Asthma / Pulmonary Fibrosis / Traumatic Brain Injury / Cellular Aging / Physical Activity & Mortality / Alcohol Withdrawal / Pharmaceutical Gifts

Educational Objectives

After hearing and assimilating this program, the listener will be better able to: 

1. Increase his/her basic knowledge of important advances in medicine
2. Identify a broad range of clinical research reported in the medical literature
3. Synthesize research findings through one-on-one interviews with authors, editorialists, or experts in the field
4. Integrate new treatments reviewed in the summaries into current practice
5. Challenge oneself with thoughtful, clinically relevant questions

Summary

Summary Narrators

Carole Wyand

Tom Linden, MD
Professor of Medical Journalism
University of North Carolina, Chapel Hill

GUIDELINE WATCH: 2020 ASTHMA GUIDELINE UPDATE

The U.S. National Asthma Education and Prevention Program guidelines were last refreshed back in 2007. An update in the December 8, 2020 issue of JAMA (https://doi.org/10.1001/jama.2020.21974) addresses managing asthma in children, adolescents, and adults.

Key Recommendations are:

• When using intermittent inhaled corticosteroids (ICS):

  – Step 1 or mild intermittent asthma is still managed with as-needed short-acting β-agonists (SABAs).

  – In adolescents (12 or older) and adults, step 2 therapy for mild persistent asthma is either a daily inhaled corticosteroid plus a rescue short-acting β-agonist or as-needed inhaled corticosteroids plus short-acting β-agonists. A recommended regimen is 2 to 4 puffs of albuterol, followed by 80 to 250 μg of beclomethasone equivalent, every 4 hours as needed. (This requires 2 separate inhalers.)

  – Children (4 or older) and adults treated with, and adherent to, daily inhaled corticosteroids should not temporarily double, quadruple, or quintuple their inhaled corticosteroid dose for managing acute exacerbations. Single maintenance and reliever therapy (SMART) seems to be effective because extra inhaled corticosteroid doses are given early (with every dose of rescue bronchodilator during asthma worsening), whereas waiting to increase the dose of maintenance inhaled corticosteroids until an acute exacerbation occurs is too late.

  – Children (age, ≥4 years) and adults with moderate-to-severe asthma (steps 3 and 4) should also use single maintenance and reliever therapy with both a daily and an as-needed combination of an inhaled corticosteroid and formoterol. During an exacerbation, the maximum recommended daily dose is 12 puffs for adolescents and adults (with currently available inhalers, this would be 2 puffs twice/day as maintenance therapy, and an additional 2 puffs as often as 4 times/day as reliever therapy).

  – In children younger than 4 who have recurrent wheezing only with colds and who aren’t treated with daily inhaled corticosteroids, a 7-to-10 day course of inhaled corticosteroids at the onset of a respiratory tract infection can be used to prevent exacerbations.

  • Adolescents and adults whose asthma is uncontrolled with an inhaled corticosteroid plus a long-acting β-agonist (LABA) should add a long-acting muscarinic antagonist (LAMA) for step 5 therapy.

  • In children 5 or older and adults, the use of fractional exhaled nitric oxide (FeNO) is recommended for diagnosing and monitoring asthma in conjunction with history, clinical findings, and spirometry results. Fractional exhaled nitric oxide is a simple in-office breath test that’s typically performed by asthma specialists. It’s helpful when the diagnosis of asthma is in question, and it can help tailor therapy in patients with frequent exacerbations. It should not be used in isolation to make clinical decisions.

  • In patients who have symptoms and exposure to indoor allergens (based on history, skin prick testing, or IgE testing), allergen-specific mitigation should be used (including dust mite, mold, and pet dander reduction and pest management for roaches and rodents). For well-controlled mild-to-moderate allergic asthma, subcutaneous (but not sublingual) allergen immunotherapy is recommended in conjunction with optimal pharmacotherapy.

This long-awaited update does a really good job of addressing these topics, using published evidence available through October of 2018, but asthma care is addressed more comprehensively in the annually updated Global Initiative for Asthma (or GINA) guidelines (https://ginasthma.org/gina-reports/). GINA recommends using an as-needed combination of an inhaled corticosteroid plus formoterol for both intermittent and mild persistent asthma and discourages using a short-acting β-agonist without an inhaled corticosteroid in any patient. Clinicians may prefer using the as-needed inhaled corticosteroid/formoterol combination in a single device (since there are two U.S. FDA-approved products, whereas no single inhaled corticosteroid/short-acting β-agonist device is available yet). As a final reminder, only formoterol, and not salmeterol, is suitable for as-needed use because of its quicker onset of action.

