Aqueous intradermal low-dose house dust mite immunotherapy in tropical settings: a valid cost-effective approach for developing nations?

INTRODUCTION: Aqueous allergen injections, an effective and century-old technique, is considered a second-line approach in daily clinical practice. Inconveniences still surround conventional subcutaneous immunotherapy (SCIT) administration, such as a need for frequent injections, prolonged up-dosing schedules, elevated costs, and the unlikely possibility of a systemic reaction. The intradermal immunotherapy route (IDR) might favorably impact many of the aforementioned issues (Table 1). House dust mite (HDM) allergens are the main perennial sensitizers in the tropics, and as such, are solely employed in immunotherapy treatments. METHODS: We carried out a year-long real-life study in 25 perennial allergic rhinitis children, symptomatic on exposure to house dust, employing an intradermal low-dose allergen mix consisting of 50 ng of Dermatophagoides pteronyssinus/Dermatophagoides farinae and 120 ng of Blomia tropicalis, under a unique cost-wise protocol. Basal symptoms/signs and face Visual Analog Scale (fVAS) scores were recorded for 2 weeks and later compared with those registered throughout the 1-year treatment. Serum-specific IgG4 and IL-10 levels were employed in the assessment of the immune responses. RESULTS: Symptoms/signs and fVAS scores were significantly reduced from days 42 and 49, respectively, and remained so until treatment completion. Increases in specific IgG4's and IL-10 levels reflected significant immune responses. Injections were well tolerated and families reported improved health status (quality of life, QoL). CONCLUSIONS: A unique cost-effective immunotherapy alternative for deprived allergic communities in tropical settings is depicted; further research is needed.

New and Potential Treatments for Atopic Dermatitis: Biologicals and Small Molecules.

PURPOSE OF REVIEW: An update on new therapies currently approved or potentially useful in the future for the management of patients suffering moderate-to-severe atopic dermatitis. RECENT FINDINGS: New pathogenic mechanisms involved in atopic dermatitis have permitted to propose novel therapeutic approaches devised to control the inflammatory process observed in involved cutaneous tissues by neutralizing mediators, cytokines, and their receptors. Recent research findings have disclosed important and previously unrecognized pathogenic mechanisms that have resulted in innovative targeted therapies, such as dupilumab, and potentially other biologicals and small molecules. Further studies should permit the sub-classification of patients according to the relevance of different mediators and inflammatory cells. It can be concluded that the treatment of atopic dermatitis has entered into the era of personalized/precision medicine.

Review of Physical Urticarias and Testing Methods.

PURPOSE OF REVIEW: This review aims to update the information available on the prevalence, clinical picture, diagnostic methods, and treatment of urticarias induced by external physical stimuli. RECENT FINDINGS: Physical urticarias are present in up to 5% of the general population, and in 10 to 50% of patients with chronic urticaria. Recent investigations have provided evidence that the presence of physical urticaria alone or when comorbid with chronic spontaneous urticaria is associated with a worse prognosis and duration. Most frequent subtypes of physical urticaria are dermographism and delayed pressure urticaria. The diagnosis is established through specific provocation tests and the management encompasses avoidance measures, pharmacologic therapy with nonsedating antihistamines, and alternative medications in refractory cases.

Anaphylaxis from ingestion of mites: pancake anaphylaxis.

Oral mite anaphylaxis is a new syndrome characterized by severe allergic symptoms occurring immediately after eating foods made with mite-contaminated wheat flour. This syndrome, which is more prevalent in tropical environments, is triggered more often by pancakes, and for that reason, it has been designated "the pancake syndrome." Because cooked foods are able to induce the symptoms, it has been suggested that thermoresistant allergens are involved in its pathogenesis. A variety of this syndrome can occur during physical exercise (dust mite ingestion-associated exercise-induced anaphylaxis).

Oral mite anaphylaxis: who, when, and how?

