Alpha-1 Antitrypsin Deficiency Research Articles

Augmentation Therapy Modulates Systemic Inflammation in Individuals with Alpha-1 Antitrypsin Deficiency and Chronic Obstructive Pulmonary Disease.

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder that leads to chronic obstructive pulmonary disease (COPD) and lower circulating levels of AAT, which is a protease inhibitor with potent anti-inflammatory effects. In order to better understand the presence of systemic inflammation in AAT-deficient individuals with COPD, we investigatedthe plasma levels of C-reactive protein (CRP). AAT-deficient individuals and a matched cohort with a normal AAT genotype were recruited from the Alpha-1 Foundation DNA and Tissue Bank. AAT genotypes were determined by a combination of a Taqman-based assay. AAT and CRP levels were determined by nephelometry. Comparisons were determined by unpaired t-test and standard Pearson's correlation. Our study included 40 control participants and 742 AAT-deficient participants, of which 498 received augmentation therapy. In the AAT-deficient participants, the plasma AAT was 20.2±11.6µM and 4.5±1.3µM (P<0.0001) with and without augmentation therapy, respectively, and the CRP was 0.32±0.53mg/dL and 0.69±1.97mg/dL (P=0.0169), respectively. There was a negative correlation between the percentage predicted of forced expiratory volume in 1 second and CRP in the group not receiving augmentation therapy (r=-0.2528, P<0.05), and there was no correlation in participants receiving augmentation therapy. Compared to healthy individuals, AAT-deficient individuals with COPD have higher levels of circulating CRP, suggesting increased systemic inflammation. However, AAT-deficient individuals receiving augmentation therapy had lower plasma CRP levels compared to those who are not.

Association of Alpha-1 Antitrypsin Pi*Z Allele Frequency and Progressive Liver Fibrosis in Two Chronic Hepatitis C Cohorts.

(1) Background: The inherited alpha-1 antitrypsin (A1AT) deficiency variant 'Pi*Z' emerged as a genetic modifier of chronic liver disease. Controversial data exist on the relevance of heterozygous Pi*Z carriage ('Pi*MZ' genotype) as an additional risk factor in patients with chronic viral hepatitis C to develop progressive liver fibrosis. (2) Methods: Two prospectively recruited cohorts totaling 572 patients with therapy-naïve chronic viral hepatitis C (HCV) were analyzed. The Frankfurt cohort included 337 patients and a second cohort from Leipzig included 235 patients. The stage of liver fibrosis was assessed by liver biopsy, AST-to-platelet ratio index (APRI) score and Fibrosis-4 (FIB-4) score (Frankfurt) as well as liver stiffness measurement (LSM) via transient elastography (Leipzig). All patients were genotyped for the Pi*Z variant (rs28929474) of the SERPINA1 gene. (3) Results: In the Frankfurt cohort, 16/337 (4.7%) patients carried the heterozygous Pi*Z allele while 10/235 (4.3%) in the Leipzig cohort were Pi*Z carriers. In both cohorts, there was no higher proportion of Pi*Z heterozygosity in patients with cirrhosis compared to patients without cirrhosis or patients with cirrhosis vs. no liver fibrosis. Accordingly, Pi*Z frequency was not different in histological or serological stages of liver fibrosis (F0-F4) and showed no clear association with LSM. (4) Conclusions: Evaluation in two representative HCV cohorts does not indicate Pi*Z heterozygosity as a clinically relevant disease modifier in chronic HCV infection. However, validation in even larger cohorts with longitudinal follow-up is warranted.

