The following is a brief account of a talk given on the 21st July in Sheffield by Dr. Graeme Wild. Dr. Wild is Deputy Director of the Protein Reference Unit, Northern General Hospital, Sheffield

What is Alpha 1 Antitrypsin?

Alpha 1 Antitrypsin is a protease inhibitor. It is a slow acute phase reactant which means that it builds up 4-5 days after an infection. The job of alpha 1 antitrypsin is to inactivate elastase, particularly neutrophils and prevent the production of pancreatic elastase. Elastase destroys cells, both bad and good. When you have an infection elastase is produced. It destroys cells within the infected area, however, it continues to do this until stopped by alpha 1 antitrypsin. A person with alpha 1 antitrypsin deficiency (A1AD) does not produce enough alpha 1 antitrypsin and so the elastase is not successfully inhibited and thus causes damage. The normal range for alpha 1 antitrypsin is 1.1-2.2g/L (mm). There are 50 different deficient states with the most common being Pi Z and PiS.

How can Alpha 1 Antitrypsin Deficiency be tested?

It can be tested for during a normal blood test by electrophoresis. An electrophoretic strip is produced showing bands of molecules separated from the blood. If there is no staining around the alpha 1 region this indicates a deficient person. Another indicator of alpha 1 antitrypsin deficiency is prolonged neo-natal jaundice. The level of deficiency is determined by phenotyping. In the 1960s in Sweden they found that the levels fall into three main bands - fast, medium and slow.

Gene Frequencies.

PI Phenotype Distribution in UK.

60% of A1AD Pi ZZ don't even realise they have it. This is one of the problems with A1AD as not everyone suffers health problems. Dr Wild suggested that some insult to the organ (lung or liver) may be required to cause problems.

What is the difference between Phenotype and Genotype?

The Phenotype is what is seen, that is the level of alpha 1 antitrypsin in the blood. The genotype is the genetic code which is found in the DNA and is transferred to children. Thus someone who has a genotype Pi ZZ but has had a liver transplant would have a phenotype Pi MM. They would have normal levels of alpha 1 antitrypsin as a result of the transplant but any children they had would still inherit the Z gene. The Z gene must be advantageous in some way otherwise it would have been eliminated from the gene pool by nature.

How does Alpha 1 Antitrypsin work?

It is thought that some sort of insult to the organ occurs to trigger the onset of damage. In the case of lung sufferers this is probably due to pollutants and in liver sufferers probably due to a previous virus infection. This would explain why some Pi MZ people are affected and why some Pi ZZ people have no symptoms at all. Elastase is also found in the pancreas where it is used to breakdown food. Smoking inactivates alpha 1 antitrypsin which stops any alpha 1 antitrypsin that you may have from workinR A Stockley Alpha-1-antitrypsin deficiency was first identified in 1963, together with its association with the early onset of severe lower zone emphysema. Although the mechanisms for the development of emphysema were not clearly understood, it was reasonably assumed that the alveolar destruction was a direct consequence of the release of neutrophil elastase which was then able to digest lung connective tissue because of the low concentrations of a1-antitrypsin. This led to the concept and development of augmentation therapy which was shown to restore both the serum and alveolar concentration of a1-antitrypsin to a level thought to be protective. This represented a relatively simplistic approach and augmentation therapy became an accepted form of management, initially in the USA, but subsequently in Germany and, more recently, for some patients in several other European countries. The efficacy of such an approach remains contentious. For many years it has been thought that an appropriate clinical trial would not be feasible in view of patient numbers required and the expense of designing and monitoring such a trial.

This has led to recent editorials raising the issue of whether an appropriate clinical trial will ever be conducted, although most clinicians and research workers remain firmly supportive of such a trial. In 1996 the WHO held a meeting of world experts and concluded that many questions still needed answering, including the nature of the lung pathology of a1-antitrypsin deficiency, the relative impact of deficiency on disease development, and rationalisation of the standards of care, and concluded that further research was necessary into the pathological processes in order to facilitate the design of adequately powered controlled clinical trials. This review addresses the more recent developments in a1-antitrypsin deficiency and outlines the potential methodologies that may enable the implementation of such a trial to clarify the efficacy of augmentation therapy.

Epidermiology

Alpha1-antitrypsin deficiency is classically associated with the early onset of severe basal emphysema, but is also associated with the development of cirrhosis, primary carcinoma of the liver and vasculitides. All these decrease life expectancy although the pulmonary condition dominates, as emphasised by the additive effect of cigarette smoking on mortality in patients with deficiency. However more recent epidemiological data from Sweden have indicated that airflow obstruction can develop even in non-smokers. In longitudinal studies based on their extensive national data base, Pittulainen and colleagues confirmed that lung function in non-smokers was well maintained until middle age. However, over the age of fifty a proportion of the deficient subjects developed increasing airflow obstruction which was shown to be related to a history of wheezing and occupational exposure to irritants. This raises the possibility that asthma may be a predisposing factor to the development of permanent airflow obstruction in non-smokers with a1-antitrypsin deficiency and supports one of the WHO recommendations that all adults with asthma should be tested for deficiency. Whether this, other volatile chemicals, and pollution within the environment play a role in the development of airflow obstruction in a1-antitrypsin deficiency remains to be determined.

