Gina Battaglia, PhD

 has shifted toward more targeted, microbiome-sparing approaches to decrease recurrence and improve clinical outcomes. Demonstrating the return on investment will be important to increase the uptake of these new, more expensive agents, according to panelists who participated in a 

: Updates to Clinical Practice Guidelines

, noted that an update to the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) guidelines prioritized fidaxomicin as the primary agent recommended for patients with initial and recurrent episodes of CDI. The update was based on data showing lower rates of recurrence with fidaxomicin than with vancomycin, including from the initial phase 3 trial (NCT00314951)1 in patients with clinically diagnosed CDI (initial or recurrent) and the phase 3b/4 EXTEND trial (NCT02254967) that used an extended-pulsed fidaxomicin in hospitalized patients 60 years or older.2 The update was delivered as provisional recommendations at IDWeek 2020.

“Fidaxomicin seems to come to the forefront for treatments with the initial episode,” said 

. “When fidaxomicin came out, I don’t think many people were familiar with the term ‘sustained clinical response.’ That seems to be the advantage of using [fidaxomicin] in many patients, that they are less likely to have recurrences.”

Lodise added that the provisional IDSA/SHEA recommendations included an additional recommendation for bezlotoxumab, a human monoclonal antibody that targets toxin B, in individuals who are at high risk for recurrence, aged 65 or older, are immunosuppressed, have a history of CDI, or have severe CDI. The MODIFY I and MODIFY II trials (NCT01241552 and NCT01513239) showed that bezlotoxumab was associated with lower rates of recurrence in multiple prespecified subgroups, including patients who were 65 years or older, had immunocompromised status or severe CDI, or who had had a CDI episode within the past 6 months.3

Adequate treatment of CDI is particularly challenging because it requires eradicating the 

 organism while attempting to restore the microbiota, according to 

. He added that optimally effective treatment involves antimicrobial therapy (such as vancomycin or fidaxomicin) followed by modulation of the immune system with bezlotoxumab or microbiota restoration therapy to “give 

Most patients who receive either fidaxomicin or vancomycin will respond and will get better,” said Feuerstadt. “What we’re talking about with other therapies are those subgroups that are at greater risk: age over 65, history of immune suppression, history of 

, the NAP1/B1/027 strain, severe infection, patients on PPIs [proton pump inhibitors], [and] patients who received concomitant antimicrobials. Those are the individuals that we’re really focusing on [to gain a] better understanding of how we get rid of this.”

Feuerstadt added that the “entire clinical gestalt” of a patient should be considered in the approach to therapy; factors that may affect management decisions include source of infection (community or health care setting) and presence of multiple risk factors for recurrence, severe disease, and high white blood cell count and creatinine.

“Deciding between vancomycin and fidaxomicin to me really boiled down to those factors and risk factors for recurrence,” said Feuerstadt. “Fidaxomicin’s sweet spot is that it is associated with statistically significant reduction in rates of recurrence. Patients who have multiple high-risk factors for recurrence would benefit from that product.”

Fidaxomicin is a macrolide-like antibiotic that inhibits RNA synthesis by binding to bacterial RNA polymerase4 and has potent activity against CDI, according to Lodise. He added that the more targeted approach, less disruption of the gut microbiota, and lower minimum inhibitory concentration with fidaxomicin likely contribute to the lower rates of recurrence compared with vancomycin. “It’s that prolonged disruption of the microbiota [with vancomycin] that drives a lot of the adverse outcomes we see in some of our CDI patients,” he said.

“When we think about treating CDI from a stewardship standpoint, our thought [is], ‘How do we stop that event from moving forward?’ Although we appreciate the similar clinical response, we were very impressed with a lot of the lower recurrence data and particularly with some of the altered dosing with fidaxomicin in one of their 2 trials.”

Lodise noted that the tapered and pulsed regimen of fidaxomicin may be beneficial for treating a recurrent episode while facilitating recovery of the microbiota, but that developing additional methods to replenish the microbiota will be important moving forward.

Reilly noted that although the data appear to support the use of fidaxomicin in the first-line setting, the high acquisition cost of the drug relative to vancomycin remains a concern. However, he and Salgo agreed that using the more expensive fidaxomicin could reduce overall costs of care in the long run and improve patient outcomes by reducing readmission rates and other comorbidities.

“It’s that silo budget mentality, just looking at how much we’re spending and not looking at the outcomes,” said Reilly. “If I spend more money and it’s saved somewhere else by decreasing admissions that might lose money…people often don’t take that into consideration.”

