إياك أن تتلاعب بفتاة انحنى ظهر أبيها لتصل إلى ما هي عليه فتهدم ما بناه .. فيكون لك بناءً يهدمه أحدهم يوماً ما كن قويا" كجراح ينجز عملية في الدماغ لمعلم أخبره ذات يوم انه طالب فاشل اختر الألم قبل أن يختارك فألم الإجتهاد أهون بكثير من ألم الندم أراك فتضحك الدنيا لعيني وتبتسم الأماكن والزوايا أرى كل الوجوه تفيض حبًا كان شعوري اكتنف البرايا. القلم الذي لا يحمل ضمير الإنسانية وهموم المظلومين وجوع الفقراء وأنين الوطن لا يصلح للكتابة. كنتُ أبرر فقدان شغفي بأنها استراحة محارب، ولكنه يبدو أنني رميت سيفي وغادرت المعركة.. سيُحبك الحظ أن احببتها صنعانية.. اللهم صل وسلم وبارك علـّۓ نبينا محمد وعلى آله❤️ «سأبـدع فـي نسـيانك وإن رأيتـك سأقـول يخـلق مـن الشـبه اربعـين..!🖤» " ‏نحن نتكئ دوماً على من نثق بقلوبهم لا بأيديهم.. فقوّة البدن قد تخون ، لكن قوّة المشاعر لا تخون أبداً " لن يفهمك إلا إثنان ، أحدهما مرّ بنفس حالتك ، والآخر يحبك جداً ..

1. 0
1
2
3
4
5

2. Entroviruses
Supervisor is:
Dr. Ahmed Mohsen
Prepared by:
Laboratory students batch 22

3. Contents
• Introduction.
• Properties of Enteroviruses.
• Pathogenesis of Enteroviruses.
• Serotypes of human Enteroviruses.
• History.
• Poliovirus.
• Coxsackie virus A.
• Coxsackie virus B.
• Echovirus.
• New Enteroviruses.
• Disease associated with Enteroviruses.
• Vaccination.
• Laboratory Diagnosis.
• Management and Prevention.

4. Introduction
- Enteroviruses are a large group within the picorna family of viruses,
which replicate mainly in the gut; nevertheless, they rarely cause
intestinal symptoms. Enterovirus diseases are the result of spread of
the viruses to other sites of the body-particularly the CNS.
- Enteroviruses are a group of viruses that cause a number of
infectious illnesses which are usually mild. However if they infect the
Central Nervous System, they can cause serious illness.
- A small proportion of infections give rise to febrile illness due to
viraemia. Still fewer cases progress to aseptic meningitis and- more
rarely still-to paralysis: spread of virus to the CNS or other organs
and tissues is a rare complication of enterovirus infection.

5. Introduction Cont…
- Early classification of enteroviruses involved groupings based on cyto- pathologic
effect in tissue culture.
- Newly discovered enteroviruses are now simply assigned enterovirus type numbers.
- Enterovirus 72 is hepatitis A virus, which differs from the other entero- viruses by
having only one serotype and replicating only in liver cells. It will not be included in
this review. The virion consists of an icosa- hedral-shaped protein capsid and an RNA
core.
- Although the capsid proteins determine antigenicity, there are no significant
antigens common to all members of this group of viruses.
- The virus can withstand the acidic pH of the human gastrointestinal tract and can
survive at room temperature for several days.
- These features enable the fecal-oral mode of trans- mission.
- Most enteroviruses can grow in primate (human or non- human) cell cultures,
exhibiting cytopathic effect in 3 to 7 days.

