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As a result of climate change, wildfire frequency, duration, and severity are increasing in the United States. Exposure to wildfire-related air pollutants can lead to negative health outcomes, particularly among patients with preexisting respiratory diseases (e.g., asthma and chronic obstructive pulmonary disease) and those who are at higher risk for developing these conditions. Underserved communities are disproportionately affected for multiple reasons, including lack of financial and social resources, increased exposure to air pollutants at home and at work, and impaired access to health care. To best serve clinically high-risk and underserved populations, health systems must leverage community public health data, develop and mobilize a wildfire preparedness action plan to identify populations at high risk, and implement interventions to mitigate the consequences of poor air quality. University of California, Davis Health, located at the epicenter of the largest wildfires in Californias history, has developed the 5 pillar Wildfire Population Health Approach: (1) identify clinically at-risk and underserved patient populations using well-validated, condition-targeted registries; (2) assemble multidisciplinary care teams to understand the needs of these communities and patients; (3) create custom analytics and wildfire-risk stratification; (4) develop care pathways based on wildfire-risk tiers by disease, risk of exposure, and health care access; and (5) identify outcome measures tailored to interventions with a commitment to continuous, iterative improvement efforts. The Wildfire Population Health Approach provides an action plan for health systems and care teams to meet the needs of clinically at-risk and underserved patients affected by the increasing health threat posed by climate change-related wildfires.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT. METHODS: In this phase 1 dose-escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX-101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX-101. RESULTS: INBRX-101 was well tolerated. Most treatment-emergent adverse events were grade ≤2. In part 2 (n=18; each dose, n=6), dose-related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21 µM target for up to 4 weeks after the final dose in the 120-mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX-101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady-state serum fAAT ≥21µM at 120 mg/kg Q3W (average concentration ≈43µM; trough concentration ≈28µM) and Q4W (≈34µM; ≈21µM). CONCLUSION: The favorable safety profile and ability to maintain serum fAAT levels >21µM with extended-interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX-101.

Background: Alpha-1 antitrypsin deficiency (AATD) is associated with increased susceptibility to chronic obstructive pulmonary disease (COPD). AATD results from mutations in the SERPINA1 gene and over 500 rare mutations have been identified. Despite these findings and recommendations from major healthcare organizations, testing of COPD patients and their family members for AATD remains inadequate. Methods: We examined genotypes and clinical characteristics of COPD patients (index cases; n = 14) treated at Recep Tayyip Erdoğan University Chest Diseases Department and their relatives (n = 17). Results: When index cases were compared with screened relatives positive for AATD (n = 14), index cases were older and more predominantly male than screened relatives. Both groups had extensive smoking histories. All of the index cases and one of the screened relatives had been diagnosed with COPD. Clinical characterization of the COPD cases (14 index cases; 1 screened relative) showed that they had moderate to severe COPD with pre-treatment AAT levels of 0.59 ± 0.40 g/L (mean ± SD) and a COPD Assessment Test (CAT) score of 16.0 ± 8.12. The majority of these patients (73.3%) had panlobular emphysema. Five of the patients were treated with AAT augmentation which led to a decrease in the number of COPD exacerbations. Genotyping revealed that the most common rare allele identified in this population was MPalermo (c.227_229delTCT mutation on the M1(Val213) allelic background). Conclusions: More testing and research need to be done to identify the relative prevalence of rare AATD variants. Earlier identification could lead to more effective treatment of affected individuals and improvement in their quality of life. [ABSTRACT FROM AUTHOR]

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that predisposes a person to certain diseases over their lifetime, mainly including lung disease (in the form of emphysema) and liver disease (liver cirrhosis). Quality of life questionnaires are instruments designed to quantify the deterioration of a patient's health. Background/Objectives: This study aimed to assess whether certain quality of life tests that are routinely used in clinical practice can be useful for patients with AATD. Methods: A sample of AATD patients, with various genotypes, but with the common characteristic that they must have both altered alleles (Pi* ≠ M), participated in the study. Different quality of life tests were used, including the COPD Assessment Test (CAT), COPD and Asthma Sleep Impact Scale, the short form of the Short Form Health Survey, and EuroQol 5 dimensions, and were related to differing clinical and functional characteristics. Results: The sample was composed of 54 patients, and slightly more than half of the participants were women (57.4%), with a mean age of 51.5 ± 13.7. The main genotypes were Pi*SZ (43.4%) and Pi*ZZ (34%). In patients under 65 years of age (n = 47), those who were actively working could walk a greater distance in the walking test, namely, 573 m (511–629), compared to those who were not actively working, namely, 415.5 m (392–469; p < 0.001). Active non-workers had a worse CAT (13.6 ± 7.8 vs. 4.6 ± 4.3; p < 0.001). In total, 80% of non-working patients had exacerbations, but only 46. 9% of those who were active, although the association did not reach statistical significance (p = 0.068). Having a lower score in the physical component of SF-12 was related to suffering from lung disease (46.0 ± 11.4 vs. 38.4 ± 11.1 (p = 0.026)). Conclusions: Quality of life tests were able to detect differences and relate them to functional factors such as the distance covered in the walking test, being sensitive and specific in this regard. [ABSTRACT FROM AUTHOR]

Identifying patients with rare diseases like alpha-1 antitrypsin deficiency (AATD) is challenging. Machine-learning models may be trained to identify patients with rare diseases using large-scale, real-world databases, whereas electronic medical records have low numbers of confirmed cases and have limited use in training such models. We applied a machine-learning model to a large US claims database to identify undiagnosed symptomatic patients with AATD. Using deidentified data from the Komodo US claims database (April 26, 2016–January 31, 2023), a model was trained to identify symptomatic patients with high probability of AATD. Eighty claims records for high-probability candidates identified by the model were independently reviewed and validated by 2 clinical experts. The experts independently indicated that of the 80 high-probability candidate patients, 65 (81%) and 62 (78%) patients, respectively, should be tested for AATD. Feedback from this validation step informed model optimization. The optimized model was applied to claims data to identify symptomatic patients with probable AATD. Eleven and 14 "features" of the claims data were informative in distinguishing patients with AATD from patients with COPD without AATD and from unspecified chronic liver diseases. Moreover, patients with diagnosed AATD and COPD without AATD had unique cadences of similar medical events in their diagnostic journeys. Our work shows that a machine-learning model trained on a large US claims database can accurately identify symptomatic patients with AATD and provides useful insights into the diagnostic journey of patients with AATD. [ABSTRACT FROM AUTHOR]

Joshua De Soyza, Hung-Yeh Chien, Adeola Ayodotun Onasanya, Alice M Turner Institute of Applied Health Sciences, University of Birmingham, Birmingham, UKCorrespondence: Joshua De Soyza, Email j.desoyza@bham.ac.ukAbstract: Alpha-1 antitrypsin deficiency (AATD) is a rare cause of chronic lung and liver disease without its own patient reported-outcome measure (PROM). PROMs for Chronic Obstructive Pulmonary Disease (COPD) are commonly used instead, but AATD differs from COPD in several ways. We reviewed whether the PROMs used in the AATD literature adequately assess quality-of-life in these patients. 11 studies used PROMs as their primary outcomes; 21 included them as secondary outcomes. The St George’s Respiratory Questionnaire (SGRQ) was the most commonly used PROM, used by 7 of the 11 primary outcome studies. Others included the COPD Assessment Tool, SF-36, LCOPD, EQ-5D, and the Chronic Respiratory Diseases Questionnaire. Several studies assessed SGRQ as being associated with respiratory disease severity as measured by FEV1% predicted, exacerbation rate, oxygen use and exercise tolerance. However, no studies used PROMs which included assessment of liver-related symptoms, other extra-pulmonary manifestations of AATD, or concerns related to genetics or finances. These factors are likely to have an impact on quality of life in AATD. A specific AATD-PROM is therefore required to holistically address the quality of life effects of an AATD diagnosis.Keywords: alpha-1 antitrypsin deficiency, COPD, chronic liver disease, rare diseases

