ARENAVIRUSES
Arenaviruses, of the family Arenaviridae, include
29 spherical, enveloped RNA viruses that have T-
shaped glycoprotein spikes 7 to 10 nm long
surrounding the surface membrane of the virion
(Table 66-4). The viruses can readily infect a
variety of mammalian species, especially rodents
and bats, often resulting in a deleterious effect on
the reservoir rodent host. Human transmission
usually occurs through inhalation of aerosols of
infected rodent excrement (urine, saliva, feces, nasal
secretions) or by direct contact with infected
rodents. Disease in humans clinically displays a
broad range of symptoms, from asymptomatic (no
symptoms) to fever, prostration, headache and
vomiting, to the more severe cases of meningitis
and hemorrhagic fever.
The arenaviruses capable of causing disease in
humans include lymphocytic choriomeningitis
(LCM) virus and Lassa fever virus (first detected in
Lassa, Nigeria). LCM has been identified in cases
of aseptic meningitis in Europe and the Americas.
Lassa has been associated with hemorrhagic fever,
shock, and death in 5% to 15% of symptomatic
patients (80% of cases are asymptomatic).
Lassa fever virus is a significant cause of morbidity
and mortality in West Africa, where economic
resources are limited. Capillary leak and widespread
organ involvement, accompanied by shock,
respiratory distress, and/or hemorrhage, are
responsible for most deaths fromLassa fever. Other,
less commonly reported arenaviruses may also
cause hemorrhagic fever.
Arenavirus infection is diagnosed using serologic
tests or reverse transcriptase polymerase chain
reaction (RT-PCR) to detect viral nucleic acid. Viral
isolation using cell culture is not routinely
recommended. Cell culture for viral isolation has
proven to be unreliable because of inconsistent
sensitivity. In addition, handling cultures and
specimens puts laboratory personnel at high risk.
Samples and cultures containing LCM virus require
Biosafety Level (BSL) 3 facilities, and Lassa fever
virus requires a BSL 4 laboratory. Serologic
diagnosis is also difficult because the immunologic
antibody response is delayed for several days and
often weeks following symptomatic illness. An RT-
PCR assay has been developed to detect
arenaviruses, but it is not widely available in the
acute care setting.
BUNYAVIRUSES
Bunyaviruses, first detected in Bunyamwera,
Uganda, belong to the family Bunyaviridae (Table
66-5). The virus is an RNA virus consisting of
three, single-stranded RNA segments enclosed in a
helical nucleocapsid that is surrounded by a lipid
envelope. A unique feature of this family of viruses
is their tripartite genome. The genomic structure
provides a mechanism for genetic reassortment in
nature, much like the orthomyxovirus family of
viruses. Bunyaviruses comprise a large, diverse
group of viruses
(approximately 300 total members with 12 human
pathogens), most of which are transmitted by
mosquitoes(arboviruses). The most important
human pathogens in the United States consist of the
California serogroup (CAL), which includes the
California encephalitis and Lacrosse viruses (LAC).
Although the name California encephalitis implies
that these cases are related to the state of California,
they are identified primarily in Minnesota,
Wisconsin, Iowa, Illinois, Indiana, and Ohio.
Disease is typically mild and self-limiting; however,
severe, even fatal, encephalitis ensues in
approximately 2% of patients infected. Other human
disease–causing members of the family
Bunyaviridae include the Cache Valley (CV),
Jamestown Canyon (JC), Snowshoe hare (SSH),
Tahyna, Rift Valley fever, and Inkoo viruses.
Bunyaviruses that belong to the Hantavirus genus
are not arboviruses. The viruses are rodent borne
and transmitted through exposure (inhalation) to
aerosolized rodent excreta. Rodents develop a
chronic infection that results in shedding of the
virus in saliva, feces, and urine. Disruption of these
animal excreta by vacuuming, sweeping, or shaking
rugs aerosolizes infected particles, which are then
inhaled. Evidence indicates that the chance of
inhaling these particles is greater in indoor, poorly
ventilated spaces than through outdoor exposure.
The disease that ensues is called hantavirus
pulmonary syndrome (HPS). It was originally
discovered in 1993 in the four corners area of the
southwestern United States (Arizona, New Mexico,
Colorado, and Utah). The discovery of this virus
resulted from the outbreak of an unexplained
pulmonary illness among several young, healthy
people who died from acute respiratory failure.
