Alpha-1 antitrypsin (AAT) is a protease inhibitor with important anti-inflammatory, immunomodulatory, and anticoagulation effects. It is also involved in cell death and the formation of neutrophil extracellular traps.

Therefore, AAT has been considered an interesting therapeutic target for the treatment of coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In fact, emerging evidence suggests that alpha-1-proteinase inhibitors might inhibit SARS-CoV-2 infection.

Accordingly, 4 clinical trials are ongoing to evaluate the safety and efficacy of alpha-1-proteinase inhibitors in COVID-19 treatment. They involve a liquid alpha-1-proteinase inhibitor (NCT04547140), Glassia® (NCT04385836), and Prolastin® (NCT04495101 and EudraCT 2020-001391-15).

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Alpha-1 antitrypsin deficiency (AATD) is an inherited, genetic condition in which AAT is abnormally shaped. This inhibits its proper release from the liver into the bloodstream and consequently limits the amount of AAT found in the lungs. This increases the likelihood of chronic lung inflammation and disease.

Learn more about AATD etiology

AATD arises from mutations in the SERPINA1 gene. These mutations can result in the abolishment of AAT production or the production of an abnormally structured AAT. Twenty-four AAT variants have been identified, which can be classified as normal, deficient, null, or dysfunctional.

Risk of COVID-19 in AATD Patients

Given the proposed role of AAT in fighting SARS-CoV-2 infection, it is speculated that patients with AATD might have an increased risk of infection and development of severe COVID-19.

Ferrarotti et al surveyed patients with severe AATD during phase 2 of the lockdown in Italy. They stated, “We found [a] 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 <.0001) for symptomatic SARS-CoV-2 infection.”

Moreover, they found a higher relative risk (RR) in AATD patients with pre-existing lung diseases (RR, 13.9; 95% CI, 8.0-33.6; P <.001). The death rate in AATD patients was comparable to that of the general population (12.5% vs 13.9%, respectively).

Patients with AATD have a high prevalence of comorbidities, such as hypertension, chronic kidney disease, chronic obstructive pulmonary disease (COPD), and diabetes. These diseases are, in turn, independent risk factors for the development of COVID-19 and are associated with poor prognosis.

Individuals With COPD Should Be Tested for Alpha-1 Antitrypsin Deficiency

Yang et al enumerated several reasons that might explain the increased susceptibility of AATD patients to COVID-19:

  • TMPRSS2, a protease that facilitates the entry of SARS-CoV-2 and other viruses into cells, may become more easily activated in AATD patients with minimally functional AAT
  • Patients with AATD might be at a higher risk for coagulation disorders
  • The compromised action of AAT in patients with AATD may increase the likelihood of severe acute lung injury

Management of Cormorbid AATD and COVID-19

Yang et al proposed a number of measures to increase the knowledge on COVID-19 in patients with AATD and improve the clinical management of these patients.

To better understand the impact of AATD genotypes on the incidence and severity of COVID-19, patients who are recovering from infection should be screened for AATD. The assessment should include not only AAT measurements, but also genotyping to determine SERPINA1 status.

“Patients with AATD and their immediate family members should be aware of the higher risk of infection by SARS-CoV-2 and the possibility of worse clinical outcomes, if they are infected, than in the general population,” Yang et al advise. These patients should be strictly followed up if diagnosed with COVID-19.

New Study Supports the Use of AAT Augmentation Therapy in AATD

Regarding therapeutics, clinicians should plan to continue infusions for AATD patients receiving augmentation therapy at standard doses (ie, 60 mg/kg per week) if they become acutely ill. Moreover, they might consider higher than standard maintenance doses if required.

COVID-19 Vaccination in AATD Patients

The efficacy of COVID-19 vaccines in patients with AATD and other genetic pulmonary diseases is yet to be determined. However, in Yang and Zhao’s opinion, the currently approved COVID-19 vaccines may provide limited benefit to patients with AATD.

Given the lessons learned from previous studies on influenza and pneumococcal vaccination in this population, they stated, “the immune responses to antigen provocation in individuals with AATD appear to be far more complex, and protection from SARS-CoV-2 might not necessarily be afforded with vaccination alone.”

In a comment published in The Lancet Respiratory Medicine, they disclose several reasons to support their opinion:

  • Patients with AATD are usually not included in clinical trials; therefore, the efficacy and safety profiles of vaccination in these patients are unknown
  • AATD compromises the response to the typhoid vaccine since the antitrypsin capacity observed after its injection is due to an increase in the concentration of AAT – in fact, increasing evidence suggests a correlation between concentrations of circulating AAT and induction of trained immunity
  • AATD enhances the spread of the SARS-CoV-2 subtype with a spike 614Gly mutation, which shows increased virulence and morbidity
  • The efficacy of COVID-19 vaccines might not reach 100%; several factors may contribute to this, including the rapid increase in new variants, such as B.1.351, which might decrease vaccine-mediated neutralization of the virus by 6 to 86 times
  • Some AATD genotypes have been linked to greater odds of unhealthy behaviors, including sedentary lifestyle, smoking, and not obtaining the pneumococcal or influenza vaccine; thus, patients with Pi*MZ, Pi*SZ, or an unknown AATD genotype might benefit from more education and steps to mitigate the risk of SARS-CoV-2 infection

Further studies are needed to uncover the role of COVID-19 vaccination in patients with AATD. “As the ongoing pandemic persists in the foreseeable future, we strongly advocate that public health officials and health-care professionals should encourage the population of people with AATD to adopt protective behaviors,” according to Yang and Zhao. These behaviors include “lifestyle changes, pharmacotherapy, alpha1-proteinase inhibitor therapy, surgery, and other therapeutic approaches in addition to COVID-19 vaccine uptake.”


Yang C, Chapman KR, Wong A, Liu M. α1-antitrypsin deficiency and the risk of COVID-19: an urgent call to action. Lancet Respir Med. 2021;9(4):337-339. doi:10.1016/S2213-2600(21)00018-7

Yang C, Zhao H. COVID-19 vaccination in patients with α1-antitrypsin deficiency. Lancet Respir Med. 2021;9(8):818-820. doi:10.1016/S2213-2600(21)00271-X

Ferrarotti I, Ottaviani S, Balderacchi AM, et al. COVID-19 infection in severe alpha 1-antitrypsin deficiency: looking for a rationale. Respir Med. 2021;183:106440. doi:10.1016/j.rmed.2021.106440

Trial of alpha one antitrypsin inhalation in treating patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). May 13, 2020. Updated May 13, 2020. Accessed October 20, 2021.

Study to evaluate the safety and efficacy of Prolastin in hospitalized subjects with COVID-19. July 31, 2020. Updated July 8, 2021. Accessed October 20, 2021.

Study to evaluate the safety and efficacy of liquid alpha1-proteinase inhibitor (human) in hospitalized participants with coronavirus disease (COVID-19). September 14, 2020. Updated October 6, 2021. Accessed October 20, 2021.

A randomized double-blind placebo-controlled, pilot trial of intravenous plasma-purified alpha-1 antitrypsin for severe COVID-19 illness. EU Clinical Trials Register. March 31, 2020. Accessed October 20, 2021.