Menu
Back to Journals » Patient Related Outcome Measures » Volume 16
Is It Time Alpha-1 Antitrypsin Deficiency Had a Specific Patient Reported Outcome Measure? A Review
Authors De Soyza J , Chien HY, Onasanya AA, Turner AM
Received 9 August 2024
Accepted for publication 5 January 2025
Published 15 January 2025 Volume 2025:16 Pages 23—35
DOI https://doi.org/10.2147/PROM.S490849
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Lynne Nemeth
Joshua De Soyza, Hung-Yeh Chien, Adeola Ayodotun Onasanya, Alice M Turner
Institute of Applied Health Sciences, University of Birmingham, Birmingham, UK
Correspondence: Joshua De Soyza, Email [email protected]
Abstract: Alpha-1 antitrypsin deficiency (AATD) is a rare cause of chronic lung and liver disease without its own patient reported-outcome measure (PROM). PROMs for Chronic Obstructive Pulmonary Disease (COPD) are commonly used instead, but AATD differs from COPD in several ways. We reviewed whether the PROMs used in the AATD literature adequately assess quality-of-life in these patients. 11 studies used PROMs as their primary outcomes; 21 included them as secondary outcomes. The St George’s Respiratory Questionnaire (SGRQ) was the most commonly used PROM, used by 7 of the 11 primary outcome studies. Others included the COPD Assessment Tool, SF-36, LCOPD, EQ-5D, and the Chronic Respiratory Diseases Questionnaire. Several studies assessed SGRQ as being associated with respiratory disease severity as measured by FEV1% predicted, exacerbation rate, oxygen use and exercise tolerance. However, no studies used PROMs which included assessment of liver-related symptoms, other extra-pulmonary manifestations of AATD, or concerns related to genetics or finances. These factors are likely to have an impact on quality of life in AATD. A specific AATD-PROM is therefore required to holistically address the quality of life effects of an AATD diagnosis.
Keywords: alpha-1 antitrypsin deficiency, COPD, chronic liver disease, rare diseases
Introduction
Alpha-1 Antitrypsin Deficiency (AATD) is a genetic disorder characterized by low circulating levels of alpha-1 antitrypsin (AAT), a protease inhibitor. Circulating AAT levels are dependent on a combination of SERPINA1 alleles, which exist in the community in M (normal variant), S and Z forms, along with some rarer variants, with ZZ having the lowest circulating AAT levels of the most common phenotypes.1 AATD is a rare disease, with the ZZ phenotype affecting approximately 250,000 people worldwide, mostly of north and/or western European ancestry.2 With unopposed protease activity, particularly of neutrophil elastase, pulmonary tissue damage occurs, manifesting as Chronic Obstructive Pulmonary Disease (COPD) and bronchiectasis. Extra-pulmonary effects also occur; polymerisation of misshapen AAT occurs in the liver, leading to hepatocellular death due to protein overload. This causes clinically significant chronic liver disease in a minority of patients.3 Rarer manifestations have also been reported, including panniculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis.4,5
Quality of life is known to be impaired in those with AATD across a range of genotypes, particularly with regard to physical activity.6 Uncertainty about the future regarding disease progression and outcomes can result in anxiety and low mood;7,8 such uncertainty may be felt more intensely in countries where disease-modifying treatment is not licensed. Consequently, it is important to assess the quality of life when reviewing AATD patients.
In many other chronic diseases, patient-reported outcome measures (PROMs) have become a key tool in monitoring quality of life both clinically, and increasingly in research. They exist as an acknowledgement of the discrepancy between physicians’ assessment of objective markers of disease severity, and patients’ own impression of the disease’s impact on them. Such a discrepancy is seen both in medicine in general, and in COPD.9,10 Therefore, in AATD it is also possible that subjective symptoms may not fully correlate with objective markers of disease severity.
Despite their importance in chronic disease management, no dedicated AATD patient-reported outcome measure (PROM) exists. This has two main reasons: firstly, since it is implicated in less than 2% of COPD,11 AATD is only infrequently encountered in general respiratory clinics, reducing demand for development of a specific PROM – consequently tools such as the COPD assessment tool (CAT),12 St George’s Respiratory Questionnaire (SGRQ),13 and the less specific EQ-5D-5L score14 have been used.15–17 Secondly, in many countries including the UK, AATD-COPD treatment does not differ from treatment for other types of COPD, since specialist treatments such as exogenous replacement (AAT augmentation therapy) are not available. This leads to a perception among those unfamiliar with the disease that AATD is simply a genetic cause of COPD; however, this is likely to be an oversimplification, since AATD differs from usual COPD in a multitude of ways (Table 1), as follows.
 |
Table 1 Major Differences Between AATD and COPD: AATD is Not Simply a Genetic Cause of COPD |
Objectively, emphysema in AATD appears different to usual COPD, with a lower lobe predominance compared to a more widespread distribution in smoking-related lung disease.18,19 Asthma-like features are less prevalent.20,21 Patients are younger and less likely to be smokers, with lower rates of cardiac co-morbidities.22,23 Exacerbations last longer in AATD-COPD than in usual COPD.24,25 Concomitant liver disease affects a significant minority of patients, and can be independent of lung disease,3 meaning those without significant emphysema or breathlessness may still require monitoring and treatment.