, said that patient-centered outcome research could help demonstrate the overall improvement in clinical outcomes and cost savings with fidaxomicin. Chopra and her colleagues performed an analysis of a patient discharge database that showed that the 30-day readmission rate was higher for patients with CDI than those without CDI (30.1% vs 14.4%).5 In addition, results from a single-center retrospective study demonstrated that, on average, treatment with fidaxomicin saved the hospital $3207 per patient compared with vancomycin treatment (even though the drug costs were higher with fidaxomicin), largely attributable to the lower readmission costs associated with fidaxomicin.6

Lodise noted that the financial penalties associated with high rates of CDI and readmission and the escalating costs associated with multiple recurrences should encourage the shift toward fidaxomicin. He added that the 2020 IDSA/SHEA provisional recommendations were an important step forward in the acknowledgment of return on investment by including the number needed to treat.

“I think we need to stop talking about drugs in terms of dollars and cents, which we’re never going to get away from, and rather say, ‘If I do this, these are the adverse events I’m going to prevent,’” said Lodise. “We must change the script a bit. Cost is always going to be the common denominator, but we need to talk about how, with this investment, this is going to be [the] return, and we must make that return in terms of dollars and cents as well.”

Choosing Between Vancomycin and Fidaxomicin for 

Feuerstadt highlighted the fact that the lower recurrence rates observed in multiple trials comparing fidaxomicin with vancomycin were also observed in real-world data from the United Kingdom.7 This study, which assessed recurrence rates in the year before and after local introduction of fidaxomicin in 7 UK hospitals, showed that 2 hospitals that used fidaxomicin in the first-line setting for all primary and recurrent infections had a decrease in recurrence rate (10.6% to 3.1% and 16.3% to 3.1% for hospitals “A” and “B,” respectively).7 Feuerstadt noted that even the hospital that used fidaxomicin only for first recurrences (hospital “D”) had a decrease in recurrence rate (12.5% vs 21.1%, prior to fidaxomicin), suggesting that the real-world data reflect the results observed in phase 3 clinical trials.7

“What we’re seeing is no matter how fidaxomicin is being used, if a health care system commits to it, it seems to remarkably reduce those rates of recurrence,” concluded Feuerstadt.

Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. 

. 2011;364(5):422-431. doi:10.1056/NEJMoa0910812

Guery B, Menichetti F, Anttila VJ, et al; EXTEND Clinical Study Group. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. 

. 2018;18(3):296-307. doi:10.1016/S1473-3099(17)30751-X

Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. 

. 2017;376(4):305-317. doi:10.1056/NEJMoa1602615

Dificid. Prescribing information. Merck & Co, Inc; 2020. Accessed June 18, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213138lbl.pdf

Chopra T, Neelakanta A, Dombecki C, et al. Burden of Clostridium difficile infection on hospital readmissions and its potential impact under the Hospital Readmission Reduction Program. 

. 2015;43(4):314-317. doi:10.1016/j.ajic.2014.11.004

Gallagher JC, Reilly JP, Navalkele B, Downham G, Haynes K, Trivedi M. Clinical and economic benefits of fidaxomicin compared to vancomycin for Clostridium difficile infection. 

. 2015;59(11):7007-7010. doi:10.1128/AAC.00939-15

Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations. 

. 2016;35(2):251-259. doi:10.1007/s10096-015-2538-z

Articles

Paradigm Shift in the Management of Clostridioides difficile Infections


Columbia University Irving Medical Center
New York, NY


School of Medicine—Wayne State University
Detroit, MI


Edward Hines Jr Veterans Affairs Hospital
Chicago, IL


Albany College of Pharmacy and Health Sciences
Albany, NY


AtlantiCare Regional Medical Center
Atlantic City, NJ

Identification of patients to undergo testing for 

 infection (CDI) is largely based on a high index of suspicion, although the role of asymptomatic carriage in transmission highlights the importance of infection control in inpatient and outpatient settings, according to experts who participated in a 

, also discussed recommendations for treatment of recurrent CDI and considerations for selecting the most appropriate treatment method.

The 2017 guidelines from the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) state that patients with unexplained and recent onset of at least 3 unformed stools in a 24-hour period are the “preferred target population for testing” of CDI.1 However, 

 noted that presentation of CDI can range from mild symptoms to severe sepsis, fulminating colitis, or death and that clinical judgment is the most important consideration when selecting patients for testing. She said that presence of risk factors for CDI along with fever, elevated white blood cell (WBC) count, and frequent diarrheal stools increases suspicion; however, she added that diarrhea can also be associated with antibiotics, parasites, or consumption of contaminated food or water and that testing every patient with diarrhea would likely lead to overdiagnosis because individuals may be colonized with nontoxigenic forms of 

, noted that with the increase in pay-for-performance initiatives and public reporting of CDI rates, hospitals are particularly motivated to ensure that the CDI rates are low to prevent financial penalties and that positive tests for patients who are colonized with nontoxigenic 

, added that, rather than testing for CDI in any patient with diarrhea as a “knee-jerk reaction,” clinicians should broaden the differential diagnosis and evaluate the clinical presentation, such as assessing for the presence of blood in the diarrhea or whether the diarrhea is secretory or osmotic.

