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]Cafer Zorkun, M.D., Ph.D. [3]

Overview

Alpha 1-antitrypsin deficiency (A1AD) may be treated through intravenous infusions derived from donated human plasma.

Medical Therapy

In the United States, Canada, and several European countries, lung-affected A1AD patients may receive intravenous infusions of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy is thought to arrest the course of the disease and halt any further damage to the lungs. Long-term studies of the effectiveness of A1AT replacement therapy are not available. It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.

Augmentation therapy is not appropriate for liver-affected patients; treatment of A1AD-related liver damage focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.

As α₁-antitrypsin is an acute phase reactant, its transcription is markedly increased during inflammation elsewhere in response to increased interleukin-1 and 6 and TNFα production. Any treatment that blunts this response, specifically paracetamol (acetaminophen), can delay the accumulation of A1AT polymers in the liver and (hence) cirrhosis. A1AD patients are therefore encouraged to use paracetamol when slightly to moderately ill, even if they would otherwise not have used 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.

• 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 deficiency 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
  • Enquire about their smoking habits
  • Advice the patients to quit smoking
  • Assit patients to quit smoking with encouragement,education and nicotine replacement.
  • Follow-up with these patients.

Improving lung function

Provide similar efforts to improve lung function in patients with AATD emphysema as those provided to patients with emphysema from the usual causes. Administer short-acting beta-adrenergic agents and ipratropium bromide bronchodilators to maximize lung function. Metered-dose inhalers are the preferred method of administration because they have a lower incidence of adverse effects than other routes. No matter how they are administered, no evidence indicates that these drugs have any long-term effect on disease progression. Inhaled corticosteroids have not been studied in patients with AATD emphysema, but many patients have significant bronchoreactivity. In this group, inhaled steroids probably help control symptoms. Patients with frequent exacerbations may also benefit. Evidence of infection can be an adverse effect. Long-acting inhaled beta-adrenergic drugs and anticholinergics provide improved bronchodilation and symptoms for patients with COPD. They have not been studied in a population with AATD, but they are likely to provide the same benefits. Reserve oral corticosteroids for acute exacerbations with increased cough and sputum. Long-term administration of corticosteroids does not protect the lung from progressive emphysema, but it 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. Theophylline may lessen the degree of dyspnea in some individuals, and a therapeutic trial may be indicated for selected patients. The therapeutic range of theophylline is relatively small, and its metabolism frequently is altered by other drugs or illness, which can lead to frequent episodes of drug toxicity or the need for frequent monitoring of serum levels. It also should be noted that theophylline is metabolized by the liver. Likewise, when smoking, metabolism is actually increased; thus, smoking cessation may effect levels.

References

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