Respiratory Insufficiency Correlated Strongly with Mortality of Rodents Infected with West Nile Virus

John D. Morrey,Venkatraman Siddharthan,Hong Wang,Jeffery O. Hall,Tian Wang

doi:10.1371/journal.pone.0038672

Abstract

West Nile virus (WNV) disease can be fatal for high-risk patients. Since WNV or its antigens have been identified in multiple anatomical locations of the central nervous system of persons or rodent models, one cannot know where to investigate the actual mechanism of mortality without careful studies in animal models. In this study, depressed respiratory functions measured by plethysmography correlated strongly with mortality. This respiratory distress, as well as reduced oxygen saturation, occurred beginning as early as 4 days before mortality. Affected medullary respiratory control cells may have contributed to the animals' respiratory insufficiency, because WNV antigen staining was present in neurons located in the ventrolateral medulla. Starvation or dehydration would be irrelevant in people, but could cause death in rodents due to lethargy or loss of appetite. Animal experiments were performed to exclude this possibility. Plasma ketones were increased in moribund infected hamsters, but late-stage starvation markers were not apparent. Moreover, daily subcutaneous administration of 5% dextrose in physiological saline solution did not improve survival or other disease signs. Therefore, infected hamsters did not die from starvation or dehydration. No cerebral edema was apparent in WNV- or sham-infected hamsters as determined by comparing wet-to-total weight ratios of brains, or by evaluating blood-brain-barrier permeability using Evans blue dye penetration into brains. Limited vasculitis was present in the right atrium of the heart of infected hamsters, but abnormal electrocardiograms for several days leading up to mortality did not occur. Since respiratory insufficiency was strongly correlated with mortality more than any other pathological parameter, it is the likely cause of death in rodents. These animal data and a poor prognosis for persons with respiratory insufficiency support the hypothesis that neurological lesions affecting respiratory function may be the primary cause of human WNV-induced death.

Highlights

West Nile virus infection is fatal in less than 1% of human cases [1]
Different disease states were evaluated as possible causes of death in West Nile virus (WNV)-infected rodents, i.e., cerebral edema, starvation, seizures, and vital organ failure due to disease of the organ or autonomic nervous system failure
Brain edema was not the cause of death since there was no difference in the ratio of wet/total brain weight between moribund WNV-infected and sham-infected hamsters (Figure 1A)

Summary

Introduction

West Nile virus infection is fatal in less than 1% of human cases [1]. The fatality rate in experimentally infected mice and hamsters is typically reported to be between 20–80% [2,3,4]; rodents provide an opportunity to investigate the cause of WNV death that might be applicable to human fatality. WNV encephalitis stage includes symptoms such as acute flaccid paralysis, limb weakness, and poliomyelitis-like syndrome, which probably reflect infection in motor neurons of the anterior horn of the spinal cord. Respiratory insufficiency is recognized to have a poor-prognosis in human with West Nile neurological disease WNND [8]. In a cohort of 54 patients approximately 1.5 years after WNV diagnosis, a minority of subjects had persistent neurocognitive deficits. These clinical findings suggest involvement of areas of the CNS controlling motor functions and possibly in areas controlling higher-order central nervous system (CNS) functions

Methods

Results

Conclusion