Decalogue of Best Practices in Alpha-1 Antitrypsin Deficiency

Abstract

Alpha-1 antitrypsin (AAT) deficiency is an underdiagnosed genetic disorder that predisposes individuals to the development of pulmonary emphysema and liver disease. This document establishes ten priorities for the optimal management of AAT deficiency (AATD) in clinical practice, as identified by the Spanish AAT Deficiency Network (REDAAT). The need to establish an appropriate plasma AAT concentration cutoff to identify individuals who require phenotyping/genotyping studies is emphasized. Furthermore, in cases of reduced AAT values, it is recommended to implement automatic alerts suggesting SERPINA1 genotyping using reliable and accessible laboratory methods. Diagnostic and therapeutic protocols should be tailored to the patient's genotype and serum AAT concentration. In patients with levels ≤57 mg/dL and severe deficiency genotypes, a multidisciplinary approach is required, including systematic respiratory and hepatic evaluation, specialized follow-up, consideration of augmentation therapy, and inclusion in prospective registries. Nursing plays a key role in conducting screening in pulmonary function laboratories, promoting accessibility and efficiency. The crucial role of primary care in ordering tests, early identification, and appropriate referral to hospital units for patients with chronic obstructive pulmonary disease (COPD) or unexplained liver disease is highlighted. The decalog also proposes quality-of-care indicators to monitor the implementation of screening across different levels of care. A comprehensive, personalized, and multidisciplinary approach to patients with AAT deficiency is recommended, promoting collaboration among pulmonology, hepatology, primary care, and pediatrics, and establishing reference centers to ensure equity and quality of care.

Resumen

El déficit de alfa1 antitripsina (AAT) es un trastorno genético infradiagnosticado que predispone al desarrollo de enfisema pulmonar y hepatopatía. El presente documento establece diez prioridades para el abordaje óptimo del déficit de AAT (DAAT) en la práctica clínica asistencial identificadas por la Red Española de Déficit de AAT (REDAAT). Se destaca la necesidad de establecer un punto de corte adecuado de la concentración de AAT en plasma para identificar a los sujetos que precisan un estudio del fenotipado/genotipado. Asimismo, ante valores disminuidos de AAT, se recomienda incorporar alertas automáticas que sugieran el genotipado SERPINA1 utilizando métodos de laboratorio fiables y accesibles. El protocolo diagnóstico y terapéutico debe adaptarse al genotipo y concentración sérica de AAT. En pacientes con niveles ≤ 57 mg/dL y genotipos deficitarios graves, se requiere un abordaje multidisciplinar con evaluación respiratoria y hepática sistemática, seguimiento especializado, valoración del tratamiento aumentativo e inclusión en registros prospectivos. La enfermería desempeña un papel clave en la realización del cribado en laboratorios de función respiratoria, promoviendo accesibilidad y eficiencia. Se subraya el papel crucial de la atención primaria en la solicitud de pruebas, la identificación precoz y la derivación adecuada a unidades hospitalarias de pacientes con enfermedad pulmonar obstructiva crónica (EPOC) o hepatopatía no filiada. El decálogo también propone indicadores de calidad asistencial que permitan monitorizar la implementación del cribado en diferentes niveles asistenciales. Se propone un abordaje integral, personalizado y multidisciplinar del paciente con déficit de AAT, promoviendo la colaboración entre neumología, hepatología, atención primaria y pediatría, y estableciendo centros de referencia para garantizar equidad y calidad en la atención.

Introduction

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition caused by mutations in the SERPINA1 gene, which confer an increased lifetime risk of developing various clinical manifestations, primarily pulmonary emphysema and liver involvement.¹ Pulmonary disease constitutes the most frequent cause of morbidity and mortality in patients with severe AATD and accounts for approximately 2–3% of all patients with chronic obstructive pulmonary disease (COPD).² One of the main challenges in managing AATD is its high rate of underdiagnosis. Although various national and international guidelines recommend systematic screening of patients with COPD,^3–5 implementation remains far from optimal. This diagnostic delay results in postponed treatment initiation with clinically relevant consequences.⁶ Consequently, it is essential that all healthcare professionals responsible for the care of patients with respiratory and hepatic conditions are aware of the key interventions to be implemented in the management of AATD.

