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Study Description

AAT deficiency is a genetic disorder associated with emphysema. Spirometry, the lung function test that measures how well the lungs exhale air, is used to diagnose and track the progression of emphysema. Some studies have suggested that forced expiratory volume in 1 second (FEV1) measurements, a type of spirometry test, may lack accuracy in detecting disease progression in cases of severe AAT deficiency. Another method, high resolution chest CT scans, may be more accurate at measuring the progression of emphysema. The purpose of this study is to determine if high resolution CT scans are better at detecting the progression of emphysema than lung function tests. Results from this study may lead to the development of a more accurate way to assess lung tissue loss and may improve the understanding of lung destruction in AAT deficiency.

This study will last 4 years and will enroll people with AAT deficiency who have nearly normal lung function test results. Study visits, each lasting about 4 hours, will occur at baseline and months 6, 12, 18, 24, and 36. At each visit, participants will undergo lung function tests, a CT scan, blood collection, and a physical exam. Female participants will have urine collected for a pregnancy test. All participants will also complete questionnaires to assess health status and lung function. Study researchers will call participants every 2 months to collect information on lung disease symptoms and medication changes.

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Study Inclusion/Exclusion Criteria

Inclusion Criteria

  1. Males and Females
  2. Aged 18 or over
  3. Signed and Dated informed consent
  4. Diagnosis of alpha1-antitrypsin deficiency as determined by both:
      (i) serum A1-PI levels >11μM or 80 mg/dl and
      (ii) a PiZZ or Znull phenotype confirmed by gene probe analysis. Previous serum levels and phenotype results are acceptable if documented from a CLIA certified laboratory.
  5. An FEV1 >80% predicted

Exclusion Criteria

  1. Pregnant individuals
  2. Women intending to become pregnant during the 4 years of this study
  3. Previous lung transplantation
  4. Sibling of a participant enrolled in the study
  5. Inability to attend scheduled clinic visits
  6. Inability to give informed consent
  7. Current or ex-smoker of cigarettes or marijuana that quit within the year prior to enrollment
  8. Current or planned use of oral tobacco products or nicotine replacement products
  9. Evidence of significant chronic or acute inflammation outside the lung such as connective diseases, panniculitis or acute infection
  10. Unwillingness to alter bronchodilator medications for 24 hours prior to scheduled QCT scans
  11. Musculoskeletal disease that limits exercise by walking
  12. Requirement to continue taking any of the following anticholinergic drugs within 48 hours of scheduled lung function testing: dicyclomine (Bentyl), propantheline (Pro-Banthine), mepenzolate (Cantil), methscopolamine (Pamine), and scopolamine (Transderm-Scop)
  13. Known allergy or intolerance to tiotroprium or albuterol

Study History

Background

Alpha-1 antitrypsin deficient (AATD) individuals often have early-onset chronic obstructive pulmonary disease (COPD). Among AATD subjects with COPD, panacinar emphysema with predominant involvement of the lung bases has been classically described. However, recent chest computed tomography (CT) data indicate that PiZ subjects (phenotypes PiZZ and PiZnull, the most common severely deficient alleles) with COPD frequently have diffuse emphysema, without a basilar predominance1. Chest CT scans have been suggested as a more sensitive means than pulmonary function tests of detecting the lung parenchymal destruction that occurs in many but not all AATD individuals.

Variability in the development of lung disease in AATD individuals has been noted since the initial description of this disorder 2. Published series of PiZ individuals have usually included many PiZ subjects with COPD; however, these studies have largely included PiZ individuals who were tested for AATD because they already had COPD 3,4,5,6. Thus, the fraction of AATD individuals who will develop COPD and the age-of-onset distribution for the development of COPD in AATD subjects remains unknown. Several large series of AATD individuals clearly demonstrate that PiZ subjects who smoke cigarettes develop more severe pulmonary impairment at an earlier age than nonsmoking PiZ individuals 7,3,5,6. Few studies have considered whether factors other than smoking influence the development of lung disease. Black and Kueppers compared 18 nonsmoking PiZ individuals with 36 PiZ subjects who were current or ex-smokers8. They found significant variability in pulmonary function, particularly the forced expiratory volume in 1 second (FEV1), and clinical symptoms, especially among nonsmoking PiZ individuals. They speculated that unidentified host factors contribute to this variability. Dr. Silverman and colleagues have previously demonstrated marked variability in the development of pulmonary function abnormalities in AATD individuals, with evidence from genetic modeling to suggest that genetic modifiers influence the development of lung disease in AATD individuals9, 10. In this longitudinal study, we will employ quantitative chest CT scans to assess lung parenchymal destruction in AATD individuals with and without airflow obstruction. Thus, we will employ state-of-the-art radiological approaches to provide insight into the natural history of AAT deficiency.

CT densitometry has previously been used in AATD and in non AATD emphysema to measure the distribution and severity of disease. Few studies have defined longitudinal changes in emphysema by lung density measurement. Quantitative emphysema assessments are often based on determining the percentage of lung voxels below a specific threshold, such as -910 or -950 HU. 11 Alternatively, correlations between the lowest percentiles of HU distribution and extent of emphysema measured pathologically can be made12. These techniques are the foundation of quantitative parenchymal analysis. Although there have been modifications to the HU or percentile cutoff value used, the basic analysis approach is still the same. Both measurements are highly correlated although prelimary work suggest that the percentile density methodology is less sensitive to change with thoracic gas volume13. The CT scan is effective at predicting clinical response following LVRS. Some recent studies suggest that the distribution of emphysema is important. Flaherty et al. demonstrated that the apical/caudal ratio of pixel density <900 HU predicts improvement in FEV1 and transitional dyspnea index in patients undergoing lung volume reduction surgery (LVRS)14. As emphysematous holes grow in size, they decrease in number, and the relationship between hole size and number can be expressed as a fractal dimension. Fractal analysis was applied to patients undergoing lung-volume reduction surgery and showed that patients with large emphysematous holes in the upper regions of the lung had better outcome than patients with smaller holes or disease distributed throughout the lung15 Nakano divided the lung into apical and basal regions, as well as an inner core and outer rind, and reported a correlation between extent of emphysema in the upper-outer region and lung volume reduction surgery outcome16. Parr recently demonstrated that basilar emphysema is more likely to produce changes in diffusion than in FEV1 17.

Longitudinal change in CT has been studied before and after medication with less success. Dirksen used a 15th percentile cutoff value to study treatment effects in AATD, but showed only a trend in improved lung structure with treatment18. Mao, in a pilot study of all-trans-retinoic acid treatment of human emphysema, similar to other studies, could not measure a difference in emphysema defined by a density mask using a small group of subjects and a short study design19.

All studies agree that the reproducibility of the findings using low-radiation dose CT scans of humans is dependent on the details of scanning technique and quality control. Important quality initiatives that have been incorporated into this protocol include regular use of air and density phantoms20. Standardization of reconstruction algorithms 21 and minimizing the number of CT scanners17 used on any subject can minimize the variability in the density mask measurements. In addition, the use of 16-128 multidetector scans and use of whole lung imaging in this protocol hold promise to improve the outcome of this study in AATD individuals with normal FEV1 values22

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