 1-Antitrypsin
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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Subjects 
18 yr of age with serum 
1-antitrypsin (1-AT) levels 
11 µM or a ZZ genotype were followed for 3.5 to 7 yr with spirometry measurements every 6 to 12 mo as part of a National Heart,
Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1-Antitrypsin. Among
all 1,129 enrollees, 5-yr mortality was 19% (95% CI: 16 to 21%). In multivariate analyses of 1,048 subjects who had been contacted 6 mo after enrolling, age and baseline FEV1% predicted were significant predictors of mortality. Results also showed that those subjects receiving augmentation therapy
had decreased mortality (risk ratio [RR] = 0.64, 95% CI: 0.43 to 0.94, p = 0.02) as compared with
those not receiving therapy. Among 927 subjects with two or more FEV1 measurements 1 yr apart, the mean FEV1 decline was 54 ml/yr, with more rapid decline in males, those aged 30 to 44 yr, current smokers, those with FEV1 35 to 79% predicted, and those who ever had a bronchodilator response. Among all subjects, FEV1 decline was not different between augmentation-therapy groups
(p = 0.40). However, among subjects with a mean FEV1 35 to 49% predicted, FEV1 decline was significantly slower for subjects receiving than for those not receiving augmentation therapy (mean difference = 27 ml/yr, 95% CI: 3 to 51 ml/yr; p = 0.03). Because this was not a randomized trial, we cannot exclude the possibility that these differences may have been due to other factors for which we
could not control.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Alpha-1-antitrypsin (1-AT) deficiency is an hereditary disorder characterized by low serum levels of 1-AT, an increased risk of emphysema at an early age, and less commonly, an increased risk for liver disease, particularly in children (1). Individuals with the deficiency lack protection normally provided
by 1-AT against neutrophil elastase released by neutrophils
in the lower respiratory tract, leading to destruction of lung
parenchyma and to emphysema (4). Currently, the only approved therapy for this disorder is to augment the serum level
of 1-AT, and thereby lung levels of this protein, by weekly intravenous infusions of a purified preparation of human 1-AT
(augmentation therapy [5, 6]). Such therapy has been shown
to increase levels of serum and lung 1-AT and of antineutrophil elastase appropriately (5), but its clinical efficacy in improving survival or reducing the rate of decline in lung function has never been demonstrated. We examined decline in
FEV1 and mortality in relation to augmentation therapy and
other factors among subjects enrolled in a National Heart,
Lung and Blood Institute (NHLBI) Registry of Patients with Severe Deficiency of 1-AT.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Design
The Registry was initiated in 1988 as a means of collecting information on the natural history of 1-AT deficiency, after sample sizes for a
randomized clinical trial of augmentation therapy were deemed infeasible to obtain (8, 9). Details of study design and baseline characteristics have been described previously (10, 11). The Registry protocol
was reviewed and approved by the appropriate institutional review
board at each of the 37 participating clinical centers. Eligible subjects
were 18 yr of age and either had serum 1-AT levels 11 µM, confirmed by a central laboratory (n = 1,026), or a ZZ genotype, confirmed by DNA gene-probe analysis (n = 103). From March 1989 through October 1992, 1,129 eligible subjects were enrolled from 37 centers. Follow-up continued through April 1996, with individuals returning for annual or semiannual visits. Spirometry was performed before and after bronchodilator treatment, using a standard protocol (10). As previously described, great attention was given to assuring
high-quality, reproducible spirometry results, and baseline FEV1 measurements achieved high reproducibility rates for both prebronchodilator (95.0%) and postbronchodilator (95.7%) measurements (12).
Smoking status was based on subjects' self-reports. The baseline (initial) smoking status was examined in relationship to survival, and current (last reported) smoking status was examined in relationship to
FEV1 decline. Dosing frequency of augmentation therapy was self-
reported by the subject and was verified with augmentation-therapy
logs when available. Regular medical care for participants may have
been provided by physicians not associated with the Registry. If a subject was unable to return for a follow-up visit, a telephone-contact
form was used to ascertain vital status and collect updated information on use of augmentation therapy. The National Death Index (National Center for Health Statistics, Hyattsville, MD) and Equifax, Inc.
(McLean, VA) were used to search for unreported deaths. A Death
Review Committee reviewed available records to ascertain causes of
death.
Use of Augmentation Therapy
Augmentation therapy refers to the intravenous infusion of purified,
pooled human 1-AT (5, 13). The 1-AT preparation Prolastin
(Bayer, Inc., West Haven, CT), currently the only commercially available preparation, has been approved by the U.S. Food and Drug Administration (FDA) for once weekly use at 60 mg/kg. Decisions about
treatment with intravenous 1-AT were made by the participants' physicians, not by the Registry. Logs recording use of augmentation therapy were completed by the subjects and turned in at clinic visits.
