West Nile virus encephalitis: an emerging disease in renal transplant recipients

West Nile virus (WNV) has emerged as an important cause of several outbreaks of febrile illness and encephalitis in North America over the past few years. The most common manifestation in symptomatic patients is a transient febrile illness. Neuroinvasive disease, that can be fatal, occurs most often in elderly and immunocompromised hosts. The role of this virus as a cause of meninoencephalitis in organ transplant recipients is becoming better recognized. We describe herein the clinical course of two renal allograft recipients who developed WNV encephalitis. One patient developed status epilepticus and eventually died, while the other had a full recovery. In both cases, the diagnosis was confirmed by detection of WNV-specific IgM in CSF or serum, with a delayed antibody response in one patient. This viral infection should be considered in all renal transplant recipients who present with a febrile illness associated with neurological symptoms.     

West Nile encephalitis, status epilepticus and West Nile pneumonia in a renal transplant patient

West Nile neuroinvasive disease (WNND) represents a small fraction of cases of West Nile Virus (WNV) infection. Organ transplantation is associated with increased risk of acquiring WNND. We report a patient with living-related renal transplantation who developed unusual manifestations of WNND. First, fatal status epilepticus unresponsive to pentobarbital ensued. Status epilepticus from WNV has been described very rarely in the medical literature. Second, this patient grew WNV on broncho-alveolar lavage samples. To our knowledge, this is the first case of culture positive West Nile pneumonia. Third, the finding in cerebrospinal fluid (CSF) of a negative West Nile immunoglobulin M (IgM) and a positive West Nile polymerase chain reaction is striking. It is consistent with a high-viral burden and impaired immune response. This finding raises questions about the appropriateness of relying on CSF IgM assays to rapidly diagnose WNV encephalitis in organ transplant patients, as has been recommended.     

First isolation of West Nile virus in Zambia from mosquitoes

Mosquito surveillance studies to identify mosquito‐borne flaviviruses have identified West Nile Virus (WNV ) for the first time in Zambia. The Zambian WNV isolate from Culex quinquefasciatus mosquitoes collected in the Western Province was closely related genetically to WNV lineage 2 South African strains which have been previously shown to be highly neuroinvasive. These data provide the first evidence of the circulation of WNV in Zambia and suggest there should be an increased awareness of possible associated human and animal diseases in that country.     

West Nile virus encephalitis in organ transplant recipients: another high-risk group for meningoencephalitis and death

West Nile virus infection has been spreading westward across the continental United States since 1999. Although it often presents as a mild, self-limiting viral illness, it can result in a devastating meningoencephalitis in some patient populations, particularly the elderly. We report in this article on two immunosuppressed transplant patients who developed a severe meningoencephalitis caused by mosquito-borne West Nile virus infection. Suggestions for the prevention, diagnosis, and treatment of West Nile virus infection in this patient population are described.     

West Nile virus associated with equid encephalitis in Brazil, 2018

Mosquito‐borne arboviruses are a major public health concern worldwide and are responsible for emerging and re‐emerging diseases. Taken together, the arboviruses have a strong impact on public health and are the most common causes of equine encephalitis. In‐depth diagnostic investigation of equine viral encephalitis is of utmost importance for the epidemiological surveillance and control of this disease. Regarding neurological disorders in equids, in April–May 2018, at least 12 cases of equid mortality with acute neurological signs were reported in six farms from Espirito Santo state, Brazil. To investigate the aetiological agent of this neurological disease outbreak, central nervous system (CNS) fragments from two horses and two donkeys were submitted for virologic diagnosis. Rabies, equine herpesvirus‐1, and arbovirus‐associated encephalomyelitis were investigated using differential diagnosis techniques. West Nile virus (WNV) was detected by nested RT‐PCR in CNS fragments from each of the four animals in the study and confirmed by nucleotide sequencing. This is the first case of neurological disease in equids confirmed to be associated with WNV infection in Brazil. This finding unveils a new and urgent field of research and the need to understand the epidemiological and clinical characteristics of the disease and the risk to public health.     

