Eight years ago, a mysterious virus hit New York City. It caused encephalitis in eight patients at Flushing Hospital in Queens, who all lived within a two-mile radius of each other. After some confusion about the origin of the virus, researchers soon realized that these were, in fact, the first reported cases of West Nile virus (WNV) in North America.
In the following years, the virus rapidly spread west, with human infections following in areas where animal infections were reported the year before. In 2002, the epidemic soared to 4,156 cases nationwide, from a mere 66 the year before. Reports started to come in of infections that were spread by blood transfusions from subclinically infected people. Baxter Scientific, a healthcare products company, conducted a study to ensure that its plasma products weren't also contaminated with WNV.
Thomas Kreil and his colleagues at Baxter led that study and gathered the intravenous immunoglobulin (IVIG) therapy lots, each a mix of plasma from several thousand donors. They found that Baxter's blood products were clear from infectious agents (Transfusion, 43:1023-8, 2003). But the experiment led them to think about something else.
Kreil and his colleagues realized that if most patients were surviving the virus, they were probably making protective antibodies against it. So Kreil went back and tested the IVIG lots collected across the United States and in Europe. The IVIG lots from Europe showed no neutralizing effect, which wasn't surprising given the low incidence of WNV cases there. But US lots were a different story.
The United States had an average neutralizing titer of about 1.4, but the titers of individual lots from different geographic areas were as much as 400-fold different from one another. "We were surprised by the neutralizing capacity," says Kreil (J Infect Dis, 196:435-40, 2007). Since the pooling centers collect serum from overlapping states, he can't tell which states are home to the highest titers, although he suspects the southwest, which saw a high incidence of WNV cases.
While the United States reported around 24,000 cases of West Nile since 1999, as many as 80% of WNV infections show no symptoms of disease. Based on other studies (Busch et al., Emerg Infect Dis, 12:395-402, 2006), Kreil estimates that the actual number of US infections may be closer to 2.5 million. Could serum from these "immunized" donors treat the few who develop WNV symptoms? Patients likely to be at risk for severe cases of WNV may be the elderly and those with compromised immune systems. For them, new treatments are needed. Currently, says Kreil, "WNV infections are treated with supportive care - that's it."
In the second part of their investigation, Kreil and his colleagues tested the IVIG from the United States in a mouse model, and found that the mice injected with IVIG had a 90% survival rate when challenged with a usually lethal dose of WNV. In contrast, only 10% and 20% of control and European IVIG-treated mice survived.
Using IVIG to treat and prevent infection is an attractive proposition, but for viral infections, "there just aren't enough data to support it," says Kathleen Sullivan, who studies and treats immune deficiency at Children's Hospital of Philadelphia. Sullivan says that most clinicians save IVIG for treatment of bacterial infections or as a weekly prophylactic treatment for immune-compromised patients. "People have tried HIV antibodies for the last 20 years, and there is a lack of clinical efficacy," Kreil concurs. He notes that part of the reason is that certain viruses require a cellular immune response, whereas others require antibodies. "HIV, it appears, requires both," says Kreil. It's not clear if WNV - or other more deadly viruses, such as H5N1 - will behave differently from HIV in the body. His mouse study suggests that it might. Kreil is thinking about clinical trials, to determine if the same pattern holds true in humans.