Colds, Viruses &

SARS:
Disease & Protection
 UPPER RESPIRATORY TRACT
INFECTIONS
• Commonest cause of acute physical illness in
the developed world.
• 189 million days of absence from school and
70 million days of absence from work.
• 110 million physician consultations, $2.9
billion of OTC remedies.
• Most common cause of inappropriate
antibiotic use (c. 40%).
• Total cost $40 billion per annum.
Fendrick AM. Arch Intern Med. 2003;163(4):487-94
 The Common Cold Viruses
• Rhinoviruses

• Coronaviruses

• Influenza

• Parainfluenza viruses
• Respiratory syncytial virus (RSV)
• Human metapneumovirus (2001)
 The Common Cold Viruses
• Rhinoviruses

• Coronaviruses

• Influenza

• Parainfluenza viruses
• Respiratory syncytial virus (RSV)
 RHINOVIRUSES
• RNA viruses.
• Commonest causative agent of the
common cold accounting for 40 – 60%
of colds.
• Occur throughout the year but most
prevalent in September/October (80%
of colds).
• >100 serotypes exist.
 CLINICAL SYNDROMES CAUSED
BY RHINOVIRUS

CHILDREN ADULTS
• Otitis media Sinusitis
• Bronchiolitis Asthma exacerbations
• Pneumonia COPD exacerbations
• Bronchitis
 The Common Cold Viruses
• Rhinoviruses

• Coronaviruses

• Influenza

• Parainfluenza viruses
• Respiratory syncytial virus (RSV)
 The Common Cold Viruses
• Rhinoviruses

• Coronaviruses

• Influenza

• Parainfluenza viruses
• Respiratory syncytial virus (RSV)
 INFLUENZA
• Influenza A – main virus found in
epidemics and pandemics.
• Influenza B – causes less severe
disease than A.
• Influenza C – rare.
 EPIDEMIOLOGY
• Winter predominance in non-pandemic
years.
• Causes considerable morbidity and
mortality especially in the elderly and
those with chronic medical conditions.
 Structure of Influenza Viruses
Orthomyxovirus

Neuraminidase
(9 subtypes)

Viral RNA

Haemagglutinin
(15 subtypes)
 ANTIGENIC SHIFT AND DRIFT

• Antigenic drift – minor changes in the

influenza antigens and lead to
epidemics.
• Antigenic shift – a major change in the
antigenicity of the H and N proteins and
leads to pandemics.
 Influenza A Pandemics
1918 H1N1 (20 – 50 million deaths)
1957 H2N2
1968 H3N2
1977* H1N1
*Affected mainly young people born after 1957.

1997 H5N2 virus killed 6/18 humans infected in

Hong Kong - pandemic averted by
slaughter of all chickens in Hong Kong?
Epidemics have greater overall mortality
than pandemics
4-weekly deaths 4-weekly influenza reports
70 000 1600

60 000 Deaths Influenza A Influenza B 1400

1200
50 000
1000
40 000
800
30 000
600
20 000
400

10 000 200

0 0
1975 1980 1985 1990
 The Common Cold Viruses
• Rhinoviruses

• Coronaviruses

• Influenza

• Parainfluenza viruses
• Respiratory syncytial virus (RSV)
 PARAINFLUENZA VIRUS
• Similar spectrum of respiratory disease
to RSV but less severe.
• Mostly URTI but often complicated by
otitis media.
• 15% of PIV infections involve the lower
respiratory tract, commonest
manifestation is croup.
 The Common Cold Viruses
• Rhinoviruses

