Fecal microbiota transplantation in patients after allogeneic hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective method of treatment of malignant, hematological and hereditary diseases. Common complications after allo-HSCT, which may decrease its effectiveness, include infectious lesions of the gastrointestinal tract of viral etiology and Clostridium difficile on the background of immunodeficiency, antibiotic-associated diarrhea and graftversus-host disease (GvHD). Transplantation of fecal microbiota (FMT) from a healthy donor can lead to eradication of pathogens, modulation of the recipient’s immune system and as a consequence to a decrease in intestinal GVHD activity. Aim of our study was to increase treatment efficiency of complications associated with Clostridium difficile and intestinal GvHD in patients after allo-HSCT.
Patients and methods
From 2015 to 2018 in Raisa Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation 11 patients after allo-HSCT from matched unrelated donor – 36.5% (n=4), related donor – 9% (n=1), haploidentical donor – 54.5% (n=6) with acute lymphoblastic leukemia – 18.3% (n=2), acute myeloid leukemia – 27.4% (n=3), myelodysplastic syndrome – 18.3% (n=2), beta-thalassemia – 9% (n=1), chronic myeloid leukemia – 9% (n=1), Hodgkin’s lymphoma – 9% (n=1), Fanconi’s anemia – 9% (n=1) were included in a single-center prospective study. All patients underwent FMT for the treatment of posttransplant complications. The median age was 24 years (2-45). Three patients were excluded from the study due to violation of FMT technique (n=2), development of severe systemic inflammatory response syndrome (n=1). The duration of diarrhea before FMT was from 1 to 6 months (median – 2.3) and was observed in all patients. Active intestinal bleeding with the need of daily blood transfusions for the correction of anemic syndrome was registered in 5 (45.5%) patients, additionally blood impurity in stool was determined in 4 (36.4%) patients. 5 patients had sepsis (45.5%) and one patient was in septic shock associated with Klebsiella pneumoniae and received antibiotic therapy, vasopressors, mechanical ventilation. Abdominal pain requiring analgesia with opioids was noted in 9 (81.8%) patients. Gastrointestinal paresis was observed in 5 (45.5%) patients. 8 (72.7%) patients had positive clostridial toxin-B in stool. Elevated fecal calprotectin level – 600 μg/g (220-6706) before FMT was identified in 7 (63.6%) patients. FMT was performed on D+168 (27-1107). Microbiota donors were patient’s relatives or unrelated donors who met all infectious safety requirements. Before and after FMT D+3, D+8, D+16, D+30, D+45, D+60, D+75, D+90 real-time multiplex PCR (“Colonoflor-16”) was performed to determine the main groups of intestinal microorganisms. 3 patients underwent 16S RNA stool sequencing prior FMT.
A complete clinical response was observed in 64% of patients. The reduction in the frequency and volume of diarrhea by 2 times was observed on D+18 (1 – 39) and D+14 (1 – 11) after FMT, respectively. Complete regression of pathological impurities in the stool (blood, mucus) was recorded at D+13 (2-11), D+30 (1-97) and abdominal pain syndrome at D+15 (5-31), respectively. Clostridial toxin-B in stool samples at D+30 was not detected in 4 (50%) previously positive cases. The results of multiplex PCR showed changes in gut microbiota after FMT. The maximum increase in the main groups of intestinal microorganisms was recorded after FMT for the total bacterial mass at D+8 from 3E+08 (9,E+05/ 1E+11) to 1,65 E+12 (7E+10/ 7E+12), for Lactobacillus spp. on D+3 7E+05 (1E+04/2E+09) to 3E+08 (7E+05/ 3E+09) and for Bifidobacterium spp. on D+30 3E+06 (9E+04/ 3E+08) to 1E+08 (3E+06/ 6E+09), Escherichia coli on D+3 7E+05 (0.0 E+00/7E+06) to 3E+07 (2E+06/ 3E+09), for Bacteroides fragilis group on D+8 1.1 E+07 (0.0 E+00/4E+08) to 1.6 E+12 (3E+06/7E+12), Faecalibacterium prausnitzii on D+3 3E+05 (0.0 E+00/8E+07) to 3E+08 (1E+05/ 3E+09). 16S RNA stool sequencing before FMT revealed marked disturbances of intestinal microbiota with predominance of microorganisms of the following families: Streptococcaceae, Staphylococcaceae, Enterococcaceae.
FMT is effective and safe method of treatment for infectious complications associated with Clostridium difficile and intestinal GvHD in patients after allo-HCST.
Hematopoietic stem cell transplantation, fecal microbiota transplantation, graft-versus-host disease.