Indications for Active Case Searches and Intravenous Alpha-1 Antitrypsin Treatment for Patients With Alpha-1 Antitrypsin Deficiency Chronic Pulmonary Obstructive Disease: An Update

Abstract

The effect of hereditary alpha-1 antitrypsin (AAT) deficiency can manifest clinically in the form of chronic obstructive pulmonary disease (COPD). AAT deficiency (AATD) is defined as a serum concentration lower than 35% of the expected mean value or 50mg/dl (determined by nephelometry). It is associated in over 95% of cases with Pi*ZZ genotypes, and much less frequently with other genotypes resulting from combinations of Z, S, rare and null alleles. A systematic qualitative review was made of 107 articles, focusing mainly on an active search for AATD in COPD patients and intravenous (iv) treatment with AAT. On the basis of this review, the consultant committee of the Spanish Registry of Patients with AATD recommends that all COPD patients be screened for AATD with the determination of AAT serum concentrations, and when these are low, the evaluation must be completed with phenotyping and, on occasions, genotyping. Patients with severe AATD COPD should receive the pharmacological and non-pharmacological treatment recommended in the COPD guidelines. There is enough evidence from large observational studies and randomized placebo-controlled clinical trials to show that the administration of iv AAT reduces mortality and slows the progression of emphysema, hence its indication in selected cases that meet the inclusion criteria stipulated in international guidelines. The administration of periodic infusions of AAT is the only specific treatment for delaying the progression of emphysema associated with AATD.

Full text

Arch
Bronconeumol.
2015;51(4):185–192
www.archbronconeumol.org
Special
article
Indications
for
Active
Case
Searches
and
Intravenous
Alpha-1
Antitrypsin
Treatment
for
Patients
With
Alpha-1
Antitrypsin
Deficiency
Chronic
Pulmonary
Obstructive
Disease:
An
Update夽
Francisco
Casas,aIgnacio
Blanco,bMaría
Teresa
Martínez,cAna
Bustamante,dMarc
Miravitlles,e
Sergio
Cadenas,fJosé
M.
Hernández,gLourdes
Lázaro,hEsther
Rodríguez,eFrancisco
Rodríguez-Frías,i
María
Torres,jBeatriz
Larak,∗
aUnidad
de
Gestión
Clínica
de
Neumología,
Hospital
Universitario
San
Cecilio,
Granada,
Spain
bRegistro
Espa˜
nol
de
pacientes
con
déficit
de
alfa-1
antitripsina,
Fundación
Espa˜
nola
de
Pulmón,
Respira,
SEPAR
cServicio
de
Neumología,
Hospital
Universitario
Doce
de
Octubre,
Madrid,
Spain
dServicio
de
Neumología,
Hospital
de
Sierrallana,
Torrelavega,
Cantabria,
Spain
eServicio
de
Neumología,
Hospital
Universitari
Vall
d’Hebron,
CIBER
de
Enfermedades
Respiratorias
(CIBERES),
Barcelona,
Spain
fServicio
de
Neumología,
Hospital
Clínico
Universitario
de
Salamanca,
Salamanca,
Spain
gServicio
de
Neumología,
Hospital
General
de
la
Palma,
La
Palma,
Santa
Cruz
de
Tenerife,
Spain
hServicio
de
Neumología,
Hospital
Universitario
de
Burgos,
Burgos,
Spain
iServicio
de
Bioquímica,
Hospital
Universitari
Vall
d’Hebron,
Barcelona,
Spain
jServicio
de
Neumología,
Complexo
Universitario
de
Vigo,
Pontevedra,
Spain
kServicio
de
Neumología,
Hospital
Universitario
Arnau
de
Vilanova,
Lleida,
Spain
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
7
February
2014
Accepted
26
May
2014
Available
online
14
January
2015
Keywords:
Alpha-1
antitrypsin
deficiency
Diagnoses
Treatment
Spanish
Registry
of
Patients
with
alpha-1
antitrypsin
deficiency
a
b
s
t
r
a
c
t
The
effect
of
hereditary
alpha-1
antitrypsin
(AAT)
deficiency
can
manifest
clinically
in
the
form
of
chronic
obstructive
pulmonary
disease
(COPD).
AAT
deficiency
(AATD)
is
defined
as
a
serum
concen-
tration
lower
than
35%
of
the
expected
mean
value
or
50
mg/dl
(determined
by
nephelometry).
It
is
associated
in
over
95%
of
cases
with
Pi*ZZ
genotypes,
and
much
less
frequently
with
other
genotypes
resulting
from
combinations
of
Z,
S,
rare
and
null
alleles.
A
systematic
qualitative
review
was
made
of
107
articles,
focusing
mainly
on
an
active
search
for
AATD
in
COPD
patients
and
intravenous
(iv)
treat-
ment
with
AAT.
On
the
basis
of
this
review,
the
consultant
committee
of
the
Spanish
Registry
of
Patients
with
AATD
recommends
that
all
COPD
patients
be
screened
for
AATD
with
the
determination
of
AAT
serum
concentrations,
and
when
these
are
low,
the
evaluation
must
be
completed
with
phenotyping
and,
on
occasions,
genotyping.
