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Abstract Background Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. Methods In this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research. Results 1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed. Conclusions 2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes. more...

Alpha-1 antitrypsin deficiency, a genetic disorder caused by mutations within the SERPINA1 gene, increases the risk for early emphysema and chronic obstructive pulmonary disease in both never- and active-smokers. Short of a curative approach, alpha-1 antitrypsin deficiency lung disease benefits from standard medical treatment with inhaled bronchodilators and corticosteroids, intravenous augmentation therapy with human alpha-1 antitrypsin purified from pooled plasma, and, in advanced stages, from lung transplantation. This review's learning objectives are to provide mechanistic and evidence-based data, as well as patient-related outcomes regarding the management of alpha-1 antitrypsin deficiency lung disease. Established and novel therapies for alpha-1 antitrypsin deficiency lung disease with published clinical efficacy and safety data are discussed. [ABSTRACT FROM AUTHOR] more...

AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung. Inherited serum deficiency disorders, such as hemophilia and AATD, have been considered ideal candidates for gene therapy. Although viral vector-meditated transduction of the liver has demonstrated utility in hemophilia, similar success has not been achieved for AATD. The challenge for AAT gene therapy is achieving protective levels of AAT locally in the lung and mitigating potential liver toxicities linked to systemically administered viral vectors. Current strategies with ongoing clinical trials involve different routes of adeno-associated virus administrations, such as intramuscular and intrapleural injections, to provide consistent therapeutic levels from nonhepatic organ sites. Nevertheless, exploration of alternative methods of nonhepatic sourcing of AAT has been of great interest in the field. In this regard, pulmonary endothelium-targeted adenovirus vector could be a key technical mandate to achieve local augmentation of AAT within the lower respiratory tract, with the potential benefit of circumventing liver toxicities. In addition, incorporation of the CRISPR/Cas9 (CRISPR-associated protein 9) nuclease system into gene-delivery technologies has provided adjunctive technologies that could fully realize a one-time treatment for sustained, lifelong expression of AAT in patients with AATD. This review will focus on the adeno-associated virus- and adenoviral vector-mediated gene therapy strategies for the pulmonary manifestations of AATD and show that endeavoring to use genome-editing techniques will advance the current strategy to one fully compatible with direct human translation. [ABSTRACT FROM AUTHOR] more...

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Purpose of Review: Commonly categorized as a rare disease, alpha-1 antitrypsin deficiency (AATD) is neither rare, when compared to many other genetic disorders, nor an actual disease, but rather a predisposition toward a wide variety of diseases. It is one of the most common genetic disorders which can lead to a spectrum of clinical manifestations, ranging from no symptoms to progressively debilitating systemic disease, most commonly affecting the lung and liver. It is therefore imperative for clinicians to recognize and be familiar with the spectrum of presentations, methods of diagnosis, and clinical management of AATD. It is also imperative for scientists to recognize the potential for progress in the management of this disorder. Recent Findings: This review focuses on the current state of knowledge of AATD, including the wide range of presentations, diagnosis, and clinical management. In addition to the clinical implications of severe AATD, we discuss the relevance of heterozygous state with mild or moderate AATD in the development of both lung and liver disease. While our understanding of the multiple roles of alpha-1 antitrypsin (AAT) is on the rise, with appreciation of its immunomodulatory, anti-infective, and anti-inflammatory properties, this knowledge has yet to impact our ability to predict outcomes. We discuss nuances of augmentation therapy and review novel therapeutic approaches currently under investigation. Summary: With the expanding knowledge about the complexities of AAT function and its clinical relevance, and with the increasing ability to diagnose early and intervene on AATD, it should be our goal to change the perception of AATD as a correctable inherited disorder rather than a fatal disease. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency is a hereditary disorder characterized by a low serum level of the enzyme. We present the case of a 2-year-old boy referred to us for a persistent hepatocytolysis syndrome (ALT=134 U/l, AST=110 U/l) which persisted for six months since the first evaluation. The patient was asymptomatic, except for reduced appetite. Infectious and autoimmune causes, along with Wilson disease were excluded. We found low levels of serum alpha-1 antitrypsin (26-28 mg/dl). The genetic tests identified a Pi*SZ genotype. The severity of the symptoms is variable in children with Pi*SZ genotype. Neither the phenotype of the disease, nor the serum level of the alpha-1 antitrypsin are enough to identify which one of these patients will develop pulmonary and/or hepatic disease. There is no specific treatment for the liver disease associated with alpha-1 antitrypsin deficiency in childhood. [ABSTRACT FROM AUTHOR] more...