Subjects were also questioned about augmentation therapy at regular
visits or, when they were unable to come in for regular visits, by telephone. Subjects were classified as always, partly, or never receiving
1-AT augmentation therapy while in the Registry. The "always receiving" therapy group included those on therapy continuously, beginning at or within 3 mo of enrollment. The "partly" on therapy
group included those who began therapy > 3 mo after enrollment or
who discontinued therapy for > 1 mo after enrollment. Classifications
of "always," "partly" and "never" receiving therapy were made irrespective of dosing frequency, which was determined by the subjects'
managing physicians. Measurement of "trough" serum 1-AT levels in
augmentation-therapy recipients was not required. Although these
measurements were recorded when submitted, they were infrequently
available.
Statistical Analysis
Continuous distributions were compared through Wilcoxon's rank-sum test, and categorical variables were compared through the chi-square test.
Survival. For statistical analysis of survival from the time of enrollment, we used the Kaplan-Meier method (17), the log-rank test (18),
and Cox's proportional hazards regression (19). Survival times of subjects receiving liver transplants were censored at the time of transplantation, and receipt of a lung transplant was treated as a time-varying covariate. The baseline or first available postbronchodilator
measurement of FEV1% predicted was used as a covariate in the survival models, using American Thoracic Society (ATS) staging strata
(20) (i.e., FEV1% predicted < 35% [Stage III], 35 to 49% [Stage II],
50 to 79% [Stage I], and 80% [Normal]). Mortality was compared
among groups never, partly, and always receiving augmentation therapy, and also by using a time-varying covariate, classifying each subject as receiving or not receiving therapy at each time point. To reduce
the possibility of bias toward a positive effect of augmentation therapy caused by including subjects who were not on therapy at enrollment and who later died before returning for a follow-up visit (and
presumably before they could begin augmentation therapy), a "landmark analysis" (21) was performed, including only subjects who were
contacted 6 mo after enrollment.
Decline in FEV1. Analyses of decline in FEV1 included subjects
with two or more postbronchodilator FEV1 measurements obtained 1 yr apart. FEV1 measurements obtained following lung or liver transplants were excluded from all analyses. Rates of FEV1 decline were estimated for individual subjects through least-squares regression of FEV1 versus time since enrollment. We analyzed decline in
FEV1 with a linear mixed-effects model (22), in which the responses were the changes in FEV1 between the first available measurement and all available subsequent measurements, with random effects for
individual subjects' intercepts and rates of FEV1 decline. The mean
FEV1% predicted, calculated from all available visits, was used as a
covariate, rather than using initial FEV1% predicted, in order to avoid
problems of regression to the mean (23). Bronchodilator responsiveness, coded as whether the subject ever versus never had a bronchodilator response (defined as postbronchodilator increase in FEV1 of at
least 200 ml and 12% over the prebronchodilator value [20, 24]) at any
visit, was examined as a covariate. The cumulative time (since enrollment) for which each subject had received augmentation therapy at
each follow-up visit was included in the model as a time-dependent
covariate, allowing estimation of the average rates of decline in FEV1
while receiving and not receiving augmentation therapy. We also used
a simpler approach, classifying subjects as either always or never receiving therapy in the mixed-effects model. In this approach, FEV1
data from subjects partly receiving therapy were used for the period
during which they were continuously receiving or not receiving therapy, whichever was the longer period, provided that this period was
1 yr. The nonlinear relationship between decline in FEV1 and FEV1%
predicted was examined in the mixed-effects model by modeling
FEV1% predicted with cubic polynomial splines (25). Values are reported as means ± 1 SD; all reported p values are two-tailed, without
adjustment for multiple comparisons.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Of the 1129 subjects in the study, 204 (18.1%) expired (including 11 who had previously dropped out), 39 (3.5%) dropped
out, and 886 (78.5%) remained in the study as of April 30, 1996. The multivariate survival analysis excluded 76 subjects
(54 deaths) who did not have follow-up contact 6 mo after
enrollment, and five subjects (one death) because data for initial FEV1% predicted or education were missing. Deaths following liver transplantation were censored, leaving 1,048 subjects and 147 deaths used in the analysis. The analyses of FEV1
decline excluded 202 subjects who did not have at least two
postbronchodilator FEV1 measurements, obtained at least
1 yr apart (76 of whom were also excluded from the survival
analysis because of lack of follow-up contact 6 mo after enrollment.
Follow-up
Among subjects eligible to return for each annual visit, rates of return for follow-up visits were 80%, 75%, 72%, 71%, and 69%, respectively, for visits in the first through fifth years. Rates of contact by visit or telephone ranged between 81 and 84% for the first through fifth years. Six hundred ninety (78%) of the 886 subjects remaining in the study in April 1996 had returned for a follow-up visit in the year immediately preceding, and 807 (91%) were contacted (visit or phone) in that same year.
