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Introduction Though picornaviruses are named for their small (ÒpicoÓ
+ ÒRNAÓ =
picorna) size,
they include a large and diverse array of viruses Ð over 200 serotypes. These viruses can be traced all the way
back to Ancient Egyptian records of polio epidemics, but are still around and
cause a menagerie of diseases today, from polio to hepatitis A to the Òcommon
cold.Ó ¯
Picornaviruses
contain positive
sense, single-stranded RNA that is approximately 7-8 kilobases long. ¯
The
genome is monopartite and polyadenylated at the 3Õ end, but has a VPg
protein at the 5Õ
end in place of a cap. ¯
The
viral RNA is infectious and replication takes place in the cytoplasm. ¯
The
virus has an IRES (Internal Ribosomal Entry Site) which distinguishes it from many other
RNA viruses. ¯
The
virus is naked
with an icosahedral capsid. ¯
The triangulation
number is 3, while
the capsid has four unique proteins: VP1, 2, 3, and 4. ¯
The
capsid is one of the smallest of all viruses with a diameter of only 27-30nm. ¯ Translation and cleavage of viral polypeptides produces eleven distinct proteins. |
There are
four picornavirus genera that cause human disease:
¯
Enteroviruses
¯
Rhinoviruses
¯
Hepatovirus
¯
Parechoviruses
¯
Enteroviruses (more than 60 known serotypes):
á Poliovirus 1-3
á Coxsackie A1-24
á Coxsackie B1-5
á ECHOvirus 1-7, 9, 11-21, 24-27, 29-33
á Enterovirus 68-71
á Viluisk human encephalomyelitis virus
v Enteroviruses are transmitted through the fecal-oral route and are highly
communicable. Generally, viral
shedding persists long after symptoms cease so that transmission occurs
frequently, particularly in schools, childcare centers, and with close
contact. Enteroviruses cause a
wide variety of syndromes that range in severity from mild and non-neurologic
to neurologic, paralytic, and fatal:
á Assorted enteroviral exanthems (rashes)
á Acute hemorrhagic conjunctivitis (AHC)
á Hand, foot, and mouth disease
á Poliomyelitis
á Encephalitis
á Summer colds
á Herpangina
á Myocarditis
á Pericarditis
á Meningitis
á Pleurodynia
á Myalgia
For
more information on poliomyelitis, see the Polio Viral Profile
below.
v Rhinoviruses are transmitted through the respiratory route and replicate in the nose
(ÒrhinoÓ). The many serotypes are divided into ÒmajorÓ and
ÒminorÓ groups and all cause a similar syndrome Ð the Òcommon cold.Ó The large number of serotypes allows many
rhinovirus infections to occur in one person over time, since immunity only
develops for one serotype and each newly acquired rhinovirus causes a new
Òcold.Ó About half of all colds
can be attributed to rhinoviruses, particularly those that occur in the winter.
v Hepatovirus is the lone virus in its own genus. The virus is transmitted through the fecal-oral route, which is manifested most often by ingestion of contaminated food or water. The resulting disease is hepatitis A. For more information, see the Hepatitis A Viral Profile below.
v Parechoviruses are limited to two serotypes of human parechovirus, formerly known as
echovirus 22 and 23. These viruses
are closely related to the ECHOvirus group, a name that refers to Enteric Cytopathic
Human Orphan virus.
Neither the ECHOviruses nor the Parechoviruses are now considered orphan
viruses, but the name remains unchanged.
Sources:
Poliomyelitis (commonly known as ÒpolioÓ) is an infectious disease caused by polioviruses 1, 2, and 3 in the enterovirus genus of the picornaviridae viral family. From a public health standpoint, it is the most important of the enteroviruses. Like all enteroviruses, poliovirus is transmitted through the fecal-oral route, either directly from person-to-person or indirectly through contaminated water sources. It is characterized by permanent paralysis due to spinal nerve damage and muscular wasting, particularly in young children who are most commonly affected.
Poliovirus
has been a primary subject of medical research and public health intervention
for most of the 20th century, as it continues to devastate communities
worldwide. Though the summer
epidemics of the 1940s and 1950s caused panic and widespread paralysis in the
United States and Western Europe, polio has since become more of a concern in
less developed countries. Since it
can be transmitted both indirectly though contaminated food and water and
directly from person-to-person, polio prevalence is highest in countries with
poor sanitation and among children who generally have poor hygiene
practices. Indeed, two thirds of
cases occur in children under age 9 and nearly all cases occur in less
developed countries. As
development improves sanitary conditions in these countries, polio incidence
drops significantly. As children
are not exposed to the virus during childhood, adults may become infected when
exposed at an older age. These
adult cases carry a much higher risk of paralytic poliomyelitis, which is a
serious concern that accompanies the positive trends in polio reduction.