Diagnostic testing failed to identify a known cause
of death. Through exhaustive analysis by the
virologists at the Centers for Disease Control and
Prevention (CDC) using molecular testing, the
scientists were able to link the pulmonary syndrome
with a previously unknown type of hantavirus. The
new virus originally was called Muerto Canyon
virus, but later the name was changed to sin
nombre (no name) virus (SNV).
HPS begins with generalized symptoms that include
headache, fever, and body aches, typically after an
incubation period of 11 to 32 days. Subsequently,
the symptoms become much more severe, leading to
hemorrhagic fever, kidney disease, and acute
respiratory failure. The deer mouse (Peromyscus
maniculatus) is the primary host for the sin nombre
virus. Transmission of the virus from rodent to
human has been the only documented mode of
human infection. No person-to-person transmission
of HPS has ever been documented in the United
States. Since the discovery of SNV, several
hantaviruses that cause HPS have been discovered
throughout the United States. The Bayou virus,
carried by the rice rat (Oryzomys palustris), was
first discovered in a male from the state of
Louisiana. The cotton rat (Sigmodon hispidus) is the
carrier of the Black Creek Canal virus, discovered
in a resident from Florida. The white-footed mouse
(Peromyscus leucopus) has been implicated in a
case of a hantavirus infection called the New York-
1 virus. Cases of HPS stemming from related
hantaviruses have been documented in Argentina,
Brazil, Canada, Chile, Paraguay, and Uruguay,
making HPS a panhemispheric disease. Laboratory
diagnosis relies on the identification of hantavirus-
specific IgM and or IgG antibody. By the time
symptoms have appeared, all patients have formed
hantavirus-specific IgM antibody, and most have
also developed hantavirus-specific IgG antibody.
Enzymelinked immunosorbent assay (ELISA) is
usually the method of choice for diagnosis. Other
available diagnostic methods include identification
of viral antigen in tissue using
immunohistochemistry or the presence of
amplifiable viral RNA sequences in blood or
tissues. Although RT-PCR assays have been
developed for some hantaviruses, the variation in
the viral genome reduces sensitivity, making routine
identification by RT-PCR complicated for the
diagnosis of hantavirus infections. Virus isolation
from human sources is difficult, and to date no
isolates of SNVlike viruses have been recovered
from humans.
FILOVIRUSES
The Filoviridae family of viruses (Table 66-8) is
considered the most pathogenic of the hemorrhagic
fever viruses. The term filo means threadlike,
referring to the virus’s long, filamentous structural
morphology seen with electron microscopy. The
viruses are pleomorphic, enveloped, nonsegmented,
single-stranded, negative sense RNA viruses. The
filamentous morphology appears in many forms or
configurations under the electron microscope, such
as the number “6,” “U,” or circular. Marburg
hemorrhagic fever virus displays the characteristic
“shepherd’s hook” morphology. The term “viral
hemorrhagic fever” is used to describe a severe
multisystem syndrome in which multiple organ
systems are affected throughout the body. The
patient’s vascular system becomes damaged, and
the body’s ability to regulate itself is impaired.
Infection with the Marburg or Ebola virus, endemic
in Africa, results in severe hemorrhages, vomiting,
abdominal pain, myalgia, pharyngitis,
conjunctivitis, and proteinuria. Human case fatality
rates for Ebola virus infection exceed 80%; the toll
for Marburg virus infection is somewhat lower, with
a case fatality rate of 23% to 25%. These diseases
have no cure or established drug treatment. The first
filovirus was detected in Marburg, Germany, when
a group of German laboratory workers became ill
and developed hemorrhagic fever after handling
imported African green monkeys or monkey tissue
while preparing polio vaccine. Simultaneous
hemorrhagic fever outbreaks occurred in
laboratories in Frankfurt, Germany, and Belgrade,
Yugoslavia (now Serbia). Thirty one individuals
became symptomatic, and seven individual fatalities
were recorded. Symptomatic individuals
included the laboratory workers, their family
members, and medical personnel. The Marburg
virus was isolated from the African green monkeys
and determined to be the etiologic agent of
infection. Ebola virus is the only other member of
the Filovirus family. It is named after a river in
Zaire (now the Democratic Republic of the Congo),
where it was first identified. The genus Ebolavirus
has five subspecies, based on the first location
where the virus was identified: Zaire ebolavirus,
Sudan ebolavirus, Cote d’Ivoire ebolavirus
(formerly
referred to as Ebola–Ivory Coast), Bundibugyo
ebolavirus, and Reston ebolavirus. All of the Ebola
subspecies cause disease in humans and nonhuman
primates (i.e., chimpanzees, gorillas, and monkeys)
except for Reston ebolavirus, which causes disease
only in nonhuman primates. The Ebola virus was
first recognized in 1976, when a total of 602 people
became ill in Zaire and Sudan.
