AATD by itself is not a disease, but rather a predisposition to a later development of several disorders. In fact, it is believed that low serum levels of AAT together with other genetically determined characteristics and environmental influences result in the development of a disease state that may result in premature death. The available data on penetration (the percentage of AATD individuals with clinical disease) is currently scant and the spectrum of AATD-related disorders and their ages of onset are quite broad.28

In clinical practice, the risk of disease is mainly restricted to the deficient Z allele, accounting for approximately 95% of AATD cases. The remaining individuals at risk carry rare alleles including null and dysfunctional variants.8

Low levels of AAT represent a syndrome of clinical entities, some more related to a deficiency condition while others resulting, in contrast, from a negative effect of protein overload. Its main clinical manifestations primarily involve the lungs, liver, and – less frequently – the skin. Since patients with AATD are susceptible to developing all these diseases throughout their lives, the disorder is considered a systemic disease.29

Individuals may be identified after presenting clinical consequences of the deficiency or through family screening of an index case.13,30

Currently, the understanding of the natural history of AATD is still incomplete. Within the first three decades of life, liver disease is the major threat and pulmonary dysfunction is not common. Besides that, the natural history of AATD patients is less clear, and survival estimates vary widely among series.

In the lung, AATD predisposes individuals to premature onset of chronic obstructive pulmonary disease (COPD). Indeed, it is the major and best proven genetic risk factor for COPD, with 1-2% of all cases estimated to be due to severe AATD.28,31

Liver disease does not occur frequently. AATD is only diagnosed through finding of liver disease in 3% of AATD cases.80 Unlike pulmonary disease, AATD-related hepatopathy is not caused by functional loss or low protein serum levels but rather by the accumulation of AAT polymers in hepatocytes.81 In this context, liver disease is the result of a disrupted balance between the accumulation of AAT polymers and the capacity of cellular mechanism to degrade those protein aggregates.81,82 Hence, those AATD variants linked to polymerization in the liver, such as SIiyama, MDuarte, MMalton, and particularly Z allele, may all show signs of hepatopathy. Liver disease has never been reported in Null (Q0Q0) patients. Unlike pulmonary disease, which is typically a disorder of adulthood, liver disease may occur throughout a patient's life; it is a frequent cause of disease in non-smokers. The prevalence of post-mortem liver disease in non-smokers is 28%. Approximately 10-15% of newborns with severe AATD are at risk of developing some form of liver disease. Similarly, about 10 to 15% of adults show some evidence of liver disease, and although it may occur at any given age, it occurs more frequently later in life.80 Cholestatic jaundice and hepatitis (neonatal hepatitis syndrome) can be observed in some new-borns with AATD, while later during childhood AATD patients may experience an unexplained increase in aminotransferases, hepatomegaly, or on rare occasions, cirrhosis and liver failure. In some cases, the only signs of liver disease in young children may be anorexia and a growth delay.83 On the other hand, adults may show asymptomatic changes in transaminases, clinical signs of cirrhosis, and hepatocellular carcinoma. Clinical manifestations in patients with chronic liver disease due to AATD may not be differentiated from those of any other etiology.

The development of liver disease and its evolution towards cirrhosis is the most common clinical sign after pulmonary disease. It is estimated to occur in 2-43% of ZZ patients. It may be a frequent cause of death in non-smokers with the ZZ phenotype.84 According to a Swedish study, out of a population of 200 000 newborns, 22/120 Z individuals (18%) showed signs of some liver dysfunction, which included obstructive jaundice (12%) and discrete lab changes (7%).85 The risk of cirrhosis in these cases was approximately 50%, approximately 25% died during the first decade, and 2% developed cirrhosis later on in their childhood.86 The follow-up of 127 ZZ newborns until their 30s showed that 3-7% had high transaminase levels, but none of them showed any clinical symptoms of liver disease.87 In a second study where 246 ZZ patients were followed over an 11-year period, Larsson observed liver disease in 12% of the cases (cirrhosis in 11.8%, neonatal hepatitis in 0.4%, and hepatoma in 3.3%).32 ZZ individuals who develop cirrhosis are at an increased risk of developing hepatocellular carcinoma,88 especially middle-aged or older men, although there have been some rare cases described in children.89 However, this risk has been difficult to quantify and may vary across studies.88