• Coronaviruses

• Influenza

• Parainfluenza viruses
• Respiratory syncytial virus (RSV)
Respiratory Syncytial Virus
• Annual winter epidemics beginning in
late autumn in children and the elderly.
• Can present with wide spectrum of
disease severity – from mild URT
symptoms only to severe lower
respiratory tract involvement .
• Most common cause of bronchiolitis.
• Main cause of hospitalisation for
respiratory tract disease in children.
• Its role in adult disease has only
recently become appreciated.
• Significant cause of pneumonia and ‘flu’
especially in the elderly.
• High mortality rate in transplant
patients.
Shay et al J Am Med Assoc 1999;282:1440
 IMMUNE RESPONSE TO
VIRUS INFECTION
• The immune response is essential to
clear virus infections.
• In patients with impaired immune
systems virus infections are more
severe and infection with cold viruses
can be fatal.
• However the immune response can
also cause pathology.
• Two broad types of immune response:
• Innate immunity (non-specific).
• Adaptive immunity (specific).
• The 2 work in combination to prevent
and resolve virus infections.
 INNATE IMMUNITY
• Physical factors: - airway epithelium,
mucus, cilia.
• Soluble factors: - antibacterial peptides
(defensins), enzymes (lysozyme) IgA.
• Cells: - macrophages, NK cells,
neutrophils.
• The innate response is early but non-
specific.
Innate immunity to virus
infections
 Innate Immunity to virus
infections

Mannose
Mucus Binding Lectin
 ADAPTIVE IMMUNITY
• Cellular response: - cytotoxic T
lymphocytes.
• Humoral response: - antibody.
• Response is later than the innate
response but specific.
• Has memory!
Specific immunity to virus
infections: antibodies

B Cell
CD8 T cell immunity to
+

respiratory viruses

FAS Ligand
Perforin
 INNATE ACQUIRED
NEUTROPHILS MACROPHAGES
ANTIBODY

VIRUS
DENDRITIC
CELL
IFN-γ B LYMPHOCYTES

T LYMPHOCYTES

NK CELLS

IFN-α CYTOTOXICITY

DAY 3 DAY 4 DAY 7

• Normal immunity to respiratory viruses
is complex involving innate and specific
defences.
• Immunity must be balanced to produce
effective viral clearance without
excessive immunopathology.
• Imbalance either way leads to disease.
 MEDIATORS OF THE IMMUNE RESPONSE
Virus Entry Replication
Immune Mediators
Cytokines
Histamine
Leukotrienes
Prostaglandins

Glandular secretion
Lymphocytes
Eosinophils
Neutrophils

Vascular leakage

{
Upper and
lower Granule proteins

Production of airway Cytokines

Mediators

symptoms inflammation
 HISTAMINE
• Induces sneezing and rhinorrhea. First
generation H1 antihistamines reduce
cold symptoms but second generation
non-sedating anti-histamines do not.

• Induces vasodilatation – blocked by α-

adrenoceptor agonists.
 PROSTAGLANDINS
• Lipid mediators synthesised by the
enzyme cyclo-oxygenase (COX).
• Induce sneezing, sore throat and cough
but not nasal blockage/rhinorrhea.
• Non-steroidal anti-inflammatory drugs
(NSAIDs) – aspirin, ibuprofen – inhibit
COX.
 INTERFERON-α
• Intra-nasal interferon has little effect on
alleviating symptoms. Probably
because the inflammatory cascade has
been triggered.
• However when administered
prophylactically can reduce risk of
acquiring a cold by 60%
 COMBINED ANTIVIRAL-
ANTIMEDIATOR TREATMENT FOR
THE COMMON COLD

• The greatest benefit in cold symptoms

is seen with a combination of
chlorpheniramine, ibuprofen and
interferon.
Gwaltney JM Jr J Infect Dis. 2002 Jul 15;186(2):147-54.
 IMMUNITY TO SPECIFIC
VIRUSES
• Immunity to specific viruses depends on
a combination of humoral and cell-
mediated immunity.
• The relative contribution of each varies
in different viral infections.
• Immune responses may contribute to
the disease pathogenesis.
 RHINOVIRUSES
• Antibodies responsible for most
protection against viral re-infection.
• However antibodies are serotype-
specific.
• Cell-mediated immunity does have a
role as different severity of symptoms is
seen in subjects with the same antibody
titre infected with rhinovirus.
 INFLUENZA
• Antibodies to HA protective against
infection.
• Antibodies to NA do not prevent
infection but reduce spread of the virus.
• Antibody response is subtype specific
so antigenic drift results in virus escape.
• Cytotoxic T cells essential for clearance
of virus.
 RSV
• High frequency of recurrent infections.
• Immunity is neither complete nor long-
lasting.
• Both antibody and cellular components
involved.
• Immunopathology believed to contribute
to disease severity.
 IMMUNE PATHOLOGY
CAUSED BY RSV VACCINE
• Trials of formalin-inactivated RSV
vaccine in 1966-67.
• When infected with RSV the vaccinated
children had more severe illness and 2
died.
• Intense inflammatory infiltrate seen in
the lungs.
• Still no vaccine for RSV.
 THE SPREAD OF SARS
•November 2002: New type of severe atypical pneumonia in
Guangdong

