Abstract
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder characterised by reduced levels of circulating alpha-1 antitrypsin and an increased risk of lung and liver disease. Recent reviews of AATD have focused on diagnosis, epidemiology and clinical management; comprehensive reviews examining disease burden are lacking. Therefore, we conducted literature reviews to investigate the AATD disease burden for patients, caregivers and healthcare systems. Embase, PubMed and Cochrane libraries were searched for AATD publications from database inception to June 2021, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Most published AATD studies were small and short in duration, with variations in populations, designs, measures and outcomes, complicating cross-study comparisons. AATD was associated with significant pulmonary and hepatic morbidity. COPD, emphysema and bronchiectasis were common lung morbidities, where smoking was a key risk factor. Fibrosis and steatosis were the most common liver complications reported in patients with a PiZ allele. Health status analyses suggested a poorer quality of life for AATD patients diagnosed with COPD versus those with non-AATD-associated COPD. The burden for caregivers included loss of personal time due to caring responsibilities, stress and anxiety. AATD was also associated with high direct medical costs and healthcare resource utilisation.
Abstract
AATD is a rare genetic disorder associated with a considerable burden of lung and liver disease and high healthcare resource utilisation. However, available data are scarce and further research is needed to better understand the burden of this disease. https://bit.ly/3IWtQQ1
Introduction
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder characterised by reduced levels of the proteinase inhibitor alpha-1 antitrypsin (AAT) in the circulation [1]. Individuals with AATD typically have a mutation in the SERPINA1 (or protease inhibitor (Pi)) gene, leading to a change in the structure of the AAT protein [1]. Normal alleles are known as PiM, while the most common deficiency alleles are PiS and PiZ, with PiMS, PiMZ, PiSS, PiSZ and PiZZ genotypes accounting for most variants [2]. >90% of patients with AATD express the PiZZ genotype; however, there are hundreds of rare and ultra-rare genotypes that result in circulating AAT concentrations of <11 µM, including the null/null genotype, which produces no AAT [2, 3]. Worldwide, it has been estimated that there are 3.4 million individuals with deficiency allele combinations (PiZZ, PiSZ or PiSS genotypes), and ⩾116 million carriers of deficiency alleles (i.e. heterozygous for the PiZ and PiS genotypes) [4].
AAT is produced mainly in the liver and circulates to the lungs, where it inhibits neutrophil elastase [5, 6]. If AAT is significantly reduced or absent, excess neutrophil elastase can degrade the lung extracellular matrix, as well as alveolar structures and blood vessels [7]. Individuals with AATD are therefore at increased risk of developing pulmonary disease, especially emphysema, which is often found in the basal areas of the lung [6]. AATD affects males and females equally, and the approximate age of diagnosis is 40–45 years [8].
Some individuals with AATD are prone to developing liver disease, which is secondary to accumulation of mutant AAT in hepatocytes [1, 6]. Patients with the Z variant (both heterozygotes and homozygotes) can develop liver disease due to abnormal folding of the Z AAT protein, which enables individual PiZ AAT proteins to polymerise and aggregate within the endoplasmic reticulum with eventual apoptosis of hepatocytes leading to toxicity, liver injury and increased risk of liver disease [9]. Liver complications are not observed in patients who have the null/null phenotype, because of the lack of aggregation of mutant proteins in the endoplasmic reticulum [10].
Infusion of purified human plasma-derived AAT protein (AAT therapy) has been available to treat AATD since it was first authorised by the United States Food and Drug Administration in 1987. Approval of this therapy was based on biochemical efficacy outcomes, i.e. inhibiting neutrophil elastase activity ex vivo, and maintaining AAT concentrations above presumed therapeutic thresholds in both serum and bronchoalveolar lavage fluid samples in patients with AATD [11]. In 2015, the RAPID trial reported a significantly reduced rate of lung density decline as measured by computed tomography (CT) for AAT therapy versus placebo [12, 13].
Although CT densitometry is useful for evaluating patients’ responses to AATD therapies [14], the assessment of disease severity and progression is conventionally based on pulmonary function tests, such as forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO), where declines over time are largely accepted as indicative of disease progression [2]. These measures can correlate with changes in quality of life (QoL), as measured by QoL instruments specifically designed for patients with obstructive airways disease, such as the St George's Respiratory Questionnaire (SGRQ) [14]. As for most pulmonary diseases, exacerbation severity and frequency can accelerate disease progression in AATD. Dyspnoea is a common complaint among patients with AATD and can be assessed using the modified Medical Research Council (mMRC) dyspnoea scale. These measures provide a means to assess disease burden in patients with AATD, comparing it with observations in patients with non-AATD-associated COPD.
