Preparing for the "tripledemic": RSV, influenza, and COVID-19

 - Kenny Lin, MD, MPH

During the first two winters of the pandemic, social distancing and mask wearing protected many persons - particularly infants and older adults - from SARS-CoV-2 and other potentially serious viral respiratory infections. With most people having returned to pre-pandemic social interactions, the viruses are making a comeback. Children's hospitals in several states are filled to capacity with patients infected with respiratory syncytial virus (RSV); high levels of influenza-like illness are being reported across most of the South; and with waning immunity and low uptake of bivalent vaccine booster shots, many scientists predict another COVID-19 winter surge. Health officials are concerned that the combination of RSV, influenza, and SARS-CoV-2 variants may produce a "tripledemic" that could overwhelm outpatient practices and hospitals.

Prior to 2020, 2 to 3 percent of U.S. infants younger than 12 months were hospitalized for RSV bronchiolitis, and RSV was estimated to cause 177,000 hospitalizations and 14,000 deaths annually in adults aged 65 years and older. For the family physician evaluating a child with bronchiolitis, accurate risk stratification remains a key skill. Unfortunately, aside from oxygen supplementation, no other therapies offer significant benefit: bronchodilators do not improve oxygen saturation, hospitalization rate or duration; and the American Academy of Pediatrics practice guideline recommends against using systemic corticosteroids, antibiotics, nebulized hypertonic saline (unless the child is hospitalized), or chest physiotherapy. RSV prophylaxis in the first year of life with the monoclonal antibody palivizumab (Synagis) is recommended only for infants born before 29 weeks of gestation or infants with chronic lung or heart disease, neuromuscular disease, or profound immunocompromise. No vaccines have been approved by the U.S. Food and Drug Administration (FDA) to prevent RSV infections in infants or older adults.

Although not in time for this RSV season, new prevention tools are around the corner. Earlier this year, a placebo-controlled trial of 1490 late-preterm (>35 weeks gestation) and term infants reported that the monoclonal antibody nirsevimab provided reduced medically attended RSV bronchiolitis by 75 percent and hospitalization by 62 percent, with no difference in adverse events. The FDA and the European Medicines Agency are both considering approval. Several companies are also in the late stages of developing a vaccine against RSV for older adults, with two reporting positive outcomes in unpublished Phase 3 trials.

In the meantime, nonpharmacologic interventions (handwashing, avoiding sick persons, and mask wearing) remain the mainstay of preventing respiratory virus infections. Finally, to increase lagging COVID-19 and influenza vaccine uptake, the American Academy of Family Physicians has assembled an Immunizations & Vaccines web page with up-to-date clinical and patient education resources.

Meet the newest antidepressant: dextromethorphan/buproprion (Auvelity)

 - Jennifer Middleton, MD, MPH

Dextromethorphan/bupropion (Auvelity), was recently approved by the United States (US) Food and Drug Administration (FDA) for the treatment of depression. Until now, dextromethorphan has been best known as a cough suppressant, and bupropion is currently FDA-approved to treat major depressive disorder and to facilitate tobacco cessation. While the combination of the two may seem surprising, it turns out that dextromethorphan affects NMDA, glutamate-1, and sigma-1 receptors in the brain, all of which have been implicated in the pathophysiology of depression, while bupropion's cytochrome P450 inhibition boosts dextromethorphan's blood levels to allow for once daily dosing. Auvelity was approved based on promising data from its phase 2 trial, ASCEND, and its phase 3 trial, GEMINI; time will tell whether longer trials affirm these benefits.

The FDA's investigational new drug process consists of 4 phases. After appropriate studies in the lab and in animal models, the FDA grants permission to begin phase 1 studies in a small number of healthy volunteers to determine safety and dosing. In phase 2, the new drug is studied in a few hundred persons with the target health condition to determine efficacy and side effects. In phase 3, the new drug's efficacy is further studied in up to 3,000 more people along with more attention to adverse side effects. Sufficient data regarding efficacy and data from phase 2 and phase 3 trials are typically required for FDA approval. Then, in the post-approval phase 4, the drug continues to be studied to confirm its safety and efficacy. 

Auvelity's phase 2 trial, ASCEND, enrolled participants between the ages of 18-65 years with moderate or severe major depressive disorder without psychotic features. Persons with additional and/or other psychiatric diagnoses (bipolar disorder, obsessive compulsive disorder, panic disorder) as well as persons with "treatment-resistant depression," defined as "having had at least two failed adequate antidepressant treatments in the current major depressive episode," were excluded. 80 participants were randomized to dextromethorphan/bupropion (45 mg/105 mg) or bupropion (105 mg) once daily for the first 3 days and then twice daily thereafter. Participants completed a four week "washout" of any recent antidepressant medications prior to beginning the trial. The primary outcome was change in baseline score on the Montgomery-Asberg Depression Rating Scale (MADRS) assessed weekly for 6 weeks. The average change in MADRS scores after six weeks was greater with dextromethorphan/bupropion than with bupropion (-13.7 points vs -8.8 points, 95% confidence interval [CI] = -3.1, -6.8), and remission rates were statistically significantly higher with dextromethorphan/bupropion beginning in week 2. 

