron además en dos grupos en función de la época en la que tenían los síntomas: pacientes con síntomas tempranos o pacientes con síntomas tardíos. Se les realizó la prueba del prick con una batería de pólenes, pruebas de exposición conjuntival con extractos de polen de olivo y de fresno y la determinación de IgE específica (EAST) frente a varios pólenes. Resultados: En el grupo O, el 100% de los pacientes tuvo síntomas tempranos, esto es, coincidiendo con la floración del fresno y antes de aparecer el polen de las gramíneas. En los grupos M y G los porcentajes de pacientes con síntomas tempranos fueron del 40% y 16%, respectivamente. Las pruebas de provocación conjuntival con polen de olivo y fresno resultaron positivos en el 100% y 70%, respectivamente, de los pacientes del grupo O, en el 78% y 50% del grupo M y en el 58% y 31% del grupo G. Los pacientes con síntomas tempranos tuvieron con mayor frecuencia pruebas cutáneas positivas frente al polen de F. excelsior (p < 0,05) y unas concentraciones de IgE específica frente a F. excelsior significativamente mayores (p < 0,05) que los pacientes con síntomas tardíos. Las pruebas de provocación conjuntival con polen de O. europaea fueron de mayor intensidad en los pacientes con síntomas tempranos. Conclusión: Los pacientes que residen en País Vasco y sufren síntomas durante el final del invierno y el comienzo de la primavera tenían una sensibilización predominante al polen del fresno y del olivo, en comparación con los pacientes que únicamente tenían síntomas tardíos (en mayo y junio). El polen del fresno puede considerarse una posible causa de polinosis en aquellos lugares donde su presencia es frecuente

Background: Ash tree belongs to the Oleaceae family; it has been recently described as a relevant allergen in some countries. The aim of this study is to demonstrate the importance of the ash pollen as a triggering factor of the allergic symptoms showed in early spring by a group of patients who live in the Basque Country, where ash are common trees and olive trees are not present. Methods: In accordance with their predominantly sensitisation we selected and classified 48 pollen-allergic-patients in three groups: oleaceae allergic patients (O), grass allergic patients (G) and oleaceae + grass allergic patients (M). Patients were also divided in two groups depending on the season when they showed the symptoms: patients with early or late symptoms respectively. Skin prick tests (SPT) and specific IgE (EAST) to Olea, Fraxinus and Lolium, patient’s scores of symptoms and rescue medication between February and July 2000, and conjunctival challenge tests with ash and olive pollen extracts were performed. Results: 100% of O patients, 40% of M patients and 16% of G patients suffered from early symptoms, coinciding with the flowering of ash, when grass pollen is not present yet. Conjunctival challenge tests with ash and olive pollen extracts were positive in 70% and 100% respectively in O patients, 50% and 78% in M patients and 31% and 58% in G patients. Conjunctival challenge tests in patients who suffered from early symptoms with olive extract were positive with lower concentrations of the extract. The patients with early symptoms had a higher rate of positive SPT with ash pollen (p < 0,05) and had significant higher levels of specific IgE to F. excelsior pollen (p < 0,05) than late symptomatic patients. Conjunctival challenge test to O. europaea pollen produced more symptoms to patients with early symptoms. Conclusion: Patients living in the Basque Country and suffering from symptoms during early spring had a predominant sensitisation to ash and olive pollen compared to those patients showing only late symptoms. Ash pollen can be considered as a potentially cause of hay fever in these areas where it is present in considerable amounts

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.

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.

Dermatitis de contacto por galatos / Contact dermatitis due to gallates

Los galatos son sustancias antioxidantes que se emplean en la industria de alimentos, cosméticos y medicamentos. Pese a que se comportan como antígenos potentes en experimentación animal, se ha descrito sólo un número limitado de dermatitis de contacto por galatos, lo que se ha atribuido a la tolerancia inmunológica de estas sustancias inducida por vía digestiva, tal como ocurre en modelos de experimentación animal. La clínica más habitual es la queilitis, aunque pueden ser causa de eczema en otras localizaciones, incluso de dermatitis generalizada. Se destaca la variabilidad de concentraciones y vehículos para las pruebas epicutáneas en los casos publicados. En cuanto al tratamiento de las dermatitis de contacto por galatos y dado que en la actualidad apenas tienen importancia en la composición de medicamentos, las medidas de prevención se limitarán al uso de cosméticos y a la manipulación de ciertos alimentos en la industria (AU)