Respiratory viruses

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Respiratory viruses
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Categories of Respiratory Viruses

• Orthomyxoviridae Influenza virus
• Paramyxoviridae Parainfluenza virus Mumps
  virus Measles Respiratory syneytical virus
• Togaviridae Rubella Virus
• Coronaviridae Corona Virus SARS virus
• Adenoviridae human Adenovirus
• picornaviridae Rhino Virus
• Reoviridae

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Influenza virus

• Orthomyxoviridae Influenza virus
• Influenza is a disease caused by Influenza virus
  ,a member of the Orthomyxoviridae.

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Genome of Influenza virus

• 8 negative sense RNA nucleocapsid segments
• The 'RNP' (RNA nucleoprotein) is in a helical
  form with the 3 polymerase polypeptides
  associated with each segment.
• The segmented genome promotes genetic diversity
  caused by mutation and reassortment of segments
  on infection with two different strains

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Virion

• spherical/ovoid, 80-120nm diameter,
• The inner side of the envelope is lined by the
  matrix protein, stable type-specific.

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Virion

• The outer surface of the particle consists of a
  lipid envelope from which project prominent
  glycoprotein spikes of two types, the
  haemagglutinin, 135Å trimer (HA), and
  neuraminidase, 60Å tetramer (NA).

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Haemagglutinin (HA)

• Encoded by RNA segment 4
• Can agglutinate red blood cells - hence the
  nomenclature
• Cleavage by host-cell protease is required
  (resulting in HA1 and HA2) for infection to occur
  
• Hemagglutinin glycoprotein is the viral
  attachment protein and fusion protein , and it
  elicits neutralizing , protective antibody
  responses

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Neuraminadase (NA)

• Encoded by RNA segment 6
• Enzyme that uses neuraminic (sialic) acid as a
  substrate
• Important in releasing mature virus from cells

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ORTHOMYXOVIRUSES
HA - hemagglutinin
NA - neuraminidase
helical nucleocapsid (RNA plus NP protein)
lipid bilayer membrane
polymerase complex
M1 protein
type A, B, C NP, M1 protein sub-types HA or
NA protein
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Influenza virus A
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Replication

• Influenza transcribe and replicates its genome in
  the target cell nucleus
• assemble and buds from the plasma membrane

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Influenza virus
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Antigen

• Soluble antigens include ribonucleoprotein and M
  protein which are much stable in antigenicity.
• Surface antigens include HA and NA which are
  much variable in antigenicity.

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Types

• Influenza viruses are divided into 3 groups
  determined by the ribonucleoprotein (RNP) antigen
  and M antigen
• Group A - This group is the cause of epidemics
  and pandemics and has an avian intermediate host
  (IH)Group B - This group causes epidemics and
  has no IHGroup C - This group does not cause
  epidemics and causes mild disease

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TYPE A yes yes yes shift,
drift yes sensitive sensitive 2
severity of illness animal reservoir human
pandemics human epidemics antigenic
changes segmented genome amantadine,
rimantidine zanamivir surface glycoproteins
TYPE B no no yes drift yes no
effect sensitive 2
TYPE C no no no (sporadic) drift yes no
effect (1)
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Subtypes

• According to antigenicity of HA and NA, influenza
  virus is divided into subtypes such as HnNm(
  H1N2, et al )

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Variation and Epidemiology

•  Antigenic drift median or small epidemic.
• Antigenic shiftlarge scale epidemic.

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Antigenic Shift Of Influenza virus

• Reassortment of genes is a common feature of
  Influenza A, but not B or C
• When two different "A" viruses infect the same
  cell, their RNA segments can become mixed during
  replication
• New viruses produced in this way may survive due
  to a selective advantage within the population

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Antigenic Drift of Influenza Virus

• Constant mutations in the RNA of influenza which
  lead to polypeptide mutations
• Changes are less dramatic than those induced by
  Shift
• If these mutations affect HA or NA they may cause
  localized epidemics

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Epidemic
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where do new HA and NA come from?

• 13 types HA
• 9 types NA
• all circulate in birds
• pigs
• avian and human

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where do new HA and NA come from?
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why do we not have influenza B pandemics?

• so far no shifts have been recorded
• no animal reservoir known

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Resistence

• The particles are relative labile ,not resistant
  to drying, etc.

