COPD: Journal of Chronic Obstructive Pulmonary Disease
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Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: A Family Perspective Antonio Anzueto To cite this article: Antonio Anzueto (2015) Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: A Family Perspective, COPD: Journal of Chronic Obstructive Pulmonary Disease, 12:4, 462-467, DOI: 10.3109/15412555.2014.974746 To link to this article: http://dx.doi.org/10.3109/15412555.2014.974746
Published online: 04 Dec 2014.
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COPD, 12:462–467, 2015 ISSN: 1541-2555 print / 1541-2563 online Copyright © Informa Healthcare USA, Inc. DOI: 10.3109/15412555.2014.974746
COMMENTARY
Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: A Family Perspective
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Antonio Anzueto South Texas Veterans Health Care System, Audie L. Murphy Hospital, and University of Texas Health Science Center, San Antonio, Texas, USA
Abstract Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic condition that can lead to the early onset of chronic obstructive pulmonary disease (COPD), a disorder that comprises elements of chronic bronchitis and emphysema. AATD is characterized by reduced levels of the AAT protease inhibitor, leading to unrestricted protease activity in the lung, which promotes destruction of lung tissue. In severe cases, patients with AATD have an increased mortality risk and, potentially, a poor quality of life due to more frequent COPD exacerbations and/or limitations on daily activity. However, the burden of AATD on members of the patient’s immediate family who may serve as caregivers has not been described. Because the age range at which most patients are diagnosed with AATD may affect the economic status of an individual and/or of a family, it is likely that a diagnosis of AATD may have negative effects that extend beyond those on the diagnosed person to include immediate family members. Here, we review the literature to investigate the impact of the caregiver role of family members in disease states that affect an age group similar to AATD. Furthermore, we provide a case study showing the effect of AATD on immediate family members.
Introduction
Keywords: augmentation therapy, caregiver, chronic bronchitis, emphysema Correspondence to: Antonio Anzueto, The University of Texas Health Science Center at San Antonio, Department of Medicine, Pulmonary Disease, Suite 111E, 7400 Merton Minter Boulevard, San Antonio, TX 78229, USA, phone: (210) 617-5256, email:[email protected]
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Diagnosis of alpha-1 antitrypsin deficiency (AATD) may negatively affect both the economic status and quality of life of the diagnosed individual and his/her family. To illustrate the topic and the discussion included in this manuscript, we include a short description of a case report regarding a middle-aged woman diagnosed with AATD with chronic obstructive pulmonary disease (COPD). Ms. L is a 42-year-old woman with chronic obstructive pulmonary COPD, which was diagnosed at the age of 32. Ms. L has a history of asthma, tobacco use, and family history of unspecified lung disease. Upon diagnosis she was started on long-acting beta-agonists and inhaled corticosteroids for relief of her COPD symptoms. A year following her COPD diagnosis, Ms. L was diagnosed with AATD. Ms. L’s condition and her pulmonary function test (PFT) results have worsened over time. She had multiple “flare-ups” that required antibiotic treatment with and without systemic corticosteroids. Long-acting anticholinergic agents were added to her maintenance treatment regimen. She had one hospitalization in the intensive care unit with bronchitis and acute respiratory failure, during which she did not require intubation but did receive non-invasive ventilation, and her condition improved. At her most recent clinic visit she had pronounced dyspnea (Modified Medical Research Council Dyspnea Scale Score of 3),
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Alpha-1 antitrypsin deficiency, COPD, and the family
daily wheezing and morning cough, and expectorated 4 ounces of white sputum. Her PFT results revealed a post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) of 55% and a post-bronchodilator FEV1% predicted of 41% (18% improvement after bronchodilators). Her worsening disease has prevented her from performing most activities of daily living and has made it difficult to raise her child. As a result, she and her child now live with her sister who assists her in completing daily tasks. Her sister now balances maintaining a full-time job and supporting Ms. L as a caregiver. Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic condition that results in reduced levels of the protein AAT in the blood, leading to an increased risk of liver and/or lung disease, which primarily manifests as early-onset COPD. Alpha-1 antitrypsin deficiency is caused by the inheritance of specific alleles of the SERPINA1 gene encoding the AAT protease inhibitor. In the homozygous state, the PiM allele is associated with normal protein levels, the PiS allele results in levels that are approximately 60% of normal levels, and the PiZ allele leads to a more severe deficiency with protein levels that are approximately 15% of normal levels (1, 2). The AAT protease inhibitor blocks neutrophil elastase; in persons with AATD, neutrophil elastase levels can accumulate to critical levels (3), leading to destruction of the delicate alveolar walls lining the lung (4). Consequently, patients with AATD, especially those who are exposed to environmental irritants such as cigarette smoke, have an elevated risk of the development of early-onset pulmonary disorders such as COPD (5, 6). Chronic obstructive pulmonary disease of both AATD and non-AATD origins has been diagnosed in approximately 14.2 million persons and, in 2009, was the 3rd leading cause of death in the United States (7). It is estimated that 1% to 3% of patients with COPD are deficient in AAT (8–10), and that as many as 95% of patients with AATD remain undiagnosed (10), potentially due, at least in part, to the lack of education about the condition among clinicians. The consequences of the underdiagnosis of AATD include a failure to receive appropriate treatment in affected patients (11). Furthermore, because diagnosis of AATD prompts physicians to test an affected patient’s family members (9), underdiagnosis has potentially cumulative consequences. Augmentation therapy, which involves the administration of exogenous alpha-1 protease inhibitor to increase serum levels of the protein, has been indicated for patients with AATD and certain clinical features (9). AATD patients with AAT serum levels < 11 μM (normal range, 20–48 μM); a FEV1 between 30% and 65% of the predicted value for age and sex; and with variant genes or proteins (S,Z) determined by genetic testing using a genotyping test or phenotyping by isoelectric focusing, respectively, may benefit from augmentation therapy with the human plasma-derived alpha-1 protease inhibitor delivered intravenously (9). www.copdjournal.com
It should be noted, however, that augmentation therapy may also benefit some patients with severe lung function impairment (FEV1 < 30%) by slowing down the decline in lung function (12). These effects are pronounced when a patient is diagnosed with AATD at an early stage (13, 14). However, the effects of a diagnosis of AATD on the family unit as a whole have not been detailed previously. Studies in disease states that affect an age group similar to AATD, such as primary pulmonary arterial hypertension (PAH), multiple sclerosis (MS), and Parkinson’s disease (15–23) have demonstrated that family members who serve as caregivers are impacted by these conditions. In those studies, health-related quality of life (HRQOL) and general wellbeing were negatively impacted as a consequence of the associated burden of their caregiving role (16–19, 21, 22, 24). Based on these findings, caregivers would likely benefit from health and social services that are tailored to deal with the challenges associated with this role. In the context of an underdiagnosed condition such as AATD, the burden of the caregiver role may also be eased by timely diagnosis and management of the condition. The purpose of this commentary is to discuss how AATD-associated COPD and its treatment affect all members of the patient’s family.
Effects of alpha-1 antitrypsin deficiency on the family The observed underdiagnosis of AATD prompted the American Thoracic Society and European Respiratory Society (ATS/ERS) to draft standards in 2003 for the diagnosis and management of patients with AATD. These standards indicated that the presence of AATD should be suspected in patients with any of the following features: early-onset emphysema (at age ≤ 45 years); emphysema in the absence of a recognized risk factor such as smoking, or emphysema with prominent basilar hyperlucency; liver disease that is otherwise unexplained; anti-proteinase 3-positive vasculitis; a family history of emphysema, liver disease, or panniculitis; and bronchiectasis with no apparent etiology (9). Early diagnosis and treatment are anticipated to improve patient outcomes. It is important to highlight that, due to the genetic nature of the disease, family members of a person diagnosed with AATD could have the disease themselves or be carriers. Therefore, if one positive diagnosis prompts a clinician to screen the family, one diagnosis has the potential to identify many individuals with an increased risk of AATD. The published standards for the diagnosis and management of patients with AATD and other efforts to enhance patient screening have increased the number of AATD diagnoses in the US (25). According to the ATS/ERS guidelines, all COPD and asthma patients with partially reversible airflow obstruction should be screened for AATD. Implementing this procedure in clinical practice could be a relatively inexpensive way to reduce the underdiagnosis and the late diagnosis of AATD (9).
