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1.
N Engl J Med ; 387(6): 514-524, 2022 Aug 11.
Article in English | MEDLINE | ID: covidwho-2031920

ABSTRACT

BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency. METHODS: We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry. RESULTS: All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. CONCLUSIONS: In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).


Subject(s)
Liver Cirrhosis , RNAi Therapeutics , alpha 1-Antitrypsin Deficiency , alpha 1-Antitrypsin , Adult , Genotype , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Injections, Subcutaneous , Liver/drug effects , Liver/enzymology , Liver/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/etiology , Liver Cirrhosis/genetics , Mutation , RNAi Therapeutics/adverse effects , RNAi Therapeutics/methods , alpha 1-Antitrypsin/analysis , alpha 1-Antitrypsin/blood , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/complications , alpha 1-Antitrypsin Deficiency/drug therapy , alpha 1-Antitrypsin Deficiency/genetics
3.
Pneumologie ; 76(7): 494-498, 2022 Jul.
Article in German | MEDLINE | ID: covidwho-1900704

ABSTRACT

METHODS: In March 2021, a 19-item survey was sent to 420 patients with AATD who were being treated with AAT replacement therapy (prolastin) and who participated in the German AlphaCare patient program. RESULTS: The majority of the respondents (55.9%; 138) had been diagnosed with AATD ≥10 years prior to the survey and most (93.5%; 231) felt adequately informed about their disease through their physician, AlphaCare and Alpha1 Deutschland. The majority of respondents were concerned/very concerned about acquiring COVID-19. Only 1.2% of the respondents reported having been infected with SARS-CoV-2, less than the infection rate in the general population at that time (3.4%). Almost all of the respondents fully agreed/agreed that they had restricted their social contacts due to the pandemic. A substantial percentage of the responding patients fully agreed/agreed that they were concerned about being infected with COVID-19 during a visit at their doctor's office or clinic. Regarding AAT augmentation therapy, only 18 respondents reported discontinuing therapy during the pandemic, but most of these discontinuations were short-term - one was permanent. CONCLUSIONS: These survey results suggest that AATD patients are well-informed about the risks of COVID-19 with their condition and practised self-protection measures. This may have resulted in an COVID-19 infection rate lower than the general population. Although respondents were concerned about exposure to COVID-19 in their doctor's office or clinic, very few discontinued therapy even temporarily.


Subject(s)
COVID-19 , alpha 1-Antitrypsin Deficiency , Humans , Information Management , Pandemics , SARS-CoV-2 , alpha 1-Antitrypsin , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/drug therapy , alpha 1-Antitrypsin Deficiency/epidemiology
4.
Med (N Y) ; 3(4): 233-248.e6, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1882364

ABSTRACT

Background: Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15). Methods: Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1ß, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints. Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1ß, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients. Conclusions: In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic. Funding: ECSA-2020-009; Elaine Galwey Research Bursary.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , alpha 1-Antitrypsin Deficiency , COVID-19/complications , Humans , Interleukin-10/therapeutic use , Interleukin-6/therapeutic use , Interleukin-8/therapeutic use , Respiratory Distress Syndrome/drug therapy , alpha 1-Antitrypsin/therapeutic use , alpha 1-Antitrypsin Deficiency/drug therapy
7.
Int J Mol Sci ; 23(5)2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1715404

ABSTRACT

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.


Subject(s)
Apolipoproteins/metabolism , Caspases/metabolism , Complement System Proteins/metabolism , Cytokines/metabolism , alpha 1-Antitrypsin/metabolism , Binding Sites/genetics , COVID-19/metabolism , COVID-19/virology , Glycosylation , Humans , Mutation , Protein Binding , Protein Domains , SARS-CoV-2/physiology , alpha 1-Antitrypsin/chemistry , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin Deficiency/metabolism
8.
EBioMedicine ; 77: 103894, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1703667

ABSTRACT

BACKGROUND: Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. METHODS: Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. FINDINGS: AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples. Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. INTERPRETATION: There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy. FUNDING: NIH Serological Sciences Network, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , alpha 1-Antitrypsin Deficiency , COVID-19/drug therapy , Humans , Peptide Hydrolases , Respiratory Distress Syndrome/etiology , SARS-CoV-2
9.
Eur J Hum Genet ; 30(8): 872-874, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1655565

ABSTRACT

The coronavirus disease of 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, continues to present an unprecedented challenge worldwide. Emerging evidence suggests that α-1 antitrypsin (A1AT), a circulating protein with protective effects on the lung and other vital organs, plays a critical role in preventing SARS-CoV-2 infection and may be a promising therapeutic option for patients with COVID-19. A1AT deficiency (AATD) is characterized by dysfunctional or insufficient levels of A1AT. Recently, we have proposed that AATD patients are a vulnerable population for COVID-19. Patients with AATD may derive limited benefit from the current COVID-19 vaccines and continue to rely on conventional medical therapy and behavioral adaptations to mitigate the risk of infection. Unfortunately, this population has not been included in the COVID-19 vaccine clinical trials and studies have yet to characterize the safety, immunogenicity, and ultimately, the efficacy of COVID-19 vaccines for AATD patients. Re-evaluation of the COVID-19 vaccine safety and immunogenicity will further promote informed decision-making for vaccination in AATD individuals and contribute to reduce morbidity and mortality from COVID-19 infection.


