The Challenge of Detecting Alpha-1 Antitrypsin Deficiency

Abstract

Alpha-1 antitrypsin deficiency (AATD) is relatively common but under-recognized. Indeed, fewer than 10% of the estimated 100,000 Americans with AATD have been diagnosed currently, with common reports of long delays between initial symptoms and first detection and the need to see multiple physicians before diagnosis. Because detection can confer benefits (e.g., identification of at-risk family members, lower smoking likelihood, consideration of augmentation therapy), targeted detection of AATD in at-risk groups such as all symptomatic adults with COPD has been endorsed.

Two general approaches to detection have been studied: population-based screening (in which testing is performed in a group for whom no increased risk of having AATD exists) and targeted detection or case-finding (in which testing is confined to those with an attributable condition such as COPD or chronic liver disease). Studies to date have suggested that population-based screening is not cost-effective, whereas targeted detection of AATD has been advocated by official society guidelines.

Efforts to enhance detection of AATD individuals have included various approaches, including educational campaigns, provision of free test kits, issuance of reminders with medical reports or within an electronic medical record, and empowering respiratory therapists to conduct testing for AATD in pulmonary function laboratories. Such programs have identified individuals with severe deficiency of alpha-1 antitrypsin in up to 12% of subjects, with considerable variation across series by testing criteria.

Overall, the persistence of under-recognition of AATD underscores the need for continued efforts to optimize detection of this potentially debilitating genetic disease.

Keywords :

• alpha-1 antitrypsin deficiency
• detection
• screening
• case-finding
• targeted detection

Introduction

Alpha-1 antitrypsin deficiency (AATD) is a relatively common but under-recognized condition (1–7). Even now, 50 years after the first description of AATD by Laurell and Eriksson (8), many individuals with AATD remain undiagnosed and affected individuals with AATD frequently experience long diagnostic delays and multiple visits to healthcare providers before initial diagnosis. Several lines of evidence support a strong imperative to make the diagnosis of AATD:

1. Because alpha-1 antitrypsin (AAT) deficiency is inherited as an autosomal co-dominant condition, family members of probands are at risk of having AATD and of developing associated disease;

2. Diagnosis of AATD can favorably affect smoking behaviors (9,10);

3. Because occupational dust exposure is associated with worsened clinical status in individuals with AATD (11), detection could affect occupational choice;

4. Specific therapy for AATD is available and has been recommended for individuals with emphysema due to AATD (1,2,12,13); and,

5. Official society guidelines endorse testing for AATD (1), establishing a standard of care that warrants compliance.

Given these imperatives to establish the diagnosis of AATD, it is important to recognize that not all individuals with severe deficiency AAT genotypes (e.g., PI*ZZ) develop attributable disease. For example, Tanash et al. (14) have shown that asymptomatic non-smoking PI*ZZ individuals who are detected by family testing experience normal survival rates.

In the context that it is important to diagnose AATD but that AATD remains under-recognized, this article will first review the evidence for under-recognition of AATD. Next, the results of various detection studies –using both population-based and targeted detection strategies –are reviewed, followed by a discussion of the reasons for persisting under-recognition. Finally, current strategies to enhance diagnosis of AATD are reviewed.

Evidence that alpha-1 antitrypsin deficiency is under-recognized

Two lines of evidence support the observation that AATD is under-recognized: 1. In all countries where the issue has been examined (15), only a small minority of expected individuals with AATD are clinically recognized, 2. Many patients with AATD experience long delays between their first symptom and initial diagnosis of AATD and require many encounters with healthcare providers before the diagnosis is made (5–7).

In the United States, of the estimated 70,000 –100,000 AAT-deficient Americans, fewer than 10% are estimated to have been diagnosed (1,2). In an early study assessing under-recognition in England, Tobin et al. (16) reasoned that asymptomatic, younger individuals with severe AATD might escape medical detection but that by age 45–54, most PI*ZZ individuals would have symptoms and would present to a pulmonologist. Yet, these investigators detected only 90 PI*ZZ individuals in the age range 45–54 years among a population predicted to include 2000 PI*ZZ individuals in that age range, suggesting that only 4.5% of AAT-deficient had been identified.

