2020, Volume 36, Number 1, Page(s) 068-072
Renal Microsporidiosis in Pediatric Bone Marrow Transplant Recipients: A Case Series
Saloni SHAH1, Sheba Sweetline JACOB1, Rama MANI1, Ashok PARAMESWARAN1, Sunil KUMAR1, Rajeev A ANNIGERI2, Raja MAHESH2, Ramya UPPULURI3
1Department of Histopathology, Apollo Hospitals, CHENNAI, TAMIL NADU, INDIA
2Department of Nephrology, Apollo Hospitals, CHENNAI, TAMIL NADU, INDIA
3Department of Hematology, Apollo Hospitals, CHENNAI, TAMIL NADU, INDIA
Keywords: Kidney, Microsporidiosis, Opportunistic infection, Pediatrics, Bone marrow transplantation
Microsporidiosis is a rare, but emerging opportunistic infection in solid organ transplant and stem cell transplant recipients. Renal involvement
in microsporidiosis is very rarely seen in these recipients. We describe two cases of pediatric renal microsporidiosis, diagnosed on renal biopsies,
following bone marrow transplantation presenting as severe acute kidney injury. The first patient died, whereas the second survived due to early
diagnosis based on high index of suspicion and prompt treatment with Albendazole. We believe these are the first such reported cases of renal
microsporidiosis in pediatric bone marrow transplant recipients.
Microsporidia are obligate, ubiquitous, intracellular
parasites resembling fungi, which infect both vertebrates
and invertebrates. More than 1200 species belonging to 143
genera of these parasites have been identified till date, of
which 14 species are known to infect humans 1
opportunistic protozoans are encountered usually in HIV
infected and only occasionally in solid organ and bone
marrow transplant recipients. Many intestinal and few extra
intestinal microsporidial infections have been reported in
solid organ and bone marrow transplant recipients. Renal
allograft microsporidiosis in renal transplant patients 2,
and disseminated forms in bone marrow
transplant recipients, and the ocular form 4
in a corneal
graft recipient, though very rare, are being reported in
increasing frequency since early 1900s.
Human microsporidiosis is an important newly emerging
opportunistic disease occurring in HIV-infected individuals,
severely immunocompromised patients such as solid
organ (SOT) and stem cell transplant (SCT) recipients,
travellers to tropical countries, the elderly, and children with
malignancies 5. The depressed cell mediated immunity
in these patients predisposes them to the infection.
Microsporidia are transmitted by direct contact, through
broken skin or eye membrane, trauma, by sexual intercourse
in humans, and by vertical transmission in animals 6.
However, it is still unclear if the infection is transmitted through the donor graft or due to predisposition following
immunosuppression itself in the SOT and SCT recipients.
We report renal microsporidiosis causing acute kidney
injury (AKI) in two pediatric bone marrow transplant
(BMT) recipients, which to the best of our knowledge are
the first such documented cases in this population.
A one-and-a-half-year-old boy presented to our centre in
September 2014 with fever, hepatosplenomegaly, bicytopenia
and intracerebral haemorrhage. Bone marrow aspiration
and biopsy were consistent with acute lymphoblastic
leukemia (ALL). He received induction chemotherapy that
included vincristine, daunorubicin, dexamethasone and
intrathecal methotrexate. Post induction, he developed
knee joint pain and fever. X rays revealed lytic lesions
of the pelvic bone and femur. The aspiration and biopsy
of the lytic bone lesions revealed myeloblasts. In view of
this revised diagnosis of biphenotypic leukemia, high
dose chemotherapy consisting of fludarabine, cytarabine,
idarubicin and melphalan was given and haplo-identical
hematopoeitic stem cell transplantation was performed on
23rd September 2014. On 104th day after transplantation,
he presented with fever, abdominal distension, anasarca
and breathlessness. He developed non oliguric AKI and
azotemia increased progressively. He was initiated on peritoneal dialysis when the blood urea increased to 197
mg/dl. Serial ultrasonography of the abdomen showed
progressive bilateral nephromegaly. In view of severe
AKI, a percutaneous renal biopsy was done to rule out
leukemic infiltration. The biopsy was received in 10%
neutral buffered formalin on which histopathological
examination and subsequently transmission electron
microscopy were performed. On hematoxylin and eosin
stained sections, the renal tissue showed diffuse and
global glomerular necrosis admixed with histiocytes,
mononuclear cells and degenerated cells. (Figure 1). The tubules showed diffuse simplification with intracytoplasmic
and luminal microsporidial organ-isms on Giemsa
stain. Transmission electron microscopy confirmed the
presence of microsporidia, with multiple oval and distorted
spores displaying a single row of multiple polar tubes
and ill-defined nuclei consistent with Encephalitozoons
(Figure 2). Albendazole was started to treat the parasitic
infection along with intravenous antibiotics to treat the
lung consolidation. He continued to have fever spikes,
leukopenia, thrombocytopenia and developed progressing
respiratory distress. He subsequently developed
encephalopathy, possibly secondary to sepsis. His condition
worsened progressively and he expired.
