Physician Alert Suggesting Alpha-1 Antitrypsin Deficiency Testing in Pulmonary Function Test (PFT) Results

Abstract

Alpha-1 antitrypsin deficiency (AATD) is under-recognized by clinicians, with long diagnostic delays between patients' first symptom and initial diagnosis. Recent recommendations by official societies encourage testing for AATD in all symptomatic adults with spirometric evidence of COPD, though compliance with this recommendation has been variable. For 6 months, the following physician alert was added to PFT reports of patients with airflow obstruction of GOLD Stage II or higher: “The American Thoracic Society recommends testing for AATD in all patients with FEV1 < 80% predicted and FEV1/FVC less than 0.70, if clinically indicated. Appropriate counseling suggested.” During the “Pre-alert Period,” 821 spirometry tests were performed; 178 of these 821 unique patients (22%) satisfied spirometric criteria of > GOLD Stage II and 11 (6%) were tested for AATD. In contrast, during the “Physician Alert” intervention period, 689 spirometry tests were performed on 689 unique patients, of whom 140 (20%) satisfied criteria for > GOLD II airflow obstruction; AAT testing was done more frequently (18 [13%], p = 0.04). The overall rate of misclassifying patients' reports for testing by the respiratory therapists was very low (3.3%). An analysis of “number needed to test” suggests that 98–290 patients must be tested to have 95% certainty to identify a single patient with severe AATD. In conclusion, implementing a physician alert on PFT reports of patients with COPD can increase physicians' testing for AATD. The incomplete rate of testing suggests the need for additional strategies to enhance clinicians' detection of individuals with AATD.

Key words: :

• Alpha-1 antitrypsin deficiency
• Pulmonary function test
• Screening
• Testing
• Respiratory therapy
• Probability

INTRODUCTION

Severe deficiency of Alpha 1 antitrypsin (AAT) predisposes to emphysema and obstructive lung disease ([1], [2], [3], [4], [5]).Alpha-1 antitrypsin deficiency (AATD) is clinically under-recognized, with evidence of long diagnostic delays between patients' first symptoms and initial clinical recognition and multiple physician visits before initial recognition of AATD ([6], [7], [8]). In the context of such severe under-recognition and the availability of specific therapy for AATD ([3], [4]), official societies (i.e., the American Thoracic Society, European Respiratory Society, American College of Chest Physicians, American Association for Respiratory Care, and Canadian Thoracic Society) have endorsed guidelines which recommend testing all symptomatic adults with airflow obstruction on pulmonary function tests for AATD ([3], [9]). In attempting to enhance detection of AAT deficient individuals, various strategies have been undertaken, including:

• The publication and distribution of management guidelines by official medical societies ([3], [9]),

• Extensive inclusion of AATD in continuing medical education programs,

• Availability of free test kits for AAT serum levels and phenotypes by various groups (e.g., the Alpha-1 Foundation and several drug manufacturers),

• Pilot programs for testing newborns for AATD (akin to routine testing for phenylketonuria and congenital hypothyroidism) ([10], [11]), and

• Identification of individuals with airflow obstruction at the time of lung function testing to offer testing for AATD.

Another potential strategy to enhance detection of individuals with AATD is to prompt and/or facilitate the patient's managing physicians to order a serum level for AAT when the results of pulmonary function tests showing airflow obstruction are reported to the ordering clinician. The current study reports the results of an initial experience in which a reminder to test for AATD was included in the pulmonary function test report of airflow obstruction returned to the ordering physician. The hypothesis was that inclusion of such a reminder would enhance both the frequency of testing for AATD and the detection of individuals with AATD.

METHODS

This study was approved by the Institutional Review Board at the Cleveland Clinic Florida.

