From Genotype to Action: Managing Dual-Deficient Alpha-1

[Amanda Atkinson] (0:00 - 0:44)

Welcome to this episode. I'm Amanda Atkinson, your guest host, and I'm joined today by Dr. Kyle Hogarth. We're focusing on what happens after a patient is found to have severe double-deficient genotype in alpha-1 antitrypsin deficiency.

For many clinicians, finding a severe genotype raises immediate questions. What does it mean for disease risk? What testing should happen next?

When should augmentation therapy be initiated? And how do we structure long-term monitoring? So today, we're going to walk through a practical roadmap.

So let's start, Dr. Hogarth, at the moment that the genotype result comes back. We know that genotype alone is not enough to determine disease severity. So when you see a confirmed severe deficiency, can you talk me through the next steps?

[Dr. Kyle Hogarth] (0:44 - 4:18)

Sure. So thanks so much for having me. Look, you know, when the genetic test comes back, and let's say, for example, someone's double C, right, the most common form of a severe deficiency that might show up clinically, the first thing to recognize is that being a double C means that you are at risk for liver disease, and you are at risk for lung disease.

But it is not a guarantee that either are going to happen. Part of it depends on how the patient was found. So for example, if they're presenting with liver disease, and they're double C, there's your cause, and there's the problem.

If they're presenting with emphysema or COPD, et cetera, to my clinic, then yes, there's the cause. But remember, consumer genetics now offer alpha one testing. And so you may be an otherwise young and healthy person who got a birthday present from one of these companies to trace your ancestry roots, et cetera.

And lo and behold, you're a double Z, and you're 22 years old, and you have nothing wrong with you. Now what do you do? And so the workup here, the further next steps really depends on what do you have in front of you.

So obviously, if someone's healthy, this is an accidental discovery. They've got normal pulmonary function tests, no symptoms, normal liver analysis. Then we watch and wait.

We get yearly pulmonary function tests. We tell you to not smoke, obviously, and not work in a polluted environment. Get your appropriate vaccines, stay physically active, maintain a normal body weight.

And the usual way that I put it to my patients is say, look, as you age, you're going to start annual testing. You're going to get a pap sphere, mammograms, prostate, colonoscopy, blood pressure checks, et cetera. This is just going to be one more thing added to your annual evaluations to ensure that you're staying healthy.

And so that's for the accidentals. For the folks who have lung disease, the immediate next step, of course, is, well, how bad are your lungs? What are the objective pulmonary function tests?

So you want body box plasmidography. I want to see your volumes. I want to see your flows.

I need to see your diffusion capacity. Usually, the patients qualify for chest imaging based on their smoking history anyway so that they need to be screened for lung cancer, period. But if they don't have much of a smoking history, I, in my own practice, will obtain a CT chest to at least establish a baseline looking for bronchiectasis, a not uncommon problem in our alpha population, and the degree of emphysema.

And this is equally important because, of course, if your patient, again, depending on their stage of COPD, that's what's going to dictate medical management. They're going to be referred to pulmonary rehab. They may or may not need oxygen, depending on the testing you've done.

And if they have really severe obstructed lung disease and have significant gas trapping on the PFTs that you obtained, beyond, obviously, initiating augmentation therapy, it's also important to consider even some of the procedures that are being offered for advanced COPD, lung volume reduction, et cetera. So there's a whole pantheon of things in front of us to offer these patients. And clearly, a lot of it's going to be dictated by the severity.

If someone's got real mild obstruction, we're not talking lung volume reduction and oxygen and so forth. We're then, at that stage, simply talking about inhalers. And the gold guidelines are a really great roadmap on how to provide what's the appropriate inhaler therapy for these patients.

Obviously, if they're smoking, smoking cessation is front and center. And then if there is, of course, the presence of obstructed lung disease, and there's obviously going to be imaging that backs that up further and resets of emphysema on CT, then they're a candidate for augmentation therapy. And it's worth discussing that and initiating that.