Purpose: Multi‐b diffusion‐weighted hyperpolarized inhaled‐gas MRI provides imaging biomarkers of terminal airspace enlargement including ADC and mean linear intercept (Lm), but clinical translation has been limited because image acquisition requires relatively long or multiple breath‐holds that are not well‐tolerated by patients. Therefore, we aimed to accelerate single breath‐hold 3D multi‐b diffusion‐weighted 129Xe MRI, using k‐space undersampling in imaging direction using a different undersampling pattern for different b‐values combined with the stretched exponential model to generate maps of ventilation, apparent transverse relaxation time constant (T2∗), ADC, and Lm values in a single, short breath‐hold; accelerated and non‐accelerated measurements were directly compared. Methods: We evaluated multi‐b (0, 12, 20, 30, and 45.5 s/cm2) diffusion‐weighted 129Xe T2∗/ADC/morphometry estimates using acceleration factor (AF = 1 and 7) and multi‐breath sampling in 3 volunteers (HV), and 6 participants with alpha‐1 antitrypsin deficiency (AATD). Results: For the HV subgroup, mean differences of 5%, 2%, and 8% were observed between fully sampled and undersampled k‐space for ADC, Lm, and T2∗ values, respectively. For the AATD subgroup, mean differences were 9%, 6%, and 12% between fully sampled and undersampled k‐space for ADC, Lm and T2∗ values, respectively. Although mean differences of 1% and 4.5% were observed between accelerated and multi‐breath sampled ADC and Lm values, respectively, mean ADC/Lm estimates were not significantly different from corresponding mean ADCM/LmM or mean ADCA/LmA estimates (all P > 0.60 , A = undersampled and M = multi‐breath sampled). Conclusions: Accelerated multi‐b diffusion‐weighted 129Xe MRI is feasible at AF = 7 for generating pulmonary ADC and Lm in AATD and normal lung. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency (AATD) is a disease inherited in codominant fashion that causes liver dysfunction and early onset emphysema due to low levels of the protease inhibitor, alpha-1 antitrypsin (AAT). Point mutations result in misfolded AAT that accumulate in hepatocytes resulting in cell death at the expense of protease inhibition in the lungs where interstitial damage commences. Isoelectric focusing is considered to be the gold standard for diagnosis of AATD. Limited therapies are available to slow the inevitable progressive damage to both the liver and lungs beginning in some pediatric patients, whereas organ transplant is considered to be the last line treatment. With only a select few treatments currently available, there are a number that are currently being studied. [ABSTRACT FROM AUTHOR] more...

Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary condition characterized by low levels of circulating alpha-antitrypsin (AAT) in plasma. It is the best understood genetic risk factor for the development of chronic obstructive pulmonary disease (COPD). The diagnosis of A1AD is under-recognized. While there is a significant heterogeneity in disease presentation in relation to the severity of symptoms and prognosis, it is not uncommon for young individuals, including pregnant women to already have moderate to advanced lung disease at the time of diagnosis. Reductions in AAT levels may have unique implications for a gravid patient beyond that of lung disease. Care of the pregnant A1AD patient with chronic lung disease follows the principles of care for the management of airways disease in general with control of symptoms and reduction in exacerbation risk the main tenets of treatment. The effect of A1AD and augmentation in pregnancy has not been studied and thus care is reliant on expert opinion and clinical experience. Providers caring for pregnant patients with A1AD should consider referral to health care systems and providers with specific expertise in A1AD. Ultimately the decision is left to the individual patient and their physician to weigh the risk benefit of cessation or continuation of therapies. In this review, we present the perinatal course of a woman with A1AD and review the available literature pertaining to AAT and pregnancy and discuss the clinical implications. [ABSTRACT FROM AUTHOR] more...

Background: Most patients with alpha-1 antitrypsin deficiency remain undiagnosed and therefore do not benefit from current therapies or become eligible for research studies of new treatments under development. Improving the detection rate for AATD is therefore a high priority for the Alpha-1 Foundation. A workshop was held on June 23, 2019 in Orlando, Florida during which stakeholders from the research, pharmaceutical, and patient communities focused on the topic of alpha-1 antitrypsin deficiency detection.Results: A variety of detection strategies have been explored in the past and new approaches are emerging as technology advances. Targeted detection includes patients with chronic obstructive pulmonary disease, unexplained chronic liver disease, and family members of affected individuals. Newborn screening, electronic medical record data mining, and direct-to-consumer testing remain options for future detection strategies.Conclusion: These meeting proceedings can serve as a basis for innovative approaches to the detection of alpha-1 antitrypsin deficiency. [ABSTRACT FROM AUTHOR] more...

We report the genetic variants associated with alpha‐1 antitrypsin deficiency (AATD) in 117 patients admitted to our outpatient clinic and characterized by a serum concentration of AAT lower than 113 mg/dL. We focused on the M‐like heterozygous variant of the SERPINA1 gene called PI*MMMalton, and describe three patients with this variant. While the role of homozygous AATD in liver and pulmonary disease is well established, the association between heterozygous AATD and chronic liver and pulmonary disease is still under investigation. The PI*MMMalton genotype was found in 5.8% of patients with a pathological genotype of AATD and in 14.3% of the subjects when considering only those with intermediate AATD. There were no liver or renal abnormalities in patients with the PI*MMMalton genotype. The PI*MMMalton patients included here showed a normal liver function, and none had renal function abnormalities or abdominal aortic aneurysm. Only a prevalence of lung disease was detected. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition present in 1 of 2,000 – 5,000 persons in Italy, which predisposes to lung disease, mainly chronic obstructive pulmonary disease (COPD)/emphysema. Similar to COPD, pulmonary rehabilitation (PR) is used in patients with AATD-associated COPD, although the scientific evidence is limited as it is a rare disease. Further studies on PR in AATD-associated COPD patients are needed as well as increased collaboration between clinical and rehabilitation centers. [ABSTRACT FROM AUTHOR] more...