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Many similar efforts to promote early detection and diagnosis of AATD have been undertaken in Europe (26,28). Currently, the two major techniques used by European laboratories to diagnose AATD include measurement of the level of AAT in the blood by nephelometry, and the determination of the genotype using polymerase chain reaction-based techniques or sequencing of exonic DNA. Phenotyping by isoelectric focusing is at present used only for the independent confirmation of diagnosis (28). Despite this promising trend, however, many patients and thus families with an elevated risk for AATD remain undiagnosed (9). Thus, there is a need for effective educational imperatives to improve patient and clinician understanding of the importance of the diagnosis and treatment of this condition. The age at which many individuals are diagnosed with AATD (10) may have a wide range of effects on their family members. Patients in their 40s or early 50s may be a critical provider for their children and/or for elderly parents. This age group encompasses a period of maximum earning capacity and maximum retirement savings contributions (29). Consequently, a diagnosis of AATD, particularly at an advanced stage of disease, can have both direct and indirect financial consequences that can affect a family. For example, due to the need for clinician visits for required check-ups and/or disease exacerbations, and hospital visits for weekly administration of augmentation therapy that may be administered during working hours, the patient may miss a significant number of work days and thus not receive the expected compensation. In addition to the direct financial impact of missing regularly scheduled work days, patients also may face treatment costs associated with their condition that are not reimbursed by their insurance plans and/or costs associated with copayments for repeated clinician visits (30). Although it has not been studied, among people who serve as the head of a household, a diagnosis of AATD could have widespread effects beyond the more measurable financial impact. Affected individuals may serve a crucial role in the socialization of a child, for example, by enabling their children’s attendance at various functions (eg, school functions). In addition, elderly parents might require various forms of assistance that become less feasible for patients with AATD to perform, such as driving parents to clinician visits.
Effects of alpha-1 antitrypsin deficiency and therapeutic intervention on family members who must serve as caregivers Family members of an individual diagnosed with AATD must adapt to the presence of the disease and, potentially, to a new role as a caregiver. As caregivers, family members may need to rearrange their schedules to incorporate the duties associated with their new responsibilities. Consequently, engagement in previously established routines, including social and extracurricular activities, may be disrupted or may cease entirely. These alterations of lifestyle
and routine resulting from the change in dependency may lead to increased stress and depression among family members, both of which can negatively impact quality of life and overall health (31). Adoption of the caregiver role has been shown to negatively affect a person’s quality of life, as demonstrated in the context of other diseases that affect an age group similar to AATD, including COPD of any etiology, idiopathic pulmonary fibrosis (IPF), primary PAH, MS, and Parkinson’s disease (15–19, 21, 23, 24). In a study examining the effect of COPD of any etiology on patient quality of life, the results confirmed that a diagnosis of COPD not only affects the patient but also his or her ability to perform daily activities with family members (22). Another study assessed criteria that contribute to the quality of life of patients with IPF and showed that the burden of the disease on family members, both financial (by reducing family savings to pay for treatment) and psychological, was an important criterion (20). In a study of patients with any form of PAH, Hwang et al (19) reported that the wellbeing of family caregivers suffered from a lack of emotional support. These findings indicate that in addition to the diagnosed patient, family members should be considered when establishing support systems, suggesting that a diagnosis of PAH has negative effects not only on patients but also on their families. Several studies have reported that MS caregivers experience poorer mental and physical health-related outcomes, worsened wellbeing and decreased HRQOL (16, 17, 21, 24), supporting the importance of health and social services for caregivers (21). Based on the published data regarding the management of AATD (Table 1), it is speculated that earlier intervention and treatment will potentially reduce many of the challenges of the caregiving role for family members. Early diagnosis of AATD, based on the clinical status of the patient or the knowledge of affected family members, may alleviate many of the negative effects experienced by family members who serve as caregivers. Early diagnosis may lead to treatment prior to the development of advanced disease. It is expected that these changes would reduce the need for caregiving by immediate family members. Furthermore, an early diagnosis might increase the screening of at-risk family members prior to the development of any disease symptoms. Such early diagnosis could lead to earlier patient education and possibly modification of some lifestyle choices, such as smoking, which could significantly reduce the patient’s risk of developing the disease and improve his or her prognosis.
