[West-Nile-Virus Infection acquired in Germany in a Kidney Transplant Recipient]. / In Deutschland erworbene West-Nil-Virusinfektion bei einem nierentransplantierten Patienten.

BACKGROUND: West-Nile-Virus (WNV) is a widely distributed flavivirus that is mainly transmitted between birds through different mosquito species (e. g. Culex, Aedes), but may also be transmitted to mammals including humans. WNV causes a spectrum of disease, ranging from asymptomatic infection to encephalitis in a minority of cases. Risk factors for severe disease are older age, cardiovascular disease and an immunocompromised state. MEDICAL HISTORY AND CLINICAL EXAMINATION: Here we report about a 60-year-old male patient who was referred to the University Hospital of Halle (Saale) with severe fever two years after kidney transplantation due to hypertensive nephropathy. No infection focus could be found and by day 6 in the course of his illness the patient developed neurologic symptoms and viral encephalitis was suspected. TREATMENT AND COURSE: The patient was initially treated with aciclovir. After initial reduction of immunosuppression, coincident graft dysfunction was treated with methylprednisolon. WNV-infection was suspected due to recent emerging human cases in the nearby area of the city of Leipzig. WNV lineage 2 was detected in the patient's urine by RT-PCR and seroconversion with presence of anti WNV IgM and IgG could be demonstrated. Consecutively, aciclovir treatment was stopped. The patient fully recovered and the transplanted kidney regained adequate function. Kidney biopsy did not reveal gross rejection of the transplant. CONCLUSION: This case highlights the need to consider rarer causes of illness like WNV-infection particularly in risk groups for more severe outcomes of infectious disease. WNV may be detected by PCR in the blood and cerebrospinal fluid early in the course of infection but it is also excreted for a prolonged period of time in the urine. Seroconversion to anti WNV IgG and IgM may be shown but serologic cross-reactivity among members of the flaviviridae family must be considered.

West Nile virus neuroinvasive disease associated with rituximab therapy.

West Nile virus neuroinvasive disease (WNVND) manifests with meningitis, encephalitis, and/or acute flaccid paralysis. It represents less than 1% of the clinical syndromes associated with West Nile virus (WNV) infection in immunocompetent patients. Immunosuppressive therapy is associated with increased risk of WNVND and worse prognosis. We present a patient with WNVND during therapy with rituximab, and a review of the literature for previous similar cases with the goal to describe the clinical spectrum of WNVND in patients treated specifically with rituximab. Our review indicates that the most common initial complaints are fever and altered mental status, brain magnetic resonance imaging often shows bilateral thalamic hyperintensities, and cerebrospinal analysis consistently reveals mild lymphocytic pleocytosis with elevated protein, positive WNV polymerase chain reaction, and negative WNV antibodies. Treatment is usually supportive care, with intravenous immunoglobulins (IVIG) plus corticosteroids and WNV-specific IVIG also used. The disease is usually fatal despite intervention. Our patient's presentation was very similar to prior reports, however demonstrated spontaneous improvement with supportive management only. WNVND is a rare and serious infection with poor prognosis when associated with rituximab therapy. Diagnosis is complicated by absent or delayed development of antibodies. The presence of bilateral thalamic involvement is a diagnostic clue for WNVND. There is insufficient evidence to recommend the use of corticosteroids or IVIG.

A case series of inactivated Japanese encephalitis virus vaccination associated with positive West Nile virus blood donor screening nucleic acid tests.

BACKGROUND: West Nile Virus (WNV) is a member of the Japanese Encephalitis (JE) serocomplex within the Flaviviridae family. We report four whole blood donors and one plasma donor with WNV nucleic acid test (NAT)-reactive donations between September 2018 and November 2019, following recent Japanese Encephalitis virus (JEV) vaccination. CASE SERIES: Cases 1 and 4 had reactive WNV NAT donations 1 day after receiving the JEV vaccine. Case 2 had a reactive WNV donation 3 days after receiving the JEV vaccine. Case 3 had a reactive WNV NAT donation 3 days after returning from Arizona and 1 day after receiving the JEV vaccine. Case 5 had a reactive WNV donation the same day as receiving the JEV vaccine. STUDY DESIGN AND METHODS: WNV screening used the Roche cobas WNV nucleic acid test (NAT) (Roche Molecular Systems). Reference testing on WNV-reactive donations was carried out by the National Microbiology Laboratory (NML). JEV vaccine dilutions were also analyzed. RESULTS: Supplemental NAT was negative for WNV and JEV for Cases 1, 3, and 5. Case 2 had a weak amplification curve for one of two JEV NAT targets. Case 4 was JEV NAT-positive, WNV NAT-negative. Serologic testing on donation specimens for Cases 2, 4, and 5 did not support recent or remote WNV infection. JEV vaccine dilutions were detected by both cobas and supplemental NAT. CONCLUSIONS: We recommend implementing a temporary blood donor deferral following a JEV vaccination, if screening utilizes a WNV assay with the capability of detecting other members of the JE serocomplex.

