Cost-effectiveness of benralizumab versus mepolizumab and dupilumab in patients with severe uncontrolled eosinophilic asthma in Spain.

OBJECTIVE: To assess the cost-effectiveness of benralizumab (benra) vs. mepolizumab (mepo) and dupilumab (dupi) for the treatment of patients with severe uncontrolled asthma from the Spanish Health System perspective. METHODS: Exacerbations avoided, quality-adjusted life years (QALYs) gained and costs in a 5-year period were estimated with a Markov model for a cohort of 1,000 patients in which, based on published evidence, 31% of the patients received biologics + oral corticosteroids (OCS) and 69% received only biologics. Efficacy data (exacerbation reduction and OCS elimination) were derived from a matching-adjusted indirect comparison. Published EQ-5D utilities per health state (biologic alone, biologic + OCS, standard of care + OCS, exacerbations, and post-exacerbations) were used for QALY estimation. Utility decrements associated with exacerbation management [-0.1 (OCS or emergency visits), -0.2 (hospitalization)] derived from the literature were applied. Costs (€, 2022) included drug acquisition (ex-factory price), administration and disease management. An expert panel (2 pneumologists and 1 pharmacist) validated all inputs. RESULTS: Benra was more effective (52.21 QALYs) than mepo (51.39 QALYs) and dupi (51.30 QALYs). Benra avoided more exacerbations (2.87 exacerbations) compared to mepo (4.70 exacerbations) and dupi (5.11 exacerbations) for the 5-year horizon. Total costs/patient were €56,093.77 (benra), €59,280.45 (mepo) and €62,991.76 (dupi), resulting in benra dominating (more QALYs with lower costs) vs. mepo and dupi. CONCLUSIONS: Benralizumab can be considered as a dominant treatment alternative vs. other biologic drugs for the treatment of uncontrolled severe eosinophilic asthma patients in Spain.

Response to Monoclonal Antibodies in Asthma: Definitions, Potential Reasons for Failure, and Therapeutic Options for Suboptimal Response.

Real-life data reveal that more than half of severe asthma patients treated with monoclonal antibodies (mAbs) do not achieve a complete response. Response to mAbs must be assessed holistically, considering all the clinically meaningful therapeutic goals, not only reduction of exacerbations and oral corticosteroids. There are 2 different ways of measuring the response to mAbs. One, qualitative, classifies patients according to the degree of disease control they have achieved, without explaining how much a given patient improves relative to the baseline (pre-mAb) clinical situation; the other, quantitative, scores the changes occurring after treatment. Both methods are complementary and essential to making clinical decisions on whether to continue treatment. The various potential causes of suboptimal response to mAbs include incorrect identification of the specific T2 pathways, comorbidities that reduce the room for improvement, insufficient dose, autoimmune phenomena, infections, change in the initial inflammatory endotype, and adverse events. Once a suboptimal response has been confirmed, a well-structured and multifaceted assessment of the potential causes of failure should be performed, with emphasis on the resulting inflammatory process of the airway after mAb therapy and the presence of chronic or recurrent infection. This investigation should guide the decision on the best therapeutic approach. The present review aims to help clinicians gain insights into how to measure response to mAbs and proceed in cases of suboptimal response.

Factors Affecting the Success of Step-up Therapy in Patients With Moderate-Severe Asthma: A Real-Life Study.

INTRODUCTION AND OBJECTIVE: Introduction: Clinical practice guidelines recommend regular adjustment of treatment to achieve control of asthma. A step-up approach based on the degree of disease control should be followed. Objective: To perform a real-life analysis of the factors that affect the success or failure of this therapeutic strategy and of the criteria applied by clinicians when applying a step-up approach in a representative sample of patients diagnosed with moderate-severe asthma. MATERIAL AND METHODS: We performed a multicenter retrospective cohort study involving 226 Spanish specialist physicians (98 allergologists, 127 pulmonologists, and 1 family physician). We included 1254 patients (787 women) diagnosed with moderate-severe asthma who underwent step-up therapy during 2016. RESULTS: Step-up was successful in 44% of cases. The factors associated with success were presence of <2 comorbid conditions, lower grade of severity and therapy step before modification, absence of exacerbations during the previous year, fewer daytime/nighttime symptoms, and limitation in activities, as well as type of inhaled corticosteroid/ long-acting ß2-agonist combination after modification, lower body mass index, and higher fractional exhaled nitric oxide. An early increase in the maintenance dose once a lack of control was detected (≤3 months, >3 to ≤6 months, >6 to ≤12 months) was more likely to be successful. CONCLUSION: The factors that determine whether or not this therapeutic strategy manages to control asthma are time since onset of clinical impairment, previous grade of severity, number of comorbid conditions, previous exacerbations, and frequency of symptoms.

