Case Report

Journal of International Medical Research

48(6) 1–11
Fecal microbiota ! The Author(s) 2020
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DOI: 10.1177/0300060520925693
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steroid-resistant graft-
versus-host disease:
two case reports and a
review of the literature

Monika Maria Biernat1 ,

Donata Urbaniak-Kujda1, Jarosław Dybko2,
Katarzyna Kapelko-Słowik1, Iwona Prajs1 and
Tomasz Wr
obel1

Abstract
Acute graft-versus-host disease (aGvHD) reduces the efficiency and safety of allogeneic hema-
topoietic stem cell transplantation (allo-HSCT). In recent years, attempts have been made to
transplant fecal microbiota from healthy donors to treat intestinal GvHD. This study presented
two cases of patients undergoing allo-HSCT who were later selected for fecal microbiota trans-
plantation (FMT). In the first patient, FMT resulted in the complete resolution of symptoms,
whereas therapeutic efficacy was not achieved in the second patient. FMT eliminated drug-
resistant pathogens, namely very drug-resistant Enterococcus spp., but not multidrug-resistant
Acinetobacter baumannii or Candida spp. Further research is needed, particularly on the safety
of FMT in patients with intestinal steroid-resistant GvHD and on the distant impact of trans-
planted microflora on the outcomes of allo-HSCT. FMT appears promising for the treatment of
patients with steroid-resistant GvHD.

1
Department and Clinic of Haematology, Blood Corresponding author:
Neoplasms, and Bone Marrow Transplantation, Wroclaw Monika Biernat, Department and Clinic of Haematology,
Medical University, Wroclaw, Poland Blood Neoplasms and Bone Marrow Transplantation,
2
Department and Clinic of Internal and Occupational Wroclaw Medical University, Pasteura Street 4, 50-367,
Diseases and Hypertension, Wroclaw Medical University, Wroclaw, Poland.
Wroclaw, Poland Email: [email protected]

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2 Journal of International Medical Research

Keywords
Intestinal microflora, allogeneic hematopoietic stem cell transplantation, acute graft-versus-host
disease, treatment, multidrug resistance, multiorgan failure, antibiotics
Date received: 6 October 2019; accepted: 17 April 2020

Introduction In recent years, the importance of intes-

tinal microflora in maintaining gastrointes-
Acute graft-versus-host disease (aGvHD)
tinal homeostasis has been increasingly
reduces the efficiency and safety of alloge-
described.5 On the basis of mouse models
neic hematopoietic stem cell transplanta-
and research studies in patients with gastro-
tion (allo-HSCT). The condition is usually
intestinal tract diseases, it has been proven
severe, and it carries a high mortality rate.
that the quantitative and qualitative com-
GvHD may manifest with skin, intestinal,
position of the gastrointestinal microflora
and liver involvement.1 Intestinal localiza-
plays an important role in the pathogenesis
tion is one of the most severe forms of the
of many human diseases, such as inflamma-
disease. Disturbance of the mechanisms
tory bowel diseases, metabolic diseases,
responsible for homeostasis of the immune
autoimmune diseases, allergies, and infec-
system in the intestine and excessive
tious diseases.1,3,6 Understanding the
responses of the donor’s cytotoxic lympho-
importance of the gastrointestinal microflo-
cytes play crucial roles in the development
ra in the course of GvHD may contribute to
of this form of GvHD. In the course of
the development of new therapeutic strate-
aGvHD, the mucosal barrier in the intestine
gies.7,8 In recent years, attempts have been
is disturbed by conditioning treatment,
made to transplant intestinal microflora
resulting in the release of bacterial lipopo-
from healthy donors as a treatment for
lysaccharides and pro-inflammatory cyto-
intestinal GvHD. Therefore, this study pre-
kines and the subsequent activation of
sented two cases of patients undergoing
immune response receptors and the cyto-
allo-HSCT who were selected for fecal
kine storm.2 In addition, earlier treatment
microbiota transplantation (FMT).
with broad-spectrum antibiotics and coloni-
zation with multidrug-resistant (MDR)
bacteria before transplantation may also
Case 1 presentation
be important in the pathogenesis of The first case concerned a 25-year-old male
aGvHD and may influence its course.3,4 patient with acute myeloid leukemia that
Corticosteroids and immunosuppressive was diagnosed in September 2016. The
drugs are used routinely as the initial ther- bone marrow examination identified 97%
apies. However, the effectiveness of these of the cells as various myeloid dendritic
treatments is unsatisfactory, and there are cells, which immunophenotypically were
no drugs with proven effectiveness against classified as CD11cþ, CD56þ, CD123þ/,
steroid-resistant GvHD. Because of the lack and CD4. On the basis of cytogenetic and
of effective treatment options for intestinal molecular studies, the patient was diag-
GvHD, it is necessary to identify new meth- nosed with 9; 11(p22; q23) translocation
ods for preventing and treating this compli- with MLL and NPM1 (þ) rearrangement,
cation after allo-HSCT. i.e., intermediate cytogenetic risk II.
Biernat et al. 3

