The ratio of Ascomycota to Basidiomycota was dramatically higher in patients with CDI than in Carrier and Control (P < .05).
Using 4 fungal operational taxonomic units combined with 6 host immune markers in the random forest classifier can achieve very high performance (area under the curve ∼92.38%) in distinguishing patients with CDI from Carrier.
My take: It is interesting that fecal fungal diversity (mycobiome), in addition to bacterial diversity, is reduced in those with Clostridium difficile infection (CDI) compared to both control groups and those with Clostridium difficile asymptomatic carriage.
In this prospective study (2012-2018) with 609 patients (median age 56 years), the authors studied long-term outcomes. Key findings:
At 1 year, 9.5% reported additional CDI episodes. Diarrhea occured in more than half of all patients, although it lasted for than a week in most patients.
Among 477 with long-term data, 188 patients post-FMT developed new medical conditions/symptoms.
Weight gain was reported by 46 patients (10.3%) post-FMT. In these patients, the median weight gained was 30 pounds (range, 10–70). Of these patients, 11 (23%) had preexisting obesity.
Approximately 3% of patients each reported new-onset diabetes mellitus and dyslipidemia, whereas 2.3% reported thyroid disease.
Gastrointestinal symptoms were the second most frequently reported (13.4%). New-onset IBS was reported by 4%, IBD by 0.3%, chronic diarrhea by 5.0%, and chronic constipation by 1.6% of patients.
Serious infections were reported by 11.8% of patients: CDI in 5.7%, Pneumonia in 4.5%, UTI in 1.8% and Sepsis in 1.2%. Median time to the infections was 29 months (range, 0–73) following FMT; only 1 patient reported an infection (CDI) within the first month after FMT.
No deaths were considered related to FMT
Limitation: no control group
My take (borrowed from authors): “FMT appears safe and effective, both in the short-term and long-term. Several new medical conditions were reported post-FMT, in particular, weight gain and IBS.”
Guideline recommends AGAINST using probiotics for prevention of C difficile infection (CDI)
Guideline cautions AGAINST testing individuals at low risk for CDI (eg. not having diarrhea)
Guideline recommends either vancomycin or fidaxomicin (lower CDI recurrence) for all cases of CDI and consideration of metronidazole for nonsevere cases. Fidaxomicin is recommended for CDI recurrence after vancomycin or metronidazole.
Guideline recommends combination of highly sensitive test and highly specific test for diagnosis of CDI. “CDI-related complications are rare in NAAT-positive, toxin EIA-negative patients, who, even when untreated, may have clinical courses similar to those without CDI…If both are positive, the diagnosis of CDI can be made reliably. If both are negative, CDI is unlikely. Discordant results when NAAT or GDH is positive and toxin EIA is negative require clinical evaluation and consideration of the possibility of colonization or that the patient has CDI but toxin levels are below the limits of detection (see below).
In this prospective study, the authors enrolled asymptomatic pediatric patients (n=225) and compared C diff testing results with symptomatic patients (n=41) with positive nucleic-acid amplification-based testing (NAAT).
Of the 225 asymptomatic children enrolled in the study, 47 (21%) were colonized with C. difficile including 9/59 (15.5%) with cancer, 30/92 (32.6%) with CF, and 8/74 (10.8%) with IBD.
Overall, “use of a multistep testing algorithm with NAAT followed by EIA failed to differentiate symptomatic CDI from asymptomatic colonization in our pediatric cohort.” When symptomatic and colonized children were compared, neither EIA (enzyme immunoassay) positivity (44% vs 26%, P = 0.07) nor CCNA (functional cell cytotoxicity neutralization assay) positivity (49% vs 45%, P = 0.70) differed significantly
My take: Don’t test children who are asymptomatic for Clostridium difficile. Even in children with symptoms, C diff positivity could reflect colonization and symptoms could be due to other etiologies.
Background: “The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers.” n=259 with 222 who completed short-term follow-up.
All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank).
90% (n=200) were considered cured at one month. Of these, 197 (98%) received only 1 FMT.
Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence.
Safety: Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%). Milder adverse events were noted in 45% with symptoms including diarrhea, abdominal pain, bloating or constipation.
My take: Overall, the findings from this prospective registry confirm that FMT works fairly well for CDI. Long-term follow-up will provide more answers on the safety of FMT.
The report recommends NOT using probiotics outside of clinical trials for irritable bowel syndrome, Clostridium difficile infection treatment, Crohn’s disease, and gastroenteritis.
It recommends a specific probiotic for pouchitis and for prevention of necrotizing enterocolitis in preterm infants <37 weeks and 3 probiotics for patients who are receiving antibiotics (to prevent Clostridium difficile infection)
“While our guideline does highlight a few use cases for probiotics, it more importantly underscores that the public’s assumptions about the benefits of probiotics are not well-founded,” said Dr. Grace L. Su, a professor of medicine and chief of gastroenterology at the University of Michigan, Ann Arbor, in a news statement. She was the chair of the panel that issued the new guidance….