Danielle M Dunlea, Laura T Fee, Thomas McEnery, Noel G McElvaney, Emer P Reeves Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland Abstract: Alpha-1 antitrypsin (AAT) is the most abundant serine protease inhibitor circulating in the blood. AAT deficiency (AATD) is an autosomal codominant condition affecting an estimated 3.4 million individuals worldwide. The clinical disease associated with AATD can present in a number of ways including COPD, liver disease, panniculitis and antineutrophil cytoplasmic antibody vasculitis. AATD is the only proven genetic risk factor for the development of COPD, and deficient individuals who smoke are disposed to more aggressive disease. Principally, AAT is a serine protease inhibitor; however, over the past number of years, the assessment of AAT as simply an antiprotease has evolved, and it is now recognized that AAT has significant anti-inflammatory properties affecting a wide range of cells, including the circulating neutrophil. Keywords: neutrophils, alpha-1 antitrypsin deficiency, alpha-1 antitrypsin augmentation, inflammation, airways disease more...

Cristina Esquinas,1,2,* Sonia Serreri,3,* Miriam Barrecheguren,1 Esther Rodriguez,1 Alexa Nuñez,1 Francisco Casas-Maldonado,4 Ignacio Blanco,5 Pietro Pirina,3 Beatriz Lara,6 Marc Miravitlles1,7 1Pneumology Department, University Hospital Vall d’Hebron, Barcelona, Spain; 2Public Health, Mental, Maternal and Child Health Nursing Department, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; 3Università di Sassari, Sassari, Italy; 4Pneumology Department, University Hospital San Cecilio, Granada, Spain; 5Alpha-1 Antitrypsin Deficiency Spanish Registry (REDAAT), Spanish Society of Pneumology (SEPAR), Barcelona, Spain; 6Coventry and Warwickshire University Hospital, Coventry, UK; 7CIBER de Enfermedades Respiratorias (CIBERES), Spain *These authors contributed equally to this work Background: The clinical course of alpha-1 antitrypsin deficiency (AATD) is very heterogeneous. It is estimated that 60% of individuals with severe AATD (Pi*ZZ) develop emphysema. The main objective of this study was to describe the outcomes of long-term lung function in individuals with AATD-associated emphysema after at least 8 years of follow-up. Materials and methods: We performed a retrospective analysis of longitudinal follow-up data of AATD PiZZ patients from the Spanish registry (AATD Spanish Registry [REDAAT]). The main follow-up outcome was the annual rate of decline in forced expiratory volume in 1 second (FEV1) calculated using the FEV1 values at baseline and in the last post-bronchodilator spirometry available. Results: One hundred and twenty-two AATD PiZZ patients were analyzed. The median follow-up was 11 years (interquartile range =9–14). The mean FEV1 decline was 28 mL/year (SD=54), with a median of 33 mL/year. Tobacco consumption (β=19.8, p more...

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d. The current study investigated the impact of C3d on circulating neutrophils. Blood was collected from AATD (n = 88) or non-AATD COPD patients (n = 10) and healthy controls (HC) (n = 40). Neutrophils were challenged with C3d, and degranulation was assessed by Western blotting, ELISA, or fluorescence resonance energy transfer (FRET) substrate assays. Ex vivo, C3d levels were increased in plasma (p < 0.0001) and on neutrophil plasma membranes (p = 0.038) in AATD compared to HC. C3d binding to CR3 receptors triggered primary (p = 0.01), secondary (p = 0.004), and tertiary (p = 0.018) granule release and increased CXCL8 secretion (p = 0.02). Ex vivo plasma levels of bactericidal-permeability-increasing-protein (p = 0.02), myeloperoxidase (p < 0.0001), and lactoferrin (p < 0.0001) were significantly increased in AATD patients. In endothelial cell scratch wound assays, C3d significantly decreased cell migration (p < 0.0001), an effect potentiated by neutrophil degranulated proteins (p < 0.0001). In summary, AATD patients had increased C3d in plasma and on neutrophil membranes and, together with neutrophil-released granule enzymes, reduced endothelial cell migration and wound healing, with potential implications for AATD-related vasculitis. more...

David G Parr, Beatriz Lara Department of Respiratory Medicine, Cardio-Respiratory Division, University Hospital Coventry, Coventry, UK Abstract: Alpha-1 antitrypsin (AAT) functions primarily to inhibit neutrophil elastase, and its deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). The putative protective serum concentration is generally considered to be above a threshold of 11 µM/L, and therapeutic augmentation of AAT above this value is believed to retard the progression of emphysema. Several AAT preparations, all derived from human donor plasma, have been commercialized since approval by the US Food and Drug Administration (FDA) in 1987. Biochemical efficacy has been demonstrated by augmentation of pulmonary antiprotease activity, but demonstration of clinical efficacy in randomized, placebo-controlled trials has been hampered by the practical difficulties of performing conventional studies in a rare disease with a relatively long natural history. Computed tomography has been applied to measure lung density as a more specific and sensitive surrogate outcome measure of emphysema than physiologic indices, such as forced expiratory volume in 1 second, and studies consistently show a therapeutic reduction in the rate of lung density decline. However, convincing evidence of benefit using traditional clinical measures remains elusive. Intravenous administration of AAT at a dose of 60 mg/kg/week is the commonest regime in use and has well-documented safety and tolerability. International and national guidelines on the management of AAT deficiency recommend intravenous augmentation therapy to supplement optimized usual COPD treatment in patients with severe deficiency and evidence of lung function impairment. Keywords: alpha-1 antitrypsin deficiency, augmentation or replacement therapy, computed tomography, emphysema, COPD more...