The treatment was based on an induction Enterococcus faecalis, Escherichia coli

regimen using the DAC protocol (daunor- extended-spectrum beta-lactamase-positive
ubicin, cytarabine, cladribine). After the (ESBLþ), Candida albicans, and Klebsiella
patient achieved complete remission with pneumoniae ESBLþ. Additionally, the
minimal residual disease, treatment was patient was diagnosed with neutropenic
continued with a consolidation regimen fever, followed by pneumonia. For treat-
using the high-dose cytarabine (HiDAC) ment, broad-spectrum antibiotics, initially
protocol. The patient qualified for allo- including meropenem and vancomycin,
HSCT using cells donated by his brother. were used, followed by meropenem and
The Cy-Bu regimen was used as the condi- linezolid, which were co-administered with
tioning regimen, and prophylaxis for anti-fungal agents (voriconazole). Because
GvHD consisted of cyclosporine and meth- the patient’s diarrhea did not improve
otrexate. In the transplant, the patient after approximately 3 weeks of treatment,
received 8.38  106 CD34þ cells/kg recipi- immunosuppressive therapy (infliximab and
ent body weight. The evidence for hemato- budesonide, followed by methotrexate and
logical restoration (engraftment) was as then cyclophosphamide) was intensified. To
follows: granulocytes >500/lL on day 16 treat severe abdominal pain, morphine was
after transplantation and platelets >20.0 added to the regimen. Additionally, immu-
G/L on day 17 after transplantation. The noglobulin was administered. Because of
patient received ciprofloxacin, fluconazole, the persistence of diarrhea and progressive
and acyclovir as routine anti-infective pro- cachexia, it was decided to include paren-
phylaxis according to the local protocol. No teral nutrition. The presence of BK virus
infection or GvHD was observed in the DNA in urine and plasma without dysuria
early post-transplantation period. The was found in viral tests. After 3 months,
post-transplant chimerism test result because of the ineffectiveness of the
revealed 100% donor T-cell chimerism. therapy, FMT was performed as a rescue
On day 34 after transplantation, the patient therapy with the prior written consent
was readmitted to the Department of of the patient and the consent of
Hematology because of diarrhea (10–12 the Bioethical Commission of Wroclaw
bowel movements/day, approximately 2 L/ Medical University. Fecal suspensions
day) and abdominal pain. Laboratory tests used for transplantation were obtained
revealed anemia, elevated concentrations of from healthy donors of Caucasian race
CRP, fibrinogen, and lactate dehydroge- (age, 20–40 years) as previously described.9
nase (LDH), and decreased total protein Briefly, active bacterial, viral, fungal, and
and serum albumin levels. An infectious parasitic infections were excluded in the
cause of diarrhea, including parasitic or donors, especially HAV, HBV, HCV,
viral infection and bloodstream infection, HIV, CMV, EBV, syphilis, intestinal para-
was excluded. The patient, who was afe- sites, Clostridium difficile, and enteropatho-
brile, underwent rectosigmoidoscopy, and genic flora. Donors were not treated with
an analysis of biopsy samples confirmed antibiotics for 3 months before sampling,
the diagnosis of grade II aGvHD. they were in good overall health, they had
Cytomegalovirus-induced enteritis was normal BMIs, and they followed a regular
excluded. The intestinal form of aGvHD diet. Each product was derived from 100 g
(grade IV) was also detected. Initially, of feces. Fecal suspensions were prepared
methylprednisolone was administered at a at the Center for Research and
dose of 2 mg/kg/day. A stool culture was Transplantation of Intestinal Microbiota,
performed, revealing the presence of Center for Preventive Medicine and
4 Journal of International Medical Research

