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).

Ventilatory constraint is more severe in walking than cycling in patients with COPD.

Due to its effectivity in assessing functional capacity and adding prognostic information to the staging of chronic obstructive pulmonary disease (COPD) patients, the 6-min walk test (6MWT) is extensively used in clinical evaluation. Currently, there is little information about the physiological response this test elicits in patients, especially when compared to cardiopulmonary exercise test (CPET). The aim of the study was to compare ventilatory and metabolic responses between these tests commonly used for the assessment of clinical outcome. A group of 20 patients with moderate to very severe COPD were tested for their pulmonary function (flow-volume curve, static lung volumes), occlusion mouth pressures and breath-by-breath measurement of flow, volumes, and oxygen (O2) and carbon dioxide (CO2) concentration during the 6MWT and CPET. All parameters measured during both exercise tests were assessed over the throughout of the tests and compared between each other at specified time points. Serially measured inspiratory vital capacity (IVC) decreased more rapidly and extensively during the walk-test (p â€‹< â€‹0,0001). This was accompanied by a limited increase in tidal volume (VT) and minute ventilation (VE), which were significantly lower in the course of the 6MWT (p â€‹= â€‹0,0003 and p â€‹= â€‹0,0097, respectively). We also noticed a significant decrease in hemoglobin oxygen saturation (SpO2) during the 6MWT which was correlated to percent decrease in IVC (p â€‹= â€‹0,0206). Over the course of the 6MWT, oxygen consumption (VO2) and VT reached plateau within 2 â€‹min, while carbon dioxide production (VCO2) and VE within 3 â€‹min. During CPET, VO2, VCO2 and VE rose continuously, while VT reached plateau within 4 â€‹min. The 6MWT seems to be a rather endurance-based test associated with more pronounced dynamic lung hyperinflation and mechanical constraint of ventilation in comparison to cycling.

Protocol for the EARCO Registry: a pan-European observational study in patients with α1-antitrypsin deficiency.

RATIONALE AND OBJECTIVES: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD. STUDY DESIGN AND POPULATION: The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level <11 µM (50 mg·dL-1) and/or a proteinase inhibitor genotype ZZ, SZ or compound heterozygotes or homozygotes of other rare deficient variants. Assessments at baseline and during the yearly follow-up visits include lung function testing (spirometry, body plethysmography and diffusing capacity of the lung), exercise capacity, blood tests and questionnaires (symptoms, quality of life and physical activity). To ensure correct data collection, there will be designated investigator staff to document the data in the case report form. All data will be reviewed by the EARCO database manager. SUMMARY: The EARCO Registry aims to understand the natural history and prognosis of AATD better with the goal to create and validate prognostic tools to support medical decision-making.

Research priorities in α1-antitrypsin deficiency: results of a patients' and healthcare providers' international survey from the EARCO Clinical Research Collaboration.

α1-antitrypsin deficiency (AATD) is a rare and under-recognised genetic condition. Owing to its low prevalence, international initiatives are key for conducting high-quality research in the field. From July 2018 to December 2019, the European Alpha-1 Research Collaboration (EARCO) developed and conducted two surveys, one for healthcare providers and one for patients and caregivers, aiming to identify research priorities and barriers in access to treatment for AATD. A survey on 164 research questions was electronically sent to 230 AATD experts in Europe, and 94 completed surveys from 24 countries were received. The top research areas identified by healthcare providers were causes of variable progression and poor outcomes, improvement in diagnosis, initiation and optimal dosing of augmentation therapy and effectiveness of self-management interventions. During the same period, 438 surveys were completed by patients and caregivers from 26 countries. The top research areas identified were improving knowledge about AATD, in particular among general practitioners, access to AATD specialised centres and access to reliable, easy to understand information about living with AATD. Regarding barriers to treatment, participants from countries where augmentation therapy was reimbursed prioritised improving knowledge in AATD, while respondents in non-reimbursed countries regarded access to AATD augmentation therapy and to specialised centres as the most relevant. The main research and management priorities identified by healthcare providers and patients included understanding the natural history of AATD, improving information to physicians, improving access to specialised reference centres, personalising treatment and having equal opportunities for access to existing therapies.

Diagnosis and management of α1-antitrypsin deficiency in Europe: an expert survey.

Despite recent improvements, α1-antitrypsin deficiency (AATD) remains a rarely diagnosed and treated condition. To assess the variability of AATD diagnosis/treatment in Europe, and to evaluate clinicians' views on methods to optimise management, specialist AATD clinicians were invited to complete a web-based survey. Surveys were completed by 15 physicians from 14 centres in 13 European countries. All respondents perceived the AATD diagnosis rate to be low in their country; 77% of physicians believed that ∼15% of cases were diagnosed. Low awareness was perceived as the greatest barrier to diagnosis. Spirometry was considered more practical than quantitative computed tomography (QCT) for monitoring AATD patients in clinical practice; QCT was considered more useful in trials. AAT therapy provision was reported to be highly variable: France and Germany were reported to treat the highest proportion (∼60%) of diagnosed patients, in contrast to the UK and Hungary, where virtually no patients receive AAT therapy. Most clinicians supported self-administration and extended dosing intervals to improve convenience of AAT therapy. This survey indicates that AATD diagnosis and management are highly heterogeneous in Europe; European cooperation is essential to generate data to support access to AAT therapy. Improving convenience of AAT therapy is an ongoing objective.

Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE).

BACKGROUND: Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. METHODS: Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. FINDINGS: Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48. INTERPRETATION: RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment. FUNDING: CSL Behring.

Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting.

