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Clinical and Translational Research

West Nile Virus Infection in Kidney and Pancreas Transplant Recipients in the Dallas-Fort Worth Metroplex During the 2012 Texas Epidemic

Yango, Angelito F.1,6; Fischbach, Bernard V.1; Levy, Marlon2; Chandrakantan, Arun3; Tan, Valerie3; Spak, Cedric4; Melton, Larry3; Rice, Kim3; Barri, Yousri3; Rajagopal, Arthi3; Klintmalm, Goran5

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doi: 10.1097/01.TP.0000438621.81686.ab
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Abstract

West Nile virus (WNV) is a mosquito-borne, single-stranded RNA flavivirus originally endemic in Africa, the Middle East, and Southwestern Asia (1). WNV was first identified in 1937 from a Ugandan patient who presented with a febrile illness and has since, spread rapidly in the Western Hemisphere with the first major outbreak in New York City in 1999 (2). By December 2012, approximately 36,801 human cases and 1,501 deaths have been reported (3).

Although infection in otherwise healthy individuals is generally asymptomatic, those who are immunosuppressed have a higher risk of developing neuroinvasive disease. This makes solid organ transplant (SOT) recipients at risk of serious complications when exposed to the WNV (4, 5).

In 2012, a massive outbreak of WNV hit the United States with human cases reported in all of the 48 contiguous states. Texas was at the epicenter of the epidemic and accounted for nearly one third of the national caseload. There were 89 deaths in Texas of 243 reported nationwide, with 30 fatalities reported in the Dallas/Fort Worth area (6). We describe cases of fulminant WNV meningoencephalitis in three kidney/pancreas transplant recipients during the peak of the 2012 Texas epidemic. These cases were treated at Baylor University Medical Center and Baylor All Saints Medical Center, which are two major solid-organ transplantation centers in the North Texas area. This study reviews reported cases of WNV infection in kidney and pancreas transplant recipients and compares their outcomes with the general population. We discuss the utility of U.S. plasma-derived IVIG as an adjuvant therapy for immunocompromised patients with complicated WNV infection.

RESULTS

Case 1

In August 2012, a 73-year-old man was admitted to the hospital for 4 days of fever, headache, diarrhea, and confusion. The patient had diabetic nephropathy and received a deceased donor kidney transplant (DDKTx) in March 2012. His past medical history was significant for hypertension, coronary artery disease, peripheral vascular disease, and obesity. He had not traveled or received a blood transfusion within the last 12 months before his admission. His immunosuppression consisted of tacrolimus 1 mg orally twice daily (trough: 4–6 ng/ml), mycophenolic acid 720 mg orally twice daily and prednisone 5 mg orally once daily.

On presentation, he had a blood pressure of 112/54 mm Hg, heart rate of 103 beats/min, O2 saturation 95%, and a temperature of 103°F. His admission laboratories and physical exam were all unremarkable.

The patient was started empirically on intravenous vancomycin, meropenem, and voriconazole. His immunosuppression was reduced to two drugs—tacrolimus and prednisone. A computed tomography (CT) scan of the brain was unremarkable. Electroencephalogram showed nonspecific encephalopathy. Blood and urine cultures were negative. Serum polymerase chain reaction (PCR) for cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as serum cryptococcal and urine histoplasma Ag, were all negative.

A lumbar puncture performed 4 days after admission showed normal glucose, elevated protein (64 mg/dL), and pleiocytosis (20 leukocytes /μL) with lymphocytic predominance (55%). Cerebrospinal fluid (CSF) WNV IgM and viral PCR were both negative. However, a serum sample sent on the same day had detectable WNV IgM antibody with an index of 4.96 (IgM>1.1 considered positive).

Three doses of IVIG at 400 mg/kg were given on hospital days 6, 8, and 10. Despite treatment, his neurologic status deteriorated requiring mechanical ventilation . On hospital day 16, the patient became hemodynamically unstable. After consultation with his medical team and his family, life support was withdrawn, and the patient expired on hospital day 20.

Case 2

In October 2012, a 49-year-old man presented with 2 days of fever accompanied by chills, headache, myalgia, and polyarthralgia. He received a combined kidney-pancreas transplant in February 2012 with an unremarkable posttransplant course. His past medical history was significant for gout and hyperlipidemia. He had no history of blood transfusion or travel after his transplant. He received thymoglobulin induction and was maintained on tacrolimus 2 mg orally twice a day (trough: 6–8 ng/mL), mycophenolic acid 720 mg orally twice daily and prednisone 10 mg orally once daily.

On admission, he had a blood pressure of 140/84 mm Hg, heart rate of 102 beats/min, and a temperature of 104°F. Admission laboratories were unremarkable except for a mildly elevated lipase of 494 U/L.

Over the next 8 hours, he became progressively obtunded, requiring mechanical ventilation. Broad spectrum antimicrobials were started and included intravenous vancomycin and meropenem. Given the high incidence of WNV infection in the area, the possibility of WNV encephalitis was considered. Within 12 hours of admission, his immunosuppression was completely withdrawn and was started on IVIG at 400 mg/kg (four doses) given on days 1, 2, 3, and 5.