Infections are acute, with no carrier state, and
humans become ill after contact with an infected
animal, usually a primate. Transmission of the virus
is rapid. Individuals caring for the sick who come in
contact with the patient’s secretions quickly develop
symptoms. In fact, many of the early Ebola
outbreaks were attributed to “nosocomial”
infections. Personal protective equipment (e.g.,
gowns, masks, and gloves) often were not used by
those caring for sick patients. Also, objects such as
needles and syringes often were not sterilized before
reuse, and many people were exposed to the virus
through contaminated syringes and needles. In the
initial Ebola outbreak, 431 people
died, a fatality rate greater than 70%. The natural
animal reservoir for the Ebola and Marburg viruses
has never been determined, although the animal
source is believed to be native to Africa. Disease
outbreaks in monkeys have occurred in the United
States in research facilities. Several monkeys
housed in separate cages became ill simultaneously.
Laboratory workers working in these facilities were
also infected and developed antibodies but never
developed symptoms of the disease. Reston
ebolavirus is known to have caused
infections through aerosolization of secretions. RT-
PCR is used to identify the Ebola and Marburg
viruses. Electron microscopy is also available in
some research facilities. Cell culture is available in
laboratories with BSL 4 facilities. Antibody
production occurs after an Ebola virus infection,
and an antigen-capture ELISA is available to detect
IgM and IgG antibodies to Ebola virus.
PAPILLOMAVIRUSES
Papilloma viruses are small, nonenveloped, circular,
double-stranded DNA viruses. These viruses are
abundant in nature and cause infections in humans,
dogs, cattle, monkeys, and many other species. The
Papillomaviridae family (Table 66-14) includes the
human papillomaviruses (HPVs). HPVs cause
human warts. They exhibit a tissue tropism for
either cutaneous or mucosal tissue. The viruses have
not been cultivated in cell culture, which prevents
the production of type-specific antigens
and corresponding typing antisera. HPVs are
divided into more than 200 genotypes based on the
viral DNA sequences; approximately 80 of those
have been well characterized. Much attention has
been focused on the more than 30 sexually
transmitted genotypes and their role in the
pathogenesis of cancer. The various HPV genotypes
have differing cellular tropisms, resulting in defined
variation in the clinical presentation of the warts.
For example, HPV-1 is associated with plantar
warts; HPV-2 and HPV-4 are associated with
common warts of the hands; and HPV-6, HPV-11,
and others are associated with genital warts. Fifteen
to 20 types of HPV cause virtually all cases of
cervical cancer, with types 16 and 18 causing more
than 60% of cases. Type 16 is also responsible
for a subset of cancers of the oropharynx and penile
cancer in men (Table 66-14). HPV infection is the
most prevalent sexually transmitted viral disease in
the United States; it is estimated that more than 65
million Americans are living with an incurable
STD, such as HPV or HSV infection. Infection is
detected using histopathologic or cytologic
examination of cutaneous biopsy or cells,
respectively, and DNA probe assays for
identification of specific genotypes in infected
epithelial cells. A single, liquid-based cytology
sample can be used for cytology and genotyping.
Several commercial HPV assays currently are
available in the United States, including HC2
(Qiagen), Cervista HPR HR (Hologic), Roche
Amplicor HPV Test (Roche Molecular
Diagnostics), GenProbe Aptima HPV Test
(GenProbe), Abbott
RealTime High Risk HPV Test (Abbott Molecular),
PreTect HPV-Proofer (Norchip) and NucliSENS
Easy Q HPV v1 Test (bioMeriéux). Two vaccines
for HPV are currently licensed by the FDA:
Cervarix (Glaxo Smith Kline, United Kingdom and
Gardasil (Merck & Co., Inc, Whitehouse Station,
N.J.). The vaccines are a derivative of the protein
viral coat and provide some protective immunity to
HPV16.