Rehabilitation in Warsaw according to a his bilirubin level, extracorporeal photo-

previously described protocol and immedi- pheresis (ECP) was performed. On the
ately transported to the Wroclaw fifth day of hospitalization, the patient
Transplant Center within 5 hours.9 FMT developed a bloodstream infection caused
was performed as follows. Patients were by MDR Acinetobacter baumannii related
fasted on the day of transplantation, and to the indwelling catheter, and he died in
no medications were administered. In the the intensive care unit of multiorgan failure.
morning and 30 minutes before the proce-
dure, pantoprazole was administered at a Case 2 presentation
dose of 40 mg intravenously, and approxi-
mately 150 to 250 mL of fecal samples sus- The second case concerned a man with cere-
pended in physiological salt were bral palsy who was admitted to the
administered through an intranasal probe Department of Hematology at an age of
previously installed by a physician, after 32 years. The patient was diagnosed with
which the probe was removed. An easily osteomyelofibrosis at an age of 31 years
digestible diet was applied, and a control and categorized as intermediate risk 1
examination of feces was performed 7 according to the DIPSS plus scale. The
days after the procedure. The second pro- patient was scheduled for allo-HSCT
cedure was performed no sooner than 7 to using cells obtained from an unrelated
10 days after the first procedure. Antibiotics donor. The diagnosis of osteomyelofibrosis
were temporarily stopped prior to each was made in the regional hematological
FMT administration. ward on the basis of trepanobiopsy (pres-
The patient underwent FMT three times ence of fibrosis [collagen fibers], MF1/2
without complications. Fecal culture was approximately 80%), and the presence of
performed 7 days after each transplantation the V617F mutation in the JAK2 gene.
(Table 1). A gradual improvement of gas- On admission, the patient was in a good
trointestinal symptoms, mainly a decrease condition. The morphological examination
in the amount of diarrheal stools, was revealed severe normocytic and normochro-
observed after the second FMT, and the mic anemia, mild leukopenia according to
symptoms were completely resolved a the World Health Organization classifica-
couple of days after the third FMT, occur- tion, and elevated LDH levels. For condi-
ring in the sixth month of hospitalization. tion, the patient was treated according to
The patient was discharged in good general the Cy-Bu protocol. On day 0, stem cells
condition. After 1 month, he was readmit- were administered at 7.43  106 CD34þ
ted to the Department of Hematology cells/kg recipient body weight. The patient
because of malaise, weakness, and vomit- received ciprofloxacin, fluconazole, and
ing. There was no history of diarrhea since acyclovir as routine anti-infective prophy-
the prior discharge. Laboratory analyses laxis according to the local protocol. The
uncovered pancytopenia, elevation of trans- evidence of hematological restoration
aminases to 4 the upper limit of normal, (engraftment) was as follows: granulocytes
and a total bilirubin level exceeding >500/lL on day 21 after transplantation
12 mg/dL, whereas CMV or EBV reactiva- and platelets >20.0 G/L on day 19 after
tion was excluded. The patient was diagnosed transplantation. The post-transplant chime-
with liver GvHD. Methylprednisolone was rism test result revealed 100% donor T-cell
readministered at a dose of 2 mg/kg/day. chimerism. On day 17 after transplantation,
Additionally, because of deterioration of dysuria with hematuria was observed, and
the patient status and further increases of the virological examination uncovered the
Biernat et al. 5

Table 1. Results of the analysis of stool specimens from patients.