In an American study examining under-recognition, Silverman et al. (17) showed that only ∼4% of the AAT-deficient individuals in St. Louis were clinically recognized. Reasoning that having AATD neither predisposed toward nor against donating blood, they tested 20,000 blood specimens in the St. Louis blood bank and detected 7 individuals with PI*ZZ AATD. Extrapolating to the entire population of St. Louis (2 million at that time), they estimated that 700 AAT-deficient individuals lived in the area. Yet, when they systematically polled clinicians in St. Louis, only 28 of the expected 700 individuals (4%) were reportedly recognized.

Also, combining data from the Alpha-1 International Registry in 2007 (18) with data from the U.S. Alpha-1 Foundation Research Network Registry in 2000 (19), approximately 2350 registered individuals with the PI*ZZ phenotype were identified. Yet, concurrent genetic epidemiologic surveys from those countries estimated a prevalence of 100,000 PI*ZZ individuals (20), suggesting that only 2.4% of individuals from these 21 countries (on 4 continents) had been identified. Finally, in a review of international studies examining the frequency of expected vs. detected individuals with AATD, Luisetti and Seersholm (15) reported that only a small minority of the expected individuals had come to clinical attention (Table 1).

Table 1  Alpha-1 antitrypsin deficiency is. under-recognized

Country	Expected Cases*	Diagnosed Cases	% of Expected
Canada	42,372	144	0.69%
Italy	46,068	100	0.22%
Holland	9,740	136	1.4%
N. Zealand/Austria	33,707	93	0.28%
Spain	86,899	90	0.10%
Sweden	6,717	181	2.7%
United Kingdom	79,456	324	0.41%
Total	305,009	1,068	0.35%

*PI*ZZ and PI*SZ data on diagnosed from A.I.R. after Reference 15, with permission.

The second line of evidence supporting under-recognition of AATD is that individuals with AATD frequently experience long delays between developing symptoms and first being diagnosed. Also, affected individuals may see multiple physicians before the diagnosis of AATD is first made (4–7). In the earliest of several such studies (in 1994), Stoller et al. (5) surveyed 300 subscribers to an AATD newsletter who self-reported having PI*ZZ AATD. On average, the mean diagnostic delay interval (i.e., the time between reporting first symptom and being first diagnosed) was 7.2 ± 8.3 years. Furthermore, while 25% of respondents reported having the diagnosis of AATD made by the first physician they consulted for their symptoms, 43.7% reported seeing at least 3 physicians before initial diagnosis and 12% reported seeing 6–12 physicians.

Two later studies confirmed that similar under-recognition of AATD persisted a decade later (6,7). In a 2005 report, Stoller et al. (6) queried a cohort of 1953 AAT-deficient individuals regarding both the interval between experiencing their first symptom of AATD and initial diagnosis, and the number of physicians they saw before first being diagnosed. In keeping with the finding of under-recognition in the earlier 1994 study, the mean diagnostic delay interval was 5.6 ± 8.5 years, and AAT-deficient individuals diagnosed since the year 2000 reported seeing more physicians before initial diagnosis than AAT-deficient individuals diagnosed before 1980.

Trends over time actually suggested that the diagnostic delay interval was actually lengthening for more recently diagnosed individuals, thereby discounting any recent improvement in AATD detection (Figure 1). In a similar study by Campos et al. (7) based on a separate cohort of 1020 AAT-deficient individuals and also published in 2005, similar findings emerged. Specifically, the mean diagnostic delay interval was 8.3 ± 6.9 years, multiple physicians were seen before initial diagnosis (i.e., 20% saw at least 4 physicians before initial diagnosis), and the diagnostic delays seemed to increase rather than decrease for more recently diagnosed individuals.

Taken together, the available evidence shows that AATD is under-recognized, that under-recognition is an international challenge, and that under-recognition persists without any suggestion of more recent improvement.

The prevalence of alpha-1 antitrypsin deficiency

Various studies have examined the prevalence of AATD in many populations (1,2,21). In general, these detection efforts can be characterized as having one of two detection strategies –population-based screening and case-finding or targeted detection (4).