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|Figure 1: Renal biopsy with global glomerular necrosis (thick
arrow), luminal and intracytoplasmic microsporidial organisms
within the tubules (thin arrows) (H&E; x100).
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|Figure 2: Electron micrograph demonstrating oval spores with
single row of multiple polar tubes consistent with Encephalitozoons
(Toluidine blue; x40000).
A seventeen-year-old girl presented our hospital with fever,
joint pain, intracerebral petechiae and haemorrhage on
November 2014. Investigations revealed hyperleukocytosis
and a lymph node biopsy was diagnostic of cortical T cell
leukemia. She was treated with ablative chemotherapy
followed by allogenic BMT in February 2015. On day 110
after BMT, she developed fever, lethargy, and prerenal
azotemia along with drowsiness and altered behaviour. She
was started on antibiotics and other supportive medications.
However, she developed azotemia and a percutaneous renal
biopsy was performed to determine the cause of azotemia.
Histopathological examination showed unremarkable
glomeruli. The interstitium showed granulomatous inflammation
along with mononuclear infiltrates (Figure 3). The
tubules showed luminal and intraepithelial PAS positive
organisms consistent with microsporidia (Figure 4).
Urine microscopic examination showed microsporidial spores on Trichrome stain (Figure 5). The patient was
given albendazole for seven days. The fever subsided but
she had worsening of AKI requiring dialysis for ten days.
Subsequently, renal function improved gradually and
returned to normal eventually.
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|Figure 4: Intraepithelial and luminal microsporidia in the tubules
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|Figure 5: Urine deposit showing the red spikes of the
microsporidial spores (Trichrome; x400).
Microsporidiosis as an opportunistic pathogen came into
the limelight with the emergence of the HIV epidemic.
However, microsporidiosis is quite rare in non-HIV
populations. Less than 100 cases of microsporidiosis
occurring in HIV-seronegative SOT and SCT recipients
have been reported worldwide since 1993. In SOT
recipients, microsporidiosis presents more commonly as an
intestinal infection or occasionally in disseminated form,
but very rarely affects the kidneys in isolation. Pulmonary
involvement is the commonest presentation in SCT
recipients, followed by the disseminated form. However, no
case of isolated renal microsporidiosis has been reported as
yet in the latter group.
The commonly reported microsporidial pathogens affecting
transplant recipients belong to the Enterocytozoon and
Encephalitozoon species 7. These are characterised
ultrastructurally by resistant spores with a coiled polar
filament that inject the spore cytoplasm into the host
cell under appropriate conditions 8. These spores are
extruded out in the stool, urine, and sputum and can also
be demonstrated in many tissues potentially presenting
as nephritis, pneumonitis, keratoconjunctivitis, myositis,
laryngitis and encephalopathy.
Several prospective and retrospective studies across
the globe have reported microsporidial infection in transplant recipients. Liguory et al. from France studied
microsporidial infection in stool specimens of 100 patients
over a period of six years, of which 8 were organ transplant
recipients 9. Another French study by Rabodoniria et
al. reported 23 cases of microsporidiosis in transplant
recipients, of which 5 kidney transplant recipients were
positive for microsporidiosis in a phylogenetic analysis on
E. bieneusi isolates 10. Bednarska et al. conducted a study
on medically induced immunosuppressed adults in which 8
of 48 patients (17%) had intestinal microsporidiosis 11. A
recent Indian study by Ghosal and collaborators done over
a period of 9 years reported 16 (5.8%) cases of intestinal
microsporidiosis in 272 renal transplant recipients 12.
