Alpha1 Antitrypsin Deficiency: An Underrecognized Cause of Chronic Obstructive Pulmonary Disease

1
Alpha-1 Antitrypsin Deficiency An
Underrecognized Cause of Chronic Obstructive
Pulmonary Disease

• A CME Presentation

2
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

3
Changing Face of COPD

• Historically COPD has been diagnosed late and
  more often in men1
• COPD was recognized as impaired lung function
  thatwas clinically apparent and moderately
  advanced
• Men were more likely than women to die from COPD
• COPD is now recognized earlier and in more
  women1
• Individuals with impaired lung function that is
  not clinically apparent are now recognized as
  having COPD
• In the year 2002 for the first time more women
  than men died from COPD (64103 vs. 60713)2

1American Lung Association. www.lungusa.org. 2CDC.
National Vital Statistics Reports. 200553.
4
Courtesy of H. Ari Jaffe MD
5
Percent Change in Age-Adjusted Death Rates US
1965-1998
GOLD teachingset. www.goldcopd.com
6
Risk Factors for COPD

• Exposure
• Tobacco smoke
• Occupational dusts and chemicals
• Air pollution
• Host factors
• Airway hyperresponsiveness
• Stunted lung development
• Alpha-1 antitrypsin (AAT) deficiency

Pauwels RA. Lancet. 2004364613.
7
Prevalence of AAT Deficiency in Patients With COPD

• Estimated prevalence of severe AAT deficiency in
  patients with COPD is approximately 2 to 315
• all subjects with COPD or asthma characterized
  by incompletely reversible airflow obstruction
  should be tested once for quantitative AAT
  determination.

ATS/ERS Standards
1Lieberman J. Chest. 198689370.
2Alvarez-Granda L. Thorax. 199752659. 3Cox DW.
Am Rev Respir Dis. 1976113601. 4Morse JO. NEJM.
19772961190. 5Wencker M. Eur Respir J.
200220319. 6ATS/ERS Standards. Am J Respir Crit
Care Med. 2003168181.
8
GOLD. Pocket Guide to COPD Diagnosis Management
and Prevention. 2004.
9
Management of AAT Deficiency COPD

• Symptom management is the same as typical COPD1
• Emphysema associated with AAT deficiency can also
  be treated with infusion of purified human AAT
  (AAT augmentation therapy)2
• Indicated for use in patients with congenital AAT
  deficiency AND clinically evident emphysema3-5
• Only treatment besides smoking cessation shown to
  slow disease progression and improve survival6

1GOLD. Pocket Guide to COPD Diagnosis
Management and Prevention. 2004. 2ATS/ERS
Standards. Am J Respir Crit Care Med.
2003168181. 3Prolastin prescribing information.
4Aralast prescribing information. 5Zemaira
prescribing information. 6AAT Deficiency Study
Group. Am J Respir Crit Care Med. 199815849.
10
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

11
AAT Deficiency

• AAT deficiency is an autosomal codominant
  hereditary disorder characterized by low serum
  and lung levels of AAT
• AAT gene resides at the proteinase inhibitor (PI)
  locus on chromosome 14
• The most common mutant AAT allele (PIZ) produces
  an abnormal protein that is polymerized and
  sequestered in hepatocytes
• AAT deficiency predisposes affected individuals
  to lung liver and other diseases

Tobin MJ. Br J Dis Chest. 19837714.
12
AAT

• 51 KDa glycoprotein made predominantly in the
  liver
• Secreted to blood permeates all tissues
• Circulating serum levels in normal individuals
  range from 150350 mg/dL (2048 µM)
• Protease inhibitor
• Primary target is the white blood cell protease
  neutrophil elastase (NE)

1Crystal RG. Hosp Pract (Off Ed). 19912681.
2Crystal RG. Chest. 198995196.
13
Mechanism of Neutrophil Elastase Inhibition
Reaction results in destruction of both AAT and NE
Reactive loop
AAT flings the tethered NE to the opposite end of
the AAT molecule
NE cleaves the AAT reactive loop
AAT
This distorts the NE active site and alters its
structure so it can be destroyed
Cleavage triggers AAT to snap NE backwards
NE
Courtesy of James A. Huntingon PhD University
of Cambridge.
14
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
15
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
16
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
17
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
18
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
19
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
20
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
21
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
22
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
23
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
24
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
25
Mechanism of Neutrophil Elastase Inhibition
Courtesy of James A. Huntingon PhD University
of Cambridge.
26
AAT Alleles

