Alpha-1 Antitrypsin Deficiency & COVID-19
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause a variety of symptoms, and people with chronic lung disease including chronic obstructive pulmonary disease (COPD), chronic liver disease especially cirrhosis, diabetes, and cardiovascular disease are among those who are more prone to develop severe infection. We now know that severe SARS-CoV-2 infection is mainly caused by a storm of inflammation that damages the lungs and other organs, known as the “cytokine storm,” a second stage of disease that some individuals have after the initial flu-like period.

Hasan Avcu, MD
H. Avcu, MD earned his Doctor of Medicine degree from Istanbul University Cerrahpasa School of Medicine in Istanbul, Turkey. He has been concentrating on medical communications, thought leader management, and healthcare compliance for the last decade in several therapeutic areas, mainly focusing on rare diseases.

Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder that may predispose an individual to COPD, cirrhosis, panniculitis, or antineutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis. The clinical manifestation of AATD varies significantly. Some individuals develop liver cirrhosis in childhood, whereas others get emphysema as an adult, or have late-adulthood liver and lung diseases. Similar to the diversity of clinical presentations, the severity of symptoms differs widely across patients.

There is limited knowledge about innate immune defense mechanisms in the respiratory tract against SARS-CoV-2. However, it has been shown that alpha-1 antitrypsin binds and inactivates the transmembrane serine protease 2 (TMPRSS2), which “enzymatically primes the SARS-CoV-2 spike protein for membrane fusion,” indicating that alpha-1 antitrypsin blocks SARS-CoV-2 entry by inhibiting TMPRSS2.1

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Several findings have highlighted that individuals with AATD may be at higher risk of SARS-CoV-2 infection as well as SARS-CoV-2-related mortality. These include a recently described positive association between a frequency of AATD mutations and an incidence of SARS-CoV-2 infection, the immunological background of lung disease in both severe SARS-CoV-2 infection and AATD, and similarities between the comorbidities of AATD and significant risk factors for adverse outcomes of SARS-CoV-2 infection.2-4

The Role of Alpha-1 Antitrypsin 

Human alpha-1 antitrypsin is the most abundant serine protease inhibitor in human plasma. The main function of alpha-1 antitrypsin is to protect lung tissue against the destructive effects of the enzyme neutrophil elastase enzyme.5  The SERPINA1 gene codes for alpha-1 antitrypsin, which is produced in the liver and released into the bloodstream. Low circulating alpha-1 antitrypsin concentrations or dysfunctional forms of alpha-1 antitrypsin enhance the risk of destructive diseases, including emphysema and bronchiectasis, in people with one of many hereditary mutations in SERPINA1.2

SERPINA1 alleles encoding the variant alpha-1 antitrypsin proteins were named with the prefix PI* (protease inhibitor*). Over 150 different mutations in the SERPINA1 gene have been identified to date, with PI*M, PI*Z, and PI*S being the most frequently detected alleles. PI*M is known to be the most common — and therefore is considered to be the normal allele — whereas PI*Z is the most commonly detected pathogenic allele. Individuals with the PI*SS, PI*MZ, and PI*SZ genotypes have mild AATD, with serum alpha-1 antitrypsin levels that are between 40% and 60% of normal. Individuals with the PI*ZZ (homozygous for PI*Z) genotypes have severe AATD, with serum alpha-1 antitrypsin levels that are less than 15% of normal. Other uncommon mutations, known as null, are linked with a complete lack of alpha-1 antitrypsin in the circulation due to the lack of protein production. Low serum levels of alpha-1 antitrypsin place individuals at increased risk for proteolytic damage caused by neutrophil elastase which leads to COPD.

Clinical Manifestations of AATD

The clinical picture of AATD varies depending on a number of genetic and environmental factors. Environmental variables such as cigarette smoke, chemicals, and dust are likely to influence the severity of AATD-related lung disease.

AATD is also linked to a variety of other diseases, in addition to pulmonary problems, such as chronic liver disease due to the accumulation of misfolded alpha-1 antitrypsin protein in the liver. Furthermore, as compared with individuals with other obstructive lung diseases, those with AATD have a higher risk of arterial hypertension, chronic renal disease, and diabetes. Panniculitis, bronchiectasis, and vasculitis are some of the less frequent consequences.