He added that irritable bowel syndrome (IBS) and postinfection IBS can complicate the clinical picture and that it is important to determine whether another bout of diarrhea indicates a recurrent infection or an alternative issue in a patient with a history of CDI to direct therapy appropriately. However, Feuerstadt said that patients with inflammatory bowel disease (IBD) are an exception, so all patients with IBD who experience an exacerbation should undergo testing for CDI because of the high incidence in this population.

Feuerstadt said that in addition to the IDSA/SHEA guidelines that provide recommendations for selecting candidates for testing, factors such as WBC count, creatinine level, and recent history of antimicrobials are also helpful to consider.

“If a patient has loose stools and recently received antimicrobials, they’re in the [intensive care unit], and their white [blood cell] count is 40,000, you probably know what’s going on there,” he said. “That might be a circumstance where time is of the essence and you might send off a stool assay before starting antimicrobials, but you may also want to empirically start antimicrobials due to your suspicion that [

, also pointed out that the work-up for a patient with community-acquired diarrhea needs to be different than for a patient with health care–associated diarrhea, in which CDI is high on the list of probable causes. For example, he recommended a multiplex polymerase chain reaction platform for patients with community-associated diarrhea to rule out multiple other potential causes.

In general, tests for CDI detect the organism itself or its primary toxins (toxin A and/or B). Commonly available options include toxigenic culture, nucleic acid amplification test (NAAT), glutamate dehydrogenase (GDH) assay, cell culture cytotoxicity neutralization assay, and toxin A and B enzyme immunoassays. Gerding noted, however, that the cell culture cytotoxicity neutralization assay has become obsolete because it is time consuming and difficult to perform.1

The NAAT is among the more commonly used tests in the United States and detects several toxin gene targets in the organism, although it has a low to moderate specificity and may pick up cases of patients colonized with 

, according to Gerding. He added that specific toxin tests, typically performed using enzyme immunoassays for toxin A and/or B, identify toxigenic 

 strains but have low sensitivity and that GDH assays are commonly used but need paired with another diagnostic test because GDH is found in toxigenic and nontoxigenic strains.

The IDSA/SHEA guidelines recommend using a stool toxin test as part of a multistep algorithm for diagnosis, which may involve GDH plus toxin test, GDH plus toxin test followed by NAAT as an arbitration test, or NAAT plus toxin test.1 However, Gerding noted that the difference in diagnostic yield among the algorithms may be introducing inconsistencies with diagnosis of CDI in current practice.

According to Chopra, asymptomatic carriage is an important consideration because carriers can act as reservoirs of transmission and probable vehicles of transmission to other patients. She added that the rate of asymptomatic carriage varies, with rates as high as 50% among older adults and approximately 5% to 10% among healthy adults.

“It’s important that we understand and realize that...these asymptomatic carriers don’t have diarrhea, but we are detecting [

 and they can transmit it,” she said, emphasizing the importance of infection control with hand hygiene and contact precautions in outpatient care settings and dialysis units and in inpatient care settings.

However, Chopra added that testing asymptomatic patients for carriage in the hospital setting is not routinely performed and would be a poor use of resources, and even hospitalized patients with risk factors for asymptomatic carriage are only put in contact isolation to prevent transmission if the hospital is facing an outbreak. Gerding noted that the data are currently insufficient to recommend universal screening for CDI, in part, because testing is invasive and isolation of positive patients would use a large number of isolation rooms. “I think we need more data before we jump on the colonization bandwagon, even in hospitals,” he said.

 Clinical Practice Guidelines and Treatment Options

According to the 2018 IDSA/SHEA guidelines, the recommendations for management of the first recurrence of CDI are a prolonged tapered and pulsed vancomycin regimen or fidaxomicin (if a standard vancomycin regimen was used previously) or a standard vancomycin regimen (if metronidazole was used for the previous infection).1 However, 

, noted that metronidazole has largely fallen out of favor for CDI infection because it has a broad spectrum of coverage (likely eliminating gut bacteria that are protective against CDI) and has been shown to have lower rates of efficacy than vancomycin. The inferior response rate of metronidazole to vancomycin was demonstrated in a pooled analysis of 2 multinational trials designed to compare clinical success of tolevamer, a nonantibiotic toxin-binding polymer, with vancomycin and metronidazole, respectively, in patients with CDI.2 Tolevamer was found to be inferior to both antibiotics, and rates of clinical success were higher with vancomycin than with metronidazole (81.1% vs 72.7%).2

“That’s what built up this concept on the clinical side [that] metronidazole is less targeted and alters the gut microbiota, which leads to higher risk for recurrence,” Feuerstadt said.