Bronchoscopic Lung Volume Reduction in Patients with Emphysema due to Alpha-1 Antitrypsin Deficiency

Background: Bronchoscopic lung volume reduction using one-way endobronchial valves (EBVs) is a valid therapy for severe emphysema patients. However, alpha-1 antitrypsin (AAT)-deficient patients were excluded from the majority of clinical trials investigating this intervention. Objectives: The aim of this study was to investigate the feasibility, efficacy, and safety of EBV treatment in patients with AAT deficiency (AATD) or a reduced AAT level. Method: A retrospective analysis was performed of all patients treated with EBV with confirmed AATD or with a reduced AAT serum level at the University Medical Center Groningen between 2013 and 2021. Baseline and 6-month follow-up assessment included chest CT, pulmonary function measurement, 6-min walking distance (6MWD), and St. George’s Respiratory Questionnaire (SGRQ). Results: In total, 53 patients were included, 30 patients in the AATD group (AAT <0.6 g/L or confirmed ZZ phenotype) and 23 patients in the reduced AAT group (AAT 0.6–1 g/L). In both groups, all response variables improved significantly after treatment. There was a median increase in forced expiratory volume in 1 s of 105 mL (12% relative) and 280 mL (31% relative) in the AATD and reduced AAT groups, respectively. 6MWD increased by 62 min and 52 min, and SGRQ decreased by 12.5 patients and 18.7 patients, respectively. A pneumothorax occurred in 10% and 13% of patients, and no patients died. Conclusions: EBV treatment in patients with emphysema and AATD or a reduced AAT level is feasible and results in significant improvements in pulmonary function, exercise capacity, and quality of life and has an acceptable safety profile.

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

BackgroundAlpha-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.MethodsThe 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.ResultsA 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(%).ConclusionsEARCO 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 registrationwww.clinicaltrials.gov (ID: NCT04180319)

Genetic and Serum Screening for Alpha-1-Antitrypsin Deficiency in Adult Patients with Cystic Fibrosis: A Single-Center Experience.

Cystic fibrosis (CF) and alpha-1 antitrypsin (AAT) deficiency are two of the commonest genetic diseases affecting the Caucasian population. Neutrophil-mediated inflammation due to protease-antiprotease imbalance leads to progressive pulmonary involvement in both diseases. The aim of this study was to investigate the prevalence of AAT deficiency in CF adults. A prospective study enrolling CF adults was conducted at the Adult CF Center based in Milan from January 2018 to March 2019. Patients were tested for AAT serum protein quantification and expanded genotyping characterization of SERPINA1 during clinical stability. Genotyping characterization of SERPIN1 was compared to a control population of 2848 Caucasian individuals with the same geographical origin and similar demographic characteristics. Among 173 patients included in the study, the prevalence of AAT deficiency was 0. Genotype analysis was piMM in 166 (94.9%) patients and piMS in 9 patients (5.1%), respectively. No differences in terms of genotype characterization were found between the CF population and the control population. These data show that AAT deficiency is not common among adults with CF.

Recombinant Alpha-1 Antitrypsin as Dry Powder for Pulmonary Administration: A Formulative Proof of Concept.

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder associated with pulmonary emphysema and bronchiectasis. Its management currently consists of weekly infusions of plasma-purified human AAT, which poses several issues regarding plasma supplies, possible pathogen transmission, purification costs, and parenteral administration. Here, we investigated an alternative administration strategy for augmentation therapy by combining recombinant expression of AAT in bacteria and the production of a respirable powder by spray drying. The same formulation approach was then applied to plasma-derived AAT for comparison. Purified, active, and endotoxin-free recombinant AAT was produced at high yields and formulated using L-leucine and mannitol as excipients after identifying compromise conditions for protein activity and good aerodynamic performances. An oxygen-free atmosphere, both during formulation and powder storage, slowed down methionine-specific oxidation and AAT inactivation. This work is the first peer-reviewed report of AAT formulated as a dry powder, which could represent an alternative to current treatments.

Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity.

Individuals homozygous for the "Z" mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function.

Registry-based cohort study of alpha-1 antitrypsin deficiency prevalence, incidence and mortality in Denmark 2000–2018

ObjectiveTo estimate the prevalence of diagnosed alpha-1 antitrypsin deficiency (dAATD) in Denmark as of 31 December 2018, and dAATD incidence and mortality from 1 January 2000 to 31 December 2018.Study...