Population-based screening regards testing for AATD in a group for whom no increased suspicion of their having AATD exists. Examples of population-based screening strategies include testing consecutive newborns for AATD (4,9,10) or testing random visitors to a shopping mall or blood donors. In contrast to population-based screening, case-finding or targeted detection studies consist of testing populations whose clinical characteristics raise suspicion of AATD (4). Examples of targeted detection studies include testing patients with COPD for AATD, testing family members of AAT-deficient individuals, and testing individuals with panniculitis or C-ANCA positive vasculitis for AATD.

As presented in Table 2, many population-based screening studies for AATD have been conducted, of which the two largest consist of newborn screening studies performed in Oregon and in Sweden (9,10). In the former, O'Brien et al. (9) screened 107,038 infants with heel stick blood specimens. They detected 32 newborns with two or more abnormal screening tests: 21 with homozygous deficient genotypes (PI*ZZ or PI*Z Null) and 11 heterozygotes for variant genotypes (including PI*MZ, PI*SZ and unspecified others). Overall, the results suggested a prevalence of severe deficiency of AAT of 1/5097.

Table 2.  Prevalence of specific AATD phenotypes in selected population screening studies

Main Language Origin* First Author (Ref)	Year	Location	Subject Population	Number Screened	Prevalence of Selected AAT Genotype (%)
					ZZ	SZ	MZ	SS	MS
Western Slavic
Kaczor (45,46)	2007	Poland	Random sample	859	0	0	2.10	0.12	3.26
Uralic
Saris (47)	1972	Finland	College	664	0.15	–	5.12	–	–
Northern Germanic
Sveger (10)	1976	Sweden	Newborns	200,000	0.06	0.02	–	–	–
Sveger (48)	1979	Sweden	Military recruits	11,128	0.04	0.08	0.03	–	–
Dahl (49)	2002	Denmark	Random sample	9,187	0.07	0.11	4.90	0.13	5.00
Western Germanic
Hoffman (50)	1976	Netherlands	Population survey	1,474	0.07	0.07	2.24	0	2.84
Dijkman (51)	1980	Netherlands	Newborns	95083	0.03	–	–	0.04	–
Kimpen (52)	1988	Belgium	Newborns	10,329	0.06	0.12	0.97	0.01	0.88
Cook (53)	1975	United Kingdom	Population survey	5,588	0.04	0.21	2.02	0.32	7.19
Webb (54)	1973	New York	Population survey	500	0	0	3.6	0.2	6
Lieberman (55)	1976	California	High school	1,841	0	0.27	1.85	0.05	6.90
Evans (56)	1977	New York	Newborns	1,010	0	0	1.19	0.89	3.07
Morse (57)	1977	Arizona	Population survey	2,944	0.07	0.20	3.0		7.1
O'Brien (9)	1978	Oregon	Newborns	107,038	0.02	0.01		–
Dykes (58)	1984	Minnesota	Blood donors	904	0	–	2.77	0.22	4.09
Silverman (17)	1989	Missouri	Blood donors	20,000	0.04	0.01	0.01
Spence (59)	1993	New York	Newborns	11,081	0.03	0.05	0.53	0.01	0.09
Eastern Romanic
Klasen (60)	1978	Italy	Outpatients	202	0	0	1.98	0	4.95
Corda (61)	2011	Italy	Town screening	817	0.12		5.6	0.12	6.3
Western Romanic
Goedde (62)	1973	Spain	Population survey	576	–	–	1.04	–	22.7
Spínola (63)	2009	Madeira	Volunteers	200	0	1	4	3	29
Spínola (64)	2010	Cape Verde	Volunteers	202	0	0	0.5	1.49	3.5
Afro-Asiatic
Vandeville (65)	1973	Zaire	Population survey	132	0	0	0	0	0
Massi (66)	1977	Somalia	Newborns	347	0.86	0.28	0.28		2.59
Aljarallah (67)	2011	Saudi Arabia	Volunteers	158	0	3.8	2.53	1.9
Altaic
Harada (68)	1977	Japan	Blood donors	856	0	0	0.23	0	0.23

* Classification is based on the notion that linguistic phyla align with genetic clusters, reflecting their common origins.

From Reference 2, with permission.

