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Alpha-1-Antitrypsin Deficiency: Emphysema Without Smoking.

Christin Nott

Table of Contents

Introduction……………………………………………………3

History....................................................................................…3

Alpha-1-antitrypsin therapies………………………………….4

Risk factors of acquiring emphysema…………………...…….6

Knowledge in the medical community………………………...7

Medical treatments for emphysema……………………………9

Summary...................................................................................14

References cited…………........................................................15

INTRODUCTION

Alpha-1-Antitrypsin Deficiency (AATD) is a devastating genetic disease that literally steals the breath away from people, silently destroying lung tissue, then revealing itself in the prime of one’s life, leaving that person unable to do anything about what has already been lost. Although smoking is the usual cause of emphysema, AATD can also cause emphysema, and not only can it cause emphysema without a prior smoking history, it does so in people in their 30’s and 40’s rather than in later life. One would think that something this significant would require knowledge in the medical community so that steps could be taken to prevent the destruction, but there has not been a great deal of research on this issue until recently. Even now, many respiratory therapists are unaware of what AATD is, what causes it, and what it means to care for someone with this affliction.

HISTORY

Knowing what causes a disease is an important first step in finding a way to help the patients who have the disease. AATD is an autosomal co-dominant genetic disease that predisposes a person to develop COPD. The protease inhibitor, Alpha-1-Antitrypsin (AAT), helps inhibit the neutrophil elastase from damaging the lung.1 In AATD, the AAT is very low and therefore unable to keep elastase from doing damage. Every time a person has an allergic reaction, a cold, or any kind of foreign object within the lungs, elastase is recruited to the lungs to inhibit the damage from inflammatory or infectious assaults. Unfortunately, without AAT, elastase does not know when to quit. Instead of just taking care of the infiltrates and stopping, elastase will destroy healthy lung tissue as well.1

Although there is not a cure for AATD, there are ways to halt the destruction of the lungs. One such method is genetic testing at the newborn level so the parents and affected child will know about the disease. They can avoid smoke and other irritants that could cause the lungs to become emphysematous. Another approach, if there is already damage to lungs, is augmentation therapy, which will replace the AAT in the deficient patient.2 Augmentation therapy has been very helpful to those afflicted with AATD, although it will not repair damage already acquired, it will prevent further damage.2 However, that should not give anyone the notion that with augmentation therapy a person with AATD will be able to smoke and not have to worry about emphysema worsening. Anyone with emphysema, whether AATD or not, should quit smoking or they will risk damaging the lungs further.

ALPHA-1-ANTITRYPSIN THERAPIES

Because it is a disease with a respiratory component, respiratory therapists are going to be involved in therapies concerning this disease. For now, IV is the route chosen for augmentation therapy; therefore, the respiratory therapists are not involved in this form of the therapy. However, although the augmentation is an important part of therapy, if a patient already has emphysema due to AATD, they will need other therapies such as bronchodilators and oxygen therapy.3 Also, a new form of augmentation is emerging, AAT inhalation therapy.3 In that case, therapists will have an opportunity to be even more involved with the AATD treatment plan.

Since augmentation is the front line defense in keeping the lungs from sustaining further damage, safety for the patient is a concern. There have been many studies on augmentation in AATD patients to include survival rate, side effects, FEV1 decline, lung disease progression, and cost effectiveness of the treatment. Once such study by National Heart, Lung, and Blood Institute (NLBI) showed the rate of decline was significantly slower during the treatment in comparison to pre-treatment.4 Furthermore, the study showed that augmentation was “particularly effective in patients with baseline FEV1 >65% of predicted.”4 (p 197) In another study conducted by the Canadian AIR Registry, “the results of this study, reported as an abstract, suggested a slower decline in FEV1 in patients receiving augmentation therapy compared with the subjects who did not.”4(p 197) It is a general belief in the medical community that augmentation therapy is safe and is tolerated quite well by patients. There are a few reported side effects, mainly nausea, vomiting, and fatigue. Localized swelling at the IV site and bruising can be troublesome and unsightly, but not life threatening. However, since the augmentation therapy is made from human plasma, there is a small chance that one could acquire HIV or hepatitis. With advances in screening, the risk is slight, but it is still a possibility.4

