Spanish Consensus on Remission in Asthma (REMAS).

The concept of "remission" in asthma has been around for a long time and it has been a controversial topic. Despite the attempts of some studies to characterize this entity, the discussion continues. In the case of asthma there is still no clear definition, either in terms of its meaning or the parameters that should be included or whether it should be divided into clinical or complete remission. To help defining these controversial concepts, SEPAR has advocated the multidisciplinary working group REMAS (REMission in ASthma). Following the Delphi methodology and with the involvement of more than 120 specialists in asthma management, this group has arrived at a consensus on the definitions of remission in asthma and establishing the criteria and characteristics that will be of use in future studies evaluating the efficacy or effectiveness of treatments.

Patient-reported outcome measures in severe asthma: an expert consensus.

OBJECTIVE: The study aimed to reach a consensus on the most relevant patient-reported outcomes (PROs), the corresponding measures (PROMs), and measurement frequency during severe asthma patient follow-up. METHODS: Two Delphi rounds were conducted. The questionnaire was developed based on a systematic literature review, a focus group with patients, and a nominal group with experts. It assessed PROs' relevance and the appropriateness (A) and feasibility (F) of PROMs using a Likert scale (1=totally agree; 9=totally disagree). The consensus was established when ≥75% of participants agreed (1-3) or disagreed (7-9). RESULTS: Sixty-three professionals (25 hospital pharmacists, 14 allergists, 13 pulmonologists, and 11 nurses) and 5 patients answered the Delphi questionnaire. A consensus was reached on all PROs regarding their relevance. Experts agreed on the use of ACT (A:95.24%; F:95.24%), mini AQLQ (A:93.65; F:79.37%), mMRC dyspnea scale (A:85.71%; F:85.71%), TAI (A:92.06%; F:85.71%), MMAS (A:75.40%; F:82%), and the dispensing register (A:96.83%; F:92.06%). Also considered suitable were: SNOT-22 (A:90.48%; F:73.80%), PSQI (A:82.54; F:63.90%), HADS (A:82.54; F:64%), WPAI (A:77.78%; F:49.20%), TSQM-9 (A:79.37; F:70.50%) and knowledge of asthma questionnaire (A:77%; F:68.80%); however, their use in clinical practice was considered unfeasible. Panelists also agreed on the appropriateness of EQ-5D, which was finally included despite being considered unfeasible (A: 84.13%; F:67.20%) in clinical practice. Agreement was reached on using ACT, TAI, mMRC, and a dispensing register every three months; mini-AQLQ and MMAS every six months; and EQ-5D every twelve months. CONCLUSION: This consensus paves the way toward patient-centered care, promoting the development of strategies supporting routine assessment of PROs in severe asthma management.

Treatment Patterns of Monoclonal Antibodies in Patients With Severe Uncontrolled Asthma Treated by Pulmonologists in Spain.

Introduction and objectives: The use of monoclonal antibody (mAb)-based therapies is becoming the new standard of care for severe uncontrolled asthma (SUA). Even though patients may qualify for one or more of these targeted treatments, based on different clinical criteria, a global vision of mAb prescription management in a large sample of hospitals is not well characterised in Spain.The objective was to give a global vision of mAb prescription management in a large sample of hospitals in Spain. Materials and methods: We used an aggregate data survey method to interview pulmonology specialists in a large sample of Spanish centres (90). The following treatment-related information was obtained on patients treated with mAbs: specific mAbs prescribed, treatment interruption, switch and restart and the reasons for these treatment changes. Results: mAb prescription was more frequent in females (13.3% females vs 7.4% males; p < 0.001). There were no differences in prevalence by hospital complexity level. In contrast, there were differences by geographical area. Omalizumab was the most prescribed mAb (6.2%), followed by mepolizumab (2.9%). Discontinuation of Omalizumab (due to a lack of effectivity) and switches from this mAb to mepolizumab were more frequent. Very few restarts to the first treatment were observed after a switch from ≥2 mAbs. Conclusions: Omalizumab appeared as the most prescribed mAb in SUA but was also the most withdrawn; a specific and objective characterisation of patients with SUA, along with asthma phenotyping, and together with further evaluation of safety and effectiveness profiles, will lead to future progress in the management of SUA with mAbs.