[Amanda Atkinson] (4:20 - 4:43)

Thank you so much. Yeah, we know that every patient's different and every patient's disease process is unique. So you've established your baseline.

What clinical features would you be looking for that might suggest an acceleration in decline? And what tips could you offer clinicians that might help them identify patients that need earlier or different intervention than maybe what they're already doing?

[Dr. Kyle Hogarth] (4:44 - 9:10)

Sure. So if someone just comes to me with kind of relatively mild obstructed lung disease or even moderate, you know, yes, they have alpha-1. And I know that's the etiology of their obstructed lung disease.

But their degree of disease indirectly dictates the frequency in which I see you, right? If you have really mild disease, I'm going to see you once or twice a year because that's the nature of your lung disease. More moderate to severe, you're going to get to seeing, you know, three to four times a year.

You know, it's someone's personal practice on cadence of all their COPD patients. But of course, what we're looking for and what we're very interested in is exacerbation prevention, right? So in all COPD patients, an exacerbation is a critical event.

It leads to worsening lung function. It leads to massive health resource utilization, exposure to toxic medications like prednisone, plus or minus getting admitted to the hospital. So there's a reason why our goal has always been to avoid all exacerbations.

In an alpha-1 patient, this is even more imperative because though we are providing augmentation therapy to counter all of this inflammatory response, these folks do not respond well to inflammation. We want to minimize that at all times. So it's a major stress of, you know, of being adherent to our inhalers, ensuring appropriate inhaler technique, making sure they have done pulmonary rehab.

As we know, that improves quality of life, reduces risk of exacerbations, reduces length of exacerbations, obviously appropriate vaccinations, etc. And again, if depending on their severity, the use of oxygen, and then other advanced procedures. So at each clinic visit, it's important to obviously measure spirometry in these patients.

We want to trend it over time. Obviously, spirometry is a noisy number. The FEV1, you know, fluctuates a little bit up and down.

And so we're always looking for a trend with our patients. You know, if they're going up and down, I'm not as worried. If they're going up and down, but kind of steadily going down, then clearly our current management, whether that is just inhalers and augmentation therapy or inhalers augmentation therapy, plus or minus, if they've, you know, if they've had exacerbations, maybe the biologics or chronic azithromycin, etc., all, you know, it's an evaluation of smoking and vaping, as I tell all my patients, smoke a smoke. I think as clinicians, one of the important things for us to remember is when I ask a patient if they smoke to the average patient, that just means cigarettes. So I live in a state with legal marijuana.

So if I say, do you smoke? I get a no. Do you smoke marijuana?

Oh, for sure. You know, and so it's tailoring, and then do you vape? Because vaping is not smoking as far as, you know, our patients are concerned.

Now, and any other kind of inhaled drug, and what, you know, what's their, what's their work? You know, is your patient work in a place that still allows, you know, public smoking? They're a dealer at a casino or whatever, you know.

I mean, there's a lot of secondhand smoke exposure potential or, you know, pollution with their job. And then obviously, if all that's negative, then if there is a change, and so, you know, I can, I can use a nice end of one patient anecdote to explain. One of my gentlemen with fairly advanced lung disease had been stable, you know, PFTs and Spiro year after year and clinic visit after clinic visit, more or less stayed the same, stayed the same.

And then he came to clinic one day and said, you know, I'm definitely, like, I'm worse. And he's done rehab, so he's got a good baseline level of exercise, limited as it is. And he's not a complainer either.

He's, you know, he came to me and said, something's wrong. And that should be my first hit, right? You know, and so sure enough, I said, let's, let's explore this.

So we did a CT on him because everything, you know, his lung function had declined. And sure enough, not only did he have, you know, the prior we had known very mild, almost non-existent, but bronchiectasis, but now he had a real clear tree and bud sign on radiograph, aka high risk for mycobacterium infection. He was bringing up no sputum.

