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Abstract

Severe alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of emphysema. However, the clinical manifestations are very heterogeneous, and an individual prognosis is very difficult to establish. Intravenous augmentation therapy with alpha-1 antitrypsin (AAT) from pooled blood donors is the only specific treatment available, but it requires weekly or biweekly administration for life. Several guidelines provide the indication criteria for the initiation of AAT augmentation therapy. However, in clinical practice, there are situations in which the decision as to when to start treatment becomes uncertain and some studies have shown great variability in the indication of this treatment even among specialists. The usual dilemma is between initiating augmentation therapy in individuals who may not develop significant lung disease or in whom disease will not progress or delaying it in patients who may otherwise rapidly and irreversibly progress. We illustrate this dilemma with five clinical cases: from the case of a patient with normal lung function who requests initiation of therapy to a moderately stable patient without augmentation or a mild patient who, after several years of remaining stable without treatment, deterioration in lung function initiated and, consequently, augmentation therapy was begun. All the nuances associated with the indication of augmentation justify a personalised approach and the decision about initiating augmentation therapy must be made after careful consideration of the pros and cons with the patient in reference centres with experience in treatment. These reference centres can work in collaboration with local hospitals where patients can be closely followed and augmentation therapy can be administered to avoid unnecessary travelling, making periodical administrations more comfortable for the patient.

Keywords

Alpha-1 antitrypsin deficiency case report guidelines treatment

Introduction

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder caused by mutations in the SERPINA1 gene.^1,2 The most frequent mutation causing severe deficiency is known as the Z mutation. This mutation produces an AAT protein that polymerises in the liver and is not effectively secreted from the hepatocytes, which may lead to chronic liver disease.³ The polymerisation and accumulation in the liver generate a severe deficiency of circulating AAT that is not able to provide enough protection to the lungs against free neutrophil elastase and increases the risk of developing pulmonary emphysema, particularly in smokers.^1,2 The typical presentation of lung disease is in the form of panacinar emphysema starting in the fourth or fifth decade of life; however, the clinical expression of lung disease is very variable and may include from asymptomatic disease to different phenotypes of chronic obstructive pulmonary disease (COPD), asthma with chronic airflow limitation and bronchiectasis.⁴ This heterogeneity makes it important to test all adults with COPD for the deficiency, since early diagnosis allows a change in habits, particularly quitting smoking, pharmacologic and non-pharmacologic treatment, and specific augmentation therapy with intravenous alpha-1 antitrypsin (AAT) in patients in whom it is indicated.²

In the late 1980s, augmentation therapy was approved by the US Food and Drug Administration based on the demonstration of its biochemical efficacy in restoring anti-elastase activity in serum and bronchoalveolar lavage fluid. To demonstrate its clinical efficacy, the US National Heart, Lung, and Blood Institute designed a prospective registry that followed 1129 patients on and off treatment for 5 years. This registry demonstrated a significant reduction in the rate of decline in forced expiratory volume in 1 second (FEV₁) only in patients receiving augmentation with a baseline FEV₁ between 35% and 49% predicted.⁵ Later, randomised, placebo-controlled, clinical trials have demonstrated the capacity of augmentation to significantly slow the progression of emphysema with an overall magnitude of the effect of 0.74 g/L year versus placebo and with an excellent safety profile,⁶ and large observational studies have shown a significant improvement in survival in treated versus untreated patients.^6,7 However, the lack of demonstrated efficacy of augmentation therapy on the usual outcomes considered for smoking-related emphysema, such as exacerbations, respiratory symptoms and quality of life, together with the large heterogeneity of clinical manifestations and prognosis of patients with AATD,^8–11 make the indication of augmentation therapy challenging. As an example, it has been observed that non-index cases (i.e. those diagnosed by family or population screening) without augmentation therapy have the same survival as the general population.¹² Considering these factors, it is not surprising that healthcare providers often have different opinions about whom and when to initiate augmentation therapy.^13,14

In everyday clinical practice, the decision dilemma is between initiating augmentation therapy in individuals who may not develop significant lung disease or in whom disease will not progress or delaying it in patients who may otherwise rapidly and irreversibly progress. In the following cases from our clinics, we will illustrate different aspects of this dilemma. All the cases have been diagnosed with severe AATD, genotype homozygous PI★ZZ and with serum AAT values between 20 and 30 mg/dL.

