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Augmentation
Therapy Reduces Frequency of
Lung Infections in Antitrypsin Deficiency*:
A
New Hypothesis with Supporting Data
Jack
Lieberman, MD, FCCP
Study
objectives: To propose an hypothesis
that antiprotease augmentation therapy reduces the incidence of lung
infections in a 1 -antitrypsin (AAT)-deficient patients, and to present
supporting data.
Design:
The proposed concept is based on a survey taken via the Internet of
patients receiving augmentation therapy for 1 to 10 years compared
to similar patients not receiving such therapy.
Setting:
A questionnaire was submitted to patients with a ZZ phenotype for
AAT deficiency to determine whether those receiving antitrypsin augmentation
therapy were aware of any personal benefit, and whether the therapy
had an effect on the frequency of lung infections.
Patients:
Ninety-six adult patients receiving human a 1 -proteinase inhibitor
(a 1 -PI) responded, as did 47 similar patients not receiving augmentation
therapy.
Results:
Seventy-four of 89 patients who had received a 1 -PI infusions for
> 1 year believed that they had definitely benefited from such
therapy. Fifty-six of the 74 patients claiming a benefit attributed
this to a reduction in the number of lung infections since starting
therapy with a 1 -PI infusions. Before starting a 1 -PI, the majority
of patients had three to five infections per year, dropping to zero
to one infection per year during a 1 -PI therapy (p < 0.001).
Conclusions:
Replacement therapy for AAT deficiency-associated emphysema appears
to be associated with a marked reduction in the frequency and severity
of lung infections. This association must be evaluated further in
future, more rigid, prospective studies of AAT augmentation therapy.
Findings support the hypothesis that antiprotease therapy with a 1
-PI reduces the incidence of lung infections in addition to slowing
the deterioration of lung function and causing a reduction in mortality.
(CHEST 2000; 118:1480–1485)
Key words:
antitrypsin; augmentation therapy; emphysema; infections; a 1
-proteinase inhibitor
Abbreviations:
AAT 5 a 1 -antitrypsin; a 1 -PI 5 human a 1 -proteinase inhibitor
T
he discovery of a 1 -antitrypsin (AAT) deficiency in 1963 has led
to an understanding of the mechanism whereby lung damage takes place
in the pathogenesis of pulmonary emphysema. A genetic deficiency of
this blood protein is strongly associated with a predisposition to
the development of emphysema and, in some instances, to chronic bronchitis
or bronchiectasis.1 The association of lung disease with the severe
deficiency state (ie, homozygous ZZ phenotype) is widely accepted,
and an association with the intermediate deficiency state (ie,
heterozygous MZ phenotype) is now receiving wider acceptance, especially
when it is present in cigarette smokers.2–4 Even though the severe
deficiency has been reported in only 2 to 8% of emphysema patients,2,3
and the intermediate deficiency has been reported in 8 to 18% of such
patients, the same mechanism for lung damage involving proteolytic
enzymes is now believed to take place in essentially all patients
with pulmonary emphysema. Knowledge of this enzymatic pathway for
the development of pulmonary emphysema has led to a potential therapy
utilizing antitrypsin augmentation via the infusion of human a 1 -proteinase
inhibitor (a 1 -PI; Prolastin; Bayer Pharmaceuticals; West Haven,
CT) extracted from human blood plasma.5–7 Such therapy
was devised and approved with the knowledge that the infusions were
safe and would raise the blood level of AAT to at least that usually
found in heterozygotes for the genetic defect (commercial standard,
. 80 mg/dL) with a transient increase to a high level of approximately
400 mg/dL and an associated increase of AAT in fluid of the lung epithelial
lining. A blind study to confirm the clinical benefit of replacement
therapy was not undertaken by the developers of augmentation therapy,
because it would have been exceedingly costly and difficult.