Pathogenesis

The early concept of the development of emphysema in deficient subjects was based on a simple "balance" theory where the amount of elastase released in the lung exceeded the amount of a1-antitrypsin present in deficient subjects. However, recent elegant experiments involving neutrophil cell biology have clarified the mechanism involved. The studies also provide data to explain why subjects with partial deficiency ( such as MZ heterozygotes ) or moderate deficiency ( such as SZ heterozygotes ) do not appear at increased risk for the development of emphysema despite significantly reduced concentrations of a1-antitrypsin in the plasma ( and, by implication, in the lung ). Alpha1-antitrypsin is predominantly a serum protein that enters the lung by passive diffusion. Early physiological studies showed that the endothelium is relatively permeable with interstitial protein concentrations approximately 80% of that present in plasma. On the other hand, the epithelium presents a relatively impermeable barrier to protein movements such that concentrations of proteins within the epithelial lining fluid are approximately one tenth of that in plasma. It is generally believed that destruction of lung elastase in the interstitial space is the key to the development of emphysema.

Thus, the concentration of proteinase inhibitors in this compartment is critical in the protection of elastin and this will be broadly similar to the plasma concentration. Neutrophil elastase is stored within the azurophil granule of the mature polymorpho-nuclear leucocyte. These granules are exocytosed during activation of the cell and their protease content is released in active form and diffuses gradually away from the granule. The concentration of elastase within these granules is approximately 5mM and thus over two orders of magnitude higher than the normal concentration of a1-antitrypsin within the plasma ( 30µM ) and hence within the interstitium (24µM ). This major disparity in concentration explains why the neutrophils are able to digest connective tissue even when bathed in supernormal concentrations of a1-antitrypsin. Liou and Campbell described this process as quantum proteolysis and developed a mathematical model to determine the concentration of elastase as it diffuses away from the azurophil granule.

They argued that the enzyme would retain its ability to digest connective tissue until its concentration had dropped sufficiently to equal that of the surrounding inhibitors. Subsequent experiments with normal neutrophils produced experimental data to support this theoretical concept. The authors were able to demonstrate that the concentration of elastase, as it diffuses away from the neutrophil, follows an exponential curve. Initially, the concentration falls rapidly in close proximity to the granule. However, concentrations of elastase below 10µmol are retained over a wide area.The implication of this observation is that the elastase concentration drops rapidly to equal the likely concentration of a-antitrypsin for most patients with normal of heterozygote deficiency. The proteolytic damage would therefore be limited to an area close to the granule even for subjects with partial deficiency. However the only common phenotype with a serum a-antitrypsin concentration below 10µmol is the PiZ phenotype which has an increased risk for development of rapidly progressive emphysema. The mean concentration of a1-antitrypsin in plasma of these subjects is 5µM, which theoretically results in an interstitial concentration of 4µM and is thus well below the threshold of the exponential part of the elastase dilution curve.These theories and observations, together with the increased neutrophil recruitment to the lung of a1-antitrypsin deficient patients ( thought to be related to excess leukotriene B4 generation by macrophages), explains the particular susceptibility of deficient subjects to develop extensive and rapidly progressive lung destruction.

Understanding this process has major implication for the design of clinical trials. Intravenous therapy restores and retains the circulating concentration above 11µM. This will predictably lead to a basal interstitial a1-antitrypsin concentration of 8-9µM which would be predominantly protective ( as for the SZ phenotype ). On the other hand, approaches to deliver a1-antitrypsin to the alveolar surface could prove less effective unless the concentration that can be achieved

is sufficiently high to allow adequate quantities of a1-antitrypsin to pass through the tight epithelial layer into the interstitium and raise the concentration to a protective level. However it is possible that a strategy of delivery of a1-antitrypsin to the airway could also have a beneficial effect even if the protein does not reach the interstitium. This is based on the concept that, if neutrophil recruitment to the lung can be reduced, then protection of the interstitium becomes less critical. Hubbard and colleagues had provided evidence that excess neutrophil recruitment to the lung was based on the release of leukotriene B4 (LTB4) by alveolar macrophages due to the presence of uninhibited elastase activity in the alveolar space. Direct augmentation of a1-antitrypsin in the alveolar region would be predicted to inhibit any elastase released, thus switching off LTB4 production by the macrophage and hence subsequent neutrophil traffic would lead to less elastin degradation and hence cessation or modulation of the progression of emphysema. Clearly, this concept is testable by appropriately designed research studies and should be included in clinical trial design.