Patients
with
severe
AATD
COPD
should
receive
both
the
pharmacological
and
non-pharmacological
treatments
recommended
in
the
COPD
guidelines.
There
is
enough
evidence
from
large
observational
studies
and
randomized
placebo-controlled
clinical
trials
to
show
that
the
admin-
istration
of
iv
AAT
reduces
mortality
and
slows
the
progression
of
emphysema,
hence
its
indication
in
selected
cases
that
meet
the
inclusion
criteria
stipulated
in
international
guidelines.
The
administration
of
periodic
infusions
of
AAT
is
the
only
specific
treatment
for
delaying
the
progres-
sion
of
emphysema
associated
with
AATD.
©
2014
SEPAR.
Published
by
Elsevier
España,
S.L.U.
All
rights
reserved.
夽Please
cite
this
article
as:
Casas
F,
Blanco
I,
Martínez
MT,
Bustamante
A,
Miravitlles
M,
Cadenas
S,
et
al.
Actualización
sobre
indicaciones
de
búsqueda
activa
de
casos
y
tratamiento
con
alfa-1
antitripsina
por
vía
intravenosa
en
pacientes
con
enfermedad
pulmonar
obstructiva
crónica
asociada
a
déficit
de
alfa-1
antitripsina.
Arch
Bronconeumol.
2015;51:185–192.
∗Corresponding
author.
E-mail
address:
beat1135@gmail.com
(B.
Lara).
1579-2129/©
2014
SEPAR.
Published
by
Elsevier
España,
S.L.U.
All
rights
reserved.
Document downloaded from http://www.archbronconeumol.org, day 04/05/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

186
F.
Casas
et
al.
/
Arch
Bronconeumol.
2015;51(4):185–192
Palabras
clave:
Déficit
de
alfa-1
antitripsina
Diagnóstico
Tratamiento
Registro
de
Pacientes
con
Déficit
de
Alfa-1
Antitripsina
Actualización
sobre
indicaciones
de
búsqueda
activa
de
casos
y
tratamiento
con
alfa-1
antitripsina
por
vía
intravenosa
en
pacientes
con
enfermedad
pulmonar
obstructiva
crónica
asociada
a
déficit
de
alfa-1
antitripsina
r
e
s
u
m
e
n
El
déficit
hereditario
de
la
alfa-1
antitripsina
(AAT)
se
puede
manifestar
clínicamente
como
una
enfer-
medad
pulmonar
obstructiva
crónica
(EPOC).
Se
define
por
una
concentración
sérica
por
debajo
del
35%
del
valor
medio
esperado,
o
50
mg/dL
(medida
por
nefelometría)
y
está
relacionado
en
más
del
95%
de
los
casos,
con
genotipos
Pi*ZZ,
y
muy
infrecuentemente
con
otros
genotipos
resultantes
de
combina-
ciones
entre
alelos
Z,
S,
raros
y
nulos.
Se
ha
realizado
una
revisión
sistemática
cualitativa
de
107
artículos,
centrados
principalmente
en
la
búsqueda
activa
del
déficit
de
AAT
(DAAT)
en
pacientes
con
EPOC
y
en
el
tratamiento
con
AAT
por
vía
intravenosa
(iv).
El
comité
asesor
del
Registro
Espa˜
nol
de
pacientes
con
DAAT,
sobre
la
base
de
esta
revisión,
considera
que
se
debe
descartar
el
DAAT,
mediante
la
cuantificación
de
las
concentraciones
séricas
de
AAT,
en
todos
los
pacientes
con
EPOC
y
cuando
sean
bajas
se
debe
completar
el
estudio
mediante
la
determinación
del
fenotipo
y,
en
ocasiones,
del
genotipo.
El
tratamiento
de
los
individuos
con
EPOC
asociado
a
DAAT
grave
debe
incluir
el
tratamiento
farmacológico
y
no
farmacológico
recomendado
en
las
normativas
de
la
EPOC.
Existe
suficiente
evidencia,
derivada
de
grandes
estudios
observacionales
y
de
ensayos
clínicos
aleatorizados
con
placebo,
que
demuestran
que
el
tratamiento
con
AAT
iv
disminuye
la
mortalidad
y
reduce
la
velocidad
de
progresión
del
enfisema,
por
lo
que
está
indicado
en
casos
seleccionados
que
cumplan
los
criterios
de
inclusión
establecidos
en
las
normativas
internacionales.
La
terapia
con
infusiones
iv
periódicas
de
AAT
es
el
único
tratamiento
específico
que
existe
para
frenar
la
progresión
del
enfisema
asociado
al
DAAT.
©
2014
SEPAR.
Publicado
por
Elsevier
España,
S.L.U.
Todos
los
derechos
reservados.