• There are more than 100 distinct AAT alleles
  with varying clinical significance1
• Deficiency alleles encode abnormal protein that
  is not secreted normally resulting in decreased
  circulating levels of AAT12
• Most common alleles12
• PIM (normal)
• PIS (moderately deficient)
• PIZ (severely deficient)
• The null allele (rare) which produces no
  protein results in the most severe deficiency12

1Crystal RG. Chest. 198995196. 2Tobin MJ. Br J
Dis Chest. 19837714.
27
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

28
Prevalence of AAT Deficiency

• 3.4 million individuals with mutant AAT allele
  combinations worldwide1
• PIZZ 175268
• PISZ 929014
• PISS 2260801
• Based on direct population screening studies
  prevalence of PIZZ in the US may be
  800001000002-4
• Only approximately 5000 individuals in the US
  are currently diagnosed with PIZZ
• 95 undiagnosed

1de Serres FJ. Chest. 20021221818. 2Colp C.
Chest. 1993103812 3OBrien ML. J Pediatr.
1978921006 4Silverman EK. Am Rev Respir Dis.
1989140961.
29
Prevalence in the US vs. Genetic Disorders and
Certain Cancers
Based on US population of 260M. Only 5000 have
been diagnosed.
1Colp C. Chest. 1993103812 2OBrien ML. J
Pediatr. 1978921006 3Silverman EK. Am Rev
Respir Dis. 1989140961. 4www.sbaa.org
5www.hdsa.org 6www.cff.org 7SEER Cancer
Statistics Review 1975-2001.
30
Gene Frequency

• PIS and PIZ found in ALL ethnicities worldwide1
• PIZ
• Highest in Northern Europe where it may have
  originated24
• PIS
• Highest on Iberian Peninsula where it may have
  originated2
• In the US PIZ frequency is highest in
  individuals of Northern and Western European
  descent5

PIZ
PIS
1de Serres FJ. Chest. 20021221818. 2Hutchison
DC. Respir Med. 199892367. 3Cox DW. Nature.
198531679. 4Seixas S. Hum Genet. 200110820.
5Dykes DD. Hum Hered. 198434308.
31
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

32
Lung Disease Associated with AAT Deficiency

• A common manifestation of AAT deficiency
• Defining characteristics12
• Panacinar emphysema
• Early-onset of disease (3550 years of age) in
  presence of additional risk factors
• Airway obstruction not completely reversible with
  treatment

1Larsson C. Acta Med Scand. 1978204345.
2Wittes J. In Crystal RG ed. Alpha-1
Antitrypsin Deficiency Biology Pathogenesis
Clinical Manifestations Therapy. New York
NYMarcel Dekker Inc.1996.
33
Pathogenesis of Lung Destruction Due to AAT
Deficiency
34
Pathogenesis of Lung Destruction Due to AAT
Deficiency
35
Risk Factors of Lung Disease Associated with AAT
Deficiency

• AAT deficiency has a highly variable clinical
  course of disease
• In absence of additional risk factors
  individuals with AAT deficiency can have an
  almost normal life span12
• Risk factors3
• Smoking
• Passive smoking
• Occupational/environmental exposures
• Lung infections

1Seersholm N. Thorax. 199449695. 2Larsson C.
Acta Med Scand. 1978204345. 3ATS/ERS
Standards. Am J Respir Crit Care Med.
2003168181.
36
Other Diseases That May Be Associated With AAT
Deficiency

• Liver disease is another primary manifestation of
  AAT deficiency
• Childhood and adult liver disease12
• AAT deficiency is also more rarely associated
  with
• Panniculitis3
• C-ANCApositive vasculitis45
• Wegeners granulomatosis

1Larsson C. Acta Med Scand. 1978204345. 2Sharp
HL. J Lab Clin Med. 196973934. 3Hendrick SJ. J
Am Acad Dermatol. 198818684. 4Elzouki AN. J
Intern Med. 1994236543. 5Griffith ME. Nephrol
Dial Transplant 199611438.
37
Liver Disease Associated With AAT Deficiency

• A common manifestation of PIZZ (1543)
• In children
• Common cause of neonatal cholestasis and liver
  transplantation (accounts for 1446 of
  transplants)12
• Most individuals are healthy throughout
  childhood3
• In adults
• Can cause cirrhosis and hepatic carcinoma
• Prevalence of cirrhosis in PIZZ individuals
  ranges from 15434-7
• Prevalence of hepatoma in PIZZ individuals
  ranges from 152867

1ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818. 2Sveger T. NEJM. 19762941316.
3Sveger T. Hepatology. 1995221316. 4Larsson C.
Acta Med Scand. 1978294345. 5Cox DW. Am J Med.
198374221. 6Eriksson S. Acta Med Scand.
1975198243. 7Elzouki AN. Eur J Gastroenterol
Hepatol. 19968989.
38
AAT is Secreted by the Liver
AAT
To all tissues
Liver
Blood vessel
Hepatocytes
Blood vessel
39
Mutant AAT is not Secreted Efficiently
AAT
To all tissues
Liver
Blood vessel
Sequestered AAT polymers
Hepatocytes
Blood vessel
40
Inclusion Bodies in Hepatocytes of a Patient With
AAT Deficiency
The Alpha-1 Foundationset.
www.alphaone.org. Courtesy of J. Stoller MD MS
41
Panniculitis

• Skin disease characterized by inflammatory and
  necrotizing lesions of subcutaneous fat
• Rare but well-recognized complication of AAT
  deficiency

1ORiordan K. Transplantation. 199753480. 2Smith
KC. J Am Acad Dermatol. 1989211192.
42
Vasculitis Associated With AAT Deficiency

• Relationship between AAT deficiency and
  anti-PR-3/C-ANCA small vessel-necrotizing
  vasculitides12
• Wegeners granulomatosis
• AAT inhibits proteinase-3 (PR-3)3
• NE-like serine protease
• Protease/antiprotease imbalance may contribute to
  disease4

1Elzouki AN. J Intern Med. 1994236543.
2Griffith ME. Nephrol Dial Transplant
199611438. 3Duranton J. Am J Respir Cell Mol
Biol. 20032957. 4Esnault VLM. Exp Clin
Immunogenet. 199714206.
43
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

44
Inheritance of AAT Alleles
MZ
MZ
45
Third Generation Inheritance Prior to Clinical
Disease
F2
F1
F2
F3
46
AAT Phenotypes

• AAT phenotype refers to the AAT protein type
  characterized by position of the protein on
  isoelectric focusing (IEF)
• Can define the heterozygous or homozygous states
• Phenotype can be confirmed with genotyping (DNA
  analysis)
• Serum levels of AAT and risk of disease vary by
  phenotype

1Brantly M. In Crystal RG ed. Alpha-1
Antitrypsin Deficiency Biology Pathogenesis
Clinical Manifestations Therapy. New York
Marcel Dekker Inc.1996. 2Crystal RG. J Clin
Invest. 1998851343.
47
Range of Serum Levels by Phenotype
Adapted from The Alpha-1 Foundationset.
www.alphaone.org. Courtesy of H. Ari Jaffe MD
48
Range of Serum Levels by Phenotype
Bottom normal level
Adapted from The Alpha-1 Foundationset.
www.alphaone.org. Courtesy of H. Ari Jaffe MD
49
Range of Serum Levels by Phenotype
Bottom normal level
Protective threshold
Adapted from The Alpha-1 Foundationset.
www.alphaone.org. Courtesy of H. Ari Jaffe MD
50
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

51
AAT Deficiency is Underdiagnosed

• Only 5 of individuals with PIZZ in the US are
  currently diagnosed
• 80000100000 PIZZ12 only 5000 diagnosed
• Misdiagnosed as COPD
• Average time from first pulmonary symptom to
  initial diagnosis is 7.2 years4
• 44 of patients with pulmonary symptoms saw gt3
  physicians before initial diagnosis4
• Early diagnosis can allow for treatment that can
  slow lung disease progression4

1Colp C. Chest. 1993103812. 2OBrien ML. J
Pediatr. 1978921006. 3Silverman EK. Am Rev
Respir Dis. 1989140961. 4Stoller JK. Cleve
Clin J Med. 199461461.
52
AAT Deficiency is Misdiagnosed

• Misdiagnosed as
• COPD due to smoking/environmental/occupational
  exposure
• Asthma
• Allergies
• Bronchitis
• Clinical recognition confounded by symptoms
  typical in patients with COPD
• Clinician must differentiate AAT deficiency from
  other causes of lung disease
• Definitive diagnosis is simple via a blood test

1Brantly ML. Am Rev Respir Dis.
1988138327. 2McElvaney NG. Chest. 1997111394.
53
AAT Deficiency Only1-4
COPD Only1-4
COPD AAT Deficiency1-4

• Panacinar emphysema
• Early onset (lt 50 years)of symptoms in
  patientswith smoking history
• Airflow obstruction not reversible with treatment
• Family history of COPD