PURPOSE OF REVIEW: To present an update on the recent advances in the understanding of the mechanisms and practical management of oral mite anaphylaxis (OMA, pancake syndrome). RECENT FINDINGS: Among novel observations regarding OMA, this review highlights the increased prevalence of aspirin/NSAID hypersensitivity inpatients affected by OMA, the association of OMA with exercise-induced anaphylaxis, the presentation of OMA simulating acute asthma, the occurrence of OMA in childhood, the high severity and lethal potential of OMA, the contamination of other foods, such as oat and corn flour with mites, and the simultaneous induction of OMA symptoms in more than one individual exposed to the same food source. SUMMARY: OMA is a severe, potentially lethal, acute allergic condition that should be suspected whenever symptoms begin soon after the intake of mite-contaminated foods. Physician awareness on this clinical picture is of paramount importance to establish a correct diagnosis and to implement adequate preventive measures to help patients at risk to avoid its occurrence.

Diagnosis of allergic sensitization in patients with allergic rhinitis and asthma in a tropical environment.

BACKGROUND: Few studies in tropical developing countries have utilized molecular diagnosis to characterize allergen-specific responses to aeroallergens. OBJECTIVE: To investigate the in vivo and in vitro responses of IgE antibodies to inhalant allergens in allergic patients with rhinitis and/or asthma. METHODS: A prospective study in which patients with allergic rhinitis and/or asthma were included. Skin prick tests with 16 inhalant extracts of allergens were carried out and total and specific IgE levels for allergens and their molecular components in the serum were determined. RESULTS: In a total of 189 patients, 73.5% showed high levels of total IgE in the serum. The prick tests were positive for the following allergens: Dust mite extracts; more than 60 %, cat; 29.6 %, dog; 23.4 %, and Periplaneta Americana; 21.6 %. Specific IgE for Dermatophagoides farinae and Pteronyssinus was present in 66.6 % of the patients; for Blomia tropicalis; in 45.0 %, for Ascaris lumbricoides; in 24.7 %, for cat; in 17.3 %, for parrot feathers; in 14.8 %, and for Penicillium notatum; in 12.3 %. IgE antibodies to mite allergens of group 1 and 2 were present in 59.0 % and 70.1 % of the sera; 39.1 % contained IgE to rBlo t5, 30.4 %contained rBla g4, 19.9 % contained rFel d1, 11.8 % contained rArt v3, 11.2 % contained Der p10, 9.9 % contained rBla g2, 9.3 % contained rPer a7, 9.3 % contained nFel d2, and 8.7 % contained rCan f1. CONCLUSIONS: This study confirms that mites are the main sensitizing agents in patients with respiratory allergic diseases in a tropical environment. There was a good correlation between the results of the skin tests and the results of the in vitro tests.

Antecedentes: Pocos estudios en países tropicales y en desarrollo han utilizado el diagnóstico molecular para caracterizar las respuestas específicas a los aeroalérgenos. Objetivo: Investigar las respuestas de anticuerpos IgE in vivo e in vitro a alérgenos inhalantes en pacientes alérgicos con rinitis o asma. Métodos: Estudio prospectivo que incluyó pacientes con rinitis alérgica o asma. Se realizaron pruebas cutáneas por punción con 16 extractos de alérgenos inhalantes y se determinaron los niveles de IgE total y específica para alérgenos y sus componentes moleculares en el suero. Resultados: De 189 pacientes, en 73.5 % se observó niveles elevados de IgE total en el suero. Las pruebas de punción fueron positivas a los siguiente alérgenos: extractos de ácaros más de 60 %, gato 29.6 %, perro 23.4 % y Periplaneta americana 21.6 %. La IgE específica para Dermatophagoides farinae y pteronyssinus estuvo presente en 66.6 %, para Blomia tropicalis, Ascaris lumbricoides, gato, plumas de perico, Penicillium notatum en 45.0, 24.7, 17.3, 14.8 y 12.3 %, respectivamente. Anticuerpos de clase IgE a alérgenos de ácaros de los grupos 1 y 2 estuvieron presentes en 59.0 y 70.1 % de los sueros; 39.1, 30.4, 19.9, 11.8, 11.2, 9.9, 9.3, 9.3 y 8.7 % contenían IgE a rBlot5, rBla g4, rFel d1, rArt v3, Derp 10, rBla g2, rPer a7, nFel d2 y rCan f1, respectivamente. Conclusiones: Se confirma a los ácaros como los principales agentes sensibilizantes en pacientes con enfermedades alérgicas respiratorias en el trópico. Existió buena correlación entre los resultados de las pruebas cutáneas y las pruebas in vitro.

