Obstacles to Early Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency: Current Perspectives

Figures & data

Table 1 Screening Criteria in Relation to AATD

Classic Screening Criteria	Does AATD Meet This Criterion?	Genomic Age Screening Criteria	Does AATD Meet This Criterion?
The condition sought should be an important health problem	Maybe: varies by prevalence, typically about 5% of COPD patients^Citation22	The screening program should respond to a recognized need	Probably
There should be an accepted treatment for patients	Sort of: augmentation is acceptable for the lung, nil for the liver	The objectives of screening should be defined at the outset	No, but would be possible with international consensus
Facilities for diagnosis and treatment should be available	Yes, in most countries	There should be a defined target population	No, but international consensus could define, eg, family screening, people with COPD
There should be a recognizable latent or early symptomatic stage	Probably: most people are not very symptomatic until COPD progresses	There should be scientific evidence of screening program effectiveness	Not much; possible reduction in smoking uptake in Sweden^Citation17
There should be a suitable diagnostic test	Yes	The program should integrate education, testing, and clinical services	Very few countries are fully set up like this, but could be addressed
Diagnostic test should be acceptable to the population	Yes	There should be quality assurance (QA), with mechanisms to minimize potential risks of screening	Ongoing QA project in Europe. Ought to be possible in most countries
Natural history should be adequately understood	Partly; some factors determining describing progression are known but it is not fully explained in the lung. Less is known about the liver	The program should ensure informed choice, confidentiality, and respect for autonomy	Ought to be possible in most countries
There should be an agreed policy on whom to treat	No. Highly variable between countries with respect to many aspects including augmentation therapy^Citation18	The program should promote equity and access to screening for the entire target population	Ought to be possible in most countries
Cost of case-finding (including diagnosis and treatment) should be balanced in relation to expenditure on medical care overall	Debatable; most countries have systems that will address this	Program evaluation should be planned from the outset	International consensus on outcomes would be helpful first
Case-finding should be a continuing process	Variable by location	The overall benefits of screening should outweigh the harm	Probably true
Not wholly met and likely to vary by location		Majority met or possible to meet

Table 2 Methods to Reduce Under-Diagnosis or Delayed Diagnosis of AATD

Strategy	Results of Implementation	Citation
Public health campaign	Rate of detection higher, but link to free testing means effect cannot be attributed to campaign alone	^Citation27
Point of care/patient led testing	Rate of AATD detection higher than in general clinics, but most studies did not have a formal control	^Citation27^–^Citation29
Education of physicians	Increase in AATD testing of COPD patients after written materials/quiz (74–81%; P<0.05) Greater knowledge of AATD, self-reported increase in testing after educational video	^Citation36 ^Citation37

Figure 1 Optimized detection of AATD, In the above system patients or healthcare professionals could access AATD testing, and it would also be automatically triggered by identification of emphysema or liver fibrosis on tests done for other reasons. Educated healthcare professionals would always test for AATD in relevant respiratory and hepatic presentations, and patients aware of (for example) a family history of AATD or COPD would know that they should get tested and would access it themselves either before or after a healthcare professional saw them. Referral to specialist centers would occur early after a positive laboratory test.

Table 3 Studies of Augmentation Therapy

Study	Included Patients	Augmentation Regime	Effect of Treatment	Adverse Events	NCT Number
McElvaney et al 2017 (RAPID-OLE)^Citation62	Subjects who had completed the RAPID study (below)	60 mg/kg/week for 2 years. Divided into early start and late start groups	Rate of lung density loss lower in early start group compared to late start (−1.55 g/L vs −2.26 g/L)	51/140 (36.43%) reported serious adverse events	00670007
Chapman et al 2015 (RAPID)^Citation57	AATD diagnosis with serum conc. <11 µM FEV1 >35% and <70%	60 mg/kg, or placebo, infusions at weekly intervals for 24 months	Annual rate of lung density loss at TLC significantly less on Rx compared to placebo P=0.03	71 serious adverse events in 25 pts (27%) in Rx group and 58 in 27 subjects (31%) in placebo. 1 death in Rx (respiratory failure) and 3 in placebo (sepsis, pneumonia, metastatic breast Ca)	00261833
Dirksen et al 2009 (EXACTLE)^Citation63	AATD with serum conc. <11 μM, emphysema, FEV1 30–80% predicted	60 mg/kg, or placebo, infusions at weekly intervals for 24–30 months	Trend towards deceleration of emphysema progression compared to placebo	28 serious adverse events in 10 pts (26.3%) in Rx group and 40 in 18 subjects (46.2%) in placebo. 1 AE in each group deemed drug-related – psoriasis in Rx and PE in placebo	00263887
Dirksen et al 1999^Citation64	AATD of PiZZ, moderate-to-severe emphysema, FEV1 30–80% predicted	250 mg/kg, or placebo, infusions at 4 week intervals for 3 years	Trend towards a favorable effect on CT densitometry compared to placebo	No SAEs	n/a

