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

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Title: 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 (64,103 vs. 60,713)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 teaching slide set. 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 AAT1,2
  • Most common alleles1,2
  • PIM (normal)
  • PIS (moderately deficient)
  • PIZ (severely deficient)
  • The null allele (rare), which produces no
    protein, results in the most severe deficiency1,2

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 175,268
  • PISZ 929,014
  • PISS 2,260,801
  • Based on direct population screening studies,
    prevalence of PIZZ in the US may be
    80,000100,0002-4
  • Only approximately 5,000 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 5,000 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 characteristics1,2
  • 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 span1,2
  • 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 disease1,2
  • AAT deficiency is also more rarely associated
    with
  • Panniculitis3
  • C-ANCApositive vasculitis4,5
  • 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)1,2
  • 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 15286,7

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 Foundation slide set.
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
    vasculitides1,2
  • 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 Foundation slide set.
www.alphaone.org. Courtesy of H. Ari Jaffe, MD
48
Range of Serum Levels by Phenotype
Bottom normal level
Adapted from The Alpha-1 Foundation slide set.
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 Foundation slide set.
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
  • 80,000100,000 PIZZ,1,2 only 5,000 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 Tested?Type 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 Tested?Type 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 ratio1,2
  • Fixed airflow obstruction1,2
  • 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
    profiles2,4

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 patients1,2
  • 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
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