The study was conducted during two intervals at the Cleveland Clinic Florida:

1. A “Pre-alert Period” (11/1/2005–5/1/2006) in which results of spirometry testing were returned to the managing physician in the usual way, i.e., copies of the pulmonary function test report results were sent to the referring physician with the usual physiologic description of the spirometry results but with no text suggesting testing for AATD, and

2. A “Physician Alert” intervention period (7/3/06–1/03/2007) in which the PFT reports of individuals with airflow obstruction (defined as GOLD Stage II or higher [i.e., FEV1/FVC < 0.70 with FEV1 < 80% predicted on the post-bronchodilator spirometry] were accompanied by the following text, inviting the referring physician to send a test for the AAT serum level as a test for AATD ([12]): “The American Thoracic Society recommends testing for alpha-1 antitrypsin deficiency in all patients with FEV1 < 80% predicted and FEV1/FVC less than 0.70, if clinically indicated. Appropriate counseling suggested.”

All pulmonary function tests were performed at the Pulmonary Function Laboratory at the Cleveland Clinic Weston (Florida) using spirometric techniques consistent with American Thoracic Society guidelines ([13]). Spirometry was performed both before and again after administering inhaled albuterol to assess reversibility of airflow obstruction.

Pulmonary function test reports during the Physician Alert period were uniformly reviewed by one of 2 respiratory therapists for inclusion of the alert and notification of the ordering physician. The decision to include the alert was reviewed by one of the investigators to validate inclusion or exclusion. Results of spirometry were returned to the ordering physicians, all of who were members of the Staff at the Cleveland Clinic Florida, via hospital mail. All patients were seen at the Cleveland Clinic Florida and were under the care of staff physicians there. For all patients with airflow obstruction on spirometry results, an exhaustive search was undertaken to ascertain evidence that specimens were sent for AAT deficiency testing, Specifically, multiple sources were interrogated for any evidence of AAT testing (serum levels, phenotype, and/or genotype testing), including the laboratory at the Cleveland Clinic Florida, the Alpha-1 Antitrypsin Center in the University of Utah Health Sciences Center (Salt Lake City, Utah) and the Alpha-1 Foundation-funded laboratory at the University of Florida (Gainesville, FL).

To avert bias related to alpha-1 antitrypsin testing by the investigators, tests ordered by the lead investigators (FR, IO) were excluded. As the study was not discussed with other pulmonologists or clinicians at the Cleveland Clinic Florida, their testing practices were considered unbiased. Also, to avert external influences on testing, all educational efforts regarding alpha-1 antitrypsin deficiency were suspended and pharmaceutical representatives refrained from visiting the Cleveland Clinic or distributing promotional materials during the study interval.

Statistical analysis was conducted using Microsoft Excel, 2003 with Statistical Package. Values of p < 0.05 were considered statistically significant. Calculation of the “number needed to test” was performed using algebraic probability calculations, modeled in Microsoft Excel 2003 (Microsoft Corporation, Seattle, WA)

RESULTS

Spirometry test results of 1510 patients were included in the 2 study periods, 821 in the Pre-Alert Period and 689 in the Physician Alert intervention period. In the Pre-Alert Period, 178 of the 821 unique patients tested (22%) had evidence of airflow obstruction of GOLD Stage > II on post-bronchodilator spirometry, whereas in the Physician Alert Period, 140 of the 689 (20%) had evidence of airflow obstruction on spirometry. Table 1 presents the characteristics of the patients with airflow obstruction in both study intervals. Patients in both groups were similar with moderately severe airflow obstruction (i.e., GOLD Stage II with mean FEV₁% predicted [53.7% predicted and 54.6% predicted]).

Table 1 Characteristics of patients with airflow obstruction (of GOLD stage > II on post-bronchodilator spirometry) in the “pre-alert period” and the “physician alert” intervention period

Patient Characteristics	“Pre-Alert Period”, N = 178 Patients	“Physician Alert Period”, N = 140 Patients
% Male	56%	58%
Age (Mean ± S.D.)	68.7 ± 12.7	68.1 ± 12.4
FEV1 % Predicted (Mean ± S.D.)	53.7 ± 14.6	54.6 ± 16.5
FVC % Predicted (Mean ± S.D.)	65.8 ± 12.3	63.6 ± 14.6
FEV1/FVC (Mean ± S.D.)	56.9 ± 10.6	58.7 ± 10.1
Pack-Years of Smoking (Mean ± S.D., [Range 0-200]	40.4 ± 41.1	39.6 ± 34.1
White	144 (80.1%)	109 (77.8%)
Black	4 (2.2%)	4 (2.9%)
Hispanic	11 (6.2%)	9 (6.4%)
Other	19 (10.7%)	18 (12.9%)

Table 2 presents the monthly and overall rate of misclassifying reports during the Physician Alert Period (either including reports without cause or excluding eligible reports.). The two respiratory therapists performing this activity had a low misclassification rate (3.3% overall).

