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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.

Confirmed case of polio in the US signals need to increase vaccination rates

 - Jennifer Middleton, MD, MPH

In the Midwest United States (US) in the early 1950s, two of my uncles contracted poliomyelitis ("polio"). One recovered uneventfully; the other required months of respiratory support with an iron lung. Thanks to vaccination against poliovirus, those of us born in the US since 1955 mostly have known only of polio through family stories like these. News of a confirmed polio case in New York (NY) state earlier this summer, however, has brought polio back into our awareness. 

According to the US Centers for Disease Control and Prevention (CDC), most cases of poliovirus infection are asymptomatic. Approximately 25% of infected persons will experience flu-like symptoms, 1-5% will have meningitis, and between between 1 out of 200 persons to 1 out of 2000 persons will experience paralysis of limbs and, potentially, the muscles that control breathing. The CDC notes that only persons with paralytic disease, by definition, have poliomyelitis (or "polio"). Poliovirus "lives in an infected person's throat and intestines," and infected persons can shed the virus for weeks. The New York State Department of Health launched a poliovirus wastewater surveillance program after this individual's diagnosis was confirmed, which has since detected poliovirus in 4 counties in and around where the diagnosed individual lives. 

In the US, only inactivated polio vaccine (IPV) is administered, but many other countries rely on oral polio vaccine (OPV). OPV is attentuated but live, and unvaccinated persons can contract this attenuated virus:

VDPVs [vaccine-derived poliovirus] can emerge when live, attenuated OPV is administered in a community with low vaccination coverage. Replication of OPV in a person who was recently vaccinated can result in viral reversion to neurovirulence, which can cause paralytic poliomyelitis in unvaccinated persons who are exposed to the vaccine-derived virus.

The individual in NY state with polio had "[v]accine-derived poliovirus type 2 (VDPV2) ...detected in stool specimens obtained on days 11 and 12 after initial symptom onset." Since OPVs haven't been administered in the US since 2000, this individual would presumably have caught poliovirus from an individual vaccinated outside of the US; "[e]pidemiologic investigation [has] revealed that the patient attended a large gathering 8 days before symptom onset and had not traveled internationally during the presumed exposure period." 

The wastewater reports indicate that VDVP2 has spread through this four-county area in the southeast corner of the state. Vaccination levels in the diagnosed individual's county are relatively low, with "3-dose polio vaccination coverage among infants and children aged <24 months living in Rockland County [at] 67.0% in July 2020 [which] declined to 60.3% by August 2022, with zip code–specific coverage as low as 37.3%." The NY State Department of Health has been working with local physicians and health care systems to increase IPV vaccination.

The COVID-19 pandemic has resulted in delayed and missed preventive care for countless persons, including a marked decrease in routine vaccination administrations. The reemergence of polio in NY state should prompt all of us to reassess our patients' vaccination status and engage in targeted, deliberate efforts to increase vaccinations. Office reminder and recall interventions can increase vaccination rates, as can physician face-to-face counseling with parents. This 2016 AFP article on "Strategies for Addressing and Overcoming Vaccine Hesitancy" has many useful tips, and a new online guide developed by Canadian researchers to address COVID-19 vaccine hesitancy, which was recently described in the Annals of Family Medicine, also contains useful strategies.

The evidence is in: WIC improves maternal and child health

 - Kenny Lin, MD, MPH

Food insecurity is increasingly recognized as a modifiable social determinant of health. The American Academy of Family Physicians has endorsed "sustained funding for evidence-based policies and programs to eliminate disparities in healthy food access, including ... the Special Supplemental Nutritional Program for Women, Infants, and Children (WIC)." In a 2019 editorial about interventions to reduce maternal mortality, Drs. Katy Kozhimannil and Andrea Westby recommended postpartum screening for food insecurity. But how strong is the evidence that WIC improves maternal and child health?

Since 2012, American Family Physician's Implementing AHRQ Effective Health Care Reviews feature has summarized dozens of primary care-relevant systematic reviews from the Agency for Healthcare Research and Quality's Effective Health Care Program with accompanying clinical commentaries. A team of investigators in this program recently reviewed maternal and child outcomes associated with WIC and published a synopsis of their report in Annals of Internal Medicine. Investigators identified 82 studies that examined associations between WIC participation and maternal, birth, infant, and child health outcomes.

