West Nile Virus Encephalitis in Haematological Setting: Report of Two Cases and a Brief Review of the Literature
1 Section of
Hematology, Cancer Research and Cell Biology Laboratory, Department of
Medicine, University of Verona, Verona, Italy.
2 Pediatrics Section, Department of Surgical, Odontostomatological and Maternal-Infantile Sciences, University of Verona, Verona, Italy.
Received: January 29, 2019
Accepted: April 3, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019033 DOI 10.4084/MJHID.2019.033
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nile virus is a zoonotic agent causing life-threatening encephalitis in
a proportion of infected patients. Older age, immunosuppression, and
mutations in specific host genes (e.g., CCR5 delta-32 mutation)
predispose to neuroinvasive infection. We report on two cases of severe
West Nile encephalitis in recently-treated, different-aged, chronic
lymphocytic leukemia patients. Both patients developed high-grade fever
associated with severe neurological impairment. The younger one
harboured germ-line CCR5 delta-32 mutation, which might have played a
role in the pathogenesis of its neuroinvasive manifestations.
Here we describe two cases of severe WNV encephalitis occurring in recently-treated CLL patients in August 2018. Both cases have been recorded during the infection spike, taking place in Eastern Italy in the same period.
(b) An 85-year-old woman was diagnosed with Rai III/Binet C CLL in June 2014. For progressive and symptomatic anemia due to bone marrow failure, the patient underwent treatment with Chlorambucil and Rituximab in 2016, achieving a temporary improvement in her peripheral blood counts. In June 2018 she experienced a new worsening of anemia with high need of transfusion support. FISH and TP53 mutational status were negative, but cytogenetic analysis using B-cell mitogens showed del(3) (p13p21) and del(14) (q24) in 8 metaphases out of 20. Because of progressive disease, the patient started the second line Ibrutinib treatment. However, she autonomously discontinued drug assumption due to poor gastrointestinal tolerance as soon as thirty days after beginning. At the end of July 2018, she was admitted to the emergence department with fever, myalgias, anorexia and worsening fatigue. Her blood cell counts showed moderate lymphocytosis (24000/μL) with mild anemia and thrombocytopenia, whereas C-reactive protein and procalcitonin were in the normal range. Empirical antibiotic therapy was initially administered. However, her neurological conditions rapidly worsened over the following days, developing psychomotor agitation with stereotyped afinalistic movements of the lower limbs and altered mental status. Cranial computed tomography scan was unremarkable, and EEG showed diffuse slowing of background activity without focal spikes. Diagnostic lumbar puncture was performed, with normal opening pressure, clear CSF, pleocytosis of 44 leukocytes/μL (mononuclear prevalent), hyperglycorrhachia (66 mmol/L) and hyperprotidorrachia (67 mg/dL). As there was the clinical suspicion of viral encephalitis, intravenous Acyclovir treatment was initially administered. Serum and CSF WNV IgM returned positive, whereas all the other microbiological tests performed on serum and CSF did not. Also, serum WNV PCR was positive. Despite supportive measures, the patient’s state of consciousness progressively declined, becoming unresponsive to any external stimuli. She finally died sixteen days after her hospital admission. Sequencing of Ccr5 gene revealed no alterations.
Sequencing method. Genomic DNA was extracted from 200 μL of whole blood by use of QIAamp DNA mini kit (Hilden, DE), according to with manufacturer’s instructions. DNA was amplified by Platinum Taq DNA polymerase High Fidelity (Invitrogen, Carlsbad, CA) using primers flanking the site of the 32 base pair deletion: 5’-CGCATCAAGTGTCAAGTCCAATC-3’ and 5’- TGTAAACTGAGCTTGCTCGCT-3’ (M-Medical, Cornaredo, IT). PCR products were purified with FastGene extraction kit (Nippon Genetics, Tokyo, JP). The reverse PCR primer was then used for Sanger sequencing with GenomeLab DTCS quick start kit (Sciex, Framingham, MA) and CEQ 8000 Genetic Analysis System (Sciex) following the manufacturer instructions.
|Table 1. Reported cases of WNV encephalitis in haematological patients.|
The two cases we described well recapitulate the main clinical and laboratoristic features of severe WNV infection. Both of them were affected by CLL and were recently treated in an outpatient setting with chemoimmunotherapy and Ibrutinib, respectively. To our knowledge, only two patients affected by WNV encephalitis previously diagnosed with CLL have been described in the literature.[10,18] Our patients presented with fever and went through a rapid deterioration of neurological conditions. C-reactive protein was not elevated, CSF analysis showed alterations consistent with blood-brain barrier (BBB) damage and neuroimaging was insignificant. This latter occurs in about 50% of patients affected by WNV encephalitis, the other half developing abnormal MRI findings, which commonly involve thalami, basal ganglia, mesial temporal structures, brain stem, and cerebellum. In the first, Rituximab-treated, patient, the diagnosis was based on positive WNV PCR, as serology returned negative. The fatal outcome of the second patient was likely favoured by older age and female gender, usually associated with worse recovery from coma.
Since most neuroinvasive WNV disease in non-haematological setting occur in the elderly, the development of such a severe clinical picture in the first, young patient prompted us to investigate the presence of Ccr5 delta-32 mutation as an additional risk factor for neuroinvasive infection. CCR5 is the G protein-coupled receptor binding to three CC chemokines, namely CCL3, CCL4 and CCL5, involved in T lymphocyte trafficking through the BBB. It is mainly expressed by T helper 1 subset upon antigen recognition, whereby coupling the amplification of the inflammatory response with the appropriate environmental context.[23,24] By sequencing the Ccr5 gene, we found the patient was heterozygous for the delta-32 mutation, which generates a truncated form of CCR5 persistently retained within the endoplasmic reticulum, thus lowering its surface expression. Of note, delta-32 CCR5 has been reported to act as a dominant negative mutant, further reducing the cell sensing for CCR5 cognate ligands. Therefore, impairment of CCR5-based chemotactic system, along with low T CD4 cell count due to previous chemotherapy, may have played a non-negligible role in the pathogenesis of his neuroinvasive WNV infection. We speculate that Ccr5 genotyping might be of some importance to identify immunocompromised patients particularly at risk for life-threatening neurological complications. Effective preventive strategies, mostly still to be uncovered, might be primarily directed to them.
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