Ignacio Blanco,1 Patricia Bueno,2 Isidro Diego,3 Sergio Pérez-Holanda,4 Beatriz Lara,5 Francisco Casas-Maldonado,6 Cristina Esquinas,7 Marc Miravitlles7,8 1Alpha1-Antitrypsin Deficiency Spanish Registry (REDAAT), Lung Foundation Breathe, Spanish Society of Pneumology (SEPAR), Barcelona, Spain; 2Internal Medicine Department, County Hospital of Jarrio, Principality of Asturias, Spain; 3Materials and Energy Department, School of Mining Engineering, Oviedo University, Principality of Asturias, Spain; 4Surgical Department, University Central Hospital of Asturias, Oviedo, Spain; 5Respiratory Medicine Department, Coventry and Warwickshire University Hospital, Coventry, UK; 6Pneumology Department, University Hospital San Cecilio, Granada, Spain; 7Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 8CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain Abstract: The alpha-1 antitrypsin (AAT) haplotype Pi*S, when inherited along with the Pi*Z haplotype to form a Pi*SZ genotype, can be associated with pulmonary emphysema in regular smokers, and less frequently with liver disease, panniculitis, and systemic vasculitis in a small percentage of people, but this connection is less well established. Since the detection of cases can allow the application of preventive measures in patients and relatives with this congenital disorder, the objective of this study was to update the prevalence of the SZ genotype to achieve accurate estimates of the number of Pi*SZ subjects worldwide, based on studies performed according to the following criteria: 1) samples representative of the general population, 2) AAT phenotyping characterized by adequate methods, and 3) selection of studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop tables and maps with an inverse distance-weighted (IDW) interpolation method, to provide numerical and geographical information of the Pi*SZ distribution worldwide. A total of 262 cohorts from 71 countries were included in the analysis. With the data provided by these cohorts, a total of 1,490,816 Pi*SZ were estimated: 708,792 in Europe; 582,984 in America and Caribbean; 85,925 in Africa; 77,940 in Asia; and 35,176 in Australia and New Zealand. Remarkably, the IDW interpolation maps predicted the Pi*SZ prevalence throughout the entire world even in areas lacking real data. These results may be useful to plan strategies for future research, diagnosis, and management of affected individuals. Keywords: SERPINA1, alpha-1 antitrypsin deficiency, protease inhibitor, genetic epidemiology, SZ genotype, inverse distance-weighted interpolation, geographic information system more...

Abstract Alpha-1 antitrypsin deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT; also known as alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released by activated neutrophils during inflammation. Absence or deficiency of A1-PI leads to an imbalance between elastase and anti-elastase activity, which results in progressive, irreversible destruction of lung tissue, and ultimately the development of chronic obstructive pulmonary disease with early-onset emphysema. AATD is under-diagnosed, patients can experience long delays before obtaining an accurate diagnosis, and the consequences of delayed diagnosis or misdiagnosis can be severe. Currently, A1-PI therapy is the only available treatment that addresses disease etiology in patients with AATD; however, demonstrating clinical efficacy of A1-PI therapy is challenging. In order to show therapeutic efficacy with traditional endpoints such as forced expiratory volume in one second and mortality, large sample sizes and longer duration trials are required. However, AATD is a rare, slow progressive disease, which can take decades to manifest clinically and recruiting sufficient numbers of patients into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect of A1-PI therapy in patients with AATD. These findings suggest that the early introduction of treatment in patients with severe emphysema-related AATD may delay the time to death, lung transplantation or crippling respiratory complaints. In addition, there is now limited evidence that A1-PI therapy provides a gain of more than five life-years, supporting previous observations based on registry data. With the clinical efficacy of A1-PI therapy now demonstrated, further studies are required to assess long-term outcomes. more...

Ross G Edgar,1,2 Mitesh Patel,3 Susan Bayliss,4 Diana Crossley,2,5 Elizabeth Sapey,2,5 Alice M Turner4,6 1Therapy Services, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 2Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; 3Division of Primary Care, University of Nottingham, Nottingham, UK; 4Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 5Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 6Department of Respiratory Medicine, Heart of England NHS Foundation Trust, Birmingham, UK Background: Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.Methods: Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology.Results: In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.Conclusion: Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group. Keywords: alpha-1 antitrypsin deficiency, treatment, emphysema, transplantation more...