In the larger Swedish study, Sveger (10) screened 200,000 infants who represented 95% of all infants born in Sweden between November 1972 and September 1974. Of the 200,000 newborns who were screened, 127 PI*Z and 48 PI*SZ individuals were found, suggesting a prevalence of 1/1639. Combining the results of both large population-based screening studies yields a frequency estimate of 1/4,455 which, when applied to a United States population of ∼310,000,000, suggests that there are approximately 70,000 Americans with severe AATD.

As reviewed in Table 3, many targeted detection studies have been undertaken and have used a variety of specific testing and programmatic approaches. Studies vary with regard to the types of patients tested (e.g., COPD of varying severities, bronchiectasis, asthma, vasculitis, pneumothorax, etc.), the specific assay used, whether studies were conducted at a single or at multiple centers, and whether or not the detection program was linked with a campaign to enhance patient awareness of AATD.

Table 3.  Results of targeted detection studies for alpha-1 antitrypsin deficiency

First Author (Reference)	Detection Strategy	Number of Patients	Prevalence of Specific AAT Phenotype (%, N)
			PI*ZZ	PI*SZ	PI*MZ	PI*SS	PI*MS	Other
Wencker (69)	Targeted detection (Patients with COPD, emphysema, asthma, or bronchiectasis)	1060 evaluable samples from 1156 (Germany)	0	0.2% (N = 3)	3.7% (N = 39)	0.09% (N = 1)	3.4% (N = 36)	PI*M Null –0.09% (N = 1)
Bals (70)	Case-finding linked to an AATD awareness program	2696 (Germany)	9.9% (N = 268)	2.0% (N = 53)	18.1% (N = 488)		3.6% (N = 97)	Rare phenotypes –0.5% (N = 13)
de la Roza (71)	Case-finding (Patients with COPD)	2137 (Spain)	0.37% (N = 8)	0.14% (N = 3)		0.14% (N = 3)
Corda (72)	Case-finding (Emphysema without risk factors or of early-onset, spontaneous pneumothorax, cervical artery dissection, PAS positive bodies in liver, isolated transaminase elevation, ANCA positive, or low alpha-1 proteins on protein electrophoresis)	285 specimens collected over 9 years (Italy)	12% (N = 26)	8% (N = 17)	62% (N = 131)		14% (N = 29)	PI*ZI 0.35% (N = 1)PI*ZMmalton –0.35% (N = 1)PI*MMmalton 2.1% (N = 6)
Brantly (38)	Case-finding (Targeted detection in COPD with education program and free testing)	969 (Florida)	3.2% (N = 31)	0.4% (N = 4)	11% (N = 107)
Luisetti (73)	Case-finding (missing or reduced alpha-1 globulin band, early onset emphysema, familial cluster, first degree relative of subjects with ascertained AATD or MZ heterozygosity)	1841 (Italy)	6.4% (118)	0.9% (17)				Null Null 0.4% (8)Z null 0.2% (4)Rare variants 0.2% (4)
Matzen (74)	Case-finding (individuals with abnormal PFTs)	225	0		2.7% (N = 6)		7.1% (N = 16)	PIFF 0.4% (N = 1)
Lieberman (22)	Case-finding (Patients with advanced COPD admitted for carotid body surgery)	965	1.9% (N = 18)	0.3% (N = 3/965)	7.7% (N = 74/965)	0.3% (N = 3/965)	10.1 (N = 75/742)
Rahaghi (33)	Case-finding	29	0		1
Jain (34)	Case-finding (Physicians receiving results of pulmonary function tests showing fixed airflow obstruction were prompted in the electronic medical record to test for AATD)	624 (baseline) vs. 979 (after implementing the electronic alert)	1/38 whose phenotype was checked after implementing rge electronic alert	0	1/38	0	2/38	No difference in the rate of detecting AAT deficient patients (serum level <100 mg/dl) before (8.9%) vs. after (5.3%) implementing the electronic alert

Legend: PAS - periodic acid-Schiff.

ANCA - antineutrophil cytoplasmic antibodies.

From: Reference (4), with permission.