Based on direct evidence from 49 studies, they concluded that WIC participation likely reduces the incidence of preterm birth, low birth weight, and infant mortality. Lower strength of evidence suggested WIC is associated with less inadequate gestational weight gain and alcohol use and better diet quality during pregnancy, and it may increase child preventive care visits and immunizations. WIC was not associated with differences in breastfeeding rates or premature (before 4 months) introduction of solid foods. Children of families receiving WIC had better diet quality, increased household purchasing of healthy foods compared to less healthy foods and beverages, and higher cognitive development than WIC-eligible children not receiving benefits. There was insufficient evidence that WIC reduced childhood obesity or affected health status or risk of hospitalization.

The U.S. Department of Agriculture (USDA) found that food insecurity in households with children declined to its lowest rate in two decades in 2021, despite the negative impact of the COVID-19 pandemic on the economy. The nonpartisan Center on Budget and Policy Priorities observed:

About 10.2 percent of U.S. households were food insecure in 2021, meaning they struggled to afford enough food for an active, healthy life year-round. That the rate held steady during the pandemic — when accounting for statistical noise it’s not significantly different from the 10.5 percent rate for 2019 and 2020 — is a testament to robust relief measures policymakers enacted. These include Economic Impact Payments, an expanded Child Tax Credit, improved unemployment insurance, and expanded food assistance, along with [the Supplemental Nutrition Assistance Program]'s built-in ability to respond to increased need.

On the negative side, food insecurity increased from 2020 to 2021 in households without children and for women and older people living alone. Households headed by Black, Hispanic, and American Indian / Alaska Native persons were more likely to experience food insecurity than other households. Finally, the expiration of temporary pandemic emergency relief measures, such as free meals for all children attending public schools, may worsen food insecurity in families ineligible for WIC.

COVID bivalent booster vaccines ("updated boosters") roll out across the US

 - Jennifer Middleton, MD, MPH

On August 31, the United States (US) Food and Drug Administration (FDA) authorized Pfizer and Moderna's new bivalent COVID booster vaccines, also described as "updated boosters." The FDA amended  Emergency Use Authorizations to authorize the Pfizer and Moderna bivalent vaccines for persons aged 12 years and older and 18 years and older, respectively. The bivalent vaccines "add Omicron BA.4 and BA.5 spike protein components to the current vaccine composition, helping to restore protection that has waned since previous vaccination by targeting variants that are more transmissible and immune-evading." Bivalent/ updated booster vaccines are anticipated to be available later this fall for younger ages. 

Although Pfizer and Moderna ran trials in humans earlier this year with a bivalent vaccine designed to protect against both the original SARS-CoV-2 strain and the B.1 subvariant, the FDA asked both companies to switch their strategy to targeting the B.A.4/5 subvariants this spring. To fast track their vaccines and hopefully get them approved before the virus can mutate again, the FDA approved the use of data from mouse models only instead of waiting for further human trials:

Regulators [relied] on those results, along with the human neutralizing antibody data from the BA.1 bivalent booster studies, to decide whether to authorize the boosters....The companies will continue to gather more data from human studies; those results probably won't be available until late October or early November.

The FDA emphasized that this strategy has been used successfully for many years to update annual influenza vaccination components and emphasized that they "'have worked closely with the vaccine manufacturers to ensure the development of these updated boosters was done safely and efficiently.'"

Persons who have not yet received their primary COVID vaccinations need to complete that series prior to receiving the bivalent/updated booster; the bivalent/updated boosters "come in booster-sized doses" and "contain less vaccine than the primary series." For persons eligible for a COVID vaccine booster, the EUA recommends only the use of the bivalent/updated booster vaccines going forward. They also recommend a minimum of 2 months' time between the final dose of the primary series and/or last monovalent booster prior to receiving the bivalent/updated booster. Persons recovering from recent COVID-19 infection may "consider waiting a minimum of 3 months."  Some infectious disease experts, though, are recommending longer intervals:

An advisory panel to the C.D.C. voted to recommend the same interval between doses, although several members voiced concerns that two months was too short. Doctors and immunologists said that in general, people should wait around four to six months after immunization or infection. "That’s because your body will probably not generate much of an immune response so soon after a previous encounter with the virus," Aubree Gordon, an epidemiologist at the University of Michigan, said. “Your immunity level is so high that you’ll just neutralize immediately the antigen that’s being produced — you kind of reach a ceiling."

