Download Respiratory syncytial virus

The growing problem of viral
respiratory infections
5th ESCMID School of Clinical Microbiology
and Infectious Diseases
Santander, Spain, 10 - 16 June 2006
Núria Rabella
Respiratory tract
Major portal of entry
Most common afflictions in humans
Wide range of clinical manifestations:
from self-limited to devastating
Children half a dozen each year, adults two
or three.
Most caused by viruses.
Considerable impact on quality of life
and productivity of society
Respiratory tract
Majority trivial colds and sore throats
Serious lower respiratory tract infections
tend to occur at the extremes of life
Influenzavirus killing the elderly and
respiratory syncytial virus killing the
very young
Altogether over 200 known viruses
Respiratory tract infection
High prevalence:
large number of infectious agents and serotypes
efficiency of transmission
incomplete immunity
Frequency:
higher in children under 4 years
it declines in teenagers
rises again in parents
lowest in the elderly
Major reservoir
schoolchildren
Epidemiology (1)
• Transmission: respiratory route
• Shedding: sneezing, coughing or talking
• sneeze:
– 106 droplets < 10m  evaporation  smallersuspended in the air for several minutes
– larger droplets fall to the ground
• Spreading:
• inhalation
• direct contact
Epidemiology (2)
* Sneezing:
1.940.000 viral particles
*
To begin an infection:
Adenovirus: 7
Influenza A virus: 3
Enterovirus: 6
* Some viruses remain infectious
for prolonged periods
Direct contact transmission
Viral persistence
Respiratory syncytial virus:
porous surfaces for 30’
non-porous 6h
Parainfluenzavirus:
porous surfaces for 4h
non-porous 10h
Influenza A virus:
porous surfaces for 8-12h
In the hands 5 minutes
non-porous 24-48h
Nosocomial infection
If health care workers do
not wash hands between
patients they can easily
transmit the infection from
one patient to another
Epidemiology (3)
160
140
120
100
80
60
40
20
0
1 11 21 31 41 51 9 19 29 39 49 7 17 27 37 47 5 15 25 35 45 2 12 22 32 42 52 10 20 30 40 50 7 17 27 37 47 5 15 25 35 45
1997
1998
RSV
1999
FLUAV
2000
FLUBV
2001
CRV
2002
TOTAL
2003
2004
Epidemiology (4)
Winter incidence:
• Not attributable to cold or wet “per se”
• Predilection for shutting ourselves
ventilated centrally-heated buildings
in
ill-
• Ex: tropics, during the wet season people spend
more time indoors in crowded conditions
Respiratory viruses
Influenza A, B, C virus
Respiratory syncytial virus
Parainfluenzavirus 1-4
Metapneumovirus
Adenovirus
Enterovirus
Rhinovirus
Coronavirus
Characteristics of infection
• Short incubation period (2-7 days)
• Large number of virions, even before symptoms
• Small number necessary to infect
• Epidemic outbreaks
When the proportion of uninfected susceptible
persons in the community falls,
the epidemic burns itself out.
Viral entry
• Inhaled droplets > 10 m Ø are
trapped in turbinates of the
nose
• Inhaled droplets 5 -10m Ø often
reach the trachea and
bronchioles
Clinical features
• Above the epiglottis
URTI
Described according to
the anatomical site of
maximal involvement
• Below the epiglottis
LRTI
Rhinitis
Copious watery nasal discharge,
congestion,
sneezing, and
a mild sore throat or cough.
Little or no fever
50% last longer than 1 week and
25% last up two weeks
LRTI in 60% in elderly persons
common in young children
Rhinitis
Acute inflammation of the mucosa may
contribute to the pathogenesis of otitis
and sinusitis.
Abnormalities observed in the
sinus cavity in these patients
appear to result from the
entrapment of secretions and
resolve 2 to 3 weeks later.
Genus
Rhinovirus
Species
More than 100
Responsible for about 50% of common colds
• > 100 serotypes of Rhinovirus
• re-infection can occur
• infections year-round, most prevalent in fall
and spring
• incubation period about 2 days
• symptoms peak on the 2nd and 3rd days
Genus
Coronavirus
Species
HCoV-229E
HCoV-OC43
HCoV-NL63
HCoV-HKU1
SARS-CoV
• Responsible for about 10-20% of common colds
• re-infection is common
• infections year-round, most prevalent in fall
and spring
• incubation period about 2 to 5 days
SARS Coronavirus
• SARS: Severe Acute Respiratory Syndrome
Respiratory infection was caused by a
coronavirus named SARS-CoV.
• Disease extended to more than 24 countries in
North-America, South-America, Europe and
Asia.
• 8,098 persons presented the disease and 774
died.
