Augmentation Therapy Reduces Frequency of Lung Infections in Antitrypsin Deficiency A New Hypothesis With Supporting Data April 17, 2000 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 The 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 ge-netic 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, homozy-gous 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 Ha-ven, 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 (com-mercial 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 augmen-tation therapy had a decreased mortality rate com-pared 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 ob-served 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 anti-trypsin 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" (ie, 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 -anti-trypsin 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 reac-tive" 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 percent-age 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 in-volved in the study were actually aware of the interest in a potential effect of a 1 -PI on the fre-quency 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 avail-able 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 a 1 -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
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