Furthermore, on a psychosocial level, the earlier age of diagnosis in AATD is likely to bring different considerations, such as impact on careers, physical activity, and family planning.26,27 Anxiety related to the hereditary nature of the disease is a burden not shared by usual COPD patients.28 In those who wish to fund AAT augmentation privately, financial matters will be a concern. AATD specialist services are few and far between, requiring long journeys to attend clinics for some patients; those who cannot commit to such travel may be anxious about the quality of their disease management, however comprehensive their local team may be.29 Given these distinct differences between AATD and usual-COPD, it is reasonable to suggest the need for the development of AATD-specific PROMs for monitoring purposes. This article reviews the use of PROMs in AATD research, and assesses the need for a specific AATD PROM.
Methods
To assess the range of PROMs currently in use in AATD, databases were searched for peer-reviewed articles mentioning alpha-1 antitrypsin deficiency and quality of life scores or patient reported outcome measures. The search strategy included all permutations of “alpha-1 antitrypsin deficiency”, and “quality of life” or “patient reported outcomes”. PubMed, Embase, and Cochrane databases were searched in April 2024.
Results were limited to peer-reviewed published research articles of adult patients. Review articles were excluded. Studies with the primary aim of exploring the quality of life of patients with AATD, with or without comparison among genotypes, or to control groups, were included and reviewed. Studies exploring patients’ changes in quality of life as secondary outcomes following clinical interventions, or observational studies for other exposures, were reviewed only to assess the popularity of different PROMs selected for these purposes. We then performed a narrative synthesis according to published guidance.30 The initial theory was that existing questionnaires would not adequately assess quality of life in AATD. Studies were grouped by type of PROM used, and by whether quality-of-life was a primary or secondary outcome of the work, and compared with each other within these groups.
Results
A total of 31 studies were found. 11 studies explored the quality of life of patients with AATD as their primary aim. 20 studies explored patients’ changes in quality of life as secondary outcomes. A total of 11 PROMs were reported in these studies and the St George Respiratory Questionnaire (SGRQ) was the most commonly used PROM. Studies included in the review are summarised in Tables 2 and 3. An overview of the PROMs found is highlighted below.
 |
Table 2 Research Studies of Quality of Life in AATD |
St George Respiratory Questionnaire (SGRQ)
The SGRQ is by far the most commonly used PROM in the available literature. It has 2 sections: the first consists of questions about the last 3 months, with the patient asked to report the frequency and duration of cough, phlegm, shortness of breath, wheezing, and exacerbations. The second section asks about the impact of the respiratory disorder and treatment on work and day-to-day living. Elevated scores have been associated with more severe lung function baseline measurements and decline, and higher exacerbation rate. The maximum score is 100: a difference of 4 points or more is considered clinically significant, except in severe COPD, where this threshold may be higher.40,41
SGRQ has been used in the study of QoL in AATD. In 2013, Holm et al8 found that AATD patients had higher SGRQ scores than non-AATD COPD patients, by 4.75 points on average, using multivariate regression analysis which accounted for age, smoking history, and oxygen use, and limited the AATD to those with a “severely deficient” genotype. Scores were also higher in those with shorter education duration, and uncoupled persons. However, since this study used a pre-existing cohort, results could not be adjusted for severity of COPD, as spirometry data was not available. When adjusting for COPD severity, Karl et al’s 2017 study found no significant differences in SGRQ between 131 AATD-COPD patients and 2049 usual-COPD patients.
In the Italian registry, Luisetti et al33 found higher SGRQ scores in index cases (the first case in a family) (mean 41.2, SD 24.4) vs non-index cases (mean 6.2, SD 8.3), but this was not adjusted for the presumed lower age of non-index cases, who will have been identified from family screening processes.
Gauvain et al34 summarised health-related QoL in the patients with COPD in their French AATD registry, and found SGRQ score was associated with shortness of breath, 6-minute walking distance, FEV1 and gas transfer, but not with age or current smoking. Stockley et al36 went into temporal detail, and found that SGRQ score was relatively stable over time, was greater for patients with COPD than those without, and correlated with FEV1 decline. Choate et al in 2024 also studied SGRQ score over time, and found long-term stability of SGRQ score, as well as an association between SGRQ decline and exacerbation frequency and use of oxygen.39 Like Holm et al, their study also used the AlphaNet cohort, a health management organization for United States patients with AATD who are prescribed augmentation therapy,42 and therefore could not be adjusted for COPD severity. However, due to its stability over time, both Stockley et al and Choate et al concluded that SGRQ score is not a suitable choice for a primary outcome measure in AATD research trials.
Werdecker and Bals in 2023 demonstrated a positive correlation between SGRQ score and negative emotions, stress, and deterioration of health status following the Covid-19 pandemic, although they reduced health status to a binary outcome of “unchanged” or “worsened” based on an unpublished questionnaire.37 They also found that SGRQ mediated the relationship between FEV1 and stress, although stress had also been reduced to a binary outcome of “yes” or “no”, and is itself a subjective term.