Table 4 RCTs of Treatments Ongoing and Potentially Applicable to Early Disease

Intervention	Eligible to Enroll
Drug Class and/or Name	Emphysema with Normal Spirometry	Mild COPD (FEV1 >80%)	Study Status	NCT Number
ADVM-043 gene therapy (ADVANCE)	Yes	Yes	Completed	02168686
Recombinant adeno-associated virus vector expressing human AAT	Yes	Yes	Completed	01054339
Alpha-1 proteinase inhibitor solution (GLASSIA)	Yes	Yes	Active, not recruiting	02525861
VX-814	Yes	Yes	Terminated	04167345
Oral neutrophil elastase inhibitor, Alvelestat (ATALANTa)	Yes	Yes	Recruiting	03679598
Recombinant human AAT with fusion protein (INBRX-101)	Yes	Yes – for some dosage arms	Recruiting	03815396
Inhaled Alpha-1-Antitrypsin (InnovAATe)	Yes	Yes	Recruiting	04204252
VX-864	Yes	Yes	Recruiting	04474197
Oral neutrophil elastase inhibitor, Alvelestat (ASTRAEUS)	Yes	Yes	Recruiting	03636347
Alpha-1 proteinase inhibitor (SPARTA)(68)	No	No	Recruiting	01983241#
Carbamazepine (Tegretol XR)	Yes	Yes	Recruiting	01379469*
Subcutaneous injection of ARO-AAT	Yes	Yes	Recruiting	03946449*

Notes: *Denotes study relevant only to liver disease. ^#Indicates lung inclusion criteria that may exclude early disease, depending on the definition applied.

Brode SK, Ling SC, Chapman KR. Alpha-1 antitrypsin deficiency: a commonly overlooked cause of lung disease. CMAJ. 2012;184:1365–1371. doi:10.1503/cmaj.111749

 Google Scholar

Casas F, et al. Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update. Arch Bronconeumol. 2015;51:185–192. 10.1016/j.arbres.2014.05.008

 PubMed Web of Science ®Google Scholar

Greulich T, et al. European screening for alpha1 -antitrypsin deficiency in subjects with lung disease. Clin Respir J. 2017;11:90–97. 10.1111/crj.12310

 PubMed Web of Science ®Google Scholar

Greulich T, Nell C, Herr C, et al. Results from a large targeted screening program for alpha-1-antitrypsin deficiency: 2003–2015. Orphanet J Rare Dis. 2016;11:75. 10.1186/s13023-016-0453-8

 PubMed Web of Science ®Google Scholar

Greulich T, et al. Real world evaluation of a novel lateral flow assay (AlphaKit (R) QuickScreen) for the detection of alpha-1-antitrypsin deficiency. Respir Res. 2017;Volume 12:151. 10.1186/s12931-018-0826-8

 Web of Science ®Google Scholar

de Miguel-diez J, Jiménez-García R, López de Andrés A, et al. Effectiveness of an intervention to improve management of COPD using the AUDIT methodology: results of the neumo-advance study. Clin Drug Investig. 2019;39:653–664. 10.1007/s40261-019-00787-4

 PubMed Web of Science ®Google Scholar

Nolte JL, Ataya A, Merrill H, et al. Alpha1-antitrypsin deficiency—increased knowledge and diagnostic testing after viewing short instructional video. COPD. 2017;14:52–55. 10.1080/15412555.2016.1245280

 PubMedGoogle Scholar

McElvaney NG, et al. Long-term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused by severe alpha1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med. 2017;5:51–60. 10.1016/S2213-2600(16)30430-1

 PubMed Web of Science ®Google Scholar

Chapman KR, et al. Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386:360–368. 10.1016/S0140-6736(15)60860-1

 PubMed Web of Science ®Google Scholar

Dirksen A, et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J. 2009;33:1345–1353. 10.1183/09031936.00159408

 PubMed Web of Science ®Google Scholar

Dirksen A, et al. A randomized clinical trial of alpha (1)-antitrypsin augmentation therapy. Am J Respir Crit Care Med. 1999;160:1468–1472. 10.1164/ajrccm.160.5.9901055

 PubMed Web of Science ®Google Scholar