Feb. 05, 2021
Incidence of recurrent Clostridioides difficile infection (CDI) after a primary infection is escalating. After treatment with antibiotics is stopped, the risk of recurrent CDI is 20% to 30% after a single infection, 40% to 50% after a second infection, and over 60% among patients who have experienced three or more infections.
Primary and first recurrence CDIs are typically treated with oral vancomycin or fidaxomicin regimens. Although it has not yet been approved by the Food and Drug Administration, fecal microbiota transplantation (FMT) is widely used to manage recurrent CDI. FMT has demonstrated success rates of over 85% in preventing CDI recurrences compared with a 40% to 50% success rate with antibiotic regimens.
Because FMT therapies are derived from donor stool samples, transmission of infectious agents from asymptomatic stool donors to FMT recipients is a possible risk. Donor screening procedures to prevent this exist, but serious adverse events related to transmission of infectious agents (including extended-spectrum beta-lactamase-producing Escherichia coli, enteropathogenic E. coli and Shiga toxin-producing E. coli) have been documented.
The current COVID-19 pandemic presents additional concerns for providers to consider when making decisions about the use of FMT. Our understanding of this virus and its transmission pattern is still evolving. Right now, experts believe that the average incubation period for COVID-19 is five days, and that individuals who are asymptomatic can be responsible for community spread of this novel coronavirus. Although respiratory droplets are believed to be the primary mode of virus transmission, reports of feco-oral transmission and reports of prolonged shedding in the stool after recovery from respiratory illness are also emerging.
To update clinicians on the current state of knowledge about FMT and issues to consider during the COVID-19 pandemic, Mayo Clinic researchers published an article in the Red Section of The American Journal of Gastroenterology in 2020. Co-authors Sahil Khanna, M.B.B.S., M.S., and Darrell S. Pardi, M.D., are gastroenterologists at Mayo Clinic's campus in Rochester, Minnesota, whose research focuses on the epidemiology, risk factors and treatment of CDI.
The importance of diagnostic accuracy
According to Dr. Khanna, symptoms of CDI recurrences sometimes mimic those of other illnesses, making an accurate diagnosis essential. "About 20% of patients develop post-infectious irritable bowel syndrome, and there is also a high risk of persistently positive nucleic acid-based assay after resolved CDI," explains Dr. Khanna. In general, patients with primary and recurrent CDI typically meet all of these four criteria:
- Presence of CDI risk factors such as antibiotic exposure
- Diarrhea with or without abdominal pain
- Positive nucleic acid-based or toxin-based assay
- Response to treatment with vancomycin or fidaxomicin, with symptoms recurring shortly after stopping the antibiotic
"It's important to note that primary nonresponse to antibiotic treatment is extremely rare and suggests an alternate diagnosis," explains Dr. Khanna.
In individuals who do not meet all four criteria, especially numbers two and four in the list above, Dr. Khanna notes that an alternate diagnosis should be considered. "In general, patients who meet all four criteria in this list are good candidates for FMT," says Dr. Khanna. "Some patients with refractory or fulminant CDI also may benefit from FMT."
Challenges of stool banking during the COVID-19 pandemic
Dr. Khanna emphasizes that to prevent transmitting COVID-19 via FMT using donor stool, especially if this virus continues to spread populationwide, testing and COVID-19 status matching of both stool donors and FMT recipients must occur.
Screening and testing stool donors for COVID-19
"Several factors underscore the importance of screening stool donors for COVID-19," explains Dr. Khanna. "We know that patients with COVID-19 can present with diarrhea, that individuals who are asymptomatic can shed in stool and enable feco-oral transmission, and that the virus is also detectable in stool, even when it's undetectable in the respiratory tract."
Unfortunately, multiple issues also make donor screening for COVID-19 challenging at this time. Current obstacles include a shortage of available tests for those who are symptomatic, the fact that respiratory swab-based tests are not validated for asymptomatic donors, a lack of validated stool assays for asymptomatic donors, and the fact that the fecal carriage and transmission may be possible in asymptomatic donors who don't have a positive nasal swab test.
To address these challenges, Dr. Khanna recommends screening stool donors for travel history, COVID-19 symptoms and contact with individuals infected with COVID-19. Donors who meet these screening criteria should be considered for COVID-19 testing (nasal swab or stool). Stool from these donors should be processed, stored and held for at least 14 days. After the 14-day hold, the donors in this group should be rescreened and retested for COVID-19. Stool taken from donors who fail the second round of screening should be discarded.
As COVID-19 diagnostic tests become more widely available and validated for screening asymptomatic individuals, Dr. Khanna says that stool donors should undergo routine screening using nasal swab and stool tests. "The use of multiple tests may also be appropriate to compensate for low testing sensitivity and to reduce the occurrence of false-negative," explains Dr. Khanna.
"Protocols for accepting stool from donors post-exposure could include the use of serological tests like an immunoglobulin G response to denote recovery from previous exposure."
Managing recurrent CDI during the COVID-19 pandemic
Microbiome replacement therapies such as FMT can be considered for about 5% to 10% of patients with CDI. Patients diagnosed with recurrent CDI should first complete antibiotic therapy for acute diarrhea. According to Dr. Khanna, most patients with CDI will require about four to five days of vancomycin until diarrhea resolves, followed by a regimen tapering to the lowest effective dose: 125 mg four times daily for two weeks, twice daily for one week, once daily for a week and then every other day.
For patients with response to antibiotics, Dr. Khanna notes that FMT could be delayed until the pandemic is better controlled. However, surgery or rescue FMT may be appropriate for patients with fulminant CDI or those who do not respond to maximal guideline-based combination therapy. If FMT is required, Dr. Khanna lists these three options to consider:
- Use banked stool donated before December 2019.
- Use stool obtained from a donor within the recipient's household.
- Screen the recipient for COVID-19 (noting symptoms, travel history and, if available, test results). If the recipient tests positive for COVID-19, any otherwise well-screened donor may be used.
If FMT is regarded as the only option for a recipient who tests negative for COVID-19, use of donor stool obtained before December 2019 or stool from a donor who tested negative for coronavirus is appropriate.
Dr. Khanna is hopeful that the guidance outlined in the article in The American Journal of Gastroenterology will help providers manage recurrent CDI in the era of a pandemic such as COVID-19. He also acknowledges use of FMT to treat CDI requires additional surveillance of the recipient and the development of additional laboratory tests to detect this virus.
"Follow-up after fecal transplant is needed for patients undergoing FMT during the pandemic. A validated stool assay for detection of COVID-19 is also needed," explains Dr. Khanna. "Dr. Pardi and I are working together to make progress on these steps."
Dr. Khanna emphasizes that future research related to microbiome replacement therapies must also focus on developing methods to remove viruses and bacterial pathogens in donor stool and creating synthetically grown, defined microbial consortia to avoid the risk of transmitting pathogens, including the novel coronavirus.
Even after the current COVID-19 pandemic ends, producers of microbiome replacement therapies will need to eliminate the possibility of transmitting pathogens to FMT recipients.
For more information
Khanna S, et al. Fecal microbiota transplantation for recurrent Clostridioides difficile infection: The COVID-19 era.The American Journal of Gastroenterology. 2020;115:971.