eMedicine Specialties > Pulmonology > Obstructive Airways Diseases

Alpha1-Antitrypsin Deficiency: Treatment & Medication

Author: Paul Fairman, MD, Director, Pulmonary Hypertension Service, Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University
Coauthor(s): Rajiv Malhotra, DO, Fellow, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University Health System
Contributor Information and Disclosures

Updated: Apr 16, 2009

Treatment

Medical Care

Preventing or slowing the progression of lung disease is the major goal of alpha1-antitrypsin (AAT) deficiency management. Decreasing any proinflammatory stimuli in the alveolus, including smoking, asthma, or respiratory infection facilitates this goal. Alternatively, augmenting or replacing the deficient enzyme, and thereby moderating inflammatory stimuli, is possible. Most patients are identified only after they develop lung disease, and the goals of treating alpha1-antitrypsin deficiency emphysema are similar to those for treating all forms of emphysema.

• Quitting smoking
  • No treatment for emphysema has a greater effect on survival than quitting smoking.
  • Make a concerted effort to inform patients about the serious consequences of smoking on alpha1-antitrypsin deficiency and provide them with one of the many aids to help them quit.
  • Remember the 4 stages in the process of helping patients become nonsmokers: (1) Ask about smoking habits; (2) Advise about health effects; (3) Assist the patient with encouragement, education, and nicotine replacement; and (4) Arrange follow-up.
  • Most patients with alpha1-antitrypsin deficiency quit successfully.
• Improving lung function
  • Provide similar efforts to improve lung function in patients with alpha1-antitrypsin–deficiency 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 alpha1-antitrypsin–deficiency emphysema, but many patients have significant bronchoreactivity. In this group, inhaled steroids probably help control symptoms. Patients with frequent exacerbations may also benefit.
  • 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 alpha1-antitrypsin deficiency, 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 g 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.
• Preventing respiratory infections
  • Pneumonia and annual influenza vaccines will help prevent respiratory infections.
  • The ATS/ERS AAT Deficiency Task Force recommends early antibiotic therapy for all exacerbations with purulent sputum. Aggressively treatment of infections may help decrease the potential for additional lung injury from an influx of neutrophils into the alveolus.
• Providing pulmonary rehabilitation
  • According to a National Institutes of Health (NIH) workshop, pulmonary rehabilitation is defined as "a multi-disciplinary continuum of services directed to persons with pulmonary disease and their families, usually by an interdisciplinary team of specialists, with the goal of achieving and maintaining the individual's maximum level of independence and function in the community."
  • Most programs combine education, exercise conditioning, breathing training, chest physical therapy, and respiratory muscle training with nutritional counseling and psychological support.
  • Therapy does not improve pulmonary function test results, but well-controlled studies document significant improvement in exercise endurance, exercise work capacity, level of dyspnea, quality of life, and reduction of health-related expenses.
• Reducing hypoxemia
  • Hypoxemia accelerates mortality in patients with severe airflow obstruction, and oxygen supplementation prolongs survival for this group.
  • Oxygen also increases exercise capacity, improves mental performance, decreases dyspnea with exercise, and improves sleep quality.
  • Stable patients with resting hypoxia benefit most if they wear their oxygen mask continuously. The benefits for patients with hypoxemia only during exercise or sleep are not as clear, and oxygen may be prescribed for those intervals when the oxygen saturation is likely to be low.
• Replacing enzymes
  • Alpha1-antitrypsin–deficient individuals who have or show signs of developing significant emphysema can be treated with Prolastin, a pooled, purified, human plasma protein concentrate replacement for the missing enzyme that has been screened for HIV and hepatitis viruses although practitioners should immunize patients against hepatitis regardless. It also is heat-treated as an additional precaution against transmission of infection The US Food and Drug Administration (FDA) has approved 2 other alpha1-antitrypsin protein concentrates, Aralast and Zemaira, for augmentation therapy.
  • Weekly IV infusions of alpha1-antitrypsin protein concentrates restore serum and alveolar alpha1-antitrypsin concentrations to protective levels. Although other dosing regimens have been used, only the weekly infusion schedule has US FDA approval.
  • No controlled studies have proven that IV augmentation therapy improves survival or slows the rate of emphysema progression. Results from the NIH patient registry and a comparison of Danish and German registries have been published, and both suggest that augmentation therapy has beneficial effects. Although they were not controlled treatment trials, the similarity of the results suggests that the findings are significant.
  • The NIH report described an overall death rate 1.5 times higher for those who did not receive augmentation therapy and a rate of FEV₁ decline (54 mL/y) in alpha1-antitrypsin–deficient individuals about twice that of healthy nonsmokers but about 50% that of smokers (108 mL/y). Prolastin augmentation therapy did not improve the average FEV₁ decline (54 mL/y); however, participants with moderate airflow obstruction (FEV₁ 35-60% of predicted value) had a slower rate of decline (mean difference 27 mL/y). These findings bolster the long-held belief that augmentation therapy provides clinical benefit. Studies of Aralast and Zemaira have shown equivalency with Prolastin in achieving and maintaining alpha1-antitrypsin serum levels and alveolar epithelial levels above the target level. No studies of Aralast or Zemaira have been done to show affects on FEV₁, rate of decline of FEV₁, or survival.
  • While no firm guidelines have been developed for initiating or continuing augmentation therapy, most pulmonary physicians require the serum level to be below the threshold protective value and that the patient have one or more of the following: signs of significant lung disease: chronic productive cough or unusual frequency of lower respiratory infection, airflow obstruction, accelerated decline of FEV₁, or chest radiographic or CT evidence of emphysema.
  • The ATS recommends starting treatment when the FEV₁ is less than 80% of the patient's predicted value, though the benefits of augmentation therapy for individuals with severe (FEV₁ <35%) or mild (FEV₁ >60%) airflow obstruction are less, as shown in studies with Prolastin.
  • Evidence for the use of alpha1-antitrypsin augmentation in patients after lung transplantation for alpha1-antitrypsin deficiency is insufficient. However, observational studies do show that inflammation from acute rejection or infection allows for free elastase activity in the epithelial lining fluid of individuals who have undergone lung transplantation. Therefore, the ATS/ERS Task Force favors the use of augmentation therapy for lung transplant recipients during episodes that provoke inflammation.
  • A 2008 commentary by the authors of the Medical and Scientific Advisory Committee of the Alpha-1 Foundation comments on the use of augmentation therapy for PI*MZ heterozygotes. Currently, until supportive data in the subset of heterozygotes becomes available, the only approved use for augmentation therapy is for PI*ZZ individuals.⁶