Transplants and Chest Surgeries
There were 74 single-lung, 37 double-lung, one heart/lung, and seven liver-transplant recipients among Registry subjects. All liver transplants and 106 of 112 (95%) of the lung transplants were performed after enrollment. Twenty additional subjects underwent lung surgery after enrollment, 19 with resections (17 with bullectomy or lung-volume-reduction surgery).
Use of Augmentation Therapy
Among the 1,129 subjects enrolled in the study, 382 (34%) never received augmentation therapy, 390 (35%) always received therapy, and 357 (32%) were partly receiving therapy while in the Registry. When this evaluation was restricted to subjects included in the analysis of FEV1 decline (Table 1), 277 (30%) never, 389 (42%) always, and 261 (28%) partly received augmentation therapy while in the Registry. Of the 357 subjects classified as partly receiving therapy, 55% started augmentation therapy > 3 mo after enrollment, 38% permanently discontinued therapy, and 7% temporarily stopped and then restarted therapy. The 357 subjects classified as partly receiving therapy were followed for a total of 20,564 mo in the Registry, and were receiving augmentation therapy for 13,627 mo, or 66% of the total period. Reported reasons for permanently discontinuing augmentation therapy were receipt of a lung transplant (80 of 137 subjects; 59%), financial constraints (16 of 137 subjects; 12%), adverse reactions ascribed to augmentation therapy (four of 137 subjects; 3%), and other/unknown causes (37 of 137 subjects; 27%). Among those never receiving augmentation therapy, predominant reasons for not starting therapy included: not recommended by physician because of normal lung function (54%); cost (17%); receipt or anticipation of a lung transplant (6%); not recommended by physician because of poor lung function (5%); and presence of a medical contraindication (5%), with 13% other/unknown.
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Initial dosing frequencies were 383 (51.3%) weekly, 189 (25.3%) biweekly, and 163 (21.8%) monthly, with 12 (1.6%)
unknown. Over time, frequencies changed such that among
633 subjects who had multiple reports of dosing frequency, at
last report, 33% were receiving weekly, 43% biweekly, and
24% monthly therapy. Also, 66% of subjects had not changed
dosing frequency, 25% had decreased frequency (18% from
weekly to biweekly, 5% from weekly to monthly, 2% from biweekly to monthly), and only 9% had increased the frequency
of infusion (2% from monthly to weekly, 4% from monthly to
biweekly, 3% from biweekly to weekly). Of these 633 subjects,
the numbers of subjects who remained on a fixed dosage interval for 90% of the time they were receiving therapy were 168 (26.5%) on weekly, 158 (25.0%) on biweekly, and 118 (18.6%) on monthly dosages; another 189 (29.9%) were not
on a constant dosage for 90% of the time.
Baseline Characteristics
The 927 subjects included in the analysis of FEV1 (Table 1)
had a mean age of 46 yr; 55% were male, 71% were ex-smokers, and the subjects' mean FEV1 was 49 ± 30% predicted.
Most (71%) were ascertained because they had pulmonary
symptoms. Compared with those who received augmentation
therapy, subjects who never received augmentation therapy
were more likely to have FEV1 80% predicted (53%, versus
6% and 4% for those partly and always receiving therapy, respectively), were less likely to be ascertained because of pulmonary symptoms, had lower family income, and were less
likely to have insurance coverage (Table 1).
Compared with the 927 subjects included in the FEV1 analysis, the 202 subjects excluded did not differ significantly with respect to gender, smoking, ascertainment method, education,
income, or insurance coverage (Table 1). However, subjects
excluded from the analysis had more severe airflow obstruction at baseline, with a mean FEV1% predicted of 36 ± 27%,
as compared with 49 ± 30% for subjects included in the analysis (p 0.0001), and also were older (p = 0.0008), had higher
serum 1-AT levels (p = 0.04), and were less likely to exhibit a
bronchodilator response at the initial visit (p 0.001).
Survival
The mean length of follow-up of survivors was 57 ± 17 mo.
Kaplan-Meier estimates ± SE of cumulative mortality for the
entire Registry cohort at 3 and 5 yr after enrollment were
10.5 ± 0.9% and 18.6 ± 1.3%, respectively. As has been previously shown (20, 26, 27), initial FEV1% predicted was a major
determinant of survival; for example, 5-yr Kaplan-Meier mortality rates (± SE) were 30.3 ± 2.2%, 12.0 ± 2.4%, and 4.3 ± 1.2%, respectively, among subjects with an initial FEV1% predicted of 35% (n = 535), 35 to 49% (n = 228), and 50%
(n = 360) (log-rank p value 0.001).