Many studies have used SGRQ score as a secondary outcome in observational studies, or interventional trials. Overall, these studies would suggest that SGRQ is a useful tool in assessment of QoL in AATD, showing significant results in various trials including augmentation, endobronchial valves and coils (Table 3), with the notable exception of 2 studies of augmentation therapy: Dirksen et al in 200943 and Chapman et al in 2015,44 who both found no significant differences in SGRQ scores between intervention and control groups; however both these studies had relatively small numbers (65 and 180 individuals respectively). By contrast, Ellis et al’s 2023 case-control study of AAT augmentation included 541 patients, and did find reduced SGRQ score decline in those who had received AAT augmentation.45
 |
Table 3 Choice of PROMs as Secondary Outcome Measures in AATD Research |
COPD Assessment Tool
This questionnaire uses Likert scales to assess various chest-related and functional symptoms.12 It is much shorter than the SGRQ and SF-36, and therefore easier to perform in clinic, but contains less functional assessment than longer questionnaires.
Manca et al assessed CAT score in their study of 2014,32 but found it did not associate with FEV1% predicted, despite the COPD Severity Score, EQ-5D and LCOPD score (Table 4) both having significant associations with this outcome measure. Karl et al also used CAT score in their article analysing healthcare-related costs, but only to compare AATD patients against COPD patients, finding no significant difference in CAT, SGRQ or EQ-5D between the 2 groups.17
 |
Table 4 Patient Reported Outcome Measures Used in AATD |
Sf-36
A less commonly used measure of quality of life in AATD has been the SF-36 score. Unlike the SGRQ, the SF-36 is not focused only on chest symptoms, aiming to be holistic by assessing the following 9 domains: physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy and fatigue, emotional well-being, social functioning, pain, general health, and change in health.86
The SF-36 has been used to study quality-of-life in AATD. In a cross-sectional study of 26 patients in 2017, Redondo et al35 found several aspects of SF-36 score to correlate with disease outcomes, including the “physical health” domain with FEV1 and mMRC score, the “role limitation due to physical health” domain with mMRC score, and the “bodily pain” domain with 6 minute walk test. However, they did not analyse the total SF-36 score in comparison to outcomes. If only some domains associate with disease outcomes, rather than the total score, its use by clinicians less familiar with the score may be limited.
Choate et al assessed the use of the SF-36 score in the AlphaNet cohort, and found both the mental health components and the physical health components to be associated with MRC shortness of breath score and exacerbation rate.38
Other PROMs
Other COPD PROMs used by AATD studies included the Chronic Respiratory Disease Questionnaire, the COPD severity score (COPD-SS) and the LCOPD score. Generic or mental health PROMs used included the EQ-5D and HADS scores. These other PROMs are summarised in Table 4.
PROMs in AATD Liver Disease
Although articles focused on quality of life in AATD liver disease were not excluded from the search criteria, no such articles were identified. This may be because liver disease in alpha-1 antitrypsin deficiency is less common than lung disease, only affecting 10–35% of those with the most severe PiZZ genotype,87,88 and highlights this under-researched area.
PROMs as Secondary Outcomes in AATD Research
A variety of studies have used PROMs as secondary outcomes in AATD research. SGRQ is again the most common, with 18 of the 20 articles (85.7%) identified using this PROM. Three of these also used another PROM: two used the SF-36 score, one used the CAT score. Two further papers opted not to use the SGRQ: Hogarth et al in 202415 used the CAT and SF-36 scores; and McGrady et al57 used a bespoke scoring system.
Discussion
Currently, the vast majority of research uses COPD-specific PROMs to assess the impact of lung disease in AATD. The strengths of this approach are that they are generally well validated for patients with COPD, in both stable and exacerbating patients. They are generally widely used, and easy to complete. They have also been widely translated and validated in these translations, making them more accessible to different patient populations. There is evidence that they correlate well with the progression of emphysema clinically, which is a key marker of AATD disease progression.55 Although the validity of SGRQ for COPD assessment has been doubted,65 several studies reviewed here have shown that, in alpha-1 antitrypsin deficiency, SGRQ score correlates with FEV1% predicted, exacerbation rate, oxygen requirement, MRC breathlessness score, gas transfer impairment, 6-minute walk test score, phlegm production, and stress levels, suggesting it is a valid way of assessing COPD severity in AATD.
Much of the research into PROMs in AATD relies on pre-existing cohorts, particularly the AlphaNet cohort, which features in many of the studies reviewed here. The use of such cohorts provides numerous practical advantages, but will naturally select the most motivated patients, who may have been exposed to a high level of information in conferences, awareness days and other research, meaning they may not be representative of all AATD patients. AlphaNet participants also tend to be on augmentation. Studies which rely on responding to questionnaires sent by post risk exclusion of the sickest patients who cannot get out to post items, and those which use digital means of data collection risk other exclusions (eg by age or socio-economic status).