Factors affecting quality of life of asthma patients in Spain: the importance of patient education.

OBJECTIVES: Assessment of demographic and clinical factors that have an impact on the quality of life (QoL) of patients with asthma in Spain. PATIENTS AND METHODS: Multicenter, prospective, observational, cohort study, conducted in 40 Spanish Pneumology Units during a 12-month period. Data on sociodemographic, clinical variables, asthma treatment and QoL were collected in a case report form. RESULTS: 536 patients (64.6% women, mean age: 54) were recruited. Reported QoL was better for patients from Northern and Central Spain as compared with those from the South and the East (p<0.001), students and employed patients as compared with housewives and unemployed (p<0.01), for those who had received asthma information (p<0.01), for those with milder daytime symptoms (p<0.01) and for patients with higher level of education (p<0.05). CONCLUSIONS: Among the factors that have a significant effect on patients' QoL only symptom control and patient education on asthma control are modifiable. Therefore, all the strategies should be tailored to improve such factors when managing asthma patients.

Factors that determine the loss of control when reducing therapy by steps in the treatment of moderate-severe asthma in standard clinical practice: A multicentre Spanish study. / Factores que condicionan la pérdida de control al reducir escalones terapéuticos en el tratamiento del asma moderada-grave en la práctica clínica habitual: estudio español multicéntrico.

BACKGROUND: Although the clinical practice guidelines recommend continuous adjustment of asthma treatment and reducing the maintenance drugs when achieving control (step-down), there are few studies of standard clinical practice aimed at collecting information on the factors that determine step-down failure. OBJECTIVE: To determine the factors that determine step-down failure in standard clinical practice of patients with moderate-severe asthma controlled by a combination of inhaled glucocorticoids and long-acting beta agonists. METHODS: A multicentre retrospective study included 374 patients with moderate-severe asthma controlled with inhaled glucocorticoids and long-acting beta agonists for whom the physician indicated a step-down in 2016. RESULTS: The step-down failed in 41.7% of the patients. The following factors were related to failure: greater patient age (P=.006), presence of at least 2 comorbidities (P=.016), greater severity level (severe persistent vs. moderate persistent) (P<.001), greater age at diagnosis (>40 years) (P=.045), the higher the therapeutic step before (P=.003) and after the change (P<.001), the shorter the time of improvement/control prior to the change (P=.019), lower FEV1 (P=.001) and a poorer Asthma Control Test score or Asthma Control Questionnaire score before the step-down (P<.001). The logistic regression analysis showed a higher probability of step-down failure in the more elderly patients (OR, 0.983; 95% CI 0.969-0.997) and those with severe asthma compared to those with moderate asthma (OR, 0.537; 95% CI 0.292-0.985), as well as an increased probability of success if the patients had the disease controlled for more than 6 months (OR, 2.253; 95% CI 1.235-4.112). CONCLUSION: In standard clinical practice conditions, step-down fails in a high percentage of patients, and the suggestion is to indicate step-down when the patient has had more than 6 months of disease control.

Empiric treatment in hospitalized community-acquired pneumonia. Impact on mortality, length of stay and re-admission.

