Vol. 73, No. 2, 2006
Issue release date: March 2006
Respiration 2006;73:185–190
Clinical Investigations
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Results of a Survey of Patients with Alpha-1 Antitrypsin Deficiency

Strange C.a · Stoller J.K.b · Sandhaus R.A.c · Dickson R.a · Turino G.d
aDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, S.C.; bDivision of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio; cDivision of Pulmonary and Critical Care Medicine, National Jewish Medical Center, Denver, Colo., and dDivision of Pulmonary Medicine, St. Luke’s/Roosevelt Hospital, New York, N.Y., USA
email Corresponding Author


 goto top of outline Key Words

  • α1-Antitrypsin deficiency
  • COPD
  • Emphysema
  • Chronic bronchitis
  • Asthma
  • Augmentation therapy
  • Lung transplantation
  • Liver transplantation

 goto top of outline Abstract

Background: α1-Antitrypsin deficiency (AATD) is an uncommon genetic disease which occurs in 1–2.5% of Americans with chronic obstructive pulmonary disease (COPD). Little is known about current demographics of AATD. Objectives: This survey study reviews the clinical characteristics of diseased individuals in North America. Methods: A survey of members from the mailing lists of US AATD patient support organizations was commissioned with duplicate persons omitted. The survey was mailed to 5,222 unique individuals with AATD. Questionnaires were returned by 1,953 individuals, including 1,810 with severe deficiency, 93 with the carrier state and 41 who were caregivers of others. Results: The majority (81%) of participants reported COPD with symptoms of asthma, chronic bronchitis, and emphysema, usually in combination. The mean age of respondents [53.1 ± 13.2 (SD) years] is older than the general US population. Lung or liver transplantation was reported by 9% of all respondents (n = 175), including 66 single lung transplants, 68 double lung transplants, and 47 liver transplants. Another 6.6% (n = 128) reported that they were currently on a transplant list. Twenty-one percent of lung transplants report continuing augmentation therapy use. Augmentation use is reported by 75% of those with obstructive lung disease. The majority of patients with liver disease also have COPD. Conclusions: AATD remains a devastating illness for many of those affected as reflected in a high incidence of transplantation for liver and lung disease.

Copyright © 2006 S. Karger AG, Basel

goto top of outline Introduction

α1-Antitrypsin deficiency (AATD) is an uncommon genetic disease which occurs in 1–2.5% of Americans with chronic obstructive pulmonary disease (COPD) [1]. Although gene frequency studies suggest that there are 269,000 persons with severe deficiency (PiSZ and PiZZ) in the United States [2], no accurate figures are available to define the number and demographics of currently diagnosed individuals.

Three patient-centered nonprofit organizations have been actively helping AAT-deficient individuals for many years. To better define the issues for the AATD community, the three organizations commissioned a joint national survey to focus on health status, healthcare and community issues. This paper presents a summary of these survey results, especially regarding the characteristics of this large cohort of AAT-deficient individuals.


goto top of outline Methods

The mailed survey was conducted in the spring of 2003 through Schulman, Ronca, and Bucuvalas, Inc. (SRBI), an international research organization. To assure the confidentiality of all survey recipients, SRBI signed a confidentiality agreement with each of the three sponsoring organizations. A single sample population with US addresses omitting duplicates was constructed from the mailing list of the three organizations. From these lists, 5,222 unique potential participants were identified.

A four-page 28-question self-administered questionnaire was sent to the 5,222 participants with a cover letter stating the study purpose and a toll-free number for questions. The questionnaires were mailed out beginning April 14, 2003 and reminder post-cards were mailed to nonrespondents on May 7, 2003. If the AATD deficient individual was too young or too ill to complete the survey, a caregiver could participate on his or her behalf.

Only yes/no and multiple choice questions were used for this report. Data were collated by SRBI and a de-identified dataset was made available for analysis.

