Preventing mumps and COVID-19: don't let perfect be the enemy of good

 - Kenny Lin, MD, MPH

The lower efficacy of COVID-19 vaccines against the SARS-CoV-2 Omicron variant due to viral mutations and waning immunity of the initial series has unfortunately fueled an anti-vaccination narrative that a less-than-perfectly protective vaccine has little clinical value. A comparison to a well-established childhood vaccine exposes the flaw in this argument. According to a 2020 Cochrane review, the effectiveness of measles, mumps, and rubella (MMR) vaccine in preventing mumps is 72% after one dose and 86% after two doses. After the two-dose MMR vaccine was added to the U.S. childhood immunization schedule, though, the number of reported cases of mumps fell from >150,000 in 1968 to 231 in 2003. In the past two decades, outbreaks have occasionally increased the incidence to several thousand reported cases per year. 

A recent study in Pediatrics examined the epidemiology of mumps in U.S. children and adolescents from 2007 to 2019. It found that 87% of children diagnosed with mumps during this period had received at least one dose of MMR vaccine, including most of the 2% of children who required hospitalization. Also, only 2% of cases were associated with international travel. The authors concluded that "clinicians should suspect mumps in patients with parotitis or mumps complications, regardless of age, travel history, and vaccination status."

For family physicians who have never seen a patient with this infection, a 2014 American Family Physician article on salivary gland disorders noted that mumps typically causes bilateral pain and edema of the parotid glands, otalgia, and trismus. Rarely, it can cause meningitis and encephalitis, as illustrated in a recent BMJ case report. Mumps spreads through airborne droplets (salivary, nasal, and urinary secretions) and is highly contagious. The diagnosis should be confirmed with reverse transcriptase-polymerase chain reaction (RT-PCR) or viral culture of a sample obtained with a buccal swab.

In fully vaccinated individuals, giving a third or "booster" dose of MMR vaccine was shown to reduce the risk of mumps during a 2015-16 U.S. college outbreak and 3 separate outbreaks in Queensland, Australia in 2017-18. Based on these studies, in 2018 the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommended that MMR-vaccinated individuals who are "part of a group or population at increased risk for acquiring mumps because of an outbreak" should receive a third dose of MMR vaccine "to improve protection against mumps disease and related complications." Sound familiar? Family physicians should continue to recommend that patients receive authorized COVID-19 vaccines and booster doses and not let the perfect be the enemy of the good.

Does periodontal disease contribute to other chronic diseases?

 - Jennifer Middleton, MD, MPH

Small studies have implicated periodontal disease with an increased risk of several chronic diseases, and a much larger cohort study now seeks to confirm this connection. Researchers in the United Kingdom reviewed over 15 million patient records from across the country and found that patients with a documented diagnosis of periodontal disease were more likely than those without to have additional chronic diseases, including cardiovascular disease (CVD), autoimmune disease, and mental illnesses.

The researchers reviewed records from general practices across the UK, identified over 64,000 patients with documented periodontal disease (inflammation of the gums and/or teeth ranging in severity from gingivitis to tooth loss), and matched them with 251,000 patients without documented periodontal disease by age, sex, and socioeconomic status. Records were followed for a median of 3.3 years (cases) and 3.5 years (controls):

At study entry, the exposed cohort had an increased likelihood of having a diagnosis of cardiovascular disease (aOR [adjusted odds ratio] 1.43; 95% CI 1.38 to 1.48), cardiometabolic disease (aOR 1.16; 95% CI 1.13 to 1.19), autoimmune disease (aOR 1.33; 95% CI 1.28 to 1.37) and mental ill health (aOR 1.79; 95% CI 1.75 to 1.83) compared with the unexposed group. During the follow-up of individuals without pre-existing outcomes of interest, the exposed group had an increased risk of developing cardiovascular disease (HR 1.18; 95% CI 1.13 to 1.23), cardiometabolic disease (HR 1.07; 95% CI 1.03 to 1.10), autoimmune disease (HR 1.33; 95% CI 1.26 to 1.40) and mental ill health (HR 1.37; 95% CI 1.33 to 1.42) compared with the unexposed group.

