Javier Domínguez-Ortega

Cost-effectiveness of asthma therapy: a comprehensive review.

Abstract Background: Asthma has an important impact in terms of both direct and indirect costs. In Europe, the disease costs € 19 000 million a year. Moreover, the cost is greater among patients with severe uncontrolled asthma and is even higher when the work productivity is also taken into account. Improved control of the disease results in cost savings. In this context, cost-effectiveness and cost-utility studies offer important information for clinicians in deciding the best treatment options for asthmatic patients and contribute to ensure an efficient use of the available healthcare resources. Methods: An English and Spanish literature search using electronic search engines (PubMed and EMBASE) was conducted in peer-review journals, from 2009 to June 2014. In order to perform the search for the most suitable and representative articles, key words were selected (“asthma”, “cost-effectiveness”, “cost-utility”, “QALY”, “cost-benefit”, “economic impact of asthma” “healthcare cost”, “asthma treatment” and “work productivity with asthma”). Results: Two-hundred forty-three titles and abstracts were identified by the primary literature search. The full text of the potentially 76 eligible papers was reviewed, and 22 articles were qualified to be finally included. Conclusions: This article provides a comprehensive review on the evidence of cost-effectiveness of asthma treatments derived from the published literature and offers an overall summary of the socioeconomic burden of asthma and its relationship with the degree of disease control. Management alternatives, such as the use of combination therapy with ICS/LABA or omalizumab, when administered according to their current therapeutic indications, have been shown to be cost-effective.

Futuras terapias biológicas en el asma

Despite the administration of appropriate treatment, a high number of patients with asthma remain uncontrolled. This suggests the need for alternative treatments that are effective, safe and selective for the established asthma phenotypes, especially in patients with uncontrolled severe asthma. The most promising options among the new asthma treatments in development are biological therapies, particularly those monoclonal antibodies directed at selective targets. It should be noted that the different drugs, and especially the new biologics, act on very specific pathogenic pathways. Therefore, determination of the individual profile of predominant pathophysiological alterations of each patient will be increasingly important for prescribing the most appropriate treatment in each case. The treatment of severe allergic asthma with anti-IgE monoclonal antibody (omalizumab) has been shown to be effective in a large number of patients, and new anti-IgE antibodies with improved pharmacodynamic properties are being investigated. Among developing therapies, biologics designed to block certain pro-inflammatory cytokines, such as IL-5 (mepolizumab) and IL-13 (lebrikizumab), have a greater chance of being used in the clinic. Perhaps blocking more than one cytokine pathway (such as IL-4 and IL-13 with dulipumab) might confer increased efficacy of treatment, along with acceptable safety. Stratification of asthma based on the predominant pathogenic mechanisms of each patient (phenoendotypes) is slowly, but probably irreversibly, emerging as a tailored medical approach to asthma, and is becoming a key factor in the development of drugs for this complex respiratory syndrome.

Dupilumab in the management of moderate-to-severe asthma: the data so far

Severe asthma constitutes illness in a relatively small proportion of all patients with asthma, but it is a major public health problem – with considerable effect on morbidity, mortality, as well as a high burden on health care resources. Regardless of effective treatments being widely available and the existence of treatment guidelines, a large population of severe asthma cases remain uncontrolled. Achieving and maintaining asthma control in this group of patients is, therefore, of utmost importance. The recognition of distinct inflammatory phenotypes within this population has driven the development of targeted biological therapies – particularly, selective targeted monoclonal antibodies (mAbs). It is noteworthy that in approximately 50% of these patients, there is strong evidence of the pathogenic role of T helper type-2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, orchestrating the eosinophilic and allergic inflammatory processes. Among the recently developed antiasthma biologic drugs, the mAb dupilumab is very promising given its ability to inhibit the biological effects of both IL-4 and IL-13. In this review, we focused on IL-4 and IL-13, as these interleukins are considered to play a key role in the pathophysiology of asthma, and on dupilumab, an anti-IL-4 receptor human mAb, as a forthcoming treatment for uncontrolled severe asthma in the near future.

