In medicine, as in life, it is important to take stock of what we know and what we do not know. Oprah Winfrey, the prominent US talk show host, is renowned for asking her guests the question, “What do you know for sure?” It is a potent question because in answering it honestly, the person inadvertently realizes the edges of his or her knowledge, thus revealing what the person does not know as well.
When a disease is rare, usually the research into the disease is scarce and slow moving. Diagnostic and treatment guidelines do change but ever so slowly. Make no mistake—our knowledge of most diseases does expand over time; some of it just takes more time to notice.
Alpha-1 antitrypsin deficiency (AATD) is largely manifested in the lungs as emphysema and chronic obstructive pulmonary disease (COPD). Barjaktarevic and Campos wrote a paper published in Therapeutic Advances in Chronic Diseases that broke down the knowns and unknowns about AATD as they relate to lung disease.
What We Know
One lifestyle change that has drawn scientific consensus on its power to impact change in AATD patients is smoking cessation. In fact, studies have linked smoking to a higher risk of AATD countless times; therefore, it is beyond argument that it contributes in some way to its etiology. Santos and Turner, in a paper on the current diagnostic and management practices in AATD published in Faculty Reviews, wrote that “smoking cessation is the most important protective measure in AATD” and that “tobacco cessation must be a priority” in AATD patients regardless of their genotype.
Read more about AATD etiology
How does smoking contribute to AATD symptoms? Barjaktarevic and Campos quoted research that suggested that it oxidizes AAT and thus diminishes its anti-elastase function, resulting in lung pathology. In addition, they wrote, “Patients with AATD who have never smoked are usually asymptomatic, typically identified through family testing, and often have a normal lifespan.” Therefore, smoking cessation must be highlighted as a modifiable lifestyle choice in improving the clinical condition of AATD patients.
In terms of AATD treatment, there is an abundance of data that have suggested that augmentation therapy works. Augmentation therapy first came into approval after a study found that weekly intravenous (IV) AAT therapy increased AAT levels significantly in both serum and lung epithelial lining fluid in AATD patients.
Santos and Turner identified France and Germany as among the European countries most frequently offering augmentation therapy for AATD patients, with positive results. They wrote that augmentation therapy “has produced beneficial consequences, like ameliorating lung function decline and emphysema progression, prolonging survival, and delaying the decline in quality of life, especially in severe AATD.”
What We Do Not Know
Lung transplantation is a last-resort treatment option for AATD patients at advanced stages of the disease. Although studies have generally associated it with beneficial outcomes, the long-term benefits of this and other forms of lung surgery offered (such as lung volume reduction surgery) are controversial.
Santos and Turner wrote, “When comparing survival rates after lung transplantation, between AATD recipients and usual COPD, no difference in long-term survival was observed in the majority of the studies, albeit AATD patients are usually younger and have fewer comorbidities.”
Even before we get to the stage where surgical intervention is necessary, there is an interesting debate underway about the best route of drug delivery — inhalation vs IV. This is an important debate because it ultimately deals with the quality of life of patients and the disease burden that they carry. Every patient who has had to undergo a routine administration of drugs through the IV route knows all too well about the inconvenience and pain that it entails.
In contrast, the benefits of the administration of drugs through inhalation include “convenience for patients to self-administer, lower cost, and avoiding risks associated with IV administration such as thrombosis and infection,” wrote Barjaktarevic and Campos.
Read more about AATD diagnosis
A recent study involved randomizing a group of patients to either receive twice-daily inhalation of 80-mg AAT or placebo. The result of that trial was that there was no significant difference between the 2 groups in terms of time to the first event-based exacerbation or mean rate of annual exacerbations.
However, researchers performed a post hoc analysis and discovered that the inhalation group had a much lower decline in forced expiratory volume in 1 second (FEV1) compared to the placebo; the difference in FEV1 decline was 48 mL/year between the inhalation group and the control group. There is, however, debate about whether this was merely a result of the bronchodilator effect (due to the inhalation route). In addition, there were some adverse effects reported from the inhalation group.
In other words, the jury is still out. However, even if we were to continue with the IV administration of augmentation therapy, physicians are thinking of creative ways to make it as comfortable for the patient as possible. For example, instead of the standard 60 mg/kg per week AAT dose, there have been studies to administer 120 mg/kg every other week or 250 mg/kg every 4 weeks to reduce the frequency of injections.
This article details some of the points about AATD that we have more confidence in relative to others. However, the fact remains that AATD still carries a very poor prognosis. Hopefully, the column of “what we know” about AATD keeps growing until the threshold needed for discovering a cure is reached.
Barjaktarevic I, Campos M. Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know. Ther Adv Chronic Dis. Published online July 29, 2021. doi:10.1177/20406223211010172
Santos G, Turner AM. Alpha-1 antitrypsin deficiency: an update on clinical aspects of diagnosis and management. Fac Rev. 2020;9:1. Published online October 28, 2020. doi:10.12703/b/9-1