Patient 1 Patient 2

Pre-transplant Clostridium difficile-negative Clostridium difficile-negative

Candida albicans Enterococcus faecium (S)
Enterococcus faecalis (S) Enterococcus faecalis HLGR
Post-transplant GvHD Clostridium difficile-negative C. difficile-negative
Candida albicans (S) Enterobacter cloacae ESBLþ
Klebsiella pneumoniae (ESBLþ) Klebsiella pneumoniae (S)
Enterococcus faecalis (S) Candida albicans (S),
Escherichia coli ESBLþ Candida parapsilosis (S-voricon-
azole, R-fluconazole,
anidulafungin)
Post 1st FMT Escherichia coli (S) Enterococcus faecium HLGR
Klebsiella pneumoniae MDR Candida albicans (S)
Candida albicans Candida parapsilosis
(S – voriconazole, R – flucon-
azole, anidulafungin)
Stenotrophomonas maltophilia
(S – trimethoprim/
sulfamethoxazole),
Klebsiella pneumoniae (S)
Post 2nd FMT Enterococcus faecium GRE*** Stenotrophomonas maltophilia
Klebsiella pneumoniae PDR**** (S- trimethoprim/
Acinetobacter baumannii MDR***** sulfamethoxazole)
Candida albicans Enterococcus faecium VRE
Candida albicans
Post 3rd FMT Klebsiella pneumoniae (S) Escherichia coli ESBLþ
Candida albicans (S) Enterococcus faecium VRE
Acinetobacter baumannii MDR***** Candida albicans
Post 4th FMT Not done Escherichia coli (S)
Citrobacter freundii (S)
FMT, fecal microbiota transplantation; S, susceptible to all tested antibiotics; R, resistant to at least one of the tested drugs;
GvHD, graft-versus host disease, ESBLþ, extended-spectrum beta-lactamase positive; MDR, multidrug-resistant; PDR,
pan-drug-resistant; HLGR, high-level aminoglycoside-resistant
E. coli ESBLþ *(S – netilmicin, meropenem, ertapenem, piperacillin/tazobactam, gentamicin, amikacin; R – ciprofloxacin,
cefuroxime, ceftazidime, ampicillin/sulbactam, levofloxacin, trimethoprim/sulfamethoxazole), Klebsiella pneumoniae MDR**
– all, S – colistin, imipenem, tigecycline), Enterococcus faecium GRE*** (R – ampicillin, imipenem, vancomycin, teicoplanin,
gentamicin, S – linezolid), Klebsiella pneumoniae PDR* (R – all, S – colistin), Enterococcus faecium HLGR (S – vancomycin,
teicoplanin, linezolid, R – ampicillin, imipenem, gentamicin), Acinetobacter baumannii MDR***** – all, S – colistin, tobra-
mycin), Enterobacter cloacae ESBLþ (R – all, S – meropenem, ertapenem, imipenem, colistin).

presence of BK virus with viral loads of 15 stools/day, approximately 2.5 L/day).

1465 copies/mL in plasma and 1.3078  The patient was afebrile, and infectious
107 copies/ml in urine). Intensive fluid ther- parameters (e.g., C-reactive protein, procal-
apy was administered, resulting in the reso- citonin) were negative. The patient under-
lution of symptoms and reduced viral loads went ultrasonography and CT, which
in urine and plasma. On day 42 after trans- revealed thickening of the intestinal wall
plantation, diarrhea occurred (up to in the ileum. The patient was disqualified
6 Journal of International Medical Research