6. Properties of Enteroviruses
The enteroviruses are a subgroup of single-stranded RNA, non- enveloped viruses
belonging to the Picornaviradae family (Pico-small, rna-ribonucleic acid).
They include: the polioviruses, coxsackie- viruses, echoviruses (echo-enteric
cytopathogenic human orphan), and unclassified enteroviruses.
• Enteroviruses have the following properties:
• Enter the body via ingestion by mouth.
• Primary site of multiplication is the lymphoid tissue of the alimentary tract including
the pharynx.
• Spread from the gut is in two directions:
1. Outwards into the blood (viraemia) and so to other tissues and organs.
2. Inwards into the lumen of the gut and to excretion into the feces.
• General features of enterovirus infections: most infections are confined to the
alimentary tract and are symptomless : enteroviruses do not cause diarrhea.

7. Pathogenesis of Enteroviruses
• Entry of virus via oral and/or respiratory route.
• Viral replication in regional lymph nodes of upper respiratory and gastrointestinal tracts.
• Minor viremia; onset of symptoms.
• Viral replication in heart, liver, skin, and other organs.
• Major viremia with secondary seeding of central nervous system.

8. TABLE 1. Serotypes of human Enteroviruses
Serotypes
Group
1-3
Poliovirus
1-22, 24
group A
Coxsackievirus
1-6
group B
1-9, 11-27, 29-33
Echovirus
68-72*
Enterovirus
*Hepatitis A virus was enterovirus type 72, but recently has been
reclassified as a Heparnavirus.

9. History
•Poliovirus: First identified in 1909 by inoculation of specimens into monkeys.
The virus was first grown in cell culture in 1949 which became the basis for vaccine.
•Coxsackieviruses: In 1948, a new group of agents were identified by inoculation into
newborn mice from two children with paralytic disease. These agents were named
coxsackieviruses after the town in New York State. Coxsackieviruses A and B were
identified on the basis of the histopathological changes they produce in Newborn mice
and their capacity to grow in cell culture.
• Echoviruses: were later identified which produced cytopathic changes in cell culture
and was nonpathogenic for newborn mice and subhuman primates.
• More recently, new enterovirus types have been allocated sequential numbers (68-71).

10. Poliovirus
• There are 3 serotypes of poliovirus (1, 2, and 3) but no common antigen.
• Humans are only susceptible hosts.
• Polivirus is composed of an RNA genome and a protein capsid.
• The genome is a single-strand positive-sense RNA genome that is about 7500
nucleotides.
• The viral partical is about 30 nm in diameter with icosahedral symmetry.
• Poliovirus is an enterovirus, its infection occurs via the fecal-oral route,
meaning that one ingest the virus and viral replication occurs in the alimentary
tract.
• In about 5% of cases, the virus spreads and replicates in other sites such as
brown fat, reticuloendothelial tissue, and muscle
• The sustained viral replication causes secondary viremia and leads to the
development of minor symptoms such as fever, headache, and sore throat.

11. Poliovirus Cont…
• Paralytic poliomyelitis occurs in less than 1% of poliovirus infections.
•Paralytic disease occurs when the virus enters the central nervous system
(CNS) and replicates in motor neurons within the spinal cord, brain or motor
cortex.
• Poliovirus is the causative agent of poliomyelitis ( commonly known as polio).
Poliomyelitis: Polio = gray, Myelitis = inflammation of spinal cord.

12. Poliovirus Cont…
• Pathogenesis
Stool
Lymph nodes
Payer patches
Stomach
Fecal oral route
Blood
(Viraemia)
CNS
( Anterior horn cells)
(Brainstem)
Lower motor neuron lesion (Flaccid
paralysis)

13. Coxsackie A virus
Coxsackie A virus (CAV) is a cytolytic Coxsackievirus of the Picornaviridae family, an
enterovirus (a group containing the polioviruses, coxsackieviruses, and echoviruses).
• Viral structure and genome: Coxsackie A virus is a subgroup of enterovirus A, which
are small, non-enveloped, positive-sense, single-stranded RNA viruses.
Its protective, icosahedral capsid has an external portion that contains sixty copies of
viral proteins (VP1,-2,-3) and an internal portion surrounding the RNA genome
containing sixty copies of VP4 viral proteins.
This capsid mediates cell entry and elicits the humoral immune responses.
• Transmission: The main ways the Coxsackie Virus spreads are: 1.By direct transmission
(when an infected person coughs or sneezes into any mucous membranes of the face i.e.
eyes, nose, and mouth) 2.Fecal-oral transmission (virus in the fecal matter of an infected
individual end up in the mouth of another person.