The reporting of this study conforms to the CARE guidelines.¹⁵

Case 1. Asymptomatic, non-index case

This patient is a 45-year-old asymptomatic female, who smoked 8 pack-years until the age of 37. She was diagnosed with severe AATD by family screening. Her lung function showed an FEV₁ of 3.1 L (118%), FEV₁/forced vital capacity (FVC) of 0.84 and a carbon monoxide coefficient factor (KCO) of 85%. The thorax computed tomography (CT) scan was normal.

She obtained information about the disease from her respiratory specialist and through the internet and requested a visit to our reference centre to initiate augmentation therapy to prevent further deterioration of lung function.

Augmentation therapy was not recommended, but the patient was advised against resuming smoking and warned about inhalation of second-hand smoke or other sources of inhaled toxins, and yearly appointments including spirometry, and measurement of KCO were arranged. In addition, the patient was visited by a liver specialist to rule out significant liver disease.¹⁶ Other diagnostic tests, such as blood arterial gases, 6-min walking test or thorax CT scan, should only be performed in cases in which they are clinically indicated and should not routinely be performed in individuals with otherwise normal lungs.

This case is a clear illustration of the main dilemma with augmentation therapy: to start as early as possible to prevent deterioration or to wait until some signs of deterioration appear. National and international guidelines on the treatment of AATD recommend augmentation therapy only in individuals with lung disease, but not in those with normal lungs^2,17–21 (Table 1). Furthermore, epidemiological studies have shown that the prognosis of non-index cases may be the same as that of the general population.

Table 1.

Variables considered in the prescription of augmentation therapy in clinical practice are divided by those included in guidelines/statements and those not included.

Variables included in guidelines/statements	Criteria	Comments
AAT deficiency	AAT serum levels below 11 mM (or 50 mg/dL or 57 mg/dL)
Deficient phenotype/genotype	Genotype PIZZ, PISZ or other deficient or null variants
Age	Indicated in patients older than 18 years	No mention of age as a possible indicator of the evolution of the disease
Smoking	Never or former smokers	No discrimination by the time since quitting or the accumulated smoking consumption
Airflow obstruction	Presence of airflow obstruction (FEV₁/FVC < 0.7)	No discrimination by the severity of airflow obstruction (FEV₁ value), combined with age and smoking
IgA deficiency	Rule out IgA deficiency
Not included in guidelines/statements
CT scan		No guidance in cases of emphysema and normal lung function. No indication of bronchiectasis.
Diffusion capacity		No clear indication of reduced DLCO and normal spirometry
Exacerbations		No mention of exacerbations for the indication of therapy
Respiratory symptoms		No mention of symptoms (dyspnoea) in the indication of therapy

AAT, alpha-1 antitrypsin; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity.

Case 2. Symptomatic, stable COPD patient without augmentation

A 61-year-old male who complained of exertional dyspnoea was visited in 2007. He had smoked up to 24 pack-years until the age of 44 and his lung function showed a FEV₁ of 1.8 L (54%), FEV₁/FVC = 0.36 and a KCO of 64%. The CT scan showed multiple areas of panacinar and centrilobular emphysema. This patient fulfilled all the criteria for augmentation therapy and was invited to initiate therapy but refused. The pharmacological and non-pharmacological treatment for his lung disease was optimised and 4 years later his spirometry was stable, but with a KCO of 46%; however, 1 year later, the KCO was 69%. The patient was followed annually for 17 years and in 2024, at 79 years of age, he presented the following values: FEV₁ of 1.45 L (56%), FEV₁/FVC of 0.42 and KCO of 52%. Figure 1 shows the evolution of the patient’s lung function values.