Introduction
Hereditary
alpha-1
antitrypsin
(AAT)
deficiency
can
manifest
clinically
in
the
form
of
chronic
obstructive
pulmonary
disease
(COPD)
(typically
as
panacinar
pulmonary
emphysema),
liver
cir-
rhosis
at
any
age
and,
less
commonly,
as
panniculitis,
systemic
vasculitis
and
other
diseases.1Severe
AAT
deficiency
(AATD)
is
defined
as
a
serum
AAT
level
lower
than
35%
of
the
expected
mean
value
or
less
than
50
mg/dl
(determined
by
nephelometry).
It
is
associated
with
Pi*ZZ
genotypes
in
over
95%
of
cases,
and
much
less
frequently
with
other
genotypes
resulting
from
combinations
of
Z,
S,
rare
and
null
alleles.2
Since
the
detection
of
severe
AATD
cases
involves
genetic
coun-
seling,
the
study
of
first-degree
relatives
and,
in
selected
cases,
the
administration
of
regular
intravenous
(IV)
AAT
infusions,
in
2006,
the
Spanish
Society
of
Pulmonology
and
Thoracic
Surgery
(SEPAR),
in
collaboration
with
the
Spanish
Registry
of
Patients
with
AATD
(REDAAT)
advisory
committee,
published
guidelines
on
the
diagnosis
and
treatment
of
AATD,
the
basic
concepts
of
which
remain
valid
today.3However,
several
subsequent
studies4–7 have
provided
new
data
supporting
the
importance
of
detecting
AATD
in
individuals
with
COPD
and
the
use
of
replacement
therapy
in
patients
with
COPD
and
severe
AATD,8–13 all
of
which
justify
this
update.
Methodology
The
authors
performed
a
literature
search
of
articles
published
between
1985
and
2013
in
the
MEDLINE,
EMBASE
and
Cochrane
Library
databases,
using
the
keywords:
“alpha-1
antitrypsin
deficiency”,
“COPD”,
“asthma”,
“bronchiectasis”,
“augmentation
therapy”
and
“replacement
therapy”.
Meta-analyses
and
system-
atic
reviews
by
other
authors,
based
on
quality
of
scientific
evidence,
as
well
as
some
articles
cited
in
those
selected
previ-
ously
and
not
detected
in
the
databases,
were
also
included
for
analysis.
A
total
of
289
abstracts
were
obtained
using
the
terms
“alpha-1
antitrypsin
deficiency”
and
“COPD”;
154
using
“alpha-1
antitrypsin
deficiency”
and
“asthma”;
87
using
“alpha-1
antitrypsin
deficiency”
and
“bronchiectasis”;
129
using
“alpha-1
antitrypsin
deficiency”
and
“augmentation
therapy”;
and
71
using
“alpha-1
antitrypsin
deficiency”
and
“replacement
therapy”.
After
3
general
meetings
and
1
final
single-subject
meeting,
we
performed
a
qualitative
systematic
analysis
of
the
articles
selected
in
order
to
draw
up
this
document.
After
deleting
dupli-
cates
found
in
the
various
searches,
and
using
the
information
provided
in
the
abstract
of
the
articles
selected
(or
the
full
text
when
this
was
not
sufficiently
explicit),
107
articles1–107 were
cho-
sen
by
consensus.
Most
were
focused
on
the
active
search
for
AATD
in
COPD
patients
and
on
replacement
therapy
in
patients
with
severe
AATD-associated
COPD.
The
authors
individually
assessed
the
manuscripts
considered
potentially
useful,
and
rated
them
according
to
GRADE
System
criteria
for
grading
the
quality
of
evi-
dence
and
strength
of
recommendations,
Regulations
for
Writing
SEPAR
Guidelines108,109 and
American
College
of
Chest
Physicians
Task
Force110 criteria,
amended
by
the
Canadian
Thoracic
Soci-
ety
COPD
Clinical
Assembly
Alpha-1
Antitrypsin
Deficiency
Expert
Working
Group.13 After
reviewing
the
results,
the
conclusions
described
below
were
agreed
among
the
members
of
the
advisory
committee.
Results
The
results
of
the
qualitative
systematic
analysis
are
summa-
rized
in
Tables
1
and
2.
It
should
be
noted
that
the
REDAAT
working
group
detected
major
shortcomings
in
the
literature,
which
high-
light
the
need
for
future
high
quality
studies
to
address
several
of
the
issues
raised.
Even
so,
analysis
of
the
4
papers
selected49,54,71,93
and
a
recent
high-quality
meta-analysis13 focusing
on
research
of
AATD
in
COPD
suggest
that
AATD
should
be
ruled
out
by
measur-
ing
serum
AAT
concentrations
in
all
patients
with
COPD,
and
when
these
are
low,
the
study
should
be
completed
by
phenotyping
and,
occasionally,
genotyping
(consistent
recommendation
with
high
quality
evidence,
which
confirms
the
recommendations
proposed
in
the
2006
guidelines).3
The
working
group,
based
on
the
level
of
evidence
provided
by
13
specific
studies
on
IV
AAT
treatment,4,5,10,12,13,37,40,42,46,53,55,83,96
considers
that
replacement
therapy
is
indicated
in
patients
Document downloaded from http://www.archbronconeumol.org, day 04/05/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

F.