Among all subjects with initial FEV1 < 50% predicted
(Figure 1A), mortality was significantly higher (p 0.001) for
subjects who never as opposed to sometimes or always received
augmentation therapy. Mortality rates were low for subjects
with initial FEV1 50% predicted (Figure 1B), and did not
differ between augmentation-therapy groups. Similar results
were seen when the analysis was restricted to subjects having
follow-up contact 6 mo after enrollment (Figures 1C and D).
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In multivariate analyses based on 1,048 subjects (147 deaths)
with follow-up contact 6 mo after enrollment (Table 2), increased age, lower education, lower FEV1% predicted, receipt
of a lung transplant, and not receiving augmentation therapy
(modeled as a time-varying covariate) were all significantly associated with increased mortality risk. In addition, gender was
included in all multivariate models even though it was not a
significant predictor of mortality. When adjustment was made
for gender and the other significant predictors, mortality risk was
significantly lower among subjects receiving augmentation therapy than among those not receiving therapy (risk ratio [RR] = 0.64; 95% CI = 0.43 to 0.94; p = 0.02; Table 2). In addition,
the interaction between FEV1% predicted and use of augmentation therapy was statistically significant (p = 0.01; Table 2,
Footnote 2), indicating that the effect of augmentation therapy differed across strata of FEV1. We therefore examined the
effect of augmentation therapy on survival separately by level
of FEV1% predicted, as well as for the entire group. Use of
augmentation therapy was associated with lower mortality in
the subgroup with initial FEV1 values of 35 to 49% predicted (ATS Stage II) (RR = 0.21, 95% CI = 0.09 to 0.50, p 0.001).
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When added to the multivariate model including gender
and other significant predictors, ascertainment method (ascertained on the basis of symptoms, family screening, or other basis), serum 1-AT as a continuous variable, bronchodilator response at the initial visit (yes/no), and initial smoking status
(never/ex-/current smoker) were not significantly related to
survival. In similar analyses, oxygen use (i.e., ever receiving
oxygen 12 hr/d while enrolled) was associated with increased
mortality (RR = 1.46, p = 0.04), but the association between
augmentation therapy and survival remained statistically significant. Further adjustment for clinical centers (n = 1) found
to have significantly higher mortality than other centers, or for
centers with poorer follow-up rates (n = 8 centers with < 80%
follow-up in the final year), did not alter the findings with respect to augmentation therapy.
Similar results were obtained with an alternative approach to modeling augmentation therapy; in proportional hazards regressions adjusting for the same covariates as in Table 2, mortality risk ratios in comparisons of subjects who sometimes or always as opposed to those who never received augmentation therapy were 0.67 (p = 0.04) among all subjects, and 0.29 (p = 0.005) for subjects with initial FEV1 values of 35 to 49% predicted. Additionally, initial frequency of therapy was not related to survival in subjects receiving therapy after adjustment for factors in the multivariate model (p > 0.10).
Analyses were also repeated with survival times of lung-transplant recipients censored at the time of transplant, rather than using lung transplantation as a covariate in the model, and findings were unchanged. A detailed examination of survival of transplant recipients will be the subject of a separate report.
In analyses restricted to subjects with follow-up contact
12 mo after-enrollment (1,020 subjects; 125 deaths), the
pooled RRs for augmentation therapy from the two modeling
approaches (i.e., using a time-varying covariate to compare those
receiving versus not receiving augmentation therapy, and using the second statistical model, which compared subjects who
sometimes or always received therapy with those who never received therapy), with control for age, gender, education, and
transplant status, were 0.63 (p = 0.04) and 0.70 (p = 0.10), respectively.
Among 118 deaths for which sufficient information was available to determine cause of death, predominant underlying causes of death were emphysema (n = 85; 72%) and cirrhosis (n = 12; 10%), followed by malignancy (n = 3), diverticulitis (n = 2), sepsis/infection (n = 2), and trauma/accident (n = 2). Twelve other causes accounted for a single death each.
Decline in FEV1
The average rate of decline in FEV1 among all 927 subjects
was 54 ml/yr. Histograms of rates of FEV1 decline for individual subjects (Figure 2) confirmed that the majority of subjects,
both receiving and not receiving augmentation therapy, experienced a decline in FEV1. In univariate analyses (Table 3),
statistically significant differences in mean rates of FEV1 decline were seen by gender, age, current smoking status, serum
1-AT level, mean FEV1% predicted, and ever versus never
having a bronchodilator response.
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In multivariate analyses, significant predictors of decline in
FEV1 (Tables 4 and 5) included gender, age, current smoking status, bronchodilator response, and mean FEV1% predicted.