This study does have some potential limitations. It makes intuitive sense that persons less able to access preventive dental care may also have other chronic diseases caused or exacerbated by lack of access to medical care; the design of a retrospective cohort study cannot establish causation. Given how under-diagnosed and prevalent periodontal disease is worldwide, it's also possible that a significant portion of the control group had periodontal disease that was simply not noted in their electronic medical record. On the other hand, plausible biologic mechanisms suggest that chronic inflammation from periodontal disease may activate inflammatory cascades elsewhere in the body, the study's researchers used appropriate statistical techniques to mitigate confounding variables as much as possible, and the number of patient cases included is, by far, the largest to date.

No study has definitively demonstrated that treatment of periodontal disease improves outcomes in any of these chronic disease states (though low-quality studies have shown that treatment of periodontal disease may lower A1c values in persons with diabetes). Perhaps this new study's findings will inspire further research. In the meantime, it still  makes sense for family physicians to include assessment and counseling regarding oral health in our practices; at a minimum, treating periodontal disease can improve quality of life for persons regarding its associated mouth pain, difficulty with chewing food, and/or difficulty with enunciation.

Periodontal disease is the most common chronic disease in childhood, and at least 25% of U.S. adults over the age of 65 have lost all of their teeth as a consequence of untreated periodontal disease. Let's collectively make a New Year's resolution for 2022 to screen all of our patients for periodontal disease and routinely encourage regular dental care. There's an AFP By Topic on Oral and Dental Conditions, developed in collaboration with the Academy of General Dentistry, with a wealth of resources if you'd like to read more.  

The top ten AFP Community Blog posts of 2021

 - Kenny Lin, MD, MPH

Two years into the pandemic, our most popular blog posts continue to focus on prevention or treatment of COVID-19. As you are hopefully enjoying time with family and friends over the holidays, here is an opportunity to catch up on the top 10 most-read AFP Community Blog posts of 2021.

1. Patient-centered discussion of COVID-19 infection and mRNA vaccines (June 1) - 2188 views

Few patients understand what the SARS-CoV-2 virus does to the human body or how a COVID-19 messenger RNA (mRNA) vaccine works. The following patient-centered explanation utilizes readily understood metaphors and two clear, simple illustrations that you may use in your vaccine counseling visits.

2. Can Choosing Wisely prevent acute low back pain from becoming chronic? (March 8) - 1142 views

Can guideline-discordant care for patients with acute low back pain increase the risk of progression to chronic low back pain? In an study published in JAMA Network Open, researchers enrolled 5233 adults with acute low back pain from 77 U.S. primary care practices, assessed their baseline risk of transition to chronic pain, and followed them for 6 months.

3. Discussing COVID-19 vaccine risks with patients (July 6) - 861 views

Researchers reviewed two-and-a-half months of data from vaccine safety surveillance systems, including over 35,000 pregnant persons, and found rates of preterm birth and miscarriage comparable to established rates pre-pandemic.

4. COVID vaccine boosters: now, later, or never? (August 2) - 816 views

Reports of breakthrough infections in persons fully vaccinated have contributed to many alarming headlines, though public health experts have been quick to emphasize that the vast majority of severe infections are occurring in unvaccinated persons.

5. COVID vaccine update: new data and new vaccines (February 1) - 807 views

Assuming supply and distribution challenges are eventually overcome, vaccine hesitancy may pose another threat to decreasing SARS-CoV-2 transmission, which is critical to slowing the development of additional COVID variants.

6. New (old) treatments for COVID: inhaled budesonide and the -umabs (February 15) - 796 views

Researchers have identified two classes of medications that may benefit patients with symptomatic COVID-19, both well-known medications already in use for other conditions.

7. Interpretation and use of COVID-19 diagnostic tests: key resources (April 20) - 746 views

A analysis in the Annals of Internal Medicine estimated that a weekly home-based antigen testing program could avert 2.8 million infections and 15,700 deaths in the U.S. over a 60-day time frame, at a cost of less than $8000 per infection averted.