Figure 1.

Evolution of FEV₁ (%) and KCO (%) in a patient with symptomatic COPD and severe AATD not on augmentation (case 2).

When the patient first came to the clinic, he fulfilled all the criteria for augmentation therapy (Table 1) and was invited to initiate treatment. However, the patient refused treatment due to the distance he lived from the hospital, and at that time, there was no option to receive home treatment or self-administration.^22,23 He started follow-up visits every 6 months with yearly lung function tests and a significant drop in KCO(%) was observed in the first year, not associated with any impairment in FEV₁ (%) or symptoms and with no history of exacerbations. In the next follow-up assessment, the KCO (%) returned to the baseline levels and remained at similar levels over 17 years of follow-up, similar to the FEV₁ (%).

This case illustrates several aspects: (A) the difficulties in establishing an individual prognosis while also suggesting that most of the lung damage had already occurred before diagnosis, before being aware of the importance of preventative measures and before initiating adequate treatment. (B) Only two measurements of either FEV₁ or KCO 1 year apart may not be enough to identify rapid decliners. Several studies on AATD and smoking-associated COPD have demonstrated that at least 3 years is needed to reliably identify rapid decliners.^24,25 (C) It is possible to stop the progression of the respiratory disease in some patients with AATD providing they avoid exposures, receive adequate treatment and do not have other risk factors, such as coexistent asthma or bronchiectasis or a history of frequent exacerbations or pneumonia. However, it is not possible to predict the individual risk of a patient with emphysema due to AATD and the decision about initiating augmentation therapy must be made after careful consideration of the pros and cons with the patient.^14,26

Case 3. Young, severe and symptomatic COPD patient on augmentation therapy

A 42-year-old female patient complained of dyspnoea and exacerbations. She had smoked 12 pack-years until 3 years previously. Her lung function showed FEV₁ of 1.6 L (58%), FEV₁/FVC of 0.51 and KCO of 53%. She had presented two ambulatory exacerbations the previous year. She initiated augmentation therapy and after 3 years her lung function was stable and without exacerbations.

This patient also fulfilled all the criteria for augmentation therapy and accepted the treatment. Augmentation was strongly recommended because, despite being only 42 years of age and having smoked 12 pack-years until 3 years previously, her FEV₁ (%) and KCO (%) were approaching 50% predicted. This suggested that she was particularly susceptible to lung damage by smoking or other factors and that her remaining lung function should be preserved as much as possible. It is impossible to rule out that her emphysema might not progress after quitting smoking and initiating appropriate COPD treatment, but the risk of delaying the initiation of augmentation therapy, in this case, outweighed the possible benefits of a more conservative approach.

Case 4. Very severe COPD patient stable on augmentation therapy

A 46-year-old male patient, a former smoker of 24 pack-years was referred for evaluation of lung transplantation in 1994. His FEV₁ was 0.7 L (21%), FEV₁/FVC of 0.38 and KCO of 41% and during assessment as a possible candidate for lung transplant he was diagnosed with AATD and referred to our clinic. After a discussion with the patient, he decided to postpone his inclusion on the transplant waiting list and initiated augmentation therapy. In 2006, after 12 years of augmentation, his FEV₁ (%) was 15%, and in 2013 his last spirometry available after 19 years of augmentation therapy showed an FEV₁ (%) of 14%. He died in 2016 from decompensated liver failure after 22 years of augmentation therapy.

