Correspondence

Cytokine Induction after Laboratory-Acquired West Nile Virus Infection

N Engl J Med 2009; 360:1260-1262March 19, 2009

Article

To the Editor:

We report a case of laboratory-acquired West Nile virus infection after a needlestick injury in a 29-year-old, immunocompetent female scientist in South Africa, who was not infected with the human immunodeficiency virus. The needlestick exposed the scientist to cell-culture fluid containing the neuroinvasive-lineage 2 West Nile virus strain SPU93/01 at a tissue culture infectious dose (the concentration that has a cytopathic effect in 50% of cultures inoculated) of 50 copies per cubic millimeter. The strain had previously been isolated from a patient with nonfatal encephalitis in South Africa.1,2 Blood specimens obtained on the day of infection (upon reporting the accident to the occupational health officer) and from the day after symptoms started up until recovery provide the rare opportunity to investigate cytokine expression from the time of infection to recovery. Institutional-review-board approval and informed consent were obtained.

Symptoms, which developed on day 7 after infection, included backache, neck stiffness, malaise; on day 8, the patient had rash, mild fever, and symptoms of meningoencephalitis, including neck stiffness, severe headache, and photophobia, and on day 9, she had arthralgia, plus tenderness of the spleen and liver. Symptoms persisted for 19 days and were biphasic. Second-phase symptoms included headaches, malaise, and arthralgia. Recovery was complete by day 26, but photosensitivity persisted for several months. The patient had received yellow fever virus vaccine (YF-VAX, Aventis Pasteur) 6 months before the accident, with satisfactory seroconversion (see the Supplementary Appendix, available with the full text of this letter at NEJM.org), contradicting the notion that the vaccine may protect patients from West Nile virus disease. This case confirms the neurovirulent potential of this particular lineage 2 strain in humans, complementing reports of severe disease associated with lineage 2 strains in countries in which the strains are endemic.1,3

Levels of 16 cytokines with pathogenic and protective potential were measured in serum collected on days 0, 8, 9, 10, 11, 13, 16, and 26 after infection (Figure 1Figure 1Cytokine Expression in Serum Samples Obtained from a Patient with a Neuroinvasive Infection with Lineage 2 West Nile Virus., and the Supplementary Appendix). The most markedly changed levels, relative to the levels in a serum-negative control specimen obtained from the patient 5 years after the accident, were noted for interferon-α on days 8, 9, and 13 after infection; interferon-inducible protein-10 (IP-10) on day 8; and interleukin-13, the level of which was increased from day 0 to day 11. Levels of the proinflammatory cytokines interleukin-6 and interleukin-8 were increased moderately on day 16, as was the interleukin-15 level on day 11. Levels of tumor necrosis factor α (TNF-α) and interleukin-5 were increased slightly on day 11, whereas no significant change from control levels was noted for eotaxin, interferon-γ, macrophage inflammatory protein (MIP)-1α, MIP-1β, RANTES (regulated upon activation normal T-cell expressed and secreted), interleukin-4, interleukin-9, or interleukin-10.

A significant increase in interferon-α levels may contribute to the successful control of neurologic infection with West Nile virus. Experimental treatment with synthetic interferon alfa-2b in patients with encephalitis caused by West Nile virus resulted in improvements in mentation and speech and eventual recovery.4 IP-10 deficiency was associated with an increase in viral burden in the brain and elevated morbidity and mortality in mice infected with West Nile virus, suggesting a potential protective role.5 Interleukin-13 promotes a type 2 helper T cell response and B-cell growth but has been associated with pathogenesis in patients infected with certain flaviviruses. A lack of interferon-γ and TNF-α induction was observed in our patient. Since interferon-γ may prevent dissemination of West Nile virus into the central nervous system, this cytokine may be important in preventing neuroinvasive disease in humans.

The cytokines identified in the current study may serve as additional targets for the development of therapeutic interventions by suppressing proinflammatory responses (by interleukin-13, interleukin-6, and interleukin-8) or supplementing type 1 helper T cell responses (TNF-α, interferon-γ and interferon-α). The role of IP-10 in pathogenesis or viral control requires further investigation.

Marietjie Venter, Ph.D.
University of Pretoria, Pretoria 0001, South Africa
marietjie.venter@up.ac.za

Felicity J. Burt, Ph.D.
University of the Free State, Bloemfontein 9300, South Africa

Lucille Blumberg, M.B., Ch.B., M.Med.
National Institute for Communicable Diseases, Sandringham 2131, South Africa

Heidi Fickl, Ph.D.
University of Pretoria, Pretoria 0001, South Africa

Janusz Paweska, D.V.Sc., Ph.D.
Robert Swanepoel, B.V.Sc., Ph.D.
National Institute for Communicable Diseases, Sandringham 2131, South Africa

Supported by a grant (2006042100015) from the National Research Foundation of South Africa.

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Citing Articles (2)

Citing Articles

1. 1

   Marietjie Venter, Robert Swanepoel. (2010) West Nile Virus Lineage 2 as a Cause of Zoonotic Neurological Disease in Humans and Horses in Southern Africa. Vector-Borne and Zoonotic Diseases 10:7, 659-664
   CrossRef

2. 2

   Iglika K. Djoumerska-Alexieva, Jordan D. Dimitrov, Elisaveta N. Voynova, Sebastien Lacroix-Desmazes, Srinivas V. Kaveri, Tchavdar L. Vassilev. (2010) Exposure of IgG to an acidic environment results in molecular modifications and in enhanced protective activity in sepsis. FEBS Journal 277:14, 3039-3050
   CrossRef