Subject(s)
COVID-19 Vaccines , COVID-19 , alpha 1-Antitrypsin Deficiency , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Lung , Pandemics/prevention & control , SARS-CoV-2
10.
Int J Chron Obstruct Pulmon Dis ; 16: 2983-2996, 2021.
Article in English | MEDLINE | ID: covidwho-1511885

ABSTRACT

Alpha 1 Antitrypsin deficiency (AATD) is a hereditary condition characterized by low serum Alpha 1 Antitrypsin (AAT) levels and a predisposition towards early-onset emphysema. Infusion of AAT is the only disease-modifying therapy that can sufficiently raise plasma AAT levels above the putative protective threshold and reduce the decline in lung density loss. Several randomized controlled trials (RCTs) and registry studies support the clinical efficacy of AAT therapy in slowing the progression of AATD-related emphysema and improving survival outcomes. The COVID-19 pandemic has prompted physicians to develop additional strategies for delivering AAT therapy, which are not only more convenient for the patient, but are "COVID-19 friendly", thereby reducing the risk of exposing these vulnerable patients. Intravenous (IV) self-administration of AAT therapy is likely to be beneficial in certain subgroups of patients with AATD and can remove the need for weekly hospital visits, thereby improving independence and well-being. Increasing the awareness of self-administration in AATD through the development of formal guidelines and training programs is required among both physicians and patients and will play an essential role, especially post-COVID-19, in encouraging physicians to consider self-administration for AATD in suitable patients. This review summarizes the benefits of AAT therapy on the clinical endpoints of mortality and quality of life (QoL) and discusses the benefits of self-administration therapy compared with conventional therapy administered by a healthcare professional. In addition, this review highlights the challenges of providing AAT therapy during the COVID-19 pandemic and the potential considerations for its implementation thereafter.


Subject(s)
COVID-19 , Pulmonary Disease, Chronic Obstructive , alpha 1-Antitrypsin Deficiency , Humans , Pandemics , Registries , SARS-CoV-2 , alpha 1-Antitrypsin , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/drug therapy , alpha 1-Antitrypsin Deficiency/epidemiology
14.
Clin Respir J ; 15(9): 1019-1024, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1258918

ABSTRACT

In this work, we provide an up-to-date summary of the available molecular- and cell-related mechanisms by which alpha1-antitrypsin (AAT) protein could be of benefit in treating COVID-19 patients. As well, we demonstrate the current status in terms of the ongoing clinical trials using AAT in COVID-19 patients. Finally, we touch on the potential role gene therapy and stem cell-based gene therapy could have in such emerging and serious condition caused by the SARS-CoV-2 virus.


Subject(s)
COVID-19 , alpha 1-Antitrypsin Deficiency , Humans , SARS-CoV-2 , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin Deficiency/therapy
16.
Respir Med ; 184: 106466, 2021 08.
Article in English | MEDLINE | ID: covidwho-1230754

ABSTRACT

Alpha1-antitrypsin deficiency arises due to mutations in alpha1-antitrypsin (AAT) gene and represents the most prominent genetic predisposition to chronic obstructive pulmonary disease and emphysema. Since AAT plays important immunomodulatory and tissue-protective roles and since it was suggested to protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we assessed this association in United Kingdom Biobank, a community-based cohort with >500,000 participants. The most common, mild AATD genotypes were associated neither with increased SARS-CoV-2 infection rates nor with increased SARS-CoV-2 fatalities, while the numbers of severe AATD cases were too low to allow definitive conclusions.


Subject(s)
COVID-19/prevention & control , Genetic Predisposition to Disease/genetics , alpha 1-Antitrypsin Deficiency/genetics , Acute Disease , COVID-19/epidemiology , COVID-19/mortality , Cohort Studies , Female , Humans , Male , Mutation , Negative Results , Peptide Fragments/genetics , Peptide Fragments/physiology , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Emphysema/genetics , Severity of Illness Index , United Kingdom/epidemiology , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin/physiology
17.
Respir Med ; 183: 106440, 2021 07.
Article in English | MEDLINE | ID: covidwho-1219243

ABSTRACT

The clinical manifestations of COVID-19 are heterogeneous: 46.4% of patients admitted into hospital reported to have at least one comorbidity. Comorbidities such as COPD, diabetes, hypertension and malignancy predispose patients with Covid-19 to adverse clinical outcomes. Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder caused by pathological mutation(s) in the SERPINA1 gene resulting in an imbalance in proteinase activity which may lead to premature emphysema and COPD. Our aim was to investigate whether people with severe AAT deficiency (AATD) have an increased risk of (severe) COVID-19 infection. We collected data on COVID-19 symptoms, laboratory-confirmed infection, hospitalization and treatment by means of a telephone survey, directly administered to Italian severe AATD subjects in May 2020. We then compared our findings with data collected by the Istituto Superiore di Sanità on the total population in Italy during the same period. We found an higher frequency of SARS-CoV-2 infection in our cohort (3.8%) compared to national data regarding infection, thus giving severe AATD a relative risk of 8. 8 (95%CI 5.1-20,0; p<0.0001) for symptomatic SARS-CoV-2 infection. Moreover, the relative risk (RR) was higher in AATD patients with pre-existing lung diseases (RR 13.9; 95%CI 8.0-33.6; p<0.001), but with a similar death rate (1 in 8, 12.5%) compared to the general population (13.9%; RR 0.9). These preliminary findings highlight the importance of close surveillance in the spread of COVID-19 in patients with severe AATD and underlines the need for further studies into the role of the antiprotease shield in preventing SARS-Cov-2 infection.