Alpha-1 antitrypsin deficiency: epidemiology, etiology, pathophysiology, clinical manifestation, diagnosis, treatment (literature review)

Gabija Žemgulytė1, Aistė Šidlauskaitė1, Miglė Jurgelėnaitė2 1 Lithuanian University of Health Sciences, Faculty of Medicine, Kaunas, Lithuania 2 Lithuanian University of Health Sciences Kaunas Clinics, Department of Pulmonology, Kaunas, Lithuania Abstract Introduction. Alpha-1 antitrypsin (A1AT) is a glycoprotein that protects the body’s tissues from damage caused by substances released by the immune system. It’s deficiency is one of the most common genetic diseases that is underdiagnosed. The main clinical manifestations of A1AT deficiency involve damage to the lungs, liver and rarely the skin. Lung damage can put people at risk for obstructive pulmonary disease (COPD), while liver damage can be manifested by cholestasis, cirrhosis, and increased risk of hepatocellular carcinoma. Aim: to review the epidemiology, etiology, pathophysiology, clinic, diagnosis and treatment options of alpha-1 antitrypsin deficiency. Materials and methods: a literature review was performed using PubMed, Science direct and other databases. Keywords used in the search: alpha-1 antitrypsin; alpha-1 antitrypsin deficiency; AATD; SERPINA1; COPD; hepatic cirrhosis. Articles and clinical case publications up to five years old were selected for analysis. The results are described in terms of etiology, pathophysiology, clinical presentation, diagnosis and treatment. Results: approximately 1 in 2,500 people worldwide suffer from alpha-1 antitrypsin deficiency, but most of them are undiagnosed. This genetic disorder can cause damage to the lungs, liver or, less commonly, to the skin. Conclusions: alpha-1 antitrypsin deficiency remains largely undiagnosed because the clinical symptoms of this pathology are not specific. To confirm the diagnosis, blood levels of alpha-1 antitrypsin protein should be determined. Specific treatment is only available for patients with lung damage. Keywords: alpha-1 antitrypsin deficiency, COPD, cirrhosis, A1AT diagnosis, A1AT treatment.

Structural characterization and conformational dynamics of alpha-1 antitrypsin pathogenic variants causing alpha-1-antitrypsin deficiency.

Background: Alpha-1 antitrypsin deficiency (A1ATD) is a progressive lung disease caused by inherited pathogenic variants in the SERPINA1 gene. However, their actual role in maintenance of structural and functional characteristics of the corresponding α-1 anti-trypsin (A1AT) protein is not well characterized. Methods: The A1ATD causative SERPINA1 missense variants were initially collected from variant databases, and they were filtered based on their pathogenicity potential. Then, the tertiary protein models were constructed and the impact of individual variants on secondary structure, stability, protein-protein interactions, and molecular dynamic (MD) features of the A1AT protein was studied using diverse computational methods. Results: We identified that A1ATD linked SERPINA1 missense variants like F76S, S77F, L278P, E288V, G216C, and H358R are highly deleterious as per the consensual prediction scores of SIFT, PolyPhen, FATHMM, M-CAP and REVEL computational methods. All these variants were predicted to alter free energy dynamics and destabilize the A1AT protein. These variants were seen to cause minor structural drifts at residue level (RMSD = <2Å) of the protein. Interestingly, S77F and L278P variants subtly alter the size of secondary structural elements like beta pleated sheets and loops. The residue level fluctuations at 100ns simulation confirm the highly damaging structural consequences of all the six missense variants on the conformation dynamics of the A1AT protein. Moreover, these variants were also predicted to cause functional deformities by negatively impacting the binding energy of A1AT protein with NE ligand molecule. Conclusion: This study adds a new computational biology dimension to interpret the genotype-protein phenotype relationship between SERPINA1 pathogenic variants with its structural plasticity and functional behavior with NE ligand molecule contributing to the Alpha-1-antitrypsin deficiency. Our results support that A1ATD complications correlates with the conformational flexibility and its propensity of A1AT protein polymerization when misfolded.