Abstract Background Alpha-1 antitrypsin deficiency (AATD) is associated with increased susceptibility to chronic obstructive pulmonary disease (COPD). AATD results from mutations in the SERPINA1 gene and over 500 rare mutations have been identified. Despite these findings and recommendations from major healthcare organizations, testing of COPD patients and their family members for AATD remains inadequate. Methods We examined genotypes and clinical characteristics of COPD patients (index cases; n = 14) treated at Recep Tayyip Erdoğan University Chest Diseases Department and their relatives (n = 17). Results When index cases were compared with screened relatives positive for AATD (n = 14), index cases were older and more predominantly male than screened relatives. Both groups had extensive smoking histories. All of the index cases and one of the screened relatives had been diagnosed with COPD. Clinical characterization of the COPD cases (14 index cases; 1 screened relative) showed that they had moderate to severe COPD with pre-treatment AAT levels of 0.59 ± 0.40 g/L (mean ± SD) and a COPD Assessment Test (CAT) score of 16.0 ± 8.12. The majority of these patients (73.3%) had panlobular emphysema. Five of the patients were treated with AAT augmentation which led to a decrease in the number of COPD exacerbations. Genotyping revealed that the most common rare allele identified in this population was MPalermo (c.227_229delTCT mutation on the M1(Val213) allelic background). Conclusions More testing and research need to be done to identify the relative prevalence of rare AATD variants. Earlier identification could lead to more effective treatment of affected individuals and improvement in their quality of life.

Abstract Purpose Patients with alpha-1 antitrypsin deficiency (AATD) often experience substantial delays from the onset of symptoms to a diagnosis. We explored the impact of delayed diagnosis of AATD on healthcare costs and utilization by assessing costs/utilization before and after diagnosis. Methods Retrospective claims data was used to conduct a longitudinal analysis of a cohort of patients with follow-up over four years in a commercial claims database was conducted. Patients with at least four years of claims experience between the years 2011 – 2017 were included in this study. Outcome measures were calculated for each year (Year 1 pre-index diagnosis, and Years 1, 2, and 3 post-index follow-up). Measures included healthcare costs (pharmacy and medical costs), medical costs, inpatient events, and emergency room visits. Unadjusted measures in the follow-up Year 1, Year 2, and Year 3 were compared to Year 1 pre-index. A separate multivariate analysis adjusting for age, sex, and comorbidities was conducted. Results Among 1258 patients, mean adjusted healthcare costs were significantly higher in Year 1 post-index compared to Year 1 pre-index ($51,785 vs $41,441, p =

Purpose: Patients with alpha-1 antitrypsin deficiency (AATD) often experience substantial delays from the onset of symptoms to a diagnosis. We explored the impact of delayed diagnosis of AATD on healthcare costs and utilization by assessing costs/utilization before and after diagnosis. Methods: Retrospective claims data was used to conduct a longitudinal analysis of a cohort of patients with follow-up over four years in a commercial claims database was conducted. Patients with at least four years of claims experience between the years 2011 – 2017 were included in this study. Outcome measures were calculated for each year (Year 1 pre-index diagnosis, and Years 1, 2, and 3 post-index follow-up). Measures included healthcare costs (pharmacy and medical costs), medical costs, inpatient events, and emergency room visits. Unadjusted measures in the follow-up Year 1, Year 2, and Year 3 were compared to Year 1 pre-index. A separate multivariate analysis adjusting for age, sex, and comorbidities was conducted. Results: Among 1258 patients, mean adjusted healthcare costs were significantly higher in Year 1 post-index compared to Year 1 pre-index ($51,785 vs $41,441, p = < 0.05). In Year 2 ($36,937 vs $41,441, p = < 0.05) and 3 ($28,558 vs $41,441, p = < 0.05) post-index, mean adjusted healthcare costs decreased compared to Year 1 pre-index. Adjusted medical costs were similar in Year 1 ($25,034) post-index compared to Year 1 ($22,952) pre-index but were significantly lower in Year 2 ($15,242 vs $25,034, p = < 0.05) and Year 3 ($8,779 vs $25,034, p = < 0.05) post-index. The frequency of inpatient and emergency room events was significantly lower in all three observation periods following diagnosis in the unadjusted analysis. The adjusted analysis showed similar findings, except for emergency room visits, which were similar across all observation periods. Conclusion: Patients with AATD had substantial healthcare costs/utilization in the year before diagnosis. Costs were significantly higher in the first year following diagnosis. However, subsequent years showed cost reductions to levels below pre-diagnosis. These data support the need for strategies to reduce the time from symptom onset to diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the number and clinical characteristics of hospital admissions in Spain between 2016 and 2022 in which alpha-1-antitrypsin deficiency (AATD) was coded; to describe and analyze differences in these parameters between men and women; and to identify variables associated with a worse prognosis. Methods: We used a nationwide discharge database to select all admissions featuring an AATD diagnostic code (ICD-10 code E88.01) in any position. Results: We found 5142 hospital admissions with a diagnosis of AATD and detected a significant increase in their number from 2016 to 2022 (p = 0.034 for trend). Males accounted for 58.21% of the hospitalizations and had a higher Charlson Comorbidity Index than women (1.86 vs. 1.33; p < 0.001), were hospitalized more frequently (21.18% of men were hospitalized more than once vs. 17.76% of women, p < 0.001), and had a higher probability of severe disease (OR 1.39; 95%CI 1.10–1.75). Crude in-hospital mortality (IHM) was 6.85% in men and 4.8% in women (p = 0.007). The variables associated with IHM in both sexes were older age, more hospital admissions, and liver disease or lung cancer. Invasive and non-invasive mechanical ventilation and admission to the ICU were also associated with IHM in men and women. Multivariable adjustment revealed no association between sex and IHM. Conclusions: The number of hospitalizations for AATD increased in Spain from 2016 to 2022. Men represented almost 60% of hospitalizations, were admitted more frequently and with more comorbidities, and had a higher probability of severe disease than women. There was no association between sex and IHM. [ABSTRACT FROM AUTHOR]

Background: Alpha-1 antitrypsin deficiency (AATD) is an inflammatory disorder where neutrophils play a key role. Excessive neutrophil activation leads to local hypoxia and tissue damage. Most research on neutrophil function has been conducted under atmospheric conditions (21% O2), which may not represent physiological or pathological conditions. This study aimed to determine the effects of hypoxia on neutrophil degranulation and cytokine production in AATD patients. Methods: Neutrophils isolated from 54 AATD patients (31 MZ; 8 SZ; 15 ZZ) and 7 controls (MM) were exposed to hypoxia (1% O2) for 4 h. Neutrophil degranulation was assessed by measuring elastase (NE), myeloperoxidase (MPO), lactoferrin, and matrix metalloproteinase-9 (MMP-9) levels using immunoassay-based methods. Pro-inflammatory (IL-8, IL-1 beta, IL-6, and TNF-alpha) and anti-inflammatory (IL-4 and IL-10) cytokine levels were assessed by a Luminex-based method. Results: Our results indicate a significantly increased release of NE (p = 0.015), MPO (p = 0.042), lactoferrin (p = 0.015), and MMP-9 (p = 0.001) compared to controls. Pro-inflammatory cytokines show a significant rise in IL-8 (p = 0.019), a trend towards increased IL-1 beta (p = 0.3196), no change in IL-6 (p = 0.7329), and reduced TNF-alpha (p = 0.006). Anti-inflammatory cytokines show increased IL-4 (p = 0.057) and decreased IL-10 (p = 0.05703). Conclusions: Increased neutrophil degranulation and inflammatory phenotype are observed in AATD neutrophils under physiological hypoxia. [ABSTRACT FROM AUTHOR]

Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced plasma levels of alpha-1 antitrypsin (AAT), often leading to pulmonary diseases primarily emphysema and/or chronic obstructive pulmonary disease (COPD), but also bronchiectasis, bronchial asthma, or other less common disorders. Early diagnosis enables AAT augmentation therapy, which has proven to be effective in slowing down functional decline and improving survival rates. This article presents two cases of pregnant women with rare allelic variants of AATD who received AAT augmentation therapy, exploring the limited evidence on its safety during pregnancy and the potential role of decreased serum AAT levels in pregnancy-related complications.

The article discusses the risk of lung disease associated with the Pi*SS genotype of alpha-1 antitrypsin deficiency (AATD). The authors analyze data from the EARCO registry and compare the Pi*SS genotype to other severe genotypes like Pi*SZ and Pi*ZZ. They find that individuals with the Pi*SS genotype have a lower prevalence of lung disease compared to Pi*ZZ individuals, but similar to Pi*SZ. The study raises concerns about ascertainment bias in registry data and emphasizes the need for careful consideration when discussing severe states of AATD, suggesting that Pi*SZ should no longer be described as a severe deficiency. [Extracted from the article]

Severe inherited alpha-1 antitrypsin deficiency (AATD) is an autosomal genetic condition linked to chronic obstructive pulmonary disease (COPD). The significance of heterozygous, milder deficiency variants (PiSZ, PiMZ, PiMS) is less clear. We studied AATD genotypes in 145 children (up to 72 months old) with assessed wheezing severity using the Pediatric Respiratory Assessment Measure (BCCH PRAM score). A control group of 74 children without airway obstruction was included. AAT concentration and Pi phenotype were determined from dry blood spot samples using nephelometry and real-time PCR; PiS and PiZ alleles were identified by isoelectrofocusing. Among the wheezers, the Pi*S allele incidence was 2.07% (3 cases) and the Pi*Z allele was 6.9% (10 cases). The Pi*Z allele frequency was higher in wheezers compared to controls (44.8% vs. 20.27%) and the general Lithuanian population (44.8% vs. 13.6%) and was similar to adult COPD patients in Lithuania: Pi*S 10.3% vs. 15.8% and Pi*Z 44.8% vs. 46.1%. No association was found between AAT genotypes and wheezing severity. Finding that wheezer children exhibit a frequency of Z* and S* alleles like that found in adults with COPD suggests a potential genetic predisposition that links early wheezing in children to the development of COPD in adulthood. Larger cohort studies are needed to confirm this finding.

May Hagiwara,1 Victoria Divino,2 Swapna Munnangi,2 Mark Delegge,2 Suna Park,1 Ed G Marins,3 Kaili Ren,4 Charlie Strange5 1Global Evidence and Outcomes, Takeda Development Center Americas, Inc., Cambridge, MA, USA; 2Medical and Scientific Services, IQVIA Inc., Falls Church, VA, USA; 3Global Medical Affairs, Takeda Development Center Americas, Inc., Cambridge, MA, USA; 4Statistics and Quantitative Sciences, Takeda Development Center Americas, Inc., Cambridge, MA, USA; 5Department of Medicine, Medical University of South Carolina, Charleston, SC, USACorrespondence: May Hagiwara, Takeda Development Center Americas, Inc., 500 Kendall Street, Cambridge, MA, 02142, USA, Tel +1 781-482-0426, Email may.hagiwara@takeda.comBackground and Aims: Real-world analyses on burden of illness in patients with alpha-1 antitrypsin deficiency (AATD) are limited. We investigated the real-world burden of liver-related clinical events among adult and pediatric patients with AATD in the USA.Methods: This was a retrospective, observational analysis of administrative claims data from the IQVIA PharMetrics® Plus and Ambulatory Electronic Medical Records databases from 2011 to 2022. Patients had a diagnosis of liver and/or lung disease with ≥ 180 days of continuous enrollment in the IQVIA PharMetrics Plus database before and ≥ 90 days after their first diagnosis. Follow-up time was assigned to the AATD with liver disease health state or AATD with both liver and lung disease health state (for patients aged ≥ 18 years only). Baseline demographic characteristics and liver-related clinical events of interest were reported.Results: Of 5136 eligible patients, 771 adult and 123 pediatric patients contributed time to the AATD with liver disease health state; 541 adults contributed time to the AATD with both liver and lung disease health state. Among adults, patients with both liver and lung disease had higher rates of liver-related clinical events than patients with liver disease alone. Ascites was the most frequently observed clinical event among adults in both health states, and the median time to the composite of any liver-related clinical event was 26.5 days among all adults combined. Across all pediatric age groups, ascites, gastrointestinal bleed and hepatic encephalopathy were more common than spontaneous bacterial peritonitis and hepatocellular carcinoma, but median time to liver-related clinical event varied by age group at index date and type of event. No liver transplantations occurred in patients aged 6– 17 years.Conclusion: Diagnosed AATD with liver disease carries a substantial burden on adult and pediatric patients; new treatment options are warranted to avoid disease progression to decompensating events.Keywords: alpha-1 antitrypsin deficiency, genetic disease, liver disease, lung disease, pediatric, adult

Severe alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of emphysema. However, the clinical manifestations are very heterogeneous, and an individual prognosis is very difficult to establish. Intravenous augmentation therapy with alpha-1 antitrypsin (AAT) from pooled blood donors is the only specific treatment available, but it requires weekly or biweekly administration for life. Several guidelines provide the indication criteria for the initiation of AAT augmentation therapy. However, in clinical practice, there are situations in which the decision as to when to start treatment becomes uncertain and some studies have shown great variability in the indication of this treatment even among specialists. The usual dilemma is between initiating augmentation therapy in individuals who may not develop significant lung disease or in whom disease will not progress or delaying it in patients who may otherwise rapidly and irreversibly progress. We illustrate this dilemma with five clinical cases: from the case of a patient with normal lung function who requests initiation of therapy to a moderately stable patient without augmentation or a mild patient who, after several years of remaining stable without treatment, deterioration in lung function initiated and, consequently, augmentation therapy was begun. All the nuances associated with the indication of augmentation justify a personalised approach and the decision about initiating augmentation therapy must be made after careful consideration of the pros and cons with the patient in reference centres with experience in treatment. These reference centres can work in collaboration with local hospitals where patients can be closely followed and augmentation therapy can be administered to avoid unnecessary travelling, making periodical administrations more comfortable for the patient. [ABSTRACT FROM AUTHOR]