In an early study of COPD patients receiving care at the Sepulveda Veterans Administration Hospital, Lieberman et al. (22) performed AAT testing (with a trypsin inhibitory capacity assay) in 965 consecutive Veterans attending the COPD Clinic. Individuals with the PI*ZZ phenotype comprised 1.9% of the COPD patients who were tested.

Taken together, the range of prevalence estimates among these targeted detection studies was 0 to 12% for PI*ZZ individuals and 0 to 2.0% for PI*SZ individuals (Table 3).

Reasons that alpha-1 antitrypsin deficiency is under-recognized

Although no systematic study of the reasons that AATD is under-recognized has been conducted, at least three factors seem likely to contribute:

1. Awareness of AATD and of its clinical manifestations by healthcare providers is inadequate (4,23);

2. Even in the face of evidence-based guidelines that are based on rigorous research, physicians frequently fail to implement evidence-based recommendations (24–26); and,

3. Physicians may be ìtherapeutic nihilistsî regarding AATD, i.e., because they may doubt that available specific therapy is effective (i.e., augmentation therapy), they therefore believe that testing is not warranted (or even that it might do harm by surfacing a diagnosis that could prompt psychologic harm to the patient or to a family member).

In fact, regarding the first factor, evidence does demonstrate that physicians and allied health providers’ knowledge of AATD is inadequate. Specifically, in a study of 202 responding respiratory therapists (RTs) and internal medicine residents (61% response rate), Taliercio et al. (23) administered a 30-item email questionnaire regarding AATD; 10 questions specifically regarded recognizing the clinical manifestations of AATD and how and when to test. Overall performance on the examination was poor (54% and 52% correct responses for the internal medicine trainees and RTs, respectively).

Performance on the 10 questions specifically regarding recognition and diagnosis of AATD was slightly better but still mediocre (63% and 61%, respectively) and there was no evidence of a trend suggesting improved performance by year of training seniority among the internal medicine residents. Overall, the results support the opportunity and need for enhanced education regarding AATD and suggest that inadequate knowledge might contribute to under-recognition of AATD. The implication is that better educating healthcare providers of all types can enhance detection of individuals with AATD.

Although direct evidence demonstrating explicit disregard of guidelines that recommend AATD testing by physicians is not available, the fact that under-recognition of AATD persists even after the publication of guidelines (from the American Thoracic Society and European Respiratory Society [1]) that strongly endorse testing for AATD in all symptomatic adults with COPD is suggestive.

Furthermore, disregard for evidence-based guidelines or for treatments that have been shown to enhance survival has been shown in the management of many conditions, including the acute respiratory distress syndrome (24) and deep venous thrombosis prophylaxis (25). Again, underlying reasons for persisting failure to implement guidelines regarding AATD testing include lack of awareness of the evidence or disbelief in the conclusions of published reports.

Finally, although evidence that therapeutic nihilism contributes to under-recognition of AATD is only anecdotal, the frequency with which colleagues have expressed this view regarding testing for AATD suggests that nihilism may contribute importantly to under-recognition of AATD.

Strategies to enhance detection of individuals with alpha-1 antitrypsin deficiency

In the face of longstanding and persisting under-recognition of AATD, a variety of novel strategies have been undertaken to try to enhance recognition of AATD (4). These include: campaigns to enhance awareness of AATD among primary care physicians and respiratory therapists (27–29) using a variety of media, including targeted publications (27–29); presentations at grand rounds and at national meetings, and in web-based instructional programs (30); distributing free test kits for AATD and providing free, confidential home-based testing for AATD (31,32); evolving interest in developing a rapid point-of-care test for AATD; issuing written recommendations to physicians to test for AATD in the written results of pulmonary test reports (33); using clinical decision support within an electronic medical record to prompt physicians to test for AATD in appropriate clinical settings (34); and renewing consideration of widespread, mandatory newborn screening for AATD (35). Several of these strategies warrant further discussion.

As an example, based on reasoning that many patients with COPD do not see pulmonologists but may encounter RTs while undergoing pulmonary function tests or during pulmonary rehabilitation and that the number of RTs in the United States far exceeds the number of pulmonologists, the American Association for Respiratory Care and the Alpha-1 Foundation have recently launched a web-based educational program for RTs that certifies participants as having special AATD expertise (28). Although the program is too new to fully assess any impact on AATD detection, the hope is that by developing an AATD-informed community of RTs, testing for AATD and recognition of affected individuals by RTs and by the physicians with whom they practice will increase. In the first 5 months since program launch, ∼200 RTs had enrolled in the program (36).

