PART PART TWOTWO

SYSTEMIC VIROLOGYSYSTEMIC VIROLOGY Prepared by Professor Dr Hassan J Prepared by Professor Dr Hassan J HasonyHasony

Dept Med Microbiology, Basrah Medical Dept Med Microbiology, Basrah Medical CollegeCollege

OBJECTIVES:OBJECTIVES: Viral infections attributed to each Viral infections attributed to each

system will be discussed system will be discussed concentrating on :concentrating on :

- properties of viral aetiologic agent- properties of viral aetiologic agent - clinical finding and case - clinical finding and case

presentationpresentation - Epidemiology of viral infections- Epidemiology of viral infections - prevention and control measures- prevention and control measures - Laboratory diagnosis and - Laboratory diagnosis and

interpretation of lab. Test results interpretation of lab. Test results

LEARNING OBJECTIVESLEARNING OBJECTIVES

student should be able to answer student should be able to answer the questions attached to each the questions attached to each lecture concerning the target lecture concerning the target system and having a skil to system and having a skil to identify and interprept the identify and interprept the results of any related results of any related investigations for linking the investigations for linking the presented case to the viral presented case to the viral aetioloigic agent(s)aetioloigic agent(s)

THE FAMILY OF VIRUSESRNA VIRUSES

A. OrthomyxoviridaeB. ParamyxoviridaeC. RhabdoviridaeD. FiloviridaeE. FlaviviridaeF. PicornaviridaeG.ReoviridaeH.TogaviridaeI. Retroviridae

RESPIRATORY RESPIRATORY VIRUSESVIRUSES

Replication Sites and Replication Sites and Clinical Manifestations Clinical Manifestations

Why so many?Why so many? Constant exposure: 21,000 L of air/dayConstant exposure: 21,000 L of air/day RT is a favorable environment for viruses:RT is a favorable environment for viruses:

Warm, moist, and darkWarm, moist, and dark Plenty of cell types (25), which are good “tissue Plenty of cell types (25), which are good “tissue

culture media” culture media” Optimal temperatureOptimal temperature

Easy transmission via:Easy transmission via: Sneezing – aerosol 100-200 Sneezing – aerosol 100-200 m particles at 100 m particles at 100

ft/secft/sec Cough – disperses nasopharyngeal content at Cough – disperses nasopharyngeal content at

850 ft/sec850 ft/sec Intimate and non-intimate contact Intimate and non-intimate contact

Determinants of Viral Determinants of Viral Respiratory DiseaseRespiratory Disease

Viral FactorsViral Factors Tissue tropismTissue tropism Route of infectionRoute of infection Stability of the Stability of the

virus virus Replication and Replication and

release of viruses release of viruses into aerosolsinto aerosols

Host FactorsHost Factors AgeAge Immune statusImmune status Underlying diseaseUnderlying disease• adaptationadaptation

Environmental Environmental FactorsFactors DosageDosage ExposureExposure OccupationOccupation Life Style:Life Style:

OccupationOccupation Day care settingDay care setting Public transportPublic transport

INFLUENZA VIRUSINFLUENZA VIRUS

RNA VIRUSESRNA VIRUSESEnveloped, Single-stranded RNA Viruses

Orthomyxoviruses: Influenza - spherical particles with an average diameter of 80-120 nm - contains 7 structural proteins :

PB1, PB2, PA – bound to viral RNA ; responsible for RNA

transcription and replicationNucleoprotein ( NP ) – associates with viral RNA to form a

structure 9 nm in diameter that assumes a

helical configurationMatrix ( M ) protein – forms a shell underneath the viral

lipid envelope; important in particle morphogenesis

HA ( hemagglutinin ) } determines antigenic variation NA ( neuraminidase ) } of influenza viruses

11

ORTHOMYXOVIRUSES

M1 protein

helical nucleocapsid (RNA plus NP protein)

HA - hemagglutinin

polymerase complex

lipid bilayer membrane

NA - neuraminidase

type A, B, C : NP, M1 protein sub-types: HA or NA protein

Influenza virus genome:

- divided into eight separate segments reassorting during viral assembly antigenic nature of proteins change

- antigenic drift : changes in a single amino acid

- antigenic shift : the accumulation of enough changes to create a new subtype different from the original strain - 16 H and 9 N ( H= 2 to the power 16 ,N=2 to power 9

Classification and nomenclature :

- antigenic differences between NP and M proteins divides influenza viruses into :

type A : highly variable antigenically ; responsible for most cases of epidemic influenza

type B : may exhibit antigenic changes and sometimes causes epidemics

type C : antigenically stable ; causes only mild illness

Properties :

- relatively stable; may be stored at 4 degrees C for a week

- infectivity destroyed by heating at 56 degrees C for a few minutes, treatment with ether, formaldehyde, phenol and other protein denaturants

- initial isolation best accomplished by amniotic inoculation of embryonated chicken eggs and monkey cell cultures

EPIDEMIOLOGY: Influenza A

- acute, highly contagious , respiratory illness afflicting people of all ages marked by seasonal regularity and pandemics at predictable intervals

- five pandemics in recorded history : the worst was in 1918 where there were at least 50 million deaths

- the most virulent among the three types of influenza viruses

( cont. epidemiology )

- influenza A strains are also known for pigs, horses,ducks and chicken

- antigenic changes in group A > B; group C appears to be antigenically stable - interpersonal spread due to formation of virus-laden aerosol droplets when an infected patient sneezes or coughs if virus is not neutralized ( e.g. local IgA specific anti- hemagglutinin Ab ), initial replication occurs

Mode of influenza transmission: - inhalation of aerosol and droplets major route of infection - transmission greatly facilitated by crowding and poor ventilation usually in late fall and winter in temperate countries throughout the year in the tropics - occupational contact with ducks, other poultry,and swine constitutes a special high-risk category for disease - OVERALL MORTALITY FOR INFLUENZA A : 0.1 % of cases with deaths occurring among the elderly and small children

Pathogenesis: Virus binds to ciliated columnar cells (respiratory mucosa) rapid shedding of mucosal cells together with a load of viruses trachea and bronchial epithelia are stripped to the basal layer leading to severe inflammation and irritation viruses remain in respiratory tract (viremia is rare); ciliated columnar epithelium restored w/in 1-2 wks

FACTORS AFFECTING EFFICIENCY OF AEROSOL SPREAD:

1. direct proportion to the number of particles generated 2. density of susceptibles3. physical and temporal contiguity to aerosols4. degree of stagnation of ambient atmosphere

- high attack rates : nursing homes, classrooms, ships, barracks, aircraft

- smokers : increased susceptibility to infection- young children ( pre-school or grade school ) : most

effective disseminators of the disease- periodicity of influenza epidemics/pandemics:

determined by the surface antigens of the virus and the antibodies induced within a population

Recovery from infection depends on: a. general health b. immunity from previous exposure c. vaccination d. age

DIAGNOSIS:

1. Virus isolation /detection of viral antigen in respiratory secretions ( nasal/throat swabs; nasal washes ; combined nose-and-throat swab ; sputum ) which are inoculated into :

a. rhesus monkey kidney or Madin-Darby canine kidney cell cultures CPE or hemadsorption

b. embryonated hens’ eggs ( allantoic or amniotic cavity )

2. Rapid diagnosisa. samples centrifuged directly onto cells in shell

vials detection of viral antigens by IF or ELISA

* sensitivity higher in nasophrayngeal washes and swabs

b. PCR

3. serologic testing- compares acute and convalescent sera ( 10-20 days

apart ): 4 fold rise in titer

a. CFb. HAI

4. epidemiologic diagnosis

- when infection is confirmed within a region by the local health department

PREVENTION: - primary means of prevention : vaccines - vaccines not used much because:

a. offers only a short duration of protectionb. possibility of sensitization or severe allergic reactions in

persons hypersensitive to eggs ( vaccine viurs grown in chick embryo )

c. possibility of toxic reactions to the high concentration of virus material administered parenterally

d. uncertainty of protection because of the changing antigenicity of the circulating influenza strains

- vaccination recommended for high-risk groups: a. the chronically ill b. the elderly ( > 65 years old ) c.persons with high degree of exposure to the public

-standard vaccines containing viruses grown in embryonated eggs have an overall effectiveness of 70 % ( accompanied by side effects of chills and fever)

- newer subunit vaccines made by disrupting virus with detergents or solvents have fewer side reactions but are more limited in scope of protection

- recent tests being done on influenza vaccine administered intra-nasally ( greater potential for immunogenicity)