Casas
et
al.
/
Arch
Bronconeumol.
2015;51(4):185–192
187
Table
1
Summary
of
REDAAT
Recommendations
on
ATTD
Screening
in
COPD,
Bronchiectasis
and
Bronchial
Asthma,
and
on
the
Use
of
Replacement
Therapy.
Strength
of
recommendation
REDAAT
recommendations
Quality
of
evidence
Consistent
recommendation
The
working
group
recommends
determination
of
plasma
AAT
concentrations
in
all
subjects
with
COPDa
High
quality
evidence
Consistent
recommendation
This
working
group
does
not
recommend
routine
determination
of
AAT
concentrations
in
patients
with
bronchiectasis.
Testing
should
be
on
a
case-by-case
basisb
Low
quality
evidence
Consistent
recommendation
This
working
group
does
not
recommend
routine
determination
of
AAT
concentrations
in
asthmatic
patients.
Testing
should
be
on
a
case-by-case
basisb
Low
quality
evidence
Consistent
recommendation IV
AAT
replacement
therapy
is
indicated
in
patients
who
are
never-smokers
or
former
smokers
with
COPD
associated
with
severe
AAT
deficiencyd,
whose
FEV1is
less
than
80%
of
predicted,
and
who
are
correctly
treated
(pharmacological
and
non-pharmacological
treatment
of
COPD),
in
whom
respiratory
functional
decline
and/or
emphysema
progression
has
been
documentedc
Moderate
quality
evidence
AAT:
alpha-1
antitrypsin;
IV:
intravenous;
AATD:
alpha-1
antitrypsin
deficiency;
COPD:
chronic
obstructive
pulmonary
disease;
FEV1:
forced
expiratory
volume
in
the
first
second;
REDAAT:
Spanish
Registry
of
Patients
with
Alpha-1
Antitrypsin
Deficiency.
aConsistent
recommendation,
high
quality
evidence.
Can
be
applied
to
most
patients
in
most
circumstances.
bConsistent
recommendation,
low
quality
evidence.
May
change
when
other
tests
are
available.
cConsistent
recommendation,
moderate
quality
evidence.
May
change
when
other
tests
are
available.
dSevere
deficiency
is
defined
as
serum
AAT
concentrations
≤50
mg/dl,
measured
by
nephelometry.
It
is
generally
associated
with
PIZZ
phenotypes
and
combinations
of
rare
and
null
alleles,
with
each
other
or
with
Z
and
S.
AATD
is
not
considered
severe
when
it
is
associated
with
the
MZ
phenotypes
or
most
SZ
phenotypes,
except
for
those
with
AAT
concentrations
≤50
mg/dl.
with
severe
AATD
(defined
as
an
AAT
concentration
≤50
mg/dl,
measured
by
nephelometry),
never-smokers
or
former
smok-
ers,
diagnosed
with
COPD
and
lung
function
decline
(FEV1<80%
of
predicted
value),
with
documented
loss
of
lung
function
or
emphysema
progression,
despite
optimal
pharmacological
and
non-pharmacological
treatment
of
COPD.
Replacement
therapy
is
not
indicated
in
Pi*MZ
heterozygotes
or
in
most
Pi*SZ
individuals,
except
in
rare
cases
of
SZ
heterozygotes
with
serum
AAT
concen-
trations
less
than
or
equal
to
50
mg/dl
who
meet
the
other
criteria
listed
in
Tables
3
and
4
(consistent
recommendation
with
moder-
ate
quality
evidence,
and
in
accordance
with
SEPAR
guidelines).3
Replacement
therapy
is
not
indicated
for
liver
disease
caused
by
AATD.
With
regard
to
the
results
of
3
studies6,33,48 on
the
prevalence
of
AATD
in
patients
with
bronchiectasis
and
1
meta-analysis,13 the
REDAAT
working
group
does
not
recommend
routine
determina-
tion
of
AAT
concentrations
in
patients
with
bronchiectasis.
This
practice
should
be
determined
on
a
case-by-case
basis
(consistent
recommendation
with
low
quality
evidence).
Considering
the
results
of
5
studies
on
the
prevalence
of
AATD
in
asthmatic
patients7,49,54,56,70 and
1
meta-analysis,13 the
authors
do
not
recommend
routine
measurement
of
AAT
concentrations
in
these
patients.
This
practice
should
be
determined
on
a
case-by-
case
basis
(consistent
recommendation
with
low
quality
evidence).
Discussion
The
results
shown
support
the
recommendation
to
rule
out
AATD
in
all
patients
with
COPD.