[Intradermal immunotherapy with low-dose house dust mite allergens in patients with allergic rhinitis: A proof-of-concept study]. / Inmunoterapia intradérmica con alérgenos de ácaros a bajas dosis en pacientes con rinitis alérgica: un estudio conceptual.

BACKGROUND: High-dose aqueous subcutaneous immunotherapy is a validated and effective administration route for house dust mite and pollen allergens. OBJECTIVE: A proof-of-concept study using intradermal immunotherapy (IDIT) with low-dose house dust mite allergens (Dermatophagoides pteronyssinnus/Dermatophagoides farinae [Dp/Df] and Blomia tropicalis [Bt]) was carried out in children with allergic rhinitis symptomatic upon exposure to house dust. METHODS: Eight immunotherapy-naïve patients with positive prick skin tests and specific serum IgE to a Dp/Df mixture and to Bt were weekly administered 0.05 mL of an IDIT consisting of a phenolyzed albumin-saline preparation containing low-dose dust mites (8.3 AU [5 ng] of Dp/Df and 2.5 DBU of Bt), for 3 months. Nasal (Total Nasal Symptom Score) and facial symptoms (Visual Analog Scale) were recorded 2 weeks prior to treatment and once weekly during its course. Serial dilutions skin prick tests (1/100-1/1.000.000) and serum allergen-specific IgG4 determinations were performed at baseline and at treatment conclusion. RESULTS: Values on the scales suggested clinical improvement. There was a significant decrease in serial dilutions skin prick tests' wheal diameters, as well as an increase in serum IgG4 values at treatment completion. IDIT was well tolerated. CONCLUSION: If the present results are confirmed by further studies, allergen-specific immunotherapy wider use could be promoted.

Antecedentes: La inmunoterapia subcutánea acuosa a altas dosis es una ruta validada y efectiva de administración de alérgenos para el ácaro del polvo doméstico y alergias al polen. Objetivos: Estudio de definición conceptual empleando inmunoterapia intradérmica (ITID) con alérgenos de ácaros (Dermatophagoides pteronyssinus/Dermatophagoides farinae [Dp/Df] y Blomia tropicalis [Bt]) a bajas dosis; se llevó a cabo en niños con rinitis alérgica sintomáticos a la exposición de polvo de casa. Métodos: A ocho pacientes sin uso previo de inmunoterapia, con pruebas de punción cutánea positivas e IgE sérica específica a una mezcla de Dp/Df y Bt, se les administraron por tres meses 0.05 mL de ITID semanalmente, provenientes de una preparación fenolizada albúmino-salina y contentiva de bajas dosis de ácaros (8.3 AU= 5 ng de Dp/Df y 2.5 DBU de Bt). Los síntomas nasales (Total Nasal Symptom Score) y los faciales (Escala Análoga Visual) fueron registrados dos semanas antes del tratamiento y en el transcurso una vez a la semana. Al comienzo y al final se realizaron pruebas cutáneas diluidas y seriadas (1/100-1/1.000.000) y determinaciones de IgG4 en el suero para los alérgenos. Resultados: Los valores de las escalas sugirieron mejoría clínica. Existió disminución significativa de los diámetros de las pápulas de las pruebas diluidas y seriadas, así como aumento de los valores de la IgG4 sérica al final del tratamiento. La ITID fue bien tolerada. Conclusión: Si estudios ulteriores confirman los presentes hallazgos, se podría promover una mayor utilización de la inmunoterapia alérgeno-específica.

International consensus (ICON) on: clinical consequences of mite hypersensitivity, a global problem.

Since mite allergens are the most relevant inducers of allergic diseases worldwide, resulting in significant morbidity and increased burden on health services, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), the European Academy of Allergy and Clinical Immunology (EAACI), and the World Allergy Organization (WAO), has proposed to issue an International Consensus (ICON) on the clinical consequences of mite hypersensitivity. The objectives of this document are to highlight aspects of mite biology that are clinically relevant, to update the current knowledge on mite allergens, routes of sensitization, the genetics of IgE responses to mites, the epidemiologic aspects of mite hypersensitivity, the clinical pictures induced by mites, the diagnosis, specific immunotherapeutic approaches, and prevention.