Because the effect of augmentation therapy differed across
levels of mean FEV1% predicted (p = 0.05), effects of augmentation therapy were examined separately by category of
FEV1% predicted, as well as for the overall cohort. Serum 1-AT level was significant in the multivariate model (Table 5);
however, it was not included in the final model because to do
so would have excluded 79 subjects with missing serum 1-AT
levels, and its inclusion in the model did not substantially alter
the results. Income, insurance coverage, and education were
not significantly related to FEV1 decline in the multivariate
analyses. Occupational exposure to dust or fumes, defined as
any prior exposure and also as any exposure while enrolled in
the Registry, was not significantly related to FEV1 decline. Among all subjects, mean rates of FEV1 decline did not differ for those receiving versus those not receiving augmentation
therapy (Table 5) (difference in means = 4 ml/yr, p = 0.40).
However, among subjects with mean FEV1 values of 35 to
49% predicted (Stage II), the rate of FEV1 decline was slower
for those receiving than for those not receiving augmentation
therapy (difference in means = 27 ml/yr, 95% CI: 3 to 51 ml/
yr, p = 0.03). For Stage I and II subjects combined (i.e., FEV1
of 35 to 79% predicted), the mean difference in rates of decline when receiving versus not receiving augmentation therapy was 14 ml/yr (95% CI: 
4 to 31 ml/yr; p = 0.13). In keeping with an earlier subgroup analysis by Buist and colleagues
(28), we also examined the subgroup with a mean FEV1 of 30 to 64% predicted. This analysis showed a decreased rate of
FEV1 decline for those receiving augmentation therapy (difference in means = 18 ml/yr, 95% CI: 2 to 34 ml/yr; p = 0.03).
Similar results were obtained when the analysis was done on
an expanded cohort of 979 subjects, obtained by including an
additional 52 subjects who had two or more postbronchodilator FEV1 measurements that were less than 1 yr apart.
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The analyses were repeated with adjustment for the baseline rather than the mean FEV1% predicted, yielding similar results. The interaction between augmentation and initial FEV1% predicted approached statistical significance (p = 0.06). In Stage II subjects (initial FEV1 of 35 to 49% predicted), FEV1 decline was slower for those receiving than for those not receiving augmentation therapy (difference in means = 22 ml/yr, p = 0.04). In an analysis of change in FEV1/ height3, conducted to adjust for body size, gender and bronchodilator responsiveness were not statistically significant, whereas age and smoking status remained significant. Among Stage II subjects the decline in FEV1/height3 was less for those receiving than for those not receiving augmentation therapy (p = 0.04).
In multivariate analyses, average rates of FEV1 decline among subjects always receiving therapy did not differ significantly among those always receiving weekly, biweekly, monthly, or other regimens (p > 0.10).
The relationship between FEV1 decline and mean level of FEV1% predicted, estimated through cubic spline techniques separately for those receiving versus those not receiving augmentation therapy (Figure 3A), appears U-shaped. Differences in mean rates of decline with and without augmentation therapy (Figure 3B) suggest that among subjects with an FEV1 in the range of 20 to 80% predicted, those receiving augmentation therapy tended to have a slower decline in FEV1. This trend appears to have reversed for subjects with FEV1 values above 80% predicted (Table 5), although the number of such subjects receiving augmentation therapy was quite small (n = 21; Figure 2D).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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In interpreting our findings, two important limitations of this
study must be considered. First, the Registry is not a population-based study, and our findings may not be generalizable to
the universe of individuals severely deficient in 1-AT. Second,
decisions about treatment with intravenous augmentation therapy were made by the managing physicians of participants.
Thus, differences in outcomes between individuals receiving
and those not receiving augmentation therapy may be biased
by systematic differences between these groups, and there is
no assurance that statistical modeling will completely account
for these imbalances. For example, other factors, such as intensity of care received, may be associated with augmentation
therapy, and could confound the relationship between use of
augmentation therapy and survival or FEV1 decline.
With these limitations kept in mind, our findings suggest a
relationship between intravenous 1-AT augmentation therapy and improved survival. Although no overall effect of augmentation therapy was found on rate of FEV1 decline, we
found a slower rate of FEV1 decline in individuals with FEV1
values of 35 to 49% predicted. These observations buttress the
rationale for intravenous augmentation therapy for individuals with 1-AT deficiency, which up to now has been based
mainly on reports demonstrating the "biological efficacy" of
intravenous augmentation therapy (5).
The observed overall yearly mortality rate of approximately 3.5% in the Registry is consistent with estimates based
on earlier studies. Among 246 adult ZZ homozygotes followed for as long as 14 yr, Larsson (29) reported an overall
mortality rate of 37% (91 of 246). Wu and Eriksson (26) reported a crude mortality rate of 41% (65 of 158) for 158 ZZ
homozygous adults followed for as long as 19 yr. Most recently, Seersholm and colleagues (27, 30, 31) reported a crude
mortality rate of 28% among 397 individuals with severe 1-AT deficiency in the Danish Registry over a median of 5.6 yr
of follow-up. Our finding that the most common underlying
causes of death among Registry subjects were emphysema
(72%) and cirrhosis (10%) confirm Larsson's (29) findings that the predominant causes of death among 91 adult ZZ homozygotes were respiratory insufficiency (59%) and complications of liver cirrhosis (13%).