However, beginning in 1988, a National Heart,
Lung, and Blood Institute Registry of Patients with Severe Deficiency
of a 1 -Antitrypsin was set up for those patients receiving a 1 -PI
infusions as well as for untreated AAT-deficient patients; this was
not a randomized study. These patients had been followed up by the
registry for 3.5 to 7 years with spirometry measurements every 6 to
12 months 8 when an evaluation revealed that subjects receiving augmentation
therapy had a decreased mortality rate compared to those not receiving
therapy. In addition, subjects with a mean FEV1 of 35 to 49% of predicted
showed an FEV1 decline that was significantly slower for subjects
receiving augmentation therapy than for those not receiving such therapy.
The major concept behind augmentation therapy for AAT deficiency has
been that a rise in the level of AAT in blood and tissues would protect
the lung from continued destruction by blood and tissue proteases
(ie, primarily leukocyte elastase). The observed reductions in mortality
and in FEV1 decline reported by the registry suggest that this may
indeed be taking place. Neither the National Heart, Lung, and Blood
Institute Registry, nor other similar studies in Denmark and Germany,9,10
ever focused in on the possibility that augmentation therapy might
have an effect on the incidence of lung infections. I now present
a new hypothesis regarding antitrypsin augmentation therapy; the concept
is that such therapy reduces the incidence of lung infections in antitrypsin-deficient
patients receiving infusion of a 1 -PI. This hypothesis was developed
when a few so-called “Alphas” (.i.e, patients with a ZZ
phenotype) participating in the a 1 Internet List reported that they
experienced a reduction in the number and severity of respiratory
infections since starting augmentation therapy with a 1 -PI. I was
familiar with the literature suggesting that a 1 -antitrypsin had
an immunosuppressive action,11 that trypsin inhibitors had been shown
to have an antibiotic action,12 and that antiproteases were effective
in the treatment of HIV infections.13 It is also well-known that AAT
normally is an “acute-phase reactive” protein the blood
level of which increases during infections or other inflammatory,
estrogenic, or neoplastic states. Therefore, I postulated that a rise
of antiprotease levels in blood may play an important role in resistance
to infection in AAT-deficient subjects.
To further
investigate this hypothesis, a questionnaire was prepared that was
directed toward subjects with a ZZ phenotype receiving augmentation
therapy with a 1 -PI, and another questionnaire was prepared for those
subjects with the same phenotype who were not receiving augmentation
therapy. In this report, I will present the following data that were
obtained from these questionnaires: (1) the percentage of patients
receiving a 1 -PI who feel that they have benefited from therapy;
(2) the impressions of these patients as to how they benefited; and
(3) the frequency of respiratory infections per year before starting
replacement therapy and since starting such therapy compared to a
group of similar patients who never received a 1 -PI infusions. The
findings of these surveys suggest that a reduction in the frequency
of respiratory infection may be a major effect of augmentation therapy
with a 1 -PI for AAT deficiency-related emphysema. This was not a
survey of the general AAT-deficient population but, rather, was a
survey only of patients enrolled in an international Internet support
group. There is a possibility that the sampling method may have introduced
biases into the conclusions. However, few of the patients involved
in the study were actually aware of the interest in a potential effect
of a 1 -PI on the frequency of lung infections, and the questionnaire
contained many unrelated questions dealing with other types of health
problems associated with AAT deficiency.
Materials
and Methods
Patients:
Patients were recruited through announcements
on the a 1 Internet List. The appropriate questionnaires were made
available to all participants on the list and were then returned by
the responders by private e-mail to one person who sorted the replies
and forwarded them to Dr. Lieberman for evaluation.
Questionnaires:
The questionnaires prepared for ZZ patients
who were participants on the a 1 Internet List included information
on sex, age, and age when patients had received a diagnosis of AAT,
as well as on smoking history. For those receiving a1 -PI infusions,
the year of starting such infusions and the frequency of the infusions
was elicited. Key questions dealt with the frequency per year.
*From
the Department of Medicine, UCLA School of Medicine, Los Angeles,
CA. Manuscript received November 29, 1999; revision accepted April
17, 2000. Correspondence to: Jack Lieberman, MD, FCCP, Professor of
Medicine, 17813 Lemarsh St, Northridge, CA 91325; e-mail: JLIEBERMAN@prodigy.net.
opinions/hypotheses
1480 Opinions/Hypotheses
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