David J. Amrol, MD

NO BENEFIT FROM TMP-SMX IN IDIOPATHIC PULMONARY FIBROSIS

Unfortunately, idiopathic pulmonary fibrosis has limited treatment options and a poor prognosis. Findings of pathologic bacterial burden in the lungs of patients with idiopathic pulmonary fibrosis led to small treatment trials of trimethoprim-sulfamethoxazole (TMP-SMX) with encouraging results. In a large multicenter study in the December 8, 2020 issue of JAMA (https://doi.org/10.1001/jama.2020.22960), researchers randomized 340 patients with moderate-to-severe idiopathic pulmonary fibrosis (forced vital capacity, ≤75% predicted) to either TMP-SMX or placebo. The patients were treated until they reached a study endpoint (which was death, lung transplant, or emergency hospitalization) or until the study’s end; median treatment duration was a year.

Study endpoints were seen with similar frequency in the two groups (0.45 and 0.38 per person-year, respectively); median survival was also similar. The researchers saw some potential beneficial differences in secondary symptom scores (for coughing, wheezing, and breathlessness), but considered those findings to be hypothesis generating. Adverse events were similar in type and frequency in both of the groups.

These findings show that the use of TMP-SMX in patients with idiopathic pulmonary fibrosis can’t be justified.

Thomas L. Schwenk, MD

EXPERIMENTAL COMPOUND REPAIRS TRAUMATIC BRAIN INJURY IN MICE

Often, traumatic brain injury leads to subsequent neurodegeneration and increases the risk for Alzheimer disease, Parkinson disease, vascular dementia, and chronic traumatic encephalopathy. Damage to the blood–brain barrier happens in each of these conditions.

In a study in the November 3, 2020 Proceedings of the National Academy of Sciences of the United States of America (https://doi.org/10.1073/pnas.2010430117), researchers caused sham traumatic brain injury in some young adult mice, and real traumatic brain injury in other mice. About 10 months later, at the midpoint of their lives, the mice with real traumatic brain injury were treated either with a compound known to protect the blood–brain barrier (an aminopropyl carbazole, called P7C3-A20) or with a sham treatment. As expected, the mice with a sham traumatic brain injury suffered no neurodegeneration, and the mice with a real traumatic brain injury plus sham treatment did experience neurodegeneration. But in the mice with a real traumatic brain injury that were given the protective compound, injury to the blood–brain barrier was mostly repaired, neurodegeneration was arrested, and cognition improved — all to nearly the level seen in the mice without brain injury.

These studies in mice might not apply to people, but if this protective compound passes toxicity studies in humans, its efficacy in protecting patients against chronic traumatic encephalopathy, Alzheimer disease, vascular dementia, and Parkinson disease following traumatic brain injury — and possibly in others at risk for these diseases — could be tested. The study also adds to the evidence that injury to the blood–brain barrier is an important part of the pathology of these diseases.

Anthony L. Komaroff, MD

AGED AND INJURED NEURONS MADE YOUTHFUL AND HEALTHY AGAIN IN LIVING ANIMALS

Our cells, particularly neurons, lose regenerative potential as they grow older. With aging come a series of changes in the expression of genes (epigenetic changes). Genetic manipulations in a laboratory dish can reverse aging in adult human cells (https://www.jwatch.org/jw200812290000014). Could aging cells, even neurons, also be made more youthful in living animals? Researchers sought to find out in a study in the December 3, 2020 issue of Nature (https://doi.org/10.1038/s41586-020-2975-4).

Inserting a combination of three genes into mouse and human retinal neurons seemed to restore the youthful pattern of the neurons and enhanced regeneration after injury. The researchers created a viral vector carrying these three genes and injected it into the vitreous humor of the eyes of two groups of mice: Mice going blind from aging, and mice becoming blind from glaucoma. In the aging mice, vision was fully restored; in the mice with glaucoma, vision was restored by about half. The intervention caused no apparent adverse effects. The biochemical mechanisms by which this genetic cocktail restored neuronal health were identified.

In the past 2 decades, biologists have discovered that cellular aging is reversible, not inevitable, and that aging can be delayed by genetic manipulations in worms and in some other animals. This report claims that the effects of aging and injury in mammalian neurons can be reversed in a living animal. Some scientific reports are admirable, some are truly remarkable, and a precious few are simply stunning. If replicated, this report could become a landmark in biomedical history.