Overall, the studies in this review appear to support the use of some existing PROMs in AATD assessment, including SGRQ and SF-36. However, since the PROMs used are not designed for the patient population affected by AATD, they will not have been able to assess the quality-of-life effects of extra-pulmonary AATD-specific issues, and SGRQ has proven insensitive to change in RCTs of the only licensed therapy for AATD lung disease (augmentation). This is a key weakness, especially as we move into an era where showing patient centred efficacy is important – more sensitive scores are needed for use in future trials. Furthermore, AATD patients vary from COPD patients in a number of key ways (Table 1), many of which are not assessed by the PROM scores mentioned in this review – none of them assess the impact of liver disease, the implication of hereditary disease, or the financial dilemma when disease-modifying treatment is not subsidised. If patients are not asked these questions, confirmation bias can influence the interpretation - we might be falsely reassured by better PROM scores.
The paucity of PROMs assessing liver disease in AATD is a particularly clear limitation to a holistic assessment, as a diagnosis of chronic liver disease can be expected to have a high impact on patients. At the less invasive end of the scale, more stringent alcohol and fluid intake restrictions may impact social plans; in more severe disease, invasive endoscopies, biopsies or even liver transplants would clearly influence quality of life. Additionally, social stigma and lack of effective treatments for end-stage liver disease have been shown to have a negative effect on quality of life in other forms of chronic liver disease.89 Furthermore, a significant minority of AATD patients with biopsy-proven liver fibrosis have only mildly impaired FEV1.88 Such patients would therefore be expected to have low SGRQ and CAT scores despite the burden of liver disease; in fact, it has been proven that there is no relationship between CAT score and non-invasive liver fibrosis.90 Therefore, there is an unmet need for an AATD-specific PROM to assess this and other extra-pulmonary manifestations of AATD. This has been identified as a priority by the 2017 ERS statement on areas for future research in AATD.91
Conclusions
The most commonly used PROMs in AATD are sufficient to assess the COPD element of AATD, but may lack sensitivity, and there is a need for a PROM which includes the extra-pulmonary quality of life effects of a diagnosis of AATD.
Abbreviations
AAT, Alpha-1 Antitrypsin; AATD, Alpha-1 Antitrypsin Deficiency; ANCA, Anti-Neutrophil Cytoplasmic Antibody; CAT, COPD Assessment Tool; COPD, Chronic Obstructive Pulmonary Disease; COPD-SS, COPD Severity Score; EBV, Endobronchial Valve; FEV1, Forced Expiratory Volume in 1 second; LCOPD, Living with COPD; PROM, Patient-Reported Outcome Measure; SF-36, Short Form 36; SGRQ, St George’s Respiratory Questionnaire.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
AMT is funded by Vertex Pharmaceuticals, the NIHR Midlands Patient Safety Research Collaboration (PSRC) and Applied Research Collaborative West Midlands (ARC-WM). A grant from the Alpha 1 Foundation to AMT’s institution has funded staff time for this work, as part of a wider project about PROMs in AATD. The views expressed are those of the author(s) and not necessarily those of Vertex Pharmaceuticals, the Alpha-1 Foundation, the NIHR or the Department of Health and Social Care.
Disclosure
AMT has had grants to her institution and/or honoraria from CSL Behring, Grifols, Vertex, Takeda, Chiesi, AstraZeneca, GSK, Sanofi and Boehringer Ingelheim. The authors report no other conflicts of interest in this work.
References
1. Brantly ML, Wittes JT, Vogelmeier CF, Hubbard RC, Fells GA, Crystal RG. Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha 1-antitrypsin phenotypes. Chest. 1991;100(3):703–708. doi:10.1378/chest.100.3.703
2. Blanco I, Bueno P, Diego I, et al. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update. Int J Chron Obstruct Pulmon Dis. 2017;12:561–569. doi:10.2147/COPD.S125389
3. Patel D, Teckman JH. Alpha-1-Antitrypsin Deficiency Liver Disease. Clin Liver Dis. 2018;22(4):643–655. doi:10.1016/j.cld.2018.06.010
4. Smith KC, Su WP, Pittelkow MR, Winkelmann RK. Clinical and pathologic correlations in 96 patients with panniculitis, including 15 patients with deficient levels of alpha 1-antitrypsin. J Am Acad Dermatol. 1989;21(6):1192–1196. doi:10.1016/S0190-9622(89)70328-5
5. Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214–223. doi:10.1056/NEJMoa1108735
6. Choate R, Holm KE, Sandhaus RA, Mannino DM, Strange C. Health-related Quality of Life in Alpha-1 Antitrypsin Deficiency-associated Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2023;208(10):1132–1134. doi:10.1164/rccm.202304-0697LE
7. Worthington AK, Parrott RL, Smith RA. Spirituality, Illness Unpredictability, and Math Anxiety Effects on Negative Affect and Affect-Management Coping for Individuals Diagnosed with Alpha-1 Antitrypsin Deficiency. Health Commun. 2018;33(4):363–371. doi:10.1080/10410236.2016.1266576
8. Holm KE, Borson S, Sandhaus RA, et al. Differences in adjustment between individuals with alpha-1 antitrypsin deficiency (AATD)-associated COPD and non-AATD COPD. COPD. 2013;10(2):226–234. doi:10.3109/15412555.2012.719049
9. Miravitlles M, Ferrer J, Baro E, Lleonart M, Galera J. Differences between physician and patient in the perception of symptoms and their severity in COPD. Respir Med. 2013;107(12):1977–1985. doi:10.1016/j.rmed.2013.06.019
10. Celli B, Blasi F, Gaga M, et al. Perception of symptoms and quality of life - comparison of patients’ and physicians’ views in the COPD MIRROR study. Int J Chron Obstruct Pulmon Dis. 2017;12:2189–2196. doi:10.2147/COPD.S136711
11. Lieberman J, Winter B, Sastre A. Alpha 1-antitrypsin Pi-types in 965 COPD patients. Chest. 1986;89(3):370–373. doi:10.1378/chest.89.3.370
12. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648–654. doi:10.1183/09031936.00102509
13. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85(Suppl B):25–31. discussion 33-27. doi:10.1016/S0954-6111(06)80166-6
14. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727–1736. doi:10.1007/s11136-011-9903-x
15. Hogarth DK, Delage A, Zgoda MA, Nsiah-Dosu S, Himes D, Reed MF. Efficacy and safety of the Spiration Valve System for the treatment of severe emphysema in patients with Alpha-1 antitrypsin deficiency (EMPROVE). Respir Med. 2024;224:107565. doi:10.1016/j.rmed.2024.107565
16. Piloni D, Ottaviani S, Saderi L, et al. Comparison among populations with severe and intermediate alpha 1-antitrypsin deficiency and chronic obstructive pulmonary disease. Minerva Med. 2023;2023:1.