The Spanish AAT Deficiency Network (REDAAT) has reflected on some of the main areas for improvement in AATD patient care. To promote dissemination, REDAAT has compiled the ten most important measures that should be considered in the care of patients with AATD. This decalog (Fig. 1) was developed to address uncertainties and provide solutions that facilitate the implementation of measures aimed at improving disease management within our healthcare system. The study employs an expert consensus methodology supported by a solid evidence base, ensuring that the conclusions integrate both current scientific knowledge and clinical practice.

Fig. 1.

Ten-point guide for the management of alpha-1 antitrypsin deficiency.

Plasma alpha-1 antitrypsin cutoff levels in clinical laboratories according to guidelines

Traditionally, the lower limit of normal for a laboratory analyte is established based on the distribution obtained in its reference population. The most commonly used method is the 5th percentile, which sets the lower limit as the value excluding the lowest 5% of the population distribution. In many reference laboratories, the plasma AAT lower limits commonly used range between 90 and 120 mg/dL. However, these values have been obtained without considering the distribution of different genotypes in the reference population. This implies that within this range, up to 20% of individuals may have the PiMS genotype and 3% the Pi*MZ genotype, prevalences described in the general Spanish population.⁷ Consequently, reference values should be determined in samples from individuals with a normal, non-deficient Pi*MM genotype. In Italy, Ferrarotti et al.⁸ found a value of 105 mg/dL for the 5th percentile in their laboratory. In Barcelona, normal AAT values in serum samples from healthy adults show a reference interval for Pi*MM individuals between 116 and 232 mg/dL.^9,10 REDAAT considers samples with values below 116 mg/dL to be potentially deficient and recommends analyzing them according to the AATD diagnostic algorithm.^10,11

Adopting a reference value of 116 mg/dL by nephelometry can optimize detection of carriers of the S and Z alleles, who will require family studies to identify potential individuals with severe deficiency (Pi*SZ or Pi*ZZ).⁹ However, most hospitals maintain a cutoff of 90 mg/dL because commercial kits are pre-set within this range. In the absence of additional national population studies to establish normal values in Pi*MM individuals, 116 mg/dL is proposed as the reference value to advance AATD diagnosis.

Confirmation of alpha-1 antitrypsin deficiency

The clinical laboratory plays a central role in the diagnosis of AATD and its function should not be limited to reporting a numerical value. In cases where values are <116 mg/dL, the laboratory could incorporate an alert recommending SERPINA1 genotyping to rule out potential AATD. A suggested message might be: “According to current recommendations, SERPINA1 genotyping is considered appropriate to rule out possible alpha-1 antitrypsin deficiency.” Additionally, the laboratory could provide information on genetic diagnostic resources, interpretation, and how to request genetic testing. This would render the laboratory report more comprehensive, providing the clinician with integrated information.

When plasma levels are below 116 mg/dL, initial genotyping of at least the S and Z alleles should be performed, as they represent the most frequent pathogenic mutations (Fig. 2). This allele-specific determination is performed using various techniques based on polymerase chain reaction (PCR) amplification of the regions containing these mutations. Differences between techniques lie in how the amplified fragments are analyzed. One option is high-resolution melting (HRM) analysis. This method uses SYBR Green® to detect amplified fragments; the dye fluoresces only in the presence of double-stranded DNA. Software then analyzes the melting curves of the amplified DNA fragments to determine whether the sample carries a normal allele (M) and/or the S and Z alleles, in homozygosity or heterozygosity.^12,13 This method is simple, rapid, cost-effective, does not require expensive equipment, and is available in any genotyping laboratory.

Fig. 2.

Diagnostic algorithm for alpha-1 antitrypsin deficiency. 1. Evaluation of the patient with AATD and their partner to assess the risk for offspring. 2. Quantification by nephelometry. For other techniques, apply the conversion factor. 3. In centers without access to a genetics laboratory, the Progenika-REDAAT pathway may be used. Abbreviations: COPD: chronic obstructive pulmonary disease; AAT: alpha-1 antitrypsin; REDAAT: Spanish Network for Alpha-1 Antitrypsin Deficiency; CRP: C-reactive protein; AATD: alpha-1 antitrypsin deficiency.

Another alternative available in many countries is the free AAT Genotyping Test provided by Grifols S.A., developed by Progenika Biopharma (Derio, Vizcaya, Spain). This test uses Luminex technology to detect 14 of the most frequently AATD-associated mutations from a single saliva or dried blood sample. Several positive experiences have been reported with this test in Spain¹⁴ and internationally, demonstrating that it can serve as an outpatient diagnostic method for AATD.¹⁵ Therefore, REDAAT recommends this diagnostic approach.