For second or subsequent recurrences, regimens recommended by the 2018 IDSA/SHEA guidelines include tapered and pulsed regimen of vancomycin, standard vancomycin regimen followed by rifaximin, fidaxomicin (if not used for prior infections), and microbiota replacement therapy or fecal microbiota transplantation (although the expert panel recommended appropriate antibiotic regimens for at least 3 episodes of CDI prior to trying this strategy).1

Feuerstadt noted that these recommendations in the 2018 guidelines have changed substantially from 2010, as metronidazole was largely removed from 2018 guidelines in favor of vancomycin or fidaxomicin in the first-line setting and fidaxomicin was introduced as an option for treatment of first recurrence.

Reilly concluded that assessing likelihood of patient compliance with the regimens, particularly the 8-week pulsed tapered vancomycin regimen, is important when selecting a treatment plan. He said in his experience, compliance tends to drop off after getting past the twice-per-day portion of the regimen. Salgo added that compliance is particularly difficult when dosing frequency drops to once every 2 to 3 days.

“We have to think about the patients we see who have [

 infection],” Reilly said. “Are they going to be compliant with this, taking vancomycin 4 times per day for possibly 2 weeks, then another 2 times per day for a week, once per day for another week, and every 2 to 3 days for up to 8 weeks? That’s a demanding regimen that we have to put a patient on. I understand the efficacy behind it, but we shouldn’t approach it and say, ‘Oh, I’ll just use that’ when there’s an alternative available that might be easier [and] that the patient might be more compliant with.”

McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). 

. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085

Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. 

. 2014;59(3):345-354. doi:10.1093/cid/ciu313

Investigators apply guidelines into practical management strategies.

Clostridioides difficile Infection: Diagnosis, Testing, Screening, and Treatment

Clostridioides difficile (C difficile) infection

, particularly in the recurrent setting, is associated with substantial disease and economic burdens for patients and health care systems. Utilizing patient care strategies that minimize infection risk is vital, according to experts who participated in a recent 

 infection (CDI) is “huge.” An estimated 462,100 cases of CDI occurred in the United States in 2017,1 and the economic cost of CDI was estimated to be $5.4 billion overall ($4.7 billion in health care settings) in 2014, according to a decision-analytic model.2 Recurrence is common and can be debilitating for patients, according to 

“I’ve had patients who’ve had recurrent disease, and they’ve [lost] jobs because of the nuisance it causes with the diarrhea they experience,” she said.

Feuerstadt added that although much of the focus is on the vegetative stage, during which the spores germinate to produce toxins that cause symptoms, the pathogen is hardier and more easily spread in the spore phase, because the spores are resistant to gastric acid and alcohol-based hand sanitizers.

“When we swallow the spore phase, it can get through our gastric acid, it gets to our small bowel,” Feuerstadt said. “In the small bowel, there’s a convergence to the vegetative phase where the vegetative phase multiplies, divides, and multiplies some more.”

Feuerstadt added that CDI risk factors include age greater than 65 years; female gender; immunocompromised state such as chronic kidney disease, HIV infection, or inflammatory bowel disease; recent use of antimicrobials, proton pump inhibitors, or histamine blockers; and residence in a skilled nursing facility or prolonged hospital stay. Chopra added that highly virulent toxigenic strains, such as the North American strain that caused outbreaks in the United States and Canada, are also of concern when considering transmission in the hospital or community setting.

 have been identified, although toxin-producing strains are the only ones associated with illness.3 Colonization by toxigenic strains leads to production of toxin A and toxin B in the gut, which leads to the diarrhea associated with CDI.3 Mortality is relatively higher and may exceed 5% with ribotypes 027 and 078, which have been epidemic since 2000, according to 

. He attributed the high mortality rate in part to the fact that the strain tends to infect older and immunocompromised patients, with the highest rates of mortality reported in patients in their 80s and 90s.

