Curr Infect Dis Rep (2013) 15:478–485 DOI 10.1007/s11908-013-0367-8

TRANSPLANT AND ONCOLOGY (M ISON AND N THEODOROPOULOS, SECTION EDITORS)

West Nile Virus Infection in the Immunocompromised Patient Marilyn E. Levi

Published online: 15 November 2013 # Springer Science+Business Media New York 2013

Abstract West Nile virus infection has become the predominant cause of flavivirus-associated encephalitis in the US. While 80 % of infected individuals are asymptomatic, 20 % develop symptoms including fever, headache, transient rash and gastrointestinal symptoms. Among the immunocompetent population, 1 in 150 develop neuroinvasive disease characterized by acute flaccid paralysis, Parkinsonian cogwheel rigidity, meningitis, encephalitis, meningoencephalitis and asymmetric muscle weakness (Mostashari et al. in Lancet 358:261–264, 2001). In the immunocompromised population such as transplant recipients and HIV-infected and chemotherapy patients, the incidence of neuroinvasive disease may be increased. The largest population studied is recipients of solid organ transplants, with data on both donor-derived and naturally occurring transmissions. The risk of neuroinvasive disease in donor-derived infection is estimated to be between 50 % and 75 % while in those with mosquito-borne transmission the risk is estimated at 40 % of those infected (Kumar et al. in Am J Transplant 4:1883–1888, 2004). With significant morbidity associated with donor transmission, specific pretransplant screening recommendations are reviewed. Treatment includes supportive care and consideration for the use of intravenous immunoglobulin. Keywords West Nile virus . Immunocompromise . Transplant . HIV

Africa, India, Europe and parts of Asia until 1999 when it was identified as the cause of an encephalitis outbreak in New York City involving 59 patients [2, 3]. Over the ensuing years, the virus has had a rapid geographic expansion across the continental US, northward to Canada, and southward to the Caribbean Islands and Latin America. Between 1999 and 2012, ArboNET, a national surveillance system for arboviral disease in the US instituted by the Centers for Diseases Control (CDC) in 2000 reported a total of 37,088 cases of WNV in the US, including 16,196 with neuroinvasive disease [4]. Additional calculations from the CDC using recent sexand age-stratified ratios of infections to neuroinvasive disease estimated that over 3 million individuals in the US have been infected with WNV, resulting in symptomatic disease in 780,000 [5•]. Based on these numbers, WNV is considered endemic in the US, and the most common etiologic agent associated with arboviral encephalitis. The elderly, diabetics and other immunocompromised individuals, such as recipients of both solid organ and stem cell transplants, HIV-infected and oncology patients as well as others on immunosuppression have been identified as groups at greater risk of severe neurologic complications of WNV compared to the general population [6–11]. This paper provides general information about WNV infection and a review of the literature on specific immunocompromised populations. Screening modalities, clinical syndromes and treatment options are discussed.

Introduction Background In 1937, the first case of West Nile virus (WNV) infection was reported in a female patient from the West Nile district of Uganda [1]. WNV remained endemic in the Middle East,

Ecology

M. E. Levi (*) Transplant Infectious Diseases, University of Colorado Denver, Denver, CO, USA e-mail: [email protected]

WNV is maintained in an enzootic cycle between mosquitos most commonly of the Culex genus, and birds, such as the American robin, crows and blue jays. Birds function as the primary amplifiers for the virus throughout the mosquito season

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and are maximally viremic in the late summer and early fall. Human infection is most commonly acquired by mosquito bites; humans are considered “incidental hosts” or “dead end hosts” outside the enzootic cycle. Human cases of WNV have been identified throughout the year, but the highest incidence of infection is limited to the summer and early fall months, with the CDC reporting 94 % of human cases occurring between July through September [12]. A more recent CDC guidance document on WNV states that nearly two-thirds of reported cases occur during a 6-week period between mid-July through the end of August [13]. On a national level, there is a wide yearly variability in the number of cases and incidence per region that is attributable to multiple factors, particularly weather and temperature variations [14], as mosquitos are unable to survive in temperatures less than 50 °F (10 °C). The highest average yearly incidence of WNV disease is seen in the West Central and Mountain regions [12], predominantly in the central plains states including South Dakota, Wyoming and North Dakota [5•]. In 2003, close to 3000 cases were reported from Colorado. Texas reported the greatest number of cases in 2012, with 2,012 cases submitted to ArboNET [15]. Virology WNV is a single-stranded RNA virus of the family Flaviviridae and is a member of the Japanese encephalitis virus serocomplex which contains other viruses that are also associated with human disease such as St. Louis encephalitis, Japanese encephalitis, Dengue, Yellow fever, Murray Valley encephalitis and Kunjin virus. These particular Flaviviridae and vaccines such as the Japanese encephalitis virus and Yellow fever vaccines share antigens that result in serologic cross-reactions and potential false-positive serum WNV antibody testing [16]. This has potential important clinical implications when screening for active and past WNV infections. Modes of Transmission WNV is usually transmitted to humans by mosquito bites, commonly called “naturally occurring” WNV. Additional modes of infection include transmission via breast milk, in utero via the placenta [11], blood donation [17–20], percutaneous inoculation of laboratory workers and organ transplantation. In February of 2013, due to concern over donor-derived WNV infection, the Organ Procurement and Transplantation Network (OPTN) and Human Resources and Services Administration (HRSA) mandated screening of live kidney donors “from an endemic area” [25], emphasizing the significant potential morbidity and mortality associated with donor transmission of these pathogens.