CONCEPT QUESTIONSCONCEPT QUESTIONS- -Mention the major groups of viruses causes RTI.-Mention the major groups of viruses causes RTI.-- What are the determinants of viral respiratory - What are the determinants of viral respiratory diseases ?diseases ?--What are the properties of orthomyxoviruses ?-What are the properties of orthomyxoviruses ?-- What is the major characters of influenza virus genome - What is the major characters of influenza virus genome ??-- On what basis influenza viruse can be classified ?- On what basis influenza viruse can be classified ?-- What is the possible mechanism for influenza virus - What is the possible mechanism for influenza virus antigenic changes?antigenic changes?-- What is the mode of influenza virus trasmission ?- What is the mode of influenza virus trasmission ?-- Illustrate the pathogenesis of influenza virus ?- Illustrate the pathogenesis of influenza virus ?-- What are the factors affecting efficiency of aerosole - What are the factors affecting efficiency of aerosole spread ?spread ?-- Recovery from influenza virus infection depends on:- Recovery from influenza virus infection depends on:-- What are the diagnostic methods for influenza - What are the diagnostic methods for influenza infections? infections? -- What are the strategies for influenza prevention ?- What are the strategies for influenza prevention ?-- Who are the target for influenza virus vaccinatio ?- Who are the target for influenza virus vaccinatio ?--What are the types of influenza vaccines, giving the -What are the types of influenza vaccines, giving the advantages of each ?advantages of each ?

ENVELOPED, RNA VIRUSESENVELOPED, RNA VIRUSES PARAMYXOVIRUSES

The important human paramyxoviruses: a. Paramyxovirus ( parainfluenza and mumps ) b. Morbillivirus ( measles virus ) c. Pneumovirus ( respiratory syncytial virus )

- resembles the influenza virus but are larger - all are transmitted thru respiratory droplets - envelope has HN spikes and F glycoprotein spikes that allow the virus to infect neighboring cells :

HN ( hemaglutinin and neuraminidase ) : responsible for host cell attachment

F glycoprotein : mediates membrane fusion andhemolysin activity

ParamyxoviridaeParamyxoviridaeProperties of the Paramyxoviridae

2. Morphology & structural proteins

ParamyxoviridaeParamyxoviridaeProperties of the Paramyxoviridae

2. Morphology & structural proteins

PARAMYXOVIRUSES:

Mechanism of infection: cell membrane of infected cell modified by insertion of spikes HN spikes immediately bind an uninfected neighboring cell in the presence of F spikes two cells permanently fuse

chain reaction of multiple cell fusions produce a syncytium or a multinucleate giant cell (with cytoplasmic inclusion bodies)

I. PARAINFLUENZA 4 major serotypes :

1. Parainfluenza virus types 1 and 2- usually infects infants and children

2. Parainfluenza virus type 3- infects infants < 2 years- year round infections- more severe than types 1 and 2

3. Parainfluenza virus type 4- mild disease

Epidemiology and Pathology

- primary infection with virus occurs throughout the year ( seasonal peaks in late fall and winter )

- droplets and respiratory secretions disseminate the virus into the air and onto fomites

- usual route of transmission: inhalation or inoculation of mucous membranes by contaminated hands

- usually seen most frequently in children

- NO transplacental immunity ; babies in first year are particularly susceptible ( more severe symptoms )

Characteristic symptoms of parainfluenza:

a. minor upper respiratory tract disease (a cold)- caused by all types b. bronchitis – usually caused by type 3 c. bronchopneumonia – usually caused by type 3 d. laryngotracheobronchitis ( croup)- afflicts larynx of infants and young children causing labored ,noisy breathing with hoarse cough; usually asso. with types 1& 2

* second only to RSV as a cause of lower respiratory tract infection* commonly cause croup

LABORATORY DIAGNOSIS :

1. Isolation and identification of the virus * specimens : throat and nasal swabs and

nasal washes

* inoculated on primary human and monkey kidney cells -> isolates typed by IF or hemadsorption inhibition or HI

2. Serology : uses paired sera

CONCEPT QUESTIONSCONCEPT QUESTIONS

-Mention the important human paramyxoviruses . Mention the important human paramyxoviruses . - What is the mechanism of infections with What is the mechanism of infections with paramyxoviruses ? paramyxoviruses ? - Four serotypes of parainfluenza, mention the Four serotypes of parainfluenza, mention the host range and host range and

disease caused by each type .disease caused by each type .-What are the epidemiologic feature and What are the epidemiologic feature and pathology of pathology of

parainfuenza virus infections?parainfuenza virus infections?-What are the characteristic symptoms of What are the characteristic symptoms of parainfluenza ?parainfluenza ?- Mention the main laboratory diagnostic Mention the main laboratory diagnostic methods for methods for

parainfluenza. parainfluenza.

Adenovirus

Penton FiberWhat might be its function ??

What are these components?

CONCEPT QUESTIONS:CONCEPT QUESTIONS:- Mention the main characteristic of adenoviruses Mention the main characteristic of adenoviruses ..-- Describe the pathogenesis of adenovirus - Describe the pathogenesis of adenovirus infections.infections.-- What are the epidemiological feature of - What are the epidemiological feature of adenovirus infection?adenovirus infection?-- What are the clinical significane of addenovirus - What are the clinical significane of addenovirus infections?infections?-- What are the main clinical finding associated - What are the main clinical finding associated with acute with acute - febrile pharyngitis?febrile pharyngitis?-- In what ways adenovirus can evade host - In what ways adenovirus can evade host immune response?immune response?

II. MUMPS ( EPIDEMIC PAROTITIS ) :

- self-limited, mildly epidemic illness associated with painful at the angle of the jaw with occasional swelling of the testes

- virus bears morphologic and antigenic characteristics similar to the parainfluenza virus

- has only one serological type

- grows readily in embryonated eggs esp. in the amniotic sac

- can be grown in cell culture to produce large multinucleated giant cells ( syncytia ) and a hemagglutinin

- infectivity of virus destroyed by heating at 56 degrees C for 20 mins.

Mumps

Inflammation, parotitis in a child with mumps

Mumps

Parotid gland

Epidemiology and Pathology of Mumps:

- humans are the exclusive natural hosts

- occurs worldwide, epidemics occur in the late winter and early spring

- high rate of infection among crowded populations

- most cases occur in children under 15 years ( 40 % subclinical)

- lasting immunity follows any form of mumps infection

- communicated thru salivary and respiratory secretions ( less contagious than measles or varicella )

( cont. epidemiology and pathology of mumps )

- incubation period : 2-3 weeks followed by symptoms of fever, nasal discharge, muscle pain, and malaise

- inflammation of salivary glands ( esp. the parotids) produce the classic “gopher-like” swelling of the cheeks on one or both sides

- viral multiplication in salivary glands viremia and invasion of other organs ( e.g. testes, overies, thyroid gland, pancreas, meninges, heart, kidney)

-PROGNOSIS: most will have complete, uncomplicated recovery

Complications of Mumps:

1.Orchitis and epididymitis : occurs in 20-30% of young adult males : painful but no permanent damage occurs

2. Pancreatitis : virus replicates in beta cells and pancreatic epithelial cells

3. Viral meningitis : fever, headache, nausea, vomiting, and stiff neck : common in mumps : appears 2-10 days after onset of parotitis : lasts 3-5 days, dissipates with few or no adverse side effects

4. Hearing loss : a rare occurrence : affects only one side : virus replicates in the organ of Corti causing permanent deafness

( cont. mumps ) Diagnosis:

1. history ( exposure ) and PE ( parotid swelling )2. serologic studies

* IgM antibodies by ELISA or 4 fold increase between acute and convalescent sera

3. viral isolation* virus present in saliva for about 1 week aftre onset of parotitis

Treatment : Symptomatic treatment usually adequate

Prevention : a live, attenuated mumps vaccine given routinely as part of the MMR vaccine at 15 months of age ( powerful and effective control agent ) : protection often lasts a decade

CONCEPT QUESTIONSCONCEPT QUESTIONS- -What are the characteristic of mumps disease ?-What are the characteristic of mumps disease ?-- What are the epidemiologic feature and - What are the epidemiologic feature and pathology of mumps?pathology of mumps?-- What are the major complication of mumps ?- What are the major complication of mumps ?-- What are the diagnostic methods for mumps?- What are the diagnostic methods for mumps?-- What are the main method s for prevention & - What are the main method s for prevention & control ofcontrol of

mumps ? mumps ?