This
was
proposed
by
the
World
Health
Organization
as
far
back
as
1997,35 and
was
subsequently
included
in
various
guidelines,
including
those
of
the
American
Thoracic
Society
(ATS),
the
European
Respiratory
Society
(ERS)
and
SEPAR.1,3 Furthermore,
although
there
are
insufficient
studies
to
precisely
establish
a
strength
of
recommendation,
the
authors
also
advise
ruling
out
AATD
in
first-degree
relatives
of
the
index
case,
even
if
they
are
asymptomatic,
due
to
the
high
probability
that
some
may
be
carriers
of
severe
mutations
and
may
benefit
from
genetic
counseling
and
preventive
measures
(the
most
important
being
to
avoid
inhaling
cigarette
smoke
and
other
pollutants).1,3
With
respect
to
other
obstructive
airways
diseases,
the
REDAAT
working
group
agrees
with
other
authors13 in
not
recommending
routine
determination
of
AAT
levels
to
rule
out
severe
deficiency
in
patients
with
either
bronchiectasis
or
asthma,
leaving
the
decision
to
request
this
test
in
specific
cases
at
the
discretion
of
the
attending
physician,
e.g.
in
patients
with
emphysema
lesions
associated
with
the
aforementioned
conditions.
Quantitative
serum
AAT
measurement,
most
often
by
neph-
elometry,
is
the
basis
for
diagnosing
AATD.
When
the
AAT
concentration
is
lower
than
the
reference
range,
the
study
should
be
completed
by
phenotyping
(protein
or
allele
variants).
The
com-
bination
of
both
techniques
is
sufficient
to
clarify
most
cases
of
AATD.
Isoelectric
focusing
is
the
most
widely
used
method
to
iden-
tify
allelic
variants,
and
can
characterize
up
to
30
AAT
deficiency
variants.
Since
each
phenotype
has
its
own
range
of
AAT
values,
in
cases
in
which
the
AAT
concentration
is
not
consistent
with
the
phenotype,
the
presence
of
null
or
rare
deficient
alleles
should
be
suspected,
and
consequently,
the
genotype
should
be
determined.95 AAT
gene
sequencing
by
real
time
polymerase
chain
reaction
(PCR)
is
the
reference
method
for
clarifying
these
discordant
cases
(Fig.
1).3,95
The
dried
blood
spot
samples
used
in
screening
programs
indi-
cate
the
presence
or
absence
of
the
alleles
studied,
but
cannot
exclude
the
presence
of
other
deficiency
alleles.
Genotyping
must
therefore
be
performed
in
cases
in
which
the
AAT
concentration
is
not
consistent
with
the
phenotype.
Dried
blood
spot
samples
can
currently
be
genotyped
using
PCR
sequencing.
These
methods
are
reliable,
but
each
laboratory
must
report
the
method
used
and
its
possible
limitations.
With
respect
to
treatment,
the
REDAAT
working
group
considers
that:
–
Treatment
of
individuals
with
severe
AATD-associated
COPD
should
include
the
pharmacological
and
non-pharmacological
treatment
recommended
in
COPD
guidelines.111
–
There
is
sufficient
evidence
available
(although
of
moderate
quality4,5,10,12,13,37,40,42,46,53,55,83,96)
to
recommend
replacement
therapy
in
individuals
with
COPD
associated
with
severe
AATD
(serum
AAT
concentrations
≤50
mg/dl),
never-smokers
or
former
smokers,
whose
FEV1is
less
than
80%
of
predicted
and
who
have
loss
of
lung
function
or
emphysema
progression,
despite
standard
COPD
treatment.
–
Regular
AAT
replacement
therapy
is
the
only
specific
treatment
to
slow
the
progression
of
AATD-associated
emphysema.
Its
efficacy
has
been
demonstrated
in
randomized,
double-blind,
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188
F.
Casas
et
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/
Arch
Bronconeumol.
2015;51(4):185–192
Table
2
Summary
of
Studies
Evaluating
Augmentation
Therapy.
Authors
Dose
Type
of
study
Results
measure
Results
Level
of
evidence
Non-randomized
studies
Seersholm
et
al.37 (1997)
60
mg/kg/7
days
Observational
study
with
control
group
(n=295)
FEV1decline
Reduction
in
FEV1decline
in
the
treatment
group
(56
vs
75
ml/year;
P=.02).
