PARAMYXOVIRIDAE • Replicates in cells of the conjunctiva, respiratory tract,

gastrointestinal tract, urinary tract, lymphatic system,

The family Paramyxoviridae consist of three genera: blood vessels and central nervous system
1. Morbilivirus • Rash is caused by T-cell response to virus-infected
2. Paramyxovirus epithelial cell lining the capillaries
3. Pneumovirus • Cell-mediated immunity is essential to control of
infection, antibody is not sufficient due to measles
THE PARAMYXOVIRUS FAMILY ability to spread cell to cell
• Sequelae in the central nervous system may result from
immunopathogenesis (postinfectious measles
encephalitis) or development of defective mutants
(subacute sclerosing panencephalitis, SSPE)

UNIQUE FEATURES OF THE PARAMYXOVIRIDAE

• Large virion consisting of a negative RNA genome in a

helical nucleocapsid surrounded by an envelope
containing a viral attachment protein (HN:
paramyxovirus; H: morbilivirus; G: pneumovirus) and a
fusion glycoprotein (F)
• The three genera can be distinguished by the activities
of the viral attachment protein: HN of paramyxovirus
has hemagglutin and neuraminidase activity; H of
morbilivirus has hemagglutin activity; G of pneumovirus
lacks these activities
• Virus replicates in the cytoplasm
• Virions penetrate the cell by fusion with the plasma
membrane
• Viruses induce cell-cell fusion, causing multinucleated
giant cells
• Paramyxoviridae are transmitted in respiratory droplets
and initiate infection in the respiratory tract
• Cell-mediated immunity causes many of the symptoms
but is essential for control of the infection

1. MORBILLIVIRUS (measles virus)

Epidemiology of Measles
Clinical Consequences of Measles Virus Infection
• DISEASE/VIRAL FACTORS
○ Large relatively unstable envelope virion,
easily inactivated
○ Contagion period precedes symptoms
○ Host range is limited to humans
○ Only one serotype
○ Immunity is lifelong

• TRANSMISSION
○ Inhalation via large droplet aerosols

• WHO IS AT RISK
○ Unvaccinated individuals
○ Immunocompromised individuals; more serious
outcome

• GEOGRAPHY/SEASON
○ Worldwide
○ Endemic in fall to spring, possibly because of A Defective measles virus
crowding indoors persists in the
Disease Mechanism of Measles Virus brain and acts as a slow virus

• Infects epithelial cells of respiratory tract

• Spread systemically in lymphocytes and by viremia
 determine past infection or immunization is being used
to document childhood immunization.
Time course of Measles Virus Infection Treatment, Prevention and Control]

• A live attenuated measles vaccine in use since 1963.

Live attenuated vaccine is given to all children after 6
months of age, in combination with mumps and rubella
vaccine (MMR vaccine) at 15 months
• Inactivated “killed” vaccines are no longer available,
even for the immunocompromised, because of the
subsequent effect on naturally acquired measles virus
infection (atypical measles). No specific antiviral
treatment is available for measles.
• Exposed susceptible individuals who are
immunocompromised should be given immune serum
globulin to modify their measles infection. This product
is most effective if given within 6 days of exposure.

2. PARAMYXOVIRUS

a. PARAINFLUENZA VIRUS

Epidemiology of Parainfluenza Virus Infection

• DISEASE/VIRAL FACTORS
○ Large relatively unstable enveloped virion,
easily inactivated
○ Contagion period precedes symptoms and may
occur in the absence of symptoms
○ Host range is limited to humans
○ Reinfection later in life can occur

• TRANSMISSION
○ Inhalation of large droplet aerosols

• WHO ARE AT RISK?

○ Children: mild diseaae, croup
○ Adults: reinfection with milder symptoms

• GEOGRAPHY/SEASON
○ Ubiquitous and worldwide

Disease Mechanism of Parainfluenza Viruses

• Four serotypes of viruses

• Infection is limited to respiratory tract, upper
respiratory tract disease is most common, but significant
disease can occur upon lower respiratory tract infection
• Parainfluenza viruses are not systemic and do not cause
viremia
• Diseases include coldlike symptoms, bronchitis
(inflammation of bronchial tubes), bronchiolitis
(inflammation of bronchioles), croup
(laryngotracheobronchitis)
• Infection induces protective immunity of short duration

Laboratory Diagnosis

• Parainfluenza virus isolated from nasal washings and

respiratory secretions grow well in primary monkey
kidney cells. However, like the other paramyxovirus,
the virions are labile during transit to the lab. Virus-
infected cells in aspirates or in cell culture can be
identified by immunofluorescence.
Laboratory Diagnosis
• Clinically, measles is usually so characteristic that it is Treatment, Prevention and Control
rarely necessary to perform laboratory tests to make a
diagnosis. Measles virus is difficult to isolate and grow. • No specific antiviral agents are available.
The virus can be grown in primary human or monkey cell • Vaccination with killed vaccines is ineffective possibly
cultures. because they fail to induce local secretory antibody and
• Respiratory tract secretions, urine, blood, and brain appropriate cellular immunity. No live attenuated
tissue are recommended specimens. Respiratory and vaccine is presently available.
blood specimens are best collected during the
prodromal stage up to 1 to 2 days after the appearance
of the rash. a. MUMPS VIRUS
• Measles antigen can be detected by immunofluorescence
in pharyngeal cells or urinary sediment, but this test is Epidemiology of Mumps Virus
not generally available. Characteristic cytopathologic
effects including multinucleated giant cells with • DISEASE/VIRAL FACTORS
cytoplasmic and nuclear inclusion bodies can be seen in ○ Large relatively unstable enveloped virion,
Giemsa-stained cells taken from the upper respiratory easily inactivated
tract and urinary sediment. ○ Contagion period precedes symptoms
• Antibody, especially IgM, can be detected when the rash ○ May cause asymptomatic shedding
is present. Seroconversion or a fourfold increase in ○ Host range is limited to humans
measles-specific antibodies between acute and
○ Only one serotype
convalescent sera represent the best method of
○ Immunity is lifelong
confirming measles. Immune status testing to
 • TRANSMISSION
○ Large droplet aerosols
• WHO IS AT RISK? Treatment, Prevention and Control
○ Unvaccinated individuals
○ Immunocompromised individuals, more serious • Given the difficulties of controlling the spread of
outcome mumps, vaccine provide the only effective means for
reducing infection. Since the introduction of the live
• GEOGRAPHY/SEASON attenuated vaccine (Jeryl Lynn vaccine) in the United
○ Worldwide States in 1967 and its administration as part of the MMR
○ Endemic in late winter and early spring vaccine, the yearly incidence of cases has declined from
76 to 2 per 100,000. Unfortunately, use of this vaccine
Disease Mechanism of Mumps Virus in the world is limited. Antiviral agents are not
available.
• Infects epithelial cells of respiratory tract
• Spreads systemically by viremia 3. PNEUMOVIRUS (Respiratory Syncytial Virus)
• Systemic infection, especially of parotid gland, testes,
and central nervous system Epidemiology of Respiratory Syncytial Virus
• Principal symptom is swelling of parotid glands because
of inflammation • DISEASE/VIRAL FACTORS
• Cell-mediated immunity is essential for control of ○ Large relatively unstable enveloped virion,
infection and responsible for a portion of the symptoms. easily inactivated
Antibody is not sufficient due to mumps’ ability to ○ Contagion period precedes symptoms and may
spread cell to cell occur in the absence of symptoms
○ Host range is limited to humans

• TRANSMISSION
○ Inhalation of large droplet aerosols

• WHO ARE AT RISK?