This case illustrates the problem of late diagnosis of AATD. Although it happened in the 1990s, some studies suggest that AATD is still a highly undiagnosed disease.^27–29 This patient was diagnosed during a routine assessment for evaluation for a lung transplant, and when he was informed about the option of initiating augmentation therapy, he decided to start this therapy and postpone his inclusion on the transplant waiting list. Due to the stability of lung function impairment and the preserved quality of life on augmentation, he decided to no longer consider lung transplantation and survived for 22 years after the first evaluation for transplant. It is true that lung transplant significantly improves the quality of life in most cases, but it is unclear whether it improves survival in patients with AATD.^30,31 On the other hand, different observational studies have described improved survival with augmentation therapy.^6,7,32 This evidence must be considered for an informed discussion about the therapeutic options in patients with AATD and severe emphysema. In particular, they strongly suggest that augmentation should not be denied or discontinued in patients with very severe airflow obstruction.¹⁴

Case 5. Delayed augmentation in a stable COPD patient

A 70-year-old female, never a smoker, the patient was attended for symptomatic bronchiectasis. In 2011, at the age of 58, she was diagnosed in another centre with bronchiectasis due to recurrent episodes of purulent bronchitis, and severe AATD (PI*ZZ) was found. Her FEV₁ was 2.4 L (84%), FEV₁/FVC of 0.79 and KCO of 76%. The CT scan showed bilateral cylindrical bronchiectasis without evidence of significant emphysema. The patient has been followed annually in our centre since 2016 and the evolution of lung function is shown in Figure 2. The patient presented COVID-19 infection without hospital admission in 2021 followed by two bacterial exacerbations. No lung function test was available in 2020 and 2021 due to COVID-19 preventative measures. A significant decline in FEV₁ was observed in 2022 and was confirmed in subsequent measurements. A new CT scan showed bilateral bronchiectasis with mucus plugging and some mild centrilobular and panacinar emphysema. The patient was invited to initiate augmentation therapy and she accepted.

Figure 2.

Evolution of FEV₁ (%) and KCO (%) in a patient with bronchiectasis and severe AATD (case 5).

In this case, due to the lack of emphysema or airflow limitation at the first visit to our centre, together with the preserved quality of life and the lack of risk factors, and the reluctance of the patient to attend the day hospital for weekly or biweekly treatments, we decided not to initiate augmentation therapy at the first consultation and organise twice yearly follow-up visits with the annual evaluation of lung function. After 11 years of functional and clinical stability, the lung function started to deteriorate coincident with an episode of COVID-19 infection and a series of moderate bacterial exacerbations. Furthermore, CT scans showed initial lesions of pulmonary emphysema in addition to her bronchiectasis. At this stage, it was therefore decided to start augmentation therapy. With this strategy, the patient has been free from the commitment of weekly intravenous treatments for 11 years without significant clinical and functional impairment, and thanks to close follow-up, augmentation therapy was initiated as soon as some deterioration was confirmed. As shown in case 2, just one follow-up is not enough to identify a significant decline in either FEV₁ or KCO.^24,25

Discussion

The cases presented illustrate the heterogeneity of the clinical manifestations of individuals with AATD (Table 2). The large series of individuals affected with this disease consistently describe a mean age at diagnosis of between 40 and 50 years of age, but the standard deviation is huge, indicating that there is great variability in the presentation of lung disease,^4,6,33 with some individuals being severely affected at a young age, while others may have preserved lungs until very advanced age.^9–11 This heterogeneity makes it very difficult to establish an individual prognosis and, therefore, the indication of augmentation therapy,²⁶ a treatment that is costly and requires weekly intravenous administration of AAT for life.

Table 2.

Summary of clinical and functional characteristics of the five cases presented.

Variables	Case 1	Case 2	Case 3	Case 4	Case 5
	Asymptomatic, non-index case	Symptomatic, stable COPD without AT	Severe and symptomatic COPD on AT	Very severe COPD, stable on AT	Delayed initiation of AT
Age (years)	45	61	42	46	70
Sex	Female	Male	Female	Male	Female
Pack-years	8	24	12	24	Never smoker
AAT (mg/dl)	21	30	23.3	26	20.6
FEV₁ (%) at referral	118	54	58	21	84
KCO (%) at referral	85	64	53	41	76
CT scan	Normal	Emphysema	Emphysema	Emphysema	Bronchiectasis. Emphysema during FU
Exacerbations	None	None	Yes	None	Yes (during FU)
Augmentation therapy	No	Refused	Yes	Yes	Yes (delayed)
Challenge	Initiate treatment with healthy lungs	Identify individual prognosis/rapid decliners	Identify individual prognosis/rapid decliners	Obtain an early diagnosis and do not discontinue AT in very severe patients	Decision about initiating AT during FU
Comments	Guidelines recommend AT only in subjects with lung disease	Individual risk for a patient with emphysema is not yet predictable	Risk of delaying AT in a young patient with severe lung disease should be avoided	AT improves survival	Close follow-up allows AT initiation if (and when) deterioration occurs

