ENTEROVIRUS

7/11/2554

Abbreviation
h/o b/o usu occ p/w w/ w/o CVA CVB EV

history of because of usually occasionally present with with with out coxsakievirus A coxsakievirus B Enterovirus

HFM

Hand-foot-mouth

P M

plasma cell macrophage

Virology

Non-enveloped, icosahedral capsid ssRNA family Picornaviridae

Unlike other picornaviruses, Enterovirus are stable over the wide range of pH

http://pathmicro.med.sc.edu/virol/picorna.htm

Original 5 subgenera
1. 2.

Polioviruses serotypes 1-3 Group A coxsackieviruses serotypes 1-22, 24

3.
4. 5.

Group B coxsackieviruses serotypes 1-6

Echoviruses serotypes 1-9, 11-21, 24-27, 29-33 Enteroviruses serotypes 68-71

Virology

named b/o ability to multiply in GI not a prominent cause of gastroenteritis Susceptible to chlorine but resistant to alcohol, detergents Persist for days at room temperature

How Important

second most common viral infection after Rhinovirus Infants, children, and adolescents are more likely to be susceptible

BACK TO THE PAST

h/o enteroviruses is h/o poliovirus Michael Underwood, a British physician, in 1789 reported children w/ paralysis & fever 1840 sporadic poliomyelitis were published 1890 neurologic complication were recorded in Sweden by Karl Oskar Medin 1908; Poliovirus was discovered to be cause of poliomyelitis by Viennese Landsteiner and Popper 1948, antigenically distant virus was isolated from feces of a paralytic child in Coxsackie, NY, during epidemic poliomyelitis; when 2nd diverse virus was isolated in the same area from cases of aseptic meningitis, 1st Coxsackie A, 2nd Coxsackie B 1951; stool of normal, several antigenically independent viruses were isolated named ECHOviruses (enteric isolates, cytopathogenic, isolated from humans and orphans) 1952, Bodian and Horstmann had independently discovered viremia After 1969, new serotypes were numbered sequentially

PATHOGENESIS
Derived from studies of poliovirus Epithelium in GI submucosal lymphoid regional LN (minor viremia) replication in RE (MAJOR viremia) Spread directly from muscle to CNS Limited to primates, bz their cells express viral receptor BCx 3-5 d after infection Shed from oropharynx up to 3 weeks, from GI tract up to 12 weeks

IMMUNITY
Serotype specific Neutralizing Ab target on Capsid protein VP1 Humoral & Secretory immunity

IgM in 1-3 days disappear w/n 2-6 mo IgG in 7-10 days (mostly IgG1, IgG3) persist for life IgA (nasal/alimentary) in 2-4 wks/ persists for 15 yrs

CMI
Pt w/ CMIR defect severe enterovirus infection

Epidemiology
Worldwide > 50% nonpoliovirus/ >90% poliovirus are subclinical Low socioeconomic (crowded, tropical, poor hygiene) Infants, young children Temperate climate; more in summer and fall Tropics; no seasonal pattern

TRANSMISSION

Shed in feces and respiratory tract secretions Direct and Indirect transmission Swimming in seawater EV 70, which causes acute hemorrhagic conjunctivitis, is spread by fomites, fingers, and ophthalmologic instruments via Placenta severe disease in Newborn Infants in diapers who shed virus in the feces are the most efficient disseminators of infection No infected via blood transfusions or insect bites

http://www.discoverymedicine.com/Didier-Hober/2010/08/27/enteroviral-pathogenesis-of-type-1-diabetes/

POLIOVIRUS

Introduction

Polios gray Myelos marrow or spinal cord 3 serotypes

1. 2. 3. Wild type Live attenuated OPV Vaccined derived poliovirus (cVDPVs)

Involve neurons in the grey matter, esp in anterior horns of spinal cord Incubation 9-12 d Poliovirus can be isolated from spinal cord for first few days after onset of paralysis Permanent weakness 2/3 of pt Poor prognosis; severe, require ventilator

Clinical manifestations
unapparent illness severe paralysis death Asymptomatic Abortive poliomyelitis

manifested by fever, malaise, sore throat, anorexia, myalgias, headache, resolve in 3 d