BACKGROUND: Oral corticosteroids (OCS) are commonly administered in patients with severe persistent allergic asthma. Despite their efficacy, they are associated with a wide variety of adverse events. The eXpeRience registry was set up to investigate real-world outcomes among patients receiving omalizumab for the treatment of uncontrolled allergic asthma. Here, we present the effect of omalizumab treatment on OCS use. METHODS: eXpeRience was a 2-year, multinational, non-interventional, observational registry of patients receiving omalizumab for uncontrolled allergic asthma. OCS use (proportion of patients on maintenance OCS, mean total daily OCS dose and change in status of OCS therapy) was assessed at baseline, 16 weeks, and 8, 12, 18, and 24 months after the initiation of omalizumab. Response to omalizumab was assessed using the physician's Global Evaluation of Treatment Effectiveness (GETE) at approximately Week 16. Safety data were also recorded. RESULTS: A total of 943 patients (mean age, 45 years; female, 64.9%) were enrolled in the registry, 263 of whom were receiving maintenance OCS at baseline. The proportion of patients taking maintenance OCS was markedly lower at Months 12 (16.1%) and 24 (14.2%) than at baseline (28.6%; intent-to-treat population). GETE status was determined in 915 patients receiving omalizumab: 64.2% were responders (excellent or good response), 30.7% were non-responders (moderate, poor or worsening response); 5.1% had no assessment. The frequency of serious adverse events was comparable to that seen in controlled trials of omalizumab. CONCLUSIONS: Omalizumab use is associated with an OCS-sparing effect in patients with uncontrolled persistent allergic asthma in the real-world setting.

Chronic Obstructive Pulmonary Disease: official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care.

BACKGROUND: COPD is a global concern. Currently, several sets of guidelines, statements and strategies to managing COPD exist around the world. METHODS: The Czech Pneumological and Phthisiological Society (CPPS) has commissioned an Expert group to draft recommended guidelines for the management of stable COPD. Subsequent revisions were further discussed at the National Consensus Conference (NCC). Reviewers' comments contributed to the establishment of the document's final version. DIAGNOSIS: The hallmark of the novel approach to COPD is the integrated evaluation of the patient's lung functions, symptoms, exacerbations and identifications of clinical phenotype(s). The CPPS defines 6 clinically relevant phenotypes: frequent exacerbator, COPD-asthma overlap, COPD-bronchiectasis overlap, emphysematic phenotype, bronchitic phenotype and pulmonary cachexia phenotype. TREATMENT: Treatment recommendations can be divided into four steps. 1(st) step = Risk exposure elimination: reduction of smoking and environmental tobacco smoke (ETS), decrease of home and occupational exposure risks. 2(nd) step = Standard treatment: inhaled bronchodilators, regular physical activity, pulmonary rehabilitation, education, inhalation training, comorbidity treatment, vaccination. 3(rd) step = Phenotype-specific therapy: PDE4i, ICS+LABA, LVRS, BVR, AAT augmentation, physiotherapy, mucolytic, ABT. 4(th) step = Care for respiratory insufficiency and terminal COPD: LTOT, lung transplantation, high intensity-NIV and palliative care. CONCLUSION: Optimal treatment of COPD patients requires an individualised, multidisciplinary approach to the patient's symptoms, clinical phenotypes, needs and wishes. The new Czech COPD guideline reflects and covers these requirements.

Pulmonary function in patients with hereditary motor and sensory neuropathy: a comparison of patients with and without spinal deformity.

We assessed pulmonary function in hereditary motor and sensory neuropathy. Fourteen neuropathy patients without spinal deformity (group 1), 14 with spinal deformity (group 2), and 16 individuals with idiopathic spinal deformity (group 3) matched to group 2 for age, height and Cobb angle, were included. Hereditary motor and sensory neuropathy severity was measured with Charcot-Marie-Tooth Neuropathy Score. All participants exhibited mild decrease in maximal inspiratory pressure at the mouth. One-way analysis of variance yielded significant main effects for lung volumes - slow vital capacity, forced expiratory volume in 1s, and total lung capacity (p's<.01), attributable to greater volumes in group 1 compared to groups with spinal deformity - and transfer factor for carbon monoxide (p=.013), reflecting differences between groups 1 vs. 2. Slow vital capacity and total lung capacity correlated with maximal inspiratory pressure at the mouth in group 2, whereas slow vital capacity correlated with muscle work in group 3 (p's<.05). Decreased lung volume may be due to impaired respiratory muscle strength in hereditary motor and sensory neuropathy with spinal deformity and due to spinal deformity in idiopathic patients.

Spontaneous breathing of heliox using a semi-closed circuit: a bench study.

INTRODUCTION: The use of helium-oxygen mixture (heliox) for ventilation has an advantage in patients with obstruction of the airways. The physical properties of helium enable an easier gas flow through the airways; this enables easier breathing for the patient when compared to standard ventilation of air. A high cost of heliox falls within the factors that limit the use of heliox in clinical practice. At present, heliox is administered by use of an open circuit. The aim of this study is to propose a way of heliox administration that reduces heliox consumption but does not affect the positive heliox effects upon the airway resistance. METHODS: To minimize consumption of heliox, a semi-closed circuit has been designed. The circuit is a modification of an anesthetic circuit composed of parts with the lowest possible resistances. As any circuit has its own resistance, the evaluation of its possible negative effect upon the work of breathing of patients with exacerbation of chronic obstructive pulmonary disease (COPD) has been conducted. RESULTS: A semi-closed circuit for heliox administration has been constructed and evaluated. The intrinsic resistance of both the inspiratory and expiratory limbs of the circuit is less than 140 Pa.s/l. This resistance does not represent a significant workload for a patient with COPD exacerbation whose airway resistance is 10 to 20 fold higher. CONCLUSIONS: The designed semi-closed circuit offers a potential benefit of heliox in patients with COPD exacerbation.