14. Coxsackie A virus Cont…
• Transmission Cont.. : 3.Via surface contact (when an infected person touches their
face then a surface, the surface is contaminated with that virus. The next person
comes along and touches the same surface then touches their face).
4.Via airborne transmission (when an uninfected person inhales respiratory droplets of
an infected person)Although adults are less susceptible to infection, it is still possible
for an adult to get infected with the Coxsackie virus. If a pregnant mother is infected,
there is a 30-50% chance the infection will be passed on to the infant.
• Diseases : Coxsackievirus infection on skin of adult. The most well known Coxsackie
A disease is hand, foot and mouth disease (unrelated to foot-and-mouth disease),
a common childhood illness which affects mostly children aged 5 or under,[7] often
produced by Coxsackie A16.. Other diseases include acute haemorrhagic conjunctivitis
(A24 specifically), herpangina, and aseptic meningitis (both Coxsackie A and B viruses).
Coxsackievirus A7 is associated with neurological diseases and can cause paralytic
poliomyelitis.

15. Coxsackie A virus Cont…
• Signs and Symptoms: Coxsackie A virus leads to a number of diseases, however the
most common signs and symptoms that appear with infection are fever and flu-like
symptoms, mouth sores, and skin rashes' mild fever and sore throat, and a general
discomfort three to six days subsequent to exposure. Painful mouth sores (herpangina)
may be present in the back of the mouth. These sores usually appear 24 hours after the
flu like symptoms begin, and may blister, causing further discomfort when eating or
drinking.
Rash will commonly present on the bottom of the feet, palm of hands, and other areas
of the body, and persists upwards to ten days. When the symptoms are incredibly
severe, some may require hospitalization due to dehydration caused by inability to
swallow food or water without pain, or seizures and convulsions can occur due to high
fever.
Signs of dehydration include dry skin, unintentional weight loss, or decreased urine
output/darkened urine and if present should refer to a health care provider for
intervention.

16. Coxsackie A virus Cont…
• Treatment: is dependent on the disease process initiated by the virus. There is no
known cure or vaccine against this virus.
*Most Coxsackie A virus infections are mild and self-limiting meaning the infection has
the ability to resolve on its own without requiring treatment.
Symptoms of a Coxsackie A infection tend to dissipate on their own within 7–10 days.
Treatment tends to focus on supportive care where the symptoms of the infection are
targeted but not the virus itself.
NSAIDs such as *ibuprofen/*naproxen and *acetaminophen can be used to manage the
flu-like symptoms, fever, and any other pain the infected individual may be feeling. *Do
not give a child aspirin as it may increase the risk of Reye syndrome. *Fluids are
recommended as to decrease the chances of dehydration. Mouth sores will make ,
antibiotics will have no effect on the infection as they only work on bacterial infections.

17. Coxsackie A virus Cont…
• Complications include: inflammatory brain conditions, such as viral meningitis or
encephalitis, which require medical intervention. A professional health care may need
to monitor if the some one infected is immunocompromised
،
or the symptoms do not
improve within ten days.
• The diagnosis of this disease: collecting samples from mouth sores and skin blisters,
or a stool sample may also be ordered to rule out any other causes.
Investigations includes: CBC, PCR,CT SCAN for brain.
• Prevention: There is no vaccine to reduce the chances of infection and spread.
It is critical to use non-pharmacological interventions to reduce the spread and
transmission of Coxsackie virus. The best and most effective strategy for prevention is
adopting proper hand hygiene, avoiding contact with the infected, abstain from
touching mucous membranes of the face, and sanitizing frequently touched surfaces.

