When I was actively serving as a doctor, I was struck by how passive much of medicine is. Oftentimes, we are handed the updated diagnostic and management guidelines of a particular disease and are expected to follow them to a T—no questions asked.
The basic assumption here is that guidelines were created only after stringent research and were meant to streamline the decision-making process of doctors. This minimizes the risk that the discretionary choices of doctors are faulty and therefore harmful to their patients.
However, guidelines are a one-way street; hardly any doctor is willing to criticize them in his or her capacity, even if their own professional experience raises doubts about certain aspects of those guidelines. Therefore, medicine can sometimes feel like the select few making sweeping recommendations for the many.
Today, experts are increasingly recognizing the positive role that ordinary physicians can play in refining diagnostic and management guidelines, and some are taking the extraordinary step to garner feedback from them. When medical researchers and clinicians work together to improve some of the more challenging aspects of clinical decision-making, a win-win scenario is ultimately created.
In this article, we will be looking at an example of such work: a study conducted by Greulich and colleagues on the opinions and attitudes of pulmonologists concerning augmentation therapy in patients with alpha-1 antitrypsin deficiency (AATD).
The Current Mainstay of AATD Treatment
AATD is characterized by the low circulating levels of the serine protease inhibitor AAT and is inherited in an autosomal recessive manner. Its most common clinical manifestation is the emphysematous destruction of the lung.
Scientists are gaining a firm grasp of the genetics behind this disease, and the next frontier in medicine appears to be gene therapy. AATD is an excellent candidate for gene therapy for a number of reasons: it is a monogenic disorder, the augmentation of AAT in the serum to protective levels can significantly preserve lung function, and the supraphysiological levels of AAT do not have any deleterious effects. Lorincz and Curiel wrote, “Taken together, targetable genome editing as a therapeutic tool is moving closer to reality.”
Read more about AATD treatment
However, while gene therapy for AATD is being refined, AAT augmentation therapy remains the mainstay of AATD treatment. Rahaghi wrote, “At present there is only one disease-modifying pharmacological intervention available specifically for the treatment of alpha-1 antitrypsin deficiency (AATD): intravenous (IV) infusion of alpha-1 antitrypsin (AAT).” The treatment was approved by the FDA in 1987 for AATD-associated emphysema.
The weekly IV infusion of plasma-derived AAT can reduce the frequency of acute exacerbations, delay emphysema progression, and improve the quality of life of AATD patients. However, it incurs significant annual healthcare costs; in the US, augmentation therapy costs around $82,000 per patient per year. In addition, many studies have recorded patients expressing their frustration at the disruption that this weekly therapy causes in their lives.
A Variety of Viewpoints
What do the pulmonologists treating AATD day in and day out think about augmentation therapy? This is the question driving the study conducted by Greulich et al, in which 63 AATD experts from 13 European countries were surveyed about their opinions and attitudes regarding augmentation therapy.
The participants were emailed a questionnaire in which they were asked to respond to the importance of a number of variables for the decision to initiate augmentation therapy. The questionnaire was designed with a Likert-type ordinal scale (with 1 being not important and 10 being very important). In addition, the participants were asked their opinions on the indication for augmentation therapy in 30 out of 500 hypothetical cases, which were also evaluated by 3 experts for concordance.
The results demonstrated that the variables that scored highest for the initiation of augmentation therapy were AAT genotype, AATD serum level, and FEV1 (forced expiratory volume in 1 second) decline. There was a slight difference in what pulmonologists believed to be indicating factors for augmentation therapy between AATD patients of different genotypes. As for the 500 hypothetical scenarios, there was an agreement in the indication of augmentation therapy among the 3 experts in 291 cases, accounting for 58.2% of the total.
The research team wrote, “The current survey conducted on experts in AATD from 13 European countries has shown a large variability in their approach to [augmentation therapy]. When hypothetical cases were presented to groups of 3 randomly selected participants, their indication of AT was concordant in only 58% of cases.”
Read more about AATD complications
This is perhaps unsurprising, given that national guidelines differ, and that the rarity of AATD means that few physicians are thoroughly equipped to deal with cases that present at their clinics. Hence, the EU Council and the European Respiratory Society recommend that AATD patients should be referred to expert treatment centers.
Interestingly, Greulich and colleagues noted “some authors have proposed a personalized approach to AT considering variables such as age, rate of decline of lung function and CT imaging of the lungs; our results indicate that most experts consider these variables for the prescription of AT despite the lack of definitive evidence.”
The bigger picture here is whether ordinary physicians should continue to be empowered, or whether decision-making should be concentrated in the hands of a smaller number of experts/specialists. At the end of the day, our common objective should be the improvement of AATD patient outcomes, regardless of how we choose to get there.
Greulich T, Albert A, Cassel W, et al. Opinions and attitudes of pulmonologists about augmentation therapy in patients with alpha-1 antitrypsin deficiency. a survey of the EARCO group. Int J Chron Obstruct Pulmon Dis. 2022;17:53-64. doi:10.2147/COPD.S346051
Lorincz R, Curiel DT. Advances in alpha-1 antitrypsin gene therapy. Am J Respir Cell Mol Biol. 2020;63(5):560-570. doi:10.1165/rcmb.2020-0159PS
Rahaghi FF. Alpha-1 antitrypsin deficiency research and emerging treatment strategies: what’s down the road?. Ther Adv Chronic Dis. 2021;12_suppl:20406223211014025. doi:10.1177/20406223211014025