When there is a discrepancy between plasma AAT levels and genotyping results, gene sequencing is necessary. In such cases, some patients have been found to carry a second mutation responsible for abnormally low plasma AAT levels.^1,3,5

Management protocol according to allelic variants and alpha-1 antitrypsin concentration

After identifying AATD, it is essential to define the appropriate management for each case. Although more than 500 allelic variants have been described, the management protocol depends on the detected allelic combination and plasma AAT concentration.^3,5,15 Management can be summarized in two main clinical scenarios:

• 1.

  Low-risk group: Heterozygotes and Pi*SS homozygotes with AAT concentrations above the protective threshold (11 μM, corresponding to 57.2 mg/dL).

• 2.

  High-risk group: Pi*ZZ homozygotes, null-null, other severe deficient homozygotes, or compound heterozygotes with AAT concentrations below the protective threshold (≤57 mg/dL).

In both scenarios, certain interventions should be applied to all AATD patients, including avoiding inhaled toxins (tobacco and other forms of smoking, as well as occupational or environmental pulmonary irritants), avoiding hepatotoxic exposures, and preventing respiratory infections via age- and comorbidity-appropriate vaccinations (influenza, COVID-19, pneumococcus, and respiratory syncytial virus). Comorbid respiratory and hepatic conditions, including COPD, should be treated according to current guidelines.¹⁶ Additionally, family screening is recommended for first-degree relatives.

In cases at low risk of developing COPD or liver disease, management focuses on the measures previously mentioned, routine laboratory monitoring including liver function tests, while follow-up can be conducted in primary care. If the patient is a current smoker or a former smoker with a cumulative consumption of ≥10 pack-years and presents symptoms, spirometry with a bronchodilator test should be performed to confirm or rule out a diagnosis of COPD. Although primary care can manage follow-up, Pi*SS homozygotes are recommended to be monitored by respiratory physicians, as studies by Martín et al. showed similar disease behavior to PiSZ patients,¹⁷ with inclusion in the international EARCO registry (European Alpha-1 Research Collaboration).¹⁸

For high-risk patients, referral to pulmonology is recommended for full pulmonary evaluation, including spirometry with bronchodilator testing, lung volumes, carbon monoxide diffusion capacity, and high-resolution chest CT (HRCT) at diagnosis. Hepatic assessment should include liver enzyme studies, abdominal ultrasound, and transient elastography for all allelic variants at risk for liver disease.^3,5,19 Follow-up should be multidisciplinary (pulmonology and hepatology), preferably in reference centers, with inclusion in EARCO. Suggested follow-up diagnostics for high-risk patients include^3,5,19:

• •

  Spirometry and carbon monoxide diffusion every 6–12 months.

• •

  Hepatic assessment according to age and risk factors (including liver enzymes, ultrasound, elastography, and alpha-fetoprotein).

• •

  HRCT if clinical changes or complications arise.

• •

  Hepatitis B vaccination for candidates for AAT augmentation therapy.

• •

  Assessment for lung or liver transplantation in advanced disease.

• •

  For individuals diagnosed in childhood, pulmonary function evaluation at the end of adolescence and, if normal, every 2–3 years thereafter.

Role of nursing in genetic diagnosis of AATD

Nursing professionals play a key role in AATD management, including risk identification, patient education, and performing genetic testing. These tasks can be conducted in pulmonology clinics or primary care.

A useful strategy to reduce underdiagnosis is performing SERPINA1 genotyping^3,5 in pulmonary function laboratories where respiratory patients are routinely evaluated. This enables early, integrated diagnosis. Some tertiary hospitals in Spain and the U.S. have implemented similar protocols with positive results, increasing the detection of deficient cases.²⁰ Nursing-led testing in pulmonary function laboratories offers advantages:

• 1.

  Greater accessibility, as these facilities are frequently visited by the target population.

• 2.

  Cost-effectiveness, as the additional cost is low relative to the benefit of early treatment.

• 3.

  A multidisciplinary, integrated approach involving nursing, pulmonologists, pediatricians, geneticists, and hepatologists, improving coordination in patient referral and management.

Successful implementation requires specific training on clinical suspicion criteria, proper interpretation of pulmonary function tests, available diagnostic procedures, result management, and coordination across care levels.²¹ Integrating genetic diagnosis into pulmonary function laboratories, with nursing as the central axis, is a viable strategy to improve early detection. Its success depends on standardized protocols and adequate training, and pilot programs support its efficacy.

