Neuroinvasive West Nile virus infections after solid organ transplantation: Single center experience and systematic review

Abstract West Nile virus (WNv) is a major cause of viral encephalitis in the United States. WNv infection is usually asymptomatic or a limited febrile illness in the immunocompetent hosts, although a small percentage can develop neuroinvasive disease. Neuroinvasive disease due to WNv in solid organ transplant recipients occurs at higher rates than observed in the general population and can have long term neurological sequalae. Methods We retrospectively reviewed medical records of all solid organ transplant recipients at our institution who tested positive for WNv from 2010 to 2018. Two reviewers performed electronic searches of Medline, Embase, Cochrane Library of literature of WNv infections in SOT. Descriptive statistics were performed on key variables. Results Eight recipients (mean age 54, five males) were diagnosed with neuroinvasive WNv infection at our institution. Distribution of infection was as follows: five kidney transplants, one in each kidney‐pancreas, liver, and lung. Diagnoses included meningitis (3), encephalitis (1), meningo‐encephalitis (4). Median time from transplant to infection was 49.8 months (2.7–175.4). No infections were considered donor‐derived. Five patients received treatment with IVIG. Six patients were alive at median follow‐up of 49.5 months (21.7–116.8). We identified 29 studies published from 2002 to 2019. Median time from transplant to infection was 14.2 months, with similar allograft distribution; 53% were donor‐derived infections. Conclusion WNv infections in solid organ transplant recipients can be a consequence of organ donation or can be acquired via the community. Infections can be more severe in SOT recipients and lead to neuroinvasive disease.


INTRODUCTION
West Nile virus (WNv), a positive single-stranded RNA virus, is the most common cause of epidemic viral encephalitis in the United States.
The majority of WNv infections are related to infected mosquito bites; blood transfusions, solid organ transplant (SOT), breast milk, trans-placental, and percutaneous injuries are less common modes of transmission. 1 WNv infection mostly presents as a nonspecific febrile illness or is asymptomatic, but neuroinvasive disease can develop in <1% of those infected. 2,3 In more than two decades since the first detection of WNv infections in United States, over 25,000 neuroinvasive cases have been reported. 4 SOT recipients are at higher risk of developing neuroinvasive disease with WNv infections and can acquire infection via organ transplantation. Several reviews of donorderived WNv infection report a high incidence: 87% of the recipients of an organ from WNv positive donor were diagnosed with infection; 75% of the infected recipients had neuroinvasive disease and 25% remained asymptomatic; 30% of recipients died or had severe neurological impairment 5,6 .
We describe experience of WNv infections in SOT recipients at a large academic transplant center and provide a systematic review of the literature.  12 None of the cases in the current series were considered to be donor-derived infections, most likely due to low number of cases included. Almost 25% of cases in the systematic review were classified as donor-derived.
During the study period of our series, the overall incidence of neuroinvasive disease in the state was higher; a total of 358 neuroinvasive cases reported in the state. 13 Donor screening practices and having a high index of suspicion during mosquito active months have contributed to decreased transmission from donors and earlier detection in recipients.
The clinical presentation of WNv in SOT seems to be more severe than in general population with a higher likelihood of neurological involvement. Neuroinvasive disease, which is estimated to occur in <1% in the general population, is around 2.5% in solid organ transplant recipients with incidence up to 75% when infection is acquired via blood or organ donation. 1 The initial clinical presentation can be nonspecific; therefore a high index of suspicion for WNv infections should be present during high mosquito activity period and in SOT recipients with fever and CNS (central nervous system) manifestations. The most common presentation for WNv infection is fever, followed by neurological manifestation (abnormal movements, weakness, mental status alteration) and gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain). [9][10][11][14][15][16][17][18][19][20][21][22][23][24][25][26] Neuroinvasive WNv infections, although diagnosed in a minority of patients, can lead to long-term neurologic, neuropsychologic and cognitive impairment and is associated with increased mortality 1 and isolated acute flaccid paralysis. 27 Older age (>60 years), male gender, diabetes, hypertension, chronic renal disease, history of cancer, and alcohol abuse are risk factors for severe disease and encephalitis, while hypertension was a risk factors for meningitis. 27,28 Immunosuppression was not a risk factor for severe illness or neuroinvasive disease but was associated with increased risk of death 27,29,30. Most transplant recipients with WNv infections have been on MMF, calcineurin inhibitor and steroids regimen, that has an impact on both, B and T cells. [9][10][11]14,16,18,22,23,26 Temporary reduction in immunosuppression is recommended for all patients to allow recovery of the immune system. 1,21 WNv, as with other flaviviruses, seems to be more susceptible to enhanced humoral immunity rather than cell mediated immunity, explaining why IVIG has been used to treat WNv infections. Cell mediated immunity also plays a role in control of infection by production of interferons/cytokines and limiting progression to CNS disease, thus, impaired cell mediated immunity in SOT recipients may limit ability to clear infection. 34 There is no specific dose or length of treatment with IVIG recommended at this time and the benefit remains unclear. 10,11,14,[22][23][24]26 The titer of specific immunoglobulin in these studies has not been determined. Even more, immunoglobulins do not cross the blood-brain barrier to alter the course of neurological disease. 24 Fatality-to case ratio in neuroinvasive disease was reported at 2% for meningitis and 12% for encephalitis. 33 Mortality due to WNv is very high in SOT recipients. Patients with WNv encephalitis and flaccid paralysis were reported to have more prolonged hospitalization (mean 8-25 days and 11-68 days) than patients with WNv meningitis or fever (mean 4-12 days and 7 days). 28 Mortality for WNv fever and meningitis was <2% in comparison with up to 46% for WNv encephalitis and reaching 100% in combination with flaccid paralysis. 28 Altered mental status was reported to be a predictor factor of mortality. We had two attributable deaths to WNv neuroinvasive disease in our series.

CONCLUSIONS
Our