Role of augmentation therapy

As indicated above, augmentation therapy seems a logical step to take in the management of patients with a1-antitrypsin deficiency. However, cessation of smoking clearly remains critical and identification and hence avoidance of other pollutants or risk factors becomes equally important. Indeed, there is currently a combined ERS/ATS task force addressing the current standards of care for a1-antitrypsin deficiency and the guidelines should be published within the next year. In a previous editorial Stoller reviewed historical data from European countries, one of which had augmentation therapy available, and the final data from the NHLBI registry in the USA comparing patients who had or had not received augmentation therapy. Both studies provided evidence that subjects who received augmentation therapy retained their lung function better, although in the latter study this was confined to subjects with moderate impairment. More interestingly, the mortality rate appeared to be reduced in American subjects who were able to receive augmentation therapy. Clearly neither study was a controlled trial and the fact that the groups were not matched for either country, health care insurance, or exposure to health care workers still leaves doubts concerning efficacy. More recently a combined study between Holland and Denmark conducted over three years showed no effect of augmentation on decline in lung function. This was a double blind controlled study although unfortunately the study was insufficiently powered to demonstrate an effect on lung function (28 versus 28 patients ). Of interest, however, this study suggested that augmentation prevented deterioration in the degree of emphysema as assessed by CT scanning, although this just failed to achieve conventional levels of statistical significance. Nevertheless, since a1-antitrypsin deficiency is specifically thought to be associated with the development and progression of emphysema, this observation is likely to be of major importance. It raises the critical issue of whether progression of the CT scan should be a primary outcome measure and, if so, this would reduce the number of patients to 130 and the length of study required to three years to demonstrate efficacy.

Future clinical trials

Demonstrating the efficacy of augmentation therapy requires appropriate phase II (proof of principal) studies and adequately powered controlled clinical trials with accepted primary and secondary outcome measures.

Phase II Studies

In the past, phase II studies have been confined to demonstrating the restoration of a1-antitrypsin concentration and function. Whereas this is clearly important, it does not demonstrate an effect on the central pathogenic progresses involved in disease development, progression, and health status.

Inflammatory markers

Studies of bronchoalveolar lavage fluid and sputum from the large airways have shown that inflammation is increased in a1-antitrypsin deficiency. This provides a surrogate of the processes thought to be central to the development of disease in a1-antitrypsin deficiency. It should be possible to determine whether a1-antitrypsin augmentation influences both the biochemical and cellular processes in the lung. Indeed, if the theory proposed by Hubbard et al concerning the perpetuation of neutrophil recruitment in a1-antitrypsin deficiency is correct, augmentation therapy should lead to a reduction in neutrophil numbers as recruitment decreases. Preliminary studies are underway to determine whether these effects are of importance.

Bacterial colonisation

Many patients with a1-antitrypsin deficiency have evidence of chronic bronchial disease with bacterial colonisation.
Recent data have suggested that, although this is considered to be a benign process in the stable clinical state, it may be a major contributing factor to inflammation in the airway in some patients. Indeed, studies have shown that patients with a1-antitrypsin deficiency have a greater degree of inflammation in the presence of bacterial colonisation than in non-deficient subjects. Bacterial colonisation may be facilitated by epithelial damage, reduction in ciliary beating and mucus hypersecretion. All these are features that can be induced by inflammation with uncontrolled neutrophil elastase activity. Alpha -1- antitrypsin augmentation in deficient subjects would increase the inhibitory capacity of the lung secretions and may protect these important defence mechanisms. This could reduce colonisation and airway inflammation. Whether this bacterial colonisation is responsible for disease progression, morbidity, or recurrent exacerbations remains uncertain. Nevertheless, short term studies of the effect of augmentation on airway colonisation, mucociliary clearance, or inflammation may also form the basis of sound phase II studies.

Biochemical Markers

Biochemical markers of progression of lung disease have been extensively investigated as tools to determine efficacy for phase II studies but have so far proved too insensitive. Destruction of lung elastin is thought to be central to the development of emphysema but monitoring elastin breakdown products such as sesmosine and iso-desmosine has not proved helpful. Levels are raised in chronic obstructive pulmonary disease (COPD) but not in a1-antitrypsin deficiency, although this may reflect methodological differences. Snider and colleagues, however, have indicated that augmentation therapy reduced the quantity of these breakdown products excreted in the urine in a limited study involving only two patients.

Recent data have suggested that, although this is considered to be a benign process in the stable clinical state, it may be a major contributing factor to inflammation in the airway in some patients. Indeed, studies have shown that patients with a1-antitrypsin deficiency have a greater degree of inflammation in the presence of bacterial colonisation than in non-deficient subjects. Bacterial colonisation may be facilitated by epithelial damage, reduction in ciliary beating and mucus hypersecretion. All these are features that can be induced by inflammation with uncontrolled neutrophil elastase activity. Alpha -1- antitrypsin augmentation in deficient subjects would increase the inhibitory capacity of the lung secretions and may protect these important defence mechanisms. This could reduce colonisation and airway inflammation. Whether this bacterial colonisation is responsible for disease progression, morbidity, or recurrent exacerbations remains uncertain. Nevertheless, short term studies of the effect of augmentation on airway colonisation, mucociliary clearance, or inflammation may also form the basis of sound phase II studies.