○ Infants: lower tract infection; bronchiolitis
and pneumonia
○ Children: spectrum of disease; mild to
pneumonia
○ Adults: reinfection with milder symptoms

• GEOGRAPHY/SEASON
○ Ubiquitous and worldwide
○ Seasonal

Disease Mechanisms of Respiratory Syncytial Virus

• Localized infection of respiratory tract

• Does not cause viremia or systemic spread
• Pneumonia results from cytopathic effect of virus
(including syncytia)
• Narrow airways of young infants readily obstructed by
virus-induced pathology
• Maternal antibody does not protect infant from infection
• Natural infection does not prevent reinfection
• Vaccination increases severity of disease

Upper respiratory infection in

older children and adults
who
are being reinfected against
a
background of partial
immunity

Laboratory Diagnosis
Laboratory Diagnosis
• Respiratory syncytial virus is difficult to isolate in cell
• Virus can be recovered from saliva, urine, pharyx,
culture. Direct detection of viral antigen in infected
secretions from Stensen’s duct, and cerebrospinal fluid.
cells and in nasal washings has been developed using
Virus is present in saliva for approximately 5 days after
immunofluorescence and enzyme immunoassay
the onset of symptoms and in urine for as long as 2
weeks. Mumps virus grows well in monkey kidney cells
Treatment, Prevention and Control
and can be recognized by the development of a
cytopathogenic effect characterized by multinucleated
• In otherwise healthy infants, treatment is supportive,
giant cells.
with oxygen, intravenous fluids, and nebulized cold
• A clinical diagnosis can be confirmed by serologic
stream. Ribavarin, a guanosine analogue, is
testing. A fourfold increase in virus-specific antibody
administered by inhalation (nebulization) and is
level or the detection of mumps-specific IgM antibody
approved for treatment of patients predisposed to a
indicates active infection. Hemagglutination inhibition
more severe course (e.g. premature or
(HI), ELISA and immunoflourescence tests can be used to
immunocompromised infants.
detect mumps virus, antigen or antibody.
• Currently no vaccine is available for RSV prophylaxis. A
previous vaccine containing inactivated RSV actually
 caused recipients to have more severe RSV infection
when subsequently exposed to live virus. This is thought
to have resulted from a heightened immunological
response at the time of wild virus exposure.
RUBELLA VIRUS (Rubivirus of the Togaviridae and Flaviviridae
Family)

Epidemiology of Togaviruses (Rubella Virus)

• DISEASE/VIRAL FACTORS
○ Enveloped virus must stay wet and can be
inactivated by drying, soap and detergents
○ Rubella infects man and can be asymptomatic
○ Virus causes asymptomatic disease
○ There is one serotype

• TRANSMISSION
○ Rubella: respiratory route

• WHO ARE AT RISK?

○ Rubella: children: mild exanthematous disease
○ neonates (<20 weeks): congenital defects
○ Adults: more severe disease with arthritis or
arthralgia Laboratory Diagnosis

• GEOGRAPHY/SEASON • Isolation of rubella virus is difficult and rarely done.

○ Rubella: worldwide The diagnosis is usually confirmed by the presence of
anti-rubella-specific IgM. A fourfold increase in specific
IgG antibody titer between acute and convalescent sera
is also used to indicate a recent infection

Treatment, Prevention and Control

• No treatment has been found for rubella

• The best means of preventing rubella is vaccination with
the live cold-adapted RA27/3 vaccine strain of virus.
The live rubella vaccine is usually administered in
conjunction with the measles and mumps vaccines (MMR
vaccine). The triple vaccine is included routinely in
well-baby care. Vaccination induces both humoral and
cellular immunity

ORTHOMYXOVIRUSES (Orthomyxoviridae)

Influenza Virus
• belong
to
family
Clinical Syndromes

• Rubella infection is usually not cytolytic, and the

disease is normally benign in children. The symptoms in
children are a 3-day rash and swollen glands. Infection
of adults can be more severe, leading to outcomes such
as arthralgia, arthritis and (rarely) thrombocytopenia,
and a postinfectious encephalitis similar to
postinfectious measles encephalitis.

Orthomyxoviridae
• Ortho – true or regular (to differentiate them from
paramyxoviruses)
• Myxo – mucus (refers to their ability to attach to
mucoproteins on the cell surface

100-200 nm in diameter

spherical

500 projecting spikes

80% hemagglutinin antigen

20% neuraminidase
 Three Species of Influenza Virus (based on matrix (M) and
nucleoprotein (NP) antigens):
Hemagglutinins 1. Influenza A
2. Influenza B
• rod-shaped glycoprotein with 3. Influenza C (does not cause significant human disease)
a triangular cross-section
• first identified by its ability to Genetic Variation in Influenza Virus A:
agglutinate erythrocytes
• plays a role in the attachment 1. Antigenic Drift:
and entry of the virus to the – involves Influenza A and B viruses
host’s cells – due to point mutation (two or three amino
• determines virulence acid substitution on the viral polypeptides)
– slowly progressive and cumulative
– cases more frequent but localized outbreaks
(epidemics)
1. Antigenic Shift:
– only in Influenza A
– involves gene swapping or reassortment
between two viruses
Neuraminidase – herd immunity of previously infected
population will not be effective against the
• mushroom-like spikes reassortant strains
• an enzyme that destroy – results in pandemics
neuraminic (sialic) acid, a
component of the specific Human Influenza Pandemics in the 20th Century
cell receptor for these
viruses • SPANISH FLU
• main function is the ○ Year – 1918-1919
release of the new virus ○ Subtype – H1N1
from cells ○ Origin – China? Europe? North America?
○ Viral genes – contain mammalian and avian
Unique Features of the Influenza A and B Virus
genes
• Enveloped virion with a genome of 8 negative-sense ○ Mortality – 25-50 million worldwide;500T in US
• ASIAN FLU
RNA nuclocapsid segments
• The hemagglutinin, (HA) glycoprotein is the VAP, fusion ○ Year – 1957
protein, and elicits neutralizing, protective antibody ○ Subtype – H2N2
responses ○ Origin – China
• Influenza transcribes and replicates its genome in the ○ Viral genes – reassortment with avian virus
target cell nucleus but assembles and buds from the
plasma membrane
○ Mortality - >1 million worldwide; ~70T in US
• The antiviral drugs amantadine and rimatadine inhibit • HONGKONG FLU
an uncoating step and most likely target the M2 protein ○ Year – 1968
• The segmented genome promotes genetic diversity
caused by mutation and reassortment of segments upon
○ Subtype – H3N2
infection with two different strains ○ Origin – China
○ Viral genes – reassortment of avian virus
Epidemiology of Influenza A and B ○ Mortality - >1 million worldwide; ~34T in US
• DISEASE/VIRAL FACTORS • RUSSIAN FLU
○ Influenza is enveloped and is inactivated by ○ Year – 1977
detergents
○ Subtype – H1N1
○ Segmented genome facilitates major genetic
strain changes, especially the targets of the ○ Origin – China, Russia
humoral immune response, HA and NA ○ Viral genes – reappearance of 1950s H1N1 virus
(from frozen source?)
• DISEASE/VIRAL FACTORS ○ Mortality – low mortality worldwide and in the
○ Influenza infects many vertebrate species US
including other mammals and birds
○ Co-infection with animal and human strains of
virus can generate very different virus strains
by genetic reassortment
○ Transmission of virus often precedes
symptoms

• TRANSMISSION
○ Inhalation of small aerosol droplets released
by talking, breathing, coughing
○ Virus “likes cool,” less humid atmosphere
(e.g. winter heating season)
○ Spread extensively by school children

• WHO ARE AT RISK?

○ Seronegative individuals
○ Adults” Classic “flu syndrome”
○ Children: Asymptomatic to severe respiratory
infections
○ High-risk groups: elderly, immunosuppressed
individuals with underlying cardiac or
respiratory problems including asthma and
smokers

• GEOGRAPHY/SEASON
○ Worldwide occurrence; epidemics local;
pandemics worldwide
○ Disease more common in winter
 slow to aid the diagnosis and is generally used for
epidemiological purposes.

Treatment, Prevention and Control

• Amantadine and its analogue, rimantadine, are effective

for prophylactic use and for treatment during the first
24 – 48 hours after the onset of Influenza A illness.
• Immunization
• Natural – from prior exposure
• Formalin inactivated vaccine (strain of the year)

AVIAN INFLUENZA (AI) “Bird Flu”

• an infectious disease of birds caused by Type A strains

of the influenza virus
• first identified in Italy in 1878 affecting chickens
• occurs worldwide

Clinical Syndromes Epidemiology

• Depending on the degree of immunity to the infecting • highly contagious, affecting all avian species
strain of virus and other factors, the infection may • incubation period is 3-5 days
range from asymptomatic to severe. Patients with • highly pathogenic avian influenza isolates have been
underlying cardiorespiratory disease or immune obtained primarily from chickens and turkeys
deficiency, even that associated with pregnancy, are
more predisposed to severe diseases. Sources of Virus
• After an incubation period of 1 to 4 days, the “flu”
syndrome begins with a brief prodrome of malaise and • Feces
headache lasting a few hours. This is followed by the • Respiratory secretions
abrupt onset of fever, severe myalgia, and usually a
nonproductive cough. The illness persists for Characteristics of Influenza Virus
approximately 3 days, then, unless a complication
occurs, recovery is complete. • can survive in feces for several months
• can survive in water for up to 4 days at 22oC, more than
Acute Influenza Infection in Children 30 days at 0oC and indefinitely in frozen material
• killed by alcohol, bleach, formalin, or iodine compounds
• Acute disease similar to adults but having higher fever, • 5% bleach solution is appropriate for dealing with
gastrointestinal symptoms (abdominal pain, vomiting) biohazardous spillage
otitis media, myositis, and croup more frequently • killed by heat
Time Temperature
Complications of Influenza Virus Infection 3 hrs 56o C
30 mins 60o C
• Primary viral pneumonia 1 min 70o C
• Secondary bacterial pneumonia
• Myositis and cardiac involvement Transmission:
• Neurological syndromes
○ Guillain-Barre syndrome • direct contact with secretions from infected birds,
○ Encephalopathy especially feces
○ Encephalitis • contaminated feed, water, equipment and clothing
○ Reye’s syndrome • clinically normal waterfowl and sea birds may introduce
the virus into the flocks
Laboratory Diagnosis • broken contaminated eggs may infect chicks in the
incubator