Alpha1-antitrypsin (A1AT) is an anti-inflammatory mediator with antiprotease activity associated with anti-inflammatory and immunomodulatory effects in various inflammatory conditions. A1AT deficiency (A1ATD) has been associated with various hyperinflammatory diseases, such as lung disease (emphysema and bronchiectasis), liver disease (chronic hepatitis, cirrhosis, and hepatoma), and skin diseases (panniculitis). Migraine with aura is one of the common migraine subtypes associated with neuroimmunologic activation and neuroinflammation which is associated with cortical spreading depression and glial hyperinflammation in etioradiopathogenesis, and the main mechanisms explained so far are hyperinflammation of pro-inflammatory mediators, sensitivity of trigeminal nerve fibers and pain-conjugated glial cells activation. In this case report, a causative perspective of migraine with aura and A1ATD was presented through etioradiopathogenetics mechanisms that show the central reflections of systemic hyperinflammatory processes, and the importance of peripheral hyperinflammatory conditions in migraine etiology was examined. [ABSTRACT FROM AUTHOR]

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses. Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved. Results: AAT significantly reduced NE and PR3 activity footprints, with themaximal reduction achieved at concentrations above 10 µM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone. Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell (iPSC) and CRISPR-Cas9 gene-editing technologies have become powerful tools in disease modeling and treatment. By harnessing recent biotechnological advancements, this review aims to equip researchers and clinicians with a comprehensive and updated understanding of the evolving treatment landscape for metabolic and genetic disorders, highlighting how iPSCs provide a unique platform for detailed pathological modeling and pharmacological testing, driving forward precision medicine and drug discovery. Concurrently, CRISPR-Cas9 offers unprecedented precision in gene correction, presenting potential curative therapies that move beyond symptomatic treatment. Therefore, this review examines the transformative role of iPSC technology and CRISPR-Cas9 gene editing in addressing metabolic and genetic disorders such as alpha-1 antitrypsin deficiency (A1AD) and glycogen storage disease (GSD), which significantly impact liver and pulmonary health and pose substantial challenges in clinical management. In addition, this review discusses significant achievements alongside persistent challenges such as technical limitations, ethical concerns, and regulatory hurdles. Future directions, including innovations in gene-editing accuracy and therapeutic delivery systems, are emphasized for next-generation therapies that leverage the full potential of iPSC and CRISPR-Cas9 technologies. [ABSTRACT FROM AUTHOR]

Radmila Choate,1 Kristen E Holm,2,3 Robert A Sandhaus,2,3 David M Mannino,4 Charlie Strange3,5 1University of Kentucky College of Public Health, Lexington, Kentucky, USA; 2Department of Medicine, National Jewish Health, Denver, Colorado, USA; 3Alphanet, Inc., Coral Gables, Florida, USA; 4University of Kentucky College of Medicine, Lexington, Kentucky, USA; 5Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, South Carolina, USACorrespondence: Radmila Choate, University of Kentucky College of Public Health, Lexington, Kentucky, USA, Tel +1 859-218-2237, Email Radmila.choate@uky.eduBackground: Health-related quality of life (HRQoL) assessments such as St. George’s Respiratory Questionnaire (SGRQ) are often used as outcome measures to evaluate patient-perceived changes in health status among individuals with lung disease. Several factors have been linked to deterioration in SGRQ, including symptoms (dyspnea, wheezing) and exercise intolerance. Whether these findings apply to individuals with alpha-1 antitrypsin deficiency (AATD) remains incompletely studied. This longitudinal study examines the trajectory of SGRQ scores in a cohort of United States individuals with AATD-associated lung disease and defines factors associated with longitudinal change.Methods: Individuals with AATD-associated lung disease enrolled in AlphaNet, a disease management program, who had ≥ 3 SGRQ measurements collected between 2009 and 2019, and baseline data for clinically important variables were included in these analyses. Data collected after lung transplants were excluded. Mixed-effects model analyses were used to evaluate the changes in SGRQ total and subscale scores over time and by modified Medical Research Council (mMRC) Scale, use of oxygen, age, sex, productive cough, and exacerbation frequency at baseline. Sensitivity analyses were conducted to examine the potential effect of survivor bias.Results: Participants (n=2456, mean age 57.1± 9.9 years, 47% female) had a mean SGRQ total score of 44.7± 18.9 at baseline, 48% used oxygen regularly, and 55% had ≥ 2 exacerbations per year. The median length of follow-up was 6 (IQR 3– 9) years. The SGRQ total score and subscales remained stable throughout the observation period. Age, mMRC categories, presence or absence of productive cough, frequency of exacerbations, and use of oxygen at baseline were significantly associated with the rate of change of SGRQ total (p< 0.0001).Conclusion: We observed long-term stability in HRQoL and an association between the rate of change in SGRQ and baseline mMRC, exacerbation frequency, productive cough, and use of oxygen in this cohort of individuals with AATD-associated lung disease.Keywords: COPD, alpha-1 antitrypsin deficiency, quality of life

Abstract Background Generic measures of health-related quality of life (HRQoL), such as the 36-Item Short Form Survey (SF-36), are widely used in assessing chronic conditions. These tools have an advantage over disease-specific instruments, as they allow comparisons across different health conditions and with the general population. In alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD), HRQoL research remains scarce. This cross-sectional study evaluates the factors associated with HRQoL in a cohort of patients with AATD-associated COPD. Methods Our study included participants of AlphaNet (2008-2019), a health management organization for people with AATD in the US who are prescribed augmentation therapy. Norm-based SF-36 scores for the mental and physical component summary scores (MCS and PCS, mean of 50 ± 10 in the general US population) and 8 individual scales were evaluated. Individuals with lung disease and data available on ≥1 measurement on any SF-36 scale and clinically relevant characteristics such as modified Medical Research Council (mMRC) scale, exacerbation frequency, productive cough, and use of oxygen were included in these analyses. Generalized linear regression models were fit to examine the association of baseline characteristics with MCS and PCS scores. Age, sex, regular use of oxygen, exacerbation frequency, mMRC, and productive cough were included in these models. Results Participants (n=4398, mean age 57.6 [SD=10.6] years, 45.4% female) had a mean MCS score of 51.2 ± 10.8 and PCS of 36.3 ± 9.8. The average mMRC score was 2.4 ± 1.3, and 56.4% had 2 or more exacerbations per year. Overall, the physical component of SF-36 was more severely impacted compared to the mental component. In multivariable regression analyses, PCS scores were significantly associated with exacerbation frequency, mMRC, regular use of oxygen, and productive cough; MCS was associated with age, sex, exacerbation frequency, mMRC, and productive cough. Conclusions These findings demonstrate that patient-perceived physical health is significantly impaired in this cohort of people with AATD-associated COPD compared to mental health. Longitudinal studies are needed to evaluate the change in physical and mental health status over time in this population.