Greater
benefit
in
patients
with
FEV131%–65%
C2
American
AAT
Deficiency
Registry
Study
Group40 (1998)
33%
weekly
doses;
43%
fortnightly
and
24%
monthly
Observational
study
with
control
group
(n=1129)
FEV1decline
Mortality
Reduction
in
mortality
(OR=0.64;
P=.02)
The
FEV1decline
is
slower
in
patients
receiving
IV
replacement
therapy
with
FEV135%–49%
(66
vs
93
ml/year;
P=.03)
C2
Wencker
et
al.53 (2001)
60
mg/kg/7
days
Observational
cohort
with
no
control
group
(n=96)
FEV1decline
The
rate
of
FEV1decline
was
slower
during
the
treatment
period
(49.2
vs
34.2
ml/year,
P=.019)
and
was
slower
in
patients
with
FEV1>65%
(256
vs
53
ml/year,
P=.001)
C2
Tonelli
et
al.83 (2009)
Observational
study
with
control
group
(n=164)
FEV1decline
Mortality
Gain
in
FEV1of
10.6
±
21.4
ml/year
vs
loss
of
36.96
±
12.1
ml/year;
P=.05)
No
differences
in
mortality
C2
Ma
et
al.42 (2013)
60
mg/kg/7
days
Observational
cohort
study
with
control
group
(n=100)
Plasma
desmosine
and
isodesmosine
A
significant
reduction
in
desmosine
and
isodesmosine
levels
in
the
patient
cohort
on
IV
AAT
replacement
therapy
vs
untreated
patients
(P<.0001),
with
values
similar
to
the
normal
population
C1
Ma
et
al.42 (2013)
60
mg/kg/7
days
Observational
study
with
no
control
group
(n=10)
Desmosine
and
isodesmosine
in
bronchoalveolar
lavage
and
plasma
Significant
reduction
in
desmosine
and
isodesmosine
levels
in
bronchoalveolar
lavage
(P=.0273)
and
in
plasma
at
12
(P=.0038)
and
24
weeks
(0.0038)
after
receiving
IV
replacement
therapy
C2
Randomized
studies
Dirksen
et
al.4(2009)
60
mg/kg/7
days
Randomized,
double-blind,
placebo-controlled
study
(n=77)
(COPD
with
FEV1=
25%–80%)
Lung
function,
quality
of
life,
exacerbations
and
loss
of
CT
lung
density
Reduction
in
loss
of
CT
lung
density
in
treated
patients
(P=.049)
No
differences
in
FEV1or
DLCO
No
differences
in
frequency
of
exacerbations,
but
less
severe
in
the
treatment
group
B1
Meta-analyses
Chapman
et
al.12 (2009)
Meta-analysis
of
studies
in
patients
on
replacement
therapy
vs
controls
in
the
Canadian
Registry
(n=1509)
FEV1decline
Reduction
in
FEV1decline
in
patients
on
IV
replacement
therapy
by
26%
(17.9
ml/year).
Effect
due
to
subgroup
of
subjects
with
FEV1
30%–65%
B1
Gøtzsche
and
Johansen10
(2010)
60
mg/kg/7
days
Cochrane
meta-analysis
of
2
randomized,
placebo-controlled
studies
(n=140)
Decline
in
FEV1,
DLCO
and
loss
of
CT
lung
density
Exacerbations
The
lung
density
loss
was
less
in
patients
on
IV
replacement
therapy
(P=.03)
No
differences
in
lung
function
No
difference
in
exacerbations
B2
Stockley
et
al.5(2010)
60
mg/kg/7
days
Comprehensive
analysis
of
lung
density
(n=119)
Decline
in
lung
density
and
FEV1
Less
lung
density
loss
in
treated
patients
(1.73
vs
2.74
g/l,
P=.006)
No
differences
in
FEV1decline
A1
Marciniuk
et
al.13 (2012)
Meta-analysis
of
all
studies
in
patients
on
IV
replacement
therapy
vs
controls
All
parameters
Reduction
in
CT
lung
density
loss
and
reduction
in
mortality
B1
Studies
in
exacerbations
Lieberman46 (2000)
55%
weekly
doses,
37%
fortnightly
and
8%
monthly
Observational
(internet
survey)
(n=89)
Frequency
of
exacerbations
Reduction
in
the
frequency
of
exacerbations
from
3–5/year
to
0–1/year
after
starting
IV
replacement
therapy
C2
Stockley
et
al.55 (2002)
60
mg/kg/7
days
Descriptive
study
(n=12)
Inflammatory
markers
in
sputum
Significant
reduction
in
LTB4
in
sputum
following
treatment
C2
Barros-Tizón
et
al.96
(2012)
180
mg/kg/21
days
Retrospective
study
(pre–post
IV
replacement
therapy)
Frequency
and
severity
of
exacerbations
and
hospitalization
costs
Reduction
in
the
number
and
severity
of
exacerbations
and
hospitalization-derived
costs
C1
AAT:
alpha-1
antitrypsin;
IV:
intravenous;
AATD:
alpha-1
antitrypsin
deficiency;
DLCO:
carbon
monoxide
diffusing
capacity;
FEV1:
forced
expiratory
volume
in
the
first
second;
LTB4:
leukotriene
B4;
CT:
computed
tomography.
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F.
Casas
et
al.
/
Arch
Bronconeumol.
2015;51(4):185–192
189
Clinical suspicion of AATD
No AATD
Normal
Severe deficiency
<35% 35%-80%. Mild-
moderate deficiency
Low
Phenotype
Genotype
SZ
MZ
SS
MS
ZZ (95%)
Null-Null
Z-Null
Z-Rare
Null-Rare
Serum AAT concentration
(in stable clinical condition)
Fig.
1.
Diagnostic
algorithm
for
AAT
deficiency
(AATD).
Taken
from
Vidal
et
al.3
placebo-controlled
studies,
with
analysis
of
the
decline
in
lung
density
as
the
primary
outcome
measure.
Table
3
specifies
the
REDAAT
requirements
for
replacement
therapy.
Table
4
provides
more
detail
on
the
procedure
to
be
fol-
lowed
before
commencing
treatment.
Table
2
lists
the
main
studies
Table
3
REDAAT
Criteria
for
IV
AAT
Therapy.a
1.
