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Treatment of alpha-1 antitrypsin deficiency

Treatment of alpha-1 antitrypsin deficiency
Literature review current through: Jan 2024.
This topic last updated: Nov 17, 2023.

INTRODUCTION — Severe deficiency of alpha-1 antitrypsin (AAT) is associated with early onset pulmonary emphysema and with several forms of liver disease, including cirrhosis, neonatal hepatitis, and hepatocellular carcinoma.

The discovery of the structure and function of the AAT protein, and its subsequent isolation and purification, have allowed augmentation therapy (so-called because of less than total replacement) aimed at preventing progression of emphysema [1,2]. The goal of most specific treatment approaches for AAT deficiency is to raise the serum AAT level (and therefore the concentration of AAT in the lung interstitium) above the "protective threshold." Organ transplantation is another option for patients with end-stage lung or liver disease.

The treatment of AAT deficiency will be reviewed here. The clinical manifestations, genetics, and diagnosis of AAT deficiency are discussed separately. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

SUPPORTIVE CARE AND STANDARD MEDICAL THERAPY — Supportive care and standard medical therapy for patients with AAT deficiency follow the guidelines for the management of chronic obstructive pulmonary disease (COPD) [3]. (See "Stable COPD: Initial pharmacologic management".)

The following components should be included (table 1):

Cigarette smoking is known to accelerate progression of lung disease in AAT deficiency. Patients with genetic variants of AAT associated with lung disease should avoid active and passive exposure to cigarette smoke [3,4]. (See "Overview of smoking cessation management in adults".)

Medical therapy with bronchodilators (such as beta agonists and muscarinic antagonists) and inhaled or oral glucocorticoids should follow guidelines for COPD [3]. (See "Stable COPD: Initial pharmacologic management".)

Pulmonary rehabilitation is appropriate for patients with decreased exercise tolerance. (See "Pulmonary rehabilitation".)

Nutritional support should be provided as appropriate to maintain a healthy body weight. (See "Malnutrition in advanced lung disease".)

Patients should be assessed for resting hypoxemia and supplemental oxygen prescribed if the pulse oxygen saturation (SpO2) is 88 percent or lower at rest. Preliminary evidence suggests that patients with AAT deficiency may have more severe desaturation on ambulation than AAT-sufficient patients with COPD [5]. Thus, assessment of oxygenation during exertion (eg, during a six-minute walk test) may be appropriate. (See "Long-term supplemental oxygen therapy".)

Prompt treatment of lower respiratory tract infections (eg, influenza, bacterial bronchitis, flares of bronchiectasis, pneumonia) to minimize the inflammatory cell burden in the lung.

Preventive vaccination (eg, influenza and pneumococcal vaccines). (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".)

INTRAVENOUS AUGMENTATION THERAPY — Intravenous augmentation via the infusion of pooled human alpha-1 proteinase inhibitor (alpha-1 antitrypsin, AAT) is currently the most direct and efficient means of elevating AAT levels in the blood and lung interstitium [6,7]. The goal of AAT augmentation is to slow the progression of emphysema.

Patient selection — Recommendations from official organizations regarding the specific indications for pooled human AAT augmentation vary [3,8,9]. We suggest augmentation for never or ex-smokers age 18 or older with an AAT genetic variant consistent with severe AAT deficiency, a low serum level of AAT (ie, <11 micromol/L or <57 mg/dL), and evidence of airflow limitation (algorithm 1). Treatment decisions may benefit from consultation with a referral center with expertise in AAT deficiency.

Serum AAT level – Most patients with PI*ZZ (protease inhibitor Z) or PI*Null genetic variants have a serum AAT level <11 micromol/L (enzyme-linked immunosorbent assay) or <57 mg/dL (nephelometry) (table 2). For other genetic variants, the same range of serum levels (<11 micromol/L or <57 mg/dL) is considered the minimum "protective threshold," and these serum levels should be used as a general guide for considering augmentation therapy [4]. Individuals with rare genetic variants like the PI*FF genotype may have relatively normal serum levels of AAT but a dysfunctional AAT protein that poses risk for emphysema.