Controlled Trials

The efficacy of treatments for patients with chronic lung disease has focused on forced expiratory volume in one second (FEV1) as the primary outcome measure. Indeed, although a reduction in FEV1 in emphysema is largely dependent on dynamic airways collapse, treatments that can acutely increase the FEV1 are often prescribed even in the absence of clear physiological improvement. However, the FEV is also considered the outcome measure of choice for treatments designed to prevent progression of chronic lung disease. Whereas this may be reasonable, measurement of FEV1 is effort dependent and can vary from day to day even in a stable patient. Thus, clinical trials designed to assess modification of FEV1 require large numbers of patients followed for several years. In the case of chronic lung disease in general, and the emphysema of a1-antitrypsin deficiency in particular, alternative outcome measures for long term disease modification should be considered. These might include tests of dynamic airways collapse such as maximum expiratory flow (MEF), air trapping, flow limitation, exercise capacity, or more specific tests of alveolar function such as the carbon monoxide transfer coefficient (Kco). However the most specific way of assessing the extent of emphysema is with computed tomographic (CT) scanning as studies have shown that analysis of the scans correlates well with the degree of emphysema in pathological specimens.

CT scanning relates well to tests of airflow obstruction and gas transfer in patients with emphysema and preliminary studies have shown that, in patients with a1-antitrypsin deficiency, progression of emphysema assessed by CT scanning is detectable in a small number of patients over as little as 12 months. Indeed the recent Dutch/Danish controlled trial would suggest that CT scanning is a sensitive way of determining the efficacy of replacement therapy and should clearly be included as a secondary, if not primary, outcome measure in controlled clinical trials.

Exacerbations

Exacerbations are a common occurrence in patients with chronic lung disease and such episodes are associated with a worsening of quality of life which may take some months to recover. Patients with a1-antitrypsin deficiency often experience regular exacerbations of their lung disease and, indeed, the inflammation associated with these episodes is much more severe than that seen in corresponding patients without deficiency. This might be expected since a1-antitrypsin is an acute phase protein and in normal subjects the serum concentration rises during exacerbations and, together with increased protein leakage, leads to a corresponding increase in lung a1-antitrypsin levels. In subjects with severe deficiency there is virtually no acute phase rise in serum concentration and, although the concentration rises in the lung as a result of increased inflammation, it remains well below that seen for non-deficient subjects. The normal physiological response of a1-antitrypsin during such episodes may help to control the increased elastase released by the greater neutrophil recruitment during exacerbation, thereby containing and curtailing the degree of inflammation. This raises the possibility that intravenous boluses of a1-antitrypsin may play a key role in the modulation of exacerbations, although whether this will influence long term progression remains currently uncertain . Nevertheless, the number of exacerbations exacerbation days have been used in other studies to demonstrate clinical efficacy of therapeutic intervention and such a clinical design is feasible in a1-antitrypsin deficiency. In other studies as few as 30 patients have been necessary to prove efficacy and this would clearly be possible in a1-antitrypsin deficiency.

Health status

From a patients point of view, health status is more meaningful than abnormal physiology of CT scan. There are many tools currently available to assess health status including, most notably, the St George's Respiratory Questionnaire and the more generic SF36 questionnaire. It has been shown in particular that the score derived from the St George's Respiratory Questionnaire deteriorates with time as lung disease progresses and this is related ( although loosely) to the FEV1 . Furthermore, the ability of patients to exercise is also reflected in their health status as well as their physiological impairment. Recent data in a1-antitrypsin deficiency have shown that both exercise and health status are related not only to the physiology but also to the degree of abnormality on the CT scan. Although health status tools are now becoming widely accepted for patients assessment, it remains uncertain whether these will be sensitive enough to be included as primary or secondary outcome measures in clinical trials of augmentation therapy.

Is a controlled trial possible ?

Research in the last few years in a1-antitrypsin deficiency has provided a much better understanding of the processes involved in the development of emphysema and its progressionStudying lung inflammation through a variety of biochemical and cellular markers provides a simple means to determine whether intervention therapy reduces airway inflammation and this can be established in a limited number of patients. Such studies would appear to be far more relevant and critical than the early work merely demonstrating an increase in lung a1-antitrypsin levels with augmentation therapy. High resolution CT scanning is relatively specific for the presence of emphysema an is objective, reproducible , and demonstrates progression indicating greater sensitivity to change than the FEV1. Furthermore, objective analysis of the CT scan relates not only to health status but also to other tests of physiological impairment which strengthens its role as a major outcome measure in any clinical trial of augmentation therapy. Such an approach would markedly reduce the number of patients required to demonstrate a positive effect and the period of time over which monitoring would be necessary, thereby strengthening the feasibility of implementing such a trial. However, in order to facilitate a controlled trial it will be necessary to identify sufficient patients who have not yet received augmentation therapy. As indicated earlier, many countries routinely prescribe augmentation therapy to a significant proportion of patients. In 997 interested clinicians in charge of national registries from 12 countries joined together to develop an international registry for a1-antitrypsin deficiency.