from endoscopy because of the severe clin- upper limit of normal and total bilirubin
ical condition and the increased risk of per- levels exceeding 15 mg/dL, the patient qual-
foration. The diagnosis was the intestinal ified to undergo ECP. No episode of CMV
form of aGvHD (grade IV). Fecal culture or EBV reactivation was detected. He
revealed positivity for E. coli ESBL (þ), required parenteral nutrition, blood,
Enterococcus faecium GRE, Candida albi- platelets, and plasma substitution. Only
cans, C. parapsilosis, K. pneumoniae, temporary improvement of the patient’s
Stenotrophomonas maltophilia, and C. diffi- condition was achieved with the applied
cile GDH antigens, whereas C. difficile treatment. Death occurred on day 128
toxins A and B were not detected. after transplantation with symptoms of
Corticosteroids (methylprednisolone 2 mg/ multiorgan failure.
kg/d IV) were administered for 2 weeks,
followed by calcineurin inhibitors and
Discussion
infliximab (anti-TNF-a) at a dose of
10 mg/kg recipient body weight. Moreover, In recent years, the role of the microbiome
because of pneumonia and neutropenic and its evolution in patients who underwent
fever, empiric antibiotic therapy (ceftazi- allotransplanation have been reported.10,11
dime and vancomycin followed by It was demonstrated that a conditioning
imipenem-cilastatin and linezolid) and anti- chemotherapy regimen and total-body irra-
fungal drugs (voriconazole) were adminis- diation lead to changes in the quantitative
tered. CMV DNAemia in the early stage and qualitative composition of the intesti-
of replication was detected on day 51 after nal flora. Chemotherapeutic agents used in
transplantation. Intravenous ganciclovir conditioning regimens decrease the counts
(5 mg/kg every 12 hours) was administered, of species, mainly Clostridium and
and after 14 days, the treatment was Bifidobacterium spp., and increase those of
changed to maintenance therapy. Control bacteria in the genus Enterococcus.1,12 The
CMV quantitative PCR was negative. reduction in the diversity of the intestinal
Because of the lack of clinical improvement microflora appears to be an independent
and persistence of diarrhea, the patient factor influencing mortality in the course
underwent FMT as a rescue therapy based of GvHD.13–15 Patients undergoing allo-
on the prior written consent of the patient HSCT develop long-term dysbiosis, which
and the consent of the Bioethical plays an essential role in GvHD pathogen-
Commission of Wroclaw Medical esis.11,12,16 Of importance, dysbiosis leads
University. FMT was repeated four times to the prevalence of one type of bacterium
with a minimum interval of 7 days. Fecal or fungus and acute inflammation.14 In
culture was performed after each transplan- addition, it was demonstrated that the
tation (Table 1). After the third and fourth early use of broad-spectrum antibiotics,
rounds of FMT, a temporary reduction in especially carbapenems and piperacillin/
symptoms, i.e., pain and the amount of tazobactam, in the treatment of infections
stool, was observed (approximately 1/day). after allo-HSCT increased mortality associ-
E. coli and Citrobacter freundii were ated with intestinal GvHD.17–19 The use of
detected in stool samples after administra- FMT to restore the normal microbiome can
tion of the fourth round of FMT without be an attractive option in the treatment of
resistance mechanisms. Because of the intestinal GvHD. To date, there have been
recurrence of diarrhea within 1 week and few reports on this subject. FMT was used
the presence of liver dysfunction character- in auto-HSCT and allo-HSCT recipients to
ized by elevated liver enzymes above 3 the treat C. difficile infection.20 Bilinski et al.9
Biernat et al. 7

used FMT in eight allo-HSCT recipients administration on the eradication of

who developed infections caused by MDR Acinetobacter and other non-fermenting
bacteria. These researchers observed that rods is unknown. In the second patient,
these bacteria were eradicated in 75% of the therapeutic effect was mediocre, but
the patients within 1 month.9 The use of FMT eliminated drug-resistant pathogens
FMT in patients with steroid-resistant and temporarily improved the patient’s
intestinal GvHD was discussed in single- symptoms. No adverse events were
institution studies and in one pilot observed after FMT in either patient.
study.21–23 The authors observed an However, both patients ultimately died.
almost complete resolution of symptoms As demonstrated by the culture results, pre-
and few adverse effects of the treatment in viously detected bacteria such as K. pneu-
most patients. In our center, FMT was moniae and MDR Enterococcus species
applied in two patients as described previ- were not isolated after the second and
ously. In both cases, patients underwent all- third rounds of FMT, confirming the
HSCT, and post-transplantation chimerism reports of other authors on the elimination
analysis revealed 100% donor T-cell chime- of MDR bacteria by this procedure.
rism. Both patients were diagnosed with However, it should be noted that FMT car-
severe intestinal aGvHD and treated with ries some risks for adverse infectious events,
standard therapy, which was ineffective. which was demonstrated by DeFlilipp
CMV reactivation was identified in et al.35 The authors described two patients
one patient, whereas BK virus-associated who developed bacteremia caused by
viremia was detected in both patients. The ESBL-producing E. coli after FMT from
frequency of BK virus infection in the the same stool donor. The effect of FMT
post-transplant period is estimated to be on the mycobiome is unknown, and few rel-
approximately 7% to 70%, whereas CMV evant reports have been published.36–38 The
reactivation develops in more than 60% of observations in our patients indicate the
seropositive recipients.24–27 CMV reactiva- constant presence of Candida fungi in
tion may exacerbate GvHD and increase patients’ feces independent of FMT.
transplant-related mortality.28–30 In the Invasive mycoses are common and
first patient, three rounds of FMT resulted extremely serious complications in the
in complete symptom resolution, and the post-transplant period, and prophylactic
death of the patient was not related to fluconazole reduces the frequency of these
the FMT procedure. However, according infections as well as the severity of GvHD.
to the culture analysis, the patient Van der Velden et al.39 found that dysfunc-
developed a catheter-related bloodstream tion of dectin-1, an innate receptor for fungi,
infection by A. baumannii with the same was associated with increased colonization
phenotype as the strain previously isolated by Candida species in human recipients and
from the patient’s feces. It appears that the the aggravation of aGvHD. Moreover, stud-
patient was permanently colonized by this ies using mouse models reported that the
Acinetobacter strain, but the occurrence of injection of fungal mannan and heat-killed
a new infection cannot be excluded. The C. albicans exacerbated GvHD in the
aspect of the eradication of MDR microor- lungs.37 The effect of colonization with
ganisms, especially of the genus non-fermenting rods and Candida fungi on
Enterococcus VRE and MDR rods of the the course of GvHD requires further
Enterobacteriaceae family, using FMT has research. Another aspect is the use of ECP
resulted in conflicting results.31–34 in patients with steroid-refractory GvHD
Moreover, the impact of FMT and its interaction with FMT. We used
8 Journal of International Medical Research