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Clinical Presentation The incubation period for WNV averages between 2–14 days [26]. Among immunocompetent individuals, 80 % have asymptomatic infection. The remaining 20 % present with an acute febrile illness, often accompanied by gastrointestinal symptoms such as anorexia, nausea and vomiting, malaise, headaches, retroorbital pain, lymphadenopathy and myalgias lasting 3–6 days [27]. A generalized maculopapular, papular or morbilliform erythematous eruption may occur in days 5– 12 of illness, involving the neck, trunk, arms or legs [28]. In 1 in 150 patients cases, a more severe neuroinvasive disease develops, characterized by: 1. Altered mental status with encephalitis, meningitis or meningoencephalitis 2. Severe muscle weakness and flaccid paralysis that is often clinically identical to poliovirus-associated myelitis and may develop into respiratory paralysis and the need for ventilatory support. Patients commonly present with asymmetric weakness without an obvious viral prodrome or fever [29]. Clinicians often include Guillain-Barré syndrome in the differential diagnosis of acute flaccid paralysis, although this may be differentiated from WNV by electromyelography and nerve-conduction velocities, which are described below. 3. Parkinsonian-like cogwheel rigidity 4. Less common neurologic manifestations have included ataxia and extrapyramidal signs, polyradiculitis, optic neuritis, cranial nerve abnormalities and seizures [30]. In the presence of a normal immune system, patients with non-neuroinvasive disease will often have complete recovery although they may have prolonged weakness, fatigue and malaise persisting for weeks to months. Permanent residual neurologic deficits may occur with WNV encephalitis or myelitis as opposed to meningitis. Based on ArboNET data, the case fatality rate among patients with neuroinvasive disease between 1999 and 2012 ranged between 6 % and 16 % [31]. In review of donor-derived WNV infections, the mortality rate during the 2005 transmission was 25 %. As opposed to neuroinvasive disease developing in 1 in 150 immunocompetent patients with symptomatic WNV, the attack rate in donor-derived transmission cases averages in the range 50–75 % [17, 18, 21, 22, 23•, 24•].

Timeline and Diagnostic Studies A key tool for the diagnosis of WNV infection is a high index of suspicion when patients present with consistent symptoms during the mosquito season and is aided by surveillance reports from local health departments. When diagnostic studies are obtained, familiarity with the timeline of WNV infection is helpful in interpreting results (Fig. 1) which involves

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screening, this is not approved for organ screening. Therefore, a false-positive NAT or RT-PCR result may result in a delay in transplantation or even organ loss. 2. There are logistical difficulties in obtaining NAT results in real-time when donors are located in remote areas without access to a local laboratory with testing capabilities. Serum WNV IgM and IgG antibody testing may be performed by a local laboratory, but does not infer infectivity. IgM and IgG seroconversion may not be detected for 6–7 days and 16 days after infection, respectively, known as the window periods, so that there is often a delay in identifying recent or past disease. Fig. 1 Dynamics of WNV RNA and WNV-specific antibody positivity and negativity. The top three intervals represent window periods that start with the index donation (i.e., the donation that tested positive for WNV in minipools of 16 donor specimens (MP) by transcription-mediated amplification (MP-TMA). Although positive results of MP-TMA can occur at any time during the 6.9-day window period when the results of MP nucleic acid amplification testing (NAT) are positive, for illustrative purposes the first three window periods are depicted as beginning at the midpoint of this window period. Values are not additive (i.e., the time from RNA detection to IgM detection, 3.9 days, plus the time from IgM antibody to IgG antibody detection, 3.4 days, does not equal the time from RNA detection to IgG antibody detection, 7.7 days). ID individual donation, 1×ID single replicate, 6×ID six replicates [32] (copied with permission). Copied with permission from Busch MP, Kleinman SH, Tobler LH, Kamel HT, et al. Virus and antibody dynamics in acute West Nile virus infection. J Infect Dis. 2008;198:984–93 [35]

serum and cerebrospinal fluid examination for WNV IgM, IgG and RNA testing by reverse transcriptase polymerase chain reaction (RT-PCR) or nucleic acid amplification testing (NAT) by transcription-mediated amplification (TMA). Most commonly, viremia is asymptomatic and develops approximately 6 days after a mosquito bite, lasting for 6.9 days (average between 3 and 14 days). Prolonged viremia lasting for over 14 days has been reported, particularly in immunocompromised individuals [32]. Transmission of WNV infection occurs during the viremic period and may be identified by screening blood and organ donations by NAT or RT-PCR. Standard screening for viremia was implemented by blood banks in 2003 after a report of a transmission by transfusion of blood products containing WNV in 2002 [19, 20]. Blood banks implement year-round minipool testing (MP-NAT) for WNV, screening either 6 samples by RT-PCR (Cobas TaqScreen MPX test®; Roche Molecular Diagnostics Products [33]) or 16 specimens by NAT (Procleix WNV assay®; GenProbe, San Diego, CA [34]). If WNV is detected during MP screening, blood banks are “triggered” to switch to individual donation (ID-NAT). There are several challenges related to donor screening by WNV RNA testing: 1. Both MP-NAT and ID-NAT have potential false-positive results which may vary between blood banks. While confirmatory testing has been FDA-approved for blood

