Recent advancements in understanding the genetic involvement of alpha-1 antitrypsin deficiency associated lung disease: a look at future precision medicine approaches

Management of lung disease in patients with alpha-1 antitrypsin deficiency (AATD) includes both non-pharmacological and pharmacological approaches. Lifestyle changes with avoidance of environmental pollutants, including tobacco smoke, improving exercise levels and nutritional status, all encompassed under a disease management program, are crucial pillars of AATD management. Non-pharmacological therapies follow conventional treatment guidelines for chronic obstructive pulmonary disease. Specific pharmacological treatment consists of administering exogenous alpha-1 antitrypsin (AAT) protein intravenously (augmentation therapy). This intervention raises AAT levels in serum and lung epithelial lining fluid, increases anti-elastase capacity, and decreases several inflammatory mediators in the lung. Radiologically, augmentation therapy reduces lung density loss over time, thus delaying disease progression. The effect of augmentation therapy on other lung-related outcomes, such as exacerbation frequency/length, quality of life, lung function decline, and mortality, are less clear and questions regarding dose optimization or route of administration are still debatable. This review discusses the rationale and available evidence for these interventions in AATD.

Alpha-1 antitrypsin deficiency as a common treatable mechanism in chronic respiratory disorders and for conditions different from pulmonary emphysema? A commentary on the new European Respiratory Society statement

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2018.200 ◽

2018 ◽

Vol 13 ◽

Author(s):

Stefano Aliberti ◽

Andrea Gramegna ◽

Marco Confalonieri ◽

Angelo Corsico ◽

Luca Richeldi ◽

...

Keyword(s):

Lung Disease ◽

Pulmonary Emphysema ◽

Future Research ◽

Common Mechanism ◽

Main Body ◽

New Paradigm ◽

European Respiratory Society ◽

Antitrypsin Deficiency ◽

Background: The European Respiratory Society recently published an important statement reviewing available evidence on diagnosis and treatment of lung disease associated to alpha-1 antitrypsin deficiency (AATD). Several issues on this topic still remain unresolved and subject of interpretation according to different standard procedures and healthcare systems worldwide. The purpose of this commentary is to offer a critical contribution to most of these controversial issues in light of an Italian perspective for the management of this disease. Main body: The clinical spectrum of AATD lung disease might include different manifestations and the traditional paradigm of a younger emphysematous patient has been revealing insufficient. Targeting with appropriate testing only COPD patients might be considered a limited approach leading to underestimation of the real prevalence of the disease. Several reports have suggested the association between AATD and other chronic respiratory conditions, as asthma and bronchiectasis. A deeper evaluation of clinical, radiological, microbiological and functional variables is, therefore, needed in order to investigate different phenotypes in AATD patients. In addition, a new line of translational research in AATD might focus on the development of personalized therapeutic regimens taking into account the patient clinical profile and needs. Conclusions: Over the past years, AATD has been interpreted as a common mechanism of inflammatory disequilibrium and tissue damage across different conditions. Future research is gradually pointing toward this new paradigm by expanding the evidence of the role of AAT as a potent immunomodulatory and anti-inflammatory drug in conditions different from pulmonary emphysema.

Alpha-1 antitrypsin deficiency: a commonly overlooked cause of lung disease

Canadian Medical Association Journal ◽

10.1503/cmaj.111749 ◽

2012 ◽

Vol 184 (12) ◽

pp. 1365-1371 ◽

Cited By ~ 39

Author(s):

S. K. Brode ◽

S. C. Ling ◽

K. R. Chapman

Keyword(s):

Lung Disease ◽

Antitrypsin Deficiency ◽

Relationship of CT densitometry to lung physiological parameters and health status in alpha-1 antitrypsin deficiency: initial report of a centralised database of the NIHR rare diseases translational research collaborative

BMJ Open ◽

10.1136/bmjopen-2019-036045 ◽

2020 ◽

Vol 10 (6) ◽

pp. e036045

Author(s):

Diana Crossley ◽

James Stockley ◽

Charlotte E Bolton ◽

Nicholas S Hopkinson ◽

Ravi Mahadeva ◽

...

Keyword(s):

Health Status ◽

Lung Function ◽

Lung Disease ◽

Clinical Features ◽

Obstructive Lung Disease ◽

Chronic Obstructive Lung Disease ◽

Chronic Obstructive ◽

Antitrypsin Deficiency ◽

ObjectivesTo establish a database network for the study of alpha-1 antitrypsin deficiency (AATD) and compare the results to CT lung density as the most direct measure of emphysema.DesignA central electronic database was established to permit the upload of anonymised patient data from remote sites. Prospectively collected CT data were recorded onto disc, anonymised, analysed at the coordinating centre and compared with the clinical features of the disease.SettingTertiary referral centres with expertise in the management of AATD focused on academic Biomedical Research Units and Wellcome Clinical Research Facilities.ParticipantsData were collected from 187 patients over 1 year from eight UK academic sites. This included patient demographics, postbronchodilator physiology, health status and CT. Analysis was undertaken at the coordinating centre in Birmingham.ResultsPatient recruitment in the 12 months reached 94% of target (set at 200) covering the whole spectrum of the disease from those with normal lung function to very severe chronic obstructive lung disease. CT scan suitable for analysis was available from 147 (79%) of the patients. CT density, analysed as the threshold for the lowest 15% of lung voxels, showed statistically significant relationships with the objective physiological parameters of lung function as determined by spirometric Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity staging (p<0.001) and carbon monoxide gas transfer (p<0.01). Density also correlated with subjective measures of quality of life (p=0.02).ConclusionsEstablishment of the network for data collection and its transfer was highly successful facilitating future collaboration for the study of this rare disease and its management. CT densitometry correlated well with the objective clinical features of the disease supporting its role as the specific marker of the associated emphysema and its severity. Correlations with subjective measures of health, however, were generally weak indicating other factors play a role.