Special announcement from HRSA regarding West Nile Virus

Published on: Friday, January 9, 2004

The Health Resources and Services Administration, Special Programs Bureau, Division of Transplantation is issuing this notice to the transplant community to provide clarification about available West Nile virus (WNV) diagnostic and screening tests, and to provide guidance for the use of these tests in the setting of organ donation and transplantation.

Background

WNV is a flavivirus transmitted to humans from birds through the bite of infected mosquitoes. In immunocompetent individuals, the incubation period ranges from about 2-14 days, but may be longer in immunocompromised individuals. Although the majority of infected individuals are asymptomatic, WNV produces flu-like symptoms such as fever, headache, malaise, and body aches in approximately 20% of infected individuals. Less than 1% of infected individuals develop severe disease such as encephalitis or meningitis. However, immunocompromised individuals may be at greater risk for severe disease.

WNV IgM tests are available for diagnostic use in individuals with clinical symptoms suggestive of WNV infection. Detectable levels of IgM antibody to WNV may not be present during the first week of illness; antibody production in an immunocompromised individual may be delayed or absent. By the time antibody is detectable, the viremia may be at a very low level or resolved. Testing with WNV IgM antibody-capture enzyme-linked immunosorbent assay is available through the Centers for Disease Control and Prevention (CDC), many state and local health departments, and a few commercial laboratories. The Food and Drug Administration (FDA) recently approved a WNV IgM test kit manufactured by Pan-Bio; any accredited laboratory may purchase this kit. Because there may be cross-reactivity with other closely related flaviviruses, a positive WNV IgM test should be confirmed by more specific testing (e.g. plaque reduction neutralization test available only at CDC and a few State public health laboratories). Also, IgM antibodies to WNV may persist for 6 months or longer; a positive test for IgM therefore is not suggestive of an acute infection by WNV unless it is associated with a recent compatible illness. In general, IgM tests should not be used for screening asymptomatic individuals.

WNV polymerase chain reaction (PCR) assays, which detect nucleic acid sequences, also are available through a few commercial laboratories for diagnosing WNV infection. WNV nucleic acid amplification tests (WNV-NAT) can detect viremia early in the course of infection before antibodies are produced. Because viremia may peak before the onset of symptoms and because the majority of infected individuals do not develop symptoms, WNV-NAT may be effective for screening of asymptomatic individuals. Nucleic acid tests manufactured by Roche and Gen-Probe currently are in use under Investigational New Drug applications (IND) for screening blood donors. False positive and false negative results may occur. The investigational protocols include confirmatory testing of initially reactive samples. All civilian blood donations in the U.S. have been screened with WNV-NAT since July 14, 2003.

No specific therapy has been found and the treatment of WNV illness is supportive. Omr-IgG-am,^TM an Israeli source intravenous immunoglobulin containing high titers of WNV neutralizing antibodies, is currently under Phase I/II study to assess its safety and efficacy in treating patients with, or at high risk for progression to WNV encephalomyelitis. Further information about this randomized, placebo-control trial sponsored by the National Institutes of Health is available on the Internet at www.clinicaltrials.gov.

Screening of Organ Donors and Recipients

The nucleic acid tests manufactured by Roche and Gen-Probe are now available for investigational use in screening organ and tissue donors; the specimen must be obtained while the donor's heart is still beating. There still are some factors that may make WNV-NAT screening impractical for use in decision-making about organ acceptance and counseling of potential recipients:

Under the current INDs, WNV-NAT is performed at a limited number of testing sites. In addition, only a limited number of these sites have expressed interest in testing samples from organ donors.
Many of the testing sites use a mini-pool format to perform the initial screening. If the mini-pool is reactive, the component samples then are tested individually to identify the reactive sample(s). A single donor format is preferable for screening organ donors.
Although it may take as little as 4-6 hours to actually perform the WNV-NAT, the turn-around from the time that the donor blood sample is drawn until the result is reported back to the hospital may be 24 hours or longer. This delay is due to factors such as transport of the sample to a distant site, validation steps in the investigational protocol, and procedures for reporting results. Some testing sites may be able to provide faster turn-around.
For non-urgent living donor transplants, the long turn-around time should not pose a problem. However, for deceased donors, it is likely that some or all of the organs will have been transplanted prior to availability of the screening test result.