WNV IgM develops within 6–7 days of viremia [35] (Table 1) and may persist for more than 900 days (personal communication, Dr. Erin Staples, CDC). Therefore its presence may not be indicative of active or recent infection. Within 3– 4 days, IgM is followed by IgG production which persists lifelong and provides protection against reinfection. Commonly, patients develop symptoms of WNV after viremia resolves and IgM is detected. The risk of transmission of WNV from asymptomatic donors with positive serologies but undetectable NATs is unknown. There are however reports of WNV transmission during donations that are negative by NAT/RT-PCR but positive on IgM/IgG testing [21, 22••, 36], suggesting that prolonged low-level viremia may be present below the limits of detection of the assay. Therefore, in patients in whom WNV infection is suspected, serum IgM, IgG and PCR should be obtained. Several important caveats in the interpretation of serologies should be considered. First, patients who are unable to mount antibody responses, such as those receiving rituximab [37•] or antibody-depleting chemotherapy [8, 38] may have falsenegative WNV IgM and IgG antibodies, so that PCR testing should be performed to try to detect infection. Secondly, falsepositive WNV IgM and IgG antibodies may be detected in patients with other previous flavivirus infections such as St. Louis encephalitis or Dengue, or following vaccinations against Flaviviridae such as Yellow Fever and Japanese encephalitis virus. In order to differentiate between these viruses serologically, plaque reduction neutralization testing (PRNT) Table 1 Clinical signs of WNV infection Signs Asymptomatic (80 %) Symptomatic (20 %) Neuroinvasive disease

Less common

– Fevers, myalgias, rash, headache, nausea, vomiting, mental status changes Meningitis, encephalitis, meningoencephalitis, tremors, asymmetric muscle weakness, acute flaccid paralysis, areflexia, Parkinsonian cogwheel rigidity, seizures, myoclonus Pancreatitis, pneumonia, hepatomegaly, conjunctivitis, myocarditis, pericarditis, hepatitis

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may be obtained through the CDC, although the results are not available in real time. Thirdly, WNV IgM and IgG interpretation may be aided by acute and convalescent measurements to discern the presence of active or past infection. In the event of altered mental status and suspicion for WNV neuroinvasive disease, examination of the cerebrospinal fluid for the presence of WNV IgM and PCR should be obtained. WNV IgM antibody does not cross the blood–brain barrier, so that its presence in spinal fluid is pathognomonic for neuroinvasive disease [30]. CSF findings in 250 patients with WNV meningitis and encephalitis confirmed by serology have shown average cell counts of 226 cells/mm3 for meningitis and 227 cells/mm3 for encephalitis, although there was a wide variation between 5 and 500 cells/mm3. CSF differentials indicated approximately 50 % neutrophilic or lymphocytic predominance with elevated CSF protein levels, some exceeding 100 mg/dl and normal glucose levels. A multivariate analysis showed only a modest correlation between these parameters and clinical outcomes [39]. In addition to serologic and PCR testing, MRI examination of the brain may have varied findings, such as hyperintensity in the basal ganglia, thalami, brainstem, caudate nuclei and spinal cord on T2-weighted images. Diffusion-weighted images or isolated restricted diffusion images may show specific signal intensity abnormalities, while FLAIR images may show increased signal intensity in the brain and brainstem with meningeal involvement and abnormalities within the spinal cord, cauda equina and nerve roots [40]. In comparison, CT scans of the brain are insensitive for detection of these changes. In the presence of flaccid paralysis, the use of electromyelography and nerve conduction studies may help differentiate between WNV and Guillain-Barré syndrome, in which demyelinating lesions with axonal changes are specifically prominent with WNV infection [41].

WNV in the Immunocompromised Patient Immunocompromised patients, particularly stem cell and solid organ transplant recipients, have been identified as specific groups at risk of increased morbidity and mortality when infected with WNV. Additional groups at risk described in case reports include recipients of chemotherapy [42] and HIV-infected individuals [9•, 43, 44]. These groups are discussed individually.