• Onset gt 50 years
• Airflow obstructionreversible withtreatment
• Centriacinar or paraseptal emphysema

• Chronic cough
• Shortness of breath with activity
• Wheezing
• Increased sputum production
• Increased lower respiratory infections

1McElvaney NG. Chest. 1997111394. 2Brantly ML.
Am Rev Respir Dis. 1988138327. 3Janus ED.
Lancet. 19851152. 4Larsson C. Acta Med Scand.
1978204345.
54
ATS/ERS Range of Recommendations for Testing

• Type A
• Testing is recommended
• Type B
• Testing should be discussed could be reasonably
  accepted or declined
• Type C
• Testing should not be encouraged
• Type D
• Testing should be discouraged

ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818.
55
Who Should Be TestedType A Recommendations

• Adults with COPD or emphysema
• Adults with asthma not reversible with treatment
• Asymptomatic individuals with persistent
  obstructive pulmonary dysfunction with smoking or
  occupational exposure

• Newborn child or adult with unexplained liver
  disease
• Adults with necrotizing panniculitis
• Siblings of individual with AAT homozygosity

ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818.
56
Who Should Be TestedType B Recommendations

• Adults with bronchiectasis of unknown cause
• Adolescents with persistent obstructive pulmonary
  dysfunction
• Asymptomatic persistent obstructive pulmonary
  dysfunction with no risk factors
• Family history of lung or liver disease

• Adults with multisystemic vasculitis
  (anti-PR-3-positive vasculitis)
• Relatives of individual with AAT homozygosity or
  heterozygosity
• Adults and adolescents in areas where prevalence
  of AAT deficiency and smoking rates are high

ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818.
57
Why Arent Patients Tested for AAT Deficiency
58
Advantages of Detection of AAT Deficiency

• Lifestyle changes to prevent/slow disease
  progression can be implemented
• Smoking cessation or prevention
• Exercise
• Nutrition
• Occupational decisions
• Influenza and hepatitis vaccinations
• Disease-specific therapy (e.g. AAT augmentation
  therapy) can slow progression of lung disease and
  decrease mortality
• Disease-specific support
• Meaningful genetic data to family members

ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818.
59
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

60
Diagnostic Tests for AAT Deficiency Quantitative
Testing

• Immunoassay to determine serum AAT levels

Value obtained by commercially available
standards. Value obtained by NIH standard.
1ATS/ERS Standards. Am J Resp Crit Care Med.
2003168818. 2Brantly M. Chest.
1991100703. 3Brantly M. Am J Med. 198884(suppl
6A)12. 4Dati LF. Eur J Clin Chem Clin Biochem.
199634517.
61
Range of Serum Levels and Risk of Disease by AAT
Phenotype
Table adapted from ATS/ERS Standards. Am J Respir
Crit Care Med. 2003168818. Data from Brantly M.
Am J Med. 19888413 and Fagerhol MK. Adv Hum
Genet. 1981111371.
62
Diagnostic Tests for AAT Deficiency Qualitative
Testing

• Phenotyping
• Isoelectric focusing (IEF) is used to determine
  the AAT protein type(s)1
• Genotyping
• Identifies the AAT allele(s) present at the PI
  locus of chromosome 14
• PCR with allele-specific amplification of genomic
  DNA1
• Direct sequencing2

1ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818. 2Brantly M. In Crystal RG ed.
Alpha 1-Antitrypsin Deficiency Biology
Pathogenesis Clinical Manifestations Therapy.
New York NY Marcel Dekker Inc.1996.
63
Pulmonary Function Tests

• Spirometry (pre- and postbronchodilator)
• Considered fifth vital sign
• Reduced FEV1 FVC and FEV1/FVC ratio12
• Fixed airflow obstruction12
• In contrast to asthma spirometry in patients
  with AAT deficiency does not return to normal
  with treatment3
• Should be included in yearly follow-up1

1ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818. 2McElvaney NG. In Crystal RG ed.
Alpha 1-Antitrypsin Deficiency Biology
Pathogenesis Clinical Manifestations Therapy
New York NYMarcel Dekker1996. 3Eden E. Am J
Respir Crit Care Med. 199715668.
64
Spirometry Normal vs. AAT Deficiency
Adapted from GOLD. Pocket Guide to COPD
Diagnosis Management and Prevention. 2004.
65
Radiology

• Computed tomography14
• Most definitive assessment of emphysema
• Panacinar emphysema
• Basilar hyperlucency
• Reduced lung markings
• Bullae formation

