146b Os 213 Viral Respiratory Infections

OS 213 Pulmo

Respiratory Viral Infections

Exam 1 Trans146B

Dr. Lilen Sarol

Cdop Outline Modes of Transmission Viruses Causing Respiratory Infections Adenoviruses Rhinoviruses Paramyxoviridae Respiratory Syncytial Virus Parainfluenza Viruses Influenza Viruses Coronaviruses Viral Diagnosis

UPPER RESPIRATORY

β

LOWER RESPIRATORY

Modes of TRANSMISSION 

same mode of transmission for respiratory infections Communicable Infectious Disease DIRECT

INDIRECT

Figure 2. Common Sites of Infections in the Respiratory Tract

ADENOVIRUSES

• • •

Figure 1. Routes of Transmitting Infection

A.

Characteristics Double-stranded (ds) DNA • sole DNA-containing viruses • incorporate in genome of host cell • causes latent infection (cannot be produced by RNAViruses except HIV)

1.

Table 1. Comprarison of Modes of Transmission DIRECT MODES

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•

INDIRECT MODES

droplets (macrodroplet s) larger so it settles immediately

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ex. Kissing, Sex

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droplet nuclei (microdroplets: <5 µm) remain suspended in air, travel in wider scope of environment (susceptible individuals are more exposed) ex. Contaminated fomites and food and infected humans (through sneezing, coughing and talking)

VIRUSES CAUSING RESPIRATORY INFECTIONS

2.

Naked Less susceptible to degradation thus more resistant than enveloped viruses • can withstand adverse condition i.e. GI tract •

3.

Icosahedral symmetry

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unique characteristic of adenoviruses

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Can produce empty capsids (without genome) because of symmetry (unlike other respiratory infections with helical symmetry) resulting to an abortive infection

Table 2. Common Viruses

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• •

Local Invaders primary target: respiratory tract affect both URT (primarily) and LRT Same port of entry and target organ  Adenovirus  Rhinoviruses  Parainfluenza  Respiratory Syncytial virus 23, (RSV) August 2007  Influenza  Coronavirus

Systemic Invaders • different organs other than the RT  Enteroviruses  Polio  Coxsackie  Echoviruses  Herpesviridae  HSV  CMV  EBV  Measles SSuperSS

Adenoviridae family divided into mammalian genera (Mastadenoviruses) and avian genera (Avadenoviruses) mammalian genera are the ones that affect humans Causative agent in 5% of common colds

4.

20 equilateral triangles with 12 apices/vertices slender fiber projections from the 12 vertices of the icosahedron o 12 hexons o Elicit type-specific immunity

47 human serotypes distributed in 6 subgroups

•

Each serotype elicits type-specific immunity preventing cross immunity (i.e. one can be immune to 1 serotype but not to others)

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OS 213 Pulmo

Respiratory Viral Infections

Cdop B.

Trans146B

Dr. Lilen Sarol

Serotypes Notes 1,2,3 and 5 : most common 1 and 2 : childhood infection 3 and 5 : in later life 7 : most pathogenic; not exclusive to RT 1 to 9 : commonly associated to human

Like adenoviruses, they have: • Icosahedral symmetry • Naked capsid • Environmentally stable to:  Temperature  Acid  Proteases  Detergents  Drying • Consequences:  Can be spread easily  Can dry out and retain infectivity  survive the adverse conditions of the gut  resistant to poor sewage treatment

3.

Can be differentiated from adenoviruses because they have: • (+) single-stranded RNA  can be used directly as mRNA

disease Classification

Subgrp A B

Representative 12, 18, 31 3* , 7*, 11, 21

Target organ Epidemiology GIT Endemic Pharynx, lungs, Epidemic UT, conjunctiva C 1, 2*, 5*, 6 Pharynx Latent throat D 8, 9, 19 Eye Epidemic E 4 Upper RT Epidemic F 40, 41 GIT Endemic *most common all over the world • Respiratory infections seen more in SubGrps B, C &E • Adenoviruses are not only seen in the respiratory tract but also in the GI tract(subgrp A & F) and conjunctival infections(subgrpD) C.

