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Alpha1-register in Lithuania
Brigita Sitkauskiene, MD, PhDAssoc.Professor and Head
Division for Clinical Immunology and AllergologyKaunas University of Medicine, Lithuania
Malmö 2008
Kaunas Universityof Medicine
Kaunas MedicalUniversity Hospital
Sydney Burwell, DeanHarward Medical School 1900
“… half of what you are taught as medical students will in 10 years be shown to be wrong.
And the trouble is none of your teachers knows which half…”
ASTHMA COPD
Chronic persistent inflammation + airflow obstruction
EosinophilsCD4+ cellsMacrophages+Mast cellsNeutrophils?
NeutrophilsCD8+ cellsMacrophages++Eosinophils ?
Linden M 1993, Saetta M 1994Villar MTA 1995, Chanez P 1997
COPDAsthma
60-80% 80-90%
Li JT et al. 2006Boulet LP et al. Chest 2006
Weiss ST et al. Am J Respir Crit Care Med 2000Sitkauskiene B et al. Respir Med 2003
Adapted from Wood et al. Respir Res 2006
Activation of macrophages
Neutrophil
Neutrophilic inflammation
Activation of epithelial cells
Proteases
LTB4IL-8etc.
IL-8
Concentration of IL-8 in BAL fluid
Stravinskaite K et al. Lung 2008
0
50
100
150
200
250
300
COPDsmokers
COPD ex-smokers
‘Healthy’smokers
Healthy neversmokers
IL-8
(pg/
ml)
*
*
#p<0.05
*p<0.05 compared to healthy never-smokers
#p<0.05 compared to ‘healthy’ smokers
Correlation between BALf IL-8and smoking history
Pac
k-ye
ars
0
10
20
30
40
50
100 200 300 400IL-8 (pg/ml), BAL
COPD smokers Rs=0.81
COPD ex-smokers Rs=0.83
‘Healthy’ smokers Rs=0.80
12
BAL cells staining (ICC) positively for MMP-12
1- MMP12+ macrophage; 2- MMP12- macrophage
• Metalloproteinases (MMPs) mediate airway inflammation and remodelling• Indirect effect of smoke induced increase of MMP-12 is inactivation of α1-antitrypsin and emphysema
• MMP-12 mediates recruitment of neutrophils to the lung in response tocigarette smoke Gronski et al. 1997
Churg et al. 2003
COPD smokers
COPD ex-smokers
'Healthy' smokers
Healthy never- smokers
0
10
20
30
40
50
60
70
Induced sputum BAL
80
* #
* #
*
* #
* #
p<0.05
*
MMP-12+ macrophages (ICC) in different tissue compartments
MM
P-12
+ -m
acro
phag
es(%
of t
otal
mac
roph
ages
)
Babusyte A et al. Respir Res 2007
Asthma smokers
Asthma never- smokers
Pack-years
0
10
20
30
40
50
60
70
80
10 20 30 40 50 60
MM
P-12
+ -m
acro
phag
esin
BAL
(%)
100 COPD smokers (Rs=0.86*)
COPD ex-smokers (Rs=0.68*)
‘Healthy’ smokers (Rs=0.63*)
Babusyte A et al. Respir Res 2007
Correlation between smoking history andBAL MMP12+ macrophages
*p<0.05
γδ TCR+ lymphocytes in BAL
Urboniene D et al. ERS 2007
γδTC
R+
lym
phoc
ytes
(%)
COPD Asthma Control
p<0.001 NS
p<0.001
0123456789
10
γδ cell-deficient mice are fatally defective in their immune response to a gram-positive bacterium, have low mucosal IgA synthesis Fujihashi KJ et al. 1996
Smoking induces variety of inflammatory
responses;
modulates respiratory defense mechanisms
Many immunological changes in smokers are
not completely reversible after quitting smoking
Only 15-30% of smokers develop COPD
The risk results from a gene-environment interaction
• Severe hereditary deficiency of alpha1-antitrypsin (AAT) is the best described genetic risk factor for COPD
• AAT deficiency is most commonly seen in Caucasians
• AAT deficiency is an under-diagnosed condition world-wide
Blanco I et al. Eur Respir J 2006Sitkauskiene B et al. Respir Med 2008
WHO and ATS/ERS guidelines recommend
Establishment of screening programs for the detection of AAT deficiency in patients with COPD
• Family screening
• Appropriate management (including lifestyle changes
such as quitting smoking and replacement therapy)
• Specific counseling for these patients and families
ATS/ERS Statement. Am J Respir Crit Care Med 2003De Serres FJ et al. COPD 2006
Lithuanian Alpha-1 Research Association
Objective
• To estimate the AAT (mainly S and Z) gene frequencyand prevalence in a large cohort of Lithuanian patients with COPD
• To identify AAT deficiency cases in COPD patients
COPD patients (n=1580→1167) from the different Lithuanian regions
GOLD spirometric criteria for COPD
• FEV1/FVC < 0.7
• FEV1 < 80% pred.
