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Respiratory viruses
Dr. Maeve M. Doyle
SpR in Clinical Microbiology
Respiratory Viruses
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Influenza
Parainfluenzaviruses
Respiratory syncitial virus (RSV)
Rhinovirus
Adenovirus
Coronavirus – SARS
Human metapneumovirus
Clinical syndromes
• Bronchiolitis
– RSV
– Parainfluenzavirus
– Adenovirus
• Croup
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RSV
Parainfluenzavirus
Influenzavirus
Measles virus
Clinical syndromes cont’d
• Upper respiratory tract
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Rhinovirus
Coronavirus
Adenovirus
Influenzavirus
Parainfluenzavirus
RSV
Enterovirus
• Influenza
– Influenza A and B
• Tonsillitis
– EBV
– Adenovirus
Clinical syndromes cont’d
• Pneumonia
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Influenza
Adenovirus
RSV
Parainfluenza
Enterovirus
CMV
VZV
• Infectious mononucleosis
– EBV
– CMV
Respiratory Syncitial Virus
• LRTI in young children
– Bronchiolitis
• Usually children under 12 months
• Wheezing, increased respiratory rate. Cyanosis and
apnoea in severe.
– Pneumonia
• May be life threatening
• URTI in adults
– Common cold
– Elderly may develop pneumonia
Respiratory Syncitial Virus
• The Virus
– RNA virus
– Family Paramyxoviridae
• Therapy
– Ribavirin
• Given as an aerosol
• Reduces virus shedding and duration of illness
• Laboratory diagnosis
– Detect antigen by immunofluoresence or
ELISA
– Culture
Rhinovirus
• Most frequent cause of common cold (approx
half)
– Droplet spread
– Incubation period 2-4 days
– Limited to URT
• The virus
– RNA virus
– Family Picornaviridae
– >100 different serotypes
• Therapy
– Not available
• Laboratory diagnosis
– Culture
Coronovirus
• Second most common cause of common
cold (15-20%)
• Usually milder infection
– 50% of infection may be asymptomatic
– Exception is SARS CoV
• The virus
– RNA virus
– Family Coronaviridae
– Club shaped spikes on surface (crown-like on
EM)
Adenovirus
• Infections of respiratory tract, the eye, the GIT.
– Transmission by droplet and contact
– Incubation period 5-10 days
– Usually causes URTI
• 50% of infections are asymptomatic
• Occaisionally severe bronchopneumonia in infants
• May cause whooping cough-like disease.
• The virus
– DNA virus
– 47 or more serotypes
• Therapy – not available
• Laboratory diagnosis
– Viral antigen detection by IF,ELISA and PCR
– Culture
– CF antibody titre – paired sera
Human metapneumovirus
• Discovered in 2001
• Related to RSV
• Infection in infants and young children
– May be mild URTI
– Bronchiolitis
– Pneumonia
• Therapy – none available
Parainfluenzavirus
• Major cause of croup, bronchiolitis and
pneumonia.
• Second to RSV as cause of serious RTI in infants
and children
• Four serotypes
• Transmission is by contact or droplet spread.
• The virus
– RNA virus
– Family Paramyxoviridae
• Therapy – none available
• Laboratory diagnosis
– Culture, PCR, antigen detection by IF
– Serodiagnosis by paired sera 1-3 weeks apart
Influenza
• Sixth leading cause of death in Canada
• Responsible for between7000 and 72000 deaths in
the US in any given year.
• Studies have shown, that between 4-39% of adults
hospitalised with CAP have evidence of viral
infection
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UK study, Thorax 2001:
267 patients with CAP
23% had evidence of viral infection
20% with influenza (4% with RSV)
Influenzavirus
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Causes illness in all age groups
Transmitted by aerosols
Mean incubation period is 2 days (1-4)
Symptoms
– Sudden onset
– Fever, chills, myalgia
– Complications include secondary bacterial pneumonia,
rarely viral pneumonia, myocarditis, encephalitis.
Reyes syndrome has been associated with influenza B
• Laboratory diagnosis
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IF
EM
Serology
Culture
Influenza - the virus
• RNA virus (orthomyxovirus group)
• Large virus
– Confined to infecting cells of URT and LRT
– Viraemia is rarely detected
• Three types A,B,C
– B and C are believed to have man as the only host
– Type A is found in swine, birds, horses and man.
• Two major proteins on the surface
– Haemaglutinin (HA)
– Neuraminidase(NA)
• Segmented viral genome
– Allows for formation of viral reassortants
(recombinants) between different strains and subtypes.