Pathogenesis • Present with a dense central intranuclear inclusion body in host cell

D.

Laboratory Diagnosis

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• •

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method of choice grapelike clusters type of cytopathic effect intranulcear inlcusions

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ELISA (Enzyme-linked Immunosorbent Assay) Immunofluorescence • For direct detection in specimens like nsopharyngeal aspirate • For confirmation of viral isolates

A.

Major cause of upper respiratory tract infection (causes 50% of common colds cases) exclusive in RT exclusive in humans

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member of family Picornaviridae of which Enteroviruses are also a member

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Enteroviruses o Polioviruses (3) o Coxsackieviruses A (24) o Coxsackieviruses B (6) o Echoviruses (34) o Enteroviruses (5) o Enterovirus 72 (Hepatitis A)

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•

Both the genome which acts as mRNA and the complete virion are infectious; unlike other viruses that lose infectivity with removal of capsule >100 serotypes (in some reports, around 150 and still growing)  Difficult to produce vaccine  Difficult to diagnose specific serotype

Difference Between Enteroviruses & Rhinoviruses

pH stability Buoyant density Growth requirements

Enteroviruses 3-9 1.43 g/ml 37oC

Rhinovirus >6 1.45 g/ml 33oC

Implications



Rhinoviruses can only grow in the RT, where pH>6, and not in GIT where pH<6



Rhinoviruses prefer the lower temperature in the upper RTrather than lower RT

C.

Pathogenesis

 D.

Infection through iCAM type- host cell receptor: exclusively infects humans Laboratory Diagnosis • Seldom requested • Self limiting • Too many serotypes • Virus isolation

• •

Characteristics 1. Small • measures around 18–30 nm • characteristic of the members of the family Picornaviridae August 23, 2007

Consequences:  mRNA is translated immediately to proteins (polymerase)  RNA-polymerase is now used for succeeding cycles of replication

Table. 3. Characteristics of Entero and Rhino Viruses

RHINOVIRUSES

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•

B.

Virus Isolation

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2.

to 7 : pharyngitis

Table 2. Serotypes of Family Adenoviridae

Exam 1

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SSuperSS

Rounding necrosis type of cytopathic effect Neutralization Test • Confirmatory test to differentiate with enteroviruses ELISA

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OS 213 Pulmo

Respiratory Viral Infections

Cdop

Trans146B

Dr. Lilen Sarol

C. Paramyxoviridae in RT • causes repeated infections • No available vaccine

1.

PA R A M Y XO V I R I D A E A.

2.

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

B.

Characteristics 1. Envelope • Fusion protein (F)  found in all Paramyxoviridae  responsible for viral entry where envelopd fuses with the plasma membrane of the target cell  responsible for fusion of cells seen in culture or what is known as the formation of giant multinucleated cell • Attachment protein (G,H & N)- basis of difference among different groups. Table 4. Attachment Proteins of Paramyxoviridae

Attachment Protein Genus Examples G Protein (G) Pneumovirus RSV Hemagglutinin (H) Morbilivirus Measles Hemagglutinin & Paramyxovirus Neuraminidase (HN) 1-4  All promote cell attachment and necessary to infect a cell.



Hemagglutinin (in H and HN) agglutinates RBCs (hemagglutination and hemadsorption),

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G protein for attachment only, NO agglutination For diagnostic purposes. If RBCs do not agglutinate, the more probable causative agents are those that do not have H protein.

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2.