Currently,
there are only a handful countries in which polio is endemic (countries which
have not successfully eliminated the virus). India, Pakistan, and Nigeria have 98 percent of polio cases
in the world, with particular regions most affected: Uttar Pradesh and Bihar in
India, North West Frontier Province in Pakistan, and Kano in Nigeria. Egypt, Niger, and Afganistan are also
endemic. At the time of the World
Health Assembly in 1988, there were more than 125 countries with significant
poliovirus prevalence which paralyzed more than 1000 children every day. At the end of 2003, reports indicated
that there were only 677 cases during the whole year Ð a reduction of 99
percent from 1988. This reduction
is due to improvements in sanitary conditions in combination with widespread
vaccination efforts. By 1993, wild
poliovirus was eliminated from the Western Hemisphere and many parts of the
world:
Images: WHO Polio Eradication: http://www.polioeradication.org/vaccines/polioeradication/all/global/default.asp
Poliovirus enters the body orally and makes its way
to the upper gastrointestinal tract where it replicates in the epithelial and lymphoid
tissues. The incubation period
between infection and clinical presentation may last anywhere from 4-35 days,
though it usually lasts 7-14 days.
Once the virus reaches the gastrointestinal tract, it can spread to
other locations in the body, including the central nervous system. PoliovirusÕ unique ability to cross the
blood-brain barrier allows it to travel to the peripheral spinal nerves Ð the
axons and perineural sheaths.
Anterior motor neurons are particularly vulnerable to infection. Viral infection induces an inflammatory
response that can cause extensive neural destruction. This destruction is irreparable and often leads to paralysis
and muscular wasting. After
clinical symptoms cease, the virus may persist in the body for up to four weeks.
Though
polio infection can be devastating in its paralytic form, 9 out of 10
infections are actually asymptomatic or have symptoms that are too mild to be
noticed. There are three types of
disease caused by poliovirus:
á Abortive poliomyelitis: a non-specific febrile illness that lasts for 2-3
days without central nervous system involvement; has complete recovery.
á Aseptic meningitis: a non-paralytic poliomyelitis that includes
irritation of the meninges (back pain, neck stiffness), in addition to signs of
abortive poliomyelitis, has complete recovery.
á Paralytic poliomyelitis: a rare disease that occurs in less than 2% of
infections; it often begins with minor illness that appears to improve but then
results in asymmetric flacid paralysis.
In the most severe cases, all four limbs may be paralyzed or the
brainstem may be damaged with cranial nerve paralysis and respiratory muscle
damage. Recovery may begin within
a few days and can last six months, at which point the remaining paralysis is
permanent.
The
disease of greatest concern is paralytic poliomyelitis, since it can be
permanently debilitating.
Generally, acute flaccid (floppy) paralysis of the legs is more common
than the arms. In some cases, more
extensive paralysis results and can reach muscles of the trunk and result in
quadriplegia. Bulbar polio is the
most severe form of paralysis that reaches the brainstem and can impair
breathing, speaking, and swallowing capacity. Death by asphyxiation is possible in such severe cases.
Post-polio
syndrome (PPS) is a condition that occurs in 25-40 percent of polio survivors
from 30-40 years after initial polio disease. Muscles that were damaged in the initial infection may
become weaker and symptoms such as fatigue, joint pain and in some cases forms
of scoliosis may occur. Some
patients may even develop symptoms that resemble Lou GehrigÕs disease
(amyotropic lateral sclerosis Ð ALS).
Post-polio syndrome is not usually life-threatening and does not involve
infectious virus.
Source: The Pink Book, 8th
Edition, pp 90.
Image:
http://www.unicef.org/immunization/index.html
Treatment
for poliovirus infection is non-specific and targets alleviation of symptoms only,
since no effective antiviral treatment is currently available. One anti-picornal drug, pleconaril, is
currently being studied and has been delayed in clinical trials (see ÒDrug
ProfileÓ section for more information).
In symptomatic cases, moist heat and physical therapy can help to
stimulate and relax muscles to improve patient comfort. When paralysis occurs, it is almost
always permanent, since motor nerve damage cannot be repaired. There are cases such as that of runner
Wilma Rudolf in which wasted muscles might be strengthened with additional
stimulation, but recovery is extremely rare. Most paralytic patients lose function of one or more limbs
and often use crutches to assist with walking and daily tasks.