Recent reviews of AATD have focused on the epidemiology and distribution of genetic variants, disease screening, diagnosis and care, as well as AAT therapy [2, 3, 15–19]. In contrast, comprehensive reviews that assess the burden of AATD on patients, caregivers and healthcare systems are lacking. An increased understanding of this burden may help improve awareness and diagnosis rates, as well as healthcare resource planning and allocation. Consequently, we conducted systematic and structured literature reviews to assess the clinical, economic and QoL-related disease burden associated with AATD worldwide.
Methods
Systematic reviews of the AATD literature were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20]. The objective of this analysis was to assess 1) clinical burden and mortality associated with AATD; 2) QoL for patients; 3) caregiver burden; and 4) healthcare costs and resource utilisation.
Data sources
Embase, MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews and the Essential Reference Tool for Economics Literature were collectively searched from database inception to June 2021 to identify English-language studies on AATD using defined search strategies. Congress proceedings from 2017–2021 were also searched. In addition, registry websites (including the Tufts Cost-effectiveness Analysis Registry, the Alpha-1 Antitrypsin Deficiency Spanish Registry (REDAAT) and EUROCAT) and health technology assessment reports were searched for relevant studies. Finally, relevant systematic reviews identified through database searches were used for bibliography searching.
Population characteristics
The patient population of interest was adults (aged ≥18 years) of any race or gender with AATD. There were no restrictions on inclusion of studies based on intervention and comparator, country or publication timeframe. Publications that included patients with other diseases and studies that enrolled a mixed population of children and adults were excluded if subgroup data for adult patients with AATD were not available.
Search strategy, procedures and information extraction
All titles were downloaded into a systematic review database. Citations obtained from the searches were initially screened by two independent reviewers and conflicts resolved by a third independent reviewer/consensus. Citations that did not match the eligibility criteria were excluded, as were any duplicates due to overlap in coverage of the databases. Full-text papers were then screened in a similar fashion, with any discrepancies between the two reviewers resolved by a third independent reviewer. One reviewer then extracted data into a pre-defined extraction grid, which was validated by another independent reviewer. Where more than one publication was identified as describing a single study, the data were compiled into a single entry to avoid double counting of patients and studies. The search strategies used are shown in the supplementary figures.
Critical appraisal
Critical appraisal of included randomised controlled trials was conducted using comprehensive assessment criteria based on recommendations by the National Institute for Health and Care Excellence [21]. Observational studies were critically appraised using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [22].
Results
Clinical burden review
A total of 38 studies were included in the clinical burden review (supplementary figure S1), 17 of which were conference abstracts. 23 studies were conducted in Europe; nine in North America; and the remainder did not report the study location. Study sample size ranged from 19 patients in a small case–control study [23] to 422 506 patients from a UK population-based cohort [24]. 31 of the included studies reported clinical characteristics of patients with AATD (supplementary table S1). Mean age ranged from 39.9 to 69.6 years across 29 studies, and the proportion of males was ≥50% in 18 studies. Data on smoking status were reported in 17 studies; in 15 of these, most patients were current or former smokers (52–84%) [25–35]. The remaining two studies involved nonsmoking patients, who comprised all patients in one study [36] and 73% of patients in the other study [29]. PiZZ was the most commonly identified genotype, and was the only genotype identified in 10 studies [25, 27, 30, 31, 37–42].
Of the 38 included studies, all reported data regarding specific morbidities in patients with AATD including pulmonary, liver and skin disease; overall, 50 different morbidities were reported (table 1) [23–30, 32–59]. Pulmonary morbidity was commonly reported, and included COPD with a prevalence of 36.3–75.8% [25, 26, 33, 43, 49], emphysema (14.4–53.8%) [29, 43, 46, 47] and bronchiectasis (3.8–73.1%) (table 1) [29, 45–47].
Clinical burden review: morbidity associated with alpha-1 antitrypsin deficiency (AATD)
One study reported lung nodules in 26.8% of patients [40]. Risk factors for developing lung morbidity in individuals with AATD were reported in 10 studies. Smoking was cited as a risk factor in six studies [26, 35, 47–50], and current smoking, age (40–59 years) and frequent severe exacerbations of COPD were associated with an accelerated decline of FEV1 in individuals with severe AATD [26, 35]. The remaining studies did not examine the influence of smoking on risk.
