Why are infants less likely to have Clostridium difficile infection?
Adult clinicians are quite familiar with Clostridium (or Clostridioides) difficile infection (CDI). But this infection is remarkably rare in infants. The explanation is both fascinating and has important implications.
Beginning at the beginning, Clostridium difficile was first isolated in 1935 by two microbiologists, Elizabeth O’ Toole and Ivan Hall, who were examining the stool flora of 10 newborn babies. Of these 10, four were colonized with a bacteria that had never been isolated before. It was a spore-forming anaerobic rod that was difficult to culture given its propensity for slow growth. They called it Bacillus Difficilis. All four babies were asymptomatic. But Hall and O’Toole used an inverted version of Koch’s postulates and tested to see what would happen after inoculation of this newfound bacteria into guinea pigs. The animals experienced severe colitis and 16 of the 22 died over the next nine days. The authors rightly noted that this is a pathogenic organism, given how sick the guinea pigs got, but for some reason, the babies were unscathed. They published their report in JAMA Pediatrics.
One explanation for the low rates of CDI might be that rates of colonization are lower in babies. But this doesn’t seem to be the case. A 1989 study published in the European Journal of Clinical Microbiology and Infectious Disease looked at the rates of detectable Clostridium difficile in children 18 months of age or younger using rectal swabs. They found that of the 343 children they sampled, 25% were colonized with C. difficile at 6 months of age or younger, whereas the colonization rate decreased dramatically by age 18 months to just 3%. Babies are presumably picking up the bacteria from contamination and exposure to the environment in the hospital and at home. But quite surprisingly, clinical CDI in babies 6 months or younger is vanishingly rare. Technically possible and there are case reports of it happening, but far less frequent than in older children and adults.
Little was written about C. difficile after the initial 1935 report. Then, in 1978, a group out of the Los Angeles VA reported a case of a patient who developed pseudomembranous colitis after taking clindamycin. They found that the patient’s stool contained C. difficile and the C. difficile toxin. They theorized that this might be a primary cause of antibiotic-associated diarrhea in general. A couple of other reports had been published around the same time, showing similar results.
There are at least three host factors and one C. difficile factor that likely explain the difference in the propensity to experience CDI based on age. These include:
1. Decreased toxin receptor production in neonatal colons
2. Maternal antibodies transmission
3. The neonatal microbiome
4. C difficile virulence
To understand how decreased toxin receptor production might play a role, notice that human babies are not alone in being resistant to symptomatic C. difficile infection. Newborn baby rabbits are similarly protected. And a 1992 study in the Journal of Clinical Investigation found a dramatically reduced binding of C. difficile toxin to the neonatal rabbit colonic mucosa. This strongly suggests that immature colons simply have not had a chance to make enough receptors to promote damage to the colon or the receptor they do make is not structurally able to bind and internalize the toxin.
A human cell culture study from 1986 compared the ability of fetal and colonic enterocytes to bind and internalize C. difficile toxin. The researchers tested both toxins A and B, and found that the fetal enterocytes essentially took up no toxin – they tested the toxin concentration in the cell culture after 60 and 120 minutes and found the levels of toxin did not decrease when mixed with fetal enterocytes. But the adult cells readily internalized the toxins, with a decrease in toxin concentration by as much as 25-fold during the experiment. This result supports the notion that something in the C. difficile toxin receptor machinery is not yet functional in baby’s colons, which would help them be resistant to symptomatic infection. This explanation succinctly explains why babies are so commonly colonized with C. difficile but almost never get a symptomatic infection.
Maternal antibody transmission plays a role too. It has been shown that asymptomatic carriers of C. difficile have higher anti-toxin A antibody titers than those with active colitis. This suggests that these antibodies are protective against colitis. Newborns and infants have immature immune systems and are therefore entirely reliant on maternal antibodies being passively transferred both across the placenta in utero and through breast milk. And as humans in the world, birth mothers are commonly exposed to C. difficile in their lives, and breast milk has been found to commonly contain antibodies against C. difficile toxin A. Such antibodies would block toxin A from binding to its receptor, and after passing to a breastfed baby, likely contribute to protection from Cdiff colitis.
As with any colonic disease, the microbiome is a key factor as well. It is well known that the resident microbiota in our intestines prevents C. difficile spores from germinating into active, toxin-producing bacteria. That is why exposure to antibiotics is the main risk factor for C. difficile colitis. Babies who are less than a year old have different microbial flora than older children and adults. It is less complex in terms of species composition. It is not known with certainty if this difference plays a protective role, but it might. It’s interesting to note that infants colonized with C. difficile have a different bacterial flora profile than those who are not colonized. Does this difference reflect a cause or effect in terms of C. difficile colonization and protection from colitis? Possibly, based on everything we know about the suppressive role of the intestinal microbiome against C. difficile colitis. Presumably, the evolving microbiota profile over the first 1-2 years of life eventually out-competes C. difficile as a routine colonizer.
Finally, with all bacteria that are human pathogens, some strains are more or less virulent. In the case of C. difficile, the breakdown involves toxigenic and non-toxigenic strains. Non-toxigenic strains do not produce toxins and if they do not produce toxins then they cannot cause colitis. Toxigenic strains produce toxins and can lead to colitis. A review article from 2010 in the Journal of Pediatric Gastroenterology and Nutrition noted that babies are more often colonized with non-toxigenic strains. This tendency to harbor non-toxigenic strains may play a role in lower rates of CDI.
Finally, it’s fascinating to note there does seem to be a benefit to having C. difficile colonization in one’s colon as an infant, as it may impact susceptibility to CDI later in life. As we’ve seen being colonized with C. difficile leads to production of antibodies against the bacteria, including against toxins. A study from NEJM in 2000 showed that patients with pre-existing antibodies against toxin A were less likely to develop CDI after exposure to antibiotics.
Take Home Points
- Humans have a paradoxical situation where babies are protected from C. Diff colitis but are very commonly colonized by it
- This results from a confluence of both host and bacterial factors
- It may help protect us from CDI later in life by way humoral immunity
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Credits & Citation
◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Cooper AZ, Abrams HR, Breu AC. DIFFerent Babies. The Curious Clinicians Podcast. July 26, 2023.
Image credit: https://www.cidrap.umn.edu/antimicrobial-stewardship/prior-bed-occupants-may-raise-risk-hospital-c-diff
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