Allergic respiratory disease: Different allergens, different symptoms

Spanish population is rather homogeneous in its genetic and sociocultural characteristics, but allergen sensitization shows wide geographical variations. We aimed at assessing whether sensitization to different allergens in the diverse geographical areas induced different clinical and quality‐of‐life characteristics in adult patients with a first‐time diagnosis of rhinitis and/or asthma.

Allergy to several local anesthetics from the amide group

Local anesthetics (LAs) are classified into 2 groups: ester and amide compounds. Adverse reactions are frequent, but most of them are attributed to vasovagal reflexes or hemodynamic changes after the injection of LAs with epinephrine. Allergic reactions to LAs are uncommon. The preponderance of evidence suggests that there is no cross-reactivity between ester and amide LAs. Contact dermatitis (type IV) has been described, particularly induced by the ester group of anesthetics, and rarely to lidocaine in the amide group. Some isolated cases of immediate allergic reactions with mepivacaine or lidocaine have been previously reported. In most of those cases, tolerance to other amide anesthetics was demonstrated as a safe alternative. We present the case of a 41-year-old woman, previously diagnosed with endometriosis, who had a back nevus surgically removed. Three hours after the local administration of mepivacaine, she experienced an episode of pruritic maculopapular eruption and hives involving the upper side of the trunk, neck, and arms. She recovered completely 48 hours after the administration of intramuscular 6-methylprednisolone and dexchlorpheniramine maleate as well as oral antihistamines for 2 days. She denied any history of urticarial episodes or an adverse reaction to the ingestion of any food or medication. She reported no adverse reaction with the use of cosmetics or after the intake of foods or beverages containing sulphites. Skin prick testing results with (1) a standard panel of commercially available (ALK-Abelló, Madrid, Spain) allergen extracts (aeroallergens, foods, profilin, gliadin, latex, Anisakis simplex), (2) undiluted lidocaine (1%) (Normon, Madrid, Spain), mepivacaine (2%) (Scandinibsa, Inibsa, Barcelona, Spain), and bupivacaine (0.75%) (Inibsacain, Inibsa, Barcelona, Spain), (3) phenolated normal saline solution, and (4) histamine 0.1 mg/mL were all negative with the exception of the histamine control. Total serum IgE level was 11.1 kU/L (normal total serum IgE level range, <100 kU/L) (ImmunoCAP System, Thermo Fisher Scientific, Uppsala, Sweden), and total serum tryptase level was 3.9 mg/L (normal tryptase level range, <11.4 mg/L) (ImmunoCAP system). Complement factors (C3 and C4) and IgG, IgM, and IgA levels in serum were within the normal range. A single-blind subcutaneous challenge test with lidocaine was performed. Four hours after the administration of a cumulative dose of 1.5 mL, the patient experienced a similar but milder reaction affecting the same involved body area as occurred in the first reaction. Rather than pursuing further in vivo testing such as intradermal skin tests to evaluate hypersensitivity and given the very low rate of cross-reactivity among the amide group of LAs, we elected to proceed with another subcutaneous challenge test with bupivacaine 2 weeks later. Two hours after the administration of a cumulative dose of 0.5 mL, she again experienced pruritic exanthema on the torso and neck. She was treated with 60 mg of intravenous 6-methyl-prednisolone and 5 mg of dexchlorpheniramine maleate, with complete resolution of the reaction in 2 hours. In an attempt to clarify the underlying mechanism of this hypersensitivity reaction, a basophil activation test with bupivacaine, lidocaine, and mepivacaine (10, 5, and 0.5 mg/mL) was performed. Negative results (<3% activation) were obtained for all the drugs tested. A case report of elevated serum eosinophilic cationic protein (ECP) levels associated with a drug-induced perioperative hypersensitivity has been previously described. On this basis, we performed a novel in vitro test at the Clinical Laboratory of the Department of Immunology. One milliliter of heparinized whole blood was incubated with 5 mg/mL of mepivacaine, lidocaine, and bupivacaine for 16 hours at 37 C, 5% CO2. ECP was quantified with a Phadia 250 assay (Thermo Fisher Scientific) according to the manufacturer’s instructions. The Clinical Laboratory of the Department of Immunology meets ISO 9001:2008, and it is certified by the International Certification Network (IQNet). From baseline ECP levels of 18.4 mg/L, a significant rise in ECP levels was obtained with mepivacaine (38.7 mg/L), lidocaine (58.5 mg/L), and bupivacaine (25.2mg/L), whereas no significant changes were observed when the sample was incubated without drugs (20.4 mg/L). We described a patient who experienced a delayed cutaneous hypersensitivity reaction following the administration of mepivacaine during a surgical procedure and following positive subcutaneous challenge tests with bupivacaine and lidocaine. We have demonstrated a significant increase in ECP levels after the incubation of whole blood with these drugs in vitro. To our knowledge, this is the first reported case in which this procedure has been used to confirm a positive challenge test with these types of drugs. If further utilization of this novel in vitro methodology proves predictive of drug hypersensitivity, it would help avoid subsequent costly and untoward challenge procedures. Furthermore, the elevation in ECP level suggests a possible role of eosinophils in these hypersensitivity reactions, although the underlying mechanism of the reaction is not clear. A classical hypersensitivity mechanism appears unlikely due to the negative skin prick testing and basophil activation test results with the drugs involved. It has been recently suggested that meta-xylene, which is present in some amide and ester LAs as well as parabens, could play a role in certain cases of reactions to LAs. For this

