Respiratory

viruses

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:

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

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
4

Virion
spherical/ovoid, 80120nm diameter,
The inner side of
the envelope is
lined by the matrix
protein, stable typespecific.
5

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

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
7

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

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

Influenza virus A

10

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

11

Influenza virus

12

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.

13

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 IH
Group C - This group does not cause
epidemics and causes mild disease
14

severity of illness
animal reservoir
human pandemics
human epidemics
antigenic changes
segmented genome
amantadine, rimantidine
zanamivir
surface glycoproteins

TYPE A

TYPE B

TYPE C

++++
yes
yes
yes
shift, drift
yes
sensitive
sensitive
2

++
no
no
yes
drift
yes
no effect
sensitive
2

+
no
no
no (sporadic)
drift
yes
no effect
(1)
15

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

16

Variation and Epidemiology

Antigenic drift: median or small epidemic.
Antigenic shift:large scale epidemic.

17

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
18

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

19

20

Epidemic

21

where do new HA and NA come

from?
13 types HA
9 types NA
all circulate in birds

pigs
avian and human

22

where do new HA and NA come

from?

23

why do we not have influenza B

pandemics?
so far no shifts
have been
recorded
no animal
reservoir known

24

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

25

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
26

Transmission
Source of infection: patients and
carriers.
AEROSOL
100,000 TO 1,000,000 VIRIONS
PER DROPLET

18-72 HR INCUBATION

27

Aerosol
Inoculation
Of virus

28

NORMAL TRACHEAL MUCOSA

3 DAYS POST-INFECTION

7 DAYS POST-INFECTION
29

SYMPTOMS

FEVER
HEADACHE
MYALGIA( )
COUGH
RHINITIS( )
OCULAR SYMPTOMS
30

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

31

NON-PULMONARY COMPLICATIONS
myositis (rare, > in children, > with
type B)
cardiac complications
liver and CNS
Reyes syndrome

peripheral nervous system

32

33

Immunity

34

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
35

 Serology
hemagglutination inhibition
Hemadsorption inhibition
ELISA
immunofluoresence
complement fixation.
NT.
36

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.
37

Types of Vaccine
Killed Whole Virus
Rather pyrogenic, not used today.
Live Virus
Attenuated strains were widely used in Russia but not
elsewhere.
Virus Subunit
HA 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 ]

Synthetic
Much research is being done to try and find a neutralising
epitope that is more stable, and can therefore be used for a
38
universal vaccine.

CDC

39

PB2
PB1
PA
HA
NA
NP
M
NS

Attenuated Donor
Master Strain
Attenuated Vaccine Strain:
Coat of Virulent strain with
Virulence Characteristics of
Attenuated Strain

PB2
PB1
PA
HA
NA
NP
M
NS

PB2
PB1
PA
HA
NA
NP
M
NS

New Virulent
Antigenic Variant
Strain

40

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
41

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

42

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

43

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

44

Paramyxoviridae

45

Paramyxoviridae
Genus
Morbillivirus
Paramyxovirus

Pneumovirus

Human pathogen
Measles virus
Parainfluenza viruses,
Mumps virus
Respirtory syncytical
virus
46

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
47

PARAMYXOVIRUSES
pleomorphic

HN/H/G glycoprotein
SPIKES
F glycoprotein
SPIKES
helical nucleocapsid (RNA plus
NP protein)
lipid bilayer membrane
polymerase
complex

M protein

48

PARAMYXOVIRUS FAMILY
properties of attachment protein
GENUS

GLYCOPROTEINS

TYPICAL MEMBERS

Paramyxovirus

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

genus

49

50

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
51

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

52

53

Measles virus

54

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.
55

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.
56

viremia

57

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

58

MEASLES - Kopliks spots

59

Murray et al. Medical Microbiology

Koplik's spots

60

MEASLES - RASH

CDC - B.Rice

61

Murray et al. Medical Microbiology

DISEASE
FEVER
RESPIRATORY TRACT SYMPTOMS
rhinorrhea, cough

KOPLIKS SPOTS
MACULOPAPULAR RASH
T-cells ->endothelial cells

CONJUNCTIVITIS
epithelial cells

62

MEASLES GIANT CELL PNEUMONIA

Murray et al. Medical Microbiology

63

Mims et al., Medical Microbiology 1993

64

MEASLES ENCEPHALITIS
1/1000 cases
sequelae
deafness
seizures
mental disorders

65

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
66

67

68

Treatment
No

69

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!
70

Mumps virus

71

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

72

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.
73

Prevention and treatment

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

74

MUMPS

CDC - B.Rice

75

Mims et al., Medical Microbiology 1993

76

Mims et al., Medical Microbiology 1993

77

Parainfluenza virus

78

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

79

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.
80

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
81

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)

82

Prevention
No, vaccines is not available

83

Respiratory syncytial virus

84

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.

85

Pathogenesis and immunity

Disorder
Bronchiolitis
pneumonia,
or both
Febrile rhinitis
and pharyngitis
Common cold

Age
Fever, cough, dyspnea, and
cyanosis in children younger
than 1 year
Children
Older children and adults
86

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

87

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

88

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.

89

Adenoviruses

90

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.

91

Adenovirus

92

Important Characteristics

93

94

Replication

95

Pathogenesis and Immunity

Disease:
Acute Respiratory Illness
Pharyngitis
Gastroenteritis
Conjunctivitis
Pneumonia
Keratoconjunctivitis

At Risk:
Military recruits, boarding schools,

Infants
Infants
All
Infants, military recruits
All
Acute Haemorrhagic Cystitis Infants
Hepatitis
Infants, liver transplant patients
96

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.
97

swimming pool conjunctivitis

98

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.
99

Treatment
No

100

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

101

Rubella Virus

102

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)

103

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
104

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
infection105

EFFECTS ON FETUS
HEARING LOSS
CONGENITAL HEART DEFECTS
NEUROLOGICAL
PYSCHOMOTOR AND/OR MENTAL
RETARDATION

OPHTHALMIC
CATARACT, GLAUCOMA, RETINOPATHY
106

EFFECTS ON FETUS

thrombocytopenia
hepatomegaly
splenomegaly
intrauterine growth retardation
bone lesions
pneumonitis
107

EFFECTS ON FETUS
First trimester
65-85% of neonates have sequelae

108

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
109

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

110

CONGENITAL INFECTIONS
EYE PROBLEMS
GLANDULAR COMPLICATIONS
diabetes,
thyroid problems
deficiency growth hormone

111

CONGENITAL / VERY EARLY

INFECTIONS
PROGRESSIVE RUBELLA
PANENCEPHALITIS

112

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.
113

Treatment
There is no antiviral therapy available

114

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

115

Coronavirus

116

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
117

Virion structure
S-Spike
glycoprotein:
receptor binding,
cell fusion, major
antigen
M-Membrane
glycoprotein:
transmembrane budding &
envelope
formation

118

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
119

Rhinovirus

120

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
121

Reovirus
( )

122

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

123