WNV and Solid Organ Transplantation SOT recipients may acquire WNV via: 1. Mosquito bites (naturally occurring WNV) – this mode of transmission represents a majority of reported cases of

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WNV in SOT [6, 45, 46]. While the incidence of WNV neuroinvasive disease in the immunocompetent population is estimated to be 1 in 150 of the 20 % who have symptoms (80 % are asymptomatic), one study estimated the incidence of neuroinvasive disease in the SOT population to be as high as 40 % [47••], although this was not corroborated in another seroprevalence study [32]. The diagnosis of acute WNV infection relies on both serum WNV IgM and IgG antibodies and PCR testing, as antibody production may be inhibited in the presence of immunosuppressive agents that inhibit B-cell activity such as rituximab [32, 37•]. This finding emphasizes the important role of humoral immunity, in addition to T-cell mediated immunity in clearing WNV infection, with a cumulative effect of both Tcell and B-cell defects worsening the ability to clear viremia and neuroinvasive disease. The diagnosis of neuroinvasive disease requires cerebrospinal fluid examination, as discussed above, with cell count, protein and glucose findings similar to those in the immunocompetent population [2, 6, 30, 45]. CSF WNV IgM and IgG antibody testing and PCR should be performed, again with the caveat that PCR should be performed routinely, as immunosuppression may decrease antibody production resulting in falsely negative serologies. Numerous case reports have described devastating neurologic sequelae associated with WNV neuroinvasive disease in transplant recipients [48–51], underscoring the particular importance of counseling immunocompromised patients to prevent mosquito bites through the use of insect repellent such as DEET and avoiding outdoor activities between dusk and dawn when mosquito activity is highest. 2. Donor transmission – this occurs by transplanting organs harvested from actively viremic individuals. In 2002, the first donor transmissions were identified in the US from a woman who died as a result of severe injuries sustained during a motor vehicle accident and had received 53 units of blood components. While her WNV IgM and PCR were initially negative prior to harvesting, three of the four recipients developed WNV encephalitis followed by one death; the fourth patient had WNV fever. This transmission indicated a 75 % incidence of neuroinvasive disease in the recipients. Subsequent investigation revealed that repeat PCR testing of the donor on the day of harvesting was found to be positive for WNV as well as one of the transfused blood products [52]. To date, at least nine cases of donor transmission have been reported in the literature, occurring in both the US and Italy ([17, 18, 21, 22••, 23•, 24•, 36]; personal communication, Dr. Marian Michaels) with neuroinvasive complications estimated to occur in 50–75 % of recipients [53].

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As viremia and hence infectivity is commonly found within 5–7 days of mosquito bites, live donor screening should ideally be performed within 1 week of organ procurement [54]. However, given potentially prolonged viremias and logistical challenges in obtaining results in a timely fashion in remote areas of the US, donor screening may be considered within 14 days of donation. An additional challenge in donor screening is the fact that two of nine documented cases of transmission in deceased organ donors have occurred with negative RT-PCR testing and positive IgM and IgG antibodies, possibly due to the presence of viremia below the level of detection of the assays. Conversely, there have also been concerns about false-positive PCR results, with potential organ loss or delay in donation. One may interpret a positive NAT or serology based on the positive predictive value of each case, such as the prevalence of WNV in the community or travel history of the prospective donor. Therefore, due to the complexity of issues regarding screening, several transplant infectious diseases groups are currently evaluating specific screening recommendations. WNV Infection in Stem Cell Transplant Recipients Naturally occurring WNV infection has been reported in seven bone marrow transplant recipients, ranging between 118 days and 2 years posttransplant. Four of these patients (57 %) developed neuroinvasive disease [8, 55–58]. Three of the four patients with neuroinvasive disease had positive CSF WNV PCR and IgM. The fourth patient had positive serum and CSF IgM and IgG but no PCR was performed. Among the three patients who recovered, serum IgM and IgG were positive, with positive CSF RT-PCR in only one patient. There was no difference between the two groups in terms of timing of stem cell transplantation or incidence of neuroinvasive disease. The persistence of WNV viremia reported in these patients was related to the lack of (1) humoral immunity, i.e., IgM and IgG, in preventing dissemination of WNV to the CNS, and (2) cellular immunity, i.e., CD8+ T cells which prevent persistence of virus and clearance of virus from tissue [59]. Thus far, no stem cell or bone marrow donor transmission of WNV has been reported.

WNV and HIV WNV infection has been reported in only five HIV patients [9•, 43, 44, 60, 61], all with neuroinvasive disease including quadriplegia, acute flaccid paralysis and meningoencephalitis. CD4 counts in the range 93–351/mm3 were reported in three of these patients. It is possible that WNV meningoencephalitis may be attributed to HIV-associated central nervous system disease and therefore under-reported. An additional issue relevant to HIV is the role of the CCR5 chemokine coreceptor, which is needed by

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the HIV virion to bind to the CD4 cell, but conversely mediates resistance to WNV infection [62]. In the treatment of HIV infection, CCR5 receptor antagonists such as maraviroc are used to block HIV binding to CD4 lymphocytes, and individuals with genetic CCR5 deletions are resistant to HIV infection. However, since CCR5 is needed to control WNV infection, deficiency of this chemokine receptor may increase the risk of symptomatic WNV infection. Therefore, the use of CCR5 blockers may increase the risk of neuroinvasive complications in HIV/WNV coinfected patients [63].

