Goals, Organization of the Project, and Timeline: The goal of the AAT Deficiency Task Force was to prepare and present for the medical and interested lay communities the reasoned, current views of a large international group of experts regarding the current diagnosis and management of individuals with AAT deficiency, using a systematic review and the evidence-based approach. The Task Force undertook to evaluate the full clinical and management dimensions of this multisystem illness, including lung, liver, and other organ manifestations. Also, issues relating to the ethical, legal, social, psychological, and economic implications of genetic testing for AAT deficiency were addressed. A planning group was assembled in the Fall of 1997, when sponsorship and funding by the major sponsors - the American Thoracic Society, the European Respiratory Society, and the Alpha-1 Foundation - was finalized. Additional support from the Alpha-1 Foundation, the American College of Chest Physicians, and the American Association for Respiratory Care allowed the Planning Committee to assemble the full membership of the Task Force and to proceed. As presented in Figure 1, the AAT Deficiency Task Force consisted of an Executive Committee, three individual Writing Groups comprising international experts, and a Steering Committee (composed of the Executive Committee and the Chairs of each of the three Writing Groups). Preparation of the systematic review was aided by members of the Health Care Technology Assessment Program of the Department of Veterans Affairs, who provided ongoing input and guidance to the project regarding literature searches and evidence-based medicine methods. Administrative assistance was provided by the American Thoracic Society. The membership of the Task Force was fully constituted by September 1998, at which point Writing Groups began to review literature and to draft documents for subsequent review by the Steering Committee. The Steering Committee conducted a number of conference calls and five face-to-face meetings between Fall 1998 and Fall 2001 to review the evolving documents. Individual Writing Group documents were finalized by Fall 2001 for final editing by the Executive Committee and subsequent submission to the sponsoring organizations. Reviews were received in June 2002 and the revised document was resubmitted in Fall 2002 for final approval. Approval was granted by the American Thoracic Society in December 2002, when an additional review of salient literature led to a final update of the document. While the Executive Committee has attempted to minimize overlap between the three documents, the Task Force's stated goal of preparing three individual documents, each complete and with its own emphasis, references, and supportive tables and figures, will inevitably lead to some overlap. Finally, in the context that research is ongoing and that current understanding of AAT deficiency and optimal management is evolving, the Task Force recognizes the need for periodic review and updating of management recommendations. Summary of Main Recommendations Regarding Diagnosis and Management by the Alpha-1 Antitrypsin Deficiency Task Force: Clinical recognition of AAT deficiency. Available evidence suggests that PI*ZZ AAT deficiency is frequently underrecognized or misdiagnosed by clinicians. The following features should prompt suspicion by physicians that their patient may be more likely to have AAT deficiency: • Early-onset emphysema (age of 45 years or less) • Emphysema in the absence of a recognized risk factor (smoking, occupational dust exposure, etc.) • Emphysema with prominent basilar hyperlucency • Otherwise unexplained liver disease • Necrotizing panniculitis • Anti-proteinase 3-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-positive vasculitis) • Family history of any of the following: emphysema, bronchiectasis, liver disease, or panniculitis • Bronchiectasis without evident etiology (see below) Notably, in recognizing the discordance of studies concerning whether bronchiectasis is specifically associated with AAT deficiency, the Task Force recommends discussing AAT testing with individuals who have bronchiectasis without evident etiology, with the understanding that testing could reasonably be accepted or declined. Genetic testing for AAT deficiency. Recognizing that identifying individuals as having AAT deficiency can expose them to risks (e.g., of psychologic burden or genetic discrimination), the Task Force recommends that clinicians weigh these risks and discuss them with those for whom testing (by serum level or phenotype) is being considered. In evaluating the strength of the Task Force's recommendation to test various individuals for AAT deficiency, the Task Force recognized four clinical purposes for which testing for AAT deficiency might be undertaken: (1) diagnostic testing (i.e., to identify symptomatic or otherwise affected individuals), (2) predispositional testing (i.e., to identify asymptomatic individuals who may be at high risk of having AAT deficiency), (3) assessment of carrier status in relation to reproduction, and (4) population screening. Recommendations for genetic testing in specific situations were graded from type A to type D (see Table 1). Each recommendation type was based on the level of supportive evidence for each issue regarding testing (e.g., the penetrance of AAT deficiency, population prevalence of AAT deficiency, clinical impact, accuracy of genetic testing, efficacy of treatment, psychologic and social effects, and economic costs) and the weighing by the Task Force of the issues for or against testing. In the context of this grading scheme, recommendations for the four types of genetic testing are as follows. 1. Diagnostic testing. A type A recommendation for diagnostic testing was made in the following settings: • Symptomatic adults with emphysema, chronic obstructive pulmonary disease (COPD), or asthma with airflow obstruction that is incompletely reversible after aggressive treatment with bronchodilators. (Notably, in populations where the prevalence of AAT deficiency is known to be much lower than the general North American and Northern European prevalence, a Type B recommendation for diagnostic testing in this setting is offered.) • Individuals with unexplained liver disease, including neonates, children, and adults, particularly the elderly • Asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors (e.g., cigarette smoking, occupational exposure) • Adults with necrotizing panniculitis A type B recommendation for diagnostic testing was made in the following settings: • Adults with bronchiectasis without evident etiology • Adolescents with persistent airflow obstruction •.
