Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to the approved COVID-19 vaccines are provided in this activity in an effort to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Advances in medicine are continuously emerging, challenging all members of the healthcare team to remain aware of important updates and how they may improve clinical practice; however, increasing demands on the time and resources of healthcare practitioners make it difficult to stay up-to-date on the latest clinical research and guidelines, as well as the implications for patient care. This article highlights recent advances in our understanding of infectious diseases, including transmission of mpox, ties between COVID-19 and gut dysbiosis, and strategies for management of Clostridioides difficile infections.

PRESYMPTOMATIC TRANSMISSION OF MPOX (MONKEYPOX): WHAT ARE THE IMPLICATIONS FOR INFECTION CONTROL?

More than 80,000 cases of mpox have been confirmed worldwide to date, almost exclusively in countries without previous known endemic spread of this virus.^[1] After the initial surge in cases between May and August, the number of new infections continues to decrease; however, it remains to be seen whether this signifies the end of the outbreak or whether intermittent surges may continue.^[2] To address this question, a recent study performed in the United Kingdom sought to better understand the transmission dynamics of mpox and how this should inform infection control.

This investigation, which was recently published in The BMJ,^[3] found evidence of mpox virus transmission taking place up to 4 days before the onset of symptoms and estimated that more than half of transmission occurred in the presymptomatic phase. Requiring patients diagnosed with mpox to self-isolate to control the spread of the virus might be less effective than previously thought, after research suggested "substantial" presymptomatic transmission. Previous research on pox viruses did not rule out transmission before symptoms, but the researchers from the UK Health Security Agency said their work represented the first evidence to support this.

Study Synopsis

The scientists focused on the serial interval of time from symptom onset in the primary case to symptom onset in the secondary case and the incubation period.^[3] That information was extracted from routine surveillance and contact tracing data for 2746 people who tested positive for mpox virus in the United Kingdom between May 6 and August 1. The mean age of the cohort was 38 ± 9 years, and 95% had reported being gay, bisexual, or men who have sex with men.

The mean incubation period of mpox was 7.6 days (95% CI: 6.5, 8.9) in one model used and 7.8 days (95% CI: 6.6, 9.2) for another model. The estimated serial interval was 8 days (95% CI: 6.5, 9.9). for one model and 9.5 days (95% CI: 7.4, 12.3) in the other. For both models, the median serial interval was between 0.3 and 1.7 days shorter than the median incubation period, which the researchers said indicated a significant space for mpox virus transmission before symptoms appeared. When they analyzed individual patient-level data, results seemed to confirm the findings, with 10 of 13 case-contact patient pairs reporting presymptomatic transmission.

They estimated that 53% (95% CI: 43, 62) of transmission occurred in the presymptomatic phase. They cautioned, however, that "since serial intervals depend on the incubation period, this finding is an approximation of the proportion of infections due to pre-symptomatic transmission."

Figure. Transmission Kinetics of Mpox

 

According to the results, the researchers suggested that an isolation period of 16 to 23 days after exposure to the mpox virus would be required to identify 95% of infected individuals.

The study authors acknowledged some weaknesses in their analysis, including its observational nature and the reliance on contact tracing to identify the correct case-contact pairs.

Perspectives and Clinical Implications for Infection Control

In an accompanying editorial,^[2] researchers based in the United States, United Kingdom, and Nigeria said that if the findings were backed by further research, "then pre-symptomatic transmission, or transmission before symptoms are detected, would have important implications for infection control globally". In particular, "postexposure or 'ring' vaccination of contacts identified only through individuals with symptoms, could be inadequate," they argued.

Separately, Boghuma Kabisen Titanji, MD, assistant professor of medicine at Atlanta, Georgia's Emory University in the United States, said the scientists had carried out a "robust" analysis, using adjustments to reduce the risk for bias. She told the Science Media Centre: "The point the authors make about asymptomatic transmission based on the serial interval being shorter than the incubation period is interesting and convincing based on the analysis performed and also confirms observations made from clinical studies where mpox has been detected in samples collected for routine [sexually transmitted infection (STI)] screening from asymptomatic individuals. This needs confirmation by more studies but has implications for vaccination-based disease elimination strategies which should be seriously considered."

Dr Titanji said questions requiring answers were "What proportion of cases are asymptomatic?" and "How much do these cases contribute to seeding new transmission chains?".

 

The study authors declared no financial relationships with any organizations that might have an interest in the submitted work in the previous three years. Dr Titanji declared no conflicts of interest.

CAN COVID-19-RELATED GUT DYSBIOSIS INCREASE THE RISK FOR SECONDARY BLOODSTREAM INFECTIONS?