Clinical Types

1. Low Pathogenic Avian Influenza (LPAI)

– causes mild disease (decreased egg
production, mild respiratory symptoms)
– as it circulate, may mutate w/in 6-9 months
into a highly pathogenic strain
1. Highly Pathogenic Avian Influenza (HPAI) (Fowl
Plague)
– coughing, sneezing, excessive lacrimation
– cyanosis of unfeathered skin
– edema of the head
– ruffled feathers
– diarrhea
– nervous system disorders
– sudden death without clinical signs
– due to subtypes H5 0r H7
– 100% mortality
• The characteristic symptoms of influenza combined with
the presence of community outbreak are often Previous Outbreaks of Highly Pathogenic Avian Influenza
sufficient for a diagnosis. Influenza viruses from
respiratory secretions can generally be isolated in • ITALY
primary monkey kidney cell cultures or Madin Darby ○ Year – 1999-2000
Canine Kidney (MDCK) cell line. Occasional strains may
require chick embryo inoculation for primary isolation.
○ Domestic bird affected – turkey
• Specific identification of the influenza virus requires ○ Strain – H7N1
immunological tests such as immunofluorescence or
inhibition of hemadsorption or hemagglutination with • HONGKONG (CHINA)
specific antibody. ○ Year – 2002
• Enzyme immunoassay or immunofluorescence can be ○ Domestic bird affected – chicken
used to detect viral antigen in exfoliated cells, ○ Strain – H5N1
respiratory secretion, or cell culture. Serology is too
 ○ diffuse, multifocal, patch infiltrates or
• CHILE segmented/lobular consolidations
○ Year – 2002
○ Domestic bird affected – chicken Laboratory Diagnosis
○ Strain – H7N3
• Optimal specimen for Influenza virus detection is
• NETHERLANDS nasopharyngeal aspirate obtained within 3 days of the
○ Year – 2003 onset of symptoms, however, nasopharyngeal swabs and
other specimen can be used
○ Domestic bird affected – chicken
• rapid antigen detection assay - commercially available,
○ Strain – H7N7 provides results in 15-30 minutes but not sensitive or
specific
Control Measures in Outbreaks • Virus culture
○ Enables further antigenic and genetic
• slaughtering of all birds (culling) characterization, drug susceptibility and
• disposal of carcasses and all animal products vaccine preparation
• clearing and disinfection of poultry ○ Takes 2-10 days
• allow at least 21 days before restocking ○ Must be performed under Biosafety level 3+
laboratory conditions
Problems associated with outbreaks • Reverse Transcriptase PCR
1. Extremely difficult to control even under favorable
○ Detects diverse Influenza A viruses including
conditions Avian H5N1 strains
○ Can be performed in standard Biosafety level
– 1983 Pennsylvania (USA) outbreak took 2 years 2 laboratory
to control
Treatment, Prevention and Control
– 1995 Mexico outbreak – H5N2 strain has never
been entirely eliminated up to the present
• Indication for laboratory testing
1. Severe Economic Loss
1. Hospitalized Patients
– 1983 Pennsylvania (USA) outbreak:
○ Radiographically confirmed pneumonia, acute
○ 17 million birds were destroyed respiratory distress syndrome, or other severe
○ direct cost in US is $62 million respiratory illness for which an alternate
diagnosis has not been established and
○ indirect cost in US is $250 million
○ History of travel to a country with
– 1999-2001 Italy
documented H5N1 avian influenza within 10
○ 13 million birds were destroyed
days of symptom onset
– 2003 Netherlands (reached Belgium and
Germany) 1. Case to case basis
○ birds destroyed: ○ Temperature > 38°C and
 30M in Netherlands ○ One or more of the following: cough, sore
 2.7M in Belgium throat, shortness of breath and
 400T in Germany ○ History of contact with domestic poultry (eg.
Visited a poultry farm, household raising
poultry, or bird market) or a known or
1. Bird to human transmission suspected human case of influenza H5N1
-affected country within 10 days of symptom
– close human contact with live animals onset.
provides an ideal environment for the zoonotic • Antiviral Treatment:
transfer and evolution of infectious disease ○ Current H5N1 strains are resistant to
agent (live animal market or wet markets)
Amantadine and Rimantandine but sensitive to
– since 1977, 7 confirmed outbreaks of human
neuraminidase inhibitors (Oseltamivir and
infections with avian influenza
Zanamivir)

• Preventive Measures:
○ avoid contact with poultry
○ thorough and frequent hand hygiene using
soap and water or alcohol - based hand rubs
○ poultry, including eggs should be cooked
thoroughly
○ Persons involved in outbreak eradication
should use appropriate personal protective
equipment (gloves, disposable clothing, shoe
covers, safety goggles, and particulate
respirators.

Clinical Features • Isolation Precautions for patients hospitalized with

suspected or confirmed Avian Influenza H5N1
• HONGKONG 1997 ○ Standard Precaution – strict hand hygiene
○ influenza-like illness with pneumonia before and after all patient’s contact
○ liver dysfunction ○ Contact Precautions – use gloves and gown for
○ abnormal clotting profiles all patient’s contact
○ gastrointestinal manifestations ○ Eye Protection – wear when within 3 feet (1
○ renal failure m) of the patient
○ pancytopenia (hemophagocytic syndrome) ○ Airborne Precaution –
 Place patient in an airborne
• VIETNAM 2004 isolation room (negative air pressure
○ of the 10 patients, 9 had direct contact with with 6-12 air exchange per hour)
poultry (chicken or ducks)  Use of fit tested respirator when
○ incubation period of 2-4 days (mean 3 days) entering a room (N-95 filtering
○ fever facepiece respirator
○ cough
○ diarrhea • Vaccination
○ shortness of breath ○ Human Influenza Vaccine
○ lymphopenia  current inactivated trivalent human
influenza vaccine provides no
 protection against H5 and H7 avian ○ All ages
influenza strains.
 given to people at risk of avian and Clinical Syndromes
human influenza viruses
simultaneously and to decrease the • Most common cause of common cold – sneezing followed
possibility of reassortment. by rhinorrhea then nasal obstruction
○ H5N1 Vaccine • Mild sore throat
 a prototype vaccine have been • Headache
developed using plasmid-based • Malaise
reverse genetic technology. • Fever
 clinical trials and safety testing must • Chills
be completed before it can be
commercially available. Laboratory Diagnosis

REOVIRUS (Reoviridae) • Unnecessary unless the physician needs to establish

which of the many respiratory viruses cause the illness
• Culture
• Serology

Treatment, Prevention and Control

• Supportive
• No effective antiviral drug
• Handwashing and disinfection of contaminated objects
are the best means of preventing the spread of the virus

Unique Features of Reoviridae

• Double-layered capsid virion (60 to 80 nm) has

icosahedral symmetry containing 10 to 12 double-
stranded genomic segments (depending on the virus)
• Virion is resistant to environmental and gastrointestinal
conditions (e.g. detergents, acidic pH, drying0
• Rotavirus and orthoreovirus virions are activated by mild
proteolysis to intermediate/infectious subviral particles
(ISVP), increasing their infectivity
• Inner capsid contains a complete transcription system,
including enzymes for 5’ capping and polyadenylate
addition.
• Viral replication occurs in the cytoplasm. Double-
stranded RNA remains in the inner core
• Rotavirus inner capsid aggregates in the cytoplasm and
then buds into the endoplasmic reticulum, acquiring its
outer capsid and a membrane, which then lost
• Virus is released by cell lysis

Viruses in GIT Infections

Laboratory Diagnosis
• Rotaviruses
• Serologic diagnosis of infection requires the • Norwalk-like agent
documentation of a fourfold or greater increase in virus • Coronaviruses
specific antibody between an acute and convalescent • Fastidious(Enteric) Adenoviruses
specimen, since antibodies to orthoreoviruses typically • Astroviruses
are present in healthy children and adults. • Caliciviruses
• The techniques used to detect orthoreovirus antibody • others: Picorna-Parvo-like viruses
include hemagglutination inhibition, neutralization,
complement fixation and indirect immunofluorescence Generalities
but are not routinely performed
• Disease is manifested mainly as diarrhea
Treatment • Affect all age group
• Sporadic or epidemic form
• No specific antiviral therapy available. • Most cases are self-limited
• Infection is usually asymptomatic