Neuroinvasive West Nile Virus Disease in an Elderly Patient with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Case Report

Background: West Nile virus is an arthropod-borne virus (arbovirus) and emerging cause of significant illness in European and Mediterranean countries. West Nile virus infection can cause severe and potentially fatal neurological illnesses, including encephalitis, meningitis, and acute flaccid paralysis. Additionally, immunosuppression, alcohol abuse, old age, and diabetes mellitus are common factors associated with West Nile neuroinvasive disease. Case Report: In August 2018, a 60-year-old male patient with a history of diffuse large B-cell lymphoma initially presented with symptoms including abdominal pain and distention, nausea, and vomiting. Three days after open abdominal surgery due to adhesive small bowel obstruction, he developed fever, prominent tremors, and rapidly progressing flaccid paralysis. The identification of West Nile virus RNA in the serum sample led to the diagnosis of West Nile neuroinvasive disease. Conclusion: Clinicians should evaluate patients with acute flaccid paralysis for the evidence of West Nile neuroinvasive disease. It is particularly important for healthcare providers to consider West Nile neuroinvasive disease in the differential diagnosis of aseptic meningitis, encephalitis, and acute paralysis cases, especially in endemic areas.

Community-acquired meningitis in older adults: clinical features, etiology, and prognostic factors.

OBJECTIVES: To investigate the epidemiology and outcomes of community-acquired meningitis in older adults. DESIGN: Retrospective study. SETTING: Participants adults in Houston, Texas, with community-acquired meningitis hospitalized between January 1, 2005, and January 1, 2010 (N = 619; n = 54, 8.7%, aged ≥65; n = 565 aged <65). METHODS: An adverse clinical outcome was defined as a Glasgow Outcome Scale score of 4 or less. RESULTS: Older adults had higher rates of comorbidities, abnormal neurological and laboratory (serum white blood cell count >12,000/µL, and cerebrospinal fluid protein >100 mg/dL) findings (P < .001), abnormalities on computed tomography and magnetic resonance imaging of the head (P = .002), and adverse clinical outcomes (ACOs) (P < .001). The majority of participants (65.8%) had meningitis of unknown etiology. Bacterial meningitis was an infrequent cause of community-acquired meningitis (7.4%). Of the known causes, bacterial meningitis and West Nile virus were more common in older than younger adults; younger participants more frequently had cryptococcal and viral meningitis. On logistic regression, female sex was predictive of a poor outcome in the older participants (P = .002), whereas abnormal neurological examination (P < .001), fever (P = .01), and a cerebrospinal fluid glucose level less than 45 mg/dL (P = .002) were significant poor prognostic factors in younger participants. CONCLUSION: Most cases of community-acquired meningitis are of unknown origin. Older adults are more likely than younger adults to have bacterial meningitis and West Nile virus infection when a cause can be identified. They also have more neurological abnormalities, laboratory and imaging abnormalities, and adverse clinical outcomes.

West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis.

West Nile virus (WNV)-mediated neuronal death is a hallmark of WNV meningitis and encephalitis. However, the mechanisms of WNV-induced neuronal damage are not well understood. We investigated WNV neuropathogenesis by using human neuroblastoma cells and primary rat hippocampal neurons. We observed that WNV activates multiple unfolded protein response (UPR) pathways, leading to transcriptional and translational induction of UPR target genes. We evaluated the role of the three major UPR pathways, namely, inositol-requiring enzyme 1-dependent splicing of X box binding protein 1 (XBP1) mRNA, activation of activating transcription factor 6 (ATF6), and protein kinase R-like endoplasmic reticulum (ER) kinase-dependent eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation, in WNV-infected cells. We show that XBP1 is nonessential or can be replaced by other UPR pathways in WNV replication. ATF6 was rapidly degraded by proteasomes, consistent with induction of ER stress by WNV. We further observed a transient phosphorylation of eIF2alpha and induction of the proapoptotic cyclic AMP response element-binding transcription factor homologous protein (CHOP). WNV-infected cells exhibited a number of apoptotic phenotypes, such as (i) induction of growth arrest and DNA damage-inducible gene 34, (ii) activation of caspase-3, and (iii) cleavage of poly(ADP-ribose) polymerase. The expression of WNV nonstructural proteins alone was sufficient to induce CHOP expression. Importantly, WNV grew to significantly higher viral titers in chop(-)(/)(-) mouse embryonic fibroblasts (MEFs) than in wild-type MEFs, suggesting that CHOP-dependent premature cell death represents a host defense mechanism to limit viral replication that might also be responsible for the widespread neuronal loss observed in WNV-infected neuronal tissue.

