Where Are They? Patients with Alpha-1 Antitrypsin Deficiency (Podcast)

Although the genetic condition, Alpha-1 Antitrypsin Deficiency (AATD), is fairly common in the United States, affecting an estimated 100,000 Americans, its presentation and diagnosis remain low. AATD is inherited and is associated with several lung conditions, including lung disease, emphysema and COPD. Those affected are also predisposed to an inflammatory skin condition called panniculitis. AATD is also associated with C-ANCA vasculitis.

“Of the 100,000 Americans we estimate to have AATD, fewer than 12,000 are clinically recognized, leaving the majority of affected individuals and their family members, because this is a genetic disease, unrecognized,” says James Stoller, MD, Chairman of the Education Institute at the Cleveland Clinic, on a recent episode of Respiratory Exchange. “Some of those patients go through life unaffected, particularly if they don't smoke. But there are many patients who we see in clinic who are afflicted by COPD or liver disease, who actually have unrecognized AATD.”

There are several reasons for this discrepancy, according to Dr. Stoller. Although 15 international guidelines on AATD recommend testing patients with fixed airflow obstruction on pulmonary function tests for AATD at least once in their lifetime, many providers are slow to come around on guideline implementation.

He also points to a sense of therapeutic nihilism and the idea that there is no effective therapy and a hesitancy to burden patients with the psychological aspects of a genetic disease.

“This is not true because there are effective therapies,” says Dr. Stoller. “Importantly, we are on the doorstep of a number of very innovative treatments that will likely come into the armamentarium in our lifetimes.”

Beyond the reasons for the lagging diagnoses of AATD, Dr. Stoller discusses several other aspects of the condition in the episode. These include:

• The underlying pathogenesis of AATD and how it occurs.
• The presentation of AATD in patients and what to look for.
• The progression and natural history of the condition in patients.
• The impact of smoking on AATD.
• Available tests to help diagnose potential cases and suggestions for testing effectively and efficiently.
• Therapies to treat and manage AATD.
• Genetic implications for family members of patients with AATD.

Click the podcast player above to listen to the episode now, or read on for a short, edited excerpt. Check out more Respiratory Exchange episodes at https://my.clevelandclinic.org/podcasts/respiratory-exchange or wherever you get your podcasts.

Podcast excerpt

Dr. Stoller: Well, at the end of the day, every patient with COPD should be tested. Now, when we read textbooks, we're used to thinking of alpha-1 presenting in a young never-smoker with lower lobe emphysema as the classic clinical picture. And while those are characteristic features, I will tell you that if you depend on those clinical criteria to hone your testing, you will miss most of the patients.

We know, as part of this under-recognition, for example, that patients — we studied this years ago and it regrettably remains true today — that these patients will spend about six to eight years from the initial onset of dyspnea to initial recognition of alpha-1, and will, in some series, see as many as 12 physicians before the diagnosis is initially made. I see this in my practice quite commonly. And so, there really is an impetus to have a low threshold to test. Again, guidelines suggest that every patient with fixed airflow obstruction on PFDs should undergo testing once in their lifetime.

Raed Dweik, MD (Podcast host): I mean, the testing sample is a simple blood test, so that makes it easy. It's not a complicated test, it's not a biopsy or anything, so I think that should make it easy to do. But what about the expense? Is this covered by most insurances?

Dr. Stoller: It is, and in addition to that, many groups, obviously, the companies that produce drugs for alpha-1 as well as the Alpha-1 Foundation, offer free testing. So, the Alpha-1 Foundation offers what they call the alpha-coded testing trial, where one would go online, sign up, receive a dried blood spot test kit and a lancet, prick the finger, put a little bit of a blood spot on a card and send it in.

This is analyzed by Dr. Mark Brantly's lab at the University of Florida, which is subsidized by the Foundation. And the patient would receive, confidentially at home and at no cost, their serum level and genotype. So, insurance covers most testing, but if one is disinclined to do that, one can avail oneself of these alternative testing strategies. And there really is no financial disincentive in that context.

Dr. Dweik: That's a great service. And if I understood correctly from you, it doesn't even need a physician order, the patient can just request that and do it on their own.

Dr. Stoller: A patient can go online, sign up, it's sort of like a home pregnancy test in a way.

Dr. Dweik: Yes, that's impressive. For an unrecognized disease, that's almost the only way to make sure that we recognize more and more of these patients. And that takes me to my next question, which is, why is it important to recognize this? You know, why do we want to diagnose it? Are there effective therapies for this? And how do they work?

Dr. Stoller: First of all, we recognize that delayed recognition is associated with worse clinical outcomes. A paper published by our colleague, Dr. Vic Tejwani, and I showed that the diagnostic delay interval was directly associated with worsened CAT score, worsened in St. George's respiratory questionnaire and a trend towards a lower FEV1. So, diagnostic delay is ill-advised in a progressive disease.

We also know, as you suggest, that there are interventions even short of specific therapy, for example, smoking cessation. In the studies done at birth, in Sweden and in this country, individuals tested and identified at birth had a lower likelihood to ever initiate cigarette smoking in their teens than did their age and gender matched normal colleagues. So smoking prevention is very important. Occupational choice, as well - it would be ill-advised to be a coal miner exposed to dusty environmental exposures with alpha-1. So, there are those interventions.

Of course, all the usual interventions in chronic obstructive pulmonary disease for patients who are afflicted apply, with the possible exception of lung volume reduction surgery, where we know from a subset analysis of the NETT Trial in which we at the Cleveland Clinic, as you know, participated, we identified that individuals with alpha-1 undergoing lung volume reduction surgery tend to experience lower increments in their FEV1 of shorter duration than their normal matched colleagues. So, with that possible exception, all the other interventions, bronchodilators, supplemental oxygen, vaccinations and pulmonary rehab certainly apply.

Lung transplant, in extreme cases, is clearly available. And about 5 percent of lung transplants performed worldwide are performed for individuals with severe COPD due to alpha-1 antitrypsin deficiency. Beyond that, there are specific therapies. And the specific therapy is called augmentation therapy, which, in the current state, is the intravenous infusion of pooled human plasma-derived alpha-1 antitrypsin. So, donors give blood, that blood is highly extracted, purified, and the alpha-1 component extracted, prepared in either a lyophilized preparation or several liquid preparations, and then is given intravenously to these individuals once weekly at a dose of 60 milligrams per kilogram, which is the FDA-approved dose and dosing interval, for life.

We do know, from three randomized clinical trials, that the weight of evidence suggests that such therapy is effective in slowing the rate of COPD progression as assessed by CT densitometry in the most recent so-called rapid trial. But the weight of evidence is clear, even though no one individual randomized trial, which is always a challenge in a rare disease, can assemble a large enough cohort to have adequate power, et cetera. Although no one randomized trial in my view is definitive, the weight of evidence is quite clear that augmentation therapy is effective, and I certainly prescribe it in my practice.