Community-acquired West Nile virus infection in solid-organ ... : Transplantation (original) (raw)
West Nile virus (WNV) is a single-stranded positive-sense RNA virus that belongs to the family Flaviviridae, genus Flavivirus (1,2). WNV is maintained and amplified in nature in an enzootic bird-mosquito-bird cycle. When environmental factors promote sufficient viral amplification, “spill over” infections of humans and other mammals may occur from mosquito vectors (1,2). In previously healthy individuals, the majority of infections caused by WNV are asymptomatic. About 20% of infected people will have a self-limited febrile illness. It has been estimated that the rate of meningitis or encephalitis in the normal population is approximately 1 in every 150 infections, with higher attack rates in older persons (3,4). Encephalitis typically presents as fever and headache accompanied by signs and symptoms of encephalitis such as confusion, coma, and other neurologic signs. Although the clinical presentation does not allow for accurate distinction from other viral encephalitides, the presence of severe muscle weakness or flaccid paralysis may be a clue to WNV infection (1,2). A polio-like syndrome has been described in more recent outbreaks (5,6).
WNV first appeared in the United States in New York in 1999 (7). The virus’ rapid geographic expansion and persistence indicate that WNV is likely here to stay. In 2002, the geographic range and the reported numbers of human and animal infections increased dramatically (8). The 2002 WNV epidemic in the United States and Canada was the largest arboviral meningoencephalitis epidemic documented in the western hemisphere and the largest reported WNV meningoencephalitis epidemic (this term includes cases of encephalitis or meningitis) (8). Several unique findings were also noted during the 2002 WNV epidemic, including the first documented cases of person-to-person WNV transmission through organ transplantation, blood transfusion, breast feeding, and intrauterine transmission from mother to fetus (9–12).
In addition to acquiring infection through the donor organ or blood transfusion, transplant patients may acquire disease by community-acquired exposure from the bite of an infected mosquito. Very few transplant patients with WNV infection have been described in the literature. The risk of severe disease and clinical presentations and outcomes are not well known in this population. We report four cases of community-acquired severe WNV infection and compare the incidence with that seen in the general population in the same geographic area.
METHODS
During the epidemic of WNV in the Greater Toronto area (Ontario, Canada) in the summer and fall of 2002, four solid-organ transplant recipients were identified with neurologic disease caused by WNV. Chart review of patients’ presentation and hospital course was performed. In addition, a search of the transplant electronic chart and database was performed for all transplant patients followed in the Toronto area to search for other potentially undiagnosed cases of acute meningitis or encephalitis in transplant patients that occurred during the summer or early fall.
Laboratory testing was performed through the Canadian National Health Laboratory. Acute and convalescent serology was performed using hemagglutination inhibition assays (HIA), which tests for total antibody (immunoglobulin [Ig]G and IgM). A fourfold rise in titer or a seroconversion from negative to positive by HIA was used to diagnose acute WNV infection. Specificity of antibody for WNV was confirmed by plaque-reduction neutralization assay.
Active surveillance was being carried out by the Public Health authority at the time of the outbreak. Surveillance data for the greater Toronto area was accessed from the Health Canada Web site to compare estimated rates of severe neurologic disease in our transplant population versus the general population.
RESULTS
A total of four cases of WNV in solid-organ transplant recipients were identified and confirmed through laboratory testing (Table 1).
Summary of transplant patients with West Nile virus infections
Case 1
This patient was a 58-year-old female who had received a liver transplant 2 years earlier for cryptogenic cirrhosis. She had an uncomplicated course and had been well since her transplant. She had not received any blood products since the time of her transplant. Her current immunosuppression was cyclosporin and mycophenolate mofetil (MMF). She was not working and spent several hours a day walking outside. One week before her illness, she had spent the weekend at her cottage just north of the city and was primarily outdoors. She used no insect protection measures. She presented with sudden onset of fever and chills. Blood cultures and cytomegalovirus (CMV) antigenemia were negative. After 4 days of fever in the hospital, she developed progressive confusion and a headache. Lumbar puncture demonstrated a lymphocytic pleocytosis (WBC 58 mil/L) and elevated protein (0.6 g/L). WNV serology at that time was negative. Computed tomography (CT) of the head was normal, and magnetic resonance imaging (MRI) revealed subtle attenuation in the pons. All cerebrospinal fluid (CSF) cultures and enterovirus and herpesvirus polymerase chain reaction (PCR) (Herpes simplex virus (HSV), Varicella-zoster virus (VZV), CMV, Human herpesvirus-6 (HHV-6)) were negative. A presumptive diagnosis of WNV encephalitis was made, immunosuppression was stopped, and the patient was empirically treated with antibiotics, acyclovir, and ribavirin. She progressed to deep coma and was intubated. A repeat MRI demonstrated increasing attenuation in the brainstem and thalamus. Repeat WNV serology 7 and 14 days after hospitalization was negative. However, repeat serology taken 1 month after hospitalization was strongly positive for WNV, and a separate IgM enzyme-linked immunoadsorbent assay was strongly positive. She failed to have meaningful neurologic recovery, developed multiple complications, and eventually died of a bacterial pneumonia. Autopsy was consistent with viral encephalitis with predominant brainstem involvement, and she also demonstrated significant anterior horn-cell involvement in her spinal cord.
