to a clear understanding of one of COPD’s most
important pathophysiologic mechanisms. This
glycoprotein serves an important protective role
in the lung. Neutrophil elastase can injure lung
parenchyma if not neutralised by normal amounts
of AAT glycoprotein. In those with a severe
deficiency, normal amounts of neutrophil elastase
are present unopposed with resulting injury to lung
structures. This appears to be the predominant
mechanism for the development of emphysema in
affected individuals but this protease–anti-protease
imbalance is probably not limited to AATD.
We understand that elastase levels are increased
by tobacco smoking and that an excess of neutrophil
elastase is may play a role in non-alpha forms of
COPD as well.
There is one way in which AATD emphysema
remains unique among the various forms of COPD.
It is possible to remedy the deficiency to halt or
at least slow the progression of emphysema by
infusing supplemental amounts of purified AAT to
achieve protective levels. This treatment strategy
was developed more than a quarter of a century ago
and such therapy has been approved by regulatory
authorities in several countries for almost that
long. Initial studies were based on the premise that
it would be sufficient to maintain serum levels at
or above a protective threshold typically regarded
as 11µM. This was an estimate based upon the
observation that individuals with mild or moderate
deficiencies of AAT and serum levels generally
above this mark seemed to have little or no
4 | 2019 | hospitalpharmacyeurope.com
In the era of
personalised
medicine, we are
well positioned to
detect the
disorder and to
offer specific
therapy
predisposition to emphysema. Proof of concept
studies by Wewers and colleagues showed that
infusions of AAT at a dose of 60mg/kg/week
could maintain serum levels above the protective
threshold and also showed that the infused AAT
protein was detectable in bronchoalveolar lavage. 5
This evidence of biochemical efficacy was sufficient
for widespread adoption of this therapy in the
United States and Germany but uptake in other
countries was much slower. 6 Typical was the view
of the Canadian Thoracic Society demanding that
proof of efficacy required spirometric evidence that
the progression of emphysema was slowed by such
treatment. 7 Unfortunately, such studies have not
been feasible. Spirometry changes slowly with the
development of emphysema and spirometry is
a relatively noisy and imprecise measure of
disease progression.
A clinical trial using spirometry as its endpoint
would require that almost 1000 patients with AATD
be randomised to active therapy or placebo and
followed for up to five years. To date, the largest
randomised and controlled trial of AATD has been
of 180 patients receiving an intervention of two
years’ duration. That study required the coordinated
efforts of 24 international sites specialising in this
comparatively rare form of emphysema. In the
absence of a large randomised and controlled trial
based on forced expiratory volume in 1 second
(FEV1), a number of observational studies have
examined the natural history of the disorder in
registries. The largest of these demonstrated that