Hepatic cirrhosis with portal hypertension secondary to alpha-1 antitrypsin deficiency and autoimmune hepatitis in pregnancy: A case report

Introduction: Previously, women with cirrhosis rarely became pregnant due to hypothalamic-pituitary dysfunction. However, with advancements in the care of patients with chronic liver disease, pregnancy is becoming more common in this cohort. We will outline the complex, multidisciplinary approach toward managing an obstetrics patient with portal hypertension in the context of previously decompensated liver cirrhosis. Case Report: A 29-year-old primigravida woman was referred to the Obstetric Medicine Clinic with an unplanned pregnancy at 16 weeks’ gestation. This was on a background of previously decompensated liver cirrhosis and portal hypertension, in the context of alpha-1 antitrypsin deficiency and autoimmune hepatitis. The patient had one upper gastrointestinal bleed at 19 weeks’ gestation and underwent three gastroscopies throughout her pregnancy. At 32+6 weeks gestation, she had an elective lower uterine segment Caesarean Section and delivered a healthy liveborn female. Conclusion: Currently, there are no studies that explore pregnancy outcomes in women with cirrhosis secondary to alpha-1 antitrypsin deficiency. This case describes the pregnancy of a woman with previously decompensated liver cirrhosis and portal hypertension, in the context of alpha-1 antitrypsin deficiency and explores the associated management dilemmas.

Liver cirrhosis in children

Liver cirrhosis in children and adolescents is a consequence of a variety of chronic liver diseases, metabolic disorders, and genetic diseases. In infants, cirrhosis is most often due to biliary atresia and genetic-metabolic diseases, while in older children it usually occurs as a result of autoimmune hepatitis, Wilson’s disease, alpha-1 antitrypsin deficiency, and primary sclerosing cholangitis. Symptoms of cirrhosis in children and adolescents are not specific. In pediatric patients, the first sign of cirrhosis may more often be low weight gain, weakness, loss of appetite, low-grade fever, as well as more specific signs: transient jaundice, mild pruritus, epistaxis, heaviness in the right hypochondrium, changes in liver density on palpation, hyperbilirubinemia, hyperenzymemia, etc. Complications of pediatric cirrhosis are similar to those observed in adult patients and include gastrointestinal bleeding caused by esophageal varices, ascites, and spontaneous bacterial peritonitis. In pediatric practice, special attention should be paid to nutritional correction in liver cirrhosis since children have higher requirements for protein and micronutrients for growth and development. Treatment of cirrhosis-induced portal hypertension in children and adolescents is mainly based on methods developed for adults. The article deals with diagnostic and differential diagnostic aspects of the terminal stage of liver disease in children. The therapeutic management of patients with cirrhosis of the liver and acute renal failure is based on support of various organ functions. Hemodialysis/ plasmapheresis may serve in some patients as an interim therapy before liver transplantation. The indications for liver transplantation and problems arising after surgery are considered.

Proteolysis and Deficiency of α1-Proteinase Inhibitor in SARS-CoV-2 Infection.

