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West Nile Virus Neutralization by Plasma Immunoglobulin
Abstract & Commentary
By Joseph F. John, Jr., MD, FACP, FIDSA, FSHEA, Associate Chief of Staff for Education, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, SC., is Associate Editor for Infectious Disease Alert.
Dr. John is a consultant for Cubist, Genzyme, and bioMerieux and is on the speaker's bureau for Cubist, GSK, Merck, Bayer, and Wyeth.
Source: Planitzer CB, et al. West Nile Virus neutralization by US plasma-derived immunoglobulin products. J Infect Dis2007;196:435-440.
There is no proven therapy for infection due to the mosquito-borne flavivirus West Nile Virus, introduced to a fully susceptible U.S. population in 1999. There have been more than 2 million cases since its introduction and the spectrum of disease has expanded to include diverse neurological manifestations. Nevertheless, most infection due to WNV is asymptomatic so it is anticipated that, with time, that an increasing proportion of the American population will have been infected.
Most of the plasma distributed globally as fractionated products (including immunoglobulin) comes from the United Staes. So, with an ever-increasing proportion of the U.S. population exposed to WNV, we would expect a higher rate of neutralizing antibody to WNV in U.S. immunoglobulin lots compared, for example, to European-derived immunoglobulin.
Workers at Baxter BioScience in Vienna, Austria, sought to 1) determine if the concentration of WNV neutralizing antibody in U.S. vs European immunoglobulin lots and 2) determine the potential for WNV antibody in commercial preparations of immunoglobulin would be protective in a WNV animal model.
Planitzer et al used a WNV isolated from a snowy owl to determine neutralizing antibody titres against an inoculum of 10,000 TCID50 for various immunoglobulin lots from Europe and the United States. Female BALB/c mice infected with WNV were treated subcutaneously with either U.S. or European immunoglobulin, neutralizing titers of 2.4 or 0.1 respectively.
Results of these experiments showed that U.S.-sourced products averaged titers of 1.4 but they ranged from 0.3 to 2.9. The reason for this broad range emerged when state-by-state incidence analyses were performed. The states with > 5 cases per 100,000 were Nebraska, South Dakota, North Dakota, Wyoming, Colorado, and Idaho. Almost no cases from the Eastern United States emerged from these state-specific analyses.
Using a mouse model and a sc challenge of 100,000 TCID50, only 10% of mice would be expected to survive. When mice were treated with the U.S.-derived product (Gammagard Liquid/KIOVIG with a neutralization titre of 2.4) 90% of mice survived as compared to only 20% of mice treated with the European-derived product and to 10% survival in controls. (P < 0.001 vs control).
The major findings of this study supported by Baxter BioScience was that U.S.-based immunoglobulin had substantial titers of WNV neutralizing antibody and that immunoglobulin protected WNV-infected mice. To make a leap of faith and apply these findings by treating WNV-infected patients with immunoglobulin may at first glance seem reasonable.
The 2 reports suggesting that immunoglobulin may be effective at treating WNV (those quoted by the authors) are more than several years old [J Infect Dis 2003;188:1-4; Emerg Infect Dis 2001;7:759]. Clinical trials are now underway to evaluate more thoroughly the efficacy of Omr-IgG-am in patients with or at high risk for WNV disease (http://www.clinicaltrials.gov).
If physicians choose to use commercial U.S.-derived immunoglobulin to treat WNV-infected patients, they would like to assume the highest possible titre of anti-WNV antibody in these preparations. Further geographic seroanalysis is necessary to verify the findings of this report that some states have significantly higher titres. Moreover, it would be very helpful if Baxter BioScience itself could provide some real-time information to prescribers about the neutralization capacity of immunoglobulin lots available for use. The authors touch on this idea but stop short of suggesting that the company could provide a rapid response as a clinical service. If such a rapid response is not economically feasible, perhaps those lots distributed for use could be designated of high, medium, or low anti-WNV antibody.
Of course, any empirical therapy with IVIG should not include European lots since, as shown in this study, those lots have neither adequate neutralization titres nor are they protective in the mouse WNV. As WNV spreads, as this summer's trends suggest, there may be value in WNV serological testing of immunosuppressed patients. Substitution therapy with IVIG for immunodeficient individuals would ideally be done with lots with good neutralization levels.
West Nile Virus is a relatively new virus for North American populations. Our strategies for prevention, prophylaxis and therapy of WNV are evolving with the virus. Creative discoveries like the one by Planitzer et al will be needed to deal more effectively with disease due to WNV, particularly when it presents in its more severe forms.