Nonparalytic poliomyelitis
Present of meningeal irritation More systemic symptoms

Manifestations

Spinal paralytic

Biphasic phase but adult usu experience single phase w/ prolonged prodrome symptoms Severity varies from weakness of one muscle to complete quadriplegia Asymmetrical distribution Proximal > distal Large muscle > small muscle Most common pattern is one leg > one arm > all limbs Progression of weakness stops when afebrile Sensory loss is rare

Manifestations

Bulbar paralytic
Dysphagia,pooling of secretions, nasal speech, sometimes dyspnea 9th and 10th CN are most common Most serious = involve circulatory and respiratory centers

Polioencephalitis
Uncommon form Principally in infants Seizure are common, indistinguishable from other viral encephalitis

Complications
Paralysis of respiratory muscle Airway obstruction due to CN involvement Myocarditis GI hemorrhage Paralytic ileus Gastric dilatation

Diagnosis
CSF indistinguishable from other viral Isolated from throat in 1st week, from feces for several weeks Unlike other enterovirus, polioviruses rarely isolated from CSF Isolation from CSF in evaluating cVDPVs Serologic tests can not distinguish between wild type and vaccine type infection

Postpoliomyelitis Syndrome
New onset of weakness, fatigue, fasciculations, pain w/ atrophy, many years after illness Typically, involved muscles are the same Peak 25-35 y after acute poliomyelitis Prognosis is good Plateau in 1-10 y

Poliovirus Immunization

Live attenuated vaccine

immunity probably lifelong 2, 4, 6, 18 4-6

Inactivated vaccine

DPT, HiB, HeB 4, 5 6

http://en.wikipedia.org/wiki/Polio_vaccine " ...

Vaccine associated Poliomyelitis

OPV 1 in 2.5 million doses 2000x in immunodeficient, esp hypo/agammablobulinemia No case report since 1999

Treatment
Supportive Hot moist packs Physical therapy Mechanical ventilation Postural drainage, suction Catheterization

ENTEROVIRUSES

SUMMER GRIPPE (Nonspecific febrile illness)

Grippe (old term) = Influenza Freq occurs in summer and early fall other respiratory virus often late fall and early spring Most common manifestation of Enterovirus Manifestations

Incubation 3-6 d Last for 3-4 d Indistinguishable from rhinovirus, mycoplasma pneumonia, unless accompanied by aseptic meningitis, exanthem or other clinical features of enterovirus Coryza Laryngotracheobronchitis (Croup) Bronchiolitis Pneumonia; interstitial/ patchy

GENERALIZED DISEASE OF THE NEWBORN

Most serious in 1st week of life but up to 3 mo Resembling bacterial sepsis Vertical transmission Fever, irritability, lethargy Leukocytosis w/ left shift, thrombocytopenia, elevated in liver function, CSF pleocytosis Complication; myocarditis, hypotension, fulminant hepatitis, DIC, meningitis, meningoencephalitis, pneumonia Management;
Supportive IVIG justified given in extremely poor prognosis b/o lack of evidence

Acute viral meningitis

90% of children/young adult class B enteroviruses (CVB, Echovirus) Manifestation in infants < 3 mo

highest rates of aseptic meningitis, bz LP are routinely performed minority have symptoms more severe, onset is gradual or abrupt Fever, chills headache, meningismus in 1/3, photophobia, pain on EOM Pharyngitis and URI often present sometimes biphasic, as in poliomyelitis May take weeks to return to normal activity

Manifestations in Children/young Adult

Acute viral meningitis

CSF
WBC usu 10-500 and occ 500-1,000 or <10 , glucose normal, or protein, diff count (d1-2; PMN ) (d2-3; Lym ) PCR sensitivity 60 - 90++ %

Complications 5-10%
febrile seizures, complex seizures lethargy, coma movement disorders

Acute viral meningitis

DDx
incompletely rx bacterial meningitis Arboviruses Lymphocytic choriomeningitis virus Leptospirosis Lyme borreliosis HIV Mumps TB meningitis

Management/ Prognosis
conscious, weakness, petechial/purpura more serious illness Paracetamol Pleconaril, progress in clinical trials reduce duration Children, fever and meningismus subside in few days 1 wk