Purpose: This study examined characteristics of clinical trials that influence interest in participation among individuals with alpha-1 antitrypsin deficiency (AATD)., Procedures: A cross-sectional survey was completed by individuals with AATD. Thirty-four items described characteristics of clinical trials, which were rated from 1 (would not participate) to 5 (highly interested in participating). Logistic regression was used to compare participants with high interest in trials (defined as scores of 4 or 5 on ≥50 % of responses) to all remaining participants., Results: Data were provided by 1664 participants (91.6 % with lung disease, 16.3 % with liver disease, 14.9 % with lung and liver disease). Nearly one-third (31.8 %) indicated that they would not participate in a trial if there was a chance of getting a placebo. If the trial included three liver biopsies, 53.3 % would not participate. More than two-thirds (69.8 %) of participants who were using augmentation therapy would not participate in a trial that required twelve months off therapy. Individuals with two or more exacerbations in the prior year were more likely to have high interest in trials (OR = 1.4, 95 % CI = 1.1-1.7, p = 0.009). In addition, individuals with a score of 10 or higher on the COPD Assessment Test were more likely to have high interest (OR = 1.4, 95 % CI = 1.1-1.8, p = 0.010)., Conclusions: A sizeable percentage of participants indicated that they would not participate in clinical trials that include a placebo, involve multiple liver biopsies, or involve discontinuing augmentation therapy. Individuals who are more affected by AATD have more interest in trial participation than individuals who are less affected., Competing Interests: Declaration of competing interest KEH receives consulting income from AlphaNet. RAS is a paid medical director for AlphaNet. He has grants in alpha-1 antitrypsin deficiency paid to National Jewish Health from Inhibrx, the Alpha-1 Foundation, and Mereo. He has consulted for Astra Zeneca, CSL Berhing, Vertex, Grifols, Takeda, Dicerna, Inhibrx, Peak Bio, and Beam Therapeutics. SA has no competing interests to declare. CS is a paid medical director for AlphaNet. He has grants in alpha-1 antitrypsin deficiency or COPD paid to the Medical University of South Carolina from Arrowhead, AstraZeneca, CSA Medical, Dicerna, Grifols, Krystal, Nuvaira,OCI, Pandorum, Renovion, Takeda and Vertex. CS has consulted for Astra Zeneca, CSL Behring, Morair, Pulmanage, UpToDate, and Vertex for Alpha-1 and/or COPD., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition caused by decreased plasma and tissue levels of alpha-1 antitrypsin (AAT) that can lead to serious lung and liver disease in children and adults. AATD patients face challenges such as under diagnosis, clinical variability, and limited treatment options for liver disease. Early detection and biomarkers for predicting outcomes are needed to improve patient outcome. Currently, the only approved pharmacological therapy is augmentation therapy, which can delay the progression of emphysema. However, alternative strategies such as gene therapy, induced pluripotent stem cells, and prevention of AAT polymerization inside hepatocytes are being investigated. This review aims to summarize and update current knowledge on AATD, identify areas of controversy, and formulate questions for further research., (Copyright © 2023 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.) more...

Neutrophilic panniculitides are a heterogeneous group of inflammatory disorders encompassing many different entities. This review article focuses on the epidemiology, pathogenesis, clinicopathological features, diagnosis, and treatment of selected diseases. Patients often seek care due to systemic involvement, but the variable presentation of panniculitides can present a diagnostic challenge. Most therapeutic modalities for neutrophilic disorders are anecdotal at best with a notable lack of standardization of the responses to medications. There is an urgent need for a larger multi-institutional collaboration to address the unmet needs of these challenging, yet rare conditions., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...

Objectives: Alpha-1 antitrypsin deficiency (AATD) is a hereditary condition associated with emphysema. This study analyzed the efficacy and safety of Spiration Valve System TMipt> (SVS) among AATD patients with severe emphysema., Methods: This multicenter prospective study included 20 patients demonstrating AATD as assessed by quantitative levels of AAT and genotype containing two ZZ alleles. Most diseased lobe based on high resolution computed tomography was selected for treatment with endobronchial SVS. The change from baseline in forced expiratory volume in 1 s (FEV 1 ) at 6 months (Primary outcome) and at 12 months, quality-of-life (QoL) measured by St. George's Respiratory Questionnaire (SGRQ) as health status, dyspnea scale measured by mMRC, Chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), 36-item Short Form Health Survey (SF-36) physical component summary (PCS) and safety were assessed., Results: Lung function (FEV 1 ) significantly improved at 6 months (P = 0.02); but did not reach statistical significance at 12 months (P = 0.22). Significant improvement was observed in dyspnea (at all time points), QoL measures (3, 6, and 12 months), CAT score and PCS of SF-36 (1, 3 and 6 months). Response rates based on minimal clinically important difference reached 50-80% for all variables. Overall, 4.4 valves/patient were used to isolate the target lobe, with a mean procedure time of 20.3 min. Serious adverse events included COPD exacerbations (5%), pneumonia (10%), pneumothorax (15%) and death (5%), occurring within first three months., Conclusion: SVS endobronchial valve treatment showed improvement in lung function, dyspnea, and QoL in AATD patients with severe emphysema., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Hogarth is a consultant for Olympus/Spiration. Dr. Hogarth is a consultant for PulmonX and teaches courses for PulmonX. Dr. Hogarth is a consultant for Takeda (maker of AAT replacement product) and is on the MASEK committee for the Alpha One Foundation. He is a consultant for Wave Lifesciences., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Background and aims: Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases. Methods: We have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures. Results: Transcriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4). Conclusions: Liver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin (AAT) is an acute-phase protein with strong inhibitory activity towards proteolytic enzymes, mainly elastase but also trypsin, chymotrypsin and thrombin. The biological role of the protein and the effects of its deficiency have been subjects of scientific research for years, yet in many areas our knowledge remains incomplete. Alpha-1 antitrypsin deficiency (AATD), a defect in AAT synthesis and functionality, is one of the most frequently inherited genetic disorders among Caucasian populations. Its severe form is characterized by very low serum levels of AAT, and it most often affects the lungs (causing early-onset emphysema or chronic obstructive lung disease (COPD)) and/or liver (leading to jaundice and liver cirrhosis in children and adults). However, little is known about other possible clinical consequences of AAT deficiency. We discuss AAT's potential role in mechanisms regulating human fertility and gestation, with a particular emphasis on the clinical context and on indications for AATD diagnostic testing. [ABSTRACT FROM AUTHOR] more...