17. Karl FM, Holle R, Bals R, et al. Costs and health-related quality of life in Alpha-1-Antitrypsin Deficient COPD patients. Respir Res. 2017;18(1):60. doi:10.1186/s12931-017-0543-8
18. Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema distribution in alpha 1-antitrypsin deficiency influences lung function impairment. Am J Respir Crit Care Med. 2004;170(11):1172–1178. doi:10.1164/rccm.200406-761OC
19. Stavngaard T, Shaker SB, Bach KS, Stoel BC, Dirksen A. Quantitative assessment of regional emphysema distribution in patients with chronic obstructive pulmonary disease (COPD). Acta Radiol. 2006;47(9):914–921. doi:10.1080/02841850600917170
20. Piras B, Ferrarotti I, Lara B, et al. Clinical phenotypes of Italian and Spanish patients with alpha 1-antitrypsin deficiency. Eur Respir J. 2013;42(1):54–64. doi:10.1183/09031936.00104712
21. Marsh SE, Travers J, Weatherall M, et al. Proportional classifications of COPD phenotypes. Thorax. 2008;63(9):761–767. doi:10.1136/thx.2007.089193
22. Fahndrich S, Biertz F, Karch A, et al. Cardiovascular risk in patients with alpha-1-antitrypsin deficiency. Respir Res. 2017;18(1):171. doi:10.1186/s12931-017-0655-1
23. Piitulainen E, Mostafavi B, Tanash HA. Health status and lung function in the Swedish alpha 1-antitrypsin deficient cohort, identified by neonatal screening, at the age of 37-40 years. Int J Chron Obstruct Pulmon Dis. 2017;12:495–500. doi:10.2147/COPD.S120241
24. Needham M, Stockley RA. Exacerbations in alpha 1-antitrypsin deficiency. Eur Respir J. 2005;25(6):992–1000. doi:10.1183/09031936.05.00074704
25. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608–1613. doi:10.1164/ajrccm.161.5.9908022
26. Stoller JK, Smith P, Yang P, Spray J. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey. Cleve Clin J Med. 1994;61(6):461–467. doi:10.3949/ccjm.61.6.461
27. Anzueto A. Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: a Family Perspective. COPD. 2015;12(4):462–467. doi:10.3109/15412555.2014.974746
28. Klitzman R. The impact of social contexts in testing for alpha-1 antitrypsin deficiency: the roles of physicians and others. Genet Test Mol Biomarkers. 2009;13(2):269–276. doi:10.1089/gtmb.2008.0106
29. Strange C, Wienke S, Walker D, et al. Social impact identified in and by the alpha-1 antitrypsin deficiency community. Rare Diseases and Orphen Drugs. 2014;1(3):76–82.
30. Dissemination, C. f. R. a. Systematic Reviews: CRD’s Guidance for Undertaking Reviews in Health Care. York: University of York; 2008.