“The industry is largely unregulated and marketing of product is often geared directly at consumers without providing direct and consistent proof of effectiveness,” said the new guidelines. “This has led to widespread use of probiotics with confusing evidence for clinical efficacy,” it said…
“Not all probiotics are created equal. Some probiotic strains and mixtures are very effective for some types of diseases and should not be overlooked due to studies that lump all probiotics together as one”
My take: Probiotics are overhyped and underperform for most conditions. This report suggests that most people should NOT be taking probiotics.
IBS does not increase mortality in a nationwide cohort study (>300,000 in study) Full text: Mortality Risk in Irritable Bowel SyndromeKey finding: After adjustment for confounders, IBS was not linked to mortality (HR = 0.96; 95% CI = 0.92–1.00) …and patients with IBS not undergoing a colorectal biopsy were at no increased risk of death (HR = 1.02; 95% CI = 0.99–1.06).
Mongerson was not effective for active Crohn’s disease in a large phase 3 study, n=701 Full text: Mongersen (GED-0301) for Active Crohn’s DiseaseKey finding: The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo.
Treatment of H pylori did not increase the risk of C difficile infection (retrospective study) Full text: Treatment of Helicobacter pylori & Clostridium difficileKey finding: Of these 38,535 patients with H pylori based on endoscopic pathology, urea breath testing, or stool antigen, 284 (0.74%) had subsequent CDI. Those who developed CDI were less likely to have received treatment for HP within the VHA (66.2% vs 74.8%, P < 0.001)
Percutaneous liver biospy was not safer when done by experienced clinician compared to a fellow, n=212 biopsies Full text: Major Complications of Pediatric Percutaneous Liver Biopsy Do Not Differ Among Physicians With Different Degrees of Training Key finding: No significant differences were found between groups (fellows vs staff) regarding number of punctures (median of 1.7 for both), nonrepresentative biopsies (4.2% vs 2.6%), and hemoglobin drop (median of 0.7 vs 0.5 g/L). Interestingly, in the discussion, the authors assert: “previous studies do not support the conclusion that ultrasound-guided biopsies are superior in terms of safety or adequacy when compared with the use of ultrasound to mark the puncture” (this is based on a study referenced from 2007: J Gastroenterol Hepatol 2007;22(9):1490–3.) However, given that severe complications from liver biopsy are infrequent, this current study may be underpowered to detect a small difference between experienced clinicians and fellows.
We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector–infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25–69%) of secondary cases were infected during the index cases’ presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.
A recent retrospective multi-center study (MR Nicholson et al. Clin Gastroenterol Hepatol 2020; 18: 612-9) provides data on fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI). Congratulations to one of my partners, Jeffery Lewis, who is one of the coauthors. This paper’s abstract is noted in a separate blog: Large Study Show FMT Efficacy/Safety in Children.
Though this is a pediatric study, the authors included patients up to 23 years. 335 of the patients had followup for at least 2 months following FMT.
81% of patients had a successful outcome after a single FMT and 86.6% after single or repeated FMT
Higher success rates were associated with fresh donor stool (OR 2.66), FMT via colonoscopy (OR 2.41), and with not having a feeding tube (OR 2.08)
Though not reaching statistical significance, patients with inflammatory bowel disease had a high failure rate of 23% (26/111). Short bowel syndrome patients had a 50% failure rate (5/10), solid organ transplant recipients had a 56% failure rate (5/9), and patients with feeding tubes had a 32% failure rate (21/65).
Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations; however, the majority were unrelated to FMT. Specific adverse reactions that were related or may have been included aspiration pneumonia on day of procedure (n=1), IBD flare/colectomy (n=5), and vomiting/dehydration (n=1)
Common adverse reactions included diarrhea, abdominal pain, and bloating. (These symptoms have been reported in up to 70% of adults following FMT.)
The authors note that a prior systematic review had indicated that delivery of FMT via colonoscopy was more successful in adults (95% vs 88%), though there are some additional risks with colonoscopy.
It is worth considering that the failure rate in some patients could be due to misdiagnosis, particularly in certain populations like patients with IBD and or organ transplant recipients. In these populations, PCR assays may result in false-positive diagnosis and should be confirmed with an ELISA assay. While eradication of CDI with FMT improves clinical symptoms and reduces the use of antibiotics the true benefit and risks will not be known for a long time. Does FMT increase or reduce the risk of downstream infections, autoimmune disease, and metabolic syndrome?