Anthony L. Komaroff, MD

INTENSITY OF PHYSICAL ACTIVITY AND RISK FOR DEATH

Among people who engage in the same amount of physical activity every week, is vigorous physical activity (vs. moderate activity) associated with a lower risk for death? To find out, researchers analyzed data collected from more than 400,000 U.S. residents with an average age of 43. Moderate physical activity was defined as activity that causes light sweating or slight increases in heart or breathing rates, and vigorous physical activity was defined as activity that causes heavy sweating or large increases in heart or breathing rates. Findings appear on the website of JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2020.6331).

During an average follow-up of 10 years, there were nearly 40,000 deaths. A third of the participants reported no moderate or vigorous activity. Compared with no activity, any moderate or vigorous activity was associated with a lower risk for death. For a given total amount of moderate-plus-vigorous activity, a greater proportion of vigorous activity was associated with lower all-cause mortality. For example, in adjusted analyses, people with more than 50% vigorous activity had a 17% lower risk for death than did the people with no vigorous activity, whereas those with less than 50% vigorous activity had a 10% lower risk. The people with 150 to 300 minutes/week of moderate activity that included at least 150 minutes of vigorous activity had the lowest risk for death.

Guidelines recommend that adults engage in 150 to 300 minutes/week of moderate activity or 75 to 150 minutes/week of vigorous activity to optimize health (https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf). This study, although subject to confounding, showed that for the same amount of activity, a higher proportion of vigorous activity is better. The practical message here is that patients should engage in physical activity for at least 20 to 25 minutes/day, and that some of it should be vigorous.

Paul S. Mueller, MD, MPH, FACP

CHOICE OF BENZODIAZEPINES FOR TREATING ACUTE ALCOHOL WITHDRAWAL

Managing acute alcohol withdrawal in the emergency department consists primarily of administering benzodiazepines. But there’s little evidence to help clinicians choose between diazepam and lorazepam, which are the two most commonly used benzodiazepines. In a retrospective study in the December 2020 Annals of Emergency Medicine (https://doi.org/10.1016/j.annemergmed.2020.05.029), researchers in Canada asked whether the initial choice of a benzodiazepine resulted in different outcomes among 900 patients with acute alcohol withdrawal who were treated with benzodiazepines at three emergency departments.

Initially, 500 patients got diazepam, and the rest got lorazepam. Most of the outcomes were virtually identical in the two groups, namely, hospital admissions (≈18%), intensive care unit admissions (≈0.3%), and 1-week return visits (≈24%). But a higher proportion of patients who got lorazepam needed rescue doses of an alternative benzodiazepine (11% vs. 4%).

These findings suggest that there’s no significant patient-oriented difference between lorazepam and diazepam for the initial treatment of acute alcohol withdrawal. But many patients in the lorazepam group got additional benzodiazepines, which might point toward an insufficient control of withdrawal with the initial dose of lorazepam. The initial drug choice might not matter, as long as symptoms are quickly controlled. Some clinicians prefer using phenobarbital, which wasn’t studied here, but which is increasing in popularity in the United States for treating patients with symptoms of alcohol withdrawal.

Lauren M. Westafer, DO, MPH, MS

PHARMACEUTICAL GIFTS STILL GET RESULTS

Back in 2013, the “Sunshine Act” mandated that all pharmaceutical company payments or gifts to physicians greater than US$10 in value be made public. It turns out that about two thirds of all physicians in the United States are on the receiving end of this largesse, for a total value exceeding US$2 billion in 2018. The granularity of the resulting “Open Payments” data set has been a bonanza for researchers drawn to explore the old question of whether gifts and payments influence prescribing patterns.

In a systematic review on the website of the Annals of Internal Medicine (https://doi.org/10.7326/M20-5665), researchers culled, from thousands of Medline articles, 36 studies whose methodology was relatively free from bias. All but one were written after 2015, and most correlated Medicare prescribing data with Open Payments data. Nearly all of the individual analyses showed clear correlations between payments and the prescription of specific drugs of interest. To answer the question of which came first, payment or prescription, timing was evaluated in nine studies: All concluded that payments were made before prescriptions were written for a “quid pro quo” (rather than a simple reward system for high prescribers). All 25 studies in which the correlation between payment and prescription was evaluated (meaning, the more gifts or money offered, the more prescriptions written) showed a “dose-response” association.

Visits and gifts from pharmaceutical “detail reps” have been a fact of medical life for many decades now, and of course they influence prescription patterns: If they didn’t, pharmaceutical companies would hardly continue such an expensive practice. The newest data now confirm this conclusion. Plus, it seems that bringing the practice out into the open “sunshine” hasn’t mitigated it much. Maybe stronger weapons than disclosure are needed to do so.

Abigail Zuger, MD

Readings

Disclosures

The planning committee members reported that they had nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

JW320204

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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