Severity of airflow limitation – The Global Initiative for Chronic Obstructive Pulmonary Disease guidelines suggest that the most suitable patients for augmentation have severe AAT deficiency and an forced expiratory volume in one second (FEV1) of 35 to 65 percent of predicted [3]. The rationale for selecting this range of FEV1 is that AAT deficient patients with a higher FEV1 may not develop clinically evident emphysema. The American Thoracic Society suggests weekly augmentation therapy with human pooled AAT for individuals who have serum levels of AAT less than 11 micromol/L and established airflow obstruction, defined as an FEV1 <80 percent predicted [8]. In comparison, the Canadian Thoracic Society suggests reserving AAT augmentation therapy for AAT-deficient patients (AAT level less than 11 micromol/L) with an FEV1 of 25 to 80 percent predicted who have quit smoking and are on optimal medical therapy [9]. Indications for use of AAT augmentation outside these thresholds for airflow limitation have not been uniformly agreed upon [10].

In our practice, if the FEV1 is >65 percent of predicted, but declines by ≥100 mL/year in an AAT deficient patient, we initiate augmentation therapy.

A lower limit of FEV1 below which augmentation therapy should be withheld has not been determined, although available studies do not demonstrate clinical efficacy as measured by FEV1 in patients with severe airflow obstruction (eg, FEV1 <35 percent predicted). Advocates suggest that defending against any decrement in lung function is important in these patients. On the other hand, opponents suggest that the efficacy of therapy in preventing loss of the little remaining FEV1 is negligible.

Evidence of emphysema on HRCT – Though some disagree, guidelines suggest including chest computed tomography to identify emphysema as part of the initial assessment of the AAT deficient patient [11]. In clinical trials, sensitive measures of lung density by high resolution computed tomography (HRCT) have demonstrated a decreasing rate of loss of lung density over time in patients with severe AAT deficiency who receive augmentation therapy. In addition, some patients have HRCT evidence of emphysema without airflow limitation on spirometry. In the absence of data to support initiating AAT augmentation in this setting, our approach is to follow these patients closely (eg, every six months) with spirometry and diffusing capacity measurements in order to identify early or progressive declines in FEV1 (eg, ≥100 mL/year) or diffusing capacity (eg, >15 percent decline), at which time augmentation therapy can be begun.

Additional selection criteria – Anticipated adherence to the protocol for weekly infusions may contribute to the decision about initiating augmentation.

Guidelines suggest augmentation for patients with necrotizing panniculitis in association with AAT deficiency [11]. Panniculitis is an off-label indication for augmentation therapy. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

Augmentation therapy is not recommended for patients who are PI*MZ heterozygotes, whose serum AAT level almost invariably exceeds 11 micromol/L or 57 mg/dL [12] or those with emphysema in the absence of documented AAT deficiency. Heterozygous individuals with the PI*MZ, PI*SZ, or PI*MS genetic variants are generally not candidates for AAT augmentation, as they are not at increased risk for panacinar emphysema in the absence of smoking.

Pretreatment preparation — For patients who meet criteria for AAT augmentation, we obtain a baseline serum IgA level (as all commercial preparations of AAT augmentation therapy contain some IgA and patients with severe deficiency of IgA are at risk of anaphylaxis with infusion of pooled human AAT). We also obtain baseline spirometry and diffusion capacity for carbon monoxide (within a year of initiation).

Selective immunoglobulin A (IgA) deficiency (<7 mg/dL) affects approximately 0.1 to 1 percent of the population. A minority of patients with undetectable IgA in serum form antibodies to IgA that can be associated with systemic reactions to pooled human plasma containing IgA. We avoid AAT augmentation in these patients, due to concerns about anaphylaxis. Consultation with an allergy/immunology specialist and measurement of a serum antibodies to IgA can help define the risk of anaphylaxis due to IgA sensitivity in individual patients. (See "Selective IgA deficiency: Management and prognosis", section on 'Reactions to blood products'.)

Vaccination against hepatitis A and B for those who are not already immune can help prevent superimposed insults to the liver, but is not necessary prior to AAT augmentation therapy, due to the low risk of transmission.

