Alpha 1-antitrypsin deficiency medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overview

Treatment guidelines for AATD include alpha 1 antitrypsin enzyme repletion, smoking cessation, long-acting inhaled bronchodilators, preventive vaccinations against influenza and pneumococcus, pulmonary rehabilitation for patients with functional impairment, supplemental oxygen if needed lung transplantation, treatment of COPD exacerbation in all patients of AATD should include AAT repletion.

Medical Therapy

• Across developed countries, A1AD patients presenting with pulmonary symptoms may receive intravenous infusion of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy arrests the course of the disease and halts any further damage to the lungs. It is recommended that patients must begin augmentation therapy only after the onset of emphysema symptoms.

• Augmentation therapy is not recommended for liver-affected patients; treatment of A1AD-associated liver damage focuses on symptomatic relief. In severe cases, liver transplantation may be necessary.

• α₁-antitrypsin is an acute phase reactant. Its transcription is markedly increased during inflammation as a result of increased interleukin-1 and 6 and TNFα production. Any treatment that blunts this response, for example acetaminophen, can delay the accumulation of A1AT polymers in the liver and resultant cirrhosis. A1AD patients are therefore encouraged to use acetaminophen when ill, even if they do not need antipyretics.

• Treatment guidelines for AATD include:
  • Alpha 1 antitrypsin enzyme repletion
  • Smoking cessation
  • Long-acting inhaled bronchodilators
  • Preventive vaccinations against influenza and pneumococcus
  • Pulmonary rehabilitation for patients with functional impairment
  • Supplemental oxygen if needed
  • Lung transplantation
• Treatment of COPD exacerbation in all patients of AATD should include AAT repletion.
• 1 Alpha 1-antitrypsin deficiency (A1AD)
  • 1.1 Associated lung disease
    • 1.1.1 Adult
      • Preferred regimen (1): Purified pooled human plasma alpha 1-antitrypsin 60 mg/kg/wk iv
      • Preferred regimen (2): Short-acting beta-adrenergic agents and ipratropium bromide bronchodilator MDI
      • Preferred regimen (3): Inhaled corticosteroids
      • Alternative regimen (1): Alpha1-proteinase inhibitors such as Prolastin-C, Aralast NP, Glassia, Zemara
      • Alternative regimen (2): Long-acting beta-adrenergic agents MDI
      • Alternative regimen (2): Oral theophylline
      • Alternative regimen (3): Oral corticosteroids
• Augmentation therapy is the specific therapy for Alpha 1-antitrypsin deficiency (A1AD) associated lung disease.
• Augmentation therapy includes intravenous infusion of purified pooled human plasma alpha 1-antitrypsin to raise and maintain serum Alpha 1-antitrypsin levels above the threshold and to slow emphysema progression and enhance the duration and quality of life.
• Food and Drug Administration has approved four preparations of purified AAT.
• Following infusion AAT levels remain above the protective threshold for most of the dosing interval.
• The infused AAT has the ability to neutralize neutrophil elastase activity.
• Augmentation therapy recipients demonstrate a slower rate of FEV1 decline than nonrecipients.
• Wencker and colleagues conducted a before-after study and found that the greatest effect of augmentation therapy in changing FEV1 slope was observed in individuals with a rapid FEV1 decline before augmentation therapy was initiated (ie, FEV1 decline 256 mL/y before therapy vs 53 mL/y during therapy).

• Bronchodilators are used for symptomatic relief of airflow obstruction and symptoms resulting from AATD and associated emphysema.
• Antibiotics can be used to treat bacterial complications, such as pneumonia or purulent bronchitis.
• Bronchodilators and antibiotics do not have any effect on disease progression.
• Corticosteroids can be used for short-term relief but have no proven long-term benefit in inhaled or oral preparations.
• Avoid oral steroids because of their long-term adverse effects.
• Oxygen is prescribed if patients are hypoxemic at rest or with activity.
• Replacement/Augmentation therapy is indicated to slow the progression of emphysema.
• Currently, IV augmentation therapy is the only FDA-approved treatment specific for AATD. It is indicated for patients with moderate degrees of airflow obstruction (FEV1 35-65% of predicted).
• Recommended dosage and route of administration is, 60 mg/kg/wk given IV.
• Respiratory enzymes are drugs used for long-term replacement in patients with clinical emphysema.
• Alpha1-proteinase inhibitor like Prolastin-C, Aralast NP, Glassia, Zemara is available for use in the United States.
• Respiratory enzymes are prepared from pooled human plasma by using a cold alcohol fractionation process followed by further purification steps to obtain a sterile, stable, lyophilized preparation of purified human alpha1-antiprotease inhibitor.
• Plasma is tested for HIV, hepatitis B, and hepatitis C before adding it to the product.
• In order to reduce the potential risk of infectious-agent transmission, the solvent detergent mixer is added to the product, which serves to inactivate the viral agents
• the main goal of medical therapy is to slow down or halt the progression of lung disease in AATD.
• The most effective treatment approach is to quit smoking, associated with the greatest effect on survival of patients with AATD.
• Strategies to help and motivate patients to quit smoking include:
  • Inform patients about the consequences of smoking on AATD
  • Inquire about their smoking habits
  • Advice the patients to quit smoking
  • Assist patients to quit smoking with encouragement, education and nicotine replacement.
  • Follow-up with these patients.

• Improving lung function:
  • Efforts should be made to improve lung function in patients with AATD associated emphysema.
  • Administration of short-acting beta-adrenergic agents and ipratropium bromide bronchodilator can help maximize lung function. The preferred route of administration is metered-dose inhalers because they have a lower incidence of adverse effects than other routes. These drugs have no long-term effect on disease progression.
  • Inhaled corticosteroids provides symptomatic relief in patients with frequent exacerbations. Adverse effect includes infection.
  • Long-acting inhaled beta-adrenergic drugs and anticholinergics improve bronchodilation in the patient population with AATD.
  • Reserve oral corticosteroids for acute exacerbations with increased cough and sputum.
  • Long-term corticosteroid use is associated with many detrimental adverse effects. Limit oral steroid use to brief courses of 1-2 weeks. Start therapy to prevent osteoporosis when long courses are administered.
  • A therapeutic trial of theophylline may be indicated for selected patients. Theophylline administration requires frequent monitoring of serum levels as it has a narrow therapeutic range and its metabolism is frequently altered by other drugs or illness, which can lead to episodes of drug toxicity. Theophylline is metabolized by the liver. Smoking increases the metabolism of theophylline.

References

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