A head CT performed on the second hospital day showed no acute intracranial process. Blood and urine cultures were negative. Initial viral studies, including serum PCR for EBV, CMV, and herpes simplex virus (HSV), were negative. CSF analysis performed on his second hospital day showed pleocytosis (56 leukocytes/μL), with lymphocytosis. CSF glucose was normal, but CSF protein level was elevated at 106 mg/dL. CSF bacterial cultures, as well as PCR testing for EBV, CMV, HSV, and human herpes virus 6 (HHV6), were negative. WNV PCR was negative in both CSF and serum. CSF WNV IgG and IgM antibody levels were also undetectable, but serum IgM antibody levels were detectable and showed a rising titer from an index of 1.79 to 5.13 onsamples obtained on the 2nd and 10th hospital days, respectively.

With supportive care, his fever subsided by days 4 and 6, and his mental status had improved. By his 12th hospital day, his immunosuppressive drugs were resumed. His kidney and pancreas allografts remained normal. He completed 4 weeks of physical therapy and was discharged home.

Case 3

In August 2012, a 51-year-old man was admitted to the hospital for a 4-day history of fever and headaches. He had diabetic nephropathy and received a DDKTx in 2006. His past medical history was also significant for hypertension, gout, and remote left transmetatarsal amputation. He had a baseline creatinine of 1.8 mg/dL and had not traveled nor received blood transfusion recently. His maintenance immunosuppression consisted of cyclosporine 300 mg orally twice a day (trough: 100–150 ng/mL), mycophenolic acid 720 mg orally twice a day, and prednisone 5 mg orally once daily.

On presentation, he had a blood pressure of 130/70 mm Hg, heart rate of 84 beats/min, and a temperature of 99.6°F. His physical examination was significant for a holosystolic murmur and mild tremors. His admission laboratories were unremarkable, except for a creatinine of 2.8 mg/dL.

Initial workup that included blood and urine cultures, as well as PCR for CMV and EBV, were all negative. Forty-eight hours after his admission, he remained febrile and confused. A lumbar puncture was performed, which showed CSF pleocytosis (WBC 226 cells/μL) with neutrophilic predominance (76%). Cerebrospinal fluid glucose was normal, but the protein level was elevated at 87 mg/dL. Cerebrospinal fluid culture, cryptococcal Ag, histoplasma Ag, WNV PCR, and IgG/IgM antibodies were all negative. However, the serum sample taken on hospital day 2 had detectable WNV IgM (index 3.1). The patient was promptly initiated on IVIG therapy starting on hospital day 2 and received four doses at 400 mg/kg per dose. His immunosuppression was also reduced to two drugs with tacrolimus and prednisone.

The patient required mechanical ventilation due to worsening encephalopathy. Both head CT and magnetic resonance imaging (MRI) showed no acute intracranial abnormalities. His electroencephalogram was consistent with severe encephalopathy. Over the next 7 days, his mental status improved and was subsequently transferred to a rehabilitation facility and made an uneventful recovery.

DISCUSSION

West Nile virus is an emerging virus in SOT. Since 2002, approximately 24 cases of WNV infection in kidney and kidney/pancreas transplant recipients have been reported in the United States (Table 1) (7–19). There were 6 reported deaths resulting in a mortality rate of 25%, in contrast to a mortality rate of 4% reported in the general population (3). Twenty-three (92%) of these reported cases presented with neuroinvasive disease suggesting that neurologic complications are more common in SOT recipients. These data compare poorly with the general population, where neuroinvasive disease occurs in approximately 1 in every 150 WNV infections (20, 21). Although striking, these data should be interpreted with caution because the true incidence of WNV infection in both transplant and nontransplant patients is difficult to determine because patients with self-limited infections may not necessarily seek medical care.

TABLE 1
TABLE 1:
Reported cases of WNV infection in kidney/pancreas transplant recipients

A diagnosis of WNV infection is confirmed by detection of IgM antibody in the serum or CSF during acute illness (22). In some cases, nucleic acid amplification by real-time PCR has been used particularly in immunosuppressed patients who may not be able to mount an adequate antibody response (23). Our cases were diagnosed based on clinical presentation and demonstration of WNV-specific IgM antibodies. Immunoglobulin M antibodies were detected in the serum of all three patients but not in the CSF. In contrast, viral PCR in serum or CSF collected on all three patients during the acute illness was negative. This highlights a limitation of PCR testing for the diagnosis of WNV infection. Because viremia is often transient, nucleic acid amplification tests have low sensitivities and have not been recommended for routine use (23, 24).