Another option for an advanced case of emphysema caused by AATD is LVRS (lung volume reduction surgery). Although a person with AATD acquired emphysema genetically rather than by smoking, the premise and end result is the same, lung damage. Generally, smoking generated emphysema is in all lung lobes and scattered throughout, thus called diffuse centrilobular emphysema. AATD presents differently; it is predominately in the lower part of the lobes, or panlobular emphysema.5 Certain criteria must be met before LVRS will be considered, such as, severe obstruction (FEV1 < 40%), hyperinflation, severe dyspnea, and CT scan evidence of advanced emphysema with some degree of heterogeneity in the distribution of the emphysema.5 There is also exclusion for those > 75 years of age, or with the presence of giant bulla, severe left ventricular dysfunction, or BMI (body mass index) of < 18 kg.5 There was significant improvement in the FEV1 of the patients after surgery, a significant gain in PaO2, and a significant decrease in dyspnea.5 Although the surgery seems to benefit patients with smoking related emphysema more than AATD patients due to the location of the damage, there is still improvement and therefore surgery is beneficial to use on an end-stage AATD patients.5

RISK FACTORS OF AQUIRING EMPHYSEMA

There are several risk factors for someone with AATD to end up with emphysema including occupational exposures, dust, allergens, and lower respiratory infections.6 Since smoking causes emphysema in a smoker with normal AAT levels, imagine the increase of damage to the lungs for someone with a severe deficiency of AAT if they are exposed to smoke. This is why those who have AATD will show up with emphysema in their 30’s and 40’s rather than in their late 50’s and 60’s as is the norm with emphysema. Smoking need not be direct to cause damage; it may be indirect by passive or second hand smoke.

National Jewish Hospital in Denver, Colorado studied AATD patients exposed to second hand smoke as children and those who had smoked themselves. In those who had childhood exposure, chronic cough, wheezing, as well as continuous respiratory infections were a common denominator amongst AATD patients.6 Although childhood respiratory infections were associated with earlier symptoms in both never-smokers and smokers, the onset of cough and wheeze were earlier in those who smoked.6

The best thing a person can do for their lungs is to not have any exposure to smoke of any kind, and to quit if they do smoke. This is even more important for those with AATD. “Complete smoking cessation continues to be the best nonpharmacological approach to deter the relentless decline of lung function in COPD and, polymorphisms in antioxidant,A1AT, and MMPs genes, seem associated with fast FEV1 decline.”7 (p 118) It was found that just cutting down on smoking, even up to 50%, would not change the decline in lung function of an AATD patient. Only those that totally abstained and remained abstinent for a year saw any significant improvement in FEV1, although lung function steadily declined in a fashion comparable to never-smokers.7 Prevention of acute exacerbations of COPD and combined treatment with long-acting bronchodilators and inhaled corticosteroids is also important as exacerbations can cause a more rapid decline of FEV1 over time.7 The amount one smokes directly correlates with the rate at which lung function declines: heavy smokers are going to have a rapid decline and once the damage is done there is no way to repair it short of a lung transplant. Therefore, it is imperative to direct smokers with AATD towards smoking cessation.

At one time it was thought that AATD was strictly a European descent disease because gene-mapping studies indicated that the PiZ allele, the cause of AATD, probably arose in Northern Europe.8 However, further studies revealed that AATD is more of an equal opportunity disease like cystic fibrosis rather than a disease like Tay Sachs which afflict those of Jewish descent, or sickle cell which strikes those of African descent. There is not a racial or ethnic group that is immune from acquiring this genetic defect, it is considered one of the most common and serious hereditary disorders in the world.8

