ENTEROVIRAL INFECTIONSENTEROVIRAL INFECTIONS

Dr.B.Boyle

ENTEROVIRAL INFECTIONSENTEROVIRAL INFECTIONSContents of LectureContents of Lecture

ENTEROVIRUSESAlso Discuss , Viruses that cause

GastroenteritisROTAVIRUSSMALL ROUND STRUCTURED

VIRUSES e.g Norwalk virus or Novovirus etc.

ROTAVIRUSROTAVIRUS

ROTAVIRUSROTAVIRUS

Description Epidemiology Pathogenesis Clinical Features Diagnosis Treatment The Future

ROTAVIRUSROTAVIRUS

First described in 1973 by electron microscopy from duodenal biopsy specimens

Causes 40-60% of cases of diarrhoea in cooler months in infants and children < 2 years

Morphology-RotavirusesMorphology-Rotaviruses Reoviridae Family Non-enveloped icosahedral

structure, 70nm EM: Wheel shape Capsid: Outer(VP7 and 4)

and Inner(VP6) proteins Core encloses 11 segments

of DS RNAGenome encoded Structural

proteins VP1-7 and NSP 1-5, NSP4 has enterotoxinlike activity

Epidemiology of RotavirusEpidemiology of Rotavirus

Incubation period : 2-4 days Those affected :4-24 month old infants,

infection before and reinfection after this usually asymptomatic (Breastfeeding results in milder disease)

Spread within families and institutions Human to human, faecal-oral routeFound on fomites in childcare

Epidemiology of RotavirusEpidemiology of Rotavirus

Main cause of severe diarrhoea in children < 5 years

130 million episodes per year in the world Between 600,000-870,000 deaths, mostly in the

developing world Rate of hospitalisation in developed world 2.5% Seasonal pattern Most persons infected by 3 years of age Group A predominates

Classfication-RotavirusClassfication-Rotavirus

Groups,Subgroups and serotypes depending on the antigenic properties of the capsid proteins

Group-VP6, seven exist A-G, 2 subgroups 1-2

Groups A,B,C cause human infection

Rotavirus-PathogensisRotavirus-Pathogensis

Mature Enterocytes(on tips of Small Intestine villi)

Infects

Villous Atrophy

Compensatory Repopulation by immature Secretor cells and secondary hyperplasia

Cell death because of villous ischaemia

Mechanism of diarrhoea?Mechanism of diarrhoea?

Villous epithelium in relation To secretory capacity of

Crypt cells

Loss of permeability to Macromolecules e.g Lactose,

Due to loss of disaccharideases

Enteric nervous system stimulates InductionOf intestinal Water

And electrolyte secretion

Rotavirus Damage to Small Rotavirus Damage to Small IntestineIntestine

Immune Response to Immune Response to RotavirusRotavirus

Localised Immune response protects against severe subsequent infections

NSP4 protein results in cell mediated immunity

Outcome of Infection with Outcome of Infection with VirusesViruses

Lysis of cells e.g Influenza or polio Persistent infection e.g. cell remains alive and

continues to release virus particles e.g. Hepatitis B , CHRONIC CARRIER STATE

Latent Infection , no replication – Varicella Zoster or retrovirues , if triggered leads to lysis

Transformation of host cells e.g. warts or papovaviruses, HTLV 1 and 2

Clinical Presentation-Clinical Presentation-RotavirusRotavirus

Abrupt onset of vomiting followed within hours by watery, brown copious diarrhoea, often lasts 3-8 days

If Severe Dehydration and death or hospitalisation

DIAGNOSISDIAGNOSIS

Clinically Latex agglutination

Kit testing for Group A

Rv antigen in stool

Enzyme Immunoassay

Group A

Rv antigen in stool

Less common EM and molecular methods

Pos and neg Pos and neg

TREATMENTTREATMENT

REHYRATE, oral and if severe parenteral

Some studies in immunocompromised persons showing the use of Human Immunoglobulin results in a reduction in the duration of symptoms and decreases viral sheeding

