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 percutaneous or mucosal exposure to blood

- current for recent IDU

- household contacts of HBsAg-positive person

- residents and staff of facilities for development disabled persons.

- Healthcare and public safety workers with risk for exposure to blood or blood-contaminated

body fluids.

- Persons with end-stage renal disease

- Persons with diabetes mellitus.

Hepatitis B Treatment

 For acute infection, no medication is available; treatment is supportive.

 For chronic infection, several antiviral drugs (adefovir dipivoxil, interferon alfa-2b, pegylated

interferon alfa-2a, lamivudine, entecavir, and telbivudine) are available.

- Persons with chronic HBV infection require medical evaluation and regular monitoring to

determine whether disease is progressing and to identify liver damage or hepatocellular

carcinoma.

Hepatitis B Elimination

 CDC’s national strategy to eliminate transmission of HBV infection includes:

1. Prevention of perinatal infection through routine screening of all pregnant women for

HBsAg and immunoprophylaxis of infants born to HBsAg-positive mothers and infants born

to mothers with unknown HBsAg status

2. Routine infant vaccination

3. Vaccination of previously unvaccinated children and adolescents through age 18 years

4. Vaccination of previously unvaccinated adults at increased risk for infection

Hepatitis B Vaccine

 Composition Recombinant HBsAg

 Efficacy 95% ( Range , 80%-100%

 Duration of Immunity 20 years or more

 Schedule 3 Doses

 Booster doses not routinely recommended

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6.Enteroviruses

 Enteroviruses are a genus of the picornavirus family which replicate mainly in the

gut.(Figure2-61)

 Single stranded naked RNA virus with icosahedral symmetry

 Unlike rhinoviruses, they are stable in acid pH

 Capsid has 60 copies each of 4 proteins, VP1, VP2, VP3 and VP4 arranged with icosahedral

symmetry around a positive sense genome.

 At least 71 serotypes are known: divided into 5 groups

1. Polioviruses

2. Coxsackie A viruses

3. Coxsackie B viruses

4. Echoviruses

5. Enteroviruses (more recently, new enteroviruses subtype have been allocated sequential

numbers (68-71) Figure(2-62)

History

 Poliovirus - first identified in 1909 by inoculation of specimens into monkeys. The virus was

first grown in cell culture in 1949 which became the basis for vaccines.

 Coxsackieviruses - In 1948, a new group of agents were identified by inoculation into

newborn mice from two children with paralytic disease. These agents were named

coxsackieviruses after the town in New York State. Coxsackieviruses A and B were identified

on the basis of the histopathological changes they produced in Newborn mice and their

capacity to grow in cell cultures.

 Echoviruses - were later identified which produced cytopathic changes in cell culture and

was nonpathogenic for newborn mice and subhuman primates.

 More recently, new enterovirus types have been allocated sequential numbers (68 - 71).

Figure(2-61)Enterovirus Particles

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Table(2-5) Categories of Enteroviruses

Figure(2-62)

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Poliovirus

- 3 serotypes of poliovirus (1, 2, and3) but no common antigen.

- Have identical physical properties but only share 36-52% nucleotide homology.

- Humans are the only susceptible hosts.

- Polioviruses are distributed globally. Before the availability of immunization, almost 100% of

the population in developing countries before the age of 5.

- The availability of immunization and the poliovirus eradication campaign has eradicated

poliovirus in most regions of the world except in the Indian Subcontinent and Africa.

- Poliovirus is on course of being eradicated worldwide by the end of 2000 or 2001.

Pathogenesis

The incubation period is usually 7 - 14 days.

Following ingestion, the virus multiplies in the oropharyngeal and intestinal mucosa.

Figure(2-63)Pathogenesis of enterovirus infection

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The lymphatic system, in particular the tonsils and the Peyer's patches of the ileum are invaded and

the virus enters the blood resulting in a transient viraemia.

In a minority of cases, the virus may involve the CNS following dissemination. (Figure 2-63)

Figure (2-64) Population infection A-Indene children with poliomyelitis B-outbreak au early 20th country C- Evidence of poliomyelitis in

the pharaohs

B

A

C

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Born in 1882 at Hyde Park, New York--now a national historic site--he attended Harvard

Universityand Columbia Law School. On St. Patrick's Day, 1905, he married Eleanor Roosevelt .

Following the example of his fifth cousin, President Theodore Roosevelt, whom he greatly admired,

Franklin D. Roosevelt entered public service through politics, but as a Democrat. He won election to

the New York Senate in 1910. President Wilson appointed him Assistant Secretary of the Navy, and

he was the Democratic nominee for Vice President in 1920 .

In the summer of 1921, when he was 39, disaster hit-he was stricken with poliomyelitis.

Demonstrating indomitable courage, he fought to regain the use of his legs, particularly through

swimming. At the 1924 Democratic Convention he dramatically appeared on crutches to nominate

Alfred E. Smith as "the Happy Warrior." In 1928 Roosevelt became Governor of New York .