Table 2 The monthly and overall rate of misclassifying spirometry reports for inclusion of the physician alert during the physician alert period

Month	Misclassification Rate
1	11.0%
2	1.4%
3	0.8%
4	0.7%
5	2.2%
6	3.8%
Average	3.3%

Of these 178 patients with airflow obstruction in the Pre-Alert Period, 11 (6%) underwent testing for AATD based on the review of multiple test sources as described above.

In contrast, in the Physician Alert Period, of the 140 patients with airflow obstruction, testing for AATD was more frequent than in the Pre-Alert Period (N = 18 (13%), p = 0.04 versus the Pre-Alert Period). However, in neither the Pre-Alert nor the Physician Alert period was a patient with severe AATD (e.g., PI*ZZ) detected. One patient with PI*MZ was detected in the Physician Alert period.

To better understand the number of patients needed to test for AATD before a severely deficient individual would be detected, we evaluated the “number needed to test” over a range of assumptions about the prevalence of severe deficiency of AAT and probabilities of detecting a severely deficient individual. This analysis (Table 3) suggests that between 298 and 98 patients must be tested to achieve 95% confidence of detecting one severely AAT deficient individual in a population in which the prevalence of severe AATD is 1% to 3%. In the current study, assuming a population prevalence of severe AATD of 2% ([14]), the likelihood of detecting a patient with severe AATD after testing 29 individuals (as was done in this study) was 44%.

Table 3 Number of tests needed to identify a severely deficient AATD patient at 95% certainty, based on various estimates of the prevalence of severe AATD among patients with COPD

Estimated prevalence of severe AATD among patients with COPD	1.00%	1.50%	2.00%	2.50%	3.00%
Average number of tests needed (1/Prevalence of severe AATD among COPD patients)	100	67	50	40	33
Number of tests needed to be sent to identify a single individual with severe AATD with 95% confidence	298	198	148	118	98

DISCUSSION

The main finding of this initial study is that including a physician alert advising testing for AATD to accompany pulmonary function test reports of patients with airflow obstruction was associated with an increased frequency of testing for AATD by the managing physician. However, issuance of a physician alert was associated with only a modest increase in the frequency of testing and still only a minority of candidate patients were tested. Also, in this study with relatively few tested patients (total of 29 patients in both groups), no patient with severe AATD was detected with the model predicting only a 44% likelihood of detecting an individual in the population under these conditions.

In the context of the “number needed to test” calculation in which 148 patients are needed to test for AATD before a single individual with severe AATD is detected with 95% confidence (given a 2% midrange estimate of the prevalence of severe AATD in COPD patients), the failure to identify a single severely AAT deficient patient in this series is perhaps not surprising; only 11 and 18 patients, respectively were tested for AATD in the Pre-Alert and Physician Alert Periods.

Our results suggest that physician alerts can enhance diagnostic suspicion of and testing for AATD and justify additional, confirmatory studies to explore strategies to increase the frequency of testing yet further. While awaiting confirmatory studies that are currently under way (Zamudio J, Alpha-1 Foundation, personal communication), we believe that directors of pulmonary function laboratories should consider including physician alerts encouraging testing for AATD, such as the one included in this study, with eligible reports of pulmonary function tests.