III. MEASLES ( Morbillivirus Infection ) - also known as red measles and rubeola - entirely unrelated to rubella ( German MEASLES ) - characterized by maculopapular eruption , URTI,conjunctivitis

Epidemiology:- one of the most contagious infectious diseases- rare under 6 months of age: transplacental IgG- transmitted principally by direct contact with respiratory aerosols

- epidemic spread favored by crowding, a prevalence of nonimmune children, malnutrition

- 1986 measles epidemic linked to lack of immunization in children or the failure of a single dose of vaccine in many children- no reservoir other than humans- person considered infectious during period of incubation, prodrome, and skin rash

- single attack confers lifelong immunity

Measles (measles or rubeola)

maculopapular rash

“Maculopapular rash” on buttocks of boy during 3rd day of the rash

Conjunctivitis Eyes of child with measles

CPE typical of measles virus infection of Hela cells(Hematoxylin & Eosin staining)

( The large syncytia, or multinucleated giant cells, result

from fusion of cell membranes bearing viral glycoproteins e syncytia, or multinucleated giant

cells, result from fusion of cell membranes bearing viral

glycoproteins.)

( cont. Measles ) Infection and Disease: * incubation period : 2weeks : invasion of mucosal lining of respiratory tract, followed by viremia Symptoms : sore throat, dry cough, headache, conjunctivitis, lymphadenitis, and fever Signs : Koplik’s spots( on lateral buccal mucosa ) appear as a prelude to the red maculopapular exanthem that erupts on the head which progresses to the trunk and extremities : rash gradually coalesce into red patches that fade to brown

“Koplik’s spot”

Patient who presented with Koplik’s spots on palate due to pre-eruptive measles on day 3 of the illness

Complications : in most instances, a self-limited infection

: may be severe enough to cause death in about 1 in 500 children

: laryngitis, bronchopneumonia, bronchitis, pneumonitis , bacterial secondary infections , otitis media and sinusitis

: children with leukemia predisposed to pneumonia due to lack of natural T-cell defense

: SSPE ( subacute sclerosing panencephalitis ) ( manifests 5-7 years after initial infection)

Diagnosis : 1. Clinical

- age, history of recent exposure to measles, ( useful clues to diagnosis) - cough, coryza, conjunctivitis, Kopliks’ spots,

a maculopapular rash beginning on the face

2. Laboratory a. virus isolationb. identification of measles antigen in infected

tissues ( IF from nasal exudates/urine sedi- ments and RT-PCR )

c. demonstration of specific serologic response ( ELISA, HI on paired serum samples )

Treatment : symptomatic treatment for most cases : antibiotics may be given for bacterial complications : large doses of immune globulin may be therapeutic

Prevention : vaccination is the most practical, economical, and enduring strategy to combat measles

Measles vaccine :

- attenuated virus given subcutaneously

- immunity persists for about 20 years

- may cause atypical infection

- recommended for all healthy children at the age of 15 months ( MMR vaccine , with mumps and rubella ) and a booster prior to entering school

- any person who received the vaccine prior to 1980 or whose immunization history is in doubt should be revaccinated

CONCEPT QUESTIONSCONCEPT QUESTIONS-Define measles.Define measles.-- What are the epidemiologic picture of - What are the epidemiologic picture of measles.measles.-- What are the major sign and symptoms - What are the major sign and symptoms of measles.of measles.-- What are the complications of measles ?- What are the complications of measles ?-- What are the basis for the diagnosis of - What are the basis for the diagnosis of measles measles

clinically or laboratory?clinically or laboratory?-What are the major preventive measures What are the major preventive measures of measles?of measles?- What is the schedule of measles What is the schedule of measles vaccination andvaccination and

what type of vaccine ?what type of vaccine ?

RubellaRubella

Electron micrograph of rubella virus

RubellaRubella

Epidemiology of Rubella Virus

Disease / Viral Factors

- Rubella infects only humans. - Virus can cause asymptomatic disease.

- There is one serotype.

RubellaRubella Epidemiology of Rubella Virus

Transmission

- Respiratory route

Who Is at Risk?

- Children: mild exanthematous disease.

- Adults: more severe disease with arthritis / arthragia- Neonates younger than 20 weeks: congenital

RubellaRubella

Rash of rubella on skin of

child's back.Distribution is similar to that of measles but the lesions are less intensely red .

RubellaRubella

Prenatal or congenital rubella

The risk to a fetus is highest in the first few weeks of pregnancy and then declines in term of both frequency and severity, although there is still some risk in 2nd trimester.

The virus infects the placenta and then spreads to the fetus. If non-immune mothers are infected in the 1st trimester, up to 80% of neonates may have sequelae.

RubellaRubella

The sequelae of congenital rubellar syndrome are:

• Hearing loss: This is the most common sequella of congenital rubella infection especially when the latter occurs after 4 months of pregnancy.

• Congenital heart defects

• Neurologic problems: psychomotor retardation : mental retardation

• Ophthamic problems: cataract, glaucoma, retinopathy

RubellaRubella

Prominent Clinical Findings in congenital rubella Syndrome

• Cataracts & other ocular defects

• Heart defects

• Deafness

• Intrauterine growth retardation

• Failure to thrive

RubellaRubella

Prominent Clinical Findings in congenital rubella Syndrome

• Mortality within the first year

• Microcephaly

• Mental retardation

RubellaRubella

This infant has the rash of congenital rubella (German measles).These infants are at great risk for severe mental retardation, deafness, blindness (atrophic eyes, cataracts and chorioretinitis) as well as congenital heart disease and other abnormalities. .

RubellaRubella

  

Baby born with rubella : Thickening of the lens of the eye that causes blindness (cataracts )

RubellaRubella Immune response

  

- Specific IgM antibody appears within a few days of the rash, and is followed soon after by IgG.

- The titer of IgM increases rapidly, reaching a peak about 10 days after onset and thereafter declining to undetectable amounts over several weeks or months.

* Humoral Immunity

RubellaRubella Immune response

  

- The rapid appearance of specific IgM antibody is invaluable for diagnostic purposes. - IgG antibody peaks at about the same time as IgM, and persists for many years, as does IgA antibody, which appears in the serum and nasopharyngeal secretion.

* Humoral Immunity

RubellaRubella Immune response

  

- The cell-mediated response precedes the appearance of antibody by a few days, reaches a peak at about the same time, and is also detectable for many years.

* Cellular Immunity

RubellaRubella Diagnosis of rubella

  

- Many (~ 50%) infections are apparently subclinical and many infections go unrecognized, even if symptoms develop (rash is not always present).

- Infections with many other agents give similar symptoms to rubella (e.g. infection with human parvovirus, certain arboviruses, many of the enterovirus group of piconaviruses, some adenoviruses, EBV, scarlet fever, toxic drug reactions).

RubellaRubella

Diagnosis of rubella

  

- Serological tests or isolation of virus (immunofluorescence) are needed to confirm infection of individual Cord blood rubella- IgM

RubellaRubella Epidemiology

  

- Human is the only host and rubella occurs world wide. - Periodic epidemics occur in an unvaccinated population.

- Natural infection protects for life (there is a single serotype).

RubellaRubella

Prevention

  

- 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 with the measles & mumps vaccines (MMR vaccine) at 24 months of age.

RubellaRubella

Prevention

  

- A live vaccine (attenuated strain) is available. The vaccine virus is grown in human diploid fibroblasts. Since there is only 1 serotype, a univalent attenuated vaccine can provide lifelong immunity.

RubellaRubella

Prevention

  

- It is important that women are vaccinated prior to their 1st pregnancy.

- United States recommendations are for childhood vaccination to prevent epidemics, combined with vaccination of susceptible, non-pregnant adolescent and adult females.

RubellaRubella

Prevention

  

- The vaccine is contraindicated for pregnant women, but when unwittingly used, no problems have been seen. - If the patient is pregnant and seronegative, the pregnancy should be monitored carefully and the patient vaccinated postpartum.

RubellaRubella

Treatment

  

There is no specific treatment. Supportive care should be used.