Auvelity's phase 3 trial, GEMINI, had identical enrollment criteria to ASCEND: adults between the ages of 18-65 years with moderate or severe major depressive disorder without psychotic features; their exclusion criteria also mirrored ASCEND. 327 participants were randomized to either dextromethorphan/bupropion or bupropion (same dosing as ASCEND), and outcomes were also measured weekly using the MADRS score:

Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points.

These trials were both quite brief (participants were only followed for 7 weeks), and GEMINI's enrollment was relatively small for a phase 3 trial. Regardless, the newly approved Auvelity is expected to be available on the US market by the end of 2022, likely with a hefty price tag. Auvelity's rates of side effects are similar to currently available antidepressants, though the side effects themselves are somewhat different. In GEMINI, Auvelity's most common side effects were dizziness, nausea, headache, somnolence, and dry mouth, and "[t]he percentage of patients in whom adverse events occurred during the treatment period was 61.7% in the dextromethorphan-bupropion group and 45.1% in the placebo [bupropion] group." That 61.7% is similar to second generation antidepressants (SSRIs, SNRIs, and TCAs), as about 2/3 of patients on those medications also note side effects. Participants in GEMINI's Auvelity group, however, did not report more sexual dysfunction or weight gain than placebo, which may appeal to some patients if longer term studies confirm these findings.

While we await Auvelity's arrival, be sure to check out the AFP By Topic on Depression and Bipolar Disorder for helpful articles about about other treatment options for depression, both pharmacologic and non-pharmacologic.

Novel strategies against malaria and cancer create new clinical conundrums

- Kenny Lin, MD, MPH

Two recent articles in American Family Physician highlight novel prevention and detection strategies against age-old health threats. In "Malaria: Prevention, Diagnosis, and Treatment," Drs. S. David Shahbodaghi and Nicholas Rathjen review not only prescribing prophylaxis for travelers to malaria-endemic regions, but also "the first malaria vaccine approved for widespread use ... for the prevention of P. falciparum malaria in children living in endemic areas," which has already been given "to more than 1 million children in Ghana, Malawi, and Kenya." In a previous AFP Community Blog post, Dr. Jennifer Middleton discussed the World Health Organization's endorsement of Mosquirix and research evidence that it lowers the incidence of malaria infection, complications and death in combination with seasonal chemoprophylaxis.

A New York Times article elaborated on the financial, logistical, and trust challenges of getting an estimated 100 million vaccine doses into children's arms every year. A full series of Mosquirix consists of 4 doses administered between 5 and 18 months of age. Its limited (40%) efficacy compared to other malaria vaccines in development has raised concerns that "every dollar directed to Mosquirix now is a dollar less for developing other tools" and paying for low-tech prevention measures such as distribution of insecticide-treated bed nets.

Despite a 27% decline in cancer mortality in the U.S. over the past two decades, cancer trails only heart disease as the leading cause of death, and most cancer types do not have screening tests recommended by the U.S. Preventive Services Task Force (USPSTF). The October issue's Diagnostic Tests feature by Dr. Natasha Pyzocha discusses the Galleri test, a blood test that is used to detect more than 50 cancer types in older adults. The test's manufacturer recently reported results of a prospective study of the test that detected a "cancer signal" in 1.4% of participants, 38% of whom ultimately had cancer confirmed after additional diagnostic testing. A much larger study currently underway in the United Kingdom's National Health Service should go a long way toward determining if this test is a "game changer" or "overhyped" for improving cancer outcomes and mortality.

Several other multi-cancer early detection (MCED) tests are in various stages of development, and the future impact of MCEDs on family physicians who may be ordering these tests in practice is uncertain. A review in the American Journal of Medicine mentioned "concerns about patient counseling, costs, frequency of testing, patient anxiety, and subsequent testing for a positive result." Similarly, the director of the National Cancer Institute's Division of Cancer Prevention wrote that "there is still a substantial level of uncertainty and many unknowns surrounding these tests," including "how best to maximize their benefits and minimize their potential harms." To provide primary care clinicians with more context, AFP has an editorial in production that will discuss basic test evaluation principles and data requirements needed to justify routinely using these tests for cancer screening in practice, particularly for cancers that already have USPSTF-recommended screening tests.