Fatal West Nile Virus infection after rituximab/fludarabine--induced remission for non-Hodgkin's lymphoma.

West Nile virus (WNV) infections are potentially life threatening in immunocompromised hosts. Currently, the best diagnostic test is serology. Reverse-transcriptase polymerase chain reaction (RT-PCR) testing has a role, but, because WNV is a cell-associated neurotropic virus, RT-PCR results are frequently negative even in cases of active infection. We present a case in which serology results were persistently negative because the patient was immunocompromised following lymphoma treatment. The role of humoral immunity in resolution of WNV is also discussed.

West Nile virus blood transfusion-related infection despite nucleic acid testing.

BACKGROUND: A case of West Nile virus (WNV) encephalitis associated with transfusion of blood that did not react when tested for WNV by minipool (MP) nucleic acid testing (NAT) is described. A Nebraska man developed clinical encephalitis 13 days after surgery and transfusion of 26 blood components. Antibody testing confirmed WNV infection. An investigation was initiated to determine the source of this infection. STUDY DESIGN AND METHODS: The patient's family members were interviewed to identify risk factors for WNV infection. Residual samples were retested for WNV RNA using transcription-mediated amplification (TMA) assay and two polymerase chain reaction (PCR) assays. Blood donors' follow-up serum samples were collected. All samples were tested for WNV-specific immunoglobulin M antibodies. RESULTS: The patient's family denied recent mosquito exposure. The 20 blood components collected after July 2003 did not react when tested for WNV in a six-member MP-NAT at the time of donation. Retrospective individual testing identified one sample as WNV-reactive by the TMA assay and one of the PCR assays. Seroconversion was demonstrated in the donor associated with this sample. CONCLUSION: WNV RNA detection by individual donation NAT demonstrates viremic blood escaping MP-NAT and supports transfusion-related WNV transmission. MP-NAT may not detect all WNV-infected blood donors, allowing WNV transmission to continue at low levels. WNV NAT assays might vary in sensitivity and pooling donations could further impact test performance. Understanding MP NAT limitations can improve strategies to maintain safety of the blood supply in the United States.

Role of CD8+ T cells in control of West Nile virus infection.

Infection with West Nile virus (WNV) causes fatal encephalitis more frequently in immunocompromised humans than in those with a healthy immune system. Although a complete understanding of this increased risk remains unclear, experiments with mice have begun to define how different components of the adaptive and innate immune response function to limit infection. Previously, we demonstrated that components of humoral immunity, particularly immunoglobulin M (IgM) and IgG, have critical roles in preventing dissemination of WNV infection to the central nervous system. In this study, we addressed the function of CD8(+) T cells in controlling WNV infection. Mice that lacked CD8(+) T cells or classical class Ia major histocompatibility complex (MHC) antigens had higher central nervous system viral burdens and increased mortality rates after infection with a low-passage-number WNV isolate. In contrast, an absence of CD8(+) T cells had no effect on the qualitative or quantitative antibody response and did not alter the kinetics or magnitude of viremia. In the subset of CD8(+)-T-cell-deficient mice that survived initial WNV challenge, infectious virus was recovered from central nervous system compartments for several weeks. Primary or memory CD8(+) T cells that were generated in vivo efficiently killed target cells that displayed WNV antigens in a class I MHC-restricted manner. Collectively, our experiments suggest that, while specific antibody is responsible for terminating viremia, CD8(+) T cells have an important function in clearing infection from tissues and preventing viral persistence.

West Nile encephalitis in 2 hematopoietic stem cell transplant recipients: case series and literature review.

Most human cases of West Nile virus infection are acquired via bites from an infected mosquito. In some cases, infection may also be transmitted by infected blood products or transplanted organs. There have been recent publications suggesting that chemotherapy and immunosuppression may increase a person's risks of developing central nervous system disease if the person is infected with the West Nile virus. Because patients undergoing hematopoietic stem cell transplantation not only are immunocompromised, but also receive multiple blood products, they are at a particularly high risk for acquiring symptomatic disease if exposed to the West Nile Virus. We describe here 2 patients who underwent hematopoietic transplantation at our institution and subsequently developed fatal West Nile virus infections.