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Testimony of
Sidney Andrew Houff, MD, PhD
Professor and Chairman
Department of Neurology
Director, Neuroscience and Aging Institute
Loyola
University
Medical
Center
Maywood
,
IL
To
the
Senate Health, Education, Labor, and Pensions Committee
and the
Governmental Affairs Subcommittee on Oversight of Governmental
Management, Restructuring and the
District of Columbia
The
outbreak of West Nile Virus (WNV) infections in the
United States
has challenged government, medical and veterinary resources.
The rapid geographic expansion and persistence of the
virus in newly established enzootic areas in
North America
indicate WNV has become permanently established in the
United States
(1). Renewed
efforts to understand human disease and the biology of the
virus will be necessary as we are likely to continue to
experience outbreaks of WNV for the foreseeable future.
I
have divided my testimony into two areas.
I will first address the clinical features of WNV
infections in humans including our experience in 2002.
I will then turn to the biology of WNV.
Here I will describe additional studies of WNV that
will be required to address the needs of populations at risk
of infection, including domestic and wild animals.
The
response of the Centers for Disease Control and Prevention and
the Illinois Department of Health have been outstanding.
Both federal and state agencies have provided needed
information in a timely manner to physicians and other health
care providers grappling with patients with WNV.
Essential information has been presented on the
Internet, allowing easy access to health care providers.
In
Illinois
, we have been able to access up to date information on human
and animal infections. CDCP
and IDPH sites have offered valuable information for
submission of specimens for testing and other essential
information needed by health care providers.
At
Loyola
University
Medical
Center
various avenues of communication have been used to provide the
latest information on WNV to attending and resident
physicians, nurses, and allied health personnel.
A “high index of suspicion” for WNV infection has
been instituted to assure cases of infection are not
overlooked. The
Department of Neurology at
Loyola
University
Medical
Center
has developed protocols to assure WNV infection is considered
in the differential diagnosis of patients with neurological
syndromes other than meningitis, encephalitis and
meningoencephalitis.
Clinically,
West Nile Virus infection usually results in an unapparent
infection in humans (1). A
serological survey for WNV antibodies conducted in
New York City
in 1999 found that approximately 20% of persons infected with
WNV had developed
West Nile
fever. Most
patients who developed symptoms often complain of the sudden
onset of fever, malaise, anorexia or loss of appetite, nausea,
vomiting, eye pain, headache, muscle pain, skin rash and
lymphadenopathy (swollen lymph nodes).
The risk of developing serious neurological disease is
based on experience in previous WNV outbreaks in
Romania
,
Israel
and
New York City
. In the Romanian
outbreak of 1996, 1 in 140 to 320 infections led to disease of
the nervous system. In
New York
, 1 in 150 infections resulted in neurological disease.
The experience in
Israel
is similar to that seen in
New York City
. These findings
suggest that the WNV strain circulating in the
United States
and
Israel
is associated with a higher rate of neurological infections.
Meningoencephalitis, encephalitis and meningitis have
been the predominant forms of neurological disease associated
with WNV infection (2). Profound
muscle weakness and muscle pain have been a prominent feature
in WNV outbreaks in the
United States
(3).
Our
experience suggests that nervous system infection with WNV
during 2002 may have several unusual features.
The profound myalgias encountered in
New York City
in 1999 and subsequent outbreaks in 2000 and 2001 have not
been a prominent feature of our cases in 2002.
We have also encountered involvement of the optic nerve
and basal ganglia more frequently than expected.
Whether or not our experience reflects a true change in
the clinical features of WNV meningoencephalitis must await
more extensive study of the clinical features of cases seen in
2002. If the
clinical features of WNV meningoencephalitis are indeed
changing, it will be important to recognize these changes as
we confront future outbreaks of WNV infection.
Treatment
for West Nile Virus infection has been limited to supportive
measures to control cerebral edema, seizures, and systemic
complications of the infection.
Ribavirin in high doses and Interferon-a
are effective in vitro (4).
Control studies have not yet been completed for either
agent. One patient
has been treated with intravenous gamma globulin containing
high antibody titers to WNV (5).
The efficacy of intravenous gamma globulin cannot be
determined from this one case.
Hyper
immune gamma globulin with high antibody titers to WNV could
offer an additional treatment for WNV neurological infections.
Antiviral antibody therapy has been shown to be
effective in experimental and human virus infections of the
central nervous system. Antibody
treatment of mice with Sindbis virus infection of the brain
results in clearing of virus from neural cells.
Humans with hypogammaglobulinemia who develop central
nervous system enterovirus infections have been successfully
treated with hyper immune gamma globulin.
Gamma globulin therapy can be instituted without the
long delays required for drug development.
Individuals infected with West Nile Virus during the
2002 outbreak are likely to have high titers of antiviral
antibodies in the serum. These
patients could serve as donors for hyper immune gamma globulin
that can then be stored for use in future outbreaks of WNV
infection. The
genetic stability of WNV suggest antibodies generated during
the 2002 outbreak should be effective in neutralizing WNV in
outbreaks in the near future.
West Nile
virus presents a serious threat to human health for several
reasons. Many,
including some members of the news media, underestimated the
magnitude of the problem at the beginning of the epidemic when
only a small number of human cases had appeared.
The current 424 human cases and 22 deaths in
Illinois
illustrate the difficulty in predicting the seriousness of
these epidemics.
Experience
over the last 4 years suggest that we are likely to see
continued outbreaks of WNV infection.
The spread of the virus across the
United States
will likely be followed by new outbreaks of WNV infection in
humans and animals. Spread of the virus to
Canada
, Central and
South America
by migrating birds will place additional human populations at
risk of disease. The
WNV strain circulating in the
United States
appears to have a higher rate of neurological infections than
those seen in
Romania
and other areas of the world.