ISOLATION of patient in hospital with contact prescautions

MANAGEMENTMANAGEMENT

In Home: Washing of surfaces with soap and water which may be contaminated with Rotavirus

70% ethanol solution will kill the virus on environmental surfaces

FAMILY: PICORNAVIRIDAEFAMILY: PICORNAVIRIDAE

ENTEROVIRUSESOver 72+

RHINOVIRUSType 1-100+

POLIO virus type 1,2,3COXSACKIE A virus type 1-22,24

COXSACKIE B virus type 1-6E.C.H.O virus type 1-7,11-27,29-34

Numbered ENTEROVIRUSES type 68-71,73

Since 1967-all new ones are numbered

CardiovirusAphthousvirusetc

E.C.H.O = enteric cytopathic human orphan

CharacteristicsCharacteristics

VIRON= naked , small (25-30 nm) icosahedral capsid enclosing postive sense single stranded RNA

Enteroviruses are resistant to p H 3-9, Heat, Mild sewage treatment and detergents, conditions in GIT = FACILATES faecal oral spread

CharacteristicsCharacteristics

Rhinovirus labile to acidic p H

Genome of Enteroviruses is m RNA

Naked genome is sufficient for infection

Replication in cytoplasm Cytolytic viruses

Clinical Manifestations of EV Clinical Manifestations of EV Infections(Mostly Children)Infections(Mostly Children)

Neurological: e.g Poliomyelitis, Aseptic meningitis and encephalitis

Neonate: neonatal sepsis EV 11

Non-specific febrile illness Hepatitis gi etc Haemorrhagic

conjunctivitis, COX A24 and EV 71

Respiratory Symptoms e.g colds, herangina

Skin Exanthem with meningitis

Myocarditis Those associated with

Coxsackie viruses Spread: Faecal oral route ,

respiratory route and peripartum mother to infant or fomite transmission

IP: 3-6 DAYS

COXSACKIE VIRUSESCOXSACKIE VIRUSES

29+ immunogenic typesDivided into A and B on the basis of

different pathogenic potential for miceResult in a number of different clinical

presentations

COXSACKIE VIRUSESCOXSACKIE VIRUSES

Herangina Summer minor

illness Aseptic meningitis Neonatal Disease Colds

Hand , Foot and mouth illness

Myocarditis ? Diabetes mellitus Epidemic myalgia

(Bornholm Disease)

HAND/FOOT/MOUTHHAND/FOOT/MOUTH

Coxsackie Coxsackie A16A16

H/F/MH/F/M

ECHO VirusesECHO Viruses

General properties similar to other enteroviruses

30+ antigenic typesResults in: - 1. Aseptic meningitis 2. Rash 3.Conjunctivits 4. Upper Respiratory Tract

Infection

ENTEROVIRUS 71ENTEROVIRUS 71

ManagementManagement Supportive Capsid function inhibitors: Pleconaril, broad

spectrum, potent to Rhino and enteroviruses, good oral bioavailibility

This compound binds to the floor of a VP1 and VP3 canyon floor , prevents binding to receptor on cells

Used in cases of meningoencephalitis shown to be effective

As humoral immunity is the body`s defence for enteroviruses, those who have deficiencies (congenital –or acquired)are given Intravenous Immunoglobulin

POLIO VIRUSPOLIO VIRUS

PoliovirusesPolioviruses

are RNA , ENTEROVIRUSES

3 Serotypes 1, 2 ,3 Major cause of paralytic

poliomyelitis and now seeing post polio syndrome

Global Eradication Programme of WHO

EPIDEMIOLOGYEPIDEMIOLOGY Human host Spread: Faecal oral or Respiratory routes More common in infants and young children, but

risk of paralytic disease increases with age No indigeous wild type polio in U.S since 1979,

imported in 1993, last wild type case in Ireland 1984 Vaccine Associated Paralytic Polio(VAPP) WHEN