These results extend results of earlier studies (2, 26, 28, 31-
33) which have reached widely varying estimates of the rate of
FEV1 decline in individuals with 1-AT deficiency. Because of
the Registry's large sample size, prospective design, long-term follow-up, and quality-assurance measures, we believe that
the rates of FEV1 decline reported here represent the most accurate available estimates, subject to limitations stated earlier.
Estimates of FEV1 decline for 161 subjects in the Danish Registry (30) who never received augmentation therapy (132 ml/
yr for current smokers, 58 ml/yr for ex-smokers, and 86 ml/yr
for never smokers) are similar to those reported here. This
close agreement between two large cohorts of 1-AT deficient
individuals strengthens confidence in our estimates.
Features we found associated with more rapid decline in
FEV1 included: male gender, current smoking, age 30 to 44 yr,
FEV1 of 35 to 79% predicted, ever having had a bronchodilator response, decreased serum 1-AT level, and nonuse of
augmentation therapy. The greater FEV1 decline observed in
those subjects with bronchodilator responses is of interest,
suggesting a link between pathogenesis of disease and the
presence of airway hyperresponsiveness (AHR). Although
the ascertainment method was not associated with FEV1 decline, "index cases" (i.e., subjects identified because of symptoms of chronic obstructive pulmonary disease [COPD]) did
have more severe airflow obstruction at baseline than did
"nonindex" participants (generally identified as family members of affected individuals). In this regard, the Registry confirms previous observations (34).
Prior data relating the effect of augmentation therapy to
the rate of FEV1 decline in 1-AT deficient individuals are
sparse. In a retrospective analysis of the German registry (35),
27 of 323 recipients of augmentation therapy (8%) reported
experiencing fewer bronchitic episodes after augmentation
therapy was implemented. In this subset of patients, the rate
of FEV1 decline was slower (130 ± 467 ml/yr [mean ± SD])
than the rate of FEV1 decline among participants for whom
the rate of bronchitic episodes did not change (246 ± 352 ml/
yr). Also, a recently published comparison of the rate of FEV1
decline among 97 Danish 1-AT-deficient ex-smokers not receiving augmentation therapy versus 198 German 1-AT-deficient ex-smokers receiving augmentation therapy (36) showed
a significantly lower rate of FEV1 decline among the recipients
of augmentation therapy (53 ml/yr) than among the nonrecipients (75 ml/yr, p = 0.02). Stratification by initial FEV1% predicted demonstrated a significantly decreased decline in FEV1
in individuals with moderate airflow obstruction (i.e., FEV1 of
31 to 65% predicted). The results of the current Registry, although observational, are consistent with the observation of a
slowing in the decline of FEV1 in augmentation-therapy recipients with moderate airflow obstruction, but extend this observation. Features of the current study include measurement of
survival as a primary outcome, extensive attention to quality
control of spirometric measurements, assurance that all FEV1
measurements were postbronchodilator values and statistical
modeling to consider the impact of concurrent therapies (e.g.,
supplemental oxygen).
Furthermore, although the lack of trough serum levels of
1-AT in augmentation-therapy recipients precluded assurance that values exceeded the "protective level" target value
of 11 µM throughout the dosing interval, available studies of
intravenous augmentation therapy suggest that protective levels are exceeded for at least most of the dosing interval with
weekly, biweekly, and monthly therapy (5, 37).
Our finding that recipients of augmentation therapy have better survival than do nonrecipients, and that the rate in decline of FEV1 was slowed in recipients with FEV1 values of 35 to 49% predicted suggests the clinical efficacy of augmentation therapy, although these differences may have been due to factors for which we could not control. A definitive conclusion will require a randomized controlled trial.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Mark Schluchter, Ph.D., Department of Biostatistics, Desk P-88, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: mschluch{at}bio.ri.ccf.org
(Received in original form December 2, 1997 and in revised form February 17, 1998).
* A full list of institutions and investigators participating in this Registry is provided in the APPENDIX.1 Steering Committe Member, 2 Steering Committee Consultant, 3 Principal Investigator.
Acknowledgments: Supported by contract number NO1-HR-86036 from the National Heart, Lung, and Blood Institute, National Institutes of Health.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Gadek, J. E., and R. G. Crystal. 1982. Alpha 1-antitrypsin deficiency. In J. B. Stanbury, J. B. Wyngaarden, D. S. Frederickson, J. I. Goldstein, and M. S. Brown, editors. The Metabolic Basis of Inherited Disease, 5th ed. McGraw-Hill, New York. 1050-1067.