The risk of heterozygous patients developing liver disease is not well established. Many studies have shown that there is a greater prevalence of the MZ genotype among patients with cirrhosis than in control populations with non-cirrhosis liver disease or cryptogenic cirrhosis.90–94 However, a more recent study has not shown any association between the MZ genotype and liver disease.95 The risk of individuals with one Z allele developing hepatocellular carcinoma is also not as well defined as for homozygous patients. Heterozygosity for the Z allele may increase the risk or change it in patients with other liver diseases, such as chronic hepatitis C.96

Panniculitis was described for the very first time by Warter in 1972 and it has been associated with AATD in approximately 50 reported cases. Panniculitis is very rare with an estimated prevalence of 1 per 1000 AATD cases,30 and with an average age of appearance of 40 years. As with emphysema, panniculitis is thought to occur due to a lack of protease inhibitory activity in the skin. It is characterized by pain and one or more nodules showing exuding liquid and redness, and painful and warm cutaneous plaques, which may suffer necrosis and be recurrent. Although it occurs more often on the thighs and buttocks, in one third of cases it will occur in places of trauma. There are rare situations where it may be accompanied by polyserositis. It may occur in several disease genotypes, including ZZ, SZ, SS, and MS.97 Diagnosis requires deep excisional biopsy, which shows areas of fat necrosis interspersed among normal areas. A differential diagnosis with other causes of panniculitis is difficult and that is why AAT levels should be measured in every case of necrotising panniculitis.

An association between antiproteinase 3 (PR3) antibody vasculitis (c-ANCA positive) and AATD was first reported in 1993.98,99 Since then, several series have established a correlation between AATD phenotypes and anti-PR3 vasculitis. However, there is a low incidence of antiproteinase 3 antibodies in patients with AATD and its presence may not be related to the development of systemic vasculitis.100 Taking into account this association, AATD testing must be carried out in adults with c-ANCA positive vasculitis.28

The concentrations of AAT serum levels may be measured using several different methods: immunoelectrophoresis, radial immunodiffusion and nephelometry, and normal values will vary depending on the method used101 (Table 1). Nowadays, the most commonly used method is nephelometry. Radial immunodiffusion and nephelometry tend to overestimate the concentration of AAT when compared to the purified standard test developed by the US National Institute of Health. In order to differentiate the values obtained using the non-purified standard test from those obtained using the purified standard test, the former are expressed in mg/dl while the latter are in μM. Both units are frequently used and are interchangeable in many European countries, whatever the test used. In order to convert mg/dl (nephelometry) to μM, one must multiply the concentration in mg/dl by 0.1923.79

The reference values for each method are shown in Table 1. In order to make it easier to interpret results, each laboratory must previously determine the normal values of AAT in the serum samples of normal individuals.79

Bearing in mind that different alleles determine a different percentage of protein production, there are expected serum levels for each phenotype79 (Table 2).

AAT behaves like an acute phase protein, which is why its serum levels may be falsely augmented during inflammatory and infectious processes. Therefore, AAT tests must be carried out preferably outside these episodes. Higher AAT values can be also found during pregnancy and after taking oral contraceptives. In these cases, normal serum levels may be detected in patients with moderate deficiency. Serum levels are lower in children than in adults.79

In rare circumstances, another test may be used to assess if a patient with normal circulating levels has an AATD. The inhibition of NE by AAT is directly related to its serum concentration in such a way that a greater amount of AAT circulating will have greater inhibitory effect. However, some patients may present normal or high AAT levels and little anti-elastase activity due to the fact that not every protein is active (80% be oxidised, destroyed, or not capable of linking to neutrophils).

Measuring the capacity to inhibit elastase from neutrophils is especially indicated in the following cases: 1) studying patients with COPD where AATD is suspected although with a normal AAT serum level; 2) when determining if during an exacerbation of COPD the increase in AAT is proportional to anti-elastase activity; 3) when assessing the implication of AAT deficiency in the severity of pulmonary disease, since quite often AAT serum concentration is not related to clinical progress.79

Qualitative tests detect the different mutations of the SERPINA1 gene. While phenotyping is carried out using isoelectric focusing (IEF) techniques that allow for the identification of several protein variants in the blood (S, Z, M, and others), genotyping usually covers different variations to the polymerase chain reaction (PCR) method, which enables the analysis of different mutations in more or less extensive regions of the SERPINA1 gene.