There are mixed results reported for the influence of genotype on lung disease, with some studies reporting that PiSZ is a risk for exacerbation of lung disease [44, 47], others that PiZZ results in more severe disease [34, 46, 50] and one study reporting no increased risk of COPD due to PiSZ (table 1) [33]. One study reported on the effects of PiSS and PiMM and reported a significant four-fold increase in lung cancer risk in never-smokers with PiSS compared with PiMM genotypes (OR 4.64, 95% CI 1.08–19.92) [36].
Liver fibrosis was the most reported hepatic morbidity, with a wide variation in prevalence (1–88%) in those with AATD [23, 24, 27, 31, 38, 39, 52, 53, 55]. Advanced liver fibrosis was reported in 0.5–25.6% of patients [23, 31, 38, 53]. Cirrhosis was seen in 4–11% of patients [23–25, 37, 56]. A single study reported hepatocellular carcinoma in 2% of patients and hepatitis in 1% [25]. Genotype was an important risk factor for liver morbidity, with PiZZ associated with an increased risk of advanced liver fibrosis [38] and steatosis [53] (table 1). Among individuals with a PiZZ genotype, additional risk factors for liver disease included male sex [25, 38, 39] and the presence of metabolic dysfunction including diabetes [25, 27], metabolic syndrome and obesity [27]. Age >50 years, elevated liver enzyme levels, hepatitis viral infection and COPD were also associated with liver disease [25]. In addition, while PiZZ individuals had more liver stiffness and raised liver enzymes than individuals with an PiMZ or a wild-type PiMM genotype, PiMZ carriers appeared to have an intermediate risk of hepatic morbidity versus those without AATD-associated genotypes [55].
Panniculitis, a neutrophilic inflammation of subcutaneous fat, was reported in <1–8.6% of patients with AATD across three studies [25, 37, 44] (table 1). Other complications associated with AATD included increased psychiatric disorders [59], inflammatory bowel disease [37], venous thromboembolism [30] and cancer [24, 25, 36, 42, 44], and decreased ischaemic heart disease [41].
Mortality
13 publications discussed mortality associated with AATD (table 2) [60–72], four of which were conference abstracts. Four Swedish studies included the same population, although different aspects were analysed [61, 62, 70, 71].
Sample sizes of the studies ranged from 143 to 8039; however, one study examined death certificate records from the United States National Center for Health Statistics, which comprised >26 000 000 cases [64]. In general, these studies showed that mortality in patients with AATD resulted primarily from respiratory diseases, followed by liver complications. The Attaway et al. [60] study, which examined inpatient hospitalisations among patients with AATD, reported an in-hospital mortality rate of 3.1%. One study from Sweden reported a standardised mortality ratio of 3.6 compared with the general population [61], whereas another reported a standardised mortality ratio of 6.3 among National Heart, Lung, and Blood Institute AATD registry patients [63]. Respiratory disease, hepatic disease, diverticulitis and pulmonary embolism were associated with a higher risk of mortality among patients with AATD in the Swedish study [61]. Another study confirmed that patients who were treated with AAT therapy had prolonged survival or time to lung transplantation compared with those who were AAT therapy-naïve [68]. Although patients with the PiZZ genotype had a higher rate of mortality compared with patients without AATD [61, 65, 71], one study observed no difference in mortality rates between never-smoking PiZZ individuals and never-smoking controls [61, 71].
Mortality associated with alpha-1 antitrypsin deficiency (AATD)
Quality of life
The QoL review included 30 studies (supplementary figure S2), 23 of which were journal articles. The sample size ranged from 16 patients [73] to 922 patients [74]. Where reported, the mean age ranged from 40.7 years [14] to 60.3 years [75], and there were more males than females in 19 out of 30 studies, with the proportion of males ranging from 50.3% to 83% (supplementary table S2) [12, 76–78]. Most studies assessed QoL using the SGRQ (22 studies; table 3 [12, 14, 73–76, 78–93]). Other disease-specific patient-reported outcomes included the COPD Assessment Test (CAT), the Chronic Respiratory Disease Questionnaire (CRQ) and the Living with COPD (LCOPD) scale. The generic 36-item short-form survey (SF-36) was used in eight studies and the EQ-5D in two [75, 77] (see supplementary table S2 for the QoL instruments used in each study).