, said that the mortality rate increases substantially in patients older than 65 years, with an estimated rate of 10%. Chopra noted that CDI has been labeled as an urgent threat by the Centers for Disease Control and Prevention (CDC) because of the high rate of associated morbidity and mortality. She added that, although the rate of hospital-acquired infections has plateaued in recent years, the increase in community-acquired infection indicates the need for improvement in community stewardship programs.

 spores are ubiquitous in the environment and even are present at low levels in meat, root vegetables, and lettuce, but health care environments are more contaminated with the spores, Gerding said. A news release from the CDC stated that 82% of patients with community-associated CDI had been in an outpatient setting (eg, doctor’s or dentist’s office, chronic dialysis unit, or ambulatory surgery unit) in the 12 weeks prior to receiving a diagnosis of CDI.4 Gerding attributed this risk to the high rate of patients being prescribed antibiotics as well as the high level of contamination of 

 spores also contributes to their ability to spread infection.

“Those spores can live for a significant period of time on many surfaces, even when exposed to sunlight,” he said. “You’ll see some data that say, ‘Alcohol and certain products can kill the spores,’ but they really have to be used properly, [to have] the liquid [sit] on a surface for a significant period of time to have effect. The fact that the spores can be taken home with you on your lab coat and [remain] in your house and on surfaces for 6 months, a year, or longer, certainly puts [individuals] at risk.”

Recurrence of symptomatic CDI is relatively common, difficult to treat effectively, and a cause of significant morbidity and economic costs. Recurrence occurs in 20% to 30% of cases, with higher rates reported with each subsequent episode.5

“If we saw 100 patients with [CDI] and we treated them all…about 25 patients would come back with their first recurrence,” Reilly said. “If we treated those 25 successfully, about 40% of those patients would come back with their second recurrence. And if we treated those patients successfully, about 60% would come back for their third recurrence. So, for every 100 patients we treat, you wind up [with much more than 100 visits], which is the nature of the beast.”

Lodise added that the level of risk varies among antibiotics and increases with longer duration spent in a health care setting. He said that fluoroquinolones and third-generation cephalosporins are among the most commonly used antibiotics and have a higher risk for selecting for CDI compared with other drugs. “One thing I would say with antibiotics is that every day matters,” he said. “Even 1 dose of an antibiotic can put a patient at a greater risk for [CDI] relative to no antibiotics. That risk increases substantially after 3 days of antibiotics.”

He added that for patients who are older and have a high risk of mortality, morbidity, or recurrences, keeping them on an antibiotic without an indication is “often the worst thing you can do” because the risk of CDI is elevated for at least 3 months after taking antibiotics. Through his stewardship efforts, Lodise communicates how important it is to get patients off antibiotics, particularly broad-spectrum antibiotics.

According to Feuerstadt, the burden of disease with recurrent CDI is significant. Physical manifestations include abdominal cramps, diarrhea, dehydration, and syncope related to the frequent loose stools. There also are psychological, adaptation, relational, and productivity effects. He added that these effects are observed in patients with active disease as well as those with a distant history of infection.

“One of the concepts that is very important is to acknowledge for patients is that this is real and that what they’re going through is not just them,” Feuerstadt said. “[Patients] feel stressed about this. They have posttraumatic stress disorder; they feel anxiety or depression. Sometimes they feel [as though] they can’t be the person they were before. Educating ourselves as clinicians about this disease, both the physical manifestations and the emotional manifestations, will make all of us better clinicians and better equipped to approach these individuals and help them get better physically and emotionally.”


Professor of Anesthesiology
Columbia University Irving Medical Center
New York, New York


Professor of Internal Medicine, Division of Infectious Diseases
Wayne State University School of Medicine
Detroit, Michigan


Gastroenterologist, Department of Internal Medicine
Yale New Haven Hospital
New Haven, Connecticut


Research Physician
Edward Hines Jr Veterans Administration Hospital
Chicago, Illinois


Professor
Albany College of Pharmacy and Health Sciences
Albany, New York


Pharmacy Residency Program Director
Clinical Pharmacist Specialist
AtlantiCare Health System
Galloway, New Jersey

Guh AY, Mu Y, Winston LG, et al; Emerging Infections Program Clostridioides difficile Infection Working Group. Trends in U.S. burden of 

. 2020;382(14):1320-1330. doi:10.1056/NEJMoa1910215

Desai K, Gupta SB, Dubberke ER, Prabhu VS, Browne C, Mast TC. Epidemiological and economic burden of 

 in the United States: estimates from a modeling approach. 

. 2016;16:303. doi:10.1186/s12879-016-1610-3

Dayananda P, Wilcox MH. A review of mixed strain 

. 2019;10:692. doi:10.3389/fmicb.2019.00692

Nearly half a million Americans suffered from 

 infections in a single year. News release. Centers for Disease Control and Prevention. Updated March 22, 2017. Accessed January 31, 2021. 

https://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html

Cole SA, Stahl TJ. Persistent and recurrent 

. 2015;28(2):65-69. doi:10.1055/s-0035-1547333

Experts discuss the bacteria’s transmission in the community setting, how to reduce disease and economic burdens, and ways to improve quality of life for patients.