31. Knebel AR, Leidy NK, Sherman S. Health related quality of life and disease severity in patients with alpha-1 antitrypsin deficiency. Qual Life Res. 1999;8(4):385–391. doi:10.1023/A:1008945316646
32. Manca S, Rodriguez E, Huerta A, et al. Usefulness of the CAT, LCOPD, EQ-5D and COPDSS scales in understanding the impact of lung disease in patients with alpha-1 antitrypsin deficiency. COPD. 2014;11(5):480–488. doi:10.3109/15412555.2014.898030
33. Luisetti M, Ferrarotti I, Corda L, et al. Italian registry of patients with alpha-1 antitrypsin deficiency: general data and quality of life evaluation. COPD. 2015;12(Suppl 1):52–57. doi:10.3109/15412555.2015.1023393
34. Gauvain C, Mornex JF, Pison C, et al. Health-related quality of life in patients with alpha-1 antitrypsin deficiency: the French experience. COPD. 2015;12(Suppl 1):46–51. doi:10.3109/15412555.2015.1022645
35. Torres Redondo M, Campoa E, Ruano L, Sucena M. Health-Related Quality of Life in Patients With alpha 1 Antitrypsin Deficiency: a Cross Sectional Study. Arch Bronconeumol. 2017;53(2):49–54. doi:10.1016/j.arbres.2016.05.024
36. Stockley RA, Edgar RG, Starkey S, Turner AM. Health status decline in alpha-1 antitrypsin deficiency: a feasible outcome for disease modifying therapies? Respir Res. 2018;19(1):137. doi:10.1186/s12931-018-0844-6
37. Werdecker C, Bals R. Impact of the COVID-19 pandemic on well-being and quality of life of patients with alpha-1-antitrypsin deficiency. Respir Res. 2023;24(1):258. doi:10.1186/s12931-023-02553-9
38. Choate R, Holm KE, Sandhaus RA, Mannino DM, Strange C. Characteristics associated with SF-36 in alpha-1 antitrypsin deficiency-associated COPD: a cross-sectional analysis. BMC Pulm Med. 2024;24(1):138. doi:10.1186/s12890-024-02953-7
39. Choate R, Holm KE, Sandhaus RA, Mannino DM, Strange C. Long-Term SGRQ Stability in a Cohort of Individuals with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease. Int J Chron Obstruct Pulmon Dis. 2024;19:889–900. doi:10.2147/COPD.S443183
40. Jones PW. St. George’s Respiratory Questionnaire: MCID. COPD. 2005;2(1):75–79. doi:10.1081/COPD-200050513
41. Welling JB, Hartman JE, Ten Hacken NH, Klooster K, Slebos DJ. The minimal important difference for the St George’s Respiratory Questionnaire in patients with severe COPD. Eur Respir J. 2015;46(6):1598–1604. doi:10.1183/13993003.00535-2015
42. Campos MA, Alazemi S, Zhang G, Wanner A, Sandhaus RA. Effects of a disease management program in individuals with alpha-1 antitrypsin deficiency. COPD. 2009;6(1):31–40. doi:10.1080/15412550802607410
43. Dirksen A, Piitulainen E, Parr DG, et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha 1-antitrypsin deficiency. Eur Respir J. 2009;33(6):1345–1353. doi:10.1183/09031936.00159408
44. Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe alpha 1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360–368. doi:10.1016/S0140-6736(15)60860-1
45. Ellis PR, Holm KE, Choate R, et al. Quality of Life and Mortality Outcomes for Augmentation Naive and Augmented Patients with Severe Alpha-1 Antitrypsin Deficiency. Chronic Obstr Pulm Dis. 2023;10(2):139–147. doi:10.15326/jcopdf.2022.0339
46. Everaerts S, Hartman JE, Van Dijk M, Koster TD, Slebos DJ, Klooster K. Bronchoscopic Lung Volume Reduction in Patients with Emphysema due to Alpha-1 Antitrypsin Deficiency. Respiration. 2023;102(2):134–142. doi:10.1159/000528182
47. Schramm GR, Mostafavi B, Piitulainen E, Wollmer P, Tanash HA. Lung Function and Health Status in Individuals with Severe Alpha-1-Antitrypsin Deficiency at the Age of 42. Int J Chron Obstruct Pulmon Dis. 2021;16:3477–3485. doi:10.2147/COPD.S335683
48. Annunziata A, Lanza M, Coppola A, Andreozzi P, Spinelli S, Fiorentino G. Alpha-1 Antitrypsin Deficiency: home Therapy. Front Pharmacol. 2021;12:575402. doi:10.3389/fphar.2021.575402
49. Crossley D, Stockley J, Bolton CE, et al. Relationship of CT densitometry to lung physiological parameters and health status in alpha-1 antitrypsin deficiency: initial report of a centralised database of the NIHR rare diseases translational research collaborative. BMJ Open. 2020;10(6):e036045. doi:10.1136/bmjopen-2019-036045
50. Perotin JM, Leroy S, Marquette CH, et al. Endobronchial coil treatment in severe emphysema patients with alpha-1 antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis. 2018;13:3645–3649. doi:10.2147/COPD.S176366
51. Bernhard N, Lepper PM, Vogelmeier C, et al. Deterioration of quality of life is associated with the exacerbation frequency in individuals with alpha-1-antitrypsin deficiency - analysis from the German Registry. Int J Chron Obstruct Pulmon Dis. 2017;12:1427–1437. doi:10.2147/COPD.S130925