Viral evolution can result in changes in virulence,
disease pattern, host cell range, and other properties of the
virus. While it is
true that viruses transmitted by insects to mammals are
constrained in their ability to mutate, the possibility of
changes in the virus are real and require study.
Transmission of WNV by unusual means such as blood and
organ transplantation are of uncertain significance at the
present time. However,
since most patients with WNV infection are asymptomatic, these
individuals would not provide a history to blood collection
agencies that would preclude their donation of blood and blood
products. It is
important, therefore, to determine the risk of transmission
from patients with asymptomatic infection to better assess the
risk to the blood supply.
Although
much is known about arthropod transmitted virus infections in
humans, we also have much to learn.
The epidemiology, wildlife enzootic cycles, and the
pathogenesis of animal and human disease of WNV are important
areas requiring further study.
The enzootic cycle of virus circulation is a critical
factor in the biology of virus transmission.
A rural or sylvatic cycle of wild birds and
ornithophilic mosquitoes and an urban cycle with domestic
birds and mosquitoes feeding on humans and birds support WNV
transmission.
Illinois
offers an excellent site to study wildlife factors involved in
outbreaks of arthropod transmitted neurological diseases.
The state has experienced significant outbreaks of both
Saint Louis Encephalitis virus and WNV infection.
Elucidation of the factors that support these outbreaks
in
Illinois
may provide valuable information that will be applicable in
other regions of the country.
The
molecular biology of WNV also needs further study (6).
The strain of WNV circulating in the
United States
originated in
Israel
. It has several
unique properties. For
instance, high avian mortality has only been encountered in
outbreaks of WNV in the
United States
and
Israel
. The rate of
neurological disease also appears to be higher in urban
outbreaks of WNV compared to those in rural areas.
The viral properties responsible for these and other
features of WNV infection are only beginning to be understood.
Continued efforts are needed to define viral factors
associated with virulence, host cell range, and the
possibility of viral persistence.
The evolution of WNV strains in nature may help us
understand how viruses “jump” to other species and present
new threats to human health.
The immune response to WNV infection is also an
important area of future study that will be important in
attempts to control virus replication in infected patients.
A
multidisplinary approach will be needed if we are to
understand the challenges of outbreaks of arthropod
transmitted infections such as WNV.
The Conversation Medicine Center of Chicago is a
collaborative effort of
Loyola
University
Medical
Center
, the Brookfield Zoo, and the
University
of
Illinois
that includes physicians, veterinarians, entomologists, field
biologists and others. The
Center is currently examining areas of research that would
benefit from the collaborative expertise of its members.
The enzootic cycle for WNV is one important area of
interest. Isolation
of WNV from squirrels and dogs suggest the virus is spreading
to other mammalian species during the 2002 outbreak.
Infection of other mammalian species has been noted in
past outbreaks. In
most species WNV infection does not result in titers of WNV
sufficient to serve as a source of infection for mosquitoes or
ticks. However,
lemurs in
Madagascar
and several reptile species have been shown to develop virus
titers in the blood that are sufficient to infect mosquitoes.
Surveys need to be conducted to determine which species
have been infected during the 2002 outbreak and if any support
virus replication to levels sufficient to infect mosquitoes.
If such species are found, the range of mosquito
species infected with WNV may increase.
Additional studies of WNV infection in mosquitoes,
evolution of WNV strains in the laboratory and nature, and the
factors associated with spread of infection to incidental
hosts are currently being discussed.
We are currently finishing a submission to study the
pathogenesis of WNV infection in the brain in experimental
animals. We
believe the multidisplinary approach used by the Conservation
Medicine Center of Chicago and other such groups around the
country offer the best opportunity to successfully address the
challenges of WNV and other vector borne diseases.
The
experience gained meeting the challenges of WNV outbreaks will
improve our readiness to successfully address the challenges
of bioterroism. Many
of the same technological and epidemiological approaches used
in the investigation of the WNV outbreak will be helpful in
the event we are attacked using similar agents.
I would also suggest consideration should be given to
reopening surveillance laboratories, such as those supported
by the Rockefeller Foundation.
These laboratories closed during an era of increased
international travel and increased risk of emerging
infections, provided vital information for the study and
control of insect borne viruses.
Reestablishing surveillance laboratories that can warn
the emergence of known viruses or new viruses will be
invaluable in the future.
In
closing, I wish to thank the committees for the opportunity to
present my views. I
look forward to answering any questions you may have at the
hearing on
September 24,2002
References:
- Peterson
LR, Marafin AA:
West Nile
Virus: A Primer for the Clinician.
Ann Intern Med 2002;137:173-179
- Klein
C, Kimiager I, Pollak L, et al.: Neurological features of
West Nile Virus infection during the 2000 outbreak in a
regional hospital in
Israel
. J of Neurol
Sci 2002;200:63-66
- Weiss
D, Carr D, Kellachan J, et.al.: Clinical Findings of West
Nile Virus Infection in Hospitalized Patients, New York
and New Jersey, 2000.
Emerg Inf Dis 2001;7:654-658
- Anderson
JF, Rahal JJ: Efficacy of interferon alpha-2b and
Ribavirin against
West Nile
virus in vitro [Letter]
Emerg Inf Dis 2002;8:107-108
- Shimoni
Z, Niven MJ, Pitlick S, Bulvik S: Treatment of
West Nile
Virus Encephalitis with Intravenous Immunoglobulin.
Emerg Inf Dis 2001;7:759
- Brinton
MA: The Molecular Biology of
West Nile
Virus: A New Invader of the
Western Hemisphere
. Annu Rev
Microbiol 2002;56:371-402
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