BACKGROUND: Alpha-1 antitrypsin deficiency is frequently underrecognized. Individuals with symptoms often experience long diagnostic delays. Although a delayed diagnosis is logically presumed to be associated with adverse effects, confirmatory evidence that a delay in diagnosis confers harm is sparse. The current study characterized the association between a delayed diagnosis and the clinical status at the time of diagnosis. METHODS: Patients with newly diagnosed severe deficiency of alpha-1 antitrypsin received questionnaires that assessed self-reported diagnostic delay, the St George Respiratory Questionnaire (SGRQ) and COPD Assessment Test. Results of spirometry were retrieved and the relationship between the diagnostic delay interval and FEV1% predicted, SGRQ, and COPD Assessment Test were assessed. RESULTS: Forty subjects were recruited (31 with PI*ZZ, 9 with PI*SZ). Values for FEV1% predicted, SGRQ, and COPD Assessment Test were available for 17, 40, and 32 subjects, respectively. The relationship between the diagnostic delay interval and all outcomes was directionally consistent with an adverse impact of increasing diagnostic delay. For each additional year of diagnostic delay, the subject's FEV1%predicted decreased by 0.3% (P = .66), The SGRQ Total score increased by 1.6 points (P < .001), and the COPD Assessment Test score increased by 0.7 points (P = .004). CONCLUSIONS: The results of this analysis were consistent with a delayed diagnosis of alpha-1 antitrypsin deficiency being associated with worse COPD-related symptoms and functional status, and with a trend toward worsened air-flow obstruction. Given that alpha-1 antitrypsin deficiency is associated with accelerated emphysema progression, these findings underscore the importance of early detection of alpha-1 antitrypsin deficiency and reinforce guidelines that endorse alpha-1 antitrypsin deficiency testing in all adults with fixed air-flow obstruction and first-degree relatives of individuals with severe deficiency of alpha-1 antitrypsin. [ABSTRACT FROM AUTHOR] more...

Rationale: Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven.Objectives: To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy.Methods: Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained.Measurements and Main Results: DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val360), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers.Conclusions: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421). [ABSTRACT FROM AUTHOR] more...

Chronic obstructive pulmonary disease can be attributed to genetic conditions and predispositions, among other factors. Alpha-1 antitrypsin deficiency (AATD) is a significant risk factor for COPD development and progression, and aggressive screening for all patients with COPD or adult-onset asthma is encouraged. [ABSTRACT FROM AUTHOR] more...

Background: Multi-b diffusion-weighted hyperpolarized-gas MRI measures pulmonary airspace-enlargement using apparent diffusion coefficients (ADCs) and mean-linear-intercepts (Lm ).>Purpose: To develop single-breath 3D multi-b diffusion-weighted 3 He and 129 Xe MRI using k-space undersampling. Rapid, cost-efficient, single-breath acquisitions may facilitate clinical translation.Study Type: Prospective.Subjects: We evaluated 12 participants, including nine subjects (mean age = 69 ± 9) who were included in the retrospective experiment and three chronic pulmonary obstruction disease (COPD) patients (mean age = 81 ± 6) who participated in the prospective study.Field Strength: A whole-body 3 T 2D/3D fast gradient recall echo (FGRE) sequence.Assessment: Hyperpolarized 3 He/129 Xe MRI, spirometry, plethysmography computed tomography (CT). We evaluated 129 Xe ADC/morphometry estimates by retrospectively undersampling previously acquired fully sampled multibreath, multi-b diffusion-weighted data. Next, we prospectively evaluated the feasibility of accelerated (AF = 7) 3 He MRI static-ventilation/T2 * (extra short-TE, b = 0 image) and ADC/morphometry (five b-values) maps using a single gas-dose and 16-second breath-hold. To conservatively evaluate cost-improvement, we compared total costs of single vs. multiple 129 Xe doses.Statistical Tests: Multivariate analysis of variance, independent t-tests and voxel-by-voxel basis difference test.Results: For the retrospectively undersampled 129 Xe data, a nonsignificant mean difference for ADC/Lm of 14%/12%, 12%/8%, and 11%/9% was observed (all, P > 0.4) between the fully sampled and accelerated data for the never-smoker, COPD, and alpha-1 antitrypsin deficiency (AATD) groups, respectively. The control never-smoker group had significantly lower ADC (P < 0.001) and Lm (P < 0.001) than the COPD/AATD group for both fully sampled and accelerated data. For the prospectively acquired 3 He MRI data, static-ventilation, T2 *, ADC, and morphometry maps were acquired using a single 16-second breath-hold scan and single gas dose. Accelerated imaging resulted in cost savings of ~$US 1000/patient, a conservative estimate based on 129 Xe MRI dose savings (single vs. five doses).Data Conclusion: This is a proof-of-concept demonstration of accelerated (7×) morphometry that shows that less cost- and time-efficient multibreath methods that lead to variability and patient fatigue may be avoided in the future.Level Of Evidence: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018. [ABSTRACT FROM AUTHOR] more...