KNOWLEDGE IN THE MEDICAL COMMUNITY

It is amazing that something so common worldwide, and serious is still relatively an unknown disorder amongst the medical community, especially among respiratory therapists and physicians. To show that AATD is under-recognized by those that needs to be knowledgeable, a web-based test with 30 multiple choice answers was given to internal medicine house officers and respiratory therapists at Cleveland Clinic main campus hospital to test their knowledge of AATD.9 The test scores were assessed according to years of training and experience, as well as personal knowledge of AATD. The results were shocking. Out of the 99 respiratory therapists and 66 physicians, the scores were 54% for physicians and 52% for RT’s.9 It did not matter if the physician was a pulmonologist or if the RT had a 4 year degree, the only participants that scored better were those who claimed they had personal knowledge of AATD. These results are an indicator that the people who should be most knowledgeable about this disease are not very knowledgeable.9 This is a grave disservice to a group in need of informed caregivers.

Although the medical community is still somewhat in the dark where AATD is concerned, a patient advocacy group, the Alpha-1 Foundation, is committed to helping those affected by this disease. Because the Alpha-1 Foundation has business partners from all occupations including physicians, pharmaceuticals, the government, and scientific communities; they are able to promote awareness and research.10 AATD is an expensive disorder. Augmentation costs approximately $76,500 per year and this is a lifetime maintenance therapy. The Alpha-1 Foundation collaborating with pharmaceutical companies helps fund augmentation therapy for patients who are unable to afford it.10 Patient advocacy groups are very influential when it comes to initiating interest in research of unknown conditions. The Alpha-1 Foundation is particularly interested in providing resources to increase research, improve health, promote worldwide detection of the disease, and to find a cure.10 Early detection, access to augmentation and other maintenance drugs such as bronchodilators and inhaled steroids, in addition to educating medical personnel will go a long way in helping those with this disorder.10 Fortunately, the Alpha-1 Foundation is paving the way for this to become a reality. Perhaps there will come a day when all newborns are routinely screened for this disorder in the same way cystic fibrosis is, early detection is always the best way to prevent damage from occurring.

Unfortunately, the word emphysema brings to mind a smoker who has caused damage to their lungs themselves. Those with AATD may never have smoked a day in their life, but they are condemned because they have a “smoker’s disease” and they are judged even by the medical community who are unaware of what AATD is. At this time, there is not a cure for AATD, but there are ways to keep from losing lung function and creating more damage in the lungs. Not smoking and keeping away from smoke will go a long way in keeping the lungs from deteriorating faster. Also, getting flu vaccinations yearly, augmentation therapy, avoiding those with illnesses, and exercising will help keep lung function up. The best thing that could happen for AATD patients is for the medical community to become aware of this disorder on a worldwide basis. The Alpha-1 Foundation is working on getting the word out and doing all it possibly can to shine a light on a devastating disease that debilitates and kills people in the prime of their life.

MEDICAL TREATMENTS FOR EMPHYSEMA

Although Alpha-1-antitrypsin is a genetic form of emphysema, it is still a chronic obstructive pulmonary disease (COPD), and medically must be treated as such. Several treatments are beneficial for maintenance of this disease. Advair (salmeterol and fluticasone propionate) is on the front line of maintenance pharmaceuticals for COPD. Although there is not a pharmaceutical agent out there right now that will cure COPD, Advair is beneficial in that it reduces inflammation in the airways. Reducing the inflammation will help to prevent exacerbations.11

So does Advair have an effect on survival for those with COPD patients? Glaxo-SmithKline, makers of Advair, conducted a TORCH (Towards a Revolution in COPD Health) study in order to see for themselves. In this randomized double-blind trial, they compared a twice-daily dose of 50 µg of salmeterol with 500 µg fluticasone propionate alongside a placebo.11 It was found that although Advair did not significantly reduce the mortality rate in its users, it was beneficial in other areas such as keeping them from having to use systemic corticosteroids, and keeping them from severe exacerbations that would require hospitalization.11 Another benefit to using Advair, is that although it only modestly increased FEV1, it did slow the FEV1 decline rate.11