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ParaInfluenza 1- laryngotrvheobronchitis/ croup

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Parainluenza 2-minor URTi Parainfluenza 3- croup < 6 mons ParaInfluenza 4- least pathogenic

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D. Laboratory Diagnosis • Virus Isolation • Slow growth • syncytium type of cytopathic effect • intracytoplasmic inclusions • Immunofluorescence • For direct detection in specimens like nasopharyngeal aspirate • For confirmation of viral isolates • Hemagglutination • Presumptive test for the presence of virus • Viral titer can be determined • Cannot be applied for RSV since no hemagglutinin • Hemagglutination Inhibition Test • Confirmatory test • Can be used to ID type of influenza virus • Cannot be applied for RSV since no hemagglutinin

INFLUENZA

INFLUENZA A • Infects not only human but also animals e.g. horses, pigs, ferrets and birds • most associated with epidemics and pandemics • 15 known hemagglutinin (H) serotypes and 9 known neuraminidase (N) serotypes • H & N responsible for subtyping of influenza

INFLUENZA C (from 2010 trans NoT discussed) • infect humans only • cause milder disease • do not cause epidemics • genetically & morphologically distinct from A & B types

Nucleic acid • Negative ssRNA have RNA-dependent RNA-polymerase: RNA is transcribe first to mRNA before being translated to early proteins • Non-segmented Nucleocapsid • Helical symmetry o Can have different forms o Can undergo pleiomorphism

August 23, 2007

Secretory IgA main protective mechanism

Parainfluenza viruses  common in all age groups (also in children)

INFLUENZA B • infect humans only • disease generally not as severe as A types • do not have distinguishable serotypes

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3.

Respiratory syncytial virus (RSV)  One antigenic type  In children <2 y.o.  About 100% exposed when 2 y.o.  Can have repeated infection

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Classification 1. Family Paramyxoviridae Subfamily Paramyxoviridae Respirovirus(paramyxovirus) – Parainfluenza 1 & 3, Sendai virus  Rubulavirus – Parainfluenza 2 & 4, Mumps  Morbillivirus – Measles, Rinderpest  Henipavirus – Hendra virus, Nipah virus  Avulavirus – Newcastle Disease virus Subfamily Pneumovirinae  Pneumovirus – Respiratory Syncytial Virus (RSV)  Metapneumovirus The Parainfluenza virus 1-4 are not grouped in the same genera. Classification is primarily based on molecular typing or sequencing of the viral agents.

β

Genome of Rhinovirus is associated with capsid so it is not possible for them to produce an empty capsid

 Clinical Manifestation: common cold with rhinorhea, sneesing. Last 4-9 days without sequalae Rx: generally mild and self limiting, Therapy includes ist generation antihistamines and NSAIDs Immunity: serotype specific and is function of

Exam 1

SSuperSS

A.

Viral structure polymerases envelope proteins - protrusions in the envelopehemagluttinin and neuraminidase • matrix proteins • nucleoproteins • segmented RNA - vs paramyxoviridae which is non-segmented  segments dictate ability to cause a pandemic • •

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OS 213 Pulmo

Respiratory Viral Infections

Trans146B

Dr. Lilen Sarol

Cdop • negative ssRNA  Viruses having segmented



nucleic acid have bigger capacity to mutate or be reassorted, so this segmentation of the nucleic acid augments the inherent capacity of the RNA to undergo minor mutation. With segmented nucleic acid, they can have major mutations (2010 trans).

B.

Attachment proteins

1. “H“ spike ( hemagglutinin)

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binds to host cell receptors (sialic acid) in the host respiratory cell allows entry into cell

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Antibodies agiants “H” prevents infection

Exam 1

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β

Influenza have both group-specific and typespecific antigens Antigenic changes (2 types):

Antigenic Drift  minor mutations in the hemagglutinin antigen  due to lack of proofreading capability (as compared with DNA dependent viruses)  related to polymerase error and selective pressure of antibody  accumulation of point mutations in HA or NA  makes prior immunity less effective and ensures that enough susceptible people are available for the survival of the virus

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it is advisable to have influenza shots every year because of accumulation of mutations in the virus in a short period of time

Antigenic Shift

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Figure 3. Envelope Antigens of Influenza Virus.The neuraminades and hemagglutinin occur at different spikes, unlike paramyxovirus where H & N are on same spikes

2.