8. Understanding and managing long COVID (May 3) - 725 views

The racial health disparities seen in acute COVID-19 will likely translate into similar disparities in long COVID, exacerbated by structural barriers to health and care access (economic, geographical, housing and segregation, and occupational) that could impede recovery.

9. Should we choose ARBs over ACEis for hypertension? (October 25) - 703 views

There was no statistically significant difference between the ACEi and the ARB groups regarding risk of CVD events, but ACEi patients had more adverse medication reactions.

10. Pharmacogenetic testing's promise, problems and pitfalls (July 27) - 673 views

Though pharmacogenetic testing holds promise for improving clinical decision-making, race-based testing recommendations are problematic. Even a racially homogenous European country such as Switzerland exhibits wide genetic diversity in the frequency of the HLA-B*58:01 allele, with one city (Basel) actually having a higher frequency than the U.S. African American population.

Studying sildenafil's potential to prevent Alzheimer's disease

 - Jennifer Middleton, MD, MPH

As the controversy over aducanumab's FDA approval for Alzheimer's disease continues, another potential treatment for Alzheimer's has been garnering attention. Using a complex gene-mapping technique, a team of U.S. researchers identified sildenafil (Viagra, Revatio), out of a group of more than 1,600 FDA approved medications, as having the potential to target both amyloid and tau protein formation. Further case-control analysis demonstrated a decreased risk of Alzheimer's among individuals who had received a sildenafil prescription compared to those who had not.

The researchers began with the hypothesis that an effective Alzheimer's medication should target both amyloid and tau, given the failure to date of attempts to create effective, separate anti-amyloid and anti-tau therapies:

“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” said Dr. Cheng [the study's lead investigator]. “Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”

The researchers then used a "large gene-mapping network" which "integrated genetic and other biologic data" and scored each medication based on its effect on amyloid and tau, with higher scores for medications that targeted both. When sildenafil received the top score, the researchers then analyzed over 7 million insurance claims records and found that "sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio 0.31, 95% confidence interval 0.25–0.39, P < 1.0 × 10–8)." The study team correctly notes that "[t]he association between sildenafil use and decreased incidence of AD does not establish causality, which will require a randomized controlled trial," which the study team is currently planning.

The implications of this "big data" approach to identifying novel treatments among approved FDA medications ("drug repurposing") is tantalizing, and the sildenafil/Alzheimer's research team is reportedly already investigating applying this approach to Parkinson's disease and amyotrophic lateral sclerosis. Perhaps this study portends a new wave of research to benefit patients with diseases that, to date, have limited therapeutic options. 

None of the study researchers is advising the use of sildenafil yet for Alzheimer's disease, though you can find an overview of currently approved treatment options (minus aducanumab, which was not yet available at the time of publication) in this AFP article on "Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms." There's also an AFP By Topic on Dementia if you'd like a more in-depth review.

Mitigating the impact of substance use disorders on family members

- Kento Sonoda, MD, AAHIVS

In the United States, the estimated number of overdose deaths between May 2020 and April 2021 surpassed 100,000, even worse than a record 93,000 last year. As 20.4 million people age 12 years or older were diagnosed with a substance use disorder (SUD) in 2019, the number of the impacted family members is likely 50 million or more. Numerous studies have examined the negative health impacts on individuals with SUD, but studies about the effects of addiction on family members are limited. SUD can negatively affect family members’ health, especially mental health, along with their quality of life, work, and finances. Barriers such as stigma, limited support services, hopelessness, and feeling undervalued deter affected family members from seeking help. Sacrificing their time and money for loved ones who are suffering from SUD can lead family members to neglect their own chronic medical conditions.

For instance, I cared for a woman in her early 50s whose husband struggles with alcohol use disorder, which caused him to lose his job. She developed new heart failure with reduced ejection fraction secondary to uncontrolled hypertension, likely from stopping all of her antihypertensive medications due to financial burden and self-neglect. She disclosed that she does not have enough time and energy to take care of herself. She had not asked for help or received medical care because of stigma and isolation until she could not tolerate her symptoms any more.