Prevention
of poliovirus infection is possible with improvements in sanitary conditions
and with immunization. Because
poliovirus is often transmitted through water sources, efforts to improve
sewage treatment and to ensure a clean water supply have had very positive
effects in reducing polio prevalence in less developed countries, along with
reductions in many other illnesses.
However, more intervention is required since the virus can also be
transmitted from person-to-person and can then spread rapidly where there is no
immunity.
Prevention
of polio through immunization has been proven to be tremendously successful in
reducing polio incidence for the past 40 years. Development of the inactivated Salk vaccine in 1955 and the
live attenuated Sabin vaccine in 1963 dramatically changed the face of the
polio panic that engulfed the United States in the preceding decades. While both vaccines are effective in
preventing most poliovirus infections, they differ in some characteristics:
á The Salk Vaccine
o Known as ÒIPV,Ó inactivated
o Contains all 3 viral serotypes
o Given in 3 subcutaneous injections
o Has no serious side effects
o Induces antibody response in 98 percent of recipients
o Standard childhood vaccine in the United States and
most developed countries
á The Sabin Vaccine
o Known as ÒOPV,Ó live attenuated
o Contains all 3 viral serotypes
o Given in 3 oral doses
o Induces antibody response in 95 percent of recipients
o Boosters required to maintain antibody levels
o Small risk of vaccine-associated paralytic
poliomyelitis (VAPP) in 1 out of every 2.4 million doses, higher risk with
immunodeficiency
o Can lead to herd immunization
o No longer used in the United States since 1999
o Used frequently in less developed countries, easier to
administer because it does not require injection by needle.
Vaccine-associated
paralytic poliomyelitis (VAPP) is a concern with administration of the Sabin
vaccine and has motivated many countries (including the United States) to use
only the Salk vaccine. This
paralytic disease occurs when the live attenuated virus in OPV reverts or
mutates to a more neurotropic form and causes permanent neural damage. VAPP cases comprised the great majority
of polio cases in the United States for many years:
Global
polio eradication efforts have been largely successful in eliminating wild
poliovirus from most countries and even continents. In 1988, the World Health Organization set a goal to
eradicate polio from the world by 2000 in cooperation with The Global Polio
Eradication Initiative (GPEI), Rotary International, the U.S. Centers for
Disease Control, UNICEF, and over 200 national governments. It has been one of the worldÕs largest
public health initiatives and has immunized over 2 billion children and has
cost US$ 3 billion since it began.
Source: The Pink Book, 8th Edition,
pp 98.
Sources:
The
hepatitis A virus occupies its own Hepatovirus genus of the Picornaviridae
viral family. It is one of two
hepatitis viruses that is transmitted through the fecal-oral route and most
often travels from person-to-person through contaminated water or food. Though its symptoms are usually mild
and self-limited, this virus infects over 90 percent of the population in many
less developed countries where clean water and sanitation are lacking, and is
therefore a major public health concern.
Hepatitis
A is a disease that affects both adults and children worldwide. It occurs most frequently in less
developed countries or countries in transition where water and sanitation
systems are often contaminated. In
such countries, it affects communities of lower socio-economic status where
people may live in more crowded conditions and without access to clean water
sources. More than 90 percent of
the population may show evidence of previous infection, and is therefore immune
to further infection. In these
countries, most hepatitis A infection occurs during childhood and is usually
asymptomatic. International
travelers are at increased risk, since they often are not immune, and
vaccination is recommended.
Hepatitis
A causes disease in more developed countries as well, particularly under
crowded conditions, as in child-care centers, residential living centers, and
residential hospitals. Outbreaks may
occur, but are difficult to trace to specific sources. In the United States, as many as 35,000
people have been infected in outbreaks, sometimes linked to contaminated
shellfish or vegetables exposed to contaminated water. Only about one third of the population
has immunity due to previous infections. Transmission can also occur directly from
person-to-person through close contact.
Men who have sex with men, drug users, people with chronic liver
disease, and people with clotting factor disorders are at increased risk. With improving sanitation and wide
vaccination initiatives, hepatitis A incidence has been decreasing since the
1970s.
Hepatitis A Cases in the United States:
Source: http://www.cdc.gov/ncidod/diseases/hepatitis/a/vax/index.htm
Hepatitis
A infection causes clinical symptoms in about half of infected adults. It is more than five times more likely
to be symptomatic in adults than children, so most children have asymptomatic
infection. Presentation of
clinical symptoms begins quickly after incubation with fever, nausea, diarrhea,
loss of appetite, and abdominal pain.