Summary A diagnosis of AATD has the potential to negatively impact not only persons diagnosed with the condition but also their entire immediate family. Early intervention and treatment, which are anticipated to increase with Copyright © 2015 Informa Healthcare USA, Inc
www.copdjournal.com No augmentation therapy
The rate of decline in FEV1 in these treated patients (57 mL/yr) was approximately half that reported (historical data) for untreated controls
No augmentation therapy
Decreased mortality in patients receiving therapy (P = 0.02); slower decline in lung function in treated patients with moderately decreased lung function (p = 0.03)
No augmentation therapy
Slower decline in lung function in treated group vs untreated group (p = 0.02)
Comparator
Study findings
NA
Albumin (625 mg/ kg) at 4-week intervals
Slower decline in FEV1 during treatment period vs pretreatment period for entire group (p = 0.019)
Alpha-1 protease inhibitor (60 mg/ kg) weekly
Lung density measurements by CT are promising for future randomized clinical trials of AATD
96
56
Multicenter, retrospective cohort study
2001
Wencker et al. (34)
Alpha-1 protease inhibitor (250 mg/ kg) at 4-week intervals
Randomized, parallel, double-blind, placebo-controlled trial at 2 centers
1999
Dirksen et al. (35)
CT more sensitive measure of emphysemamodifying therapy than physiology and health status, and demonstrates a trend of Alpha-1 MP treatment benefit
Placebo
Alpha-1 protease inhibitor (60 mg/kg) weekly
77
Randomized, doubleblind, placebocontrolled, parallel group
2009
EXACTLE (36)
Alpha-1 MP (120 mg/ kg) weekly was well tolerated and provided more physiologic alpha-1-PI levels than Alpha-1 MP (60 mg/kg)
Alpha-1 protease inhibitor (60 mg/kg) weekly
Alpha-1 protease inhibitor (60 mg/kg) weekly
PK of Alpha-1 MP are equivalent to alpha-1-PI
Alpha-1 protease inhibitor (120 mg/kg) weekly
30
Randomized, doubleblind, crossover
2013
SPARK (38)
Alpha-1 protease inhibitor (60 mg/kg) weekly
24
Multicenter, randomized, double-blind, crossover
2010
ChAMP (37)
NA
Alpha-1 protease inhibitor (60 mg/ kg) weekly and placebo (0.9% NaCl)
Alpha-1 protease inhibitor (120 mg/kg) weekly
339
Randomized, double-blind, placebocontrolled
2013
SPARTA (39)
AATD = alpha-1 antitrypsin deficiency; ChAMP = Comparability pharmacokinetics of Alpha-1 Modified Process trial; CT = computed tomography; EXACTLE = EXAcerbations and Computed Tomography scan as Lung End-points trial; FEV1 = forced expiratory volume in 1 second; MP = modified process; NA = not applicable; NHLBI = National Heart, Lung and Blood Institute; PK = pharmacokinetics; SPARK = Safety and PhARmacoKinetic trial; SPARTA = Study of ProlAstin-c Randomized Therapy with Alpha-1 augmentation trial.
Alpha-1 protease inhibitor (60 mg/kg) weekly
Alpha-1 protease inhibitor (60 mg/kg) weekly
Alpha-1 protease inhibitor (60 mg/kg) weekly
Experimental drug dose and regimen
287
Prospective, longterm multicenter observational study
927
Prospective, multicenter, nonrandomized study
Retrospective nonrandomized, random effects modeling study
1998
Wencker et al. (12)
295
1998
1997
NHLBI AATD Registry Study Group (33)
Number of patients
Study design
Year
Seersholm et al. (32)
Table 1. Characteristics of clinical trials conducted to evaluate the treatment of patients with alpha-1 antitrypsin deficiency.
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improved physician education, may mitigate some of these negative effects. The case report described clearly illustrates the impact of AATD on the family. At 10 years after the initial COPD diagnosis, Ms. L’s health was so poor that she could no longer live alone and take care of herself and her child, and she was forced to seek help from her family. Early AATD diagnosis may have led to treatment prior to the development of advanced disease. Based on the present review and case study, the following tactics are suggested as ways to palliate the effects of the disease on the patient and the immediate family unit: earlier screening, prompt therapeutic intervention, and education and screening of family members. Ultimately, more frequent application of this process may have profound effects for both patients with AATD as well as their immediate family members.
Declaration of Interest Statement Dr. Antonio Anzueto has served on the speakers’ bureaus of Pfizer Inc., Boehringer Ingelheim GmbH, GlaxoSmithKline plc, and Grifols Therapeutics Inc. (manufacturer of alpha-1 antitrypsin augmentation therapy); and on the advisory boards of GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca plc, Novartis Pharma AG, Bayer Healthcare AG, and Pfizer. Medical writing assistance was provided by Jill See, PhD, of QSci Communications, LLC, and funded by Grifols Inc.