Comparative statistics were performed in Stata (College Station, Tex., USA). p values <0.05 were considered significant. Two-sided t tests were used for continuous data. Categorical data were analyzed using the =χ2 statistic. Comparisons among three groups with continuous outcome were performed using ANOVA coupled with Bonferroni correction for multiple comparisons. Three-way comparisons for data with Likert outcome used the Kruskal-Wallis test. The Wilcoxon rank sum test was used for two-way comparisons for data with Likert outcome.


goto top of outline Results

By June 11, 2003, 1,953 questionnaires had been returned to SRBI, representing 37.4% of the study population. Not all participants answered every question. Sixty-eight percent of survey respondents were on the AlphaNet mailing list, 46% were on the Alpha-1 Foundation mailing list and 46% were on the Alpha-1 Association mailing list.

Severe deficiency of AAT (i.e. associated with a PiSZ, PiZZ, Pi Znull phenotype) was present in 92.7% of the survey participants (n = 1,810). Two percent of respondents were caregivers answering on behalf of a deficient individual (n = 41) and 4.8% were PiMZ carriers (n = 93). The mean age of participants was 53.1 ± 13.2 (SD) years, and the ages of respondents were distributed normally (fig. 1). Forty-nine percent of participants were female. Carriers are excluded from the remainder of the analyses unless specifically reported.

Fig. 1. Age in the AATD survey population compared to the general United States population.

Figure 2 shows the prevalence of asthma, chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), and liver disease in respondents who were able to self-report any combination of diagnoses associated with AATD [1]. Sixteen percent of respondents reported no pulmonary or hepatic symptoms. Among AATD carriers (n = 93), 46% reported no symptoms, 33% reported asthma, 29% chronic bronchitis, 15% emphysema, 14% COPD and 8% reported liver disease. Among severely AAT-deficient individuals, 1,219 participants reported chronic bronchitis or emphysema, yet only 775 participants reported COPD. Conversely, 95 participants reported COPD, but neither emphysema nor chronic bronchitis.

Fig. 2. Self-reported diagnoses from the 1,851 survey respondents with severe or carrier deficiency. a The obstructive lung disease cohort (n = 69) reported COPD without asthma, chronic bronchitis or emphysema. b The liver disease cohort with obstructive lung disease (n = 95) also included in other places in the Venn diagram) reported asthma (n = 69), chronic bronchitis (n = 45), emphysema (n = 60) and chronic obstructive lung disease (n = 44).

Lung or liver transplantation was reported by 9% of all respondents (n = 175), including 66 single lung transplants, 68 double lung transplants, and 47 liver transplants. Another 6.6% (n = 128) reported that they were currently on a transplant list, with 127 of these individuals having severe AAT deficiency. Two carriers report having had a single lung transplant and 1 is currently on a transplant list. Table 1 shows a comparison between respondents with and without current or pending transplantation. Eighteen of 66 single lung transplants and 10 of 68 double lung transplants report current augmentation therapy use.

Table 1. Comparisons among severely AAT-deficient respondents stratified by transplantation status

Figure 3 shows the self-reported health status of the participants. Table 2 presents the type of physicians visited by respondents in the preceding year. More than half (56%) of the patients reported that their lung function has been tested more than once in the preceding year. Contrary to recent management standards (ATS/ERS), 10% of severely deficient AAT-deficient individuals reported they have not had their lung function tested in the past year. Almost half (45%) of respondents reported using supplemental oxygen therapy on a regular basis outside a hospital in the past 12 months.

Table 2. Types of physicians visited in the preceding year

Fig. 3. Self-reported health status in the AATD survey population.

Nearly three quarters (74%) of the severely AAT-deficient respondents (n = 1,347) report that they are currently infusing augmentation therapy. Frequency of augmentation infusion is shown in figure 4. The frequency with which participants infused less frequently than scheduled were often (3%), sometimes (25%), rarely (50%) and never (22%). Table 3 compares respondents who were using intravenous augmentation therapy with non-users. Notably, augmentation therapy recipients were older, older at first diagnosis of AATD, more likely to have emphysema, less likely to lack insurance, more likely to be using supplemental oxygen, and had a lower quality of life.

Table 3. Comparison of participants using and not using intravenous augmentation therapy

Fig. 4. Frequency of augmentation therapy in the survey population.


goto top of outline Discussion

In this large and representative sample of Americans with AATD, the burden of obstructive lung disease is enormous. Although some of the reported disease impact may reflect the selection bias of including affected individuals, the overall significance of the results is not diminished. In this cohort where 82% are below age 65, 52%rate their quality of life less than good, and 16% have had or are awaiting solid organ transplantation.