Determination of serum AAT levels in primary care

Primary care should have maximal autonomy in AATD management (Table 1). Serum AAT determination is crucial for characterizing COPD patients, investigating unexplained liver disease, to study relatives of diagnosed individuals, and in cases of low alpha-1 globulin fractions on protein electrophoresis.^5,22 It should also be considered in severe asthma and bronchiectasis.^3,5 Therefore, all primary care physicians should be able to request serum AAT testing.

Table 1.

Candidates for serum alpha-1 antitrypsin measurement.

1. COPD.

2. Consanguineous relatives of patients with known AATD.

3. Chronic dyspnea and cough in multiple family members.

4. Liver disease of unknown etiology.

5. Absence of the alpha-1 band on protein electrophoresis.

6. Adults with bronchiectasis of unexplained cause.

7. Adult-onset asthma with progressive bronchial obstruction or evidence of pulmonary emphysema.

8. Neutrophilic panniculitis.

9. Granulomatosis with polyangiitis.

Abbreviations: COPD: chronic obstructive pulmonary disease; AATD: alpha-1 antitrypsin deficiency.

Criteria for referral of respiratory patients from primary care, including serum AAT measurement

Although World Health Organization and international guidelines recommend at least once-in-a-lifetime serum AAT determination in all COPD patients, it remains underutilized, requested in only 15.8% of cases in Spain.^23–25 Primary care physicians are often the first and main point of contact and play a key role in AATD detection.²³ In this context, it is essential to incorporate the evaluation of AATD into the initial assessment of every patient with obstructive respiratory disease from their first visit. Early detection enables interventions such as AAT augmentation therapy, genetic counseling, and family screening, representing a crucial differential diagnostic opportunity in primary care.¹

It is proposed that serum AAT testing be systematically included in the referral process for any patient with COPD or suspected COPD from primary care. This ensures the pulmonologist has essential information at the first consultation, avoiding diagnostic delays and optimizing patient care.²⁶

Establishing clinical practice improvement indicators

Quality indicators are key tools for measuring, evaluating, and improving healthcare quality. Incorporating them into care models enables monitoring, continuous improvement, and more efficient, safe, outcome-focused care. However, quality indicators for AATD are scarce. The Spanish Society of pneumology and thoracic surgery (SEPAR) referral criteria document,²⁷ endorsed by national pulmonology and primary care societies, proposes an indicator to assess the percentage of COPD patients with AAT determination (patients with AAT measured/total COPD patients × 100), setting a quality standard at >95. According to the data from the EPOCONSUL 2021 study,²⁸ conducted in specialized COPD clinics, AAT levels were measured in only 38.7% of patients. Even so, this represents a significant improvement compared to the results of the first EPOCONSUL 2014–15 study,²⁹ in which the percentage was 18.9%. This trend demonstrates that clinical audits such as EPOCONSUL can be useful for identifying areas for improvement and promoting changes in clinical practice.

It is necessary to advance in the definition and implementation of additional quality-of-care indicators for AATD across all healthcare settings. In the hospital environment, it is particularly important to include indicators that not only measure the number of tests performed but also assess the quality of the diagnostic process, such as the proportion of cases with genotyping, referral to specialized pulmonology units, and coordination with hepatology when deficient cases are detected. To achieve these objectives, collaboration with clinical laboratories is essential. Establishing predefined workflows, automating test requests, and streamlining diagnostic processes will facilitate a systematic, efficient, and high-quality screening approach that can effectively help reduce the underdiagnosis of AATD within our healthcare system.

AATD diagnostic and treatment protocols

The REDAAT-SEPAR diagnostic algorithm⁹ offers two pathways: starting from plasma AAT measurement or genetic study. Findings determine the need for complementary studies: genetic analysis for low AAT levels or AAT measurement to confirm mutation severity. Discordant results require gene sequencing. C-reactive protein should be measured simultaneously to ensure the sample reflects a stable state. Genetic testing options are detailed in Section 2. REDAAT recommends the use of the Progenika Biopharma S.A. system (Derio, Vizcaya, Spain) through the “A1AT Genotyping Test” diagnostic kit.