21% health workers
Pharyngitis
• sore throat is the prominent symptom
• erythema
• swelling of the affected tissues
• exudates: inflammatory cells overlaying mucous
membranes
• low-grade fever, mild general symptoms
• difficult to differentiate from streptococcal infection
Caused by the same viruses that cause common cold and
adenovirus, enterovirus and influenza virus.
Adenovirus
51 serotypes
• Immunity correlates with the presence of typespecific neutralizing antibodies
• Endemic or epidemic, often during summer
• Incubation period 4-7 days
• Moderate to severe pharyngitis sometimes exudative
• Fever and systemic symptoms
• Rhinitis and follicular conjunctivitis are common
Adenovirus
51 serotypes
Pharyngo-conjunctival fever
sporadical or epidemic outbreaks
association with swimming pools
Epidemic acute respiratory disease
in military recruits
pneumonia in 10-20%
Pneumonia in immunocompromised pts
BMT recipients: mortality 60%
Nosocomial transmission: epidemic keratoconjunctivitis
Genus
Enterovirus
• Great variety of clinical syndromes including
respiratory manifestations
• Numerous serotypes related to respiratory illness
• Pharyngits is a common manifestation
concomitant with other respiratory clinical
findings that could be more prominent.
Croup
Laryngitis and croup : laryngeal obstruction
• varying degrees of inspiratory stridor
• cough, hoarseness
• initially cold with fever
• symptoms last 3 to 7 days
• children < 4 years and boys > girls
Important:
must be differentiated from epiglottitis
Laryngitis
10%
PIV 3
15%
PIV
15%
CMV
31%
PIV 3
8%
ADV
Croup
31%
RSV
14%
FLUAV
10%
PIV
5%
EV
14%
ADV
5%
CMV
42%
RSV
In our experience:
Parainfluenzavirus are responsible for about 46% of cases of
laryngitis and 20% of cases of croup.
Parainfluenzavirus
The major cause of LRTI in young children and URTI
in older children and adults
There are 4 types named 1-4
Distinct seasonal pattern:
type 1 and 2: fall, every other year
type 3: endemic
Parainfluenzavirus
• More severe disease between 6 months and 3 years
One third of children with primary infection during
the first 2 years of age had involvement of the
LRT
• PIV 1, 2 - related to croup.
PIV 3 - bronchiolitis or pneumonia
PIV 4 - very mild illness
• Re-infections are frequent at any age, usually mild
Bronchitis
Cough, severe or prolonged,
fever, upper respiratory
tract involvement
Inflammatory disease of the larger
air passages
• Direct viral damage of the mucosa
• Release of inflammatory mediators
• Stimulation of airway irritant receptors
Any of the respiratory viruses
Influenzavirus
• There are 3 influenza viruses: A, B, C
• Depending on the internal protein
• Winter . Sporadic and epidemic
• Highly contagious
• Period transmission: 7 days or throughout
duration of symptoms
Influenza A virus
Neuraminidase (9)
Hemagglutinin (16)
• RNA fragmented genome: 8
• Drift: point mutation = variant could
evade immunity
• Shift: reassortment of two viruses =
new virus
Influenzavirus. Clinical features
NO SYMPTOMS
MILD DISEASE
UPPER RESPIRATORY TRACT INVOLVEMENT
INFLUENZA:
abrupt onset, headache, chills,
dry cough, high fever,
myalgias, malaise, anorexia
Influenzavirus
Complications
Benign:
Sinusitis, otitis media, and bronchitis
Severe:
Viral or bacterial pneumonia
Exacerbation of underlying illnesses
Nosocomial infection
Influenza A virus
Nº 5
Brots epidèmics intrahospitalaris (Grip A).
S. Microbiologia. Hospital de la Santa Creu i Sant Pau.
140
VRS
VGA
Mostres
120
41 patients
11 health workers
4 relatives
nombre de mostres
100
80
60
40
20
0
1
3
5
7
9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 1
1999
3
5
7
9 11 13 15 17 19 21 23 25 27 29 31 33 35 37
2000
Clinical manifestations : light/moderate RD, URTI 10,
LRTI 4, digestive symptoms 4, high fever 5, 2 died.