So we did a bronchoscopy, lavaged, found the mycobacterium, and then of course, immediately started treating it. And again, as the clinicians watching this know, you know, we don't always treat that bug in a general sense because it's tough and it's ubiquitous. But in this particular case, I had one of my alpha one patients stable for the longest time, now starting to decline in his lung capacity.

And that, as soon as that happened, we found out why, in this case, mycobacterium, and we immediately started treating it. 

[Amanda Atkinson] (9:10 - 9:40)

So you talked about forming your clinical decisions and your treatment based on what's going on with the patient. You know, we know that just some patients live in an area where maybe they don't have access to a pulmonologist. So primary cares is managing, you know, their disease or the disease process, or maybe they're at a local level with a pulmonologist.

At what point would you recommend that somebody would be referred to the more alpha one specialty center? When would that become more appropriate?

[Dr. Kyle Hogarth] (9:41 - 12:18)

That's a great question. And not wanting to appear self-serving as a guy who runs an alpha one specialty center. You know, all kidding aside, my thought process on a referral for anything is always at the stage when you as the clinician, whatever your background is, you know, if you're at a stage where you say, I'm not feeling like I've got total control over this patient situation, I think it's very appropriate then to bring in additional resources.

And I mean, it goes for any disease, doesn't it? Right? The easiest answer is it never hurts to go see an alpha one specialist once, right?

You know, you've, you've had this patient, you've made the diagnosis, you've established a treatment plan, they're doing fine. And, you know, if you go, maybe you should just go see someone, you know, an alpha one specialist once, just to basically, you know, is there anything else we're missing? Is there anything that's new and, you know, exciting happening in the field?

Is there any other thought processes to, you know, is this is correct? And, you know, if nothing else, because I've had patients who come to me with that, they said, you know, my doc has been doing great. I, you know, the nurse practitioner has been taking care of me.

She's great. And I just, I wanted, and then the healthcare provider also wanted just sort of the like, almost the equivalent of I call it the blessing, you know, in the sense of, hey, any other thoughts, you know, and, and once in a while, we unearth like something, it's minor, it's never like some glaring, obvious error or anything like that. And for me, the first thing I always say, as a as a specialty center, is, you know, you have yourself an amazing physician that you're working with a nurse practitioner, because they always look at me, I go, Well, how do you know, I mean, you don't know them, I said, one, they found you since we know so many alphas get, you know, ignored or never tested for two, they are treating you appropriate.

And three, they worry enough about you that they basically squash their ego to ask for additional help. I said, that is an amazing provider, you've got go back home and cling to them and, and, and work with this person. And I say that every time because it is, it's true, the patient will come to me and say, like, Well, I just wanted another opinion, because, you know, my person said, I, you know, I'm their only alpha.

Well, you know, okay, so okay, fine. But again, what a great healthcare provider to recognize. And look, it goes both directions.

I work at a major university, I've diagnosed twice now an extremely rare disorder. And I know the guy who's the national specialist on it. And I said, pack your bags, you're going to see this guy.

And they're like, Well, yeah, but you're a specialist. I'm like, not in this one. I'm not off you go, right?

Because you need to be in front of the expert at least once, right? I'll take care of you locally.

[Amanda Atkinson] (12:19 - 12:38)

But, you know, yeah, and we do know, I know that, you know, a lot of times patients will have concerns regarding insurance and are things going to be covered. There are programs, and I believe through the Alpha One Foundation, even where they will get connected with an Alpha One specialty center. So just, you know, the physicians and the patients can both look into those.

[Dr. Kyle Hogarth] (12:39 - 14:30)

Well, for sure. So the foundation, of course, is an amazing resource for all things Alpha One. And they have a provider map, so you can essentially find a specialist near you.