Formulations — Four pooled human plasma AAT products are available, Aralast NP, Prolastin-C (also available as Prolastin C – Liquid), Zemaira, and Glassia. The first three are supplied in a powdered, lyophilized form and Glassia and Prolastin C - Liquid as liquid preparations. For the lyophilized preparations, the directions for reconstitution provided in the package insert should be followed closely. After reconstitution, pooled AAT should be used within three hours.

Dosing — The only US Food and Drug Administration (FDA)-approved regimen for AAT is 60 mg/kg body weight, given as weekly infusions. Studies have shown that weekly infusions of human pooled AAT at a dose of 60 mg/kg maintain AAT levels in serum and epithelial lining fluid above the protective threshold, both throughout the week and over the long-term (figure 1) [1,2,13]. Serum levels are more consistently above the protective threshold with weekly than biweekly or monthly therapy, although differences in clinical outcomes have not been formally assessed.

Although effective, weekly infusions can be difficult for patients and support staff. To reduce the frequency of treatment, the efficacy of giving larger doses biweekly has been studied. In a series of 23 patients, simply doubling the dose of AAT to 120 mg/kg and administering every other week was not sufficient to maintain the serum level above the protective threshold through the entire dosing interval [14]. Pharmacokinetic modeling suggested that a dose of 200 mg/kg could be required for biweekly infusions [14].

In comparison, monthly infusions of 250 mg/kg appear biochemically effective. In one small study (9 patients) with AAT deficiency (eight PI*ZZ and one PI*Z null), monthly infusions of human pooled AAT at a dose of 250 mg/kg (ie, four times the weekly infusion dose) effectively raised serum and epithelial lining fluid (ELF) AAT levels (figure 2), as well as anti-neutrophil elastase activity, above the protective thresholds [15]. This effect was maintained until the next dose and over the long-term. This study was subsequently extended as monthly infusions were given for up to 24 months in eight severely deficient patients [2]. Further study would be needed to determine the efficacy of monthly dosing.

Infusion — A protocol for intravenous AAT augmentation therapy is summarized in the table (table 1). As noted above, weekly infusions of AAT 60 mg/kg actual body weight is the only FDA-approved regimen. (See 'Dosing' above.)

The infusion rate is typically 0.08 to 0.2 mL/kg body weight per minute, depending on the individual preparation, such that the average weekly infusion takes 15 minutes (table 1). Emergency equipment (including epinephrine) should be immediately available during the infusion. The infusion rate may need to be reduced or interrupted if the patient develops an adverse event.

Monitoring — The guidelines for AAT augmentation do not advise routine monitoring of serum AAT levels during therapy [11]. Annual monitoring of spirometry, diffusing capacity, and ambulatory oximetry is advised.

Computed tomography (CT) densitometry is a more sensitive measure for assessing emphysema progression than spirometry; however, radiation exposure has generally discouraged the use of serial chest CT scans for routine monitoring in patients with AAT deficiency [16].

The role of annual low dose CT scans for lung cancer screening in high risk individuals (eg, ages 50 to 80 years with 20 pack-year history of smoking, and current smoker or quit within past 15 years) is discussed separately. (See "Screening for lung cancer", section on 'Summary and recommendations'.)

Some guidelines suggest that adults with AAT deficiency undergo annual monitoring for liver disease with measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), albumin, bilirubin, prothrombin time/international normalized ratio (INR), and platelets [11]. Liver elastography to assess fibrosis is increasingly being used to monitor patients whose AAT genotype causes protein misfolding and intra-hepatic accumulation of unsecreted abnormal AAT. The most common such variant is PI*ZZ. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Adult onset'.)

Adverse effects — Infusion therapy with intravenous pooled human AAT appears to be safe, well tolerated, and without significant adverse effects [17-21]. Although all current AAT products are pooled human plasma derivatives, no cases of HIV or hepatitis transmission or of viral antibody development have been reported in recipients [2,22]. (See "Pathogen inactivation of blood products".)

Investigators from the National Heart, Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1 Antitrypsin reported their experience with adverse reactions to augmentation therapy [23]. The overall incidence of adverse events was 0.02 per patient-month of treatment. Most events were of moderate severity, and included dizziness, chest tightness, rash, hives, and fever. A small number of severe adverse effects, including wheeze, hypotension, and loss of consciousness were reported. Over 80 percent of patients involved in the survey reported no adverse events associated with treatment.