Mechanisms Involved in Hypersensitivity Reactions to Polysulfone Hemodialysis Membranes

Several cases of patients with anaphylactic or systemic hypersensitivity reactions to polysulfone (PS) hemodialysis (HD) membranes and tolerance to cellulose triacetate (CTA) membranes have recently been reported. To investigate the mechanisms involved in PS hypersensitivity, basophil, T cell, and complement activation were analyzed in acute-phase samples from two patients with systemic reactions to PS-based membranes. Basophil and T cell activation, as well as higher serum tryptase levels were detected in acute-phase samples compared with basal levels. Complement levels (C3 and C4) were decreased in acute-phase samples from PS-allergic patients to a higher extent than in samples from control donors taken at the same time points, indicating complement activation during the acute reactions. An experimental external circuit was established on pediatric membranes after rinsing with low or high priming volumes of saline solution, to analyze basophils, T cells, and complement activation in blood samples from 10 PS-allergic and 8 nonallergic HD patients upon contact with PS-based or CTA membranes. Predialysis and postdialysis samples were collected. Basophils from PS-allergic patients exhibited increased degranulation, and T cells showed significantly increased activation after contact with PS-based membranes primed with low volumes of saline. No activation was detected in leukocytes from nonallergic patients under the same experimental conditions. Membrane priming with high volumes of saline abrogated activation of basophils and T cells. However, basophils from allergic donors showed significantly higher responses to Fcεc stimulation after contact with PS membranes. Basophil degranulation and elevated serum tryptase levels in allergic patients during acute reactions support the systemic activation of mast cells and basophils during hypersensitivity reactions to PS-based membranes. A leachable component of the membranes might be responsible for cell activation in some patients.

‘hidden’ occupational allergens such as additives

Purpose of review With the development of innovative technologies, new agents are continually introduced to the workplace. Some of these agents can act as hidden allergens whenever they are not declared in the product labels or whenever their health hazards are unknown. This review article focuses on the identification and description of unusual and/or hidden allergens recently incriminated in occupational diseases. Recent findings Occupational exposure is an important global health issue that can induce respiratory and cutaneous disorders, as well as life-threatening anaphylaxis. Apart from the classic forms of occupational exposure, reports have emerged from nonconventional or newly identified allergens or additives. These compounds are substances added to another in order to alter or improve the general quality or to counteract undesirable properties, and some of them may behave as potent and frequently hidden allergens. These highly uncommon and/or hidden allergens belong to several categories: foods, spices, cosmetics, insects, enzymes, chemicals, drugs, preservatives, and coloring agents, among others. Summary A high level of suspicion and awareness about the potential hidden allergens is necessary to ascertain the allergens implicated. It is of utmost importance to identify the specific eliciting agents of the occupational diseases in order to avoid strictly further exposure to them.