Quality of life review: St George's Respiratory Questionnaire (SGRQ) scores in patients with alpha-1 antitrypsin deficiency (AATD)
Two of the 30 included studies were randomised controlled trials. One of these studies evaluated AAT therapy which used the SGRQ [12] and another that assessed endobronchial valves in patients with AATD which used the SGRQ, mMRC and CAT [86]. The overall STROBE scores [22] among the remaining 24 studies are shown in supplementary table S3.
SGRQ scores (table 3) tended to be worse in patients with AATD who were diagnosed with COPD at baseline versus those with AATD, but without COPD at baseline [12, 88, 90] and in those with frequent exacerbations versus those without [74].
In addition, SGRQ scores were better in patients who never smoked compared with current or former smokers [79, 80, 83]. Several studies examined correlations between SGRQ score, lung function and other measures of physiological decline in AATD [14, 76, 82, 85, 88, 89, 91, 92], while others evaluated the impact of treatment on SGRQ score (table 3 and supplementary table S2) [12, 75, 81, 82].
Finally, a study reported worse QoL among patients with AATD diagnosed with chronic sputum expectoration versus those without chronic sputum expectoration [78].
Among studies reporting CAT scores, one reported similar scores between AATD patients diagnosed with COPD and a non-AATD COPD cohort, despite the AATD group being significantly younger, and having significantly fewer pack-years of smoking and significantly less comorbidity [77]. Regression analysis to assess the relationship between CAT scores and FEV1 showed that the relationship approached statistical significance in the group of AATD patients diagnosed with COPD [77]. A second study reported no significant differences in CAT scores between patients with COPD who were receiving AAT therapy versus those who were not (supplementary table S4) [75].
Other disease-specific measures were reported in several studies. One study reported no differences in LCOPD scores between AATD patients diagnosed with COPD and patients with general COPD (7.2 versus 7.9, p=0.60) [77]. Linear regression analysis showed a significant correlation between FEV1 (%) and LCOPD in both groups with a stronger relationship in AATD patients diagnosed with COPD (r2=0.252, p=0.002 versus r2=0.092, p=0.017 for general COPD) [77]. In another study, patients with AATD-related COPD were found to have a similar level of QoL impairment to patients with AATD and non-AATD-related COPD, but there was no correlation between CRQ scores and FEV1 over time [94].
Six studies evaluated QoL in patients with AATD diagnosed with COPD using the nonspecific SF-36 instrument [74, 87, 89, 91, 92, 95], and two studies evaluated patients with AATD and emphysema with this tool [78, 96] (supplementary tables S2 and S5) [74, 87, 89, 91, 92, 95]. Higher SF-36 scores, indicating better health status, were reported in patients with AATD diagnosed with COPD and a PiZZ genotype (n=30) compared with patients diagnosed with general COPD (n=9) who had the same COPD severity, as measured by FEV1 and DLCO [87]. Exacerbation frequency was associated with significantly poorer SF-36 scores across all domains in patients with AATD diagnosed with COPD receiving AAT therapy [74]. Better QoL was reported for patients with AATD diagnosed with COPD receiving AAT therapy (pulmonary rehabilitation) compared with patients with non-AATD-related COPD [95]. Two studies in patients with AATD diagnosed with COPD suggested that obesity or increased body mass index (BMI) were associated with poorer QoL compared with patients with normal BMI, where obesity was associated with greater comorbidity (table 3) [89, 91]. The association of poorer QoL in patients with a BMI >30 kg·m−2 versus normal BMI was shown to be independent of FEV1 decline in one of these studies [91]. SF-36 scores improved following implementation of comprehensive pulmonary rehabilitation in patients with AATD diagnosed with emphysema awaiting lung transplant [96].
The majority of the papers identified in this review focused on physical aspects of QoL, although mental component scores were reported for the SF-36 questionnaire; most of these were baseline measurements (supplementary table S5) [74, 92, 95]. One study utilising a patient survey reported that patients with severe deficiency were found to have adverse effects on their relationships [97]. No studies within the scope of this review reported on emotional or psychological burden in patients with AATD.
There is no consensus on the difference in QoL burden in patients with AATD with COPD compared with patients with general COPD. No difference between these patient groups was reported in two studies [77, 94]. Better QoL was reported in patients with AATD with COPD versus general COPD in patients with the PiZZ AATD genotype in two studies [87, 95].