RHINOVIRUS (Picornaviridae) 1. ROTAVIRUSES (from the family Reoviridae)

Characteristics • Most common cause of epidemic diarrhea in infants

• Can also cause diarrhea in animals
• Belong to family Picornaviridae • Genome: 11 segments of ds:RNA
• More than 100 serotypes • Groups A-F have been described
• Most important cause of the common cold and upper • Group A: most common cause of GE in children
respiratory tract infections
Epidemiology
Epidemiology
• Transmission: fecal-oral route
• VIRAL FACTORS • Most cases are sporadic
○ Resistant to drying and detergent • Cases are worse in developing countries
○ Labile at acidic pH
○ Optimum growth is at 33°C Clinical Manifestations

• TRANSMISSION • Abrupt onset of diarrhea

○ Direct contact via infected hand and fomites • Usually non-bloody & non-mucoid
○ Inhalation of infected droplets • Other S/S: fever & vomiting
• Most severely affected: infants 6-24 months old
• WHO ARE AT RISK? • Incubation period: 2-5 days
Duration of Illness

• About one week

• Usual complications: dehydration & metabolic acidosis
• Diarrhea is due to decreased absorption

Host Response

• Initially: IgM
• Followed by: IgG & secretory IgA

Diagnosis

• Cell culture
• EM, IEM, ELISA
• LPA, Gel Electrophoresis

Treatment & Prevention

• Supportive
• Immunization

Epidemiology
2. NORWALK-LIKE GROUP (miscellaneous virus)
• Tend to occur in small outbreaks & sporadic cases
• Small, non-enveloped 27nm particle with ss-RNA genome • Re-infection is frequent
• Self-limited gastroenteritis
• 1969: GE outbreak in Norwalk, Ohio Clinical Manifestations

• Diarrhea in older children & young adults

• Prolonged viral excretion (about 18 months)
• Usually: poor-hygiene environment

Epidemiology Treatment

• Usually occurs in schools, recreational camps, nursing • supportive

homes
• Infection is mainly through food & water and person-to-
person 4. FASTIDIOUS (ENTERIC) ADENOVIRUSES
• Agent occurs worldwide & outbreaks all-year round
• 1st described in 1975
Clinical Infection • Do not grow easily in cell culture
• Causally associated with enteric illness
• Most have: nausea, vomiting, abdominal pain • Significant pathogen of diarrheal illness in children (2nd
• About half: diarrhea to Rotavirus in frequency)
• Some: chills & fever • All belong to serogroup F & only serotypes 40 & 41
• Symptoms lasts for 24 hours Responsible for diarrhea in infants < 1 year old
• Stools: non-bloody & non-mucoid
Incubation period
Diagnosis
• 3-10 days
• Best: IEM & RIA
• RIA & ELISA: most efficient in detecting soluble & Other S/S
particulate antigens
• cough
• rhinorrhea
3. CORONAVIRUSES • wheezing
• pneumonia
• Pleomorphic, enveloped ss-RNA • conjunctivitis
• Can cause respiratory & intestinal disease in animals
• Human strains: 1st associated with URTD & LRTD Duration

• Illness: mild to moderate, lasts 6-9 days, occurs any

month of the year
Diagnosis • Often results from: eating contaminated shellfish or
other food & water
• virus in stool (EM, ELISA, etc.) • Rarely causes fatal disease

5. ASTROVIRUSES (miscellaneous virus) The picornavirus structure of the HAV. The icosahedral capsid is made up of
four viral polypeptides (VP1 to VP4). Inside the capsid is a single-stranded,
• Described in 1975 positive-sense RNA (ssRNA) that has a genomic viral protein (VPg) on the 5’
end.
• 28-30 nm particle
• Shed in stools in very large numbers
• Present in the stools of infants with or without acute
gastroenteritis
• 5-to 6-pointed star-shaped particles
• Associated with disease in many countries: pediatric
wards, schools, nursing homes
• See Box 64-3

S/S

• Malaise
• low-grade fever
• watery diarrhea for 3 days

Diagnosis

• EM, IEM, IF of cell cultures

Incubation period

• 1-3 days
Epidemiology
6. CALICIVIRUSES (miscellaneous virus) • Responsible for about: 40% of all hepatitis cases
• High concentration of virus in feces esp. 2 weeks before
• 35-39 nm particles
jaundice
• ‘star of David’ appearance
• 5 antigenic types
• 90% of children & 50% of adults: have inapparent but
productive infections
• Almost all children are (+) for antibodies by 5 years
• Diarrhea & asymptomatic infections have been
• Outbreaks usually originate from a common source (eg.
Water supply
documented
• Incidence directly related to: poor hygiene & over-
• See Box 64.3 crowding
• Seropositivity in adults:
Illness 13%- Sweden
• similar to Rotavirus diarrhea 88%- Taiwan
Transmission

• Fecal-oral spread occurs, as well as food-borne

Diagnosis

• EM, IEM, ELISA

7. OTHER VIRUSES

A. PICORNA-PARVOVIRUS-LIKE

• have also been isolated in stools of patients with

diarrhea & asymptomatic patients

B. MINIREOVIRUS & MINIROTAVIRUS

• have been visualized in stools of children with diarrhea Clinical Syndromes

& in infants who have acquired diarrhea within hospital
setting • Due to immune-mediated damage to the liver
• Disease in children: milder & usually asymptomatic
• Symptoms usually wanes during icteric phase
HEPATITIS VIRUSES • Complete recovery: about 99%
• Fulminant hepatitis: 1-3 per 1000 with 80% mortality
• 5 types: A-E
• Main target organ: liver Laboratory Diagnosis
• Differ: structure, mode of replication, course of disease,
mode of transmission • Serology: Igm anti-HAV (by ELISA or RIA)
• Classic signs: jaundice plus elevated liver enzymes
• Agents are readily spread (infected persons are Tx, Prev’n, Control
contagious before or even without symptoms)
• Hygienic measures
• Water chlorination
HEPATITIS A
• Immune globulin (Ig): 80% effective if given before or
• Caused by a picornavirus, Enterovirus 72 early in the incubation period
• Spread by fecal-oral route
• Incubation period: about 1 month
• Does not cause HEPATITIS B
chronic liver
disease • Due to a DNA virus
• Spread parenterally (blood, needle, sex, perinatal)
• Median incubation period:3 months
• 5-10%: develops chronic hepatitis
 • Causally associated with primary hepatocellular
carcinoma

1. Hep B: Acute infection

• Only 25% of those clinically infected are clinically

apparent
• Characterized by: long incubation period & an insidious
onset
• S/S: fever, malaise, anorexia
• Then: nausea, vomiting, abdominal discomfort, chills…
• Next: jaundice, dark urine, pale stools
• 1st sign of recovery: renewed appetite
• Fulminant cases: 1% of icteric cases

Epidemiology

• US: 300,000 infected annually

• High rates of sero-positives: Italy, Greece, Africa,
Southeast Asia
• Chronic carrier: HBsAg positive on 2 occasions at least 6
months apart
• Major risk factors: sexual promiscuity & drug abuse

Clinical Syndromes

1. Acute Infection
2. Chronic Infection
3. Primary Hepatocellular Carcinoma

Spread of HBV in the body. Initial infection with HBV occurs through
injection, heterosexual and homosexual sex, and birth. The virus then
spreads to the liver, replicates, induces a viremia, and is transmitted in
various body secretions in addition to blood to start the cycle again.
Symptoms are caused by cell-mediated immunity and immune complexes
between antibody and HBsAg

2. Hep B: Chronic infection

• Occurs in 5-10% of HBV infections

• Usually occurs after mild or inapparent illness
• Usually detected by: elevated liver enzyme on routine
chemistry
• 10% of chronic cases: develops cirrhosis & liver failure

Major determinants of acute and chronic HBV injection. HBV infects the
liver but does not cause direct cytopathology. Cell-mediated immune lysis
of infected cells, potentially triggered by interferon action, produces the
symptoms and resolves the infection. Insufficient immunity can lead to
chronic disease. Chronic HBV disease predisposes a person to more serious
outcomes. Purple arrows indicate symptoms; green arrows indicate a
possible outcome.

Development of the chronic HBV carrier state. Routine serodiagnosis is

difficult during the HBsAg window when HBs and anti-HBs are undetectable.

3. Primary Hepatocellular Carcinoma

• WHO: 80% of all PHC cases are secondary to chronic

Hepatitis B infection
• Usually fatal
• Latent period between HBV infection & PHC: 9-35 years
Pathophysiology: PHC ○ Virus causes chronic disease with potential
shedding.
• The virus induces carcinoma by promoting continued
liver repair and cell growth in response to tissue damage • TRANSMISSION
OR by integrating into host chromosome & stimulates ○ In blood, semen, and vaginal secretions (HBV);
growth saliva and mother’s milk).
○ Via transfusion, needlestick injury, shared
Laboratory Diagnosis drug paraphernalia, sex, and breast-feeding.

