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.
CASE 2
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.
Figure 3: Interstitial granulomatous inflammation (PAS; x400).
Figure 4: Intraepithelial and luminal microsporidia in the tubules (PAS; x400).
Figure 5: Urine deposit showing the red spikes of the microsporidial spores (Trichrome; x400).
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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