**6. Acknowledgement**

202 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

be mistakenly classified as M, unless specific primers for M AAT are used. This rare mutation should of course be termed "non-Z" but this important distinction is not always made. To avoid any errors in diagnosis, any genotype result should be correlated to the AAT concentration. For example, a Null/Z individual will be classified MZ on a typical genotyping assay, however, consideration of the AAT concentration in this individual

Fig. 10. Genotyping assay for the Z mutation by melting curve analysis on a real-time PCR

The fact that cigarette smoking is often a coincident historical finding in the assessment of COPD has probably contributed to the remarkable global under-diagnosis of AATD. For example, of the 2,000 estimated ZZ individuals in Ireland, only 200 or 10% have been diagnosed (unpublished data). Unfortunately, COPD in a patient with a history of cigarette smoking is often assumed to be purely environmental and testing for AATD is not considered. This is one of a host of misconceptions that have surrounded AATD and prevented optimal management of AATD patients (Stoller and Aboussouan 2009). We strongly believe that increased testing for AATD is desperately needed in the COPD patient community, and stress once again the clinical guidelines that all patients with COPD should be screened for AATD. The model for COPD diagnosis, assessment and management must include testing for AATD as one of the first steps. Unfortunately, AATD is often relegated to a footnote in many clinical guidelines for COPD. A summary of the ATS and ERS document outlining standards for the diagnosis and treatment of patients with COPD published in 2004 mentioned AATD once, stating that "patients presenting with airflow limitation at a relatively early age (4th or 5th decade) and particularly those with a family history of COPD should be tested for alpha-1 antitrypsin deficiency" (Celli and MacNee 2004). This narrow definition is damaging to efforts at identifying all cases of AATD. Large variability exists in the clinical course of lung disease in AATD and therefore all COPD patients should be tested for AATD, regardless of age or smoking history. Any management strategy for COPD must include testing for AATD. The under-diagnosis of AATD in the COPD population is a

**MM**

**MZ**

should prompt further investigation by sequencing.

system (Roche LightCycler 480).

situation that cannot be allowed to continue.

**5. Conclusion** 

**ZZ**

The Irish National Targeted Detection Programme for Alpha-1 Antitrypsin Deficiency is supported by funding from the Irish Government Department of Health and Children. We would like to thank Geraldine O'Brien in the Alpha One Foundation (Ireland) for helpful discussions and John Walsh and Angela McBride of the Alpha-1 Foundation (USA) for support and advice. We wish to thank Pat O'Brien and Eric Mahon in the Biochemistry Department, Beaumont Hospital for invaluable discussions and help with patient sampling and electrophoresis and nephelometry techniques, Professor Maurizio Luisetti and Dr. Ilaria Ferrarotti at the University of Pavia in Italy for sequencing of rare SERPINA1 mutations, and Dr. Marc Miravitlles in the Department of Pneumology at the Hospital Clinic of Barcelona, Spain for help with the genotyping assay. We are grateful to Professor Dermot Kenny and the RCSI Clinical Research Centre in Beaumont Hospital for the ongoing use of their facilities. We would finally like to thank all the members of the Respiratory Research laboratory in the Department of Medicine, and AATD patients attending Beaumont Hospital for their continuing help.