Some with acute infection present with jaundice within 2-3 days of
clinical onset, due to elevated serum bilirubin and aminotransferase levels
resulting from liver swelling and damage.
Jaundice is a common sign of most hepatitides. This liver malfunction causes stools to be reddish and urine
to be dark before jaundice becomes evident in the skin. Clinical disease may last days or
sometimes weeks, but 99 percent of cases are self-limiting and leave no lasting
damage. Fewer than one sixth of
people have relapse of mild symptoms over a period of 6-9 months. In very rare cases (0.01%), severe liver
necrosis may occur, which can lead to fulminant disease that can also cause
death.
Treatment
of acute hepatitis A is non-specific and targets alleviation of symptoms
only. Nutritious foods and
adequate rest are recommended until symptoms improve, which they almost always
do without intervention.
Prevention
of hepatitis A infection is possible with both behavioral interventions and
with immunization. Avoiding
exposure to water and food that may be contaminated whenever possible is the
most direct approach to avoid infection.
In less developed countries, improvements in sanitation and access to
clean water sources have reduced hepatitis A infection rates significantly. Travelers to these countries are advised
to avoid drinking tap water and foods (especially vegetables) that have been
peeled or rinsed in unpurified water.
Effective
vaccines against hepatitis A virus have been available for many years and are
in widespread use in the United States.
The inactivated, formalin-killed vaccine is almost 100 percent effective
in inducing long-lasting immunity.
Live attenuated vaccines are not nearly as effective. Hepatitis A vaccination is common,
though not universal, and is highly recommended for international travelers to
endemic areas. Passive
immunization is also widely available and consists of immune serum globulin
(ISG) collected from a large group of donors. It can be effective (80-90%) in preventing hepatitis A
infection when administered to people with determined exposure before the
appearance of clinical symptoms.
This can also be given to travelers who need vaccination right before
travel, with short-term notice.
Overall, vaccine immunization is preferred over passive ISG
immunization.
Though
an effective hepatitis A vaccine is available, universal immunization may not
be the most cost-effective method to reduce disease burden. Because hepatitis A causes a mild
disease that is severe only in extremely rare cases, health programs in less
developed countries may not find immunization campaigns necessary. With limited financial resources, their
money may be better spent on prevention efforts for more severe diseases such
as polio, tuberculosis, measles, and malaria, which cause much higher fatality
and have a larger socio-economic impact.
Sources:
¯
Rapid RT-PCR
amplification of full-length poliovirus genomes allows rapid discrimination
between wild-type and recombinant vaccine-derived polioviruses.Boot HJ, Schepp
RM, van Nunen FJ, Kimman TG. J Virol Methods. 2004 Mar
1;116(1):35-43. Laboratory of Vaccine-preventable Diseases, National Institute
for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The
Netherlands. hein.boot@rivm.nl
This
Dutch study sought to develop a full-length reverse transcriptase-PCR that
would allow for characterization and amplification of wild-type and recombinant
vaccine-derived poliovirus genomes.
Differentiation between wild-type and recombinant vaccine-derived
polioviruses is useful in determining the causative source of poliomyelitis in
people who fall ill but have no clear, identifiable risk for infection. Vaccine-induced poliomyelitis has long
been a concern of public health officials adopting universal vaccination
programs using the live attenuated oral poliovirus vaccine, since
vaccine-induced conditions like Guillan-Barre Syndrome have occurred at low but
significant rates. This project
used SuperScript II (RT) and expand (PCR) to develop a full-length reverse
transcriptase that then allowed researchers to examine the full-length genomes
of all polioviruses Ð wild-type, vaccine, and recombinant vaccine-derived. Endonuclease nuclease analysis was then
used to differentiate recombinant from non-recombinant viruses. Upon close examination, there appeared
to be preservation of the quasi-species nature of the recombinant
vaccine-derived virus. This method
proved successful and can now be used by epidemiologists and public health
officials during local polio outbreaks to determine the source of viral
emergence, particularly as the wild-type becomes more rare with vaccination
campaigns and as possible vaccine-derived strains become more common.
¯ Cell-dependent role for the poliovirus 3' noncoding
region in positive-strand RNA synthesis. Brown DM, Kauder SE, Cornell CT, Jang
GM, Racaniello VR, Semler BL. J
Virol. 2004 Feb;78(3):1344-51. Department of Microbiology and Molecular
Genetics, College of Medicine, University of California, Irvine, California
92697, USA.
This study is a continuation of a previous study that
successfully isolated a mutant poliovirus which lacked an entire RNA 3Õ
noncoding region in its genome.