• Screening: agglutination test • WHO IS AT RISK?

• Confirmatory: ELISA (antigen & antibody detection) ○ Children: mild asymptomatic disease with
• Serologic Markers: Hepatitis B establishment of chronic infection.
Exposure 0 time ○ Adults: insidious onset of hepatitis.
HBsAg 2 weeks ○ HBV-infected people co-infected or
HBeAg 1 month superinfected with HDV: abrupt, more severe
Anti-HBc 6 weeks symptoms with possible fulminant disease.
Anti-HBe 5 months ○ Adults with chronic HBV: at high risk for
Anti-HBs 6 months primary hepatocellular carcinoma.

(SGPT: 2-5mon; symptoms: 21/2-4mon) • MODES OF CONTROL

○ Avoidance of high-risk behavior
○ HBV: vaccine and screening of blood supply.

Clinical Syndrome

• HCV can cause acute infection but is more likely to

establish chronic infections.
• A viremia can be detected w/in 1-3 weeks of a
transfusion of HCV-contaminated blood
• The viremia lasts 4-6 months in people with an acute
infection
• In acute infection, it is similar to HAV and HBV but
symptoms are usually milder
• Chronic persistent hepatitis caused by HCV is even
more prevalent than that caused by HBV, often
progressing to chronic active hepatitis, cirrhosis, and
finally liver failure
• Cell-mediated immunopathology is responsible mainly
Serologic events associated with the typical course of acute hepatitis B for producing the tissue damage.
disease. • Continual liver repair and induction of cell growth
occurring during chronic HCV infection are predisposing
Tx, Prev’n, Control factors in the dev of PHC.

• No specific treatment Laboratory Diagnosis

• Trials: interferon, adenine arabinoside, steroids,
azathioprine • ELISA detection of Antibody
• Blood screening • Seroconversion occurs w/in 7-31 weeks of infection
• Vaccination • The presence of the virion RNA in serum I s a better
• Hepatitis B Immune-globulin indicator of the disease
• RT-PCR can detect HCV RNA in seronegative people
Hep B immune-globulin
• For post-exposure prophylaxis for newborns of HBsAg(+) Treatment, Prevention and Control
mothers & per mucosal exposure to secretions of
individuals who are HBsAg positive • Recombinant interferon-alpha is the only known
HEPATITIS C effective treatment for HCV.
• Supportive therapy
•

HEPATITIS D

• Approx. 15 M people are infected with HDV (delta

agent)
• Responsible for causing 40% of fulminant hepatitis
infections
• Uses HBV and target cell proteins to replicate and
produce its one protein
• A viral parasite
• The HBsAg is essential for packaging the virus

Laboratory Diagnosis

• ELISA and RIA to detect the delta antigen or antibodies

• Delta agent can be detected in blood in acute phase
accounts for 90% of the cases of NANBH virus infection and is
the major cause of posttransfusion hepatitis. Pathogenesis
• a flavivirus with a positive sense RNA genome and is
enveloped. • the delta agent is spread in blood, semen, and vaginal
• HCV has an inclination to establish noncytolytic secretions.
persistent infections and therefore chronic disease • It can only replicate and cause disease only in people
with active HBV infections
Epidemiology of HBV, HCV, and HDV • It is transmitted through the same routes as HBV. A
person then becomes co-infected with HBV and the
• DISEASE/VIRAL FACTORS
delta agent.
○ Enveloped virus is labile to drying. HBV is less
• A person w/ chronic HBV can also be superinfected with
sensitive to detergents than other enveloped
the delta agent
viruses.
• A more rapid, severe progression occurs in HBV carriers
○ Virus is shed during asymptomatic periods.
superinfected w/ HDV than in co-infected w/ HBV and
the HDV.
 • Replication of delta agent results in cytotoxicity and
liver damage
• Protection stems from the immune response to HBsAg
because it is the external antigen and viral attachment
protein for HDV
• Damage to the liver occurs as a result of the direct CPE
of the delta agent combined with immunopathology of
the HBV disease

Clinical Syndromes

• fulminant hepatitis is more likely to develop in people

infectd with the delta agent than in those infected with
the other hepatitis virus
• can result in hepatic encephalopathy (w/ altered
metnal capacity) and massive hepatic necrosis

Treatment, Prevention and Control

• no specific treatment for HDV hepatitis

• prevention of infection w/ HBV will prevent HDV
infection

HEPATITIS E

• HEV (E-NANBH) (the E stands for “enteric” or

“epidemic”) is predominantly spread by the fecal-oral
route, esp in contaminated water
• Resembles calicivirus and Norwalk agent in size and
structure
• Problematic in developing countries
• Symptoms and course of HEV are similar to those of HAV
disease
• Causes only acute disease
• Poor serum IgG response
• Has a ss-polyA RNA genome RHABDOVIRUSES

HEPATITIS F

• round 27-37 nm Virus-Like Particle (VLP)

• genome is a 20 kb dsDNA
• seen in the cytoplasm of hepatocytes only in one
experimental monkey
• infection is sporadic and enterically transmitted
• viral antigens (feces) and elevation of transaminases
appear in 20 days
• assume a fatality course in 20% of cases
• HFV antigen has been detected by ELISA in 66% of cases

PHYSIOLOGY, STRUCTURE AND REPLICATION

HEPATITIS G
• within the envelope, the helical nucleocapsid is coiled
• GB was a 34 year-old surgeon who contracted hepatitis symmetrically into a cylindrical structure, giving the
• “GB Agent” in his serum ahs been passed in monkeys appearance of striations.
over the years • The nucleocapsid is composed of:
• GB Agent contains 2 flavivirus sequences related to but ○ 1 ss (-) RNA
distinct from HCV ○ nucleoprotein (N) – major structural protein of
• ssRNA virus of family Flaviviridae the virus
• A transfusion-transmitted infection  maintains RNA in a configuration
• HGV co-infection is observed in 6& of chronic HBV acceptable for transcription
infections and 10% in chronic HCV infections  protects RNA from ribonuclease
• Unclear if HGV is actually pathogenic digestion
• Diagnostic tests: Anti-HGV, HGV RNA by PCR. ○ large (L) proteins
○ nonstructural proteins (NS)
• Matrix (M) protein lies between the envelope and the
nucleocapsid
• L and NS constitute the RNA polymerase
• Assembly of the virion occurs in 2 places:
○ Nucleocapsid – cytoplasm
○ Envelopment and release – at cell plasma layer
 ° Enveloped virus must stay wet but can be
inactivated by soap and detergents
DISEASE MECHANISMS OF RABIES VIRUS
• TRANSMISSION
• Rabies is usually transmitted in saliva and is acquired ° Zoonosis:
from the bite of a rabid animal  Reservoir: wild animals
• Rabies virus is not very cytolytic and seems to remain  Vector: wild animals and
cell associated unvaccinated dogs and cats
• Virus replicates in the muscle at the site of the bite, ° Source of virus:
with minimal or no symptoms (incubation phase)  Major: saliva in bite
• The length of the incubation phase is determined by the  Minor: aerosols in bat caves
infectious dose and the proximity of the infection site to containing rabid bats
• WHO IS AT RISK?
the CNS and brain.
° Vets and animal handlers
• After weeks to months, the virus infects the peripheral ° Countries w/ no vaccine programs
nerves and travels up the CNS to the brain (prodrome
phase). HISTORICAL DEVELOPMENT
• Infection of the brain causes classic symptoms, coma, 1884 Pasteur vaccine. Historical interest
and death (neurological phase). 1911 Sample vaccine. Phenol-inactivated virion. Vaccine prepared from
• During the neurological phase, the virus spreads to the brains of rabbit, sheep or goats. Widely used in dev. Countries.
glands, skin, and other body parts, including the salivary Cheap. Liable to cause neuroparalytic rxn
glands, from where it is transmitted. 1957 Duck embryo vaccine. B-propiolactone inactivated. Cause allergic
• Rabies infection does not elicit an antibody response rxn. Ineffective antigen
until the late stages of the disease, when the virus has 1964 Human diploid cell strain virus (HDCS). Virus inactivated w/ B-
propiolactone
spread from the CNS to other sites.
• Antibody can block the progression of the virus.
• The long incubation period allows active immunization TREATMENT
as a postexposure treatment. Nature of contact Status of animal treatment
Indirect contact Appears healthy or No needed
only has signs suggesting
PATHOGENESIS AND IMMUNITY rabies
Licks to skin Appear healthy or has
1. virus may directly infect nerve endings by binding to signs
nicotinic acetylcholine receptors or muscle at the site of a. u
inoculation n
2. virus remains at the site for days to months before d
progressing to the CNS er Start immediately
3. virus travels by retrograde axoplasmic transport to the o Start immediately
dorsal root ganglia and to the spinal cord bs
4. affected areas include the hippocampus, BS, ganglionic er
cells of the pontine nuclei and purkinje cells v
5. virus disseminates via afferent neurons to highly at
innervated sites io
6. after the virus invades the brain and SC, an encephalitis n
develops and neurons degenerate <
• neutralizing antibodies are not apparent until after the 1
clinical disease is well established 0
• antibody can block the spread of virus to the CNS and to d
the brain if administered or generated during the a
incubation period ys
• period is often long enough to allow generation of a b. es
therapeutic protective antibody response c
a
p
e
d
c. ki
ll
e
d
Bites HRIG (passive –
immunization) –