Exposure to West Nile virus and tick‐borne encephalitis virus in dogs in Spain

In the past decade, the spread of emerging zoonotic flaviviruses (genus Flavivirus , family Flaviviridae ) has been reported in many regions worldwide, representing a threat to both human and animal health. A serosurvey was carried out to assess exposure and risk factors associated with antigenically related flaviviruses, particularly West Nile virus (WNV ), Usutu virus (USUV ) and tick‐borne encephalitis virus (TBEV ), in dogs in Spain. Flavivirus antibodies were detected in 39 of 815 dogs (4.8%; 95% CI : 3.3–6.3) by bELISA . Significantly higher seropositivity was observed in hunting dogs compared to pet dogs. Virus neutralization tests confirmed WNV ‐specific and TBEV ‐specific antibodies in 11 and 14 bELISA ‐positive dogs, respectively. This is the first serosurvey of WNV and TBEV in dogs in Spain and the first report of TBEV circulation in this country. The seropositivity obtained indicates widespread, but not homogeneous, distribution of WNV and TBEV in dogs in Spain. In 2013 and 2015, WNV ‐seropositive dogs were detected in those areas of Andalusia where the highest number of WNV outbreaks were reported in both horses and humans. Antibodies against TBEV have been found in dogs sampled in two different periods and regions in Spain. Serosurveillance in dogs could be a complementary way of monitoring the activity of emerging flaviviruses in Spain.     

Arenaviruses and West Nile Virus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the epidemiology, diagnosis, prevention, and management of infection due to Arenaviruses and West Nile Virus (WNV) in the pre‐ and post‐transplant period. Arenaviruses and WNV have been identified as causes of both donor‐derived and post‐transplant infection. Most data related to these infections have been published in case reports and case series. Transplant recipients may become infected with Arenaviruses if they, or their donors, are exposed to wild rodents or infected pet rodents. Lymphocytic choriomeningitis virus is the most commonly recognized Arenavirus among transplant recipients and should be considered when transplant recipients present with fever, hepatitis, meningitis/encephalitis, and/or multisystem organ failure. WNV is a mosquito‐borne virus, and as such, its incidence varies yearly depending on environmental conditions. WNV in transplant recipients typically presents with fever, myalgias, and rash; approximately one in 40 develop neuroinvasive disease. Due to its morbidity, the Organ Procurement and Transplantation Network recently mandated that transplant centers screen living donors for WNV infection in endemic areas. Little is known about the optimal treatment of Arenaviruses or WNV; reduction in immunosuppression and supportive care are the mainstays of management at present.     

Emergence of West Nile virus lineage 2 in Europe: Characteristics of the first seven cases of West Nile neuroinvasive disease in horses in Austria

We report details of the first seven equine cases of confirmed West Nile neuroinvasive disease in Austria. The cases presented during summer and autumn of 2016 (n = 2), 2017 (n = 3) and 2018 (n = 2). All horses showed gait abnormalities and 6 of 7 horses exhibited fasciculations and/or tremors, and we provide video recordings of these. Three horses also showed cranial nerve involvement. Following rapid improvement, three horses were discharged. Four horses were euthanized due to the severity of clinical signs and subjected to neuropathological examination. West Nile virus (WNV) lineage 2 nucleic acid was detected in 5 of 7 horses, and WNV‐specific neutralizing antibodies in all 7 horses. In addition, serologic evidence of WNV infection was found in two out of fourteen in‐contact horses. Horses may be considered a sentinel species for human WNV infections, integrating human and veterinary medicine and thus contributing to the one health concept.     

Transplantation of solid organ recipients shedding Epstein‐Barr virus DNA pre‐transplant: A prospective study

Epstein‐Barr virus (EBV) poses a significant threat to patient and graft survival post‐transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post‐transplant. To test this hypothesis, we conducted a 5‐year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre‐transplant samples were available from 98 subjects. EBV DNA was detected pre‐transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre‐transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival (P = .6 for both comparisons) or post‐transplant EBV viremia‐free survival (P = .8). There were no cases of EBV‐related disease or post‐transplant lymphoproliferative disorder (PTLD) in any of the patients with detectable EBV DNA pre‐transplant. In conclusion, detectable EBV DNA pre‐transplant was not associated with differences in patient/graft survival, post‐transplant EBV viremia, or EBV‐related diseases including PTLD.     