Case 2
This patient was a 51-year-old male 5 years postcadaveric kidney transplant for end-stage renal disease caused by hypertension. He had recently been well and was on cyclosporin, prednisone, and MMF. He had no recent transfusions. He worked as a construction worker and spent most of the day outdoors. He used no specific insect protection measures. He presented with a 3-day history of fever. After an additional 4 days in the hospital, he developed headache and progressive confusion. CT of the head was normal. A lumbar puncture demonstrated a lymphocytic pleocytosis (WBC 98 mil/L) and elevated protein (0.7 g/L). CSF was negative by culture, and PCR was negative for herpesviruses and enterovirus. MRI revealed increased signal intensity in bilateral parietal and frontal lobes. A presumptive diagnosis of WNV encephalitis was made, and cyclosporin and MMF were withheld. He was treated with antibiotics, acyclovir, and ribavirin. Baseline serology was positive for WNV, and convalescent serology 2 weeks later demonstrated a fourfold rise in titer. He initially progressed to coma but then rapidly improved over the next few days. He is currently at home with only mild neurologic dysfunction.
Case 3
This patient was a 26-year-old male who had received a heart transplant 8 years earlier for idiopathic cardiomyopathy. He had no recent complications and was on cyclosporin, prednisone, and MMF. He worked outdoors as a golf course grounds keeper. He used no specific insect protection measures. He presented with a 2 to 3-day history of high fevers, progressive headache, neck stiffness, and photophobia. He had no confusion. CT of the head was normal, and lumbar puncture demonstrated a pleocytosis (WBC 9 mil/L) with normal protein and glucose. Blood cultures and CMV antigenemia were negative as were cultures and PCR (HSV, VZV, CMV, HHV-6, enterovirus) of the CSF. A presumptive diagnosis of WNV meningitis was made, and his MMF and Neoral (cyclosporine) dose were decreased. WNV serology at presentation was positive, and he had a fourfold increase between acute and convalescent titers taken 2 weeks later. He continued to have fevers and headache for approximately 8 days while in the hospital. Eventually, he recovered fully and was discharged home and is currently doing well.
Case 4
This patient was a 43-year-old female approximately 2 months postliving-related kidney transplant for acute tubular necrosis. She had had an uncomplicated course and was discharged home 1 week posttransplant. She had received no blood products during or after her transplant. Her immunosuppression was with tacrolimus, prednisone, and MMF. One week before her illness, she had been at a cottage just north of Toronto and had spent most of her time outdoors. Again, no specific insect protection measures were used. She presented with fever, headache, confusion, and progressive lower-limb muscle weakness for 3 to 4 days. CT of the head was normal, and MRI demonstrated diffuse inflammatory changes. Spine MRI showed inflammation consistent with an anterior myelitis. CSF examination demonstrated a pleocytosis (WBC 115 mil/L) with abnormal protein (1.2 g/L). All routine microbiologic investigations, including CSF culture and PCR, were negative. Serology at presentation was positive for WNV, and she had a fourfold rise between acute and convalescent titers. Immunosuppression was decreased, but she still had progressive neurologic deterioration requiring intubation. She eventually displayed partial recovery, but continues to have a complete flaccid paralysis of both lower limbs with intact sensation and is unable to ambulate.
Surveillance Data
On review of all transplant charts through the electronic transplant database, no other cases of neurologic disease suspicious for WNV were identified. A review of active-population surveillance data revealed that 360 cases of probable and confirmed WNV meningitis or encephalitis were reported in the Ontario region during this epidemic. In the greater Toronto area, the number of reported cases is approximately 270 confirmed or probable cases. Therefore, the rate of WNW encephalitis or meningitis in the general population in the Toronto area during the outbreak was approximately 5 per 100,000. This compares with four cases in a transplant population of approximately 2,000 patients residing in the greater Toronto area (rate 200 per 100,000) (P <0.001).