Encephalitis
Less common (Aseptic meningitis >> Encephalitis) CVA 9, CVB 2,5, Echovirus 6,9, EV 71 Perinatal; only one of generalized viral symptoms

Manifestions in children/Adult
mild encephalopathy to severe generalized encephalitis w/ seizure, paresis, coma Partial motor seizure Hemichorea Acute cerebellar ataxia EV 71 brainstem encephalitis noncardiogenic pulmonary edema

Hypogammaglobulinemia, agammaglobulinemia, severe combined immunodeficiency chronic meningitis, encephalitis

Paralytic diseases by non-polio Enterovirus

CVA, CVB, EV Outbreaks of poliomyelitis-like in Russia, Eastern Europe, Thailand, Taiwan, India

Manifestations
Less severe than poliovirus Weakness > Flaccid CN involvement unilateral oculomotor palsy GBS; CVA 2, 5, 9, Echovirus 6, 22 Transverse myelitis; CVB 4, Echovirus 5 Chronic fatigue syndrome Dancing eye syndrome; opsoclonus-myoclonus , CVB 3

Chronic meningoencephalitis in Immunocompromised

Agammaglobulinemic host

Echoviruses Manifestations

Varies from absent, nuchal rigidity, headache, papilledema, seizure, weakness, tremors, ataxia Fluctuation, disappear, steadily progress Dermatomyositis like syndrome > 50% Some w/ Chronic hepatitis CSF; lym, protein Enterovirus recovered from CSF over mo-yr

Chronic meningoencephalitis in Immunocompromised

Prophylaxis/Management
IVIG but relaspe even after long term use Pleconaril?

Other Immunocompromised host CVA 1

Hematopoietic cell allograft

Difficult to distinguish from GVH enteritis

Receiving Anti-CD 20 (rituximab)

CNS infection Paralysis

1. Rubelliform and Morbiliform 2. Roseoliform 3. Herpetiform 4. Petechial and Purpuric

Exanthems
1.

Rubelliform or morbiliform
Echovirus 9 Common < 9 year-old Rash w/ fever simultaneously Face Neck Chest Extremities
LN + Pruritus + + Koplik spot Coryza Conjunctivitis Enanthem Koplik like

Season Echovirus Rubella Measle Summer

Exanthems
2.

Roseoliform

As in roseola, rash does not appear untill defervescence Fever last 24-36 h then; Discrete, nonpruritic, salmon-pink MP ~ 1 cm on face, upper part of chest (persist 1-5 d) Boston exanthem; Echovirus 16 CVB 1, 5, Echovirus 11, 25

Exanthems
3.

Herpetiform exanthems
HFM Herpangina

4.

Petechial
Echovirus 9, CVA 9 Confused w/ meningococcus if aseptic meningitis occur simultaneously Gianotti-Crosti syndrome; a/w CVA 16

Hand-Foot-Mouth Disease
EV 71 outbreaks in SEA a/w severe CNS CVA 16, EV 71 Incubation 4-6 d < 10 y Manifestations

Fever, anorexia, malaise sore throat tender vesicular on buccal mucosa, tongue, dorsum of hands, palms Vesicle may form bullae and quickly ulcerate

Hand-Foot-Mouth Disease
Eczema coxsakium; disseminated in infant w/ preexisting atopic eczema Highly infectious; attack rate 100% among young children Resolve in 1 wk Herpes simplex Chicken pox; oral lesion is less Herpetic gingivostomatitis; more ill, CLN +ve Herpangina; posterior pharynx

DDx

Complications; CNS disease, myocarditis, pulmonary hemorrhage

Herpangina

Herpes = vesicular eruption Angina = quinsy or inflammation of throat Vesicular enanthem of fauces, soft palate + fever sorethroat, odynophagia CVA > CVB, Echovirus, EV Sorethroat precede enanthem several hr to day Fever subside w/n 2-4 d papulovesicular lesion on erythematous base persist for week

Herpangina
Variant: Acute lymphonodular pharyngitis Constrast to herpes stomatitis, EV is not a/w gingivitis