Leishmaniasis in solid organ and hematopoietic stem cell transplant recipients

Leishmaniasis occurs in <1% of solid organ and hematopoietic stem cell transplant recipients in endemic countries in which transplants are performed. Visceral leishmaniasis (VL) makes up the bulk of reported cases. The onset generally occurs months after transplantation and the mode of acquisition is often impossible to determine, but de novo vector‐borne infection and reactivation of inapparent infection are thought to be the principal means. The potential role of clinically inapparent donor infection is uncertain and screening is not currently recommended, nor is it recommended for recipients from endemic areas, some of whom may have detectable circulating protozoan nucleic acid. While transplant recipients with VL often present with the non‐specific findings of fever and cytopenia, the additional presence of hepatosplenomegaly in patients from endemic areas should lead to a directed diagnostic evaluation with bone marrow examination and PCR testing of marrow and peripheral blood having a high yield. Management may often be complicated by the presence of concomitant infections. A lipid formulation of amphotericin B is the preferred treatment, especially for VL, but the relapse rate in transplant recipients is approximately 25%. PCR monitoring of blood for either secondary prophylaxis or preemptive therapy requires further study.     

West Nile Virus Encephalitis in a Kidney Transplant Recipient

We describe a case of West Nile virus encephalitis in a 54-year-old kidney transplant recipient. The clinical course was rapid and fatal. Serial CSF samples showed an evolving mononuclear pleiocytosis and serial MRIs showed increasing signs of cytotoxic edema in her basal ganglia. Seroepidemiological testing indicated that the infection was most likely acquired from transfusion of fresh frozen plasma at the time of transplantation.     

Post‐transplant lymphoproliferative disorders,Epstein‐Barr virus infection,and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, management, and prevention of post‐transplant lymphoproliferative disorders (PTLD) and other Epstein‐Barr virus (EBV) syndromes after solid organ transplantation. PTLD are a heterogeneous spectrum of predominantly B‐cell disorders, often extra‐nodal, with complex distinct pathogeneses and variable clinical presentations determined by pathologic subtype. Recent epidemiologic studies report a decrease in early EBV‐positive (+) PTLD and an increase in late EBV‐negative (?) PTLD. Pre‐transplant EBV‐seronegativity and primary EBV infection, often from donor‐transmitted infection, are an important risk factors for EBV syndromes and early EBV + PTLD. Low‐quality evidence supports preemptive prevention strategies for early EBV + PTLD in EBV‐seronegative recipients that involve EBV DNA measurement in peripheral blood using assays requiring further result harmonization, combined with interventions to lower viral load. Reduction in immunosuppression (RIS) is the best validated intervention. WHO pathology classification of a tissue biopsy remains the gold standard for PTLD diagnosis; optimal staging procedures are uncertain. Treatment of CD20⁺ PTLD with the response‐dependent sequential use of RIS, rituximab, and cytotoxic chemotherapy is recommended. Evidence gaps requiring future research and alternate treatment strategies including immunotherapy are highlighted.     

West Nile Virus-Associated Meningoencephalitis in Two Chronically Immunosuppressed Renal Transplant Recipients

West Nile virus is a mosquito-borne, single-stranded RNA virus of the Flaviviridae family. Approximately 1 in 150 patients who have serologic evidence of West Nile virus infection develop encephalitis or meningitis. We report two chronically immunosuppressed renal transplant recipients with confirmed West Nile virus meningoencephalitis acquired through community exposure. Both patients presented with fever and neurological changes in the autumn of 2002. Flavivirus-specific immunoglobulin M in antibodies in the cerebral spinal fluid and serum were detected by antibody-capture enzyme immunoassay, and antibodies for West Nile virus were confirmed by the plaque neutralization reduction assay. Reduction in immunosuppression and supportive care were successful in treating both patients. West Nile meningoencephalitis should be considered in transplant recipients that present with signs and symptoms of meningoencephalitis.     