And they offer support from a, you know, travel perspective, obviously, not for insurance and the medical care and all that, but to cover travel costs to say, Look, you know, that guy's four hours away. And, you know, that's going to be hard for us to do. And we've got all these other expenses.

Okay. There's, there's, there's always some amount of resources. And nowadays, honestly, with telehealth, you have the ability to receive care sometimes, you know, and again, in appropriate situations where you don't have to drive to come see me, for example, we can do it through video.

Now there's limitations to that, you know, dumb rules in regards to what state you're in and all that kind of stuff. But allowing for that, there's plenty of ways for us to be able to help. Frequently, too, when you arrive at a specialist, or at least an Alpha One specialist, we don't necessarily need to get any additional testing on the assumption that you've had already, you know, PFTs and or CT, and we usually get those sent to us ahead of time.

So I have your data in front of me, as I can go through it with you, or the patient may have it themselves. And if we're doing a video visit, we can pull it up together. So there's, there's lots of ways to do this.

It's just it's getting around the initial inertia of, you know, making it happen. And look, that doesn't mean you'd ever need to come see an Alpha One specialist. If you're doing well, and your infusions are going well, and you're not having exacerbations, and your, you know, lung function has been stable, then everything is being done right at the local level.

But you know, if you if there's that, if the patient says, Yeah, but I just want that one additional, you know, I would like the next set the blessing, great, come on into any of the Alpha specialists will confirm that everything is great. And then you have that direct confidence, right. But most of the time, that's not even needed.

It just depends. It depends on that person's individual scenario.

[Amanda Atkinson] (14:31 - 14:57)

Yeah. So you've mentioned a few times augmentation therapy. Can you talk because we know that that is one of the most important clinical decisions for a severe deficient Alpha One patient.

Yeah, we talk about, like when a double deficient Alpha One patient becomes a candidate for IV augmentation, are there clinical thresholds that would guide that decision making just provide a little bit of, you know, guidance for the providers that may not be as comfortable with that?

[Dr. Kyle Hogarth] (14:58 - 18:40)

Yeah, sure. So I mean, I think the first thing to recognize is that, you know, like any, any clinician, if this is the first time you're prescribing something, people are obviously understandably like, Oh, I've never given this drug before. But I think the first thing to recognize if we want to split hairs is that augmentation therapy is not technically a drug, you are giving someone else's purified protein into your patient.

And so, yeah, again, I'm splitting hairs there, but, but, you know, this is protein that's been purified from someone's plasma. And so some point in your training, you probably gave a patient in the hospital plasma or red cells or platelets, right? So you've already augmented someone in your career just for a different disorder.

So that's all this is. You're just, they don't make enough Alpha, you're giving it to them. So from a like, Hey, should I be worried?

Not really. And the system around Alpha-1 is very well maintained in the sense of both from the manufacturing side of the production of the products, but then also through specialty pharmacy that delivers and administers and takes care of your patient. And many clinicians have experienced with specialty pharmacies across multiple different disorders.

So it's just usually frequently in that same wheelhouse of a SP that you may already have a relationship with. And if not, then there's ones that are specific for Alpha-1. But the decision to say, we need to treat you.

So there needs to be the presence of symptoms, but obviously that's usually why they got tested, right? They came to me obstructed. We got to have proof of obstructed lung disease.

You'll run into some insurances that will require the proof of emphysema on imaging. Now, this is an important thing to note. The CT scan, you know, you did it and there's nothing in the report that says emphysema, but you didn't look at the images.

And so look at the images, because in deference to our radiologists who are reading hundreds of scans a day, you know, they're looking at the scan and I don't see any lung masses. I don't see any lymph nodes, no blood clotting or whatever. And there's emphysema present, but it may not be the severest of emphysema, but they may not comment on it because it's just sort of there in the background and they're busy, right?

So whatever, if I'm ordering a CT specifically to quantify emphysema, to see if there's emphysema, I will tell the radiologist in my note that I specifically need to know, is it there or not? You know, and if it's not there, it's not there. But if it is there, even if it's mild, I need it commented upon so that it's present in the record, you know, appropriately.