The SARS-CoV-2 pandemic had stimulated the emergence of numerous publications on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), especially when it was found that the regions of high mortality corresponded to the regions with deficient α1-PI alleles. By analogy with the data obtained in the last century, when the first cause of the genetic deficiency of α1-antitrypsin leading to elastase activation in pulmonary emphysema was proven, it can be supposed that proteolysis hyperactivation in COVID-19 may be associated with the impaired functions of α1-PI. The purpose of this review was to systematize the scientific data and critical directions for translational studies on the role of α1-PI in SARS-CoV-2-induced proteolysis hyperactivation as a diagnostic marker and a therapeutic target. This review describes the proteinase-dependent stages of viral infection: the reception and penetration of the virus into a cell and the imbalance of the plasma aldosterone-angiotensin-renin, kinin, and blood clotting systems. The role of ACE2, TMPRSS, ADAM17, furin, cathepsins, trypsin- and elastase-like serine proteinases in the virus tropism, the activation of proteolytic cascades in blood, and the COVID-19-dependent complications is considered. The scientific reports on α1-PI involvement in the SARS-CoV-2-induced inflammation, the relationship with the severity of infection and comorbidities were analyzed. Particular attention is paid to the acquired α1-PI deficiency in assessing the state of patients with proteolysis overactivation and chronic non-inflammatory diseases, which are accompanied by the risk factors for comorbidity progression and the long-term consequences of COVID-19. Essential data on the search and application of protease inhibitor drugs in the therapy for bronchopulmonary and cardiovascular pathologies were analyzed. The evidence of antiviral, anti-inflammatory, anticoagulant, and anti-apoptotic effects of α1-PI, as well as the prominent data and prospects for its application as a targeted drug in the SARS-CoV-2 acquired pneumonia and related disorders, are presented.

CASE STUDY OF CONCURRENT ALPHA-1 ANTITRYPSIN DEFICIENCY AND ASTHMA.

<h3>Introduction</h3> Asthma and alpha-1 antitrypsin deficiency (AATD) differ in pathogenesis but can present with similar clinical symptoms, such as dyspnea, wheezing and cough. The similarity of symptoms can often lead to delayed or missed diagnosis of AATD in patients with concurrent asthma. Our abstract focuses on the importance of assessing for AATD in those with fixed obstructive lung disease. <h3>Case Description</h3> Patient A is a 65-year-old male with a history of longstanding asthma, who exhibited rapid progressive decline in FEV1 on serial pulmonary function tests (PFTs). Subsequent workup revealed MZ genotype of alpha-1 antitrypsin deficiency. His symptoms were thought to be primarily asthma-related, given air trapping and bronchodilator reversibility on PFTs. Patient B is a 58-year-old male with known alpha-1 antitrypsin deficiency (ZZ genotype), although he was only mildly symptomatic. Increasing episodes of wheezing and decreasing FEV1 prompted FeNO testing, which supported superimposed asthma. <h3>Discussion</h3> Concurrent asthma and AATD can worsen pulmonary inflammation. Alpha-1 antitrypsin can have immunomodulatory effects on inflammatory cells and inactivate elastase, thus preserving lung function. Shared symptoms and vague screening guidelines for coincident asthma and AATD can often delay diagnosis in patients with both diseases, potentially worsening patient outcomes. In our patients, further testing was only prompted due to progressive clinical decline, which ideally could have been preempted. We hope that these cases will bring increased awareness to diagnostic and therapeutic challenges in patients with AATD and asthma.

Pulmonary Function and Respiratory Diseases in Different Genotypes of Alpha-1 Antitrypsin Deficiency.

Respiratory disease is the major cause of morbidity and mortality in patients with alpha-1 antitrypsin deficiency, mainly in homozygous PI*ZZ individuals. However, this association is uncertain in subjects with other deficiency genotypes. The objective of this study was to assess, in the context of alpha-1 antitrypsin deficiency, the existence of further risk factors that have been associated with respiratory diseases. Lung function was assessed by spirometry in a sample of 1334 patients with a known genotype for the SERPINA1 gene whose serum alpha-1 antitrypsin levels had been previously determined. Patients with a normal genotype (PI*MM) were compared to 389 patients carrying a deficiency allele. Statistically significant associations were detected between (i) PI*ZZ genotype and abnormal FEV1 values (χ2 = 26.45; P <.0002), FEV1/FVC (χ2 = 14.8; P < .02) or forced mid-expiratory flow 25%-75% (χ2 =22.66; P < .0009); (ii) chronic obstructive pulmonary disease and PI*ZZ odds ratio: 26.5; 95% CI: (2.6-265.9); P <.005 and or PI*SS genotype odds ratio: 9; 95% CI: (2-40.1); P < .004; (iii) prevalence of COPD in PI*MZ subjects and smoking habit (P < .01), low body weight (P < .01) or older age (P < .0001). The PI*ZZ and PI*SS genotypes seem to be associated with the prevalence of chronic obstructive pulmonary disease. Tobacco use, low body weight, and older age are risk factors that increase the probability of prevalence of chronic obstructive pulmonary disease by up to 70% in PI*MZ individuals.