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Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: A Family Perspective Antonio Anzueto To cite this article: Antonio Anzueto (2015) Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: A Family Perspective, COPD: Journal of Chronic Obstructive Pulmonary Disease, 12:4, 462-467, DOI: 10.3109/15412555.2014.974746 To link to this article: http://dx.doi.org/10.3109/15412555.2014.974746
Published online: 04 Dec 2014.
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Date: 05 November 2015, At: 21:02
COPD, 12:462–467, 2015 ISSN: 1541-2555 print / 1541-2563 online Copyright © Informa Healthcare USA, Inc. DOI: 10.3109/15412555.2014.974746
COMMENTARY
Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: A Family Perspective
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Antonio Anzueto South Texas Veterans Health Care System, Audie L. Murphy Hospital, and University of Texas Health Science Center, San Antonio, Texas, USA
Abstract Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic condition that can lead to the early onset of chronic obstructive pulmonary disease (COPD), a disorder that comprises elements of chronic bronchitis and emphysema. AATD is characterized by reduced levels of the AAT protease inhibitor, leading to unrestricted protease activity in the lung, which promotes destruction of lung tissue. In severe cases, patients with AATD have an increased mortality risk and, potentially, a poor quality of life due to more frequent COPD exacerbations and/or limitations on daily activity. However, the burden of AATD on members of the patient’s immediate family who may serve as caregivers has not been described. Because the age range at which most patients are diagnosed with AATD may affect the economic status of an individual and/or of a family, it is likely that a diagnosis of AATD may have negative effects that extend beyond those on the diagnosed person to include immediate family members. Here, we review the literature to investigate the impact of the caregiver role of family members in disease states that affect an age group similar to AATD. Furthermore, we provide a case study showing the effect of AATD on immediate family members.
Introduction
Keywords: augmentation therapy, caregiver, chronic bronchitis, emphysema Correspondence to: Antonio Anzueto, The University of Texas Health Science Center at San Antonio, Department of Medicine, Pulmonary Disease, Suite 111E, 7400 Merton Minter Boulevard, San Antonio, TX 78229, USA, phone: (210) 617-5256, email:[email protected]
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Diagnosis of alpha-1 antitrypsin deficiency (AATD) may negatively affect both the economic status and quality of life of the diagnosed individual and his/her family. To illustrate the topic and the discussion included in this manuscript, we include a short description of a case report regarding a middle-aged woman diagnosed with AATD with chronic obstructive pulmonary disease (COPD). Ms. L is a 42-year-old woman with chronic obstructive pulmonary COPD, which was diagnosed at the age of 32. Ms. L has a history of asthma, tobacco use, and family history of unspecified lung disease. Upon diagnosis she was started on long-acting beta-agonists and inhaled corticosteroids for relief of her COPD symptoms. A year following her COPD diagnosis, Ms. L was diagnosed with AATD. Ms. L’s condition and her pulmonary function test (PFT) results have worsened over time. She had multiple “flare-ups” that required antibiotic treatment with and without systemic corticosteroids. Long-acting anticholinergic agents were added to her maintenance treatment regimen. She had one hospitalization in the intensive care unit with bronchitis and acute respiratory failure, during which she did not require intubation but did receive non-invasive ventilation, and her condition improved. At her most recent clinic visit she had pronounced dyspnea (Modified Medical Research Council Dyspnea Scale Score of 3),
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Alpha-1 antitrypsin deficiency, COPD, and the family
daily wheezing and morning cough, and expectorated 4 ounces of white sputum. Her PFT results revealed a post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) of 55% and a post-bronchodilator FEV1% predicted of 41% (18% improvement after bronchodilators). Her worsening disease has prevented her from performing most activities of daily living and has made it difficult to raise her child. As a result, she and her child now live with her sister who assists her in completing daily tasks. Her sister now balances maintaining a full-time job and supporting Ms. L as a caregiver. Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic condition that results in reduced levels of the protein AAT in the blood, leading to an increased risk of liver and/or lung disease, which primarily manifests as early-onset COPD. Alpha-1 antitrypsin deficiency is caused by the inheritance of specific alleles of the SERPINA1 gene encoding the AAT protease inhibitor. In the homozygous state, the PiM allele is associated with normal protein levels, the PiS allele results in levels that are approximately 60% of normal levels, and the PiZ allele leads to a more severe deficiency with protein levels that are approximately 15% of normal levels (1, 2). The AAT protease inhibitor blocks neutrophil elastase; in persons with AATD, neutrophil elastase levels can accumulate to critical levels (3), leading to destruction of the delicate alveolar walls lining the lung (4). Consequently, patients with AATD, especially those who are exposed to environmental irritants such as cigarette smoke, have an elevated risk of the development of early-onset pulmonary disorders such as COPD (5, 6). Chronic obstructive pulmonary disease of both AATD and non-AATD origins has been diagnosed in approximately 14.2 million persons and, in 2009, was the 3rd leading cause of death in the United States (7). It is estimated that 1% to 3% of patients with COPD are deficient in AAT (8–10), and that as many as 95% of patients with AATD remain undiagnosed (10), potentially due, at least in part, to the lack of education about the condition among clinicians. The consequences of the underdiagnosis of AATD include a failure to receive appropriate treatment in affected patients (11). Furthermore, because diagnosis of AATD prompts physicians to test an affected patient’s family members (9), underdiagnosis has potentially cumulative consequences. Augmentation therapy, which involves the administration of exogenous alpha-1 protease inhibitor to increase serum levels of the protein, has been indicated for patients with AATD and certain clinical features (9). AATD patients with AAT serum levels < 11 μM (normal range, 20–48 μM); a FEV1 between 30% and 65% of the predicted value for age and sex; and with variant genes or proteins (S,Z) determined by genetic testing using a genotyping test or phenotyping by isoelectric focusing, respectively, may benefit from augmentation therapy with the human plasma-derived alpha-1 protease inhibitor delivered intravenously (9). www.copdjournal.com
It should be noted, however, that augmentation therapy may also benefit some patients with severe lung function impairment (FEV1 < 30%) by slowing down the decline in lung function (12). These effects are pronounced when a patient is diagnosed with AATD at an early stage (13, 14). However, the effects of a diagnosis of AATD on the family unit as a whole have not been detailed previously. Studies in disease states that affect an age group similar to AATD, such as primary pulmonary arterial hypertension (PAH), multiple sclerosis (MS), and Parkinson’s disease (15–23) have demonstrated that family members who serve as caregivers are impacted by these conditions. In those studies, health-related quality of life (HRQOL) and general wellbeing were negatively impacted as a consequence of the associated burden of their caregiving role (16–19, 21, 22, 24). Based on these findings, caregivers would likely benefit from health and social services that are tailored to deal with the challenges associated with this role. In the context of an underdiagnosed condition such as AATD, the burden of the caregiver role may also be eased by timely diagnosis and management of the condition. The purpose of this commentary is to discuss how AATD-associated COPD and its treatment affect all members of the patient’s family.
Effects of alpha-1 antitrypsin deficiency on the family The observed underdiagnosis of AATD prompted the American Thoracic Society and European Respiratory Society (ATS/ERS) to draft standards in 2003 for the diagnosis and management of patients with AATD. These standards indicated that the presence of AATD should be suspected in patients with any of the following features: early-onset emphysema (at age ≤ 45 years); emphysema in the absence of a recognized risk factor such as smoking, or emphysema with prominent basilar hyperlucency; liver disease that is otherwise unexplained; anti-proteinase 3-positive vasculitis; a family history of emphysema, liver disease, or panniculitis; and bronchiectasis with no apparent etiology (9). Early diagnosis and treatment are anticipated to improve patient outcomes. It is important to highlight that, due to the genetic nature of the disease, family members of a person diagnosed with AATD could have the disease themselves or be carriers. Therefore, if one positive diagnosis prompts a clinician to screen the family, one diagnosis has the potential to identify many individuals with an increased risk of AATD. The published standards for the diagnosis and management of patients with AATD and other efforts to enhance patient screening have increased the number of AATD diagnoses in the US (25). According to the ATS/ERS guidelines, all COPD and asthma patients with partially reversible airflow obstruction should be screened for AATD. Implementing this procedure in clinical practice could be a relatively inexpensive way to reduce the underdiagnosis and the late diagnosis of AATD (9).