Although our understanding of COVID-19 and the SARS-CoV-2 virus continues to expand, there is an ongoing need to better understand the pathogenesis of this disease and the factors that lead to severe complications. Gastrointestinal (GI) symptoms are common in patients with COVID-19, and studies have shown that this virus can lead to substantial alterations in the gut microbiome.^[4] Disturbances in the normal gut microbiome are particularly common in patients who receive broad-spectrum antibiotics, which was common practice in patients with COVID-19 who were admitted to the hospital. This gut dysbiosis may unfortunately increase the risk for invasion of drug-resistant bacteria in the GI tract and subsequent severe bloodstream infections in critically ill patients with COVID-19.

A studied recently published in Nature Communications^[4] examined the relationship among SARS-CoV-2 infection, the gut microbiome, and the risk for secondary bloodstream infections. This research suggests SARS-CoV-2 infection disrupts the normal mix of gut bacteria, allowing harmful bacteria to enter the bloodstream and raising the risk for potentially life-threatening secondary bloodstream infections.

"Collectively, these results reveal an unappreciated link between SARS-CoV-2 infection, gut microbiome dysbiosis, and a severe complication of COVID-19, bloodstream infections," the study team reported.

"Our findings suggest that coronavirus infection directly interferes with the healthy balance of microbes in the gut, further endangering patients in the process," microbiologist and co-senior author Ken Cadwell, PhD, New York University Grossman School of Medicine, New York, New York, added in a news release.^[5] "Now that we have uncovered the source of this bacterial imbalance, physicians can better identify those coronavirus patients most at risk of a secondary bloodstream infection."

Study Synopsis

In a mouse model, the researchers first demonstrated that the SARS-CoV-2 infection alone induces gut microbiome dysbiosis and gut epithelial cell alterations, which correlate with markers of gut barrier permeability.^[4]

Next, they analyzed the bacterial composition of stool samples from 96 adults hospitalized with COVID-19 in 2020 in New York, New York, and New Haven, Connecticut. In line with their observations in mice, they found that the SARS-CoV-2 infection is associated with "severe microbiome injury," characterized by the loss of gut microbiome diversity.

They also observed an increase in populations of several microbes known to include antibiotic-resistant species. An analysis of stool samples paired with blood cultures found that antibiotic-resistant bacteria in the gut migrated to the bloodstream in 20% of patients. This migration could be due to a combination of the immune-compromising effects of the viral infection and the antibiotic-driven depletion of commensal gut microbes, the researchers said.

Patients are also uniquely exposed to other potential factors predisposing them to bacteremia, including immunosuppressive drugs, long hospital stays, and catheters, the investigators noted. The investigators added that the study is limited in its ability to investigate the individual effects of these factors.

Clinical Implications for Patients With Viral Infections

"Our findings support a scenario in which gut-to-blood translocation of microorganisms following microbiome dysbiosis leads to dangerous bloodstream infections during COVID-19, a complication seen in other immunocompromised patients, including patients with cancer, acute respiratory distress syndrome, and in [intensive care unit] patients receiving probiotics," the researchers wrote.

Investigating the underlying mechanism behind their observations could help inform "the judicious application of antibiotics and immunosuppressives in patients with respiratory viral infections and increase our resilience to pandemics," they added.

 

Funding for the study was provided by the National Institutes of Health and by the Yale School of Public Health, the Beatrice Kleinberg Neuwirth Fund, the Howard Hughes Medical Institute, the Crohn's and Colitis Foundation, the Kenneth Rainin Foundation, the Judith and Stewart Colton Center of Autoimmunity, the Jan Vilcek/David Goldfarb Fellowship Endowment Funds, The G. Harold and Leila Y. Mathers Charitable Foundation, the Yale COVID-19 Research Resource Fund, and the Bristol-Myers Squibb Foundation. Cadwell has received research support from AbbVie Inc.; Genentech, Inc.; Pacific Biosciences; Pfizer Inc.; and Takeda Pharmaceuticals North America, Inc. and consulted for or received an honoraria from AbbVie Inc.; Genentech, Inc.; and PureTech Health; and is named as an inventor on US patent 10,722,600 and provisional patents 62/935,035 and 63/157,225.

ARE ORAL AND COLONIC FMT EQUIVALENT FOR RECURRENT C DIFFICILE?

Fecal microbiota transplantation (FMT) has emerged as a treatment option for patients with recurrent C difficile infection that does not respond to standard treatment.^[6] The FDA allows FMT to be used for patients who have failed standard treatment for recurrent C difficile infection under a policy of enforcement discretion.

