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

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2

4

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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

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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