There are, however, some problems that can occur [20,23]:

Flu-like symptoms – Low-grade fever (1 to 5 percent) and mild flu-like symptoms are usually self-limited.

Hypersensitivity – Anaphylaxis with IgE antibody formation to AAT has been reported, but is extremely rare (<1 percent) [24]. Anaphylaxis may be due to antibodies to human alpha1-protease inhibitor or to IgA, if the patient is IgA deficient. Rash, urticaria, and angioedema are also reported, but uncommonly. (See 'Pretreatment preparation' above and "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Anaphylactic reactions to blood products' and "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions'.)

Potential volume overload – Pooled human AAT is a colloid solution and can transiently increase blood volume. Patients at risk for volume overload should be monitored during and after intravenous infusion. Sometimes the rate of infusion needs to be slowed, or diuretic agents administered.

Transmission of infectious agents – More than 20 years ago, several lots of the original Prolastin preparation were withdrawn from the market when it was discovered that some of the intermediates used to produce the drug derived from two individuals diagnosed with Creutzfeldt-Jakob disease (CJD) [25]. However, there have been no reports of human-to-human transmission of CJD through blood products, and there is no known association between blood transfusion and the development of CJD [26-29]. Thus, the risk to recipients is deemed very low.

While the risk of transmission of human pathogenic agents cannot be entirely eliminated, all pooled human AAT products are serologically negative for HIV, hepatitis B, and hepatitis C [26-29]. Viral reduction and inactivation steps are followed to reduce the possibility of transmission of viruses, such as hepatitis A, Creutzfeldt-Jakob disease, and parvovirus. (See "Creutzfeldt-Jakob disease" and "Pathogen inactivation of blood products".)

Clinical efficacy — Data in support of clinical efficacy of intravenous AAT are largely comprised of randomized trials that assessed outcomes such as serum AAT levels, lung function, and lung density on computed tomography [17,21,22,30-32]. Long-term clinical trial data on patient-important outcomes, such as frequency of exacerbations, quality of life, need for lung transplantation, and mortality, are more limited.

A systematic review and meta-analysis that included 1509 patients concluded that augmentation had a modest effect in slowing lung function decline [31]. The decline in FEV1 was slower by 23 percent (absolute difference, 13.4 mL/year, 95% CI 1.5-25.3 mL/year) among all patients receiving augmentation therapy, compared with placebo. Patients with moderate airflow obstruction (FEV1 from 30 to 65 percent predicted) appeared most likely to benefit. A Cochrane systematic review of three randomized trials (283 participants) that included the RAPID trial described below found that the rate of loss of CT density was significantly lower among augmentation therapy recipients, but that no effect was observed in exacerbations, quality of life, or rate of decline of FEV1 [33].

In the RAPID randomized trial, the rates of change of CT lung density were compared between 93 patients receiving weekly AAT augmentation therapy and 87 placebo recipients [21]. The rate of loss of lung density among augmentation therapy recipients tended to be lower on the coprimary endpoint of CT density assessed at functional residual capacity (FRC) and at total lung capacity (TLC) and achieved significance on the density measured at TLC. No differences were observed between the compared groups regarding change in FEV1 or diffusing capacity for carbon monoxide (DLCO), scores on the St George's Respiratory Questionnaire, or exacerbation frequency.

In a follow-up study to the RAPID trial (called RAPID-OLE for "open label extension"), augmentation therapy was provided to 76 participants from the original augmentation therapy group (early start) and 64 participants from the placebo group (start of augmentation therapy delayed by two years) for an additional two years [34]. The rate of lung density loss was slower in the early start patients, compared with delayed start patients. The rate of decline in lung density manifest by the delayed start group decreased during RAPID-OLE compared with their rate of lung loss during the RAPID trial, but lost lung density was never recovered.

Reduction in exacerbations – Other studies have found that AAT augmentation is associated with fewer exacerbations of COPD [35,36]. In an observational study, the rate of exacerbations decreased from 3 to 5 infections/year before therapy to 0 to 1 infections/year after starting therapy [35]. While randomized trials of augmentation therapy have not shown an overall effect on exacerbation frequency, a post hoc analysis of a clinical trial reported a decrease in severity of exacerbations [17].