Treatment of WNV in the Immunocompromised Patient Supportive care is the cornerstone of treatment of WNV infection in all patients. However, immunocompromised individuals will also benefit from the lowering of immunosuppression in order to maximize cellular and most importantly, humoral immunities, key defenses against WNV infection [37•]. No specific antiviral agents have WNV activity, but several agents have been utilized with varying results. The most promising agent thus far has been intravenous immunoglobulin (IVIG) containing WNV-specific antibodies. Animal models have shown that passive transfer of both monoclonal and polyclonal antibodies have benefit in both the prophylaxis and treatment of WNV [64, 65]. Prior to the advent of WNV in the US, high-titer WNV-specific IVIG (Omr-IgG-am®; Omrix Biopharmaceutical Ltd, Kiryat-Ono, Israel) was developed in Israel where WNV is endemic, and was shown to have therapeutic benefit in individual patients [66, 67]. However, the CASG 210 study, a small randomized controlled trial of Omr-IgG-am versus standard IVIG for the treatment of WNV infection, failed to show a clinical benefit, although there was inadequate enrollment. Subsequently, due to the lack of alternative agents for the treatment of WNV, additional work on IVIG has indicated the presence of protective antibody in significant concentrations in US-derived IVIG. It is estimated that almost 1 % of the US population has been infected with WNV [68] varying from state to state. It is of interest, however, that there was no correlation between the WNV neutralization titers measured for each lot of IVIG and the incidence of WNV in the respective counties [65]. As a result of this finding, US-derived IVIG has been used for the treatment of WNV neuroinvasive disease in transplant recipients with reports of successful outcomes. In one report, a patient received two doses of IVIG, initially 1 g/kg followed by 500 mg/kg [69]; in the second report, the patient received a single dose of IVIG at 0.4 mg/kg [22••]. Subsequently, IVIG was used successfully for WNV prophylaxis in the recipient of a liver from a donor who was found to have a positive WNV NAT after organ transplantation. The recipient initially received fresh frozen plasma from healthy blood donors from areas recognized to have WNV, followed by Omr-IgG-am at a dose of 0.4 g/kg with no

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evidence of symptomatic infection. More studies are needed for the use of IVIG for both prophylaxis in the event of inadvertent transplant of WNV infected organs or bone marrow, and treatment. Based on the literature, the early administration of IVIG, particularly during the initial period of viremia, may have better outcomes than delayed use. Interferon-α 2b has been studied for the treatment of WNV. The mechanism of action is activation of cytotoxic T-cell responses, resulting in suppression of viral replication [70, 71]. However, studies in transplant recipients have not been performed due to concern over potential interferon-associated organ rejection. A report of dosing with 3 million units per day for 14 days has been published [72]. Overall, the literature on the efficacy of interferon-α 2b has been less positive than that on immunoglobulin treatment. Conclusions WNV infection in immunocompromised individuals, particularly with donor-derived transmission to transplant recipients, is an area of increasing interest and importance due to increased morbidity and mortality compared to the immunocompetent population. Potential WNV donor-derived infections may be considered based on seasonal factors and reports of WNV infection within the region of the donor. Clinicians may consider WNV infection in the presence of acute flaccid paralysis, meningitis, encephalitis, meningoencephalitis or cogwheel rigidity, particularly during the mosquito season. The treatment will include supportive care, lowering of immunosuppression and consideration for the expeditious use of IVIG. Compliance with Ethics Guidelines Conflict of Interest Marilyn Levi declares no conflict of interest. Human and Animal Rights and Informed Consent With regard to the author’s research cited in this paper, all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the studies. This article does not contain any studies with animal subjects performed by the author.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. Smithburn KC, Hughes TP, Burke AW, Paul JH. A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med Hyg. 1940;20:471.