In those with mild COPD, a short-acting bronchodilator such as albuterol, or a bronchodilator with an added anticholinergic such as albuterol with ipratropium, can be used for treatment. For those with moderate to severe COPD, these medications are used more for rescue purposes rather than a maintenance regimen.12 Fast acting β2-adrenergic agonists such as albuterol are essential when there is reversible bronchospasm during an exacerbation. A long-acting bronchodilator is added to a maintenance regimen when symptoms are poorly controlled or when someone is using more than one canister of their rescue inhaler per month. Studies have shown that using albuterol with ipratropium lessened the amount of acute exacerbations, helped with the overall quality of life, helped with exercise tolerance, and helped the person in pulmonary rehabilitation get the most out of their program. Although there can be side effects to using albuterol or albuterol with ipratropium, such as tachycardia, in general, side effects are mild and not life threatening.12

For those patients categorized in the moderate to severe range, adding tiotropium to the regimen gave added benefits. Using tiotropium lessened emergency room visits and hospital admissions when compared to a patient using Serevent alone. Not only was there the added benefit of having less breathing problems, this also helped with costs due to hospitalizations.13 When comparing tiotropium to ipratropium, once again, tiotropium users were less likely to have hospitalizations when compared to ipratropium users. As a side note, patients must be careful when using several different maintenance pharmaceuticals, using Duo-Neb (albuterol and ipratropium) or Atrovent (ipratropium) is contradicted when using Spiriva (tiotropium) because of an unintended increase in the dose of anti-cholinergic bronchodilator. However, Advair and Spiriva may be used together along with albuterol.13

Possibly the most beneficial treatment in COPD, is oxygen therapy. Although pharmaceutical agents help with inflammation, oxygen therapy is the only treatment available to a COPD patient shown to help prolong life.14 Giving a patient supplemental oxygen helps to lower pulmonary hypertension as well as improve the patient’s dyspnea.14 Not all COPD patients need supplemental oxygen, but for those that do, it is important that they use it as prescribed. Tests which guide the prescription of supplemental oxygen are arterial blood gas studies, 6 minute walk tests, and pulse oximetry. If a patient is hypoxemic at rest, that patient may need supplemental oxygen both at rest and during activity.14

While every precaution is taken to keep a patient with COPD out of the hospital, exacerbations happen, sometimes this is due to a viral or bacterial infection within the lungs. A patient with COPD, may not have the cardiopulmonary reserve to overcome an acute exacerbation, and hospitalization in this case will happen more often than not. When hospitalization does occur, every effort is made to keep the patient off mechanical ventilation. It was found that the use of 2 consecutive days of an antibiotic for acute exacerbations of COPD started on hospital day 1 or 2, meant less use of invasive treatment such as mechanical ventilation.15

Another approach to manage acute exacerbations in the hospital is with the use of intravenous or oral corticosteroids. Intravenous and oral corticosteroid use resulted in a measurable FEV1 improvement that continued over the course of 10 days in comparison to the group that was not given intravenous or oral corticosteroids.16 However, the improvement comes with a price. Systemic steroid use has been linked to some devastating side effects, side effects that can last a lifetime. Glucose intolerance which can cause diabetes, increased risk of infection due to the immunosuppressive quality of the drug, osteoporosis, obesity, psychosis, hypokalemia, and metabolic alkalosis just to name a few.16 Because of the severity of the side effects, one must balance the need and the outcome before considering this option. A patient starting on this medication must be watched closely for side effects.16 It is a miracle drug, but not something to take lightly.

Depression and anxiety may also lead to hospitalization for a COPD patient.17 Although depression and anxiety do not directly cause exacerbations, they do appear to cause a worse health-related quality of life with a statistically significant increased risk of mortality.17 When one is faced with a debilitating disease and is unable to breathe, depression would make sense. When a person is depressed, they give up. It is somewhat of a vicious cycle, the effects of the disease cause depression, the depression makes the effects of the disease worse, and on it goes in a never-ending cycle.