Serum concentrations of AAT -by means of nephelometry
AAT phenotyping - by means of isoelectric-focusing
Presence of PI*Z allele by ELISA, qualitative method
EVALUATIONSPATIENTS
RESULTS
Sitkauskiene B et al. Respir Med 2008
Demographic characteristics and AAT genotypes Lithuanian cohort of COPD patients
P-value (ZZ vs other groups) 0.06 0.54
AAT N Sex Age (SD) Cumulativegenotypes % M pack-years (SD)
MM 1076 84 66 (10.4) 22.4 (12.4)MS 39 56 64 (7.8) 20.4 (11.6)MZ 40 65 67 (11.2) 21.3 (12)SS 1 0 61 22 (-)SZ 3 66 63 (2.8) 18 (2.8)ZZ 8 62 54 (11.3) 19 (11)
Total 1167 82 62 (10.3) 22.1 (12.2)
Smoking habits in Lithuania
Finbalt Health Monitor programGrabauskas V et al. Publication of National Public Health Institute 2003
Lithuanian Statistics 2007
Females FemalesMales MalesIn cities In villages
Occasionalsmokers
Everyday smokers
%
Smoking among males and femalesin different Lithuanian regions
Finbalt Health Monitor programGrabauskas V et al. Publication of National Public Health Institute 2003
Lithuanian statistics 2007
Males
Females
Total Alytus Kaunas Klaipeda Marijam- Paneve- Šiauliai Taurage Telšiai Utena Vilniuspole žys
%
Sitkauskiene B et al. Respir Med 2008
AAT genotypes and spirometric values Lithuanian cohort of COPD patients
P-value (ZZ vs other groups) 0.01 0.31 0.00
AAT N FEV1/FVC FEV1% pred. AAT serumgenotypes (CD) concentration
MM 1076 54.8 (10.5) 46 (15.8) 164.7 (39.8)MS 39 55.7 (11.2) 50.8 (16.1) 102 (11)MZ 40 58.6 (9.5) 51.5 (14.5) 99 (14)SS 1 65 48 88SZ 3 56.5 (6.3) 70 (4.2) 77 (19.7)ZZ 8 36.2 (18.6) 38.5 (18.1) 30 (12.4)
Total 1167 54.7 (10.9) 46.5 (15.9) 158 (43.6)
Beckman L et al. Hum Hered 1999Stakisaitis D et al. Med Sci Monit 2001Sitkauskiene B et al. Respir Med 2008
Calculated PI*S and PI*Z gene frequencyin COPD patients and healthy unrelated people
Samples Gene frequency per 1000 (95% Cl)
PI*S PI*Z
COPD N: 1167 18.8 (13.9-25.4) 25.3 (19.4-32.7)
Healthy unrelated 15.6 (12.5-19.6) 13.6 (10.7-17.4)
people N: 2491
Case control studies in other countries
Spain ZZ among COPD 0.37%
Italy 6.4%
Germany ZZ / chr. respir.diseases 0
Germany 14.7%
Denmark ZZ among COPD 0.8%
De la Roza C et al. Eur Respir J 2005
Luisetti M et al. Respir Med 1999
Wencker M et al. Eur Respir J 2002
Bals R et al. Respir Med 2007
Dahl M et al. Ann Intern Med 2002
021
14
2519
1725
19
27
28
22
12
27
23
2645 35
4
25
6 11
13
4
1 4
00
4
5
3
4
0
0
0
128
16
31
20 17
13 8
9
30
0
0
11
17
15
175
1213
31 20
2111
16
7
16
14
7
0
0
0
24 23
14 8
117 4
4 0
11
12 1011 11
18
2930
33
29
19
21
0
04
5 0
RUSSIA
RUSSIABELARUS
DEMMARK
NORWAY
SWEDEN
FINLAND
Gotland
Aland Arch.
ICELAND
LITHUANIA
LATVIA
ESTONIA
24 23
Beckman L et al. Hum Hered 1999De Serres F et al. Monaldi Arch Chest Dis 2007
Distribution of PI*S and PI*Z gene frequencies in Northern Europe countries
Z values are showed in grey circles
The highest incidence of PI*S:• South of the Scandinavian
Peninsula• Latvia• Denmark
The highest incidence of PI*Z:• Latvia• Southern Norway• Denmark• Southern Sweden• Estonia
Estimated number of subjects for each AAT genotype in COPD Lithuanian population
Estimated number of COPD patients over 40 yrs in the Lithuanian population
Calculated number of normal (MM) and deficiency genotypes in COPD (95% CI)
MM MS SS MZ SZ ZZ
159 829146 034
(143 193-148 428)
5 760(4 202-7 842)
57(31-104)
7 724(5 888-10 076)
152(86-266)
102(61-171)
Statistics Lithuania [accessed 08.07]Sitkauskiene B et al. Respir Med 2008
Alpha-1 antitrypsin augmentation therapy
Candidates
Young patients with severe hereditary AAT deficiencyand established emphysema
However, this therapy is very expensive, is not available in most countries
GOLD updated 2007
Therapy at each stage of COPD
GOLD updated 2007
Lung transplantation
Criteria for referral for lung transplantation:
• FEV1 < 35% predicted• PaO2 < 7.3-8.0 kPa (55-60 mmHg)• PaCO2 > 6.7 kPa (50 mmHg)• Secondary pulmonary hypertension
GOLD updated 2007
A case of lung transplantation in patient with hereditary AAT deficiency
Male, 52 yrs oldAlpha1- antitrypsin concentration 0.33 g/l
FVC 3.12 L – 70 %FEV1 1.12 L – 31 %FEV1/FVC 36 %
III° bronchial obstruction
Lung transplantation was performed 14 Oct 2008
III° decrease of gas diffusion,DLCO – 29% predicted
Pi MZ Pi MZ
Pi ZZ Pi ZZ
Pi MZ Pi MZ
Pi MZ
A case of lung transplantation in patient with hereditary AAT deficiency
-inheritance of AAT deficiency-
The OR for each genotypic class demonstrated a significant increase of MZ, SZ and ZZ genotypes in COPD patients.
The results of our study, with a significant number of ZZ individuals detected, support the general concept of targeted screening for AAT deficiency in countries like Lithuania, with a large population of COPD patients and low awareness among care-givers about this genetic condition.
Conclusions
Sabina Janciauskiene
Raimundas SakalauskasDanielius Serapinas
Agne BabusyteKristina Stravinskaite
Acknowledgements
Millennium Lithuaniae 2009
