i “nuovi” patogeni respiratori
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I “NUOVI” PATOGENI RESPIRATORI
Susanna EspositoIstituto di Pediatria, Università di MilanoFondazione IRCCS “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”
Milano
NEWER RESPIRATORY VIRUS INFECTIONS
• Acute respiratory tract infections are responsible for considerable morbidity and mortality
• A variety of viruses are associated with RTIs
• Since the beginning of the millenium, the Paramyxoviridae, the Coronaviridae and Parvoviridae virus families have been expanded
• In the past five years, we have also become reacquainted with several influenza A virus subtypes that crossed the species barrier
0
5
10
15
20
25
30
45 46 47 48 49 50 51 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14
I nfluenza RSV hMPV Coronaviruses Rhinovirus Adenovirus
Weeks
% cases
DISTRIBUTION OF RESPIRATORY VIRUSES DURING THE WINTER SEASON 2003-2004
(Children enrolled = 2,060)Esposito S et al. J Med Virol 2006
2003 2004
IN JUNE 2001 VAN DEN HOOGEN ET AL. AT THE ERASMUS MEDICAL CENTER, ROTTERDAM,
REPORTED THE DISCOVERY OF A NEW RESPIRATORY PATHOGEN
Van Den Hoogen et al. Nat Med 2001;7:719-24
hMPV EPIDEMIOLOGY
PHYLOGENETIC ANALYSIS OF STRAINS DEMONTRATED 2 MAIN LINEAGES OF hMPV (A, B) AND 4 SUBLINEAGES (A1, A2, B1,B2)
SEROLOGICAL DATA INDICATED THAT hMPV CAN CAUSE
MULTIPLE INFECTIONS IN HUMAN BEINGS
STUDIES SUGGESTED A SEASONAL DISTRIBUTION
UNDERLYING CONDITIONS MAY PREDISPOSE PATIENTS TO
SEVERE hMPV DISEASE
COINFECTION WITH hMPV MIGHT BE A DETERMINANT OF RSV
DISEASE SEVERITY
DISTRIBUTION OF HMPV-INFECTIONS IN ITALY
2003-2004
• 49 (2.4%) of the cases were single hMPV infections: hMPV A in 24 (49.0%), hMPV B in 14 (28.6%) and untyped hMPV in 11 (22.4%)
• 11 children (0.5%) were co-infected by hMPV and another respiratory virus
Esposito S et al., 25th ESPID 2007
CLINICAL PRESENTATION OF THE STUDY CHILDREN WITH HMPV INFECTION WAS
DIAGNOSED (from Principi et al. NEJM 2004)
IMPACT AMONG HOUSEHOLD CONTACTS OF THE STUDY CHILDREN IN WHOM HMPV
INFECTION WAS DIAGNOSED (from Principi et al NEJM 2004)
CLINICAL OUTCOME OF THE STUDY CHILDREN IN WHOM HMPV
INFECTION WAS DIAGNOSED
hMPV-A (n=24)
hMPV-B (n=14)
Untyped hMPV (n=11)
hMPV-coinfected
(n=11)
HOSPITALIZATION (%)
4 (16.7) 1 (7.1) 1 (9.1) 1 (9.1)
SCHOOL ABSENCE, MEDIAN DAYS (range)
8 (1-15) 5 (1-10) 5 (1-10) 7 (1-15)
Esposito S et al., 25th ESPID 2007
PHARMACOLOGICAL TREATMENT IN THE STUDY CHILDREN IN WHOM hMPV INFECTION WAS DIAGNOSED (%)
hMPV-A (n=24)
hMPV-B (n=14)
Untyped hMPV (n=11)
hMPV-coinfected
(n=11)
ANTIPYRETIC PRESCRIPITIONS
15 (62.5) 9 (64.3) 5 (45.5) 9 (81.8)
ANTIBIOTIC PRESCRIPTIONS
12 (50.0) 8 (57.1) 5 (45.5) 6 (54.6)
BRONCHODILATOR PRESCRIPTIONS
5 (20.8) 4 (28.6) 2 (18.2) 2 (18.2)
STEROID PRESCRIPTIONS
3 (12.5) 0 (0.0) 2 (18.2) 1 (9.1)
Esposito S et al., 25th ESPID 2007
IMPACT AMONG HOUSEHOLD CONTACTS OF THE STUDY CHILDREN IN WHOM HMPV
INFECTION WAS DIAGNOSED
hMPV-A (n=85)
hMPV-B (n=47)
Untyped hMPV (n=39)
hMPV-coinfected
(n=41)
DISEASE SIMILAR TO THAT OF THE INFECTED CHILD (%)
12 (14.1) 4 (8.5) 3 (7.7) 5 (12.2)
ADDITIONAL MEDICAL VISITS (%)
7 (8.2) 5 (10.6) 1 (2.6) 2 (4.9)
ANTIPYRETIC PRESCRIPTIONS (%)
8 (9.4) 4 (8.5)3 (7.7) 5 (12.2)
ANTIBIOTIC PRESCRIPTIONS (%)
2 (2.4) 2 (4.3) 1 (2.6) 2 (4.9)
LOST WORKING DAYS, MEDIAN (range)
3 (1-7) 3 (1-5) 2 (1-4) 3 (1-5)
LOST SCHOOL DAYS, MEDIAN (range)
2 (1-5) 2 (1-3) 2 (1-3) 3 (1-5)
Esposito S et al., 25th ESPID 2007
VIRAL LOAD (MEAN + SD cp/mL) AND DISEASE SEVERITY IN CHILDREN
WITH HMPV INFECTION
LRTI involvement URTI involvement
p
1,424,270 + 3,401,326
3,276 + 5,545 <0.001
Hospitalized children Outpatient children
p
4,817,875 + 5,467,264
74,177 + 115,661
<0.001
Children who had households with a
similar disease
Children who had not
households with a similar disease
p
1,769,850 + 3,736,830
9,721 + 16,189 <0.001