FEV₁ and KCO are expressed in % predicted.

AAT, alpha-1 antitrypsin; AT, augmentation therapy; CT, computed tomography; DLCO, Diffusing capacity for carbon monoxide; FEV₁, forced expiratory volume in one second; FU, follow-up; FVC, forced vital capacity.

The indication of augmentation therapy is clearly established in national and international guidelines^2,17–21 and can be summarised as the presence of emphysema in an adult, non-current smoker, with severe AATD (AAT serum levels below 56 mg/dL; Table 1). However, the use of this therapy in clinical practice varies greatly and is often implemented outside the approved indications.³⁴ A recent survey amongst specialists in AATD demonstrated a low level of concordance in the indication of augmentation when confronted with hypothetical clinical cases.¹³ This situation underscores the importance of reference centres for the indication of treatment and follow-up of patients with AATD. These centres can accumulate experience with treatment and are prepared to make an informed decision about the initiation of augmentation therapy together with the patient.³⁵ They can also work in collaboration with local hospitals where patients can be closely followed and where augmentation therapy can be administered to avoid unnecessary travelling, making periodical administrations more comfortable for the patient.

Furthermore, there are disparities in access to augmentation therapy. For instance, augmentation is not reimbursed in some European countries, such as Sweden or the United Kingdom, among others, and this represents an important barrier to equity in access to therapy across Europe.²

The Vall d’Hebron University Hospital in Barcelona was the first to administer augmentation therapy in Spain in 1988 and since then it has become an established reference centre for AATD in the country.³⁶ It was instrumental in the creation and development of the Spanish registry of AATD,³⁷ the Alpha-1 antitrypsin deficiency International Registry (A.I.R.),³⁸ and more recently the EARCO (European Alpha-1 antitrypsin deficiency Research Collaboration) International Registry.³³ This reference centre has accumulated experience in augmentation therapy over the last 35 years, which has been summarised in the five cases selected here to illustrate frequent situations that healthcare providers may face when deciding the initiation of this treatment in patients with AATD.

The five cases presented here were AATD Pi★ZZ patients. Other genotypes such as Pi★SZ and nulls might also be considered for augmentation therapy. The implications of treatment for other deficient genotypes have been described in previous publications.^14,35,39,40 The first case illustrates the demand for augmentation therapy of a non-index case patient who was asymptomatic and with normal lung function. It is clear that the objective of augmentation therapy is the preservation of lung tissue and lung function and, from this perspective, the earlier the initiation of therapy the better.⁵ However, it is also true that some non-index individuals with the deficiency will not develop significant lung disease,^9–11 and the survival of these subjects is no different from that of the general population¹² and the approved indication of augmentation therapy requires the demonstration of some degree of lung disease.^2,17–21 In conclusion, augmentation was not initiated in this individual, but regular annual follow-up visits were scheduled.

The second case is an example of a patient who fulfilled all the criteria for augmentation therapy, but treatment was not initiated and the lung disease remained stable over 17 years without augmentation therapy. Two important observations can be made from this case; the first is that most lung damage is produced before diagnosis, when patients are unaware of their condition and do not adopt any preventative measure, such as quitting smoking, avoiding other exposures or adequately managing their lung disease; and the second is that, in some cases, these preventative measures and optimal pharmacological and non-pharmacological treatment for COPD may be enough to stop the progression of emphysema, at least for some years. This observation implies that in subjects of advanced age with moderate severity of lung disease and good ventilatory reserve it may be justified to delay the indication of augmentation therapy, always after careful discussion about the pros and cons with the patient, as in the case of patient two, who declined the treatment, and patient five, in whom we recommended not to treat due to the absence of chronic airflow limitation and the absence of significant emphysema in the chest CT scan.