Caregiver burden
Five studies were included in the caregiver burden review (supplementary figure S3). The studies were performed in the USA [98–100], Sweden [101] and England (table 4) [102]. All studies were qualitative, with no specific instruments used to measure this burden.
Caregiver burden review: summary of included studies
A review of the key issues for caregivers and family members of patients with AATD reported loss of flexibility in their work and social lives as the partner or spouse was forced to change schedules to provide care [103]. Caregivers also reported anxiety, stress and despair as a result of having to see their diagnosed family members struggling with their condition (table 4) [98, 101, 102]. In addition, some felt guilty that their genetic makeup may have been responsible for the disease in the affected family member, with many reporting fears for future generations [99, 100]. A study examining outcomes 20 years after an AATD neonatal screening programme in Sweden reported more anxiety among mothers of children with AATD than those without [101].
Financial pressure for caregivers in England was reported to result from the need to work reduced hours or taking time off work to attend medical appointments or provide care [102]. There was also concern about the lack of public and healthcare provider knowledge on AATD, as well as a lack of access to information for both patients and caregivers in the USA [99].
Economic burden
The cost and resource use review included 21 studies (supplementary figure S4): 10 were from the USA, and nine out of 21 were presented as conference abstracts. The sample size of studies ranged from five [104] to 9117 [105] patients, and the mean age of AATD patients was 48.3–64.6 years across studies. Where smoking status was reported, patients were typically former smokers (72.9–100%) (supplementary table S6). 14 studies reported the years for which costs were estimated, which ranged from 1997 to 2017 (table 5).
Economic burden review: cost and resource use associated with alpha-1 antitrypsin deficiency (AATD)
Resource use overall was higher in patients with AATD diagnosed with COPD versus those with general COPD [75, 106–108] and those with more severe disease [43]. AlphaNet's Disease Management and Prevention Program in the USA reported greater resource use (primary care, lung specialist visits and hospitalisation) for patients with PiSZ versus PiZZ genotypes who had lung disease, but the authors noted that this may have been due to the latter having better adherence to management recommendations and maintaining a healthier lifestyle [44].
Across studies, the mean length of hospital stay ranged from 2.3 to 8.2 days [60, 75, 109–112] (table 5 [43, 44, 60, 75, 104–121]). The hospitalisation rate and length of stay increased with age [109, 110].
The annual direct medical cost for patients with AATD in the USA was estimated to be USD 127 537 for users of AAT therapy versus USD 15 874 for nonusers [105]. A second US study reported that the median annual total healthcare costs were USD 9753, and the median total medical costs were USD 4927 and total pharmacy costs were USD 2063, although the proportion of patients receiving AAT therapy was not reported [43] (table 5). In Germany, the mean annual direct medical costs per patient were EUR 6099 for users of AAT therapy versus EUR 7117 for nonusers, excluding costs for AAT therapy [75].
Discussion
This review summarises the available evidence on various facets of disease burden in patients with AATD. Based on the studies reviewed, the evidence suggests that AATD is a significant burden for patients, caregivers and healthcare systems. However, the included studies differed greatly in their sample sizes, populations, observational periods, designs, measures and outcomes, making meta-analysis or cross-study comparisons and generalisations difficult.
Many studies in this review included <100 patients, which is expected given the rarity of AATD, and study follow-up also tended to be relatively short, with many prospective studies assessing patients for ≤1 year. Only the larger registries [25, 26, 122] or retrospective, population-based studies [43, 60, 64, 109] were able to include a robust sample size and consider a longer time frame. Moreover, many studies were published only as conference abstracts, particularly those discussing the clinical burden (20 out of 40 studies) and economic burden (nine out of 21), limiting the details available for analysis. Approximately half of all the papers included in this review were published in 2015 or later, particularly those that discussed clinical burden, of which only six studies of clinical burden were published before 2015. Other publications that discussed QoL and costs were ⩾10 years old, with some published in the 1990s. Therefore, the standards of care that are discussed are likely to be outdated. In addition, standards of care and medical costs vary regionally and between countries, making it particularly difficult to compare studies from the USA and Europe that report resource use and costs.