In 1999 AIR ( Alpha-1-International Registry) was formed with a coordinating committee, council, and formal statutes. The aims of this group are to continue research into a1-antitrypsin deficiency and its treatment and to develop a major database ( which currently includes patients from Sweden, Denmark, Holland, Belgium, Austria, Germany, Spain, Italy, Switzerland, Australia/New Zealand, South Africa, Canada, Japan and the USA). This together with Sweden ( more than 900 patients), Denmark
( more than 900 patients ), and Holland ( more than 400 patients ), provides an extensive resource from which patients can be recruited to suitably powered controlled clinical trials. However, this remains a valuable yet limited resource. At present several pharmaceutical companies are exploring the possibility of controlled trials using human purified or transgenic a1-antitrypsin , anti-elastase drugs that can replace a1-antitrypsin function, and anti-inflammatory therapy to circumvent the need for antiproteinase protection of the lung. It is critical that such programmes are coordinated but,in addition, are based on sound science and state of the art drug delivery and clinical monitoring. It would be tragic if, after all this time, a poorly thought through trial based on historical data fails because of attempted expediency. Such a disaster would destroy the carefully laid groundwork of the international community and prevent the instigation of better studies.

Respiratory Medicine (1999) 93, 481-490 Report
Chronic obstructive pulmonary disease, with and without Alpha -1-Antitrypsin Deficiency : management practices in the U.K. A.T.Hill ; E.J.Campbell ; A.Milford Ward and R.A.Stockley Department of Medicine, Queen Elizabeth Hospital, Birmingham, U.K. Department of Medicine, University of Utah Health Sciences Centre, Salt Lake City, U.S.A. Northern General Hospital, Supraregional Protein Reference Unit, Department of Immunology, PO Box 894, Sheffield U.K.

Alpha-1-antitrypsin deficiency is a common genetic defect associated with the development of severe and rapidly progressive lung disease. This study was undertaken to determine whether respiratory
physicians manage patients with alpha-1-antitrypsin deficiency (AAT) deficiency differently from patients with chronic obstructive pulmonary disease (COPD) without alpha-1-antitrypsin deficiency. In addition we obtained physicians views on who should be tested for AAT deficiency. A questionnaire was administered to 88 respiratory physicians based throughout the U.K. (44 in teaching hospitals ).

The main outcome measures were pulmonary function tests, radiological assessment, frequency of repeat testing, follow-up and screening protocol for alpha-1-antitrypsin deficiency. Subjects with homozygous (PiZ) AAT deficiency were more likely to : 1. have baseline and full pulmonary function testing including dynamic flow rates, static lung volumes, and gas transfer; 2. gave more comprehensive assessment which high resolution computed tomography (HRCT) thorax and repeated radiological assessment ( with annual chest radiography ); 3. be followed-up routinely; and 4. have family members tested for alpha-1-antitrypsin deficiency. Testing remains limited for AAT deficiency and is mainly restricted to young patients with COPD. COPD assessment and management is influenced by the presence of AAT deficiency, which may reflect the poorer prognosis of such patients due to more rapid decline. Assessment and monitoring could be simplified to forced expired manoeuvres, although limited HRCT thorax and tests of gas transfer may prove more sensitive to progression of emphysema.

Testing for AAT deficiency in the U.K. remains restricted, which will influence the detection rate for AAT deficiency. A wider policy of testing as advocated by the WHO will detect more patients and also influence our understanding of the natural history of the condition.

Introduction

Alpha-1-antitrypsin deficiency (AAT) deficiency is one of the commonest genetic deficiencies of Caucasians with an incidence as high as one in 1600 in Scandinavia. The protein is the major plasma inhibitor of serine proteinases and it is believed to play a critical role in the protection of the lung from proteolytic damage by the enzyme elastase released from activated neutrophils. The deficiency was first recognised in 1963 and subsequent studies have confirmed its association with the early development of emphysema and bronchitis. Deficient subjects have an increased risk for severe airflow obstruction and have accelerated decline in lung function, especially if they smoke. In addition to the lung disease, deficient subjects develop neonatal jaundice which may be fatal as well as cirrhosis and primary liver cancer in later life. Although AAT deficiency is relatively common, few of the subjects are identified unless population screening is undertaken. This is clearly important since early identification of the deficiency prior to the establishment of lung disease in particular can lead to a successful modification of lifestyle, especially with respect to smoking habit, which will have a major effect upon the long-term health cost burden. At a recent World Health Organisation (WHO) meeting it was highlighted that only 5% of the deficient subjects in the U.K. have been identified by physician testing, as opposed to the predicted number by population screening. The reasons for this were unknown but may relate to the possibility that most subjects remain reasonably healthy and thus do not present to health-care services. Alternatively, testing could be restricted to the wrong patient population. For instance, the first patients identified were young with marked chronic obstructive pulmonary disease (COPD) and this has generally resulted in continued testing of mainly younger patients.Indeed, recent guidelines on the management of COPD by the
European Respiratory Society (ERS) and the British Thoracic Society (BTS) have emphasized testing for young patients. This restricted policy may have led to a predominance of such patients in the American NIH registry of AAT deficiency and continued testing bias. For these reasons the WHO has recommended much wider testing for AAT deficiency. Furthermore, the WHO has recognised that none of the COPD guidelines published by specialist societies specifically addressed the standards of care required for AAT deficiency. The purpose of the present study was to determine the current practice of U.K. hospital physicians, with an interest in respiratory disease, in the management of AAT deficiency. In particular we wished to clarify the current policy of the physicians for testing for AAT deficiency in advance of the publication of the BTS guidelines and the WHO report.