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APPENDIX |
|---|
The following institutions and individuals are participants in the Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. A full list of individuals is provided in Reference 10.
National Heart, Lung and Blood Institute, Bethesda, MD
Carol E. Vreim, Ph.D.1 (Program Director), Margaret Wu, Ph.D.2 (Biostatistician).
Steering Committee
Ronald G. Crystal, M.D. (Chairman), The New York Hospital/Cornell University, New York, NY; A. Sonia Buist, M.D., Oregon Health Sciences University, Portland, OR; Benjamin Burrows, M.D., University of Arizona, Tucson, AZ (through 12/95); Allen B. Cohen, M.D. (deceased), University of Texas Health Center, Tyler, TX; Robert J. Fallat, M.D., California Pacific Medical Center, San Francisco, CA; James E. Gadek, M.D., Ohio State University, Columbus, OH; Ralph H. Rousell, M.D., F.F.P.M., Bayer Corporation, Berkeley, CA; Richard S. Schwartz, M.D., Cutter Biological/Miles, Inc., Berkeley, CA (through 9/92); Gerard M. Turino, M.D., St. Luke's/Roosevelt Hospital, New York, NY.
Clinical Coordinating Center
The Cleveland Clinic Foundation, Cleveland, OH: Mark D. Schluchter, Ph.D.1,3; James K. Stoller, M.D.2 (Co-director); Herbert P. Wiedemann, M.D.; George W. Williams, Ph.D.3 (through 6/91); DeAnn M. Barrett; Gerald J. Beck, Ph.D.; Kevin McCarthy, RCPT; Venita Midcalf, M.B.A.; Betty Moore; Paul Sartori; Susan G. Sherer, B.S.; Rebecca Zhang, M.S.
Consultants: Thomas L. Petty, M.D., University of Colorado, Denver, CO.; Joseph F. Tomashefski, Jr., M.D., MetroHealth Medical Center, Cleveland, OH.
Central Phenotyping Laboratory
National Institutes of Health, NHLBI, Pulmonary-Critical Care Branch, Bethesda, MD: Mark L. Brantly, M.D.2,3; Jeffrey Hildesheim, B.A.; Barbara Rundquist, B.S.
Clinical Centers
Arapahoe Pulmonary Consultants, Denver, CO: Robert A. Sandhaus, M.D., Ph.D.3; C. William Bell, Ph.D.; Janis Berend, M.S.N., C.N.P.
William Beaumont Hospital, Royal Oak, MI: K. P. Ravikrishnan, M.D.3; Robert Begle, M.D.; David Erb, M.D.; Joel Seidman, M.D.; Stanley Sherman, M.D.; Barbara Cameron, R.N.
Beth Israel Hospital, Boston, MA: Steven Weinberger, M.D.3; Mitchell Rosenberg, M.D.; Richard Johnston, CPFT.
California Pacific Medical Center, San Francisco, CA: Robert J. Fallat, M.D.1,3
The Cleveland Clinic Foundation, Cleveland, OH: Alejandro C. Arroliga, M.D.3; David P. Meeker, M.D.3 (through 6/94); Atul Mehta, M.D.; Daniel Laskowski, RPFT.
Dallas Pulmonary Associates, Dallas, TX: W. John Ryan, M.D., F.C.C.P.3; James P. Loftin, M.D.; Kathy Johnson, P.A.-C.
Danbury Hospital, Danbury, CT: Arthur Kotch, M.D.3; Trudy Clark, R.N., RCPT.
Graduate Hospital, Philadelphia, PA: Paul E. Epstein, M.D.3; Pam Del Buono, RCPT.
Group Health Cooperative Puget Sound, Redmond, WA: Robert E. Sandblom, M.D.3; Richard C. Hert, M.D.; James B. DeMaine, M.D.; Loretta Collar, B.S.N.
Henry Ford Hospital, Detroit, MI: Michael S. Eichenhorn, M.D.3
Indiana University Medical Center, Indianapolis, IN: Joseph P. McMahan, M.D.3; W. Mark Breite, M.D.3 (through 12/93).
Lahey Hitchcock Medical Center, Burlington, MA: David Webb-Johnson, M.D.3; Joyce Corbett, CRTT; Deborah McManus, R.N.
Mayo Clinic Jacksonville, Jacksonville, FL: Michael J. Krowka, M.D.3; Tonya Zeiger, RRT, CPFT.
Mayo Clinic Rochester, Rochester, MN: Udaya B. S. Prakash, M.D.3; Bruce Staats, M.D.; Deb Nesler, CPFT.
Medical University of South Carolina, Charleston, SC: Charlie Strange, M.D.3; Michael Baumann, M.D.; Marc Judson, M.D.; Ruth Oser, R.N., M.S.
Memphis Tennessee Clinical Center, Memphis, TN: Norman T. Soskel, M.D.3; Vicki Smith.