Advances in the Management of C difficile

On September 10, 2020, MJH Life Sciences™ introduced the 

, a partnership with renowned health care thought leaders across multiple medical disciplines. The coalition will present biweekly webinars that give providers resources to improve patient outcomes during the 

 pandemic. The first 5 webinars addressed issues related to influenza and COVID-19, myths and controversies, treatments, vaccines and prophylactic therapies, and long-term physical and psychological effects.

Battling Dual Threats: Influenza and COVID-19 Coverage

, of Columbia University Mailman School of Public Health; 

, of the College of Public Health at the University of Georgia; and 

, of the University of California, Riverside, participated in this webinar on September 15, 2020.

COVID-19 and Influenza: A Tale of 2 Viral Pathogens

Rasmussen noted that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses have distinct taxonomy, genomics, and evolutionary origin, as well as modes of entry into and replication inside the cell. In addition, the higher mutation rate of the influenza virus is related to its ability to reassort its genome. She added that SARS-CoV-2 appears to have a stronger effect on the central nervous system and gastrointestinal tract and infects the cardiovascular system directly. Pathogenic strains of the influenza virus, on the other hand, affect the cardiovascular system through the increased entry of macrophages. Rasmussen also noted that the differential pattern of pathway induction in the immune response suggests that these viruses induce distinct host responses. She added that case reports show coinfection of SARS-CoV-2 and influenza does occur, but the effect on disease severity is unclear. “We need more data from a broader range of patients,” she concluded.

Population-level Patterns of COVID-19 and Influenza: What Should We Expect?

Handel said that behavior changes and the nonpharmaceutical interventions (NPIs) implemented for COVID-19 have likely had an effect on the influenza rate. He pointed to data showing that rates in the 2019-2020 season were lower than expected in multiple countries which, along with lower test positivity rates in China and a minimal number of influenza-related hospitalizations in Australia, suggests a true decrease in influenza cases (versus reduced reporting of cases). He concluded that key factors that will dictate the interaction between COVID-19 and influenza in the long-term include the effects of a COVID-19 vaccine on influenza vaccine uptake, NPIs, and individual behavior patterns; development of a universal flu vaccine; and COVID-19 treatments.

Morrison noted that although several COVID-19 vaccines are currently in phase 3 trials, their rapid development has contributed in part to high levels of vaccine hesitancy among the general public. She added that this skepticism has prompted vaccine developers to make a historic pledge stating that they will uphold the integrity of the scientific process, and ensure that regulatory filings and approvals are up to par and no corners are being cut. Morrison cited the example of AstraZeneca putting their trial on hold when a participant developed an illness that may have been related to the vaccine. She concluded that educating the public about the perceived threat of COVID-19 and the effectiveness and safety of the vaccines that become available are key to fighting vaccine hesitancy.

Fact or Fiction? COVID-19 Myths and Controversies

 infectious disease epidemiologist and infection preventionist in Phoenix, Arizona; 

 of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; and 

, addressed common COVID-19 myths and controversies in a COVID-19 Coalition webinar on September 29, 2020.

MYTH 1: “SARS-CoV-2 is totally airborne”

Rasmussen said that SARS-CoV-2 is primarily transmitted through short-range respiratory droplets or aerosols between individuals in close contact for long periods of time. “The word ‘airborne’ is often misleading because a lot of times people think of long-range transmission,” she said.

Ricotta added, “We need to be clearer in the way that we’re communicating this, and I think that’s where some of the confusion has come in.” However, both panelists agreed that these discrepancies in definition do not affect current recommendations for preventing transmission (such as mask usage).

MYTH 2: “Herd immunity is achievable through natural infection”

Ricotta said that herd immunity through natural infection would likely require 40% to 70% of the population to be infected and have sustained immunity. In addition, as not all the long-term effects of COVID-19 are known, many people would be put at risk with this strategy. Rasmussen added that global herd immunity through natural infection has not been achieved for any pathogen and does not keep the pathogen out of the environment in the long-term.

MYTH 3: “We can’t trust data quality”

Ricotta said that the data source, consistency in data reporting, interruptions in data collection, and consistency in criteria for positivity can affect data. “It’s not necessarily the quality of data. You just have to be really careful when you’re working with and interpreting them,” she said.

Rasmussen added that communicating with the public about the appropriate use of mathematical models has been a “tremendous challenge.” They’re only as good as the information that goes into building them at the time, and that’s constantly changing.”