52. Bernhard N, Lepper PM, Vogelmeier C, et al. Intensive smoking diminishes the differences in quality of life and exacerbation frequency between the alpha-1-antitrypsin deficiency genotypes PiZZ and PiSZ. Respir Med. 2017;130:1–8. doi:10.1016/j.rmed.2017.07.004
53. Fahndrich S, Bernhard N, Lepper PM, et al. Exacerbations and duration of smoking abstinence are associated with the annual loss of FEV(1) in individuals with PiZZ alpha-1-antitrypsin deficiency. Respir Med. 2017;129:8–15. doi:10.1016/j.rmed.2017.05.011
54. Lessard E, Young HM, Bhalla A, et al. Pulmonary (3)He Magnetic Resonance Imaging Biomarkers of Regional Airspace Enlargement in Alpha-1 Antitrypsin Deficiency. Acad Radiol. 2017;24(11):1402–1411. doi:10.1016/j.acra.2017.05.008
55. Green CE, Parr DG, Edgar RG, Stockley RA, Turner AM. Lung density associates with survival in alpha 1 antitrypsin deficient patients. Respir Med. 2016;112:81–87. doi:10.1016/j.rmed.2016.01.007
56. Stone HM, Edgar RG, Thompson RD, Stockley RA. Lung Transplantation in Alpha-1-Antitrypsin Deficiency. COPD. 2016;13(2):146–152. doi:10.3109/15412555.2015.1048850
57. McGrady T, Mannino DM, Malanga E, et al. Characteristics of Chronic Obstructive Pulmonary Disease (COPD) Patients Reporting Alpha-1 Antitrypsin Deficiency in the WebMD Lung Health Check Database. Chronic Obstr Pulm Dis. 2015;2(2):141–151. doi:10.15326/jcopdf.2.2.2015.0160
58. Tanash HA, Nystedt-Duzakin M, Montero LC, Sveger T, Piitulainen E. The Swedish alpha 1-Antitrypsin Screening Study: health Status and Lung and Liver Function at Age 34. Ann Am Thorac Soc. 2015;12(6):807–812. doi:10.1513/AnnalsATS.201410-452OC
59. Campos MA, Alazemi S, Zhang G, et al. Clinical characteristics of subjects with symptoms of alpha 1-antitrypsin deficiency older than 60 years. Chest. 2009;135(3):600–608. doi:10.1378/chest.08-1129
60. Campos MA, Alazemi S, Zhang G, et al. Exacerbations in subjects with alpha-1 antitrypsin deficiency receiving augmentation therapy. Respir Med. 2009;103(10):1532–1539. doi:10.1016/j.rmed.2009.04.008
61. Holme J, Stockley RA. Radiologic and clinical features of COPD patients with discordant pulmonary physiology: lessons from alpha 1-antitrypsin deficiency. Chest. 2007;132(3):909–915. doi:10.1378/chest.07-0341
62. Swigris JJ, Esser D, Wilson H, et al. Psychometric properties of the St George’s Respiratory Questionnaire in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2017;49(1):1601788. doi:10.1183/13993003.01788-2016
63. Azarisman MS, Fauzi MA, Faizal MPA, Azami Z, Roslina AM, Roslan H. The SAFE (SGRQ score, air-flow limitation and exercise tolerance) Index: a new composite score for the stratification of severity in chronic obstructive pulmonary disease. Postgrad Med J. 2007;83(981):492–497. doi:10.1136/pgmj.2006.052399
64. Vogelmeier CF, Alter P. Assessing Symptom Burden. Clin Chest Med. 2020;41(3):367–373. doi:10.1016/j.ccm.2020.06.005
65. Loubert A, Regnault A, Meunier J, Gutzwiller FS, Regnier SA. Is the St. George’s Respiratory Questionnaire an Appropriate Measure of Symptom Severity and Activity Limitations for Clinical Trials in COPD? Analysis of Pooled Data from Five Randomized Clinical Trials. Int J Chron Obstruct Pulmon Dis. 2020;15:2103–2113. doi:10.2147/COPD.S261919
66. Langhammer A, Jones R. Usefulness of the COPD assessment test (CAT) in primary care. Prim Care Respir J. 2013;22(1):8–9. doi:10.4104/pcrj.2013.00022
67. Dodd JW, Hogg L, Nolan J, et al. The COPD assessment test (CAT): response to pulmonary rehabilitation. A multicentre, prospective study. Thorax. 2011;66(5):425–429. doi:10.1136/thx.2010.156372
68. Gupta N, Pinto L, Benedetti A, et al. Canadian Respiratory Research, N. & the Can, C. C. R. G. The COPD Assessment Test: can It Discriminate Across COPD Subpopulations? Chest. 2016;150(5):1069–1079. doi:10.1016/j.chest.2016.06.016
69. Reizes Z, McNamara RJ, Dale M, McKeough Z. Establishing the Validity of Using the COPD Assessment Test to Screen for Fatigue in People With Chronic Obstructive Pulmonary Disease Referred to Pulmonary Rehabilitation. Phys Ther. 2023;103(8). doi:10.1093/ptj/pzad064
70. Omachi TA, Yelin EH, Katz PP, Blanc PD, Eisner MD. The COPD severity score: a dynamic prediction tool for health-care utilization. COPD. 2008;5(6):339–346. doi:10.1080/15412550802522700
71. Miravitlles M, Llor C, de Castellar R, Izquierdo I, Baro E, Donado E. Validation of the COPD severity score for use in primary care: the NEREA study. Eur Respir J. 2009;33(3):519–527. doi:10.1183/09031936.00087208
72. Miravitlles M, Izquierdo I, Herrejon A, Torres JV, Baro E, Borja J. COPD severity score as a predictor of failure in exacerbations of COPD. The ESFERA study. Respir Med. 2011;105(5):740–747. doi:10.1016/j.rmed.2010.12.020
73. Pickard AS, Wilke C, Jung E, Patel S, Stavem K, Lee TA. Use of a preference-based measure of health (EQ-5D) in COPD and asthma. Respir Med. 2008;102(4):519–536. doi:10.1016/j.rmed.2007.11.016