In patients with AATD-related pulmonary disease, intravenous AAT augmentation therapy may be indicated. This therapy slows lung tissue loss, potentially increasing life expectancy.³⁰ Clinical guidelines define indications, and treatment is recommended in early disease stages.³¹ However, significant inequalities in access to this treatment persist between different countries and even between regions within the same country.³²

Currently, REDAAT recommends augmentation therapy for patients with pulmonary emphysema, FEV₁ < 80%, severe deficiency (serum AAT ≤57 mg/dL), non-smokers (>6 months abstinent), willing to receive IV treatment, and without IgA deficiency. Individualized assessment is necessary due to variability in disease expression and progression.³³ Traditionally, augmentation therapy in Spain has been considered a hospital-based treatment; however, in recent years, programs have been developed to facilitate home administration by healthcare professionals or self-administration by the patient.³⁴

Personalized and multidisciplinary care of diagnosed patients

Due to variability in clinical manifestations, a personalized, often multidisciplinary approach is essential. Patient-specific factors include age, employment, distance to reference centers, and family/social support, as well as disease-specific factors, ranging from asymptomatic individuals diagnosed via family screening to patients with emphysema or liver disease of varying severity.³⁵

The approach should also be multidisciplinary, tailored to the specific disease. If the patient has COPD, comprehensive management should include physical exercise, respiratory physiotherapy, support for smoking cessation, avoidance of environmental and occupational toxins, a proper diet to prevent overweight or malnutrition, pharmacological treatment according to clinical practice guidelines, and, if indicated, augmentation therapy. In advanced stages of the disease, oxygen therapy, ventilatory support, lung volume reduction surgery, lung transplantation, or palliative care may be required. It is recommended to include the patient in self-management programs.³⁶ If the patient has liver disease, it is important to control risk factors such as obesity, alcohol intake, or medications, and in advanced stages, to consider liver transplantation. Addressing these challenges often requires psychological support for both patients and their families.

Therefore, collaboration among pulmonology, hepatology, nutrition-dietetics, psychology, and rehabilitation-physiotherapy professionals is essential to facilitate and coordinate consultations, complementary tests, and treatments. Coordination with primary care teams is also necessary so they are aware of the diagnosis and health implications for these patients, enabling them to assist in disease monitoring, management of exacerbations, and vaccination programs.

The European Commission and the European Respiratory Society recommend that care for patients with AATD be organized in national or regional reference centers.⁵ These centers can provide optimal clinical care and ensure access to treatment in accordance with established guidelines. They offer comprehensive, multidisciplinary care that may include specialist physicians, nurses, geneticists, psychologists, social workers, and other healthcare professionals. They provide a holistic approach that focuses not only on medical treatment but also on emotional, social, and quality-of-life aspects.

Enhanced collaboration between AATD-related specialties

The comprehensive management of patients with AATD should be coordinated by pulmonology in adults and by pediatrics in children. Consequently, collaboration between pulmonology and pediatrics represents a strategic and essential partnership for the holistic care of patients with AATD and for their transition from pediatric to adult care. Within each center, it is necessary to identify a team responsible for AATD patient care in both specialties, and these two teams should maintain a close relationship with joint protocols for transitioning between specialties. This transition is influenced by two key aspects: the health empowerment of adolescents and young adults, who progressively take a leading role in decision-making as part of their maturation, and the dynamic, individualized adaptation of each case to the new environment according to its specific characteristics and the patient's personal development between ages 12 and 21.³⁷

Given the potential hepatic involvement in AATD, another strategic collaboration in both pediatric and adult care is with hepatologists, particularly due to the bimodal pattern of liver involvement, with one peak in childhood and another in adulthood. This need is twofold: on one hand, hepatologists must consider AATD as a possible cause of liver disease and implement screening protocols, and on the other hand, joint evaluations and referral protocols between pulmonology and hepatology must be established to detect liver involvement in carriers of AATD-associated alleles and respiratory involvement in patients with liver disease carrying AATD mutations.³⁸

Therefore, the creation of liver-lung collaborative teams is essential in both pediatric and adult care. Finally, other specialties such as internal medicine, allergy, otolaryngology, dermatology, or geriatrics,³⁹ as well as patient associations, may play an important role in the active screening of patients at risk for AATD, implementing systematic AATD screening through serum AAT determination and referral protocols to pulmonology or pediatrics when decreased levels are identified.

Ethical considerations

This is an original article that has not been published in any other journal. All authors agree with its content and have contributed equally to its preparation. No experiments were conducted on animals, no patients or human subjects were involved, and this is not a clinical trial.

Use of artificial intelligence

The authors declare that this manuscript was not created, in whole or in part, with the assistance of any artificial intelligence software or tools.