As NPs play an increasingly vital role in primary care, they must be well versed in a variety of conditions. Alpha-1 antitrypsin (AAT) deficiency is a respiratory disease for which there is particularly low awareness in both the nursing profession and the wider medical community. This article provides an overview of AAT deficiency and includes guidance for diagnosing the disease. As NPs play an increasingly vital role in primary care, they must be well versed in a variety of conditions. Alpha-1 antitrypsin (AAT) deficiency is a respiratory disease with a particularly low awareness in both the nursing profession and the wider medical community. This article provides an overview of AAT deficiency and includes guidance for diagnosing the disease. [ABSTRACT FROM AUTHOR] more...

Ignacio Blanco,1 Patricia Bueno,2 Isidro Diego,3 Sergio Pérez-Holanda,4 Francisco Casas-Maldonado,5 Cristina Esquinas,6 Marc Miravitlles6,7 1Alpha1-Antitrypsin Deficiency Spanish Registry (REDAAT), Fundación Respira, Spanish Society of Pneumology and Thoracic Surgery (SEPAR), Barcelona, 2Internal Medicine Department, County Hospital of Jarrio, 3Materials and Energy Department, School of Mining Engineering, Oviedo University, 4Surgical Department, University Central Hospital of Asturias (HUCA), Oviedo, Principality of Asturias, 5Pneumology Department, Complejo Hospitalario Universitario de Granada, Granada, 6Pneumology Department, Hospital Universitari Vall d’Hebron, 7CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain Abstract: In alpha-1 antitrypsin deficiency (AATD), the Z allele is present in 98% of cases with severe disease, and knowledge of the frequency of this allele is essential from a public health perspective. However, there is a remarkable lack of epidemiological data on AATD worldwide, and many of the data currently used are outdated. Therefore, the objective of this study was to update the knowledge of the frequency of the Z allele to achieve accurate estimates of the prevalence and number of Pi*ZZ genotypes worldwide based on studies performed according to the following criteria: 1) samples representative of the general population, 2) AAT phenotyping characterized by adequate methods, and 3) measurements performed using a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop maps with an inverse distance weighted (IDW)-interpolation method, providing numerical and graphical information of Pi*Z distribution worldwide. A total of 224 cohorts from 65 countries were included in the study. With the data provided by these cohorts, a total of 253,404 Pi*ZZ were estimated worldwide: 119,594 in Europe, 91,490 in America and Caribbean, 3,824 in Africa, 32,154 in Asia, 4,126 in Australia, and 2,216 in New Zealand. In addition, the IDW-interpolation maps predicted Pi*Z frequencies throughout the world even in some areas that lack real data. In conclusion, the inclusion of new well-designed studies and the exclusion of the low-quality ones have significantly improved the reliability of results, which may be useful to plan strategies for future research and diagnosis and to rationalize the therapeutic resources available. Keywords: SERPINA1, alpha-1 antitrypsin deficiency, protease inhibitor, genetic epidemiology, inverse distance weighted interpolation, geographic information system more...

Stanley I Ejiofor,1,2 Jan Stolk,3 Pablo Fernandez,4 Robert A Stockley1,2 1Centre for Translational Inflammation Research, University of Birmingham, 2ADAPT Project, University Hospital Birmingham, Birmingham, UK; 3Leiden University Medical Centre, Leiden, the Netherlands; 4Independent consultant, Penn, UK Introduction: Patients with chronic obstructive pulmonary disease often experience exacerbations. These events are important as they are a major cause of morbidity and mortality. Recently, it has been increasingly recognized that patients may experience symptoms suggestive of an exacerbation but do not seek treatment, which are referred to as unreported or untreated exacerbations. Symptom diaries used in clinical trials have the benefit of identifying both treated and untreated exacerbation events. Methods: The Kamada study was a multicenter, double-blind randomized controlled trial of inhaled augmentation therapy in alpha-1 antitrypsin deficiency (AATD). A retrospective review of daily electronic symptom diary cards was undertaken from the two leading centers to identify symptomatic episodes consistent with a definition of an exacerbation. The aims were to explore the relationship between exacerbation events and classical “Anthonisen” symptoms and to characterize treated and untreated episodes. Results: Forty-six AATD patients with airflow obstruction and history of exacerbations were included in the analysis. Two hundred thirty-three exacerbation episodes were identified: 103 untreated and 130 treated. Untreated episodes were significantly shorter (median 6 days; interquartile range [IQR] 3–10 days) than the treated episodes (median 10 days; IQR 5–18.25 days: P more...