CONCEPT QUESTIONSCONCEPT QUESTIONS-What is the epidemiologic feature of rubella ?What is the epidemiologic feature of rubella ?-- Who is at risk of rubella infections?- Who is at risk of rubella infections?-- What are the differences between measles and - What are the differences between measles and rubella ?rubella ?-- What is CRS ?- What is CRS ?-- Describe the consequences of congenital rubella ?- Describe the consequences of congenital rubella ?-- What are the sequellae of congenital rubella syndrome - What are the sequellae of congenital rubella syndrome ??-- What are the prominant clinical findings in CRS ?- What are the prominant clinical findings in CRS ?-- Describe the humoral responses to rubella virus - Describe the humoral responses to rubella virus infection?infection?-- Describe the cellular responses to rubella virus - Describe the cellular responses to rubella virus infection?infection?--Is the diagnosis of rubella virus infection always feasible -Is the diagnosis of rubella virus infection always feasible ??-- What are the diagnostic methods for rubella and CRS ?- What are the diagnostic methods for rubella and CRS ?-- What are the epidemiologic feature of rubella?- What are the epidemiologic feature of rubella?-- Mention the main methods for rubella prevention?- Mention the main methods for rubella prevention?-- In what situations rubella vaccine can be - In what situations rubella vaccine can be contraindicated ?contraindicated ?

( cont. RSV infections )Pathogenesis

- transmission : respiratory route

- portal of entry : epithelia of the nose and eye

- main site of replication: nasopharynx

- symptoms : ( 1o infection) fever that lasts for three days : rhinitis, pharyngitis, and otitis : infection of the bronchial tree and lung parenchyma gives rise to croup ( acute bouts of coughing, wheezing, dyspnea and rales )

Clinical Disease:- major cause of respiratory illness in young children- < 24 months : devastating disease-> 4 months : no protective maternal antibody

1. Lower respiratory tract infections- pneumonia, bronchiolitis, tracheobronchitis

2. Upper respiratory tract infections- presents as common cold

3. Complications - otitis media: common

Diagnosis - critical in babies than in older children

- positive identification of RSV must be made as rapidly as possible 1. Viral isolation on nasal wash / naspharyngeal and throat swab ( done ASAP since virus is labile )

2. Direct and indirect fluorescent staining from a fresh sample ( the virus is very fragile) 3. ELISA testing and DNA probes

( cont. RSV )

Treatment : Ribavirin (virazole) appears beneficial since it interferes with the replication of the virus in

infected cells : Ribavirin is administered as an aerosol ( cannot be given to persons whose ventilation is compromised) : costly treatment with some adverse side effects : supportive measures Prevention : intranasal live vaccine presently being developed

•CONCEPT QUESTIONSCONCEPT QUESTIONS--In what age groups the incidence of RSV -In what age groups the incidence of RSV is highest ?is highest ?-- Describe the pathogenesis of RSV .- Describe the pathogenesis of RSV .-- Mention the clinical diseases caused by - Mention the clinical diseases caused by RSV andRSV and

their complications .their complications .--What are the diagnostic methods of RSV -What are the diagnostic methods of RSV infections?infections?- - What are the treatment of RSV and the - What are the treatment of RSV and the methodsmethods

for prevention? for prevention?

HUMAN RHINOVIRUS (HRV )- an extremely large group of picornaviruses ( > 110 serotypes )

- associated with the common cold- characteristics which distinguish the rhinovirus from the other picornaviruses: 1. Rhinoviruses are sensitive to acidic environments ( e.g. stomach ) 2. Optimum temperature for multiplication is not normal body temperature, but 33o C, the average temperature in the human nose

structure of the Rhinovirus: - the capsid units are of two types: a. protruberances (knobs), which are antigenically diverse among the rhinoviruses b. indentations (pockets) of which there are two types

RHINOVIRUS 14

1. KNOBS

2. INDENTATIONS(POCKETS)

2 Antigenic Sites

Pathogenesis and Pathogenesis and Clinical Manifestations Clinical Manifestations

Portal of entry: nose, mouth, eyesPortal of entry: nose, mouth, eyes Replication: in the noseReplication: in the nose Primarily infects upper airway Primarily infects upper airway common common

coldcold Binds to ICAM-1 as cellular receptorsBinds to ICAM-1 as cellular receptors Causes lysis of cellsCauses lysis of cells Infected cells release bradykinin and Infected cells release bradykinin and

histamine histamine rhinitis & rhinorrhea rhinitis & rhinorrhea Sore throat, cough, headache, malaiseSore throat, cough, headache, malaise Immunity is serotype specific Immunity is serotype specific

Rhinoviruses-the surface antigens are the only ones accessible to the immune system ( i.e. a successful vaccine would have to contain hundreds of different antigens- not practical )-the indented antigens are too deeply situated for either immune surveillance or antibody fit

Epidemiology and Infection of Rhinoviruses:- infection occurs in all areas, and all age groups at all times of the year.- many strains circulate in the population at one time ( occasionally a single type may cause epidemics)- children are the most successful disseminators of colds, often introducing the virus to the whole family- virus is shed from infected respiratory tract for several days – weeks- transmission is linked very closely to inoculation by hands and fomites ( to a lesser extent to droplet nuclei )

Rhinovirus

Control of infection:

- combined antiviral-antimediator treatment: In a trial using interferon-alpha 2 + ipratropium (both instilled into the nose) + oral naproxen - > viral shedding and progression of illness were reduced in the treatment group

-Other measures: a. hand washing b. avoiding finger-eye and finger-nose contact c. covering coughs and sneezes with disposable nasal tissues

Rhinovirus

Symptomatic therapy:-Combination of a 1st generation antihistamine and a non-steroidal anti-inflammatory compound effective treatment-Treatment started a early as symptoms are recognized and continued every 12 hours for 4-5 days-Antibiotics have no place in therapy

Antiviral therapy:- the most promising results have been obtained with recombinant interferon-alpha 2 applied topically in the nose - interferon-alpha 2 is given prophylactically on doses of approximately 5 million units or greater per day highly effective in prevcnting experimental infection or illness- side effects of chronic topical interferon-alpha 2 include : nasal irritation, stuffiness, pinpoint mucosal ulcerations

CONCEPT QUESTIONCONCEPT QUESTION--What are the characteristics of -What are the characteristics of Rhinoviruses ?Rhinoviruses ?-- What are the pathogenesis and clinical - What are the pathogenesis and clinical manifestationmanifestation

of rhinoviruses?of rhinoviruses?-- what are the epidemiologic feature of - what are the epidemiologic feature of Rhinoviruses?Rhinoviruses?-- How can we control rhinovirus - How can we control rhinovirus infections?infections?-- mention the strategies for rhinovirus - mention the strategies for rhinovirus infection therapyinfection therapy

: symptomatic therapy: symptomatic therapy

: antiviral therapy : antiviral therapy

Single-stranded RNA, + Single-stranded RNA, + strand, envelopedstrand, enveloped

• Coronavirus

• Upper respiratory infections

SARSSARS

Cause: SARS-associated corona (RNA) virusCause: SARS-associated corona (RNA) virus Respiratory illness with onset 2-1-2003Respiratory illness with onset 2-1-2003 T T >> 100.5°F (>38° C) 100.5°F (>38° C) Cough, shortness of breath, difficulty breathing, Cough, shortness of breath, difficulty breathing,

hypoxia, or radiographic findings of either hypoxia, or radiographic findings of either pneumonia or acute respiratory distress syndrome pneumonia or acute respiratory distress syndrome

Travel within 10 days of onset of symptoms to an Travel within 10 days of onset of symptoms to an area with documented or suspected community area with documented or suspected community transmission of SARS transmission of SARS

Close contact with a person with SARS within 10 Close contact with a person with SARS within 10 days of onsetdays of onset

Define: CoronavirusesDefine: Coronaviruses

Define: SARSDefine: SARS- Mention the main clinical feature of - Mention the main clinical feature of SARSSARS- Mention the main routes of - Mention the main routes of transmission.transmission.