Lung function and survival in observational studies – The results of some observational studies of augmentation therapy not included in the Cochrane meta-analysis support a beneficial effect on survival and lung function [32] and strengthen support for the clinical efficacy of intravenous augmentation therapy.

The National Registry of Patients with Severe Deficiency of Alpha-1 Antitrypsin conducted a multicenter, prospective, observational cohort study of 1129 patients and reported enhanced survival in recipients of augmentation therapy compared with non-recipients [18,37]. In the subset of patients with FEV1 35 to 49 percent predicted, the rate of FEV1 decline was also slowed in recipients of augmentation therapy, though the observational nature of the study precludes certainty about the finding.

A retrospective observational study of 615 persons with severe AAT deficiency compared patients from Ireland, where augmentation was rarely available, with those from Switzerland and Austria, where it was supplied for those with moderately impaired or worsening lung function [38]. Despite a similar age distribution and fewer lung symptoms at baseline, Irish patients had increased mortality compared with those from the other two countries. AAT augmentation decreased mortality (HR 0.61, 95% CI 0.45-0.83) in the cohort but did not have a significant effect on FEV1 decline.

A similar observational study compared the rate of FEV1 decline among 97 Danish former smokers with severe AAT deficiency who did not receive augmentation therapy with that of 198 severely deficient German former smokers who received weekly infusions (60 mg/kg) over a mean of 3.2 years [39]. Overall, the rate of decline of FEV1 was lower among the treated patients than among the untreated (-53 mL per year versus -75 mL per year, p = 0.02).

A longitudinal study following 96 patients with severe alpha-1 antitrypsin deficiency analyzed the rate of decline in FEV1 before and after initiation of weekly augmentation therapy [40]. In distinction to other observational studies discussed above, this study showed that the rate of decline in FEV1 during augmentation therapy was slowest in those patients with mild airflow obstruction.

Protective threshold – Achieving certain serum values does not necessarily correlate with protection against lung function decline. The protective threshold levels of AAT in serum and ELF reflect estimates of values that separate affected from unaffected individuals. Because a "true" protective threshold value is not available, the amount of augmentation needed to prevent or retard disease is not precisely known. As some severely deficient patients have normal lung function, it is apparent that serum levels and genotype alone do not predict disease, but only assign a risk for developing disease. Ideally, outcomes such as mortality, exacerbations, exercise tolerance, quality of life, and lung function would be used to assess efficacy. The slow rate of disease progression (in the absence of cigarette smoke exposure) and the need for a placebo group make it more difficult perform long-term studies with robust patient-important outcomes in an uncommon disease like AAT deficiency [41].

Cost and availability — High cost remains an issue for AAT augmentation, and all of the preparations available in the United States are costly (estimated >$100,000/year). Due to the high cost, AAT augmentation is not available in many countries.

LUNG VOLUME REDUCTION SURGERY — Lung volume reduction surgery (LVRS, also called reduction pneumoplasty or bilateral pneumectomy) is a surgical technique that entails reducing the lung volume by wedge excision of emphysematous tissue. Small studies of LVRS in AAT deficient patients suggest caution in advising LVRS for AAT deficient patients [16]. (See "Lung volume reduction surgery in COPD".)

In one trial, 10 AAT deficient patients who underwent LVRS had a higher two year mortality than similar patients randomly assigned to medical therapy [42]. In addition, AAT deficient patients had a smaller increase in exercise tolerance and a smaller and less sustained improvement in forced expiratory lung volume in one second (FEV1), compared with AAT nondeficient patients. Statistical analysis was limited due to the small sample size.

In a separate study, 17 AAT deficient and 35 AAT nondeficient patients underwent unilateral LVRS [43]. When assessed at one year after surgery, the nondeficient group had sustained improvements in lung function, dyspnea score, and walking distance, while the deficient group had nonsustained or marginal improvement.

Basal predominance of emphysema or diffuse emphysema with a low diffusing capacity for carbon monoxide may make LVRS more difficult in AAT deficient patients [11].