Aged
18
years
or
over
2.
AATD
demonstrated
by
serum
concentrations
≤50
mg/dl
3.
Never-smokers
or
ex-smokers
for
at
least
the
last
6
months
4.
Pulmonary
emphysema
demonstrated
by
lung
function
tests
and/or
chest
HRCT
5.
COPD
with
FEV1<80%
of
predicted,bwho
are
receiving
optimal
pharmacological
and
non-pharmacological
treatment
6.
Do
not
have
immunoglobulin
A
deficiency
7.
Prepared
to
receive
regular
treatment
at
a
day
hospital
AAT:
alpha-1
antitrypsin;
IV:
intravenous;
AATD:
alpha-1
antitrypsin
deficiency;
COPD:
chronic
obstructive
pulmonary
disease;
FEV1:
forced
expiratory
volume
in
the
first
second;
REDAAT:
high
resolution
computed
tomography.
aAll
criteria
must
be
met.
bIntravenous
AAT
therapy
should
not
be
discontinued
in
a
patient
who
has
already
been
treated
if
their
lung
function
deteriorates
and/or
their
FEV1falls
below
25%.
Table
4
Procedure
to
be
Followed
Prior
to
Commencing
IV
AAT
Replacement
Therapy.
Informed
consenta
Additional
tests
Determination
of
serum
immunoglobulins
Complete
liver
function
tests
Serology
for
hepatitis-B
virus
and
human
immunodeficiency
virus
Lung
function
tests:
spirometry,
lung
volumes
and
carbon
monoxide
diffusing
capacity
Arterial
blood
gases:
if
peripheral
oxygen
saturation
is
less
than
92%
Chest
HRCT
scan
Hepatitis
B
vaccination
AAT:
alpha-1
antitrypsin;
IV:
intravenous;
HRCT:
high
resolution
computed
tomo-
graphy.
aAvailable
on
the
website
of
the
(http://www.redaat.es/presentacion.php)
and
the
Andalusia
Regional
Government
Health
website,
in
the
area
on
Informed
Consent
for
Respiratory
Medicine
procedures
(http://www.juntadeandalucia.es/
salud/sites/csalud/contenidos/Informacion
General/p
3
p
11
procedimiento
consentimiento
informado/neumologia?perfil=org).
on
its
efficacy
or
effectiveness
in
patients
with
COPD
and
severe
AAT,
and
the
quality
of
evidence.
The
efficacy
of
replacement
therapy
is
defined
on
the
basis
of
biochemical
and
clinical
criteria.
Biochemical
efficacy
has
been
demonstrated,
as
IV
AAT
administration
increases
serum
values
above
those
considered
protective,
increases
its
concentra-
tion
in
alveolar
fluid,
and
neutralizes
neutrophil
elastase.18,19 It
has
been
agreed
that
the
serum
AAT
value
that
protects
the
lung
against
free
neutrophil
elastase
should
be
greater
than
or
equal
to
50
mg/dl
(if
determined
by
nephelometry),
80
mg/dl
(if
measured
by
radial
immunodiffusion)
or
11
␮M/l
(if
the
NHLBI
standard
from
the
US
Registry
is
used).
This
widely
disseminated
and
applied
laboratory
criterion
is
based
on
studies
by
Wewers
et
al.
(1987)18 and
Turino
et
al.
(1996).34 The
former18 shows
the
biochemical
efficacy
of
AAT
replacement
therapy
(moderate
quality
evidence)
but
is
insufficient
to
establish
a
protective
cut-off
value.
The
latter34 describes
the
clinical
characteristics
of
59
SZ
subjects,
of
whom
52%
were
receiv-
ing
or
had
received
IV
AAT
treatment,
and
has
been
used
to
justify
the
biochemical
criteria
for
patient
selection
for
AAT
replacement
therapy.
However,
the
quality
of
scientific
evidence
is
very
low,
and
its
findings
cannot
be
extrapolated
to
the
other
SZ
subjects.
Simi-
lar
arguments
are
applicable
to
another
descriptive
study
in
25
SZ
subjects.17
Various
studies
have
shown
the
clinical
efficacy
of
replace-
ment
therapy,4,10,12,13,37,40,42,46,53,55,83,96 the
most
important
being
the
study
by
Dirksen
et
al.,4a
randomized,
double-blind,
placebo-
controlled
trial
in
which
the
primary
endpoint
was
loss
of
lung
density
measured
by
computed
tomography
(CT).
This
showed
a
significantly
lower
annual
loss
of
lung
density
in
subjects
who
received
AAT
replacement
therapy
compared
to
those
who
did
not.
There
were
no
differences
in
lung
function,
exacerbations
and
quality
of
life
(St.
George’s
questionnaire)
between
groups.
A
sub-
sequent
analysis
by
Stockley
et
al.,5combining
data
from
these
2
trials,
confirmed
lung
tissue
loss
was
lower
in
subjects
treated
with
IV
AAT
vs
placebo
(P=.006).
