Alpha1-register in Lithuania Brigita Sitkauskiene, MD, PhD
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1 Alpha1-register in Lithuania Brigita Sitkauskiene, MD, PhD Assoc.Professor and Head Division for Clinical Immunology and Allergology Kaunas University of Medicine, Lithuania Malmö 2008
2 K A U N A S
3 Kaunas University of Medicine Kaunas Medical University Hospital
4 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 Sydney Burwell, Dean Harward Medical School 1900
5 ASTHMA COPD Chronic persistent inflammation + airflow obstruction Eosinophils CD4 + cells Macrophages+ Mast cells Neutrophils? Neutrophils CD8 + cells Macrophages++ Eosinophils? Linden M 1993, Saetta M 1994 Villar MTA 1995, Chanez P 1997
6 60-80% 80-90% Asthma COPD Li JT et al Boulet LP et al. Chest 2006 Weiss ST et al. Am J Respir Crit Care Med 2000 Sitkauskiene B et al. Respir Med 2003
7 Activation of epithelial cells Activation of macrophages IL-8 LTB 4 IL-8 etc. Neutrophil Proteases Neutrophilic inflammation Adapted from Wood et al. Respir Res 2006
8 Concentration of IL-8 in BAL fluid IL-8 (pg/ml) * # p<0.05 * *p<0.05 compared to healthy never-smokers #p<0.05 compared to healthy smokers COPD smokers COPD ex-smokers Healthy smokers Healthy never smokers Stravinskaite K et al. Lung 2008
9 50 Correlation between BALf IL-8 and smoking history 40 Pack-years COPD smokers COPD ex-smokers Healthy smokers Rs=0.81 Rs=0.83 Rs= IL-8 (pg/ml), BAL
10 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 to cigarette smoke Gronski et al BAL cells staining (ICC) positively for MMP-12 Churg et al MMP12 + macrophage; 2- MMP12 - macrophage
11 MMP-12 + macrophages (ICC) in different tissue compartments 80 p<0.05 COPD smokers MMP macrophages ( % of total macrophages) * # * # * * # * # * COPD ex-smokers 'Healthy' smokers Healthy never- smokers Asthma smokers Asthma never- smokers 10 0 Induced sputum BAL Babusyte A et al. Respir Res 2007
12 Correlation between smoking history and BAL MMP12 + macrophages MMP macrophages in BAL (%) COPD smokers (Rs=0.86*) COPD ex-smokers (Rs=0.68*) Healthy smokers (Rs=0.63*) *p< Pack-years Babusyte A et al. Respir Res 2007
13 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 γδ TCR + lymphocytes in BAL γδ TCR+ lymphocytes (%) p<0.001 p<0.001 NS COPD Asthma Control Urboniene D et al. ERS 2007
14 Smoking induces variety of inflammatory responses; modulates respiratory defense mechanisms Many immunological changes in smokers are not completely reversible after quitting smoking
15 Only 15-30% of smokers develop COPD The risk results from a gene-environment interaction
16 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 worldwide Blanco I et al. Eur Respir J 2006 Sitkauskiene B et al. Respir Med 2008
17 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 2003 De Serres FJ et al. COPD 2006
18 Lithuanian Alpha-1 Research Association
19 Objective To estimate the AAT (mainly S and Z) gene frequency and prevalence in a large cohort of Lithuanian patients with COPD To identify AAT deficiency cases in COPD patients
20 COPD patients (n= ) from the different Lithuanian regions
21 PATIENTS EVALUATIONS GOLD spirometric criteria for COPD Serum concentrations of AAT - by means of nephelometry FEV 1 /FVC < 0.7 FEV 1 < 80% pred. Presence of PI*Z allele by ELISA, qualitative method AAT phenotyping - by means of isoelectric-focusing
22 RESULTS
23 Demographic characteristics and AAT genotypes Lithuanian cohort of COPD patients AAT N Sex Age (SD) Cumulative genotypes % M pack-years (SD) MM (10.4) 22.4 (12.4) MS (7.8) 20.4 (11.6) MZ (11.2) 21.3 (12) SS (-) SZ (2.8) 18 (2.8) ZZ (11.3) 19 (11) Total (10.3) 22.1 (12.2) P-value (ZZ vs other groups) Sitkauskiene B et al. Respir Med 2008