18. Coxsackie virus B
Coxsackie B virus belongs to the Picornavirus family, genus enterovirus.
It can cause a variety of diseases.
• Virology: The enterovirus (EV) is a positive-sensed, single-stranded RNA virus named
for their enteric or gastrointestinal route of transmission .Coxsackie B is a group of six
serotypes of coxsackievirus (CVB1-CVB6).
• Diseases: Group B coxsackieviruses cause infection of the heart, pleura, pancreas,
and liver, causing pleurodynia, myocarditis, pericarditis, and hepatitis. It also causes
systemic neonatal disease.
• Epidemiology: Infection usually occurs during warm summer months.
• Transmission: Infections are most commonly spread by the oral-fecal route,
emphasizing the importance of good hygiene, especially hand-washing. Oral-oral and
respiratory droplets can also be means of transmission.

19. Coxsackie group B Cont…
• Etiology : Viral
prodrome including fever, fatigue, malaise, myalgia, gastrointestinal upset such as
nausea, vomiting, diarrhea and abdominal pain. Aseptic meningitis Encephalitis
Pleurodynia Myopericarditis Symptoms include: headache, fever, sore throat,
gastrointestinal distress, extreme fatigue, chest pain, and myalgia. The severity of
infection varies depending on the host's age, and immune status.
Sex incidence: Coxsackie group B affects males and females equally,
CBC Erythrocyte sedimentation rate “ESR” Chest X-ray Abdominal CT PCR
• Treatment: The virus is self-limited with no specific recommended treatment and no
vaccine. Symptomatic and supportive care for the associated syndromes is appropriate.
Patients with neurological complications may need antiepileptics for seizures and
sedation for delirium.

20. Echovirus
- Echoviruses are members of the Enterovirus genus in the Picornaviridae family.
- They make up the largest Enterovirus subgroup, consisting of 29 serotypes.
- Initial viral isolates were extracted from the feces of asymptomatic children in the
1950s, and failed to cause observable disease in suckling mice.
- Since then, several echovirus strains have been identified as the causative agents of
various illnesses including aseptic meningitis, enteritis, and paralysis.
- Echovirus infections are generally initiated in the gastrointestinal tract, Following an
incubation period ranging from 2 to 7 days, the infection may turn systemic as viruses
infect and replicate within peripheral and distal body tissues.
- Echoviruses are rarely highlighted as prominent infectious viral agents of concern to
public health. However, echovirus serotypes 13 and 30 have been increasingly
implicated in outbreaks of aseptic meningitis in the U.S. and abroad, with person-to-
person contact and ingestion of contaminated water identified as the principal
transmission routes.

21. Echovirus Cont…
• Structure: Non-enveloped , linear , single - stranded , positive sense RNA virus with
an icosahedral capsid. Family: Picornaviridae, Host(s): Humans, demographics: male >
female children > adults.
• Pathogenesis: echovirus binds to decay accelerating factor , a receptor o the virus
then replicates in Peyer's patches ,it travels to regional lymph nodes and central
nervous system.
• Disease(s): Caused Several manifestations, ranging from mild to life-threatening.
• Symptoms: Skin rashes, upper respiratory distress, sore throat, mouth sores Potential
Complications, Severe neonatal disease, aseptic meningitis, encephalitis myocarditis,
pericarditis.
• Transmission Mode: Fecal-oral, person-to-person contact, water, contaminated
fomites.
• Sites of Community Outbreaks: Schools, hospitals, daycare centers.