As the number of patients with SUD has been increasing, family physicians play a central role in taking care of these patients and their family members. Additionally, the COVID-19 pandemic has worsened mental conditions and potentially exacerbated the negative consequences for family members. When uncontrolled chronic conditions or mental illnesses are identified in the outpatient setting, screening for family members with SUD can be considered as a means to better understand the full situation and provide support and helpful resources as needed.

The following resources are available for family members and loved ones of individuals with substance use disorders: Adult Children of Alcoholics World Service Organization (a 12-step, 12-tradition program of people who grew up in dysfunctional homes due to substance use disorder), Al-Anon (a mutual support program for people whose lives have been affected by someone else’s drinking), Alateen (a part of the Al-Anon Family Groups for young people), Family Anonymous (a 12-step fellowship for the family and friends of those individuals with substance-related issues), Nar-Anon (a 12-step program for family and friends with SUD), and National Association for Children of Addiction (the only national membership organization focusing on the children of parents struggling with SUD).

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Dr. Sonoda is an Addiction Medicine Fellow at the University of Pittsburgh Medical Center and the 2021 AFP Resident Representative.

Will COVID antivirals help end the pandemic?

 - Jennifer Middleton, MD, MPH

The U.S. Food and Drug Administration (FDA)'s advisory committee voted last week in favor of approving molnupiravir, Merck's oral antiviral medication for COVID-19. The FDA is expected to follow the committee's recommendation and authorize use of the drug this week under an Emergency Use Authorization (EUA). Pfizer is also preparing an EUA application for its antiviral medication, ritonavir. While the development of additional treatments to combat COVID-19 is cause for some optimism, it may be too early to celebrate given the limited, preliminary nature of both medications' efficacy to date.

Data from molnupiravir's phase 2a trial has not yet been peer reviewed; outcomes demonstrated reasonable tolerability and a substantial reduction of viral load. Merck also announced phase 3 data demonstrating a nearly 50% reduction in death and hospitalization for outpatients with laboratory-confirmed COVID-19 infection who began taking it within 5 days of symptom onset. This data came from an interim analysis of 775 trial participants with "mild to moderate COVID-19" and "one risk factor associated with poor disease outcome." The trial's independent data review committee recommended terminating the trial early given these findings, but continued follow-up of study participants has demonstrated a lower efficacy of about 30%. That trial's data is not yet available for public review but was reportedly considered by the FDA advisory committee. The advisory committee vote was close (13-10); committee members who voted "yes" despite molnupiravir's modest efficacy cited the lack of other antiviral treatments available, with some suggesting that approval could be later rescinded if better treatments are developed. Members voting "no" raised concerns about the drug's risk of teratogenesis as well as its potential to induce dangerous mutations into the SARS-CoV-2 virus:

“Even if the probability is very low, 1 in 10,000 or 100,000, that this drug would induce an escape mutant from which the vaccines we have do not cover, that could be catastrophic...” Dr. James Hildreth, CEO of Meharry Medical College in Nashville, Tenn., told the panel.

Pfizer's ritonavir has had more promising results. Its phase 2/3 trial enrolled just over 1200 "non-hospitalized adults aged 18 and older with confirmed COVID-19 who are at increased risk of progressing to severe illness" who were randomized to either receive placebo or ritonavir within 5 days of laboratory-confirmed COVID-19 infection. Pfizer reported an 85% reduction in the risk of hospitalization or death in enrolled participants with a no significant difference of adverse events between groups (21% placebo vs 19% ritonavir). This study was also stopped early due its positive interim findings; it remains to be see whether these positive findings will persist with further analysis.

While oral antiviral medications may be "another tool in our toolbox" as touted by U.S. President Biden, vaccination remains the most critical element to stem the development of new SARS-CoV-2 mutations as well as the pandemic. The worldwide vaccine supply is adequate to meet the World Health Organization's ambitious vaccination goals if "distributed equitably."

In the meantime, the AFP By Topic on COVID-19 continues to be regularly updated, with sections on Prevention (including this Lown Right Care article on "Helping Ambivalent Patients Make Healthy Decisions About COVID-19") and Treatment.