OBJECTIVE: To evaluate adherence to guidelines when choosing an empirical treatment and its impact upon the prognosis of community-acquired pneumonia (CAP). METHODS: A prospective multicentre study was conducted in 425 CAP patients hospitalized on ward. Initial empirical treatment was classified as adhering or not to Spanish guidelines. Adherent treatment was defined as an initial antimicrobial regimen consisting of beta-lactams plus macrolides, beta-lactam monotherapy and quinolones. Non-adherent treatments included macrolide monotherapy and other regimens. Initial severity was graded according to pneumonia severity index (PSI). The end point variables were mortality, length of stay (LOS) and re-admission at 30 days. RESULTS: Overall 30-day mortality was 8.2%, the mean LOS was 8+/-5 days, and the global re-admission rate was 7.6%. Adherence to guidelines was 76.5%, and in most cases the empirical treatment consisted of beta-lactam and macrolide in combination (57.4%). Logistic regression analysis showed that other regimens were associated with higher mortality OR=3 (1.2-7.3), after adjusting for PSI and admitting hospital. Beta-lactam monotherapy was an independent risk factor for re-admission. LOS was independently associated with admitting hospital and not with antibiotics. CONCLUSIONS: A high adherence to CAP treatment guidelines was found, though with considerable variability in the empirical antibiotic treatment among hospitals. Non-adherent other regimens were associated with greater mortality. Beta-lactam monotherapy was associated with an increased re-admission rate.

[Does experience influence perception of dyspnea?]. / Influye la experiencia en la percepción de disnea?

OBJECTIVE: The perception of somatic sensations like dyspnea can be influenced by such factors as an individual s personality, experiences, or ability to adapt to stimuli. Our aim was to determine whether the perception of acute bronchoconstriction is different for patients with asthma and patients who have never experienced an episode of airway obstruction. PATIENTS AND METHOD: We studied 2 groups of patients. The first consisted of 24 subjects with intermittent rhinitis and asthma (10 females and 14 males) with a mean (SD) age of 25 (7) years. All reported not feeling dyspnea at rest on a Borg scale. The second group consisted of 24 subjects who only had rhinitis but no lung disease (no episode of asthma) or dyspnea at rest (12 females and 12 males) with a mean age of 27 (6) years. There were no significant differences between the groups with regard to sex, smoking, economic or educational level, anxiety (determined by the trait portion of the State-Trait Anxiety Inventory), depression (Beck Depression Inventory), or spirometric parameters. All took a histamine bronchial provocation test in which the patient assessed dyspnea on a modified Borg scale after each histamine dose. The provocation dose needed to produce a 20% decrease (PD20) in forced expiratory volume in the first second (FEV1) was calculated. We also recorded dyspnea perception score when FEV1 fell 5%, 10%, 15%, and 20%. RESULTS: No dyspnea was perceived at PS20 by 12.5% of the asthmatics and by 45% of nonasthmatics (P< .0001). The mean PS20 was 2.4 (2.1) (range, 0-7) in the first group and 0.37 (0.48) (range, 0-3) in the second (P< .0001). More asthma patients than nonasthmatics perceived dyspnea at all degrees of bronchial obstruction. PD20 was different in the 2 groups (1.6 [2] vs 6.03 [5] for the first and second groups, respectively; P< .003), but there was no significant relation between PD20 and PS20 (Spearman s correlation coefficient, 0.19; P= .221). CONCLUSION: Our findings support the hypothesis that appropriate perception of dyspnea is grounded in prior experience and learning.

[Evolution over time in over perceivers of dyspnea in asthma]. / Evolución temporal de la percepción exagerada de disnea en los pacientes con asma.