Background: Generic measures of health-related quality of life (HRQoL), such as the 36-Item Short Form Survey (SF-36), are widely used in assessing chronic conditions. These tools have an advantage over disease-specific instruments, as they allow comparisons across different health conditions and with the general population. In alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD), HRQoL research remains scarce. This cross-sectional study evaluates the factors associated with HRQoL in a cohort of patients with AATD-associated COPD. Methods: Our study included participants of AlphaNet (2008-2019), a health management organization for people with AATD in the US who are prescribed augmentation therapy. Norm-based SF-36 scores for the mental and physical component summary scores (MCS and PCS, mean of 50 ± 10 in the general US population) and 8 individual scales were evaluated. Individuals with lung disease and data available on ≥1 measurement on any SF-36 scale and clinically relevant characteristics such as modified Medical Research Council (mMRC) scale, exacerbation frequency, productive cough, and use of oxygen were included in these analyses. Generalized linear regression models were fit to examine the association of baseline characteristics with MCS and PCS scores. Age, sex, regular use of oxygen, exacerbation frequency, mMRC, and productive cough were included in these models. Results: Participants (n=4398, mean age 57.6 [SD=10.6] years, 45.4% female) had a mean MCS score of 51.2 ± 10.8 and PCS of 36.3 ± 9.8. The average mMRC score was 2.4 ± 1.3, and 56.4% had 2 or more exacerbations per year. Overall, the physical component of SF-36 was more severely impacted compared to the mental component. In multivariable regression analyses, PCS scores were significantly associated with exacerbation frequency, mMRC, regular use of oxygen, and productive cough; MCS was associated with age, sex, exacerbation frequency, mMRC, and productive cough. Conclusions: These findings demonstrate that patient-perceived physical health is significantly impaired in this cohort of people with AATD-associated COPD compared to mental health. Longitudinal studies are needed to evaluate the change in physical and mental health status over time in this population. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a lung disease which is the third most common cause of premature death globally. Inhaling dangerous gases, cigarette smoking, and exposure to pollution are the main factors contributing to the development of COPD. These factors may harm lung tissue and create COPD causes. Increased synthesis of inflammatory mediators and proteases because of cigarette smoking exposure to transcriptional factors. Dysfunction of mitochondria essential part to lead and development of several human illnesses, such as chronic obstructive pulmonary disease. Alpha-1 antitrypsin deficiency boosts neutrophil elastase activity, which promotes tissue deterioration and emphysema (particularly in smokers because cigarette smoke also boosts protease activity). In this review, we discussed all these factors and summarized the conventional drug currently present for the treatment of COPD. In addition, we also focused on various natural compounds categorized under the flavonoids, polyphenols, alkaloids, glycosides and marine compounds which were reported for the effective treatment of COPD.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses.Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved.Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10 μM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone.Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management.

Paul Ellis,1,2 Emily Bailey,2 Radmila Choate,3 Kristen E Holm,4,5 Robert A Sandhaus,5,6 Alice M Turner,1,2 Michael Newnham1,2 1Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 2University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 3University of Kentucky College of Public Health, Lexington, KY, USA; 4Division of Neurology and Behavioural Health, National Jewish Health, Denver, CO, USA; 5AlphaNet, Kissimmee, FL, USA; 6Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USACorrespondence: Paul Ellis, Email p.ellis@bham.ac.ukAim: Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD.Methods: Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE.Results: Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001).Conclusion: In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.Keywords: chronic obstructive pulmonary disease, COPD, alpha-1 antitrypsin deficiency, AATD, cardiovascular disease

During the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully understood. Governmental non-pharmaceutical interventions (NPI’s), an increase in community treated exacerbations, or healthcare avoidance by patients, are potential reasons. For the current study, the impact of Dutch governmental NPI’s on the COPD exacerbations and respiratory infections rate in patients with severe alpha-1 antitrypsin deficiency (AATD) was analyzed. The patients participated in the NCT04204252 study, a randomized controlled trial evaluating the efficacy and safety of inhaled alpha-1 antitrypsin. Data collected in the time-period from March 2020 until February 2022 was analyzed. In this period the Dutch government imposed variable NPI’s to contain the spread of SARS-CoV-2. Patients were required to document their daily symptoms in an electronic diary. The strictness of the governmental NPI’s was measured by the COVID-19 Stringency Index. 19 patients participated in this study during the analysis period. A total of 40 respiratory infections and COPD exacerbations occurred. The Spearman’s correlation coefficient of the monthly average COVID-19 Stringency Index and respiratory infections and COPD exacerbations rate was −0.316 (p = 0.132). When months known for a low respiratory infection rate were excluded, the correlation coefficient was −0.625 (p = 0.010). This study showed a significant negative correlation between the COPD exacerbations and respiratory infection rate and the COVID-19 Stringency Index in patients with AATD related COPD in the autumn-winter months.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is an under-recognized hereditary disorder and a significant cause of chronic obstructive pulmonary disease (COPD), a disease that contributes to global mortality. AAT is encoded by the SERPINA1 gene, and severe mutation variants of this gene increase the risk of developing COPD. AATD is more frequently screened for in non-Hispanic White populations. However, AATD is also observed in other ethnic groups and very few studies have documented the mutation frequency in these other ethnic populations. Here, we review the current literature on AATD and allele frequency primarily in Black populations and discuss the possible clinical outcomes of low screening rates in a population that experiences poor health outcomes and whether the low frequency of AATD is related to a lack of screening in this population or a truly low frequency of mutations causing AATD. This review also outlines the harmful SERPINA1 variants, the current epidemiology knowledge of AATD, health inequity in Black populations, AATD prevalence in Black populations, the clinical implications of low screening of AATD in this population, and the possible dangers of not diagnosing or treating AATD.

Background: Alpha-1 antitrypsin deficiency (AATD) is an inflammatory disorder where neutrophils play a key role. Excessive neutrophil activation leads to local hypoxia and tissue damage. Most research on neutrophil function has been conducted under atmospheric conditions (21% O2), which may not represent physiological or pathological conditions. This study aimed to determine the effects of hypoxia on neutrophil degranulation and cytokine production in AATD patients. Methods: Neutrophils isolated from 54 AATD patients (31 MZ; 8 SZ; 15 ZZ) and 7 controls (MM) were exposed to hypoxia (1% O2) for 4 h. Neutrophil degranulation was assessed by measuring elastase (NE), myeloperoxidase (MPO), lactoferrin, and matrix metalloproteinase-9 (MMP-9) levels using immunoassay-based methods. Pro-inflammatory (IL-8, IL-1 beta, IL-6, and TNF-alpha) and anti-inflammatory (IL-4 and IL-10) cytokine levels were assessed by a Luminex-based method. Results: Our results indicate a significantly increased release of NE (p = 0.015), MPO (p = 0.042), lactoferrin (p = 0.015), and MMP-9 (p = 0.001) compared to controls. Pro-inflammatory cytokines show a significant rise in IL-8 (p = 0.019), a trend towards increased IL-1 beta (p = 0.3196), no change in IL-6 (p = 0.7329), and reduced TNF-alpha (p = 0.006). Anti-inflammatory cytokines show increased IL-4 (p = 0.057) and decreased IL-10 (p = 0.05703). Conclusions: Increased neutrophil degranulation and inflammatory phenotype are observed in AATD neutrophils under physiological hypoxia.