He was elected President in November 1932, to the first of four terms.)Figure2-65)

Immunity

 Antibody is the major protective immune response to the enteroviruses . Secretory antibody

can prevent the initial establishment of infection in the oropharynx and gastrointestinal tract,

and serum antibody prevents viremic spread to the target tissue and therefore disease.

 Cell-mediated immunity is not usually involved in protection but may play a role in

pathogenesis.

Clinical Manifestations

Figure(2-65)Franklin D. Roosevelt

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There are 3 possible outcomes of infection:

1. Subclinical infection (90 - 95%) - inapparent subclinical infection account for the vast

majority of poliovirus infections.

2. Abortive infection (4 - 8%) - a minor influenza-like illness occurs, recovery occurs within a

few days and the diagnosis can only be made by the laboratory. The minor illness may be

accompanied by aseptic meningitis

3. Major illness (1 - 2%) - the major illness may present 2 - 3 days following the minor illness or

without any preceding minor illness. Signs of aseptic meningitis are common. Involvement

of the anterior horn cells lead to flaccid paralysis. Involvement of the medulla may lead to

respiratory paralysis and death.

Laboratory Diagnosis

 Virus Isolation

a. Mainstay of diagnosis of poliovirus infection

b. poliovirus can be readily isolated from throat swabs, faeces, and rectal swabs. It is rarely

isolated from the CSF

c. Can be readily grown and identified in cell culture

d. Requires molecular techniques to differentiate between the wild type and the vaccine type.

 Serology

- Very rarely used for diagnosis since cell culture is efficient. Occasionally used for immune

status screening for immunocompromised individuals.

Prevention (1)

No specific antiviral therapy is available. However the disease may be prevented through

vaccination. There are two vaccines available.

Intramuscular Poliovirus Vaccine (IPV)

consists of formalin inactivated virus of all 3 poliovirus serotypes.

Produces serum antibodies only: does not induce local immunity and thus will not prevent local

infection of the gut.

However, it will prevent paralytic poliomyelitis since viraemia is essential for the pathogenesis of the

disease.

Oral Poliovirus Vaccine (OPV)

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Consists of live attenuated virus of all 3 serotypes.

Produces local immunity through the induction of an IgA response as well as systemic immunity.

Rarely causes paralytic poliomyelitis, around 1 in 3 million doses.

Prevention (2)

 Most countries use OPV because of its ability to induce local immunity and also it is much

cheaper to produce than IPV.

 The normal response rate to OPV is close to 100%.(Figure2-64)

 OPV is used for the WHO poliovirus eradication campaign.

 Because of the slight risk of paralytic poliomyelitis, some Scandinavian countries have

reverted to using IPV. Because of the lack of local immunity, small community outbreaks of

poliovirus infections have been reported.

 Poliovirus was targeted for eradication by the WHO by the end of year 2000 (now 2005). To

this end, an extensive monitoring network had been set up.

 Poliovirus has been eradicated from most regions of the world except the Indian

subcontinent and sub-Saharan Africa. It is possible that the WHO target may be achieved.

Figure(2-64)The

differences of

immune response

between OPV and

IPV vaccination

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Coxsackieviruses

 Coxsackieviruses are distinguished from other enteroviruses by their pathogenicity for

suckling rather than adult mice. They are divided into 2 groups on the basis of the lesions

observed in suckling mice.

- Group A viruses produce a diffuse myositis with acute inflammation and necrosis of fibers of

voluntary muscles.

- Group B viruses produce focal areas of degeneration in the brain, necrosis in the skeletal

muscles, and inflammatory changes in the dorsal fat pads, the pancreas and occasionally the

myocardium.

 Each of the 23 group A and 6 group B coxsackieviruses have a type specific antigen.

 In addition, all from group B and one from group A (A9) share a group Ag. Cross-reactivities

have also been demonstrated between several group A viruses but no common group

antigen has been found.

Echoviruses

 The first echoviruses were accidentally discovered in human faeces, unassociated with

human disease during epidemiological studies of polioviruses. The viruses were named

echoviruses (enteric, cytopathic, human, orphan viruses).

 These viruses were produced CPE in cell cultures, but did not induce detectable pathological

lesions in suckling mice.

 Altogether, There are 32 echoviruses (types 1-34; echovirus 10 and 28 were found to be other

viruses and thus the numbers are unused)

 There is no group echovirus Ag but heterotypic cross-reactions occur between a few pairs.

New Enteroviruses

 Newly identified picornaviruses that are not polioviruses are no longer classified separated

into the species coxsackie and echovirus because of the ambiguities presented by

overlapping host range variations.

 4 new enteroviruses have been identified (68 - 72). Enterovirus 70 is the causative agent

epidemics of acute haemorrhagic conjunctivitis that swept through Africa, Asia, India and

Europe from 1969 to 1974. The virus is occasionally neurovirulent.