The mailing list of the current study included 5,222 unique individuals of whom 94.7% (n = 4,945) characterize themselves as having severe AAT deficiency rather than as carriers. This number represents the current best estimate of the number of diagnosed AATD individuals in the US. While some affected individuals may never contact one of the three sponsoring organizations for this disease, the prolonged high visibility of these groups supports the idea that such individuals are few in number. Using conservative estimates of PiZ frequency [2], our data suggest that fewer than one in ten AATD individuals in the United States are currently diagnosed.

The differences in the age distribution between the survey population and the general US population highlight several important aspects of the natural history of AATD. The small number of pediatric patients in this survey suggests that childhood diagnoses are predominantly limited to those who present with liver disease in childhood, a small proportion (2.5%) of all AATD individuals [3]. Since the majority of participants in every previous survey [4, 5] have been diagnosed on the basis of symptoms, the increased representation of age 45- to 65-year-old individuals confirms that early onset obstructive lung disease has been the driving force for disease detection. Since obstructive lung disease has been shown to be the consequence of genetic variation [6], environmental exposure [7] and cigarette smoking [5], the presenting age of COPD in AATD varies widely. If testing is performed preferentially on early onset emphysema patients, the self-fulfilling prophecy of finding young patients remains true. Life expectancy into the sixth and seventh decades in AATD previously has been described [8]. The 10% of the patients diagnosed after age 60 in the current study suggests that many more AATD patients in this age range remain undiagnosed.

Although individuals with severe AATD are classically characterized as having emphysema, this series and the previous NHLBI Registry of Patients Severely Deficient in AAT [5] highlight the high prevalence of wheezing and sputum production, features more usually associated with bronchospasm and bronchitis. The clinical message is that AATD may present with chronic bronchitis, asthma or emphysema. In this context, testing only those who have a classic emphysema presentation will fail to diagnose the majority of patients with AATD. Instead, recent standards documents recommend diagnostic testing in all adults with COPD, including chronic bronchitis, emphysema, and asthma with incompletely reversible airflow obstruction [1].

Our results show inconsistencies of diagnostic labeling as participants describe their lung problems, suggesting the need for more uniform patient education. For example, 1,253 participants reported emphysema or chronic bronchitis, yet only 788 participants reported COPD. Conversely, 95 participants reported COPD without emphysema, chronic bronchitis, or asthma. These inconsistencies suggest the opportunity for physicians to better explain to patients the relationship between COPD, chronic bronchitis, emphysema, and asthma.

In this series, the 16% of severely AAT-deficient respondents who reported being listed for or having received a transplant were younger at initial diagnosis than nonlisted respondents (mean age 39.7 ± 11 versus 45.2 ± 12 years). Possible explanations include the earlier onset and greater severity of disease in those affected earlier in life and the impact of age on transplant candidacy. Young age may affect the likelihood of an impaired individual to seek transplantation, independent of the degree of impairment. This survey was unable to differentiate between the two potential explanations.

Our findings suggest gender differences in the course of AATD. Men in this series reported lower quality of life than women and were more likely to have received or be listed for a transplant. Oxygen use was more common among men, suggesting that the gender difference represents a difference in disease severity rather that differences in psychosocial variables that impact quality of life and transplantation listing. The reasons for more severe presentations in males remain unstudied although FEV1 decline has been measured to be more severe in men in one AATD series [9]. Smoking incidence was not studied in this survey to determine if this important variable is the cause of the gender differences.

Our findings also offer several insights about augmentation therapy use. Consistent with other US series [4, 5], most respondents (75%) reported using augmentation therapy. Yet, surprising findings regarding augmentation therapy use were that 3 liver transplant patients reported continuing augmentation therapy use posttransplant, i.e. after serum AAT concentrations would have returned to normal. Also, 3 subjects reported receiving augmentation therapy every 5 weeks, which is less frequently than recommended. While neither the accuracy of these reports, nor reasons can be ascertained from these data, the fact that some patients were receiving infusions at unconventional frequencies is consistent with other reports [5, 10].