RHABDOVIRUSES Rabies virus ( Lyssavirus ):

- have a distinctive bullet –like appearance ( round on one end and flat on the other end )

- helical nucleocapsid with spikes that protrude thru the envelope

- family contains approximately 60 different viruses

- only the rabies virus affect humans ( rarely, other mammalian lyssaviruses )

- killed by UV irradiation or sunlight

RABIES VIRUS

Epidemiology - slow , progressive zoonotic disease characterized by a fatal meningitis - worldwide distribution in various mammals ( skunks, foxes, raccoons, wolves, mongooses, and badger ) - humans become accidental hosts thru dog bites, cat scratches and contact with sylvan animal reservoirs

1.Sylvatic rabies- rabies in wild animals ( bats, skunks, racoons, foxes )- fruit and herbivorous bats are known to transmit rabies

2. Urban rabies- rabies in domestic animals ( dogs, cats, horses, cattle)- vampire bats in S. America ( source of rabies in cattle)

TRANSMISSION- primarily affects wild animals- humans and animals : accidentally infected

1. animal bite – majority2. via a scratch3. inhalation of contaminated aerosolized animal material4. transplantation of infected tissue ( cornea )5. inoculation through intact mucous membrane

* virus found in saliva of infected animal few days before clinical signs* bat infection : latent ( bats excrete virus in saliva for

months )

110 Murray et al., Medical Microbiology

Note: no viremia

Infection and Disease

- begins when an infected animal’s saliva enters a puncture site ( it may also be inhaled or inoculated orally) - virus multiplies at the trauma site, up to a week upon transmission - virus gradually enters sensory nerve endings or neuromuscular junction and advances toward the sensory ganglia, spinal cord and brain - virus multiplies throughout the brain with migration to other sites ( eye, heart, skin, and oral cavity ) - viral replicates in the salivary glands and is shed into the saliva - considered a slow, progressive infection

Clinical phases of Rabies: Average incubation period: 1-2 months ( extremes of 1 week to more than a year )

Incubation period : depends on wound site, its severity, virus concentration in inoculum, host’s age, host’s immune status : shorter in facial, neck and scalp wounds due to their proximity to the brain : prodrome begins with fever, anorexia, nausea, vomiting, headache, fatigue, some may have pain, burning, pricking or tingling sensation at the site of the wound

Forms of Rabies:

1. Furious form – agitation, disorientation, seizures, and twitching - spasms in the neck and pharyngeal muscles lead to severe pain on swallowing ( even the sight of liquids can bring about hydrophobia ) - the patient is fully coherent and alert

2. Dumb form – patient is paralyzed, disoriented and stuporous

*Both forms eventually lead to coma and death from cardiac or respiratory arrest.*Only 3 patients have recovered from rabies with minimal residua

Diagnosis

- when symptoms appear after a rabid animal attack the diagnosis is readily made

- often the diagnosis is made at autopsy

- the laboratory criteria most diagnostic of rabies are : 1. intracelllular inclusions ( Negri bodies ) 2. identification, isolation of rabies virus in saliva or brain tissue 3. demonstration of rabies virus antigens in brain, serum , CSF

Section of brain showing rabies viruses

Bullet-shapedRabies virus

Rabies virus infected - Negri body - note dark blue basophilic granules (Sellers stain)

Rabies Prevention and Control:

Measures that effectively prevent and limit rabies are: 1. Postexposure vaccination 2. Animal control - 3 IM injections of HDCV ( human diploid cell vaccine) are recommended for high risk groups ( veterinarians, animal handlers, lab personnel, and travelers to endemic areas )- other control measures such as vaccination of domestic animals elimination of strays, strict animal quarantine have reduced the virus reservoir

•A new genetically engineered vaccine made with a vaccinia virus that carries the gene for rabies virus surface antigen have been incorporated into bait placed in habitats of wild reservoir species. It is hoped eating this bait will render animals immune to rabies.

Postexposure Prophylaxis:1. A wild animal especially a skunk, raccoon, fox, or coyote that bites without provocation is considered to be rabid and treatment is commenced2. If the animal is captured, brain samples, and other tissues are examined for verification of rabies3. In an apparently healthy dog or cat they are quarantined for 10 days for observation4. Following an animal bite the wound should be scrupulously washed with soap or detergent and water, followed by debridement and application of an antiseptic that inactivates the virus ( alcohol or peroxide ) 5. Combination of passive and active postexposure immunization is very effective: wound is infused with ( HRIG) human rabies immunoglobulin to impede spread of virus , also injected IM -a full course of (HDCV) is given simultaneously

CONCEPT QUESTIONSCONCEPT QUESTIONS-- Is the rabies virus morphology distinctive ? Is the rabies virus morphology distinctive ?--Define: rabies -Define: rabies -- Mention the epidemiologic feature of rabies - Mention the epidemiologic feature of rabies virus.virus.-- What is sylvanic rabies, and whatis urban - What is sylvanic rabies, and whatis urban rabies ?rabies ?-- What are the of rabies virus transmission ?- What are the of rabies virus transmission ?--Describe infection and disease development of -Describe infection and disease development of rabies.rabies.-- Mention the cliniocal phases of rabies .- Mention the cliniocal phases of rabies .-- Enumerate the forms of rabies .- Enumerate the forms of rabies .--Mention the lab. Criteria most diagnostic to -Mention the lab. Criteria most diagnostic to rabies.rabies.-- Define negri bodies.- Define negri bodies.-- What are the measures that effectively prevent - What are the measures that effectively prevent rabies?rabies?-- What are thew postexposure prophylaxis ?- What are thew postexposure prophylaxis ?

OTHER ENVELOPED RNA VIRUSES

Arboviruses: viruses spread by arthropod vectors

: includes members of several virus families ( see table)

: named according to place of discovery

* rubella virus : only member of the genus Rubiviridae that is also a member of the Togaviridae family

: not an arbovirus because it is transmitted from person to person

FAMILYFAMILY STRUCTURALSTRUCTURAL

CHARACTERISCHARACTERIS- -

TICSTICS

GENUSGENUS EXAMPLESEXAMPLES

( virus )( virus )

TogviridaeTogviridae + RNA+ RNA

envelopedenveloped AlphavirusesAlphaviruses

Eastern equine Eastern equine encephalitis;encephalitis;

Western Western equineencephalitis;equineencephalitis;

California equine California equine encepha-encepha-

litis; Venezeluan litis; Venezeluan equine encephalitisequine encephalitis

FlaviviridaeFlaviviridae + RNA+ RNA

envelopedenveloped FlavivirusesFlaviviruses

Yellowfever ; Dengue;Yellowfever ; Dengue;

St. Louis encephalitis;St. Louis encephalitis;

Japanese B Japanese B encephalitis;encephalitis;

Central European Central European ence-ence-

PhalitisPhalitis

BunyaviridaeBunyaviridae - RNA- RNA

envelopedenveloped

BunyavirusesBunyaviruses

PhlebovirusesPhleboviruses

NairovirusesNairoviruses

California encephalitis;California encephalitis;

Lacross encephalitis;Lacross encephalitis;

Sandfly feverSandfly fever

Crimean-Congo Crimean-Congo hemorrhagic feverhemorrhagic fever

ReoviridaeReoviridae

Segmented, Segmented, doubledouble

Stranded RNA, Stranded RNA, nakednaked

OrbivirusesOrbiviruses Colorado tick feverColorado tick fever

ArbovirusesArboviruses

These viruses multiply inside the vertebrate host as These viruses multiply inside the vertebrate host as well as the vector .well as the vector .

The vector transmits the disease to human and other The vector transmits the disease to human and other mammals , through the bite .mammals , through the bite .

Man generally plays no role in the natural history of Man generally plays no role in the natural history of arboviruses .arboviruses .

Humans are not the natural reservoir for the virus .Humans are not the natural reservoir for the virus .

Arboviruses associated with Arboviruses associated with hemorrhagic fever .hemorrhagic fever .

1- Dengue virus .1- Dengue virus .

Family: Flaviviridae .Family: Flaviviridae .

2- Yellow fever virus .2- Yellow fever virus .

family : Flaviviridae .family : Flaviviridae .

3- Rift valley fever virus .3- Rift valley fever virus .

Family : Bunyaviridae .Family : Bunyaviridae .

4- Crimean congo hemorrhagic fever virus .4- Crimean congo hemorrhagic fever virus .

Family : Bunyaviridae .Family : Bunyaviridae .

Arboviruses with hemorrhagic fever Arboviruses with hemorrhagic fever

2- 2- yellow fever :yellow fever : Geographical distribution : Africa and South Geographical distribution : Africa and South

America .America . Vector : Mosquitoes .Vector : Mosquitoes . Vertebrate host : Human , monkeys.Vertebrate host : Human , monkeys. Symptoms: Most cases are mild or asymptomatic .Symptoms: Most cases are mild or asymptomatic . The severe form of the disease is characterized by The severe form of the disease is characterized by

fever, myalgia, arthralgia, nausea, vomiting, fever, myalgia, arthralgia, nausea, vomiting, jaundice, mucosal bleeding, bleeding under the jaundice, mucosal bleeding, bleeding under the skin, vomiting blood, seizures and coma .skin, vomiting blood, seizures and coma .

Yellow fever cycle .Yellow fever cycle .

1- Jungle yellow fever :1- Jungle yellow fever :

Involves transmission between mosquitoes and non-Involves transmission between mosquitoes and non-human primate, with human as accidental host.human primate, with human as accidental host.

2- Urban yellow fever :2- Urban yellow fever :

Involves transmission between mosquitoes and Involves transmission between mosquitoes and human human

2- Arboviruses associated with 2- Arboviruses associated with encephalitis .encephalitis .