PARVOVIRUSES
Parvoviruses (the Latin term parvus means small)
have a wide distribution among warm-blooded
animals (Table 66-16). Parvovirus B-19 is the single
human pathogen among the Parvoviridae. The virus
is a nonenveloped, icosahedral, single-stranded
DNA virus that may appear spherical on electron
microscopy. Because its replication in human cells
is largely restricted to erythroid progenitor cells,
adult bone marrow and fetal liver cells (thesite of
erythropoiesis during fetal development) are the
major sites of viral replication. Important diseases
associated with parvovirus B-19 infection are fifth
disease (the fifth of the childhood exanthems),
aplastic crisis in patients with underlying
hemoglobinopathies, and fetal infection (hydrops
fetalis) resulting from transplacental inoculation.
Parvovirus causes a biphasic illness in humans. The
first phase, marked fever, malaise, myalgia, and
chills, corresponds to peak levels of virus and
destruction of erythroblasts. This phase, when mild,
may be overlooked or considered a nonspecific viral
disease. The second phase involves rash and
arthralgia, which occur after the virus has
disappeared but at a time when parvovirus-specific
antibody can be detected. This is consistent with the
appearance of the rash caused by immune complex
deposition in the capillaries of the skin. IgM
antibodies appear within 7 days after infection,
followed by IgG at approximately 14 days.
Laboratory diagnosis is accomplished using
parvovirus-specific IgM or virus specific IgG
antibody testing with paired acute and convalescent
sera or by detection of viral DNA using PCR.
Parvovirus cannot be cultivated in the typical cells
available in clinical virology laboratories.
POXVIRUSES
The poxviruses (Table 66-20) are the largest and
most complex of all viruses. The virions consist of a
double stranded DNA genome. The virions appear
as oval or brick-shaped structures 200 to 400 nm in
length. Because of their large size, poxvirus virions
may be visualized through a light microscope. One
of the most feared viruses of history, smallpox, is
a member of this family. Smallpox played a crucial
role in demonstrating the importance of vaccination
to protect against disease. In 1798 Edward Jenner
recognized that milkmaids previously infected with
cowpox were immune to the disease of smallpox.
This discovery led to the practice of inoculating
humans against smallpox by using the actual
organism (virus) responsible for the disease.
Smallpox is known to infect only humans and exists
as two distinct subtypes. Variola major, which
caused the most severe disease (case fatality rate of
30%), occurred mainly in Asia; variola minor was
associated with less severe disease and case fatality
rates of 0.1% to 2%. As a result of an intensive
vaccination campaign, WHO declared naturally
occurring variola virus eradicated in 1980. The
variola virus no longer circulates in nature. The
virus is feared as a possible biologic weapon, and
testing capability for this organism is maintained by
hundreds of Laboratory Response Network (LRN)
laboratories throughout the nation. All known
stocks of the virus are held at two WHO
collaborating laboratories: the Centers for Disease
Control and Prevention (CDC) in Atlanta, Georgia,
and the State Center of Virology and Biotechnology
(VECTOR) in Kotsovo, Russia. WHO has
requested destruction of the remaining stocks of this
virus, but that has been postponed to evaluate the
need for developing vaccines, rapid diagnostics, and
antiviral
therapy. Since the eradication of smallpox in 1980,
most vaccination campaigns against this virus have
stopped, and most of the world’s population lacks
any protective immunity against this disease or any
related poxviruses. Besides the smallpox virus, 10
other poxviruses are capable of infecting humans.
Except for the smallpox virus and the molluscum
contagiosum virus, most of these are zoonoses, or
infections that result from contact with animals.
Fortunately, other than monkeypox and the
eradicated smallpox virus, none of these viruses can
sustain human-to-human transmission. The viruses
normally are acquired through abrasions of the skin
and contact with an infected animal, or in the case
of human monkeypox, through the oropharynx or
nasopharynx in addition to through abrasions on the
skin. Poxvirus replicates in the epidermal cells and
causes change in the cellular structure, characterized
by the “pocks” on the skin. Poxvirus infection can
take one of two courses: it can cause a localized
infection at the site of inoculation, with little spread
from the original site of inoculation, or it can cause
a fulminant, systemic infection with spread of the
virus throughout the body. The second type of
infection is associated with variola virus (smallpox)
and also monkeypox, and an increased mortality
rate. Monkeypox is almost indistinguishable from
smallpox infection
except that it lacks the same level of mortality and
transmissibility. The monkeypox virus is found in
the tropical rain forests of Africa, and its host
reservoir is one or more rodent species. After the
individual is exposed to the virus, symptoms of
fever and headache occur first, followed by the
development of a rash and lymphadenopathy. The
rash typically first appears on the face, beginning as
macules (small, round changes in skin color),
progressing to papules (slightly elevated with no
fluid) to vesicles (containing a bubble of fluid) and
then pustules (containing purulent material
consisting of necrotic inflammatory cells).