“N“ spike ( neuraminidase)  hydrolyzes the mucus of the respiratory tract

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cleaves neuramic acid in mucin and exposes other host cell receptors (sialic acid) which then assists in the viral budding and release Antibodies to “N” does not prevent infection, it only helps to limit its spread Responsible for exit of virus

Table 5. Occurrence of H and N Serotypes of Influenza Serotypes Found in humans Found in birds

C.

  

D.

Hemagglutinin 16 types 1,2,3 All

Table 6. Comparison of Antigenic Shift and Antigenic Drift Major change, new subtype Exchange of gene segments Occurs in A subtypes only Occurs infrequently

Antigenic Drift Minor change, w/in subtype Point mutation Occurs in A&B subtypes Occur continuosly

Internal ribunucleoprotein: group specific antigen and distinguishes Influenza A,B, and C (internal location) H and N: type specific antigens located on cell surface; Antibody against hemagglutinin neutralizes the infectivity (prevents disease) of the virus whereas antibody against group-specific antigen does not. Antibody against neuraminidase does NOT neutralize infectivity but reduce disease, decreasing the amount of virus released from the

Influenza viruses can undergo major mutations (antigenic shift resulting to oandemics) Segment 1 – translation into transcriptase Segment 4 – for translation of hemaggultinin Segment 6- for translation of neuraminidase

Nucleoprotein coded by segment 5 and matrix protein coded by segment 7 are the basis for differentiation for types A,B, and C. ANTIGENECITY in Influenza Virus

August 23, 2007

Figure 4. Antigenic Shift and Drift in Influenza virus

Antigenic Shift

Neuraminidase 9 types 1,2 All

Segmentation of Genome  each segment corresponds to one viral protein  Influenza A and B have 8 segmentations as compared to influenza C (7 only) because the hemagluttinin and neuraminidase are combined together in influenza C.

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will produce a totally different subtype, virus strains appear more different antigenically from previously seen strains occur when two separate strains of influenza infect the same cell simultaneously – reassortment of segments occur  2 different species from human and avian population affect the human cell any number of segments can reassort sudden appearance of a new antigenic type major mutations that can occur cause of pandemics only influenza A can undergo antigenic shift because it is the only one that can infect both humans and animals

SSuperSS

E. Laboratory Diagnosis • Virus Isolation • Seldom show cytopathic effect • Hemadsorption • Presumptive test for the presence of virus • Hemeagglutination • Presumptive test for the presence of virus Page 5 of 5

OS 213 Pulmo

Respiratory Viral Infections

Cdop • •

B.

Case Definition Suspect Case  Respiratory disease of unknown etiology after 2-01-2003  Fever (>100.4ºF) and cough or shortness of breath  >1 of cough, shortness of breath, dyspnea, hypoxia, or X-ray of pneumonia or ARDS  AND Exposure History - Recent travel to an area with SARS transmission or close contact with a suspected SARS case

4.

5.

Characteristics

MOST IMPT, OTHERWISE don’t consider this infection) Probable Case  Suspect case with chest X-ray or autopsy findings of pneumonia or unexplained ARDS Transmission Observations  Preponderance of cases in HCW or household contract workers  Infrequent instances of community transmission  Super-spreading events  Prolonged detection of virus Modes of Transmission  Close contact – droplet, fomites, direct contact  Airborne  Fecal-oral - vs influenza which is through respiratory secretions Risk Factors for Severe Outcome  Age - estimated mortality rate nearly 50% if >60 years; 13.2% if <60 years  increase LDH  increase neutrophil count  Diabetes or other comorbid conditions Diagnosis  Clinical characteristics of illness  Epidemiologic link to SARS, i.e., travel or contact  Laboratory evidence of SARS-CoV infection  Type of specimen : respiratory specimens, stool, urine  Timing of specimen collection - easier to locate the virus during the end of the first week and during the second week

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Enveloped virus with + sense ssRNA Have club-shaped surface spikes helical capsid viral particle is pleomorphic 13 serotypes • 3 human, including SARS • 10 animals and birds Infect humans, animals and birds All human coronaviruses (2 serotypes) cause respiratory infections

August 23, 2007

2. 