•21st Feb 03: Prof. Liew came from Guangdong, booked into
the Metropole
•23rd Feb: Admitted to Kwong Wah hospital: warned staff!
(at least 70 hospital staff infected)

•23rd Feb: Jonnie Chang flew to Hanoi

•26th Feb: Admitted to hospital with fever. Examined by
Carlo Urbani, who alerted WHO (Dr Urbani and 3 other staff
died, and 63 were infected)

•Canadian visitor to the Metropole returned to Toronto

(infected her son; both died)
 SARS: Clinical course
• Incubation period – average: 4 days

Fever 99% Sputum 20%

Chills 74% Shortness of breath 20%
Myalgias 52% Diarrhoea 15%
Cough 43% Sore throat 14%
Headache 33%

• Recurrent fever in 85%

Case fatality rate: often in 3rd or 4th week.

– Around 12% overall, 43% in over 60’s
– Strongly related to age/intercurrent illness
– 26% required ITU admission.
 Amoy Gardens
Hong Kong
• 33 floor apartment
blocks
• 41% of 321 cases
concentrated in Block E,
units 7 and 8
• 66% of cases reported
diarrhoea
• Cracked sewage pipes
in kitchens
• Contamination of U-
traps in bathroom floors
• Droplets may have
spread when fan in use
 CORONAVIRUSES

•Two known human coronaviruses

(15 – 30% of colds).

•Widespread in domestic animals

(enteric, lung, liver etc)

•RNA genome 27-30 kb

(largest RNA virus)

•SARS coronavirus
Completely novel genetically
 Points of Interest
• Spreads fast in hospital wards
• Does not respect international
boundaries
• Fit, healthy people affected
• Strong suggestion of immunopathology
– Break in fever - delayed second phase
– Possible response to steroids
 Protective Measures Reported by
Infected and Non-Infected Staff (Lancet
2003; 361: 1519-20)
Protective Infected staff Non-infected p value
measures (n-13) staff (n=241)
Masks 2 (15%) 169 (70%) .0001

Gloves 4 (31%) 117 (48%) .364

Gowns 0 (0%) 83 (34%) .006

Hand- 10 (77%) 227 (94%) .047

washing
 Animal Reservoir?
• Beijing - no SARS-like coronaviruses in 732
animals from 54 wild and 11 domestic
species in southern China, including palm
civets.
• Hong Kong - related viruses have so far been
found in about half-a-dozen species including
wild civet.
• Against the advice of the WHO restrictions on
the sale of wild animals in markets in China
have been lifted.
Civet cat: nocturnal animal related to mongoose.
 SARS: Global effort, spread and effects
• SARS does not respect national borders.
• Speed of spread of information is unprecedented.
• Scientific discovery has been extremely fast.
• Very large negative economic impact on tourism,
travel and trade.
• May have devastating impact on poor countries
with insufficient infrastructure.
 The Future?
• First recognized as a global threat in mid-March
2003, SARS was successfully contained in less than
four months.

• On 5 July 2003, WHO reported that the last human

chain of transmission of SARS had been broken.

• While much has been learned including discovery of

a new coronavirus (SARS-CoV), our knowledge
about SARS coronavirus infection remains limited.

• Resurgence of SARS remains a distinct possibility

and does not allow for complacency.
 KEY POINTS
• Colds are caused by a number of different
respiratory viruses.
• Usually mild self-limiting illness but can have
more serious consequences.
• Efficiently cleared by the immune system but
the large number of viruses and their capacity
to change means recurrent infection
inevitable.
• The emergence of SARS is an illustration of
how new pathogens can emerge and how
rapidly worldwide spread can occur.
 ACKNOWLEDGEMENTS
• PRFOESSOR PETER OPENSHAW

• PROFESSOR SEBASTIAN JOHNSTON