patients receiving AAT therapy had lower rates of
FEV1 loss than those who did not receive therapy
and, amongst those with the lowest FEV1, mortality
was reduced. 8,9 These observations have encouraged
the more widespread use of AAT therapy but have
not slowed calls for a randomised controlled trial
of efficacy for AAT therapy.
A feasible clinical trial demonstrating the
efficacy of AAT therapy required the development
of a new specific and sensitive endpoint for the
emphysema associated with AATD. In 1999, Asger
Dirksen and colleagues explored the endpoints used
to monitor emphysema using both serial spirometry
and computerised tomographic estimates of lung
density. 10 In a small population studied over three
years, repeated spirometry remained insensitive
to differences between treated and placebo-
treated patients while lung density estimates
traced a difference that was close to statistically
significant. That is, individuals randomised to
receive AAT therapy showed a slower loss of lung
density than individuals who received placebo
infusions. A subsequent pilot study further refined
the technology (and showed similarly suggestive
results). 11
In 2015, results of the RAPID trial were reported
and showed that CT scan lung density measured
at full inflation (total lung capacity) was better
preserved in treated patients compared with those
who received placebo. 12 This was the two-year trial
noted above and was followed in the majority of
subjects by a two-year open label extension in
which all subjects received therapy. This extension
provided further evidence of benefit; the rate of
lung density loss remained low and constant in
those who had been treated in the first two years
and who continued to be treated in the second two
years while the more rapid loss of lung density
in those who received placebo in the first two
years slowed to the rate of loss seen in the treated
group when the therapy was started belatedly. The
RAPID trial has been a rich source of observations.
Elastin breakdown products measured through
the trial showed a decrease in the treated subjects
but not in those who received placebo suggesting
a possible role for this endpoint in the monitoring
of therapy. 13 Moreover, the protective effect of
therapy was independent of age and initial FEV1.
Although definitive changes in lung density were
statistically significant in two years, spirometry
and other conventional measures of lung function
were insensitive to these differences although after
four years of treatment, changes in FEV1 showed a
statistical association with changes in lung density. 14
The availability of a specific therapy remains
unique to emphysema caused by AATD. This
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therapeutic avenue may be replaced in future by
interventions to correct the genetic abnormality.
Using viral vectors, it has been possible to stimulate
the production of normal AAT protein in deficient
individuals although such success has been short-
lived. Newer techniques may lead to sustained
genetic correction. 15 If so, such intervention is
likely to be limited to this special form of COPD
given its single gene abnormality. More typical
forms of COPD are likely associated with polygenic
abnormalities either obviating genetic correction or
requiring multiple corrections.
Phenotyping
In the 21st century, there is increasing use of
the term personalised medicine. We are hopeful
that a better understanding of each individual’s
genetic background may lead to more precise use
of medications and other interventions. This is
happening in a rudimentary way with respiratory
diseases. Patients with asthma are being challenged
to ask their physicians “which asthma do I have?” 16
This simple phenotyping has immediate and
practical consequences. Highly effective biological
therapies are available for subtypes of asthma:
severe allergic asthma (omalizumab); severe
eosinophilic asthma (mepolizumab, reslizumab
and benralizumab); and severe Type 2 asthma
(dupilumab). Practical phenotyping and its
consequences have been slower in the setting of
COPD. However, we now recognise that patients
with COPD of the common variety may differ in
their clinical characteristics. We seldom use the
terms chronic bronchitis or emphysema but we do
recognise that some patients exacerbate frequently
while others seldom exacerbate.
This leads to practical consequences with respect
to prescribing. Although all patients with significant
COPD are likely to benefit from bronchodilator
therapy, only those who exacerbate seem to benefit
from inhaled corticosteroids. 17 Thus, exacerbation
history and blood eosinophil counts have led to
differential prescribing and COPD. In this context,
identifying the small subset of individuals with
deficient serum levels of AAT must become a routine
part of our phenotyping.
Conclusions
We have expanded our understanding of COPD
genetics and pathophysiology during the 50 years
following the description of AATD and its pulmonary
consequences. Nonetheless, emphysema related to
severe AATD remains the most distinctive endotype
of COPD. In the era of personalised medicine, we are
well-positioned to detect the disorder and to offer
specific therapy.
12 Chapman KR et al.
Intravenous augmentation
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in severe alpha1 antitrypsin
deficiency (RAPID): a
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placebo-controlled trial. Lancet
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alpha-1 proteinase inhibitor
on biomarkers of elastin
degradation in alpha-1
antitrypsin deficiency: An analysis
of the RAPID/RAPID extension
trials. Chronic Obstr Pulm Dis
2016;4(1):34–44.
14 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(1):51–60.
15 Chiuchiolo MJ, Crystal
RG. Gene therapy for Alpha-1
Antitrypsin Deficiency Lung
Disease. Ann Am Thorac Soc
2016;13 Suppl 4:S352–69.
16 Kleinert S, Horton R. After
asthma: airways diseases need
a new name and a revolution.
Lancet 2018;391(10118):292–4.
17 Chapman KR et al. Long-term
triple therapy de-escalation to
indacaterol/glycopyrronium in
patients with chronic obstructive
pulmonary disease (SUNSET):
A randomized, double-blind,
triple-dummy clinical trial.
Am J Respir Crit Care Med
2018;198(3):329–39.
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