Introducción y objetivos: El uso de terapias basadas en anticuerpos monoclonales (mAb) se está convirtiendo en el nuevo estándar de atención para el asma grave no controlada (AGNC). A pesar de que los pacientes pueden optar a uno o varios de estos tratamientos dirigidos, con base en diferentes criterios clínicos, en España no se ha caracterizado bien una visión global de la gestión de la prescripción de mAb en una gran muestra de hospitales.El objetivo fue dar una visión global de la gestión de la prescripción de mAB en una amplia muestra de hospitales en España. Materiales y métodos: Se utilizó un método basado en una encuesta de datos agregados para entrevistar a especialistas en Neumología en una amplia muestra de centros españoles (90). Se obtuvo la siguiente información relacionada con el tratamiento de los casos tratados con mAbs: mAbs específicos prescritos, interrupción del tratamiento, cambio y reinicio, y las razones de estos cambios de tratamiento en consultas de Neumología. Resultados: La prescripción de mAB fue más frecuente en mujeres (13,3% mujeres vs. 7,4% hombres; p < 0,001). No hubo diferencias de prevalencia por nivel hospitalario. En cambio, hubo diferencias por área geográfica. Omalizumab fue el mAb más prescrito (6,2%), seguido de mepolizumab (2,9%). La interrupción y los cambios (debido a la falta de efectividad) también fueron más frecuentes para omalizumab. Conclusiones: Omalizumab fue el mAb más prescrito en el manejo de AGNC, pero también fue el mAB que presentó más retiradas; una caracterización específica y objetiva de los pacientes con AGNC, mediante fenotipificación de asma, junto con una evaluación adicional de los perfiles de seguridad y efectividad, conducirá a nuevos avances en el manejo del AGNC con mABs.

Achieving clinical outcomes with benralizumab in severe eosinophilic asthma patients in a real-world setting: orbe II study.

BACKGROUND: The ORBE II study aimed to describe the characteristics and clinical outcomes of adult patients with severe eosinophilic asthma (SEA) treated with benralizumab in a real-world setting in Spain. METHODS: ORBE II (NCT04648839) was an observational, retrospective cohort study in adult SEA patients who had been prescribed benralizumab. Demographic and clinical data of 204 SEA patients were collected 12 months prior to benralizumab initiation (baseline) and at follow-up. Exacerbation rate, asthma symptoms, maintenance oral corticosteroid (OCS) use and lung function were evaluated, among other variables. RESULTS: A total of 204 SEA patients were evaluated. Mean (standard deviation, SD) age of the study population was 56.4 (12.4) years, 62.3% were women and mean (SD) duration of asthma was 15.1 (12.7) years. Median (Q1-Q3) follow-up duration was 19.5 (14.2-24.2) months. At baseline, 72.6% of the overall population (OP) presented blood eosinophil counts ≥ 300 cells/µL; 36.8% had comorbid chronic rhinosinusitis with nasal polyps (CRSwNP); 84.8% reported at least one severe exacerbation, and 29.1% were OCS-dependent. At 1 year of follow-up, patients receiving benralizumab treatment had a 85.6% mean reduction in exacerbations from baseline, and 81.4% of patients achieved zero exacerbations. We also found a clinically relevant mean (SD) increase in pre-bronchodilator (BD) FEV1 of 331 (413) mL, with 66.7% of patients achieving a pre-BD FEV1 increase ≥ 100 mL, and 46.3% of patients achieving a pre-BD FEV1 ≥ 80% of predicted. Regarding symptom control, 73.8% of the OP obtained an ACT score ≥ 20 points. After 1 year of follow-up, mean reduction in the daily OCS dose was 70.5%, and complete OCS withdrawal was achieved by 52.8% of the OCS-dependent patients. Almost half (43.7%) of the OP on benralizumab met all four criteria for clinical remission. Patients with concomitant CRSwNP obtained similar or enhanced outcomes. CONCLUSIONS: These data support the real-world benefits of benralizumab in SEA patients, and particularly in those with concomitant CRSwNP. TRIAL REGISTRATION: NCT04648839.

Recommendations for the Implementation of the Self-Administration of Alpha-1 Antitrypsin.

Purpose: Administration of exogenous alpha-1 antitrypsin (AAT) is the only specific therapy for the management of pulmonary morbidity in patients with AAT deficiency. It requires weekly or biweekly intravenous infusions, which may impact patient independence and quality of life. Self-administration of AAT therapy is an alternative to reduce the burden for patients who require AAT therapy. We presented herein experts' recommendations for the implementation of a program for the self-administration of AAT. Methods: This project was conducted using a modified nominal group technique and was undertaken in two online meetings involving the participation of 25 experts: specialists in pulmonology (n=17), nurses (n=5) and hospital pharmacists (n=3). Results: The following issues were discussed, and several recommendations were agreed upon on the following topics: a) patient profile and clinical evaluation, establishing selection criteria that should include clinical as well as social criteria; b) role of health care professionals, suggested roles for specialists in pulmonology, nurses, and hospital pharmacists; c) training by the nurse, including recommendations before initiating the training and the content of the training sessions; and d) logistic issues and follow-up, adherence, and patient support. Conclusion: We expect this proposal to increase awareness of this therapeutic alternative and facilitate the implementation of self-administration programs, thus contributing to optimizing the patient experience with AAT therapy. Further research on the outcomes of these programs, especially from the patient perspective, will also help to improve their design and implementation.