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Pathogenesis

• Influenza is characterised by fever, myalgia,
  headache and pharyngitis. In addition there may
  be cough and in severe cases, prostration. There
  is usually not coryza??(runny nose) which
  characterises common cold infections.
• Infection may be very mild, even asymptomatic,
  moderate or very severe

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Transmission

• Source of infection patients and carriers.
• AEROSOL
• 100,000 TO 1,000,000 VIRIONS PER DROPLET
• 18-72 HR INCUBATION

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Aerosol Inoculation Of virus
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NORMAL TRACHEAL MUCOSA
3 DAYS POST-INFECTION
7 DAYS POST-INFECTION
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SYMPTOMS

• FEVER
• HEADACHE
• MYALGIA(??)
• COUGH
• RHINITIS(??)
• OCULAR SYMPTOMS

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PULMONARY COMPLICATIONS

• CROUP (YOUNG CHILDREN)
• PRIMARY INFLUENZA VIRUS PNEUMONIA
• SECONDARY BACTERIAL INFECTION
• Streptococcus pneumoniae
• Staphlyococcus aureus
• Hemophilus influenzae

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NON-PULMONARY COMPLICATIONS

• myositis (rare, gt in children, gt with type B)
• cardiac complications
• liver and CNS
• Reyes syndrome
• peripheral nervous system

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Immunity
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Lab Diagnosis

• Viral detection
• Respiratory secretions
• ( direct aspirate , gargle , nasal
  washings )
• 1. Cell culture in primary monkey kidney or
  madindarby canine kidney cells
• 2. Hemagglutination (inhibition)
• Hemadsorption (inhibition)
• 3. IFA/ ELISA

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• Serology
• hemagglutination inhibition
• Hemadsorption inhibition
• ELISA
• immunofluoresence
• complement fixation.
• NT.

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Prevention

• Vaccines at best give about 70 protection. They
  may sometimes not be effective against the most
  recently evolved strains because the rate of
  evolution outpaces the rate at which new vaccines
  can be manufactured.
• This constant antigenic change down the years
  means that new vaccines have to be made on a
  regular basis.

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Types of Vaccine

• Killed Whole VirusRather pyrogenic, not used
  today.
• Live VirusAttenuated strains were widely used in
  Russia but not elsewhere.
• Virus SubunitHA extracted from recombinant virus
  forms the basis of today's vaccines.For example,
  the WHO Recommendation for Influenza Vaccine,
  1995-1996, contains two A strains and one B
  strain-A / Singapore / 6 / 86 (H1N1)A /
  Johannesburg / 33 / 94 (H3N2)B / Beijing / 84 /
  93
• SyntheticMuch research is being done to try and
  find a neutralising epitope that is more stable,
  and can therefore be used for a universal
  vaccine.

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CDC
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Treatment

• Amantadine and rimantadine are active against
  influenza A viruses. The action of these closely
  related agents is complex and incompletely
  understood, but they are believed to block
  cellular membrane ion channels, and inhibit an
  uncoating step and target the M2 membrane protein

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PREVENTION - DRUGS

• RIMANTADINE???? (M2)
• type A only
• AMANTADINE???? (M2)
• type A only
• ZANAMIVIR (NA)
• types A and B, not yet approved for prevention
  but studies show effective
• OSELTAMIVIR (NA)
• types A and B

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TREATMENT - DRUGS

• RIMANTADINE (M2)
• type A only, needs to be given early
• AMANTADINE (M2)
• type A only, needs to be given early
• ZANAMIVIR (NA)
• types A and B, needs to be given early
• OSELTAMIVIR (NA)
• types A and B, needs to be given early

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OTHER TREATMENT

• REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN
  FOR AGES 6MTHS-18YRS)
• BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY

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Paramyxoviridae
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Paramyxoviridae

• Genus Human pathogen
• Morbillivirus Measles virus
• Paramyxovirus Parainfluenza viruses,
  
• 
  Mumps virus
• Pneumovirus Respirtory syncytical
• 
  virus

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Virion

• Large virion consists of a negative RNA genome in
  a helical nucleocapsid surrounded by an enevlope
  containing a viral attachment protein
• HN of paramyxovirus and mumps virus has
  hemagglutinin and neuraminidase.
• H of measles virus has hemagglutinin activity
• G of RSV lacks these activities