Methods

We administered a questionnaire to 88 consultant respiratory physicians who were based throughout the U.K. and selected at random at a single BTS meeting. Physicians were informed that the questionnaire was to determine how they believed an elderly patient ( greater than 50 years of age ) with COPD should be managed. Once the answers had been obtained they were asked ( with the same questions ) if their policy would change if the patient were 50 years of age or less. Finally, they were also asked if patients with the diagnosis of homozygous (PiZ) or heterozygous (PiMZ) AAT deficiency should be managed in the same or a different way. At the end of the questionnaire all physicians were asked who they felt should be tested for AAT deficiency.The questionnaire inquired into which investigations were routinely
undertaken as a baseline to include pulmonary function tests, blood tests ( i.e. full blood count and biochemical profile with liver function ) and an electrocardiograph. In addition, physicians were asked what further tests they would carry out including an oral steroid trial and inhaled steroid trial ( and whether these influenced management), as well as which radiological assessment would be undertaken. Finally, we inquired about he usual frequency of repeat testing for monitoring disease progression as well as the usual follow-up practice for the patient and whether this would be influenced by age or the AAT phenotype. The questionnaire also inquired about treatment given routinely, including the use of bronchodilators, inhaled steroid and vaccination as well as the use of oral steroids and antibiotics for acute exacerbations as generically defined ( a worsening of any symptoms ).

Results

Eighty-eight randomly chosen respiratory physicians ( which accounts for 20-25% of the physicians with an interest in respiratory medicine in the U.K. ) were questioned at a single BTS meeting. The age of the physicians ranged from 34-65 years and there was an equal representation of teaching and district general hospital physicians. All physicians requested answered the questionnaire.

Spirometry And Radiology

All respiratory physicians felt that all COPD patients should have baseline spirometry and a chest radiograph irrespective of age or AAT phenotype. Fewer physicians arrange full lung function tests (57 or 69%,
depending on the age of the patient ), although 80% would assess lung function fully in PiZ AAT deficient subjects. Serial peak flow monitoring to rule out asthma would be carried out by approximately 40% of physicians, although more (69%) would arrange this if the patient with COP was young with normal AAT. Eighty-five per cent of physicians would carry out a steroid trial (75% with oral steroids and approximately 10% with inhaled steroids ) prior to introducing steroid therapy. Only 2.3% of physicians would request high resolution computed tomography (HRCT) for patients with a diagnosis of COPD unless they were young (28.4%), or had the PiMZ (13.6%) or PiZ phenotype for AAT deficiency (47.7%).

Annual Review

Few physicians carry our annual lung function testing, although more (35%0 would do this for patients with PiZ AAT deficiency. Less than 20% of physicians would arrange for annual repeat chest radiograph unless the patient had PiZ AAT deficiency when a greater number (27.3% ) felt this was important.

General Investigations and Management

In all groups approximately 85% of physicians would arrange a baseline full blood count, approximately 70% a biochemical profile and approximately 55% an electrocardiograph.A small proportion of physicians (23.9%) would empirically use
inhaled steroids over the long term, independent of the results of a steroid trial or pulmonary function reversibility testing. The remainder would use long-term inhaled steroids only if there was a positive steroid trial. Treatment with inhaled bronchodilator therapy was based on the bronchodilator reversibility results by 42% of physicians but of the remainder, 42.1% would use a B2-agonist agent alone and 11.4% would use combined bronchodilators irrespective of the reversibility testing. Influenza vaccination would be advised annually by 90.9% of physicians and 55.7% would advise pneumovax. Oral steroids and antibiotics would be used routinely by 71.6% and 78.4% of physicians respectively, for any exacerbations of COPD that led to hospital admission. However if the exacerbation did not require admission, fewer (31.8%) would use oral steroids ( P<0.001) but a similar proportion ( 70.4%) would use antibiotics ( P=0.3).

Patient Follow-Up

Most physicians (78%) would regularly review patients with PiZ AAT deficiency irrespective of the lung function. However more (90%) would follow-up these patients if the forced expiratory volume in sec ( FEV1) were impaired to less than 50% predicted. Fewer physicians (42% if FEV1 > 70% predicted ) would review patients who were heterozygous for AAT deficiency and the least ( 11% if the FEV1 >70% predicted) would review COPD patients over 50 years of age with normal AAT. However, there was again a tendency for a greater number to review each of the patient groups as lung function deteriorated. The average interval between appointments was similar for each patient group ( approximately 7 months ; range 1-12 months ).Testing for AAT Deficiency Most young patients ( less than 50 years
of age) with COPD would be tested for AAT deficiency by most physicians, whereas this would be infrequently carried out in elderly patients, those with bronchiectasis of patients with other causes of airflow obstruction including asthma. Testing is more likely to be carried out in patients with a family history of chronic lung disease or in family members of a known patient with AAT deficiency.