That study then used the mutant strain to infect HeLa cells and observed
that viral replication was only minorly affected, despite the significant
genomic mutation in the original mutant.
This study applied the mutant poliovirus to a different set of cells,
namely the neuroblastoma cell line (SK-N-SH cells). It found that while replication defects were minor in HeLa
cells, defects were major in SK-N-SH cells. Major defects greatly impaired mutant viral replication in these
cells. Researchers subsequently
suspected that the deleted 3Õ noncoding region must have resulted in a defect
in the positive RNA strand. Thus,
the defects in SK-N-SH cells were not due to major errors in protein processing
or translation. In order to test
for neurovirulence of this mutant strain, the study went further to examine its
effects in transgenic laboratory mice.
Comparing the wild-type poliovirus with the mutant strain, the study
found that in order to paralyze 50% of the mice, the mutant virus would have to
be innoculated in a quantity 1000 times that of the wild-type poliovirus. This outcome suggests that the 3Õ
noncoding region is indeed involved in RNA synthesis. It also implies that cell type factors also play a role in
determining severity of disease outcome.
The finding gives insight into the potential for reduced poliovirus
disease with mutation and removal of certain genomic regions. Studies of this type help us to better
understand the mutation and recombination patterns of picornaviruses and the
outcomes of the diseases they cause.
¯ Effect of maternal antibody on immunogenicity of
hepatitis A vaccine in infants*1 G.
William Letson MD , Craig N. Shapiro MD , Deborah Kuehn RN/CNP, MSN , Charlotte
Gardea RN , Thomas K. Welty MD , David S. Krause MD , Stephen B. Lambert MS and
Harold S. Margolis MD. The Journal
of Pediatrics, Volume 144, Issue 3 , March 2004, Pages 327-332.
This
study sought to determine the effect of maternal antibodies on hepatitis A
immunogenicity in newborn infants.
Two groups of infants were studied. Group 1 was comprised of infants born to mothers who did not
have antibodies to hepatitis A. Groups 2 and 3 were comprised of infants born
to mothers who did have antibodies to hepatitis A. The infants in group 1 were given the hepatitis A vaccine at
2, 4, and 6 months of age. The
remaining infants were randomly divided into group 2, where infants received
the hepatitis A vaccine at 2, 4, and 6 months of age, and group 3, where
infants received the hepatitis B vaccine on the same schedule. Group 3 later received the hepatitis A
vaccine at 8 and 10 months of age.
Infants were tested for HAV antibodies at 15 months. Results showed that 100% of infants in
group 1 had HAV antibodies, while 93% in group 2 and 92% in group 1 had HAV
antibodies. Despite the presence
of antibodies, the geometric mean concentration of antibodies in group 1 was
significantly higher than in either group 2 or group 3 (GMC of 231 mIU/mL in
group 1, 85 mIU/mL in group 2, 84 mIU/mL in group 3, P<.001, group 1 vs. group 3). This suggests that while most infants
in all groups had antibodies, the infants in group 1 had many more antibodies
and thus, better protection from HAV.
The study concluded that infants who had passive immunity to hepatitis A
passed down from their mothers at birth had fewer anti-hepatitis A antibodies
even after immunization. Active
immunity in infants immunized without presence of maternal antibodies proved
more effective in building an immune response.
¯ RNA Recombination Plays a Major Role in Genomic
Change during Circulation of Coxsackie B Viruses. Oberste MS, Penaranda S, Pallansch MA. J Virol. 2004 Mar;78(6):2948-55. Respiratory and Enteric Viruses Branch,
Division of Viral and Rickettsial Diseases, National Center for Infectious
Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333.
This recent study chose to focus on the role of RNA
recombination in the evolution of coxsackie B viruses (CVB), a group that is not
often the subject of research attention.
Using the six main clinical isolates of CVB, the group sequenced four
genomic intervals for multiple isolates of each: the polymerase (3D, 491 nt),
the 5Õ-nontranslated region (5Õ-NTR, 350 nt), and two capsid intervals
(VP4-VP2, 416 nt, and VP1, approximately 320 nt). Based on the results of this sequencing, the group was able
to create phylogenetic trees for each region and each isolate. An observation was made that Òthe
partial VP1 sequences of each CVB serotype were monophyletic with respect to
serotype, as were the VP4-VP2 sequences, in agreement with previously published
studies.Ó Not all trees were
consistently congruent, as some incongruency between regions of VP2 and VP1 led
researchers to believe that there must be some degree of recombination between
serotypes (not hard to believe).