FILOVIRUSES

• includes the Marburg and Ebola viruses

• are filamentous, enveloped, negative-strande RNA
1) virus inoculated 2) viral replication in muscle 3) virion enters PNS 4) viruses
passive ascent via sensory fibers 5) replication in dorsal ganglion 6) rapid • agents cause severe or fatal hemorrhagic fevers and are
ascent in spinal cord 7) infection of SC, BS, cerebellum and other brain endemic in Africa
structures 8) descending infection via nervous system to eye, salivary
glands, skin and other organs.
STRUCTURE AND REPLICATION
EPIDEMIOLOGY • ssRNA genome that encodes 7 proteins
• DISEASE/VIRAL FACTORS • replicates in the cytoplasm similar to the rhabdoviruses
° Disease has long, asymptomatic incubation
period
PATHOGENESIS
 • filoviruses replicate efficiently, producing large amounts
of virus and causing tissue necrosis in parenchymal cells
of liver, spleen, lymph nodes and lungs
• widespread hemorrhage causes edema and hypovolemic
shock

EPIDEMIOLOGY
• Marburg virus was first detected in laboratory workers in
Marburg, Germany who had been exposed to tissues
from African green monkeys
• Also in Zimbabwe and Kenya
• Outbreaks of Ebola have occurred in Zaire and Sudan
CLINICAL SYNDROME
• most severe causes of viral hemorrhagic fevers
• begins w/ influenza-like symptoms
• death occurs in as many as 90% of patients w/ clinically • spongiform encephalopathy – characteristic
evident disease degeneration of neurons and axons of the gray matter
that occurs in affected patients
LABORATORY DIAGNOSIS • vacuolation of the neurons, formation of amyloid-
• handling requires level 4 isolation procedures containing plaques and fibrirls, proliferation and
• Marburg – can be grown on tissue culture hypertrophy of astrocytes, fusion of neurons and
• Ebola – needs animal host adjacent glial cells
• Infected cells have large eosinophilic cytoplasmic • no inflammation or immune response to the agent is
inclusion bodies generated
• Antigens can be detected by immunofluorescence • incubation for CJD and kuru may be as long as 30 yrs but
the patient dies w/in a year when symptoms become
TREATMENT evident
• antibody-containing serum and interferon therapies

SUBACUTE SPONGIFORM ENCEPHALOPATHIES AND

UNCONVENTIONAL AGENTS

• cause spongiform encephalopathies (slow

neurodegenerative diseases)
• include the human diseases kuru, Creutzfeldt-jakob
disease (CJD), Gerstmann-Straussler-Scheniker (GSS)
EPIDEMIOLOGY
disease, and fatal familial insomnia (FFI)
• include the animal diseases scrapie, bovine spongiform • DISEASE/VIRAL FACTORS
encephalopathy (mad cow disease), chronic wasting ° Agents are impervious to standard viral
disease and transmissible mink encephalopathy disinfection procedures
• it has no virion structure or genome, no immune ° Diseases have very long incuation periods (30
response is elicited and agents are resistant to yrs)
inactivation by heat, disinfectants and radiation
• The slow virus agent appears to be a modified host • TRANSMISSION
protein known as a prion (a small proteinaceous ° Transmission is via infected tissue, or
infectious particle) syndrome may be inherited
• Long incubation period which can last 30 years in ° Infection occurs through cuts in skin,
humans transplantation of contaminated medical
devices and potentially through ingestion of
infected tissue

• WHO IS AT RISK?
° Women and children of the Fore tribe in New
Guinea were at risk for kuru
° Surgeons, transplant and brain surgery
patients

CLINICAL SYNDROME

• cause a progressive, degenerative neurological disease

w/ long incubation period but with rapid progress to
death after onset of symptoms
• loss of muscle control, leading to shivering, myoclonic
jerks, tremors, loss of coordination and progressive
STRUCTURE AND PHYSIOLOGY dementia
• the slow virus agents were suspected to be viruses
because they can pass through filters that block the
passage of particles greater than 100nm LABORATORY DIAGNOSIS
• the prototype of these agents is scrapie; scrapie-
infected hamsters have scrapie-associated fibrils in their • no methods for directly detecting virus using EM,
brain; these are infectious and contain prions antigen detection or nucleic acid probes
• prions lack detectable nucleic acids and consists of • no serological tests can detect antibody
aggregates of protease-resistant, hydrophobic • diagnosis is made on clinical grounds w/ confirmation by
glycoprotein the characteristic histological changes in brain tissue

PATHOGENESIS TREATMENT, PREVENTION, CONTROL

• no treatment for kuru or CJD

• autoclaving at 15 psi for 1 hr, treatment w/ 5%
hypochlorite solution or 1.0M sodium hydroxide

ENTEROVIRUS
 EPIDEMIOLOGY

• DISEASE/VIRAL FACTORS
° Infection is often asymptomatic
° Virion is resistant to environmental conditions
(detergents, acid, drying, mild sewage
treatment and heat)

• TRANSMISSION
° Fecal-oral route; poor hygiene, dirty diapers
° Ingestion via contaminated food and water
° Contact w/ infected hands and fomites
° Inhalation of infectious aerosols

• WHO IS AT RISK?
° Young children: at risk for polio
(asymptomatic or mild disease)
° Older children/adults: polio (asymptomatic or
paralytic disease)
° Newborns and neonates: highest risk for
coxsackievirus and enterovirus disease

CLINICAL SYNDROMES ASSOCIATED WITH MAJOR ENETROVIRUS

GROUPS

• infections are usually asymptomatic SYNDROME OCCURRENCE POL COXA COXB ECHO
• do not usually cause enteric disease but are transmitted Paralytic disease Sporadic + + + +
by the fecal-oral route Encephalitis, meningitis Outbreaks + + + +
• Poliovirus is the prototype carditis Sporadic + + +
• The upper respiratory tract, oropharynx and intestinal Neonatal disease Outbreaks + +
tract are portals of entry Pleurodynia Outbreaks +
Herpangina Common +
• Virions are impervious to stomach acid, proteases and
Hand-foot-and-mouth Common +
bile disease
• Replication is initiated in the mucosa and lymphoid Rash disease Common + + +
tissue of the tonsils and pharynx, it later infects the Acute hemorrhagic Epidemics +
peyer’s patches and underlying intestinal mucosa conjunctivitis
• Primary viremia – spreats virus to receptor-bearing Respiratory tract Common + + + +
target tissues (where 2nd phase of replication begins) infections
• In polioviruses – the virus must cross the blood-brain Undifferentiated fever Common + + + +
barrier or may gain access to the brain by infecting Diarrhea, Uncommon +
skeletal muscle and traveling up the innervating nerves gastrointestinal disease
Diabetes, pancreatitis Uncommon +
to the brain
Orchitis Uncommon +
• Polio virus has one of the narrowest tissue tropisms, Disease in + + +
recognizing a receptor expressed on anterior horn cells immunodeficient
of the spinal cord, dorsal root ganglia, motor neurons, patients
skeletal muscle cells, lymphoid cells Congenital anomalies Uncommon + +
• Coxsackieviruses and echoviruses recognize receptors
expressed on more cell types and tissues
• Receptors are rpesent on cells of the CNS, heart, lung,
pancrease, mucosa CLINICAL SYNDROMES
• Most enteroviruses are cytolytic, replicating rapidly and
causing direct damage to target cells • incubation period for enterovirus disease varies from 1-
• Antibody is the major protective immune response to 35 days, depending on the virus, target tissue and the
the enteroviruses; it can prevent initial infection in the person’s age
oropharynx and GIT; prevents spread to target tissue • viruses that affect oral and respiratory sites have the
• Cell-mediated immunity is not usually involved in shortest incubation periods
protection but may play a role in pathogenesis
Polio infections