Autoantibody profile in sarcoidosis, analysis from the GRADS sarcoidosis cohort.

BackgroundSarcoidosis, a multi-systemic granulomatous disease, is a predominantly T-cell disease but evidence for a role for humoral immunity in disease pathogenesis is growing. Utilizing samples from the Genomic Research in Alpha-1 anti-trypsin Deficiency and Sarcoidosis (GRADS) study, we examined the prevalence of autoantibodies in sarcoidosis patients with pulmonary-only and extra-pulmonary organ involvement compared to normal controls.Study design and methodsWe analyzed serum samples from sarcoidosis patients who participated in the GRADS study utilizing an autoantigen microarray platform for both IgM and IgG antibodies. The cohort included sarcoidosis patients with pulmonary-only disease (POS, n = 106), sarcoidosis patients with extra-pulmonary disease (EPS, n = 120) and a normal control cohort (NC, n = 101). Organ involvement was assessed following a standardized format across all GRADS participating centers.ResultsSarcoidosis patients overall had increased levels of IgM and IgG autoantibodies compared to normal controls. In addition, several autoantibodies were elevated in the POS and EPS cohorts compared to the NC cohort. Differences in autoantibody levels were also noted between the POS and the EPS cohorts. When comparing organ involvement with sarcoidosis, bone, spleen and ear, nose and throat involvement had higher IgM expression than other organs.ConclusionSarcoidosis patients have elevated IgM and IgG autoantibody levels compared to normal controls. In addition, individuals with pulmonary as well as additional organ involvement had higher IgM expression. Further research is needed focusing on specific organ-autoantibody pairs and role of autoantibodies in disease pathogenesis.

Characterization of hepatic inflammatory changes in a C57BL/6J mouse model of alpha1-antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by a hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT). Individuals with AATD are prone to develop a chronic liver disease that remains undiagnosed until late stage of the disease. Here, we sought to characterize the liver pathophysiology of a human transgenic mouse model for AATD with a manifestation of liver disease compared with normal transgenic mice model. Male and female transgenic mice for normal (Pi*M) and mutant variant (Pi*Z) human alpha-1 antitrypsin at 3 and 6 mo of age were subjected to this study. The progression of hepatic ZAAT accumulation, hepatocyte injury, steatosis, liver inflammation, and fibrotic features were monitored by performing an in vivo study. We have also performed a Next-Gene transcriptomic analysis of the transgenic mice liver tissue 16 h after lipopolysaccharide (LPS) administration to delineate liver inflammatory response in Pi*Z mice as compared with Pi*M. Our results show hepatic ZAAT accumulation, followed by hepatocyte ballooning and liver steatosis developed at 3 mo in Pi*Z mice compared with the mice carrying normal variant of human alpha-1 antitrypsin. We observed higher levels of hepatic immune cell infiltrations in both 3- and 6-mo-old Pi*Z mice compared with Pi*M as an indication of liver inflammation. Liver fibrosis was observed as accumulation of collagen in 6-mo-old Pi*Z liver tissues compared with Pi*M control mice. Furthermore, the transcriptomic analysis revealed a dysregulated liver immune response to LPS in Pi*Z mice compared with Pi*M. Of particular interest for translational work, this study aims to establish a mouse model of AATD with a strong manifestation of liver disease that will be a valuable in vivo tool to study the pathophysiology of AATD-mediated liver disease. Our data suggest that the human transgenic mouse model of AATD could provide a suitable model for the evaluation of therapeutic approaches and preventive reagents against AATD-mediated liver disease.NEW & NOTEWORTHY We have characterized a mouse model of human alpha-1 antitrypsin deficiency with a strong manifestation of liver disease that can be used as an in vivo tool to test preventive and therapeutic reagents. Our data explores the altered immunophenotype of alpha-1 antitrypsin-deficient liver macrophages and suggests a relationship between acute inflammation, immune response, and fibrosis.