Mercy Hospital, Portland, ME: Dermot N. Killian, M.D.3; William Demicco, M.D.; Lewis Golden, M.D.; Rebecca Hitchcock, R.N., CRNP.
National Heart, Lung, and Blood Institute, Bethesda, MD: Joel Moss, M.D., Ph.D.3; Shyan C. Chu, M.D.; N. Gerard McElvaney, M.D.; Pauline Barnes, R.N.
National Naval Medical Center, Bethesda, MD: Kevin O'Neil, M.D.3; David Holden, M.D.3 (8/92-12/95); Bruce M. Meth, M.D.3 (through 8/92); Richard W. Ashburn, M.D.; Joseph Forrester, M.D.; Robert F. Sarlin, M.D.; Ronald P. Sen, M.D.; Thomas E. Walsh, M.D.; Sheila Jones, R.N.
Ohio State University, Columbus, OH: Mark Wewers, M.D.3; Janice Drake, RRT.
Oregon Health Sciences University, Portland, OR: Alan F. Barker, M.D.3; Lynn Oveson, R.N., M.N.
Pulmonary Care, P.C., Fall River, MA: William C. Sheehan, M.D.3; Robert M. Aisenberg, M.D.; Nick Mucciardi, M.D.; Patricia Demers, R.N.
St. Luke's/Roosevelt Hospital, New York, NY: Gerard M. Turino, M.D.1,3; Edward Eden, M.D.
University of Arizona, Tucson, AZ: Russell R. Dodge, M.D.3; Benjamin Burrows, M.D.1,3 (9/91-12/95); Mary Klink, M.D.3 (through 9/91); Martha Cline, M.S.
University of California, Davis Medical Center, Sacramento, CA: Carroll E. Cross, M.D.3; Andrew Chan, M.D.; Jo Ann Booth, R.N.
University of California, Los Angeles, Los Angeles, CA: Donald F. Tierney, M.D.3; Bertrand Shapiro, M.D.; Kathleen Ellstrom, R.N., M.S.
University of California, San Diego Medical Center, San Diego, CA: Jack L. Clausen, M.D.3; JoAnna Borders, M.S.
University of Iowa, Iowa City, IA: Jeff Wilson, M.D.3; Jan Buchmayer, R.N.
University of Minnesota Hospital and Clinic, Minneapolis, MN: Peter Bitterman, M.D.3; Keith Harmon, M.D.; Marshall Hertz, M.D.; Cheryl Edin, R.N.
University of Nebraska Medical Center, Omaha, NE: Stephen I. Rennard, M.D.3; Richard A. Robbins, M.D.3 (through 4/96); Richard Fogelman, RRT.
University of North Carolina, Chapel Hill, NC: James F. Donohue, M.D.3; Steven Turpin, M.D.; Katherine Hohneker, R.N.; John Winders, B.S.
University of Rochester Medical Center, Rochester, NY: Richard W. Hyde, M.D.3; Barbara Spohn, R.N.
University of Texas Health Center, Tyler, TX: James M. Stocks, M.D.3; Debbie Waldrop, R.N., CCRC.
University of Utah Health Sciences Center, Salt Lake City, UT: Edward J. Campbell, M.D.3; Richard E. Kanner, M.D.3 (through 6/90); Cathy Pope, R.N.
Veterans Administration Hospital, Hines, IL: Nicholas Gross, M.D., Ph.D.3; Frank King, B.S.
Victoria General Hospital, Victoria, British Columbia, Canada: Ian Waters, M.D., F.R.C.P.C.3
Washington University Medical Center, St. Louis, MO: Mitchell Horowitz, M.D., Ph.D.3; Patricia Nelson, M.D.3 (through 12/93); Jack A. Pierce, M.D.; Edward Silverman, M.D.; Pamela Wilson.
Data and Safety Monitoring Board
Gordon L. Snider, M.D. (Chairman), Boston VA Medical Center, Boston, MA; Katherine Detre, M.D., Dr. P.H., University of Pittsburgh, Pittsburgh, PA; Herbert Y. Reynolds, M.D., The Milton S. Hershey Medical Center, Hershey, PA; Melvyn S. Tockman, M.D., Ph.D., Johns Hopkins University, Baltimore, MD; Janet Wittes, Ph.D., Statistics Collaborative, Washington, DC.
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S. R. JOHNSON and A. E. TATTERSFIELD Decline in Lung Function in Lymphangioleiomyomatosis . Relation to Menopause and Progesterone Treatment Am. J. Respir. Crit. Care Med., August 1, 1999; 160(2): 628 - 633. [Abstract] [Full Text]
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J K STOLLER Augmentation therapy for severe alpha 1-antitrypsin deficiency: is the jury still out on a trial? Thorax, December 1, 1998; 53(12): 1007 - 1009. [Full Text]
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