22. New Enteroviruses
• Newly identified picornaviruses that are not polioviruses are no longer classified
separated into the species coxsackie and echovirus because of the ambiguities presented
by overlapping host range variations.
• 4 new enteroviruses have been identified (68-72). Enterovirus 70 is the causative agent
epidemics of acute epidemics of acute haemorrhagic conjunctivitis that swept through
Africa, Asia, India and Europe from 1969 to 1974. The virus is occasionally neurovirulent.
• Enterovirus 71 appears to be highly pathogenic and has been associated with
epidemics of a variety of acute diseases, including aseptic meningitis, encephalitis,
paralytic poliomyelitis- like disease and hand-foot-mouth disease.
• Enterovirus 72 was originally assigned to hepatitis A virus, but it had now been
assigned to a new family called heptoviruses.

23. Disease associated with Enteroviruses
Echoviruses
Coxsackieviruses B
Coxsackieviruses A
Poliovirus
Syndrome
+
+
+
+
Paralytic disease
+
+
+
+
Meningitis encephalitis
+
+
+
+
Carditis
+
+
-
-
Neonatal disease
-
+
-
-
Pleurodynia
-
-
+
-
Herpangina
+
+
+
-
Rash disease
-
-
+
-
Hemorrhagic conjunctivitis
+
+
+
+
Respiratory infections
+
+
+
+
Undifferentiated fever
-
+
-
-
Diabetes/ Pancreatitis

24. Vaccination
Enterovirus A71 (EV-A71) is a major causative agent of hand, foot, and mouth disease
(HFMD) and herpangina . Moreover, EV-A71 infection can lead to neurological
complications and death. Vaccination is the most efficient way to control virus infection.
There are currently three inactivated, whole EV-A71 vaccines licensed by the China NMPA
(National Medical Products Administration). Several other types of vaccines, such as virus-
like particles and recombinant VP1 (capsid protein), are also under development. In this
review, we discuss recent advances in the development of EV-A71 vaccines . Currently,
there is no US FDA-approved antiviral agent or vaccine against EV-A71. However, there are
three inactivated, EV-A71 whole-virus vaccines approved by the China National Medical
Products Administration (NMPA) and are commercially available in China. Large-scale
clinical trials showed that vaccine efficacy against EV-A71-associated Hand, foot, and
mouth disease (HFMD) was at least 90%.
Vaccine effectiveness in HFMD patients under five years old was 100% for severe cases and
~80% for mild cases, suggesting that the vaccine performs well in practice [8,12].
Vaccination is the most effective countermeasure against EV-A71 infection and epidemic.

25. Vaccination Cont..
Two vaccines are available against the three polioviruses:
1. Sabin live attenuated virus vaccine.
Now the main vaccine used for the poliomyelitis immunization.
Contains: the three polioviruses as attenuated strains which have just neurovirulence
for monkeys; grown in monkey kidney tissue cultures.
Administration : in three oral doses along with triple vaccine starting at 2 months of
age and with an interval of 1 month between each dose: boosters at school entry and
when leaving school.
2. Salk inactivated virus vaccine.
This was first polio vaccine to be used on a large scale, but is now less widely used than
Sabin vaccine.
Contains: the three polioviruses, inactivated by formaldehyde.
Administration: It is given in three subcutaneous injections.

26. Vaccination Cont..
- The vaccine efficacy against EV-A71-associated HFMD was 95.1%. Sinovac then
conducted a five-year follow-up survey to study the long-term immunogenicity.
- The study results showed that the Sinovac vaccine demonstrated the long-term
persistence of immunogenicity within five years.
During this time, the Sinovac EV-A71 vaccine production capacity had reached more
than 20 million doses/ year.
- WHO organized a working group meeting in 2019 to develop WHO recommendations
to assure the efficacy, safety and quality of EV-A71 vaccines. In view of its cross-
reactivity with different genotypes of EV-A71, WHO recommendations suggested that
the EV-A71-C4 a vaccine could be used worldwide.