24 Smoking habits in Lithuania % Everyday smokers Occasional smokers Females Males Females Males In cities In villages Finbalt Health Monitor program Grabauskas V et al. Publication of National Public Health Institute 2003 Lithuanian Statistics 2007
25 Smoking among males and females in different Lithuanian regions % Males Females Total Alytus Kaunas Klaipeda Marijam- Paneve- Šiauliai Taurage Telšiai Utena Vilnius pole žys Finbalt Health Monitor program Grabauskas V et al. Publication of National Public Health Institute 2003 Lithuanian statistics 2007
26 AAT genotypes and spirometric values Lithuanian cohort of COPD patients AAT N FEV1/FVC FEV1% pred. AAT serum genotypes (CD) concentration MM (10.5) 46 (15.8) (39.8) MS (11.2) 50.8 (16.1) 102 (11) MZ (9.5) 51.5 (14.5) 99 (14) SS SZ (6.3) 70 (4.2) 77 (19.7) ZZ (18.6) 38.5 (18.1) 30 (12.4) Total (10.9) 46.5 (15.9) 158 (43.6) P-value (ZZ vs other groups) Sitkauskiene B et al. Respir Med 2008
27 Calculated PI*S and PI*Z gene frequency in COPD patients and healthy unrelated people Samples Gene frequency per 1000 (95% Cl) PI*S PI*Z COPD N: ( ) 25.3 ( ) Healthy unrelated 15.6 ( ) 13.6 ( ) people N: 2491 Beckman L et al. Hum Hered 1999 Stakisaitis D et al. Med Sci Monit 2001 Sitkauskiene B et al. Respir Med 2008
28 Case control studies in other countries Spain ZZ among COPD 0.37% De la Roza C et al. Eur Respir J 2005 Italy 6.4% Luisetti M et al. Respir Med 1999 Germany ZZ / chr. respir.diseases 0 Wencker M et al. Eur Respir J 2002 Germany 14.7% Bals R et al. Respir Med 2007 Denmark ZZ among COPD 0.8% Dahl M et al. Ann Intern Med 2002
29 Distribution of PI*S and PI*Z gene frequencies in Northern Europe countries ICELAND NORWAY FINLAND 13 RUSSIA DEMMARK SWEDEN Aland Arch ESTONIA LATVIA Gotland BELARUS 11 8 RUSSIA LITHUANIA The highest incidence of PI*Z: The Latvia highest incidence of PI*S: Southern of the Norway Scandinavian Peninsula Denmark Latvia Southern Sweden Denmark Estonia Z values are showed in grey circles Beckman L et al. Hum Hered 1999 De Serres F et al. Monaldi Arch Chest Dis 2007
30 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 ( ) ( ) 57 (31-104) ( ) 152 (86-266) 102 (61-171) Statistics Lithuania [accessed 08.07] Sitkauskiene B et al. Respir Med 2008
31 Alpha-1 antitrypsin augmentation therapy Candidates Young patients with severe hereditary AAT deficiency and established emphysema However, this therapy is very expensive, is not available in most countries GOLD updated 2007
32 Therapy at each stage of COPD GOLD updated 2007
33 Lung transplantation Criteria for referral for lung transplantation: FEV 1 < 35% predicted PaO 2 < kpa (55-60 mmhg) PaCO 2 > 6.7 kpa (50 mmhg) Secondary pulmonary hypertension GOLD updated 2007
34 A case of lung transplantation in patient with hereditary AAT deficiency Male, 52 yrs old Alpha1- antitrypsin concentration 0.33 g/l FVC 3.12 L 70 % FEV L 31 % FEV 1 /FVC 36 % III bronchial obstruction III decrease of gas diffusion, DLCO 29% predicted Lung transplantation was performed 14 Oct 2008
35 A case of lung transplantation in patient with hereditary AAT deficiency -inheritance of AAT deficiency- Pi MZ Pi MZ Pi ZZ Pi MZ Pi ZZ Pi MZ Pi MZ
36 Conclusions 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 caregivers about this genetic condition.
37 Acknowledgements Sabina Janciauskiene Raimundas Sakalauskas Danielius Serapinas Agne Babusyte Kristina Stravinskaite
38 Millennium Lithuaniae 2009
Screening for alpha1-antitrypsin deficiency in Lithuanian patients with COPD
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