Depending on the severity of the disease, the illness
can last 2 to 4 weeks. Two clades of monkeypox
exist, and the Congo Basin clade has the highest
fatality rate (up to 12%). In 2003 the importation of
rats as pets led to an outbreak of monkeypox in the
United States, proving that international travel can
be a significant portal of disease from anywhere and
to anywhere in the world. RT-PCR (real-time)
offers a rapid diagnostic identification tool for cases
of monkeypox. Another member of the poxvirus
family is the molluscum contagiosum virus, which
causes single or small
clusters of lesions. Its only host is humans, and
infection occurs either nonsexually, through direct
contact or fomites, or sexually, through intimate
contact. Usually a self-limiting disease in healthy
individuals, molluscum contagiosum can cause a
more severe form of disease in
immunocompromised patients, resulting in large
lesions, especially on the face, neck, scalp, and
upper body. Laboratory diagnosis of molluscum
contagiosum usually is through biopsy of the
lesions and histologic examination. Molecular
assays, such as traditional PCR, restriction fragment
length polymorphism (RFLP), and real-time-PCR,
are still under development. Orf is another member
of the poxvirus family and is transmitted from sheep
to humans through human direct contact with
infected sheep. This virus causes single or multiple
nodules, usually on the hands. These nodules may
be painful and may be accompanied by symptoms
such as low-grade fever and lymph node swelling.
The infection usually resolves in 4 to 6 weeks
without further complication, although
autoinoculation of the eye can have more serious
consequences. An orf diagnosis is made through
direct examination of the nodule, along with
epidemiologic evidence of a recent history of
contact with sheep or lambs. Continued
development of PCR assays for identification of
parapoxviruses will aid the diagnosis and
identification of these viruses.
RHABDOVIRUSES
Rhabdoviruses (Table 66-23) infect plants,
arthropods, fish, and mammals. The virion consists
of single-stranded RNA with a helical nucleocapsid
surrounded by a lipid bilayer envelope. Spikelike
projections approximately 10 nm long extend from
the surface of the lipid bilayer. Electron microscopy
has shown that the virion has a bullet-shaped or
conical appearance. The rabies virus is
a neurotropic virus that infects all mammals; with
very few exceptions, infection terminates in the
death of the infected mammal. The rabies virus is
transmitted through the saliva of infected animals,
usually by a bite. After inoculation, the virus may
invade the peripheral nerves or nerve endings
directly. Following infection of the nerve cells, the
viral genome progresses centripetally
transneuronally, through retrograde axoplasmal
flow to the central nervous system. In the CNS it
proceeds from first-order neurons to second-order
neurons. the neurons are the site of viral replication,
mainly in the brain and spinal cord; from there the
virus spreads to peripheral nerves and to some
nonnervous tissue, including the salivary glands.
After a variable incubation period, human disease
usually begins with generalized symptoms of
malaise, fever, fatigue, anorexia, and headache.
Frequently (and characteristically for this disease),
symptoms include pain and sometimes “tingling” at
the site of exposure, which can be the first “rabies-
specific” symptom. After this prodromal phase,
behavioral changes may start to manifest, followed
by rapidly progressing neurologic symptoms that
lead to coma and death.
Only six cases of survival of a rabies infection have
been documented worldwide. These cases include
patients who survived without any complications;
other patients have experienced significant
neurologic impairment. In 2004, Randy Willoughby
developed a treatment protocol for rabies referred to
as “The Milwaukee Protocol.” This protocol
requires that the patient remain in a prolonged state
of generalized anesthesia, anti-viral drugs, and
supportive, life-sustaining care until the individual’s
natural active immunity is capable of clearing
and/or fighting the infection. Updated protocol and
statistics related to patient treatment and survival
are maintained by the Medical College of
Wisconsin and can be accessed at
mcw.edu/Pediatrics/Infectious Diseases/
PatientCare/Rabies.htm Animal rabies presents
much as do human rabies cases. After the prodromal
phase of the disease, a period of increased excitation
occurs, with or without aggression. Clinical
presentations of rabies often are described as
“furious” or “dumb”; the furious type is associated
with heightened aggression and agitation, and the
dumb type with lethargy and paralysis. Rabies is
diagnosed by postmortem examination of brain
tissue using a direct immunofluorescent assay.