ORAL POLIO VACCINE (OPV) was in use( Reversion to wild type) now inactivated polio vaccine used(IPV) used in Ireland since 2001

EPIDEMIOLOGYEPIDEMIOLOGY

Risk of VAPP is one case per 2.5 million doses, greatest risk with first dose

If using OPV strict hygiene after nappy changing or toileting should be observed for 6 weeks

PRESENT VACCINE PRESENT VACCINE SCHEDULESCHEDULE

At birth- 1 month BCG Usually in maternity hospitals

*At 2 months Diphtheria

Whooping Cough

Tetanus

Hib

Inactivated Polio

+

Meningococcal C

5-in-1(G.P)

*At 4 months Diphtheria

Whooping Cough

Tetanus

Hib

Inactivated Polio

+

Meningococcal C

5-in-1(G.P)

PRESENT SCHEDULEPRESENT SCHEDULE

*At 6 months Diphtheria

Whooping Cough

Tetanus

Hib

Inactivated Polio

+

Meningococcal C

5-in-1(G.P)

*At 12- 15 months Measles

Mumps

Rubella,

Hib1

MMR

Hib1

PRESENT SCHEDULEPRESENT SCHEDULE

**4-5 YEARS Diphtheria

Whooping Cough

Tetanus

Inactivated Polio

+

Measles

Mumps

Rubella

4-in-1

MMR

**11-12 YEARS Measles

Mumps

Rubella MMR

Omit if 2 previous doses have been given

PRESENT SCHEDULEPRESENT SCHEDULE

**11-14 years Tetanus

Diphtheria (low dose)Td

**10-14 years if not protected(immune)

Under 23 years(Colleges etc)

BCG2

(AN INTERVAL OF 4 WEEKS AFTER MMR)

Meningococcal C

•From Family Doctor1: A single dose of Hib vaccine if child presents after 13 months and has no previous Hib vaccine2: Only those known to be tuberculin negative and have no previous BCG**These immunizations are generally administered in schools by Health Boards

Clinical Presentations of Clinical Presentations of Poliovirus Infection Poliovirus Infection

Approx. 95% of infections are ASYMPTOMATIC Minor illness in 4-8% of lowgrade fever, sore throat Aseptic Meninigits in 1-5% Asymmetrical acute flaccid paralysis with areflexia of

limbs involved in 0.1%-2% of infections (Respiratory Muscles may be involved)

Residual Paralytic Diease in 2/3 of these Some develop Post-Polio syndrome 30-40 years post

infection with return of muscle pain and weakness

PoliomyelitisPoliomyelitis

PoliomyelitisPoliomyelitis

Pathogenesis of Enteroviral Pathogenesis of Enteroviral InfectionInfection

Virus Replicates in Nasopharnyx

Binds Enterocytes Receptor coded by Ch 19

Evades

Acidic PH

Endocytosed , replication inPeyer`s patches

Minor Viraemia,Replication in organs

Major Viraemia+ Trophism+ Virulence

Skeletal MuscleNeuromuscular

Endplate

Ascends alongMotor Nerves

Anterior MotorNeuron horn

cellsTo CNS*

*Spinal, Bulbar, Medullary Red=specifc for polio

CommunciabilityCommunciability

This is greatest shortly before and after onset of clinical illness when virus in the throat and it is excreted in high concentrations in faeces

For OPV RECIPIENTS, VIRUS IN THE THROAT 1-2 WEEKS AND FAECES FOR SEVERAL WEEKS USUALLY MAX 6-8 WEEKS IN NORMAL IMMUNOCOMPOTENT INDIVIDUAL.