In normal hosts, up to 90% will have detectable IgM in the CSF within 8 days of illness (25). Although the ability to mount an early immune response has been shown in animal studies to protect against lethal infection, viral dynamics and Ab response have not been fully defined in immunosuppressed patients (26). For example, all three patients described had undetectable IgM antibodies in their CSF at presentation (days 2 and 4). However, because serial CSF analysis was not performed, we are unable to confirm seroconversion in these patients. Of note, cases of seronegative WNV encephalitis in SOT recipients have been previously reported (11). Recently, Koepsell et al. (19) reported a fatal case of WNV encephalitis in a kidney/pancreas transplant recipient who failed to mount an IgM/IgG response for up to 3 weeks after initial exposure. Therefore, although the presence of IgM antibodies in the CSF is a strong indicator of CNS infection, its absence may not rule out infection.

One patient succumbed to the disease, whereas the other two patients made a full recovery. Age and comorbidities may have contributed to the difference in outcome, as the patient who died was a 73-year-old man with other active medical issues and poor functional status. In contrast, the other two patients were younger and fully functional and had no active cardiac disease at the time of infection.

There is no proven therapy for WNV. Immunosuppression reduction remains the primary strategy to augment humoral response to WNV. Specific agents have been previously investigated including ribavirin, interferon-α, and small-molecule inhibitors, but their efficacy has not been established (27–30). A review of all published cases of WNV infection in kidney and pancreas transplant recipients (Table 1) precludes analysis of efficacy of any particular agent, given the small sample size and wide variation in treatment strategies. Interestingly, there were no deaths in the eight cases where the use of specific antiviral treatment (IVIG and/or interferon) was reported.

In addition to reduction in immunosuppression, all patients received IVIG based on evidence that passive transfer of antibodies may be effective in established WNV infection (31, 32). For passive immunization to be effective, it must contain a sufficient titer of virus-specific neutralizing antibodies. Therefore, the anti-WNV property of IVIG, which is pooled from thousands of healthy plasma donors, will depend on the exposure and humoral immune response of the donor pool. This raises the potential for IVIG lot variability in WNV antibody levels, thus making it difficult to assess the efficacy of commonly used IVIG preparations without specifically testing for antibody titers to WNV. In fact, because WNV was originally endemic in Israel, early IVIG preparations pooled from U.S. donors had undetectable WNV antibodies (31). Because we did not test for specific antibody titer to WNV, an association between clinical improvement and IVIG therapy cannot be fully established. However, as a result of the rising prevalence of WNV in the United States since 1999, IVIG lots from U.S.-sourced plasma have now been shown to have sufficient titer of WNV neutralizing antibodies (33).

Since 2000, there have been numerous reports on the successful use of IVIG in SOT recipients infected with WNV. Earlier reports used IVIG from Israeli donors for itshigh anti-WNV antibody titer (31, 34, 35). Recently, U.S.-sourced immunoglobulins have been used with encouraging results (11). We previously reported on a kidney transplant recipient with WNV encephalitis who had a complete recovery after treatment with IVIG (17). A similar outcome was also recently described for a liver transplant recipient with WNV encephalitis treated with IVIG (32). In both cases, U.S. plasma-derived immunoglobulin products were used.

Although all our patients received IVIG therapy, the two surviving patients were treated early in their disease course compared with the single patient who succumbed to the infection. The latter received IVIG treatment 10 days after the onset of clinical symptoms, whereas IVIG therapy was started within 2 to 6 days from onset of symptoms for the two surviving patients. Such association between early treatment and favorable outcome has previously been reported. For example, Makhoul et al. (35) reported excellent outcomes in patients with WNV encephalitis treated with IVIG within 5 days of initial presentation but a mortality rate of 50% for those who received late treatment.

The importance of immunosuppression reduction in these cases cannot be understated. We believe that prompt reduction in immunosuppressive therapy was crucial in hastening recovery in two of our patients; whereas advanced age, comorbidities, poor functional, and delay in IVIG therapy may have contributed to the demise of the third patient.

For an infection with no definitive therapy, our report suggests that IVIG may have a protective effect and may be used as an adjuvant treatment for WNV infection, particularly for those who are immunosuppressed. It has an advantage over other agents as being readily available and generally well tolerated. It has also been used extensively in transplantation for treatment of acute rejection (36). In theory, it may provide protection against rejection at a time when it is necessary to lower immunosuppression in an infected patient. The rising prevalence of WNV infection in the U.S. population coupled with devastating outcomes in the immunosuppressed patients should provide cause for larger trials to clarify the mechanisms of antibody-mediated protection against WNV. Further studies are also needed to determine clinical efficacy, optimal dosing, timing of therapy, and the patient population that will benefit the most from treatment.

CONCLUSION

In conclusion, WNV infection in immunosuppressed patients tends to be more aggressive, with a higher risk of neurinvasive disease and mortality. To date, there are no established or approved therapies for WNV infection; however, previous reports as well as our limited but favorable experience in two of three transplant patients suggest that passive transfer of virus-specific antibodies using IVIG therapy may play a role in controlling active infection. Because early intervention is beneficial, WNV infection should be considered when evaluating transplant recipients who present with fever and neurologic symptoms, particularly in endemic areas.

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Keywords:

West Nile virus; Solid organ transplants; Meningoencephalitis; Intravenous immunoglobulin

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