Esposito S et al., 25th ESPID 2007
CORONAVIRUS
Nidovirales
Coronaviridae
Coronavirus - Grp I
- Grp II
- Grp III
RNA virus Found everywhereCause of mild as well as severe infections sometimes with epidemic peaks that could involve mainly respiratory and gastroenteric tracts
CORONAVIRUS HOST AND DISEASES
Disease (site of infection) Genetic group
Virus Host Respiratory Enteric Other
1
HcoV-229E HCoV-NL63 TGEV PRCoV PEDV FIPV FcoV CcoV
Human Human Pig Pig Pig Cat Cat Dog
X X
(X) X
X
X X
X X X X
Sistemic
2
HcoV-OC43 HCoV-HKU1 MHV RcoV HEV BcoV
Human Human Mouse Mouse Pig Bovin
X X X X
X
X X X
X X
CNS, sistemic eye, urinary
tract
3 IBV TCoV
Chicken Turkey
X
X X
Kidney
4?? SARS-CoV Human X (X) (Kidney)
34
36
38
40
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Viral Immune response Organ involvementreplication
C°
Days from the beginning of the disease
CORONAVIRUS INFECTIONS: PATHOGENESIS
EPIDEMIOLOGIC RESULTS
2,060 children < 15 yrs (1,112 males)
Mean age + SD, 3.46 + 3.30 yrs
HCoVs were detected in 79 children (3.8%) as against influenza in 235 (11.4%;
p<0.0001), RSV in 171 (8.3%; p<0.0001), adenovirus in 136 (6.6%; p<0.0001),
rhinoviruses in 130 (6.3%; p<0.05), hMPV in 48 (2.3%; p<0.05) and parainfluenza
viruses in 29 (1.4%; p<0.05)
Esposito S et al. J Med Virol 2006
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF CHILDREN WITH CORONAVIRUS INFECTION
Esposito S et al. J Med Virol 2006
DIAGNOSIS, THERAPY AND CLINICAL OUTCOME IN CHILDREN
WITH BOCAVIRUS INFECTION
Esposito S et al. J Med Virol 2006
RES PI RA T O RY I N FECT I O N S I N H O US EH O LDS CO N T A CT S BY VI RA L I N FECT I O N I N T H E
S T UDY PO PU LA T I O NEsposito S et al. J M ed Virol 2006
0
2
4
6
8
10
12%
SARS in pediatric age
• Under 12 years of age, SARS appears as a moderate disease clinically less aggressive than in adults
• Radiographic alterations appear low and not
severe
• The main signs were cough and nasal
congestion
• No death is observed in the first 12 years of age
FIRST DETECTION OF CORONAVIRUS HKU1 IN AN ITALIAN INFANT WITH
BRONCHIOLITIS • While studying the epidemiology of viral
respiratory infections in Italy during the winter seasons from 2002-2003 to 2004-2005, we detected HCoV-HKU1 in the nasopharyngeal secretions of a pre-term infant hospitalized for bronchiolitis
• This finding not only allows a better definition of the disease’s possible etiology, but also confirms that coronaviruses can cause mild, as well as moderate/severe respiratory infections
Bosis S et al. J Clin Virol 2007
HUMAN BOCAVIRUS (hBoV)
• Latest addition to the list of novel respiratory virus
• Described by Allander et al. in Swedish children in 2005
• DNA virus closely related to the Bovine Parvovirus (BPV)
• Classified in the genus Bocavirus within the Parvoviridae
FREQUENCY OF hBoV INFECTIONS
AUTHORS (YRS) PREVALENCE STUDY POPULATION
Allander et al. (2005) 3.1% Swedish children with LRTIs
Sloots et al. (2006) 5.6% Respiratory samples from Australian adults
and children
Ma et al. (2006) 5.7% Japanese children with LRTI
Bastien et al. (2006) 1.5% Respiratory samples from Canadian adults
and children
Foulongne et al. (2006)
3.4% Respiratory samples from French children <5
yrs
Weissbrick et al. (2006)
10.3% Respiratory samples from German children
<8 yrs
SYMPTOMS OF PATIENTS WITH hBoV INFECTIONS
Arnold et al., CID 2006
FREQUENCY OF DETECTION OF RESPIRATORY VIRUSES AMONG 1,332
CHILDREN ATTENDING THE EMERGENCY ROOM
0
2
4
6
8
10
12
14
16
Influenza RSV Adenovirus Rhinovirua Bocavirus Coronavirus PIV HMPV
%
Esposito S et al., J Clin Microbiol 2008
AGE DISTRIBUTION OF BOCAVIRUS INFECTIONS
Age (yrs)BOCAVIRUS
(N=99)
<1 17 (17.2%)
1-2 47 (47.4%)
2-5 25 (25.3%)
>5 10 (10.1%)
Esposito S et al., J Clin Microbiol 2008
FREQUENCY OF HUMAN BOCAVIRUS (HBOV) CO-
DETECTION
Virus detection status HBoV-positive samples, no.