Cutaneous reactions to aspirin and nonsteroidal antiinflammatory drugs.

Soon after the introduction of aspirin for the treatment of pain, fever, and inflammation more than a century ago, clinicians were challenged by the frequent observation of ASAtriggered allergic and pseudoallergic reactions occurring in the skin. This problem was further enhanced by the development of a number of other analgesic and antiinflammatory drugs that, having different chemical structures, cross-reacted with acetilsalycilic acid in many patients. This paper reviews the information presently available for the management of individuals who develop urticaria and angioedema when exposed to drugs that inhibit cyclooxygenase isoenzymes. The immune and nonimmunologic mechanisms leading to the pathogenesis of such reactions, their prevalence in selected groups of the population, clinical picture, and useful diagnostic approaches are described, and current guidelines used in our institutions for the clinical orientation of the patients, taking advantage of the recent introduction of various new and more selective NSAIDS that inhibit preferentially the COX-2 enzyme, are proposed.

NSAID-induced urticaria and angioedema: a reappraisal of its clinical management.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in urticaria and angioedema, is being observed with increasing frequency. Prevalence rates range from 0.1-0.3%, which is partly due to the large size of the exposed (at risk) population. Some predisposing factors for these cutaneous reactions have been identified, among them atopic diathesis, female sex, young adulthood, a history of chronic urticaria and the use of the NSAID for the relief of acute pain. The description of two different arachidonic acid cyclo-oxygenases (COX) about a decade ago, designated COX-1 and COX-2, and the incorporation into the therapeutic armamentarium of more selective enzyme inhibitors for the control of inflammation and pain, has led to an improved understanding of the pathogenesis of adverse reactions to NSAIDs. This has allowed investigators to study 'sensitive' individuals to see if they can safely receive these new pharmaceutical compounds. The reasons why some people react to NSAIDs are not completely clarified. The prevalent theory about the pathogenesis of urticaria and angioedema due to NSAIDs in cross-reactive patients assumes that the inhibition of COX-1 leads to a shunting of arachidonic acid metabolism towards the 5-lipoxygenase pathway, which results in an increased synthesis and release of cysteinyl leukotrienes. Although COX-2 inhibitors are well tolerated by the majority of classic NSAID-sensitive patients, cutaneous reactions to highly selective inhibitors of COX-2 have been described in some of these individuals, casting some doubts about the relevance of such hypotheses. On the other hand, in patients who react to a single NSAID and chemically similar products (single-reactors), specific immunoglobulin E antibodies to haptenated NSAID metabolites have been suspected, although these metabolites are not easily demonstrated by means of routine in vivo or in vitro techniques. Facial (periorbital) angioedema constitutes the most common form of clinical presentation, and one-third of the patients show a mixed clinical pattern of cutaneous (urticaria and/or angioedema) and respiratory symptoms which include upper respiratory tract edema, rhinorrhea, cough, breathlessness and tearing. When necessary, diagnosis is confirmed by means of controlled peroral drug challenges done by experienced physicians in the hospital setting and test results are helpful for clinical management, which will be based on strict avoidance, and the use of alternative tolerated medications. This approach is specially indicated in hypersensitive patients with chronic medical conditions who require continuous NSAID therapy, such as those with arthritis and coronary heart disease.

Montelukast for the high impact of asthma exacerbations in Venezuela: a practical and valid approach for Latin America?