Images from reference 2 used with
permission. 1ATS/ERS Standards. Am J Respir Crit
Care Med. 2003168818. 2Wilson JS. Chest.
2000118867. 3Beinert T. Chest. 1995108998.
4Schwaiblmair M. Eur J Med Res. 19983527.
66
Radiology

• Chest radiography
• Not sufficient to use as a diagnostic tool
• Recommended as an initial test for emphysema1
• Advanced disease may show13
• Hyperinflation
• Basilar hyperlucency
• Reduced lung markings
• Bullae formation

1ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818. 2Brantly ML. Am Rev Respir Dis.
1988138327. 3Foster WL. Radiographics.
199313311.
67
Radiology
68
Radiology
69
Liver Function Studies

• Standard liver function tests
• Aspartate aminotransferase (AST)
• Alanine aminotransferase (ALT)
• Alkaline phosphatase
• Total and direct bilirubin
• Additional blood testing
• Albumin clotting studies (PT INR PTT)
• Alpha fetoprotein
• Imaging
• Liver ultrasound

ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818.
70
Outline

• Chronic Obstructive Pulmonary Disease (COPD)
• Alpha-1 Antitrypsin (AAT) Deficiency
• Epidemiology of AAT Deficiency
• Pathophysiology of AAT Deficiency
• Genetics of AAT Deficiency
• Diagnosis of AAT Deficiency
• Diagnostic Tests
• Treatment of AAT Deficiency

71
AAT DeficiencySpecific Therapy for Lung Disease

• IV augmentation therapy
• Purified human AAT concentrate
• 60 mg/kg weekly maintains serum AAT levels above
  protective threshold (11 µM/80 mg/dL)13
• Increases AAT levels in lung epithelial lining
  fluid (ELF)13
• Goal is to slow progressive lung tissue
  destruction

1Gadek JE. J Clin Invest. 198168889. 2Wewers
MD. NEJM. 19873161055. 3Schmidt EW. Am J Med.
198884(6A)63.
72
ATS/ERS Recommendations for Use of Augmentation
Therapy

• Patients with AAT serum level lt11 µM with
  obstructive lung disease independent of
  phenotype
• Patients with FEV1 30 to 65 predicted have
  greatest benefit
• Benefits for severe or mild airflow obstruction
  less clear
• Possible benefit in post-lung transplant during
  respiratory tract inflammation or acute or
  chronic rejection

1ATS/ERS Standards. Am J Respir Crit Care Med.
2003168818.
73
Human AAT Preparations

• 3 human AAT preparations are approved in the US
  for use in patients with AAT deficiency who have
  lung disease
• Pasteurized only1
• Solvent-detergent (SD)-treated and nanofiltered2
• Pasteurized and ultrafiltered3
• Clinical studies suggest that all 3 preparations
  are bioequivalent and have similar safety
  profiles24

1Prolastin prescribing information. 2Aralast
prescribing information. 3Zemaira prescribing
information. 4Stoller JK. Chest. 200212266.
74
Safety of Augmentation Therapy

• Relatively few side effects reported
• Most frequent
• Headaches
• Myalgias
• Arthralgias
• Low back pain
• No treatment or occasional analgesic use required

1Seersholm N. Eur Respir J. 1997102260. 2AAT
Deficiency Study Group. Am J Respir Crit Care
Med. 199815849. 3Dirksen A. Am J Respir Crit
Care Med. 19991601468. 4Wencker M. Chest.
2001119737. 5Stoller JK. Chest. 200212266.
75
Augmentation Therapy Efficacy Studies

• Two registry studies (Danish and National Heart
  Lung and Blood Institute NHLBI) demonstrated
  decreased annual decline in FEV1 in treated vs.
  untreated registry patients12
• A mortality benefit was demonstrated with
  treatment in the NHLBI Registry study2
• A randomized study demonstrated decreased loss of
  lung tissue in treated vs. untreated patients3
• A longitudinal study demonstrated a slower
  decline in FEV1 in patients after vs. before they
  received augmentation therapy4

1Seersholm N. Eur Respir J. 1997102260. 2AAT
Deficiency Study Group. Am J Respir Crit Care
Med. 199815849. 3Dirksen A. Am J Respir Crit
Care Med. 19991601468. 4Wencker M. Chest.
2001119737.
76
Study of Efficacy of Augmentation Therapy in
Danish Registry