Teaching / District General Hospital

Based The answers to this questionnaire indicated no difference in patient management between consultants who were based in a teaching hospital and those based in a district general hospital.

Discussion

This survey has shown that few patients with COPD are tested for AAT deficiency. This practice differs from that recommended by the WHO but the survey preceded publication of the report. However, once identified the patients are investigated more extensively and most patients with PiZ AAT deficiency are kept under regular review although there are wide variations in management. Although consensus documents for the management of COPD have been published, the identification and management of patients with AAT deficiency have not been addressed specifically. At present a combined European Respiratory Society and American Thoracic Society Task Force has been established to develop specific guidelines but it will not report until the year 2000.It therefore seems appropriate to assess present views on the
management of AAT deficiency and consider their validity in light of current practical and theoretical evidence. AAT deficiency is common and is associated with several disease conditions. The lung disease is more rapidly progressive in smokers than subjects without deficiency and siblings also have a one in four chance of having deficiency. The pathogenic processes which result in the development and progression of the lung disease have been well defined and this should lead to a different and perhaps more aggressive strategy in management of deficient subjects.

Baseline Lung Function Testing

Optimal clinical practice would indicate that full lung function testing, including dynamic flow rates, static lung volumes and gas transfer, should all be assessed at baseline in order to document fully the physiological status of patients with COPD. The results of the present survey indicate that just over half of the physicians arrange this for COPD patients, although all would carry out dynamic flow rates in line with the BTS guidelines. However more ( approximately 80%0 would obtain full lung function if the patient had AAT deficiency. This did not relate to whether the physician was practising in a teaching hospital and is likely to reflect the unusual nature of the patient and a wish to document the patient more completely.

Serial Peak Flows

Of more interest is the use of serial peak expiratory flow rate (PEFR) monitoring at baseline.

This practice enables marked diurnal variations to be identified
suggesting a diagnosis of asthma. Significantly more clinicians assess this in young patients with COPD, indicating that asthma is either suspected more frequently in this group or that a different management strategy is believed to be more critical in younger patients who have both a longer life expectancy and may have greater life-style expectations. Surprisingly, PEFR monitoring was no more frequently used to assess patients with AAT deficiency than older COPD patients despite the general belief that such patients present at a young age. This difference in practice probably reflects a conceptional bias that AAT deficient subjects mainly develop fixed airflow obstruction. Studies have, however, shown that many such patients have symptoms suggestive of asthma and reversible airflow obstruction. Indeed a recent study highlighted that lung function deterioration occurs in middle-aged non- smokers with AAT deficiency who have a history of wheezing. It would therefore seem appropriate to assess variability of airflow obstruction in all subjects with AAT deficiency and, where indicated, to treat appropriately.

Disease Monitoring

All physicians felt that an initial chest X-ray should be performed in all patients with COPD, even though this would not help in the assessment or diagnosis of generalised emphysema. It is likely that this is performed as a screening test for incidental lung lesions or possibly for identification of localised bullous disease as advocated in the guidelines. HRCT scan, however, has now become the best method for assessing the presence, extent and progression of emphysema, proving more effective than lung function testing. Despite this, HRCT is rarely performed although almost half the
physicians felt that is should be performed in AAT deficiency. Recent studies, however, have indicated that limited HRCT ( with appropriate reduction radiation dosage ) provides a sensitive assessment of progression of emphysema in AAT deficiency. Despite this observation few physicians repeat the test, whereas chest X-rays, which are poorly sensitive, are repeated by one-third of physicians. On the other hand, full lung function is repeated annually in AAT deficiency by over one-third of all physicians. Current epidemiological data on progression of lung disease are related to FEV1 measurements alone which are simple ( and hence cost effective ) and may reflect prognosis and hence referral for transplantation. However, tests of gas transfer are a more specific measure of the presence of emphysema and clearly relate to the changes on CT scan.
It therefore remains possible that these more specific tests ( though more expensive ) may provide a clearer measure of progression. Clearly, further studies of the use of these tests in disease monitoring are indicated although preliminary data from our registry indicate that both HRCT and carbon monoxide transfer coefficient (KCO) show significant changes over 12 months. The extent of disease monitoring should depend on the phenotype, smoking status and whether the patients have lung disease or not. Disease monitoring is of importance in determining prognosis in PiZ AAT deficient individuals with lung disease and annual follow-up is probably indicated and should, at present, include FEV1 ( which may decline exponentially ). In addition PiZ AAT deficient individuals without lung disease should undergo periodic monitoring ( for example every 2-3 years), even for non-smokers, as lung disease may develop later in life. Furthermore, such information will be critical in the understanding of the natural history of the deficiency.
Heterozygous subjects are not thought to be at increased risk for
development of COPD. Thus at present it seems reasonable to monitor such patients in a similar way to no-deficient COPD patients. In the absence of lung disease (asymptomatic siblings) monitoring seems inappropriate except for research purposes. However it is probably reasonable to check the phenotype of any spouse or partner to determine the risks of deficiency (PiZ) in any children.