BACKGROUND: Asthma affects mainly Venezuela's urban and poor majority. Exacerbations bring about a high demand in health services, thus becoming a significant public health problem. In general, asthma control programs (GINA) with use of inhaled steroid medications have proven effective, although their implementation in real life remains cumbersome. Montelukast could be a useful and practical tool for these deprived socioeconomic sectors. METHODS: This real-life pilot study was conducted in a prospective, double blinded, placebo-controlled manner with randomized and parallel groups. Asthmatics that had never used leukotriene modifiers were recruited and followed-up every three months. The main outcome was the number of exacerbations meriting use of nebulized bronchodilators administered by the health care system. RESULTS: Eighty-eight asthmatic patients were enrolled, between children and adults. Groups were comparable in: demographic data, previous use of other medications, ACT scores, pulmonary functions (Wright Peak Flow meter), allergy status (Skin Prick Test) as well as adherence to the prescribed Montelukast treatment. By an intention to treat (ITT), a total of 64 patients were included for analysis. For the three and six months time points the difference between placebo and Montelukast was found to be significant (p < 0.03 and p < 0.04, respectively). Such trends continued for the rest of the year, but without statistical significance, due to patient attrition. CONCLUSIONS: This real-life pilot study shows that a simplified strategy with oral Montelukast was practical and effective in controlling exacerbations in an asthmatic population of a vulnerable community from Caracas. Such an approach reinforces the role of primary care in asthma treatment.

[Common mistakes in the treatment of patients with anaphylaxis]. / Errores comunes en el tratamiento de pacientes con anafilaxia.

Anaphyaxis is a situation threatening life and may occur at any age. Unfortunately, despite of the existence of up-dated guidelines for its treatment, many patients are wrongly diagnosed and treated and, sometimes, deaths are reported. This paper summarized the most common difficulties and mistakes that we have seen repeatedly in patients consulting to our services due to have suffered episodes of anaphylaxis in order to give orientation about implementation of plans of treatment of these reactions. The recommendations included in this document are derived from mentioned guidelines.

La anafilaxia es una situación que pone en peligro la vida y puede ocurrir a cualquier edad. Desafortunadamente, a pesar de que existen lineamientos actualizados para su tratamiento, muchos pacientes son diagnosticados y tratados erróneamente y en ocasiones se reportan muertes. En este artículo se resumen las dificultades y errores más comunes que hemos observado repetidamente en pacientes que consultan a nuestros servicios por haber padecido episodios de anafilaxia con el objeto de proporcionar orientación acerca de la implementación de los planes para el tratamiento de estas reacciones. Las recomendaciones incluidas en este documento se derivan de los lineamientos mencionados.

[Urticaria in children attending allergy services]. / Urticaria en niños atendidos en servicios de alergología.

BACKGROUND: There is little information on urticaria occurring in children, especially in limited resource countries. OBJECTIVE: To determine the demographic and clinical features of urticaria in children living in a developing country. PATIENTS AND METHOD: A prospective study was done in children from two allergy outpatient clinics were prospectively studied. Clinical data was obtained from the medical history and physical examination. Laboratory evaluations and immediate-type skin tests with food and aeroallergen extracts were done in selected cases. Urticaria subtypes were defined according to current EAACI/GA²LEN/WAO guidelines. RESULTS: One hundred and twenty-three subjects were studied, 71 with acute urticaria and 52 with chronic urticaria. In patients with chronic urticaria, but not in those with acute urticaria, there was a significant predominance of girls. Triggers of urticaria were more common in acute than in chronic urticaria. Insects, foods, and drugs were the most common inducers of symptoms in acute urticaria, while urticaria induced by skin pressure was referred more often in chronic urticaria. In patients with acute or chronic urticaria there was a higher involvement of the head, upper and lower limbs. In patients with chronic urticaria, generalized urticaria, angioedema, and wheals on pressure sites were more frequent than in patients with acute urticaria. Spontaneous, papular, drug-induced, and dermographic urticaria were the most common subtypes in both groups of children. CONCLUSIONS: In children attending allergy services, acute urticaria was more frequent than the chronic type. Symptom triggers were different in acute than in chronic urticaria. Most common subtypes were spontaneous, papular, drug-induced, and dermographic urticaria.