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 Enterovirus 71 appears to be highly pathogenic and has been associated with epidemics of a

variety of acute diseases, including aseptic meningitis, encephalitis, paralytic poliomyelitislike disease and hand-foot-mouth disease.

 Enterovirus 72 was originally assigned to hepatitis A virus, but it had now been assigned to a

new family called heptoviruses.

Disease Associations (1)

 Paralytic Disease - most commonly associated with polioviruses but other enteroviruses

may also be responsible, notably enterovirus 71

 Meningitis - caused by all groups of enteroviruses, most commonly seen in children under 5

years of age.

 Encephalitis - focal or generalized encephalitis may accompany meningitis. Most patients

recover completely with no neurological deficit.

 Undifferentiated febrile illness - may be seen with all groups of enteroviruses.

 Hand foot mouth disease - usually caused by group A coxsackieviruses although group B

coxsackieviruses and other enteroviruses have been caused outbreaks.

 Herpangina - caused by group A coxsackieviruses.

 Epidemic Pleurodynia (Bornholm disease) - normally caused by group B coxsackieviruses.

Disease Associations (2)

 Myocarditis - group B coxsackieviruses are the major cause of myocarditis, although it may

be caused by other enteroviruses. It may present in neonates as part of neonatal infection and

is often fatal. In adults, the disease is rarely fatal.

 Respiratory Infections - several enteroviruses are associated with the common cold.

 Rubelliform rashes - a rash disease resembling rubella may be seen with several coxsackie

A, B, and echoviruses.

 Neonatal Infection - some coxsackie B viruses and echoviruses may cause infection in

newborn infants. The virus is usually transmitted perinatally during the birth process and

symptoms vary from a mild febrile illness to a severe fulminating multisystem disease and

death.

 Conjunctivitis - associated with several types of enteroviruses, notably Coxsackie A24 and

Enterovirus 70 (haemorrhagic conjunctivitis)

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 Pancreatitis/Diabetes - associated with Coxsackie B virus infection. The extent of the role of

the virus in diabetes is unknown.

Laboratory Diagnosis

 Virus Isolation (Figure 2-67)

- Mainstay of diagnosis of enterovirus infection

- Coxsackie B and Echoviruses can be readily grown in cell culture from throat swabs, faeces,

and rectal swabs. They can also be isolated from the CSF

- Coxsackie A viruses cannot be easily isolated in cell culture. They can be isolated readily in

suckling mice but this is not offered by most diagnostic laboratories because of practical

considerations. Molecular techniques may provide a better alternative.

 Serology

- Very rarely used for diagnosis since cell culture is efficient.

- Neutralization tests or EIAs are used but are very cumbersome and thus not offered by most

diagnostic laboratories

Management and Prevention

There is no specific antiviral therapy available against enteroviruses other than polio.

Some authorities use IVIG in the treatment of neonatal infections or severe infections in

immunocompromised individuals. However, the efficacy is uncertain.

HNIG have been to prevent outbreaks of neonatal infection with good results.

There is no vaccine available mainly because of the multiplicity of serotypes. There is little interest in

developing a vaccine except against enterovirus 71 and coxsackie B viruses.

Figure(2-67)Cytopathic Effect

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7.Adenoviruses

Human Adenoviruses

 Adenoviruses were first isolated in 1935 from human adenoid tissues.

 Since then, at least 49 distinct antigenic types have been isolated from humans and many

other types from animals.

 All human serotypes are included in a single genus within the family Adenoviridae.

Morphology

 ds-DNA viruses,

 media sized in diameter,

 icosahedral

 Nonenveloped

Antigenic structure

All human Adenoviruses share a common group-specific antigen.

- Type specific antigens are important in serotyping.

- Adenoviruses have a characteristic morphology (Stewart et al., 1993 ), with an icosahedral

capsid consisting of three major proteins, hexon (II), penton base (III) and a knobbed fiber

(IV), along with a number of other minor proteins, VI, VIII, IX, IIIa and IVa2 .The virus

Figure(2-68) Adenovirus structure

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genome is a linear, double-stranded DNA with a terminal protein (TP) attached covalently to

the 5´ termini (Rekosh et al., 1977)

Classification

Adenoviruses are divided into six groups (A to F) based on:

1. physical,

2. chemical

3. biological properties

- Antigenic structure divides adenoviruses into:

- 49 serotypes:

 About 1/3 of the 49 known human serotypes are responsible for most cases of Adenovirus

disease.(Figure 2-69)

Pathogenesis:

Adenoviruses spread by:

 direct contact,

 respiratory droplets

 feco-oral route.

Pathogenesis:

Adenoviruses infect and replicate in the epithelial cells of the:

1. pharynx,

2. conjunctiva,

3. urinary bladder

4. small intestine.

Figure(2-69) Adenovirus Attachment

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