Subject(s)
COVID-19/epidemiology , Pandemics , SARS-CoV-2 , alpha 1-Antitrypsin Deficiency/epidemiology , Biomarkers/blood , COVID-19/blood , Comorbidity , Global Health , Humans , Peptide Hydrolases/blood , Severity of Illness Index , alpha 1-Antitrypsin Deficiency/blood
19.
Inflamm Res ; 70(4): 375-377, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1141394

ABSTRACT

INTRODUCTION: Coronavirus disease 2019 (COVID-19), a new disease that we do not know yet how to treat, is rapidly evolving and has forced us to stay indoors. Surprisingly, a broad range of symptoms has been reported since COVID-19 emergence. Individual variations in susceptibility to SARS-CoV-2 can be due to non-genetic and genetic factors. Alpha-1-antitrypsin deficiency (AATD) is an inherited condition that is associated with an increased risk of liver and lung diseases which may increase susceptibility to COVID-19 infection. At the same time, there could be a possibility of developing non-hereditary AATD. DISCUSSION: In addition to some evidence showing the role of vitamin D deficiency in COVID-19 pathology, it has been recognized that there is a biological link between AAT and vitamin D. Therefore, here we offer a new perspective that lower vitamin D levels in COVID-19 patients can cause acquired AATD that provide a condition with more disease severity and a higher risk of death. As a consequence, COVID-19 individuals with vitamin D deficiency may have a higher risk of morbidity and mortality. CONCLUSION: Therefore, early vitamin D and AAT assessments and optimal interventions could be helpful to prevent severe COVID-19 outcomes.


Subject(s)
COVID-19/blood , COVID-19/complications , Vitamin D Deficiency/complications , Vitamin D/blood , alpha 1-Antitrypsin Deficiency/complications , Disease Susceptibility , Humans , Liver Diseases/complications , Lung Diseases/complications , Risk Factors , Severity of Illness Index , Treatment Outcome , Vitamin D Deficiency/mortality , alpha 1-Antitrypsin Deficiency/mortality
20.
Hepatology ; 74(3): 1674-1686, 2021 09.
Article in English | MEDLINE | ID: covidwho-1103301

ABSTRACT

Pulmonary disease in liver cirrhosis and portal hypertension (PH) constitutes a challenging clinical scenario and may have important implications with regard to prognosis, liver transplantation (LT) candidacy, and post-LT outcome. Pre-LT evaluation should include adequate screening for pulmonary diseases that may occur concomitantly with liver disease as well as for those that may arise as a complication of end-stage liver disease and PH, given that either may jeopardize safe LT and successful outcome. It is key to discriminate those patients who would benefit from LT, especially pulmonary disorders that have been reported to resolve post-LT and are considered "pulmonary indications" for transplant, from those who are at increased mortality risk and in whom LT is contraindicated. In conclusion, in this article, we review the impact of several pulmonary disorders, including cystic fibrosis, alpha 1-antitrypsin deficiency, hereditary hemorrhagic telangiectasia, sarcoidosis, coronavirus disease 2019, asthma, chronic obstructive pulmonary disease, pulmonary nodules, interstitial lung disease, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension, on post-LT survival, as well as the reciprocal impact of LT on the evolution of lung function.


Subject(s)
Hypertension, Portal/complications , Liver Cirrhosis/complications , Liver Transplantation/mortality , Lung Diseases/complications , Adult , Asthma/diagnosis , Asthma/epidemiology , Asthma/mortality , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/mortality , COVID-19/virology , Child , Cystic Fibrosis , End Stage Liver Disease/complications , Hepatopulmonary Syndrome/diagnosis , Hepatopulmonary Syndrome/epidemiology , Hepatopulmonary Syndrome/mortality , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , Liver Transplantation/methods , Lung Diseases/epidemiology , Lung Diseases/pathology , Lung Diseases/physiopathology , Mass Screening , Patient Selection/ethics , Prognosis , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/mortality , Respiratory Function Tests/methods , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Sarcoidosis/diagnosis , Sarcoidosis/epidemiology , Sarcoidosis/mortality , Survival Rate/trends , Telangiectasia, Hereditary Hemorrhagic/diagnosis , Telangiectasia, Hereditary Hemorrhagic/epidemiology , Telangiectasia, Hereditary Hemorrhagic/mortality , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/epidemiology , alpha 1-Antitrypsin Deficiency/mortality
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