On the contrary, we strongly recommended the initiation of augmentation therapy as soon as possible for patients three and four because, despite their relatively young age, they had clearly non-reversible airflow obstruction with a significant reduction in diffusion capacity and important emphysema on CT scans. Although it may have been possible to stabilise their lung disease without augmentation therapy, the risk of further irreversible loss of lung tissue was too great to justify this conservative approach. The evolution of case four was remarkable. This patient had very poor lung function at presentation to our clinic, making him a candidate for lung transplantation, but he survived for 22 years on augmentation therapy without transplantation and with a reasonable quality of life until the very last years. This case is in agreement with the results of the observational studies showing improved survival of patients on augmentation therapy,^7,32 and also illustrates the benefits of augmentation therapy in very severe patients (i.e. those with an FEV₁ (%) <30%.³² It is of note that there is currently no lower limit of FEV₁ (%) to start augmentation therapy, either in guidelines or in the summaries of product characteristics of the existing products.^2,17–21

Finally, the importance of regular follow-ups in reference centres, both for treated and untreated patients, is illustrated in case 5. This patient did not initiate treatment in the first visits because she had bronchiectasis without signs of emphysema⁴¹ or airflow limitation and, consequently, did not fulfil the criteria for augmentation therapy. However, after 11 years of follow-up, it was decided to initiate treatment after a decline in lung function was observed in more than one consecutive spirometry, and some initial lesions of emphysema appeared in the CT scan after several episodes of exacerbation and COVID-19 infection.⁴² A similar evolution was reported by Wencker et al.⁴³ in a case with an accelerated rate of decline in a patient with severe AATD as a consequence of repeated severe exacerbations. It could have been argued that this impairment could have been prevented if the patient had initiated augmentation therapy at the initial visit, but this would have represented weekly intravenous infusions for 11 years for limited benefits since the patient is now 70 years of age and, despite this mild impairment, still has a well-preserved lung function and good exercise capacity and quality of life. Furthermore, the decline in lung function associated with exacerbations in the case by Wencker et al.⁴³ occurred while the patient was on augmentation therapy, suggesting that in some individuals the current dosage of augmentation may be insufficient.⁴⁴ This case again exemplifies the trade-off between the risk of delayed initiation of augmentation therapy and indiscriminate initiation of this therapy at the first visit in all patients with AATD and some degree of pulmonary involvement.²⁷

Conclusions

The great heterogeneity in the clinical presentation and prognosis of lung disease in severe AATD patients makes it difficult to decide when to start augmentation therapy. As indicated in guidelines and by the European Council, these patients must be followed in reference centres at a regional level or national level. Nevertheless, at present, the main challenge is to remind healthcare providers that AATD is not so rare and that early diagnosis is key for implementing preventative measures when they will be more effective.

Footnotes

Acknowledgements

Cristina Aljama is a recipient of a SEPAR (Spanish Society of Pneumology and Thoracic Surgery) 2023-2024 Research Fellowship.

Declarations

ORCID iD

Marc Miravitlles

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Personalised indication of augmentation therapy for emphysema associated with severe alpha-1 antitrypsin deficiency: a case series

Abstract

Keywords

Introduction

Case 1. Asymptomatic, non-index case

Case 2. Symptomatic, stable COPD patient without augmentation

Case 3. Young, severe and symptomatic COPD patient on augmentation therapy

Case 4. Very severe COPD patient stable on augmentation therapy

Case 5. Delayed augmentation in a stable COPD patient

Discussion

Conclusions

Footnotes

Acknowledgements

Declarations

ORCID iD

References