The Use of Probiotics in Respiratory Allergy

There is a high and steadily increasing prevalence of respiratory allergy throughout the world, especially in paediatric population and in industrialized and developing countries. A complex interplay between genetic and environmental factors has been implicated to explain this dramatic increase in prevalence of allergic diseases. It has been suggested that exposure to microbes plays a critical role in the development of the early immune system and may contribute to allergic diseases through their effect on mucosal immunity. Probiotics, microorganisms exerting beneficial effects on the host, are used in a great number of paediatric and adult diseases, mainly gastrointestinal disorders, but they have been proposed to be beneficial also in allergic diseases. Different trials have been published finding benefits in the use of probiotics in prevention and treatment of atopic dermatitis, but to date, studies have yielded inconsistent findings to support a protective association between their use on prevention of allergic rhinitis or asthma. However, probiotics may be beneficial in improving symptoms and quality of life in patients with allergic rhinitis although it remains limited due to study heterogeneity and variable outcome measures. As a result of these controversies, future investigations with a better standardization are needed. In this review, we summarize recent clinical research to elucidate the mechanisms of probiotics and their effect in respiratory allergy. According to published data, probiotics could emerge as a novel, complementary treatment option for allergic rhinitis but not for asthma.

Non-eosinophilic asthma: current perspectives

Although non-eosinophilic asthma (NEA) is not the best known and most prevalent asthma phenotype, its importance cannot be underestimated. NEA is characterized by airway inflammation with the absence of eosinophils, subsequent to activation of non-predominant type 2 immunologic pathways. This phenotype, which possibly includes several not well-defined subphenotypes, is defined by an eosinophil count <2% in sputum. NEA has been associated with environmental and/or host factors, such as smoking cigarettes, pollution, work-related agents, infections, and obesity. These risk factors, alone or in conjunction, can activate specific cellular and molecular pathways leading to non-type 2 inflammation. The most relevant clinical trait of NEA is its poor response to standard asthma treatments, especially to inhaled corticosteroids, leading to a higher severity of disease and to difficult-to-control asthma. Indeed, NEA constitutes about 50% of severe asthma cases. Since most current and forthcoming biologic therapies specifically target type 2 asthma phenotypes, such as uncontrolled severe eosinophilic or allergic asthma, there is a dramatic lack of effective treatments for uncontrolled non-type 2 asthma. Research efforts are now focusing on elucidating the phenotypes underlying the non-type 2 asthma, and several studies are being conducted with new drugs and biologics aiming to develop effective strategies for this type of asthma, and various immunologic pathways are being scrutinized to optimize efficacy and to abolish possible adverse effects.

Estudio de los mecanismos implicados en la génesis y evolución del asma (proyecto MEGA): creación y seguimiento a largo plazo de una cohorte de pacientes asmáticos

The general aim of this study is to create a cohort of asthma patients with varying grades of severity in order to gain greater insight into the mechanisms underlying the genesis and course of this disease. The specific objectives focus on various studies, including imaging, lung function, inflammation, and bronchial hyperresponsiveness, to determine the relevant events that characterize the asthma population, the long-term parameters that can determine changes in the severity of patients, and the treatments that influence disease progression. The study will also seek to identify the causes of exacerbations and how this affects the course of the disease. Patients will be contacted via the outpatient clinics of the 8 participating institutions under the auspices of the Spanish Respiratory Diseases Networking System (CIBER). In the inclusion visit, a standardized clinical history will be obtained, a clinical examination, including blood pressure, body mass index, complete respiratory function tests, and FENO will be performed, and the Asthma Control Test (ACT), Morisky-Green test, Asthma Quality of Life Questionnaire (Mini AQLQ), the Sino-Nasal Outcome Test 22 (SNOT-22), and the Hospital Anxiety and Depression scale (HADS) will be administered. A specific electronic database has been designed for data collection. Exhaled breath condensate, urine and blood samples will also be collected. Non-specific bronchial hyperresponsiveness testing with methacholine will be performed and an induced sputum sample will be collected at the beginning of the study and every 24 months. A skin prick test for airborne allergens and a chest CT will be performed at the beginning of the study and repeated every 5 years.