ECP in our patients, mainly because of the Conclusion

worsening of the condition of both patients.
In the future, FMT may emerge as a sup-
The utility of ECP in the treatment of
portive treatment for GvHD, but additional
GvHD has not yet been established.
Although the exact mechanism of action is research is needed to assess its safety and
unknown, reports on small groups of efficacy in patients with intestinal steroid-
patients are promising, especially resistant GvHD. Future research should
concerning the treatment of cutaneous and also be conduct to improve donor selection
intestinal GvHD.40–42 and remotely monitor recipients. It appears
The present report had some limitations. that monitoring of the occurrence of the
We presented only two cases, both of which main groups of microorganisms responsible
were fatal despite the use of all available for maintaining intestinal homeostasis in
treatment methods, illustrating the difficul- patients undergoing HSCT during the
ty in treating GvHD. We were unable to post-transplantation period may be one of
perform metagenomic analyses, which the elements that will clarify the relation-
would be useful for analyzing material ship between the intestinal microbiome
from donors and tracking changes in the and infections in the post-transplantation
microflora after subsequent transplanta- period, especially in the course of GvHD.
tions. Recent studies revealed that metage-
nomic analysis targeting the 16S rRNA of
Acknowledgments
intestinal bacterial flora permit the analysis
of the molecular mechanisms by which We thank Richard Ashcroft for the correction of
the microbiota affect the clinical outcomes the manuscript. Dr Pawel Grzesiowski and
of patients and assessments of changes Bo_zena Rychwalska were involved in donor
selection and fecal microbiota preparation
in the composition and fluctuations of
procedure.
microbiota after transplantation, which
cannot be achieved using standard culture
methods.43 In particular, classical culture Declaration of conflicting interest
methods do not allow analyses of the The authors declare that there is no conflict of
composition of particular bacterial genera interest.
because many of these microorganisms do
not grow on standard culture media.
Furthermore, reports have found that Ethics and consent to publish
using next-generation sequencing analysis The study protocol was approved by Bioethical
that it is possible to demonstrate the prog- Commission of Wroclaw Medical University.
nostic significance of each intestinal The patients participating in the study provided
bacterial genus in patients who underwent verbal informed consent for publication.
allo-HSCT. It has been demonstrated
that increased abundance of the genus Funding
Enterococcus as detected using 16S rRNA This research received no specific grant from any
sequencing, but not using stool culture tech-
funding agency in the public, commercial, or
niques, was associated with poor survival in
not-for-profit sectors.
patients who underwent -allo-HSCT.44
Little is known regarding the relationship
between FMT and CMV reactivation and ORCID iD
the impact of FMT on the intestinal Monika Maria Biernat https://orcid.org/
mycobiome. 0000-0003-3161-3398
Biernat et al. 9

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