Massachusetts General Hospital oversaw trial that led to the first death from a fecal transplant, a new paper shows

This spring, a 73-year-old man with a rare blood condition became the first person to die from drug-resistant bacteria found in a fecal transplant. New details about that unprecedented incident emerged on Wednesday.

The man was a participant in a clinical trial run at Massachusetts General Hospital and received fecal transplant capsules made in November with fecal material from one stool donor, according to a paper published Wednesday in the New England Journal of Medicine. Tests after the man’s death revealed that material contained a rare type of E. coli bacteria.

MGH scientists started screening for those kinds of bacteria in January. However, the hospital did not test capsules they’d already produced, researchers disclosed in a paper published in the New England Journal of Medicine.

“We didn’t think of it. The prevalence of these organisms in healthy individuals is so low,” Dr. Elizabeth Hohmann, an author of the paper and an infectious disease specialist who runs the central laboratory at MGH that made the capsules, told STAT. “In retrospect, it was like, ‘Oh, my gosh, of course we should have done that.’ But it didn’t happen.”

The Food and Drug Administration first publicized the man’s death in June. At the time, the agency specified the type of bacteria that led to his death and that the person had a weaker-than-usual immune system. But it wasn’t clear where he died — nor was it clear how many other people may have been exposed to the bacteria.

Twenty-one other people also received capsules made with material from the same donor, the NEJM paper said. One other person reported serious side effects, but recovered; several others tested positive for the resistant bacteria but weren’t made sick.

The paper’s publication comes just days before the FDA will hold a Nov. 4 meeting about the safety and regulation of fecal transplants, a procedure that has garnered an increasing amount of interest as scientists learn more about gut bacteria’s relationship to human health.

For years, doctors have offered fecal transplants to people with C. difficile, a serious infection that kills more than 15,000 Americans each year. Several clinical trials have shown that fecal microbiota transplants (FMTs), which involve giving person stool collected from a healthy donor in a pill or as an enema, can cure this often stubborn condition.

But a growing number of people are receiving fecal transplants to treat something else. In Boston alone, scientists have offered FMT through clinical trials to people with peanut allergies and Crohn’s disease as well as to people who are obese.

The FDA, through a spokesperson, emphasized to STAT that the procedure is still considered “investigational” — even for C. diff infections.

Participants in two trials at MGH received FMTs from the donor whose stool contained E. coli, identified as donor #46 in Wednesday’s paper.

One of those trials is investigating the effect of fecal transplants before a stem cell transplant; the other is evaluating fecal transplants as a treatment for hepatic encephalopathy, a brain disorder that can happen to people with serious, long-term liver disease.

Both trials and the others happening at MGH relied on stool donations from people who underwent intense screening, including a review of their medical history, blood tests, and tests for other drug-resistant bacteria, like methicillin-resistant Staphylococcus aureus (MRSA).

At MGH, some capsules made from donor #46’s stool were set aside and frozen, in case scientists needed to do further tests; some of the hospitals clinical trials require stool samples from participants before their transplants to be collected and frozen as well.

In May, after the hospital realized the stool capsules might be the source of the infection, researchers tested those stored samples as well as blood samples collected from each affected patient.

Those analyses showed that the bacteria found in each patient’s blood and in the capsules had similar genetic makeups and were resistant to similar antibiotics; those bacteria didn’t exist in the patients’ pre-transplant stool samples.

“It’s pretty clear that these are identical strains,” Hohmann said. “It’s more likely I’m going to win two lotteries than that this is not related [to the capsules]. I think this is definitive.”

The particular type of bacteria found in the stool capsules — extended-spectrum beta-lactamase-producing E. coli, sometimes shortened to ESBL-producing E. coli — is relatively rare in the general population. What limited data exist suggest that just 1% or 2% percent of people in the United States carry the bacteria, according to Dr. Clifford McDonald, an associate director for science at the Centers for Disease Control and Prevention’s Division of Healthcare Quality Promotion and an expert on C. difficile infections.

Despite its rarity, ESBL-producing E. coli are still considered a very serious problem. Because it is resistant to many types of antibiotics, it’s one of a dozen bacteria considered “serious” threats by the CDC.

Because donor #46 is otherwise healthy, she did not require treatment and was not told about the incidents associated with capsules made from her stool, an MGH spokesperson confirmed.

Testing for these kinds of bacteria may become increasingly important; antibiotic resistance is becoming an increasing problem.

“I’m so glad they’ve put this information out, in this detail, so we can learn from this,” said Dr. Sahil Khanna, a gastroenterologist at the Mayo Clinic who has used FMT in clinical trials and has consulted with several companies developing microbiome-based medicines, including Rebiotix, Seres Therapeutics, and Vedanta Biosciences. He was not involved in either the MGH trial or the NEJM paper. “That’s the kind of level [of detail] that myself and others were looking for.”

The information in Wednesday’s publication could also help the field moving forward, Khanna noted. Doctors have better information about the potential risks of FMTs that they can share with patients or potential clinical trial participants, and the paper could help people running clinical trials understand how others are screening for drug-resistant bacteria.

“This is bringing the science forward. We need to know this stuff. This is probably not going to be the last adverse event that is going to happen,” he added.

This incident could also encourage the adoption of universal screening standards, said Carolyn Edelstein, the executive director of OpenBiome, a stool bank based in Cambridge, Mass. “There’s a need for the clinical community to come together and establish what is state-of-the-art in this field.”

But although every clinical trial supervised by the FDA is now screening for ESBL-producing E. coli, MGH’s Hohmann warned that there is still a lot scientists don’t know.

“Yes, we can screen this one out — but who knows what else could be the next microbe that’s problematic here,” she said. “A normal human microbiome from the GI tract has thousands of microorganisms. It’s not possible to make this 100% safe. It’s not a pharmaceutical preparation. It’s a microbiome.”