DDx

Bacterial tonsillitis Viral pharyngitis HFM disease Aphthous stomatitis Herpetic gingivostomatitis

Bornholm disease (Pleurodynia)

CVB, rare echovirus, CVA Acute enteroviral infection of skeletal muscle Chest pain more common in adults Abdominal pain more common in children 1st described in 1872 by Daae and Homann as acute muscular rheumatism spread by contagion Involved muscle are tender to palpation

Pathogenesis
Believe that direct viral invasion of muscles but lack evidence support

Bornholm disease (Pleurodynia)

Manifestations
No prodrome, begin w/ abrupt onset Spasmodic and relapsing Lower rib cage or upper abdominal region Fever, sorethroat, headache may occur, but no coryza Aseptic meningitis, orchitis may occur in < 10% If severe, pt lies still in bed, appears acutely ill Persist for 4-6 days

Bornholm disease (Pleurodynia)

DDx
Pneumonia Pulmonary infarction MI Pre-eruptive phase of Zoster Acute abdomen

Management
Analgesics; Paracetamol, NSAIDs, Opioids Application of heat

Other skeletal myositis

Generalized polymyositis Focal myositis

Localized to thighs

Fever, chills, weakness, CK, edema of involved muscle groups Myoglobinemia, myoglobinuria Recovered rapidly Dermatomyositis-like; B-cell deficient w/ persistent EV infection

Myopericarditis

CVB, CVA 4, 16, Echovirus 9,22

Other; adenovirus, Influenza A, parvovirus B19, mumps virus, vaccinia virus, M.pneumoniae, RSV, EBV,VZV, measles

2/3 are male Pathogenesis

Reach the heart during MAJOR viremia Replication in myocytes myocyte necrosis focal infiltration of PMN, Lym, P, M Healing insterstitial fibrosis, myocyte loss 2/3 p/w URI 7-14 d chest pain, dyspnea, arrhytmias, HF asymptomatic intractable HF and death EKG; ST-T changes, Q waves,VT, heart block Up to 10% DCM

Manifestations

Myopericarditis

Diagnosis

Recovery agent from oropharynx, feces, serologic of recent infection Pericardial fluid, Heart muscles biopsy but rarely available

Management

Bed rest, pain relief, rx HF, arrhythmias Pleconaril, effective in small number of patients, but no RCT IVIG, prednisolone RCT failed to show benefit
Persistent abnormal EEG (10-20%), cardiomegaly (510%), chronic HF, chronic constrictive pericarditis Prognosis; children better than adults

Course and Prognosis

Acute hemorrhagic conjunctivitis

EV 70, CVA 24 Transmission

Contagious and spread rapidly Finger or fomites directly to the eye Crowding and unsanitary living, poor Reuse of water for bathing, sharing towels

Manifestation

Begin abruptly and peak w/n 24 h Severe eye pain, blurred, photophobia, watery discharge begin in one eye rapidly progress to other Edema, chemosis, subconjunctival hemorrhage 7090%

Acute hemorrhagic conjunctivitis

Punctate keratitis, conjunctival follicles Tender preauricular adenopathy Recovery in 10 days

Diagnosis

Conjunctival swabs during first 3 d

Secondary bacterial infection Acute motor paralysis Epidemic keratoconjunctivitis by adenovirus Symtomatic Good sanitation

Complications

DDx

Treatment and Prevention

Gastrointestinal diseases

Acute hepatitis
CVB, EV Mild and self limited

Acute pancreatitis
CVB 1, 5, EV 6, 11, 22, 30

Viral gastroenteritis ?
Epidemic diarrhea EV 11, 14, 18

Other manifestations
Common cold Type 1 Diabetes? Parotitis Bronchitis Bronchiolitis Croup Infectious Lymphocytosis

Polymyositis Acute arthritis Acute nephritis HUS?

http://pathmicro.med.sc.edu/virol/picorna.htm

Treatment
Mild and resolve spontaneously Intensive supportive care may be needed for cardiac, hepatic, CNS disease IVIG, ITIG, IVTIG in enteroviral meningoencephalitis and dermatomyositis in pt w/ hypogammaglobulinemia, agammaglobulinemia

References