Volume 21 - Issue 1

Case Report Biomedical Science and Research Biomedical Science and Research CC by Creative Commons, CC-BY

Early Infection by West-Nile Virus Causing Neuroinvasive Disease After Haploidentical Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

*Corresponding author: Daniele Mannina, Cancer Center, IRCCS Humanitas, Rozzano, Italy.

Received: December 20, 2023; Published: January 05, 2024

DOI: 10.34297/AJBSR.2024.21.002799


West Nile Virus (WNV), one of the most widespread arboviruses in the world, causes seasonal epidemics in summer and autumn in many temperate countries. WNV circulates with an enzootic cycle between ornithophilic mosquitoes (vectors and reservoirs) and avian host species (amplification). Humans can be infected as accidental hosts [1-3]. The virus can also be transmitted through organ transplantation and blood transfusions [4-6]. In Italy, in accordance with the National Blood Center’s WNV prevention measures against WNV, NAT testing is recommended for blood and hematopoietic stem cell donors, who have stayed at least one night in areas at high risk of WNV infection. Disease presentation ranges from mild, self-limiting flu-like syndrome to severe neurological illness [1,2]. Around 1% of infected patients develop neuroinvasive disease (WNND). WNND presents as meningitis, encephalitis, or myelitis and can lead to cognitive impairment, vigilance alteration, parkinsonian movement disorders, seizures, and/or flaccid paralysis [7]. WNND occurs more frequently in elderly or compromised patients. Blood transfusions, and organ or bone marrow transplant can increase the risk of WNND, probably due to lack or delayed formation of neutralizing antibodies in the immunodeficient host. The mechanism of Central Nervous System (CNS) invasion by WNV is still largely unknown [7]. Preclinical models show that high levels of circulating cytokines can increase the permeability of the blood-brain barrier, facilitating WNND [8]. WNV and other neurotropic flaviviruses may break blood brain barrier by endothelial permeability alteration regulated by Tumor Necrosis Factor-Alpha (TNF-a) signaling [7- 9]. Greater viral burden in serum is correlated with earlier viral CNS invasion, suggesting that WNV infects the CNS by hematogenous dissemination [9]. Infection of olfactory neurons and subsequent spread to the olfactory bulb through retrograde axonal transport is an additional “Trojan horse” mechanism that may contribute to WNND development [10]. WNV is cytolytic and triggers apoptosis in several cell types, including neurons [ 11,12]. The mechanism of WNV-induced cell death in vivo has not been thoroughly clarified, but it has demonstrated that expression of WNV specific proteins NS3 or capsid protein resulted in caspase-dependent cell death of in vitro and in vivo models [13,14].