Surgical Care

Two surgical approaches may help selected patients with alpha1-antitrypsin deficiency.

• Volume-reduction surgery⁷
  • This procedure has generated nationwide interest and hope for patients with all types of emphysema.
  • Selected patients with severe emphysema and significant air trapping have experienced symptomatic improvement by removing the most severely affected 20-35% of each lung. Spirometry and exercise tolerance generally improve following postoperative recovery. Dyspnea generally is diminished. The effects on blood gas values are variable.
  • Some of the enthusiasm for the procedure has waned, even as surgical mortality rates have diminished, because the duration of improvement seems to be brief; an accelerated rate of FEV₁ decline appears to occur after the surgery.
  • The randomized controlled National Emphysema Treatment Trial showed benefit to only those with poor exercise tolerance and predominantly upper lobe disease. Others with diffuse disease, basilar disease, and/or good exercise tolerance did not benefit from lung-volume reduction. In some instances, mortality was increased. This study included patients with emphysema of all etiologies.
  • A small prospective study of 21 patients with alpha1-antitrypsin deficiency showed improvement in the mean dyspnea score at 3 months after surgery. This finding persisted for as long as 3.5 years. Improvements were also noted in mean FEV₁, vital capacity, and the ratio of residual volume to total lung capacity; these results persisted for 1-2 years. Patients with heterogeneous emphysema with little or no inflammatory airway disease appeared to benefit most. Overall, changes in patients with advanced emphysema from alpha1-antitrypsin deficiency were inferior to those changes in patients with smoking-related emphysema, as they were decreased in magnitude and duration.
• Lung transplantation
  • If patients are at substantial risk of early mortality and are otherwise healthy, they may be candidates for lung transplantation.
  • Contact a local transplant center before patients become too ill (cachexia, inactivity, frequent infections). With a recent change in the system for allocation of lungs for transplantation, patients with emphysema are being more carefully evaluated for listing. Many transplant programs have adopted the BODE index to identify patients with emphysema who are most likely to benefit from transplantation. The uncertainties of emphysema exacerbations and complications that might prevent transplantation make it imperative that patients be referred when their BODE index is 5-6 or if they have experienced an episode of acute hypercapnic respiratory failure.⁸

Consultations

The diagnosis of alpha1-antitrypsin deficiency emphysema is not difficult, but most physicians have no experience treating a patient, in determining the need for enzyme replacement, in providing counseling, or in answering the questions that this uncommon hereditary disorder generates. Consultation with a specialist offers answers to these and other needs.

