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

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.

COVID-19's impact on care practice for alpha-1-antitrypsin deficiency patients.

BACKGROUND: Patients with alpha-1 antitrypsin deficiency (AATD), commonly categorized as a rare disease, have been affected by the changes in healthcare management brought about by COVID-19. This study's aim was to identify the changes that have taken place in AATD patient care as a result of the COVID-19 pandemic in Spain and to propose experts' recommendations aimed at ensuring humanized and quality care for people with AATD in the post-pandemic situation. METHODS: A qualitative descriptive case study with a holistic single-case design was conducted, using focus groups with experts in AATD clinical management, including 15 health professionals with ties to the Spanish health system (12 pneumologists and 2 hospital pharmacists from 11 different hospitals in Spain) and 1 patient representative. RESULTS: COVID-19 has had a major impact on numerous aspects of AATD clinical patient management in Spain, including diagnostic, treatment, and follow-up phases. The experts concluded that there is a need to strengthen coordination between Primary Care and Hospital Care and improve the coordination processes across all the organizations and actors involved in the healthcare system. Regarding telemedicine and telecare, experts have concluded that it is necessary to promote this methodology and to develop protocols and training programs. Experts have recommended developing personalized and precision medicine, and patient participation in decision-making, promoting self-care and patient autonomy to optimize their healthcare and improve their quality of life. The possibility of monitoring and treating AATD patients from home has also been proposed by experts. Another result of the study was the recommendation of the need to ensure that plasma donations are made on a regular basis by a sufficient number of healthy individuals. CONCLUSION: The study advances knowledge by highlighting the challenges faced by health professionals and changes in AATD patient management in the context of the COVID-19 pandemic. It also proposes experts' recommendations aimed at ensuring humanized and quality care for people with AATD in the post-pandemic situation. This work could serve as a reference study for physicians on their daily clinical practice with AATD patients and may also provide guidance on the changes to be put in place for the post-pandemic situation.

Correlation of alpha-1 antitrypsin levels and exosome associated neutrophil elastase endothelial injury in subjects with SARS-CoV2 infection.

BACKGROUND: Severe acute respiratory syndrome caused by a novel coronavirus 2 (SARS-CoV-2) has infected more than 18 million people worldwide. The activation of endothelial cells is a hallmark of signs of SARS-CoV-2 infection that includes altered integrity of vessel barrier and endothelial inflammation. OBJECTIVES: Pulmonary endothelial activation is suggested to be related to the profound neutrophil elastase (NE) activity, which is necessary for sterilization of phagocytosed bacterial pathogens. However, unopposed activity of NE increases alveolocapillary permeability and extracellular matrix degradation. The uncontrolled protease activity of NE during the inflammatory phase of lung diseases might be due to the resistance of exosome associated NE to inhibition by alpha-1 antitrypsin. METHOD: 31 subjects with a diagnosis of SARS-CoV2 infection were recruited in the disease group and samples from 30 voluntaries matched for age and sex were also collected for control. RESULTS: We measured the plasma levels of exosome-associated NE in SARS-CoV-2 patients which, were positively correlated with sign of endothelial damage in those patients as determined by plasma levels of LDH. Notably, we also found strong correlation with plasma levels of alpha-1 antitrypsin and exosome-associated NE in SARS-CoV-2 patients. Using macrovascular endothelial cells, we also observed that purified NE activity is inhibited by purified alpha-1 antitrypsin while, NE associated with exosomes are resistant to inhibition and show less sensitivity to alpha-1 antitrypsin inhibitory activity, in vitro. CONCLUSIONS: Our results point out the role of exosome-associated NE in exacerbation of endothelial injury in SARS-CoV-2 infection. We have demonstrated that exosome-associated NE could be served as a new potential therapeutic target of severe systemic manifestations of SARS-CoV-2 infection.

Lower serum alpha 1 antitrypsin levels in patients with severe COVID-19 compared with patients hospitalized due to non-COVID-19 pneumonia.

INTRODUCTION: Alpha 1 antitrypsin (A1AT) is the major human blood serine protease inhibitor. Transmembrane serine protease 2 (TMPRSS2), which is crucial for SARS-CoV-2 cell entry, is inhibited by A1AT. Therefore, we hypothesized that individuals with diminished levels of A1AT may be more prone to SARS-CoV-2 infection and severe COVID-19 disease. Our aim in this study was to evaluate the level of A1AT in hospitalized COVID-19 patients in comparison to hospitalized patients with non-COVID-19 pneumonia. METHODS: We conducted an observational prospective study between October 2020 and April 2021 in Rabin Medical Centre in Israel. A1AT levels were measured from the routine serum samples of hospitalized patients with COVID-19 and non-COVID-19 pneumonia (control group). The primary outcome was A1AT level, secondary outcomes were clinical outcomes and predictors of morality. RESULTS: Overall, 145 patients were included in the study, 98 in the COVID-19 group and 47 in the control group. The median A1AT level was 222 mg/dL (interquartile range (IQR) 188-269) and 258 mg/dL (IQR 210-281) in the COVID-19 and control groups, respectively (p = .045). Multivariate analysis for independent risk factors for mortality among COVID-19 patients showed that diabetes mellitus (p = .02), older age (p = .04), and high A1AT levels (p = .04) were all associated with increased mortality. CONCLUSION: Patients admitted due to severe COVID-19 had lower A1AT levels in comparison to patients admitted due to non-COVID pneumonia. This observation may suggest an association between mildly diminished A1AT and higher risk of SARS-CoV-2 infection with severe COVID-19 disease.

[Impact of COVID-19 pandemic on information management and adherence to replacement therapy with AAT of patients with alpha-1 antitrypsin deficiency (AATM)]. / Auswirkungen der COVID-19-Pandemie auf das Informationsmanagement und die Therapieadhärenz von substituierten Patienten mit Alpha-1-Antitrypsin-Mangel (AATM).

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.

A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19.

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.

A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.

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.

Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications.

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.

Leave no one behind: inclusion of alpha-1 antitrypsin deficiency patients in COVID-19 vaccine trials.

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.

Alpha 1 Antitrypsin Therapy in Patients with Alpha 1 Antitrypsin Deficiency: Perspectives from a Registry Study and Practical Considerations for Self-Administration During the COVID-19 Pandemic.

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.

Insights into the potential role of alpha1-antitrypsin in COVID-19 patients: Mechanisms, current update, and future perspectives.

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.

SARS-CoV-2 infection in alpha1-antitrypsin deficiency.

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.

COVID-19 infection in severe Alpha 1-antitrypsin deficiency: Looking for a rationale.

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.