My take: Many of the concerns with FMT can only be adequately addressed with prospective studies (with strict definitions of CDI) and longer followup.
A recent study (C Ma et al. Gastroenterol 2020; 158: 780-82) used cross-sectional data from the National Ambulatory Medical Care Survey (NAMCS) (2006-2015) with a total 7,872,115,883 weighted observations. They used this data to evaluate medication exposures and outcomes.
There was no association between PPI use and dementia, pneumonia, or intestinal infections. There was a trend towards intestinal infections (AOR 1.48, CI 0.80-2.71) but this did not reach statistical significance. “Sensitivity analysis showed an association between PPI use and C difficile.”
There was an association with chronic kidney disease (CKD) (AOR 1.26); however, this was seen with a multitude of drug classes including statins, calcium channel blockers, and beta-blockers.
This study notes that a recent large randomized controlled trial found no statistically significant differences between those receiving PPIs and those receiving placebo except for intestinal infections.
With regard to CKD, “it is extremely unlikely that all of these medications increase the risk of CKD, and therefore, it is likely that these findings are due to residual confounding.”
My take: With the exception of C difficile/intestinal infections, this study provides further evidence of the safety of PPIs and a lack of association between these medications and purported PPI-related adverse events. That said, it is still a good idea to limit use for appropriate indications.
Related blog posts:
PPIs: Good News on Safety Large randomized double-blind study of pantoprazole: “we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections.”
JM Cotter et al. (J Pediatr 2020; 218: 157-65) reviewed 1214 C difficile positive results from a total of 6841 C difficile tests 2013-15 & 2015-17). Key findings:
In the later era of multiplex tests, there was a much higher rate of C difficile detection (1.7-2.3 times higher) and a much higher rate of detection.
However, 31% of the multiplex tests identified another organism which indicates a high likelihood of a false-positive test (C difficile colonization)
Many of these “C difficile infections” were detected simply due to ease of test ordering. In addition, the test results should be viewed with suspicion particularly in low-risk individuals.
Nearly one-third of the C difficile infected patients were oncology patients who are known to have high rates of asymptomatic colonization.
In patients known to have high risk of asymptomatic colonization (eg. young, oncology, IBD), detection of C difficile infection may lead to anchoring bias resulting in diagnostic delays for other disorders.
My take: We know that we are approaching the diagnosis of C difficile infection the wrong way (see IDSA guidelines below), but it is so quick and easy.
Related blog posts:
Clostridium difficile Guidelines The diagnosis of CDI… Molecular tests (eg, nucleic acid amplification tests [NAATs], such as polymerase chain reaction), which do not differentiate colonization and infection, are now the most commonly used test for CDI among US hospitals. NAATs have the potential to misdiagnose patients with colonization as having CDI, particularly when used in patients with low likelihood of CDI. Thus, this guideline strongly reinforces the importance of practicing good diagnostic stewardship and limiting C difficile testing to patients with new-onset, unexplained, and clinically significant (ie, at least 3 unformed stools in a 24-hour period) diarrhea…formed stools should not be tested for C difficile, nor should patients be retested within 7 days of a previous negative C difficile test. In pediatric populations, because of the unclear role of C difficile as a cause of diarrhea in infants, children less than 12 months of age should not be tested…If diagnostic stewardship is not an achievable goal, use of NAAT alone is likely to lead to frequent misdiagnosis of CDI among patients with C difficile colonization. In these cases, NAAT alone should be avoided and a multistep algorithm that incorporates toxin testing is recommended.
Approval [by FDA] was based on results from SUNSHINE, a phase 3, multicenter, investigator-blind, randomized, parallel-group study in 142 pediatric patients aged between 6 months and 18 years with confirmed C. difficile infection who received either fidaxomicin or vancomycin for 10 days. Clinical response 2 days after the conclusion of treatment was similar in both groups (77.6% for fidaxomicin vs. 70.5% for vancomycin), and fidaxomicin had a superior sustained response 30 days after the conclusion of treatment (68.4% vs. 50.0%)…
The fidaxomicin pediatric trial was the first randomized, controlled trial of C. difficile infection treatment in children,” Larry K. Kociolek, MD
AY Guh et al. NEJM 2020; 382: 1320-30. The authors examined the U.S. Burden of CDI by using the Emerging Infections Program (35 counties in 10 states). Key findings:
15,461 cases of CDI in 2011 and 15,5512 in 2017 detected which extrapolates to 476,000 national cases in 2011 and 462,400 national cases in 2017
When accounting for increased use of PCR assays, the authors estimate that the C difficile infectious burden decreased by 24% from 2011 to 2017 (due to a drop in health care-associated infections.
My wife has been receiving a lot of compliments for her daily jokes which she decided to post for all of the neighborhood walkers: “If number two pencils are so popular, why are they still number 2?”