The CDC has given the green light to co-administering the bivalent/updated booster with influenza and/or any other indicated vaccinations; injection sites should be separated by a minimum of 1 inch. 

The CDC encourages all eligible persons for the bivalent/updated booster to receive it to protect against severe illness, long COVID, and the risk of transmitting the disease to those more vulnerable. If your office or care site won't be stocking it, the vaccines.gov website provides a tool to search for COVID-19 vaccine providers by zip code. The AFP By Topic on COVID-19 will continue to be regularly updated, and this recent AFP Curbside Consultation on "Vaccine Disagreement Between Parents" provides guidance regarding vaccine hesitancy. 

Neurosyphilis, ocular syphilis, and otosyphilis are don't-miss diagnoses

 - Kenny Lin, MD, MPH

When a patient with a history of migraine headaches presents with a "severe frontal headache and left-eye blurred vision and pain," neurosyphilis is unlikely to be foremost in the differential. Even after she mentions a two-month history of a diffuse maculopapular rash, clinicians may feel reassured because it doesn't involve the palms and soles. But syphilis, the great imitator, was in fact the eventual diagnosis in this patient, the subject of a case report published in Cureus.

In the August issue of AFP, Dr. Jennifer Jones-Vanderleest reviewed detection and treatment of neurosyphilis, ocular syphilis, and otosyphilis, which can occur at any stage of syphilis regardless of immune status. Early neurosyphilis (within the first few years of infection) can present with "headache, dizziness, altered mental status, cranial neuropathies, motor and sensory deficits, meningitis, or stroke." Neurosyphilis is diagnosed with the combination of neurologic signs and symptoms and reactive syphilis serology and cerebrospinal fluid (CSF) tests. The 2021 Centers for Disease Control and Prevention (CDC) Sexually Transmitted Infections Treatment Guidelines recommend that patients with neurosyphilis be treated with 18 to 24 million units of aqueous crystalline penicillin G per day for 10 to 14 days, administered as a continuous infusion or 3 to 4 million units intravenously every 4 hours. These patients should be tested for HIV and be offered HIV preexposure prophylaxis if HIV negative. After treatment, normalization of the serum RPR titer predicts normalization of CSF parameters; thus, repeated CSF sampling is not needed unless the patient is HIV positive and not receiving antiretroviral therapy.

As I discussed in a previous AFP Community Blog post, the incidence of syphilis in the U.S. has been rising for the past two decades due to stagnant health department funding for contact tracers and the recent impact of the COVID-19 pandemic. Far from being ancient history, "in 2020, 133,945 cases of all stages of syphilis were reported, including 41,655 cases of primary and secondary syphilis," according to the CDC. Although a disproportionate number of cases occur in men who have sex with men, rates in women have increased sharply since 2016.

A draft recommendation statement from the U.S. Preventive Services Task Force (USPSTF) reaffirmed screening nonpregnant adolescents and adults at increased risk for syphilis infection. The USPSTF recommends that all pregnant patients be screened for syphilis as early as possible in pregnancy. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend rescreening women at high risk for syphilis at 28 weeks of gestation and again at delivery to prevent congenital syphilis.

Their time is (past) up: Vitamin D & omega-3 supplements

 - Jennifer Middleton, MD, MPH

Recent evidence continues to challenge the routine use of two common supplements: vitamin D and omega-3 fatty acids.

A quick web search on vitamin D finds Mayo Clinic, UpToDate, and WebMD all extoling its benefits despite a lack of evidence to support its widespread use. Dr. Lin asked on the blog in 2016, "Is Vitamin D supplementation is good for anything?" Although there are a few clinical situations where vitamin D supplementation may be indicated (chronic kidney disease with secondary hyperparathyroidism, for example), vitamin D does not otherwise support mood or reduce the risk of osteoporotic fracture. An ancillary study of VITAL (Vitamin D and Omega-3 Trial) published last month in the New England Journal of Medicine randomized nearly 26,000 middle and older aged community-dwelling adults and found no benefit to vitamin D supplementation regarding fracture risk:

VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n−3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. 