We were surprised that 21% of the lung transplant respondents report continuing augmentation therapy use, since the benefits of posttransplantation augmentation remain unproven. Proponents of administering augmentation therapy posttransplant suggest benefits in the incidence of respiratory infections or lung transplant rejection. Physicians withholding augmentation therapy sug gest that emphysema took decades to progress before transplantation, and that posttransplantation survival is not dependent on emphysema progression. The fact that more single lung transplants than double lung transplants are receiving augmentation therapy suggests that some of the use is directed toward prevention of emphysema in the native lung.

The number of participants with liver disease (n = 151) improves our understanding of this incompletely described manifestation of AATD. Of these participants, 60% have concomitant obstructive lung disease. One possibility for the high frequency of obstructive lung disease is that many of the liver failure patients in the United States are seen at tertiary medical centers that also perform liver transplantation. Since spirometry is performed as a standard of care before transplantation, obstructive lung disease will usually be diagnosed if present.

Our study has some weaknesses. Only 37.4% of the population returned the survey. Survey responders may be more symptomatic or have other differences than the larger population. Smoking history was not queried. Therefore, we do not know the influence of smoking on the COPD subsets reported. With the advent of rapid screening methods to ascertain genotypes [11], the study might have requested testing from all participants to assure accurate diagnoses. Instead, the survey participants with severe disease included those with PiSZ phenotypes that have a variable degree of airflow obstruction and as a group may have less severe disease and less augmentation therapy use than PiZZ phenotypes [12]. Their inclusion has the effect of further highlighting the severity of the impairment of the PiZZ participants in this survey.

In conclusion, this survey of AATD in the United States provides a cross-sectional window to show the poor health of the average diagnosed individual with this genetic disease. This survey provides evidence that early diagnosis provides benefits to the population and supports current recommendations for screening all patients with fixed airflow obstruction regardless of age [1].

 goto top of outline References
  1. American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with alpha-1-antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818–900.

    External Resources

  2. de Serres FJ: Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 2002;122:1818–1829.
  3. Sveger T: Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1316–1321.
  4. Stoller J, Smith P, Yang P, et al: Physical and social impact of alpha1 antitrypsin deficiency: results of a study. Cleveland Clin J Med 1994;61:461–467.
  5. McElvaney NG, Stoller JK, Buist AS, et al: Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group. Chest 1997;111:394–403.
  6. Silverman E, Province M, Campbell E, et al: Family study of alpha1-antitrypsin deficiency: Effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits. Genet Epidemiol 1992;9:317–331.
  7. Mayer AS, Stoller JK, Bucher-Bartelson B, et al: Occupational exposure risks in individuals with PI*Z alpha(1)-antitrypsin deficiency. Am J Respir Crit Care Med 2000;162:553–558.
  8. Black LF, Kueppers F: Alpha 1-antitrypsin deficiency in nonsmokers. Am Rev Respir Dis 1978;117:421–428.
  9. Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 1998;158:49–59.
  10. Stoller JK, Fallat R, Schluchter MD, et al: Augmentation therapy with alpha1-antitrypsin: patterns of use and adverse events. Chest 2003;123:1425–1434.
  11. Zorzetto M, Tamburnotti C, Maschietto B, et al: A fast amplification-reverse hybridization assay kit to detect the most frequesnt deficient variants in the alpha-1-antitrypsin gene. Respiration 2002;69:81–85.
  12. Turino GM, Barker AF, Brantly ML, et al: Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. Alpha 1-antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 1996;154:1718–1725.

 goto top of outline Author Contacts

Charlie Strange, MD, FCCP
Division of Pulmonary and Critical Care Medicine
96 Jonathan Lucas Street, 812 CSB, Medical University of South Carolina
Charleston, SC 29425 (USA)
Tel. +1 843 792 2153, Fax +1 843 792 0732, E-Mail strangec@musc.edu

 goto top of outline Article Information

Received: November 15, 2004
Accepted after revision: March 3, 2005
Published online: August 31, 2005
Number of Print Pages : 6
Number of Figures : 4, Number of Tables : 3, Number of References : 12

 goto top of outline Publication Details

Respiration (International Journal of Thoracic Medicine)

Vol. 73, No. 2, Year 2006 (Cover Date: March 2006)

Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (print), 1423–0356 (Online)

For additional information: http://www.karger.com/RES

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