A
meta-analysis
conducted
by
Chapman
et
al.
on
5
studies
with
a
total
of
1509
patients
found
that
AAT
replacement
therapy
signif-
icantly
reduced
annual
decline
in
FEV1,
especially
in
patients
with
an
FEV1between
30%
and
65%
of
predicted.12
In
another
meta-analysis,
Gøtzsche
and
Johansen10 concluded
that
AAT
replacement
therapy
cannot
be
recommended,
based
on
its
lack
of
efficacy
and
high
cost.
However,
this
analysis
has
been
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190
F.
Casas
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/
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2015;51(4):185–192
widely
criticized
by
the
scientific
community
and
patient
associa-
tions,
such
as
the
Alpha-One
Foundation,
for
its
partiality.
It
bases
its
conclusions
on
2
studies
with
a
total
of
140
patients
and
downplays
the
importance
of
measuring
loss
of
CT
lung
density,
when
this
loss
is
a
central
feature
in
the
natural
history
of
these
patients.
Fur-
thermore,
it
excludes
the
results
of
some
observational
studies
that
support
the
clinical
efficacy
of
AAT
replacement
therapy,
and
which
have
been
the
basis
for
its
indication
in
ATS,
ERS
and
American
College
of
Physicians
guidelines,
including
the
multicenter
prospec-
tive
cohort
study
conducted
in
1129
patients
with
AATD
in
the
American
Registry.
This
study
showed
a
36%
reduction
in
mortality
(Relative
Risk
=
0.64)
and
a
significant
reduction
in
the
FEV1decline
in
the
subgroup
of
patients
with
FEV1values
between
35%
and
49%.40
Finally,
a
recent,
extremely
thorough
meta-analysis
by
the
Canadian
Thoracic
Society13 recommends
replacement
therapy
in
patients
with
COPD
and
FEV1between
25%
and
80%,
never-smokers
or
former
smokers,
with
documented
AATD
(11
␮mol/l),
who
are
receiving
optimal
pharmacological
and
non-pharmacological
treat-
ment
(including
rehabilitation),
because
of
the
benefits
that
it
provides
(less
loss
of
lung
density,
demonstrated
by
CT
densito-
metry,
and
reduction
in
mortality).
In
conclusion,
severe
AAT
deficiency
is
a
rare
genetic
condi-
tion
that
principally
manifests
clinically
as
pulmonary
emphysema.
There
is
sufficient
evidence
to
recommend
AAT
replacement
therapy
(Table
2)
in
patients
who
meet
certain
conditions
(Table
3).
This
working
group
is
of
the
opinion
that
further
studies
are
warranted
to
better
determine
the
mechanisms
that
lead
to
the
development
of
COPD
in
subjects
with
AATD,
and
to
determine,
with
stronger
evidence,
the
AAT
level
needed
to
protect
the
lung
from
the
elastolytic
action
of
elastase,
in
stable
conditions
and
in
the
case
of
exacerbation,
as
well
as
the
dose
of
AAT
required
to
reach
these
protective
levels.
Finally,
the
authors
believe
that
better
and
more
cost-effective
means
for
producing
and
administering
AAT
must
be
found.
Funding
The
authors
have
not
received
any
funding
for
this
article.
Conflict
of
Interest
The
Spanish
Lung
Foundation
(Respira)
received
donations
from
Laboratorios
Grifols
for
sponsoring
activities
by
the
Spanish
Reg-
istry
for
Patients
with
Alpha-1
Antitrypsin
Deficiency.
Ana
Bustamante
received
honoraria
for
lecturing
from
Grifols,
Astra,
Boheringer-Ingelheim,
Pfizer,
Chiesi,
and
Almirall.
Francisco
Casas
received
honoraria
for
scientific
advice
and/or
for
lecturing
from
Almirall,
AstraZeneca,
Boehringer
Ingelheim,
Grupo
Ferrer,
GlaxoSmithKline,
Grifols,
Laboratorios
Esteve,
Pfizer,
Novartis
and
Takeda.
José
María
Hernández
received
honoraria
from
Grifols
for
scien-
tific
advice
and
for
lecturing.
Lourdes
Lázaro
received
honoraria
from
Grifols
for
lecturing.
Beatriz
Lara
received
honoraria
for
lecturing
from
Boehringer
Ingelheim,
Pfizer,
Grifols
and
Novartis.
Marc
Miravitlles
received
honoraria
for
scientific
advice
and/or
for
lecturing
from
Almirall,
AstraZeneca,
Bayer
Schering
Boehringer
Ingelheim,
Grupo
Ferrer,
GlaxoSmithKline,
Grifols,
Laboratorios
Esteve,
Pfizer,
Novartis
and
Nycomed.
María
Torres
received
honoraria
from
Grifols
for
scientific
advice.
Acknowledgements
The
REDAAT
Committee
would
like
to
thank
Doctors
Rafael
Vidal,
Rosendo
Jardí,
Juan
Carlos
Barros-Tizón,
Pedro
Pablo
Espa˜
na
and
Carlos
Escudero
for
their
contribution
to
the
work
of
the
Reg-
istry
over
the
years.
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