(%)
HBoV-negative
samples, no. (%)
Single infection detected 49 (49.5)* 475 (72.5)
Co-infection detected 50 (50.5)* 180 (27.5)
With a total of 2 viruses 41 (41.4)* 180 (27.5)
With a total of 3 viruses 9 (9.1) 0 (0.0)
Total 99 (100.0) 655 (100.0)
*p< 0.0001; no other significant difference between the groups.
Esposito S et al., J Clin Microbiol 2008
CLINICAL MANIFESTATIONS IN CHILDREN WITH HUMAN BOCAVIRUS (HBOV)
INFECTIONS
DiagnosisNo virus
(No.=578)Single
bocavirus (No.=49)
Bocavirus co-infection (n=50)
URTI 202 (34.9%) 42 (85.7%)* 21 (42.0)
Pharyngitis 115 (19.9%) 27 (55.1%)* 9 (42.8%)
AOM 64 (11.1%) 9 (18.4%) 7 (14.0%)
Rhinosinusitis 23 (3.3%) 6 (12.2%) 5 (10.0%)
LRTI 50 (8.7%) 2 (4.0%)* 24 (48.0%)
Acute bronchitis
20 (3.5%) 1 (2.0%)* 9 (18.0%)
Wheezing 19 (3.3%) 1 (2.0%) 7 (14.0%)
Pneumonia 11 (1.9%) 0 (0)* 8 (16.0%)
Gastroenteritis 90 (15.6%) 5 (10.2%) 5 (10.0%)
Fever ws 23 (3.9%) 0 (0) 0 (0)
Exanthema 18 (3.1%) 0 (0) 0 (0)
Other diagnosis 195 (33.7%) 0 (0) 0 (0) *p<0.05
CLINICAL OUTCOME IN CHILDREN WITH HUMAN BOCAVIRUS (HBOV) INFECTIONS
No virus(No.=578)
Single bocavirus (No.=49)
Bocavirus co-infection(n=50)
Examinations
Laboratory tests 186 (32.2%) 13 (26.5%)* 25 (50.0%)
Radiographic examinations
29 (5.0%) 2 (4.1%)* 11 (22.0%)
Outcome
Hospitalization 43 (7.4%) 2 (4.1%)* 10 (20.0%)
Days lost from school
10 (1-20) 10 (1-15) 12 (2-18)
Therapies
Antibiotic 234 (40.5%) 26 (53.1%) 36 (72.0%)
Acetaminophen 297 (51.4%) 30 (61.2%) 39 (78.0%)
NSAID 13 (2.2%) 0 (0) 2 (4.0%)
Aerosol therapy 42 (7.3%) 3 (6.1%)* 15 (30.0%)
Oral steroids 14 (2.4%) 1 (2.0%)* 9 (18.0%)
*p<0.05
CLINICAL IMPACT AMONG HOUSEHOLDS OF CHILDREN WITH HUMAN BOCAVIRUS
(HBOV) INFECTIONS
Impact among households
No virus(No.=578)
Single bocavirus (No.=49)
Bocavirus co-infection(n=50)
Respiratory tract infections
92/1425 (6.5%)
14/120 (11.7%) 21/126 (16.7%)
Medical visits 48/1425 (3.4%)
9/120 (7.5%) 12/126 (9.5%)
Hospitalization 4/1425 (0.3%)
0 (0) 1/50 (2.0%)
Antibiotics 22/1425 (1.5%)
4/120 (3.3%) 7/126 (5.6%)
Antipyretics 48/1425 (3.4%)
9/120 (7.5%) 12/126 (9.5%)
TAKE HOME MESSAGES: EMERGING RESPIRATORY
VIRUSES
• Respiratory viral pathogens, old and new, continue to be an important threat to human health
• Diagnostic techniques remain crucial for the rapid identification of known and unknown pathogens
• It will be essential to further increase our understanding of virus epidemiology, pathogenesis, clinical presentation and host defense against infection
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