• poliovirus
may cause
one of four
outcomes in

unvaccinated people, depending on the progression of

the infection
1. Asymptomatic illness. Infection limited to the
oropharynx and gut. At least 90% are asymptomatic
2. Abortive poliomyelitis (minor illness). Non-febrile
illness, 5%. Fever, headache, malaise, sore throat,
vomiting
3. Nonparalytic poliomyelitis (aseptic meningitis). 1-2%.
Virus progresses into the CNS and the meningitis,
causing back pain and muscle spasms + symptoms of
minor illness
4. Paralytic polio (major illness). 0.1-2%. Appears 3-4 days
pathogenesis of enterovirus infection. The target tissue infected by the
after the minor illness has subsided, producing a
enterovirus determines the predominant disease caused by the virus.
 biphasic illness. Virus spreads from blood to anterior ° In viral meningitis, the CSF glucose level is
horn cells of SC and motor cortex of the brain. usually normal or slightly low
– Paralytic poliomyelitis. Characterized by • Culture
asymmetrical flaccid paralysis with no sensory loss. ° Poliovirus may be isolated from patient’s
pharynx
– Bulbar poliomyelitis. Involve the muscles of the
° It grows well on monkey kidney tissue culture
pharynx, vocal cords and respiration. Results in
° The specific type of enterovirus can be
death of 75% of patients
determined by using specific antibody and
– Postpolio syndrome. Sequelae of poliomyelitis that assays (IF, ELISA)
may occur much later in life (30-40 yrs) • Serology
° Detection of IgM or finding a 4-fold increase in
Ab titer bet time of acute illness and period of
convalescence

TREATMENT, PREVENTION AND CONTROL

• no specific antiviral therapy

• supportive therapy
• 2 types of polio vaccine exist
° inactivated polio vaccine (IPV)
° live attenuated oral polio vaccine (OPV).
– both are effective but OPV is used due to its ease
of delivery and capacity to elicit a lifelong
immunity

Progression of poliovirus infection. Infection may be asymptomatic or

progress to minor or major disease.

Coxsackievirus and Echovirius Infections

• coxsackie A viruses are assoc with diseases with

vesicular lesions (herpangina) whereas coxsackie B (b for
body) are associated with myocarditis and pleurodynia.
• Herpangina is casued by several types of coxsackie A
virus. Fever, sore throat, pain…
° Classic finding is vesicular ulcerated lesions
around the soft palate and uvula
° Virus can be recovered from lesions or feces
° Requires only symptomatic management
• Hand-foot-and-Mouth disease is a vesicular exanthema
caused by an enterovirus usually cox A16.
° Lesions on hands, feet, mouth and tongue
• Pleurodynia (Bornholm disease) aka devil’s grip, is a
acute illness in w/c patients have sudden onset of fever
and unilateral low thoracic, pleuritic chest pain serum and secretory antibody response to intramuscular inoculation of IPV
• Myocardial and Pericardial infections caused by coxB. and to live attenuated OPV. Note the presence of secretory IgA induced by
the live polio vaccine.
Neonates have febrile illnesses and sudden onset of
unexplained heart failure
° Cyanosis, tachycardia, cardiomegaly and
hepatomegaly occur
° Acute benign pericarditis affects young
adults; symptoms resemble those of MI but
fever is more severe.
• Viral (aseptic) meningitis, acute febrile illness
accompanied by headache and signs of meningeal
irritation including nuchal rigidity.
° Petechiae or skin rash may occur in patients
• Fever and rash may occur in Px infected with Echo and
Cox. Eruptions are usually maculopapular but may
occasionally be petechial or vesicular

Transmission of enteroviruses. The capsid structure is resistant to mild

sewage treatment, saltwater, detergents, and temp changes, allowing these
viruses to be transmitted by fecal-oral route and on hands.

LABORATORY DIAGNOSIS ARBOVIRUSES

• Clinical chemistry • The members of the Togaviridae and Flaviviridae

° CSF from poliovirus or enterovirus aseptic families are enveloped, positive, ssRNA viruses
meningitis reveals a predominantly • Most are transmitted by arthropods and are therefore
lymphocytic pleocytosis arboviruses (arthropod borne)
 • The Togaviruses can be classified into three major ○ Live attenuated vaccines are available for
genera yellow fever virus and Japanese encephalitis
1. Alphavirus virus.
2. Rubivirus (Rubella virus)
3. Arterivirus
• The Flaviviridae include:
1. flaviviruses
2. Pestivirus
3. hepatitis C and G
• Alphaviruses and Flaviviruses are discussed together
because of similarities in the disease they cause and
their epidemiology

ALPHAVIRUSES AND FLAVIVIRUSES

• Historically classified as arboviruses, because they are

usually spread by arthropod vectors: arthropod-borne
• Host: vertebrates & invertebrates
• Hepatitis C: recently classified as a Flavivirus
Patterns of alphavirus and flavivirus transmission. The cycle of arbovirus
transmission maintains and amplifies the virus in the environment. Host-
vector relationships that can provide this cycle are indicated by the double
arrow. “Dead-end” infections with not transmission of the virus back to the
vector are indicated by the single arrow. For St. Louis encephalitis, yellow
fever, and dengue viruses, humans are not dead-end hosts and support an
urban cycle. The Russian spring-summer encephalitis virus can be
transmitted to humans by a tick bite and in milk form from infected goats.

ALPHAVIRUSES

1. Venezuelan Equine Encephalitis

2. Eastern Equine Encephalitis
3. Western Equine Encephalitis
4. Chikungunya
5. Semliki
6. Sindbis
Epidemiology (of Togavirus and Flavivirus Infection)
FLAVIVIRUSES
• Both alpha- and flaviviruses are prototypical arboviruses
1. Dengue
• Most common vector: mosquito
2. Yellow Fever
• Others: ticks & sandflies
3. Japanese Encephalitis
• Usual reservoir: birds & small mammals 4. West Nile
5. St. Louis Encephalitis
• DISEASE/VIRAL FACTORS
6. Russian spring-summer encephalitis
○ Enveloped virus must stay wet and can be
7. Powassan
inactivated by drying, soap, and detergents.
○ Virus can infect mammals, birds, reptiles, and Arboviruses (main characteristics)
insects
○ Asymptomatic or nonspecific (flulike fecer or 1. Should infect both vertebrates & invertebrates
chills), encephalitis, hemorrhagic fever, or
2. Initiate a sufficient viremia in the vertebrate host to
arthritis.
allow acquisition by the invertebrate vector
• TRANSMISSION 3. Initiate a persistent infection of the salivary gland of the
○ Togaviruses and flaviviruses: specific vector to provide virus for infecting other vertebrate
arthropods characteristic of each virus hosts
(zoonosis: arbovirus).
Clinical Syndromes
• WHO IS AT RISK?
○ People who enter ecological niche of • Infection with Alphaviruses
arthropod: arboviruses ○ EEE,WEE,VEE: can progress to encephalitis in
humans
• GEOGRAPHY/SEASON ○ S/S: chills, fever, rash, aches
○ Endemic regions for each arbovirus are ○ Sindbis & Chikungunya: cause only systemic
determined by habitat of mosquito or other disease more of a problem to livestock than to
vector humans…
○ Aedes mosquito, which causes dengue and
yellow fever, is found in urband areas and in • Infection with Flaviviruses
pools of water. ○ relatively benign (although encephalitis or
○ Culex mosquito, which causes St. Louis hemorrhagic disease can still occur)
encephalitis, is found in forest and urban ○ encephalitis viruses: St. Louis, Japanese,
areas. Murray Valley, Russian spring-summer
○ Disease is more common in summer
○ hemorrhagic viruses: Dengue & Yellow Fever
• MODES OF CONTROL
○ Mosquito breeding sites and mosquitoes should
be eliminated

DENGUE
 • Usually mild & self-limited but when re-challenged with • Viruses are cytolytic, except for rubella.
a related strain can cause severe hemorrhagic/shock • Viruses establish systemic infection and viremia.
symptoms • Viruses are good inducers of interferon, which can
• DHF/DSS: due to rupture of vasculature, internal account for the influenza-like symptoms of infection.
bleeding, loss of plasma • Viruses, except rubella and hepatitis C, are arboviruses
• Flaviviruses infect cells of the monocyte-macrophage
Pathogenesis lineage.
• Non-neutralizing antibody can enhance flavivirus
• Lesions are in small blood vessels, with endothelial infection via Fc receptors on the macrophage.
swelling, perivascular edema and mononuclear
Influenza- Encephalitis Hepatitis Hemorrhage Shock
infiltrates like
syndrome
DHF/DSS Dengue + + + +
Yellow F. + + + +
• are altered manifestations of dengue, often in epidemic St. Louis E + +
form Venezuelan + +
• Pathogenesis: not well understood, but seems to involve E
pre-existing dengue antibodies Western + +
• DHF: abrupt course & is assoc with hypoprotenemia, equine E
thrombocytopenia, prolonged BT, elevated PT Eastern + +
equine E
• DSS: characterized by shock & hemoconcentration
Japanese E + +