1- 1- West Nile Encephalitis (WNE ) .West Nile Encephalitis (WNE ) . Family : Flaviviridae .Family : Flaviviridae . 2- Eastern Equine Encephalitis ( EEE ) .2- Eastern Equine Encephalitis ( EEE ) . Family : Togaviridae .Family : Togaviridae . 3-Western Equine Encephalitis (WEE ). .3-Western Equine Encephalitis (WEE ). . Family : Togaviridae .Family : Togaviridae . 4-Venezuelan Equine Encephalitis (VEE ). .4-Venezuelan Equine Encephalitis (VEE ). .

Family : Togaviridae .Family : Togaviridae .

Rift valley fever .Rift valley fever .

3- Meningoencephalitis : fever, severe headache, 3- Meningoencephalitis : fever, severe headache, stiffness of neck, back pain, hallucination. Mental stiffness of neck, back pain, hallucination. Mental confusion, lack of coordination, convulsions and confusion, lack of coordination, convulsions and coma . coma .

Transmission :By direct contact with infected Transmission :By direct contact with infected animal blood or tissue .animal blood or tissue .

Through the bite of mosquitoes.Through the bite of mosquitoes. Human to human transmission has not been Human to human transmission has not been

documented..documented..

Arboviruses associated with Arboviruses associated with hemorrhagic feverhemorrhagic fever

4- Crimean Congo H F :4- Crimean Congo H F : Geog. Dist. : Africa, Asia and middle east .Geog. Dist. : Africa, Asia and middle east . Vector : Ticks .Vector : Ticks . Vertebrate host : Sheep, goats , cattle and human .Vertebrate host : Sheep, goats , cattle and human .

Symptoms : Most cases are mild or asymptomatic .Symptoms : Most cases are mild or asymptomatic . In severe cases, the symptoms are : fever, In severe cases, the symptoms are : fever,

headache, myalgia, artheralgia, nausea, vomiting, headache, myalgia, artheralgia, nausea, vomiting, mucosal bleeding and bleeding under the skin .mucosal bleeding and bleeding under the skin .

The major arboviruses pathogenic to man: 1. Togaviruses ( Alphavirus) 2. Flavivirus 3. Bunyaviruses ( Bunyavirus and Phlebovirus ) 4. Reoviruses ( Orbivirus )

The chief vectors ( bloodsucking arthropods ) : a. mosquitos b. ticks c. flies d. gnats

Most types of illness caused by the virus: a. mild undifferentiated fevers b. some would cause severe encephalitides c. some would cause life-threatening hemorrhagic fevers

General characteristics of Arbovirus Infections :

- sudden , unexpected epidemics, sometimes with previously unreported viruses are due to the uncertain nature of host and viral cycles- travelers entering endemic areas are at special risk because, unlike the natives of that region,they have no immunity to the viruses

Arboviruses ( con’t )The influence of the Vector: - activity and distribution of arboviruses closely tied to ecology of vectors - factors to consider: a. longevity of the arthropod b. availability of breeding sites c. climactic influence ( temp. & humidity )

Epidemiology of arbovirus disease: - worldwide distribution ( being arthropod-borne ) - vectors and viruses tend to be clustered in the tropics and subtropics - many temperate zones report periodic epidemics - vertebrate host : recovers vector: carries virus for life

PATHOGENESIS :* infected vector bites -> virus injected into capillary circulation

-> viral replication in vascular endothelium -> viremia ( precedes onset of clinical symptoms ) -> circulating virus reaches the organ for which it has special tropism

ex. liver ( yellow fever virus ) ; brain ( encephalitis virus )1. incubation period : short ( 1 week ) because viruses

are introduced directly into the bloodstream

2. morbilliform rash – secondary to : a. endothelial cell damage

* if severe and disseminated : rash becomes hemorrhagic and involves the mucous membranes, GIT mucosa

and skin* may lead to disseminated intravascular coagulation

( DIC ) and thrombocytopenia

b. increased vascular permeability

CLINICAL SYNDROMES: I. Febrile Illness :

- of undifferentiated type with or without a maculopapular rash and usually benign

A. infections typified by dengue fever and Colorado tick fever: ( 1 ) mild, and self-limited, with no sequelae

( 2 ) fever of up to 40o C, prostration, headache, myalgia , orbital pain, muscle aches, and joint stiffness

( 3 ) midway thru the illness, a maculopapular or petechial rash may erupt over trunk and limbs

II. Encephalitis:( invasion of brain, meninges and spinal cord )- caused by alphaviruses, flaviviruses, bunyaviruses

a). exemplified by Western equine, eastern equine, St. Louis, and California encephalitis b). viruses cycle between wild animals ( primarily birds ) and mosquitos or ticks – humans are not the reservoir hosts c). begins with an arthropod bite release of virus into tissues replication in nearby lymphatics prolonged viremia establishes virus in brain -> swelling and inflammation causes damage to various nuclei and tracts including the meninges d). symptoms : ( variable ), may include coma, convulsions, paralysis, tremors, rigidity, loss of coordination, palsies, memory deficits, changes in speech and personality, and heart damage. e). survivors may have permanent brain damage ( young children and very old patients )

III. Hemorrhagic Fevers

a. flu-like syndrome ( mild cases )- fever, chills, headache, backache, nausea,

vomitingb. extensive hemorrhage ( severe cases ) in mucous

membranes of nose, GIT , bladder- melanemesis ( vomiting of digested blood )

- decrease in pulse pressure accompanied by a paradoxical decrease in pulse rate

- jaundice/proteinuria - certain arboviruses can disrupt vascular bed which

can cause sudden localized bleeding in the tissues leading to shock or death ( e.g. yellow fever and dengue fever viruses )

- exact mechanisms of pathology are obscure : the virus causes capillary fragility and disrupts the blood clotting mechanisms

- these “ hemorrhagic syndromes” are caused by a variety of viruses, carried by variety of vectors, and are distributed globally

- reservoir animals: small mammals : yellow fever and dengue fever can be harbored in human population

• Arenavirus

• Helical capsids contain RNA-containing granules

• Lymphocytic choriomeningitis

• VEE and Lassa Fever

• Rodent transmitted

Single-stranded RNA, – Single-stranded RNA, –

strand, multiple RNA strand, multiple RNA

strandsstrands

• Bunyavirus (CE virus)

• Hantavirus-cause hemorrhagic fevers & pulmonary syndrome assoc. with rodents.

Single-stranded RNA, – Single-stranded RNA, – strand, multiple RNA strand, multiple RNA

strandsstrands

Single-stranded RNA, + Single-stranded RNA, + strand, envelopedstrand, enveloped

• Alphavirus

• Alphaviruses are transmitted by arthropods; include EEE, WEE

• Rubivirus (rubella virus)

Single-stranded RNA, – Single-stranded RNA, – strand, one RNA strandstrand, one RNA strand

• Filovirus

• Enveloped, helical viruses

• Ebola and Marburg viruses

C. Dengue Fever ( DF) / Dengue Hemorrhagic Fever ( C. Dengue Fever ( DF) / Dengue Hemorrhagic Fever ( DHF ):DHF ):

- four serotypes ( Types 1-4 ) of dengue ( in tropics )

- transmitted by mosquitoes ( Aedes aegypti ) * principal mosquito vector which are adapted to

breed around human dwellings ( in man made water- holding receptacles, around human habitation , in tree holes or plants close to human dwelling ) ( intensification of dengue transmission in tropical cities)

* epidemics start often during rainy season whenAedes aegypti is most abundant

( cont. Dengue )* viral replication in the mosquito takes about

(1-2 weeks) then undergoes extrinsic incubation

* extrinsic incubation period required before it can transmit the virus on subsequent feedings

* feeding attempts may number several times a day

depending on the availability of hosts

* lifespan of mosquito is 1-4 weeks

* mosquitoes sheltered indoors and bite during day at 1-2 hour intervals in the morning and late afternoon

PATHOGENESIS ( DF/ DHF ):- self-limited dengue is the usual outcome of infection- an immunopathologic response in some patients

usually in the setting of a heterologous immunity produces the syndrome DHF-DSS Infectious mosquito bite viral replication inlocal lymph nodes disseminates via the blood to various tissues (w/in 2-3 days) virus circulates in blood in infected monocytes , B cells, an T cells (for 4-5 days) nearly all patients are viremic at the point of clinicalpresentation with fever virus cleared from blood within a day after defervescence local suppressionof erythrocytic, myelocytic, and thrombocyticpoeisis ( within 4-5 days)

