Abstract
Urgent haploidentical hematopoietic cell transplantation may be
considered in cases of severe aplastic anemia (SAA) without human
leukocyte antigen-matched donor and suffering from severe infection.
However, deciding on allogeneic transplantation in the setting of active
systemic infection is challenging due to poor outcomes. This report
presents a case of disseminated Magnusiomyces capitatus infection
in a 5-year-old male who underwent immunosuppressive therapy for
hepatitis-associated SAA. To address the critical situation, granulocyte
transfusion was promptly administered from the patient’s mother,
followed by unmanipulated haploidentical peripheral blood stem cell
transplantation from the patient’s father with posttransplant
cyclophosphamide, ultimately resulting in successful rescue.
Severe aplastic anemia (SAA), a critical hematological disorder marked
by pancytopenia and bone marrow failure, is treated with
immunosuppressive therapy (IST) when a suitable human leukocyte
antigen-matched related donor (MRD) is unavailable. During severe
concurrent infections in the SAA patients, rapid immune recovery is
necessary, however, selecting urgent haploidentical hematopoietic stem
cell transplantation (haplo-HSCT) amidst active infection presents a
significant challenge.1,2
A previously healthy 5-year-old male with no significant past medical
history, developed idiopathic hepatitis, for which he was treated with
oral steroids on an outpatient basis. However, two months later, he was
diagnosed with SAA (on day -55 of transplantation). At the time of the
diagnosis, his blood counts were as follows; white blood cell count
0.15×109/L, neutrophils 0.02×109/L,
hemoglobin 6.6 g/dL, reticulocytes 1×109/L, and
platelets 4×109/L. The bone marrow aspirate smear
showed markedly hypoplastic bone marrow, consistent with a diagnosis of
SAA. In particular, his C-reactive protein was 1.37 mg/dL, and his β-D
glucan level was 44.2 pg/mL, suggesting a fungal infection. However, a
whole-body contrast-enhanced CT scan showed no infectious foci. In the
absence of MRD, IST was initiated on day -32 as follows: Rabbit
anti-thymocyte globulin (rATG, 2.5 mg/kg/day for five days) and
cyclosporin A (CyA, 5 mg/kg/day for consecutive days). He developed a
fever on day -29, immediately after the completion of rATG treatment,
and a blood culture grew yeast for which liposomal amphotericin B
(L-AMB, 5 mg/kg/day) and voriconazole were started empirically from day
-28. The yeast was identified as M. capitatus ; antimicrobial
susceptibilities are summarised in Table 1. Contrast-enhanced CT scans
on day -29, revealed disseminated lesions in the spleen, kidney, and
lungs (Figure. 1A–C). Although blood cultures were negative on day -15,
fever (body temperature >38.5 ◦C) persisted. Administration
of granulocyte colony-stimulating factor (G-CSF) failed to increase the
neutrophil count. Given the critical situation with persistent
pancytopenia, granulocyte transfusions from his mother were given (four
times; days -11, -10, -4, and -3). Concurrently, an urgent
haploidentical peripheral blood stem cell transplantation (haplo-PBSCT)
from his father was planned to expedite immune cell recovery.
The conditioning regimen comprised fludarabine (25
mg/m2/day for 5 days), melphalan (70
mg/m2/day for one day), and total-body irradiation
(300 cGy in a single fraction). The infused cell counts were
1.3×109/kg for total nucleated cells and
4.6×106/kg for CD34-positive cells. For
graft-versus-host disease (GVHD) prophylaxis, posttransplant
cyclophosphamide (PT-Cy) was administered at a dose of 50 mg/kg/day on
days 3 and 4. Following this, mycophenolate mofetil was given orally at
a dose of 15 mg/kg/day from day 5 to day 35, along with tacrolimus
administered orally or intravenously to maintain a serum concentration
of 10-15 ng/mL from day 5 to day 180. Additionally, administration of
G-CSF was initiated from day 5. Voriconazole was temporarily
discontinued when the patient developed posterior reversible
encephalopathy syndrome on day -3. On day 14, invasive aspergillosis was
suspected due to a positive galactomannan antigen test and the
appearance of new well-circumscribed lesions in the lungs, for which
voriconazole had to be resumed. (Figure 1D). Micafungin was also added
for the first two weeks of the treatment. Engraftment was successfully
achieved on day 19. On day 29, the patient was diagnosed with grade 2
acute GVHD in the intestinal tract, which responded well to
methylprednisolone treatment. A CT scan on day 15 demonstrated
improvement of disseminated lesions in the liver and spleen (Figure 1E,
F). However, on day 38, a contrast-enhanced CT scan revealed multiple
pseudoaneurysms in the spleen (Figure 1G). Due to the substantial risk
of splenic rupture, an open splenectomy was performed on day 45. The
histopathological examination of the removed spleen revealed numerous
pseudoaneurysms and epithelioid granulomas, with no pathogens isolated
in the abscess culture. Contrast-enhanced CT scans on day 211 showed
resolution of the renal lesions (Figure 1H), although the nodular
lesions in the lungs were still present (Figure 1I). Weekly viral
monitoring was performed for three months post-engraftment, with no
evidence of viral reactivation or infection. The dose of L-AMB was
gradually reduced and discontinued over a period of eight months after
the transplantation due to kidney injury. He was discharged on day 190.