The past decade has seen an increase in the use of FMT in clinical practice, owing to an increase in cases of recurrent C difficile infection after failure of standard antibiotic therapy. Unlike antibiotics, which perpetuate and worsen intestinal dysbiosis, FMT restores the diversity and function of host microbiota, effectively breaking the cycle of recurrent C difficile infection, the study noted, but it has been unclear whether the efficacy and safety of FMT vary by route of administration.

A real-world analysis recently published in Clinical Gastroenterology and Hepatology confirmed that FMT is highly effective for recurrent C difficile infection, and there is no difference between delivery by capsule (cap-FMT) and colonoscopy (colo-FMT).

"We present one of the largest cohorts involving people who received capsule FMT. The finding that capsule FMT is as safe and effective as colonoscopy FMT has practical implications for anyone suffering with recurrent C difficile infection today," Byron Vaughn, MD, with the division of gastroenterology, hepatology, and nutrition, University of Minnesota, Minneapolis, Minnesota, told Medscape Medical News.

Study Synopsis

To investigate, Vaughn and colleagues evaluated clinical outcomes and adverse events in 170 patients with recurrent C difficile infection who underwent cap-FMT and 96 peers who underwent colo-FMT.^[5] Fecal microbiota transplantation was performed using 1 of 2 standardized formulations of microbiota manufactured by the University of Minnesota Microbiota Therapeutics Program: freeze-dried/encapsulated or frozen-thawed/liquid.

Overall, the cure rates of C difficile infection were 86% at 1 month and 81% at 2 months. There was no statistically significant difference at either time between cap-FMT and colo-FMT. The 1-month cure rate was 84% with cap-FMT and 91% with colo-FMT; at 2 months, the cure rates were 81% and 83%, respectively. Cap-FMT has a similar safety and effectiveness profile to colo-FMT, without the procedural risks for colonoscopy, the researchers concluded.

Table. Efficacy of Oral vs Colonic FMT for Recurrent C difficile Infection

They cautioned that although FMT is highly effective overall, patient selection is a key factor to optimizing FMT success. Older age and hemodialysis were associated with FMT failure by 2 months on multivariate logistic regression.

"These risk factors can help determine if a patient should receive FMT or an alternative therapy for recurrent C difficile infection. This is not to say FMT should be avoided in older patients or those on dialysis, but clinicians should be aware of these associations in light of other options for recurrent C difficile infection," Vaughn said.

Confirming prior studies, antibiotic use after FMT was a major factor in its failure. Patient selection for FMT should include an assessment of the potential need for antibiotics after transplant, the researchers noted.

One serious adverse event (aspiration pneumonia) was related to colonoscopy; otherwise, no new safety signals were identified. As reported in other studies, changes in bowel function, including diarrhea, constipation, gas, and bloating, were common, although it is challenging to disentangle GI symptoms related to FMT from those after C difficile infection, the researchers mentioned. Importantly, no transmission of an infectious agent related to FMT was identified.

Clinical Implications: 2 Good Options for Recurrent C difficile

The researchers said their findings are "highly generalizable" because the population reflects all FMT use by participating institutions and contains a mix of academic centers and private practices.

Many patients included in the study would not have been eligible for a clinical trial, owing to their having many comorbid conditions, including immune compromise and inflammatory bowel disease, the authors noted.

"FMT is recommended by major gastroenterology and infectious disease society guidelines," Vaughn said. "Our group, and others, have consistently found strategies that incorporate FMT as cost-effective strategies for treating recurrent C difficile infection."

Lack of access to FMT products often is a barrier to treatment, he noted.

"A stool banking model, similar to the nonprofit blood banking model, may be a useful solution to ensure equitable access to FMT to all who need it," Vaughn added.

Reached for comment, Majdi Osman, MD, MPH, told Medscape Medical News that the study is valuable, "as it nicely shows in a real-world setting that capsules and colonoscopy are good options for patients who need this."

Osman is chief medical officer of OpenBiome, a nonprofit organization that operates a public stool bank and is the major FMT source in the United States. The organization has provided more than 63,000 FMT treatments to more than 1200 hospitals in the United States.

"FMT has become standard of care for patients who failed antibiotic therapy, and certainly is being used widely as a treatment option for these patients who have often run out of existing options," Osman said.

 

Support for the study was provided by a donation from Achieving Cures Together, a nonprofit organization dedicated to advancing microbiome-based research. Vaughn receives grant support from Celgene Corporation; DiaSorin; Roche; and Takeda Pharmaceuticals North America, Inc. and has received consulting fees from AbbVie Inc. and Prometheus Laboratories Inc. Osman reports no relevant financial relationships.

Earn Credit