COVID-19's impact on care practice for alpha-1-antitrypsin deficiency patients.

BACKGROUND: Patients with alpha-1 antitrypsin deficiency (AATD), commonly categorized as a rare disease, have been affected by the changes in healthcare management brought about by COVID-19. This study's aim was to identify the changes that have taken place in AATD patient care as a result of the COVID-19 pandemic in Spain and to propose experts' recommendations aimed at ensuring humanized and quality care for people with AATD in the post-pandemic situation. METHODS: A qualitative descriptive case study with a holistic single-case design was conducted, using focus groups with experts in AATD clinical management, including 15 health professionals with ties to the Spanish health system (12 pneumologists and 2 hospital pharmacists from 11 different hospitals in Spain) and 1 patient representative. RESULTS: COVID-19 has had a major impact on numerous aspects of AATD clinical patient management in Spain, including diagnostic, treatment, and follow-up phases. The experts concluded that there is a need to strengthen coordination between Primary Care and Hospital Care and improve the coordination processes across all the organizations and actors involved in the healthcare system. Regarding telemedicine and telecare, experts have concluded that it is necessary to promote this methodology and to develop protocols and training programs. Experts have recommended developing personalized and precision medicine, and patient participation in decision-making, promoting self-care and patient autonomy to optimize their healthcare and improve their quality of life. The possibility of monitoring and treating AATD patients from home has also been proposed by experts. Another result of the study was the recommendation of the need to ensure that plasma donations are made on a regular basis by a sufficient number of healthy individuals. CONCLUSION: The study advances knowledge by highlighting the challenges faced by health professionals and changes in AATD patient management in the context of the COVID-19 pandemic. It also proposes experts' recommendations aimed at ensuring humanized and quality care for people with AATD in the post-pandemic situation. This work could serve as a reference study for physicians on their daily clinical practice with AATD patients and may also provide guidance on the changes to be put in place for the post-pandemic situation.

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. METHODS: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 µM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. RESULTS: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www. CLINICALTRIALS: gov (ID: NCT04180319).

Demographic and clinical characteristics of patients with α1-antitrypsin deficiency genotypes PI*ZZ and PI*SZ in the Spanish registry of EARCO.

Background: The Spanish registry of α1-antitrypsin deficiency (AATD) integrated in the European Alpha-1 Research Collaboration (EARCO) provides information about the characteristics of patients, in particular those with the PI*SZ genotype, which is frequent in Spain. Method: Individuals with severe AATD defined as proteinase inhibitor (PI) genotypes PI*ZZ, PI*SZ and other rare deficient variants were included from February 1, 2020, to February 1, 2022. The analysis focused on a comparison of the characteristics of PI*ZZ and PI*SZ patients. Results: 409 patients were included (53.8% men) with a mean±sd age of 53.5±15.9 years. Genotypes were PI*ZZ in 181 (44.7%), PI*SZ in 163 (40.2%), PI*SS in 29 (7.2%) and other in 32 (7.9%). 271 (67.4%) had lung disease: 175 chronic obstructive pulmonary disease (43.5%), 163 emphysema (40.5%) and 83 bronchiectasis (20.6%). Patients with the PI*SZ genotype were younger, more frequently non-index cases and had a lower frequency of respiratory diseases except asthma compared with PI*ZZ patients. Among patients with respiratory diseases, PI*SZ individuals were significantly older both at onset of symptoms and at diagnosis; only asthma was more frequent in PI*SZ than in PI*ZZ individuals. Twelve PI*SZ patients (15.4%) received augmentation therapy compared with 94 PI*ZZ patients (66.2%; p<0.001). Conclusions: There is a high prevalence of PI*SZ in Spain. Patients with the PI*SZ genotype were older at symptom onset and diagnosis and had less severe lung disease compared with PI*ZZ patients. The prevalence of asthma was higher in PI*SZ, and up to 15% of PI*SZ patients received augmentation therapy.

[Consensus document for severe asthma in adults. 2022 update]. / Documento de consenso de asma grave en adultos. Actualización 2022.