MYTH 4: “There is no asymptomatic transmission”

Rasmussen said that distinguishing asymptomatic from presymptomatic transmission and estimating the prevalence of asymptomatic cases, which is a substantial source of transmission, has been difficult. This is because most asymptomatic cases are based on self-reported data, symptoms can develop after a positive test, and people may not recognize that mild, nonspecific symptoms are related to COVID-19.

MYTH 5: “Any SARS-CoV-2 vaccine won’t be safe”

Rasmussen said the purpose of clinical trials is to ensure vaccine safety and efficacy. Ricotta added that postmarket evaluation of vaccines is performed and possible vaccine-associated events are reported in a tracking system. Although vaccines have risks, Ricotta said they are often considered acceptable relative to the risks associated with the disease.

MYTH 6: “Young people can’t get sick”

According to Ricotta, although young patients often have fewer symptoms than older patients, some require hospitalization and have had blood clots, strokes, and myocarditis. Rasmussen added that symptoms in children can be vague and difficult to associate with COVID-19, and she and Popescu pointed out that cases in children may be underreported.

The immune system response to SARS-CoV-2 immunoglobulin G (IgG) is consistent with that of other viruses, Rasmussen said. Memory immune cells likely persist, even if IgG decreases to undetectable levels, and assumptions about long-term immunity cannot be made based on antibody levels.

MYTH 8: “Hydroxychloroquine is a miracle drug”

Rasmussen said that none of the high-quality randomized controlled trials and observational studies show a clinical benefit for prophylaxis or treatment, and the drug can cause ocular problems or cardiac arrhythmias.

MYTH 9: “COVID-19 is no worse than the flu”

Although both viruses affect the respiratory tract and have similar modes of transmission, comparing COVID-19 to influenza is “like comparing apples to oranges, ” Ricotta said. Getting tested for both viruses is important to guide treatment. Rasmussen added that aside from the fundamental differences in the viruses, the 2 diseases should not be compared because of the differences in treatment and vaccination recommendations.

Navigating the COVID-19 Treatment Landscape

This October 13, 2020, webinar included moderator 

, of the University of Michigan College of Pharmacy; 

, of Temple University School of Pharmacy.

Davis said that although updated results showed differences in mortality at day 15, illness severity, hospital stay, and time to recovery are also important measures to consider when deciding whether to give remdesivir. Additionally, the guidelines for use from the National Institutes of Health and the Infectious Diseases Society of America were based on the drug’s limited availability early in the pandemic. The increase in availability and advent of new therapies since then may change when and which patients receive the drug, according to Davis.

The panelists stated that a wide range of patients, including those with minimal need for supplemental oxygen, would likely benefit from dexamethasone. Gallagher cautioned against making assumptions about when a patient is in the “inflammatory phase” of the disease, given that knowledge about its clinical course is continuing to evolve. Moving forward, he recommended focusing on clinical data when assessing clinical benefit from dexamethasone.

Although an emergency use authorization (EUA) was given, Gallagher said the data from the nonrandomized Mayo Clinic Expanded Access Program are difficult to interpret. Further, he remarked that the benefits appear to be primarily in patients who have not produced their own antibodies to SARS-CoV-2. Davis noted that the primary intention of the program was to improve access for patients and that it was not designed as a clinical trial. Pogue added that convalescent plasma may have lower levels of antibodies than the levels the patient has produced.

Although the data published in press releases appear promising, Davis said such data from pharmaceutical companies is insufficient for rational decision-making in the clinic. When companies apply for an EUA, closer communication with the FDA can expedite additional treatment options in a pandemic, but a completed clinical trial is necessary for an agent’s widespread use in the clinical setting, she continued.

“EUA is a tool for a health emergency,” said Davis. “It is not a replacement for the normal drug approval process.”

Gallagher added that monoclonal antibodies may predict progression in patients who are readmitted to the hospital but the logistical challenges, such as the need for intravenous infusion, will likely limit their overall impact on reducing transmission and improving outcomes.

Race for a Vaccine: The Latest Updates in COVID-19 Prevention

 CEO of PAX Therapeutics and chairman of the board of the International Society for Vaccines; 

, head of monoclonal antibody clinical testing in the COVID-19 Prevention Trials Network; and 

, head of vaccine testing in the COVID-19 Prevention Trials Network, participated in this webinar, held October 27, 2020.

According to Cohen, key advantages of monoclonal antibody therapy include the ability to offer immediate protection to exposed or unvaccinated individuals in high-risk settings, provide an option for patients unlikely to respond to or who are allergic to a vaccine, and stop viral replication and disease progression. Several phase 3 trials are ongoing for monoclonal antibody therapies, including one (NCT04452318) that is evaluating the efficacy of REGN10933 + REGN10987 (which prevents the receptor binding domain of the spike protein from reaching the ACE2 receptor) for preventing infection in the household contacts of individuals who test positive for COVID-19. Another is the BLAZE-2 trial (NCT04497987), which is investigating the antibody LY-CoV555 for preventing infection in residents and staff of skilled nursing and assisted living facilities.