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PARAMYXOVIRUSES
HN/H/G glycoprotein SPIKES
pleomorphic
F glycoprotein SPIKES
helical nucleocapsid (RNA plus NP protein)
lipid bilayer membrane
polymerase complex
M protein
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PARAMYXOVIRUS FAMILYproperties of attachment
protein
GENUS GLYCOPROTEINS TYPICAL MEMBERS
Paramyxovirus genus HN, F HPIV1, HPIV3
Rubulavirus Genus HN, F HPIV2, HPIV4 mumps virus
Morbillivirus genus H, F measles virus
Pneumovirus genus G, F respiratory syncytial virus

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Replication , Pathogenesis and Immunity

• Virus replicates in the cytoplasm
• Virions penetrate the cell by fusion with the
  plasma membrane
• Viruses induce cell-cell fusion, causing
  multinucleated giant cells
• Paramyxoviridae are transmitted in respiratory
  droplets and initiate infection in the
  respiratory tract
• Cell-mediated immunity causes many of the
  symptoms but is essential for control of the
  infection

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MMR vaccine

• Composition live attenuated virus
• Measles / Mumps / Rubella
• Vaccination schedule at 15-24 months and at 4 to
  6 years or before junior high school
• Efficiency 95 lifelong immunization with a
  single dose

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Measles virus(????)

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Pathogenesis and Immunity

• Childhood infection almost universal, protection
  resulting from this is probably lifelong. Both
  man and wild monkeys are commonly infected
• In culture, produces characteristic intranuclear
  inclusion bodies and syncytial giant cells.
• Transmission and initial stages of disease
  similar to mumps, but this virus can also infect
  via the eye and multiply in the conjunctivae.
  Viraemia following primary local multiplication
  results in widespread distribution to many
  organs.

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Pathogenesis and Immunity

• After a 10-12 day incubation period
• Dry cough, sore throat, conjunctivitis (virus may
  be excreted during this phase!), followed a few
  days later by the characteristic red,
  maculopapular rash and Koplik's spots
• Towards the end of the disease, there is
  extensive, generalized virus infection in
  lymphoid tissues and skin.

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viremia
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DISSEMINATED SPREAD

• LONGER TIME FOR SYMPTOMS
• IMMUNE RESPONSE
• IF SYMPTOMS DUE TO IMMUNE RESPONSE, USUALLY
  INFECTIOUS PRIOR TO SYMPTOMS

Adapted from Mims, Playfair, Roitt, Wakelin and
Williams (1993) Medical Microbiology
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MEASLES - Kopliks spots
Murray et al. Medical Microbiology
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Koplik's spots
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MEASLES - RASH
CDC - B.Rice
Murray et al. Medical Microbiology
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DISEASE

• FEVER
• RESPIRATORY TRACT SYMPTOMS
• rhinorrhea, cough
• KOPLIKS SPOTS
• MACULOPAPULAR RASH
• T-cells -gtendothelial cells
• CONJUNCTIVITIS
• epithelial cells

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MEASLES GIANT CELL PNEUMONIA
Murray et al. Medical Microbiology
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Mims et al., Medical Microbiology 1993
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MEASLES ENCEPHALITIS

• 1/1000 cases
• sequelae
• deafness
• seizures
• mental disorders

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SSPE

• sub-acute sclerosing panencephalitis
• inflammatory disease
• defective virus
• early infection with measles is a risk factor
• rare (7/1,000,000 cases of measles)
• decrease since vaccination program

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Treatment

• No

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Prevention

• Both live and killed vaccines exist. Vaccination
  with the live attenuated vaccine has been
  practised since the 1960's with a dramatic
  decline in the incidence of the disease .
• Trivalent live attenuated vaccine (MMR) usually
  given - all of these viruses best avoided during
  pregnancy!

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Mumps virus(?????)
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Mumps virus

• Droplets spread the infection via saliva and
  secretions from the respiratory tract.
• Incubation period of 2-3 weeks

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Mumps virus

• Malaise and fever is followed within a day by
  painful enlargement of one or both of the parotid
  (salivary) glands
• A possible complication in males after puberty is
  orchitis - painful swelling of one or both
  testicles.
• Inflammation of the ovary and pancreas can also
  occur.
• Disease is usually self-limiting within a few
  days
• Aseptic meningitis (usually resolving without
  problems) or postexposure encephalitis (can prove
  fatal) are the most serious complications
  associated with mumps.

