What are the treatment recommendations for patients with low alpha 1 antitrypsin (A1AT) levels?

Alpha-1 Antitrypsin Level Test Interpretation and Treatment

For patients with low A1AT levels (<11 mmol/L or <0.57 g/L) and documented COPD with emphysema, augmentation therapy should be offered if they are never or former smokers (smoke-free ≥6 months), have FEV1 <80% predicted, documented SERPINA1 deficiency genotypes, and are on optimal COPD therapy. 1

Diagnostic Thresholds and Interpretation

Serum A1AT Level Categories

• Severe deficiency: <11 mmol/L (<0.57 g/L) - associated with markedly increased risk for COPD and emphysema 1
• Intermediate threshold: <23 mmol/L (<1.2 g/L) - warrants genetic testing in patients with moderate clinical suspicion 1
• Protective threshold: ≥11 mmol/L - considered the minimum target for augmentation therapy 2, 3

Testing Algorithm Based on Clinical Suspicion

High Clinical Suspicion (perform both tests simultaneously): 1

• Early onset COPD (<40 years)
• COPD with minimal smoking history (<10 pack-years)
• Basilar pan-lobular emphysema pattern
• Family history of COPD or A1AT deficiency
• History of perinatal jaundice

Action: Measure serum A1AT levels AND perform genetic testing with DNA sequencing of SERPINA1 gene 1

Moderate Clinical Suspicion (sequential testing): 1

• COPD at any age
• Unexplained bronchiectasis
• Adult-onset asthma with persistent airflow obstruction
• Liver cirrhosis
• GPA vasculitis or panniculitis

Action: Measure serum A1AT levels first; if <23 mmol/L, proceed to genetic testing 1

Treatment Recommendations Based on A1AT Levels

Augmentation Therapy Criteria (ALL must be met):

The Canadian Thoracic Society conditionally recommends augmentation therapy for patients meeting ALL of the following: 1

1. Smoking status: Never smoker OR former smoker (must be smoke-free for ≥6 months) 1
2. Lung function: FEV1 <80% predicted 1
3. Imaging: Documented emphysema on CT scan 1
4. Genetics: Documented SERPINA1 genotypes associated with A1AT deficiency (typically Pi*ZZ) 1
5. Biochemical: Severely reduced functional A1AT level (<11 mmol/L or <0.57 g/L) 1
6. Optimization: Receiving optimal pharmacological and non-pharmacological COPD therapies 1

Augmentation Therapy Dosing and Administration

• Standard dose: 60 mg/kg body weight administered intravenously once weekly 2
• Infusion rate: 0.2 mL/kg/min 2
• Expected outcome: Post-treatment plasma A1AT levels should exceed 11 μM in all patients 2
• Evidence of efficacy: High quality evidence for preserving CT scan lung density; very low quality evidence for reducing mortality 1

Standard COPD Management (Required for ALL Patients)

Regardless of A1AT levels, all patients require: 1

• Bronchodilators: Provide symptomatic relief even without objective bronchodilator responsiveness 1
• Inhaled corticosteroids: For patients with bronchial hyperreactivity to reduce bronchial inflammation 1
• Antibiotics: Prompt treatment for purulent respiratory exacerbations 1
• Pulmonary rehabilitation: For those with established lung disease 1
• Supplemental oxygen: When indicated by standard COPD criteria 1

Critical Preventive Measures

Smoking Cessation (HIGHEST PRIORITY)

Smoking cessation is the single most important intervention and must be achieved before considering augmentation therapy. 1

• Smokers with A1AT deficiency have life expectancy <20 years after diagnosis 1
• FEV1 decline is most rapid when between 30-65% predicted 1
• Never-smokers with A1AT deficiency have normal life expectancy 1
• Use all available pharmacologic aids to achieve cessation 1

Vaccinations (MANDATORY)

• Influenza vaccination: Annual 1
• Pneumococcal vaccination: Per standard guidelines 1
• Hepatitis B vaccination: Recommended for patients with overt liver disease; follow general population recommendations for those with lung disease alone 1

Environmental Exposure Reduction

• Minimize exposure to second-hand tobacco smoke, dusts, and fumes 1
• Consider job change if occupational exposure to respiratory irritants is frequent 1
• Avoid all environmental pollutants 1

Special Populations and Considerations

Heterozygous States (PiMZ, PiSZ)

• Pi*SZ phenotype: Lower risk than Pi*ZZ but still at increased risk, especially with smoking 1
• Augmentation therapy: Not recommended for heterozygotes due to lack of evidence of effectiveness 4
• Management: Focus on smoking cessation and standard COPD therapy 1

Monitoring During Augmentation Therapy

• Serum A1AT levels: Should maintain trough levels >11 μM 2
• Lung function: Annual spirometry to assess FEV1 decline 1
• CT imaging: To monitor emphysema progression (primary outcome measure) 1

Important Caveats

The clinical efficacy of augmentation therapy in influencing the clinical course of pulmonary emphysema has not been conclusively demonstrated in adequately powered, randomized, controlled clinical trials. 2

• Augmentation therapy increases A1AT levels in blood and lung epithelial lining fluid 2
• Effect on frequency of pulmonary exacerbations and rate of emphysema progression not definitively established 2
• Therapy is derived from pooled human plasma with theoretical risk of infectious agent transmission, though risk is minimized through screening and viral inactivation processes 2
• Two-year mortality of 50% occurs when FEV1 reaches 15% of predicted 1