An accompanying NEJM editorial declares VITAL's ancillary analysis a "decisive verdict on vitamin D supplementation." Of note, the original VITAL found no benefit for vitamin D to reduce the risk of cancer or cardiovascular disease (CVD), and it found no reduction in CVD from use of omega-3 fatty acid supplementation, either.

Another trial, REDUCE-IT, published in 2019 did find CVD benefit to omega-3 supplementation (specifically, 2 grams of icosapent ethyl daily) in persons with "elevated triglyceride levels despite the use of statins," but REDUCE-IT's findings are now being called into question. A recently published biomarker substudy found that REDUCE-IT's placebo, a pharmaceutical grade mineral oil capsule, may have increased CVD event risk among participants in the placebo group, creating a false appearance of benefit in the intervention group. These unintended harms from the study's placebo may explain why REDUCE-IT purportedly found benefit when multiple, large, previous studies have not. Like vitamin D, however, omega-3 fatty acid supplements continue to be used by millions of persons in the United States.

Changing clinical habits can be challenging. In this 2018 AFP editorial, Drs. Ebell, Shaughnessy, and Slawson describe several factors that contribute to this difficulty including practice inertia, emphasis on inductive (instead of patient-oriented, evidence-based) reasoning in medical training, and limited advertising for changes that don't benefit medical and/or pharmaceutical industries. They urge "physicians [to] accept that change is uncomfortable" and remind us that "[w]e need to remain flexible in our thinking if we are to meet our goal of doing our best when caring for every patient."

If you'd like to read more, this 2021 AFP Putting Prevention into Practice article reviews the current United States Preventive Services Task Force (USPSTF) "I" statement for vitamin D screening, and this 2019 AFP Medicine By the Numbers article reviews The NNT Group "red" rating for omega-3 fatty acid supplementation to prevent CVD.

Back to school & back to sleep: melatonin supplementation in children

- Lilian White, MD

As the end of summer approaches, children are making their way back to into the classroom. With this transition and possible changes in sleep-wake schedules, sleep disorders in children and adolescents may become more apparent. Parents may ask about the use of melatonin to treat insomnia during this transitional period.

Normal sleep duration and sleep patterns change as children age. Children 5 to 12 years old usually require 9-12 hours of sleep, and only 5 in 100 need daytime naps. Adolescents typically need 8-10 hours of nighttime sleep. Daytime napping in adolescents suggests insufficient sleep at night or a potential sleep disorder. Most high school students do not get enough sleep. This lack of sleep is associated with an increased risk of obesity, diabetes mellitus, injuries, poor mental health and attention/behavioral problems.

About 10-30% of children struggle with insomnia. Children may have difficulty initiating or maintaining sleep. They may be diagnosed with an insomnia disorder if this occurs at least 3 times per week for at least 3 months. Childhood insomnias are characterized as difficulty with sleep-association (e.g., require caregiver to be present to fall asleep) or limit-setting (e.g., absence of a regular bedtime routine). Behavioral interventions are considered first line treatment. In the Choosing Wisely campaign, the American Academy of Sleep Medicine recommends not prescribing medications to treat behavioral childhood insomnia.

Adolescents are more commonly affected by delayed sleep phase syndrome, a subtype of circadian sleep rhythm disorder. The prevalence is estimated to be 7-16%. Sleep onset and awakening are delayed by more than 2 hours for at least 3 months. A sleep diary may be helpful in making this clinical diagnosis. The most powerful influence on the circadian rhythm is light. Decreased morning light exposure and/or increased evening light exposure may worsen symptoms. Treatment of delayed sleep phase syndrome includes regular sleep-wake schedules, avoiding bright or blue light prior to bedtime, bright light therapy within the first 1-2 hours of awakening, and melatonin.

Melatonin helps the onset of sleep in the circadian rhythm. Melatonin is typically recommended at a dose of 0.3 to 5 mg taken 1.5 to 6.5 hours before bed for a short duration (i.e. days). Ideally, melatonin moves sleep onset earlier. However, if taken later – such as the middle of the night or at bedtime – it may move sleep onset later. Melatonin may be particularly helpful in children with neurodevelopmental conditions such as attention-deficit/hyperactivity disorder and autism if behavioral approaches are insufficient to improve insomnia.

Melatonin is generally well-tolerated. Adverse effects most commonly include headache, daytime sleepiness, dizziness, and nausea. The effects of long-term melatonin use in children are not well established; low-quality evidence suggests that it may affect the timing of puberty through potential downstream effects on sex hormones. More research is needed to explore this relationship.