At 18 months after haplo-PBSCT, he was alive with complete chimerism and
no signs of secondary graft failure or chronic GVHD, although a nodular
lesion persisted in the right lung.
SAA is a hematological disorder for which IST is commonly chosen as the
standard treatment, particularly when suitable MRD are unavailable. In
recent years, there has been an accumulating evidence supporting the use
of haplo-HSCT as a salvage transplant strategy for relapsed/refractory
SAA following IST.3-8 In the United States, a
multicenter phase II trial (BMT CTN 1502) was conducted from 2017 to
2020 to evaluate the efficacy and safety of PT-Cy haplo-HSCT in 31
patients (median age 24.9 years, [interquartile range 10.4–51.3])
with relapsed/refractory SAA post-IST.3 The one-year
overall survival rate was 81%, and there were no cases of grade 3–4
acute GVHD or severe chronic GVHD; despite these promising results,
graft failure occurred in 5 patients (16%; 4 primary, 1 secondary). All
of them received another salvage HSCT, resulting in transplant-related
death in four cases. Furthermore, a retrospective analysis by the
EBMT4, involving 16 patients with SAA who underwent
PT-Cy haplo-HSCT following Baltimore conditioning
regimen9, demonstrated a two-year overall survival
rate of 93% and a 28-day neutrophil engraftment rate of 69%. These
findings indicate that PT-Cy haplo-HSCT is a valuable treatment option
for this condition, although graft failure may be a primary concern for
this approach. It is worth noting that these reports focused on planned
HSCT from haplo-identical donors, and did not address urgent HSCT cases.
Therefore, this strategy may not be directly apply to the case presented
here. In cases of uncontrolled fatal infections, such as the current
case, the primary objevtive of urgent haplo-HSCT is to achieve rapid
hematopoietic recovery. Due to the longer time required for engraftment
and the relatively higher risk of graft failure associated with cord
blood, we opted for haplo-PBSCT. Regarding the preparative regimen,
considering the organ reserve capacity due to severe infection, we
extrapolated it from the BMT CTN 1502 protocol, opting for a combination
of fludarabine 125 mg/m2, melphalan 70
mg/m2, and total-body irradiation 300 cGy. Ultimately,
urgent haplo-PBSCT was effective in controlling the severe fungal
infection.
Magnusiomyces species , including M. capitatus (formerly
known as Geotrichum capitatum ), are emerging as notable pathogens
in immunocompromised hosts. A European multi-center study found that
40% of infections occurred during antifungal prophylaxis, mainly with
azoles or echinocandins.10 In our case, the patient
developed a breakthrough M. capitatus infection with lesions in
the lungs, kidneys, and spleen while on micafungin prophylaxis, treated
initially with L-AMB and voriconazole as per
guidelines.11 The aforementioned study showed azoles,
alone or combined, outperformed other antifungals, with a 30-day
mortality rate of 43% and highlighted neutrophil recovery as crucial
for reducing mortality. This finding supports our management strategy
that aims for rapid immune recovery is the key to survival.
This case highlights the significance of haplo-PBSCT as an urgent
treatment option for severe infectious complications in patients with
SAA. Future research should aim to further refine the indications of
urgent haplo-PBSCT for immunocompromised hosts who require rapid immune
recovery to manage severe infections.
Acknowledgments
We are grateful to the staff of the National Center for Child Health and
Development for their support and assistance in patient care and
management. We also thank to the patient and his family for their
cooperation and consent to participate in this study.
Author contributions
Norihito Ikenobe, Kentaro Fujimori, and Hirotoshi Sakaguchi, as the
primary treating physicians, managed the care of the patients and
collaboratively wrote and approved the manuscript. Shota Myojin, Masaki
Yamada, Chikara Ogimi, and Kenichi Imadome primarily contributed to the
infection control management. Mikiko Miyasaka and Osamu contributed to
radiological diagnosis, Akihiro Yoneda was responsible for surgical
management, and Shotaro Matsumoto and Satoshi Nakagawa played key roles
in ICU management. Yoshihiro Gocho, Takao Deguchi, Akihiro Iguchi, and
Daisuke Tomizawa contributed to the diagnosis of the patients and
decision-making on the treatment strategy. Kimikazu Matsumoto oversaw
the entire process as a mentor, providing guidance and supervision to
the team. All authors reviewed, discussed, and contributed to the
improvement of the manuscript.
Funding
This study was partially supported by a grant from the National Center
for Child Health and Development (2020A-1).
Conflict of interest statement
The authors declare that they have no competing interests.
Data availability statement
For original data, please contact the corresponding author.
Ethics approval statement
This study was approved by an independent ethics committee of National
Center for Child Health and Development, Tokyo, Japan.
Patient consent statement
The patient’s guardian provided written informed consent.
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Table 1. Antifungal susceptibility test results for Magnusiomyces
capitatus