74. Payakachat N, Ali MM, Tilford JM. Can The EQ-5D Detect Meaningful Change? A Systematic Review. Pharmacoeconomics. 2015;33(11):1137–1154. doi:10.1007/s40273-015-0295-6
75. Efthymiadou O, Mossman J, Kanavos P. Health related quality of life aspects not captured by EQ-5D-5L: results from an international survey of patients. Health Policy. 2019;123(2):159–165. doi:10.1016/j.healthpol.2018.12.003
76. Nolan CM, Longworth L, Lord J, et al. The EQ-5D-5L health status questionnaire in COPD: validity, responsiveness and minimum important difference. Thorax. 2016;71(6):493–500. doi:10.1136/thoraxjnl-2015-207782
77. McKenna SP, Meads DM, Doward LC, et al. Development and validation of the living with chronic obstructive pulmonary disease questionnaire. Qual Life Res. 2011;20(7):1043–1052. doi:10.1007/s11136-011-9850-6
78. Miravitlles M, Iriberri M, Barrueco M, Lleonart M, Villarrubia E, Galera J. Usefulness of the LCOPD, CAFS and CASIS scales in understanding the impact of COPD on patients. Respiration. 2013;86(3):190–200. doi:10.1159/000341175
79. Wu Q, Chen Y, Zhou Y, Zhang X, Huang Y, Liu R. Reliability, validity, and sensitivity of short-form 36 health survey (SF-36) in patients with sick sinus syndrome. Medicine. 2023;102(24):e33979. doi:10.1097/MD.0000000000033979
80. Wilke S, Janssen DJ, Wouters EF, Schols JM, Franssen FM, Spruit MA. Correlations between disease-specific and generic health status questionnaires in patients with advanced COPD: a one-year observational study. Health Qual Life Outcomes. 2012;10(1):98. doi:10.1186/1477-7525-10-98
81. Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ. 1992;305(6846):160–164. doi:10.1136/bmj.305.6846.160
82. Mahler DA, Mackowiak JI. Evaluation of the short-form 36-item questionnaire to measure health-related quality of life in patients with COPD. Chest. 1995;107(6):1585–1589. doi:10.1378/chest.107.6.1585
83. Guyatt GH, Sackett DL, Sinclair JC, Hayward R, Cook DJ, Cook RJ. Users’ guides to the medical literature. IX. A method for grading health care recommendations. Evidence-Based Medicine Working Group. JAMA. 1995;274(22):1800–1804. doi:10.1001/jama.1995.03530220066035
84. Hajiro T, Nishimura K, Tsukino M, Ikeda A, Koyama H, Izumi T. Comparison of discriminative properties among disease-specific questionnaires for measuring health-related quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157(3 Pt 1):785–790. doi:10.1164/ajrccm.157.3.9703055
85. Rutten-van Molken M, Roos B, Van Noord JA. An empirical comparison of the St George’s Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease Questionnaire (CRQ) in a clinical trial setting. Thorax. 1999;54(11):995–1003. doi:10.1136/thx.54.11.995
86. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–483. doi:10.1097/00005650-199206000-00002
87. Tanash HA, Piitulainen E. Liver disease in adults with severe alpha-1-antitrypsin deficiency. J Gastroenterol. 2019;54(6):541–548. doi:10.1007/s00535-019-01548-y
88. Clark VC, Marek G, Liu C, et al. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol. 2018;69(6):1357–1364. doi:10.1016/j.jhep.2018.08.005
89. Gronkjaer LL, Lauridsen MM. Quality of life and unmet needs in patients with chronic liver disease: a mixed-method systematic review. JHEP Rep. 2021;3(6):100370. doi:10.1016/j.jhepr.2021.100370
90. Hamesch K, Mandorfer M, Pereira VM, et al. European Alpha1-Liver Study, G. Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation. Gastroenterology. 2019;157(3):705–719e718. doi:10.1053/j.gastro.2019.05.013
91. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1 -antitrypsin deficiency. Eur Respir J. 2017;50(5):1700610. doi:10.1183/13993003.00610-2017
© 2025 The Author(s). This work is published and licensed by Dove Medical Press Limited. The
full terms of this license are available at https://www.dovepress.com/terms.php
and incorporate the Creative Commons Attribution
- Non Commercial (unported, 3.0) License.
By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted
without any further permission from Dove Medical Press Limited, provided the work is properly
attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.
Recommended articles
Prevalence of Cardiovascular Disease and Rate of Major Adverse Cardiovascular Events in Severe Alpha-1 Antitrypsin Deficiency COPD
Ellis P, Bailey E, Choate R, Holm KE, Sandhaus RA, Turner AM, Newnham M
International Journal of Chronic Obstructive Pulmonary Disease 2024, 19:149-159
Published Date: 17 January 2024
Long-Term SGRQ Stability in a Cohort of Individuals with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease
Choate R, Holm KE, Sandhaus RA, Mannino DM, Strange C
International Journal of Chronic Obstructive Pulmonary Disease 2024, 19:889-900
Published Date: 10 April 2024