- shock in DHF-DSS follows sudden extravasation of plasma into extravascular sites including pleural and abdominal cavities usually with defervescence of fever

- the increase vascular permeability may be due to: 1. Increased levels of soluble tumor necrosis factor

2. Interferon-gamma 3. Activation of the complement system

- rapid, predictive reversibility of syndrome within 48 hours ( with paucity of histopathologic correlation) suggests an inflammatory response causing vasculopathies

- the rise of levels of neutralizing antibodies correlates with clearance of viremia

CLINICAL FEATURES:1. Dengue Fever: - acute febrile illness with headaches, musculoskeletal pain and rash - asymptomatic in 80 % of infants and children - cannot be distinguished from other common childhood infections - in adults more severe and acute incubation period ( 4-7 days) of fever, chills, severe frontal headache, retroorbital pain scarlatiniform rash develops within (3-4 days) - virtually all cases are uncomplicated - hepatitis frequently complicates dengue fever ( deaths are rare ) - vertical transmission of virus to neonates where mothers had an onset of 1o or 2o dengue fever ( 0-8 days before delivery) resulted in acute neonatal dengue fever

2. DHF-DSS: - may occur in individuals with heterologous dengue antibody ( possibly acquired as maternal antibody or endogenously produced ) - hemorrhagic phenomena and hypovolemic shock due to increased vascular permeability and plasma leakage

- clinical signs similar to DF but with defervescence within 2-7 days

condition worsens with associated :

1. hypoprotenemia 2. thrombocytopenia 3. prolonged bleeding time 4. elevated prothrombin time

may lead to Dengue Shock Syndrome- cyanosis, restlessness, diaphoresis, cool,

clammy skin

- with support, spontaneous resolution of vasculopathy and circulatory problem within

2-3 days with complete recovery

( cont. Dengue )Factors responsible for occurrence of DSS:

poorly understood ( ? hypersensitivity reactions )

secondary Dengue infection

formation of virus antibody complexes

activation of complement system

vascular dysfunction due to complement products

* due to formation of large amounts of cross-reacting antibodies at the time of second dengue infection

Dengue Prevention:- relies on public health and community-based A. aegypti control programs to remove or destroy mosquito-breeding sites

- insecticidal fogging is considered unhelpful

- in sealed houses, indoor insecticide sprays should be effectual

- vaccines: The most advanced is a tetravalent combination of attenuated dengue strains that is under phase II clinical evaluation- travelers can protect themselves by using repellents and insecticidal sprays indoors

DIAGNOSIS:

1. viral isolation ( most accurate )- most sensitive is intracebrebral inoculation of suckling mice

- successful recovery from blood only before an antibody response develops

2. PCR- identifies the presesnce of Dengue virus and serotypes ( used in specialized lanoratories )

3. serum IgM in dengue infection ( within 60 days ) by

a. antibody capture ELISA- preferred techniqueb. indirect immunofluorescence for IgM and IgG antibodies

4. Rapid immunochromatographic test- for dengue and JE IgM and IgG* high sensitivity and specificity

CONCEPT QUESTIONSCONCEPT QUESTIONS-Define: Arboviruses-Define: Arboviruses- Name the major arboviruses pathoigenic to man .- Name the major arboviruses pathoigenic to man .-The chief vectors of arboviruses include:The chief vectors of arboviruses include:-- Most types of illnesses caused by arboviruses include:- Most types of illnesses caused by arboviruses include:-- What are the general characteristicsa of arboviruses?- What are the general characteristicsa of arboviruses?-- Activity and distribution of arboviruses closely tied to - Activity and distribution of arboviruses closely tied to ecology ofecology of

vectors, what factors to be considered?vectors, what factors to be considered?-- Mention the epidemiologic feature of arboviruses.- Mention the epidemiologic feature of arboviruses.-- Describe the pathogenesis of arboviruse with an - Describe the pathogenesis of arboviruse with an example to each.example to each.-- What are the clinical syndrome associated with - What are the clinical syndrome associated with arboviral infections?arboviral infections?-- Mention the characters , members and mode of - Mention the characters , members and mode of transmission of arbov.transmission of arbov.-- Which viruses causing hemorrhagic and pulmonary - Which viruses causing hemorrhagic and pulmonary syndrome associatedsyndrome associated

with rodents?with rodents?

-What are the members of Togaviridae?What are the members of Togaviridae?-- What are the characteristic of filoviruses? mention the - What are the characteristic of filoviruses? mention the diseases caused .diseases caused .--Define : Lassa fever, Ebola virus , Marburg HF, Dengue -Define : Lassa fever, Ebola virus , Marburg HF, Dengue feverfever-- What are the main epidemiologic characteristics of - What are the main epidemiologic characteristics of DHF ?DHF ?-- Describe the pathogenesis of DF/DHF.- Describe the pathogenesis of DF/DHF.-- In DF/DHF, what are the causes for increased vascular - In DF/DHF, what are the causes for increased vascular permeability?permeability?-- What are the clinical feature of DF?- What are the clinical feature of DF?--Dengue shock syndrome(DSS), how its caused ?-Dengue shock syndrome(DSS), how its caused ?-- What are the factors responsible for occurrence of - What are the factors responsible for occurrence of DSS?DSS?-- What are the conditions that worsens DSS if - What are the conditions that worsens DSS if associated?associated?-- What are the preventive measures of DF?- What are the preventive measures of DF?-- Mention the methods for diagnosis of DF/ DHF.- Mention the methods for diagnosis of DF/ DHF.

NONENVELOPED SINGLE-NONENVELOPED SINGLE-STRANDED RNA VIRUSES: STRANDED RNA VIRUSES:

PICORNAVIRUSES AND PICORNAVIRUSES AND CALICIVIRUSESCALICIVIRUSES

PICORNA viruses are named for their small ( pico )size and their RNA core.Important representatives include: 1. Enterovirus 2. Rhinovirus 3. Cardiovirus ( infects the brain and heart in humans and other mammals)

Selected Characteristics of the human Selected Characteristics of the human picornavirusespicornaviruses

GenusGenus RepresentaRepresentativetive

11o o DiseaseDisease

EnterovirusEnterovirus PoliovirusPoliovirus poliomyeitispoliomyeitisCoxsackieviruCoxsackievirus As A

Focal Focal necrosis,myosnecrosis,myositisitis

CoxsackieviruCoxsackievirus Bs B

Myocarditis Myocarditis of newbornof newborn

EchovirusEchovirus Aseptic Aseptic meningitis,entermeningitis,enteritisitis

Enterovirus Enterovirus 7272

Hepatitis AHepatitis A

RhinovirusRhinovirus RhinovirusRhinovirus Common Common ColdCold

CardiovirusCardiovirus CardiovirusCardiovirus EncephalomyEncephalomyocarditisocarditis

AphthoviruAphthoviruss

AphthovirusAphthovirus Foot and Foot and Mouth Mouth DiseaseDisease

POLIOVIRUS:

- an acute enteroviral infection of the spinal cord that may cause neuromuscular paralysis- also called infantile paralysis ( often affects small children)

Properties :- inactivated when heated at 55 degrees C for 30 minutes- purified poliovirus is inactivated by chlorine concentration of 0.1 ppm- requires primate-specific membrane receptor for infection- undergoes replication after attaching to viral receptors : serves both as its own messenger RNA and as the source of genetic information

HUMAN POLIOVIRUS

(poliomyelitis)

Poliomyelitis: - transmission via mechanical vectors such as flies may occur - respiratory droplets are only rarely involved - has been virtually eliminated in North and South America - prevalence varies in Asia, Africa, and European countries

Infection and Disease: Ingestion of an infectious dose ( approx. 106 virions) polioviruses adsorb to receptors of mucosal cells in oropharynx and intestine viral multiplication ( precise location unknown but may be mucosal epithelia or lymphoid tissue) large numbers of viruses are shed into the throat and feces and some leak into the blood

PolioIncubation period: 1-2 weeks 4 types of infections: a. subclinical infection ( inapparent without symptoms) b. minor disease c. aseptic, nonparalytic meningitis d. paralytic disease- Most infections ( 95% ) are contained as a short-term asymptomatic viremia- a small number of persons will develop minor disease (with nonspecific symptoms of fever, headache, nausea, sore throat, and myalgia )- being neurotropic, it may gain access to the CNS via the blood-brain barrier -> infiltrate the motor neurons of the spinal cord -> invasion of nervous tissue without destruction causes nonparalytic meningitis

Paralytic Disease:

- highly virulent virus + / or highly susceptible host = destruction of nervous tissue ( various degrees of flaccid paralysis )- flaccid paralysis ensue over a period of a few hours to several days- depending on the level of damage to the motor neurons of the anterior horn of the spinal cord ( occasionally, the spinal ganglia, cranial nerves,and motor nuclei) paralysis of the muscles of the legs abdomen, back, intercostals, diaphragm, pectoral girdle, and bladder may occur.- bulbar poliomyelitis : less frequent : disintegration of the brain stem , medulla, cranial nerves : autonomic cardiorespiratory regulatory centers, palate, pharynx, and vocal cord are affected

Epidemiology

- has 3 serotypes; Types 1 and 3 cause the most severe forms of disease

- protective capsid and lack of an envelope confer chemical stability and resistance to acid and bile detergents SIGNIFICANCE: the virus is capable of passing thru the gastric environment undamaged

- incidence is more pronounced during the summer and fall in temperate

- virus is passed within the population thru food, water, hands, and objects contaminated with feces

Paralytic Disease (con’t)- antibodies to poliovirus: occur locally in the intestine and tonsils ( secretory antibodies), and in the serumOne exposure confers lifelong immunity

DIAGNOSIS: * suspected when epidemics of neuromuscular disease occurs in the summer in temperate climates * must be differentiated from Guillain-Barre syndrome, infant botulism, and encephalomyelitis caused by other enteroviruses

1. CSF : increased leucocytes and proteins; glucose normal

2. virus can be isolated by inoculating cell cultures with stool or throat washings in the early part of the disease

3. stage of infection demonstrated by testing serum samples for the type and amount of antibody

Immune response

- Infection induces antibodies with complement-fixing and neutralizing activities and they may be used retrospectively for laboratory confirmation at polio infection.

- There is the usually early specific IgM response, rapidly followed by a much longer-lasting production of specific IgG.

- Neutralizing antibodies—IgG in the blood and IgA at mucous surfaces—are important in protecting against reinfection.

- However, antibody against one of the 3 serotypes does not in general protect against the others, although there may be some cross-protection between types 1 and 2.

Treatment and Control of Polio:

- no specific therapy, treatment rests largely on alleviating pain and suffering

-respiratory failure may require artificial ventilation

-secondary pulmonary infection as a result of impairment of swallowing and coughing may require antibiotics

- after the acute febrile phase, prompt physical therapy to diminish crippling deformities and to retrain muscles

Prevention :- vaccination is the mainstay of prevention.- 2 forms of vaccine currently in use: 1. Salk Vacine – inactivated poliovirus vaccine ( IPV ) 2. Sabin Vaccine – oral poliovirus vaccine ( OPV )- both vaccines are prepared from animal cell cultures and are trivalent ( combinations of 3 serotypes )- both vaccines are effective- in tropical countries where exposure of infants to wild virus is common, both vaccines may be given- polio immunization must be instituted as early in life as possible, usually four doses starting at about two months of age-adult candidates are travelers and members of the armed forces.

NONPOLIO ENTEROVIRUSES

- commonly cause transient neonatal infections- Coxsackieviruses A and B, echoviruses, and nonpolio

enteroviruses are like polioviruses in many epidemio- logic and infectious characteristics

- spread thru fecal contamination- incidence is highest from late spring to early summer

in temperate climates- 50 % to 80 % of enteroviral infections are subclinical,

and the remainder fall into the category of “ undifferentiated febrile illness”

- initial phase of infection is intestinal after which the virus enters the lymph, blood and disseminates to other organs

COXSACKIE B

Coxsackievirus & Echovirus Infection

Coxsackie A virus :

- Herpangina is caused by several types of Coxsackie A virus & is not related to aherpesvirus infection. Fever, sore throat, pain onswallowing, anorexia, & vomiting.

The classic finding is vesicular ulcerated lesions around the soft palate & uvula

Herpangina

Coxsackievirus & Echovirus Infection

Coxsackie A virus :

- Hand-foot-and-mouth disease:a vesicular exanthem usually caused

by coxsackievirus A16.

Hand-foot-and-mouth disease caused by Coxsackie A virus.

Coxsackievirus & Echovirus Infection

Coxsackie B virus :

- Myocardial & pericardial infections(The symptoms resemble those of

myocardial infarction with fever.)

Acute Hemorrhagic ConjunctivitisAcute Hemorrhagic Conjunctivitis:

- caused by Enterovirus 70 ( responsible for tens of millions of cases since 1969 )- a variant of coxsackie A24 causes a similar, but geographi- cally more restricted disease- AHC first recognized in Ghana and Indonesia in 1969 and has spread rapidly in different parts of the world ( in Africa, some parts of Europe and Asia.)- regions of Asia where it has caused epidemics include: Vietnam, Bangladesh, Thailand, Sri Lanka, Taiwan, The Philippines, The Philippines, Samoa, and Japan- large-scale epidemics have occurred predominantly in crowded costal areas of tropical countries during the hot, rainy season

AHC: - unlike most other enterovirus infections, transmission is primarily from fingers or fomites directly to the eye- both enterovirus 70 and coxsackie A24 can be isolated from the conjunctiva early in the illness- highly contagious and spreads rapidly- contagion is favored by crowding and unsanitary living conditions- reuse of water for bathing and sharing of towels are implicated as factors contributing to spread of infection- begins abruptly, reaches its peak within 1 day- main symptoms: burning, foreign body sensation, ocular pain, photophobia, swelling of eyelids, and watery discharge- subconjunctival hemorrhage is the most distinctive feature of enterovirus infection ( much less with coxsackie)

AHC:- conjunctival edema more common in the elderly; hemorrhage more profuse in the young- recovery is noticeable on the 2nd or 3rd day and is complete by 10 days

Complications: 1. Keratitis occasionally persists but no permanent scarring occurs 2. Motor paralysis similar to polio occurs in persons who have recently recovered from AHC ( a rare occurrence consi- dering the number of AHC cases) * Bulbar paralysis can occur in half of the cases * CSF abnormalities are that of aseptic meningitis

AHC:Diagnosis: - Diagnosed easily in major epidemics but may be confused with adenovirus infection causing epidemic keratoconjunctivitis in sporadic cases - AHC has shorter incubation period ( 1 day) compared to 5-7 days with epidemic keratoconjunctivitis - Bacterial and chlamydial conjunctivitis do not cause extensive outbreaksLab: - Virus can be recovered from conjunctival swabs or scrapings of patients with AHC - Rising antibody titers in paired sera

Treatment: Symptomatic

Prevention: hand washing, use separate towels, sterilization of oph- thalmologic instruments

CONCEPT QUESTIONSCONCEPT QUESTIONS--Show the main characteristics of human picornaviruses.-Show the main characteristics of human picornaviruses.-- Mention the properties of polioviruses.- Mention the properties of polioviruses.-- Define: poliomyelitis - Define: poliomyelitis -- Describe infection and disease of polioviruses .- Describe infection and disease of polioviruses .-- Mention the 4 types of poliovirus infections.- Mention the 4 types of poliovirus infections.--What is the paralytic poliomyelitis ?-What is the paralytic poliomyelitis ?--Mention the characters of bulbar poliomyelitis.-Mention the characters of bulbar poliomyelitis.-- Show the epidemiologic feature of poliovirus.- Show the epidemiologic feature of poliovirus.-- The diagnosis of poliomyelitis include:- The diagnosis of poliomyelitis include:-- What are the clinical feature of poliomyelitis?- What are the clinical feature of poliomyelitis?-- Describe the immune responses to poliovirus - Describe the immune responses to poliovirus ionfection.ionfection.-- What are the steps for the treatment of poliomyelitis?- What are the steps for the treatment of poliomyelitis?--What are the prevention measures of poliomyelitis ? -What are the prevention measures of poliomyelitis ?

NON-POLIO ENEROVIRUSESNON-POLIO ENEROVIRUSES

--What are the general properties of Coxsackie & Echo -What are the general properties of Coxsackie & Echo viruses?viruses?-- Mention the types of infections associated with - Mention the types of infections associated with coxsackievirus A & B.coxsackievirus A & B.-- What is acute hemorrhagic conjunctivitis(AHC) ?- What is acute hemorrhagic conjunctivitis(AHC) ?-- What are the complications associated with AHC ?- What are the complications associated with AHC ?-Coxsackieviruses incriminated as a cause of:Coxsackieviruses incriminated as a cause of:-- What are the diagnostic methods and preventive - What are the diagnostic methods and preventive measures of AHC?measures of AHC?