Informed consent

Not applicable due to the nature of the manuscript.

Funding

REDAAT receives unrestricted funding for the development of various projects.

Authors’ contributions

All authors participated equally in the conception, design, execution, or interpretation of the submitted manuscript and made substantial contributions to its completion.

Conflicts of interest

• •

  JMHP has received fees over the last 3 years from AstraZeneca, Bial, CSL Behring, FAES, Gebro, Grifols, GSK, and Actelion-Janssen for courses, lectures, consultancy, and other activities related to his professional work.

• •

  FDF has received support from CSL Behring in the last 3 years for educational courses and scientific activities related to his professional work.

• •

  MM has received fees for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Glenmark Pharmaceuticals, Menarini, Kamada, Takeda, Zambon, Tabuk Pharmaceuticals, CSL Behring, Specialty Therapeutics, Sanofi/Regeneron, Grifols, and Novartis; consultancy fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, BEAM Therapeutics, GondolaBio, Chiesi, GlaxoSmithKline, CSL Behring, Ferrer, Korrobio, Menarini, Mereo Biopharma, Spin Therapeutics, Specialty Therapeutics, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi/Regeneron, Zambon, Zentiva, and Grifols; and research funding from Grifols.

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  LDC declares no conflicts of interest, direct or indirect, related to the content of this manuscript.

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  FCM has received fees in the last 3 years for scientific advisory or lectures from (alphabetical order): AstraZeneca, Boehringer Ingelheim, Chiesi, CSL-Behring, FAES, GlaxoSmithKline, Grifols, Menarini, Novartis, Pfizer, Sanofi-Regeneron, TEVA Respiratory, VERTEX. He declares no funding, direct or indirect, from the tobacco industry or its subsidiaries.

• •

  BMD declares no conflicts of interest, direct or indirect, related to the content of the manuscript.

• •

  CEL has received fees over the last 3 years for scientific advice and scientific activities from Chiesi and CSL Behring.

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  VMA has received fees in the last 3 years from FAES, Menarini, Chiesi, and GSK for courses, lectures, consultancy, and other activities related to professional work.

• •

  MCR has received fees for lectures and/or scientific consultancy from AstraZeneca, Bial, Chiesi, CSL Behring, GlaxoSmithKline, Menarini, and Grifols.

• •

  FJMR has received fees in the last 3 years from AstraZeneca, CSL Behring, TEVA Laboratories, Grifols, GSK, Novartis, and Sanofi-Regeneron for courses, lectures, consultancy, and other professional activities.

• •

  FJCG has received fees in the last 3 years for lectures and/or scientific consultancy from AstraZeneca, Gebro Pharma, GlaxoSmithKline, Bial, Chiesi, Grifols, CSL Behring, Sanofi Genzyme, and Menarini.

• •

  CRG has received fees in the last 3 years for lectures and/or scientific consultancy from AstraZeneca, GlaxoSmithKline, Bial, Chiesi, Grifols, CSL Behring, and Sanofi Genzyme.

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  MB has received fees for lectures and/or scientific consultancy from Grifols, Menarini, CSL Behring, GSK, Chiesi, AstraZeneca, Bial, and Sanofi. Is part of the Editorial board of Open Respiratory Archives and declare that they have remained outside the evaluation and decision-making process in relation to this article.

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  IPP declares no conflicts of interest, direct or indirect, related to the manuscript content.

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  MTD has received fees in the last 3 years for lectures and/or scientific consultancy from Chiesi, Grifols, CSL Behring, and GlaxoSmithKline.

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  AB has received fees in the last 3 years from AstraZeneca and Orion Laboratories for courses, lectures, consultancy, and other professional activities.

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  SCC declares no conflicts of interest, direct or indirect, related to the manuscript content.

• •

  LLA has received fees in the last 3 years for scientific consultancy, lectures, and participation in clinical studies from (alphabetical order): Adamed, Aflofarm, AstraZeneca, Bial, Chiesi, CSL Behring, Gebro, Grifols, GSK, Menarini, and Sanofi.

• •

  SCC declares no conflicts of interest, either directly or indirectly, related to the content of the manuscript.

• •

  JLLC has received fees in the last 3 years for lectures, scientific consultancy, participation in clinical studies, or publication writing from (alphabetical order): AstraZeneca, Bial, Chiesi, CSL Behring, FAES, Gebro, Grifols, GSK, Menarini, Sanofi, and Zambon.