Specific sections of the brain are examined for the
rabies
antigen using fluorescent-tagged monoclonal
antibodies and a fluorescent microscope. Prompt,
accurate diagnosis of rabies infections in animals is
important to ensure the success of postexposure
prophylaxis for human victims of animal bites and
injuries.
TOGAVIRUSES
The Togaviridae family (Table 66-24) includes
rubella virus and the alpha viruses, a large group of
mosquitoborne arboviruses. Rubella is found only
in the human population and is transmitted through
direct contact with nasopharyngeal secretions or by
congenital transmission. Rubella, sometimes called
the “German measles,” is usually a benign disease
characterized by fever and rash. Before the trivalent
vaccine, MMR (measles, mumps, and rubella), was
developed, rubella was an epidemic disease. A risk
associated with this disease is exposure and
infection of pregnant women. The virus can infect
the developing fetus, causing multiple congenital
anomalies. Intrauterine infection during the first
trimester may result in low birth weight, mental
retardation, deafness, congenital heart disease, and
neurologic defects. Infection that occurs later in
pregnancy may result in splenomegaly or
osteomyelitis, among other birth deficiencies. Fetal
infection can be prevented through vaccination of
all women before pregnancy. In arbovirus
infections, mosquitoes infect a vertebrate host (e.g.,
birds and rodents), the virus multiplies (amplifies)
in this host and is picked up and passed along in
subsequent mosquito bites. Humans are infected
incidentally and are not amplifiers of the virus;
rather, they are dead-end hosts, unable to pass on
the virus to other humans or animals. Human
disease varies from asymptomatic infection to fatal
encephalitis and includes Eastern, Western, and
Venezuelan equine encephalitides. Togavirus
disease is diagnosed through detection of specific
serum IgG and IgM antibodies. Virus isolation is
not practical in clinical laboratories.
PARAMYXOVIRUSES
Mumps is an acute, self-limiting disease
characterized by parotitis (inflamed salivary gland)
accompanied by a high temperature (fever) and
fatigue. The mumps virus is transmitted through
droplets and contact with infected saliva. The
measles virus causes an acute, generalized infection
often accompanied by a characteristic rash. The
hallmark rash of measles infection is referred to as
Koplik’s spots, which are bluish white spots with a
red halo located on the buccal or labial mucosa.
These spots are found on the inner lip or opposite
the lower molars in the mouth. The virus is
transmitted from person to person through aerosols
and infects the mucosal cells of the respiratory tract.
Measles is one of six classic childhood diseases
capable of causing a rash or skin eruption
(exanthem). The other diseases that cause an
exanthem are scarlet fever (which is caused by a
bacterium, Group A Streptococcus); rubella
(German measles), referred to as atypical scarlet
fever; erythema infectiosum (or fifth disease, caused
by parvovirus B-19); and roseola (caused by HHV-
6). Since the introduction of the live attenuated
childhood trivalent vaccine against measles,
mumps, and rubella (MMR), cases of mumps have
dropped by more than 99% and measles infections
are rare in the United States and Europe. However,
these viruses continue to circulate and remain a
common illness in developing countries. Mortality
rates from measles infections can be as high as 20%
as a result of contributing factors such as poor
hygiene and malnutrition. These viruses are often
brought into the United States by travelers or people
from other countries. The potential for an outbreak
arises when infected individuals come in contact
with unvaccinated individuals, and prompt
laboratory investigation of suspect cases is required.
Diagnostic testing for these viruses involves
serologic analysis of patient serum for IgM and IgG
antibodies and cell culture for virus detection and,
recently, nucleic acid detection. For measles cell
culture, the specimens of choice are respiratory or
throat specimens; for mumps cell culture, buccal
swabs collected from the inside of the cheek are
recommended. These viruses are also shed in the
urine; therefore, urine specimens can be examined
for their presence.
RETROVIRUSES
The retrovirus family Retroviridae (Table 66-22)
constitutes a large group of viruses that primarily
infect vertebrates. They are enveloped RNA viruses,
and each virion contains two identical copies of
single-stranded RNA. The viral nucleic acid strands
are surrounded by the structural proteins that form
the nucleocapsid and the matrix shell. On the outer
surface of the nucleocapsid and matrix protein is the
lipid envelope derived from the host cell membrane.