483 2. Nash D, Mostashari F, Fine A, Miller J, et al. The outbreak of West Nile virus infection in the New York City area in 1999. New Engl J Med. 2001;344(24):1807–14. 3. Lanciotti RS, Roehrig JT, Deubel V, Smith J, et al. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science. 1999;286:2333–7. 4. Centers for Diseases Control and Prevention. Average annual incidence of West Nile virus neuroinvasive disease reported to CDC by state, 1999–2012. ArboNET, Arboviral Diseases Branch, Centers for Diseases Control and Prevention, Atlanta, GA. http://www.cdc.gov/ westnile/resources/pdfs/cummulative/99_2012_ AvgAnnualIncidenceNeuroInvasiveState.pdf. Accessed 13 Sep 2013. 5. • Petersen LR, Carson PJ, Biggerstaff BJ, Custer B, et al. Estimated cumulative incidence of West Nile virus infection in US adults, 1999–2010. Epidemiol Infect. 2012;May 28:1–5. This paper provides an estimate of the overall incidence of WNV in the United States between 1999-2010 6. Kumar D, Prasad GV, Zaltzman J, Levy GA, Humar A. Communityacquired West Nile virus infection in solid-organ transplant recipients. Transplantation. 2004;77:399–402. 7. DeSalvo D, Roy-Chaudhury P, Peddi R, Merchen T, et al. West Nile virus encephalitis in organ transplant recipients: another high-risk group for meningoencephalitis and death. Transplantation. 2004;77:466–9. 8. Hiatt B, DesJardin L, Carter T, Gingrich R, et al. A fatal case of West Nile virus infection in a bone marrow transplant recipient. Clin Infect Dis. 2003;37:e129–31. 9. • Josekutty J, Yeh R, Mathew S, Ene A, et al. Atypical presentation of West Nile virus in a newly diagnosed human immunodeficiency virus patient in New York City. J Clin Microbiol. 2013;51:1307–9. This paper describes WNV infection manifesting as meningoencephalitis and spastic paresis in an HIV positive patient. 10. Batsis J, Phy MP. West Nile virus meningitis in a chronic immunosuppressed patient with rheumatoid arthritis. Clin Rheumatol. 2005;24:548–50. 11. O’Learn DR, Kuhn S, Kniss KL, Hinckley AF, et al. Birth outcomes following West Nile virus infection of pregnant women in the United States: 2003–2004. Pediatrics. 2006;117:e537–45. 12. Centers for Disease Control and Prevention (CDC). West Nile virus disease and other arboviral diseases – United States, 2010. MMWR Morb Mortal Wkly Rep. 2011;60:1009–13. 13. Centers for Disease Control and Prevention. West Nile virus in the United States: guidelines for surveillance, prevention, and control. Division of Vector-Borne Diseases, Centers for Diseases Control and Prevention, Atlanta, GA. http://www.cdc.gov/westnile/resources/ pdfs/wnvGuidelines.pdf. Accessed 13 Sep 2013. 14. Soverow JE, Wellenius GA, Fisman DN, Mittleman MA. Infectious disease in a warming world: how weather influenced West Nile virus in the United States (2001–2005). Environ Health Perspect. 2009;117(7):1049–52. 15. Centers for Diseases Control and Prevention. West Nile virus disease cases and presumptive viremic blood donors reported to ArboNET, United States, 2012. ArboNET, Arboviral Diseases Branch, Centers for Diseases Control and Prevention, Atlanta, GA. www.cdc.gov/ westnile/statsMaps/finalMapsData/data/2012WNVHumanInfections byState.pdf. Accessed 13 Sep 2013. 16. Martin DA, Biggerstaff BJ, Allen B, Johnson AJ, et al. Use of immunoglobulin m cross-reactions in differential diagnosis of human flaviviral encephalitis infections in the United States. Clin Diagn Lab Immunol. 2002;9:544–9. 17. Centers for Disease Control and Prevention (CDC). West Nile virus activity – United States, September 26-October 2, 2002, and investigations of West Nile virus infections in recipients of blood transfusion and organ transplantation. MMWR Morb Mortal Wkly Rep. 2002;51:884–95. 18. Centers for Disease Control and Prevention (CDC). West Nile virus transmission via organ transplantation and blood

484

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30. 31.

32.

33.

34.

Curr Infect Dis Rep (2013) 15:478–485 transfusion – Louisiana, 2008. MMWR Morb Mortal Wkly Rep. 2009;58:1263–7. Pealer LN, Martin AA, Petersen LR, Lanciotti RS, et al. Transmission of West Nile virus through blood transfusion in the United States in 2002. N Engl J Med. 2003;349:1236–45. Stramer SL, Fang CT, Foster GA, Wagner AG, et al. West Nile virus among blood donors in the United States, 2003 and 2004. N Engl J Med. 2005;353:451–9. Centers for Disease Control and Prevention (CDC). West Nile virus infections in organ transplant recipients – New York and Pennsylvania, August-September 2005. MMWR Morb Mortal Wkly Rep. 2005;54:1021–3. •• Rhee C, Eaton EF, Conception W, Blackburn BG. West Nile virus encephalitis acquired via liver transplantation and clinical response to intravenous immunoglobulin: case report and review of the literature. Transpl Infect Dis. 2011;13:312–7. This paper describes the successful empiric use of U.S.-derived intravenous immunoglobulin 0.4 mg/kg for the treatment of donor derived WNV encephalitis. • Morelli MC, Sambri V, Grazi GL, Gaibani P, et al. Absence of neuroinvasive disease in a liver transplant recipient who acquired West Nile virus (WNV) infection from the organ donor and who received WNV antibodies prophylactically. Clin Infect Dis. 2010;51: e34–7. This document reviews the use of US-derived IVIG for prophylaxis following transplantation of a WNV-infected liver. The recipient showed no subsequent evidence of neuroinvasive disease. • Inojosa WO, Scotton PG, Fuser R, Globbia M, et al. West Nile virus transmission through organ transplantation in north-eastern Italy: a case report and implications for pre-procurement screening. Infection. 2012;40:557–62. While a majority of WNV solid organ transmission has been reported in the US, cases in Italy have led to a donor screening protocol utilizing IgM capture and nucleic acid testing. Human Resources and Services Administration. US Department of Health and Human Services, http://optn.transplant.hrsa.gov/ PoliciesandBylaws2/policies/pdfs/policy_172.pdf. p 12–18. Chowers MY, Lang R, Nassar F, Ben-David D, et al. Clinical characteristics of the West Nile fever outbreak, Israel 2000. Emerg Infect Dis. 2001;7:675–8. Mostashari F, Bunning ML, Kitsutani PT, Singer DA, et al. Epidemic West Nile encephalitis, New York, 1999: results of a household-based seroepidemiological survey. Lancet. 2001;358:261– 4. Ferguson D, Gershman K, LeBailley A, Petersen L. Characteristics of the rash associated with West Nile virus fever. Clin Infect Dis. 2005;41:1204–7. Centers for Diseases Control and Prevention. Possible persistence of West Nile virus infection. Centers for Diseases Control and Prevention, Atlanta, GA. http://www.cdc.gov/westnile/healthCareProviders/ healthCareProviders-PersistentInfections.html. Accessed 13 Sep 2013. Peterson LR, Marfin AA. West Nile Virus: a primer for the clinician. Ann Intern Med. 2002;137(3):173–9. Centers for Diseases Control and Prevention. West Nile virus disease cases and deaths reported to CDC by year and clinical presentation, 1999–2012. ArboNET, Arboviral Diseases Branch, Centers for Diseases Control and Prevention, Atlanta, GA. http://www.cdc.gov/ westnile/resources/pdfs/cummulative/99_2012_CasesAndDeaths ClinicalPresentationHumanCases.pdf. Accessed 13 Sep 2013. Freifeld AG, Mez J, Schweitzer B, Shafer L, et al. Seroprevalence of West Nile virus infection in solid organ transplant recipients. Transpl Infect Dis. 2010;12:120–6. Procleix® WNVAssay. Gen-Probe Inc., San Diego, CA. http://www. fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/ InfectiousDisease/ucm090247.pdf. Accessed 13 Sep 2013. Cobas® TaqScreen West Nile Virus Test for use on the cobas s 201 system. Roche Molecular Systems Inc., Pleasanton, CA. http://www. fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/