Seda Tural Onur,1 Antonino Natoli,2 Bettina Dreger,2 Sibel Ar&inodot;nç,3 Nurhan Sar&inodot;o&gbreve;lu,4 Mustafa Çörtük,1 Dilek Karado&gbreve;an,5 Abdurrahman &Scedil;enyi&gbreve;it,6 Birsen P&inodot;nar Y&inodot;ld&inodot;z,1 Nurdan Köktürk,7 Serap Argun Bar&inodot;s,8 Sümeyye Kodalak Cengiz,7 Mehmet Polatli9 1Department of Pulmonology, Yedikule Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Türkiye; 2Scientific and Medical Affairs, Scientific Innovation Office, Grifols, Frankfurt, Deutschland; 3Clinic of Chest Diseases, University of Health Sciences Turkey, S.B.Ü. Süreyyapa&scedil;a Chest Diseases and Thoracic Surgery Training and Research Hospital, &Idot;stanbul, Türkiye; 4Department of Pulmonology, Bal&inodot;kesir University Faculty of Medicine, Pulmonology Clinic, Bal&inodot;kesir, Türkiye; 5Department of Chest Diseases, Recep Tayyip Erdo&gbreve;an University, School of Medicine, Rize, Türkiye; 6Department of Chest Diseases, Dicle University Faculty of Medicine Hospital, Diyarbak&inodot;r, Türkiye; 7Department of Pulmonary Medicine, Gazi University, School of Medicine, Ankara, Türkiye; 8Department of Pulmonary Diseases, Faculty of Medicine, Kocaeli University, Kocaeli, Türkiye; 9Faculty of Medicine, Aydin Adnan Menderes University, Aydin, TürkiyeCorrespondence: Mehmet Polatli, Faculty of Medicine, Aydin Adnan Menderes University, Zafer Mahallesi, Efeler, Aydin, 09100, Türkiye, Email mpolatli09@gmail.comPurpose: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition characterized by decreased serum alpha-1 antitrypsin (AAT) levels. We aim to identify AATD in patients with chronic obstructive pulmonary disease (COPD), bronchiectasis, or asthma and to report the frequency of AAT variants in Turkey.Patients and Methods: This non-interventional, multicenter, prospective study was conducted between October 2021 and June 2022. Adult patients with COPD, bronchiectasis, asthma, liver symptoms, or family members with AATD were included. Demographic and clinical characteristics, pulmonary diagnosis, respiratory symptoms, and AAT serum levels were assessed. Whole blood samples were collected as dried blood spots, and the most common AATD mutations were simultaneously tested by allele-specific genotyping.Results: A total of 1088 patients, mainly diagnosed with COPD (92.7%) and shortness of breath (78.7%), were assessed. Fifty-one (5%) were found to have AATD mutations. Fifteen (29.4%) patients had Pi&ast;S or Pi&ast;Z mutations, whereas 36 (70.6%) patients carried rare alleles Pi&ast;M malton (n=18, 35.3% of mutations), Pi&ast;I (n=8, 16%), Pi&ast;P lowell (n=7, 14%), Pi&ast;M heerlen (n=2, 4%), and Pi&ast;S iiyama (n=1, 2%). The most common heterozygous combinations were Pi&ast;M/Z (n=12, 24%), and Pi&ast;M/M malton (n=11, 22%). Ten patients with severe AATD due to two deficiency alleles were identified, two with the Pi&ast;Z/Z genotype, four with the genotype Pi&ast;M malton/M malton, three with Pi&ast;Z/M malton, and one with Pi&ast;Z/M heerlen.Conclusion: Our results identified AATD mutations as a genetic-based contributor to lung disease in patients with COPD or bronchiectasis and assessed their frequency in a population of Turkish patients.Keywords: alpha-1 antitrypsin deficiency, genotype, diagnosis, chronic obstructive pulmonary disease

Abstract Background A deficiency in alpha-1 antitrypsin (A1AD) leads to increased activity of proteolytic enzymes. The consequence is a damage of airways and alveoli and, ultimately, the development of emphysema and chronic obstructive pulmonary disease (COPD). Purpose Gender-specific differences in terms of comorbidities are still unclear due to the rarity of this genetic autosomal recessive disease. Patients and methods This retrospective observational study was conducted from January 1, 2005, to November 30, 2022, in the Department of Pneumology, HELIOS University-Clinic Wuppertal, University of Witten/Herdecke, Germany. Results Eleven patients with COPD due to A1AD could be included into the study (6 males, 54.5%; 95% CI 23.4–83.3%) with a mean age of 53.9 ± 11.6 years. The male study participants were of normal weight body mass index 24.17 ± 4.67, while the females were obese 31.2 ± 4.87 (p = 0.054). More women were smokers (60%, p = 0.567). Furthermore, all of the women had panlobular emphysema (100%, p = 0.455). All subjects suffered from COPD, with most male subjects in severe advanced stages (50%, p = 0.545). No case of liver involvement was observed in this study. Conclusion The findings of this study showed no statistically relevant gender-specific differences in comorbidities of patients with COPD due to A1AD.

Aim: To evaluate all-cause and liver-associated healthcare resource utilization (HCRU) and costs among patients with alpha-1 antitrypsin deficiency (AATD) with liver disease (LD) and/or lung disease (LgD). Materials & methods: This was a retrospective analysis of linked administrative claims data from the IQVIA PharMetrics R Plus and the IQVIA Ambulatory Electronic Medical Records (AEMR) databases from 1 July 2021 to 31 January 2022. Patients with AATD in the IQVIA PharMetrics Plus database were included with≥1 inpatient or≥2 outpatientmedical claims≥90 days apartwith a diagnosis of AATD, orwith records indicating a protease inhibitor (Pi)*ZZ/Pi*MZ genotype in the IQVIA AEMR databasewith linkage to IQVIA PharMetrics Plus. For a patient’s identified continuous enrollment period, patient time was assigned to health states based on the initial encounter with an LD/LgD diagnosis. A unique index date was defined for each health state, and HCRU and costs were calculated per person-year (PPY). Results: Overall, 5136 adult and pediatric patients from the IQVIA PharMetrics Plus and IQVIA AEMR databases were analyzed. All-cause and liver-associated HCRU and costs were substantially higher following onset of LD/LgD. Allcause cost PPY ranged from US $11,877 in the absence of either LD/LgD to US $74,015 in the presence of both LD and LgD. Among liver transplant recipients in the AATD with LD health state, liver-associated total costs PPY were US $87,329 1-year pre-transplantation and US $461,752 1-year post-transplantation. In the AATD with LgD and AATD with LD and LgD health states, patients who received augmentation therapy were associated with higher all-cause total costs PPY and lower liver-associated total costs PPY than their counterparts who did not receive augmentation therapy. Conclusion: Patients with AATD had increased HCRU and healthcare costs in the presence of LD and/or LgD. HCRU and healthcare costs were highest in the AATD with LD and LgD health state.

(1) Background: Few data are available on the risk of airway dysfunction in protease inhibitor (PI*) M heterozygotes carrying rare null or deficient allelic variants of the gene SERPINA-1 (PI*MR). (2) Methods: In this observational study, in a cohort of PI*MR heterozygotes, we evaluated respiratory functional parameters at baseline and at one-year follow-up. Moreover, we compared such parameters with those of the PI*MZ and PI*MS patients. (3) Results: A total of 60 patients were recruited; 35 PI*MR, 11 PI*MZ and 14 PI*MS. At the annual follow-up, the PI*MR and PI*MZ patients demonstrated a significantly higher FEV1 decline than the PI*MS group (p = 0.04 and p = 0.018, respectively). The PI*MR patients showed a significant increase in DLCO annual decline in comparison with the PI*MS group (p = 0.02). At baseline, the PI*MR smoking patients, compared with nonsmokers, showed statistically significant lower values of FEV1, FEV1/FVC and DLCO (p = 0.0004, p < 0.0001, p = 0.007, respectively) and, at the one-year follow-up, they displayed a significantly higher FEV1 and DLCO decline (p = 0.0022, p = 0.011, respectively). PI*MR heterozygotes with COPD showed a significantly higher FEV1, FEV1/FVC and DLCO annual decline in comparison with healthy PI*MR (p = 0.0083, p = 0.043, p = 0.041). (4) Conclusions: These results suggest that PI*MR heterozygotes, particularly smokers with COPD, have a greater annual decline in respiratory functional parameters and need to be monitored. [ABSTRACT FROM AUTHOR]