ANTECEDENTES: existe poca información de la urticaria infantil, especialmente en los países en vías de desarrollo. OBJETIVOS: determinar las características demográficas y clínicas de la urticaria que afecta a niños que viven en un país en vías de desarrollo. PACIENTES Y MÉTODO: estudio prospectivo con niños no seleccionados de consultas ambulatorias. La información clínica se obtuvo mediante interrogatorio y examen físico. Se realizaron evaluaciones de laboratorio y pruebas cutáneas de tipo inmediato con alimentos y aeroalergenos en casos seleccionados. Los subtipos de urticaria se definieron de acuerdo con los lineamientos de EAACI/GA(2)LEN/WAO. RESULTADOS: se incluyeron 123 sujetos, 71 con urticaria aguda y 52 con urticaria crónica; en estos últimos predominó el sexo femenino. Los desencadenantes de urticaria se observaron con mayor frecuencia en la urticaria aguda que en la crónica. Insectos, alimentos y medicamentos fueron los más comunes en el tipo agudo. La urticaria inducida por presión ocurrió más en el tipo crónico. En ambos grupos hubo mayor afectación de la cabeza y las extremidades. Los pacientes con urticaria crónica sufrieron más urticaria generalizada, angioedema y habones en los sitios de presión. Los subtipos más comunes en ambos grupos fueron la urticaria espontánea, la papular, la inducida por medicamentos y la dermográfica. CONCLUSIÓN: en niños atendidos en los servicios de alergología, la urticaria aguda es más frecuente que la crónica. Los desencadenantes de los síntomas son diferentes en cada tipo de urticaria. Los subtipos más comunes son: urticaria espontánea, papular, inducida por medicamentos y dermográfica.

Aspirin-exacerbated cutaneous disease.

It has been recognized that a high proportion of chronic urticaria patients experience symptom aggravation when exposed to aspirin and NSAIDs. This clinical picture is known as Aspirin-exacerbated cutaneous disease. The pathogenesis of these exacerbations is related to the inhibition of cyclooxygenase-1 leading to a decreased synthesis of PGE2 and an increased cysteinyl leukotriene production in the skin and subcutaneous tissues. Patient management comprises the treatment of the underlying cutaneous disease with nonsedating antihistamines and other medications, avoidance of COX-1 inhibitors, and the use of alternative NSAIDs that do not inhibit COX-1 for the relief of pain, inflammation and fever.

Mite-induced inflammation: More than allergy.

Clinical observations have suggested that there is an association of atopic conditions with hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). This relationship has been especially present in patients allergic to mites. This study was designed to review clinical and experimental evidence linking atopy, mite allergy, and hypersensitivity to aspirin and NSAIDs and discuss the possible mechanisms explaining this association. A review of the medical literature concerning the association of atopic diseases, mite hypersensitivity, and intolerance to NSAIDs using PubMed and other relevant articles is presented. NSAID-sensitive patients are frequently atopic and allergic to mites, and patients who develop oral mite anaphylaxis (OMA) show an increased prevalence of NSAID hypersensitivity. The study of atopic, mite-sensitive patients, who experience urticaria and angioedema when exposed to NSAIDs and patients with OMA suggests an interesting interaction between atopic allergy and disorders of leukotriene synthesis or metabolism. Various mechanisms that could be involved in this interaction are presented, including genetic factors, inhibition of cyclooxygenase-1, and other effects (not related to IgE sensitization) of mite constituents on the immune system. The association of mite hypersensitivity with aspirin/NSAIDs intolerance has been confirmed and provides additional clues to various nonallergic pathways that may contribute to the acute and chronic inflammatory process observed in atopic, mite-allergic, individuals. The clinical relevance of these observations is presently under investigation.

Asthma care in resource-poor settings.

Asthma prevalence in low- to middle-income countries is at least the same or higher than in rich countries, but with increased severity. Lack of control in these settings is due to various factors such as low accessibility to effective medications, multiple and uncoordinated weak infrastructures of medical services for the management of chronic diseases such as asthma, poor compliance with prescribed therapy, lack of asthma education, and social and cultural factors. There is an urgent requirement for the implementation of better ways to treat asthma in underserved populations, enhancing the access to preventive medications and educational approaches with modern technological methods.

Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs: An Update.

After beta lactam antibiotics, hypersensitivity reactions to nonsteroidal antiinflammatory drugs are the second cause of hypersensitivity to drugs. Acute manifestations affect the respiratory tract (aspirin exacerbated respiratory disease), the skin (urticaria and angioedema), or are generalized (anaphylaxis). Correct diagnosis and treatment in order to prevent unnecessary morbidity and the potential risk of death from these severe reactions, and to provide proper medical advice on future drug use frequently requires the participation of allergology specialists familiar with these clinical conditions.