The initial assessment of a patient with AATD should include: spirometry – before and after a bronchodilator –, pulmonary volumes – measured either through plethysmography or the helium dilution technique or nitrogen-washout –, carbon monoxide diffusion capacity, arterial blood gas analysis, and 6-minute walk test.28 Other respiratory function exams may be carried out in selected cases.

Spirometry is the most suitable exam for the diagnosis of COPD and for assessing its progression. There is usually an obstructive pattern (FEV1/FVC<0,7) with a decrease in FEV1 and normal or decreased forced vital capacity (FVC). The flow-volume curve shows a notch in the expiratory portion leading to a high decrease in flow with progressively lower volumes. Most patients do not have a positive bronchodilator response,28 although there may be moderate reversibility in up to 49% cases (≥12% and ≥200ml in FEV1).121,122 There may also be reversibility in 12.5% of patients with normal FEV1, suggesting that hyperreactivity may be an early characteristic of this disease.121

In the later stages of the disease, loss in the lung elastic recoil will result in an increased pulmonary compliance with hyperinflation, which translates into a decrease in FVC and an increase in total lung capacity (TLC) and in residual volume (RV). Hence, adding measurement of the pulmonary volumes to spirometry will allow for better and more complete patient assessment. Due to the effect of air entrapment, the pulmonary volumes measured by plethysmography are usually greater than those measured using helium-dilution based techniques28; therefore, they should be measured preferably using the first method.

Measuring carbon monoxide diffusing capacity (DLCO) will assess gas exchange through the alveolar-arterial membrane, which is usually reduced. Although these two aspects belong to the same process (emphysema), FEV1 and DLCO do not always correlate.28 Arterial blood gas analysis also enables us to assess gas exchange. There may not be any changes in the early stages, but as the disease progresses, hypoxemia will appear with exercise and then while resting, and will later on be associated with hypercapnia.

In the later stages of the disease the effect of emphysema on the muscular activity of the chest and diaphragm may be assessed by measuring inspiratory and expiratory muscle pressures.

Respiratory function in exercise may be assessed by means of exercise tests such as the six-minute walk test or the cardio-pulmonary exercise test. In later stages of the disease, cardio-pulmonary exercise test may show a decrease in the PaO2 and an increase in the alveolar-arterial difference. Patients suffering from AATD may have increased respiratory rates while resting and their minute ventilation may exceed 80% of predicted maximum voluntary ventilation during mild exercise, which is an indication that ventilation may limit higher levels of exercise.28 The 6-minute walk test assesses not only the exercise functional capacity, but it is also important to estimate disease prognosis by calculating the BODE index.

Chest X-ray should be carried out during the initial assessment of all patients. However, high-resolution CT of the chest in order to assess the bronchopulmonary morphology or chest CT with thicker sections for densitometry are the best exams for detecting and quantifying the presence of emphysema.

Chest X-ray is the norm in the early stages of the disease. As the disease progresses the typical signs of hyperinflation, such as an increase in the anteroposterior and lateral diameter of the chest, higher transparency of the pulmonary fields, a decrease in the vascular markings, horizontalization of the ribs, an increase in the intercostal spaces, low and rectified hemidiaphragm, and vertical heart, appear. These changes are usually more prominent in the lower lung fields.28 Bullous changes do not occur very often in AATD and when they do occur (35%) their most likely location is in the inferior lobes.123

Chest CT is the best exam in vivo for characterising the severity and morphology of pulmonary emphysema,124 better than a chest X-ray or respiratory function tests.28 It has a positive correlation with pathological findings, and that is why it has been suggested as the best method for monitoring emphysema progression.101 The possibility of measuring pulmonary density enables quantification of the extent of emphysema which can be used to monitor disease progression.

In AATD, the emphysema is usually of the panlobular type28 and in 2/3 patients it particularly affects the basal regions, in contrast to the centrilobular emphysema prevailing in the upper lobes which is typical of emphysema caused by smoking. However, in up to 36% of the cases the emphysema may be diffuse or eventually apical.55

In CT, the emphysema areas are characterised by a particularly low attenuation, in contrast to the surrounding parenchyma in density values in Hounsfield units (HU). Chest CT provides for calculation of densitometry parameters, making it possible to assess the extent of the emphysema. There are several methods for calculating these densitometric parameters: the “density mask”, the “percentile method”, and the “average parenchyma density”. The density mask method uses a cut-off value (usually -910HU) and all pixels with density below this value will be classified as emphysema and compared in percentage to the entire lung parenchyma volume. The percentile method quantifies the emphysema through the cut-off point, which defines a percentile datum from the histogram. For example, the 10th percentile density (PD10) is derived from a histogram recording the densities in HU of all lung voxels and is defined as the threshold value for which 10% of all lung voxels have a lower density. As a true density measure this value will decrease as emphysema worsens. In the average density method, the average pulmonary parenchyma density is calculated, which will be lower as the emphysema progresses.124