Indeed, this practice complies with the recommendation (made in the evidence-based systematic review on AATD endorsed and published by the American Thoracic Society and European Respiratory Society as well as the American College of Chest Physicians and the American Association for Respiratory Care) ([3]) that all symptomatic adults with airflow obstruction should undergo testing for AAT deficiency. Other strategies currently being investigated to enhance physicians' testing for AATD include inviting patients with airflow obstruction on pulmonary function testing to undergo testing for AATD at the time of pulmonary function testing and using an electronic medical record to send a prompt to the ordering physician whenever obstruction on pulmonary function testing is observed. In the context that AATD is severely underrecognized with most patients currently escaping diagnosis ([6], [7], [8]), recommendations regarding the ideal strategy to enhance testing for AATD must await the results of these additional investigations and others.

However, we believe that the current results support including physician alerts as one of a potential list of interventions to increase testing for AATD and helping to identify the population of currently unrecognized individuals, especially because specific therapy for severe AATD is available and has been recommended ([3], [9]). Notably, such testing is facilitated by the availability of free test kits that are sent to and analyzed by high-quality laboratories.

Several shortcomings of the current study warrant mention. First, the relatively small number of patients included in this study and the fact that the study was conducted in only a single institution may threaten the generalizability of these findings. As noted, the small number of patients actually tested for AATD, even in the context that a physician alert was associated with enhanced testing for AATD in this study, certainly offers a plausible explanation as to why no patient with severe AATD was identified.

Whether a strategy of physician notification will actually help identify patients with severe AATD, the important goal of such testing, must await the results of larger studies that are currently being initiated. Certainly, our analysis of “number needed to test” and the finding that it is necessary to test a large number of individuals before confidently identifying a single severely deficient individual reinforces the importance of persistent, routine testing of COPD patients, as recommended by official guidelines ([3]). This analysis of number needed to test also offers an explanation as to why physicians may express frustration at the perceived futility of testing and provides further evidence to support the practice of routine case-finding testing in symptomatic patients with COPD.

Another potential shortcoming of the study is that the “before-after” design leaves open the possibility that the increase in the frequency with which managing physicians tested for AATD related to change in practice over time rather than to the specific intervention of including the alert with the pulmonary function test report. Certainly, a randomized controlled trial with concurrent controls could offer firmer evidence of effectiveness. Still, the relatively short time interval between the Pre-alert Period and the Physician Alert Period leads us to believe that time-related changes in practice are unlikely to explain the observed increase in testing for AATD and that the increase is attributable to issuing the physician alert. At the same time, it is noteworthy that although the frequency of testing for AATD increased in the Physician Alert Period, the absolute frequency of testing for AATD (13%) remained low in the Physician Alert Period, emphasizing the importance of exploring still other interventions to increase testing. Again, the results of ongoing studies regarding direct patient invitations to be tested at the time of pulmonary function testing and physician prompts in the electronic medical record may offer additional insights about other strategies to increase testing.

A third shortcoming is that use of the GOLD criteria of FEV₁/FVC < 0.70 as the criterion for airflow obstruction has been suggested to overlook young individuals with airflow obstruction the very group in which suspicion of AAT would be especially high ([15]). Some might argue that a criterion of FEV1/FVC below the 5th percentile would be the preferred criterion.

In conclusion, the current study suggests that physician alerts accompanying pulmonary function test results showing airflow obstruction can enhance physicians' testing for Alpha 1 antitrypsin deficiency, though the frequency of testing even with such alerts remained low. These results invite ongoing consideration of other strategies to enhance diagnostic suspicion of and testing for this persistently underrecognized condition.

ACKNOWLEDGMENT

The authors would like to acknowledge Jorge Zamudio, M.D. from the Alpha-1 Foundation for his contributions to the evolution of the concept of numbers needed to find an AATD patient.

Supported by Cleveland Clinic Florida Alpha-one Educational Fund, supported in part by Baxter Healthcare and CSL Behring, Inc.

Disclosure: Dr. Stoller has served as a consultant for Talecris Biotherapeutics and has received speaker's fees from Talecris Biotherapeutics, Baxter Healthcare, Grifols, Inc., and CSL-Behring, Inc. Dr. Rahaghi has served as a consultant for and has received speaker's fees from Baxter Healthcare and CSL-Behring, Inc. None of the other authors has actual or potential conflict of interest in the subject matter in this manuscript.