Severe asthma is a heterogeneous syndrome with several clinical variants and often represents a complex disease requiring a specialized and multidisciplinary approach, as well as the use of multiple drugs. The prevalence of severe asthma varies from one country to another, and it is estimated that 50% of these patients present a poor control of their disease. For the best management of the patient, it is necessary a correct diagnosis, an adequate follow-up and undoubtedly to offer the best available treatment, including biologic treatments with monoclonal antibodies. With this objective, this consensus process was born, which began in its first version in 2018, whose goal is to offer the patient the best possible management of their disease in order to minimize their symptomatology. For this 2020 consensus update, a literature review was conducted by the authors. Subsequently, through a two-round interactive Delphi process, a broad panel of asthma experts from SEPAR and the regional pulmonology societies proposed the recommendations and conclusions contained in this document.

Monoclonal antibody treatment for severe uncontrolled asthma in Spain: analytical map.

BACKGROUND: Monoclonal antibodies (mABs) have become available to treat more efficiently patients with severe uncontrolled asthma (SUA). However, the use of mABs is lower than expected given the prevalence of SUA, with significant disparities in the use of these treatments. OBJECTIVE: To evaluate the proportion of patients with SUA treated with mABs in Spain, and to analyze some of the factors that could determine these prescription patterns. METHODS: An analysis was performed on the data provided from the Hospitals National Health System (NHS) 2018 catalogue where Chest Diseases Department and a Hospital Pharmacy were available. Random sampling was performed to determine the sample size, stratifying proportionally by geographic area and hospital level. Characteristics of the participating sites, as well as the prescribing of mABs were collected, which included geographic area, hospital levels, prescribing medical specialities, types of clinics, and mABs prescribed. RESULTS: Data from 90 hospitals were analyzed (Response rate 64.3%). Level 4 hospitals, the Canary Islands geographical area, and the presence of a high complexity Asthma Healthcare Unit (ACU) were associated with a higher probability that the SUA was treated with mABs. CONCLUSION: The map of the prescribing of mABs for SUA in Spain shows a significant variation by geographic area, hospital level, type of clinic, and the accreditation level of the ACUs. At the current time, there appears to be significant under-prescribing of these treatments.

Update on and future perspectives for the diagnosis of alpha-1 antitrypsin deficiency in Brazil.

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder caused by a mutation in the SERPINA1 gene, which encodes the protease inhibitor alpha-1 antitrypsin (AAT). Severe AATD predisposes individuals to COPD and liver disease. Early diagnosis is essential for implementing preventive measures and limiting the disease burden. Although national and international guidelines for the diagnosis and management of AATD have been available for 20 years, more than 85% of cases go undiagnosed and therefore untreated. In Brazil, reasons for the underdiagnosis of AATD include a lack of awareness of the condition among physicians, a racially diverse population, serum AAT levels being assessed in a limited number of individuals, and lack of convenient diagnostic tools. The diagnosis of AATD is based on laboratory test results. The standard diagnostic approach involves the assessment of serum AAT levels, followed by phenotyping, genotyping, gene sequencing, or combinations of those, to detect the specific mutation. Over the past 10 years, new techniques have been developed, offering a rapid, minimally invasive, reliable alternative to traditional testing methods. One such test available in Brazil is the A1AT Genotyping Test, which simultaneously analyzes the 14 most prevalent AATD mutations, using DNA extracted from a buccal swab or dried blood spot. Such advances may contribute to overcoming the problem of underdiagnosis in Brazil and elsewhere, as well as being likely to increase the rate detection of AATD and therefore mitigate the harmful effects of delayed diagnosis.

Implantación en España del nuevo registro internacional de déficit de alfa-1-antitripsina European Alpha-1-Research Collaboration (EARCO) / Spanish Implementation of the New International Alpha-1 Anitrypsin Deficiency International Registry: The European Alpha-1 Research Collaboration (EARCO)

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Results of a Diagnostic Procedure Based on Multiplex Technology on Dried Blood Spots and Buccal Swabs for Subjects With Suspected Alpha1 Antitrypsin Deficiency / Resultados de un procedimiento diagnóstico basado en tecnología multiplex que usa manchas de sangre seca y frotis bucales en sujetos con sospecha de deficiencia de alfa-1 antitripsina