• Inclusion Criteria
• Danish group
• PIZZ or AAT serum level lt12 µM ex-smokers 2
  spirometries 1 year apart 5.8 years follow-up
  no augmentation therapy
• German group
• PIZZ AAT serum level lt12 µM ex-smokers 2
  spirometries 1 year apart 3.2 years follow-up
  augmentation therapy (60 mg/kg weekly) 1 year

Seersholm N. Eur Respir J. 1997102260.
77
Study of Efficacy of Augmentation Therapy in
Danish Registry
In the treated group these patients were
required to have a decline in FEV1 gt120 mL/yr
Seersholm N. Eur Respir J. 1997102260.
78
Study of Efficacy of Augmentation Therapy in
NHLBI Registry

• Study Design
• Annual decline in FEV1 of 650 treated patients on
  registry compared with 277 untreated patients
• Followed 3.5 to 7 years
• Spirometry measured pre- and post-bronchodilator
  every 6 to 12 months

AAT Deficiency Study Group. Am J Respir Crit Care
Med. 199815849.
79
Study of Efficacy of Augmentation Therapy in
NHLBI Registry
AAT Deficiency Study Group. Am J Respir Crit Care
Med. 199815849.
80
Study of Efficacy of Augmentation Therapy in
NHLBI Registry
Patients with FEV1 lt50 predicted
AAT Deficiency Study Group. Am J Respir Crit Care
Med. 199815849.
81
Randomized Trial of Augmentation Therapy

• Study Design
• 56 ex-smokers with FEV1 30 to 80 predicted and
  PIZZ phenotype randomized to 250 mg/kg IV AAT (n
  28) or albumin (n 28) every 4 weeks for 3
  years
• Self-administered spirometry performed twice
  daily and lung density measured by annual CT

Dirksen A. Am J Respir Crit Care Med.
19991601468.
82
Randomized Trial Loss of Lung Tissue Slower With
Treatment
Obtained by daily patient-administered serial
spirometry. Obtained from FVC maneuvers every 3
months.
Dirksen A. Am J Respir Crit Care Med.
19991601468.
83
Longitudinal Study

• Study design
• 96 patients with AAT serum levels below the
  protective threshold and reduced lung function
• Patients were used as their own controls
• Decline in FEV1 1 year before they received
  treatment was compared with decline in FEV1 1
  year after receiving treatment (60 mg/kg weekly)

Wencker M. Chest. 2001119737.
84
Longitudinal Study Decline in FEV1 Significantly
Slower With Treatment
Results
FEV1 was lt 65 predicted or decline in FEV1 was
gt120 mL/yr.
Wencker M. Chest. 2001119737.
85
Change in FEV1 Slowed With Treatment in Rapid
Decliners
Wencker M. Chest. 2001119737.
86
Change in FEV1 Slowed With Treatment in Rapid
Decliners
Wencker M. Chest. 2001119737.
87
Surgical Treatment for AAT-Associated Lung
Disease

• Lung transplantation
• For patients who do not respond to more
  conservative therapy or who have extensive lung
  damage1
• 5 to 10 of lung transplants performed in the US
  each year are performed due to AAT deficiency2
• 5-year survival is approximately 503
• Lung volume reduction surgery
• May improve dyspnea and lung function
• Not recommended due to lack of evidence1

1ATS/ERS. Am J Respir Crit Care Med.
2003168818. 2UNOS OPTN data 1988-2004. 3UNOS
OPTN data 1995-2002.
88
Treatment for AAT-Associated Liver Disease

• No specific treatment
• Avoidance of alcohol
• Hepatitis A and B vaccinations
• Liver transplantation
• For patients who do not respond to more
  conservative therapy or who have extensive liver
  damage

ATS/ERS. Am J Respir Crit Care Med. 2003168818.
89
Conclusions

• AAT deficiency is underdiagnosed
• Some of your COPD patients have AAT deficiency
• Early onset of COPD (lt50 years of age)
• Emphysema in the absence of risk factors or with
  prominent basilar hyperlucency
• Asthma not completely reversible with treatment
• Family history of emphysema bronchiectasis
  liver disease or panniculitis
• Unexplained liver disease or panniculitis or
  vasculitis
• Bronchiectasis

90
Conclusions (continued)

• AAT augmentation therapy can slow the annual
  decline in FEV1 and possibly slow the loss of
  lung tissue
• If you dont test you cant
• Test family members
• Initiate interventions (smoking prevention or
  cessation occupational decisions)
• Treat with augmentation therapy
• Affect mortality associated with AAT deficiency