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I. Henig et al.
Table 1. Intestine microbial changes in diversity and abundance during pre-transplant and peri-engraftment periods, associated with outcomes of allogeneic hematopoietic stem cell transplantation
Ref. #
37; 55
38
58 56 58
38
59
gesting that this cutoff could serve as a prognosticator of a long-term outcome in this clinical setting.54 The above evidence suggests that the microbiota changes before and during allo-HSCT are significantly associated with trans- plant complications and outcomes and might even serve as a predictive marker in this setting.
Can prophylactic fecal microbiota transplanta- tion reduce the risk of infections during allo- geneic hematopoietic stem cell transplantation?
In allo-HSCT recipients, curtailment of infection risk is crucial for reducing TRM, particularly due to increased frequency of BSI with multidrug resistant (MDR) bacte- ria. MDR colonization is established to range between 16% for gram-negative bacteria and 39% for van- comycin-resistant Enterococcus (VRE). While BSI have been reported in 16-41% of patients colonized with MDR bac- teria, findings regarding a possible association of such col- onization with TRM or infection-related mortality are inconclusive.60-62 In addition, MDR gram-negative colo- nization has neither been found to correspond to an increased risk for sepsis.38,63 In the lack of clear evidence, proof-of-concept studies are becoming of increasing importance. Battipaglia et al.64 have evaluated four patients colonized with MDR bacteria who had received FMT on days -46 to -9 before transplant with an aim to limit the risk for infectious complications during HSCT. All the four patients responded with decolonization of the MDR bacteria. One patient developed grade 3 acute gut GvHD on day +30 after transplant (day +51 after FMT) and two others developed bacteremia with sensi- tive bacteria. Notably, despite receiving broad-spectrum antibiotics during the transplantation period, none of the patients had recolonization of the gut with MDR bacte-
Outcome
Pre-transplant
Peri-engraftment
Overall survival ↓ Transplant- related
Diversity ↓ Lachnospiraceae
Ref. #
37
57 54
37
40
56 38 38 38 56 56 52 58
37
57
50 50
59
ria.64 Similar results were reported in a 63-year old HSCT recipient.65
The ongoing ODYSSEE trial (clinicaltrials gov. Identifier: 02928523) is aimed at reducing complications that may arise as a result of a loss of microbiota diversity, including infectious complications, poor nutritional sta- tus, prolonged hospitalization, as well as therapy discon- tinuation due to induction treatment-related toxicity in AML patients. Twenty newly diagnosed patients collect- ed pre-induction autologous stools. This autologous FMT was later administered as enema after neutrophil recov- ery and prior to consolidation chemotherapy. Preliminary results demonstrated safety of this approach, with evi- dence of stool diversity restoration 10 days after FMT and reduction in antibiotic resistant gene copy count by 43%. Yet, clinical efficacy of this method still needs to be con- firmed.66
An important pathogen to consider for intervention with FMT is Clostridium difficile. The incidence of CDI dur- ing allo-HSCT varies between 13% and 30%, mostly in the first month after transplant.67-69 The disease is usually of mild-to-moderate severity, with good response to treatment; there is no association with TRM, and its pos- sible correlation to subsequent acute GI GvHD is indefi- nite.68-70 Given these facts, and the paucity of data on potential efficacy of prophylactic FMT in reducing the risk of CDI among Clostridium difficile carriers, FMT pro- phylaxis may not be required for this indication.
As for the treatment of recurrent CDI, results of three small studies demonstrate safety of FMT administration to a total of 16 patients with recurrent CDI after allo- HSCT, with only three patients recurring after the proce- dure.71-73
Currently available data are insufficient to definitively conclude that prophylactic FMT will reduce the infection rate in the allo-HSCT setting.
Diversity ↓
Blautia (day +12) ↓ Enterococcus RA ≥1% (day +30)
mortality ↑
Acute gastrointestinal
≤ 10% *Blautia ↓
Peri-engraftment diversity ↓ Engraftment diversity ↓
GvHD risk ↑ GvHD-related mortality ↑
≠Diversity ↓ *Fusobacterium ↑
≠Diversity ↓
¥Diversity ↓ (day+10) Lachnospiraceae (day +10) ↓ Staphylococcaceae (day +10) ↑ Bacteroidaceae ↓ Lachnospiraceae ↓ Enterococcus ↑
# Bacteroides ↑ (at engraftment)
Blood stream infections ↑
¶ Diversity ↓
Blautia (on day +12) ↓
Enterobacteriaceae
Enterococcus (RA ≥ 30%) -> VRE ↑ Proteobacteria (RA ≥ 30%) -> GN ↑
Relapse ↓
Eubacterium limosum ↑↑
(RA > 5%)
↓ represents a decrease in risk; ↑ represents an increase in risk; ↓next to diversity means loss of diversity; ↓ or ↑ next to a bacterial taxa represent decrease or increase in relative abundance, respectively. Different bacterial taxonomic rank is marked as follows: phyla (bold and italics), family (italics), genus (underlined) and species (bold). * taxa associated with grade 2-4 acute gastrointestinal graft-versus-host disease (GvHD). ≠ diversity associated with grade 3-4 acute GvHD (aGvHD). ¥ diversity associated with early aGvHD, by day 30. #a trend (P=0.05). ¶T-cell replete transplants. RA: relative abundance; VRE: vancomycin-resistant Enterococcus; GN: gram negative.
Eubacterium limosum presence
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