1. health and fitness
2. therapy

Canadian Respiratory Conference 2010
“A Breath of Fresh Air”
Orphan Disease Session
Challenges in Recognizing, Testing and Managing
Alpha-1-Antitrypsin Deficiency Patients
Jean Bourbeau, MD,
Associate Professor
Montreal Chest Institute, RVH
MUHC, McGill University,
Montréal, CANADA
Montreal Chest Institute
Royal Victoria Hospital
Disclosure Information
Personal financial relationships with commercial
interests
Served as a speaker at conferences:
• Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer
Served on advisory boards:
• AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis,
Pfizer and Talecris.
Received fundings (contract and investigator initiated research):
• AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and
Pfizer.
Personal financial relationships with non-commercial
interests
• Received research grants from CIHR, FRSQ, MUHC.
Outline
• Historic and definition
• Physiopathology and genetic
• Epidemiology and presentation in clinic
• Diagnostic and testing
• Treatment including augmentation therapy and “best
evidence”
• Conclusions and recommendations
AATD: History
Laurell and Eriksson 1963:
•
Absence of the alpha1 band in electrophoresis in patients
with panlobular emphysema
Serum protein electrophoresis of a patient with alpha1-antitrypsin deficiency
Alpha1-Antitrypsin Deficiency (AATD):
Definition
AATD is a common genetic disorder characterized by
•reduction in serum levels of AAT
(typically <11 µmol/L or 0.8 g/L)
• early onset of emphysema and cirrhosis
(also bronchiectasis, hepatoma and panniculitis)
AATD: Physiopathology
• Glycoprotein
synthesized mainly in the liver and the most abundant
of the circulating antiproteases
• Basic
physiologic function “protease anti-protease principle”:
– wide spectrum of anti protease activity
– primary function is to inhibit neutrophil elastase (NE)
• New discoveries “unfolded AAT protein forms polymers” :
– accumulate in hepatocytes and lung epithelial cells and cannot be effectively
secreted into plasma “deficiency in AAT”
– Other consequences:
•
induce local release of chemokines and recruitment of inflammatory cells
•
involve caspase-3 and apoptosis of epithelial cells
Brantly M AJM 1998;84 Suppl 6A: 13–31.
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med 2003;168(7):818−900.
Köhnlein T and Welte T. AM J Med 2008;121:3-9
Wanner A 2009; Chest; 135: 1342-1344
AATD: Genetic variants
About 100 genetic variants; not all associated with the disease1:
–The two most frequent deficiency alleles are Pi S and Pi Z.2
Inheritance of two Pi*Z alleles results in severe deficiency of AAT.
1
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med 2003;168(7):818−900.
Reviewed in Luisetti 2007; Breathe 4(1):39−46.
Adapted from Crystal RG et al. Chest 1989;95:196–208.
2
AATD: Genetic variants
M variant
Most common variant
AAT function and serum concentrations
are normal
S variant
Plasma levels slightly reduced
Minimal clinical relevance
Z variant
Protein misfolding (AAT polymerization)
Plasma levels greatly reduced
One of the most common deficiency variant
Null variant
There is no measurable AAT in the
serum (lack of synthesis)
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med 2003;168(7):818−900.
AATD: Inherited as an
Autosomal Codominant Gene1
Phenotypes
of Parents
Normal
AATD
M M
Z Z
Phenotypes
of Children
M
Z
Carrier
Carrier
Phenotypes
of Parents
M
Possible Phenotypes
of Children
M M
Normal
M M
or
Z Z
Carrier
M
Z
M
Z
Z Z
Z
Carrier
= Homozygote
AATD
M
Z
= Heterozygote
Risk of a homozygous ZZ offspring is 1 in 4 for each birth
if both parents are carriers of the Z allele
1
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med 2003;168(7):818−900.
Serum AAT (µM)
AATD:
Serum levels depending on Pi genotype
A level of less than 11 µM (80 mg/dL if measured by radial immunodiffusion; 50 mg/dL
if measured by nephelometry) is associated with an increased risk for emphysema.
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med 2003;168(7):818−900.
AATD: Epidemiology
AATD is a rare disease?
Frequency in Canada of severe AATD is thought to be comparable
to prevalence of cystic fibrosis1
More than 3 million people worldwide (69 countries) have
deficiency allele combinations (PiSS, PiSZ, PiZZ)2
~ 1 in 6000 Canadians is estimated to have the PiZZ genotype2
~ 1 in 9000 in the USA2
~ 1 in 5000 in Europe3
1
Abboud RT, et al. Can Respir J 2001;8(2):81−88.
De Serres FJ, et al. Mon Arch Chest Dis 2007;67: 4, 184–208.
3
Blanco I, et al. Eur Respir J 2006;27: 77–84, 1179–1186.