Patients with AATD typically develop pulmonary and hepatic morbidity, and our review suggests that this represents a considerable clinical burden. Among studies reporting lung morbidity in AATD, COPD and emphysema were common (occurring in up to 76% and 54% of patients, respectively). Unsurprisingly, smoking was identified as a key risk factor for the development of lung morbidity in patients with AATD. However, a single study suggested an increased risk of lung cancer in never-smokers with AATD [36]. Fibrosis was the most common liver complication in the studies reviewed here. Risk factors associated with liver fibrosis included male sex, diabetes and age >50 years. Panniculitis is a rare AATD comorbidity that was reported in <1% of patients in two studies reviewed here, whereas in a third study 8.6% of PiZZ patients had skin conditions including panniculitis [25, 37, 44]. The reason for the relatively high prevalence in the third study appears to be the reporting of panniculitis within a general comorbidity of “skin conditions” [44]. There was little consistency between the reporting of mortality rates between the studies [60, 61, 64] (table 2). Mortality data that are derived from index cases of AATD often indicate higher mortality rates compared with the general population; however, the data are difficult to interpret because severely affected individuals are systematically over-represented in registries. Survival was shown to be prolonged among patients with AATD and lung disease who received AAT therapy [68]; however, among never-smokers, there may not be any difference in survival for individuals with a PiZZ genotype versus the general population [69, 71].
Studies reporting QoL in individuals with AATD were heterogeneous, with a variety of disease-specific and generic instruments used across studies. While most studies used the SGRQ, a QoL questionnaire developed for respiratory diseases, many studies used generic QoL measures, including the SF-36, which do not account for parameters that may be unique to patients with AATD, such as having to receive weekly infusions of AAT therapy. Other disease-specific measures that assess dyspnoea and are predictive of survival in COPD, such as the CAT, CRQ and LCOPD scales, were reported in only a few studies. Among studies that used the SGRQ (table 3) and had baseline results, most reported a total mean score >40, indicating moderate impairment of QoL in patients with AATD. In general, worse QoL outcomes were reported for patients with AATD diagnosed with COPD than for patients diagnosed with general COPD, and for current smokers versus never-smokers or former smokers. No studies within the scope of this review reported on emotional or psychological burden in patients with AATD.
Tools used to measure the impact and progression of AATD, including pulmonary function tests (e.g. FEV1) and QoL instruments (e.g. SGRQ) are not sensitive to the small changes that occur over clinically feasible trial periods of 1–3 years in a disease that typically progresses over decades [2, 88]. Trials aimed at detecting a treatment effect over periods of >3 years are impractical to conduct due to the ethical concerns of prolonged placebo exposure and patient retention. Moreover, standards of care could change during study conduct, confounding data interpretation. Recruiting a large enough number of patients, e.g. >1000, to overcome the insensitivity of the measurements is also unfeasible in AATD, given its rarity [123]. The European Respiratory Society statement on AATD reported that a sample size of 550 per treatment group over 3 years would be needed to examine FEV1 decline as an outcome [2]. In addition, data from the UK AATD registry indicated that in order to detect the minimal clinically important difference in SGRQ (a four-point increase), a sufficiently powered, placebo-controlled trial of up to 8 years’ duration would be needed. In addition, this study determined that >8000 patients per treatment arm would be required to detect a 25% reduction in SGRQ score [88].
Patients with AATD and rapid FEV1 decline had worse QoL than those with slower FEV1 decline in one large study (n=772), but not in a second smaller study (n=101) [88, 92]. Clinical disease burden and QoL are likely to be influenced by the rate at which the disease progresses, the sensitivity of progression measurements and the time at which a diagnosis is finally given. Some patients with AATD have been reported to be “fast decliners”, as measured by CT lung density [13] and FEV1 [124]. However, the minimum clinically important difference for either of these outcomes in patients with AATD has not been established [13, 14, 88, 125–128].
Our review suggests that patients with AATD who have frequent exacerbations (≥3 per year) or chronic sputum expectoration have a poorer QoL than patients without [74], and that SGRQ scores may be significantly correlated with both exacerbations and dyspnoea [76]. Exacerbations are often associated with long-term sequelae including significant, permanent loss of lung function [26, 129, 130]. However, exacerbations are random events that are driven by infections and outcomes can vary substantially. The clinical trials conducted so far with either intravenous or inhaled AAT therapy showed inconclusive results in terms of prevention of exacerbations, which may be due to lack of power (or similar) [126, 131]. However, it is important to note that in these studies the event rate and sample sizes were limited, and no plausible mechanism linking the effect to AAT therapy was confirmed.