Proteins that mediate adsorption and penetration
into the host cell membrane are inserted into the
viral envelop. Retroviruses are unique,because they
have the enzyme reverse transcriptase. Reverse
transcriptase allows the viral RNA genome to be
replicated into DNA and then RNA rather than
directly into RNA. Amino acid sequencing of the
reverse transcriptase protein divides the retrovirus
family into groups. The human immunodeficiency
viruses types 1 and 2 (HIV-1 and HIV-2) are
members of this family as are the human T cell
lymphoma viruses types 1 and 2 (HTLV-1 and
HTLV-2). HIV-1 (Figure 66-6) is the more
aggressive virus and is responsible for the acquired
immunodeficiency syndrome (AIDS) pandemic.
The virus was first isolated in 1983, and a year later
was proven to be associated with early and late
stages of AIDS. HIV-2 was discovered in 1986 and
is less pathogenic. AIDS is the end stage of a
process in which the immune system and its
ability to control infections and malignant
proliferation is destroyed. The virus has an affinity
for the CD4+ surface marker of T lymphocytes. As
the number of CD4+ T lymphocytes decreases, the
risk and severity of opportunistic infections
increases. Some of the most common opportunistic
infections associated with HIV infection include
disseminated coccidioidomycosis, cryptococcosis,
cryptosporidiosis, histoplasmosis, recurrent
pneumonia, and pneumocystis pneumonia.
Detection of the HIV antibody is the mainstay of
clinical diagnosis. Repeatedly reactive antibody
tests done with EIA should be confirmed using
Western blot testing. Clinical management of
infected individuals involves the use of highly
active antiretroviral therapy (HAART) and depends
on the measurement of CD4+ lymphocytes and the
viral load. Molecular methods often are used to
quantify the viral load. Diagnosis of HIV infection
in babies born to HIV-positive mothers is
problematic because of maternal IgG in the baby’s
blood; therefore, PCR for identification of viral
DNA or RNA is recommended. Genome
sequencing is used to establish susceptibility to
antiviral agents. The risk of laboratory-acquired
infections with these viruses is a critical
consideration; the greatest caution must be
exercised in handling any specimens capable of
harboring a blood-borne agent. Infection occurs
through contamination of the hand and mucous
membranes of the eyes, nose, or mouth with
infected blood or other body fluids. No evidence
exists of airborne transmission. Proper personal
protective equipment must always be worn,
including a laboratory gown, good-quality gloves,
and eye protection. Disposable, unbreakable plastic
ware should always be used in the handling of blood
or bodily fluids. HTLV-1 is endemic in the
Caribbean, Africa, South and Central America,
Melanesia, and Japan. However, only a small
percentage of people infected (fewer than 4%)
develop symptoms and disease. Cell-to-cell contact
and TAX-induced clonal expansion of infected cells
are the major avenues for viral replication, making
detection of the virus difficult. As a result, serologic
detection has remained the gold standard for
diagnosis. Molecular detection and the development
of PCR assays are being investigated in research
laboratories. The average time from infection to the
development of adult T-cell leukemia is
approximately 40 years.
FLAVIVIRUSES
The flaviviruses (family Flaviviridae; Table 66-9)
include viruses that cause arbovirus diseases, such
as yellow fever, dengue, West Nile viral
encephalitis, and Japanese and St. Louis
encephalitis. Hepatitis C virus (HCV) is a flavivirus
but not an arbovirus. Flaviviruses are small, single-
stranded, positive sense RNA, enveloped,
icosahedral viruses. The name is derived from the
Latin word flavus, which means yellow. The first
disease identified in this group was yellow fever,
which causes yellow jaundice in humans. Diseases
in this viral group are transmitted to humans
through the bite of an infected arthropod, usually
the mosquito.
Yellow fever has been one of the great plagues
throughout history. In 1900, thousands of
individuals died during the construction of the
Panama Canal. An army physician, Dr. Walter
Reed, uncovered the source of the infection. In the
jungle habitat, monkeys serve as the reservoir and
the vector is a mosquito. This was the first virus
clearly associated with transmission by a mosquito.
The yellow fever virus also is the first flavivirus for
which an effective vaccine has been developed. In
urban outbreaks, humans can serve as the reservoir,
as long as the mosquito vector is present. The
yellow fever virus primarily infects liver cells,
resulting in fever, jaundice, and hemorrhage.