35.

36.

37.

38.

39.

40.

41.

42.

43. 44.

45.

46.

47.

48.

49.

50.

51.

52.

ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/ InfectiousDisease/UCM091938.pdf. Accessed 13 Sep 2013. Busch MP, Kleinman SH, Tobler LH, Kamel HT, et al. Virus and antibody dynamics in acute West Nile virus infection. J Infect Dis. 2008;198:984–93. Nanni Costa A, Capobianchi MR, Ippolito G, Palù G, et al. West Nile virus: the Italian national transplant network reaction to an alert in the north-eastern region, Italy 2011. Euro Surveill. 2011;16(41):pii = 19991. • Levi ME, Quan D, Ho JT, Kleinschmidt-Demasters BK, et al. Impact of rituximab-associated B cell-defects on West Nile virus meningoencephalitis in solid organ transplant recipients. Clin Transplant. 2010;24:223–8. This paper highlights the impact of rituximab in preventing production of WNV antibodies, ie IgM and IgG and the need to obtain RNA measurement to improve the detection of WNV infection. Penn RG, Guarner J, Sejvar JJ, Hartman H, et al. Persistent neuroinvasive West Nile virus infection in an immunocompromised patient. Clin Infect Dis. 2006;42:680–3. Tyler KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters BK. CSF findings in 250 patients with serologically confirmed West Nile virus meningitis and encephalitis. Neurology. 2006;66:361–5. Ali M, Safriel Y, Sohi J, Llave A, Weathers S. West Nile virus infection: MR imaging findings in the nervous system. AJNR Am J Neuroradiol. 2005;26:289–97. Asnis DS, Conetta R, Waldman G, Teixeira AA. The West Nile virus encephalitis outbreak in the United States (1999–2000): from Flushing, New York, to beyond its borders. Ann N Y Acad Sci. 2001;951: 161–71. Hindo H, Buescher ES, Frank LM, Pettit D, et al. West Nile virus infection in a teenage boy with acute lymphocytic leukemia in remission. J Pediatr Hematol Oncol. 2005;27:659–62. Szilak I, Minamoto GY. West Nile virus encephalitis in an HIVpositive woman in New York. N Engl J Med. 2000;342:59–60. Torno M, Vollmer M, Beck CK. West Nile virus infection presenting as acute flaccid paralysis in an HIV-infected patient. Neurology. 2007;68:E5–7. Kleinschmidt-DeMasters BK, Marder BA, Levi ME, Laird SP, et al. Naturally acquired West Nile virus encephalomyelitis in transplant recipients. Arch Neurol. 2004;61:1210–20. Ravindra KV, Freifeld AG, Kalil AC, Mercer DF, et al. West Nile virus-associated encephalitis in recipients of renal and pancreas transplants: case series and literature review. Clin Infect Dis. 2004;38:1257–60. •• Kumar D, Drebot MA, Wong SJ, Lim G, et al. A seroprevalence study of West Nile virus infection in solid organ transplant recipients. Am J Transplant. 2004;4:1883–8. This paper reports the estimated seroprevalence of WNV in Canadian solid organ transplant recipients and incidence of neuroinvasive disease of 1:40 as opposed to 1: 150 in the immunocompetent population. Mawhorter SD, Sierk A, Staugaitis SM, Avery RK, et al. Fatal West Nile virus infection after rituximab/fludarabine-induced remission for non-Hodgkin’s lymphoma. Clin Lymphoma Myeloma. 2005;6:248–50. Wadei H, Alangaden GJ, Willix DH, El-Amm JM, et al. West Nile virus encephalitis: an emerging disease in renal transplant recipients. Clin Transplant. 2004;18:753–8. Jain N, Fisk D, Sotir M, Kehl KS. West Nile encephalitis, status epilepticus and West Nile pneumonia in a renal transplant patient. Transpl Int. 2007;20:800–3. Shepherd JC, Subramanian A, Montgomery RA, Samaniego MD, et al. West Nile virus encephalitis in a kidney transplant recipient. Am J Transplant. 2004;4:830–3. Hardinger KL, Miller B, Storch GA, Desai NM, Brennan DC. West Nile virus-associated meningoencephalitis in two chronically immunosuppressed renal transplant recipients. Am J Transplant. 2003;3:1312–5.