There was also indication that recombination had occurred between other
regions, namely the 5Õ-NTR and the capsid and the 3D and the capsid. Overall, most isolates seemed to be
recombination products when compared to the prototypical serotype strains. The conclusion of this observational
study is that genetic recombination is quite common among coxsackie B viruses. Common recombination is a trait of many
enterovirus serotypes that helps to explain why enteroviruses are so diverse
and so common and why preventive or reactionary treatment proves so difficult
for drug development.
¯ Rhinovirus increases human beta-defensin-2 and -3
mRNA expression in cultured bronchial epithelial cells. Duits LA, Nibbering PH, van Strijen E, Vos JB, Mannesse-Lazeroms SP, van
Sterkenburg MA, Hiemstra PS. FEMS
Immunol Med Microbiol. 2003 Aug 18;38(1):59-64. Department of Infectious
Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The
Netherlands.
This study examined the role of human beta-defensin
(hBD) expression in airway epithelial cells under conditions of the common
cold. HBDs are antimicrobial
peptides that participate in the inflammatory and immune responses to
infection. They have been shown to
be mediated by pro-inflammatory mediators and micro-organisms. The study looked at cultured primary
bronchial epithelial cells (PBEC) in patients with the common cold rhinovirus
RV16, which is also associated with exacerbation of asthma. While RV16 did not affect hBD-1 mRNA
expression, it did appear to induce hBD-2 and hBD-3 mRNA expression in PBEC. The study concluded that Òviral
replication appeared essential for rhinovirus-induced beta-defensin mRNA
expression, since UV-inactivated rhinovirus did not increase expression of
hBD-2 and hBD-3 mRNA.Ó Polyinosinic polycytidylic acid, a synthetic dsRNA, was
also investigated. It appeared to
affect mRNA expression of hBDs in the PBEC in a similar was as RV16. Overall, the study showed that hBD-2
and hBD-3 mRNA expression increases in PBER in the presence of RV16
infection. In other words, in the
presence of rhinoviral infection, the immune and inflammatory response is increased,
which leads to resolution of the viral infection without external
interference. This finding may
lead towards development of better treatment of viral exacerbations of asthma
and of the common cold.
Picovirª (pleconaril)
Though
there are many drugs commonly used to treat the various symptoms of
picornaviruses, there are few drugs currently available to treat actual
picornaviral infections.
Pleconaril (brand name PicovirTM) is one of those few
antivirals that is closest to being marketed and seems to work well. It contains active, antipicornal
molecular inhibitors of rhinoviruses and enteroviruses. Rhinoviruses and enteroviruses each
contain many dozens of viral serotypes that commonly infect people in all parts
of the world and can cause mild, moderate, or severe disease in a great variety
of body systems. They cause many
diseases, including the common cold, viral meningitis, pharyngitis, bronchitis,
pneumonia, infectious asthma, pericarditis, herpangina, acute hemorrhagic
conjunctivitis, paralytic diseases, and more. These diseases affect millions of people in the United
States alone and are a widespread concern.
Pleconaril
was developed and patented by the pharmaceutical company ViroPharma. The drug was designed after close study
of picornavirus structure, which led to the observation that capsid and
envelope structure are highly conserved among rhinoviruses and enteroviruses. The drug was designed to function by
integrating into hydrophobic pockets in the virion and disrupting viral
replication. Developers used x-ray
crystallography to demonstrate the process. Metabolic processes were accounted for in order to create an
orally-administered drug that would survive metabolic breakdown and take effect
in full force. Because it is
lipophilic, Pleconaril is able to cross the blood-brain barrier to treat
diseases such as viral meningitis, which can be quite serious and even fatal.
ViroPharmaÕs
laboratory studies showed that pleconaril inhibits replication of 96% of
picornaviral replication of enteroviruses and rhinoviruses in human samples
over a short period of time (usually within 2 days). Samples were selected from a diverse patient group that
included a wide range of viral diseases from acute, mild infections to chronic
and fatal diseases. In laboratory
mouse studies, mice were given oral doses of pleconaril after induced
enteroviral infection and infection consistently improved. In subsequent clinical studies, the
drug was shown to be safe and effective in treating the common cold (its most
common intended use)
ViroPharma
is attempting to market its PicovirTM as a cure-all for the common cold. If sold as an antiviral nasal spray or
a tablet, the marketing potential of the drug is quite high. Despite its high efficacy, Pleconaril
was not approved by the FDA in early 2002. The FDA expressed concern about the drugÕs safety due to
potential interactions with common drugs such as birth control pills, in which
case birth control efficacy was reduced.