Transmission through the mosquito bite is followed
by a 3- to 6-day incubation period. The onset of
symptoms is sudden and includes fever, rigors,
headache, and backache. The patient’s clinical
condition progresses rapidly, and the patient
becomes intensely ill with nausea, vomiting, facial
edema, dusky pallor, swollen, bleeding gums, and
hemorrhagic tendencies with black vomit, melena
(black, tarry feces), and ecchymoses (bruising).
Mortality rates range from 5% to 50%; when death
occurs, it is usually within 6 to 7 days following the
onset of symptoms but rarely after 10 days. The
characteristic yellow jaundice typically is seen in
convalescing patients. Prevention in urban areas
depends on elimination of the yellow fever vector,
the mosquito, Aedes aegypti. The current vaccine is
very effective at preventing infection. Diagnosis of
yellow fever infection is often a result of correlation
of the patient’s clinical symptoms with the patient’s
location and travel history. Laboratory testing on
serum or cerebrospinal fluid (CSF) is available for
detection of virus-specific antibodies or neutralizing
antibodies. Serologic testing is also available using
IgM-capture ELISA, microsphere-based
immunoassays (MIAs), and IgG ELISA. In fatal
cases of yellow fever, patient tissues may be sent to
reference laboratories for nucleic acid amplification, in birds increases, more humans become infected.
histopathology, and cell culture. Interestingly, West Nile virus also has been
The dengue virus is the most prevalent arbovirus in transmitted person to person through blood
the world; more than 100 million people are transfusions, tissue transplantation, and in human
infected annually. It is the leading cause of illness breast milk. Infection is often accompanied by
and death in the tropics and subtropics. The virus is fever, leukopenia, and malaise and may progress to
endemic in Latin America, Puerto Rico, and encephalitis. Laboratory diagnosis typically
Mexico. Most cases reported in the United States involves detection of IgM antibody to West Nile
(more than 90%) are travel related. Humans are the virus in the patient’s serum or CSF. Several
main reservoir for this virus, and person-to-person commercial kits are available for detection of West
transmission occurs through a mosquito vector. Nile IgM and IgG specific antibodies using ELISA
Dengue virus has four serotypes that cause a variety or IFA methods. Nucleic acid amplification testing
of clinical manifestations, including nonlethal fever, has been very successful in detecting the arbovirus
arthritis, and rash. Infection with one serotype from the tissues of fatal cases and has also been
confers immunity only to the infecting serotype. used to detect the virus from the tissues of birds.
Subsequent infection with one of the three Additionally, molecular testing has used to detect
remaining serotypes results in immune-enhanced West Nile virus in mosquito pools. West Nile
disease in the form of severe hemorrhagic fever or mosquito surveillance has become increasingly
dengue shock syndrome. Of the more than 100 important in the attempt to control this disease.
million cases of dengue fever, 250,000 cases result
in dengue hemorrhagic fever, resulting in
approximately 25,000 deaths annually. Dengue
normally affects adults and older children. The
infection begins with a sudden onset of fever, severe
headache, chills, and general myalgia. Often a
macropapular rash may be visible on the trunk of
the body, which then spreads to the face and
extremities. No vaccine is available for dengue.
Laboratory diagnosis is based on the presence of
virus-specific IgM antibody, a fourfold rise in
specific IgG antibody, or a positive RT-PCR
amplification for dengue genomic sequences.
Scores of other arthropod-borne flaviviruses, most
transmitted by mosquitoes or ticks, cause
encephalitis, hemorrhagic fever, or milder disease
characterized by fever, arthralgia, and rash. West
Nile virus (first isolated in the West Nile district of
Uganda), a flavivirus closely related to the Japanese
and St. Louis encephalitis viruses, is endemic in
Africa, Israel, and Europe. West Nile virus has been
endemic in the United States since 1999. Since the
virus was identified in New York City in 1999, it
has spread westward across the entire United States
and into Canada, Mexico, Central America, South
America, and some Caribbean islands. The virus
accounts for the largest number of cases of viral
encephalitis in the United States.
West Nile virus is maintained in a bird-mosquito
cycle. Birds are the natural reservoir for the virus.
Currently, 59 species of mosquitos and more than
300 species of birds are infected with the West Nile
virus. Amplification of virus during warm months
results in the death of bird hosts, most commonly
crows, ravens, and jays. Bridge mosquitos (those
that bite both humans and birds) are responsible for
transmission to humans; as the viral populations