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Prevention and treatment

• Treatment none (passive immunization has been
  used).
• Prevention one invariant serotype therefore
  vaccines are viable - both formalin-inactivated
  and live attenuated exist, the latter now being
  widely used- see MMR.

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MUMPS
CDC - B.Rice
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Mims et al., Medical Microbiology 1993
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Mims et al., Medical Microbiology 1993
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Parainfluenza virus(?????)
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Important Characteristics

• Typing Four types (1-4) distinguished
  antigenically, by cytopathic effect, and
  pathogenically
• Hemeagglutinin and fusion F protein is found in
  the envelope

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Pathogenesis and Immunity

• Cause acute respiratory infections of man ranging
  from relatively mild influenza-like illness to
  bronchitis, croup (narrowing of airways which can
  result in respiratory distress) and pneumonia
  common infection of children.
• Transmitted by aerosols.

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Lab Diagnosis

• Nasopharynx specimen is culture in a surrogate
  cell line in AGMK. Infected cell are detected by
  hemeadsorption or DFA
• DFA also can be done rapidly to identify the
  agent in direct specimen
• Serotypes 1-3 are comfirmed by hemeagglutination
  inhibition using standardized antisera

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Treatment

• No antiviral therapy is available
• Nursing the patient in a humidified atmosphere
  was commonly advised
• Dexamethasone???? and budesonide??? have been
  approved ( for outpatient treatments)

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Prevention

• No, vaccines is not available

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Respiratory syncytial virus(???????)
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Important Characteristics

• RSV is highly infectious, transmission by
  respiratory secretions.
• Primary multiplication occurs in epithelial cells
  of URT producing a mild illness. In 50 children
  less than 8 months old, virus subsequently
  spreads into the L.R.T. causing bronchitis,
  pneumonia and croup.
• Has been suggested as a possible factor in cot
  death and asthma.

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Pathogenesis and immunity

• Disorder Age
• Bronchiolitis Fever, cough, dyspnea,
  and
• pneumonia, cyanosis in children
  younger
• or both than 1 year
• Febrile rhinitis Children
• and pharyngitis
• Common cold Older children and adults

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Lab Diagnosis

• DFA
• Cell culture of nasopharyngeal specimen
• A rise in antibody titre using ELISA

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Treatment

• Ribavirin aerosol(?(?)???,???) is recommended for
  pneumonia in infants
• RSV - IGIV has been approved for infants born
  prematurely
• IFN

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Prevention

• Currently no effective vaccine! Also, infection
  does not result in lasting protection (c.f.
  mumps, measles) therefore repeated infections
  ('colds') occur throughout life - usually without
  serious consequences in adults.

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Adenoviruses(???)
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General Concepts

• Most Adenovirus infections involve either the
  respiratory or gastrointestinal tracts or the
  eye.Adenovirus infections are very common, most
  are asymptomatic. Most people have been infected
  with at least 1 type at age 15.

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Adenovirus
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Important Characteristics
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Replication
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Pathogenesis and Immunity

• Disease At
  Risk
• Acute Respiratory Illness Military recruits,
  boarding schools,
• Pharyngitis Infants
• Gastroenteritis Infants
• Conjunctivitis All
• Pneumonia Infants,
  military recruits
• Keratoconjunctivitis All
• Acute Haemorrhagic Cystitis Infants
• Hepatitis Infants,
  liver transplant patients

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swimming pool conjunctivitis(?????????)

• Eye infections characterized by a mild
  conjunctivitis "swimming pool conjunctivitis" are
  caused by adenoviruses and have been linked to
  transmission in contaminated swimming pools.

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swimming pool conjunctivitis
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Lab Diagnosis

• Isolation of adenovirus can be accomplished in
  cell cultures derived from epithelial cells
• Immunoassays, including fluorescent antibody and
  enzyme-linked immunosorbent assays, PCR can be
  used to detect and type the virus in clinical
  samples and tissue cultures
• Serological assays such as CFA, HI, EIA and
  neutralization techniques have been used to
  detect specific antibodies.