• The Alpha-1 National Association, 1-800-4ALPHA-1, can help in locating physicians with interest and experience in caring for these patients.
• Several organizations have been created to provide support, education, advocacy, and links to ongoing research.
  • Alpha-1-Association, 275 West Street, Suite 210, Annapolis, Maryland 21401, phone 800-521-3025, fax 410-216-6983
  • AlphaNet, AlphaNet, Inc, 2937 SW 27th Ave, Suite 305, Coconut Grove, FL 33133, phone 800-577-2638
  • Alpha-1-Foundation, Alpha-1 Foundation, 2937 SW 27th Avenue, Suite 302, Miami, FL 33133, phone 877-2CUREA1 or 877-228-7321, fax 305-567-1317
  • Alpha-1 Advocacy Alliance, phone 866-FOR-A1AA or 866-367-2122

Diet

Patients with advanced COPD are characterized by a significant reduction in fat-free muscle mass. This pulmonary cachexia is common in patients with alpha1-antitrypsin deficiency and is associated with a decline in clinical status. The syndrome is a result of multiple factors, including hypermetabolism, drug therapy, inactivity, and aging. Prolonged glucocorticoid administration accelerates the process.

Protein-calorie supplementation, as 1 component of a comprehensive treatment program may reverse the loss of muscle mass, and dietary counseling may aid patients at high nutritional risk. Adding fat-based nonprotein calories may benefit patients with respiratory failure who are receiving mechanical ventilation. However, other than this special circumstance, little evidence exists to suggest that this dietary manipulation aids ambulatory patients.

Activity

Dyspnea limits activity, which results in deconditioning and further reductions in activity levels. Encourage all patients with lung disease to maintain activity levels. Pulmonary rehabilitation programs and patient support groups are particularly helpful.

Medication

The most important health intervention for a person with alpha1-antitrypsin (AAT) deficiency is avoiding cigarette smoking. Smoking clearly advances the progression of emphysema in severely deficient individuals by as much as 15 years over their nonsmoking counterparts.

Airflow obstruction and symptoms resulting from alpha1-antitrypsin deficiency can be treated in a manner similar to emphysema. Bronchodilators may provide relief of some symptoms. Use antibiotics to treat bacterial complications, including pneumonia or purulent bronchitis. Neither bronchodilators nor antibiotics demonstrate any effect on disease progression. Likewise, corticosteroids may provide some short-term relief, but they have no proven long-term benefit in inhaled or oral preparations. Because of their long-term adverse effects, avoid oral steroids.

Prescribe oxygen if patients are hypoxemic at rest, with activity, or during sleep.

Consider replacement (or augmentation) therapy to slow the progression of emphysema. At present, IV augmentation therapy is the only FDA-approved treatment specific for alpha1-antitrypsin deficiency. It is most clearly indicated for patients with moderate degrees of airflow obstruction (FEV₁ 35-65% of predicted). Three preparations are available. Although purifications and/or preparations differ, all are equivalent, and none have been a cause of hepatitis or HIV infection. Each is approved at the same dose and administration, ie, 60 mg/kg/wk given IV.

Respiratory enzymes

These drugs are used for long-term replacement in individuals with clinically demonstrable panacinar emphysema.

Alpha1-protease inhibitor (Prolastin)

Sterile, stable, lyophilized preparation of purified human alpha1-antiprotease inhibitor prepared from pooled plasma. Each unit of plasma tested for HIV, hepatitis B, and hepatitis C before inclusion in product. Product heat-treated to reduce potential risk of infectious-agent transmission. No cases of viral infections have been attributed to the product. Indicated as replacement (or augmentation) for normal serum alpha1-antiprotease to prevent progression of emphysema.

Alpha1-proteinase inhibitor (Aralast)

Sterile, stable, lyophilized preparation of purified human alpha1-antiprotease inhibitor prepared from pooled human plasma by using cold alcohol fractionation process followed by further purification steps. Each unit of plasma tested for HIV, hepatitis B, and hepatitis C before inclusion in product. Product treated with solvent detergent mixture to inactivate viral agents to reduce potential risk of infectious-agent transmission. No cases of viral infections have been attributed to the product. Indicated as replacement (or augmentation) for normal serum alpha1-antiprotease to prevent progression of emphysema in patients with congenital deficiency of AAT with clinically evident emphysema.

Alpha1-proteinase inhibitor (Zemaira)

Sterile, stable, lyophilized preparation of purified human alpha1 antiprotease inhibitor prepared from pooled plasma by using cold alcohol fractionation process followed by further purification steps. Each unit of plasma tested for HIV, hepatitis B, and hepatitis C before inclusion in product. Product treated with solvent detergent mixture to inactivate viral agents to reduce potential risk of infectious-agent transmission. No cases of viral infections have been attributed to the product. Indicated as replacement (or augmentation) for normal serum alpha1-antiprotease to prevent progression of emphysema in patients with congenital deficiency of AAT with clinically evident emphysema.

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