Severe SARS-CoV-2 Infection and AATD

Recent research, published in Respiratory Medicine and based on a community-based cohort, does not suggest any increased risk of SARS-CoV-2 infection or death associated with AATD.6

Schneider and Strnad sought to study the association between AATD and SARS-CoV-2 infection using the United Kingdom Biobank (UKB), which recruited >500,000 participants at 22 UK centers. Genotyping was available for 487,503 of the subjects. The allele frequencies of homozygous and heterozygous PI*Z genotype in the cohort were as expected (1:3460 and 1:28, respectively), while a combined presence of PI*S and PI*Z variants (i.e., PI*SZ genotype) was seen in 1:560 of participants.6

According to the results of the study, individuals without PI*Z / PI*S variants (termed noncarriers) and subjects with the analyzed AATD genotypes displayed similar rates of SARS-CoV-2 infection, ranging between 2% and 3%. Moreover, PI*MZ and PI*MS individuals displayed similar SARS-CoV-2-related mortality as noncarriers. On the other hand, the limited usefulness of data on SARS-CoV-2 infection in PI*ZZ subjects and SARS-CoV-2-related mortality in PI*SZ/PI*ZZ/PI*SS subjects did not allow meaningful conclusion due to low numbers of subjects and low numbers of fatalities, respectively.6

Schneider and Strnad concluded that “these data provide relief to subjects with mild AATD since they do not seem to carry an increased risk of SARS-CoV-2-related injury. In conclusion our study does not suggest any increased risk of SARS-CoV-2 infection or death associated with AATD, but additional prospective studies are needed for severe AATD before definitive conclusions can be made.”6

Precautions Needed for High-Risk Individuals 

There is emerging data identifying alpha-1 antitrypsin as a novel TMPRSS2 inhibitor blocking SARS-CoV-2 entry at a cellular level, as well as data showing epidemiological correlation between the severity of the SARS-CoV-2 infection and the prevalence of AATD in 68 countries throughout the world.7,8 On the other hand, there is also data that does not suggest any increased risk of SARS-CoV-2 infection or death associated with AATD.6

As more evidence becomes available, researchers are more likely to investigate the hypothesized link between the course of SARS-CoV-2 infection and severe AATD. Yet, the data are still scarce and more prospective research with bigger sample sizes is necessary. Unfortunately, the possibility of achieving bigger sample sizes for such an underrecognized rare disease is relatively low.

Alpha-1 antitrypsin, with its immunomodulatory and anti-inflammatory properties, has strong roles in the respiratory environment. Because AATD is an underlying disease that affects the lungs, and SARS-CoV-2 infection has a wide range of clinical manifestations — including chronic lung diseases — associated with poor prognosis, the symptoms of the SARS-CoV-2 infection are likely to be more severe in individuals with AATD. Therefore, I believe that it is critical for individuals with AATD, including those who are vaccinated against SARS-CoV-2, to take extra protective measures against the virus while continuing to follow all necessary precautions, such as masking and social distancing, until it is proven otherwise with strong evidence.


  1. Wettstein L, Weil T, Conzelmann C, et al. Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection. Nat Commun. 2021;12(1):1726. doi:10.1038/s41467-021-21972-0
  2. 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
  3. Faria N, Inês Costa M, Gomes J, Sucena M. Alpha-1 antitrypsin deficiency severity and the risk of COVID-19: a Portuguese cohort. Respir Med. 2021;181:106387. doi:10.1016/j.rmed.2021.106387
  4. Vianello A, Braccioni F. Geographical overlap between alpha-1 antitrypsin deficiency and COVID-19 infection in Italy: casual or causal?. Arch Bronconeumol (Engl Ed). 2020;56(9):609-610. doi:10.1016/j.arbres.2020.05.015
  5. Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med. 2020;382(15):1443-1455. doi:10.1056/NEJMra1910234
  6. Schneider CV, Strnad P. SARS-CoV-2 infection in alpha1-antitrypsin deficiency Respir Med. 2021;184:106466. Published online May 13, 2021. doi:10.1016/j.rmed.2021.106466
  7. Azouz NP, Klingler AM, Callahan V, et al. Alpha 1 antitrypsin is an inhibitor of the SARS-CoV-2-priming protease TMPRSS2. Pathog Immun. 2021;6(1):55-74. Published online April 26, 2021. doi:10.20411/pai.v6i1.408
  8. Yoshikura H. Epidemiological correlation between COVID-19 epidemic and prevalence of α-1 antitrypsin deficiency in the world. Glob Health Med. 2021;3(2):73-81. doi:10.35772/ghm.2020.01068