Alpha-1-antitrypsin deficiency (A1AT) is a cause of an orphan disease, cases of which are well described in adult patients, but as for children, they are described only in a few publications, and in most of them the description is limited to liver lesions. This article presents the results from the observation of 5 children with alpha-1-antitrypsin deficiency, including 3 boys (Z-allele homozygotes) and 2 girls (PiMZ-phenotype carriers). It is shown that in patients with A1AT deficiency the onset of the destruction of lung tissue was at the age of 2 with the signs of recurrent bronchial obstruction and at the age of 7 in the form of emphysema. Raising awareness among practicing physicians of various specialties will improve diagnostics of this form of disease and its comorbid conditions. more...

Alpha-1 antitrypsin deficiency is a rare and often underdiagnosed hereditary disorder, which mainly affects the Caucasian population. We report a case of a noncystic fibrosis bronchiectasis patient in the absence of emphysema associated with low serum alpha-1-antitrypsin (AAT) level, in the absence of the most common defective alleles associated with AAT deficiency (PI*S and PI*Z) but with a new mutation in heterozygosis. This mutation is characterized by the substitution in the coding region of exon 3, of a guanine (G) for a thymine (T), generating the replacement of a glutamine (Gln) by a histidine (His) in codon 212 (cod 212 GlnCAG > HisCAT), corresponds to a new S allelic variant. This mutation, never identified before, is called S-Napoli. more...

Landy V Luna Diaz,1 Isabella Iupe,1 Bruno Zavala,1 Kira C Balestrini,1 Andrea Guerrero,1 Gregory Holt,1,2 Rafael Calderon-Candelario,1,2 Mehdi Mirsaeidi,1,2 Michael Campos1,21Miami Veterans Administration Medical Center, Miami, FL, 2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami School of Medicine, Miami, FL, USAAlpha-1 antitrypsin deficiency (AATD) is the only well-recognized genetic disorder associated with an increased risk of emphysema and COPD.1 Identifying AATD allows genetic counseling and the chance to offer specific augmentation therapy to slow emphysema progression. Despite specific recommendations from the World Health Organization, American Thoracic Society and European Respiratory Society to screen all patients with COPD and other at-risk conditions,2–4 testing rates are low ( more...

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., (© 2024. The Author(s).) more...

Aim: The longitudinal health status of Danish children with alpha-1 antitrypsin deficiency had never previously been characterised. This study aimed to assess the changes in growth, lung and liver function through childhood in these children., Methods: Danish children diagnosed between 2005 and 2020 with pathogenic variants in the Serpin family A member 1 gene were included. Retrospective data on growth, lung and liver parameters were obtained from local databases. Anthropometric Z-scores and composite liver scores were computed. Growth and blood results were analysed using robust linear mixed models., Results: The study included 184 children (68 with ZZ-homozygosity, 116 with heterozygosity). The median follow-up time was 7 years [IQR 3.75-9.00] for children with ZZ-homozygosity and 0.5 years [IQR 0.0-2.0] for children with heterozygosity. Both groups had low weight-for-height Z-scores at diagnosis but experienced catch-up growth during the first year of life. In addition, children with ZZ-homozygosity had higher serum concentrations of γ-glutamyl transferase and alanine aminotransferase throughout childhood, when compared with children with heterozygosity. Data proved insufficient to assess lung function properly., Conclusion: Children with ZZ-homozygosity were more affected on serum liver parameters throughout childhood when compared with children with heterozygosity. Both groups experienced catch-up growth during the first year of life., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.) more...

Background: Diagnosing alpha-1 antitrypsin deficiency (A1ATD) involves two-step laboratory testing, determination of serum alpha-1 antitrypsin (A1AT) level and phenotyping if A1AT < 100 mg/dL. Whether these guidelines are effectuated in clinical practice is uncertain. To begin to address this issue, we determined whether A1AT phenotyping is performed in patients with serum A1AT 57 - 99 mg/dL at our institution., Methods: We reviewed the medical records of patients seen at Jesse Brown Veterans Affairs Medical Center from January 2019 to October 2022 with serum A1AT between 57 and 99 mg/dL. In each case, pertinent demographic, clinical, and pulmonary function tests data were extracted. Data were presented as means and standard deviation (SD) where appropriate. The Student's t -test was used for statistical analysis. P < 0.05 was considered statistically significant., Results: Thirty patients (90% males; 60 ± 18 years) with serum A1ATD < 100 mg/mL were identified. Fourteen were African Americans, four Hispanics, and 12 non-Hispanic Whites. The majority were current or ex-smokers. Fourteen (47%) patients had lung disease, 14 (47%) liver disease and one had concomitant lung and liver diseases. Mean ± SD forced expiratory volume in 1 s (FEV 1 ) and lung diffusing capacity were 2.57 ± 1.41 L (67±19% predicated) and 18.7 ± 10 mL/min/mm Hg (64±28% predicted), respectively. Only 13 patients (43%) underwent phenotype testing (seven African Americans, five Whites, and one Hispanic). Six patients had MZ phenotype, four MS, and three SZ. One patient died from acute respiratory failure during the study period., Conclusions: Phenotyping of patients with serum A1AT 57 - 99 mg/dL at our institution is inadequate. Accordingly, regular continuous medical educational programs on A1AT phenotyping targeting healthcare providers are warranted., Competing Interests: The authors declare no conflict of interest., (Copyright 2024, Elfessi et al.) more...