Is alpha 1 antitrypsin (A1AT) augmentation therapy recommended for patients with alpha 1 antitrypsin deficiency and obstructive lung disease, as indicated by Pulmonary Function Tests (PFTs), with a genotype of M/S?

From the Guidelines

Alpha 1 antitrypsin (A1AT) augmentation therapy is not recommended for patients with alpha 1 antitrypsin deficiency who have the M/S genotype, even if they have obstructive lung disease on pulmonary function tests. The M/S genotype typically produces A1AT levels that are approximately 80% of normal, which is generally considered sufficient to protect the lungs from progressive damage 1. Augmentation therapy, which involves weekly intravenous infusions of purified human A1AT, is primarily reserved for patients with severe deficiency, particularly those with the ZZ genotype or other rare severe variants who have serum levels below the protective threshold of 11 μmol/L (approximately 50-80 mg/dL) 1. For patients with the M/S genotype, management should instead focus on standard COPD treatments, smoking cessation if applicable, avoidance of environmental irritants, prompt treatment of respiratory infections, and regular monitoring of lung function. The rationale is that the risk-benefit ratio and cost-effectiveness of augmentation therapy do not support its use in individuals with moderate deficiency who maintain sufficient protective levels of circulating A1AT. According to the most recent guidelines, augmentation therapy is recommended for individuals with impaired FEV1<80% and presence of emphysema to reduce decline in lung density 1. However, the benefits of augmentation therapy for patients with A1AT deficiency and asthma with persistent airway obstruction and/or bronchiectasis but without CT scan evidence of emphysema are unknown, highlighting the need for further research in this area. In the context of real-life clinical medicine, prioritizing standard COPD treatments and monitoring for patients with the M/S genotype is the most appropriate approach, given the current state of evidence and the need for caution in the face of uncertainty. Key considerations in managing these patients include:

• Standard COPD treatments
• Smoking cessation if applicable
• Avoidance of environmental irritants
• Prompt treatment of respiratory infections
• Regular monitoring of lung function Given the recent study 1 which is the most recent and highest quality study, the current recommendation is to not use augmentation therapy for M/S genotype patients.

From the Research

Alpha 1 Antitrypsin Deficiency Treatment

The treatment of alpha 1 antitrypsin (A1AT) deficiency, particularly in patients with a genotype of M/S and obstructive lung disease as indicated by Pulmonary Function Tests (PFTs), involves several considerations.

• A1AT Augmentation Therapy: This is a disease-specific treatment that has been shown to slow the progression of emphysema in patients with A1AT deficiency 2. The therapy involves the intravenous infusion of A1AT to increase the levels of this enzyme in the lungs, thereby protecting them from the harmful effects of neutrophil elastase.
• Effectiveness and Recommendations: Studies have demonstrated that A1AT augmentation therapy can slow the decline in lung function in patients with A1AT deficiency, although it cannot prevent the eventual progression to end-stage lung disease 3, 2. The American Thoracic Society and the European Respiratory Society recommend A1AT augmentation therapy for patients with A1AT deficiency and lung disease, particularly those with a forced expiratory volume in 1 second (FEV1) below 80% of the predicted value.
• Genotype Considerations: The genotype of M/S is associated with a partial deficiency of A1AT, which may still increase the risk of lung disease. However, the decision to initiate A1AT augmentation therapy should be based on individual patient factors, including the severity of lung disease, the presence of symptoms, and the patient's overall health status.
• Pulmonary Function Tests (PFTs): PFTs, such as spirometry and diffusing capacity of the lungs for carbon monoxide, are essential for assessing the severity of lung disease in patients with A1AT deficiency. These tests can help guide treatment decisions and monitor the response to therapy.
• Other Treatment Options: In addition to A1AT augmentation therapy, other treatment options may be considered for patients with A1AT deficiency and lung disease, including bronchodilators, corticosteroids, and pulmonary rehabilitation. However, the effectiveness of these treatments may vary depending on the individual patient and the severity of their lung disease.

Key Findings

• A1AT augmentation therapy is a disease-specific treatment that can slow the progression of emphysema in patients with A1AT deficiency.
• The decision to initiate A1AT augmentation therapy should be based on individual patient factors, including the severity of lung disease and the presence of symptoms.
• PFTs are essential for assessing the severity of lung disease and guiding treatment decisions.
• Other treatment options, such as bronchodilators and pulmonary rehabilitation, may be considered in addition to A1AT augmentation therapy.