Our literature search identified limited evidence describing the impact of AATD on the life of caregivers, with only five published studies [98–102]. All studies were qualitative, and no specific instruments were used to measure the burden. This review suggests that caregivers of family members with AATD experience disruption to previously established routines and experience stress and anxiety.
Estimates of the total direct healthcare cost of AATD reviewed here came mainly from the USA and suggested median annual costs of USD 9753 excluding AAT therapy [43]. In Europe, annual costs were approximately EUR 1000 higher for patients who received AAT therapy versus those who did not [75]. The major direct cost drivers were AAT therapy, physician visits and inpatient stays. Little information was available on costs from other countries, making comparisons difficult. Only one study from Germany [75] attempted to estimate indirect costs, highlighting the need for further studies. Resource-use data suggest more annual visits, consultations and longer stays for patients with AATD compared with patients with general COPD and for patients with more severe AATD.
Disease burden is typically measured by the frequency of specific outcomes in a patient population, whether it is change in lung function, QoL or prevalence of a specific morbidity. Only registries can accurately capture such “big data” for AATD. While registries have existed historically, they were mainly national entities that were not centrally coordinated and as a result were not well harmonised in terms of the measurements used and the data collected [132]. Our review found wide variation in the clinical burden and other outcomes for patients with AATD across studies, highlighting the need for more thorough analyses with more consistent measures.
Implications for future research
This review illustrates the difficulties with drawing consistent and meaningful conclusions based on small, variable population samples and study designs. This has serious clinical consequences, as characterising efficacy and safety profiles of treatments is complex in the absence of a clear understanding of the burden, natural history and prognosis of the disease. Hence, there is an urgent need to include all affected patients in a multinational registry based on a consistent and structured reporting framework, and patients, caregivers, healthcare professionals and researchers are urged to form multinational collaborations in order to achieve this. The European Alpha-1 Research Collaboration (EARCO) [133] is seeking to coordinate clinical sites internationally and harmonise methodologies by carrying out quality control of data collection. This registry aims to provide an understanding of the natural history of the disease, to assess the value of AAT therapy in the real world, to evaluate QoL scores and to examine genotypes. This should enable more effective comparative research into the burden of AATD supporting future clinical development, which is an ongoing challenge for rare diseases. In addition, the authors would urge researchers in the field to publish their findings in peer-reviewed journals to increase the impact and reliability of the published literature.
Conclusion
This review found that AATD is associated with a significant clinical and QoL burden, and high direct medical costs and healthcare resource utilisation when compared with the general population. However, there were inconsistencies in the data, with many studies being small, of short duration and with a variety of different measures used for the same outcomes. As a result, considerable gaps in the true burden of this disease remain.
Supplementary material
Supplementary Material
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Supplementary material ERR-0262-2021.SUPPLEMENT
Acknowledgements
Editorial and writing support was provided by Jo Fetterman (Parexel International, Uxbridge, UK) and was funded by CSL Behring GmbH.
Footnotes
Provenance: Submitted article, peer reviewed.
Author contributions: All authors contributed to the study design and data interpretation, and reviewed and approved all manuscripts drafts, including the final draft.
Conflict of interest: M. Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis; consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Palobiofarma SL, Spin Therapeutics, pH Pharma, Novartis, Sanofi and Grifols; and research grants from Grifols.
Conflict of interest: M. Herepath is the owner and director of Optimal Access Life Science Consulting Limited.
Conflict of interest: A. Priyendu is an employee of Parexel.
Conflict of interest: S. Sharma is an employee of Parexel.
Conflict of interest: T. Vilchez is an employee of CSL Behring.
Conflict of interest: O. Vit is an employee of CSL Behring.
Conflict of interest: M. Haensel is an employee of CSL Behring.
Conflict of interest: V. Lepage is an employee of CSL Behring.
Conflict of interest: H. Gens is an employee of CSL Behring.
Conflict of interest: T. Greulich reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline and Novartis; grants and personal fees from Grifols; and grants from German Centre for Lung Research (DZL), Marburg, Germany (Deutsches Zentrum für Lungenforschung), all outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Support statement: This study was funded by CSL Behring GmbH. Funding information for this article has been deposited with the Crossref Funder Registry.
Published in volume 31, issue 163 of the European Respiratory Review on 23 March 2022; republished 31 March 2022 with minor amendments to the layout of tables 1 and 3.
- Received December 2, 2021.
- Accepted January 24, 2022.
- Copyright ©The authors 2022
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