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Many similar efforts to promote early detection and diagnosis of AATD have been undertaken in Europe (26,28). Currently, the two major techniques used by European laboratories to diagnose AATD include measurement of the level of AAT in the blood by nephelometry, and the determination of the genotype using polymerase chain reaction-based techniques or sequencing of exonic DNA. Phenotyping by isoelectric focusing is at present used only for the independent confirmation of diagnosis (28). Despite this promising trend, however, many patients and thus families with an elevated risk for AATD remain undiagnosed (9). Thus, there is a need for effective educational imperatives to improve patient and clinician understanding of the importance of the diagnosis and treatment of this condition. The age at which many individuals are diagnosed with AATD (10) may have a wide range of effects on their family members. Patients in their 40s or early 50s may be a critical provider for their children and/or for elderly parents. This age group encompasses a period of maximum earning capacity and maximum retirement savings contributions (29). Consequently, a diagnosis of AATD, particularly at an advanced stage of disease, can have both direct and indirect financial consequences that can affect a family. For example, due to the need for clinician visits for required check-ups and/or disease exacerbations, and hospital visits for weekly administration of augmentation therapy that may be administered during working hours, the patient may miss a significant number of work days and thus not receive the expected compensation. In addition to the direct financial impact of missing regularly scheduled work days, patients also may face treatment costs associated with their condition that are not reimbursed by their insurance plans and/or costs associated with copayments for repeated clinician visits (30). Although it has not been studied, among people who serve as the head of a household, a diagnosis of AATD could have widespread effects beyond the more measurable financial impact. Affected individuals may serve a crucial role in the socialization of a child, for example, by enabling their children’s attendance at various functions (eg, school functions). In addition, elderly parents might require various forms of assistance that become less feasible for patients with AATD to perform, such as driving parents to clinician visits.
Effects of alpha-1 antitrypsin deficiency and therapeutic intervention on family members who must serve as caregivers Family members of an individual diagnosed with AATD must adapt to the presence of the disease and, potentially, to a new role as a caregiver. As caregivers, family members may need to rearrange their schedules to incorporate the duties associated with their new responsibilities. Consequently, engagement in previously established routines, including social and extracurricular activities, may be disrupted or may cease entirely. These alterations of lifestyle
and routine resulting from the change in dependency may lead to increased stress and depression among family members, both of which can negatively impact quality of life and overall health (31). Adoption of the caregiver role has been shown to negatively affect a person’s quality of life, as demonstrated in the context of other diseases that affect an age group similar to AATD, including COPD of any etiology, idiopathic pulmonary fibrosis (IPF), primary PAH, MS, and Parkinson’s disease (15–19, 21, 23, 24). In a study examining the effect of COPD of any etiology on patient quality of life, the results confirmed that a diagnosis of COPD not only affects the patient but also his or her ability to perform daily activities with family members (22). Another study assessed criteria that contribute to the quality of life of patients with IPF and showed that the burden of the disease on family members, both financial (by reducing family savings to pay for treatment) and psychological, was an important criterion (20). In a study of patients with any form of PAH, Hwang et al (19) reported that the wellbeing of family caregivers suffered from a lack of emotional support. These findings indicate that in addition to the diagnosed patient, family members should be considered when establishing support systems, suggesting that a diagnosis of PAH has negative effects not only on patients but also on their families. Several studies have reported that MS caregivers experience poorer mental and physical health-related outcomes, worsened wellbeing and decreased HRQOL (16, 17, 21, 24), supporting the importance of health and social services for caregivers (21). Based on the published data regarding the management of AATD (Table 1), it is speculated that earlier intervention and treatment will potentially reduce many of the challenges of the caregiving role for family members. Early diagnosis of AATD, based on the clinical status of the patient or the knowledge of affected family members, may alleviate many of the negative effects experienced by family members who serve as caregivers. Early diagnosis may lead to treatment prior to the development of advanced disease. It is expected that these changes would reduce the need for caregiving by immediate family members. Furthermore, an early diagnosis might increase the screening of at-risk family members prior to the development of any disease symptoms. Such early diagnosis could lead to earlier patient education and possibly modification of some lifestyle choices, such as smoking, which could significantly reduce the patient’s risk of developing the disease and improve his or her prognosis.