Bronchiolitis
10%
FLUAV
10%
EV
4%
ADV
4%
CMV
Expiratory wheezing with tachypnea,
air trapping, and costal retractions
2%
CMV 6%
EV
5%
+ infiltrates
FLUAV
2%
FLUBV
79%
RSV
6%
ADV
70%
RSV
2%
PIV 3
Narrowing of air passages:
destruction of epithelium
mononuclear infiltration
necrosis
accumulation mucus and debris
Multiple atelectasis: image of pneumonitis
Peak incidence: 2 to 10 months
Respiratory syncytial virus
• Major cause of RTI among children
• From inapparent to severe (bronchiolitis)
• 50% develop RSV infection by 12 months of age
• Regularly produces epidemic outbreaks each winter
Adults: URTI (previously healthy) to
LRTI (elderly, immunocompromised)
40% children hospitalized for more than 7 days in winter
50% of health workers
Metapneumovirus
• Spectrum of diseases and epidemiology
resembling that of RSV
• Peak incidence between 4 and 6 months
• Frequent coinfection with RSV
• Assymptomatic or mild illness much more
common
HMPV infection in 22 patients (nº 251)
9 (41%) LRTI, 3 (33%) died
Nosocomial infection
RSV and HMPV
* 432 hematological patients followed at HSCSP.
October 1999 - May 2003
735 NPA, 170 BAL
304 episodes / 156 positive (51%).
RSV infection: 38% (total 24) nosocomial
HMPV infection: 45% (total 22) nosocomial
Pneumonia
17%
ADV
7% 2%
EV CMV
13%
FLUAV
2%
PIV
59%
RSV
Viruses are the most frequent cause in children
in adults is not uncommon (FLUAV, RSV, PIV)
Immunocompromised patients
44+ (26%) /170 BAL
432 p/7y
14%
17%
36%
18%
4%
Influenza A virus
Respiratory syncytial virus
10%
1%
Enterovirus
Adenovirus
Parainfluenzavirus
Influenza B virus
Rhinovirus
Respiratory viruses in bronchoalveolar lavages
Community-acquired pneumonia
and respiratory viruses
Period
1999
2000
2001
27
19
148
65
75
24
Total:
250
108 43%
8
15
16
39 36%
Virus
7
34
4
45 42%
Mixed
4
16
4
24 22%
Nº of patients
Diagnosis
Microorganisms:
Bacteria
69 infections (64%) with an associated virus
74 viruses: 59 FLUAV, 5 HPIV, 5 RSV, 4 FLUBV, 1 AdV. 4 mixed with 2 viruses
160
140
120
100
80
60
40
20
0
1 11 21 31 41 51 9 19 29 39 49 7 17 27 37 47 5 15 25 35 45 2 12 22 32 42 52 10 20
1997
1998
1999
VGA
VGB
2000
Muestras
2001
Virologic diagnosis
Isolation in cell culture
Antigen detection
Nucleic acid detection
Serology
Virologic diagnosis
• Isolation: gold standard.
• Antigen detection: rapid, variable sensitivity
Interpretation of the results:
Respiratory viruses can only be recovered from
the respiratory tract during acute infection
• Nucleic acid detection: sensitive and expensive
• Serology: two specimens (late, lack of sensitivity)
Methods for viral detection
Sensitivity
Nº
IF
EIA
IC
CC
RSV
270
99%
60%
76%
59%
FLUAV
206
79%
64%
78%
39%
FLUBV
67
PIV
74
74%
53%
ADV
156
33%
96%
46%
84%
2000-2001
Treatment
Influenza A, B, C virus
Amantadine and Rimantadine
oral administration
effective for the prevention of infection
and illness
resistance in 30% to 80% patients after a
few days of treatment
Zanamivir and oseltamivir
inhaled and oral administration
effective for the prevention of infection
and illness
Treatment
Respiratory syncytial virus
Parainfluenzavirus 1-4
Metapneumovirus
Ribavirin
RSV:
may be considered in infants and young children
at risk of severe RSV disease
recommended in high-risk patients (BMT)
PIV:
MPV:
reduction of PIV shedding and clinical improvement
reduction of PIV shedding and clinical improvement
Treatment
Respiratory syncytial virus
Immunoprophylactic agents for prevention:
RespiGam
Intravenous polyclonal immune globulin
Enriched in neutralizing Ab against RSV
Requires large volume infusion
Availability limited
Palivizumab
Monoclonal Ab (95% human, 5% murine)
Against RSV fusion protein
During RSV season for premature babies
Treatment
Adenovirus
There are no approved therapeutic agents against ADV infection.
Some broad spectrum antivirals have been used:
Ribavirin
Most reports are anecdotal or small series of cases
Cidofovir
Has shown some efficacy
2 of 3 patients recovered compared 3 of 13
patients treated with ribavirin
Treatment
Enterovirus
Rhinovirus
Coronavirus
There are no approved therapeutic agents against these viruses
Conclusions
1. The clinical picture caused by a specific virus is
indistinguishable from that of any other virus
2. Community-acquired pneumonia are often
related to viral infection
3. Rapid etiologic diagnosis is possible
4. Nosocomial infection is common