West Nile Virus: An Emerging Threat in Transplant Population

Currently, West Nile virus (WNV) is one of the most widely distributed emerging arboviruses. In the last decade, WNV infections are continuously reported in many parts of the world. In the United States, the annual number of disease cases varied from 712 to 5674 (Centers for Disease Control and Prevention; CDC 2019), while in Europe, the number of WNV disease cases ranged from 74 to 262 (European Centre for Disease Prevention and Control; ECDC 2019). In the 2018 transmission season, European Union Member States and neighboring countries have reported the highest number of cases so far with a total of 2083 human WNV disease cases and 181 deaths (ECDC 2019).

In nature, WNV is maintained in a bird-mosquito-bird cycle, while humans represent incidental or “dead-end” hosts. However, interhuman transmission is possible through blood products or organ transplantation (Centers for Disease Control and Prevention; CDC 2002).

Although majority of WNV infections are asymptomatic (∼80%) or present as a mild self-limited febrile illness (20%), less than 1% of infected persons develop neuroinvasive disease (meningitis, encephalitis, and myelitis). Advanced age, immunosuppression, and comorbidities, such as cancer, hypertension, diabetes, and cerebrovascular disease, are risk factors for neuroinvasive infection and long-term sequelae (O'Leary et al. 2004, Murray et al. 2006, Vilibic-Cavlek et al. 2019). Mortality in patients with neuroinvasive disease may reach up to 10% (Sejvar 2016).

Transmission of WNV by organ transplantation was first reported in 2002 (CDC 2002, Iwamoto et al. 2003). Serologic and clinical studies estimate that the risk of neuroinvasive disease in transplant patients infected with WNV is 40% and even higher (Table 1) than in the general population (1%) (Kumar et al. 2004a). In addition, WNV is associated with an increased mortality in the transplant population. In one case series of 11 transplant recipients, a mortality rate of 18% and a high incidence of neurological sequelae were reported, including mechanical ventilation dependence (Kleinschmidt-DeMasters et al. 2004). However, there are several reports of WNV neuroinvasive disease after solid-organ transplantation (SOT) with a complete recovery (Hardinger et al. 2003, Desalvo et al. 2004, Saquib et al. 2008) and asymptomatic WNV infections as well (Rabe et al. 2013, Winston et al. 2014).

There are many studies reporting donor-derived or naturally acquired WNV infections in the adult SOT recipients, mainly kidney, but also liver, heart, lungs, and pancreas. However, data on WNV infections in the pediatric SOT population are very limited (Table 1). As in the general population, it seems that risk of fatal neuroinvasive disease in the pediatric transplant population is lower compared to adults. Four reports describing post-transplant WNV meningoencephalitis in pediatric patients aged from 2.5 to 15 years showed a complete recovery in all patients (Ravindra et al. 2004, Francisco et al. 2006, Lambert et al. 2016, Wilson et al. 2017).

Detection of IgM antibodies in cerebrospinal fluid (CSF) and/or serum using enzyme immunoassay is currently the most sensitive diagnostic test for WNV infection. Because WNV IgM may not be positive until up to 8 days following disease onset, specimens collected less than 8 days after the onset may be negative for IgM, and testing should be repeated. In contrast, IgM antibodies may persist up to 500 days after primary WNV infection or even longer in some patients (Papa et al. 2011). Determination of IgG avidity may be helpful in these cases (Vilibic-Cavlek et al. 2018). Detection of WNV IgM in CSF strongly suggests acute infection, as IgM does not easily cross the blood–brain barrier. Due to high level of cross-reactivity between flaviviruses, the virus neutralization test is still the “gold standard” confirmatory testing for WNV infection (Di Gennaro et al. 2014). Other methods, including RT-PCR testing, can be helpful, but are significantly less sensitive than antibody tests and should be done in conjunction with serology. However, RT-PCR on serum, CSF, and urine samples may sometimes be the only method for WNV diagnosis in individuals who are unable to mount a detectable immune response such as transplant population (Koepsell et al. 2010).

There is no specific therapy against WNV available. Supportive treatment and reduction of immunosuppression are the first line of interventions in severe cases. Ribavirin, interferon alpha-2b, and immunoglobulins were considered in treating WNV disease with inconsistent results (Sejvar et al. 2003, Gea-Banacloche et al. 2004, Hart et al. 2014, CDC 2020). Potency of ribavirin and interferon alpha-2b was documented in vitro, although clinical efficacy was not established. Possible explanations for unfavorable outcomes could be related to drug and patients' characteristics such as: high drug concentrations, limited drug penetration into central nervous system (CNS), a consequential toxicity, along with delayed drug application, older age, female gender, and comorbidities (Chowers et al. 2001, Anderson et al. 2002, Hart et al. 2014). Administration of intravenous immunoglobulins (IVIG) with high titers of WNV antibodies in early stage of the disease could provide favorable results. Animal studies suggest the effect of passive antibody transfer after virus has reached the CNS, but efficacy declines with time indicating that administration of immunoglobulins should be as early as possible (Shimoni et al. 2001, Ben-Nathan et al. 2003, 2009, Saquib et al. 2008, Makhoul et al. 2009, Morelli et al. 2010, Rhee et al. 2011). However, further clinical trials are needed to address the timing and route of IVIG administration, as well as their therapeutic efficacy.

In an attempt to improve transplant outcomes related to WNV disease, identification of infected organ and blood donors is necessary in WNV endemic areas during increased WNV activity (Winston et al. 2014, Anesi et al. 2019). Although current recommendations and screening practices of organ donors for WNV are not harmonized, WNV nucleic acid amplification testing is recommended (Anesi et al. 2019). Deferral of organ donors with known WNV infection or recent fever or unexplained neurologic symptoms should be considered (Winston et al. 2014, Anesi et al. 2019).

In the post-transplant period, WNV infection may be prevented by avoiding mosquito bites. Patients should be counseled to avoid outdoor activities in the period of the highest mosquito activity, to use long sleeves and long pants, and to apply repellents on exposed skin (Anesi et al. 2019).

Furthermore, effective WNV vaccines for horses but no licensed vaccine for humans exist. Several clinical trials were conducted with promising results (Ulbert 2019). Implementation of a vaccine for high-risk patients may be feasible, whereas mass vaccination is not cost effective (Amanna et al. 2014).

In conclusion, WNV has become one of the new challenges for transplant programs worldwide. In light of the WNV emergence, clinicians should be aware that transplant recipients could be exposed to WNV through multiple sources, including direct infection from the bite of mosquitoes, transfusion of blood products, and graft from an infected donor. Therefore, WNV infection should be considered in all patients presented with fever and neurological symptoms after transplantation, especially during the arbovirus transmission season.