PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype and prognosis relative to PiZZ AATD and PiMM COPD

Green, Clara; Vayalapra, Sushanth; Hampson, Judith Anne; Mukherjee, Deyashini; Stockley, Robert A.; Turner, Alice

doi:10.1136/thoraxjnl-2015-206906

Cited by 61 publications

(55 citation statements)

References 30 publications

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“…PiSZ heterozygotes likely have an increased risk of emphysema in smokers but the data from studies are not conclusive . PiMS and PiSS phenotypes are not at increased disease risk …”

Section: Diagnosis Of Aatdmentioning

confidence: 94%

“…PiMZ heterozygotes have an increased risk of obstructive lung disease in smokers but not in non‐smokers . PiSZ heterozygotes likely have an increased risk of emphysema in smokers but the data from studies are not conclusive . PiMS and PiSS phenotypes are not at increased disease risk …”

Section: Diagnosis Of Aatdmentioning

confidence: 97%

“…The frequency of SZ individuals is much lower than that of MZ individuals and serum AAT levels are reduced to around 40% of those found in MM individuals . The risk of COPD is not yet well defined but studies suggest that it is increased in SZ individuals compared to their MM counterparts and more so in cigarette smokers . The risk of COPD in individuals heterozygous for other AATD mutations is unclear because of their rarity.…”

Section: Management Of Aatd (Other Than Augmentation Therapy and Surgmentioning

confidence: 99%

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Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

et al. 2020

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AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD‐associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD‐related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD‐related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non‐pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.

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“…PiSZ heterozygotes likely have an increased risk of emphysema in smokers but the data from studies are not conclusive . PiMS and PiSS phenotypes are not at increased disease risk …”

Section: Diagnosis Of Aatdmentioning

confidence: 94%

Section: Diagnosis Of Aatdmentioning

confidence: 97%

Section: Management Of Aatd (Other Than Augmentation Therapy and Surgmentioning

confidence: 99%

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Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

et al. 2020

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“…Homozygous “Z” patients have an AAT level of 1.3–7.7 μM, considerably less than the putative protective threshold of 11 μM typical of PiSZ patients 12. The primary function of AAT is protecting the lung from proteolytic enzymes, primarily neutrophil elastase (NE);13 in deficiency, uninhibited NE can therefore lead to lung damage via quantum proteolysis 14,15…”

Section: Introductionmentioning

confidence: 99%

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

Edgar¹,

Patel²,

Bayliss³

et al. 2017

COPD

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BackgroundAlpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.MethodsStandard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology.ResultsIn all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.ConclusionIntravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.

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“…AATD is a hereditary disorder which predisposes to COPD [4]. There are a number of AATD genotypes which demonstrate clinical heterogeneity; PiZZ and PiSZ are the most commonly reported, with the PiSZ form being closer to non-AATD COPD in appearance than the PiZZ form [5].…”

Section: Introductionmentioning

confidence: 99%

ICS Use May Modify FEV<sub>1</sub> Decline in α<sub>1</sub>-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils

Low

Hughes²,

Zaffarullah

et al. 2017

Respiration

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Background: α 1 -Antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease (COPD). In COPD unrelated to AATD, the role of a higher blood eosinophil count in disease and subsequent personalization of therapy has recently received much attention. We sought to investigate this concept in patients with AATD-associated COPD. Objectives: The study aims to evaluate eosinophilia status against outcomes including mortality and FEV 1 decline in patients with AATD. Methods: All patients with PiSZ and PiZZ genotypes were identified from the UK AATD registry. The participants were substratified according to inhaled corticosteroid (ICS) use. Blood eosinophil counts were assessed from baseline and annually during follow-up (range 1-18 years). Eosinophilia was defined as a level >0.2 × 10 9 /L, and classified by the frequency of such counts into "always," "intermittent," or "never present." Univariate and multivariate analyses were conducted. Results: In total, 646 participants were included, 53.9% of whom demonstrated intermittent and 7.4% persistent eosinophilia. Survival did not differ according to eosinophilic group (p > 0.05). Those with persistent eosinophilia showed a slower FEV 1 decline (p < 0.001). There was no clear association with exacerbation frequency. Patients on ICS at baseline were more likely to be eosinophilic (p = 0.002) and having a lower FEV 1 (p < 0.001) and greater pack-year exposure (16.5 vs. 7.8 pack-years, p < 0.001). When the multivariate analyses of FEV 1 decline were stratified for baseline ICS use, the association of persistent eosinophilia with slower decline persisted in those on ICS. Conclusions: Blood eosinophil levels persistently >0.2 × 10 9 /L may be an indication for ICS use in PiZZ AATD in order to reduce FEV 1 decline.

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PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype and prognosis relative to PiZZ AATD and PiMM COPD

Abstract: PiSZ patients are less susceptible to cigarette smoke than PiZZ. The pattern of emphysema may be similar at diagnosis to usual COPD.

Cited by 61 publications

References 30 publications

Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

ICS Use May Modify FEV<sub>1</sub> Decline in α<sub>1</sub>-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils

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