Anxiety is a vicious cycle. Not being able to breathe causes anxiety, when one is anxious he breathes faster, However breathing faster does not improve their disease process. In this case, the anxiety could cause an acute exacerbation that could end in a hospitalization. It was also found that those with depression and anxiety not only end up in the hospital more often, but there were significantly more deaths after discharge.18

Those with COPD need specific care in order to maximize the outcome of their lives. In answer to this, several different organizations came up with practice guidelines in order to improve health outcomes and decrease practice variation.19 In theory this could contain costs and standardize care. However in treating COPD, it is not a one size fits all scenario. Each person is different and each person responds differently to treatment. One may need lung reduction surgery in order to survive, while another may only need pharmaceuticals in order to have a good quality of life. Therefore, although there must be guidelines to follow, one must not feel like they are boxed into a particular path they must follow with every patient.19

So what is the best way for a patient to be proactive rather than just following guidelines and hoping for the best? Self-care management puts the patient in the driver’s seat alongside the medical team rather than in the backseat. Patients who take a more active role in their day-to-day care are less likely to end up in the hospital. Self-care management is formalized patient education that teaches the skills to manage medications, guides behavior changes, and provides emotional support so patients can live full and active lives.20 There is a saying, knowledge is power, and this is true for those with COPD.

The more a person knows about their disease, the more they are empowered. Anxiety may come from fear, and fear often comes from the unknown. If a person is aware of what is causing their symptoms and the ways to combat those symptoms, the anxiety may lessen. Classes taught patients about breathing techniques, nutrition, coughing techniques, conserving energy, and gave them an action plan (in case of an exacerbation). These all helped empower the patient.20 Activity increased for these patients, health-related quality of life improved, and there were far less hospitalizations for those who took self-management classes. 20 Pulmonary rehabilitation for the COPD patient is also beneficial, whether in the beginning stages of COPD or at the end. Pulmonary rehabilitation will help patients utilize their oxygen more efficiently as well as slowing FEV1 decline.20

SUMMARY

It does not matter what has caused the emphysema, AATD or smoking, the bottom line is there is destruction of lung tissue with both situations. This damage will produce symptoms that may with pulmonary rehabilitation, medications, surgery, self-help groups, oxygen, or all of the above. Depression and/or anxiety need to be taken into consideration, and every effort must be made to avoid exacerbations in order to preserve lung function.

REFERENCES

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2. Stolk J, Seersholm N, Kalsheker N. Alpha-1-antitrypsin deficiency: current perspective on research, diagnosis, and management. Int J Chron Obstruct Pulmon Dis. 2006;1(2):151-160.

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4. Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biol.: Targets Ther. 2009;3:193-204.

5. Dauriat G, Mal H, Jebrak G, Brugiere O, Castier y, Camuset J, et al. Functional results of unilateral lung volume reduction surgery in alph-1-antitrypsin deficient patients. Int J Chron Obstruct Pulmon Dis. 2006;1(2):201-206.

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17. Fan V, Ramsey S, Giardino N, Make B, Emery C, Diaz P, et al. Sex, depression, and risk of hospitalization and mortality in chronic obstructive pulmonary disease. Arch Intern Med. 2001;167(21):2345-2353.

18. Ng T, Niti M, Tan W, Cao Z, Ong K, Eng P. Depressive symptoms and chronic obstructive pulmonary disease effect on mortality, hospital readmission, symptom burden, functional status, and quality of life. Arch Intern Med. 2007;167;60-67.

19. Lacasse Y, Ferreira I, Brooks D, Newman T, Goldstein R. Critical appraisal of clinical practice guidelines targeting chronic obstructive pulmonary disease. Arch Intern Med. 2001;161:69-74.

20. Bourbeau J, Julien M, Maltais F, Rouleau M, Beaupre A, Begin R, et al. Reduction in hospital utilization in patients with chronic obstructive pulmonary disease a disease-specific self-management intervention. Arch Intern Med. 2003;163:585-591.