OBJECTIVE: In previous studies we identified a subgroup of patients whose perception of breathlessness was exaggerated during acute bronchoconstriction and who were termed "over perceivers" or "hyperperceivers". In this study we aimed to determine whether such over perception is sporadic or stable over time. We also examined whether there is an association between over perception of dyspnea and hyperventilation syndrome. PATIENTS AND METHODS: The subjects were 22 stable asthmatics (11 men, 11 women) who had been over perceivers of dyspnea in a study 9 years earlier. After a medical history was taken, a patient performed forced spirometry and a severity classification was made according to the criteria of the Global Initiative for Asthma (GINA). A bronchial histamine challenge was then administered to measure dose-related perception of dyspnea on a Borg scale, according to a procedure that was similar to the one used 9 years earlier by the same investigator. The patients were also asked for a subjective assessment of the severity of their asthma (scale, 0-10) and to respond to items on the Nijmegen hyperventilation questionnaire and the trait form of the State-Trait Anxiety Inventory. RESULTS: The overall perception of severity of disease, level of anxiety, and perception of dyspnea at rest were lower after 9 years (P<.001). No change was observed in bronchial hyperresponsiveness (dose of inhaled histamine required to provoke a 20% decline in forced expiratory volume in the first second [FEV1]-PD20) or objective parameters of severity (FEV1 and GINA classification). Fourteen asthmatics (64%) were still over perceivers and the other patients had changed: 6 were normal perceivers and 2 were "poor perceivers". Only subjective perception of disease severity improved for the patients who were still over perceivers; the other patients, on the other hand, showed improvements in subjective assessments, objective ones (except PD20), and anxiety. Finally, those who remained over perceivers had higher scores for anxiety (24 vs 15; P<.05) and hyperventilation (18 vs 13; P= not significant). CONCLUSIONS: Most over perceivers of dyspnea remain so over the years and this trait is related to anxiety. We have been unable to demonstrate an association with hyperventilation syndrome.

Multidisciplinary expert discussion. Uncontrolled asthma: causes, consequences and possible solutions / Debate multidisciplinar de expertos. Asma no controlada: causas, consecuencias y posibles soluciones.

Background. Numerous studies conclude that about half of the asthmatic population is not well controlled. The aim of this study was to discuss causes, consequences and possible solutions of uncontrolled asthma (UCA). Methods. Discussion amongst asthma experts from the fields of Pneumology, Allergy and Primary Care, structured in three phases: 1) survey to get the opinion of participants involved in different areas of UCA; 2) expert meeting, in which the results of the survey were discussed, and the diagnosis, treatment and monitoring of UCA were presented and discussed; and, 3) with the main findings, 83 items were formulated and subjected to consensus among all participants through the Delphi method. Results. There was consensus on 86.7% of the items in the Delphi questionnaire, mostly in terms of agreement. Conclusions. The UCA analysis results show the need for future improvement in the following areas: to incorporate clinical performance protocols into asthma CPG to identify aggravating factors and comorbidities; to develop an inexpensive and easy-to-use tool to identify adherence; to establish patient phenotype; to analyse treatment side effects and to provide personalized treatment, especially assessing its efficacy and safety (symptom control and future risks). It is necessary to generate new evidence to determine additional tests to be used to monitor these patients.

[Prevalence of hyperventilation syndrome in patients treated for asthma in a pulmonology clinic]. / Prevalencia del síndrome de hiperventilación en pacientes tratados por asma en una consulta de neumología.

OBJECTIVE: Although the presence of hyperventilation syndrome can affect the symptoms of patients with asthma, there is very little information available regarding its frequency in Spain. The aim of this study was to investigate the prevalence of hyperventilation syndrome in the asthmatic population treated as outpatients and establish its relationship with anxiety disorders. PATIENTS AND METHOD: We studied 157 consecutive asthmatic patients (61 men and 96 women; mean [SD] age, 45 [17] years; forced expiratory volume in the first second, 84% [21%] of the predicted value) treated in our outpatients clinic. The patients had stable disease with varying degrees of severity. After collecting demographic data and medical histories, we asked the patients to complete the Spanish versions of the Anxiety Sensitivity Index, the Asthma Symptom Checklist, and the Nijmegen questionnaire; in the latter test, a score of 23 or over was considered diagnostic for hyperventilation syndrome. Finally, patients were evaluated to determine whether they had suffered from panic disorder in the last 6 months (according to the criteria of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders). RESULTS: Hyperventilation syndrome was present in 57 asthmatic patients (36%) and panic disorder in 4 patients (2%). The majority of patients with hyperventilation syndrome were women (78% vs 51%; P=.001) and were older (49 vs 42; P=.01); they displayed more basal dyspnea (1.26 vs 0.89 on the Medical Research Council scale; P=.01), greater sensitivity to anxiety (P=.001), and went to the emergency room more often for exacerbations (P=.002). Patients with hyperventilation syndrome scored significantly higher on all subscales of the Asthma Symptoms Checklist. Finally, the variables introduced in the regression analysis (stepwise) to explain the score on the Nijmegen questionnaire (r(2)=0.57) were basal dyspnea and sensitivity to anxiety. CONCLUSIONS: Approximately one third of the asthmatic patients treated in a pulmonology clinic also present hyperventilation syndrome. This cannot be explained by comorbidity of asthma with panic disorder, and is only partly linked to the symptoms associated with hyperventilation that appear during an asthma attack.