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CO RO N AV I R USE S

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Etiologic Agent Order Nidovirales Family Coronaviridae Torovirus Coronavirus (Group I, Group II, Group III)

3. 

tetromers are crownlike that’s why they’re called coronaviruses

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1.



COMPLICATIONS • Primary viral pneumonia • Secondary Bacterial pneumonia • Myositis and cardiac involvement • Neurologic syndromes • Guillain- Barre syndrome • Encephalopathy • Encephalitis • Reye’s syndrome

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Severe acute respiratory syndrome (SARS)

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Why is it more important to become vaccinated with vaccine against human influenza ? • If you’re protected against influenza, reassortment will not be possible since you need both avian and human influenza for reassortment of genes to occur • One should have a good surveillance system in order to determine the type of strain coming out. It is based on laboratory diagnosis. The Philippines has a good one by the way. • Vaccines or immunity promote point mutation because of the pressure exerted by the antibodies (like Darwin’s natural selection) thus cannot be completely eliminated. • Vaccines are also needed because it would take 1 week to produce neutralizing antibodies if one gets infected and apparently has no pre-existing antibodies against the infecting agent. So basically, vaccines will spare you from getting sick, feeling ill, or worse experiencing the complications for 1 week while your body is producing the antibodies against the virus.

A.

 

 SSuperSS

β

Infection is confined to the ciliary epithelium of the trachea, nasal mucosa and alveolar cells of the lungs.

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Possible mechanisms for emergence of pandemic virus 1. Human and bird virus reassort gene sequence in pig resulting in banded virus in pig and normal human subject (genetic reassortment between human & animal viruses) 2. alteration of receptor specificity during replication of an avian virus in pigs may occur both before after reassortment with a human virus 3. direct transmission between animals and humans and reassortment in humans e.g. outbreak in HK in 1997 4. will result in a pandemic since new transmission is very fast and before antibodies can be produced, many people are already infected

•

Trans146B

Dr. Lilen Sarol

• Titer can be determined Hemeagglutination Inhibition Test • Confirmatory test • Can be used to ID type of influenza virus Immunofluorescence • For direct detection in specimens like nasopharyngeal aspirate and for confirmation viral isolates

Exam 1

Laboratory assay to detect infection • Virus isolation • Electron microscopy • Serology: ELISA • PCR Influenza can be detected after 3 days vs. SARS which can be detected after only 1 to 2 weeks This is why health workers are more at risk since a high titer is needed for the organism to become infectious Most of the cases were also seen in older people Page 5 of 5

OS 213 Pulmo

Respiratory Viral Infections

Cdop 

Dr. Lilen Sarol

Exam 1 Trans146B

Milder infection in younger children

Table 7. Comparison between SARS and Influenza Influenza Affects community Best isolated during start of acute phase (first week form onset) Exclusively in RT

SARS Health care workers Best diagnosed during covalescent phase (1-2 weeks form onset) Can be isolated in stool

end of trans SELF-ASSESMENT 1. Each of the following statements regarding influenza is correct EXCEPT: a. Major epidemics of the disease are caused by Influenza A rather than Influenza B and C b Likely sources of new antigens for Influenza A virus are viruses that cause influenza in animals c.Major antigenic changes (shifts) occur primarily in Influenza A rather than influenza B and C d. Antigenic changes that occur with antigenic drift are due to reassortment of the multiple pieces if the influenza virus genome Each of the following statements regarding in rhinoviruses is correct EXCEPT: Picornaviruses i.e small non-enveloped RNA virus Important cause of lower respiratory esp. in COPD Do not infect the GI tract because they are inactivated by acid pH in the stomach. No vaccine against rhinoviruses since they have too many antigenic types

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August 23, 2007

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