YELLOW FEVER
ARENAVIRUSES
• Severe systemic disease with degeneration of liver,
Generalities
kidney, heart & hemorrhage of blood vessels
• Lesions are due to the localization & propagation of the
virus in a particular organ • Include lymphocytic choriomenigitis(LCM) & hemorrhagic
• Mortality: as high as 50% fever viruses (Lassa fever, Junin, Machupo)
• Zoonoses (persistent infection of specific rodents)
Laboratory Diagnosis • Virus becomes endemic in the habitat of the rodent

• Cell culture (both vertebrate & invertebrate cell line)

• Cytopathology, IF, hemadsorption of avian erythrocytes
• ELISA, HI, LPA

Tx, Prev’n, Control

• Mainly supportive
• No specific treatment
• Vector elimination
• Avoidance of endemic places
• Vaccination: Yellow Fever, Jap enceph, EEE, WEE,
Russian spring-summer Pathogenesis
• Vaccine for VEE: only for domestic animals
• Infect macrophages, cause vascular damage and tissue
destruction

Epidemiology

• Mainly found: tropical Africa & South America

• Infect specific rodents & are endemic to their habitat
• Infection of humans: aerosol, contamination of food or
fomites
• Human-to-human: Lassa fever

Clinical Manifestations

• Lymphocytic Choriomenigitis
○ fever with myalgia occurs more often than
meningitis
○ menigeal illness: subacute & persists for
several months
○ brain & meninges: perivascular mononuclear
infiltrates
• Lassa Fever, etc.
○ endemic: West Africa, Argentina (Junin),
Bolivia (Machupo)
○ S/S: fever, coagulopathy, petechiae,
occasional visceral hemorrhages, liver &
spleen necrosis
○ others: pharingitis, diarrhea, vomiting
○ Dx: recent travel to endemic areas

Laboratory Diagnosis

• Serology (due to the danger of routine isolation)

Disease syndromes of alphaviruses and flaviviruses. Primary viremia may be
associated with mild systemic disease. Most infections are limited to this. If
Tx, Prev’n, Control
sufficient virus is produced during the secondary viremia to escape immune
protection and to reach critical target tissue, severe systemic disease or
encephalitis may result. For dengue hemorrhagic fever (DHF), which can • For Lassa fever: Ribavirin (although with limited
cause dengue shock syndrome (DSS) because of the loss of luids from the activity)
vasculature. • Supportive
• Limit contact with vectors
Disease Mechanisms of Togavirus and Flavivirus
RETROVIRUSES (RNA TUMOR VIRUSES)
SUBFAMILY CHARACTERISTICS EXAMPLES
UNIQUE CHARACTERISTICS OF RETROVIRUSES Oncovirinae Are associated with cancer -
and neurological disorders
• virus has enveloped spherical virion that is 80 to 120 nm in
diameter and that encloses a capsid containing two copies of – B Have eccentric nucleocapsid Mosue mammary
the positive-strand RNA genome core in mature virion tumor virus
• RNA-dependent DNA polymerase (reverse transcriptase) and – C Have centrally located Human T-
integrase enzymes are carried in the virion. nucleocapsid core in mature lymphotrophic virus
• Virus receptor is the initial determinant of tissue tropism. virion (HTLOV-1, HTLV-2,
• Replication proceeds through a DNA intermediate, termed HTLV-5), Rous
provirus sarcoma virus
• The provirus integrates randomly into the host chromosome (chickens)
and becomes a cellular gene. – D Have nucleocapsid core with Mason-Phizer
• Transcription of the genome is regulated by the interaction cylindrical form monkey virus
of host transcription factors with promoter and enhancer Lentivirinae Have slow onset of disease; Human foamy virus
elements in the long-terminal repeat (ltr) portion of the casue neurological disorders
genome and immunosuppression; are
• Simple Retroviruses encode gag, pol, and env genes. viruses with D-type,
cylindrical nucleoapsid core
Complex viruses also encode accessory genes (e.g., tat, rev,
Spumavirinae Cause no clinical disease but Human foamy virus
nef, vif, vpu for HIV) characteristic vacuolated
• Virus assembles and buds from the plasma membrane. “foamy” cytopathology
• Final morphogenesis of HIV requires protease cleavage of gag
and gag-pol polypeptides after envelopment.

Cross section of HIV.

The enveloped virion
contains two identical
RNA strands, RNA
polymerase,
integrase, and two
tRNAs base-paired to
the genome w/in the
protein core. This is
surrounded by
proteins and a lipid
bilayer. The envelope
spikes are the
glycoprotein (gp) 120
attachment protein
and gp4` fusion
protein.

RETROVIRUS GENES AND THEIR FUNCTION

GENE VIRUS FUNCTION

gag All Group-specific antigen: core and capsid proteins
pol All Polymerase; reverse transcriptase, protease, integrase
env All Envelope: glycoproteins
tax HTLV Transactivation of viral and cellular genes
tat HIV-1 Transactivation of viral and cellular genes
rex HTLV Regulation of RNA splicing and promotion of export to
cytoplasm
rev HIV-1 Regulation of RNA splicing and promotion of export to
cytoplasm
nef HIV-1 Alteration of cell activation signals; progression to
AIDS (essential)
vif HIV-1 Virus infectivity, promotion of assembly
vpu HIV-1 Facilitation of release of virus, decrease of cell
surface CD4
vpr HIV-1 Transport of complementary DNA to nucleus, arresting
(vpx*) of cell growth
LTR All Promoter, enhancer elements

The life cycle of HIV. HIV binds to CD4 and chemokine co-receptors and
enters by fusion. The genome is reverse transcribed into DNA in the
cytoplasm and integrated into the nuclear DNA. Transcription and
translation of the genome occurs in a fashion similar to that of HTLV-1. the
virus assembles at the plasma membrane and matures after budding from
the cell.

HUMAN IMMUNODEFICIENCY VIRUS

Morphological distinction of retrovirions. The morphology and position of

the nucleocapsid core are used to classify the viruses. A-type particles are
immature intracytoplasmic forms that bud through the plasma membrane
into mature B-type, C-type and D-type particles.

CLASSIFICATION OF RETROVIRUSES
 CD4 T cells play a critical role in the regulation of the human immune
response by mediating the release of soluble factors and the DTH response
toward intracellular pathogens. HIV-induced loss of the CD4 T cells results
in loss of the functions shown, especially the DTH responses and the
lymphokine control of immune responses.

Pathogenesis of HIV. HIV causes lytic and latent infection of CD4 T cells and
persistent infection of cells of the monocyte/macrophage family and
disrupts neurons. The outcomes of these actions are immunodeficiency and
AIDS dementia.

Time course and stages of HIV disease. A long clinical latency period follows
the initial mononucleosis-like symptoms. The progressive decrease in the
number of CD4 T cells, even during the latency period, allows opportunistic
infections to occur. The stages in HIV disease are defined by the CD4 T-cell
levels and occurrence of opportunistic diseases.
 • The virus enters the bloodstream and infects the CD4 helper
and DTH T cells

ENDOGENOUS RETROVIRUSES

• complete and partial provirus sequences with gene sequences

similar to those of HTLV, mouse mammary tumor virus and
other retroviruses can be detected in humans
• these endogenous viruses generally lack the ability to
replicate because of deletions or the insertion of termination
codons or because they are poorly transcribed.

HUMAN T-LYMPHOTROPIC VIRUS AND OTHER ONCOGENIC

RETROVIRUSES

• the oncovirinae were originally called RNA tumor viruses and

have been associated with the development of leukemias,
sarcomas, and lymphomas in many animals
• these viruses are not cytolytic
• the members of this family are distinguished by the
mechanism of cell transformation and thus the length of the
latency period between infection and the development of the
disease.
• The sarcoma and acute leukemia viruses have incorporated
cellular genes (protooncogenes) encoding growth-controlling
factors into their genome.
• These viruses can cause transformation and are highly
oncogenic.
• Transformation results from the overproduction or altered
activity of growth-stimulating oncogene product
• Increased cell growth then promotes transcription, which also
promotes viral replication
• The incorporation of the oncogene into many of these viruses
causes the coding sequences for the gag, pol, or env genes to
be replaced, such that these viruses are defective and
require helper viruses for replication.
• The leukemia viruses, including HTLV-1, are competent in
terms of replication but cannot transform cells in vitro. They
cause cancer after a long latency period of at least 30 years
• HTLV-1 is cell associated and is spread in cells after blood
transfusion, sexual intercourse, or breast-feeding.