To eliminate cost barriers to AAT testing, several manufacturers of augmentation therapy drugs have distributed free test kits for AAT serum levels and genotyping to clinicians. Laboratory testing for one of these programs is performed by the University of Florida Alpha-1 Antitrypsin Genetics Laboratory. In a national detection program sponsored by Grifols, USA, 117,966 individuals have been tested for AATD. From this total, abnormal genotypes have been detected as follows: 843 PI*ZZ, 593 PI*SZ, and 6859 PI*MZ.

The University of Florida Alpha-1 Antitrypsin Genetics Laboratory offers 2 other AATD testing programs which are supported by the Alpha-1 Foundation (37). The first of these programs provides free, confidential AAT testing through an ethics board-approved study entitled the Alpha-1 Coded Testing (ACT) and is administered by the Medical University of South Carolina (32). Individuals enrolled in the program receive a dried blood spot test kit mailed to their home and then submit a specimen for coded testing through the University of Florida Alpha-1 Antitrypsin Genetics Laboratory. The participating individual receives the results in a simple, written explanation with an offer for free telephone-based genetic counseling.

To date, 15,445 individuals have been tested through this program, of whom 450 are PI*ZZ, 392 are PI*SZ and 5102 are PI*MZ. This program has been extensively used for family testing and a number of rare variants of AAT have been identified. Importantly, both of these testing programs involve both determining the subject's AAT serum level and genotype, thereby allowing heterozygotes to be detected. Because the AAT serum levels of PI*MZ heterozygotes overlap the normal range of serum AAT levels, measuring serum levels alone would cause many heterozygotes to remain undetected. Although some might argue that failure to detect PI*MZ heterozygotes does not incur risk because PI*MZ heterozygotes are not deemed to be at increased lung risk overall, the possibility that some subsets of heterozygotes are at increased risk for emphysema and liver disease favors genotyping as well.

The third University of Florida Alpha-1 Antitrypsin Genetics Laboratory program to facilitate widespread testing for detection of AATD individuals is a State of Florida-funded, Alpha-1 Foundation-sponsored, statewide detection program which has provided free testing since 2003 (38). Over the first 9 years of the program (to July 2012), 17,567 individuals have been tested among whom individuals with abnormal genotypes have been found as follows: 120 PI*ZZ, 100 PI*SZ, and 796 PI*MZ.

In total, 150,978 individuals have been tested in the University of Florida Alpha-1 Antitrypsin Genetics Laboratory over the past 8 years and 1:9.9 of these individuals have been found to be either PI*MZ, PI*SZ, or PI*ZZ. Of particular importance are the identification rates for abnormal AAT genotypes in the individual programs. The detection rate in the State of Florida and National Detection programs for PI*MZ, PI*SZ, or PI*ZZ individuals are 1:16 and 1:14, respectively.

In the ACT program, the detection rate is 1:2.6, consistent with the observation that family testing is the most efficient approach for identifying at-risk AATD alleles. In this regard, testing all family members of a detected AATD individual is recommended as an efficient way to enhance detection of deficient individuals. With all available programs taken together, the Alpha-1 Foundation- sponsored University of Florida Alpha-1 Antitrypsin Genetics Laboratory currently tests >45,000 individuals per year, of whom >8% have been either PI*SZ, PI*MZ, or PI*ZZ.

As another strategy to enhance clinicians’ awareness of and testing for AATD, Rahaghi et al. (33) appended written suggestions to test for AATD to the pulmonary function test reports of patients found to have fixed airflow obstruction at Cleveland Clinic Florida. In a before-after study of this intervention, the rate of testing for AATD was higher after the written suggestions were issued than before (13% vs. 6%), though the absolute rate of testing remained low and no patient with severe AATD was detected during the study.