2
AATD: Clinical presentation
AATD has a distinctive clinical presentation?
Textbooks talk about symptoms of dyspnea usually not
with “bronchitis” symptoms and irreversible disease
The reality:
~ signs and symptoms resemble those of other COPD1,2
- high prevalence of cough, phlegm and wheezing
- 60% have reversible airflow obstruction
1
2
ATS/ERS. Am J Respir Crit Care Med 2003;168(7):818−900.
Stoller et al. 2005; Lancet; 365 (9478): 2225-2236.
AATD: Radiological presentation
AATD has a distinctive radiological presentation?
Textbooks talk about early-onset emphysema with distinctive
pattern of lower-lobe emphysema
The reality (with CT Scan):
~ 2/3 basilar- predominant disease1
~ 1/3 upper lobe-predominant disease1
~ AATD in the NETT: almost invariably had upper lobepredominant emphysema2
1
2
Parr et al. 2004; AJRCCM; 170 (11): 1172-1178
Stoller et al. 2007; Ann Thorac Surg; 83 (1): 241-251
AATD: Making the diagnosis
Identify
Serum Level
Identify
Mutation
Definitive
Diagnosis
√
√
AAT serum level test
• Determines AAT levels in the blood or serum
√
• May not identify heterozygotes
AAT genotyping
• Diagnosis at a molecular level by identifying abnormal AAT gene
• Typically performed using PCR
• Identifies whether a patient has S or Z allele(s)
AAT phenotyping
• Determines the type of AAT protein in the blood via isoelectric
focusing on polyacrylamide gels
• Can detect mutations that produce circulating AAT proteins
(i.e., new/rare mutations screening!)
For most
common
alleles
√
Can
detect
new/rare
mutations
• Relies on subjective analysis that requires a high level of expertise to
read; more costly; limited number of experts available for reading tests
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med 2003;168(7):818−900.
√
AATD: Making the diagnosis
Large-scale screening (newborns/adults) of AATD?
It is remarkably simple (dried blood-spot sample); should it be
done more than less…
The argument against screening as opposed to case finding:
~ We don’t know if this contribute to a better chance of successful smoking
cessation?
~ Neonatal screening1, 2:
- can have important psychological consequences on parents and child
(insufficient counseling)
- half thought that the knowledge of the AATD had affected their lives
(awareness of the danger of smoking and environment pollution)
1
2
Sveger et al. 1999; Acta Paediatr; 88: 315-318.
Sveger et al. 1997; Acta Paediatr; 86: 37-40
AATD: Treatment
The treatment does not differ basically from
symptomatic therapy of COPD:
• Particular emphasis is place on smoking cessation and avoid
environment pollution
• Vaccination
• Pulmonary rehabilitation and self-management education
(adherence to med., healthy lifestyle habits)
• Symptomatic drug treatment to improve dyspnea and prevent
exacerbation
AATD: Treatment
The most effective treatment in patients with
advances disease:
• lung transplantation
• LVRS not long lasting in this population but it has been used as
a bridging procedure1,2
1
2
Tutic et al. 2004; Ann Thorac Surg; 128: 408-413
Tutic et al. 2006; Ann Thorac Surg; 82 (1): 208-213
AATD: Augmentation therapy
IV administration of human AAT is well tolerated and has
been shown to increase the levels of AAT in blood and
alveolar lining fluid1
It seems to be safe and well tolerated
In contrast to the proven biochemical effectiveness of
augmentation therapy, the clinical benefits of AAT on PFT,
emphysema progression, morbidity and mortality has not been
demonstrated from RCT
1
Wewers et al. 1987; N Engl J Med; 316: 1055-1062
Augmentation Therapy: Clinical Trial Review
Study
N
Design
Results
Seersholm, et al.1
N=295
Prospective, controlled,
nonrandomized, random effect
modelling study
Slower decline in lung function in treated
group vs untreated group (p=0.02)
AAT Deficiency
Registry Study
Group2
N=927
Prospective, multicentre,
nonrandomized study
Decreased mortality in patients receiving
therapy (p=0.02); slower decline in LFT in
treated patients with moderately decreased
LFT (FEV135-49% pred. decline) (p=0.03)
Dirksen, et al.
Danish/Dutch
Study Group3
N=56
Double-blind, randomized,
self administered, prospective
study
No significant difference in decline in FEV1
in patients treated with AAT vs. placebo;
trend towards improved loss of lung tissue
for AAT vs. placebo (p=0.07)
Wencker, et al.4
N=96
Multicentre, retrospective
cohort study
Slower decline in FEV1 during treatment
period vs pretreatment period for entire
group (p=0.019)
Dirksen, et al. 5
N=82
Double-blind, randomized,
placebo-controlled, parallelgroup study
Mean decline in whole lung density using 4
exploratory methods: Difference in the 4
methods suggesting a trend toward a
beneficial treatment effect (0.049-0.084)
No difference FEV1, SGRQ, AECOPD
1
Seersholm N, et al. Eur Respir J 1997;10:2260−2263. 2The Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J
Respir Crit Care Med 1998;158:49−59. 3Dirksen A, et al. Am J Respir Crit Care Med 1999; 160(5 pt 1):1468–1472.