[Agreement in asthmatics' perception of dyspnea during acute and chronic obstruction]. / Concordancia entre la percepción de disnea del asmático durante la obstrucción aguda y crónica.

OBJECTIVE: Three types of asthmatic patients can be identified during periods of clinical stability: "poor perceivers," "normal perceivers," and "over perceivers." When asthmatics undergo bronchial challenge in the laboratory, the same distinctions in type of perception can be observed. The aim of the present study was to determine the level of agreement between the 2 situations. PATIENTS AND METHODS: A total of 93 patients with persistent moderate asthma (36 men and 57 women; mean age 40 years) were studied. We asked them to assess their dyspnea on a modified Borg scale when stable and after each histamine dose in a bronchial provocation test. When a patient's Borg scale assessment in stable situation was below the 25th percentile, that patient was classified as a poor perceiver. Patients were considered over perceivers if their score in stable situation was in the 75th percentile. Others were labeled normal perceivers. Type of perception during acute bronchoconstriction was defined in function of the change in Borg assessment once forced expiratory volume in the first second had decreased 20%: poor perceivers were those whose change in Borg assessment was in the 25th percentile, over perceivers were in the 75th percentile, and normal perceivers in the middle percentiles. RESULTS: In stable situation, 23 patients were poor perceivers, 58 were normal perceivers, and 12 were over perceivers. During bronchoconstriction, there were 23 poor perceivers, 47 normal perceivers, and 23 over perceivers. Agreement was estimated by a kappa index of 0.0574 for poor perception, 0.1521 for over perception, and 0.3980 for normal perception. CONCLUSIONS: Asthmatics' perception of dyspnea during periods of stability and during acute bronchoconstriction are independent phenomena. It is therefore not possible to infer how a patient will perceive an asthmatic attack by evaluating only how he or she perceives breathlessness during stable periods.

[Asthma patients' perception of dyspnea during acute bronchoconstriction]. / Percepción de la disnea durante la broncoconstricción aguda en los pacientes con asma.

The aim of this study was to analyze variations in the perception of acute bronchial obstruction among asthmatics in our practice and to try to define the variables that influence inter-individual differences. We studied 153 asthmatics in stable condition, using a Borg scale to measure dyspnea perceived during a histamine bronchial challenge test. To study individual perception we analyzed both absolute magnitude of perception of dyspnea on the Borg scale when forced expiratory volume in 1 second (FEV1) fell 20% (perception score 20-PS20) and the mathematical difference between PS20 and baseline dyspnea (change in Borg, CB). The results were as follows. 1) The factors that affected PS20 according to multiple linear regression were anxiety, baseline dyspnea and the provocative concentration required to produce a 20% fall in FEV1 (PC20). 2) Within each level of asthma severity, there were differences in dyspnea perception when FEV1 fell 20% (analysis of variance of repeated measures), such that patients with mild asthma and no bronchial obstruction perceived more change in dyspnea. 3) CB during the bronchial challenge test distinguished four ways of perceiving dyspnea: 15% were dysperceivers, 13% were hypoperceivers, 48% were normoperceivers and 24% were hyperperceivers. 4) Hypoperceivers and dysperceivers were at greater risk of severe exacerbation whereas hyperperceivers requested unnecessary medical consultations. 5) Subjects with poorer quality of life were usually dysperceivers; hyperperceivers were the second most common type among those with poorer quality of life. In conclusion, a large percentage of asthmatics do not appropriately perceive acute bronchial obstruction, and the simplest way to evaluate their perception is to calculate the change in dyspnea (on a Borg scale) during the bronchial challenge test. The manner of perceiving dyspnea can not be predicted beforehand, yet it has a significant impact on the use of medical resources and patient quality of life, among other aspects.