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Treatment

• No

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Prevention

• Inactivated vaccines have been developed and are
  routinely used for military recruits in some
  countries

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Rubella Virus(????)
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General Concepts

• Viruses have enveloped single stranded
  positive-sense RNA.
• Replication in cytoplasm and bud at plasma
  membrane
• Cause Rubella( german measles, 3-days measles)

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Epidemiology

• Occurrence worldwide in prevalence( in winter
  and spring)
• Reservoir Humans
• Mode of Transmission Vertical transmission in
  case of CRS/ Infection in nonimmune children is
  usually transmitted by droplet spread or by
  direct contact with patients
• Who is at risk Non-immunized children are at
  risk
• Incubation period 2-3 weeks

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Pathogenesis
Virus

• Rubella enters and infects the nasopharynx
  and lung and then spreads to the lymph nodes and
  reticuloendothelial system. The resulting viremia
  spreads the virus to other tissues and the skin.
  Circulating antibody can block the transfer of
  virus at the indicated points. In an
  immunologically deficient pregnant woman, the
  virus can infect the placenta and spread to the
  fetus

Congenital infection
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EFFECTS ON FETUS

• HEARING LOSS
• CONGENITAL HEART DEFECTS
• NEUROLOGICAL
• PYSCHOMOTOR AND/OR MENTAL RETARDATION
• OPHTHALMIC
• CATARACT, GLAUCOMA, RETINOPATHY

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EFFECTS ON FETUS

• thrombocytopenia
• hepatomegaly
• splenomegaly
• intrauterine growth retardation
• bone lesions
• pneumonitis

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EFFECTS ON FETUS

• First trimester
• 65-85 of neonates have sequelae

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EFFECTS ON FETUS

• 1964
• 20,000 infants with permanent problems
• 6,000 to 30,000 spontaneous abortions
• 5,000 therapeutic abortions
• 1969 to present
• maximum of 67 cases congential rubella/yr
• usually fewer than 10

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CONGENITAL INFECTIONS

• SHED VIRUS FOR A YEAR OR MORE AFTER BIRTH
• nasopharynx, urine, feces

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CONGENITAL INFECTIONS

• EYE PROBLEMS
• GLANDULAR COMPLICATIONS
• diabetes,
• thyroid problems
• deficiency growth hormone

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CONGENITAL / VERY EARLY INFECTIONS

• PROGRESSIVE RUBELLA PANENCEPHALITIS

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Lab Diagnosis

• Current rubella infection, in pregnant women can
  be confirmed by 4-fold rise in specific antibody
  titer between acute and convalescent-phase serum
  specimens by ELISA
• The Dx of CRS in the newborn may be confirmed by
  the presence of specific IgM antibody.

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Treatment

• There is no antiviral therapy available

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Prevention

• A single dose of live, attenuated rubella vaccine
  elicits a significant antibody response in
  approximately 98-99 of vaccinated individuals
• It should not be given to immunocompromised
  patients

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Coronavirus(????)
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Important Characteristics

• Virion Spherical, 80-160nm in diameter, helical
  nucleocapside
• Genome ssRNA, linear, nonsegmented, 27-30kb,
  infectious
• Proteome two glycoproteins and one
  phosphoprotein. Some viruses contain a third
  glycoprotein (hemagglutinin esterase)
• Envelope contains large, widely spaced, club-or
  petal- shaped spikes. crown-like

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Virion structure

• S-Spike glycoprotein receptor binding, cell
  fusion, major antigen
• M-Membrane glycoprotein transmembrane - budding
  envelope formation

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Pathogenesis and Immunity

• These viruses infect a variety of mammals
  birds. The exact number of human isolates are not
  known as many cannot be grown in culture.
• They cause common colds and have been implicated
  in gastroenteritis in infants.
• Transmitted by aerosols of respiratory secretions

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Rhinovirus(???)
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Important Characteristics

• Rhinoviruses are picornaviruses similar to
  enteroviruses but differ from them in having a
  buoyant density in cesium chloride of 1.40 g/ml
  and in being Acid-labile
• Rhinoviruses are isolated commonly from the nose
  and throat but very rarely from feces.
• These viruses cause upper respiratory tract
  infections, including the common cold

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Reovirus(?????)
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Important Characteristics

• Virion Icosahedal, 60-80nm in diameter, double
  capsid shell
• Genome dsRNA
• Envelope none
• Diseases Acute respiratory tract infection and
  Gastrointestinal infections