Despite these possible delays, a reactive test result reported after the organs have been transplanted has some value for counseling and monitoring the recipients, and potentially for the administration of a particular therapy (e.g. Omr-IgG-am^TM) should one be available.

Given the practical limitations of using these screening tests and given that they are still investigational, HRSA does not maintain that screening of all organ donors with WNV-NAT should be required at this time. Once a WNV-NAT is licensed and more widely available, the appropriateness of required screening should be reassessed. An OPO that desires to pursue use of one of the investigational tests to screen organ donors should contact a testing site and negotiate with the investigator at that site the cost, logistics of sample delivery and result reporting, and turn-around time (see Attachment A for list of sites).

Recommendations

HRSA encourages the following measures:

Defer potential donors with encephalitis, meningitis, or flaccid paralysis of undetermined etiology who resided in geographic areas with known human WNV activity (Consult the State or local health department for up-to-date information on human WNV activity in the particular geographic area.)
Exercise a high index of suspicion of WNV infection if an organ transplant recipient develops a febrile illness. Perform a WNV IgM test and a WNV-NAT if WNV infection is clinically suspected.
Consider screening of living donors with WNV-NAT as close to the time of donation as possible.

If WNV-NAT is performed on potential donors, HRSA recommends the following measures in response to reactive WNV-NAT results:

For Deceased Donors

1. If the donor WNV-NAT is reactive, and the organs have not been transplanted:

Consider transplanting the organs only if the potential recipient has an emergent, life-threatening illness requiring transplantation when no other organs are available and no other lifesaving therapies exist.
Inform the potential recipient of the risk and potential consequences of acquiring WNV infection.
Consider enrolling the recipient in a clinical trial of Omr-IgG-am^TM if the recipient develops symptoms suggestive of WNV infection and the recipient meets trial eligibility criteria.

2. If the donor WNV-NAT is reactive, and the organs already have been transplanted:

Inform the recipient of the risk and potential consequences of acquiring WNV infection.
Monitor the recipient closely for development of fever, headache, meningitis or encephalitis of unexplained etiology, and perform a WNV IgM test and a WNV-NAT if WNV is clinically suspected.
Consider enrolling the recipient in a clinical trial of Omr-IgG-am^TM if the recipient develops symptoms suggestive of WNV infection and the recipient meets trial eligibility criteria.

For Living Donors

1. If the donor WNV-NAT is reactive, and the transplant is non-urgent:

Defer the donor for 28 days

2. If the donor WNV-NAT is reactive, and the potential recipient has an emergent, life-threatening illness requiring transplantation when no other organs are available and no other lifesaving therapies exist:

Inform the recipient of the risk and potential consequences of acquiring WNV infection.
Monitor the recipient closely for development of fever, headache, meningitis or encephalitis of unexplained etiology, and perform a WNV IgM test and a WNV-NAT if WNV is clinically suspected.
Consider enrolling the recipient in a clinical trial of Omr-IgG-am^TM if the recipient develops symptoms suggestive of WNV infection and the recipient meets trial eligibility criteria.

Additional Resources

The FDA Guidance for Industry: Revised Recommendations for the Assessment of Donor Suitability and Blood and Blood Product Safety in Cases of Known or Suspected West Nile Virus Infection can be found on the FDA web site at http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/blood/ucm074111.htm.

Published article: Martha Iwamoto, M.D., M.P.H., Daniel B. Jernigan, M.D., M.P.H., Antonio Guasch, M.D., et al. Transmission of West Nile Virus from an Organ Donor to Four Transplant Recipients. The New England Journal of Medicine. 2003;348:2196-2203.

Information about WNV clinical studies at www.clinicaltrials.gov.