Lung attenuation values (in HU) can be converted to lung tissue density values (g/l) by adding 1000 to the HU. For example, a 15th percentile density value of -950 HU equals a lung density of 50g/l, meaning that 15% of the pixels/voxels have a density value below 50g/l.125

In chest CT, other changes besides the emphysema may be seen, such as the thickening of the bronchial walls and bronchiectasis (25%) with a widening of the bronchial diameter at the segmental and sub-segmental level. When present, bronchiectasis are cylindrical or saccular and prevail in the lobes where emphysema is more extensive.101

All patients carrying alleles leading to AAT accumulation in the liver (Z, MMalton, MDuarte, SIiyama, etc.) must undergo an initial assessment of liver changes by means of abdominal ultrasound and serum tests.76

The serum liver assessment should include transaminases (AST and ALT) as well as alkaline phosphatase, GGT, bilirubin, albumin, coagulation tests, platelets, fat soluble enzymes, and alpha-fetoprotein.76,79 An abdominal ultrasound will evaluate liver changes – steatosis, portal hypertension, and cirrhosis – and the presence of hepatocellular carcinoma.76 FibroscanTM, a noninvasive technique using a probe with an ultrasound transducer and a mechanical vibrating device, exerts dynamic stress on the body surface to generate shear waves. The shear wave velocity can then be converted into liver stiffness, which is expressed in kilopascals. It may be used as an alternative to ultrasound to assess steatosis and liver fibrosis in patients with AATD.126

Liver biopsy should not be used for diagnosis, since the pathological changes vary and are not specific. The diagnostic method should be phenotyping or genotyping. However, liver biopsy may be indicated in certain cases, particularly when it becomes necessary to assess the level of liver damage, its progression, or to investigate the presence of other related diseases. There is usually lobe inflammation, variable hepato-cellular necrosis, fibrosis, cirrhosis, steatosis, and PAS-positive diastase-resistant globules in some, but not all, hepatocytes.76

[International expert treatment guidelines indicate that optimal management of Alpha -1 should include strict lifestyle standards, including smoking cessation, exercise, diet and symptomatic treatment with regular review with augmentation therapy intended to slow down progression and increase the chances of preventing irreversible tissue damage].130

The augmentation therapy available for AATD consists of the administration of an intravenous infusion of purified human AAT extracted from a pool of donor plasma. The main rationale for this therapy is to modify the course of the disease by preventing progression of the emphysema, reducing the number of exacerbations, and improving quality of life. In 1990, the observation that non-smoking individuals with SZ phenotype showed a low risk of developing pulmonary disease led to the general acceptance that AAT serum levels found in these individuals could represent a minimum protective threshold.131 Later, Campbell132 demonstrated that the mean area of damage exerted by neutrophils was unrelated to AAT concentration, until its level dropped below 10μM. Since then, the target for circulating AAT to give proper lung protection has been widely accepted to be 11μM (57mg/dl as determined by nephelometry).

The grounds for using AAT in the treatment of pulmonary disease are based on its biochemical role and clinical efficacy. Its intravenous administration resulted in an increment of AAT serum level above the protective threshold, increased concentration in the alveolar lining fluid, and neutralised activity of the serum and alveolar elastase from neutrophils throughout the interval between doses.133–136 A decrease in the degradation of elastase has also been shown through the quantification of serum, urinary and alveolar lining fluid levels of desmosine and isodesmosine markers.137,138

Stockley demonstrated a decrease in leukotriene B4 (LTB4), myeloperoxidase (MPO) and interleukin 8 (IL8), albeit only significantly reduced in patients undergoing AAT augmentation therapy.136

Clinical efficacy should address the following questions: does AAT augmentation therapy have a positive effect in lowering the decline of pulmonary function and in delaying the progression of emphysema? Does it decrease the number and severity of exacerbations? Does it improve functional capacity, patient symptoms and survival? Is it safe and cost-effective?8 Hence, medical grounds are based on the results of various studies with different designs (observational or randomized and placebo-controlled) comparing the decline in pulmonary function, variation of lung density assessed by chest CT, mortality rate, frequency and severity of exacerbations, impact on the quality of life and functional capacity between groups of patients submitted to therapy and patients who have not been treated. Among these, the randomized studies controlled with placebo stand out, since they have demonstrated a smaller loss in lung density quantified by CT in subjects that have been submitted to AAT therapy. Table 5 summarizes the main results for studies supporting the use of the AAT therapy.