Case Report

Here we describe the case of a female 43-year-old patient with Acute Myeloid Leukemia with unfavorable risk according to ELN- 2017 classification (complex karyotype). After primary induction failure, complicated by probable pulmonary aspergillosis, she received salvage treatment with Decitabine + Venetoclax, obtaining complete morphological remission with cytogenetic persistence. She underwent T-cell replete haploidentical Hematopoietic Stem Cell Transplantation (HSCT) after myeloablative conditioning regimen with thiotepa, busulfan and fludarabine. GVHD prophylaxis consisted of post-transplant Cyclophosphamide on days +3 and +4, cyclosporine A, mycophenolate. After primary engraftment, at day +28 the patient was re-admitted to the hospital due to febrile neutropenia. Because of already known fecal colonization by Klebsiella pneumoniae ESBL, treatment with meropenem was started. Chest CT-scan, blood cultures, blood test for galactomannan, Beta-D-glucan, CMV, EBV, HHV6 viremia by PCR were negative. After two days of antibiotics, in consideration of persistent fever, negative of blood cultures and known history of fungal infection, antimycotic treatment with amphotericin-B was added. In the subsequent days, the patient experienced subacute onset of cognitive impairment and upper limb tremors without focal neurological deficits. Magnetic Resonance Imaging (MRI) of brain showed abnormal bilateral pial enhancement of both occipital lobes. At the time of the onset of the neurological symptoms, blood count was notable for leukopenia with 1300 white blood cells/μL, with Absolute Neutrophil Count (ANC) of 900 cells/μL. On day 33 after HSCT diagnostic lumbar puncture was performed, in the suspicion of encephalitis or CNS leukemia involvement. Cerebrospinal Fluid (CSF) examination showed hypoglycorrhachia (45% of glycaemia), elevated protein level and abnormal cellularity (5 cells/μl). CSF cytofluorimetry showed the prevalence of NK lymphocytes (70% of white blood cells, WBC) and the absence of abnormal myeloid cells. On day 43 after HSCT, foscarnet was started as empirical treatment of meningoencephalitis. CSF examination was negative for CMV, HHV6, EBV, VZV, HSV1/2, Enterovirus, JCV and Mycobacteria. Because of clonic seizures, levetiracetam was started. Despite the treatment, rapidly progressive worsening of vigilance status was observed, up to impaired vegetative reflexes and desaturation. The Electroencephalogram (EEG) showed a moderate global slowing of the background rhythm without epileptic signs. Due to worsening hypoxia and inadequate protection of the airways, transfer to the intensive care unit, orotracheal intubation and mechanical ventilation were needed. Diagnostic lumbar puncture was repeated, in order to extend the microbiological investigation to WNV, BKV and adenovirus. CSF analysis confirmed hypoglycorrhachia (43% of glycemia) and hypercellularity (42 cells/μl) with prevalence of NK lymphocytes (78% of WBC). WNV PCR assay resulted negative on CSF but positive on urine sample. Brain MRI was repeated on day 42 from the admission, showing bilateral focal alterations of dentate nuclei, fourth ventricle floor, anterior mesencephalon and hypothalamus on both sides without gadolinium enhancement, and persistent pial enhancement of the superior cerebellar folia. Overall, the findings were consistent with WNDD. At the time of MRI reassessment and clinical deterioration, white blood cell count was significantly improved (WBC 5280/μL, ANC 4000/μL). After the diagnosis of WNDD, foscarnet and meropenem were suspended, and switched to usual antimicrobial prophylaxis. Due to the difficult weaning, we opted for tracheostomy placement. During the next days, we observed rapid worsening of vital signs, relapse of fever and onset of severe hypotension. On day 55 the patient died for multiorgan failure.


The reported case of infection by WNV during the early immune recovery from HSCT represents a unique model of impaired host-virus interaction that facilitates the progression to WNND. We observed a rapid neurological deterioration beginning at a very early post-transplant time and worsening in conjunction with the hematopoietic reconstitution. Past evidence suggests that cell-mediated antiviral immune response within the CNS is needed for viral control, but it can also be involved in inflammatory injury of the CNS, and the pattern of cytokines and chemokines produced in response to WNV infection impacts on WNND progression [15]. These data are in line with the hypothesis that WNND depends on the synergy of viral cytotoxicity and neuroinflammation [7,8,15-17]. Among the immunocompromised patients, such as transplant recipients, HIV carriers, and patients receiving chemotherapy and transfusions, the risk of WNND is higher: 50-75% of patients with donor-derived WNV infection are at risk for WNND, compared to 40% of patients with mosquito-borne infections [18-20]. In the setting of HSCT, just a few cases of WNND have been reported, with occurrence up to 2 years after transplantation [21]. Furthermore, the time from transplantation to WNV infection is not significantly associated with the severity of WNND, whose outcome is generally poor [22]. WNND represents a diagnostic and therapeutic challenge. We reported a fatal conclusion, in absence of any specific treatment, at the end of a long and complex diagnostic process. In fact, despite the large number of reports exploring various therapeutic approaches for WNND, the treatment is still primarily palliative. Interferon and ribavirin have been used as anti-WNV agents, without any clear benefit [23]. In the setting of transplantation, administration of high-dose immunoglobulins has not been associated with a better outcome in comparison with supportive care only [24]. Due to the rarity of the condition, multicenter data collection is required to define risk factors, facilitate diagnosis and propose treatment strategies for WNND in the setting of HSCT.



Conflict of Interests



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