In the pediatric population, only four cases of microsporidiosis
have been reported in SOT recipients and none in
SCT recipients. Two seronegative girls from Cape Town in
2012 received a renal transplant from the same deceased
donor for end-stage renal disease (ESRD) of uncertain
etiology and ESRD secondary to steroid resistant nephrotic
syndrome respectively and presented with pyrexia, diarrhea
and deteriorating renal function a few months after the
transplant. Faecal smears were clean. Renal biopsy and
urine examination revealed microsporidial spores. They
were treated with Albendazole and had disease-free survival
2. Recently, Desoubeaux et al. reported two young
sisters with double liver-kidney transplant who developed
intestinal microsporidiosis for which Fumagillin treatment was administered successfully 13. In adults, 4 cases of
pulmonary and disseminated microsporidiosis respectively
following allogenic bone marrow stem cell transplantation
have been documented 3,14.
Microsporidial nephritis is a rare manifestation in SOT
and SCT recipients. Renal microsporidiosis can occur as
part of disseminated disease. However, very few cases of
isolated renal microsporidiosis have been reported in the
literature 11,15-17. Patients with renal microsporidiosis
present with longstanding fever, AKI and deteriorating
graft function about three months after the commencement
of immunosuppressive therapy and a similar pattern was
observed in our patients. Renal microsporidiosis can be
demonstrated by light microscopic examination of the tissue
biopsy by Hematoxylin and eosin, Toluidine blue, Warthin
Starry, and Brown and Brenn stains. Urine demonstrates
red ovoid spores with a clear vacuole-like zone and a
diagnostic stripe representing the polar filament on the
Trichrome stain 7. Kidneys with microsporidial nephritis
usually contain spores in the tubular epithelium along
with tubular necrosis, granulomatous interstitial nephritis,
and the glomeruli are typically spared 18. Transmission
electron microscopy is essential to validate the diagnosis
of microsporidial infection and also for its speciation.
Microsporidia demonstrate a single row of 4-7 coiled
polar tubes that occur in a parasitophorous vacuole and
presence of posterior vesicles. E. intestinalis is differentiated
from E. hellum and E. cuniculi by honeycombing of its
parasitophorous vacuole 1,18. However, complementary
studies using molecular methods and antigenic probes are
required for accurate speciation. E. intestinalis and E. cunilis
are the commonest microsporidia to affect the kidney.
Albendazole is effective in most microsporidial species and
is the drug of choice to treat intestinal and disseminated
microsporidiosis. However, Albendazole is less effective
against E. bieneusi 1. Fumagillin is an alternative drug that
is especially very effective against E. bieneusi. Reversible
thrombocytopenia and reduction in tacrolimus levels can
occur following treatment with Fumagillin and hence
patients should be monitored for these complications while
on this drug 18,19.
The diagnosis of microsporidiosis should be considered
in a febrile SOT or SCT recipient when tests for routinely
encountered pathogens are unrevealing. Renal involvement
in transplant recipients should be suspected in a febrile
patient with AKI when the cause is unclear. Evaluation of
the urine sediment by microscopy using special stains and
renal biopsy could identify renal microsporidial infection.
Identification of the pathogen was late and disease was disseminated, resulting in a fatal outcome in our first
case. Hence, early identification of the pathogen is critical,
since antimicrobial therapy is effective and curative as
demonstrated in our second case.
To the best of our knowledge, these are the first reported
cases of renal microsporidiosis causing severe AKI in
pediatric SCT recipients and the first such, from India.
In conclusion, renal microsporidiosis is an unusual infection
with a high mortality rate if untreated, typically occurring
in a setting of immunosuppression which presents with
AKI. We present two cases of renal microsporidiosis in
pediatric SCT recipients, the first such cases reported in
this population, to create awareness amongst transplant
physicians and pathologists. One of our patients survived,
possibly due to a high index of suspicion, leading to prompt
diagnosis and early initiation of treatment.
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