LUNG AND LIVER TRANSPLANTATION — Advances in solid organ transplantation have made lung and liver transplantation available as therapeutic options for AAT deficient patients. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease' and "Liver transplantation in adults: Patient selection and pretransplantation evaluation" and "Lung transplantation: General guidelines for recipient selection", section on 'Chronic obstructive pulmonary disease (COPD)'.)

Liver transplantation is reserved for patients with end-stage hepatic disease. It has the additional advantage of correcting the AAT deficiency, because a normal (PI*MM) donor liver produces and secretes AAT, which appears to slow the rate of decline in lung function in some patients [44-46]. The AAT level should be assessed after liver transplant to ensure normalization. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

Selection of candidates for lung transplantation — Selection of patients with AAT deficiency for lung transplant follows guidelines for other patients with advanced lung disease. (See "Lung transplantation: General guidelines for recipient selection", section on 'Chronic obstructive pulmonary disease (COPD)'.)

One important consideration for potential lung transplant candidates with AAT deficiency relates to the possibility of underlying liver disease. In a single institution study, a pretransplant liver biopsy was performed in all lung transplant candidates with Pi*ZZ emphysema [47]. Chronic liver disease was noted on biopsy in 20 of 23 patients and two patients met criteria for severe liver disease. The two patients with severe liver disease were asymptomatic and had normal liver function tests; one had an abnormal ultrasound. Seventeen patients underwent lung transplantation, and no evidence of decompensation of liver disease was noted; the two with severe liver disease were not listed for transplant. We assess liver function tests and elastography prior to listing a patient for lung transplantation, but do not routinely perform liver biopsy. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)

Outcomes of lung transplantation — Observational studies suggest that lung transplantation in patients with advanced lung disease due to AAT deficiency has a comparable survival to lung transplantation for AAT-nondeficient patients with chronic obstructive pulmonary disease (COPD) and improves survival compared with standard (nontransplant) care, as noted in the following studies:

In a single-center study, the outcomes of 45 patients who underwent lung transplantation for AAT deficiency were compared with those of 231 AAT-nondeficient patients who underwent lung transplantation for COPD [48]. AAT deficiency was not a risk factor for early or late post-transplant death. Single lung recipients in both groups experienced a similar rate of decline in the forced expiratory lung volume in one second (FEV1). However, among bilateral lung transplant recipients, the rate of decline in FEV1 was greater in those who were AAT deficient compared with those who had normal levels of AAT. The cause of this discrepancy is unclear. No differences in the frequency or severity of acute cellular rejection episodes were observed.

The effect of AAT augmentation on lung allograft function could not be assessed, as only six AAT-deficient patients received augmentation after transplantation. (See 'Augmentation following lung transplantation' below.)

In a retrospective case-control study, 83 patients with advanced emphysema due to AAT deficiency (PI*ZZ) underwent single (62) or bilateral (21) lung transplantation; survival was compared with 70 nontransplanted AAT deficient individuals of similar age, sex, smoking history and lung function [49]. The median survival times were significantly longer among transplanted (11 years, 95% CI 9-14) versus nontransplanted (5 years, 95% CI 4-6) patients. Given the study design, it is possible that unidentified factors contributed to early mortality among those who did not seek lung transplantation.

Augmentation following lung transplantation — Continuation of AAT augmentation therapy following lung transplantation is controversial, largely because it is costly [16,50]. Most transplant centers do not give augmentation therapy to AAT deficient lung transplant recipients, as it is not known whether it would improve outcomes or longevity during the patient's lifetime, and significant recurrent emphysema is unlikely to occur for 30 to 40 years in the absence of smoking [48,51].

In our practice, we observe lung function after transplant and initiate augmentation only if the patient has persistent lung function decline. This practice is supported by a report that two of four lung transplant recipients responded to weekly augmentation therapy after experiencing lung function decline refractory to the usual therapies for bronchiolitis obliterans syndrome [52]. Theoretically, AAT augmentation could also be initiated if characteristic radiologic changes of emphysema were to develop in the absence of lung function decline.

