Respiratory viruses

Dr. Maeve M. Doyle

SpR in Clinical Microbiology

Respiratory Viruses

• Influenza

• Parainfluenzaviruses

• Respiratory syncitial virus (RSV)

• Rhinovirus

• Adenovirus

• Coronavirus – SARS

• Human metapneumovirus

Clinical syndromes

• Bronchiolitis– RSV– Parainfluenzavirus– Adenovirus

• Croup– RSV– Parainfluenzavirus– Influenzavirus– Measles virus

Clinical syndromes cont’d• Upper respiratory tract

– Rhinovirus– Coronavirus– Adenovirus– Influenzavirus– Parainfluenzavirus– RSV– Enterovirus

• Influenza– Influenza A and B

• Tonsillitis– EBV– Adenovirus

Clinical syndromes cont’d• Pneumonia

– 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– UK study, Thorax 2001:– 267 patients with CAP– 23% had evidence of viral infection– 20% with influenza (4% with RSV)

Influenzavirus• 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– 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 virusNote: 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

• Disable M2 protein

• Blocks viral internalisation

• Prevent viral uncoating

• The virus is rendered inert

Side effects

• 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

• 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

– 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– Cell culture– PCR– Serology– EM