Other Tests

of the other baseline investigations it is worth noting that only 70% of physicians perform blood tests that include liver function, even in subjects with AAT deficiency who are particularly susceptible to the development of cirrhosis and primary liver cancer. This may reflect a lack of awareness, the reduced tendency for lung and liver disease to co-exist of a belief that the liver diseases cannot be influenced. Whereas this may be pathologically correct, alcohol avoidance and dietary modification can stabilise liver function thereby delaying the progression of liver failure leading to the need for transplantation. However, close monitoring in subjects with cirrhosis is necessary to identify hepatoma at an early stage when surgery may be possible.

Management

In general, patients with AAT deficiency are managed in the same way as other patients with COPD. Particular notice should be drawn to the use of inhaled steroids and antibiotics.

The progression of disease in the presence of AAT deficiency is
believed to be more rapid and dependent on tissue destruction or damage in close proximity to the migrating and activated neutrophil. The low concentration of AAT in the deficient subjects fails to control the area of connective tissue degradation by neutrophil enzymes adequately, leading to more extensive damage. Thus it would appear to be important to treat episodes of acute exacerbations associated with increased neutrophil influx both rapidly and effectively. In addition neutrophil traffic should, if possible, be modified even in the stable clinical state. With this in mind the use of inhaled steroids could be recommended empirically in these patients at present since such treatment has been shown to reduce the chemotactic activity of airways secretions and increase the neutrophil elastase inhibitory capacity, both of which might be expected to reduce lung damage. Confirmation of the long-term efficacy of such an approach clearly requires a controlled trial.
However, as almost 25% of physicians already use such therapy empirically in COPD it seems reasonable to adopt this approach in AAT deficiency where the theoretical arguments for their use are stronger. Replacement therapy is theoretically even more likely to be beneficial be limiting the radius of lung damage caused by migrating neutrophils. Indeed, the recent NIH survey provides tantalising evidence that replacement therapy may influence both Fev1 decline in a subset of patients with moderate impairment as well as overall mortality. Unfortunately this was not a controlled trial, the non-treated patients were not well matched and treated patients would have been exposed to more health-care workers because of their weekly infusions. Clearly a controlled trial is urgently required to determine the efficacy and need for replacement therapy.

AAT Testing

The attitude to testing for AAT deficiency are worthy of specific comment. There remains a general belief amongst respiratory physicians and those surveyed here that testing should be generally limited to young people with COPD or those with a strong family history. This is in keeping with the recent recommendations by the (BTS). However, it has long been known that bronchiectasis is present pathologically and is regularly seen on CT scans of patients with deficiency. In addition, recent studies have highlighted the presence of asthma or asthmatic symptoms in deficient subjects. Finally, it is known that the diagnosis can even be made in old age. Indeed the age range of subjects identified over the past 3 years at the protein reference laboratory in Sheffield is clearly wide and the peak age is the sixth decade. It therefore seems appropriate to emphasise the current WHO guidelines that all patients with COPD, all adult asthmatics and all patients with bronchiectasis should be tested.

In addition, testing families of AAT deficient subjects ( both PiMZ and PiZ ) will detect other deficient subjects and provide information necessary for appropriate genetic counselling. Although it could be argued that identification of more elderly patients with AAT deficiency may not influence the subsequent management, it should be remembered that such subjects have increased mortality and, in particular, other family members art risk. Indeed non-index cases are more likely to have better preserved lung function and hence will benefit more from the best clinical practice. Ultimately the aim would be to identify young family members who can successfully be advised against starting smoking, thereby providing a long-term benefit to both themselves and the health-services. Conclusion

At present is seems appropriate to assess all AAT deficient subjects as fully as possible and advise them about family screening and lifestyle. Follow-up assessment should probably be limited to forced expiratory manoeuvres at present with vital capacity although the role of limited HRCT and tests of gas transfer should be explored. Testing should be performed ( initially) on an annual basis ( except in heterozygotes with normal lungs, as such patients are unlikely to benefit from follow-up ) until it is clear that progression is not rapid when a reduction in frequency of assessment can be instigated. All patients should be under the care of physicians with an interest in this deficiency and documented on a national registry. A registry will be of major importance for learning more about the natural history of the disease and in particular why only a portion are susceptible to the liver or lung manifestation. In addition a registry will provide the core information critical for the design and implementation of careful intervention studies. At present, a U.K. registry has been established with information on over 200 patients. An international committee of 12 national registries has been established with a common database in Sweden, which makes the likelihood of controlled trials a realistic option.

Acknowledgements

We thank Dr Llewellyn-Jones, Dr Crooks, Dr S.L.Hill and Sister Leung for their help in administering the questionnaire. Funding was supplied by Bayer Pharmaceuticals as part of the ADAPT programme.