If the drug is approved, it will likely be sold on a very large scale,
since rhinoviruses and enteroviruses are so common in the general population. This potential for widespread use has
raised FDA concern about the indirect creation of potentially drug-resistant
viruses. The drug is currently in
clinical trials to examine its efficacy and safety for many serotypes of
enteroviruses and rhinoviruses. Of
particular interest are trials of Pleconaril used to treat enteroviral CNS
infection in newborns, a group that can be seriously affected by enteroviral
meningitis and enteroviral sepsis syndrome.
For more
information:
á A 2003 clinical trial of Pleconaril to treat infant
enteroviral meningitis:
Double blind
placebo-controlled trial of pleconaril in infants with enterovirus meningitis. Abzug MJ, Cloud G, Bradley J, Sanchez PJ, Romero J,
Powell D, Lepow M, Mani C, Capparelli EV, Blount S, Lakeman F, Whitley RJ,
Kimberlin DW; National Institute of Allergy and Infectious Diseases
Collaborative Antiviral Study Group. Pediatr Infect Dis J. 2003
Apr;22(4):335-41.
Abstract:
BACKGROUND: Enterovirus (EV)
meningitis is common in infants and may have neurologic complications.
Treatment of older children and adults with pleconaril has been associated with
reduced severity and duration of symptoms. This study evaluated the
pharmacokinetics, safety and efficacy of pleconaril in infants with EV
meningitis. METHODS: Infants < or =12 months old with suspected EV meningitis
were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a
day or placebo for 7 days. Evaluations included pharmacokinetic determinations,
safety laboratory testing, serial culture and PCR assays and clinical
evaluations. RESULTS: Of 21 evaluable subjects 20 were confirmed with EV
infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of
29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration
for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7.
Pleconaril was well-tolerated, although twice as many adverse events occurred
per subject in the pleconaril group. Serial cultures from the oropharynx,
rectum and serum had low yield (< or =50%) and positivity generally persisted
for <4 days in both groups. Serial PCR assays of culture-negative
oropharyngeal and rectal specimens had high positivity rates (generally > or
=50%) persisting through Day 14. No significant differences in duration of
positivity by culture or PCR, hospitalization or symptoms were detected between
groups. CONCLUSIONS: The dose of pleconaril studied provided sufficient plasma
levels and was well-tolerated; however, drug accumulation was evident. The low
yields of serial viral cultures, relatively short and benign clinical courses
and the small number of subjects enrolled precluded demonstration of efficacy.
If this medication is to be prescribed in infants, surveillance for toxicity
related to drug accumulation will be necessary.
Sources:
Mumps virus
Power: XXXÉ highly
contagious, but not usually life-threatening. |
Description: Mumps is caused by the mumps virus, a member of the
Paramyxoviridae family. It contains single-stranded RNA and
has helical morphology. This
highly infectious virus is transmitted through the respiratory route and
causes painful enlargement of one or both parotid salivary glands, typically
in children. |
Offenses: o
Attacks: Mumps virus is transmitted very easily from person to
person through oropharyngeal secretions. Children are the primary susceptible group. Mumps is characterized by visible
swelling of the parotid salivary glands that results after initial infection
of the respiratory tract. In
most cases, the virus passes into the bloodstream and spreads to glandular
and nervous tissue throughout the body, possibly including the meninges,
thyroid, pancreas, ovaries, testes, and kidneys. Mild fever and pain is common in persons with symptoms. o
Outcome: Mumps usually resolves without long-lasting
effects. Nerve damage due to
gland and organ swelling is possible in serious cases and can lead to long
term nerve damage or potential deafness in children. o
Speed: Mumps infection comes in four stages: incubation,
prodrome, swelling, and reduction in swelling. The incubation period lasts about 2-3 weeks after
exposure, at which point the virus enters the bloodstream. The viremic phase lasts 3-5 days. |
Defenses: o
Vaccine: The Mumps vaccine is given in a live attenuated trivalent
vaccine along with vaccines for measles and rubella (MMR). Universal childhood vaccination is
recommended in two doses, the first at 15 months and the second at 5
years. More than 90% of
recipients have lifelong immunity. o
Behavioral: Avoidance of persons known to have mumps
virus infection may be somewhat effective, but respiratory transmission is
difficult to prevent through behavior alone. o
Treatment: There is no commonly used treatment for mumps virus
infection, though treatment for symptoms of fever and pain is common. |
Game
Action: Skip ahead, chances are youÕll be fine once the swelling goes down. |
One-liner: Bumpy Mumpy Grumps. |
Source:
FieldsÕ Virology, pp 1255.