4
Wencker M, et al. Chest 2001;119(3):737−744. 5 Dirksen et al. Eur Respir J 2009; 33: 1345-1353.
Lack of evidence for augmentation therapy in AATD
Lack of RCT and challenges in interpreting non RCT
Although the proof of concept for potential value
of AAT augmentation has been published,
with the exception of the Danish-Dutch trials,
all other studies are at risk for confounding
Challenges in interpreting non RCT
• Concern about the validity of findings from non RCT is the
possibility of bias from uncontrolled confounding.
• Confounding arises when the groups under comparison differ
in other ways than the exposure alone (differences may include
demographic factors, behaviors, clinical characteristics,
medical conditions, or co-treatments).
• If you were taking an historical control as the comparison
group: the rate of decline of FEV1 has been decreasing over
the years without the use of replacement therapy; this may be
due to improvements in general disease management:
- 1995: 81 ml/yr
- 1998: 59 ml/yr
- 2007: 39.5 ml/yr
Questions/Conclusions
Patients to be tested?
Treatment with augmentation therapy?
AATD: Patients to be tested?
Rachelefsky G and Hogarth DK. J Allergy Clin Immunol 2008;121(4):833–838.
AATD treatment: Questions?
Is there a role of augmentation therapy for homozygotes?
• There is still a lack of properly designed study (RCT) to confirm the
therapeutic benefit (lung function, emphysema, morbidity and mortality) of
augmentation therapy
•However, in the context of acceleration of lung function decline in PI*ZZ,
augmentation therapy seems to hold promise.
Conclusion: We need a RCT designed with novel outcome
measures (CT densitometry as an alternative to traditional methods
such as FEV1 decline) and properly powered to demonstrate
whether there is a benefit to emphysema-modifying therapy.
AATD treatment: Questions?
What is the evidence that heterozygous AATD (PI*MZ
and PI*MS) are at risk for accelerated airflow
obstruction?
• No significant risk from cross-sectional studies1
• Very small acceleration decline FEV1 (25 vs 21 ml/yr decline FEV1)2
Conclusion:
•Heterozygote (PI*MZ and PI*MS) are not at higher risk of lung disease or the
difference with normal subjects is not clinically significant
1
2
Hersh et al. 2004; thorax; 59: 843-849
Dahl et al. 2002; Ann Intern Med; 136: 270-279.
AATD treatment: Questions?
Is there a role of augmentation therapy for heterozygotes
whose serum levels fall above the protective threshold
value of 11 uMOL?
• In the context that acceleration of lung function decline in PI*MZ
heterozygotes is sparse, augmentation therapy seems unlikely to hold great
promise.
Conclusions:
•The rapidly declining PI*MZ would need a RCT which is unlikely to happen
•Clinicians should avoid prescribing augmentation therapy for heterozygote
population
Guidelines for Augmentation Therapy
CTS (Abboud, et al. 2005) &
(O’Donnell 2007)
ATS/ERS Guidelines (2003)
Degree of
impairment in lung
function
Moderate impairment
(FEV1 35% to 65% predicted)
Moderate impairment
(FEV1 35% to 65% predicted)
Rate of decline in
lung function
Rapid decline in FEV1
(∆FEV1 >80 mL/yr), after an 18
month observation period
Rapid decline in FEV1
(∆FEV1 >120 mL/yr), including
those with normal or near normal
lung function
Severity of AATD
Severe (not defined)
Severe
(<11.0 µM; independent of
phenotype)
Other specifications Patients who have quit smoking
and are on optimal therapy
None
ATS/ERS. Am J Respir Crit Care Med 2003;168(7):818−900. Abboud RT, et al. Can Respir J 2001;8(2):81−88.
Abboud RT et al. Treat Respir Med 2005;4(1):1 −8. O’Donnell et al. CTS COPD Guideline 2007 CRJ
It is time for action!
Physicians
•
•
•
Increase awareness
Testing for AATD at least in patient with clinical features that
prompt suspicion (↑)
F/U and treatment
- Treatment as for any COPD (smoking cessation, etc)
- Augmentation therapy in the context of acceleration of
lung function decline (± CT Scan) in PI*ZZ
Industry
•
Doing the « right study » should be the priority
Fondations (A1AT) and Lung Associations
•
Lobbying the industry that they do the « right study » and
don’t accept less as an answer