DISCUSSION
Since its first introduction into New York in 1999, WNV has spread rapidly and established itself throughout most of North America (1,2). In 2002, a total of 3,389 human cases of WNV disease were reported in the United States compared with 149 during 1999 to 2001, and large numbers of WNV-infected birds, horses, and mosquitoes also were reported (8). Of the 3,389 cases, 2,354 (69%) patients had meningoencephalitis, 704 (21%) had West Nile fever, and 331 (10%) had an unspecified illness. The peak of the epidemic was in late summer and early fall (8). In 2002, Health Canada also reported WNV activity in five provinces (Manitoba, Nova Scotia, Ontario, Quebec, and Saskatchewan) (2). Before 2002, cases of WNV infection had not been reported in Canada. The largest number of cases by far were reported in Ontario, and especially in the greater Toronto area. To date, a total of 148 confirmed cases and 212 probable cases of WNV have been reported in Ontario (http://www.hc-sc.gc.ca). Because this 2002 North American epidemic of WNV represents the largest outbreak of WNV meningoencephalitis reported to date, it is not surprising that we should begin to see cases of community-acquired WNV in the transplant population. However, the occurrence of four cases of community-acquired WNV in a relatively small transplant population is alarming. Compared with the reported incidence of meningoencephalitis in the general population living in the same geographic area, the incidence of severe neurologic disease would appear to be much higher in the transplant population. It is likely that the reported number of cases in the general population is an underestimate of the actual number of cases (because of underreporting, missed diagnoses, etc). However, there was a very high awareness of WNV in the community at that time, and we included probable cases in our estimation of cases in the general population. Even if only half of potential encephalitis or meningitis cases in the general population were reported, this is still a much lower rate than we saw in our transplant population.
These cases illustrate several other important points. All four of the patients reported specific outdoor activity (2 work-related, 2 recreational) that would have increased their likelihood of exposure to infected mosquitoes. None of the patients used any personal protection measures such as insect repellent to prevent mosquito bites. Transplant patients living in areas of high WNV activity should be advised of the risk of WNV and counseled on the use of protective measures as well as on potentially avoiding outdoor activity during dusk and dawn, when mosquitoes are most active. Another point from these cases is that one of the patients (case 1) did not have positive serology until approximately 1 month after presentation. In the general population, approximately 90% of serum samples obtained within 8 days of symptom onset will have detectable antibodies (1,13). This delayed seroconversion is likely caused by immunosuppression. Therefore, in transplant patients with suspicious symptoms, repeated serology is mandated, even if initial testing is negative. Testing for IgM in the CSF may be more useful, but this test is currently not available in Canada. The use of molecular-based assays such as PCR may be more appropriate because it is possible that some transplant patients may not mount antibody responses at all. However, in New York, results of nucleic acid amplification testing have been positive in only up to 55% of CSF samples and 10% of serum samples (1,13). Another important observation was that two of the patients with encephalitis had only fever as their presenting symptom. It was not until these patients were in the hospital for several days before they developed any neurologic symptoms. Therefore, the initial presentation may be fairly nonspecific, but WNV should be in the differential diagnosis during periods of high viral activity in the community. Finally, it is clear that serious sequelae may result from this infection in transplant patients. One patient died, and another has serious residual neurologic dysfunction. In the general population, deaths caused by WNV usually occur in elderly patients. In the US epidemic of 2002, of the cases with meningoencephalitis, 9% died, and the median age of those who died was 78 years (8).
There is limited literature on WNV and organ-transplant recipients. In an outbreak in Israel involving 417 cases, the 16 patients who were considered immunosuppressed because of various reasons (malignancy, chemotherapy, transplantation) had a trend toward higher mortality (14). Recently, WNV infection from an infected organ donor has been reported (11). In August 2002, four organs were recovered from an organ donor and were transplanted into four recipients. WNV meningoencephalitis was confirmed in three recipients and WNV fever in one recipient. Illness began between 7 to 17 days after transplantation. The donor plasma was positive by PCR for WNV. However, the donor had received numerous blood transfusions from 63 unique donors (11). Therefore, the organ donor may have had either community-acquired infection or have been infected through blood transfusion. None of our patients had evidence to suggest that virus was transmitted through transplant or through blood products. Three of the patients were quite far from transplant (between 2–10 years). The fourth patient was only 57 days postkidney transplant but had not received any blood products. This incubation period would be significantly longer than the previous reported donor-transmitted cases of WNV (7–17 days).
Treatment for WNV infection is generally supportive. Interferon and ribavirin have in vitro activity, but clinical data is lacking (15). In a review of patients from Israel, those who received ribavirin had a higher mortality, but this may have been because of patient selection (14). We treated two of our patients with ribavirin. One of these patients died, and the other improved. However, it is difficult to determine whether improvement was spontaneous or as a consequence of treatment. There is a report of a lung-transplant recipient in Israel treated with intravenous Ig containing antibodies to WNV who appeared to respond positively to therapy (16). An important adjunct to therapy in transplant patients is likely a prompt discontinuation or a decrease in immunosuppressive therapy once WNV is suspected.
In summary, we report four cases of community-acquired WNV infection in solid-organ transplant recipients. Physicians and patients should be aware of the potential for serious infection caused by community exposure in this population. It is likely that transplant recipients are at much higher risk of severe neurologic disease caused by WNV than the general population. In areas of high WNV activity, transplant patients should take specific precautions to prevent WNV infection, including use of insect repellent when outdoors. Mosquito control may be an important public health strategy in some areas of high WNV transmission (17).
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