Intravenous augmentation therapy with human alpha-1 proteinase inhibitor for the management of respiratory disease is recommended for people with alpha-1 antitrypsin deficiency (AATD) who are nonsmokers or former smokers. Augmentation therapy usually requires weekly administration at the hospital or clinic and poses an additional burden for patients due to interference with daily life, including work and social activities. Self-administration is a useful alternative to overcome this limitation, but there is a lack of published information on clinical outcomes. We report two cases of individuals with AATD at different stages of the disease who were successfully managed with self-administered augmentation therapy, with increased satisfaction because of the independence gained, lack of interference with clinical stability, and no relevant safety issues. [ABSTRACT FROM AUTHOR]

This article discusses a study that aimed to improve the detection of Alpha-1 Antitrypsin Deficiency (AATD) through provider education. A web-based education module was developed and deployed to healthcare providers, focusing on addressing barriers to screening for AATD. The study found that provider confidence in identifying high-risk patients for AATD improved after completing the module, and the rate of screening for AATD also increased. The study highlights the importance of targeted healthcare provider education in improving AATD detection and emphasizes the value of testing in high-risk individuals. [Extracted from the article]

María Torres-Durán,1 José Luis López-Campos,2,3 Myriam Calle Rubio,4 Carmen Montero-Martínez,5 Ana Priegue Carrera,6 Rosanel Amaro Rodríguez,7 Miriam Barrecheguren,8 María Ángeles Barrio Guirado,9 Francisco Javier Callejas-González,10 Francisco Casas-Maldonado,11 Layla Diab-Cáceres,12 Pilar García-Meseguer,9 José María Hernández-Pérez,13 Lourdes Lázaro-Asegurado,14 Cristina Martínez-González,15 Carlos Martínez Rivera,16 Francisco Javier Michel,17 José-Bruno Montoro-Ronsano,18 Raquel Sánchez,19 Marta Ortiz-Pica,20 Isabel Parra,21 José Pablo Quintero García,22 María del Rosario Ruiz-Serrano-de la Espada,23 Begoña Tortajada-Goitia,24 Marc Miravitlles8 1Pneumology Department, Hospital Álvaro Cunqueiro, NeumoVigo I+i Research Group, IIS Galicia Sur, Vigo, Spain; 2Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; 3Medical and Surgery Unit for Respiratory Diseases, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Seville, Spain; 4Pneumology Department, Research Institute of Hospital Clínico San Carlos (IdISSC), Department of Medicine, Faculty of Medicine, University Complutense of Madrid, Madrid, Spain; 5Pneumology Department, Hospital Universitario de A Coruña, A Coruña, Spain; 6Nursing Unit, Hospital Álvaro Cunqueiro, Pontevedra, Spain; 7Pneumology Department, Hospital Clínic, Barcelona, Spain; 8Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 9Nursung Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 10Pneumology Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain; 11Pneumology Department, Hospital Universitario Clínico San Cecilio, Granada, Spain; 12Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; 13Pneumology Department, Hospital Universitario Nuestra Señora de La Candelaria, Santa Cruz de Tenerife, Tenerife, Spain; 14Pneumology Department, Complejo Asistencial Universitario de Burgos, Burgos, Spain; 15Instituto de Investigación Sanitaria del Principado de Asturias (FINBA-ISPA) Oviedo, Oviedo, Spain; 16Pneumology Department, Hospital Universitario Germans Trías I Pujol, Institut d’investigació Germans Trias i Pujol (IGTP), Badalona, Spain; 17Pneumology Department, Hospital Universitario Donostia, Donostia, Spain; 18Hospital Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 19Pneumology Department, Hospital Universitario Basurto, Bilbao, Spain; 20Nursing Unit, Hospital Clínico San Carlos, Madrid, Spain; 21Pneumology Department, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; 22Hospital Pharmacy Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 23Nursing Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 24Hospital Pharmacy Department, Hospital Costa del Sol, Málaga, SpainCorrespondence: María Torres-Durán, Tel +34986811111, Email maria.luisa.torres.duran@sergas.esPurpose: 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.Keywords: alpha-1 antitrypsin deficiency, disease burden, augmentation therapy, self-administration

Abstract Background Although bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features. Results Of the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis. Conclusions The data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy.

The underdiagnosis of alpha-1 antitrypsin (AAT) deficiency (AATD) has been recognized for many years, yet little progress has been made in treatment of the disease. In this review, we summarize the AATD disease process as well as its diagnosis and treatment by AAT augmentation therapy. AATD is a rare autosomal disease that primarily affects the lungs and liver. AATD is associated with an increased susceptibility to developing pulmonary emphysema. The specific pharmacological treatment for AATD is intravenous administration of exogenous AAT. Augmentation therapy with AAT increases serum and pulmonary epithelial AAT levels, restores anti-elastase capacity, and decreases inflammatory mediators in the lung. Augmentation therapy reduces the loss of lung density over time, thus slowing progression of the disease. The effects of augmentation therapy on outcomes, such as frequency/duration of flare-ups, quality of life, lung function decline and mortality, are assessed. Wider testing for AATD, potentially through primary care physicians, could result in earlier treatment and better outcomes for individuals with AATD-induced lung respiratory disease.

Alpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PI*MZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals. Here, we discuss the limited data on the PI*MZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PI*MZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed.

Management of lung disease in patients with alpha-1 antitrypsin deficiency (AATD) includes both non-pharmacological and pharmacological approaches. Lifestyle changes with avoidance of environmental pollutants, including tobacco smoke, improving exercise levels and nutritional status, all encompassed under a disease management program, are crucial pillars of AATD management. Non-pharmacological therapies follow conventional treatment guidelines for chronic obstructive pulmonary disease. Specific pharmacological treatment consists of administering exogenous alpha-1 antitrypsin (AAT) protein intravenously (augmentation therapy). This intervention raises AAT levels in serum and lung epithelial lining fluid, increases anti-elastase capacity, and decreases several inflammatory mediators in the lung. Radiologically, augmentation therapy reduces lung density loss over time, thus delaying disease progression. The effect of augmentation therapy on other lung-related outcomes, such as exacerbation frequency/length, quality of life, lung function decline, and mortality, are less clear and questions regarding dose optimization or route of administration are still debatable. This review discusses the rationale and available evidence for these interventions in AATD.

Background: A deficiency in alpha-1 antitrypsin (A1AD) leads to increased activity of proteolytic enzymes. The consequence is a damage of airways and alveoli and, ultimately, the development of emphysema and chronic obstructive pulmonary disease (COPD). Purpose: Gender-specific differences in terms of comorbidities are still unclear due to the rarity of this genetic autosomal recessive disease. Patients and methods: This retrospective observational study was conducted from January 1, 2005, to November 30, 2022, in the Department of Pneumology, HELIOS University-Clinic Wuppertal, University of Witten/Herdecke, Germany. Results: Eleven patients with COPD due to A1AD could be included into the study (6 males, 54.5%; 95% CI 23.4–83.3%) with a mean age of 53.9 ± 11.6 years. The male study participants were of normal weight body mass index 24.17 ± 4.67, while the females were obese 31.2 ± 4.87 (p = 0.054). More women were smokers (60%, p = 0.567). Furthermore, all of the women had panlobular emphysema (100%, p = 0.455). All subjects suffered from COPD, with most male subjects in severe advanced stages (50%, p = 0.545). No case of liver involvement was observed in this study. Conclusion: The findings of this study showed no statistically relevant gender-specific differences in comorbidities of patients with COPD due to A1AD. [ABSTRACT FROM AUTHOR]

