Alpha-1 Antitrypsin Deficiency and COVID-19 Infection

Strassmair, Michael; Stangl, Manfred

doi:10.1016/j.arbres.2020.10.009

Cited by 5 publications

(4 citation statements)

References 6 publications

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“…Greater understanding of the underlying biologic pathways leading to cell damage in AATD will also be of benefit for the treatment of AATD [ 7 ]. This is of special importance in the current pandemic situation with potential associations between AATD and COVID19 [ 8 , 9 ]. The Progenika diagnostic network is formed by those countries using the Progenika system as the diagnostic standard for AATD.…”

Section: Discussionmentioning

confidence: 99%

Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network

et al. 2023

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Background Knowledge of the frequency of rare SERPINA1 mutations could help in the management of alpha1 antitrypsin deficiency (AATD). The present study aims to assess the frequencies of rare and null alleles and their respiratory and hepatic pathogenicity. Methods This is a secondary analysis of a study that evaluated the viability of the Progenika diagnostic genotyping system in six different countries by analyzing 30,827 samples from cases of suspected AATD. Allele-specific genotyping was carried out with the Progenika A1AT Genotyping Test which analyses 14 mutations in buccal swabs or dried blood spots samples. SERPINA1 gene sequencing was performed for serum AAT-genotype discrepancies or by request of the clinician. Only cases with rare mutations were included in this analysis. Results There were 818 cases (2.6%) carrying a rare allele, excluding newly identified mutations. All were heterozygous except for 20 that were homozygous. The most frequent alleles were the M-like alleles, PI*Mmalton and PI*Mheerlen. Of the 14 mutations included in the Progenika panel, there were no cases detected of PI*Siiyama, PI*Q0granite falls and PI*Q0west. Other alleles not included in the 14-mutation panel and identified by gene sequencing included PI*Mwürzburg, PI*Zbristol, and PI*Zwrexham, and the null alleles PI*Q0porto, PI*Q0madrid, PI*Q0brescia, and PI*Q0kayseri. Conclusions The Progenika diagnostic network has allowed the identification of several rare alleles, some unexpected and not included in the initial diagnostic panel. This establishes a new perspective on the distribution of these alleles in different countries. These findings may help prioritize allele selection for routine testing and highlights the need for further research into their pathogenetic role.

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Section: Discussionmentioning

confidence: 99%

Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network

et al. 2023

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“…While there was no difference in mortality or ventilator-free days, the AAT-treated patients had a trend toward decreased time on the ventilator P = 0.44 [ 161 ]. Strassmair and Stangl [ 162 ] have proposed the idea that delivery of mesenchymal stem cells that express AAT, with their ability to ‘home-in’ to the lungs, might be an effective mechanism to deliver AAT.…”

Section: Current Evidence For Aat Treatment Of Covid-19mentioning

confidence: 99%

Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence

Bai

Schountz

Buckle

et al. 2023

Biochemical Society Transactions

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Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution. We next underscored that measures to prevent severe COVID-19 currently exists but teeters on a balance and that current treatment for severe COVID-19 remains grossly suboptimal. We then reviewed the epidemiologic and clinical evidence that AAT deficiency increases risk of COVID-19 infection and of more severe disease, and the experimental evidence that AAT inhibits cell surface transmembrane protease 2 (TMPRSS2) — a host serine protease required for SARS-CoV-2 entry into cells — and that this inhibition may be augmented by heparin. We also elaborated on the panoply of other activities of AAT (and heparin) that could mitigate severity of COVID-19. Finally, we evaluated the available clinical evidence for AAT treatment of COVID-19.

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“…Alpha-1-antitrypsin (AAT) is a 52 kDa glycoprotein synthesized in the liver with high concentrations at plasma level, which possesses anti-inflammatory functions (inhibition of NF-kB, IL-8), as well as inhibiting serine proteases such as metalloproteinase 17 (ADAM17) and transmembrane surface serine protease 2 (TMPRSS2), which are crucial for entry of SARS-CoV-2 into the host cell and associated with poor disease prognosis, It is found at low concentrations in patients with severe COVID-19 [302][303][304][305]. In a pre-clinical in vitro assay with HEK293T, Caco2, Vero E6, and human small airway epithelial cells (SAEC) cell lines, AAT was observed to directly inhibit TMPRSS2 by suppressing viral replication in the cell lines (83% decrease in viral titers in SAEC) at concentrations of 40-45 µM (similar to physiological concentrations of between 10-40 µM in alveolar interstitial fluid) [306].…”

Section: Alpha-1-antitrypsinmentioning

confidence: 99%

Severe COVID-19: Drugs and Clinical Trials

Ceja-Gálvez

Renteria-Flores

Nicoletti

et al. 2023

JCM

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By January of 2023, the COVID-19 pandemic had led to a reported total of 6,700,883 deaths and 662,631,114 cases worldwide. To date, there have been no effective therapies or standardized treatment schemes for this disease; therefore, the search for effective prophylactic and therapeutic strategies is a primary goal that must be addressed. This review aims to provide an analysis of the most efficient and promising therapies and drugs for the prevention and treatment of severe COVID-19, comparing their degree of success, scope, and limitations, with the aim of providing support to health professionals in choosing the best pharmacological approach. An investigation of the most promising and effective treatments against COVID-19 that are currently available was carried out by employing search terms including “Convalescent plasma therapy in COVID-19” or “Viral polymerase inhibitors” and “COVID-19” in the Clinicaltrials.gov and PubMed databases. From the current perspective and with the information available from the various clinical trials assessing the efficacy of different therapeutic options, we conclude that it is necessary to standardize certain variables—such as the viral clearance time, biomarkers associated with severity, hospital stay, requirement of invasive mechanical ventilation, and mortality rate—in order to facilitate verification of the efficacy of such treatments and to better assess the repeatability of the most effective and promising results.

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Alpha-1 Antitrypsin Deficiency and COVID-19 Infection

Cited by 5 publications

References 6 publications

Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network

Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network

Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence

Severe COVID-19: Drugs and Clinical Trials

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