Rubella virus
Power: XXXÉ highly
contagious, but not usually life-threatening. It can be very dangerous as a teratogen. |
Description:
Rubella, also known
as ÒGerman measles,Ó is caused by the rubella virus, a member of the
Rubivirus genus of the Togaviridae family. It contains single-stranded RNA and has an idosahedral
morphology. This virus is
transmitted through the respiratory route and causes a maculopapular rash,
typically in children. Rubella
can also act as a teratogen and cause Congenital Rubella Syndrome in infants. |
Offenses: o
Attacks: Rubella virus is transmitted easily from person to
person through oropharyngeal secretions. Children and pregnant women are the primary susceptible
groups. Rubella is characterized
by the appearance of pink macules on the face in about half of all
cases. Facial rash spreads to
the trunk and limbs, then fades within two days. Lymph node enlargement is common, as is fever and mild
muscle and joint pain. Women may
experience polyarthritis and may transmit the virus to an unborn fetus. o
Outcome: Rubella virus infection typically resolves without any
long-lasting effects. In rare
cases, complications such as thrombocytopenic purpura and postinfectious
encephalopathy may occur. In
infants with Congenital Rubella Syndrome, the virus may cause long-term
damage to many organs and body systems, including the eyes, ears, heart, and
nervous system. o
Speed: Rubella infection comes in three phases: incubation,
prodrome, and development of rash.
The incubation period lasts 16-18 days after exposure, or 12-23 days
at the most. The infectious
period is from 7 days before onset of rash to 7 days after. |
Defenses: o
Vaccine: The Rubella vaccine is given in a live attenuated
trivalent vaccine along with vaccines for measles and mumps (MMR). Universal childhood vaccination is
recommended in two doses, the first at 15 months and the second at 5
years. More than 90% of
recipients have lifelong immunity.
Women who may become pregnant are particularly encouraged to be
vaccinated. o
Behavioral: Avoidance of persons known to have rubella
virus infection may be somewhat effective, but respiratory transmission is
difficult to prevent through behavior alone. o
Treatment: There is no commonly used treatment for
rubella virus infection, though treatment for symptoms of fever and pain is
common. |
Game
Action: Better hope youÕre not pregnant because this could be BADÉlose one
turn. |
One-liner: MMR: protect your baby,
itÕs well worth the poke. |
Source:
FieldÕs Virology pp 2011-2045
West
Nile virus
Power: XXXÉ symptomatic infection is unlikely, but rare,
severe encephalitis or meningitis can be fatal. |
Description: West Nile is caused
by the West Nile virus, a member of the Flaviviridae family. It contains
single-stranded RNA and has icosahedral morphology. This virus is commonly found in Africa, the Middle East,
and West Asia, but has arrived in North America and Europe in recent years. It is an arbovirus that infects
humans, birds, horses, and other mammals, and is transmitted by mosquitos
from host to host. While often
asymptomatic in humans, West Nile fever, West Nile encephalitis, and West
Nile meningitis can result from serious infection. |
Offenses: o
Attacks: West Nile virus is transmitted to humans primarily
through the bite of an infected mosquito that acquires the virus from
infected birds. In rare cases
the virus has been transmitted through donor blood and organ transplants from
persons unknown to be infected.
Only about 20% of those infected will be symptomatic and experience
mild fever, headache, muscle and joint pain, eye aches, swollen lymph nodes,
nausea, vomiting, or rash on the trunk.
Only 1% of those infected will experience severe muscle weakness,
encephalitis, meningitis, disorientation, paralysis, and potentially coma. o
Outcome: In people with weakened immune systems, including the
elderly, West Nile encephalitis and meningitis can be fatal. In asymptomatic and mild cases,
outcome is normal. o
Speed: West Nile virus has an incubation period of 3-15 days,
after which symptoms may appear. |
Defenses: o
Vaccine: There is no vaccine for West Nile virus. o
Behavioral: Prevention of mosquito bites is the only
way to prevent viral infection.
Insect repellents, bed nets, clothing spray, and protective clothing
can reduce the risk of mosquito bites during temperate months. Pest control and local management of
water in which mosquitos may breed are methods of controlling the mosquito
population in a community. o
Treatment: There is no commonly used treatment for
West Nile virus infection, though treatment for symptoms of fever and pain is
common. |
Game
Action: ZZZAP! YouÕve been bitten by an infected mosquitoÉlose one turn. |
One-liner: ÒBirds, mosquitos, and
humansÉOH MY!Ó |
Source:
Department of Health and Family Services: West Nile Virus Infection
(West Nile
Encephalitis, West Nile Fever)
http://www.dhfs.state.wi.us/healthtips/BCD/WestNile.htm