Fecal microbiota transplantation in the patients after allogenic bone marrow transplantation with acute graft-versus-host disease and severe gastrointestinal damage
Oleg S. Syuskin, Oleg V. Goloshchapov, Dar’ya V. Churakina, Maksim А. Kucher, Ruslana V. Klementeva, Sergei V. Sidorenko, Vladimir V. Gostev, Vadim Е. Karev, Мariya А. Suvorova, Irina V. Shlyk, Аlexei B. Chukhlovin, Ludmila S. Zubarovskaya, Olga V. Pirogova, Olesya V. Paina, Marina O. Popova, Boris V. Afanasyev
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Contacts: Dr. Oleg S. Syuskin
Allogeneic hematopoetic stem cell transplantation (allo-HSCT) is often accompanied by severe immune and infectious complications refractory to standard immunosuppressive and antibacterial therapy. This is especially true for hard-to-sanitize loci of infection, such as the gastrointestinal tract, which is one of the main target organs in acute graft-versus-host disease (GVHD). Fecal microbiota transplantation (FMT), which has an immunomodulatory effect and is aimed for eradication of antibiotic-resistant pathogenic microbiota, in this case can be considered as a variant of «rescue therapy». Analysis of efficacy and safety of applying FMT in treatment immunocompromising patients in critical condition caused by gastrointestinal GVHD after allo-HSCT was the aim of our work. It may help to optimize therapy in these patients. The aim of our pilot study was to assess efficiency FMT efficiency.
Materials and methods
Two clinical procedures of TFM were performed for the treatment of acute GVHD with intestinal lesions, confirmed by morphological and histological studies, in patients in critical condition, treated at the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, i.e., a male recipient 45 years old (patient K.), and a girl 3 years 8 months (patient M.). In both cases, a combination of sepsis, multi-organ dysfunction syndrome and acute grade IV GVHD, was the prevalent syndrome determining the overall severity of the condition which manifested by high-volume secretory diarrhea and severe recurrent gastrointestinal bleeding.
Quantitative changes in the bacterial composition of the fecal microbiota (FM) were evaluated by real-time polymerase chain reaction (PCR). Culturing and isolation of bacteria from biological samples and evaluation of their antibiotic susceptibility was performed using standard disc diffusion methods. The genes encoding carbapenemases of groups КРС, ОХА-48, VIM, IMP, NDM, were detected by PCR in DNA separated from clinical isolates. The effectiveness of the method was evaluated by the clinical state of patients, quantitative and qualitative changes in the bacterial composition of FM.
Clinical condition of the patients after TFM has, generally, shown a similar positive dynamics. In patient K., a reduction in stool volume to 1000 mL/day was recorded at D+14. Termination of intestinal bleeding was observed on D+29. Semi-solid stool was first marked on D+119. The patient was discharged from ICU on D+92; he has left the hospital in satisfactory condition on D+192. Intestinal bleeding in patient M., was stopped at D+14. Volume of the stool was reduced to 500 ml/day on D+25. The well-formed stool was first marked on D+32. The patient was transferred from ICU on D+36, and has left clinic in satisfactory condition on D+82.
In both clinical cases, there was also a similar dynamics of FM. In patient K., the total bacterial mass of FM increased considerably (from 4*10^7/g to 6*10^12/g), due to Lactobacillus spp., Bifidobacterium spp., B. Fragilis, Bacteroides thetaiataomicron, F. Prausnitzii. Together with these changes, there was a decrease in numbers of Citrobacter spp., Enterococcus spp., K. Pneumoniae. Total bacterial mass in patient M. has not changed considerably (5*10^11/g initially, and 2*10^12/g after FMT). However, an increase in Lactobacillus spp., Bifidobacterium spp., F. prausnitzii, B. Fragilis was noted over the period from D+8 to D+30. Also, a decrease in Citrobacter spp., Enterococcus spp., K. pneumoniae, Clostridium difficile was found by D+30. After FMT, in both patients an increased proportion of anaerobic bacteria of the genus Bacteroides spp., Fecalibacterium spp., Lactobacillus spp., Bifidobacterium spp., reduction of representatives of the Enterobacteriaceae family (Citrobacter spp., K. pneumoniae) and Enterococcus spp. Moreover, the multidrug-resistant Pseudomonas spp. (KPC-type carbapenemase gene positive) was not no longer detected after FMT in bronchoalveolar lavage from patient K. Similarly, it caused elimination of K. pneumoniae with carbapenemase NDM- and OXA-48 types expression, being replaced by the carbapenem-sensitive isolate.
FMT can be considered a method of «rescue therapy» in combination treatment of children and adults in critical condition with acute intestinal GVHD combined with sepsis. FMT may increase clinical efficacy of antibacterial drugs by replacing polyresistant strains of K. pneumoniae and Pseudomonas spp. to bacterial strains which did not produce NDM-metalloproteinase, as well as ОХА-48 and КРС serine carbapenemases.
Fecal microbiota transplantation, GVHD, sepsis, decolonization, carbapenemases, metalloproteinase, NDM, OXA-48, КРС, Klebsiella pneumoniae, Pseudomonas spp.