This disparity between a demonstrable effect on densitometry and a lack of effect on FEV1 is far from surprising. Not only were these studies based on assessing lung density, the most sensitive parameter to Sorafenib Tosylate assess and monitor emphysema, but were not designed or powered to assess spirometric outcome. This raises a concern over the original NIH observation that did indicate a positive effect on FEV1 decline but only in a limited FEV1 range [9]. Recent understanding of the complexity of usual COPD, as well as of the lung disease associated with AATD has indicated the range of different pathological and clinical phenotypes [22]. Effective therapies can only be demonstrated easily if the generic COPD population is enriched for those with amplified evidence of the presence and progression of the proposed outcome measure.

Since the FEV1 progresses most rapidly in the 35-60% predicted range [14] it would be the most sensitive range to detect a treatment effect with FEV1 as the outcome. In contrast, FEV1 decline is modest in severe disease, unlike the lung transfer coefficient for carbon monoxide (Kco) decline, which is greatest in severe disease [14]. Therefore, it is essential, especially with expensive therapy, to identify the patients particularly at risk and hence most likely to benefit from treatment by using outcomes specific to the disease process and to monitor efficacy where these are changing most. In the case of AATD, emphysema and not airflow obstruction is the primary pathophysiologic alteration, and it would be those with evidence of significant and progressing emphysema who should be selected for future efficacy trials.

The assessment of emphysema should also be assessed by the most specific and sensitive test/s, in this case lung densitometry and alveolar gas transfer. Management paradigm Patients with AATD can present with varying degrees of respiratory disease that is influenced by the awareness of the medical practitioner to the condition as well as the severity of symptoms by the time medical help is sought, together with a suggestive family history. Often there is a long lapse before AATD is diagnosed [23,24] and, especially in younger subjects, the symptoms may often be attributed to a more likely diagnosis of asthma. Patients may be identified as the index case presenting with symptoms or as non index, identified by family screening.

The index group usually Dacomitinib consists mainly of smokers especially if they are young and have the classical basal panlobular emphysema or if older and a non-smoker (ie no recognised risk factors) with fixed airflow obstruction. The non-index subjects identified through family screening usually have better lung function and includes both smokers and never smokers but still with a wide range of physiological impairment [25]. Interestingly these non-index patients may have complete discordance in their FEV1 with their index siblings but more concordance with gas transfer and lung densitometry [26].