Corey said that several features of SARS-CoV-2, including its relatively high infection cure rate, mutation rate of 2 base pairs per month with little variation in neutralizing areas of the spike protein, and recent evidence of past infection protecting against acquisition, have made COVID-19 vaccine development more straightforward than that for HIV.

The conceptual framework for COVID-19 vaccine development involves developing multiple vaccine platforms (protein-, viral vector–, and RNA-based) and having a coordinated effort from the US government to involve global vaccine manufacturing companies, said Corey. He also emphasized the importance of having a common data safety monitoring board for these efficacy trials using different vaccine platforms, with decisions for a given candidate based on the context of the other trials.

According to Corey, the main goal of these trials is to evaluate each candidate vaccine for safety and efficacy for reducing COVID-19 disease, with approximately 30,000 individuals enrolled per trial; measure 150 disease end points; enroll Black, Latinx, and tribal communities; and evaluate vaccines in epidemiologic settings of individuals at greatest risk for complications based on comorbidities, age, and race.

“COVID-19 vaccines provide the leading approach for changing the societal and medical complications of the COVID-19 pandemic. A vaccine that protects from medically complicated COVID-19 disease would provide enormous help in relieving the uncertainty that accompanies work, travel, and gatherings with family, friends, and community,” said Corey.

Thinking Long-Term: COVID-19’s Clinical Consequences and Mental Health Effects

, of Feinberg School of Medicine at Northwestern University; 

, of Emory School of Medicine and Grady Health System; and 

, executive director of the Center for Childhood Resilience, participated in this November 12, 2020, webinar.

Tan pointed out that although most children and infants generally present with mild or no symptoms, they may have persistent and long-term symptoms even if they have mild illness and no underlying medical conditions. Multisystem inflammatory syndrome in children is the most serious and can result in long-term cardiac, neurologic, and gastrointestinal problems.

Long-Term Health Consequences of Covid-19

Del Rio estimated that 10% to 15% of patients do not recover quickly based on findings from the COVID Symptom Study, and the persistence of symptoms is independent of age, comorbidity burden, and severity of acute illness. He added that cardiac injury, myocarditis, arrhythmias, cardiogenic shock, and thromboembolic disease may occur in the acute phase. These can lead to myocardial fibrosis or scarring, arrhythmias with cardiac arrest outside the hospital setting, and cardiomyopathy in the postacute phase. Pneumonia, acute respiratory distress syndrome, and hypoxic respiratory failure can occur during the acute phase and be followed by restrictive lung disease in the postacute setting. In addition, major mood swings and “brain fog” can persist for several months. Del Rio added that renal function may also be compromised long-term, with persistent kidney dysfunction or requirement for dialysis even in patients who did not require renal replacement therapy during hospitalization. Finally, he cited emotional and behavioral concerns, including feelings of isolation and loneliness, a sense of hopelessness, and ongoing psychological effects, and identified the need for an integrated research agenda to conduct observational studies and randomized trials and a multidisciplinary approach to treatment in post–COVID-19 clinics.

The Uninvited Guest: Promoting Mental Health & Wellness During COVID-19

Cicchetti said that issues related to the COVID-19 pandemic, racism, and economic downturn in 2020 have contributed to multiple layers of stress in many individuals. Ongoing mental health challenges for many individuals include a sense of inequity, structural racism, heightened exposure to stress and trauma, social isolation and disconnection, limited access to community programs and support, changes to routine and structure, barriers to accessing health care and other services, and educational disruptions for children.

Cicchetti emphasized the importance of providers addressing stress directly with clients using tools such as Stoddard and Kaufman’s Coronavirus Impact Scale and the UCLA Brief COVID-19 Screen for Child/Adolescent PTSD. She recommended that parents respond to their children using principles of trauma-informed care, including creating a safe environment, building relationships and connectedness, and supporting and teaching emotional regulation. She added that the majority of children will do well, and often look to parents for coping strategies and leadership during times of crisis. Create a sense of predictability and establish routines to enhance children’s safety and security, she suggested, as well as providing them with love and support. Additionally, allowing them to ask questions, supporting their emotional regulation, and letting them figure out how to support themselves with self-care activities will help them reduce stress, cope with challenges, and enhance their sense of well-being.

The biweekly webinars hosted by renowned health care thought leaders provide resources to improve patient outcomes during COVID-19. Here's a recap of the first 5 discussions.