Summary A diagnosis of AATD has the potential to negatively impact not only persons diagnosed with the condition but also their entire immediate family. Early intervention and treatment, which are anticipated to increase with Copyright © 2015 Informa Healthcare USA, Inc
www.copdjournal.com No augmentation therapy
The rate of decline in FEV1 in these treated patients (57 mL/yr) was approximately half that reported (historical data) for untreated controls
No augmentation therapy
Decreased mortality in patients receiving therapy (P = 0.02); slower decline in lung function in treated patients with moderately decreased lung function (p = 0.03)
No augmentation therapy
Slower decline in lung function in treated group vs untreated group (p = 0.02)
Comparator
Study findings
NA
Albumin (625 mg/ kg) at 4-week intervals
Slower decline in FEV1 during treatment period vs pretreatment period for entire group (p = 0.019)
Alpha-1 protease inhibitor (60 mg/ kg) weekly
Lung density measurements by CT are promising for future randomized clinical trials of AATD
96
56
Multicenter, retrospective cohort study
2001
Wencker et al. (34)
Alpha-1 protease inhibitor (250 mg/ kg) at 4-week intervals
Randomized, parallel, double-blind, placebo-controlled trial at 2 centers
1999
Dirksen et al. (35)
CT more sensitive measure of emphysemamodifying therapy than physiology and health status, and demonstrates a trend of Alpha-1 MP treatment benefit
Placebo
Alpha-1 protease inhibitor (60 mg/kg) weekly
77
Randomized, doubleblind, placebocontrolled, parallel group
2009
EXACTLE (36)
Alpha-1 MP (120 mg/ kg) weekly was well tolerated and provided more physiologic alpha-1-PI levels than Alpha-1 MP (60 mg/kg)
Alpha-1 protease inhibitor (60 mg/kg) weekly
Alpha-1 protease inhibitor (60 mg/kg) weekly
PK of Alpha-1 MP are equivalent to alpha-1-PI
Alpha-1 protease inhibitor (120 mg/kg) weekly
30
Randomized, doubleblind, crossover
2013
SPARK (38)
Alpha-1 protease inhibitor (60 mg/kg) weekly
24
Multicenter, randomized, double-blind, crossover
2010
ChAMP (37)
NA
Alpha-1 protease inhibitor (60 mg/ kg) weekly and placebo (0.9% NaCl)
Alpha-1 protease inhibitor (120 mg/kg) weekly
339
Randomized, double-blind, placebocontrolled
2013
SPARTA (39)
AATD = alpha-1 antitrypsin deficiency; ChAMP = Comparability pharmacokinetics of Alpha-1 Modified Process trial; CT = computed tomography; EXACTLE = EXAcerbations and Computed Tomography scan as Lung End-points trial; FEV1 = forced expiratory volume in 1 second; MP = modified process; NA = not applicable; NHLBI = National Heart, Lung and Blood Institute; PK = pharmacokinetics; SPARK = Safety and PhARmacoKinetic trial; SPARTA = Study of ProlAstin-c Randomized Therapy with Alpha-1 augmentation trial.
Alpha-1 protease inhibitor (60 mg/kg) weekly
Alpha-1 protease inhibitor (60 mg/kg) weekly
Alpha-1 protease inhibitor (60 mg/kg) weekly
Experimental drug dose and regimen
287
Prospective, longterm multicenter observational study
927
Prospective, multicenter, nonrandomized study
Retrospective nonrandomized, random effects modeling study
1998
Wencker et al. (12)
295
1998
1997
NHLBI AATD Registry Study Group (33)
Number of patients
Study design
Year
Seersholm et al. (32)
Table 1. Characteristics of clinical trials conducted to evaluate the treatment of patients with alpha-1 antitrypsin deficiency.
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improved physician education, may mitigate some of these negative effects. The case report described clearly illustrates the impact of AATD on the family. At 10 years after the initial COPD diagnosis, Ms. L’s health was so poor that she could no longer live alone and take care of herself and her child, and she was forced to seek help from her family. Early AATD diagnosis may have led to treatment prior to the development of advanced disease. Based on the present review and case study, the following tactics are suggested as ways to palliate the effects of the disease on the patient and the immediate family unit: earlier screening, prompt therapeutic intervention, and education and screening of family members. Ultimately, more frequent application of this process may have profound effects for both patients with AATD as well as their immediate family members.
Declaration of Interest Statement Dr. Antonio Anzueto has served on the speakers’ bureaus of Pfizer Inc., Boehringer Ingelheim GmbH, GlaxoSmithKline plc, and Grifols Therapeutics Inc. (manufacturer of alpha-1 antitrypsin augmentation therapy); and on the advisory boards of GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca plc, Novartis Pharma AG, Bayer Healthcare AG, and Pfizer. Medical writing assistance was provided by Jill See, PhD, of QSci Communications, LLC, and funded by Grifols Inc.
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