And then that's it. That's the decision because the best way that I've approached this with patients, if I say to a patient comes to me, let's say with an FEV1 of 70% of predicted obstructed ratio, you know, they quit smoking, they're on the inhalers and they're, you know, double deficient. And so I said, Hey, you know, we need to get you started on augmentation therapy.

And again, and understandably, they're a little reluctant at first. This is a lot to hear. And I think, again, that's where, you know, all the resources in the alpha one world come to bear through the alphanet, all the information through the foundation.

But I, what I say to the patients is, okay, let's talk about your breathing, because the whole purpose of augmentation therapy is to keep your lung function from declining further, right? What was your breathing like five years ago? And they'll go, Oh, man, five years ago was a lot better.

What about 10 years ago? Oh, I got 10 years ago, I could do anything I wanted. And that's when I say, well, look, you've been in alpha deficient since the day you were born.

Five years ago, it'd have been great if I had met you, because I could have kept your breathing there. 10 years ago, it'd have been amazing. But now today, this is more or less the best we're going to get it.

I mean, obviously, with the nuances of inhalers and whatnot. But if you decide not to do anything about this, and you come back to see me five years from now, that's going to be your new normal, not today. And the reason I do big like swath of time is obviously to make people kind of mentally block through an era of their life.

But it's a great way to get people to fully recognize that there's been a decline in their lung capacity. And we know the etiology of it, and we need to protect what they have left.

[Amanda Atkinson] (18:40 - 19:06)

And you had mentioned earlier about, you know, missed diagnosis, or we know that only about 10% of those with alpha one have been diagnosed, and it's five to seven years, multiple doctors usually before somebody gets a diagnosis. So can you just walk us through really quickly just some of the maybe most common missed opportunities in diagnosis, and also in care, and then what, you know, what a clinician could do to improve outcomes?

[Dr. Kyle Hogarth] (19:07 - 22:24)

Well, the approach, of course, is to rule it out, right? This is not a rule in disease, because alpha one presents a COPD, emphysema, chronic bronchitis, and chronic obstructed asthma, obstructed lung disease. I mean, if you really want to make it simple, if you're prescribing inhalers, by definition, your patient's obstructed, right?

And there's a workup for obstructed lung disease. And it's not just alpha one, though, that's front and center. You know, nowadays, too, we need to know what your IgE is, we need to know what your eosinophil count is.

If you're a COPD exacerbator, you have to have eos if we're going to think about the biologics and things like that, or even initiating inhaled steroids. On the asthma side, I got to phenotype your asthma. These are the guidelines.

This is what we're supposed to be doing. We don't just say, oh, here's this and throw an inhaler at you. We got to work up the why.

And of course, the why is important because it's going to alter our management. And so it's not just, you know, this like, oh, you know, that's just as that alpha one guy, he's got his crazy agenda. No, these are the guidelines.

These are how we manage and work up the disease. And by the way, alpha one, not so rare when you actually go looking for it. It's just that if you don't look, of course, you never see it.

You know, I meet someone who said, I've been in practice for 25 years. I've never found an alpha one patient. And my answer always is, let me guess, you set the test about 20 times in your career.

I said, I guarantee you, statistically, about every 350 patients with obstructive lung disease are going to have alpha one, just at the back of the napkin, you know, kind of thing. And I always tell the story of a clinician I met. I had a poster.

This is when I was just finishing my fellowship. And we had implemented a like, hey, test everybody. And of course, we just kept finding patients, right?

Just keep looking, keep finding. And I have my poster up there. And this clinician came by and he's looking at it.

And he's he keeps looking at me and going, like, really? You know, he looks back, reads the poster, like, really? And I said, yeah, really.

And he keeps, you know, just like he was kind of mind blown. So off he goes. And I run into him two years later.