Curr Infect Dis Rep (2013) 15:478–485 53. Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, et al. Transmission of West Nile virus from an organ donor to four transplant recipients. N Engl J Med. 2003;348:2196–203. 54. Singh N, Levi ME. Arenavirus and West Nile virus in solid organ transplantation. Am J Transplant. 2013;13:361–71. 55. Robertson KB, Barron MA, Nieto Y. West Nile virus infection in bone marrow transplant patients. Bone Marrow Transplant. 2004;34: 823–4. 56. Busch MP, Caglioti S, Robertson EF, McAuley JD, et al. Screening the blood supply for West Nile virus RNA by nucleic acid amplification testing. N Engl J Med. 2005;353:460–7. 57. Brenner W, Storch G, Buller R, Vij R, et al. West Nile virus encephalopathy in an allogeneic stem cell transplant recipient: use of quantitative PCR for diagnosis and assessment of viral clearance. Bone Marrow Transplant. 2005;36:369–70. 58. Martin SE, Grubbs S, Della Valla J, Reinhardt JF, et al. Fatal West Nile virus encephalitis following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2004;34:1007–8. 59. Reddy P, Davenport R, Ratanatharathorn V, Reynolds C, et al. West Nile virus encephalitis causing fatal CNS toxicity after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2004;33:109–12. 60. Shrestha B, Diamond MS. Role of CD8+ T cells in control of West Nile virus infection. J Virol. 2004;78:8312–21. 61. Jamison SC, Michaels SR, Ratard R, Sweet JM, Deboisblanc BP. A 41-year-old HIV-positive man with acute onset of quadriplegia after West Nile virus infection. South Med J. 2007;100:1051–3. 62. Guarner J, Shieh WJ, Hunter S, Paddock CD, et al. Clinicopathologic study and laboratory diagnosis of 23 cases with West Nile virus encephalomyelitis. Hum Pathol. 2004;35:983–90.

485 63. Glass WG, McDermott DH, Lim JK, Lekhong S, et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med. 2006;203:35–40. 64. Ben-Nathan D, Gershoni-Yahalom O, Samina I, Khinich Y, et al. Using high titer West Nile intravenous immunoglobulin form selected Israeli donors for treatment of West Nile virus infection. BMC Infect Dis. 2009;9:18. 65. Ben-Nathan D, Lustig S, Tam G, Robinzon S, et al. Prophylactic and therapeutic efficacy of human intravenous immunoglobulin in treating West Nile virus infection in mice. J Infect Dis. 2003;188:5–12. 66. Lim JK, Glass WG, McDermott DH, Murphy PM. CCR5: no longer a ‘good for nothing’ gene – chemokine control of West Nile virus infection. Trends Immunol. 2006;27:308–12. 67. Shimoni Z, Niven MJ, Pitlick S, Bulvik S. Treatment of West Nile virus encephalitis with intravenous immunoglobulin. Emerg Infect Dis. 2001;7:759. 68. Saquib R, Randall H, Chandrakantan A, Spak CW, Barri YM. West Nile virus encephalitis in a renal transplant recipient: the role of intravenous immunoglobulin. Am J Kidney Dis. 2008;52:e19–21. 69. Planitzer CB, Modrof J, Kreil TR. West Nile virus neutralization by US plasma-derived immunoglobulin products. J Infect Dis. 2007;196:435–40. 70. Bukowski JF, Welsh RM. Interferon enhances the susceptibility of virus-infected fibroblasts to cytotoxic T cells. J Exp Med. 1985;161:257–62. 71. Kalil AC, Devetten M, Singh S, Lesiak B, et al. Use of interferonalpha in patients with West Nile encephalitis: report of 2 cases. Clin Infect Dis. 2005;40:764–6. 72. Brassard DL, Grace MJ, Bordens RW. Interferon-alpha as an immunotherapeutic protein. J Leukoc Biol. 2002;71:565–81.