Surveillance Surveillance

For Acute flaccid paralysisSince September 1998Two faecal specimens 24-48 hours apart

for viral culture as soon as possible after onset of acute flaccid paralysis

Faeces most likely to yield virus

DiagnosisDiagnosis

Clinical Presentation Laboratory

Diagnosis Faecal, Throat (2 or

more samples), CSF(Culture and RT-PCR)

TREATMENT/PREVENTIONTREATMENT/PREVENTION

Supportive Prevention is by Vaccination.Global Eradiation ProgrammePart of Routine immunisation schedule

and travellers to endemic areas should be vaccinated

Global Eradication programmeGlobal Eradication programme

SLV-NLV-Novovirus-SLV-NLV-Novovirus-CalcivirusesCalciviruses

Family: Calciviridae Single Stranded RNA, ps Consists of Single

Structural Capsid protein with icosahedric symmetry but has 32 cup-shaped depressions on the axes of the Icosahedron hence the name calyx

Multiple antigenic types

EpidemiologyEpidemiology

Genotype 1,11 and 4 are associated with outbreaks Often affecting institutions Commonest cause of gastroenteritis outbreaks in

2nd quarter 2005, with 32 outbreaks and 675 persons ill, 72% of cases

Present circulating genotype in Ireland since 2004 is Genotype 11.4 JAM strain

Review: Lopman et al Lancet Feb 2004

Pathogenesis of DiseasePathogenesis of Disease

Not fully understood although some evidence suggesting it may be simliar to Rotavirus

Causes delayed gastric emptying Immunity: infection induces specific IG G/A/M

even if there is previous exposure 2 weeks post infection there is in jejunal Ig A , ⇧

resistance to reinfection lasts 4-6 months, NO LONG TERM PROTECTION Accounts for >85% of non-bacterial outbreaks of

gastroenteritis

EPIDEMIOLOGYEPIDEMIOLOGY Sporadic cases however

causes epidemic outbreaks Examples: on cruise ships,

hotels, Institutions and hospitals

Spread: Person to person via faecal oral route or through contaminated food or water or fomites

Incubation Period: 12-72 hours

Vomitus /Faeces infectious

CLINICAL FEATURESCLINICAL FEATURES

DIARRHOEA VOMITING Commonly accompanied

by fever, malaise, myalgia and abdominal cramps

Symptoms last 1 day to 70 hours usually

Virus excreted 5 to 7 days after the onset of symptoms in half of people although may last 13 days

Diagnosis(sample: stool)Diagnosis(sample: stool)

Electron Microscopy Labour intense Relatively insensitive Used in Sporadacic cases EIAStool tested, can have a

result in a few hoursNot labour intensiveEvaluation of kits must be

carried out for sensitivity/specificity

Reverse Transcriptase Polymerase chain reaction (RT-PCR)

Used in outbreaks as large numbers can be processed efficiently

TreatmentTreatment

Supportive therapy: rehydration, electrolyte replacement

Isolation of Hospitalised patientControl Measures: Standard and

Contact precautionsNo Vaccine

Suspect an outbreak in hospital Suspect an outbreak in hospital ifif

Projectile vomiting in >50% of casesDuration of illness 12-60 hoursIncubation period 15-48 hoursStaff and patients illStools negative for bacterial pathogens and C.difficile and other viruses

Control Measures in Control Measures in Hospital OutbreaksHospital Outbreaks

Isolation or Cohort Contact Precautions-

disposable plastic apron/ gloves, Hand Hygiene

Close Ward to Admissions Non-essential personnel

excluded Avoid Transfers If Staff unwell not return to

work until free from symptoms 48 hours

Increase frequency of ward cleaning

Vomit/Faeces to be cleaned and disinfected promptly

Hypochlorite(0.1%) used to disinfect surfaces

Cohort Staff Limit Movement Ward not reopened until 72

hours after last new case or after last vomiting/diarrhoea

Terminal cleaning

The FutureThe Future

Plasmidic DNA and Antigen VaccinesInterrrupt TransmissionSupportive Therapy