Background. Alpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls. Methods. A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756. Results. The analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665–0.912; p = 0.002), a total of 24,428 individuals with AATD exhibited a significantly lower risk of ischemic heart disease compared to 534,654 non-AATD controls. Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls (OR: 0.774; 95%CI: 0.599–0.999; p = 0.049). Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex (Z-score: 3.40; p < 0.001), hypertension (Z-score: 2.31; p = 0.021), and diabetes (Z-score: 4.25; p < 0.001) were associated with a lower effect size. Conclusions. Individuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account. [ABSTRACT FROM AUTHOR]

Abstract Background Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder associated mainly with pulmonary emphysema and Chronic Obstructive Pulmonary Disease (COPD). All individuals with COPD regardless of age or ethnicity should be tested for AATD, but in Colombia its prevalence in unknown. Main objective To determine the prevalence of the genetic mutations, present in AATD in adult patients with COPD in Colombia, using a genotyping test on cells from the oral mucosa. Methods This was a multicentre, observational, cross-sectional study which included adult patients attending seven COPD care centres in Colombia. Demographic data, medical history, including history of exposure to smoking and biomass smoke, most recent spirometry, pharmacological and non-pharmacological treatment received, serum AAT levels, and mutations detected by the genotyping test were recorded for all the recruited patients. For the comparison of variables between the groups with and without mutation, we used the X2 test for the qualitative variables and the Student’s t-test or Mann-Whitney U test according to their distribution. Main findings We collected a sample of 1,107 patients, the median age was 73.8 years (87.6–79.9). Mutations were documented in 144 patients (13.01%), the majority had the M/S mutation (78.50%), followed by M/Z (9.72%). One patient had a ZZ mutation and two patients had null alleles. In total, 23 patients had mutations associated with serum AAT deficiency (levels below 60 mg/dl). Conclusions Genetic mutations were documented in 13.01% of patients with COPD in Colombia and 2.07% were AATD-related, showing that there is a significant number of underdiagnosed patients.

Abstract Background Alpha-1 antitrypsin deficiency (AATD) is characterized by reduced serum levels of the AAT protein and predisposes to liver and lung disease. The characterization at structural level of novel pathogenic SERPINA1 mutants coding for circulating AAT could provide novel insights into the mechanisms of AAT misfolding. The present study aimed to provide a practical framework for the identification and analysis of new AAT mutations, combining structural simulations and clinical data. Methods We analysed a total of five mutations (four not previously described) in a total of six subjects presenting moderate to severe AATD: Gly95Alafs*18, Val210Glu, Asn247Ser, Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile. Clinical data, genotyping and phenotyping assays, structural mapping, and conformational characterization through molecular dynamic (MD) simulations were developed and combined. Results Newly discovered AAT missense variants were localized both on the interaction surface and the hydrophobic core of the protein. Distribution of mutations across the structure revealed Val210Glu at the solvent exposed s4C strand and close to the “Gate” region. Asn247Ser was located on the accessible surface, which is important for glycan attachment. On the other hand, Asp341His, Leu383Phe were mapped close to the “breach” and “shutter” regions. MD analysis revealed the reshaping of local interactions around the investigated substitutions that have varying effects on AAT conformational flexibility, hydrophobic packing, and electronic surface properties. The most severe structural changes were observed in the double- and triple-mutant (Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile) molecular models. The two carriers presented impaired lung function. Conclusions The results characterize five variants, four of them previously unknown, of the SERPINA1 gene, which define new alleles contributing to the deficiency of AAT. Rare variants might be more frequent than expected, and therefore, in discordant cases, standardized screening of the S and Z alleles needs complementation with gene sequencing and structural approaches. The utility of computational modelling for providing supporting evidence of the pathogenicity of rare single nucleotide variations is discussed.

Intravenous augmentation therapy with human alpha-1 proteinase inhibitor for the management of respiratory disease is recommended for people with alpha-1 antitrypsin deficiency (AATD) who are nonsmokers or former smokers. Augmentation therapy usually requires weekly administration at the hospital or clinic and poses an additional burden for patients due to interference with daily life, including work and social activities. Self-administration is a useful alternative to overcome this limitation, but there is a lack of published information on clinical outcomes. We report two cases of individuals with AATD at different stages of the disease who were successfully managed with self-administered augmentation therapy, with increased satisfaction because of the independence gained, lack of interference with clinical stability, and no relevant safety issues.

Background: Although bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features. Results: Of the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis. Conclusions: The data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy. [ABSTRACT FROM AUTHOR]

Background/aim: Alpha-1 antitrypsin (AAT) deficiency is associated with several types of pathology, and the reported effects of mutations in the ATT-encoding gene vary worldwide. No Turkish study has yet appeared. We thus explored the AAT status of Turkish patients with chronic obstructive pulmonary disease (COPD). Materials and methods: This prospective cross-sectional study included outpatients and inpatients treated from June 2021 to June 2022. Serum AAT levels were checked, and dry blood samples were subjected to genetic analysis. Results: Genetic mutations were found in 21 (3.52%) of 596 patients with prior and new COPD diagnoses treated in our pneumonology outpatient department. The mean serum AAT level was 114.80 mg/dL (minimum 19, maximum 209; standard deviation 27.86 mg/dL). The most frequent mutation was M/Plowell (23.8%, n = 5), followed by M/S (23.8%, n = 5), M/I (19%, n = 4), M/Malton (14.3%, n = 3), Z/Z (9.5%, n = 2), M/Z (4.8%, n = 1), and Kayseri/Kayseri (4.8%, n = 1). Thoracic computed tomography revealed that 85.7% (n = 18) of all patients had emphysema, 28.5% (n = 6) had bronchiectasis, and 28.5% (n = 6) had mass lesions. Of the emphysema patients, 55% (n = 10) had only upper lobe emphysema, and 83.3% (n = 15) had emphysema in additional areas, but statistical significance was lacking (p > 0.05). Conclusion: In patients with emphysema and normal serum AAT levels, genetic analyses may reveal relevant heterozygous mutations, which are commonly ignored. Most clinicians focus on lower lobe emphysema. Evaluations of such patients might reveal AAT mutations that are presently overlooked because they are not considered to influence COPD status. [ABSTRACT FROM AUTHOR]

Lung disease progression in alpha-1 antitrypsin deficiency (AATD) is heterogenous and manifests in different ways. Blood biomarkers are an attractive method of monitoring diseases as they are easy to obtain and repeatable. In non-AATD COPD, blood biomarker panels have predicted disease severity, progression, and mortality. We measured a panel of seven serum biomarkers in 200 AATD patients and compared levels between those with COPD and those without. We assessed whether biomarkers were associated with baseline lung function parameters (FEV1 and TLco) or absolute change in these parameters. In total, 111 patients with a severely deficient genotype of AATD (PiZZ) and COPD were included in the analyses. Pearson's correlation coefficient was measured for biomarker correlations and models were compared using ANOVA. CRP and CCL18 were significantly higher in the serum of AATD COPD versus AATD with no COPD. Biomarkers were not predictive of cross-sectional lung function measurements, however, CC16 was significantly associated with an absolute change in TLco (p = 0.018). An addition of biomarkers to the predictive model for TLco added significant value over covariates alone (R2 0.13 vs. 0.02, p = 0.028). Our findings suggest that CC16 is predictive of emphysema progression in AATD COPD. Proteomics data may reveal alternative candidate biomarkers and further work should include the use of longitudinal biomarker measurements. [ABSTRACT FROM AUTHOR]