Age – the age range for starting treatment is unknown; however, most patients are expected to be in the fourth decade of life when diagnosed, since the emphysema usually develops approximately ten years earlier than in smoking-related COPD. The minimal age for initiating therapy is 18 and any exception must be justified. The maximum age limit may be established depending on each case. Table 6

Genotype - pulmonary disease in AATD is associated with genotypes such as ZZ, ZQ0, Q0Q0, and other combinations with rare deficient or null variants. The clinical efficacy of the AAT therapy is better documented in the treatment of ZZ patients.

Importantly, knowing that approximately 10% of patients with SZ genotype have a serum level below the protective threshold, it seems acceptable to include these subjects, as long as all other criteria for therapy are verified. However, for SZ individuals there is no scientific evidence supporting clinical efficacy of the therapy.

AAT Level – Decisional cut-off - Patients with serum levels ≤ 57mg/dl (nephelometry) are candidates for AAT replacement therapy. Table 7

Pulmonary Functional assessment and CT Densitometry

Observational studies indicate a smaller decline in pulmonary function of patients undergoing therapy with airways obstruction within FEV1 31-65% or FEV1 35-49% of predicted values. Patients with more severe obstructions do not appear to have benefitted from therapy.67,139 A study carried out in 2009 and comprising 164 patients, concluded that a beneficial effect was observed in the group of ex-smokers with FEV1 <50% predicted value.141 Furthermore, in a meta-analysis that included five clinical trials and 1509 patients undergoing therapy vs. controlled patients, the treated group registered a lower functional decline with this result showing greater significance in the group of patients with FEV1 between 30-65% of predicted value.145

The analysis of these studies suggests that the decline in FEV1 is not linear and drops faster in the moderate obstruction interval.150 Nevertheless, Wencker140 carried out a multi-centre and retrospective study to assess the progress of emphysema before and during the AAT therapy (assessment of the 47 months prior and the 50 months during therapy – in the 60mg/Kg/week dose), which included 96 patients split into three functional groups – FEV1 <30%, between 30-65% and> 65%, and they verified the existence of patients with severe deficiency, preserved pulmonary function (FEV1> 65%) and fast declining pulmonary function (> 120ml/year). Moreover, in this latter group, the loss of pulmonary function prior and during treatment was 255±70.4 and 52.7±61.3ml, respectively and according to these authors, an early implementation of AAT therapy significantly reduced patient decline of respiratory function.

More recently, randomized studies controlled with placebo, in which the emphysema progression is quantified by CT scans, have proposed this technology as the best indicator of the efficiency of this therapy. The authors find that CT densitometry is more sensitive than the variation of physiological indicators or quality of life143 as there may be loss of lung density with stable FEV1 values.150 In an initial study, which had as its primary outcome the assessment of the FEV1 decline, 56 patients with FEV1 between 30-80% were randomised for a dose of 250mg/Kg/4 weeks, for three years. No significant difference in the decline of the pulmonary function was detected between patients although there was a tendency for a reduced loss of lung density in the active treatment group.142

The EXACTLE study143 lasted for 24-30 months and included 77 patients with postbronchodilator FEV1 between 25-80% for the dose of 60mg/Kg/week vs. placebo. The endpoint goal of this study was to analyse the loss of lung density by CT measures. A marginal statistical significance was observed in only one of the four analyses performed supporting the AAT treatment as beneficial. Another objective of EXACTLE was to evaluate the frequency and severity of exacerbations among groups of patients. Only the number of hospital admissions for exacerbation was lower in the AAT treated group due to a reduction in exacerbation severity. In addition, there was also found a correlation between the decline of pulmonary function and the decline of lung density, despite no difference being observed in the functional decline rate between groups. An integrated assessment of the findings in these two studies showed a significant reduction in the decline of lung density in treated patients, where -2.297g/L (p=0.006) difference was found between groups.144

