Do probiotics reduce the risk of Clostridioides difficile colitis?

 Jennifer Middleton, MD, MPH

"Health Care-Associated Infections: Best Practices for Prevention" published by AFP online ahead of print last week reviews evidence-based recommendations to reduce the risk of hospitalized patients acquiring SARS-CoV-2, catheter-associated urinary tract infections (CAUTIs), central line-associated bloodstream infections (CLABSIs), ventilator-associated pneumonia (VAP), surgical site infections, and Clostridioides difficile (C diff) colitis. Of the authors' key recommendations for practice, the one that might be the most unexpected is the use of probiotics to prevent C diff colitis.

Clostridioides difficile colitis, also referred to as Clostridioides difficile-associated diarrhea (CDAD), caused "an estimated 223,900 cases in hospitalized patients and 12,800 deaths in the United States" in 2017, the latest year for which data is available per the Centers for Disease Control and Prevention (CDC); a 2020 study estimated the incidence of CDAD at 8.3 cases per 10,000 patient-days, increasing the length of hospital stays by at least 3 days and as much as 21.6 days. Given this morbidity and mortality burden, several studies have examined the use of probiotics to reduce the risk of acquiring CDAD, especially in hospitalized patients receiving antibiotics. 

In 2017, a Cochrane meta-analysis assessed the literature to date on the use of probiotics to prevent CDAD. The authors ended up including 39 studies:

 A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate)....However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). 

The Cochrane authors found a number needed to treat (NNT) of 42 among all study participants, and a NNT among participants at high risk of CDAD of 12. The definitions of "high risk" varied a bit among studies, but most were close to the CDC's parameters of age 65 years and older, hospital or nursing facility admission, immunocompromise, and/or a previous history of CDAD. The Cochrane reviewers acknowledged that, of the 39 included studies, "27 studies were rated as either high or unclear risk of bias."

A 2021 letter in the Journal of the American Board of Family Medicine argues further for the routine use of probiotics for all hospitalized persons receiving antibiotics. In addition to reviewing the 2017 Cochrane review's findings, the authors of this letter also discuss the findings of a 2020 systematic review regarding the cost reduction associated with use of probiotics to reduce CDAD and state that even though "[l]ack of standardization and heterogeneity of treatment remain challenges to implementing probiotic therapies," "the positive results and favorable safety profiles across studies are reassuring." The authors of this AFP article on "Probiotics for Gastrointestinal Conditions: A Summary of the Evidence" also conditionally recommend the use of probiotics to prevent CDAD and other forms of antibiotic-associated diarrhea.

As noted in this 2020 AFP article on "Clostridioides difficile Infection: Update on Management," the Infectious Disease Society of America (IDSA) does not currently recommend the use of probiotics to prevent CDAD, citing the limitations of studies done to date and the potential risks of prescribing probiotics for immunocompromised persons. It remains to be seen when the IDSA might update their 2018 guideline, but one thing the IDSA and the AFP authors agree on is the importance of antibiotic stewardship in reducing CDAD. 

While we await that guideline update and, hopefully, more robust studies, it may be reasonable to consider patient-centered decision making regarding probiotics' potential risks and benefits for our hospitalized patients who need antibiotics and are at high risk of CDAD. 

Newer glucose-lowering drugs also treat obesity and heart failure

 - Kenny Lin, MD, MPH

Last June, the U.S. Food and Drug Administration (FDA) approved a weekly semaglutide (Wegovy) subcutaneous injection for chronic weight management in adults with obesity or overweight with at least one weight-related condition, based on randomized controlled trial (RCT) evidence that it produces substantial weight loss in persons with a body mass index of 27 or greater without diabetes. A lower dose of semaglutide (Ozempic), a glucagon-like peptide-1 (GLP-1) receptor agonist, had previously been approved by the FDA as a second-line therapy for patients with type 2 diabetes that reduced risk of major adverse cardiac events (MACE) in patients with established cardiovascular disease (CVD).

A 2021 BMJ clinical practice guideline examined the benefits and harms of GLP-1 receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors and made recommendations for use of these two drug classes in persons with type 2 diabetes and different levels of CVD risk with and without chronic kidney disease, summarized in Patient-Oriented Evidence That Matters in the January issue of American Family Physician. A related editorial by Dr. Sandy Robertson discussed how evidence can inform when to recommend starting a diabetes drug from one of these two CVD risk-lowering classes:

Current data strongly support a reduction in MACE and all-cause mortality with SGLT-2 inhibitors and GLP-1 agonists in patients who have diabetes with established CVD or kidney disease. These patients should be offered one of these medications in the absence of contraindications, regardless of glucose control. Because there is no significant reduction in cardiovascular outcomes in patients who have diabetes without established CVD, patient-centered shared decision-making about adding an SGLT-2 inhibitor or a GLP-1 agonist for cardiovascular benefit is important and ... based on other established benefits such as weight control (moderate net weight loss for GLP-1 agonists and small weight loss for SGLT-2 inhibitors) against risks of genital infections (SGLT-2 inhibitors) or gastrointestinal disturbances (GLP-1 agonists).