As an extension of the strategy to prompt physicians to follow guidelines to test all COPD patients for AATD, Jain et al. (34) developed a clinical decision support tool within an electronic medical record at Cleveland Clinic (Ohio) that prompted physicians to test for AATD when results of pulmonary function tests showed fixed airflow obstruction. The use of the electronic alert was associated with a four-fold increased rate of testing for AATD (15.1% of at-risk patients after implementing the clinical decision support vs. 4.7% before, p < 0.001), though neither the rate of detecting AAT-deficient individuals (5.3% after vs. 8.9% before) nor the rate of detecting PI*ZZ individuals specifically (2.6% after vs. 3.2% before) increased.

Possible explanations for failure of the clinical decision support tool to increase detection of severely AAT-deficient individuals include: the coexistence of a co-morbid condition that could otherwise cause airflow obstruction (e.g., congestive heart failure, sarcoidosis, etc.), thereby causing clinicians to defer testing for AATD; the fact that the study was conducted in a center where the baseline rate of detecting PI*ZZ individuals already exceeded that in many targeted detection studies, thereby precluding increased detection; electronic alert fatigue by physicians (39,40); and physicians’ aversion to follow recommendations from clinical decision support tools on the premise that they challenge clinical autonomy (26).

A second study using the electronic medical record to prompt physicians’ testing for AATD has been performed at the Miami Veterans Administration Medical Center in Miami, Florida by Campos et al. (41). With an electronic clinical reminder that prompted ordering spirometry in patients deemed at risk for COPD based on a population screener and subsequent testing for AATD (in those found to have COPD), 72% of the 734 patients with confirmed COPD underwent testing for AATD. Another preliminary report by Choudry et al. (42) described using an electronic medical record to identify patients with COPD and then inviting these patients to participate in 2 scheduled testing days. Of the 1247 patients with COPD who were invited, 109 (8.7%) appeared for testing, of whom 1 (0.9%) was found to be PI*ZZ (serum AAT level 4.8 mg/dl) and 6 (5.5%) were found to be AAT heterozygotes (3 PI*MS and 3 PI*MZ).

Finally, in the context that gene chips allow testing for a variety of genetic predispositions to disease and are becoming more affordable, renewed discussion about the role of newborn testing for AATD is ongoing. Discordant recommendations regarding newborn screening for AATD have been voiced. On the one hand, a memorandum from the World Health Organization summarizing a meeting of AATD thought leaders recommended neonatal screening: ìNeonatal AAT screening programmes should be undertaken in all developed countries with Caucasian populations; limited programmes of neonatal screening should be undertaken in developing countries to determine the frequency of genes leading to deficiency and the burden of resulting disease in these populationsî (43).

On the other hand, O'Brien et al., who had conducted a neonatal screening trial in Oregon in 1978, recommended against such screening: ìNewborn screening for alpha-1 antitrypsin deficiency is not warranted at this time in view of the low frequency of significant pulmonary or hepatic involvement in childhood and the absence of specific therapy for this conditionî (44). Most recently, the Alpha-1 Foundation convened a workshop to examine the issues regarding neonatal screening for AATD (34). A summary of the proceedings of the workshop stated ìThere is insufficient knowledge of the benefit/risk ratio of newborn testing at this time.

It is recommended that pilot studies should be conducted to determine if early detection improves outcomes. Possible themes for pilot studies could include defining risk to benefit to risk ratio, and analyzing psychosocial and financial costs of early detection. A pilot study in different age cohorts could be done to analyze smoking prevention and parental smoking cessation correlating to prevention of lung disease. A pilot study analyzing liver disease management would also be beneficial, especially in children.

In summary, AATD remains under-recognized currently and strategies to enhance detection are needed, especially in the context that new and emerging therapies for the associated lung and liver diseases are likely to change the treatment landscape soon.

Declarations of Interest Statement

Dr. James K. Stoller has served as a consultant for Grifols, Talecris, Baxter, CLS-Behring, and Kamada. He has also received grant funding from the Alpha-1 Foundation. Dr. Mark Brantly receives grant and contract funding for screening for AAT deficiency from the Alpha-1 Foundation, Grifols Ltd., and NIH.

The authors alone are responsible for the content and writing of the paper.

Acknowledgements

The authors thank Dr. Michael Campos for providing updated data regarding his experience in targeted detection for AATD using an electronic medical record (reference 41).