Making nutritious foods accessible to all patients

 - Jennifer Middleton, MD, MPH

In the recent AFP editorial "Incorporating Lifestyle Medicine Into Practice: A Prescription for Better Health," Dr. Alex McDonald reviews the benefits of lifestyle medicine and provides a wealth of resources to incorporate it into practice. Dr. McDonald acknowledges that "[h]ealth and community resources greatly affect our patients' ability to benefit from lifestyle medicine," inequities addressed by the United States (US) White House Conference on Hunger, Nutrition, and Health earlier this month. The experts at this conference specifically called out the disparities in access to healthy food and laid out a strategy that each of us can play a role in enacting:

The White House report outlined a strategy based on 5 “pillars” for reducing hunger in the US and improving nutrition: improving food access and affordability; prioritizing the role of nutrition and food security in health, including in the prevention and management of disease; helping consumers make healthy food choices (and have access to healthy foods); supporting physical activity; and enhancing nutrition and food security research.

Dozens of health organizations, nonprofit organizations, and food suppliers pledged to increase access to healthy foods, expand Supplemental Nutrition Assistance Program (SNAP) benefits, and increase funding for nutrition education. Family physicians can contribute to this effort in several ways: 

1. We can improve our own knowledge of nutrition. The AFP By Topic on Nutrition is a solid place to start, as is the AAFP "Incorporating Lifestyle Medicine into Everyday Family Practice" guide referenced in Dr. McDonald's editorial above, and you might also score yourself on the "Starting the Conversation" scale.

2. We can strengthen our skills in behavioral counseling. Dr. McDonald's editorial contains links to the AAFP Lifestyle Assessment Tool which includes counseling strategies. There's also this informative 2018 AFP article on "Counseling Patients in Primary Care: Evidence-Based Strategies." 

3. We can identify persons with food insecurity in our practice settings and connect them to resources. This 2018 AFP editorial on "Food Insecurity: How You Can Help Your Patients" includes language for screening as well as links to food assistance programs. The Aunt Bertha online tool connects patients to resources by zip code. 

4. We can hold our elected officials accountable in supporting equitable access to nutritious foods. Expanding SNAP and allowing Medicaid to cover medically tailored meal delivery will require federal legislation. As election day draws near in the US, find out where your local candidates stand on eliminating health inequities.

Substituting gabapentin for opioids has significant downsides

 - Kenny Lin, MD, MPH

Although gabapentin is effective at relieving some types of neuropathic pain, namely diabetic neuropathy and postherpetic neuralgia, it is notably ineffective for treating other types, such as radicular low back pain. A 2019 editorial in American Family Physician warned of potential unintended consequences of using gabapentinoids (gabapentin and pregabalin) as alternatives to opioids for pain management. The authors observed that "as many as one in three patients taking therapeutic doses will experience dizziness or somnolence"; also, the U.S. Food and Drug Administration issued a safety communication about gabapentinoids causing serious breathing problems in patients with chronic respiratory diseases and older patients.

Illicit use of gabapentin is playing an increased role in opioid-related overdoses, according to a May 2022 report from the Centers for Disease Control and Prevention. The report found that between 2019 and 2020, toxicology results detected gabapentin in almost 10% of fatal overdoses recorded in 23 states and Washington, DC. Misuse of gabapentin occurs for several reasons: "to enhance the effects of opioids," "to achieve a 'high' when preferred substances [are] unavailable," and "to self-treat withdrawal or pain."

A recent cohort study in JAMA Internal Medicine examined gabapentin use in the perioperative period (within 2 days after major surgery) and in-hospital adverse events in nearly 1 million patients aged 65 years or older. More than 3 in 4 patients underwent orthopedic surgeries. Overall, 12.3% were prescribed gabapentin perioperatively. Those patients were statistically more likely to experience delirium, receive a new prescription for an antipsychotic drug, and develop pneumonia than gabapentin non-users. In persons using gabapentin, the risk of delirium was higher with chronic kidney disease and a high burden of comorbidities.

An accompanying commentary pointed out that the study results "are consistent with what is now a growing body of literature suggesting that gabapentin may not be the windfall medication for perioperative pain management that surgeons hoped it might be for decreasing opioid use," particularly in older adults:

We need to unwind the automaticity of gabapentin use in the perioperative period. For example, in this study, 80% of gabapentin users received gabapentin on the day of surgery, suggesting that it was started prior to any patient report of pain, representing an opportunity to de-escalate gabapentin use for some patients. Second, engaging patients and caregivers in their care could allow us to better manage expectations for pain control in the perioperative period. A multimodal approach needs to be patient centered and flexible. Finally, aside from swapping out one potentially problematic medication for another, nonpharmacological techniques that might be used to treat pain should be considered.