Although GLP-1 agonists are associated with greater weight loss than SGLT-2 inhibitors, a population-based cohort study using Medicare and two U.S. commercial claims data sets found that starting a SGLT-2 inhibitor, compared to starting a GLP-1 agonist, reduced the relative risk of hospitalization for heart failure by about 30 percent in patients with and without CVD. A recent international RCT (622 centers in 23 countries) found that adding the SGLT-2 inhibitor empagliflozin (Jardiance) to usual therapy for patients with heart failure with preserved ejection fraction improved a composite outcome of CVD mortality and hospitalization, regardless of the presence of diabetes (RRR=19%, NNT=31). Similarly, a systematic review and meta-analysis of 8 earlier RCTs found that in heart failure patients without diabetes, SGLT-2 inhibitor treatment reduced the risk of this composite outcome by 20 percent.

Based on this new data, should primary care physicians consider adding a SGLT-2 inhibitor to the standard combination of drug therapies for their patients with heart failure? A qualitative study of Australian general practitioners suggested that knowledge gaps, drug adverse effects, and a preference for subspecialists to initiate SGLT-2 inhibitor therapy may be obstacles to increased prescribing of these drugs, which remain very expensive in the U.S.

"Test-To-Stay" part of the strategy to keep children in schools

 - Jennifer Middleton, MD, MPH

As the COVID-19 pandemic continues to set records for cases and hospitalizations, some schools in the United States (U.S.) are closing schools again - some due to staff and teacher shortages, and some in an attempt to slow COVID-19 spread. Toward the end of last month, the Centers for Disease Control and Prevention (CDC) released new data demonstrating that "Test-To-Stay" can help keep schools open - and children in schools - safely.

The CDC describes its "Test-To-Stay" (TTS) strategy as:

...a practice comprised of contact tracing and serial testing (testing that is sequentially repeated) to allow school-associated close contacts who are not fully vaccinated to continue in-person learning during their quarantine period. While implementation of TTS may vary, contact tracing and testing as well as masking of contacts during their in-school quarantine period are integral to minimize risk of transmission. 

The CDC cites two U.S. studies (Los Angeles, California and Lake County, Illinois) and one study from the United Kingdom to justify TTS. The LA study compared 39 districts using TTS to 39 districts following traditional quarantine guidance and found no difference in COVID-19 case rates. The Lake County study followed 90 schools using TTS and found only a 1.5% rate of secondary transmission. The UK study randomized 86 schools using TTS to 76 schools that followed traditional quarantine guidance and found no difference in COVID-19 cases. The Lake County study estimated that "up to 8,200 in-person learning days" were saved as a result of their TTS protocol. The CDC emphasizes that TTS must be part of a "layered prevention program" that also includes masks and social distancing. 

TTS is only necessary for unvaccinated children, but vaccination rates for children aged 5-11 years in the U.S. remain quite low. "[J]ust over 17%" of children aged 5-11 years and 54% of children aged 12-17 years are fully vaccinated as of last week. If those numbers do not substantially improve, which is, unfortunately, not expected to happen, TTS may continue to be needed for the forseeable future.

TTS only works with access to rapid tests, which has proved challenging throughout the U.S. As 2 days ago, the Biden administration now requires U.S. health insurance companies to cover the cost of up to 8 rapid COVID-19 tests per person per month. The Biden administration is "strongly incentivizing health plans and insurers to set up a network of convenient locations...where people... will be able to order online or walk in and pick up at-home over-the-counter COVID-19 tests for free." The Centers for Medicare & Medicaid Services (CMS) advises consumers to check with their health insurance plan to see whether they are supporting a "convenient location" or if they will, instead, need to pay up front and then submit for reimbursement. COVIDtests.gov will also begin accepting orders on January 19 and will not require a credit card. Removing the financial and physical access barriers to testing is a must if TTS is to be successfully implemented. 

CMS has a website with answers to questions regarding access to free rapid tests, and you can read the full details of the requirements here if interested. The AFP By Topic on COVID-19 also includes this Cochrane for Clinicians article on "Rapid Point-of-Care Antigen and Molecular Tests for Diagnosis of SARS-CoV-2 Infection" if you'd like to read more.

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.