INTRODUCTION: The objective of this analysis was the evaluation of a new national circuit used for diagnosing alpha1 antitrypsin deficiency (AATD) based on multiplex technology using online registration and mail posted samples from dried blood spots (DBS) and buccal swabs. METHODS: This is an observational, ongoing study conducted in Spain since March 2018. Samples are coded on a web platform and sent by postal mail to the central laboratory. Allele-specific genotyping for the 14 most common mutations was done with the Luminex 200 Instrument System. Gene sequencing was done if none of the mutations were found and the AAT serum level was < 60 mg/dl, or by request from the clinician in charge. RESULTS: At the time of the present report, 5803 (92.9%) samples were processed, 4984 (85.9%) from buccal swab and 819 (14.1%) from DBS. The prevalence of the frequent allele combinations were: MS 19.0%, MZ 14.4%, SS 2.9%, SZ 3.7%, and ZZ: 1.4%. Globally, Z carriers represented 20.0% and S carriers 26.6% of this population, with differences seen between regions. 209 (3.6%) were identified carrying rare alleles, 12 (0.2%) carrying null alleles and 14 (0.3%) new mutations were described. Respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. CONCLUSIONS: The availability of a diagnostic system based on the simultaneous testing of 14 genetic variants from buccal swabs or DBS sent by postal mail and with web registration has proven to be useful, and the system can improve the timely diagnosis of AATD

INTRODUCCIÓN: El objetivo de este análisis fue la evaluación de un nuevo circuito nacional utilizado para diagnosticar la deficiencia de alfa-1 antitripsina (DAAT) basado en tecnología multiplex con muestras de manchas de sangre seca (DBS, por sus siglas en inglés) y frotis bucales enviados por correo postal tras un registro previo en línea. MÉTODOS: Este es un estudio observacional en curso que se está llevando a cabo en España desde marzo de 2018. Las muestras se codifican en una plataforma web y se envían por correo postal al laboratorio central. El genotipado de un alelo específico buscando las 14 mutaciones más comunes se realizó con el sistema Luminex(R) 200. Se realizó secuenciación génica si no se encontraba ninguna de las mutaciones y el nivel sérico de AAT era < 60mg/dl, o por solicitud del médico responsable. RESULTADOS: En el momento del presente informe se habían procesado 5.803 (92,9%) muestras, 4.984 (85,9%) de frotis bucal y 819 (14,1%) de DBS. La prevalencia de las combinaciones frecuentes de alelos fue: MS 19,0%, MZ 14,4%, SS 2,9%, SZ 3,7% y ZZ 1,4%. Globalmente, los portadores de Z representaron el 20,0% y los portadores de S el 26,6% de esta población, observándose diferencias entre las regiones. Se identificaron 209 (3,6%) portadores de alelos raros, 12 (0,2%) portadores de alelos nulos y se describieron 14 (0,3%) nuevas mutaciones. Otras enfermedades respiratorias que no eran EPOC, incluyendo el asma mal controlado o las bronquiectasias, también presentaron mutaciones DAAT. CONCLUSIONES: La disponibilidad de un sistema de diagnóstico con registro web basado en el análisis simultáneo de 14 variantes genéticas de frotis bucales o DBS enviados por correo postal ha demostrado ser útil, y el sistema puede mejorar el diagnóstico temprano de DAAT

Results of a Diagnostic Procedure Based on Multiplex Technology on Dried Blood Spots and Buccal Swabs for Subjects With Suspected Alpha1 Antitrypsin Deficiency.

INTRODUCTION: The objective of this analysis was the evaluation of a new national circuit used for diagnosing alpha1 antitrypsin deficiency (AATD) based on multiplex technology using online registration and mail posted samples from dried blood spots (DBS) and buccal swabs. METHODS: This is an observational, ongoing study conducted in Spain since March 2018. Samples are coded on a web platform and sent by postal mail to the central laboratory. Allele-specific genotyping for the 14 most common mutations was done with the Luminex 200 Instrument System. Gene sequencing was done if none of the mutations were found and the AAT serum level was <60mg/dl, or by request from the clinician in charge. RESULTS: At the time of the present report, 5803 (92.9%) samples were processed, 4984 (85.9%) from buccal swab and 819 (14.1%) from DBS. The prevalence of the frequent allele combinations were: MS 19.0%, MZ 14.4%, SS 2.9%, SZ 3.7%, and ZZ: 1.4%. Globally, Z carriers represented 20.0% and S carriers 26.6% of this population, with differences seen between regions. 209 (3.6%) were identified carrying rare alleles, 12 (0.2%) carrying null alleles and 14 (0.3%) new mutations were described. Respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. CONCLUSIONS: The availability of a diagnostic system based on the simultaneous testing of 14 genetic variants from buccal swabs or DBS sent by postal mail and with web registration has proven to be useful, and the system can improve the timely diagnosis of AATD.