Re-IMAGinING the Pathway for Clinical Decision Making in Rare Lung Diseases: Moving Towards a United Vision

This industry-supported symposium was held during the European Respiratory Society (ERS) International Congress and included presentations from several internationally renowned experts in rare lung diseases. The panel discussed the need to improve clinical decision making to expedite disease recognition, prognostic prediction, and early treatment in interstitial lung disease (ILD) and alpha 1 antitrypsin (AAT) deficiency-related chronic obstructive pulmonary disease (COPD). Daiana Stolz, Clinic for Pneumology, University Hospital Freiburg, Switzerland, and Marlies S. Wijsenbeek, Erasmus University Medical Centre, Rotterdam, the Netherlands, explained that although high-resolution CT (HRCT) scans may appear similar, ILD from different causes results in significantly different patient outcomes. Therefore, image analysis and the identification of sensitive and specific biomarkers are critical to improving diagnosis and monitoring treatment response and disease progression in ILD. Charlie Strange, Medical University of South Carolina, Charleston, USA, and Gerry McElvaney, Irish Centre for Genetic Lung Disease, Dublin, Ireland, described the variability in CT-based lung density measurements used to assess the progression of emphysema in patients with AAT deficiency. Clinical trial data indicate that accurate CT lung density measurements are superior to lung function measurements and other endpoints to detect disease progression. However, Strange presented data that showed the considerable impact of acute exacerbations of COPD on CT imaging measurements. One organisation working to improve the accuracy and value of imaging data in lung diseases is the Open Source Imaging Consortium (OSIC), Saugatuck, Michigan, USA. Elizabeth Estes, who works for OSIC, explained that OSIC aims to build a large, global database of anonymised patient data and CT images in ILD, with plans for future expansion into other rare lung diseases. The ultimate goals of this effort are to encourage collaboration, and to develop machine learning algorithms to improve clinical decision making in rare lung diseases.

A stacking ensemble machine learning model to predict alpha-1 antitrypsin deficiency-associated liver disease clinical outcomes based on UK Biobank data

Alpha-1 antitrypsin deficiency associated liver disease (AATD-LD) is a rare genetic disorder and not well-recognized. Predicting the clinical outcomes of AATD-LD and defining patients more likely to progress to advanced liver disease are crucial for better understanding AATD-LD progression and promoting timely medical intervention. We aimed to develop a tailored machine learning (ML) model to predict the disease progression of AATD-LD. This analysis was conducted through a stacking ensemble learning model by combining five different ML algorithms with 58 predictor variables using nested five-fold cross-validation with repetitions based on the UK Biobank data. Performance of the model was assessed through prediction accuracy, area under the receiver operating characteristic (AUROC), and area under the precision-recall curve (AUPRC). The importance of predictor contributions was evaluated through a feature importance permutation method. The proposed stacking ensemble ML model showed clinically meaningful accuracy and appeared superior to any single ML algorithms in the ensemble, e.g., the AUROC for AATD-LD was 68.1%, 75.9%, 91.2%, and 67.7% for all-cause mortality, liver-related death, liver transplant, and all-cause mortality or liver transplant, respectively. This work supports the use of ML to address the unanswered clinical questions with clinically meaningful accuracy using real-world data.

COVID-19 IN LUNG TRANSPLANT RECIPIENTS: A SINGLE CENTER EXPERIENCE

COVID-19 IN LUNG TRANSPLANT RECIPIENTS: A SINGLE CENTER EXPERIENCE