Other authors suggest providing once-weekly therapy (60 mg/kg) during conditions associated with an increased neutrophil burden in the lung (as with pneumonia or acute rejection), although data in support of this practice are lacking [48,50,53].

EMERGING THERAPIES — A number of emerging therapies that use novel treatment approaches for AATD are being investigated, though none is currently approved for use. These potential interventions include gene therapy, augmentation therapy using modified proteins that require less frequent infusion, corrector molecules that prevent misfolding and allow more normal secretion of AAT protein that might otherwise polymerize within the hepatocyte, and interfering mRNA that suppresses Z protein expression within the hepatocyte. Evolving study of these various approaches will clarify whether they have efficacy and will receive regulatory approval for use. (See "Overview of gene therapy, gene editing, and gene silencing".)

ADDITIONAL RESOURCES — The Alpha-1 Foundation in the United States provides information for patients and their caregivers and also maintains a registry and an AAT deficiency specific genetic counseling program (Alpha-1 Foundation). Information about clinical trials for patients with AAT deficiency, including many of the emerging therapies discussed above, is available at ClinicalTrials.gov and at the EU Clinical Trials Register.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)

SUMMARY AND RECOMMENDATIONS

Severe deficiency of alpha-1 antitrypsin (AAT) due to certain genetic variants (table 2) is associated with both early onset pulmonary emphysema and several forms of liver disease, including cirrhosis, neonatal hepatitis, and hepatocellular carcinoma. (See 'Introduction' above and "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

Severe deficiency of AAT is defined as a low serum level of AAT (ie, <11 micromol/L or <57 mg/dL by immunodiffusion) due to a genetic variant (algorithm 2). (See 'Introduction' above and "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis'.).

All individuals with genetic variants of AAT should be advised to avoid active or passive cigarette smoke exposure to reduce the risk of developing emphysema. (See 'Supportive care and standard medical therapy' above and "Patient education: Quitting smoking (Beyond the Basics)" and "Overview of smoking cessation management in adults".)

Supportive therapy for patients with emphysema due to AAT deficiency follows the usual guidelines for COPD and includes pulmonary rehabilitation, nutritional support, supplemental oxygen, preventive vaccination (eg, influenza and pneumococcal vaccines), and prompt treatment of lower respiratory tract infections. (See 'Supportive care and standard medical therapy' above and "Stable COPD: Initial pharmacologic management".)

Medical therapy with bronchodilators (eg, beta agonists and muscarinic antagonists) and inhaled or oral glucocorticoids should follow guidelines for COPD. (See 'Supportive care and standard medical therapy' above and "Stable COPD: Initial pharmacologic management".)

For AAT deficient patients who are never or ex-smokers, age 18 or older with an AAT genetic variant consistent with severe AAT deficiency, and evidence of airflow limitation (forced expiratory volume in one second [FEV1] 30 to 65 percent predicted), we suggest intravenous augmentation with pooled human AAT (algorithm 1) (Grade 2B). Indications for use of AAT augmentation outside these thresholds for airflow limitation have not been uniformly agreed upon. (See 'Patient selection' above.)

For the majority of patients receiving AAT augmentation, pooled human AAT is administered intravenously 60 mg/kg actual body weight, per week. The rate of infusion depends on the specific preparation (table 1). (See 'Infusion' above and 'Formulations' above.)

Pooled human plasma AAT contains small amounts of IgA. Rare systemic anaphylactic reactions to pooled human plasma AAT have been reported, possibly due to antibodies to IgA in IgA deficient individuals. (See 'Pretreatment preparation' above and 'Adverse effects' above.)

The experience with lung volume reduction surgery (LVRS) for patients with AAT deficiency is limited, but thus far LVRS has not been shown to improve survival or substantially improve lung function compared with medical therapy. (See 'Lung volume reduction surgery' above.)

Lung transplantation is reserved for patients with advanced emphysema due to severe AAT deficiency. Similarly, liver transplantation is reserved for patients with end-stage hepatic disease. After liver transplantation, the AAT deficiency is corrected, because the normal phenotype donor liver produces and secretes AAT. (See 'Lung and liver transplantation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc Rovner, MD, FACP, FCCP, who contributed to earlier versions of this topic review.

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Topic 1434 Version 42.0

References

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