And he goes, I don't know if you remember me. Of course, I do. You were the really guy.

He's like, I've been testing everybody who comes through my practice. And he goes, every two months, I find a double Z. He's like, I'm blown away.

And it's actually an interesting story, because then he became a huge Alpha One center as well. And so that made me feel good, A, from the work I had done. But B, it really just shows, like, if you just test.

And again, I think it's, you know, during medical training, when you're a medical student, all you want to do is find the so-called zebra, right? You know, COPD is COPD. You can have a hundred of those, but you find an alpha, right?

But that mentality, we got to kill that mentality. First of all, I never want to find an alpha patient. I don't want anyone to have this disease.

COPD is bad enough. But what I do is when I rule it out, I get it off the table. But of course, it's there when you just look for it.

And so you're not trying to find Alpha One. You're trying to make sure your patient doesn't have Alpha One. Just like I'm trying to make sure my patient, what I do is I run the lung cancer screening program.

I for sure want your CAT scan to come back negative. I am not interested in you having a lung nodule, right? And yeah, I am not equating the two things in their severity, but the concept's the same, right?

So rule it out. And that is why there's all these delays. That's why the patients go years and keep losing lung function, right?

Because no one's done the appropriate workup. And this is guideline based. It's in the gold guidelines, for goodness sakes.

[Amanda Atkinson] (22:24 - 23:17)

Thank you so much, Dr. Hogarth, for sharing your expertise and for walking us through the structured approach for finding, managing patients. And really, thank you for the reminder that a confirmed severe genotype isn't the end of the conversation. It's the beginning of proactive care that we can do for our patients, including establishing comprehensive baselines, ordering further testing, considering therapies, monitoring lung and health and liver health.

We didn't talk about liver, but we know that Alpha One also impacts the liver. And not overlooking family screening. So early identification, deliberate follow-up care really can meaningfully alter the disease trajectory.

And as a clinician, you have meaningfully altered tons of lives just from that last story that you told about how what you did impacted other clinicians. So thank you so much. Do you have any last thoughts?

[Dr. Kyle Hogarth] (23:17 - 24:39)

I think it's an exciting time. In the Alpha One world, there's also a lot happening on the research side, a ton right now from therapeutics and for the fact that we may soon have a therapeutic even for the liver. So it's become even more imperative to test for this disorder.

Not that it wasn't imperative enough, but in the sense of like, we're going to be able to, if we find someone with liver disease, historically, we've had little to offer. The augmentation doesn't help the liver. But the trials are interesting, ongoing.

We may soon have a therapeutic to help liver disease. There's going to be a lot of other ways to potentially help the lungs as well. Again, they all have to go through studies.

They all have to get FDA approved. But just the amount of excitement and research going into the space right now is unbelievably exciting. And it's a great future for the Alpha One patients.

We just got to find them. So we, as clinicians, just need to do our job. And our job isn't that hard.

We've got to just test these folks. Buccal swabs or blood tests, right? It's just a workup.

And you should celebrate that if you had a month of clinic and you tested 300 obstructed patients, not a single one came back as an Alpha One. That's awesome. Celebrate it.

You're going to find a lot of carriers, though, in that testing. And carriers who smoke have a much higher risk for lung disease, tenfold higher. So you can use that data as a way to personalize their care to help them quit smoking, be even more adherent to their inhalers, because, of course, as always, prevent all exacerbations with COPD.

[Amanda Atkinson] (24:39 - 25:05)

Yeah, thank you so much. And for our listeners, for any additional clinical tools, testing resources, and educational material, you can visit the COPD Foundation website at www.copdfoundation.org or the Alpha One Foundation. Thanks for tuning in.

We appreciate the work that you do every day to improve the lives of patients living with COPD and with Alpha One. We look forward to having you join us for our next episode.

[Dr. Kyle Hogarth] (25:05 - 25:06)

Thanks so much.