The RAPID study,147 which used the analysis of lung density as a primary endpoint and included 180 patients with FEV1 between 35-70%, showed that augmentation therapy contributes to the preservation of lung density when assessed in terms of TLC. This study lasted two years and patients were split into two groups (active treatment group – AAT at the dose of 60mg/Kg/week vs. placebo). Lung density loss of 1.45g/L/year was observed in the treated group vs. 2.19g/L/year in the placebo group with significant difference (p=0.03). However, no differences were found between the groups in terms of FEV1, carbon monoxide diffusing capacity, results on the shuttle test, and health-related quality of life improvement. This study also specified that treatment benefits were dose-related and more expressive in patients with higher serum trough AAT concentration. The dose of 60mg/Kg/week was not established as an optimal dose. Higher trough concentrations were achieved during treatment in heavier patients with greater AAT concentrations in pre-treatment.147

An open label period followed (RAPID Extension-2 years), showing that when patients of the placebo group began treatment with AAT, their lung density decline rate would overlap that of the actively treated group although the lost density would not be recovered, which suggested a need for early treatment. However, the authors stated that they did not know whether the preservation of lung density or structure was uniform to all deficient patients or in every stage of the disease.147

The results of these three studies described above, which included mostly ZZ patients, were presented without discrimination of any functional subgroup where the decrease in lung density decline rate could have been slower; therefore leaving the impression that those patients with FEV1 in the established intervals for the studies (FEV1 between 25/30/35 – 70/80% of predicted value) would benefit from the AAT therapy. The ATS/ERS document28 provides the possibility of treating patients with an almost normal pulmonary function as long as they are identified as rapid decliners and the Canadian151 and Spanish Pneumology Societies110 recommend, respectively, AAT treatment for patients with FEV1 between 25-80% and FEV1 <80% of predicted value.

This controversy regarding treatment of patients with FEV1>65% was approached in a review article published by Teschler in March 2015 with the recommendation based on the author's experience to functionally assess these patients every six months. Rapid decliners may initiate therapy although this is an individual decision.152

In brief, the collected evidence points towards AAT therapy being efficient in preserving lung density although there are no significant results regarding other indicators, such as health-related quality of life and/or exacerbations. Regarding functional decline, results are contradictory, with some observational studies and a meta-analysis suggesting a smaller decline in the group of patients with moderate bronchial obstruction. Randomized studies did not find a significant difference in the FEV1 decline rate between the treatment group and the placebo group. In relation to other indicators studied such as mortality, the American Registry67 has revealed a reduction in the group of treated patients with FEV1 <50% while the study led by Tonelli141 did not show any differences between the two groups.

Taking into account all these data, the Portuguese study group of AATD reached an agreement to recommend AAT augmentation therapy be provided to all patients with FEV1 between 30-70% of predicted value or, if higher, in the case of a rapid decline. Concerning treatment of liver disease, the augmentation therapy is only indicated in subjects with concomitant pulmonary involvement. In other cases only preventive measures are available (vaccination anti-A and B hepatitis, elimination of alcohol and other hepatotoxic agents).153 Still, AAT augmentation therapy may be indicated for the treatment of necrotising panniculitis due to its efficacy in some clinical cases and in the prevention or control of skin lesions related to this disease.154,155

Selective immunoglobulin A (IgA) deficiency is a contraindication to treatment as augmentation therapy may contain small amounts of IgA. Hypersensitive or anaphylactic reactions with anti-IgA antibodies may occur in these patients, therefore, testing for this deficiency is recommended before initiating therapy.156

Lung volume reduction surgery in patients with severe pulmonary emphysema has shown modest results in terms of survival and functional capacity in patients with emphysema with upper lobe predominance; experience with patients with AATD is limited but there seems to be a tendency to greater mortality within this subgroup.157 Lung volume reduction by placing endobronchial valves is an experimental intervention in patients with severe emphysema and AATD was an exclusion criterion in the biggest randomized study published.158,159

Pulmonary transplantation is reserved for patients with no other choice of therapy and the Portuguese group is following the current international recommendations. AATD is an indication for transplantation in about 5.8% of cases. Patients with no contraindications and a BODE index>5 may be referred to a pre-transplant consultation. Indications for combined liver and lung transplantation are rare but may be considered when there is documented cirrhosis in biopsy and a portal gradient> 10mmHg160,161. There is no evidence for recommending augmentation therapy after pulmonary transplantation; although some authors recommend considering it in case of infection or acute rejection. In selected cases with accelerated functional deterioration one might consider restarting augmentation therapy and maintaining it based on results.152,156