27. Laboratory Diagnosis
• Virus Isolation
•Mainstay of diagnosis of poliovirus infection.
• Specimens: Feces, throat swabs: CSF is useful for some viruses (e.g. Echovirus 9) but
not for polioviruses.
•Inoculate: Monkey kidney, human embryo lung cell cultures.
•Observe: for CPE.
•Type virus: by neutralization tests.
Note: Most Coxsackie A viruses do not grow in tissue cultures so if coxsackie A virus
infection is suspected:
•Inoculate: Suckling mice subcutaneously and intracerebrally.
•Observe: for characteristic signs of coxsackieviruses cause flaccid paralysis due to
widespread myositis.
Note: Group B coxsackie viruses cause spastic paralysis with tremor due to cerebral
lesions and fat-pad necrosis.

28. Laboratory Diagnosis Cont.…
• Serology
•Very rarely used for diagnosis since cell culture is efficient.
• Occasionally used for immune state screening for immunocompromised individuals.
•Neutralization tests are useful for the diagnosis of poliomyelitis.
• ELISA test: it used to detect IgM to group B coxsackie viruses.
•Polymerase Chain Reaction (PCR): It also can be used to detect enterovirus.

29. Management and Prevention
- No specific antiviral therapy available.
- IVIG in the treatment of neonatal infections or severe infections in
immunocompromised individuals.
- HNIG to prevent outbreaks of neonatal infection with good results.
-
No vaccine available.
• How can I protect myself?
You can help prevent yourself from getting and spreading EV-D68 by following these
steps:
1.Wash your hands often with soap and water for 20 seconds. 2.Avoid touching your
eyes, nose, and mouth with unwashed hands. 3.Avoid close contact such as kissing,
hugging, and sharing cups or eating utensils with people who are sick, and when you
are sick. 4.Cover your coughs and sneezes with a tissue or your upper shirt sleeve, not
your hands. 5.Clean and disinfect frequently touched surfaces, such as toys and
doorknobs, especially if someone is sick. 6.Stay home when you are sick.

30. Reference
1. Alexander J.P., Jr., Baden L., Pallansch M.A., Anderson L.J. Enterovirus 71 infections and neurologic disease--
United States, 1977–1991. J. Infect. Dis. 1994;169:905–908. doi: 10.1093/infdis/169.4.905. [PubMed] [CrossRef]
[Google Scholar]
2. Ooi M.H., Wong S.C., Lewthwaite P., Cardosa M.J., Solomon T. Clinical features, diagnosis, and management of
enterovirus 71. Lancet Neurol. 2010;9:1097–1105. doi: 10.1016/S1474-4422(10)70209-X. [PubMed] [CrossRef]
[Google Scholar]
3. Lee K.Y. Enterovirus 71 infection and neurological complications. Korean J. Pediat. 2016;59:395–401. doi:
10.3345/kjp.2016.59.10.395. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
4. Chang L.Y., Lin H.Y., Gau S.S., Lu C.Y., Hsia S.H., Huang Y.C., Huang L.M., Lin T.Y. Enterovirus A71 neurologic
complications and long-term sequelae. J. Biomed. Sci. 2019;26:57. doi: 10.1186/s12929-019-0552-7. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
5. -Jubelt B, Lipton HL. Enterovirus/picornavirus infections. Handb Clin Neurol. 2014;123:379-416. [PubMed]2-Kühl
U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandolf R, Schultheiss HP. High prevalence of
viral genomes and multiple viral infections in the myocardium of adults with "idiopathic" left ventricular
dysfunction. Circulation. 2005 Feb 22;111(7):887-93. [PubMed]
6.Gear JH, Measroch V. Coxsackievirus infections of the newborn. Prog Med Virol. 1973;15:42-62. [PubMed]
7.Tracy S, Gauntt C (2008). "Group B coxsackievirus virulence". Current Topics in Microbiology and Immunology.5-
Richardson M, Elliman D, Maguire H, Simpson J, Nicoll A. Evidence base of incubation periods, periods of
infectiousness and exclusion policies for the control of communicable diseases in schools and preschools. Pediatr
Infect Dis J. 2001 Apr;20(4):380-91. [PubMed]