Researchers have identified a new diarrheal syndrome that affects patients who have undergone cord-blood hematopoietic stem-cell transplantation, according to a report in the Sept. 1 issue of the New England Journal of Medicine.
It is important to distinguish the new syndrome, which they call "cord colitis syndrome," from other causes of diarrheal illness that have a similar initial presentation in this patient population – notably graft-versus-host disease (GVHD) – because treatment differs. Cord colitis syndrome responds rapidly to antibiotic therapy but tends to relapse when treatment stops, so a prolonged course is often necessary, said Dr. Alex F. Herrera of the department of medicine, Brigham and Women's Hospital, Boston, and his associates.
Severe diarrhea following hematopoietic stem-cell transplantation (HSCT) can almost always be traced to a variety of sources. Acute GVHD is perhaps the most well-recognized. Classic viral causes include cytomegalovirus and adenovirus, but more common pathogens such as rotavirus and norovirus are being recognized more frequently. Epstein-Barr virus can incite lymphoproliferative disease involving the gut, which produces diarrhea. And protozoal infections from giardia and cryptosporidium have been reported.
In addition, mucositis and neutropenic enterocolitis induced by conditioning regimens frequently cause diarrhea, as do Clostridium difficile infection and long-term medications, the investigators said.
Dr. Herrera and his colleagues noticed several cases of diarrheal illness that could not be attributed to any of these causes among patients who had undergone cord-blood HSCT at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital Hematopoietic Stem Cell Transplantation Service. They reviewed the medical records of all 104 patients who underwent the procedure between March 2003 and April 2010, to characterize the disorder.
The median patient age was 48 years (range, 19-67 years). The patients underwent cord-blood HSCT to treat numerous underlying diseases including acute myeloid leukemia (35%), non-Hodgkin’s lymphoma (22%), myelodysplastic syndrome (10%), Hodgkin’s disease (8%), acute lymphoblastic leukemia (7%), and aplastic anemia (7%).
Eleven of the 104 patients (10.6%) had the cord colitis syndrome, with persistent watery, nonbloody diarrhea associated with weight loss of up to 11 kg (median loss, 2.3 kg). Eight of the 11 required hospitalization.
Stool samples were negative for all bacterial, viral, fungal, protozoal, and parasitic organisms as well as toxins that were tested for. Nevertheless, patients showed a rapid response to empiric antibiotic therapy – usually metronidazole, either alone or in combination with a fluoroquinolone.
The median interval between HSCT and symptom onset was 131 days (range, 88-314 days).
Six patients had abdominal CT during their diagnostic work-up. Five of them showed colonic wall thickening consistent with colitis: two had diffuse colonic involvement, two had significant sigmoid thickening, and one had thickening of the cecum and ascending colon.
All 11 patients underwent diagnostic colonoscopy with biopsy. Grossly, nine showed mucosal erythema, five had edematous mucosa, and four had mucosal ulcerations. Only one patient had hemorrhagic mucosa.
The 37 biopsy specimens showed the full range of inflammatory activity, from none to severe. Histopathologically, specimens showed chronic active colitis associated with granulomas. Neutrophilic infiltration was superimposed on Paneth cell metaplasia, suggesting chronic and ongoing injury. Surface epithelial injury was common, Dr. Herrera and his associates said (N. Engl. J. Med. 2011;365:815-24).
In contrast, GVHD is not associated with granuloma formation, neutrophilic infiltration of the epithelium, or Paneth cell metaplasia. Its hallmark is increased apoptosis, predominately in crypt bases, which was seen only infrequently in cord colitis syndrome.
All the patients with cord colitis syndrome responded to empiric therapy, usually metronidazole, with or without the addition of a fluoroquinolone. Diarrhea either resolved completely or was significantly reduced after a median of 5 days. However, four patients required extended treatment of up to 90 days before symptoms resolved. Another five had relapses at 4-60 days after finishing their antibiotic course, but all five responded to a further maintenance course of antibiotics.
The investigators found no correlation between the cord colitis syndrome and factors such as patient age or race, the underlying hematologic disease, the conditioning regimen, or the regimen to prevent GVHD.
For comparison with these cord-blood stem cell recipients, Dr. Herrera and his colleagues reviewed the records of 1,261 patients who underwent allogeneic peripheral-blood or bone marrow HSCT during the same period at the same center. This included 381 patients who had 609 GI endoscopy and biopsy procedures. None of these patients showed the features of cord colitis syndrome, so it appears to be related strictly to stem cells derived from cord blood, the researchers said.
Dr. Herrera and his associates reported no financial conflicts of interest.