Specific detection and differentiation of tick‐borne encephalitis and West Nile virus induced IgG antibodies in humans and horses

Tick‐borne encephalitis virus (TBEV) and West Nile virus (WNV) are important arthropod‐borne zoonotic flaviviruses. Due to the emergence of WNV in TBEV‐endemic regions co‐circulation of both viruses is increasing. Flaviviruses are structurally highly similar, which leads to cross‐reacting antibodies upon infection. Currently available serological assays for TBEV and WNV infections are therefore compromised by false‐positive results, especially in IgG measurements. In order to discriminate both infections novel diagnostic methods are needed. We describe an ELISA to measure IgG antibodies specific for TBEV and WNV, applicable to human and horse sera. Mutant envelope proteins were generated, that lack conserved parts of the fusion loop domain, a predominant target for cross‐reacting antibodies. These were incubated with equine and human sera with known TBEV, WNV or other flavivirus infections. For WNV IgG, specificities and sensitivities were 100% and 87.9%, respectively, for horse sera, and 94.4% and 92.5%, respectively, for human sera. TBEV IgG was detected with specificities and sensitivities of 95% and 96.7%, respectively, in horses, and 98.9% and 100%, respectively, in humans. Specificities increased to 100% by comparing individual samples on both antigens. The antigens could form the basis for serological TBEV‐ and WNV‐assays with improved specificities.     

West Nile Transmission in Resident Birds in Italy

Migratory birds are considered one of the main sources for West Nile virus (WNV) introduction into European countries. Following the WNV epidemic in the late summer of 1998 in a marshy area of Tuscany (Padule of Fucecchio), an extensive ornithological surveillance programme was carried out in the infected areas from 2006 to 2008. Several species of migratory and resident birds were trapped, sampled and serologically tested. The results of this surveillance programme gave a useful indication of potential sources of WNV re‐introduction and spread into Italy. The area under study was also investigated and classified into ecological areas through satellite image processing. In August 2008, the WNV infection re‐emerged in Italy in the area surrounding the Po river delta, involving three regions: Lombardy, Emilia Romagna and Veneto. Several surveillance activities were immediately put in place, including the extensive monitoring of wild birds found dead or trapped in the framework of other surveillance programmes. These activities were also prolonged in the 2009, when the virus circulation re‐occurred at the border of the area already infected in 2008. The possible epidemiological role of the different species of migratory and resident birds is discussed, in relation to the different ecological patterns identified in the area and their potential ability to introduce, spread and support the endemization of WNV infection.     

A Seroprevalence Study of West Nile Virus Infection in Solid Organ Transplant Recipients

West Nile virus (WNV) causes severe neurological disease in less than 1% of infections. However, meningoencephalitis may be more common in immunosuppressed transplant patients. In 2002, a WNV outbreak occurred in our region. To determine the spectrum of disease of community acquired WNV infection and assess public health behavior patterns in transplant recipients, we carried out a seroprevalence study. Patients were enrolled from outpatient transplant clinics in October 2002 and sera were screened for WNV. Questionnaires about WNV were provided to patients. Eight hundred sixteen organ transplant patients were enrolled. The seroprevalence of WNV IgM was 2/816 (0.25%; 95% CI 0.03-0.88%). By extrapolation to our entire transplant population of 2360 patients, and using data from hospital-based surveillance, the risk of meningoencephalitis in a transplant patient infected with WNV is estimated to be 40% (95% CI 16-80%). With regards to knowledge and behavior, 56% patients knew of and 47% used at least one protective measure against WNV. Only 33% used insect repellent. The risk of meningoencephalitis in transplant recipients is much higher than in the general population. There is incomplete knowledge and poor rates of compliance amongst patients with regards to WNV prevention.