Although melatonin may be purchased over the counter in the United States, it may be harmful if ingested at unintended high doses. Over the past few years, physicians have seen an increase in melatonin given to children, with one study noting a 7x increase. Poison control centers have reported an 530% increase in calls regarding melatonin ingestion (94% of which were unintentional). Melatonin is available in many child-friendly forms such as gummies or chewables. If melatonin use is recommended, physicians should caution parents to store melatonin in a safe place away from children.

While melatonin may present a helpful option to treat certain sleep disorders in children, behavioral interventions are still considered the most effective and first-line treatment. Additional tips for behavioral management of insomnia can be found in a recent AFP article on Common Sleep Disorders in Children and related patient education.

Guest post: A call for family physicians’ role in combating misinformation

- Alex McDonald, MD, FAAFP, CAQSM 

For years, physicians have been discouraged from sharing information in the social media space, and, as a result, misinformation and disinformation has flourished.  Over half of younger adults get much, if not all, of their news and information from social media. Those individuals who get their information via social media channels are often only exposed to information that further aligns with their or their social circle’s own views. This phenomenon has real world consequences when it comes to an individual’s beliefs and subsequent health decisions. The average person spends 2 hours a day on social media, yet only 15 minutes four times a year with their physicians; as such, it can be challenging for physicians to correct health misinformation.

 

The COVID-19 pandemic has thrust this problem into the spotlight, leaving no easy answers or solutions. Drs. Shahjahan’s and Pasquetto's AFP editorial on “Countering Medical Misinformation Online and in the Clinic” is an excellent summary of the challenge of misinformation, both in the traditional medical setting and on social media, and also provides suggestions about how to combat it. Physicians are one of the most trusted and respected professions, and we no longer can ignore or avoid correcting or addressing misinformation when we confront it in the clinic or online. We must educate ourselves and our colleagues to learn the skills and understand the importance of consistent yet respective discourse with patients. We can no longer afford to simply avoid disagreement in the exam room or online.  These conversations are not always easy and often do not occur in a single setting, but speaking up and consistently correcting misinformation by all physicians can and will have an impact. 

 

The Federation of State Medical Boards made a strong statement in June 2021 condemning and threatening sections against licensed medical professionals who spread misinformation, yet there has been a noticeable lack of action, even for the most egregious offenders. I believe that health professionals spreading misinformation and disinformation are the most harmful and the hardest to address. As a medical community, we must find the will to confront colleagues or other medical organizations that are touting anecdotal or non-evidenced based information. There is not always a single right answer in medicine, but there are clearly wrong answers. We must not allow others to corrupt or misrepresent science for their own benefit, and we must not allow this to propagate or the trend to continue. There is often debate within the medical literature, and often evidence-based medicine begins with anecdote or case studies, but we must not mistake early emerging information, that warrants further investigation, with evidence-based science.  

 

Physicians, who specialize in relationships, trust, and understanding, are best equipped to tackle this challenge. Collaboration, connection, and compassion are all are key - who better to do this work than family physicians? A strong and trusted social media account is a tool in the bag of the 21st century physician to share accurate and trusted information beyond the walls of the clinic or hospital. We must each also acknowledge our own role in inadvertently spreading misinformation. We are human and we are all susceptible to the emotions and bias on which misinformation thrives. We must educate ourselves to spot misinformation when we see it, and not just hit the “like” or “share” button, to stop misinformation in its tracks. We must not comment or engage with misinformation as this only boosts its reach; instead, ignore, block and move on.

No single person or approach is going stem the tide of pervasive misinformation and disinformation. It’s going to take all of us to educate ourselves, our colleagues, and our patients. 

 

Additional Resources: 

UNICEF - https://www.unicef.org/eca/media/13636/file 

Washington Post - https://www.washingtonpost.com/lifestyle/2021/02/24/doctor-nurse-online-vaccine-rumors/ 

MisinforRx - https://misinforx.com/resources/ 

Health and Human Services - https://www.hhs.gov/sites/default/files/health-misinformation-toolkit-english.pdf 

World Health Organization - https://www.who.int/docs/default-source/coronaviruse/vaccine-misinformation-toolkit_desktop1.pdf?sfvrsn=1da119fb_1&download=true