The virus
• Classified as A,B or C, based on antigenic
differences in their nucleprotein(NP) and
matrix (M1)protein.
• Further subtyping is based on the
antigenicity of the two surface
glycoproteins H and N
Influenza - the virus
• Two spikes on the viral envelope (surface antigen)
– Haemagglutinin (H)
• 15 subtypes
• (viral attachment to cells)
– Neuraminidase (N)
• 9 subtypes
• (viral release from infected cells)
• In mammalian flu, those which have circulated
widely are limited to three HA (H1,H2,H3) and
two NA (N1,N2)
• The surface antigens have a tendancy for antigenic
variation.
• A doubly infected host can give rise to a new virus
Note: pathogenic avian flu viruses are generally of the H5 or
H7 subtype.
Flu – Shift/Drift
• Influenza would cease to exist except it has
evolved ways of defeating the immune system. i.e.
antigenic variation
• DRIFT
– This is due to a point mutation
– Small changes affecting H and N – occur constantly
• SHIFT
– This is due to genetic reassortment, usually between
species.
– Only in influenza A
– Major change in H or N
– Sets the stage for a new pandemic
The History of Flu
• H1N1 1918 to 1919 Spanish flu (related to
swine virus)
• H2N2 1957 Asian flu (reassortant between
human and avian)
• H3N2 1968 Hong Kong flu (reassortment)
• H1N1 1977 Russian flu
• H5N1 1997 Hong Kong (all genes avian)
• H9N2 1999 Hong Kong (avian)
• H5N1 2004 Vietnam(13) and Thialand(4) (avian)
Pathogenesis
• H allows attachment of virus to respiratory
epithelial cells via receptors.
• Virus is transported into cytoplasm in an
endosome.
• Acid pH in the endosome activates/opens an ion
channel called M2 Protein, allowing H+ ions to
enter the virus.
• The acidification of the virus is necessary for viral
uncoating, an essential step in replication.
NOTE: Flu B doesn’t have an M2 protein
• N digests neuraminic acid in respiratory mucus,
perhaps facilitating viral spread.
Anti-virals active against Flu
• Two main classes of drug:
– Ion channel blocker
• Amantadine
• Rimantidine
– Neuramidase inhibitor
• Zanamivir
• Oseltamivir
Ion Channel Blockers
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Disable M2 protein
Blocks viral internalisation
Prevent viral uncoating
The virus is rendered inert
Side effects
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0-15% incidence of ‘jitteriness’
Insomnia
Nightmares
Rarely hallucinations
Neuramidase inhibitors
• NAI drugs bind the active site on viral NA
• Viral particles cannot exit cells easily
• Tend to clump and not disperse, reducing
their ability to infect other cells and
attenuating the patients infection.
NOTE: NAI’s are active against flu A and B.
Side effects of NAI
• 8-10% incidence of nausea, vomiting lasts
1-2 days and is not severe
• ??Zanamivir associated with worsening of
asthma
Which anti-viral is best
• No published trials have compared the two agent
head to head.
• Side effect of amantadine are a potential limitation
to its use- nausea, dizziness, insomnia and
amphetamine-like effects
– Current treatment course is 5 days
– Reduce dose in impaired renal function and elderly.
• Development of resistant virus with amantadine.
– Mutation in M2 protein
• Inhaled zanamivir may be associated with
bronchospasm.
• NAI resistant isolates have been described but are
uncommon
Flu vaccine
• Egg grown virus (purified,formalin-inactivated
and extracted with ether)
• Reassortment of two strains, one a high-yielding
lab-adapted strain, the other containing the
required H and N
• Influenza A (H3N2, H1N1 strains) and Influenza
B
• Strains reviewed annually
• Protection in up to 70%
• Contraindicated if egg protein allergy
H5N1
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1961 First isolated from birds
2003/2004 affected poultry in eight countries in Asia
>100 million birds died or were killed
1997 first case of spread to a human in Hong Kong
6/18 died
Aug 2004 human cases in Vietnam and Thialand
Aug 2004-Oct2005 117 cases, 60 fatal
Human to human spread is rare
Mortality 50% of infected
SARS Co-V
• First cases, Guangdong provence, China,
2002
• WHO issued global health alert March 2003
• July 2003, WHO declared the outbreak
over.
• Clinical picture
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Fever >38C
Respiratory symptoms, SOB
CXR, with pneumonia
To diagnose, also needed history of exposure
SARS Co-V
• Droplet and contact spread
• Coronavirus
• Laboratory diagnosis
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Cell culture
PCR
Serology
EM